Method of preparation of 3-exométhylènecépham-sulfoxides.

ΐ

- An improved process for the preparation of esters 3 a-exométhylènecépham-to sulfoxides. In particular, it relates to an improved process for producing an ester of 3 a-exométhylènecépham-sulfoxide from a 2 a-chlorosulfinylazétidin-to-4 One.

According to the method of the invention, comprising reacting a 2 a-chlorosulfinylazétidinone in an inert organic solvent with stannic chloride in the presence of a ligand ("the ligand") confectioneries oxo group to obtain an insoluble complex formed with the chlorosulfinylazétidinone, stannic chloride and the ligand to oxo group. The cyclization of the 2 a-chlorosulfinylazétidinone occurs under heterogeneous conditions and it seems it can occur in the solid state at normal temperatures. By decomposing the complex using a hydroxy compound, ester 3 a-exométhylènecépham-sulfoxide separates from the complex with an excellent yield. The improvement of the method of the invention includes the use of certain compounds to oxo group constituting of ligands, ethers and ketones as, in the cyclization of a 2 a-chlorosulfinylazétidinone with the Friedel-Crafts catalyst, stannic chloride.

The ligands to oxo group yields a more stable complex with stannic chloride and the 2 a-chlorosulfinylazétidinone.

The improved method of this invention is advantageously carried out in conjunction with the preparation of a 2 a-chlorosulfinylazétidinone with an ester of penicillin sulfoxide and, without separating the 2 a-chlorosulfinylazétidinone, directly by performing complex formation of stannic chloride in the cyclization ester 3 a-exométhylènecëpham-sulfoxide.

The cyclization of 2 a-chlorosulfinylazétidinones Friedel-crafts acylation catalyst with a Lewis acid, a Friedel-Crafts catalyst protonic acid Bronsted agent or a cation forming metathesis, is described in the Patent of E.U.A. no. 4.052.387. The cyclization leads to the formation of an ester of 3 a-exométhylènecépham-sulfoxide, the method is useful in a two-step process of global. - transforming 'pénicillinesulfoxydes esters esters' 3 a-exométhy1ènecépham-tallow oxides down to 2 a-chlorosulfinyluzétidinohes intermediaries.

The two-step method ' is shown^: in the following reaction scheme. WITH

0 iR

i-it

The R-c-n-a-f -

the U

t-.

KJoule

therein

CH2

' HCC

00 κΐ.

vBE1/

0

0 iR

I-it

c i

Halogenating agent-n-chlorinated

/<

'A,

the R "=

: rOB

Catalyst

RF iedel-to-CRAs are different;

vBE1/

0 HR

I-it

The R-c-n-a-f -

the RV

0

1

WITH

I-ii

X0ri

The preparation of 2 a-chlorosulfinylazetidinones and their use in the two-step method are described in the Patent of E.U.A. no. 4.075.203. In the. patent application n° deposited the same day as the present application, there is disclosed an improved process for preparing intermediate 2 a-chlorosulfinylazétidincnes which comprises the use of a copolymer is insoluble crosslinked polyvinylpyridine as a fixing hydrochloric acid, to the. instead combinations epoxy or epoxy-calcium oxide as disclosed in of E.U.A. № 4.075.203.

The 2 a-chlorosulfinylazétidinone is used as an intermediate in the cyclization in sulfoxide. 3 a-exométhylènecépham, using a Friedel-Crafts catalyst, as aforesaid.

Accordingly, the two-step method described above is a method of preparing a compound of the cephalosporin compound from a penicillin-type, which differs from the method described by Morin and Jackson Patent of E.U.A. № 3.275.626, wherein is described the transposition heat acid catalyzed ester of penicillin sulfoxide ester désacëtoxycéphalosporine.

According to the method of the invention, comprising reacting a 2 a-chlorosulfinylazétidin-a 4 a-one represented by the following structural formula 1: the O

in which R represents the residue of a carboxylic acid and R¹ is. a protecting group of a carboxylic acid group, in an inert organic solvent under substantially anhydrous conditions, with stannic chloride in the presence of a ligand to oxo group, to obtain an insoluble complex formed from the 2 a-chlorosulfinylazétidinone, stannic chloride and the ligand. The complex can then be stirred for between about 3 to about 24 hours, during which time the cyclization of the ester 2 a-chlorosulfinylazétidinone 3 a-exomêthylènecépham-sulfoxide occurs in the solid state. The complex is then separated from the organic solvent, for example by filtration, centrifuging, decanting or any other conventional means, it is then treated by a hydroxyl compound, such as a lower alcohol, for decomposition of the complex and obtain the ester of 3 a-exométhylènecépham-sulfoxide represented by the following structural formula 2:

0

0 HR

The R-c-n-a-f -

fS

π.μ

1

fOORi

The method of the invention comprises using a ligand to oxo group during the preparation of the complex stannic chloride/2 a-chlorosulfinylazétidinone. The oxo ligand serves as a donor of a pair of electrons to form a coordinate covalent bond with a tin atom and thus becomes part of the complex. The oxo-compounds that can be used in the method of the present invention. the ethers are lower alkyl, cycloalkyl ethers, the alkylcêtones lower, the cycloalkyl ketones, oxides of tri - (lower alkyl) phosphine oxide, oxides and oxides of triarylphosphine tricycloalkylphosphine. The oxo-compounds that can be used in the method of this invention are represented by the following structural formulas. the n

Alkyl ether

lower

Cycloalkyl ethers

0

Lower Alkylcêtones

R

bSs R.

R

Cycloalkyl ketones

Y

it

O

Phosphine oxides of R ^ - P-R '

wherein each r° is a hydrogen atom or an alkyl group in c ^ - ^ C.. and n is an integer from 3 to 6.

Examples of the lower alkyl ethers represented by the formula (has) are dimethyl ether, diethyl ether, the ether is di-n-propyl, ether di isopropyl, the di-n-butyl ether, the methyl ethyl, dimethyl and n-p ropyle, the methyl s-butyl, andc... examples of cycloalkyl ethers of formula (has ') are tetrahydrofuran, tetrahydropyran, the 1 and 4-dioxane and the 1.3-dioxane. Examples of lower alkyl ketones represented by the formula (d) are acetone, methyl ethyl ketone, diethyl ketone, di-npropylcétone, di-iso-Ketone, the methyl-iso-Ketone, di-n-butyl ketone, di s-butyl ketone, the mëthyl iso-butyl ketone and the like lower alkyl ketones.

Examples cycloalkyl ketones represented by the formula (b.¹ ) are cyclobutanone in, cyclohexanone, cycloheptanone, the 3 methyl-cyclohexane, the 3.4 to-diéthylcyclopentanone, the 3.5 to-dimethylcyclohexanone, the 4 T-butylcyclohexanone and cycloalkyl - (substituted cycloalkyl) ketones and the like. Examples oxides (lower alkyl) -, cycloalkyl compounds -, . phenyl - (substituted phenyl) - and the phosphine of formula (C.) are oxide trimethylphosphine, triethylphosphine oxide, oxide tri-nbutylphosphine, oxide tri-n-propylphosphine, tricyclohexylphosphine oxide, triphenylphosphine oxide and oxides of triphenylphosphine substituted as tri (P-tolyl) phosphine oxide, tri - (p-chlorophenyl) phosphine oxide, tri - (O bromophenyl) phosphine oxides (lower alkyl) -, - a cycloalkyl, phenyl - (substituted phenyl) phosphine oxide and the like.

The oxo compounds previously described have two roles in the method of this invention. Firstly, they form, via the pair of electrons from the oxygen atom, coordinate bonding with the tin atom of the stannic chloride by lowering the reactivity of the tin halide to the 2 a-chlorosulfinylazétidinone and, secondly, they form a complex with the ligand/2 a-chlorosulfinylazétidinone stannic chloride, by making the complex more stable. Apparently, the ligand oxo group to form a coordinate covalent bond with the tin atom's central complex and thus prevents the deleterious effects of trace moisture from the reaction medium which can lead to destruction DPs complex prior to cyclization. The oxo compounds thus allow the formation of a more stable complex housing the cyclization of the 2 a-chlorosulfinylazétidinone in sulfoxide 3 a-exométhylènecépham.

In carrying out the method of the invention, the oxo compound may be added to the solution of the 2 a-chloroazetidinone prior to addition of the stannic chloride, or can be mixed stannic chloride and the oxo compound in the inert organic solvent and adding them together to the solution of the 2 a-chloroazetidinone. It is preferred, in the practice of this invention, add the oxo compound to the solution of 2 a-chlorosulfinylazétidinone prior to addition of the stannic chloride.

The compounds' oxo-preferred use in the invention are diethyl ether, acetone and diethyl ketone.

The structure of the complex stannic chloride/2 chloro-year average-to-finylazétidinone/ligand oxo acid has not yet been determined. It is believed however that the stannic chloride and the atom'd 'oxygen of the array suifinyle chloride of 1' azetidinone are linked by a coordinate covalent bond and that the compound having an oxo group forms a single coordinate covalent bond with t' MECT "to - ëtaiil" center. There are, however, other connection possibilities, for example the oxygen atom of the acylamino groups in position 3 grouoe azetidinone can also form a coordinate covalent bond with the tin atom. Similarly, the oxygen atom of the ester group may optionally form a coordinate covalent bond with a tin atom.

The inert organic solvents which can be used in the cyclization reaction of the present invention are the solvents in which the 2 a-chlorosulfinylazétidinone and the oxo compound are soluble and wherein stannic chloride is at least partially soluble. The inert organic solvents are essentially nonpolar and are, preferably, aromatic solvents such as benzene, the chlorobenzene derivatives, anisole, toluene, the chlorotoluene, xylenes - and tetralin; cycloalkyl hydrocarbon hydrocarbon solvents such as cyclopentane, cyclohexane, and like hydrocarbon solvents. Before being used in the method of the invention, the solvent is dried by any conventional means, for example by azeotropic distillation (distilling binary) or by drying with a molecular sieve, or with one of the conventional drying agents such as calcium chloride, calcium sulfate, sodium sulfate, andc. Used, of prëférence, reagent grade solvents.

Complex formation described herein can be carried out at a temperature between about and about + 45 °c -15 °c. Preferably, and what is more convenient, confectioneries the complex is formed at a temperature between about 0 °c to about 20 °c.

In one embodiment of the method of the present invention, added by stirring between about 1 and 1.5 mole of oxo compound per mole of sulfinyl chloride to a solution of 2 a-chlorosulfinylazétidinone in an inert organic solvent such as benzene or toluene. Then, added between about 2 and about 3 moles of stannic chloride per mole of sulfinyl chloride. Complex formation occurs in general quickly. In general, the complexes formed in the method of the invention are colored, a bright orange to orange red bruri.. then, stirred the complex which has precipitated in the reaction vessel for about 3 to about 24 hours, period, which terminates the cyclization reaction. Although the ' cyclization is largely completed after approximately 3 heureson leaves the complex under agitation for longer periods of time, so that it results in greater efficiencies. While the cyclization reaction occurs, there is not any significant change in the complex. After shaking, may be - separating the complex from the solvent, for example by filtration or centrifugation, or decanting the solvent of the complex, preferably followed by washing the complex with a suitable solvent such as petroleum ether, cyclohexane, toluene, diethylic ether or with acetone. Maintain the complex can be washed in a suitable container or, preferably, it is decomposed to obtain the sulfoxide ester 3 a-exométhylènecépham sought.

The decomposition of the complex formed in, the method of the invention is accomplished by adding the complex to a hydroxyl compound, for example a lower alcohol as methylic alcohol or ethyl alcohol. The complex can, similarly, be decomposed by water or by an acid such as acetic acid or dilute hydrochloric acid; however, with these agents, the decomposition results in the formation of hydrochloric acid which can react with the product so inadvertent. The complex is, preferably, added to a lower alcohol as methylic alcohol. The complex decomposes rapidly, giving a suspension, generally white color to white dirty, ester 3 a-exomêthylènecêpham sulfoxide.

The 2 a-chlorosulfinylazétidin-a 4 a-ones are represented by the structural formula above have already been described and can be prepared by the modes opératoires'opératoires' described-in the patents of no. 4.081.440 e.ü.a. et'4.075.203..

As it was mentioned previously -, R in the above formula 1 is the residue of a carboxylic acid. The starting materials preferred in the method of this invention are represented by the above formula 1 wherein R is H or an alkyl group hydrogêne ^ ^ c-c -, cyanomethyl, a benzyloxy, 4 a-nitrobenzyloxy, tbutyloxy, 2, 2, 2 a-trichloroêthoxy, 4 a-mëthoxybenzyloxy; or R is a group R 'wherein R' is a phenyl group or substituted phcnyle by one or two halogen, protected hydroxy, a nitro, a cyano, trifluoromêthyle, C alkyl ^ - ^ c-alkoxy or; or R is a group of the formula R " - (O-)_{the m} " HC2~or R "has the same meaning as R ' as defined above, or is a group 1 and 4 a-cylohexadiényle, 2-thienyl or 3-thienyl; m is 0 or 1; provided that, when Rn is in the range 1, the R" has the same meaning as R¹ ; or R is a group of the formula R "- HM (ω) - wherein R" is as defined above and W is a hydroxy group or protected amino.

The compounds of formula 1 above are herein termed 2 a-chlorosulfinylazétidin-a 4 a-ones used for convenience reasons. However, they are called formally esters of L-azetidinyl-to-buténolque. for example, the compound represented by the formula 1 wherein R is a benzyl group and R ^ t-butyl, is called 3-methyl 2 - (2 a-chlorosulfinyl-a 4 a-axoglial and 3 a-phenylacetamido-1 azetidinyl) - 3 a-butenoate T-butyl.

Examples of the starting substances represented by the formula 1 can be used in the method of this invention are:

3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3 a-phënylacétamido-to-1 azetidinyl) - 3 a-butenoate T-butyl, 3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3-a-phenoxyacetamido-to-1 azetidinyl) - 3 a-butenoate T-butyl,

3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3 a-acëtamido-to-lazétidinyl) - 3 a-isopropenyl benzyl,

3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3 a-formamidopyrimidine-1 azetidinyl) - 3 a-butenoate P-nitrobenzyl,

3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3 a-cyanoacétamido-to-1 azetidinyl) - 3 a-butenoate P-mëthoxybenzyle,

3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3 a-butyramido-to-lazétidinyl.) - 3 a-isopropenyl benzhydryl,

3-methyl 2 thereof [2 a-chlorosulfinyl-to-4 oxo-3 - (4 a-chlorophênoxyacétamido) - 1 azetidinyl] and 3 a-butenoate P-nitrobenzyl, 3 a-mëthyl and 2 thereof [2 a-chlorosulfinyl-to-4 oxo-3 - (2' a-thiénylacétamido) - 1 azetidinyl] and 3 a-isopropenyl 2, 2, 2 a-trichloroétKyle,

3-methyl 2 thereof [2 a-chlorosulfinyl-to-4 oxo-3 - (2' a-thiénylacëtamido) - 1 azetidinyl] and 3 a-butenoate P-nitrobenzyl,

3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3 a-benzamido-to-lazëtidinyl) - 3 a-isopropenyl benzyl,

3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3 a-phenylacetamido-1 a-azëtidinyl) - 3 a-butenoate of P-nitrophenyl,

3-methyl 2 thereof [2 a-chlorosulfinyl-to-4 oxo-3 - (P chlorobenzamido) - 1 azetidinyl] and 3 a-isopropenyl phenacyl,

3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3-a-phenoxyacetamido-to-1 azetidinyl) - 3 a-isopropenyl phthalimidomethyl,

3-methyl 2 thereof [2 a-chlorosulfinyl-to-4 oxo-3 - (P nitrophénylacôtciinido) - 1 azetidinyl] and 3 a-butenoate P-nitrobenzyl,

3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3 a-phenylacetamido-1 azetidinyl) - 3 a-isopropenyl 2, 2, 2 a-trichloroethyl,

3-methyl 2 thereof [2 a-chlorosulfinyl-to-4 oxo-3 - (α-benzhydryloxyphénylacétamido) - 1 azetidinyl] and 3 a-butënoate P-nitrobenzyl, and■•

3-methyl 2 thereof [2 a-chlorosulfinyl-to-4 oxo-3 - (has not butyloxycarbonylamidophénylacétamido) - L-azetidinyl] and 3 a-butenoate P-nitrobenzyl.

A preferred group of 2 a-chlorosulfinylazétidinones usable in the practice of this invention comprises the compounds of formula 1 wherein R is a group 2-thienyl-methyl, benzyl or phenoxymethyl. The starting materials preferred are the esters of 3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3 a-phenylacetamido-1 azetidinyl) - 3 a-buténoîque, acid 3-methyl 2 thereof [2 a-chlorosuifinyl-to-4 oxo-3 - (2' a-thiënylacétamido) - L âzétidinyl] and 3 a-buténoîque and of acid and 3-methyl 2 - (2 a-Ghlorosulfinyl-to-4 oxo-3 a-phénoxyacëtamido L-azétidiriyl) - 3-butenoic. In the starting materials are preferred in the method of the invention because they give esters 3 a-exométhylêne-to-cëphain-sulfoxide particularly interesting which are intermediates in the preparation of antibiotics.

Esters of 2 a-chlorosulfinylazétidin-a 4 a-ones are used as starting materials in the method of this invention may be prepared by the method described in the Patent no. 4,075 203 ou.de preferably by the MPL. improved method Patent mentioned on page 2, line 35. Advantageously, the improved method of the invention is performed as the second step of the two-step method wherein are first converted ester penicillin sulfoxide in a 2 a-chlorosulfinylazétidinone which is, without separation, used in the method of the invention as described herein, to form an ester of 3 a-exométhylènecêphamsulfoxyde. Accordingly, a preferred embodiment of the method of this invention involves the cyclization on the 2 a-chlorosulfinylazétidinone not separately, prepared using a penicillin sulfoxide ester and a halogenating agent in the presence of the n-chlorinated polyvinyl pyridine a crosslinked, as disclosed in the application referred to above.

In a preferred embodiment, reacting the 6 above-phenoxyacetamido-to-2.2-to-dimethylpenam and 3 a-carboxylate 1-oxide P-nitrobenzyl in anhydrous toluene with approximately 1.1 molar equivalent of n-chlorophthalimide in the presence of about 1 to about 3 grams, per gram of penicillin sulfoxide, poly (4 a-vinyl pyridine) - divinylbenzene crosslinked in an amount of about 2 to about 5%. The reaction is carried out at the reflux temperature for about 100 minutes and the reaction suspension is filtered to remove the insoluble copolymer and the phthalimide and cooling the filtrate containing the 3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3 a-phénoxyacétamidoazétidinyl) - 3 a-butenoate P-nitrobenzyl at a temperature of between about 0 and 10 °c. Cold filtrate is added at about 1 molar equivalent of diethyl ether, followed by adding between about 2 and 2.5 molar equivalents of stannic chloride. By addition of the stannic chloride ', the sulfinyl chloride complex/stannic chloride/ligand to oxo group precipitates in the cold filtrate and stirred in the solvent for about 3 to about 24 hours to insure the complete formation of the complex. Then, the complex is filtered, washed on the filter with a suitable solvent, such as a hydrocarbon solvent, pentane or 1' e.g. hexane, and then slowly added to methyl alcohol for decomposition of the complex with the formation of the 7 a--phenoxyacetamido-a 3 a-exométhylènecépham-to-4 carboxylate L-oxide P-nitrobenzyl. The suspension is agitated during the product to about 4 hours 2, and is filtered. Conveniently the filtered product is washed on the filter and dried.

In the method of the invention is typically obtained amount such that it does not require further purification before use in the preparation of antibiotic compounds. However, the product, if needed, can be recrystallized in a suitable solvent to improve its purity.

The preferred embodiment of the previous method of this invention is illustrated in the following reaction scheme.

H

5 -•· IH=

// V. vBE1 ^ therein

•, · 0 - 2 0 - - - ℮Η Ν - · - ·

HC:

••==

HC:

•-

VBE1

XQCHzS THE O - *^- '¹ - ' -

N Chlorcphtalimide iuene to verbs

PVP DV3 2 C/O¹

/

U

The R-II -•

.' / vBE1 VBE1

••==

/

H

3

^ - C.

HM.:

/c.

•v/x - it

thereinVBE1 ** -

XOCHz - " ^ ^ · - ΝΟ2

•=#

VBE1

C2H50Cüh5

The SnCu

To verbs iuene

/

Coextrudedthe Exe rnpI

VBE1

CHaOH

/

H

· - ·χ.

the Y/ > ■>

<!•- 3 a-HCC c-3 T--•

vBE1/

π T-

fS

/

, *=CHï

VBE1 ** - * ^ ^ - OOCHe, · - Ν 0:

1/the poly (4 a-vinyl pyridine) - divinylbenzene with cross-linking of about 2%.

The table I according gives yields 3 a-exométhylènecêpham-to-sulfoxides obtained with oxo compounds types present in the cyclization of a 2 a-chlorosulfinylazétidinone preferred catalyzed by stannic chloride.

In each case, 50 g of the converted 6-a-phenoxyacetamido-to-2.2-to-dimêthylpénam and 3 a-càrboxylate L-oxide P-nitrobenzyl ester of a P-nitrobenzyl 2 a-chlorosulfinylazétidinone corresponding with chlorophthalimide confectioneries in toluene at reflux temperature in the presence of poly (4 a-vinyl pyridine) - divinyl benzene having cross-linking of about 2%. The product of this reaction is the 3-methyl 2 - (2 a-chlorosuifiny1-to-4 oxo-3 a-phënoxyacétamido-to-1 azetidinyl) - 3 a-butenoate P-nitrobenzyl. Filtering the insoluble polymer and the phthalimide of the reaction medium, and is cyclized ester 2 a-chlorosulfinylazétidinone (45.4 grams) with stannic chloride in the presence of about 1 mole of oxo compound per mole of compound 2 a-chlorosulfinylic. in each case, the complex formed is separated, washed and then decomposes with methyl alcohol. The column 3 of table I to quality of the complex obtained in each case. The melting point of the product, the 7-a-phenoxyacetamido-a 3 a-exométhylènecépham-to-4 carboxylate L-oxide P-nitrobenzyl, observed in each case is indicated in column 4 of the table.

CLPE² I thers

(%) State of the complex

Sticky solid flowable powder flowing powder solid slightly gummy

Melting point (°C)

196.5.

196,5 - 197 193,5 - 194

196 - 197

Powder fluid flowing powder flowing powder -

Mildly sticky solid

Powder fluid flowing powder flowing powder 102'; - 193 196 - 197. W. 195 - 196

196.5 .197 - 194,5 - 196 195 - 196 196 - 197

Flowing powder 192 - 197 score 1:

The yield is expressed in weight percent (7 a--phenoxyacetamido-a 3 a-exométhylènecépham-to-4 carboxylate L - oxide P-nitrobenzyl relative to the sulfoxide pénam).

Score 2:

Analysis of the cyclized product by high pressure liquid chromatography.

Column: the Merck rp18 of 25 cm x 4 mm inner diameter.

Solvent in the column: the O ^ e 530 ml, 300 ml of THF, 150 ml of methanol and 20 ml of acetic acid, containing 1.1 g of sodium sulfonate per liter.

Flow rate: 2 ml/min

Dimensions of the sample: 8 mg to 25 ml anhydrous acetic acid or formic acid.

Esters 3 a-exométhylènecépham-to-sulfoxides provided by the method are useful intermediates in the preparation of cephalosporin antibiotics. For example, the product can be reacted with ozone to obtain an ester of 3-hydroxy 3 a-cépham-sulfoxide, the latter can be reduced to form sulfide by the methods known in the field, and may be reacted ester 3-hydroxy 3 a-cephem achieved either diazomethane, or with phosphorus trichloride in the presence of dimethylformamide to form respectively a ester 3-methoxy-3 a-cephem or ester 3-chloro 3 a-cépham. The desesterification esters provides respectively les3-methoxy-3 ~céphemsantibiotique e described in the patents of no. 3.917.587 E.U.A. and 3.917.588 or les3-chloro 3 a-céphemsantibiotiquæ described in the patents of no. 3.925.372 ee.u.a and 3.962.227.

The following examples illustrate further the method of the invention.

The following example is an example of preparation of an ester of 2 a-chlorosulfinylazëtidine-to-4 One in the presence of poly (4 a-vinyl pyridine) - divinylbenzene crosslinked and cycling stannic chloride without addition of an oxo compound 1' disclosure.

Example 1

Is heated at reflux for 2 hours 2 liters of toluene quality reagent using a water trap Dean-Stark apparatus until is collected in the trap 200 ml of liquid that are discarded. The heating stops and added

25.0 g of poly (4 a-vinyl pyridine) divinylbenzene (I-crosslinked to about 2), 50.2 g of 6 a-phênoxyacétamido and 2.2 to-dimëthylpénam and 3 a-carboxylate l~oxyde P-nitrobenzyl and 20 g of chlorophthalimide. The suspension is heated rapidly to reflux temperature and continued by stirring for reflux, about 100 mins. Is cooled, the reaction mixture to about i0 °C and the mixture is stirred 10 min. The slurry is filtered to remove the copolymer and the phthalimide and added the cold filtrate containing the 3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3-a-phenoxyacetamido-L-azetidinyl) - 3 a-butënoate (39 grams) to a cold solution of 25 ml of stannic chloride in 25 ml of toluene.

Stirred the complex red-orangle clear that forms in the temperature of the ice bath for one hour, then at room temperature for about 16 hours. The color of the complex becomes light brown. Filtering the complex is washed with 200 ml and pentane and is dried. The complex is then added slowly to 300 ml of methylic alcohol with forming a suspension of the product, the 7-a-phenoxyacetamido-a 3 a-exométhylènecépham-to-4 carboxylate L-oxide P-nitrobenzyl. The suspension is stirred at the temperature of the ice bath during 7 hours and is the filter. By washing the product with 50 ml of methylic alcohol, 50 ml of diethyl ether and dried in vacuum, giving -29.7 grams (59.5% yield) of product melts at about 187 to-188.5 degrees Celsius.

The previous example is repeated but using the penicillin sulfoxide to 2 times the concentration used previously.

Example 2

Heated at reflux 2 liters of toluene quality reagent using a water trap Dean-Stark apparatus until is collected in the trap 200 ml of-liquid that are discarded. The heating stops and hot toluene is added 50 g of poly (4 a-vinyl pyridine) - divinylbenzene (cross-linked to about 2%), 38.4 g of chlorophthalimide and 100.3 g of 6 a--phenoxyacetamido-to-2.2-to-dimêthylpénam-to-3 carboxylate L-oxide P-nitrobenzyl. The slurry is heated to the reflux temperature for 100 min, and then cooled to 10 °c. After 10 minutes of stirring, the suspension is filtered (containing 69g of^- 3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3-a-phenoxyacetamido-to-lazétidinyl) - 3 a-butenoate) in a cold solution of stannic chloride in 50 ml of 50 ml of toluene. Stirred the bright orange complex that forms, during 1 hour at the temperature of the ice bath and during 16 hours at ambient temperature.

The complex then filtered, washed with pentane and dried partially on the filter. Slowly adding the complex to 600 ml methylic alcohol to form a product slurry, the 7 a-phénoxyacëtamido and 3 a-exométhylènecépham-a 4 a-carboxylate 1-oxide P-nitrôbenzyle. The suspension is stirred at the temperature of the ice bath during 7 hours and is filtered to collect 54.0 grams (de54,l % yield) of product melts at about 193.5 and 194 degrees Celsius.

Example 3

This example is an example of the method of the invention performed at the same concentration of starting material that in the example 2 (1 g/l8 ml toluene) and using diethyl ether as oxo compound during the cyclization step.

1800 Ml of dried toluene quality reagent as described in the previous example and, while it is still hot, is added 100.3 g of 6 a--phenoxyacetamido-to-2.2-to-dimêthylpénam-to-3 carboxylate L-oxide P-nitrobenzyl, 50 g of poly (4 a-vinyl pyridine) - divinylbenzene (cross-linked to about 2%) and 38.4 g of chlorophthalimide. The reaction suspension is heated to reflux temperature for 5 min, and then cooled to 10 °c and is stirred for 10 min. It follows the course of the reaction by NMR that indicates the generation of the sulfinyl chloride in a yield of about 90%. The reaction slurry is filtered and cooled in an ice bath the filtrate containing sulfinyl chloride.

The existence of the sulfinyl chloride, the 3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3-a-phenoxyacetamido-L-azetidinyl) - 3 a-butenoate P-nitrobenzyl, is confirmed by the NMR spectrum.

NMR (CDCl ^): 61.93 (e, 3:00, methyl vinyl)

64.33 (e, 2 Η, HM -2 the side chain) 65, 03 - 5, 13 (m-, 3:00, HC₂ =C-A-CH -)

5 δ, 30 (e, 2:00, methylene ester) 65.47 (d-, 1:00, j=4, 5 Hertz, hr in c₂ the core 3-lactam)

66.30 (q-, 1:00, j=4, 5 hr_{the Z} and 9.0 Hertz, H of the core (3-lactam)

66, 8 - 7, 0 (m-, 5:00, aromatic side chain)

67, 20 - 8, 23 (2d, 4:00, j=9, 0 Hertz, aromatic ester)

67.82 (e wide, 1:00, the NH)

The slurry is filtered to remove the cold copolymer and the phthalimide and is cooled in an ice bath the filtrate containing the ester of 2 a-chlorosulfinylazétidin-to-4 One. Is added first 18.28 ml cold diethyl ether to the filtrate, followed by adding 50 ml of stannic chloride. Stirred the complex orange-red clear that forms during 30 min at temperature of the ice bath, the mixture for 16 hours at ambient temperature. It occurs in the complex a low color change.

The complex is filtered, it is washed on the filtrate with 400 ml of hexane and dried in air. The complex is added slowly, with stirring, to 600 ml methylic alcohol, with formation of a suspension of 7 a--phenoxyacetamido-to-3 exo - ^ méthylënecépham-to-4 carboxylate L-oxide P-nitrobenzyl.

The suspension is stirred for 4 hours at 0 °c, and is filtered to collect the product. The product is washed with 100 ml of methylic alcohol and dried in vacuum, thereby gives 76.15 grams (yield 76.2 I-) melts at about 194.5 and 195°.

Example 4

Using the same penicillin sulfoxide ester, the same chlorinating agent and the same copolymer and the same amounts using the same volume of toluene than those used in the previous examples, replacing diethyl ether of the example previous by 12.9 ml of acetone and is' obtains 72.63 grams (72.7% yield) of 7 a--phenoxyacetamido-a 3 a-exométhylènecépham-to-4 carboxylate L-oxide P-nitrobenzyl melts at about 195 °c.

Example 5 7 a-phenylacetamido-3 a-exométhylënecépham-to-4 carboxylate L-oxide P-nitrobenzyl

300 Ml of toluene is distilled quality reagent using a Dean-Stark apparatus§trap water and, after removal of 30 ml of liquid in the part, the edge of heating and added 2.5 g of poly (4 a-vinylpyrid-to-bly) - divinylbenzene (with cross-linking of about 2%).

The suspension is heated to reflux a few minutes to drive off any water that may have been added with the polymer. Is a new and edge heating and added, while the suspension is hot, 7.28 g of 6-phenyl-acetamido-2.2-to-dimethylpenam-to-3 carboxylate L-oxide P-nitrobenzyl and 2.88 g of chlorophthalimide. And then, the mixture is heated at the reflux temperature for 10 mins. The slurry is cooled to 10 °c and dark is filtered to remove the insoluble polymer and the phthalimide. The product of this reaction is the 3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3 a-phenylacetamido-L-azetidinyl) - 3 a-butenoate P-nitrobenzyl yield of about 78 i. the identity of the sulfinyl chloride is determined by the NMR spectrum.

NMR (CDCl ^): 61.80 (e, 3:00, methyl vinyl)

63.57 (e, 2 Η, HC2 the side chain) 65, 0 - 5, 13 (m-, 3:00, HC₂ =C-A-CH -)

65.20 (e, 2:00, HC₂ ester)

65.43 (d., 1:00, j=4, 5 Hertz, hr in c₂ o-lactam) 66.42 (Q-, 1:00, j=4, 5 and 9 Hertz, hr in c₃ p-lactam)

67.13 (e, 5:00, aromatic side chain) 67.4 and 8.18 (IDs, 4:00, j=8 Hz range, aromatic 1' esters).

The reaction mixture is dosed (0,013 mol) 1.37 ml of diethyl ether and 3.75 ml (0,032 moles) of stannic chloride, to obtain a complex is insoluble brown. The complex was stirred at the temperature of the ice bath for 30 minutes and then at room temperature for about 16 hours. Chocolate brown complex is filtered, washed with 60 ml of hexane, and then added slowly confectioneries 45 ml of ethyl alcohol to form a slurry of the product, the 7 a-phenylacetamido-3 a-exométhylenecépham-to-4 carboxylate L-oxide P-nitrobenzyl. The product suspension is stirred at the temperature of the ice bath during 4 hours, is filtered, washed with 15 ml of methyl alcohol and dried under vacuum, resulting in 4.3 grams (59.3% yield) of the dried product, melts at about 208° C-208; 5 °c after recrystallization from acetone.

Example 6■' 7-a-phenoxyacetamido-a 3 a-exométhylènecépham-to-4 carboxylate L-oxide of 2, 2, 2 a-triehloroéthyle. '*

The azeotrope is distilled so 800 ml of toluene with water trap Dean-Stark eliminating 80 ml of liquid in the trap. The heating stops. and in adding hot toluene 6.68 g of poly (4 a-vinyl pyridine) divinylbenzene with a cross-linking of about 2%_; 20 g of 6 a--phenoxyacetamido-to-2, . 2 to-dimethylpenam-to-3 carboxylate L-oxide of 2, 2, 2 a-trichloroethyl and 7.74 g of chlorophthalimide. The slurry is heated to the reflux temperature for 100 min, and then cooled in an ice bath for about 20 min. The slurry is filtered to remove the cold copolymer and the phthalimide and the filtrate is cooled in an ice bath. Production of the sulfinyl chloride, the 3-methyl 2 - (2 a-chlorosulfinyl-to-4 oxo-3 a-phénoxyacëtamido-L-azetidinyl) - 3 a-isopropenyl 2.2, ' 2 a-trichloroethyl, yield of about 83%, is demonstrated in the spectrum. NMR.

NMR (CDCly: 61.95 (e, 3:00, methyl vinyl)

64.52 (e, 2:00, 0och₂ -)

64.66 (d., 2:00, j=2 Hz range, - OH₂ CC1₃ )

5 δ, 07 - 5.33 cm ., 3:00, HC₂ =C CH -)

65.53 (d., 1:00, j=4, 5 Hertz, hr in c₂ ' p-lactam) 66.28 (Q-, 1:00, j=4, 5 and 10 Hertz, H s-lactam).

66, 83 - 7, 47 (m-, 5:00, C. - ^ the O -)

68.06 (1:00, D., j=l0, Hertz, the NH).

Added 3.66 ml of diethyl ether at. cold filtrate and, with stirring, 10 ml of stannic chloride is added.

After about 1 hour of stirring, the complex begins to precipitate. The mixture is stirred overnight at room temperature the dark complex suspension and is filtered off and washed with 80 ml of d¹ a hexane. Adding the complex yellow brown sand-like due to 120 ml of methyl alcohol and the mixture is cooled in ùn ice bath.

When, after stirring for about 4 hours, it * precipitation does more product, reducing the volume of methyl alcohol to one third of the initial volume by evaporation. The concentrate is dissolved in ethyl acetate and the solution is washed twice with 5% aqueous solution of sodium bicarbonate and with water, and then dried over magnesium sulfate. The dried solution is evaporated to siccitë, yielding 15.62 g of the crude product, the 7 a-phénophéno.xyacétamido-to-3-exo méthylènecépham-a 4 a-carboxyiate L-oxide of 2, 2, 2 a-trichloroethyl, as a brown foam.

Bringing the product suspended in 60 ml of methyl alcohol and heating the slurry to about 50 °c to obtain a solution. By cooling to room temperature, the product crystallizes. The crystalline precipitate is filtered off and dried, yielding 1.9 g of product melts at about 143.5 and 144°.

NMR (CDC1₃ ): δ 3, 75 (Q-, 2:00, j=4 and 18 Hertz, hr in c₂ )

64.58 (e, 2:00, HC₂ the side chain) 54.83 (D., 2:00, j=1.5 Hz to, HC₂ trichloroethyl ester)

64.95 (d., 1:00, j=4.5 Hz range, H C._grams )

66.06 (q-, 1:00, j=4.5 and 11 Hertz, hr in c_? ) 65.53 (e, 1:00, hr c ^),

65.42 and 5.87 (2s, HM=₂ )

68.16 (d., 1:00, j=11 Hz range, the NH) and

66, 83 - 7, 50 (w, 5:00, aromatic hr).