The preparation of 7-acyl-3-(substituted carbamoyloxy)cephem compounds

P/00/01 1 Regulation 3.2

Patents Act 1 990

ORIGINAL

COMPLETE SPECIFICATION

STANDARD PATENT

Invention Title: "The Preparation of 7-Acyl-3-(Substituted Carbamoyloxy)cephem Compounds"

The following statement is a full description of this invention, including the best method of performing it known to us:

GH&CO REF: P1 2032-U ADK/MT

THE PREPARATION OF 7-ACYL-3 - (SUBSTITUTED CARBAMOYLOXY)CEPHEM COMPOUNDS

This invention relates to processes for the preparation of 3-(substituted carbamoyloxy)-3-cephem derivatives.

2) Description of the Related Art

Japanese Patent Application Laid-Open (Kokai) No.

34794/1978 discloses unsubstituted or lower-alkylsubstituted 3-carbamoyloxy-3-cephem derivatives including the compounds represented by the following formula:

wherein Y means a hydrogen atom or a nucleophile compound residuum.

In addition, Japanese Patent Application No.

44714/1989 discloses the compounds represented by the following formula:

wherein R^ means an amino group or an acylamino group,

denotes a carboxyl group or a protected carboxyl

1^8 group, the group represented by the formula -N<_R9 represents a di(lower) alkylamino group, a (lower) alkylamino group, a saturated, 5- or 6-membered, heterocyclic (lower) alkylamino group containing 1-4 nitrogen atoms, said alkylamino group being optionally substituted by one or more lower alkyl groups, or a saturated, 5- or 6-membered heterocyclic group containing 2-4 nitrogen atoms, said heterocyclic group being

optionally substituted by one or more lower alkyl

0

, . 1

or hydroxy(lower)alkyl groups, X^x is -S- or -S-, and the dotted line indicates a 2- or 3-cephem ring.

Further, Japanese Patent Publication Ho.

46474/1991 discloses cephem compounds represented by the following formula:

N - 1 C-CONH R⁸ R-

NR⁵ O ^N I S' M . COOR Q

wherein R¹ is an amino or hydroxyl group which may optionally be protected, R³ is a hydrogen atom, R⁵ is a hydroxyl group or a substituted or unsubstituted alkoxyl group, R⁸ is a hydrogen atom, Q denotes a carbon-carbon linkage for the formation of a 3-substituted-3-cephem-4-carboxylic acid, and R represents an ester residuum.

Several types of semisynthetic cephalosporins are now used for the treatment of various infectious diseases. None of them are, however, satisfactory as antibacterial agents which have strong antibacterial activities and, in particular, are orally-dosable.

In a first aspect the invention provides a compound represented by the following formula (6).

R³a (6) wherein R²a and R³a are the same or different and individually represent a lower alkyl group, a hydroxyl-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group or a cyano-substituted lower alkyl

group or the group represented by the formula

r2 a

-N^<_R3_a means a 4-6 membered heterocyclic group, which contains one nitrogen atom, or a morpholino group, said heterocyclic group or morpholino group being optionally substituted by one or more lower alkyl, hydroxyl, hydroxyl-substituted lower alkyl groups, denotes a carboxyl group or a carboxyl group protected by a protecting group, and R⁵ represents an amino or protected amino group; or a salt thereof.

Preferably R²a and R³a are both methyl groups and R⁴ represents a carboxyl group or a carboxyl group protected by at least one group selected from the class consisting 5 of 1-(isopropyloxycarbonyloxy)ethyl group, 1-(ethoxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethyl group, pivaloyloxymethyl group and isopropyloxycarbonyloxymethyl group.

In a second aspect the invention provides a compound 10 represented by the following formula (4):

wherein R² and R³ are the same or different and individually represent a lower alkyl group, a hydroxyl-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group or a cyano-substituted lower alkyl group, R² is a hydrogen atom and R³ is a lower alkoxyl group or a lower alkyl group which may optionally be substituted by one or more halogen atoms,

or the group represented by the formula -N<_R] means a 4-6 membered heterocyclic group, which contains one nitrogen atom, or a morpholinα group, said heterocyclic group or morpholino group being optionally substituted by one or more lower alkyl, hydroxyl and/or hydroxyl-substituted lower alkyl groups; R⁴ denotes a carboxyl group or a carboxyl group protected by a protecting group; and X represents a halogen atom or a salt thereof.

5 10 In a preferred form, R² and R³ are both methyl groups and R⁴ represents a carboxyl group or a carboxyl group protected by at least one group selected from the class consisting of 1-(isopropyloxycarbonyloxy)ethyl group, 1(ethoxy-carbonyloxy)ethyl group, l(cyclohexyloxycarbonyloxy) ethyl group, pivaloyloxymethyl group and isopropyl-oxycarbonyloxymethyl group.

In a third aspect, the present invention provides a process for the preparation of a compound represented by the following formula (8):

(8)

wherein R² and R³ are the same or different and individually represent a lower alkyl group, a hydroxyl-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group or a cyano-substituted lower alkyl group, R² is a hydrogen atom and R³ is a lower alkoxyl group or a lower alkyl group which may optionally be substituted by one or more halogen atoms, or the group R²

represented by the formula -N<^3 means a 4-6 membered R² heterocyclic group, which contains one nitrogen atom, or a morpholino group, said heterocyclic group or mor-

pholino group being optionally substituted by one or more lower alkyl, hydroxyl and/or hydroxyl-substituted lower alkyl group, R⁴ denotes a carboxyl group or a carboxyl group protected by a protecting group or a salt thereof and R⁵ represents an amino or protected amino group, which comprises a compound represented by the following formula (7):

wherein R⁴ and R⁵ have the same meanings as defined above with a compound represented by the following formula :

have the same meanings as defined thereof.

HN V

,R-

V

wherein R² and R³ have the same meanings as defined above or the salt thereof.

In a preferred form R² and R³ are both methyl groups and R⁴ represents a carboxyl group or a carboxyl group 5 protected by at least one group selected from the class consisting of 1-(isopropyloxycarbonyloxy)ethyl group, 1( e t h o x y c arb onyloxy) - ethyl group, 1 (cyclohexyloxycarbonyloxy) ethyl group, pivaloyloxymethyl group and isopropyloxycarbonyloxy methyl group.

10 In a fourth aspect the present invention provides a In a fourth aspect the present invention provides a process for the preparation of a compound represented by the following formula (10):

R³ (10)

wherein R² and R³ are the same or different and individually represent a lower alkyl group, a hydroxyl-substituted lower alkyl group, a carbamoy1-substituted lower alkyl group or a cyano-substituted lower alkyl group, R² is a hydrogen atom and R³ is a lower alkoxyl group or a lower alkyl group which may optionally be substituted by one or more halogen atoms, or the group represented by the formula -N<_R] means a 4-6 membered r2 heterocyclic group, which contains one nitrogen atom, or a morpholino group, said heterocyclic group or morpholino group being optionally substituted by one or more lower alkyl, hydroxyl and/or hydroxyl-substituted lower alkyl group, and R⁵ represents an amino or protected amino group, which comprises reacting a compound represented by the following formula (9);

(9)

wherein ¥ represents a hydrogen atom, a lower alkyl group, a halogen atom or a nitro group and R⁵ has the same meaning as defined above, or a salt thereof with a compound represented by the following formula:

UN

f

\

R

R

2

3

wherein R² and R³ have the same meanings as defined above or the salt thereof.

In a preferred form R~ and R^J ai'e both methyl groups. In a fifth aspect, the present invention provides a compound represented by the following formula t. :

(9)

5 wherein R⁵ represents an amino or protected amino group and Y represents a hydrogen atom, a lower alkyl group, a halogen atom or a nitro group, or a salt thereof.

As a result of an extensive investigation, the 10 present inventors have found that certain novel 3substituted carbamoyloxy-3-cephem derivatives have excellent antibacterial actiλ’·ities against various pathogenic fungi and their pharmacologically-protected derivatives are promptly absorbed through the digestive 15 tract, form non-ester derivatives immediately after their absorption and are hence useful as antibacterial compositions for oral administration.

The 7-acyl-3-substituted carbamoyloxy-3-cephem compound is represented by the followinσ formula il) :

wherein Λ means a -CH= or -N= group; R¹- denotes a hydroxyl group, a lower alkoxyl group, a fluorine-substituted lower alkoxyl group or a hydroxyl group protected by a protecting group; R² and R³ are the same or different and individually represent a lower alkyl group, a hydroxyl-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group or a cyano-substituted lower alkyl group, R² is a hydrogen atom and R³ is a lower alkoxyl group or a lower alkyl group which may optionally be substituted by one or more

halogen atoms, or the group represented by the formula

R²

-N<_r3 means a 4-6 membered heterocyclic group, which contains one nitrogen atom, or a morpholino group, said heterocyclic group or morpholino group being optionally substituted by one or more lower alkyl, hydroxyl and/or hydroxyl-substituted lower alkyl groups; and R⁴ denotes a carboxyl group or a carboxyl group protected by a protecting group, or a pharmaceutically acceptable salt thereof#

The 7-acyl-3-substituted carbamoyloxy-3-cephem compound (1) and its pharmaceutically-acceptable salts have strong antibacterial activities and are orally dosable.

In the above formula (1), examples of the lower alkoxyl group or fluorine-substituted lower alkoxyl group represented by R¹ include C_1-4 alkoxyl groups and fluorine-substituted C_1-4 alkoxyl groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, monofluoroniethoxy, difluoromethoxy, 2-monofluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

The protecting group in "the protected hydroxyl group" represented by R¹ is an easily-removable hydroxyl-protecting group, including, for example, a protecting group removable under relatively mild conditions, such as formyl, acetyl, chloroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, ethoxycarbonyl, pnitrophenoxycarbonyl, tetrahydropyranyl, tetrahydrothiofuranyl, trityl, methoxymethy1, ethoxymethyl, trimethylsilyl, t-butyldimethylsilyl or t-butyl. Of these, acetyl and trityl are preferred.

Illustrative of the lower alkyl, hydroxyl-substituted lower alkyl, carbamoyl-substituted lower alkyl and cyano-substituted lower alkyl groups represented by R² and in the formula (1) include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3hydroxybutyl, carbamoylmethyl, 2-carbamσylethyl, 3carbamoylpropyl, 2-cyanoethyl, 3-cyanopropyl, and 2cyanopropyl. The term "the lower alkyl group" as used in the definition for R³ that "R₂ is a hydrogen atom and R₃ is a lower alkoxyl group or a lower alkyl group which may optionally be substituted by one or more halogen atoms" includes alkyl groups such as described above, with a methyl group and an ethyl group being preferred. The lower alkoxyl group is similar to that defined for R¹. Exemplary halogen atoms include fluorine, chlorine and iodine, with fluorine atom being preferred. The number of halogen atoms as substituents can range from 1 to 3.

On the other hand, examples of the 4-6 membered heterocyclic group, which contains one nitrogen atom, and morpholinyl group - said heterocyclic group and

morpholinyl group being represented by the formula

r>2

-N<_r3 and being optionally substituted ~ include the following groups:

wherein R¹⁰ represents a hydrogen atom or a lower alkyl, hydroxyl or hydroxyl-substituted lower alkyl group. Examples of the lower alkyl group include methyl, ethyl and propyl, while examples of the hydroxyl-substituted lower alkyl group include hydroxymethyl and 2-hydroxyethy1.

12

As the group -N<*3, , -NHCH₃ and -N(CH₃)₂ are preferred, with the last group being more preferred.

Illustrative of the protecting group for the carboxyl group represented by include lower alkyl groups such as methyl, ethyl and t-butyl;lower alkyl groups substituted by one or more substituted or unsubstituted phenyl groups such as p-methoxybenzyl, pnitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl or phenethyl; halogenated lower alkyl groups such as 2,2,2-trichloroethyl and 2-iodoethyl? lower-alkanoyloxy-lower-alkyl groups such as pivaloyloxymethyl, acetoxymethy1, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl and 2-pivaloylαxyethyl; higher-alkanoyloxy-lower-alkyl groups such as palmitoyloxyethyl, heptadecanoyloxymethyl and 1palmitoyloxyethyl; lower-alkoxycarbonyloxy-lower-alkyl groups such as methoκycarbonyloxymethyl, l-(butoxycarbonyloxy)ethyl, 1-(t-butoxycarbonyloxy)ethyl, 1(ethoxycarbonyloxy)ethyl and 1-(isopropoxycarbonyloxy)ethyl; carboxy-lower-alkyl groups such as carboxymethyl and 2-carboxyethyl; heterocyclic groups such as 3phthalidyl; benzoyloxy-lower-alkyl groups such as 4glycidyloxybenzoyloxymethyl and 4-[N-(t-butoxycarbonyl)glycyloxy]benzoyloxymethyl, said benzoyloxy-lσwer-alkyl groups optionally containing one or more substituent groups; (substituted dioxolene)-lower-alkyl groups such as (5-methyl-2-oxα-l,3-dioxolen-4-yl)methyl; cycloalkyl-substituted lower-alkanoyloxy-loweralkyl groups such as 1-cyclohexylacetylόxyethyl; and cycloalkyloxycarbonyloxy-lower-alkyl groups such as 1cyclohexyloxycarbonyloxyethyl.

In effect, any protecting group can be used as long as it can be removed by any means to form a carboxylic group. Preferred examples of the protecting group include 1-(isopropyloxycarbonyloxy)ethyl group, 1-(ethoxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethyl group, pivaloyloxymethyl group and isopropyloxycarbonyloxymethyl group, with 1-(isopropyloxycarbonyloxy) ethyl group being more preferred.

Further, illustrative of the pharmaceutically acceptable salt include alkali metal salts such as the sodium and potassium salts; the ammonium salt;

quaternary ammonium salts such as the tetraethylammonium and betaine salts; alkaline earth metal salts such as the calcium and magnesium salts; inorganic acid salts such as the hydrochloride, hydrobromide, hydroiodide, sulfate, carbonate and bicarbonate;

organic σarboxylates such as the acetate, maleate, lactate and tartrate; organosulfonates such as the methanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate, taurine salt, benzenesulfonate and toluenesulf onate ,* amino acid salts such as the arginine salt, lysine salt, serine salt, aspartate, glutamate and glycine salt; and amine salts such as the trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt and phenethylbenzylamine salt.

The compound of the present invention represented by the formula (1) can be prepared, far example, by the following processes:

The compound represented by the formula (1) or a salt thereof can be obtained by reacting a compound represented by the following formula:

wherein R², R³ and R⁴ have the same meanings as defined above or a salt thereof, with a compound represented by the following formula <3):

R⁶ N (3) N (3)

wherein A and R¹ have the same meanings as defined above, and R⁶ represents an amino group or an amino group protected by a protecting group, or a reactive acid derivative thereof or a salt thereof, and if necessary, removing the protecting group of the amino, carboxyl or hydroxyl group or protecting the carboxyl group with a protecting group.

Examples of the amino-protecting group represented by R^ include carbamoyl groups, aliphatic acyl groups, aromatic-ring-containing or heterocyclic-ring-containing acyl groups, sulfonyl groups and benzilidene groups.

Illustrative of the acyl group and the sulfonyl group include alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oκalyl, succinyl and pivaloyl; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, bυtoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbony1 and hexyloxycarbonyl; aralkoxycarbonyl groups such as benzyloxycarbonyl and phenethyloxycarbonyl; alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl and butanesulfonyl; arenesulfonyl groups such as benzenesulfonyl and toluenesulfonyl; aroyl groups such as benzoyl, toluoyl, naphthoyl, phthaloyl and indanecarbonyl; aralkanoyl groups such as phenylacetyl and phenylpropiony1; aryloxyalkanoyl groups such as phenoxyacetyl and phenoxypropionyl; heterocyclic carbonyl groups such as furoyl, thenoyl and nicotinoyl; heterocyclic glyoxyloyl such as thienylglyoxyloyl and thiazolylglyoxyloyl; and heterocyclic alkanoyl groups such as thienyl and thiazolylacetyl. These groups may contain one or more suitable substituents, for example, halogens such as chlorine, bromine, iodine and fluorine; nitro groups; amino groups; alkanoylamino groups such as formylamino and acetylamino groups;

cyano groups; alkyl groups such as methyl, ethyl, propyl, isopropyl and butyl; alkenyl groups such as vinyl and allyl; and groups represented by the formula =N-OR₅ wherein R₅ means a hydrogen atom; an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl; an alkenyl group such as vinyl or propenyl;

or an alkynyl group such as ethynyl or propynyl.

Illustrative of the benzylidene group includes benzylidene group, p-nitrobenzylidene group, mnitrobenzylidene group, 3,4-methylenedioxybenzylidene group and m-chlorbenzylidene group.

The compound (3) may be reacted in the presence of a condensing agent [a carbodiimide (N,N'-dicyclohexylcarbodiimide or the like), a carbonyl compound (carbonyldiimidazole or the like), an isoxazolium salt, or an acylamino compound (2-ethoxy-l-ethoxycarbonyl1,2-dihydroxyquinoline or the like)]. Usable examples of its reactive acid derivative include acid anhydrides [symmetric acid anhydrides, mixed acid anhydrides (mixed acid anhydrides of mineral acids (phosphoric acid, sulfuric acid, carbonate half-esters or the like) and organic acids (alkanoic acids, aralkanoic acids, sulfonic acids or the like), etc.], acid halides, active esters [esters with N-hydroxy compounds (esters with N-hydroxysuccinimide or N-hydrophthalimide)], thiol esters (aralkylthiol esters, heterocyclic thiol esters, etc.), and aryl esters (phenyl ester, halophenyl esters, nitrophenyl esters, etc.).

The above reaction can be conducted at a reaction temperature of from -50”C to +50®C in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, acetone, ethyl acetate, methanol, ethanol, dimethylsulfoxide, N,N-dimethylformamide, benzene, toluene or hexane.

The removal of each protecting group, the protection of a carboxyl group with a protecting group and the salt-forming reaction can be performed by methods known per se in the art.

The deprotection of the protected carboxyl group can be effected by hydrolysis in the presence of an acid. Here, preferred examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid; and Lewis acids such as boron trifluoride, aluminum trichloride, stannic chloride, ferric chloride, titanium tetrachloride an zinc chloride. - It is preferred to conduct the reaction in the presence, of a cation scavenger such as anisole, if necessary.

The hydrolysis is generally conducted in an inert solvent such as water, methanol, ethanol, propanol, tetrahydrofuran, N,N-dimethylformamide, dioxane or methylene chloride, or in a mixed solvent of two or more of such inert solvents. The acids exemplified above can be used as a solvent. Although the reaction can be conducted generally at -78°C to 80°C, it is preferred to conduct it at a temperature ranging from ice cooling to room temperature.

When R⁴ represents a carboxyl group or a salt thereof/ the protection may be conducted by a method known per se in the art. For instance, esterification can be performed by the reaction with an alcohol-reactive derivative after optional conversion into an alkali metal salt or an organic amine salt.

The conversion into the alkali metal salt is carried out using an alkali metal salt of an organic acid such as sodium acetate, potassium acetate, sodium 2-ethylhexanonate, potassium 2-ethylhexanonate; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; or an alkali metal carbonate such as sodium carbonate., potassium carbonate or sodium hydrogencarbonate; or the like. The conversion into the organic amine salt can be carried out using trimethylamine, triethylamine, dichlorohexylamine or pyridine.

The reaction is generally conducted in an inert solvent such as water, methanol, ethanol, propanol, tetrahydrofuran, N,N-dimethylfαrmamide,. dioxane, methylene chloride, ethyl acetate, methyl acetate or acetonitrile or in a mixed solvent of two or more of such inert solvents.

The reaction with the alcohol-reactive derivative is generally conducted in an inert solvent such as water, methanol, ethanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, tetrahydrofuran, dioxane, methylene chloride, ethyl acetate, methyl acetate, acetonitrile, benzene or toluene; or in a mixed solvent of two or more of such inert solvents.

The reaction can be conducted generally at -78°C to 80“C, but preferably at a temperature ranging from ice cooling to room temperature.

The removal of the protecting grdup from the protected amino group can be conducted in the presence of an acid according to a common method. Preferred examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid;

and organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid.

The reaction is conducted generally in an inert solvent such as water, methanol, ethanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, tetrahydrofuran, dioxane or methylene chloride; or in a mixed solvent of two or more of such inert solvents.

The reaction can be conducted generally at -50^βC to

:j

50°C, but preferably at a temperature ranging from ice cooling to room temperature.

The compound represented by the following formula (5) :

(5)

wherein R², R³, R⁴ and -N<^3 have the same meanings as defined above or a salt thereof can be obtained by reacting the compound represented by the following formula (4) :

(4)

„ _ . ρ2

wherein R², R^J, R^ and -N<_R3 have the same meanings as defined above and X represents a halogen atom or a salt thereof with thiourea, and, if necessary, removing the protecting group of the carboxyl group or protecting the carboxyl group with a protecting group.

The reaction is generally conducted in an inert solvent such as water, methanol, ethanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, formic acid, acetic acid, acetone, tetrahydrofuran, dioxane, methylene chloride, ethyl acetate, methyl acetate, acetonitrile, benzene or toluene; or in a mixed solvent of two or more of such inert solvents. The reaction can be conducted generally at -78°C to 80°C, but preferably at a temperature ranging from ice cooling to room temperature.

N,N’-carbonyldiimidazole is reacted with a compound represented by the following formula;

(11)

wherein R¹* R⁴, and R⁶ have the same meanings as defined above, or a salt thereof to convert the former to a reactive derivative. The reactive derivative is reacted further with a compound represented by the formula :

wherein R² , R³ and -N<^3 have the same meanings as defined above, or a salt thereof. If necessary, any protecting groups of the amino, hydroxyl and carboxyl group are removed by a method known per se in the art and further, the carboxyl group is protected by a protecting group, thereby obtaining a compound represented by the formula (1) or a salt thereof. Removal of each protecting group can be conducted by a method known per se in the art, said method having been described in Preparation Process 1.

In the above Preparation Processes 1-3 for the compounds of the present invention, the target compounds (1) and (5) can each be obtained by conducting the reaction by using the sulfoxide derivative of the corresponding cephem ring instead of the starting compound (2) , (4) or (11) .

Next, intermediates useful in the preparation of the compounds of the present invention can be prepared, for example, by the processes to be described below, a)Preparation Process A

A compound represented by the following formula:

wherein R², R³, R⁴, and -N<^3 have the same meanings as defined above and R⁵ represents an amino or protected amino group, or a salt thereof can be prepared by reacting a compound represented by the following formula (9) :

N ch₂oco (9) COOH

wherein Y is a hydrogen atom, a lower alkyl group, a halogen atom or a nitro group, said Y being optionally substituted by one to five of these groups which may be the same or different, and R⁵ has the same meanings as described above or a salt thereof with a compound represented by the following formula:

Λ Λ I\ °

wherein R , R mid -N<^] have the same meanings a;; defined above, or a salt thereof in an inert solvent and, i. f necessary, protect Lng the carboxyL group.

The reaction is conducted generally in an inert solvent such as water, methanol, ethanol, propanol, acetone, methyl ethyl ketone, tetrahydrofuran, d.ioxane, acetonitrile, M,M-dimethy Iformamide, N,M-dimethy!acetamide, benzene, methy'ene chloride or chloroform;

or in a mixed solvent of I wo or more of such inei t solvents .

Although the reaction can be conducted generally at -70°C to 0 0’’C, it is preferred to conduct it fit a temperature ranging from ice cooling to room temperature. As t tie reaction time, it js generally sufficient to conduct the reaction for only 10 minutes to 1 hour.

Examples of the amjno-protecting group represented by are similar to those of the amino-protecting group represented by R⁶.

The compound prepaj ed by this process can fie utilized as an intermediate for the compound of the present invention represented by the formula (1) by removing the amirvo-protei ·ting group or protectin'; the carboxyl group with a protecting group as needed. The removal of the amino-protecting group or the protection of t:he carboxyl group can be carried out by the method lb

known per sc in the art, so Id method having been described in Preparation Process 1.

b)Pieparation Process D

Λ compound represented by the following foi inula (7) :

ClbjOCCl (7)

wherein R'* and R⁵ have the same meanings as defined above is prepared by reacting a compound represented by the following formula (12):

(12)

whei oin R'¹ and R^ have the same meanings as defined above or a salt thereof, with phosgene or a phosgene derivative in the presence of a base, Then, the resulting compound is reacted with a compound rep?osented by the following formula:

IΠl'

R³

wherein R² find R³ have the same meanings as defined abovo or a sa.lt: thereof, thereby obtaining a compound represented by the following formula (8):

2

wherein R², R³ , R⁴ , R⁵ and -N<^3 have the same meanings as defined above.

Suitable examples of the base in' the above reaction include the hydroxides or carbonates of alkali metals or alkaline earth metals, such as sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate; tertiary amines such as triethylami ne, tributylam i.ne, N-methylmorpholime , pyridine, toluidine, lutidine, and N,M-dimethylnminopyridine.

Examples of the phosgene derivative include trichloromethyLchloroformate and bis(trichloromethyI)“ carbonate.

2K -

The inaction is conducted generally in an inert solvent such ns M , H-dimethy 1 formamide, acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform or ethyl acetal;n; or in a mixed solvent of two or more ol such inert solvent s. The reaction can be conducted generally at -100'C to 30^oC, but preferably at a temperature ranging from -78*C to O’C.

Compounds prepared by this process can be utilized as intermediates foi the compounds of the present invention reptcsented by the formula (1) by removing the amino-protecting group or protecting the caiboxyl group with a protecting croup as needed. Their removal or protection can be carried out by a method known per se in the art, said method having been described in Preparation Process 1.

c) Preparation Process C

N,H¹-carbon·yldiimidazote js reacted with a compound represented by the following formula (13)

R⁵a S.

0

R⁴

ch₂oh (13) (13) wherein R'¹ has the same meaning as defined above and R^a represents a protected amino group or with a salt thereof to convert the la! ter to an active derivai.ive.

The .active derivative is > eact ed further with a compound represented by the formula:

, o 1 Iv ·

wherein R , R and -N<_R3 have the same meanings as , o 1 Iv · defined above, or a salt thereof. If necessary, the amino group may be deprotected, thereby obtaining a compound represented by Uie following formula (H):

R- 0

r -r H Lch₂ocn; R' («) -r

H

0 R-

0

Lch₂ocn;

R'

R-

R'

(«)

whetein R², R¹, R^ , R⁵ and -!K^] have the same meanings as described above.

The reaction is conducted generally in an inert solvent such as water, methanol, ethanol, propanol, acetone, methyl, ethyl ketone, tetrahydrofuran, dioxane, acetonitrile, Π, N-dime thy 1 f oi.mamide, N,ΠdimethylacetamLde, benzene, methylene chloride or chloroform; or in a mixed solvent of two or more of such inert solvents.

3D -

Compound prepared by this process can be utilized as intermediates Cor the compounds of the present invention represented by the formula (1) by removing any amino- and/or carboxyl-pro 1 eσti ng group or protect incj the carboxyl group with a protecting group as needed.

The deprotection can be cairied out by the method known pnv sc in the ml., said method having been described in Preparation Process 1.

d) Preparation Process D

Λ compound represented by the following formula (14) :

xch_;,cocm₂conh

..s

o

ir

CE1₂0CN'_v

Ik

R-

(14)

wherei n R², R *, r4_anj -N ^3 have the same meanings ns defined above and x represents a halogen atom can be prepared by reacting the compound represented by the formula (2) or a salt thereof with a compound represented by the following Tormula:

xcπ₂coch₂c;πoh

wherein X has the same meaning as defined above, or witli a sail or carboxyl-reactive derivative thereof.

Illustrative of the reactive derivative include acid halides such as the acid chloride and acid bromide. These acid halides can each be obtained by reaction with its corresponding diketene and halogen.

The reaction is conducted generally in an inert solvent such ns water, methanol, ethanol, propanol,

N , N-dimethy L f ormnmide , N , 11-dimethylacetamide , acetone , tetrαhydrofuran, dioxane, methylene chloride, ethyl acetate, me thy L acetate, acetonitrile, benzene, toluene or pyridine? or in a mixed solvent of two or more of such inert solvents. The reaction can be conducted generally at -78°C to 80°C, but preferably at a temperature ranging from ice cooling to room temperature .

The compound represented by the following formula (4) :

wherein R², R³, R⁴, X and -N<^3 have the same meanings as defined above or a salt thereof can be prepαied by reacting a nitrosating agent with the compound represented by I ho formula (14) or its salt.

Exampins of the nitrosating agent include ni Lrous acid and its derivatives, for example, alkali metal nitrites such as sodium nitrite and potassium nitrite;

and alkyl nitrites such as butyl nitrite, pentyl nitrite and amyl, nitrite. When an alkali metal nitrite such as sodium nitrite or potassium nitrite is used, it is preferred to conduct the nitrosation in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid or acetic acid.

The reaction is carried out generally in an inert solvent such as water, methanol, ethanol, propanol, N, N-dimethy 1. f ormamide , acetone, tetrahydrofuran, dioxane or methylene chloride; or in a mixed solvent of two or more of such inert solvents. The reaction can be conducted generally at -IB'C to 80”C, but preferably at a temperature ranging from ico cooling to room temperature.

e) Preparation Process E

A compound represented by the following formula (17) :

3λ -

wherein R'^ln represents a protected carboxyl group, R⁵ and Y have the same meanings as defined above, or a salt thereof can be obtained at a high yield by reacting, in the presence of a base, a compound represented by the following formula (15):

whei.ein R'¹α and R^ have the same meanings as defined above or a salt thereof, with a compound represented by the following formula (It):

wherein X and Y have the same meanings as defined above.

In the next place, the carboxyl-protecting group .is removed ( coin the resulting compound, thereby obtaining the compound represented by the following formula (9) :

(9)

wherein and Y have the same meanings as defined above or a salt thereof. Removal of calboxylprotecting group is carried out by the method described in Preparation Process 1.

Examples of the above-described salt of the compound represented by the formula (15) include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salt, organic amine salts (trimethylam1 no salt, triethylamino salt, etc.), organic acid salts (formate, trifluoroncetate, toluenesulfonate, etc.), and inorganic acid salts (hydrochloride, sulfate, etc.).

Suitable examples of the base include alkali met al salts and alkaline earth metal salts, such as sodium hydroxide, potassium hydioxide, barium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencαibonate, potassium hydrogoπcarbonate; alkali metal or alkaline earth metal salts of organic acids, such as sodium acetate, potassium acetate, barium acetate and magnesium acetate; and tertiary amines such as triethylamine, tributylamine, N-methylmorpho 1 i lie, pyridine, toluidine, lutidine, and N,N-dimethylaminopyridine-

The reaction is usually conducted in an inert solvent such as N,N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, chloroform, ethyl acetate, methyl acetate, benzene, toluene or hexane, or in a mixed solvent of two or more of such inert solvents.

Although the reaction can be conducted generally at -78"C to 80"C, it is pioCerred to conduct it at a temperature ranging from ice cooling to room temperature .

In Preparation Processes A-E for intermediate compounds, the target compounds (4), (0) and (9) can also be obtained by using, instead of the starting compound (9), (1?.), (13), (14) and (15), their sulfoxido derivatives and then conducting reduction after the reactions.

Out of I he intermediates described above, the compounds tepresented by the following formula (6):

3(i

R·

τ( lc

υ

o

CU₂OCtJ

R^a

^X R³α

R

(<•)

whcπ'in R²a ami R³a are the same or different and individually represent a lower alkyl group, a hydroxyl-substituted lower alkyl group or a σyanα-substituted lower alkyl group or the group represented by tho

R² a • formula -N< 3^L means a 4-6 memberod heterocyclic group, k a

which contains one nitrogen atom, or a morphαlino group, said heterocyclic group or morpholino group being optionally substituted by one or more loweralkyl, hydroxyl, hydroxyl-substituted lower alkyl groups, R'¹ denotes a carboxyl group or a carboxyl group protected by a protecting group, and R~* represents an amino or piotected amino group, the compounds represented by the formula (4) and the compounds represented by the formula (9) are all novel compounds.

To demonstrate the efficacy of the compounds according to the present invention, the minimum inhibitory enneentrations (MIC) of certain representative compounds obtained in examples, which will follow, against various fungi ami their excretion rates in urine upon oral administration were measured, and an in vivo ('xperini'Mit: Lor the ti oαtnmnt of respirntoryinCc’ted model mice was conducted using such repiesentαtive compounds.

a) The results of the measurement of MICs against the various fungi are shown in Table I.

Table 1

λO

Compound Λ in Table 1 is the following compound.

Compound A:

7-[(Z)-2-(2-Λminothinεol~4-yl. )-2-hydroxy iminoacetaraido ] - 3 -carbamoy loκymethyl-3-cephem-4- carboxy ] ic.

acid.

As apparent from Table 1, the compounds according to the present invention have excellent antibacterial activities and are useful especially as those having strong antibacterial activities against Haemophilus influenzae .

b) Bioavailability

Certain representative compounds according to the present invention were each suspended in a CMC-Na solution. The resulting suspension was administered orally to mice at the dosage of 20 mg/kg. Urea excreted during 6 hours after the administration was collected.

The excreteion rate in urea and bioavailability measured are shown in Table 2.

Compounds B, C and D in Table 2 are as follows:

Compound B:

Pivaloyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)2-hydroxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem4-ca rboxyla te.

Compound C:

1-(Isopropyloxycarbonyloxy)ethyl 7-[(Z)-2-(2aminothiazo1-4-yl)-2-hydroxyiminoacetamido]-3carbαmoyloxymethy1-3-cephem-4-carboxylate.

Compound D:

Pivaloyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)2-methσxyiminoacetamido]-3-carbamoylσxymethy1-3-cephem4-carboxyla t o.

c)Treatment results of respiratory-infected mice

A bacterium-containing solution was inoculated into the nasal cavity of each mouse, followed by the oral administration of a suspension of one of the compounds in a CMC-Na solution one hour later where the bacterium was Haemophilus influenzae but four hours later where the bacterium was Klebsiella pneumoniae. The number of iπtrapulmonary viable cells of the bacterium was counted upon an elapsed time of 24 hours after the infection. The measurement limit is represented by the following formula.

Log CFU/Lung = 1.48

wherein CFU is the colony forming unit.

When no colony was observed, the bacterium was regarded as having been eradicated and Log CFU/Lung was calculated to be 1. The results are shown in Tables 3 and 4 .

Compounds E and F in Table 3 are as follows:

Compound E:

1-(Isopropyloxycarbonyloxy)ethyl 7-[(Z)-2-(2-aminothiazo.l.-4-yl) -2-methoxy iminoacetamido] -3methoxymethyl-3-cephem-4-carboxylate.

Compound F:

7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyimino acetamido]-3-vinyl-3-cephem-4-carboxylic acid.

Dosable preparation forms include tablets, granules, powders, capsules, syrups, liquids, etc.

Each of these preparations can be formulated in a manner known per se in the art, by adding a known excipient .

Examples will next be set out to describe the present invention in further detail. It is, however, to be noted that the present invention is not limited by the following examples.

Starting materials employed upon preparation of the compounds of the present invention will be described as preparation examples.

Throughout the examples, "Tr" stands for a

(^cgΠrj) 3C- group, "BII" for a (C₆H₅)₂CH- group, and Me for a methyl group.

Preparation Example 1

Benzhvdrvl 7-thienvlacetamido-3-N.N-dimethvlcarbnmoy1oxvmethvl-3-cephem-4-carboxvlate-1-oxide

A solution of benzhydryi 7-thienylacetamido-3hydroxymethyl-3-cephem-4-carbαxy]ate (30 g;0.058 mol) in tetrahydrofuran (600 mt) was stirred under ice cooling, to which N, N'-carbonyIdiimidazole (11.25 g;

0.069 mol) was added, followed by stirring under ice cooling for further three hours. The reaction mixture was added with ethyl acetate (1 i) , and the resulting mixture was washed with water (400 m?) . The organic layer was stirred under ice cooling, followed by the addition of a 50% aqueous dimethylamine solution (12 g;

0.075 mol). They were reacted for one hour. The reaction mixture was dried over anhydrous magnesium sulfate and then concentrated, whereby a mixture of benzhydryl 7-thienylacetamido-3-N,H-dimethy1carbamoyloxymethy1-3-cephem-4-carboxy.late and benzhydryl 7-thienylacetamido3 -N,N-dimethylcαrbamoyloκymethyl-2~cephem-4-carboxylate was obtained (24 g) .

To a solution of the resulting mixture in tetrahydrofuran (400 m£) , a solution of m-chloroperbenzoic acid (20 g; 0.116 mol) in tetrahydrofuran (100 m£) was added in portions, followed by stirring for one and a half hours under ice cooling. The reaction mixture was concentrated under reduced pressure and the residue was washed with ether. After further concentration under reduced pressure, the residue was purified by chromatography on a silica gel column, whereby the title compound wa$ obtained (7.5 g; yield:

NMR ( CDCl3 , Λ) :

2.0 4 ( 311, s) , 2.92(311,s), 3.2 3,3.8 8 ( 211, ΛBq, J≈lβllz ) , 3.88(2H,s), 4.48 (211,d, J = 4Hz) , 4.78,5.34 (211,ΛBq, J≈OHz) , 6.15(lH,dd,J = 4Hz,8!Iz) , G . 9 0-7.10 (211, m) , 6.97(111,s), 7.2-7.6 (1111, m)

Preparation Example 2

Benzhvdry I 7-thienvlacetamido-3-N.N-dimethylcarbamoyl oxviηethvl-3-c℮pliem-4 -carboxylate

Λ solution of benzhydryl 7-thienylacetamido-3-

N, N-dimethy Icarbamoyloxyme thy l-3-cepheπt-4-carboxy la te-l-oxide (5 g; 8.2 mmol), which had been obtained in Preparation Example 1, in N,N-dimethylformamide

(50 n\t) was stirred under ice cooling, followed by the addition of phosphorus trichloride (2.5 g; 18 mmol).

The resulting solution was stirred for 30 minutes and added witli ethyl acetate (500 mi!). The resulting mixture was washed with water and a saturated aqueous sodium chloride solution and thereafter added with anhydrous magnesium sulfate. After the organic layer was concentrated under reduced pressure, the residue was solidified from a mixed solvent of acetone and isopropyl other. The resulting solid was collected by filtration, whereby the title compound was obtained (3.0 g; yield: 79%).

NMR (CDC1₃, 5):

2.82(311, s) , 2.90(311,s), 3.40,3.55(2H,ΛBq,J=18Hz) , 3.84(211,s), 4.81,5.06(2H,ΛBq,J=12Hz), 4.98 (lH,d, J=4Hz) , 5.04 (111, dd , J = 4Hz , 0Hz) , 6.27 (111, d , J=8Πz) , 6.94 (3II, s) , 6.98-7.02 (2H,m) , 7.2 5-7.4 3 ( 1 111, m) Preparation Example 3

Be∩zhydrvl 7-ami∩o-3-N.N-dimethvlcarbamovloxvmethy1-3-cephem-4-carboxylate hydrochloride

A solution of phosphorus pentachloride (2.8 g; 13 mmol) and pyridine (1.04 g; 13 mmol) in methylene chloride (80 m£) was cooled to -10^SC. To the resulting solution, benzhydryl 7-thieny.lacetamido-3-H,N-dimet.hylcarbamoyloxymethyl-3-cephem-4-carboxylate (1.6 g? 2.7 mmol), which had been obtained in Preparation Example 2, was added, followed by stirring at -10*C for co₂dii

one hour. The resulting solution was cooled down to

-20°C and then added with 1,3-propanediol (1 ml).

They were stirred at -20*c for one hour. The reaction mixture was added with methanol (10 m£) , and the resulting mixture was heated to the room temperature and thereafter washed with water (50 mf) added. The organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was solidified with ether and isopropyl ether, whereby the title compound was obtained (1.0 g; yield:

74%) .

NMR (CDCl^ i 5):

2.83(311,s), 2.90 ( 3H, s) , 3.4 3 , 3.58 ( 2H, ABq, J=18Πz ) , 4.80,5.06(211, ΛBq, J=12Hz) , 4.8(lH,m), 4.97(lH,d, J=4Hz) , 6.98 (1H, s) , 7.25-7.50(1011,m)

Ethyl acetate was dissolved in the hydrochloride (1.0 g) which had been obtained in the above step. The resulting solution was added with an aqueous solution of sodium hydroenrbonate to neutralize the solution.

The organic layer was washed with water and then with a saturated aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure, whereby benzhydryl 7-amino-3-N,M-dimethy1carbamoyloxymethy1-3-cephem-4carboxylate (0.9 g) was obtained.

Preparation Example 4

Denziiydry 1 7-f fZ)-2-(2-tritvlaminothiazol-4-vl) 2-tri tyloxviminoacebamidol -3-N. N-dimethv.lcarbamov loxvroethvl-3-cephem-4 -carboxylate

A sαJution of (Z)-2-(2-tri ty.laminothiazol-4-yl) 2-trityloxyiminoacetic acid (1.9 g; 2.8 mmol), 1-hydroxy-lll-benz triazole (0.4 g? 2.9 mmol) and dicyclohexylcarbodiimide (0.6 g; 2.9 mmol) in dimethylformαmide (20 int) was stirred at room temperature for 30 minutes. To the resulting solution, benzhydryl 7-amino-3-N, 11 -dimethy1carbamoyloxymethy1-3-cephem-4carboxylato (1,3 g; 2.8 mmol), which had been obtained in the second step of Preparation Example 3, was added, followed by stirring for 3 hours. The reaction mixture was added with ethyl acetate (300 m£) and the resulting mixture was washed with water and a saturated aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate. After concentration under reduced pressure, the concentrate was subjected to chromatography on a silica gel column, whereby the

■1S)

title compound was obtained (1.4 g? yield: 45%).

NMR (CDC1₃, δ) :

2.82 ( 311, s) , 2.9 1 ( 3 H, s) , 3 . 36,3.48 ( 2H , ΛBq, J=18!Iz ) , 4.81,5.14(2H,ΛBq,J=12Hz), 5.05(1H,d,J=4Hz),

6.08 (111, dd , J=4 Hz , 8Hz) , 6.43(111, s), 6.80(lH,s), 6.97(111,s), 7.18-7.50 (4211,m)

Preparation Example 5

Benzhvdrvl 7-thienvlacetamido-3-N-ethyl-N-methvlcarbamovloxvmethvl-3-cephem-4-carboxvlate-l-oxide

In a similar manner to Preparation Example 1, the title compound was obtained (yield: 9%).

NMR (CDCl3 , 5):

1.0-1.18 (311,m) , 3.80 (3/2H,s) , 3.86(3/2H,s), 3.183.5(311,m), 3.80-3.90(211,m) , 3.85(2H,s), 4.444.46(111, m) , 4.74 (III, d, J=13Hz) , 5.2 4-5.3 8 (111, m) , 6.07(111, dd, J=5IIz, 8Hz) , 6.9-7.02 ( 411, m) , 7.237.50(11H,m)

Preparation Example 6

Benzhvdrvl 7-thienvlacetamido-3-N-ethvl-N-methyl-carbamoyloxvmethvl-3-c℮phem-4-carboxylate

In a similar manner to Preparation Example 2, title compound was obtained (yield: 66%).

NMR (CDC1₃, S) :

1.0-1.15 (311, m) , 2.8(3/2H,s), 2.87(3/2H,s), 3.183.3 5 ( 2M , m) , 3.4 0-3.55 ( 2H , ΛBq, J=18Hz) , 3.86(211,s) 4.8(1H,d,J=14Hz), 4.97(III, d, J=5Hz ), 5.05-5.15 (1H,m), 5.87(lH,dd,J≈5Πz,8Hz), 6.28(1H,d,J≈βHz), 6.93(111,s), 6.95-7.02 (2H, m) , 7.2-7.5 (1111, m) Preparation Example 7

Benzhvdrvl 7-amino-3-N-ethvl-N-methvl carbamovloxvmethvl-3-cephem-4-carboxvlate hvdroch]oride

In a similar manner to Preparation Example 3, title compound was obtained (yield: 81%).'

NMR (CDCI3, 5):

the the Preparation Example 8

Benzhvdrvt 7-f2-f2·-tritvlamΐnothiazol-4-vl)-2tri tv loxviiαinoacetamido 1 -3-N-ethvl-N-methvlcarbainov loxvme thv 1 -3 -cephem-4-carboxyl ate

In a similar manner to Preparation Example 4, the title compound was obtained (yield: 72%).

NMR (CDC1₃, 5):

1.1-1.2(3 H,m) , 2.79(3/2H,s), 2.87(3/2H,s) , 3.183.35(3H,m), 3.48(1H,d,J≈18Hz), 4.82(1H,d,J≈12Hz), 5.06 (lH,d, J = 5I!z) , 5.07-5.15 (lH,m), 6.07(111,dd, J = 5Hz ,0Hz) , 6.4 3 (1H_fs) , 6.83(111,s), 6.95 (lH,s), 7.1-7.4 (4011, m) , 7.4 7 (III, d , J=8Hz )

Preparation Example 9

In a similar manner to Preparation Example 1, the title compound was obtained (yield: 53%).

NMR (DMSO-dg,S)

3.3-3.4(4H,m), 3.5-3.6(4H,m), 3.64,4.03(211, ABq,J=19Hz), 4.62,5.17(2H,ΛBq,J=12Hz), 4.955.00(111,m), 5.95-6.00 (1H, m) , 6.98-7.05 (3H,m) , 7.17.6 (11H, m) , 8.4 7 (III, d , J=8Hz )

Preparation Example 10

Benzhydrvl 7-thienvlacetamido-3-(1-morpholinvl)carbonyloxvmethvl-3-c℮phem-4-carboxvlate

In a similar manner to Preparation Example 2, the title compound was obtained (yield: 52%).

NMR (CDC1₃, δ) :

3.3-3.5(411,m) , 3.55-3.70(411,m) , 3.40,3.58(211, ΛBq, J=19IIz) , 3.87(2H,S), 4.8 2,5.09 (2H, ABq, J=13Hz) , 4.97 (III,d,J=5Hz) ,

6.25(lH,d,J=8Hz),

7.25-7.45(llH,m)

5.87(lH,d,J=5Hz,8Hz), 6.94(111,s), 6.95-7.05 (211,m) ,

Preparation Example 11

Benzhvdrvl 7-amino-3-(l-moroholinvl)carbonvloxvmethvl-3-ceohem-4-carboxylate hydrochloride

In a similar manner to Preparation Example 3, the title compound was obtained (yield: 62%).

NMR (CDC1₃ , 5):

3.3-3.5(5H,m), 3.5-3.8(5H,m), 4.98,5.24(2H, ABq,J=12Hz), 5.0-5.1(lH,m), 5.14-5.1?(1H,m), 6.94(1H,s), 7.2-7.5(10H,m)

Preparation Example 12

Benzhvdrvl 7-((Z)-2-(2-tritylaminothiazol-4-yl)2-tritvloxyiminoacetamidol-3-(1-morpholinvl)carbonvloxvmethvl-3-c℮phem-4-carboxvlate

In a similar manner to Preparation Example 4, the title compound was obtained (yield: 59%).

NMR (CDC1₃,^δ)^:

3.26,3.50 (211, ABq, J=19Hz), 3.3-3.7(8H,m),

4.8 2,5.11 (211, ABq, J = 13IIz) , 5.05(1H,d,J=5Hz) , 6.2(lH,dd,J=5Hz,811z) , 6.44(111,s), 6.8 5 (1H, br. s) , 6.96 (1H, s) , 7.15-7.5(4111, m)

Preparation Example 13

Benzhvdrvl 7-1(Z^-2~(2-tritvlamlnothiazol-4-vl)2-methoxviminoacetamidol-3-H.N-dimethvlcarbamovloxvmethv1-3-cephem-4-carboxylate

To a solution of phosphorus pentachloride (3.4 g) and pyridine (1.3 g) in dichlσromethane (100 ml), a solution of benzhydryl 7-thienylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate (2 g) in N,N-dimethy1formamide (6 m£) and dichloromethane (100 ml) was added under ice cooling and the resulting solution was stirred at the same temperature for 30 minutes. The reaction mixture was then added with 1,3butanediol (4 mf) under cooling in a dry ice-methanol bath (-50‘C), followed by stirring at the same temperature for 50 minutes. After methanol (4 ml) was added to the reaction mixture at the same temperature, the dry ice-methanol bath was removed and the mixture was allowed to stand until its temperature returned to room temperature. The reaction mixture was added with water and dichloromethane, followed by collection of the dichloromethane layer and then, by further extraction of the water layer with dichloromethane. Both dichloromethane layers were combined together and were washed successively with water and a saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was dissolved in ethyl acetate and the resulting solution was washed with a dilute aqueous solution of sodium hydrogencarbonate (containing 1.1 equivalent of sodium hydrogencarbonate based on the raw material), followed by drying over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was dissolved in N,H-dimethylformamide (15 md) . To the resulting solution, (Z)-2-(2-tritylaminαthiazol-4-yl)2-methoxyiminoacetic acid (1.53 g), 1-hydroκy-lHbenztriazole (0.55 g) and dicyclohexylcarbodiimide (0.78 g) were added, followed by stirring at room temperature for 2 hours and 40 minutes. The reaction mixture was added with ethyl acetate and water. After the collection of the ethyl acetate layer, the water layer was extracted further with ethyl acetate. Both ethyl acetate layers were combined together, washed successively with water and a saturated aqueous sodium chloride solution, and dried over magnesium sulfate.

Then, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby benzhydryl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-N, N-dimethylcarbamoyloxymethyl-3·~cephem-4-σarboxylate was obtained (1.46 g, 48.2 %).

NMR (CDC1₃, 5):

2.83(311,s), 2.89(311,S), 3.36-3.50(2 H, ABq, J=18.8IIz ) , 4.04 (3H , s) , 4.84,5.10 (2H, ABq, J=13.7Hz) , 5.04(111,d, J≈4.9Hz), 5.92-5.96 (lll,jn), 6.76(111,8), 6.94 (111,s), 7.20-7.45(2511,m)

Preparation Example 14

Be∩zhvdrvl 7-T(Z)-2-(5-tritvlami∩o-1.2.4-thiazol3 - vl) -2-methoxviminoacetamido 1 -3- (N. N-dimethvl-carbamoyloxymethvl-3-c℮pheπi-4-carboxvlate

In a similar manner to Preparation Example 13, the title compound was obtained (yield: 71%).

NMR (CD₃OD, S) :

4.07(311,8), 5.18 (III, d, J=5.1Hz) , 5.94(lH,d, J=5.1Hz), 6.93(lfl,s), 7.25-7.45(2511,m)

Preparation Example 15

Benzhvdrvl 7-r(Z)-2-(2~tritvlaminothiazol-4-yl)~ 2-monofluoromethoxviminoacetarnidol-3-(N.Ndimethvlearbamoyloxvmethvl-3-cephem-4-carboxylate

In a similar manner to Preparation Example 13, the title compound was obtained (yield: 64%).

NMR (CDCI3, 6):

2.65-2.87 (611,111) , 3.47,3.72(211, ΛBq, J=18.5Hz ) , 4.82,5.09(2H,ΛBq,J≈13.9Πz) , 5.05 (III, d , J=4.9IIz) , 5.72,5.86(2H,ABq,d,J=3.6Hz,55Hz), 5.94(1H,dd, J=4.9Hz , 8.4 Hz) , 6.81(111,s), 6.93(111,s), 7.03(lII,d,J≈8.4Hz) , 7.2 8-7.4 5 (2 511, m)

Preparation Example 16

Benzhvdrvl 7-formamido-3-('l-piρeridinyllcarboπvloxvmethvl-2-cephem-4-carboxylate

To a solution of benzhydryl 7-formamidσ-3-hydroxymethyl-3-cephem-4-carboxylate (4.24 g) in tetrahydrofuran (80 mt) , N,N¹-carbonyldiimidazole (1.62 g) was added under ice cooling, followed by stirring at the same temperature for 1 hour and 25 minutes. Then, the resulting solution was added with a solution of piperidine (0.85 g) in tetrahydrofuran (10 mf) and stirred at the same temperature for 1 hour and 20 minutes. Further stirring was conducted for one hour at room temperature. The reaction mixture was added with piperidine (0.17 g), followed by stirring at room temperature for 11 hours and 10 minutes and then, the resulting reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The resulting solution was washed successively with IN hydrochloric acid, water and a saturated aqueous chloride solution, followed by drying over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby benzhydryl 7-formamido-3-(1-piperidinyl)carbonyloxy-methyl-2-cephem-4-carboxylate (2.3 g, 43.0%).

NMR (CDC1-j, δ) :

1.20-1.4 0(6H,m) , 3.30-3.40(4H,m), 4.57,4.66(2H, ABq,J=12,8Hz), 5.13(lH,s), 5.22(1H,d,J=4.0Hz), 5.70-5.75(lH,m), 6.4 4(1H,s) , 6.89(lH,s), 7.257.40(1011,m), 8.23(111,s)

Preparation Example 17

Benzhydryl 7-formamido-3-(1-piperidinvl)carbonvloχymethv-l-3-c℮phem-4-carboχylate-l-oχid℮

To a solution of benzhydryl 7-formamido-3-(1piperidinyl)carbonylσxymethy1-2-cephem-4-carboxylate

- bO -

(3.4 g) in ethyl acetate (20 m£) , m-chloroperbenzoic acid (1.53 g) was added under ice cooling, followed by stirring at the same temperature for 55 minutes. To the reaction mixture, m-chloroperbenzoic acid (0.15 g) was added, followed by stirring under ice cooling for 35 minutes. The crystals precipitated were collected by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby benzhydryl 7-formamido-3-(1-piperidiny1)carbonyloxy-ethyl-3-cephem-4-carboxylate-l-oxide (1.53 g, 43.7%) was obtained together with precipitated crystals.

NMR (DMS0-d₆, 6):

1.35-1.55(6H,m) , 3.23-3.30 (4H,m) , 3.65,4.01(2H,ABq, J-18.7HZ), 4.58,5.11(2 H, ABq,J≈13 . GHz) , 4.98(111, d, J=3.7Hz) , 6.05 (1H, m) , 6.93(111,s), 7.257.55(1011,m), 8.15 (1H, s) , 8.43 (lH,d, J=9.5Hz) Preparation Example 18

Benzhvdrvl 7-formamido-3-<l-piperidinyl)carbonyloxvmethvl-3-c℮phem-4-carboxvlat℮

To a solution of benzhydryl 7-formamido-3-(1piperidinyl)carbonyloxymethyl-3-cephem-4-carboxylate-loxide (2.07 g) in N,N-dimethyIfαrmamide (25 m£) , phosphorus trichloride (1 m£) was added under cooling in a dry ice-ethanol bath (-60*C), followed by stirring for 35 minutes. The reaction mixture was successively added with ethyl acetate and water under cooling in a dry ice-ethanol bath and then, the resulting mixture was increased to room temperature. The ethyl acetate layer was collected and the water layer was extracted further with ethyl acetate. Both ethyl acetate layers were combined together, successively washed with water and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby benzhydryl 7-formamido-3-(1-piperidinyl)carbonyloxymethyl-3-cephem-4-carboxylate (1.87 g, 93.0%) was obtained.

NMR (CDC1₃, S) :

1.35-1.55(611,m) , 3.20-3.35(4H,m), 3.3 5,3.4 6 ( 2H , ABq,J=18.7II z) , 4.76,5.03(211, ABq,J=13.9Hz) , 4.90(111, d,J=3.5Hz) , 5.80-5.85(111, m) , 6.86(111,s), 7.14-7.40(10H,m) , 7.84 {111, d, J=9.2 Hz) , 8.15(111,s) Preparation Example 19

b 2

Benzhvdryl 7-f(Z)-2-(2-tritvlaminothiazol-4-vl)2-tritvloχyiroinoacetamidol-3- (l-pioeridlnvllcarbonvloxvmβthvl-3-c℮phem-4-carboxylate

To a solution of benzhydryl 7-forwamido-3-(1piperidinyl)carbonyloxymethyl-3-cephem-4-carboxylate (1.87 g) in tetrahydrofuran-methanol (1:1, 20 m£) , 36% hydrochloric acid (2 m0 was added and the resulting solution was stirred at room temperature for 2 hours and 10 minutes. Then, the solvent was distilled off under reduced pressure. The residue was added with ethyl acetate and water. The ethyl acetate layer was collected and the water layer was extracted further with ethyl acetate. Both ethyl acetate layers were combined together, washed with a saturated aqueous sodium chloride solution and then, dried over magnesium sulfate. The solvent was thereafter distilled off under reduced pressure. The residue was dissolved in N,N-dimethylformaroide (18 mt) . To the resulting solution, (Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (2.35 g), 1-hydroxy-lH-benztriazole c-γ∩mh s ∩

(0.56 g) and dicyclohexylcarbodiimide (0.79 g) were added, followed by stirring at room temperature for 1 hour and 5 minutes. The reaction mixture was added with ethyl acetate and water. The ethyl acetate layer was collected and the water layer was extracted further with ethyl acetate. Both ethyl acetate layers were combined together, washed successively with water and a saturated aqueous sodium chloride solution and then was dried over magnesium sulfate. The solvent was thereafter distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby benzhydryl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1piperidinyl)carbonyloxymethyl-3-cephem-4-carboxylate (1.4 g, 33.7%).

NMR (CDC1₃, S) ;

1.42-1.64 (611, m) , 3.2 5-3.4 3 ( 4 H, m) , 3.26,3.48

( 2H, ABq, J=18.6II z) , 4.82,5.12 (2H , ΛBq, J-13.91Iz) , 5.05(111, d, J-4.9HZ) , 6.05-6.12(lH,m) , 6.44(lH,s), 6.96(1H, s) , 7.15-7.43 (4011, m)

Preparation Example 20

Behzhvdrvl 7-formamido-3-(1-azetidi∩vl)carbonvloxvmethvl-3-cephem-4-carboxylate

In a similar manner to Preparation Example 16, the title compound was obtained (yield: 58%).

NMR (CDC1₃, 5):

2.15-2.25(2H,m), 3,90-4.00(4H,m), 4.55,4.61 (2H,ΛBq,J=12.7Hz), 5.13(lH,s), 5.21 (1H,d,J=4.0Hz), 5.69 (111, dd ,J-4.0Hz,9.2Hz) , 6.44(111,s), 6.82(lH,d, J=9.2Hz) , 6.90(131, s) , 7.2 8-7.40 (10H, m) , 8.22(lH,s) Preparation Example 21

Benzhvdrvl 7-formamido-3-fl-azetidinvl)carbonvloxvmethvl-3-cephem-4-carboxylate-1-oxide

In a similar manner to Preparation Example 17, the title compound was obtained (yield: 44%) .

NMR (CDCI3, 5) :

2.15-2.2 5 (2H,m) , 3.20,3.82 ( 211, ΛBq, J=18.9Hz) , 3.90-4.05 (411,m) , 4.45(111,d,J≈4.8ffz) } 4.72,5.24 Preparation Example 22

Denzhvdryl 7-forma mi do-3 - (1-azetidinvllcarbonyloxvmethy1-3-c℮phem-4-carboxvlate

In a similar manner to Preparation Example 18, the title compound was obtained (yield: 97%).

In a similar manner to Preparation Example 19, the title compound was obtained (yield: 94%).

NMR (CDC1₃, δ) :

2.15-2.27(2H,m), 3.26,3.50(2H,ABq,J=18.5Hz), 3.854.10(4H,m), 4.82,5.08(2H,ABq,J=13.8Hz), 5.05(lH,d,J=4.9Hz), 6.11(1H,dd,J=4.9Hz,8.8Hz), 6.47(1H,s) , 6.9 9(1H,s) , 7.15-7.53(4OH,m) Preparation Example 24

Mixture of benzhydrvl 7-fσrmamido-3-fN-f2hvdroxvethyl)-N-methvlcarbamoyloxymethvl1-2-cephem-4-carboxvlate and benzhydrvl 7-formamido3-fN-(2-hvdroxvethyl)-N-methvlcarbamovloxvmethvll-2-cephem-4-carboxvlate

In a similar manner to Preparation Example 16, the title compound was obtained (yield: 51%).

NMR (CDCI3, 6):

2.90-2„97(3H,m), 3.24-3.35(2H,m), 3.49,3.59(10/12H, ABq,J=19Hz), 3.61-3.70(2H,m), 4.57-4.76(14/12H,m), 4.86-4.90,5.09-5.18 (10/12 H,m) , 4.99 (5/1211, d, J = 5Πz) , Preparation Example 25

Be∩zhvdrvl 7-formamido-3- (N- ( 2-hvdroxvethvl) -Nmethvlcarbamoyloxvmethvl-3-cephem-4-carboxylate-1-oxide

In a similar manner to Preparation Example 17, the title compound was obtained (yield: 49%$.

NMR (CDCl₃ , S) :

2.87(3/2H,s), 2.90(3/2H,S), 3.22-3.29(lH,m),3.363.41(lH,m), 3.59-3.62(lH,m), 3.69,3.7i(lU,m), 3.94,4.09(2H,ABq,J=20Hz) , 4.46-4.56(HI,m) , 4.774.81(111,m) , 5.23-5.29( 1H, m) , 6.08-6.10 (1H , m) ,

6.9 4 (1H, s) , 8.22(111,s)

Preparation Example 26

Be∩zhvdrvl 7-r2-tritvloxvimino-2-(2-tritvlaminothiazol-4-vl)acetamldol-3-fH-(2-hvdroxvethvl) -N-tnethvlcarbamovloxvmethyl 1-3cephem-4-carboxyl a tie

In a similar manner to Preparation Example 19, the title compound was obtained (yield: 12%).

MMR (CDC1₃, δ) :

2.94-2.97 (311,m) , 3.2 4-3.3 0 ( 31!, m) , 3 . 4 3-3.52 (3II, m) , 4.80-4.03 (lΠ,m) , 5.06 (111, d, J≈5Πz) , 5.10-5 . 15 (III, m) , 6.11 (lΠ,dd, J≈5Hz , 9ΠZ) , 6.44(111, s), 6.96(111,s), 7.27.4 (4011,m)

Preparation Example 27

Be∩zhvdrvl 7-formamid0-3-N-ca rbamovlmethvl-lime thy 1 carbamoyl ox vmethv 1-3-cephem-4-carboxyl a te~ 1-oxide

o

t

OHCMH O O

|| ^ Me

O r ocn > conh₂ r ocn > conh₂

COOB1I

To a solution mixture of benzhydryl 7-forma.midα3 - (1-imidazoryl) carbonyioκymethy1-2-cephem-4-carboxylate-i-oκide (5.4 g) in a tetrahydrofuran (90 mO , and water (18 m£) mixture, sarcosinamide hydrochloride (1.9 g) and pyridine (1.23 m£) were added, followed by stirring at room temperature for 15 hours and at 45*C for 12 hours. After the reaction mixture was concentrated, the residue was added with water and ethyl acetate. The ethyl acetate layer was successively washed with IN hydrochloric acid, water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated. The residue was purified by chromatography on a silica gel column, whereby the title compound was obtained (yield:

750 mg; 15.0%)

NMR (CDCl2 , S) :

2.78(3 H,m) , 3.7 8(2 H,m) , 3.5-4.1(2H,m) , 4.95(lH,m), 4.5-5.1 (2H,m) , 6.03(111,m), 6.9(lH,m), 7.27.5(1011,m), 8.14 (1H, s) , 8.4 2 (1H, d, J=8Hz) Preparation Example 28

Benzhvdrvl 7-formamido-3-N-cva∩om℮thyl-N-methvlcarbamovloxvmethvl-3-c℮Dhem-4-carboxvlate

In a similar manner to Preparation Example 18, the title compound was obtained (yield: 66%).

NMR (CUCI3, 5):

2.94(311, s) , 3.4-4.3(411,111),

4.87,5.15(2H, ΛBq,J=18IIz) , 5.08 (111, d, J≈4Hz) , 5.96(1H, dd, J=4Hz , 811z) , 6.45(1H,br.s) , 6.94(lH,s), 7.2-7.45 (1011,m) , 8.26(lH,s)

Preparation Example 29

Benzhydrvl 7-r(Z)-2-tritvloχyimino-2~(2-tritylaminothiazol-4-vl)acetamidol-3-N-cvanomethvl-N-methvlcarbamovloxvmethvl-3-cephem- 4-carboxviate

To a solution of benzhydryl 7-formamido-3-N-cyanomethyl-N-methylcarbamoyloxymethyl-3-cephem-4- carboxylate (430 mg) in a methanol (6 md) , and tetrahydrσfuran (6 md) mixture, concentrated hydrochloric acid (0.8 md) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated, added with ethyl acetate, successively washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated.

To a solution of the residue thus obtained

(410 mg) in N, H-dimethyl f ormamide (8 mi), (Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (610 mg), dicyclohexylcarbodiimide (197 mg) and 1hydroxybenzotriazole (123 mg) were added, followed by stirring at room temperature for 10 hours. The reaction mixture was added with water and ethyl acetate.

The ethyl acetate layer was successively washed with water, IN hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated. The residue was purified by chromatography on a silica gel column, whereby the title compound was obtained (yield: 460 mg; 44.5 %).

NMR (CDC1₃, 5):

2.87(0.6H,br.s) , 2.9 6(0.4H,br.s) , 3.08-3.48 (2H,m) , 3.8-4.3(2H,m), 4.7-5.2(2M,m), 5.04(1H,d,J≈5Hz), 6.10 (1H, dd , J=5Hz , 8Hz) , 6.45(111,s), 6.96(lH,s), 7.17.5(4 OH,m)

Preparation Example 30

Benzhvdrvl 7-formamido-3-(3-hvdrσxy-lpvrrolidi∩vl)carbonvloxvmethvl-3-cephem-4carboxvlate and 2-c℮phem derivative thereof

In a similar manner to Preparation Example 16, the title compound was obtained (yield: 28%).

NMR (CDC1₃, δ) :

1.9(211,m), 3.2-3.6 (411,m) , 4.4-4.8 ( 3H,m) , 5.01(0.3H,d,J=5Hz) , 5.17(0.711,8), 5.23 (0.711, s) , 5.70(0.711,m) , 5.94 (0.311,m) , 6.48(111,m), 6.91(0.711,8), 6.95(0.311,8), 7.25-7.45(10H,m), 8.25 (111, m)

Preparation Example 31

Be∩zhvdrvl 7-forτπamido-3- (3-hydroxy-1pyrrolidinvl) carbo∩vloxvmethvl-3-cepheτn-4-carboxvlate-l-oxlde

In a similar manner to Preparation Example 17, the title compound was obtained (yield: 68%).

NMR (DMSO-dg, δ) :

I. 6-1.95(211, m) , 3.1-3.4(4H,m), 3.84(211,m), 8.42(lH,d,J=9.8Hz)

Preparation Example 32

Benzhvdryl 7-formamldo-3-f3-hvdroxy-lpvrrolidi∩vl)carbonvloxvmethvl-3-c℮phem-4carboxvlate

In a similar manner to Preparation Example 18, the title compound was obtained (yield: 78%).

NMR (CDC1₃, S) :

2.16(211,m), 3.3-3.7 (611, m) , 4.99 (Ilf, d, J=5Hz) , 4.85.2(2H, m) , 5.48 (lH,br.s) , 5.93 (111,dd,J≈91lz, 5IIz) 6.48 (lH,d, J=9Hz) , 6.95(111,S), 7.2-7.4 (1H, Ξ) , 8.24(1H,S)

Preparation Example 33

Benzhvdrvl 7-f(Z)-2-tritvloxvimiπo-2-(2-tritylaminothlazol-4-vl)acetamidol-3-(3-hvdroχy-1-pvrrolidinvl)carbonvloxvmethvl-3-cephem-4carboxvlate

In a similar manner to Preparation Example 19, the title compound was obtained (yield: 6%).

NMR (CDC1₃, 5):

1.97(211, m) , 3.1-3.5 (6H,m) , 4.26(lH,b), 4.98(lH,d,J≈5Hz), 4.7-5.2(211,m) , 6.05(lH,dd, J=9Hz, 5Hz) , 6.4 6 (1H, s) , 6.94(lH,s), 7.1-7.5 (4 OfI, m) Preparation Example 34

Benzhvdrvl 7-formamido-3-f((S)-f-H -2-hvdroxv-methyl-l-ovrrolidinvl^ carbonvloxγmethvl1-3-cephem-4-carboxvlate and 2-ceohem derivative thereof

In a similar manner to Preparation Example 16, the title compound was obtained (yield: 16%).

NMR (CDCI3, S) :

1,7-2.1(4H,m), 3.2-4.0(4.4H,m), 4.65(lH,m), 4.65.3 (1.2H,m) , 4.86,5.15(0.8H,ABq,J=14Hz) , 5.01(0.4H,d,J≈5Hz), 5,18(0,6H,s), 5.25(0.6H,m), 8.25(lH,s)

Preparation Example 35

Benzhvdrv.1 7-formamido-3-r ((S) -( + ) -2-hydroxymethyl- 1-pyrrol idinvl)carbonvloxvmethvl1-3cephem-4-carboxylate-l-oxide

In a similar manner to Preparation Example 17, the title compound was obtained (yield: 59%).

NMR (CDC1₃, S) :

1.5-2.1(411,m) , 3.2-4.0(6H,m) , 4.53(111, m) , 4.80,5.34(2H,ABq,J=14Hz), 5.25(111,m), 6.15(lH,dd, J=9Hz,15Hz), 7.97(1H,s), 7.2-7.5(10H,m), 8.27(lH,s) Preparation Example 36

Benzhvdrvl 7-formamido-3-T ( (S) - f-f)-2-hvdroxy-methvl-l-pvrrolidinvllcarbo∩vloxymethyl1-3-c℮pheπt-4-carboxvlate

In a similar manner to Preparation Example 18, the title compound was obtained (yield: 74%).

NMR (CDCl-j, δ) :

1.80-2.10(4H,m) , 3.2 7-3.56 ( 611, m) , 3.90(lH,m),

4.97( 1H, d, J=4.8H2) , 5.01 (211, ΛBq, J=14Hz) , 5.90(111,dd,J=4.81lz, 8.911z) , 6.94(lH,s), 7.23-

7.44 (1011,m) , 8.18 (111,s)

Preparation Example 37

Benzhvdrvl 7-r CZ)-2-(2-tritvlaminothiazol-4-vl)2-tritvloxvirainoacetamidol-3-f(SI -(+ )-2-hydroxymethyl pyrrolidinolcarbonyloxvmβthvl-3-c℮phem-4carboxvlate

In a similar manner to Preparation Example 19, the title compound was obtained (yield: 6%).

NMR (CDC1₃, δ) :

1.80-2.00(411,m) , 3.21-3.60 ( 6H,m) , 3.90(111,m), 5.02(111,d,J≈4.8HZ) , 5.08 (211,ΛBq, J=14HZ) , 6.07(111, dd,J=4.81Iz, 8.8ilz) , 6.45(111, s) , 6.95(111,s), Px*eparation Example 38

Mixture of be∩zhvdrvl 7-r fZ)-2-trltvloxvimino-?.(2-tritvlaminothiazol-4-vl)acetamidol-3-(1pvrroliάinvllcarbonvloxvmethvl-3-cephem-4carboxvlate and be∩zhvdrvl 7-r2-tritvloxvimino-2(2-tritvlaminothiazol-4-vUacetamidol-3-f1pvrrolidinvlV carbonvloxvmethvl-2-cephem-4carboxvlate

In tetrahydrofuran (200 mt) , Z-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (20 g), 1hydroxybenzotriazole (6 g) and dicyclohexylcarbodiimide (9.2 g) were dissolved. The resulting solution was stirred at room temperature for 1 hour and 15 minutes (Liquid Λ).

On the other hand, 7-amino-3-hydroxymethyl-3-* cephem-4-carboxylic acid (10.3 g) was suspended in acetonitrile (500 m t) , followed by the addition of N-methyl-N-(trimethylsilyl)trifluoroacetamide (24.8 m£) at room temperature. The resulting suspension was stirred at room temperature for 20 minutes (Liquid D).

After filtration of Liquid A, the solvent was distilled off under reduced pressure. The residue thus obtained was recrystallized from a mixed solvent of nhexane and isopropyl ether so that powdery crystals were formed. They were dissolved in tetrahydrofuran (50 mt) and the resulting solution was added to Liquid B at room temperature, followed by stirring for one hour and 15 minutes.

The reaction mixture was thereafter filtered and the filtrate was added with diphenyldiazomethane (11.5 g) and methanol (8.5 g), followed by stirring at room temperature for 2 hours. The reaction mixture was distilled off under reduced pressure. The residue thus obtained was dissolved in tetrahydrofuran (120 mf) and the resulting solution was added with N,N¹-carbonyldiimizazole (4.9 g) at room temperature, followed by stirring at the same temperature for 2 hours.

In the next place, the reaction mixture was added with pyrrolidine (3.49 g), followed by stirring for 2 hours and 20 minutes. The reaction mixture was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (Si0₂ 250 g; benzene:ethyl acetate=8:1), whereby the title compound was obtained (yield: 6.94 g; 20%).

NMR (CDCl3 , δ) :

1.80-1.95(4H,m) , 3.25-3.30 (4H,m) , 4.60 ( 6/5H, s) , 4.82,5.10(2H,ΛBq,J=13Hz), 5.05(2/5H,d,J=5Hz),

5.18 (3/5H, s) , 5.25(3/511,d, J = 5Ilz) , 5.8 5 ( 3/5H , dd , J=5Hz,9Πz), 6.15(2/5H,dd,J=5Hz,9Mz), 6.22(3/5H,s), 6.42(3/5H,s), 6.44(2/5H,s), 7.01,7.03(1H,s), 7.257.40(40H,m)

Preparation Example 39

Benzhvdrvl 7-F(Z)-2-tritvlσxvimino-2-f2-tritvlaminothiazol-4-vl) acetamidol - 3- (1pyrrolidinvl)carbonyloxvmethv1-3-cephem-4carboxylate-1-oxide

To a solution of the mixture (3.7 g), which had been obtained in Preparation Example 38, in tetrahydrofuran (40 mI), m-chlorobenzoic acid (834 mδ) was added under ice cooling. The resulting solution was stirred at the same temperature for 1.5 hours. The reaction mixture was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (Siθ2 50 g, benzene:ethyl acetate=6:1), whereby the title compound was obtained (yield: 1.44 g;

38%) .

NMR (CDC1₃, 6) :

1.83-1.90{4H,m), 3.00-3.62(2H,ABq,J≈lθHz), 3.213.25(2H,m), 3.35-3.39(2H,m), 4.41-4.43(1H,m), 4.72,5.32 (2H, ABq, J=13Hz) , 6.30(1H,dd,J=5Hz, 9IIz) , 6.42(1H,s) , 6.93(1H,s) , 7.35-7.40(4 OH, m) Preparation Example 40

Benzhvdrvl 7-ffZ)-2-trityloxvimino-2-(2-tritylatπinothiazol-4-yl) ace tarn idol-3-(lpyrrolidinvl) carbonvloxvmethvl-3-cephem-4carboxvlate

To a solution of the compound (1.44 g), which had been obtained in Preparation Example 39, in N,Ndimethylformamide (15 m2) , phosphorus trichloride (0.43 m2) was added at -30*C« The resulting solution was stirred at the same temperature for 30 minutes.

The reaction mixture was poured into ethyl acetate, which had been cooled to -78*C in advance, followed by the addition of water. The ethyl acetate layer was collected, washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in ethyl acetate and the resulting solution was added to isopropyl ether. The resulting precipitate was collected by filteration and washed with isopropyl ether, whereby the title compound was obtained (yield: 895 mg, 63%).

NMR (CDCI3, δ) :

1.84-1.87 (4II,m) , 3.28-3.50 (2H, ABq, J=18Hz) , 3.203.24(2 H,m) , 3.35-3.38 (2H,m) , 4.82,5.10(2H,ABq,

J=13 H z) , 5.05(lH,d,J=5Hz) , 6.09(1H,dd,J=5Hz,9Hz) , 6.42(111,s), 6.94 (1H , s) , 7.3 5-7.4 0 (4 OH , nv)

Sodium 7-r(Z)-2-(2-aminothlazol-4-vl)-2hvdroxγiminoacβtamidol-3-H.N-dimethvl-carbamovloxvmethvl-3-cephem-carboxvlate

To the liquid mixture of trifluoroacetic acid (3 mO and anisole (2 mi), benzhydryl 2-[(Z)-2-tritylaminothiazo1-4-y1)-2-trityloxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethy1-3-cephem-4-carboxylate (1.4 g; 1.3 mmol), which had been obtained in Preparation Example 4, was added. The resulting solution was stirred for one hour. The reaction mixture was added with isopropyl ether (100 ml) and the resulting precipitate was collected by filtration. The filtrate was added to formic acid (10 m£) , followed by the reaction at room temperature for 2 hours. Formic acid was distilled off under reduced pressure, followed by the addition of ethyl ether. The resulting precipitate was collected by filtration. The filtrate was purified by reversed-phase column chromatography, whereby the title compound was obtained (yield: 240 mg, 39%).

NMR (D₂0, 5) :

2.7(6H,br.s), 3.42,3.69(2H,ABq,J=19Hz), 4.67,4.91(2H,ABq,J=12,6Hz), 5.22(lH,d,J=4.8Hz), 5.θ 5(1H,d,J=4.8 Hz) , 7.00(1H,S)

Sodium 7-r(Z!-2-(2-aminothiazol-4-vl!-2hvdroxviminoacetamido!-3-N-ethvl-N-mβthvlcarbamovloxymethvl-3-c℮Phem-4-carbόχylate The compound, which had been obtained in Prepara tion Example 8, was treated in a similar manner to Example 1, whereby the title compound was obtained (yield: 15 %).

NMR (D₂0, S) :

1.05-1.15(27/1OH,m), 1.25-1.35(3/1OH,m), 2.72(3/10H,br.s) , 2.90(27/10H,br.s) , 3.053.15(2/10Hm), 3.25-3.40(18/10H,m),3.4-3.5(1H,m), 3.7-3.78 (lH,m) , 4.70-4,78 (1H, m) , 4.90-5.00 (111,in), 5.24 - 5.27(1H,m), 5.85-5.90(1H,m), 7.02(lH,s) Example 3

Sodium 7-r (Z )-2-(2-aminothiazol·*-4-γl) -2-hvdroxviminoacetamid-ol -3-1-morpholyl)carbonyl ox vine thvl-3-cephem-4-carboxyl ate

The compound, which had been obtained in Prepara tion Example 12, was treated in a similar manner to Ex ample l_f whereby the title compound was obtained (yield: 15%).

Sodium 7-f(Z)-2-(^,2-aminothiazol-4-vl)-2methoxviminoacetamidol-3-N.N-dimethvlcarbamovloxvmethvl-3-c℮phβm-4-carboxvlate

To a solution of benzhydryl 7-((Z)-2-tritylamino-thiazol-4-yl)-2-methoxyiminoacetamido]-3-N,N-dimethyl-carbamσyloxymethyl-3-cephem-4-carboκylate (1.46 g) , which had been obtained in Preparation. Example 13, ih anisole (10 mi) , trifluoroacetic acid (20 m£) was added dropwise Under ice cooling., Λt the same temperature, the resulting solution was stirred for two hours and twenty minites. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol. The resulting solution was added with diisoprαpyl ether to precipitate crystals. The crystals precipitated were collected by filtration and dissolved in methanol, followed by dissolution of sodium acetate (600 mg). The resulting solution was added further with diisopropyl ether to precipitate crystals. The crystals thus precipitated were collected by filtration, washed with diisopropyl ether and then air-dried. The crystals thus obtained were purified by reverse-phase column chromatography, whereby sodium 7-[(Z)-2-(2-aminαthiazol-4-yl)-2-methoxyiminoacetamido-3-N,N-dimethy1carbamoyloxymethy1-3-cephem-4-carboxylate (71 mg, 8.5%) was obtained.

NMR (D₂0, 5) :

2.65-2.80(6H,m), 3.26,3.52(2H,ΛBq,J=18.1Hz), 3*83(3H,s), 4.52,4.75(2H,ABq,J≈12.6Hz),

5.05(111,d, J=4.8Hz) , 5.66 (1H,d,J=4.8 Hz) , 6.85(lH,s) Example 5

Sodium 7-r(Z)-2-(5-amino-l.2.4-thiazol-3"Vl)-2methoxγimlnoacetamido1-3-N.N-dimethvlcarbamovloxvmethvl^3-ce.pheiτi-4-car boxy late

The compound, which had been obtained in Preparation Example 14, was treated in a similar manner to Example 4, whereby the title compound was obtained (yield: 27%) .

NMR (D₂0, 6) :

2.68(6Π,s), 3.21,3.46(2H,ABq,J=18.OHz),3.89(3H,s), 4.50,4.72(2H,ABq,J=12.3Hz), 5.01(1H,d,J=4.7Hz), 5.67(1H,d,J = 4.7 H z)

Sodium 7-f(Z)-2-f2-aminothiazol-4-vl)-2monofluoromethoxviminoacetamido1-3-N.N-dimethvlc arbamo v 1 oxvr∩ethvl-3-cephem-4-carboxyl ate

The compound, which had been obtained in Preparation Example 15, was treated in a .similar manner to Example 4, whereby the title compound was obtained (yield: 10%).

NMR (D₂0, <$) :

2.62-2.73 (6U,m) , 3.22,3.48(2H,ΛBq,J=18.OHz) , 4.49,4.72(2H,ABq,d,J=12.8Hz,1.6Hz), 5.02-

5.04(1H,m), 5.63-5.66(lH,m), 5.61(2H,d,J=55.2Hz), 6.95(1H,s)

Sodium 7-r(Z)-2-(2-aminothiazol-4~yl)-2hydroxyiminoacetamidol-3-(1-pjperidΐ∩vl)carbonyloxvmethvl-3-cephem-4-carboxylate

The compound, which had been obtained in Preparation Example 19, was treated in a similar manner to Example 1, whereby the title compound was obtained (yield: 28%).

NMR (D₂0, δ) :

1.25-1.47(6H,m), 3.17-3.29(4H,m),

3.25,3.51 (2H, ABq, J=17.9 Hz) , 4.55,4.78 ( 211, ABq, J=12.5Hz) , 5.07 (lH,d, J=4.6flz) , 5.70 (111, d , J=4.6Hz ) , 6.82 (III, s)

Sodium 7-ffZ)-2-f2~aminothiazol-4-yl)-2hvdroxviminoacetamidol-3-(1-azetidinvl)carbonyloχymethvl-3-c℮phem-4-carboχylate

The compound, which had been obtained in Preparation Example 23, was treated in a similar manner to Example 1, whereby the title compound was obtained (yield: 25%).

NMR (D₂0, 6) :

2.00-2.10(211, m) , 3.21,3.47 (2H,ABq,J=17.9Hz) , 3.75-3.87(4H,m), 4.51,4.70(2H,ΛBq,J=17.6Hz), 5.05(lH,d,J=4.8Hz), 5.68(1H,d,J=4.8Hz), 6.7B(lH,s) Example 9

Sodium 7-r(Z)-2-(2-aminothiazol-4-y1)-2hydroxviminoacetarnidol-3-℮W-(2-hvdroxvethvl)-Hmethvlcarbamovloxvmethvl1-3~σ℮phem-4-carboχylate

The compound, which had been obtained in Preparation Example 26, was treated in a similar manner to Example 1, whereby the title compound was obtained (yieldr 8.8%).

NMR (D₂0, S) :

2.79-2.82 (3H,m) , 3.28-3.30(3H,m), 3.56-3.58

(311,m) , 4.57,4.75 (2H,m) , 5.09 (III, d, J=5Hz ) ,

5.73 (III, d,J = 5IIz) , 6.84(111,s)

Example 10

Sodium 7-r(Z)-2-(2-amiπothiazol-4-vl)-2hvdroxviminoacetamidol-3-N-cvanomethvl-N-methvlcarbamovloxvmethvl-3-c℮phem-4-carboxvlate

The compound, which had been obtained in Preparation Example 29, was treated in a similar manner to Example 1, whereby the title compound was obtained (yield: 21%) .

NMR (D₂0, S) :

2.85 (3H, br . s) , 3.28,3.55 ( 211, ABq, J=18IIz) ,

4.1-4.25 (2H,m) , 4.5-4.9 (2H,m) , 5.06(111,

d,J=5Hz) , 5.70(111,d,J=5IIz) , 6.77(111,s)

Example 11

Sodium 7-f(Z1 -2 - f2-aminothiazol-4-vll-2hvdroxvimi∩oacetamido1-3-f (3-hydroxy-1pyrrolidinvl)carbonyloxvmethvl-3-c℮phem-4carboxvlate

The compound, which had been obtained in Preparation Example 33, was treated in a similar manner to Example 1, .whereby the title compound was obtained (yield: 17%) .

NMR (D₂0, 5) :

2.05 ( 2H , m) , 3.2 5-3.8 ( 6H , m) , 4.4-4.5(111,

m), 4.6-4·95(2H,m), 5.20(1H,d,J=5Hz),

5.83(1H,d,J=5Hz) , 6,96(111, s)

Example 12

Sodium 7-r(Z)-2-(2-aroiπothiazol-4~vn-2hvdroxviminoacβtamido 1-3-f (S)-(f·) -2-hydroxymethyl- 1-pyrrolidinvl)carbonvloxymethy1-3-cephem-4-carboxvlate

The compound, which had been obtained in Preparation Example 37, was treated in a similar manner to Example 1, whereby the title compound was obtained.

NMR (D₂0, δ) :

1.70-1.84 (411,m) , 3.19-3.82(7H,m), 4.67

( 211, ABq , J = 13Hz) , 5.08 (11!, d, J = 4.8IIz ) , 5.70

(1JI, d , J=4.8Hz) , 6.83(111,3)

Example 13

Sodium 7-r(Z)-2-f2-aminothiazol-4-yl)-2hvdroxviminoacetamidol-3-(l-pvrrolidinyl)carbony1oxvmethy1-3-cephem-4-carboxylate

The compound, which had been obtained in Preparation Example 40, was treated in a similar manner to Example 1, whereby the title compound was obtained (17%). NMR (D₂0, S) :

1.68-1.73(4H,m), 3.15-3.23(4U,m), 3.25,

3.52 (2H,ABq,J=18Hz) , 4.52,4.75 (211, ABq, J=

12HZ), 5.15 (111, d, J=4 Hz) , 5.68 (1H, d , J=4Hz) , 6.81(1H,s)

Example 14

Pivalovloxvmethvl 7-r(Z)-2-(2-aminothiazol-4-yl)2-hvdroxviminoacetamido1-3-N.N-dimethvlcarbamoyloxvmethvl-3-c℮phein-4 -car boxy late

lodomethyl pivalate (37 mg; 0.16 mmol) was added to a solution of sodium 7-[(Z)-2-(2-aminothiazol-4-yl)2-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoy1-oxymethyl-3-cephem-4-carboxylate (80 mg; 0.162 mmol), which had been obtained in Example 1, in dimethylformamide (2 m£) , followed by stirring for one hour.

After the reaction mixture was added with ethyl acetate (100 mi) , the resulting mixture was washed with water and then with a saturated aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate and then by concentration under reduced pressure.

The residue was added with isopropyl ether and solidified, whereby the title compound was obtained (21 mg; yield: 23%).

NMR (CDC1₃, 5):

1.24{9H, Ξ), 2.92 (6II,br,Ξ) , 3.50,3.61(211, ABq, J=19Hz) , 4.89,5.17(211, ABq, J=13Hz ) , 5.07(lH,d, J=5Hz) , 5.85,5.97(111, ABq,J=5.5Hz) , 5.93(111,dd,

- 9 3 -

J=5Hz,8Hz), 7.08 (III, s) , 7.26 ( 2H, s)

Example 15

2-Ethvlbubanovloxvroebhvl 7-r f Z1-2-f 2-aminobhiazol-4-vl)-2-hvdroxviminoacebamido1-3-N. N-dimebhγlcarbamoyloxvmebhvl-3-c℮phem-4carboxvlabe

The compound obbained in Example 1 and iodomebhyl 2-ebhylbutyrabe were reached, whereby bhe hible compound was obbained (yield: 63%).

NMR (CDCl₃, 6) :

0.9 (6H,t, J=7.4Hz) , 1.5-1.7 (4H, m) , 2.25-2.35 (III, m) , 2.93 (6H,br.s) , 3,49,3.60 ( 211, ABq, J=18Hz ) , 4.91,5.15 (2H,ABq,J=14Hz), 5.07(1H,d,J=5.0Hz), 5.84-5.95

( 3H, m) , 7.07 (111, S)

Example 16

The compound obtained in Example 1 and l-iodoethyl isobutyrate were reacted, whereby the title com pound was obtained (yield: 10%).

NMR (CDC1₃, 5) :

1.18(6H,d,J=7Hz), 1.56(3H,d,J=5.5Hz), 2.552.65(lH,m), 2.92(6H,s), 3.50,3.51(together, lH,d,J≈lβHz), 3.61,3.62(together, 1H,d,J≈18Hz), 4.90,4.95(together, 1H,d,J=14Hz), 5.05,5.07 (together, 1H, d, J=5IIz) , 5.12,5.18 (together,

1H, d, J=14IIz) , 5.88-5.95(1 II,m) , 7.00,7,10 (together lH,q,J=5.5Hz), 7.09(111,s)

Example 17

1-(2-Ethvlbutanovloxv) ethvl 7-^·f (Z)-2-(2-aminothiazol-4-Vl)-2-hvdroxviminoacetamidol-3-N.N-dimethvlcarbamovloxvmethvl-3-c℮phera-4carboxvlate

The compound obtained in Example 1 and 1-iodoethyl 2-ethylbutyrate were reacted, whereby the title compound was obtained (yield: 15%).

NMR (CDC1₃, 5):

0.90 (3H, t, J = 7Ilz) , 0.91(3H,t,J=7Hz), 1.5-1.75 (7H,m), 2.2-2.3(lH,m), 2.92(6H,s), 3.48,3.53 (lH,d,J=18Hz), 3.60,3.61(lH,d,J=18Hz), 4.90, 4.97(lH,d,J=14Hz), 5.07(d,J=5Hz), 5.14,5.15 (lH,d,J=14Hz), 5.88-5.95(lH,m), 7.00-7.10(1H,m), 7.08(1H,S)

Example 18

l-(tert-Butvlacetoxv)ethyl 7-F(Z)-2-(2-aminothiazol-4-vl) -2-hvd.roxviminoacetamido 1 -3-N.N-dimethvlcarbamoyloxvmethvl-3-cephem-4carboxylate

The compound obtained in Example. 1 and 1-iodoethyl tert-butylacetate were reacted, whereby the title compound was obtained (yield: 4.5%).

NMR (CDC1₃, S) :

1.04(9H,s), 1.56(3H,d,J=5.5Hz), 2.2-2.3

(2H,m) , 2.93 (6H,s) , 3.48,3.50 (together,1H,d, J=18Hz), 3,60,3.61(together, lH,d,J=18Hz)

4.91,4.98 (together, III, d , J=12Hz) , 5.03-5.10

(1H,m), 5.12,5.17(together, 1H,d,J=12Hz), 5.86-5.93(lH,m), 6.97-7.12(1H,m), 7.12

(1H,s)

Example 19

1-(Ethoxvcarbonvloxv)ethyl 7-f(Z)-2-(2-ami∩othiazol-4-vl)-2-hydroxviminoacetamldol-3-N.N-dimethylcarbamoyloxvmethvl-3-cephem-4carboxvlate

The compound obtained in Example 1 and 1-iodoethyl ethylcarbonate were reacted, whereby the title compound was obtained.

NMR (CDC1₃, δ) :

1.33(3H,t,J=7H2), 1.58-1.63(3H,m), 2.93(3H,br.s), 3.51 (lH,d, J=18Hz) , 3.61,3.62 (together, lH,d, J=18Hz), 4.2-4.32(2H,m), 4.91,5.17(1H,ABq,J=14Hz), 4.99,5.22(1H,ABq,J=14Hz), 5.05(0.5H,d,J=4.5Hz), 5.10(0.5H,d,J=4.5Hz), 5.9-5.98(1H,m), 6.92(0.5H,q, J=5.5Hz), 7.04(0.5H,q,J=5.5Hz),7.08(1H,s)

Example 20

1-(Isopropyloxvcarbonvloxv)ethvl 7-r(Z)-2-(2-aminothiazol-4-vll-2-hvdroxvirainoacetamidol-3-N.N-dimethvlcarbamovloxvm℮thvl-3-cephβm-4carboxvlate

The compound obtained in Example 1 and 1-iodoethyl isopropylcarbonate were reacted, whereby the title compound was obtained (yield: 30%).

NMR (CDCI3, 5):

1.26-1.37 (6H,m) , 1.58-1.62 ( 3H, m) , 2.93(611,s), 3.50(lH,d,J=19Hz), 3.60,3.61(together,lH,d,J=l9Hz) 4.9-5.24 (311,m) , 5.04,5.07 (together, lH,d,J=5Hz), 5.9 3 (lH,dd, J=5Hz,BIIz) , 6.9 2,7.02 (together, lH,q, J=5.5HZ), 7.08(1H,s)

Example 21

1-(Cvclohexvlcarbonvloxv)ethyl 7-f(Z)-2-(2-aminothiazol-4-vl)-2-hvdroxviminoacetamido1-3-N.N-dimethylcarbamovloxvmethvl-3-cephem-4carboxvlate

The compound obtained in Example 1 and 1-iodoethyl cyclohexylcarbonate were reacted, whereby the title compound was obtained (yield: 19%).

NMR (CDCl₃, 5):

1.1-1.6(6H,m), 1.58-1.63(3H,m), 1.66-2.00(4H,m), 2.93(611,s), 3.52,3.40 (2H, ABq, J≈lβHz) , 4.6-4.7 (1H,m), 4.89,4.97(together,1H,d,J=12Hz), 5.055.10(1H,m), 5.12, 5.17(together, 1H,d,J=12Hz), 6.83-6.94 (lll,m) , 6.89,6.98 (together, 1H, q, J=5.5Hz) 7.15 (III, s)

Example 22

Plvalovloxvmethvl 7-f(Z1-2-(2-aminothiazol-4-vl 12-hydroxyiminoacetamidol-3-N-ethvl-N-methyl-carbamovloxvmethvl-3-c℮phem-4-carboxvlate

The compound obtained in Example 2 and iodomethyl pivalate were reacted, whereby the title compound was obtained (yield: 34%).

NMR (CDC1₃, <5) :

1.12(3H,t,J=7Hz), 1.24(9H,s), 2.89(6/3H,s),2.90 (3/3 H,s) , 3.25-3.35(2H,m), 3.47,3.48(together, lH,d,J=18Hz) , 3.61 (1H, d, J≈18Hz) , 4.89 (1H, d, J=131Iz) , 5.06(1H,d,J=5HZ), 5.1-5.2(1H,m), 5.82,5.97 (1H,ABq,J-5Hz), 5.92(1H,dd,J≈5Hz,8Hz) , 7.07(lH,s) Example 23

Pivalovloxvmethvl 7-f(Z1-2~f2-aminothiazol-4-yl)2-hvdroxviminoacetamidol-3-(1-morpholi∩yl)carbony loxymethvl-3-cephem-4-carboxylate

- LOO -

The compound obtained in Example 3 and iodomethyl pivalate were reacted, whereby the title compound was obtained (yield: 24%).

NMR (CDCl₃, S) :

3.45-3.50 (5H,m), , 3.58-3.70 (5H, m) , 4.89,5.18 (2H,ABq,J=12Hz) , 5.07(1H,d,J=5Hz), 5.84,5.97 (2H,ABq,J=5Hz), 5.9 3 (III, dd, J=5Hz , 8Hz) , 7.08(lH,s) Example 24

Pivalovloxvmethvl 7-f(Z)-2-(2-aminothlazol-4-vl)2-methoxviminoacetamidol-3-N.N-dimethvlcarbamovloxvmethy1-3-cephem-4-carboxylate

The compound obtained in Example 4 and iodomethyl pivalate were reacted, whereby the title compound was obtained (yield: 65%).

NMR (CDCI3, δ) :

1.23(911, S) , 2.92(611,s), 3.50,3.60(2 H, ABq ,J=18.7Hz) , 4.09(311, s) , 4.Θ4,5.16(2H,ΛBq, J=14Hz) , 5.09(lH,d, J=4.8Hz), 5.85-5.95(2H,m), 5.99-6.03(1H,m),

6.92 (III, s) , 7.49 (1H, d, J=7.511 z)

Example 25

Pivalovloxvmβthvl 7-r (Z)-2-(5-amino-l.2,4-thiazol-3-vl)-2-methoxvlroinoacetamidol-3-N. H-dimethylcarbamovloxyinethvl-3-cephβin-4-carboχylate

The compound obtained in Example 5 and iodomethyl pivalate were reacted, whereby the title compound was obtained (yield: 70%).

NMR (CDC1₃, δ) :

1.13(911,S), 2.92(611, s) , 3.50,3.59 (211,ABq, J=18.6Hz) , 4.12 (3 H, s) , 4.84,5.19(2H,ABq,J=13.7Hz), 5.10(111,d, J=4.8Hz) , 5.85-5.94 (2H,m) , 6.12-6.16 (111, m) , 6.42(1H,S)

Example 26

Pivalovloxvmethvl 7- f (Z 1 -2-(2-aminothiazol-4-yl) 2-monof luoromethoxvaminoacetamido 1 - 3-N . M-dimethvlcarbamovloxvmethvl-3-c℮phem-4-carboxvlate

The compound obtained in Example 6 and iodomethyl pivalate were reacted, whereby the title compound was obtained (yield: 70%).

NMR (CDCI3 , 5):

1.14(9H,s), 2.91(6H,s), 3.50,3.60(2H,ABq,J=18.4Hz), 4.85,5.16(2 II, ABq, J≈14.2Hz) , 5.10(1H,d,J=4.8Hz) , 5.6 5-6.00(311, in) ,5.86,5.93(2H,ABq,J=5.5Hz) ,

6.98(III, s)

Example 27

Pivalovloxvmethvl 7-f(Z)-2-(2-ami∩othiazol-4-vl)2-hvdroxviminoacetamidol-3-(1-pip℮ridinvl)carbonvlσxvmethvl-3-cephem-4-carboxvlate

The compound obtained in Example 7 and iodomethyl pivalate were reacted, whereby the title compound was obtained (yield: 59%).

NMR (CD₃OD, 5) :

1.13 (9H,s) , 1.48-1.66 (6H,m) , 3.37-3.46 (4H,m) , 3.54,3.69(2H,ΛBq,J=18.4Hz), 4.77,5.13(2H,ABq, J=13.4Hz), 5.20(lH,d,J=4.9Hz), 5.84,5.93(2H,ABq, J=6Hz), 5.92(1H,d,J=4.9Hz), 6.76(lH,s)

Example 28

Pivalovloxvmethvl 7-r(Z)-2-f2-aminothiazol-4-vl)2-hvdroxviminoacetamido 1-3-fl-azetidinvD-carbo∩yloxymethyl-3-cephem-4-carboxylate

The compound obtained in Example 8 and iodomethyl pivalate were reacted, whereby the title compound was obtained (yield: 54%).

NMR (CDCI3, 5):

2.24-2.30(211,m) , 3.47,3.60 ( 2H, ABq, J=18.4 Hz) , 3.954.10 ( 4H, m) , 4.87,5.12(2 H, ABq, J=14.1Hz) , 5.06(111, d,J=5.1Hz), 5.91(2H,ABq,J=5.6Hz), 5.90-5.93(1H,m), Example 29

1-(Isopropvloxvcarbonvloxv)ethyl 7-f(Z)-2-(2-aminothiazol-4-yl) -2-hvdroxvimlnoacetaimido 1 - 3- (1aZetidinvl)carbonvloxvmethvl-3-cephem-4carboxvlate

The compound obtained in Example 8 and iodoethyl isopropylcarbonate were reacted, whereby the title compound was obtained (yield: 27%).

NMR (CDC1₃, 8) :

1.30-1.35(6H,m), 2.22-2.31(2H,m), 3.45-3.65(2Π,m), 4.00-4,06 (41t,m) , 4,89-5.20 (-4II, m) , 5.9 0-5.93 (1H, m) , 6.92(1/2H,q,J=5.5Hz), 7.03(1/2H,q,J=5.5H2), 7.08 (1II,S)

Example 30

The compound obtained in Example 9 and iodomethyl pivalate were reacted, whereby the title compound was obtained (yield: 57%).

NMR (CDC1₃, δ) :

1.21-1.2 5 ( 9H, m) , 2.97(311,s), 3.41-3.45 (2H, m) , 3.463.6 0(2 H,m) , 3.71-3.77(2H,m), 4.82-4.95 (2H,m), 5.055.08 (1H, m) ,5.86,5.95(2 H, ABq, J=6Hz) , 5.88-5.91(111,

m) , 7.00(111,s)

Example 31

1-Cvclohexvloxvcarbonyloxvethvl 7-f(ZΛ-2-(2-aminothiazol-4-yl)-2-hvdroxyimi∩oacetamidol-3-N(2-hvdroxvethvl)-N-methvlcarbamoyloxvmethvl-3-cephem-4-carboxvlate

The compound obtained in Example 9 and 1iodoethyl cyclohexylcarbonate were reacted, whereby the title compound was obtained (yield: 28%).

NMR (CDC1₃, <S) :

1.4-1.6(6H,m),1.62-1.72(3H,m), 1.83-1.92(4 II, m) , 2.9 3 ( 3H, s) , 3.38-3.41(2 H,m) ,3.42-3.50(2 II,m) , 3.703.75 ( 2H, m) , 4.57-4.61 (1H , m) , 4.99(1H,q,J=5Hz), 5.05-5.14 (2H,m) , 5.82-5.86 (111, m) , 6.8 5,6.96 (1H , ABq, J = 5Hz), 6.99(1H,S)

Example 32

Pivalovloxvmethvl 7-ffZ)-2-(2-aminothiazol-4-vl)2-hvdroxviminoacetamidol - 3-N-cyanomethvl-timet hv lea rbamoyloxymethyl-3-cephem-4-carboxv late

The compound obtained in Example 10 and iσdomethyl pivalate were reacted, whereby the title compound was obtained (yield: 70%) .

NMR (CDCI3, 6):

1.1-1.25(9H,m),3.01(3H,s), 3.4-3.65(2H,m), 4.2-

4.3( 2H , m) , 4.8-5.25 (3H,m) , 5.8-6.0 (3II,m) , 6.90(111, br . s) , 7.30 ( 2II, s)

Example 33

Pivaioyloxvmethvl 7-f (Z)-2-f 2-aminothiazol-4-vn 2-hvdroxyiminoacetamidol-3-r(S)-( + )-2-hydroxymethyl -1-ρyrrol id in vl 1carbonvloxymethyl-3-c℮phem-4-carboxvlatβ

The compound obtained in Example 12 and iσdomethyl pivalate were reacted, whereby the title compound was obtained.

NMR (CD₃OD, 6) :

1.83-2.00(411,m) , 3.30-3.87 (7H, m) , 5.01(2H,ABq, J=14Hz), 5.20(1H,d,J=4.8Hz), 5.84 (1H,d,J=4.8Hz), 5.91-5.94(2H,m), 6.76(lH,s)

Example 34

Pivalovloxymethvl 7-f(Z\-2-(2-aminothiazol-4-y11-2-hvdroxviminoacetamido1-3-f1-pvrrolldinvll-■ carbonvloxymethvl-3-cephem-4-carboxylate

The compound obtained in Example 13 and iodcmethyl pivalate were reacted, whereby the title compound was obtained (yield: 28%).

NMR (CDC1₃, S) :

1.16-1.21 (9.0, m) , 1.80-1.85 (4H,m) , 3.30-3.39 (4H, m) , 3.50-3.60(2H,m), 4.80-4.90,5.05,5.13(2H,m), 5.025.04 (lll,m) , 5.75-5.80 (2H,m) , 5.85-5.91(1H,m), 6.98 (1H,S)

Example 35

1-Acetoxvethvl 7-r (7>)-2-(2-aminothiazol-4-viy-2hvdroxviminoacetamldol-3-N.N-dimethvlaminocarbonvloxvmethvl-3-cephem-4-carboxylate

The compound obtained in Example 1 and 1-bromoethyl acetate were reacted, whereby the title compound was obtained (yield: 14%)»

NMR (CDC1_3# δ) :

1.55-1.58(3 H,in) , 2.11 ( 3H, d, J=4.6Hz) , 2.92-2.95 (3H,s), 3.47-3.65(2H,m), 4.83-5.24(3H_fm), 5.835.94(1H,m) , 6.98-7.15(211,111)

Example 36

1-(Cvclohexvloxvcarbonvloxvl ethvl 7-r(Z)-2-(2-ami∩othiazol-4-vl) -2-hvdroxviminoacβtainidol - 3- (1azetidinvll carbonvloxvinethvl-3-c℮Phein-4carboxvlate

The compound obtained in Example 8 and 1-iodoethyl cycloheκylcarbonate were reacted, whereby the title compound was obtained (yield: 27%).

NMR (CDC1₃, 6):

1.24(3H,d,J=7.2Hz), 1.75-1.80(10H,m),2.25-

2.32 ( 211, m) , 3.45-3.65(211,m) , 4.00-4.06 (4H, m) , 4.91,4.98(HI, ABq, J=13.8Hz), 5.03-5.07(1H,m), 5.105.13(1H,m), 5.09,5.18(111,ABq, J≈13.8Hz), 5.905.93(111, m) , 6.93 (1/2H, q, J=5.5Hz) , 7.03 (1/2H, q, J=5.5 Hz), 7.08(1H,s)

Example 37

1-Acetoxvethvl 7-r(Z)-2-f2-amlnothiazol-4-vl)-2hvdroxvimlnoacetarnidol-3-(1-azetidinvl)carbonvl-oxvmethvl-3-cephem-4-carboxvlate

The compound obtained in Example 8 and 1bromoethyl acetate were reacted, whereby the title compound was obtained.

NMR (CDC1₃, 8):

1.54-1.56(3 H,m) , 2.10-2.21 (311, m) , 2.2 0-2.35 (2H, m) , 3.45-3.65(2H,m), 3.95-4.08(4H,m), 4.85-4.95(1H,m), 5.05-5.1(2H,m), 5.87-5.95(1H,m), 6.97-7.17(2H,m) Preparation Example 41

Benzhvdryl 7-phenvlacetamido-3-p-nitrophenoxvcarbonvloxvmethvl-3-cephβm-4-carboxvlate

Ill

To a suspension of benzhydryl 7-phenylacetamide-

3-hydroxymethyl-3-cephem-4-carboxylate (15.8 g? 0.031 mol) and p-nitrophenylchloroformate (6.19 g; 0.031 mol) in tetrahydrofuran (160 mt) , pyridine (2.43 g; 0.031 mol) was added dropwise under ice cooling, followed by stirring at the same temperature for 25 minutes.

The reaction mixture was poured into a mixed solvent of ethyl acetate and water and the ethyl acetate layer was collected. The resulting ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was added with diisopropyl ether and triturated. The resulting mixture was filtered so that the solid was collected. The solid was dried in air, whereby benzhydryl 7-phenylacetamido~3-p-nitrophenoXy-carbonyloκymethyl-3-cephem-4-carboxylate was obtained (yield: 18.8 g? 90.2%) .

NMR (CDCI3 , 6) :

3.40,3.60(2H,ΛBq,J=18.5Hz), 3.61,3.66(2H,ΛBq,

= 13.6Hz), 4.9 7(1H,d,J=8.8Hz) , 4.97,5.24

( 2H, ABq, J=13.2i!z) , 5.88 (1H, dd, J=4.9Hz , 8.8Hz) , 6.30(1H,d,J=8.8Hz), 6.92(lH,s), 7.24-7.42(17H,m), 8.23-8.28(2H,m)

Preparation Example 42 7-Phenvlacetamido-3-p-nitrophenoxvcarbonvloxv-methvl-3-cephem-4-carboxylic acid

To a solution of benzhydryl 7-phenylacetamido-3-p-nitrophenoχycarbonyloxymethyl-3-cephem-4-carboxylate (6.79 g, 0.01 mol) in dichloromethane (14 ml) , trifluoroacetic acid (17 ml) was added dropwise under ice cooling, followed by stirring for 50 minutes. The reaction mixture was poured into diisopropyl ether.

The precipitate thus obtained was collected by filtration, washed with diisopropyl ether and dried in air, whereby 7-phenylacetamido-3-p-nitrophenoxy-carbonylσxymethyl-3-cephem-4“carboxylic acid was obtained {yield: 4.50 g; 87.7%).

NMR (DMSO, 6):

3.49,3.57(2H,ΛBq,J=14.0Hz), 3.60,3.71(2H,ABq,

= 18 . lflz) , 4.95,5.24 ( 2H, ABq, J=12.5Hz) , 5.12(lH,d, J=4.9Hz), 5.72(1H,dd,J=4.9,8.6Hz), 7.19-7.28(5H,m), 7.53-7.58(2H,m), 8.28-8.35(2H,m),

9.12(lH,d,J=8.6Hz)

Preparation Example 43

Sodium 7~phenvlacetamido-3-N.N-dimethylcarbamoγl~ oxvmethvl-3-cephem-4-carboxylate

To a solution of benzhydryl 7-phenylacetamide~3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylate (5.13 g, 0.01 mol) in tetrahydrofuran (36 m«) and water (4 mi), a 50% aqueous solution of dimethylamine (1.8 g; 0.02 mol) was added dropwise under ice cooling. At the same temperature, the resulting solution was stirred for 10 minutes. The reaction mixture was poured into a mixture of ethyl acetate and IN hydrochloric acid and an organic layer was collected.

The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was suspended in methanol and the resulting suspension was added with a solution of sodium acetate (984 mg; 0.012 mol) in methanol. The vlrst solution thus obtained was concentrated under reduced pressure. The concentration was stopped when a precipitate had appeared. After the addition of 2-propanol, the precipitate was collected by filtration and dried in air, whereby sodium 7-phenylacetamido-3-N,Ndimethylcarbamoyloxymethyl-3-cephem-4-carboxylate was obtained (yield: 2.25 g; 51.0%).

NMR (D₂0, 6) :

2.74(611,s), 3.21,3 . 47 (2II,ΛBq, J=17.9llz) , 3.51,3.57 ( 2H , ABq, J≈l 4.8 Hz) , 4.51,4.74 ( 2H, ABq, J-12.6IIz) , 4.92(lH,d,J=4.6IIz) , 5.48 (HI,d, J=4.6Hz) , 7.18-

7.28 (5II,m)

Preparation Example 44

1-(IsopropoxvcarbonvloxvVethyl 7-phenylacetamido-3-N.N-dimethvlcarbamoyloxvmethvl-3-cephem-4carboxvlate

To a solution of sodium 7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephero-4--carboxylate (2.2 g; 5 mmol) in N,N-dimethylformamide (20 mt) , isopropyl-l-iodoethylcarbonate (1.29 g; 5 mmol) was added under ice cooling, followed by stirring at the same temperature for 30 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water and the ethyl acetate layer was collected. The ethyl acetate layer was successively washed with water and a saturated ,aqueous sodium chloride solution, followed by drying over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby 1-(isopropoxycarbonyloκy)ethyl 7-phenylacetamido-3-N,N-dimβthylcarbamoyloxymethyl-3-ceρhem-4carboxylate was obtained (yield : 1.43 g; 52.1%).

NMR (CDCl·j, S)

(lH,m), 6.91(0.5H,q,J = 5.5Hz), 6.94(0.5H,d,J≈B.9Hz), 7.19-7.29(5H,m)

Example 38

Benzhvdrvl 7-formar∩ido-3-H.N-dimethylcarbamovl-oxvmethγl-3-cephem-4-carboxvlate

To a solution of trichloromethylchloroformate (0.3 ml; 2.5 mmol) in tetrahydrofuran (10 mI), a solution of benzhydryl 7-formamido-3-hydroxymethyl-3-cephem-4-carboxylate (2.12 g; 5 mmol) and pyridine (0.395.g; 5 mmol) in tetrahydrofuran (15 ml) was added under ice cooling. After 70 minutes, the resulting solution was added dropwise with a tetrahydrofuran solution (1 ml) containing dimethylamine (0.45 g; 5 mmol) dissolved therein, followed by stirring for 25 minutes. The reaction mixture was added with ethyl acetate (50 m«). The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column, whereby the target compound was obtained (yield: 1.1 g;

44%) .

NMR (CDC13 , δ) :

2.82(3H,s) , 2.8 8(3 H,s) , 3.42,3.57(2H,ABq,J=18. 4Hz) , 4.82,5.09(2H,ABq,J=13.9Hz), 4.97(lH,d,J≈4. 8Hz), 5.91 (lH,dd, J=4.8IIz , 9.31Iz) , 6.66 (lH,d, J=9.3IIz) , 6.94(1H,s), 7.25,7.45(10H,m), 8.20(lΠ,s)

Example 39

7-Amino-3-N , N-dirπethvlcarbamovloxvmethyl-3-cephem-4-carboxvlic acid

Sodium 7-formamido-3-N,N-dimethy1carbamoyl-oxymethyl-3-cephem-4-carboxylate (5.0 g; 14.25 mmol) was dissolved in methanol (45 ml). To the resulting solution, a methanol solution (30 ml) containing concentrated hydrochloric acid (10 m£) dissolved therein was added at room temperature. After stirring for three hours, the reaction mixture was concentrated under reduced pressure. The concentrate was added with water (50 m£) . Under ice cooling, the resulting solution was controlled to pH 2.8 with a IN caustic soda solution. A precipitate thus formed was collected by filtration, whereby the title compound was obtained (yield: 1.82 g; 42%).

NMR (DMSO-d6, 6) :

2.81(3H,s) , 2.82(3 II,s) , 3.4 5,3.58 (2H, ΛBq, J=18.1Hz) , 4.60,4.98(211, ABq, J=13 . OMz) , 4.7 7-4.8 0 (111, m) , 4.975.00(111,m)

Example 40

1- (Isopropoxvcarbonvloxv) ethyl 7/7-r 2- (2-aminothiazol-4-vl)-2-(ZV-acetoxviminoacetamidol-3-N.N-dimethvlcarbamovloxvmethvl-3-cephemcarboxvlate hydrochloride

In tetrahydrofuran (440 mt) , 1-(isopropoκycarbonyloκy)ethyl 7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem~carboxylate hydrochloride (22 g; 47 mmol) was dissolved, to which N,O-bistrimethylsilylacetamide (35 m<!) was added.

To the resulting solution, 2-(2-aminothiazol-4yl)-2-(Z)-acetσxyiminoacetic chloride hydrochloride (15.8 g) was gradually added under ice cooling.

The reaction mixture was heated tack to room temperature, at which it was stirred for 30 minutes.

The reaction mixture was added with ethyl acetate (600 ml) , water (40 ml) and saturated aqueous sodium chloride solution (25 md) and the organic layer was collected. The organic layer was then washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby the title compound was obtained (yield: 31.5 g; 99%).

NMR (CD₃OD, S) :

1.27-1.29 ( 611, m) , 1.54 ( 31.1, d , J=5.5Hz) , 2.23(3H,s), 2.92 (6H,d,J = 8.4Hz) , 3,60 (1H , d, J=18Hz) , 3.74(111, dd,J=9Hz,18Hz) , 4.81-5.16(311,m) , 5.22(lH,dd, J=5Hz , 12Hz ) , 5.97(111,dd,5 Hz,15 Hz) , 6.8 5 ( 0.511, dd, J=5Hz , 10Hz ) , 6.94 (0.5HZ, dd , J=5Hz , lOIIz ) , 7.19(111,s) Example 41

1-(Isopropoxvcarbonvloxy)ethyl IB--(2-aminothiazol-4-vl)-2-(Z)-hvdroxvimiπoacetamidol-3-N.N-dimethvlcarbamovloxvmethvl-3-ceρhemcarboxvlate hydrochloride

In methanol (108 I), 1-(isopropoxycarbonyloxy)ethyl 7/3- ( 2 - (2-aminothiazol-4 -y 1) - 2-(Z) -acetoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephemcarboxylate (10.8 g; 15.9 mmol), which had been obtained in Example 40, was dissolved, to which concentrated hydrochloric acid (8.6 ml) was added dropwise under ice cooling. After the dropwise addition was completed, the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was added with ethyl acetate (540 ml) . The organic layer was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was added with isopropyl ether and the resulting solid was collected by filtration, whereby the title compound was obtained (yield: 8 g? 80%).

The compound obtained in this Example conformed in HPLC and TLC data with the compound obtained in Example 20.

NMR (CD₃OD, 5):

Example 42

10-r 2-(2-Aminothiazol-4-vl)-2-(Z)-acetoxyiminoacetamidol-3-N.N-dimethvlcarbamovloxvmethvl-3-cephem-carboxvlic acid

In ethyl acetate (4 m2), 7-amino-3-N,N-dimethyl-carbamoyloxymethyl-3-cephem-4-carboxylic acid (0.2 g;

0.66 mmol) was suspended. To the suspension, N,0bistrimethylsilylacetamide (0..49 m2) was added and dissolved.

To the resulting solution, 2-(2-aminothiazol-4yl)-2-(Z)-acetoxyiminoacetiσ acid chloride hydrochloride (0.189 g; 0.664 mmol) was added gradually under ice cooling.

Tlie reaction mixture was heated back to room temperature, at which it was stirred for 30 minutes.

Methanol (0.2 m£) was added to the resulting solution, followed by concentration under reduced pressure. The residue thus obtained was purified by reversed phase column chromatography, whereby the title compound was obtained (yield: 138 mg; 41%).

Example 43

1-(Isopropoxvcarbo∩vloxv)ethvl 1β-f 2 -(2aminothiazol-4-vl)-2-fZ)-acβtoxviminoacetamidol-3-N.N-dimethylcarbamovloxvmβthy1-3-cephemcarboxvlate

In ethyl acetate (30 m£) , lβ~ [ 2-(2-aminothiazol-4-yl)-2-(Z)-acetoxyiminoacetamido)-3-N,N-dimethyl-carbamoyloxymethyl-3-cephem-carboκylic acid (2.17 g,* 4.24 mmol), which had been obtained above, was dissolved. To the resulting solution, dicyclohexylamine (1.35 m0 was added and the resulting precipitate was collected by filtration. Dicyclohexylamine salt thus obtained {1.7 g; 2.45 mmol) was dissolved in N,Ndimethylacetamide (10 m£) . To the resulting solution, 1-iodoethylisopropyl carbonate (758 mg; 2.94 mmol) was added under ice cooling, followed by stirring for one hour. The reaction mixture was added with ethyl acetate, washed with water and then dried over magnesium sulfate. After concentration under reduced pressure, the concentrate was added with isopropyl ether and the resulting solid was collected by filtration, whereby the title compound was obtained. The compound obtained in this Example conformed in HPLC and TLC data with the compound obtained in Example 40.

Example 44

Sodium 7/?-r2-(2-aminothiazol-4-vl)-2-(Z) -hvdroxv-

iminoacetamidol-3-N,N-dimethvlcarbamovloxvmethvlf 3-cephem-carboxvlate

In ethyl acetate (10 mt) , 7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (0.5 g? 1.66 mmol) was suspended. To the suspension, N,O-bistriraethylsilylacetamide (1.23 m£) was added and dissolved.

To the resulting solution, 2-(2-aminσthiazol-4yl)-2-(Z)-acetoxyiminαacetic acid chloride hydrochloride (0.52 gi 1.83 mmol) was gradually added under ice cooling.

The reaction mixture was heated back to room temperature, at which it was stirred for 30 minutes.

Then, methanol (0.5 m£) and ethyl acetate (10 mέ) were added to the reaction mixture and the precipitate thus obtained was collected by filtration. The resulting precipitate was dissolved in methanol (5 mi) , followed by the addition of concentrated hydrochloric acid (0.5 m£) and then by stirring for 30 minutes. After concentration, the reaction mixture was controlled to pH 7 with an aqueous sodium hydrogencarbonate solution and then purified by reversed phase column chromatography, whereby the title compound was obtained (yield: 349 mg;

50%) .

The compound in this example conformed with the compound obtained in Example 1 in physicochemical properties such as N.M.R. spectrum, HPLC and TLC.

Preparation Example 45

Benzhvdrvl 7-f(Z)-2-(2-tritvlaminothiazol-4-vl)2-tritvloxyiminoacetamido?-3-N-methvlcarbamoyl-σχymethvl-3-ceohem-4-carboxylate

Added to benzhydryl were 7-formamido-3-monomethylcarbamoyloxymethyl-3 -cephem-4-carboxylate (3.54 g) , tetrahydrofuran (40 m£) and methanol (40 mi). Then, the resulting solution was added with concentrated hydrochloric acid (3.6 m<) at room temperature, followed by stirring at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate, followed by washing with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous sodium chloride solution and then by drying over anhydrous magnesium sulfate. The solvent was then distilled off.

At room temperature, the residue thus obtained was added with a solution which had separately been obtained by adding 2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (4.9 g), dicycloheκylcarbodiimidβ (1.52 g) and 1-hydroxy-lH-benztriazole (1.0 g) to tetrahydrofuran (30 mt) and stirring them for 30 minutes. After the resulting solution was stirred overnight at room temperature, the reaction mixture was filtered. The filtrate was diluted with an aqueous solution of ethyl acetate. The diluted filtrate was washed further with IN hydrochloric acid, saturated

aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off. The residue thus obtained was purified by column chromatography (Sio₂; benzene:ethyl acetate≈6:1), whereby the title compound was obtained (yield: 5.39 g; 66%).

NMR (CDC1₃, δ) :

2.75(3H,d,J=5Hz) , 3.25,3.52 ( 211, ABq, J=18Hz) , 4.40(1H,d,J=5Hz) , 4.77,5.07(2H,ABq,J=14Hz) , 5.05(lH,d,J=5Hz), 6.10 (1H,dd,J≈5Hz,9Hz), 6.43(111,s), 6.97 (1H, s) , 7,21-7.3 9 ( 4 OH, m) Preparation Example 46

Benzhvdrvl 7-f (1)-2-(2-tritvlarπlnothiazol-4-yl)..2-trityloxvimlnoacetamidol-3-N-(2-methoxyethγl)carbamoyloxvmethvl-3-ceρhem-4-carboxylate aqueous sodium bicarbonate solution and saturated

In a similar manner to Preparation Example 45, the title compound was obtained (yield: 53%).

NMR (CDCI3 , δ) :

3.32-3.38 (5H,m) , 3.4 2 ( 211, t, J=5Hz ) , 3.25,3.49

( 2H , ABq, J=18Hz ) , 4.78,5.05 ( 2H, ΛBq, J=12llZ) ,

5.08(1H, d, J=5Hz) , 6.1 (111, dd , J=5Hz , 9Hz ) , 6.42(lH,s), 6.94(1H,s), 7.3-7.4(40H,m)

Preparation Example 47

Benzhvdrvl 7-r(Z)-2-f2-tritvlaminothiazol-4-vll-2-tritvloxvacetamidol-3-N-<2-monofluoroethyl)carbamovloxvmethvl-3-cephem-4-carboxvlate

In a similar manner to Preparation Example 45, the title compound was obtained.

NMR (CDC1₃, δ) :

3.1-3.4 (4H,m) , 4.2-4.4 (2H,m) , 4.85 ( 211, ABq, J=14Hz) , 4.92(lH,d,J=4.9Hz), 6.04(1H,dd,J=4.9Hz,8.9Hz), 6.44(111,s), 6.95 (1H, s) , 7.1-7.5 ( 4 OH, m)

Preparation Example 48

Benzhvdrvl 7-r(Z)-2-(2-tritvlamlnothiazol-4-vl)2-tritvloxvacetamidol-3-N-(2.2.2-trifluoroethyl)carbamovloxvmethvl-3-c℮phem-4-carboxylate

In a similar manner to Preparation Example 45, the title compound was obtained.

NMR (CDC1₃):

3.21(211, ABq, J=19Hz ) , 3.52-3.58 (2H , m) , 4.88(211,ABq, J=141Iz) , 4.91(111,d,J=4.9Hz) , 6.03 (111, dd, J=4.9Hz , 8.8Hz), 6.4 5(1H,s) , 6.95(lH,s), 7.13-7.47(4 OH,m) Example 45

Sodium 7-rfZ1-2-(2-aminothiazol-4-vl1-2hvdroxviminoacetamidol-3-N-methvlcarbamoyl-oxvmethvl-3-cephem-carboxvlate

To a solution of the compound (5.35 g), which had been obtained in Preparation Example 45, in anisole (25 m£) , trifluoroacetic acid (20 m£) was added under ice cooling, followed by stirring at the same temperature for one hour. The reaction mixture was added with isopropyl ether and the precipitate was collected by filtration. The powdery solid thus obtained was added with formic acid (35 m2), followed by stirring at room temperature for one hour. The solvent was distilled off under reduced pressure and the residue was diluted with methanol. The resulting solution was added with sodium acetate (1.0 g), and methanol was distilled off. The residue thu≤ obtained was diluted with ethyl acetate and then, formed into powder in isopropyl ether. The powder thus obtained was purified by liquid chromatography, whereby the title compound was obtained (yield: 326 mg; 14%).

NMR (D₂0,5) :

2.54(311,s), 3.21,3.51(2 H, ABq, J=18IIZ) , 4.60,4.70 (2H,ABq,J=18Hz), 5.06(1H,d,J≈4.8Hz), 5.69(lH,d, J=4.8Hz), 6.83(111,s)

Example 46

Sodium 7-f(Z)-2-(2-aroinothiazol-4-yl)-2hvdroxviminoacetamidol-3-N-(2-methoxvethvl)carbamovloxvmethvl-3-c℮phem-4-carboxvlate

The compound, which had been obtained in Preparation Example 46, was treated in a similar manner to Example 45, whereby the title compound was obtained (yield: 46%),

NMR (D₂0,S) :

3.17 (2lI,t,J≈5Hz) , 3.2 0 (3H , s) , 3.26,3.53 (211, ABq,J=18Hz) , 3.4 0 (2H, t, J = 5Hz) , 4.55,4.76 (211,

ABq, J=12Hz ) , 5.09 (111, d, J=51Iz) , 5.71 (111, d, J=51Iz) , Example 47

Sodium 7-r(Z)-2-(2-aminothiazol-4-vl)-2hvdroxvimi∩oacetamidol-3-H-(2-monofluoroethvl)carbamovloxvroethvl-3-cephem-4-carboxvlate

The compound, which had been obtained in Preparation Example 47, was treated in a similar manner to Example 45, whereby the title compound was obtained.

NMR (D₂0,6) :

3.2-3.5(411, m) , 4.2-4.4 (211,m) , 4.65 (211_rΛBq, J=12IIz ) , 5.05(lH,d,J≈4.8Hz) , 5.68 (111, d, J=4.8IIz) , 6.80(lH,s) Example 48

sodium 7-r (Z) -2-f 2-ami noth iazol-4-yl) r-2-hydroxvimiπoacetamidol-3-N-(2.2.2-trif:luoro- ethvl)carbamovloxvmethvl-3-cephem-4-carboxvlate

The compound, which had been obtained in Preparation Example 48, was treated in a similar manner to Example 45, whereby the title compound was obtained.

NMR (D₂0,S):

3.39 (211,ΛBq, J≈lθHz) , 3.66-3.73 (211, m) , 4.71(2H, ADq, J = 13Hz ) , 5.08 (1H, d, J==4.8Hz) , 5.70(lH,d, J=4.8Hz), 6.81(1M,s)

Example 49

Pivalovloxvmethvl 7-f(Z)-2-(2-amiπothiazol-4-yl)2-hvdroxviminoacetamidol-3-N-methvlcarbamoyl-oxvmethvl-3-cephem-4-carboxvlate

N π C-COMH

XT 11 1

"2^{N S N}'OI[ _ay

r^s'

ch₂oconiich₃

C00℮11₂0C0C (CH3) 3

To a solution of the compound (106 mg), which had been obtained in Example 45, in N,N-dimethylacetarnide (2 mI), iodomethyl pivalate (51 mg) was added, followed by stirring at the same temperature for one hour. The reaction mixture was added with ethyl acetate and water. Then, the ethyl acetate layer was collected and washed with saturated aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure.

The residue thus obtained was dissolved in ethyl acetate and the resulting solution was added with isopropyl ether. A precipitate so formed was collected by filtration and washed with isopropyl ether, whereby the title compound was obtained (yield: 44 mg; 35%).

NMR (CDCl₃,6):

1.13-1.15(911,m) , 2.7θ(3H,s), 3.4 2-3.59 (2H , m) , 4.724.7 6 (III, m) , 4.95-5.05,(2H,m) , 5.7 8-5.81 (1H , m) , 5.815.89 (211, m) , 6.93 (1H, s)

Example 50

1-(IsoproDoxvcarbonvloxv)ethyl 7-f(Z)-2-(2-aminothia^ol-4-vl )-2-hvdroxviminoacetamido)-3-N-methvlcarbamovloxvmethvl-3-cephem-4-carboxvlate

COOCH (CII3 ) OCOOCH (CII3

2 In a similar manner to Example 49, the title compound was obtained (yield: 55%).

NMR (CD3OD,5) :

1.25-1.35(9H,m), 1.51-1.57(3H,m), 2.70(311,s), 3.403.70 ( 211, m) , 4.75-4.90(111,m) , 5.02-5.09 (III, ΛBq, J=14 Hz) , 5.16-5.21(111,m) , 5.90-5.95(111,m) , 6.75(111,s), 6.04-6.95(111,m)

Example 51

PiValovloxvmethvl 7-r fZ1-2-(2-aminothiazol-4-vl1 2-hvdroxyiminoacetamido 1-3-N-<2-roethoxyethyl1carbamovloxvmethvl-3-ceohem-4-carboxylate

The compound, which had been obtained in Preparation Example 46, was treated in a similar manner to Example 49', whereby the title compound was obtained.

NMR (CDCl3 , δ) :

1.26-1.28 (911,m) , 3.36-3.40(5 H,m) , 3.4 7-3.50 ( 3H, m) , 3.62(lH,d,J≈lβHz) , 4.84,5.10(211, ABq, J=13Hz ) , 5.04(111, d,J≈3.5HZ) , 5.8 6,5.96 (211, ΛBq, J≈5Πz) , 5.915.94(111,m), 7.05(111, s)

Example 52

Pivalovloxvmethvl 7-r(Z1-2-(2-aminothiazol-4-yl)2-hvdroxviminoacetamidol-3-N-(2-monofluoroethvl)carbamovloxvmethvl-3-cephem-4-carboxvla be

The compound, which had been obtained in Preparation Example 47, was treated in a similar manner to Example 49, whereby the title compound was obtained.

NMR (CD₃OD,δ) :

1.22(9H,s), 3.3-3.4 (2H,m) , 3.63 (211, ΛBq, J≈lSIIz) , 4.35-4,50 (211, m) , 4.96 (211,ΛBq, J=13Hz) , 5.20(lH,d,J=4.8Hz), 5.83-5.94(3H,m), 6.76(lH,s) Example 53

Pivalovloxvmethvl 7-f(Z)-2-(2-ami∩othiazol-4-vl)2-hvdroxviminoacetamido1-3-N-(2.2.2-trifluoro- ethvl)carbamov1oxvmethy1-3-cephero-4-carboxylate

The compound, which had been obtained in Preparation Example 48, was treated in a similar manner to Example 49, whereby the title compound was obtained.

NMR (CD3OD, 6) :

1.21(9 FI,s) , 3.61(2H,ABq,J=18Hz) , 3.74-3.81(2H,m), 5.00(2H,ABq,J=14Hz) , 5.10(1H,d,J = 4.9IIz), 5.835.94(3H,m), 6.76 (III, s) .

Example 54

Sodium 7-formamido-3-N,N-dimethvlcarbamovloxy-roethvl-3-cephem-4-carboxvlate

Benzhydryl 7-formamido-3-N,N-dimethylcarbamoyl-oxymethyl-3-cephem-4-carboxylate (139 g) was dissolved in methylene chloride (1.4 t) . The resulting solution was added with anisole (69.5 m£) and trifluoroacetic acid (348 m l), followed by stirring for 30 minutes.

After the reaction, the solvent was distilled off under reduced pressure. After the residue thus obtained was dissolved in a small amount of ethyl acetate, trituration was applied in a mixed solvent of diisopropyl ether and diethyl ether. Crystals precipitated were collected by filtration. Then, the crystals were dissolved in methanol (500 m£) , followed by the addition of sodium acetate (34.5 g). and isopropyl alcohol (500 mi). The resulting crystals were collected by filtration. After the crystals were washed with diisopropyl ether, they were air-dried, whereby the title compound was obtained (yield: 80.2 g ; 82%).

NMR (D₂0, 6) :

2.75(6H,s), 3.30,3.53(2H,ABq,J=18.1Hz),

4.53,4.81 (2H, ABq, J=12.8Hz) , 5.00 (1H , d, J=4.8IIz) , 5.61 (lH,d,J=4.8Hz), 8.08(1H,s)

Example 55

1-fIsopropoxvcarbonvloxv)ethyl 7-formamido-3-N.Ndimethylcarbamoyloxvmethvl-3-cephem-4-carboxylate

After the compound (84 g) , which had been obtained in Example 54, was dissolved in dimethyl formamide (420 , the resulting solution was added with iσdo-l-isopropoxycarbonyloxyethane (61.7 g) under ice cooling, followed by stirring for 2 hours. After the reaction, the reaction mixture was poured into a mixed solvent of water and ethyl acetate. The resulting mixture was allowed to stand and the organic layer was collected. The resulting organic layer was washed O

with water, a 10% aqueous solution of sodium thiosulfate and saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the residue was subjected to column chromatography, whereby the title compound was obtained (yield: 44.7 g; 40%).

NMR (CDC1₃, 5):

1.29-1.34 (611,m) , 1.57-1.59 (3U,m) , 2.91(611,a), 3.463.62 ( 2 H , m)., 4.86 - 5.22(4 H,m) ,· 5.88-5.95(1H,m>,

6.39 (0.5H,d, J = 9.3Hz) , 6.47 ( 0.511, d, J=9.2Hz ) , 6.886.92(0.5H,m), 6.98-7.02(0.5H,m), 8.27(0.5H,s), 8.28(0.5H,S)

Example 56

1-(Isopropoxvcarbonvloxv)ethyl 7-amino-3-H.Ndimethvlcarbamoyloxvmethvl-3-cephem-4-carboxylate hydrochloride

After the compound (44.2 g) , which had been obtained in Example 55, was dissolved in a mixed solvent of methanol (440 ml) and tetrahydrofuran (220 ml), the resulting solution was added with concentrated C0₂CH(CH3)0C00CH(CH₃)2 hydrochloric acid (45 m£) , followed by stirring at room temperature for 5 hours. After the reaction, the solvent was distilled off under reduced pressure. The residue was poured into a mixed solvent of water and ethyl acetate and the resulting solution was adjusted to pH 6.5 with aqueous sodium bicarbonate solution.

The organic layer was collected and then washed with saturated sodium chloride solution. After the organic layer was dried over sodium sulfate, a solution of hydrochloric acid in ethyl acetate was added. The solvent was distilled off under reduced pressure, whereby the title compound was obtained (yield: 47 g; 100%) NMR (CDC1_3/ 6):

1.23-1.3 0 (6H,m) , 1,54-1.57 (3H,m) , 2.90(6H,s), 3.49,3.81(1H,ABq,J=17.0Hz), 3.50,3.80(1H,ABq,

J= 17.211 z) , 4.86-5.29 (5H, m) , 6.83-6.86 (III, m) Example 57

1-(Isopropoxvcarbonyloxy)ethyl 7-(4-bromo-3oxobutvrvlamino)-3-N.N-dimethvlcarbamoyloxvmethvl-3-c℮phem-4-carboxvlate

After diketene (0.92 m£) was dissolved in methylene chloride (10 nU) , the resulting solution was cooled to -30'C and stirred. The reaction mixture was added dropwise with a methylene chloride solution (3 m£) containing bromine (0.66 ml) to prepare 4-bromo-3-oxobutyric acid bromide.

On the other hand, 1-(isopropylσxycarbonyloxy)ethyl 7-amino-3-N,N-dimethylcarbamoylσxymethyl-3-cephem-4-carboxylate (5.05 g) was dissolved in methylene chloride (60 m£) together with bistrimethylsilylacetamide (5.8 mi). The resulting solution was added dropwise with the 4-bromo-3-oxobutyric acid bromide solution, which had been obtained above, at

-30"C, followed by stirring for one hour under ice cooling. The reaction mixture was washed successively with water and saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate and then by concentration under reduced pressure. The concentrate was subjected to chromatography on a column packed with 150 g of silica gel, whereby the title compound was obtained (yield: 4.8 g; 68.9%).

NMR (CDC1₃, S) :

1.28-1.34(6H,m), 1.59(3H,d,J≈5Πz), 2.92(6H,s), 3.49,3.88(2H,ABq,J=19Hz), 3.51-3.75(2H,m), 4.034.07(211,m), 4.85-5.27 (4H,m) , 5.80-5.90 (1H, m) , Example 58

1-fIsopropoxvcarbonvloxv)ethvl 7-(4-bromo-3-oxo2-hvdroxviminobutvrvlamino)-3-N.N-dimethvl-carbamoyloxvmethyl-3-cephem-4-carboxvlate BrCH₂COCCONH

The compound (4.5 g), which had been obtained in Example 57, was dissolved in acetic acid (45 m£) and the resulting solution was added with sodium nitrite (0.58 g) under ice cooling, followed by stirring at room temperature for one hour. The reaction mixture was added with ethyl acetate. The resulting mixture was washed with water and a saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate and then by concentration under reduced pressure. The concentrate was subjected to chromatography on a column packed with 100 g of silica gel, whereby the title compound was obtained (yield: 3.76 g; 79.6%) NMR (CDCl₃, fi):

1.30-1.34 (6H,m) , 1.56-1.61 ( 3fl, m) , 2.93(6H,s), 3.50 3.68 ( 3H, m) , 4.54(21I,s), 4.87-5.30 (4H , m) , 5.84-

1-(Isopropvloxvcarbonvloxv)ethvl 7-f fZ)-2-(2-aminothiazol-4-vl)-2-hvdroxviminoacetamide1-3-N . N-dimethvlcarbamσvloxvmethvl-3 -c℮phem-4 carbσxvlate

The compound (1.0 g), which had been obtained in Example 58, was dissolved in dimethylacetamide (15 mi) and the resulting solution was added with thiourea (0.244 g) , followed by stirring at 5°c for 12 hours.

The reaction mixture was added with ethyl acetate (200 mi). The resulting mixture was washed with water and saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate and then by concentration under reduced pressure. The concentrate was dissolved in ethyl acetate (10 mi). The resulting solution was added dropwise to isopropyl ether (150 mi) under stirring. The resulting precipitate was collected by filtration and then dried, whereby the title C0₂CII (CII₃) OCOOCH(CII₃)₂ compound was obtained (yield: 0.6 g; 62.3%).

NMR (CDC1_3<6):

1.26-1.37 (6H,m) , 1.58-1.62(3H,m) , 2.93(611,s), 3.50(1H,d,J=19Πz), 3.60,3.61 (together, III, d,

J=19 H z) , 4.9-5.24 (3II,m) , 5.04,5.07 (together,

111, d, J=5HZ) , 5.93 (lΠ,dd, J=5llz, 811z) , 6.92,7.02 (together, lll,q, J=5.5Hz) , 7.08(lH,s)

Example 60

1-(Isopropoxvcarbo∩vloxvlethvl 7-f 4-chloro-3oxobutvrylamino)-3-H.N-dimethvlcarbamovloxγ-methvl-3-cephem-4-carboxvlate

Diketene (21 m£) was dissolved in methylene chloride. (60 m£) , followed by cooling to -30°C.

Chlorine gas was spurged through the resulting solution until the latter turned to a pale yellow color. Excess chlorine was purged out with nitrogen gas, and in addition, methylene chloride was distilled off under reduced pressure. The residue was distilled, whereby 4-chlorσ-3-oκoburyric acid chloride having a boiling point of 75-85“C (8 mm/Hg) was obtained (7.1 g).

On the other hand, 1-(isopropyloxycarbonyloxy)ethyl 7-amino-3-N,N-dimethy1carbamoyloxymethy1-3-cephem-4-carboxylate ester (3 g) was dissolved in methylene chloride (45 m£). The resulting solution was added with N,N-dimethylaniline (0.98 m£) under ice cooling, followed by stirring. The reaction mixture was added dropwise with a solution of 4-chloro^·3oxybutyric acid chloride (1.2 g), which had been obtained above, in methylene chloride (15 mO at -30*C.

After the resulting solution was stirred for one hour under ice cooling, the reaction mixture was washed successively with water and saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate and then by concentration under reduced pressure. The concentrate was subjected to chromatography on a column packed with 70 g of silica gel, whereby the title compound was obtained (yield: 0.59 g: 25.1%).

NMR (CDC1₃, S) :

1.29-1.33 (611, m) , 1.58(311, d,J≈5Hz) , 1.58 (1.511, s) , 1.59(1.5H,s), 2.92(6H,s), 3.46-4.26(6H,m), 4.855.35 (4H, m) , 5.80-5.87 (lll,m) , 6.90 ( 0.511, q, J=5Hz) , 6.99(0.5H,q,J=5Hz) , 7.53 (0.511, q, J=9Hz) , 7.61(0.5H,q,J=9Hz)

Example 61

1-(Isooropoxvcarbonvloxvlethvl 7-f 4-chloro-3-oxo2-hvdroxviminobutvrvlamino)-3-N.N-dimethvlcarbamovloxvmethvl-3-cephern-4-carboxylate

The compound (0.5 g) , which had been obtained in Example 60, was dissolved in methylene chloride (5 mL) and then, acetyl chloride (0.092 m£) and isoamyl nitrite (0.167 ml) were added to the resulting solution at room temperature. At the same temperature, the resulting solution was stirred for 5.5 hours. The reaction mixture was washed with water and saturated sodium chloride solution, followed by drying over anhydrous magnesium· sulfate and then by concentration under reduced pressure. The concentrate thus obtained was subjected to chromatography on a silica gel column, whereby the title compound was obtained (yield: 0.48 g;

77.3%)

NMR (CDC1₃, S) :

1.29-1.34 (6H,m) , 1.59 ( 3H, d, J-5.51Iz) , 2.93(3H,s), 3.51-3.66 (211, m) , 4.78(211,S), 4.8 2-4.9 8 (1.5H, m) , Example 62

1-flsopropoxvcarbonvloxvfethyl 7-r fZf-2-(2-aminothiazol-4-vl)-2-hvdroxγiminoacetamido)-3-N. N-dimethylcarbamovloxvmethvl-3-cephem-4carboxvlate

The compound (0.48 g), which had been obtained in Example 61, was dissolved in diinethylacetamide (7 md) .

The resulting solution was added with thioux'ea (0.126 g) , followed by stirring at 5*C for 16 hours. The reaction mixture was added with ethyl acetate (80 md) .

The resulting mixture was washed with water and an aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate and then by concentration under reduced pressure. The precipitate was dissolved in ethyl acetate (5 md) and the resulting solution was added dropwise to isopropyl ether (70 md) under stirring. The precipitate was collected by fil-CO2CH(CH3)OCOOCH(CH3)₂ tration and dried, whereby the title compound was obtained (yield: 0.252 g; 50.6%). NMR and HPLC data of the compound obtained in this example were consistent with those of the compound obtained in Example 59.

Example 63

Benzhvdry .1 7 -f ormamido-3 -o-πi trophenoxvcarbonvl-oxvmethvl-3-cephem-4-carboxvlate ester

Benzhydryl 7-formamido-3-hydroxymethyl-3-cephem-4-carboxylate ester (106 g) and p-nitrophenyl chloroformate (50.4 g) were stirred in tetrahydrofuran (700 mf) under ice cooling. To the resulting suspension, pyridine (19.8 g) was added dropwise over 5 minutes. After 35 minutes, the mixture was poured into a mixed solvent of ethyl acetate (1 t) and water {It) .

The organic layer was washed twice with water (0.5 mt) and once with saturated sodium chloride solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure until its volume was decreased to about 400 m£. The residue was gradually poured into isopropyl ether (2 t) and the co₂bh

resulting crystals were collected by filtration, whereby the title compound was obtained (yield: 133 g;

90%) .

NMR (DMSO-dg, δ) :

3.67,3.77 (2H,ΛBq,J≈lθHz) , 4.91,5.11(211, ΛBq, J = 12Hz ) , 5.21(1H,J=4.8MZ), 5.91(1U,dd,J=4. 8Hz,8.5Πz) , 6.91(111,8), 7.2-7.5(1211,m) , 8.14 (2H, d , J=9Hz) ,

8.31 (2H, d, J = 9J!z) , 9.11 (1H, d, J = 8.5Hz)

Example 64 7-Formamido-3-p-nitropheπoxvcarbonvloxvmethvl-3- cephem-4-carbOXvllc acid

The compound (133 g), which had been obtained in Example 63, was suspended in dichloroiαethane (265 mf) under stirring. To the suspension, trifluoroacetic acid (200 m I) was added dropwise over 25 minutes under ice cooling. Ten 10 minutes later, the resulting suspension was poured into isopropyl ether (2.5 I).

The resulting crystals were collected by filtration and then washed with isopropyl ether, whereby the title compound was obtained (yield 103 g; 97.4%).

NMR (DMSO-dg, S) :

3.62,3.72(211, ΛBq, J=18Ilz), 4.94,5.23(2H,ΛBq, J=12.6Hz), 5.15 (111, J=4.9I1Z) , 5.81(111, dd,

J=4.9IIz , 0.8Hz ) , 7.56(211,d,J = 9IIz) , 0.13(111,s),

8.30 (2II,d, J=911z) , 9.07 (111, d, J = 8 . GHz)

Example 65

Benzhydryl 7-thienylacetamido-3-p-nitrophe∩oxv-carbonvloχyτnethvl-3-cephem-4 -carboxyl a be e ster

Benzhydryl 7-thieny1acetamido-3-hydroxymethy1-3-cephem-4-carboxylate (1.6 g) and p-nitrophenylchloroformate (0.6 g) were treated in a similar manner to Example 63, whereby the title compound was obtained [yield: 2.3 g (stoichiometric)].

NMR (CDC1₃, 5):

3 . 43,3.62 (211,ΛBq, J≈l9Hz) , 4.85(211,s), 4.97,5.24 ( 2H, ΛBq, J=13Ilz) , 5.01 (111, d, J=4.511z) , 5.91(111,dd, J=4.5HZ,9Ilz) , 6.93(111,s), 6.97-7.02 ( 2H , m) , 7.247.38(1111, m) , 7.42 (2H,d, J=8Hz) , 8.26 (211, d, J=8Hz) Example 66 7-Thie∩vlacetamido-3-D-nitrophenoxvcarbo∩vloxvmethvl-3 -cephem-4 -carboxylic acid

The compound (1.4 g), which had been obtained in Example 65, trifluoroacetic acid (1 mt) and anisole (2 m£) were stirred for 30 minutes under ice cooling.

The reaction mixture was added with isopropyl ether (50 m£) and the resulting precipitate was collected by filtration, whereby the title compound was obtained (yield: 900 mg; 85%)

NMR (CD₃0D, 8) :

3.57,3.73(2H,ΛBq,J=19Hz), 3.80(2H,s), 5.06,5.33 (2H,ABq,J=12Hz), 5.09(1H,d,J=4.5Hz), 5.77(lH,d, J=4.5Hz), 6.9-7.0(2H,m), 7.23-7.28 (III, m) , 7.46(2H,d,J=8Hz), 8.29(2H,d,J=8Hz)

Example 67

Benzhydrvl 7-formamido-3-phenoxvcarbonyloxvmethv1-3-cephero-4-carboxylate

In a similar manner to Example 63 except that p-nitrophenyl chloroformate was replaced by phenyl chloroformate, the title compound was obtained (yield 90%) .

NMR (DMSO-dg, 6) :

3.66,3.75(211,ABq,J≈19Hz) , 4.8 5,5.0 5 ( 211, ABq, J=14 Hz) , 5.21(111,d,J=4.5Hz) , 5.91(1H,dd,J≈4.8Hz,8Hz) , 6.90 (1H, s) , 7.17-7.50(1511,m) , 8.14(111,s), 9.11(111, d, J=8Hz)

Example 68 7-Fσrmamido-3-phenoχycarbonyIoχymethvl-3-cephem- 4-carboxvlic acid

The compound,, which had been obtained in Example 67, was treated in a similar manner to Example 64, whereby the title compound was obtained (yield 90%).

NMR (DMΞO-dg, δ) :

3.61,3.72 (2H,ΛBq, J=18IIz) , 4.89,5.19(2Π, ΛBq, J=12IIz) , 5.14 J=4.5Hz, 8Hz) , 7.20-7.45 ( 511, m) ,

8.12(1H,s), 9.06(1H,d,J=8Hz)

Example 69

Sodium 7-formamido-3-N.N-dimethvlcarbamovl~ oxvmethyl-3-cephem-4-carboxvlate

The compound (103 g), which had been obtained in Example 64, was dissolved in methanol (600 mi).

Tetrahydrofuran (44 mi) containing 22 g of dimethylamine was added dropwise to the resulting solution over 5 minutes under ice cooling. One hour later, the resulting solution was added ψith sodium acetate (24 g), followed by concentration under reduced pressure.

To the residue, isopropyl alcohol (0.8 I) and then isopropyl ether (1.5 I) were added, respectively. The resulting precipitate was collected by filtration. The solid thus obtained was dissolved in methanol (0.5 I) .

After the crystals were formed, isopropyl ether (1.5 t) was added and then, the resulting solution was filtered, whereby the title compound was obtained (yield: 72 g; 84%).

NMR (DMSO-dg, 6):

2.7 9 ( 6H , s ) , 3.22,3.46(211, ABq , J=17.2IIz ) , 4.68,4.94 ( 2H , ΛBq, J=12 . OΠz ) , 4.9 6 (1H , d , J=4.8Hz ) , 5.55(111,dd, J=4.8Hz,9Hz) , 8.10 (1H, S) , 8.9 3 (III, d , J = 9Hz )

Example 70 7-Thienvlacetamido-3-N.N-dimethvlcarbamovloxvmethvl-3-c℮phem-4-carboxylic acid

The compound (100 mg), which had been obtained in Example 66, was dissolved in N,N-dimethylformamide (1 m℮). The resulting solution was added with a 50% aqueous solution of dimethylamine (50 mg) under ice cooling, followed by reaction for 15 minutes. To the reaction mixture, ethyl acetate (50 m£) and water (30 mi) were added. Then, the organic layer was collected, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was added with isopropyl ether. The resulting solid was collected by filtration, whereby the title compound was obtained (yield: 60 mg; 75 %) .

NMR ( DMSO-dg , δ) :

2.82(3Π,s), 2.84(3H,s), 3.48,3.60(2H,ΛBq,J=19Hz), 3.78 ( 2H, s) , 4 . 48,4.99 (2H,ΛBq, J=llllz) , 5.09(111, d,J=4,5Hz), 5.64 (III, dd , J=4.5Hz, 8Πz) , 6.92-

7.00 ( 2H, m) , 7.38 (III, d, J = 3Hz) , 9.12 (1H , d, J≈8IIz) Example 71

The compound, which had been obtained in Example 68, was treated in a similar manner to Example 69, whereby the title compound was obtained (yield: 35%).

The compound obtained in this example conformed with the compound obtained in Example 69 in all physicochemical properties such as HPLC (high performance liquid chromatography), TLC (thin-layer chromatography) and NMR spectrum.

Preparation Example 49

Tert-butvl 7-phenvlacetarnido-3-hydroxymethyl-3-cephem-4-carboxvlate-1-oxide

To a solution of tert-butyl 7-phenylacetamido-3-bromomethyl-3-cephem-4-carbσxylate-l-oxide (76.1 g;

0.158 mol) in N,N-dimethylformamide (350 ml) , ammonium trifluoroacetate (41.3 g; 0.316 mol) and sodium iodide (23.6 g; 0.158 mol) were added, followed by stirring at room temperature. The reaction mixture was added with ammonium trifluoroacetate (10.3 g; 0.079 mol) upon an elapsed time of 4 hours and 35 minutes from the initiation of the stirring and then with sodium iodide (11.8 g, 0.079 mol) upon an elapsed time of 8 hours and 5 minutes after the initiation of the stirring. Stirring was continued at room temperature for 24 hours and 25 minutes in total. The reaction mixture was poured into a mixture of ethyl acetate, and water and the ethyl acetate layer was collected. The water layer was extracted twice with ethyl acetate. Ethyl acetate co₂c(cn₃)₃

layers were combined together, successively washed with water and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, whereby tert-buty1 7-phenylacetarnido-3-hydroxymethy1-3-cephem-4-carboxylate-l-oxide was obtained (yield: 63,5 g;

96.1%).

NMR (CDC13 , S) i

1.58(911, s) , 3 . QO (111, br . s) , 3.17,3.94 ( 2H, ABq, J=18.7Hz), 3.6 2(2H,s) , 4.13,4.47 (2H,ABq,J=13.2Hz) , 4.42 (lH,d,J=4 . 8 Hz) , 6.02 (III, dd , J=4.8Hz , 9.71Iz) , 6.90(lH,d,J≈9.7Hz), 7.24-7.30(5H,m)

Preparation Example 50

Tert-butvl 7-phenvlacetamido-3-H.N-dimethvlcarbamovloxvmethvl-3-cephem-4-carboxvlate-1-oxide

To a solution of tert-butyl 7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate-l-oxide (63.5 g;

0.151 mol) in tetrahydrofuran (500 m/) , N,N'-carbonyldiimidazole (24.5 g; 0.151 mol) was added under ice cooling, followed by stirring at the same temperature for 50 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water and the ethyl acetate layer was collected. The ethyl acetate layer was washed successively with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The drying agent was filtered off and the filtrate was added with a 50% aqueous solution of dimethylamine (13.6 g; 0.151 mol) under ice cooling. Without changing the temperature, the stirring was continued for 3 hours and.45 minutes. The reaction mixture was poured into a mixture of ethyl acetate and IN hydrochloric acid, followed by the collection of the ethyl acetate layer. The water layer was extracted further with ethyl acetate. Both ethyl acetate layers were combined together and washed successively with water and saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby tert-butyl 7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephera~4-carboxylate-l- oxide was obtained (yield: 15.8 g? 21.2%).

NMR (δ, CDCl₃ ) :

1.13(911,5) , 2.88 ( 3H, s) , 2.89(311,s), 3.17,3.80 (2H,ΛBq,J=19.0Hz), 3.62(211,s), 4.42(1H,d,J=4.8Hz), 4.70,5.31(211, ΛBq, J=14 . lllz) , 6.03 (111, dd , J≈4.8Hz , 9.9Hz ) , 6.77 (111,d,J=9.911z) , 7.25-7.36 ( 511, in) Preparation Example 51

Tert-butvl 7-Phenvlacetamido-3-N.N-dimethvlcarbamovloxvmethvl-3-c℮Phei^,n-4 -carboxvla te

To a solution of tert-butyl 7-phenylacetamido-3~ N, N-dimethylcarbamoyloκymethyl-3-cephem-4-carboκylate-1-oxid℮ (15.8 g; 0.0322 mol) in N,N-dimethylformamide (120 mI), phosphorus trichloride (8.4 mδ; 0.0963 mol) was added dropwise over 5 minutes under dry ice-methanol cooling so that the solution temperature did not rise beyond -15’C. Then, stirring was continued for 20 minutes under dry ice-methanol cooling. After the reaction mixture was diluted with ethyl acetate, water was added gradually to the mixture under dry ice-methanol cooling so that the liquid temperature did not rise beyond -10*c. The ethyl acetate layer was collected and the water layer was extracted further with ethyl acetate. Both ethyl acetate layers were combined together and washed successively with water and saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby tert-butyl 7-phenylacetamido-3-N,N-dimethyl-carbamoylαxymethyl-3-cephem-4-carboxylate was obtained (9.3 g; 60.8%).

NMR (5, CDC1₃):

1.48(9H,s), 2.8 8 ( 3 H , s) , 2.89(311,s), 3.34,3.50

( 2H, ΛBq, J==18 . SHz ) , 3.63 (2H , ΛBq, J = 13.6Hz ) , 4.92(lH,d,J=4.9Π2), 4.77,5.09(2H,ΛBq,J=13.6Hz), 5.81 (III, dd, J=4.9Hz,9.2Hz) , 6.19 (1H, d , J=9.2Hz) , 7,24-7,3 6(5H,m)

Preparation Example 52

Sodium 7-phenv.lacetamido-3-N. N-dimethylcarbamoVl-oxvroethvl-3-c℮phem-4-carboxvlate

To a solution of tert-butyl 7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethy1-3-cephem-4-carboxylate (9.2 g) in anisole (4.5 ml) and dichloromethane (50 ml) , trifluoroacetic acid (9 ml) was added dropwise under ice cooling. Four and a half hours later, trifluoroacetic acid (18 τn£) was added further dropwise at the same temperature. Without changing the temperature, stirring was continued for 6 hours and 20 minutes in total from the beginning of the first dropwise addition. The reaction mixture was concentrated under reduced pressure, followed by the addition of diisopropyl ether. The supernatant was removed by decantation. The residue was dissolved in methanol. To the resulting solution, sodium acetate (1.05 g) was added,, followed by stirring until the resulting solution became a homogeneous system. The reaction mixture was added with diisopropyl ether. The precipitate was collected by filtration and, after washing with diisopropyl ether, was dried under reduced pressure. The precipitate was purified by ODS, whereby sodium 7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate was obtained (yield: 2.2 g;

NMR (5, D₂0) :

2.74 (6H , br . s) , 3,21,3.47(2H, ΛBq, J=17.9IIz) , 3.51,3.57(2H,ΛBq,J=14.8Hz), 4.51,4.74(2H,ΛBq, J=12 . GHz) , 4.92 (III, d, J=4 . 6IIz) , 5.4 8 (111, d , J = 4.6Hz) , 7.18-7.28(5H,m)

Preparation Example 53

1-(Isopropoxvcarbonvloxv)ethyl 7-phenvlacetamido3-f1-dimethvlamino)carbonγloxvmethvl-3-cephem-4carboxvlate

To a solution of sodium 7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.2 g; 0.005 mol) in N, N-dimethylf ormamide (20 m£) , isopropyl-l-iodoethyl carbonate (1.29 g; 0.005 mol) was added all at once under ice cooling, followed by stirring at the same temperature for 30 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water, and the ethyl acetate layer was collected.

The ethyl acetate layer was washed successively with water and saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby 1-(isopropoxycarbonyloxy)ethy1 7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethy1-3-cephem-4-carboxylate was obtained (yield: 1.43 g? 52.1%).

NMR (5, CDCl·j) :

1.22-1.29 (611,m) , 1.26(3H,d,J = 4.9Hz) , 2.8 5 ( 6H , br . s) , 3.35,3.48(111, ABq,J=18.4 Hz) , 3.3 6,3.4 9 (111, ABq, J=18.4Hz) , 3.55 ( 2H, s) , 4.7 5-4.88 (311, m) ,

5.04,5.10 (1H, ABq, J=13.9Hz) , 5.71-5.7 6 (111, m) , 6.776.82 (III, m) , 6.91 ( 0.5Uq, J=5.5 Hz ) ,

6.94 (0.5H,d,J=8.9112) , 7.19-7.29 ( 5H,m)

Example 72

(Isopropoxvcarbonvloxv)methvl 7-fl-r2-f2-aminoth.iazol-4-vl)-2-fZ) -hvdroxviwi∩oacetamido 1 3-N.N-dimethvlcarbamovloxvmethvl-3-c℮phemcarboxvlate hydrochloride

0

The compound, which had been obtained in Example 63, was reacted with iσdomethylisopropyl carbonate, whereby the above compound was obtained (yield: 51%).

NMR (CD₃OD,δ) :

1.29(611,m), 2.90(311,s), 2.92(311,s), 3.55,3.71 (2H,ABq,J=18Hz), 4.78,5.1j(2H,ABq,J=14Hz), 5.20(lH,d,J=5Hz), 5.80(lH,d,J=5Hz), 5.905.97·(lH,m) , 6.84 (lH,s)

Example 73

( 5-Methyl-2-oxo-1.3-dioxoleπ-4-vl) methyl 7/7-12(2-aminothiazol-4-γl)-2-(Z)-hvdroxviminoacetamido1-3-H.N-dimethvlcarbamovloxvmethvl-3-cephem-carboxvlate hydrochloride

The compound, which had been obtained in Example 63, was reacted with (5-methyl-2-oxo~l,3-dioxolen-4yi)methyl iodide, whereby the title compound was obtained (yield: 49%).

NMR (CD^OD, S) :

2.2(3H,s) , 2.87 ( 3H , ε) , 2.92(311,s), 3.52,3.69 (2II,ΛBq,J=18Hz) , 4.8-5.18 (4II,m) , 5.20(1H,d,J≈5Hz) Example 74

l-(Isopropoxvcarbonvloxv)ethyl 7-amino-3-N.N-dimethylearbamovloxymethy1-3-cephem-4-carboxylate fhydrochloride)

CΠ3

To a solution of phosphorus pentachloride

(625 mg; 3 mmol) in dichloromethane (10 mt) , pyridine (237 mg; 3 mmol) was added at room temperature, followed by stirring for 20 minutes at the same temperature. The reaction mixture was subjected to ice cooling, to which a solution of 1-(isopropoxycarbonyloκy)ethyl 7-phenylacetamido-3-N,N-dimethylcarbamoyloκy-methyl-3-cephem-4-carbσxylate (549 mg, 1 mmol) in dichloromethane (10 mI) was added without changing the temperature. Stirring was continued for one hour and 10 minutes. The reaction mixture was cooled in a dry ice-methanol bath and added with 1,4-bυtanediol (l m<) and methanol {1 mt) , followed by stirring for 30 minutes. Further, water was added to the reaction mixture at the same temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate. The water layer was controlled to pH 6.5 with a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The latter ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. The drying agent was filtered off and the filtrate thus obtained was added with HCl-saturated ethyl acetate. The solvent was distilled off under reduced pressure, whereby 1-(isopropoxycarbonyloxy)ethyl 7-amino-3-N,N-dimethylcarbamoyloxymethy1-3-cephem-4-carboxylate hydrochloride was obtained (yield:

90 mg; 19.3%).

MMR (S, CD3OD):

1.21-1.30(611,mj , 1.52-1.55 (3H, m) , 2.86-3.02 (611, m) , 3.70,3.78 (lH,ABq,J=18.1Hz) , 3.77,3.82 (HI,ABq, J=13.7HZ), 4.81-4.92 (III,m) , 4.90,5.10 ( 2H, ABq, J≈12.8Hz), 5.11-5.23(0.5,m), 5.28-5.33(0.5,m), 6.82-6.88(0.5,m), 6.91-6.97(0.5,m)