Method of preparation of esters of derived from alpha-alkyl-thyronine.

AS AFRICAN AND MALAGASY INDUSTRIAL PROPERTY PATENT

P. 887

In Yaounde (Cameroon) International Patent Classification:^{07 c.} NO. 02150

O A'm>e. I requested 4 October 1966 to 10 hr 25 min to the O.A.M.P. 1. (G.P. no. 52,616) by

GENERATING CHEMILUMINESCENCE GRUNENTHAL GMBH AND

residing in Germany.

5 May 1970 delivered

Publishes official ballot at no. 1 of 19 ™

PRIORITY:

Patent application deposited in Germany

7 october 1965 s/n * c 37,070 IVB of the Q/12

on behalf of the applicant.

"Process for making esters of alpha-to-alkylthyronine derivatives".

The present invention relates to a method for the preparation of esters of alpha-alkyl-thyronine derivatives represented by the general formula:

wherein R represents an alkyl radical ^ straight or branched chain containing 1 to 6 carbon atoms, amino or acylamino group RG represents a, the R ^ to R, _, which are the same or different, are hydrogen atoms or iodine and RG alkyl straight or branched chain, optionally substituted, containing 1 to 6 carbon atoms, or aralkyl radical eycloalkyle, as well as optionally salts with acids

5 bases inorganic or: or organic.The substituent on the R radical■^

/^R 7

in particular concerns a group, Η β formula wherein

Rof Rj . and RG are the same or different and are hydrogen, lower alkyl radicals, or in combination with the nitrogen atom, a heterocyclic ring éventuellOlement interrupted by other atoms heterogeneous. The group

preferably represents the radical morpholino, piperidine, pyrrolidine or 4 a-alkylpiperazine. The invention also aim to a process for preparing these compounds. It is known by clinical experience and pathologico-anatomical that observed I5rarement sclerosis blood vessels when the thyroid operates superabundantly. We therefore performed tests have long been known to remediate the arteriosclerotic disease and especially to the coronary sclerosis with thyroid hormones. It has been found by experience that this influence favorably 20 may be manifested by a decrease in lipid content and especially cholesterine serum.

But an action harmful side, which results from the administration of the active substances of the thyroid, resides in an increase basal metabolism, which makes 2 ^ L.' administration difficult if not impossible, particularly in the case of coronary sclerosis. For example, it has been found that fact significantly increase basal metabolism, measured by the increase in oxygen consumption by administering by subcutaneous injection to male rats a proportion of 0.1 mg 3®the 1-thyroxine through kg of rats.

It spring Irish Patent no. 362/65 that by introducing an α-branched alkyl in the molecule derivatives determined thyronine, obtained compounds that have an advantage markedly decrease the sérunchoôlestérine content, without substantially increasing the basal metabolism. For example, if administered by subcutaneous injection to rats fed a diet high in cholesterol, daily for 14 days 1000 gamma of the sodium salt of dl-α méthylthyroxine per kg rat, is that the amount setp-to-10tate serum cholesterine animals treated drops down 380 mg ^has the O / to 265 mg to fo. If it is determined basal metabolism rats, found by administration to the patient by subcutaneous injection 4 mg dl-alpha-methyl-thryoxine per kg rat, is not caused to increase consumption of oxy-to-i5gene. Compared with L-thyroxine, is observed with dl-alpha-methyl-thryoxine little increase in oxygen consumption that with a dose 2000 times stronger. The AC -.

except anti goitreuse, it is to say the suppression of the growth of the thyroid rats caused by the thiouracil 20peut serve other measurement criteria thyreomimetic detrimental action exerted by a compound. For example, the action exerted by 20 mg dl-alpha-methyl-thryoxine corresponds to that of 0,020 mg of L-thyroxine. With dl-alpha-methyl-thyroxin, not observed decrease of weight increase that

•25 experiences by administering hormones of the thyroid and which characterizes the action thyreotoxic exerted by these compounds. For example, the final weight of treated rats by 4>0 mg/kg alpha-methyl-thyroxin in rats for a period of 14 days equals the weight determined by monitoring the speed of ali-to-30mentation.

Dl-alpha-méthy1 table salt or salts thereof, which are the subject of the Irish Patent mentioned, have the disadvantage of being ineffective by buccal administration. On the contrary, the compounds of general formula (I-) are significantly dimiçnuer serum cholesterol content both by subcutaneous administration that oral, without increasing basal metabolism.

the compounds of the general formula (I-) contain

an asymmetric carbon atom and consequently may be prélOsenter in two optically active forms, the separation into forms D - 1 - and can be effected by known methods. Further, there may be used, for the preparation by the method of the invention described below the compounds of the general formula

(I-), optically active raw materials and thus obtain 15des optically active ester derivatives of¹ alpha-alkyl diiodo thyronine wanted.

Can be prepared the compounds of the general formula

(I-) by reacting an acid, a salt or a reactive derivative, such as a halide, or acid anhydride represented by the general formula O 2 $

>5 wherein R ^ to R * .have the same meaning as in the formula (I-), with a compound represented by the general formula %

The rg III wherein - Y-RG has the same meaning as in formula I are $3<) and Y is an oxy group or hydroxy, hydroxy sstérifié, mid atoms of halogen or hydroxy group in which the hydrogen atom is replaced by a metal atom.

The reaction can be performed with stoichiometric proportions of a, compound of the general formula (III) and a compound of the general formula (II), but of the compounds can also be in excess. Preferably, since neither a compound of formula (it) in the form of a salt with a of Ba-.e, nor a compound of formula (II) wherein T denotes a hydroxy group in which the hydrogen atom is replaced by a metal atom, catalysts are added acidic esterification. when at the time they form a compound of general formula (I-), an acid is freedom, it is carried out preferably in the presence of basic substances for accelerating reaction or secure the acid. If at the time when preparing a compound of the general formula (I-) from a compound of general formula (it) and a compound of general formula (II), it is formed of water, one may also remove water by azeotropic distillation.

Also can be prepared from compounds of general formula (I-) by subjecting vBE1 M. compound of general formula;

17

wherein to R ^ have the same meaning as above, with a compound of general formula O

Y wherein RG has the same meaning as above, hydrolysis of the nitrile group of esterifying the presence of acids. The compound of general formula (therein) may be excessive, but the proportions of the compounds of the general formulae (ITs) and (V-) may also be present in stoichiometric quantities. One may also isolation of intermediate products of salts of d¹ imino ethers which are produced and the 5 in a separate reaction by converting compounds of the general formula (I-).

A third solution for preparing compounds of general formula (I-) consists in subjecting a compound of general formula:

wherein R ^ ^ ^ to R and R have the same meaning as above and RG denotes an alkyl or aralkyl radical, alcoholysis i5avec a compound of general formula (T-), optionally in the presence of acidic or basic catalysts, at room temperature or at elevated temperature, as compounds of general formula;

20 VII.

wherein and Rj to R ^ have the same meaning as above TDC ^ K-jQ denotes an acylamino group or an amino group optionally "

25 A fourth solution consists in subjecting a compound of general formula:

VIII.

wherein Β, RG ^ ^ and R have the same meaning as above, the Hofmann reaction in the presence of hypochlorite or d¹hypohromîtes.

A fifth solution comprises condensing a compound of general formula:

IX.

in which R to R ^ ^ and Rg have the same meaning as above, and the pH is close to the neutral point, preferably at a pH slightly alkaline, with an acid of the general formula:

X

wherein R ^ has the same meaning as in the formula

(I IN). The condensation can be carried out by dissolving a compound of general formula (IX to) in a neutralization solution, such as aqueous solution of borax and secondary sodium phosphate, citric acid and sodium phosphate secondary, or other substances or substance mixtures of neutralization, to a weakly alkaline pH, preferably equal to 7.6 - 7.8 with the addition of a water-miscible organic solvent with water, such as a lower alkanol, dioxane, dimethylformamide, the dimétiiylacétamide, ethylene glycol monoethyl ether or the like, and adding thereto a one or panel portions a corresponding solution of an acid of general formula (X-). It can be accomplished with proportions stoeehiometric back desformules compounds (IX.) and (s) or with an excess of one of the compounds. It can be also the condensation by adding a second phase immiscible with water, such as higher alcohols, chlorinated hydrocarbons, andc. Now we can operate optionally in the presence of substances having catalytic action, such as organic peroxides or divalent manganese salts, aerobic oîi under anaerobic conditions, for example by reaching a stream of oxygen for the entire duration of the condensation, to less than 100 °c terapérature.

A sixth solution consists in reacting an activated ester, preferably the ester p tosylic of a compound of the general formula:

xL

wherein, RG and the R ^ Q have the same meaning as above and R ^ is a nitro group or the radical R ^, with a compound of general formula:

50

I

XII wherein the R ^ .has the same meaning as above and R₁₂aralkyls denotes a radical, optionally substituted, in the presence of a solvent and/or a base mineral or organic, preferably pyridine, optionally at elevated temperature, and converting the thus obtained compound of general formula;

wherein R ^, the R ^, RG and the R ^ ^ Q and R have the same meaning as above, or the nitro groups, preferably catalytic reduction in the presence of Raney nickel and by diazotization in one or more diazonium groups and replacing said groups by a known method, such as the Sandmeyer reaction, reaction or deamination by the radicals R of Rj and R ^ ^ or, by hydrogenation to remove the protecting group R^2>pnéférence in the presence of a catalyst comprising a noble metal, and transforming the R optionally ^ Q into an amino group.

It is then preparing the compounds of general formula (I-) incorporating into one compound of the general formula:

-XIV

in which R to R ^ ^ and Rg have the same meaning as above, using agents for the iodination, such as for example the system iodine/potassium iodide, n-iodo acetamide, the Riodo orboth, chlorine iodide, p-toluene sulfone iodamidure pot aces situated, andc, one or two iodine atoms optionally one after 1' other. Can be prepared for example the compounds of general formula (-XIV) by reacting the corresponding acid, a salt thereof or a reactive derivative thereof with a compound of general formula (Ill-), as described for formula (ll) general. The tablets can also be prepared by reacting an activated ester, preferably the P-tosylic ester, of a compound of general formula (IX) with a compound of general formula:

(a)

in which^has the^has same meaning as above, in the presence of a solvent and/or a " basic inorganic or organic, preferably pyridine, optionally at elevated temperature, by replacing in the obtained compound of the general formula

wherein R ^, RG and the R ^ ^ Q and R have the same meaning as-Gi-top, or the nitro groups by the radicals R ^ ^ ^ or R and R, and eliminating the radical R ^ éventuellenent and transforming the R₁₀ in an amino group. Another possible solution for preparing the compounds of general formula (-XIV) comprises reacting a compound of general formula (IX to) with a compound of general formula;

wherein R ^ has the same meaning as above and year " denotes an anion, in the presence of a reacting substance AlCa with-a 5 pipeline, preferably a metal alcoholates, the reaction is preferably performed in a solvent such as alcohol, and removing by hydrogenating the radical R ^ read resulting compound of general formula:

in which R to R ^ ^, the rg ^ and R have the same meaning as above.

If it is desired to prepare the compounds of formula (I-) interfering by-15rale wherein RG is denotes an acylamino group, can be converted in a manner known per se to the compounds produced by one of the above methods and containing one or more free amino groups by reacting them with a reactive derivative of a carboxylic acid such as an anhydride, halide or ester carboxylic acid 20.

If desired, may be transformed into corresponding salts the compounds of general formula (I-) by reacting them with a base or an acid, so that by choosing optically active compounds to form the salts, salts are obtained 25 corresponding isomeric forms that can be decomposed by methods known per se in optically active components.

The following examples indicate how the L^{the R} invention can be applied in practice.. the boiling and melting points are not corrected and no attempt is made to obtain the maximum efficiency in the examples.

Example 1

Suspended is 7" 91 g-alpha-methyl-thyroxine in 150 ml of absolute ethanol. The slurry is heated and injected therein until saturation of the anhydrous hydrogen chloride. The solvent is removed by vacuum distillation. The residue is dissolved in ethanol at 50 i° and neutralized with a solution of sodium bicarbonate to 5 $. This provides the ethyl ester ά'alpha-methyl-thryoxine melts at 156 - 157 °0 after recrystallization from ethanol.

Yield; 6.05 grams, it is to say 74 1° of theory.

Example 2

Using methanol, obtained by the process of example 1 methyl ester alpha-methyl-thryoxine 123 - 125 °0 melts, after recrystallization from methanol.

Yield: 85% of theory.

The Exe5 could become

Added 2 g-alpha-methyl-thryoxine portionwise to a mixture heated to 95 °0 of 20 ml of benzyl alcohol and 5 g of polyphosphoric acid. The clear solution is then stirred for 4 hours at 95 °c. Allowed to cool, it is poured₂₅ in 200 ml of water and is extracted by ether. The ether solution is washed with a solution of ammonia to 1 n dried on sodium sulfate and concentrated in vacuo. After dissolving the residue in ethanol, adding water obtained the benzyl ester alpha-methyl-thyroxin, flux 3oà 178 and 180 °C after recrystallization from n-butanol.

Example 4

5>7 G of dissolved ethyl ester 3.5 a-iodo-alpha-methyl - diiodo thyronine in a mixture of 60 ml of butylamine and 120 ml of ethanol. Added dropwise a solu-to-5tion of 5i1 g of iodine in 50 ml of ethanol and stirred for one hour. The solution is then neutralized using 1' concentrated hydrochloric acid while cooling with ice. By adding a solution of sodium acetate in water, obtained ethyl ester alpha-methyl-thryoxine melts at 156 and 101570c identical to the product obtained in the example 1, with a yield of 85 of the theoretical yield.

The starting material is prepared above, it is to say the ester of 3.5 a-iodo-alpha-methyl thyronine as follows:

15 Is suspended in 240 ml of absolute ethanol, 11.8 g of 3.5 a-iodo-alpha-methyl thyronine. By cooling with ice, the solution is saturated with anhydrous hydrogen chloride. By continuing the injection of anhydrous hydrogen chloride, is heated for several hours to still con-to-20rature reflux. The solution is concentrated to dryness under clear.. vacuum. The residue is dissolved in ethanol at 5 © f° and neutralizing the solution with an aqueous bicarbonate solution to #5. This gives ethyl ester 3.5 a-iodo-alpha-methyl thyronine melts at 152 and 154 °C with a yield of 73 1° 25du theoretical yield.

Example 5

It is carried out in the same manner as in the example 1 and obtained with the 3>5>3 'tri-iodo alpha-methyl thyronine, ethyl ester 177>5 - 180 °0 melts after recrystallization in 301' ethanol, with a yield of 78.5 $of theory.

The starting product prepared above, the 3" 5>3 'tri-iodo alpha-methyl thyronine, as follows:

5.4 G of dissolved 3.5 di-iodo alpha-methyl thyronine in a mixture of 26 ml of sodium hydroxide solution of 108 ml of 1 f and oauet is added dropwise at room temperature a solution of 3.15 g of p-toluene sulfone iodamidure potassium in 53 ml of water. Agitated for a period of time, and then the pH is adjusted to 6 by addition of acetic acid to 95 is filtered the precipitate to the horn and is dissolved in a mixture of 25 ml of sodium hydroxide solution 2 n and 62 ml of ethanol. After settling with coal of £aoti_therein in precipitates the product to the boiling temperature by adding hydrochloric acid 2 U-until the pH is equal to 6. Is filtered, washed with a mixture of ethanol and water to 1:2, is dried under vacuum at 100 °c and the result is the 3, 5, 3 ' tri-iodo alpha-methyl thyronine melts at 260 and 264 °C with a yield of 66 $of theory.

Example 6

Operation is carried out as in the example 1 and obtained, with alpha-ethyl-thyroxin, ethyl ester melts at 138 and 140 °C with a yield of 72 $of theory.

The starting product prepared above, it is to say 1 'alpha-ethyl-thyroxin, as follows:

Suspended is 35.6 g of 1 P-methoxy-phenylbutanol - (2), 19.5 g of potassium cyanide and 62.5 g of carbonate-D.¹ ammonium in 330 ml of ethanol to 50 $by stirring for 7 hours and, is heated at a temperature of 65 to 70 °c. Is crystallized by cooling, optionally by injecting carbon dioxide, the 5 ethyl 5 - (4-methoxybenzyl) hydan-to-30toïne as white crystals melting at 191 - 193 °0 after recrystallization in a mixture of ethanol and water. Yield of 90 with fo of theory.

Heated 24" 8 g of the above compound in 110 ml aqueous hydriodic acid 57 $for two hours at the reflux temperature for EMT ^. By cooling, there is obtained the 5 ethyl 5 - (4 hydroxy-benzyl) hydantoin, melts at 290 and 291 °C after recrystallization from ethanol yield 68. $ of theory.

Added 23.4 g of the title compound by stirring vigou -¹⁰ blinking and portionwise to 70 ml nitric acid having " a density of 1.42 heated to 35 and 37 degrees Celsius. Was stirred for two hours and the solution is diluted with 200 ml of ice water. Thus the precipitated 5 - e " fchyl and 5 - (3.5 to-âinitro-a 4 a-hydroxybenzyl) hydantoin, in crystalline form, melts at 236 and 238 °, after recristal ^ crystallizing in ethanol. Yield: 70 f° of theory.

Heated 64.8 g of the above compound and 42 g of acid chloride in 150 ml - para-pyridine during 10 minutes at reflux temperature. After cooling, added 62 g of 4-methoxy-phenol dissolved in 62 ml of substituted pyri -²⁰ dines, and heated for one hour at reflux temperature. After cooling, is obtained by thinning a volume six ice water, the 5 ethyl 5 thereof [3" 5 a-dinitrobenzoic 4 - (4' a-methoxyphenoxy) benzyl aromatic] hydantoin melts at 195 and 197 °C after recrystallization in dilute acetic acid. Yield: 93 i° of the

25 theoretical yield.

43.0 G of the compound is dissolved in a mixture of 300 ml mentioned methanol and 100 ml of tetrahydrofran and is subjected to a hydrogenation with addition of Raney nickel at atmospheric pressure and at room temperature. ^ Is separated from the catalyst by filtration and the solvent is removed

by vacuum distillation. Is obtained from the residue, after recrystallization from a mixture of ethyl acetate and petroleum ether, the 5 ethyl 5 thereof [3 "s diaminopyridine ^ - ^ ' - methoxyphenoxy) benzyl aromatic] hydantoin melts at 207 and 210 °C with a yield of 77" 5 i° of theory.

Added dropwise 37" 0 g of the above compound dissolved in 80 ml of glacial acetic acid, to 40 ml of concentrated sulfuric acid to 10 °c. Are added to this solution dropwise in two to three hours a solution cooled to a temperature of -4 -2 °c to 17.5 g of sodium nitrite in 175 ml of concentrated sulfuric acid and 200 ml of glacial acetic acid. Was stirred for one hour at 0 °0 and added rapidly the solution by vigorous agitation to a mixture of 87 g potassium iodide, 68.0 g of iodine, 10.0 g urea, 1.3 liter of water and 450 ml of chloroform. Was stirred for two hours. The chloroform layer is separated and the aqueous phase is extracted several times with chloroform. Chloroform extracts are washed combined with sodium bisulfite solution, then with water, and dried over sodium sulfate, after filtration and removal of solvent under vacuum, obtained the 5 ethyl 5 and 3.5 [a-iodo-a 4 - (4' a-methoxyphenoxy) benzyl aromatic]" * ^&therein^aβ; the K⁰ &^{i am} melts at 241 and 243 °C in a yield of 73 $> of theory.

Heated 59.2 g of the above compound with a mixture of 180 ml hydroiodic acid density 1.7 and 180 ml of glacial acetic acid for one hour at reflux temperature.

Is obtained upon cooling the 5 ethyl 5 and 3.5 [a-iodo-to-4 (4 'hydroxy-phenoxy) benzy5-hydantoin melts at 313 - 316 °0 after recrystallization from ethanol, yield 93.7% of the theoretical yield.

30 G of the compound is dissolved in said 115.6 2200 ml of the solution of a probe 2 n and the solution is heated in an autoclave for 100 hours at 140 °c. Then neutralized using hydrochloric IVacide to 16 $ to the boiling temperature. The precipitate is filtered while hot to the horn. It consists primarily of alpha ethyl-3.5 a-iodo thyronine. Is crystallized from the filtrate by cooling alpha-ethyl-3 triiodo thyronine. Is purified by dissolving the same in the two fractions of years a mixture of ethanol and concentrated hydrochloric acid, and then precipitated 1 'amino-acid using a saturated solution of sodium acetate. This provides 1 'alpha-ethyl-3.5 a-iodo thyronine melts at 285 and 288 degrees Celsius, with decomposition, a yield of 48.6 with fo of theory and alpha-ethyl-3 triiodo thyronine melts at 210 and 215 °C in a yield of 39 i° of theory. Alpha-ethyl-3 triiodo thyronine solidifies upon further heating it between 220 and 240 °0, and then back again to a temperature of 281 - 283 °0 decomposes.

22.1 Grams is dissolved alpha-ethyl-3.5 a-iodo thyronine in 130 CNR aqueous solution to 33 i° ethylamine and added dropwise to a solution of 1.85 86.5 ml n of iodine and potassium iodide (solution of iodine-iodide). Was stirred for one hour and hydrochloric acid is added to 16 foo until the pH is equal to 5. Removed by filtration 1' amino acid precipitated, washed with water and is dissolved in a mixture of 250 ml of ethanol and 100 ml of NaOH 2 hr.

After settling using activated charcoal, obtained, by adding hydrochloric acid 2, 5 to a ph=6, 1 'alpha-ethyl-thryoxine melts at 236 and 238 °C in a yield of 60 lo of theory.

7 Bxemple

Operation is carried out as in the example 1 and obtainable from 1 'alpha-n-thyroxin, ethyl ester 174 and 176 °g melts in a yield of 57 i° of theory.

1 Is obtained'alpha-n-propyl-thryoxine mentioned, which serves as raw material, in the manner described in example 6 for preparing the starting material, and by the subsequent intermediate stages:

5 n-propyl - 5 - (4-methoxy benzyl) - hydantoino 244 and 245° melts, from - ethanol, in a yield of 63 of the theoretical yield.

5 n-propyl 5 - (4 a-hydroxybenzyl) - hydantoîne melts at 186 - 288 °0 from ethanol, in a yield of 90% of the theoretical yield.

5 n-propyl 5 - (3.5 to-dinitrobenzoic 4 hydroxy-benzyl) - hydantoîne melts at 212 and 213 °C from glacial acetic acid, in a yield of 74 $of theory.

5 n-propyl 5 thereof [3" 5 a-dinitrobenzoic 4 - (4'-methoxy-phenoxy) benzyl aromatic] a-hydantoîne melts at 196 and 198 °C from dilute acetic acid, in a yield of 55 i° of theory.

5 n-propyl 5 and [3, 5 a-diamino 4 - (4'-methoxy-phenoxy) benzyl aromatic] a-hydantoîne in a yield of 96 with fo of theory

5 n-propyl 5 thereof [3" 5 a-iodo-a 4 - (4'-ethoxy-phenoxy) - ylbenzyl] hydantoin melts at 247 and 248 °C from a mixture of methanol and of éthyl-to-cellosolve.

5 n-propyl 5 and 3.5 [a-iodo-a 4 - (4¹ - hydroxy phenoxy) - ylbenzyl] hydantoîne melts at 298 and 299 °C from ethanol, in a yield of 80 The O/degrees of theory.

alpha-n-propyl 3>5 a-iodo thyronine melts at 278 - 30280 °0, in a yield of 58 % of theory.

alpha-n-propyl-thryoxine melts at 231 - 232°0, in

a yield of 46.5 f." of theory.

Example 8

Operation is carried out as in the example 1 and obtained from the (+) - alpha-methyl-thyroxin, melts at 273 - 278 ethyl ester in a yield of 84 °0 f.> of theory, [α=+ 10.0 degrees (0=5 in a mixture of hydrochloric acid 1 n and ethanol 95 f.> at a ratio of 1:2)

Affords the corresponding ethyl ester in a similar manner, from the (-) - α-born the Thyl thyroxine.

Prepared optically active amino acids which serve as starting materials in the example above as follows:

53>9 Grams is dissolved alpha-methyl-3.5 a-iodo thyronine in 270 ml of formic acid at 100 $by adding 27 ml of acetic anhydride, the H-formyl alpha méthy1 above 3.5 a-iodo thyronine crystallizes after some time. Fallopian tube is filtered, washed with water to remove the acid and dried, the yield is 45>5 gm, 80 either f.> of theory and the melting point of 221 - 223⁰ 0.

Suspended is 56.7 g of the above compound in 560 ml of isopropanol absolute and heated to boiling. Added a solution heated to boiling 47 * 3 g of (-) brucine and to 240 ml of isopropanol and the solution is held at the reflux temperature. The result is that the salt of (-) - lnd, NICE (+) - the n-formyl alpha-methyl 3>5 a-iodo thyronine separates as crystalline and still warm from the torch, the salt of (-) - (+) of brucine and n-formyl alpha ffiéthyl-to-3>5 a-diiodothyronine with crystallized from the filtrate, it is dissolved in 200 ml of ammonia 1 I and it is extracted several times with chloroform. The aqueous phase is neutralized by hydrochloric acid by chilling. This results in the (-) - n-formyl alpha-methyl-3.5 a-iodo thyronine melts at 234 - 236 °0 after recrystallization in aqueous isopropanol in a yield of 74 $of theory

[α]=" 24^{the P} " (C=5 donations ethanol at 95 ' f.).

The recrystallized salt of (-) - (+) of brucine and hence he-formyl alpha-methyl-3.5 a-iodo thyronine in a mixture of dimethylformamide TDC of ethyl acetate and its melting point is then of 258 and 262°. the pure salt of brucine is converted to acid in the manner described above for the force laevorotatory, a melting point of 234 - 236 °0 after recrystallization from 1¹ isopropyl alcohol. the efficiency is 90 foo of theory.

[α] 2² =+ 24.2 degrees (c=5 in ethanol to 95%).

14.3 G of heated (-) - n-formyl alpha-methyl-3.5 a-iodo thyronine in 150 ml of hydrobromic acid to 16 $3 during hours at reflux temperature. The hydrobromide which precipitates is separated by cooling and is dissolved in the étha -

The O/degrees. In precipitating using a solution of sodium acetate in the manner described about the racemate, the (-) obtained - alpha-methyl-3.5 a-iodo thyronine melts at 285 - 288 in a yield of 89% °0 of theory.

22

[α]=- 14, 6 degrees (0=5 in a mixture of hydrochloric acid n and ethanol at a ratio of 1s2).

Is obtained in a similar way the (+) - alpha-methyl-3.5 a-iodo thyronine melts at 286 - 288 in a yield of 86 °0 i-<> of theory.

[α]=^ + 14.5 degrees (0=5 in a mixture of hydrochloric acid⁵⁰ 1 E and ethanol to 1:2).

By operating by the method described in the example 6 for the racemate, the (+) obtained - alpha méthyl~thyroxine, 273 and 274° melts in a yield of 84 - Theo yield foo

decoding apparatus.

29

[α]=^ + 10° (0=5 in a mixture of hydrochloric acid and ethanol and 1 to 95 $to a rpport of 1:2.

Example 9

It is carried out in the same manner as in the example 5. and is obtained by choosing the initial optically active acid ethyl ester (+) - alpha 3>5>3' a-triiodoisophthalic thyronine in a yield of 67 with fo of theory.

p

[α]=^ + 10° (0=2 in glacial acetic acid) or (-) alpha-methyl 3>5>~3' a-triiodoisophthalic thyronine in a yield of 52 The O/degrees of theory.

[α]=^ -11.1 degrees (0=2 in glacial acetic acid).

physical constants of triiodo thyronines optically active obtainable as starting materials are as follows:

(-) - alpha-methyl-3.5>5' a-triiodoisophthalic thyronine: melting point "

[α]=^ ^ 12, 8⁰ (0=5 in a mixture of hydrochloric acid and ethanol to 1:2)..

(+) - alpha-methyl-3.5>5' a-triiodoisophthalic thyronine: melting point " 277.5 and 278 degrees Celsius.

22

[α]=+ 13>0° (0=5 in an acidic mixture chlorhydjric and ethanol to 1:2).