CH497446A - 2 2-disubst-3-acyl-5-hydrazino-thiazolidine-4-carboxylic acid derivs - Google Patents

Abstract

Saturated cyclic alpha-hydrazino-thioethers in which the hydrazine group is N,N'-disubst. by esterified COOH groups, especially compounds of formula:- (IVa) Ac = acyl; X is the disubst. C atom of the thiazolidine ring; R' = free or functionally converted COOH; Ra, Rb = alcohol residues; R2 = H, halocarbon group. Subclaims indicate X = where R3,R4 singly = aliphatic, aromatic, araliphatic group or a functionally converted COOH or R3 and R4 = bivalent aliphatic group, oxo, thiono or phthaloyl; Ac = thienylacetyl, chloroethylcarbamyl, phenylacetyl; R' = free or esterified COOH, CONH2, CN, CON3, CONHNH2, azocarbonyl Inters. in synthesis of 7-ACA and cephalosporins. methyl L-2,2- dimethyl-3-t-butyloxycarbonyl-5beta-(N,N'-dicarbomethoxy-hydrazin- o)-thiazolidine-4-carboxylate.

Description

  

  
 



  Process for the preparation of hydrazinothiazolidine compounds
The present invention relates to a methodological process for the preparation of hydrazinothiazolidine compounds, which was used for the preparation of valuable intermediates and in particular in the first synthetic preparation of 7-amino-cephalosporanic acid and its derivatives and is particularly suitable for this peculiar synthesis.



   7-Amino-cephalosporanic acid has the following formula:
EMI1.1
 Derivatives are primarily N-acyl compounds, in which acyl radicals in particular those of effective N acyl derivatives of 7-amino-cephalosporanic acid, such as thienylacetyl, cyanoacetyl, chloroethylcarbamyl or phenylacetyl radical, or easily cleavable acyl radicals, such as the radical of a half-ester of carbonic acid e.g. the tert. Butyloxycarbonyl radical.



   The synthesis of this compound and its derivatives, which are important for the production of valuable pharmaceuticals, is based on the idea of using a 3,5-unsubstituted 2,2-disubstituted thiazolidine-4-carboxylic acid, e.g. a compound of formula I.
EMI1.2
  and carry out the novel synthesis, for example, according to the following equation:
EMI2.1
  
The compound IX is converted into the desired 7-amino-cephalosporanic acid and its derivatives as follows:
EMI3.1
  
The compound of formula X used as an intermediate is prepared as follows:

  :
EMI4.1

The hydrazinothiazolidine compounds of the formula which are valuable as intermediates
EMI4.2
 where Ac stands for an acyl group, X stands for the disubstituted carbon atom of the thiazolidine ring, R1 stands for a functionally modified carboxyl group and each of the groups Ra and Rb stands for the remainder of an alcohol, is surprisingly obtained by using a compound of the formula
EMI4.3
 with an azodicarboxylic acid ester of the formula RaOCC- -N = N-COORb. If desired, a substituent in a compound obtained can be converted into another and / or a mixture of isomers obtained can be separated into the individual isomers.



   In the compounds obtained according to the invention, acyl radicals Ac are primarily those which occur in pharmacologically active N-acyl derivatives of 7-amino-cephalosporanic acid, e.g. the thienylacetyl, chloroethylcarbamyl or phenylacetyl radical, or easily cleavable acyl radicals, such as the radical of a half-ester of carbonic acid, e.g. the tert.Butyloxycarbonyl radical.



   The radical -X- stands in particular for the group of the formula
EMI4.4
 wherein R3 and R4 represent hydrocarbon, especially aliphatic hydrocarbon radicals such as lower alkyl, e.g. Ethyl, n-propyl, isopropyl or, preferably, methyl groups, as well as aromatic, especially phenyl groups, or araliphatic hydrocarbon radicals, especially phenylalkyl, e.g. Benzyl or phenyl ethyl groups, and for functionally modified, in particular esterified, carboxyl groups, such as carbo-lower alkoxy, e.g. Carbomethoxy or carbethoxy groups, or, when taken together, for a divalent hydrocarbon, especially divalent aliphatic hydrocarbon radical, such as a lower alkylene, e.g. 1,4 butylene or 1,5-pentylene group, as well as a phthaloyl group or an oxo or thiono group.



  The above-mentioned hydrocarbon radicals are unsubstituted or can e.g. be substituted by lower alkyl such as methyl or ethyl groups, lower alkoxy such as methoxy or ethoxy groups, halogen such as fluorine, chlorine or bromine atoms, haloalkyl such as trifluoromethyl groups or other suitable groups.



   The group R1 stands for a free or preferably functionally modified carboxyl group, in particular an esterified carboxyl group. The latter is compatible with hydroxy compounds of any kind suitable for the esterification of carboxylic acids, in particular with aliphatic alcohols such as alkanols, in particular lower alkanols, e.g. Methanol, ethanol, n-propanol or tert-butanol, cycloaliphatic alcohols such as cycloalkanols, e.g. Cyclohexanol, or araliphatic alcohols such as phenylalkanols, e.g. Benzyl alcohol, as well as with phenolic compounds, especially phenol, or with N-hydroxy nitrogen compounds, such as hydroxamic acids, e.g.



  N-hydroxycarbamic acid esters, such as methyl esters, or N-hydroxyimides, e.g. N-hydroxysuccinimide, esterified, where the above-mentioned hydroxy compounds are unsubstituted or may contain lower alkyl, lower alkoxy, nitro or trifluoromethyl groups or, in particular, halogen atoms and other groups as substituents; Halogenated lower alkanols, such as 2,2,2-trichloroethanol, are particularly suitable as substituted hydroxy compounds which esterify the carboxylic acid.



   Other functionally modified carboxyl groups R1 are e.g. nitrogen-containing, functionally modified carboxyl groups, such as carbamyl groups, which are unsubstituted on the nitrogen atom or aliphatic, aliphatic groups containing, optionally lower alkyl, free, esterified or etherified hydroxy, such as lower alkoxy, aralkoxy, lower alkanoyloxy or aroyloxy groups or halogen atoms, nitro or trifluoromethyl groups aromatic or araliphatic hydrocarbon radicals or heterocyclic radicals of aromatic character, such as lower alkyl, cycloalkyl, phenyl, phenyl-lower alkyl, phenyl-lower alkylidene or pyridyl radicals, as well as by free, etherified or esterified hydroxyl groups, such as the above-mentioned groups of this type, by phosphorus-containing residues, or by acyl residues, such as residues of carboxylic acids, for example

  Residues of half-esters or half-amides of carbonic acid or lower alkanoyl radicals, or of sulfonic acids, such as aryl sulfonic acids, e.g.



  Phenylsulfonyl radicals, mono- or disubstituted, as well as nitrile groups, azidocarbonyl groups or, optionally on nitrogen e.g. hydrazinocarbonyl or azocarbonyl groups mono- or polysubstituted by the above-mentioned substituents of the carbamyl group.



   Residues of alcohols Ra and Rb are e.g. the residues of the abovementioned alcohols suitable for esterifying the carboxyl groups R, in particular of aliphatic alcohols, such as lower alkanols or substituted, primarily halogenated, lower alkanols.



   According to the invention the reaction can e.g. be carried out in such a way that the thioether is processed with the azodicarboxylic acid diester in the absence or presence of a diluent, preferably at elevated temperature but below the decomposition temperature of the azodicarboxylic acid ester used, if necessary in an inert gas atmosphere and / or under elevated pressure.



   In the compounds obtained, substituents can be converted into others; Thus, an acid derivative obtained, such as an ester, can be converted into the free acid by methods known per se without the acyl group, especially an easily cleavable acyl group such as the tert-butyloxycarbonyl group, being removed in the 3-position. For example, a carbo-lower alkoxy, such as the carbomethoxy group, can be saponified to form the free carboxyl group by treatment with dilute lye, such as potassium hydroxide solution. In a peculiar way, e.g.



   convert a carboxy group esterified with a 2,2,2-trihaloethanol, especially 2,2,2-trichloroethanol, into the free carboxyl group by means of reducing agents.



   Suitable reducing agents are chemical reducing agents such as nascent hydrogen obtained e.g. by the action of metals, metal alloys or amalgams on hydrogen-releasing agents such as zinc,
Zinc alloys, e.g. Zinc copper, or zinc amalgam in
Presence of acids such as organic carboxylic acids, e.g. Acetic acid, or alcohols such as lower alkanols, alkali metal, e.g. Sodium or potassium amalgam or
Aluminum amalgam, in the presence of moist ether or lower alkanols, furthermore alkali metals, e.g.



   Lithium, sodium or potassium, or alkaline earth metals, e.g. Calcium, in liquid ammonia, optionally with the addition of alcohols such as a lower alkanol.



   Furthermore, an ester with a 2,2,2-trihaloethanol, in particular 2,2,2-trichloroethanol, can be obtained by treatment with strongly reducing metal salts, such as chromium-II compounds, e.g. Chromium (II) chloride or chromium (II) acetate, preferably in the presence of aqueous media, containing water-miscible organic solvents such as lower alkanols, lower alkanecarboxylic acids or ethers, e.g. Methanol, ethanol. Acetic acid, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether can be converted into the free acid.



   In a compound with a free carboxy group, this can be converted into its derivatives, e.g. into their esters, amides, hydrazides or azides. So it can e.g. by treating with a diazo compound such as a diazo lower alkane, e.g. Diazomethane or diazoethane, or a phenyl-diazo-lower alkane, e.g. Diphenyldiazomethane, or by reaction with a hydroxy compound suitable for esterification, such as e.g. an alcohol, a phenolic compound or an N-hydroxy nitrogen compound, e.g. a hydroxamic acid, in the presence of an esterifying agent such as a carbodiimide, e.g.

  Dicyclohexylcarbodiimide, as well as carbonyldiimidazole, or by any other known and suitable esterification process, such as reaction of a salt or acid with a reactive ester of the hydroxy compound, especially an alcohol, and a strong inorganic acid or a strong organic sulfonic acid, if desired, in the presence of a salt-forming Base, to be esterified. Amides such as N-sulfonylamides can be prepared by methods known per se, e.g. by treating the obtained free carboxylic acid with a sulfonyl isocyanate.



   A functionally modified carboxy group in a compound obtained can also be converted into another functionally modified carboxy group by methods known per se, e.g. esterified carboxy groups by transesterification, such as treatment with a hydroxy compound in the presence of a transesterification catalyst. Furthermore, esters and in particular activated esters, e.g. Esters with N-hydroxy nitrogen compounds or anhydrides formed with haloformic acid esters can be converted into other esters, or into amides or hydrazides, by reaction with other hydroxy compounds such as alcohols or phenols, and with ammonia, primary or secondary amines or hydrazine.

  In an amide or hydrazide compound obtained with a hydrogen-containing one
Nitrogen atom this can be substituted afterwards, e.g. by treatment with a carboxylic acid or sulfonic acid derivative, such as a halide, and / or a reactive esterified alcohol or by means of other suitable reagents; an N-unsubstituted amide can e.g. converted into nitriles by dehydration.



   Mixtures of isomers obtained can be separated into the individual isomers by methods known per se, e.g. due to physico-chemical differences, such as by fractional crystallization or distillation, column or thin-layer chromatography, as well as formation of mixtures of diastereoisomeric salts, separation of the obtained
Mixtures into the individual salts and release of the isolated salts, or other process measures suitable for separating mixtures of isomers.

 

   The process also includes those execution forms, according to which compounds obtained as intermediates are used as starting materials and the rest of the process steps are carried out with them, or the process is terminated at any stage; furthermore, starting materials in the form of derivatives, e.g. of salts, used or formed during the reaction.



   Such starting materials are preferably used and the reaction conditions are selected such that the compounds listed at the beginning as being particularly preferred are obtained.



   Some of the starting materials used in the above process are known; new starting materials can be produced either by processes known per se or as described below. They preferably contain starting materials which are suitable for the preparation of the preferred 2,2-di-substituted 3-acyl-5-hydrazino-thiazoli- dine-4-carboxylic acids in which both nitrogen atoms of the hydrazino group are each substituted by an esterified carboxyl group, and their derivatives , no acidic groups, ie In the corresponding starting materials, the 4-carboxyl group is preferably functionally modified, for example esterified.



   The new 5-unsubstituted 2,2-disubstituted 3 -tert. Butyloxycarbonyl-thiazolidine-4-carboxylic acids and their derivatives, especially esters and nitrogen-containing acid derivatives, especially the amides, hydrazides, azides or nitriles of such acids, such as acids of the formula IIa
EMI6.1
 wherein the group X has the meaning given above, and their esters and nitrogen-containing functional derivatives, in particular amides, hydrazides, azides or nitriles, in particular the acid of the formula IIb
EMI6.2
 and their esters, preferably lower alkyl and halo-lower alkyl esters, as well as nitrogen-containing acid derivatives such as amides, hydrazides, azide or nitrile, which are used as particularly preferred starting materials in the above process along with other N-acyl compounds, can be obtained,

   if one reacts a carbonic acid dihalide and tert-butanol directly with a 3,5-unsubstituted 2,2-disubstituted thiazolidine-4-carboxylic acid or stepwise with an ester thereof and, if desired, an acid obtained into a derivative, especially into an ester, as well as in a nitrogen-containing acid derivative such as an amide, hydrazide, azide or nitrile, or a derivative obtained, e.g. an ester, into the acid or into another derivative, e.g. another ester, as well as a nitrogenous acid derivative, e.g.



  an amide, hydrazide, azide or nitrile.



   The above reaction for the preparation of the specific starting materials can e.g. be carried out in such a way that the 5-unsubstituted 2,2-disubstituted thiazolidine -4-carboxylic acid, in particular an acid of the formula Ia
EMI6.3
 treated with a mixture of a carbonic acid dihalide, in particular phosgene, and tert-butanol, a tert-butyl oxycarbonyl halide, in particular tert-butyl oxycarbonyl chloride, being formed. The reaction is advantageously carried out in the presence of a base such as an organic base, e.g. Pyridine, collidine or triethylamine, and in the presence or absence of an additional solvent, expediently with cooling and / or in the atmosphere of an inert gas, e.g. Nitrogen.



   The gradual introduction of the tert-butyloxycarbonyl radical into an ester of the 3,5-unsubstituted 2,2-disubstituted thiazolidine-4-carboxylic acid, especially an ester of the acid of the formula Ia, is e.g. carried out by treating the ester with a carbonic acid dihalide and reacting the 5-unsubstituted 2,2-disubstituted 3-halocarbonyl-thiazolidine-4-carboxylic acid ester thus obtained with tert-butanol or a suitable organometallic derivative thereof.



   Treating the ester with a carbonic acid dihalide, especially phosgene, is preferably carried out in the presence of a suitable base, e.g. Dimethylaniline or pyridine, in the absence or, advantageously, presence of a solvent, if necessary, with cooling and / or in a closed vessel and / or in the atmosphere of an inert gas, e.g. Nitrogen.



   The 3-halocarbonyl, in particular 3-chlorocarbonyl-thiazolidine-4-carboxylic acid ester obtained as an intermediate product is mixed with tertiary butanol, preferably with heating and, if necessary, in a closed vessel, using e.g. Isobutylene can be used, but can also be carried out with a suitable organometallic compound of tert-butanol, such as e.g. a tert-butyloxymagnesium halide such as chloride, bromide or especially iodide, or an alkali metal such as sodium or potassium tert-butoxide, if necessary, with cooling or heating and / or in a closed vessel and / or be made in the atmosphere of an inert gas.



   In an acid obtained by the above process, the carboxy group can be functionally modified by methods known per se, e.g. esterified or amidated, or in an acid derivative obtained, the functionally modified carboxyl group can be converted into the free or into another functionally modified carboxyl group; these additional process steps are carried out as described above.



   The invention is described in more detail in the following examples. The temperatures are given in degrees Celsius.



   Example I.
219.3 g L -2,2 - dimethyl-3-tert. butyloxycarbonyl-thiazolidine-4-carboxylic acid methyl ester and 1165 g of azo-dicarboxylic acid dimethyl ester are heated in a dry glass vessel equipped with a stirrer and reflux condenser for 45 hours at 102-1080 while stirring and excluding atmospheric moisture. The liquid, which has cooled to about 45-500, is then placed in a centrifuge vessel, inoculated and left under lock and key overnight. The excess of the azo-dicarboxylic acid dimethyl ester is removed by centrifuging for about 5 minutes at 2800 rpm. separated from the crystalline material and the latter stirred up with a total of about 500 - 600 ml of benzene.

  The mixture is centrifuged again, the supernatant solution is decanted off and the crystalline material is stirred up again with a 3: 7 mixture of hexane and ether (total volume 500-600 ml) and centrifuged. The crystalline product obtained is filtered off and washed with the hexane-ether mixture; the L-2,2-dimethyl-3-tert-butyloxycarbonyl-5p- (N, N'-dicarbomethoxy-hydrazino) -thi azolidine-4-carboxylic acid methyl ester of the formula is obtained
EMI7.1
 which melts at 136-137.50; tO] D = +980 + 10 (c = 1.45 in chloroform); Infrared absorption bands (in methylene chloride) at 2.95, 5.70-5.90 yu, 7.35, 7.50; 1l, 8.61 y 9.35>, 10.06 lF, 10.34 y and 11.65.



   The resulting filtrates are evaporated and the remaining oil is distilled under high vacuum, the excess of dimethyl azo-dicarboxylate being recovered by distillation, boiling point about 900 / 0.5 mm Hg. The red viscous oil that remains is dissolved in 4000 ml of ethyl acetate and extracted 4 times with 1500 ml of ice-cold 0.1 N sodium hydroxide solution and then washed 3 times with 2000 ml of ice-cold water. After drying over magnesium sulfate, the organic solution is evaporated and a clear yellow viscous oil is obtained, which crystallizes by adding hexane and a small amount of ether.

  The crystalline product is washed with a 7: 3 mixture of hexane and ether and dried; this gives a further amount of L-2,2-dimethyl-3-tert-butyloxycarbonyl-5p- (N, N'-carbomethoxyhydrazino) -thiazolidine-4-carboxylic acid methyl ester, further material being able to be isolated from the mother liquor .



   Example 2
A mixture of 2.39 g of L-2,2-dimethyl-3-tert.butyl- oxycarbonyl-thiazolidine -4-carboxamide and 10 g of azo-dicarboxylic acid diethyl ester is heated for 12 hours at 1000 and the excess of the azo-dicarboxylic acid diethyl ester distilled off under reduced pressure at 900. The residue is in turn dissolved in 9 g of the azo-dicarboxylic acid diethyl ester by heating and the mixture is heated at 105-1100 for 17 hours. The excess of the azo-dicarboxylic acid diethyl ester is distilled off and the residue is chromatographed on a column of 100 g of anhydrous silica gel loaded with benzene.



   Fractional solvent volume weight ions (in ml) (in g)
1 benzene 250 0.46
2 do. 250 0.22
3 benzene containing 200 0.01
10% ethyl acetate
4 do. 200 0.03
5 benzene containing 200 0.28
20% ethyl acetate
6 do. 200 0.58
7 do. 200 0.68
8 do. 200 0.4
9 do. 200 0.48
10 do. 200 0.36
11 do. 200 0.25
12 do. 200 0.28
13 do. 200 0.28
14 do. 200 0.23
15 do. 200 0.16
16 do. 200 0.14
17 benzene containing 200 0.21
30% ethyl acetate Fractions 7 and 8 are taken together and recrystallized from hexane and a small amount of methylene chloride; the product obtained is the hydrazodicarboxylic acid diethyl ester, mp 134.

 

   The crystallization mother liquor is combined with fractions 9-15 of the chromatogram. Fractions 16 and 17 are taken together and chromatographed on 12 g of aluminum oxide (activity IV), the fraction (0.196 g) eluted with 50 ml of methylene chloride after prewashing with 50 ml of benzene, with the mother liquor and fractions 9-15 together at 135 g Aluminum oxide (activity IV) is chromatographed again.



   Fractional solvent volume weight ions (in ml) (in g)
1 benzene 250 0.03
2 do. 250 0.01
3 benzene containing 250 0.15
5% ethyl acetate
4 do. 250 0.29
5 do. 250 0.18
6 do. 250 0.16
7 benzene containing 250 0.35
10% ethyl acetate
8 do. 250 0.34
9 benzene containing 250 0.61
20% ethyl acetate
10 do. 120 0.14
11 do. 250 0.17
12 do. 250 0.05 Fractions 9-12 and the fraction eluted by repeated chromatography of fractions 16 and 17 of the first chromatogram using 50 ml of methylene chloride containing 10% ethyl acetate are combined;

   the L-2,2-dimethyl-3-tert-butyloxycarbonyl-5p- (N, N'-dicarbethoxyhydrazino) -thiazolidine-4-carboxamide of the formula obtained in this way
EMI8.1
 is a glassy material, [a] = + 210 + 10 (c = 0.98 in chloroform); Infrared absorption bands (in methylene chloride) at 2.85, 2.95, 5.85, (broad), 6.25, 7.35 p, 7.45 L, 8.18, 8.60, 9.25 FL and 9.45. After renewed chromatography on aluminum oxide (activity IV), a further amount of the desired product is obtained from fractions 7-8 of the second chromatogram.



   Example 3
A solution of 2.082 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxamide in 8.15 g of dimethyl azodicarboxylate is heated at 1050 for 45 hours. The excess of the azo-dicarboxylic acid dimethyl ester is distilled off at about 800 / 0.5 mm Hg, the residue is taken up in 1000 ml of methylene chloride and the solution is washed 3 times with 50 ml of water. After evaporation, a viscous product is obtained which is chromatographed on 240 g of a diatomaceous earth preparation.

  The desired L-2,2-dimethyl-3-tert-butyloxycarbonyl-5p- (N, N'-dicarbomethoxy-hydrazino) -thiazolidine-4-carboxamide is eluted with a 1: 1 mixture of benzene and ethyl acetate and the eluate was again chromatographed on 85 g of a diatomaceous earth preparation (Florisil).



  The product of the formula obtained
EMI8.2
 is dried in a high vacuum at 500; it is amorphous, = = +180 t 1.50 (c = 1.518 in chloroform); Infrared absorption bands (in methylene chloride) at 2.85, 2.95, 5.75-5.90>, 6.25. 6.72, 6.95! 19 7.05 y 7.25, 7.35-7.50p, 8.15, 8.6211, 9.25p, 9.4 41, 10.30.



  and 11.63 p.



   Example 4
A mixture of 3.5 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid-N-methyl-N-phenylsulfonylamide and 10.5 ml of azo-dicarboxylic acid dimethyl ester is for 65 - Heated at 1050 for 70 hours.



  After cooling, the excess of the azo-dicarboxylic acid dimethyl ester is removed at 60-700 / 0.1 mm Hg and the red oil obtained as residue is chromatographed on a column of 320 g of a diatomaceous earth preparation (Florisil). With benzene and 98: 2 and 95: 5 mixtures of benzene and the like Ethyl acetate (total 1500 ml) only traces are eluted.

  With 2200 ml of a 9: 1 mixture of benzene and ethyl acetate, the main part of the desired L-2,2-dimethyl-3-tert-butyloxycarbonyl-5c- (N, N'-dicarbomethoxy-hydrazino) -4-carboxylic acid-N is obtained -methyl-N-phenylsulfonyl-amide of the formula
EMI8.3
 which after crystallization from a mixture of ether and hexane melts at 161-1630; [α] 20 D = +81 + 10 (c = 1.065 in chloroform);

  Infrared absorption bands (in methylene chloride) at 2.95, 5.70 (shoulder), 5.84, 5.94 (shoulder), 7.48, 8.18, 8.55, 9.33 and 11.65 p; Ultraviolet absorption bands (in ethanol) zAmax 224 mp (E = 11,200), 260 mp (E = 1100), 267 m (E = 1350) and 2.73 miu (E = 1100).



   Example 5
A solution of 2.58 y of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolide-4-carboxylic acid methyl ester in 14 g of azo-dicarboxylic acid diethyl ester is heated at 1200 in an oil bath for 30 hours. The excess of the reagent azo-dicarboxylic acid diethyl ester is distilled off at 1000 / 0.1 mm Hg and the red, viscous residue is dissolved in 60 ml of warm benzene. The solution is chromatographed on a column containing 220 g of a diatomaceous earth preparation in benzene. No material is eluted with 300 ml of benzene and a small amount of unreacted starting material is eluted with 500 ml of a 19: 1 mixture of benzene and ethyl acetate.

  With 1950ml of the 19: 1 mixture of benzene and ethyl acetate, the L-2,2-dimethyl -3- tert is obtained. butyloxycarbonyl-5p- (N, N'-dicarbethoxy-hydrazino) -thiazolidine-4-carboxylic acid methyl ester of the formula
EMI8.4
 as a colorless syrup, [α] D = +910 + 10 (c = 1.12 in chloroform); Infrared absorption bands (in methylene chloride) at 2.95>, 5.70 y, 5.83 in, 7.35>, 7.52 u, 8.25, 8.60 and 9.45,.



   Example 6
A mixture of 2.8 g of L-2,2-dimethyl-3-tert-butyl oxycarbonyl-thiazolidine-4-carboxylic acid-2,2,2-trichloroethyl ester and 12 g of azo-dicarboxylic acid dimethyl ester is added for 47 hours 1000 heated. The excess of azo-dicarboxylic acid dimethyl ester is distilled off at 1000 / 0.1 mm Hg and the orange gummy residue is chromatographed on 240 g of a diatomaceous earth preparation (Florisil).

  Using benzene containing 5% ethyl acetate, first a small amount of the starting material and then the desired L-2,2-dimethyl-3-tert-butyloxycarbonyl-5p - (N, N'-dicarbomethoxy-hydrazino) -thiazolidine-4- 2,2,2-trichloroethyl carboxylic acid ester of the formula
EMI9.1
 eluted as an oil, CX] D20 = +630 (c = 1 in chloroform); Infrared absorption bands (in methylene chloride) at 2.90 y and 5.80 y (broad).



   Example 7
A mixture of 2.208 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine -4-carboxylic acid methyl ester and 4.57 g of azodicarboxylic acid 2,2,2-trichloroethyl ester in 5 ml of chlorobenzene is added for 24 hours heated at a bath temperature of 1200. After evaporation under reduced pressure, the reaction mixture is diluted with toluene and benzene and the solvents are evaporated again. The residue obtained is chromatographed on 400 g of aluminum oxide (activity II) in benzene.

  Unreacted L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid methyl ester is eluted with 700 ml of 99: 1 to 93: 7 mixtures of benzene and ethyl acetate; further elution with a total of 600 ml of 91: 9 to 86-14 mixtures of benzene and ethyl acetate gives the desired L -2,2-dimethyl-3-tert. butyloxycarbonyl-5p- = LN, N '- di- (carbo-2,2,2-trichloroethoxy) hydrazino] thiazolidin-4-carboxylic acid methyl ester of the formula
EMI9.2
 which as a non-crystalline product infrared absorption bands (methylene chloride) at 2.97, u, 3.4211, 5.65 p (shoulder), 5.77y, 5.90cm, 6.75So, 7.38, 7.54y, 8, 33, 9.10, 9.60 Se,

   and 10.1011 shows. Another amount of the desired product can be eluted with a total of 1100 ml of 82:18 to 60:40 mixtures of benzene and ethyl acetate.



   The azo-dicarboxylic acid 2,2,2-trichloroethyl ester used in the above example is prepared as follows:
To 270 g of liquid phosgene, 194 ml of trichloroethanol are added at -300 without a reaction taking place. The reaction mixture is diluted with 500 ml of absolute tetrahydrofuran at the same temperature and then treated dropwise at -400 with 162 ml of pyridine, which results in the immediate precipitation of pyridine hydrochloride. Shortly before the end of the addition of the pyridine, the reaction mixture warms up from -30 to +350 within 30 seconds; the reaction is stopped by immersing the reaction vessel in a mixture of acetone and dry ice. The reaction mixture is then stirred under a nitrogen atmosphere for one hour with cooling in the cooling mixture and for 18 hours at room temperature.

  After filtering the colorless crystals, they are washed with 1500 ml of absolute ether and the cloudy organic solution is filtered through an approximately 2-3 cm thick layer of magnesium sulfate, concentrated under reduced pressure and distilled. The 2,2,2-trichloroethyl chloro-carbonate is obtained at 52-530 / 9-10 mm Hg.



   About half of 211.87 g of the chlorocarboxylic acid -2,2,2-trichloroethyl ester are slowly added over 30 minutes to an ice-cold solution of 27.5 g of hydrazine hydrate in 250 ml of ethanol, the temperature of the reaction mixture being kept at 10-160 becomes. After dilution with 175 ml of ethanol, the second half of the starting material is added dropwise at the same time as 53 g of sodium carbonate in 100 ml of water (addition time 20 minutes; temperature 15-200). After adding a further 20 ml of ethanol and 50-75 ml of water, the mixture is stirred at 10-150 for 30 minutes.



  The mixture is slightly acidic. and 50 ml of a saturated sodium carbonate solution are added (pH about 7). After stirring for a further 30 minutes, the mixture is extracted 3 times with 250 ml each time and then with 100 ml of methylene chloride; the combined organic extracts are dried over magnesium sulfate and evaporated (600 /
10 mm Hg; then 600 / 0.1 mm Hg). A colorless oil is obtained which crystallizes immediately and is dissolved in 500 ml of boiling cyclohexane; after cooling, the colorless crystalline hydrazodicarboxylic acid -2,2,2-trichloroethyl ester is obtained, which is dried at 700/10 mm Hg for 48 hours and, after recrystallization from cyclohexane, melts at 105-1070.



   To an ice-cold mixture of 114.9 g of hydrazodicarboxylic acid 2,2,2-trichloroethyl ester in 300 ml of chloroform and 60 ml of nitric acid (d = 1.4), 90 ml of fuming nitric acid are added over 10 minutes with ice cooling and stirring. The reaction mixture is stirred for 4 hours in an ice bath, the aqueous phase is extracted with 100 ml of chloroform and the combined organic solutions are washed 6 times with 150 ml of ice water each time. After adding 150 ml of absolute ether, drying over magnesium sulfate and evaporation, the residue crystallizes and is left to stand in the dark for a week, nitrogen-containing gases being removed from time to time under reduced pressure.

  Recrystallization from about 500 to 600 ml of boiling hexane gives the desired 2,2,2-trichloroethyl azo-dicarboxylate, which, after recrystallization from hexane, melts at 109.5-110.50; Infrared absorption bands (methylene chloride) at 5.59 y, 7.32, 8.33 at 9.45, 9.85 ju and 12.30 u; Ultraviolet absorption bands (cyclohexane) #max = 415 mm (= 35). A further amount of the desired product can be obtained from the mother liquor.



   Example 8
To a solution of 2.82g L-2,2-dimethyl-3-tert. butyloxycarbonyl-5p- (N.N '- dicarbethoxy-hydrazino) -thiazolidine-4-carboxylic acid methyl ester in 20 ml of dioxane and 10 ml of water are added in a nitrogen atmosphere and at room temperature for 18 hours 7 ml of 1N aqueous sodium hydroxide solution with stirring. After a further 9 hours, the reaction mixture is diluted with 150 ml of water, then extracted with 150 ml and with 100 ml of ether, and the organic extracts are washed with 100 ml of water. The aqueous solutions are combined, acidified by adding 3 g of citric acid and extracted 3 times with 100 ml of methylene chloride each time.

  The organic extracts are washed with water, dried and evaporated and the oily L-2,2-dimethyl-3-tert.butyloxycarbonyl -5- (N, N'-dicarbethoxy-hydrazino) -thiazolidine-4-carboxylic acid is obtained formula
EMI10.1
    [X] 20 D = +710 # 10 (c = 1.109 in chloroform); In infrared absorption bands (methylene chloride) at 2.96! J, 5.72, u (shoulder), 5.86 z (broad), 7.34 u, 8.64, 8.96, u,
9.24 and 11.51.



   By re-esterification of 0.19 g of the obtained
Acid with diazomethane in ether gives the L-2,2-dimethyl-3-tert. butyloxycarbonyl-5p - (N, N '- dicarbeth- oxyhydrazino) -thiazolidine-4-carboxylic acid methyl ester, IZ] D20 = +760 + 10 (c = 0.877 in chloroform), its
Infrared spectrum with that of the product obtained according to Example 5 is identical.



   Example 9
To one kept under a nitrogen atmosphere
Solution of 5.06 g of L-2,2-dimethyl-3-tert.butyloxycarbo nyl - 5p - (N, N '- dicarbomethoxyhydrazino) -thiazolidine-4-carboxylic acid methyl ester in 40 ml of dioxane and 20 ml
12.8 ml of 1N aqueous sodium hydroxide solution, 0.2 ml each time, are added to water with stirring over the course of 20 hours. After stirring for a further 24 hours at room temperature, the solution is carefully concentrated after adding about 50 ml of water in a cold water bath, then washed twice with 100 ml of ether, treated with ice and with a 10% solution of
Citric acid acidified to pH about 3. The acidic solution is extracted 3 times with 200-250 ml of methylene chloride each time, and the organic extracts are dried over magnesium sulfate, filtered and evaporated.

  The white, amorphous L-2,2-dimethyl-3-tert.butyloxycarbonyl-Sf3 - (N, N'-dicarbomethoxyhydrazino) -thiazolidine-4-carboxylic acid of the formula is obtained in this way
EMI10.2
 which is dried for a few hours under high vacuum at 800, and crystallized from a small amount of ether or methylene chloride; after recrystallization from a mixture of methylene chloride and cyclohexane, it melts at 1740 (decomposition); [jn = +860 + 10 (c = 1.32 in chloroform);

  Infrared absorption bands (methylene chloride) at 2.95u, 3.0-4.0, u (broad), 5.7-5.9y (broad), 7.35-7.61l (broad), 8.65 Su, 8.95, 9.40, u, 10.35 and 11.511
Example 10
To a solution of 1.15 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-5 - (N, N'-dicarbomethoxy-hydrazino) -thiazolidine-4-carboxylic acid in 20 ml of anhydrous benzene, 0.42 ml of triethylamine and 0.42ml benzenesulfonyl isocyanate added. The reaction mixture is stirred at room temperature with exclusion of moisture, then poured into a solution of 0.6 g of citric acid in 80 ml of water and the aqueous solution is extracted 3 times with methylene chloride.

  The organic extracts are washed with water, dried and evaporated and the crude product obtained is purified by means of countercurrent distribution (6 separating funnels; lower and upper phase each 80 ml) between benzene and phosphate buffer (pH 6). Fractions 1-3 are combined and crystallized from a mixture of ether and hexane; the pure L-2,2-dimethyl-3-tert.butyloxycarbonyl-5p- (N, N'-dicarbomethoxyhydrazino) -thiazolidine-4-carboxylic acid N-phenylsulfonyl amide of the formula is obtained in this way
EMI10.3
 its analytical preparation melts at 113 - 1170; [] 20 D = -100 + 10 (c = 0.932 in chloroform);

  Infrared absorption bands (methylene chloride) at 2.9611, 5.85 IL and 7.22; Ultraviolet absorption bands (ethanol) imax = 222 mm (s = 11100), 2.60 m (± = 8000), 2.66 m = = 1100) and 2.73 m (s = 900).



   Example 11
A mixture of 2 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid-N-acetyl-amide and 7 g of azo-dicarboxylic acid diethyl ester is increased to 1000 for 15 hours, then for 22 hours heated to 1100. The excess of azo dicarboxylic acid diethyl ester is distilled off and the residue is chromatographed on 100 g of silica gel. The crude product is eluted with a 9: 1 mixture of benzene and ethyl acetate and chromatographed again on silica gel for further purification.

  The L-2,2-dimethyl-3-tert-butyloxycarbonyl-5,, 8 - (N, N'-dicarbethoxy-hydrazino) -thiazolidine-4-carboxylic acid-N-acetyl-amide of the formula
EMI11.1
 is obtained as a colorless oil; characteristic infrared absorption bands (in methylene chloride) at 2.99 p (broad), 5.85 (broad) with 6.10 (shoulder), 7.36 i, 8.25, S, 65 and 9.5.



   Example 12
A mixture of 0.698 g of L-2,2-dimethyl-3-tert.butyl oxycarbonyl-thiazolidine-4-carboxylic acid 2,2,2-trichloroethyl ester and 1.01 g azo-dicarboxylic acid di-2,2, 2-trichloroethyl ester is heated for 43 hours at 1200 in 3 ml of chlorobenzene with exclusion of moisture. After repeated dilution with toluene and benzene and evaporation of the solvent each time, the residue is chromatographed on 160 g of slightly basic aluminum oxide (activity II, absorbed with benzene).



  The amorphous L -2,2-dimethyl-3-tert-butyloxycarbonyl -SP- (N, N'-dicarbo-2,2,2-trichloroethoxy-hydrazino) -thiazolidin-4-carboxylic acid-2,2,2 -trichloroethyl ester of the formula
EMI11.2
 is eluted with a total volume of 350 ml of a 93: 7 mixture of benzene and ethyl acetate after removal of unreacted starting material by means of 50 ml fractions of a total volume of 300 ml of 99: 1 to 94: 6 mixtures of benzene and ethyl acetate.

  The product obtained shows infrared absorption bands (in chloroform) at 2.97, p, 5.6611, 5.76, 5.90>, 6.75, 7.36, 7.56, 8.30 u and 9.10 , u; IM] D = +290 + 10 (c = 0.68 in chloroform).



   Example 13
A solution of 0.407 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-5ss- (N, N'-dicarbomethoxy-hydrazino) -thiazo lidine-4-carboxylic acid and 0.1391 g of p-nitrophenol in 12 ml of methylene chloride 0.206 g of dicyclohexylcarbodiimide are added; an immediate yellow coloration occurs and the N, N'-dicyclohexylurea begins to precipitate. After standing for 4 hours at room temperature, the mixture is filtered, the filtrate is evaporated and the residue is taken up in a mixture of ether and methylene chloride and the urea compound is filtered off. The filtrate is evaporated and the residue is chromatographed on 25 g of a diatomaceous earth preparation (Florisil).

  After washing with benzene, the desired L -2,2-dimethyl-3-tert. butyloxycarbonyl -5- (N, N'-dicarbomethoxy) -thiazolidine-carboxylic acid 4-nitrophenyl ester of the formula
EMI11.3
 by eluting with 250 ml of benzene containing 5% ethyl acetate, obtained as a viscous yellowish oil; Infrared absorption bands (in methylene chloride) at 2.95, 5.6711, 5.85 (broad), 6.27, 6.53y, 6.70, 7.45>, 8.33>, 8.65, 8.87 y 9.35, 9.8711, 10.65 and
11.6011.



   The above product is also obtained by heating a mixture of 0.765 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-3-carboxylic acid 4-nitrophenyl ester and 3 g of azo-dicarboxylic acid dimethyl ester to 1000 for 36 hours. The excess of the azodicarboxylic acid ester is distilled off and the residue is chromatographed on 80 g of a diatomaceous earth preparation (Florisil). The L-2,2-dimethyl-3-tert.butyloxycarbonyl -5 ss- (N, N '- dicarbomethoxy-hydrazino) -thiazolidine-4-carboxylic acid-4-nitrophenyl ester is after washing with benzene by eluting with benzene, containing 5% ethyl acetate, obtained and is identical to the product described above.



   The required starting material is obtained as follows:
A solution of 2.61 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid in 40 ml of methylene chloride is mixed with 1.39 g of 4-nitrophenol and the resulting solution is treated with 2.12 g of dicyclohexylcarbodiimide . After a few minutes, the N, N'-dicyclohexylurea begins to precipitate; the reaction mixture is kept at room temperature for 16 hours, then filtered and the filtrate is evaporated together with the methylene chloride washing liquids under reduced pressure. The oily residue is dissolved in 25 ml of benzene, a further amount of N, N'-dicyclohexylurea is filtered off and the benzene solution is evaporated. The residue is chromatographed on 100 g of silica gel containing 5% water and prepared with benzene.

  After pre-washing with 250 ml of benzene containing 4% ethyl acetate, the desired L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid 4-nitrophenyl ester of the formula
EMI11.4
  eluted as a yellowish oil with 250 ml of benzene containing 10% ethyl acetate.



   Example 14
In a manner similar to that described above, i. By adding an azodicarboxylic acid ester to the acid derivative or converting an acid-azodicarboxylic acid diester adduct into an acid derivative-azodicarboxylic acid diester adduct, the following compounds can be produced using the appropriate starting materials:

  : N-IL-2,2-dimethyl-3-tert-butyloxycarbonyl-5 - (N, N'-di-carbomethoxy-hydrazino) -4-thiazolidinyl-carbonyloxy] - -carbamic acid methyl ester; N-IL-2,2-dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-dicarbomethoxy-hydrazino) -4-thiazolidinyl-carbonyloxy] - -succinimide; L-2,2-dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-dicarbo-methoxy-hydrazino) -thiazolidine-4-carboxylic acid azide; L-2,2-dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-dicarb-ethoxy-hydrazino) -thiazolidine-4-carboxylic acid-N'-2,4-di-nitrophenyl-hydrazide; N- [L-2,2-dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-di-carbomethoxy-hydrazino) -4-thiazolidinyl-carbonyl] -triphenyl-phosphinimine;

  ; L-2,2-Dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-dicarbo-methoxy-hydrazino) -thiazolidine-4-carboxylic acid-N, N-di-acetyl-amide; L-2,2-dimethyl-3-tert-butyloxycarbonyl-4-cyano-5- (N, N'- dicarbethoxy-hydrazino) -thiazolidine; L-2,2-dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-dicarbo-methoxy-hydrazino) -thiazolidine-4-carboxylic acid-N'-trityl-hydrazide; L-2,2-dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-dicarbomethoxy-hydrazino) -thiazolidine-4-carboxylic acid-N-benzyloxy-amide; L-2,2-dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-dicarbo-methoxy-hydrazino) -thiazolidine-4-carboxylic acid-N-cyclohexyl-N- (N-cyclohexylcarbamyl) -amide; L-2,2-dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-dicarbomethoxy-hydrazino) -thiazolidine-4-carboxylic acid-N-hydroxy-amide;

  ; L-2,2-dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-dicarbomethoxy-hydrazino) -thiazolidine-4-carboxylic acid-N- (4-methoxybenzoyloxy) -amide; L-2,2-dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-dicarbomethoxy-hydrazino) -thiazolidine-4-carboxylic acid-N'- -tert-butyloxycarbonyl-hydrazide; N- [L-2,2-dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-dicarbomethoxy-hydrazino) -4-thiazolidinyl-carbonyl] -N'- tert-butyloxycarbonyl-diimine; L-2,2-dimethyl-3-tert.butyloxycarbonyl-5- (N, N'-dicarbomethoxy-hydrazino) -thiazolidine-4-carboxylic acid -N ', N'-dimethyl-hydrazide; L-2,2-dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-di-carbomethoxy-hydrazino) -thiazolidine-4-carboxylic acid-N- -4-hydroxy-anilide;

  ; L-2,2-Dimethyl-3-tert.butyloxycarbonyl-5- (N, N'-di-carbomethoxy-hydrazino) -thiazolidine-4-carboxylic acid-N- -4-pyridyl-amide; L-2,2-dimethyl-3-tert.butyloxycarbonyl-5- (N, N'-dicarbomethoxy-hydrazino) -thiazolidine-4-carboxylic acid-N'- diphenylmethylene hydrazide; L-2,2-Dimethyl-3-tert-butyloxycarbonyl-5- (N, N'-di-carbomethoxy-hydrazino) -thiazolidine-4-carboxylic acid-N-acetyl-N-acetyloxy-amide, and L-2 , 2-Dimethyl-3-tert-butyloxycarbonyl-5 (N, N'-di-carbomethoxy-hydrazino) -thiazolidine-4-carboxylic acid-N-acetyloxy-amide.



   The starting materials used in the process of the present invention and in particular in the above examples can be prepared as follows: Example I Phosgene is for one hour by a solution of 135 g of L-2,2-dimethyl-thiazolidine-4-carboxylic acid methyl ester and 93 , 2g of dimethylaniline in 1000ml of methylene chloride passed. The temperature is kept at 20 during the reaction. The solvent and the excess of phosgene are carefully removed and a viscous material is obtained which is treated with 500 ml of a 4: 1 mixture of benzene and hexane. After standing at 0 for 10 hours, the mixture is filtered and the filtrate is washed with water and dried over magnesium sulfate.

  The solvent is removed under reduced pressure and the L-2,2-dimethyl-3-chlorocarbonyl-thiazolidine-4-carboxylic acid methyl ester is obtained as a viscous oil which boils at 95 / 0.05 mm Hg; [α] 20 D = 69 (c = 1.20 in chloroform); characteristic infrared absorption band at 5.57 (film).



   A solution of 0.898 g of the product obtained in 18 ml of tert-butanol (distilled over calcium hydride) is heated at 100 in a closed vessel for 12 hours. After evaporation under reduced pressure, a yellow glass-like material is obtained, which is dissolved in 20 ml of methylene chloride. The solution is extracted once with 10 ml of a saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated. The yellow oil thus obtained is chromatographed on 15 g of anhydrous silica gel; the column is washed with 50 ml of benzene and then with benzene which contains 50% ethyl acetate.

  The first 25 ml of the solvent mixture contains no material; a colorless oil is eluted with the following 60 ml. The L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid methyl ester of the formula obtained in this way
EMI12.1
 boils at 92-96 / 0.01 mm Hg; Cu1.20 = 77 (c = 1.50 in chloroform), infrared absorption bands (film) at 5.74p, 5.90p and 7.35>; F. 18.5-21.

 

   Example 11
A solution of 134 g of methyl iodide in 100 ml of ether is added to a suspension of 22.6 g of magnesium in 200 ml of ether with stirring. The reaction mixture is then heated for one hour at 40 and under an atmosphere of nitrogen. With vigorous stirring, 74 g of tert-butanol in 100 ml of ether are added dropwise to the methyl magnesium iodide solution and, after the addition, this is diluted with a further 950 ml of tert-butanol; the mixture is heated at 400 for one hour. 160 g of L-2,2-dimethyl-3-chlorocarbonyl-thiazolidine-4-carboxylic acid methyl ester in 200 ml of ether are then slowly added and the mixture is kept at 400 for 25 hours under an atmosphere of nitrogen.

  Most of the solvent is removed under reduced pressure at 400; the residue is diluted with 1000 ml of ice water and extracted 4 times with 500 ml portions of ether. The combined ether extracts are dried over magnesium sulfate and, after evaporation of the solvent, a viscous oil is obtained which, dissolved in 200 ml of benzene, is adsorbed on 2000 g of silica gel (anhydrous).



  The desired L-2,2-dimethyl-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid methyl ester is eluted with benzene containing 5% ethyl acetate; the product boils at 92-960 / 0.01 mm Hg and crystallizes on standing at -100.



   The intermediate used in Example I above is obtained as follows:
A suspension of 80 g of L-cysteine methyl ester hydrochloride in 1250 ml of acetone is heated under reflux for 4 hours while stirring. The reaction mixture is stirred for a further 2 hours at room temperature, the crystalline material is filtered off and carefully washed with 500 ml of acetone. After drying and recrystallization from a 5: 1 mixture of acetone and methanol, the desired L -2,2-dimethyl-thiazolidine-4-carboxylic acid methyl ester hydrochloride melts at 131.5-134.50 (decomposition): [z] D = -700 + 0.50 (c = 1.97 in methanol); Infrared absorption bands (potassium bromide) at 5.76, 7.50 7.501L and 8.0211.



   173.8 g of L-2,2-dimethylthiazolidine-4-carboxylic acid methyl ester hydrochloride are carefully added in small portions to a mixture of 69 g of sodium bicarbonate, 500 g of ice water and 500 ml of methylene chloride. The mixture is stirred, the methylene chloride phase is separated off and the aqueous solution is extracted twice with 200 ml of methylene chloride each time. The combined organic solutions are dried over magnesium sulfate and evaporated under reduced pressure.



  The oil obtained is distilled in vacuo and the L-2,2-dimethyl-thiazolidine-4-carboxylic acid methyl ester is obtained, which boils at 520 / 0.4 mm Hg; [oiD = - 1890 (c = 1.63 in chloroform); Infrared absorption bands (film) at 3.05, 5.75tj, 7.00, a and 7.5.



   Example 111
A solution of 25 g of L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid in 100 ml of dry ether, containing 1 ml of methanol, is treated in portions with an ethereal solution of diazomethane while cooling in an ice bath the yellowish green color persists for 15 minutes. After the solvent has evaporated, the yellowish oil is distilled; the main fraction boils at 91 / 0.15 mm Hg. The methyl L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylate obtained in this way is identical to the product obtained by the method of Example I.



   The above esterification can also be carried out as follows:
A solution of 52.2 g of L-2,2-dimethyl-3-tert-butyl oxycarbonyl-thiazolidine-4-carboxylic acid in 100 ml of dry toluene is mixed with 29.8 g of dimethylformamide dimethylacetal and heated to 1050 for 5 hours under a nitrogen atmosphere heated. After cooling to 0, the reaction mixture is washed twice with 50 ml each of a cold 1N aqueous sodium hydrogen carbonate solution and with water, dried over sodium sulfate and evaporated under reduced pressure.



  Distillation of the oily residue gives L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid methyl ester, boiling point 92-960 / 0.01 mm Hg.



   A small amount of unchanged L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid can be isolated from the alkaline extract by carefully acidifying it at OO and extracting it with ether.



   The L-2,2-dimethyl -3- tert used as starting material. butyloxycarbonyl-thiazolidine-4-carboxylic acid is obtained as follows:
A mixture of 1800 ml of methylene chloride, 144 ml of dry tert-butanol and 72 ml of dry pyridine is cooled to -740 under a nitrogen atmosphere. While stirring vigorously, 72 g of phosgene are added over the course of an hour, the temperature being kept at -710 to -740 and no gas evolution taking place. The reaction mixture turns slightly yellow and pyridine hydrochloride begins to precipitate. The mixture is stirred for 15 hours at 740 and under a slow stream of nitrogen; the mixture becomes colorless again.

  A further 72 ml of absolute pyridine and an hour later 57.6 g of powdered L-2,2-dimethyl-thiazolidine-4-carboxylic acid, the latter all at once, are then added. It is washed with a further 72 ml of absolute pyridine; During the addition, care is taken to ensure that air humidity is excluded.



   The reaction mixture is stirred for 21/2 hours at -740 and under a nitrogen atmosphere; the cooling bath is then replaced by an ice bath. After an internal temperature of 0 has been reached, the mixture is kept at this temperature for a further 21/2 hours, after which the ice bath is removed and the mixture is stirred for a further hour; it turns slightly yellowish in turn. The reaction mixture is poured onto a mixture of 2700 g of ice and an ice-cold solution of 180 g of sodium hydroxide and the reaction vessel is washed out with 3600 ml of a 1: 1 mixture of benzene and ether; the washing liquid is combined with the aqueous mixture and stirred for 10 minutes, with discoloration occurring.

  The organic phase is separated off and washed with 3 portions of 480 ml each of ice-cold 2N sodium hydroxide solution. The combined alkaline extracts are washed 5 times with 1400 ml of methylene chloride each time, cooled with ice, mixed with 1800 ml of cold methylene chloride and adjusted to pH 4 with solid citric acid while stirring. After the aqueous phase has been separated off, it is extracted with 3 portions of 1800 ml of methylene chloride each, the combined extracts are dried over sodium sulfate and the colorless solution is evaporated under reduced pressure at a bath temperature of 450. The pale yellowish oil obtained is dried for one hour at a pressure of 0.5 mm Hg, dissolved in about 1000 ml of warm pentane and the solution is concentrated to about 300 ml.

  After standing for several hours at room temperature, the L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid of the formula is obtained
EMI14.1
 in crystalline form. It melts at 114 - 114.50, TOS} D20 = - 800 (c = 1.34 in chloroform), and is washed with pentane at room temperature. A further amount of the desired acid is obtained from the mother liquor by chromatography.



   The L-2,2 - dimethyl-3-tert. butyloxycarbonyl-thiazolidine-4-carboxylic acid can be obtained from its esters as follows:
To a solution of 11.5 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid methyl ester in
80 ml of p-dioxane and 10 ml of water are added 41.6 times 1N aqueous potassium hydroxide solution over a period of 21 hours. The reaction mixture is stirred for a further 20 hours at room temperature and in a nitrogen atmosphere. Most of the solvent is evaporated at room temperature under reduced pressure and the residue is mixed with 20 ml of water. The aqueous solution is extracted with ether, acidified with citric acid at 0 and then extracted with ether.

  The ether extract is washed with water, dried over magnesium sulfate and evaporated at room temperature under reduced pressure. The viscous material crystallizes spontaneously and the pure 2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid is obtained by crystallization from 100 ml of hexane, mp 114-114.5; [Z] 20 D = 850 (in chloroform); Infrared absorption bands at 5.80 lot and 5.951 s (in chloroform), and 5.70 lot and 5.97 lt (potassium bromide). Another amount of the product is obtained from the mother liquor.



   Example IV
A mixture of 0.97 g of L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid and 0.338 g of N -hydroxy-carbamic acid methyl ester in 25 ml of methylene chloride is slowly stirred over 5 minutes with a solution of 0.78 g of dicyclohexylcarbodiimide in about 5 ml of methylene chloride are added. After about 2 minutes the N, N'-dicyclohexylurea begins to precipitate and, after stirring for 16 hours, the precipitate is filtered off and washed with dry benzene. By concentrating the filtrate, a further amount of urea precipitates out and is filtered off; the filtrate is evaporated at 500/12 mm Hg and then at 500 / 0.1 mm Hg and a colorless viscous material is obtained which crystallizes spontaneously.

  Recrystallization from a methylene chloride-hexane mixture at -180 gives the methyl L-N- (2,2-dimethyl-3-tert-butyloxycarbonyl-4-thiazolidinyl-carbonyloxy) -carbamic acid methyl ester of the formula
EMI14.2
 which, after recrystallization from hexane, melts at 112 to 112.20; [a] = -1220 (c = 0.734 in chloroform); Infrared absorption bands (in methylene chloride) at 2.98p, 5.69, 5.94p, 7.40F, 8.6311, 9.04, u, 9.38, 10.6011 and 11.66 p.



   Example V
A solution of 4.55 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid and 10 g of trichloroethanol in 10 ml of methylene chloride and 6 drops of pyridine is mixed with a solution of 3.62 g of dicyclohexylcarbodiimide in 10 ml of methylene chloride were added. After 16 hours, the dicyclohexylurea formed is filtered off, the filtrate is evaporated and the residue is treated with benzene. The insoluble fraction is filtered off; the filtrate is adsorbed on 240 g of a diatomaceous earth preparation.

  The desired L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid 2,2,2-trichloroethyl ester of the formula
EMI14.3
 is eluted with benzene; the product crystallizes at
Standing and in colorless rods of aqueous methanol, F. 69-710; [aio20 = 700 (c = 1 in chloroform);

  Infrared absorption bands at 5.70, u and 5.94 lot
The L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid can be recovered from the above ester as follows:
To a solution of 0.5 g of L-2,2-dimethyl-3-tert.bu tyloxycarbonyl-thiazolidine-4-carboxylic acid 2,2,2-trichloro-ethyl ester in 10 ml of acetic acid and 3 ml of water
1 g of freshly prepared chromium (II) acetate is given. The reaction mixture is stirred for 2 hours under a carbon dioxide atmosphere at room temperature and then diluted with 100 ml of ether and 80 ml of water. After filtering, the aqueous component is separated off and extracted with 80 ml of ether; the ether solutions are washed twice with water, combined, dried and evaporated.

  The residue obtained is dissolved in 40 ml of ether, the solution is extracted with 2 portions of 20 ml of 0.2 N sodium hydroxide solution and the alkaline extracts are washed with ether, acidified with crystalline citric acid and extracted with 3 portions of 40 ml of methylene chloride each time. The organic solutions are washed with water, dried and evaporated; the crystalline L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine -4-carboxylic acid is thus obtained, which, after recrystallization from pentane, melts at 115 to 1170; GOC] D = -770 + 10 (c = 0.835 in chloroform).



   A solution of 0.14 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid-2,2,2-trichloroethyl ester in 3.5 ml of 90'70 aqueous acetic acid is given 1.5 g zinc dust was added and the mixture was stirred at room temperature for 4 hours. The residue is filtered off and washed with 4 ml of glacial acetic acid; the filtrate is diluted with 200 ml of benzene and washed 5 times with 35 ml of water each time. The organic solution is evaporated in a water jet vacuum, and after recrystallization from pentane, the residue gives L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid, mp 113 to 1150.



   Example VI
To a solution of 1.305 g of L-2,2-dimethyl-3-tert. butyloxycarbonyl-thiazolidine-4-carboxylic acid and 0.575 g of N-hydroxysuccinimide in 15 ml of absolute p-dioxane are added dropwise over 5 minutes while stirring a solution of 1.031 g of dicyclohexylcarbodiimide in 10 ml of absolute p-dioxane. After stirring for 22 hours at room temperature, the N, N'-dicyclohexylurea formed is filtered off and washed with benzene; the filtrate is concentrated and the crystalline L-N- (2,2-dimethyl -3- tert. butyloxycarbonyl -4-thiazolidinyl-carbonyloxy) is obtained from the residue
EMI15.1
 which, after recrystallization from acetone-cyclohexane and methylene chloride-hexane mixtures, melts at 154-1550.

  Additional amounts of the desired product are obtained from the mother liquors.



   Example VII
A solution of 1.305 g of L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid and 0.69 times triethylamine in 10 ml of methylene chloride is cooled to 100 and, with stirring, with a solution of 0.48 kept at 0 ml of ethyl chloroformate treated in 5 ml of methylene chloride. After stirring for one hour at -100, dry gaseous ammonia at -8 to -100 is passed through the suspension for 20 minutes, triethylamine hydrochloride precipitating out. The mixture is slowly brought to room temperature (30 minutes) and, after adding a little methylene chloride, is vented with nitrogen for 30 minutes. After washing twice with 30 ml of water each time, the organic solution is dried over sodium sulfate and evaporated under reduced pressure.

  On heating, the colorless glass obtained crystallizes under hexane and a small amount of methylene chloride and the desired L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidin-4-carboxamide of the formula
EMI15.2
 is recrystallized from hexane and a trace of methylene chloride at - 200 and for analysis from hexane, F.



     113 - 1140; fa] = 910 (c = 1.04 in chloroform); Infrared absorption bands (methylene chloride) at 2.83, 2.93, u, 5.90>, 6.35, 7.32 tL and 7.45 Il.



   Example Vlll
0.2 g of the above dispersion of sodium hydride in mineral oil is added to a mixture of 0.5 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxamide and 10 ml of anhydrous benzene. The mixture is at room temperature and with the exclusion of v. Humidity was stirred for one hour and then 10 ml of a solution of 2 ml benzenesulfonyl chloride, diluted with absolute benzene to 50 ml, were added dropwise and with stirring for 20 minutes and with the exclusion of moisture.



  The reaction mixture is stirred for a further 2 hours, diluted with 30 ml of benzene and washed 3 times with 50 ml of ice-cold 0.2N sodium hydroxide solution each time and once with 15 ml of water. The insoluble material is filtered off and combined with the cold aqueous washing liquid. 100 ml of benzene are added to the aqueous mixture and this is acidified with about 65 ml of 2N sulfuric acid. The aqueous phase is extracted once with 75 mol of a 1: 1 mixture of benzene and ether and the combined organic extracts are washed with 75 ml of water, dried and evaporated.

  The resulting crude L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine -4-carboxylic acid-N-phenylsulfonylamide of the formula
EMI15.3
 is triturated with ether; the pure product is thus obtained, which melts at 1690; [io = - 1110 + 10 (c = 0.981 in chloroform); Infrared absorption bands (in methylene chloride) at 2.98, 5.80p, 5.85, 6.08, 7.23p, 7.34u, 7.43>, 7.50>, 8.46, 8, 59 8.59, u and 9.23, u; Ultraviolet absorption bands (in methanol) lmax 223 mu (± = 10600), 2.60 mm (± = 870), 2.66 mm (± = 1080) and 2.73 m (± = 895).

 

   Example IX
A solution of 2.61 g of L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid in 50 ml of anhydrous benzene is mixed with 1 ml of triethylamine and then with 20 ml of a solution of 2 ml of distilled benzenesulfonyl isocyanate , diluted to 25 ml with anhydrous benzene, added, the second reagent being added all at once. The reaction mixture is left to stand for 3 hours at room temperature with exclusion of moisture, a slightly exothermic reaction and a slow evolution of carbon dioxide being observed at the beginning.

  The reaction mixture is diluted with 100 ml of ether, washed twice with 30 ml of cold 0.1 N sodium hydroxide solution each time and once with water; the combined aqueous washing solutions are extracted with 75 ml of ether, adjusted to pH 4 by adding about 4 g of citric acid and extracted 4 times with 100 ml of methylene chloride each time. The organic extracts are washed once with water and evaporated, and by adding ether the desired L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid-N-phenylsulfonyl-amide, m.p. 161 until 1640.



   Example X
2 g of potassium tert-butoxide are added to a solution of 6 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid N-phenylsulfonyl-amide in 30 ml of dimethylformamide and 6 ml of methyl iodide; the mixture is stirred for 2 hours at room temperature and then slowly poured into 900 ml of a saturated aqueous sodium chloride solution with stirring. After a further hour, the precipitate is filtered off, washed with water and taken up in 200 ml of methylene chloride; the organic solution is washed with water, dried and evaporated.

  The pure L-2,2-dimethyl-3-tert is obtained by recrystallization from methylene chloride. butyloxycarbonyl-thiazolidine-4-carboxylic acid-N-methyl-N-phenylsulfonyl-amide of the formula
EMI16.1
 which melts at 153-1540; [α] D = 710 + 10 (c = 0.794 in chloroform); Infrared absorption bands (in methylene chloride) at 5.85 iu, 5.96 7.42, 8.30 8.65, 9.20, u, 9.371l, 9.95 u, 10.62, 10.80,, 11th , 31, and 11.62; Ultraviolet absorption bands (in ethanol) Ar ,, ax 225 m (E = 11,600), 260 mm - = 1160), 267 m (# = 1350) and 273 mJ = 1100).



   Example XI
0.9 g of an approximately 50% dispersion of sodium hydride in mineral oil is added to a solution of 3 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid amide in 75 ml of absolute benzene ; the reaction mixture is stirred at room temperature for one hour and then 16.5 ml of a solution of 2 mol of distilled acetyl chloride, diluted with absolute benzene to a volume of 25 ml, is added over the course of 40 minutes. The temperature rises to about 300; a clear yellow solution is obtained, which is diluted with 75 ml of benzene and then washed with 75 ml of dilute sodium hydrogen carbonate solution and water, the aqueous solutions being backwashed with 75 ml of benzene.

  The benzene extracts are dried over sodium sulfate and evaporated under reduced pressure, the residue is dissolved in 60 ml of dioxane and treated with 30 ml of a 2% strength aqueous potassium carbonate solution. The mixture is stirred overnight at room temperature; the organic fraction is then extracted with 200 ml of a 1: 1 mixture of benzene and ether, the extracts are washed with 75 ml each of a semi-saturated and a saturated aqueous sodium chloride solution and the wash solutions are backwashed with 75 ml of benzene. The combined organic extracts are dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on 80 g of anhydrous silica gel.

  The column is prewashed with 800 ml of hexane, 800 ml of benzene and 800 ml of a 19: 1 mixture of benzene and ethyl acetate; the next 800 ml of the same solvent mixture and 2000 ml of a 9: 1 mixture of benzene and ethyl acetate are taken together and give the L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid-N-acetyl-amide formula
EMI16.2
 which, after crystallization from an ether-pentane mixture, melts at 108-1090; [a] D = 970 + 10 (c = 0.964 in chloroform); Analysis preparation: fo55 = - 1000 + 10 (c = 1.041 in chloroform);

  Infrared absorption bands (in methylene chloride) at 3.0011, 5.70>, 5.8011 (shoulder), 5.88! 1 5.951 (shoulder), 6.05 p (shoulder), 6.85, u, 7.25> and 7.35.



   The mother liquor is combined with the first fractions obtained from the 19: 1 mixture of benzene and ethyl acetate and with the residue of the fraction which is eluted with 400 ml of a 4: 1 mixture of benzene and ethyl acetate, and in an analogous manner on 20 g of anhydrous Chromatographed silica gel again. A further amount of the desired amide is washed out with a 9: 1 mixture of benzene and ethyl acetate.



   Example Xll
A solution of 1.305 g of L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid in 20 ml of dry acetone is stirred and cooled to 60 with 0.69 ml of triethylamine and then dropwise with a cold solution of 0.45 ml of ethyl chloroformate in 10 ml of acetone are added, with 10 ml of acetone being washed. After stirring for 20 minutes at 0, a cold solution of 0.65 g of sodium azide in 5 ml of water and 20 ml of acetone is added to the reaction mixture, which has been cooled to -50 to 30 and which contains the L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine- 4-carboxylic acid carbethoxy ester, added dropwise.

  The cooling bath is then removed and, after stirring for 25 minutes, the solution is diluted with a large excess of ice and water and extracted three times with 100 ml of methylene chloride each time.



  The organic solution is washed three times with water, dried over anhydrous magnesium sulfate and carefully evaporated in a water-jet vacuum. The clear, viscous-oily residue crystallizes spontaneously on scratching and is dried under high vacuum. The L-2,2-dimethyl-3-tert.butyloxycarbonylthiazolidine-4-carboxylic acid azide of the formula is obtained in this way
EMI17.1
 which can be recrystallized from pentane, m.p. 45 to 460; [o50 = 1230 + 10 (c = 1.005 in chloro form); Infrared absorption bands (in chloroform) at 4.65, F, 5.8, 5.9, 5.95, 7.25 s, 7.35 r, 8.55 r and 9.4;

  ; Ultraviolet absorption bands (in n-hexane) #max at 195 m (final absorption E = 16,500) and 209 mlJ (shoulder, E = 10,700).



   Example XIII
To 1.305 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid in 50 ml of freshly distilled acetonitrile, 0.69 ml of triethylamine and then 0.49 ml of ethyl chloroformate in 25 ml of acetonitrile are added dropwise and the reaction mixture was stirred at -50 for 20 minutes. After adding 1.1 g of 2,4-dinitrophenylhydrazine in 150 ml of acetonitrile and washing with 100 ml of the solvent, the mixture is stirred for one hour at 0, a homogeneous solution being obtained which is stirred for a further 3 hours without cooling.



  After dilution with 200 ml of methylene chloride, the reaction mixture is extracted with 50 ml of a cold, saturated sodium hydrogen carbonate solution in water, the aqueous extract is washed with 100 ml of methylene chloride and the combined organic solutions are washed neutral with water. After the solvents have evaporated, the residue is chromatographed on 78 mol of anhydrous silica gel.

  After washing out the acetone 2,4-dinitrophenyl hydrazone and 2,4-dinitrophenyl hydrazine with a benzene-ethyl acetate mixture, the L-2,2-dimethyl-3-tert is obtained with the same solvent mixture. butyloxycarbonyl-thiazolidine-4-carboxylic acid N'-2,4-dinitrophenyl hydrazide of the formula
EMI17.2
 as a viscous, dark yellow oil which crystallizes from a mixture of methylene chloride and hexane and is recrystallized from a methylene chloride-cyclohexane mixture, mp 115-1230 (with decomposition); [iD50 = - 990 + 10 (c = 1.40 in chloroform);

  Infrared absorption bands (in methylene chloride) at 3.0 y, 5.90, 5.95 y, 6.05, 6.20., 6.30 y "7.25, 7.35, 7.50, 7.65, 10.901l, 11.701 and 12X; ultraviolet absorption bands (in ethanol) lmax 259 ml (E = 10000) and 335 mu (E = 14,600).



   Example XIV
A solution of 0.28 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid azide in 4 ml of methylene chloride is slowly mixed with 0.256 g of triphenyl-phosphine in 4 mol of methylene chloride. After standing for 15 minutes, the solvent is removed under reduced pressure and the residue is chromatographed on 20 g of silica gel.

  The fractions obtained after pre-washing with 90 ml of a 98: 2 and 30 ml of a 96: 4 mixture of benzene and methylene chloride with 30 ml of a 96: 4 and 90 ml of a 75:25 mixture of benzene and methylene chloride are obtained on High vacuum dried at room temperature and provide the pure non-crystalline L-N - (2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidinyl-carbonyl) -triphenylphosphine-imine of the formula
EMI17.3
 represents [aio = 810 i 10 (c = 1.13 in chloroform); Infrared absorption bands (in methylene chloride) at 5.88, 6.39a, 7.33, 7.45y,, 8.55 L and 9.00;

  Ultraviolet absorption bands (in ethanol) amide 268 mu (E = 3200), 275 ma (e = 2600) and 355 mu. (e = 1500).



   Example XV
A solution of 1 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid amide in 25 ml of absolute benzene is mixed with 0.3 g of an approximately 50% strength dispersion of sodium hydride at room temperature for 10 minutes stirred and then treated within 15 minutes with 5.5 ml of a solution of 2 ml of distilled acetyl chloride, diluted with absolute benzene to a total volume of 25 ml, with exclusion of moisture, the temperature rising to 300.



  After stirring for 45 minutes, the reaction mixture is diluted with 200 ml of cold pentane and washed with 250 ml of ice-cold 0.1 N sodium hydroxide solution in 5 portions and then with 50 ml of water. The aqueous extracts are taken up individually in a mixture of 100 ml of ice-cold water, 50 ml of 2N acetic acid and 200 ml of benzene and mixed well; the aqueous phase is washed with 150 ml of benzene and the organic washing solution is washed once with 100 ml of water.



   The combined benzene extracts are dried with sodium sulfate and evaporated under reduced pressure, the residue is dissolved in benzene and chromatographed on anhydrous silica gel. Using 19: 1 and 9: 1 mixtures of benzene and methylene chloride, L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid-N-acetylamide is obtained, which after recrystallization from an ether Pentane mixture melts at 108-1090.



   The benzene-pentane solution obtained in the above process after extraction with sodium hydroxide solution is dried over sodium sulfate and evaporated under reduced pressure. An oily material is obtained which crystallizes after standing at 00 to 50 for several days. The L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid N, N-diacetylamide of the formula obtained in this way
EMI18.1
 after recrystallization from pentane, it melts at 85-860; to] 20 D = 1940 + 10 (c = 1.002 in chloroform); Infrared absorption bands (in methylene chloride) at 5.66 u (shoulder), 5.80 lt '5.98, 7.23 and 7.34.



   Example XVI
A solution of 0.521 g of L-2,2-dimethyl-3-tert.butyl oxycarbonyl-thiazolidine-4-carboxylic acid amide in 20 ml of ethylene chloride is 0.48 ml of triethylamine and then with stirring and at + 20 dropwise with a solution of 0.23 ml of oxalyl chloride in 20 ml of ethylene chloride are added. The temperature rises to + 50 and the solution quickly turns dark red-brown. After stirring at 00 for 30 minutes, 160 ml of hexane are added at this temperature and the mixture is left to stand in the cold.

  After rapid filtration through anhydrous magnesium sulfate and a filter aid, the filtrate is carefully evaporated at 250 ° C and the residue is dissolved in benzene, stirred with a diatomaceous earth preparation (Florisil) and evaporated after filtration. The residue crystallizes spontaneously and is recrystallized from pentane.

  The L-4-cyano-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine of the formula
EMI18.2
 after sublimation, melts at 450 / 0.001 mm Hg at 83-860 (with decomposition); LD = 980 + 10 (c = 1.124 in chloroform); Infrared absorption bands (in methylene chloride) at 5.85 .x, 7.25, 7.35, 7.45. \ L, 8.15, 8.95>, 9.25 y, 9.41, 10.25 p and 11.73 y.



   Example XVII
A solution of 1.305 g of L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid in 20 ml of methylene chloride is mixed with 0.69 ml of triethylamine, cooled to 100 and with a solution of 0.48 ml of ethyl chloroformate in Treated 20 ml of methylene chloride. The reaction mixture is stirred for one hour at 00 to -5: 0 and then a pre-cooled solution of 1.58 g of tritylhydrazine hydrochloride and 0.7 ml of triethylamine in 50 ml of methylene chloride is added dropwise. The cooling bath is removed, the reaction mixture is stirred for 31/2 hours and washed with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and twice with water and the organic solution is dried over sodium sulfate and evaporated.



   The yellowish oily residue is chromatographed on aluminum oxide (activity II), with petroleum ether and benzene being prewashed and the amorphous L-2,2 - dimethyl-3-tert.butyloxycarbonyl-thiazolidine -4-carboxylic acid-N'-trityl- hydrazide of the formula
EMI18.3
 is eluted with a 9: 1 mixture of benzene and ethyl acetate, [Ix] D = -870 + 10 (c = 1.027 in chloroform); Infrared absorption bands at 3.00, 3.05, 5.90p, 6.00p. 7.24, 7.35 and 7.50 (potassium bromide) and at 2.93 y, 3.07>, 5.92, 7.24, 7.34 y and 7.48 lt (in methylene chloride).



   Example XVIII
A mixture of L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid (0.2613 g) and 0.266 g of dicyclohexylcarbodiimide in 5 ml of methylene chloride is mixed with 0.125 g of O-benzylhydroxylamine in 5 ml Added methylene chloride and left to stand at room temperature for 3 hours. After filtering and careful evaporation of the filtrate, the residue is dissolved in hexane and a few drops of methylene chloride and the N, N'-dicyclohexylthiourea formed is filtered off.



   The filtrate is evaporated and the oily residue is chromatographed on 13 g of a diatomaceous earth preparation (Florisil). After pre-washing with benzene and a 1: 1 mixture of benzene and methylene chloride, methylene chloride and mixtures of the latter with ethyl acetate give a viscous oil which crystallizes from a methylene chloride-hexane mixture.

  The L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazo- lidine-4-carboxylic acid-N-benzyloxyamide of the formula
EMI18.4
 melts at 900 / 0.001 mm Hg (36 hours) at 117-119.50 after sublimation; [D = 660 + 10 (c = 0.917 in chloroform); Infrared absorption bands (in methylene chloride) at 2.95 - 3.15 e, 5.90, 6.00 ils 7.25, 7.35, 7.40, 7.50 p, 8.60, 9.23 lt ' 9.40 and 11.70; Ultraviolet absorption bands (in ethanol) shoulder 215 m (E = 4120).



   The fraction washed out with benzene and the 1: 1 mixture of benzene and methylene chloride gives the L-2,2-dimethyl-3-tert. butyloxycarbonyl-thiazolidine-4-carboxylic acid N-cyclohexyl-N- (N-cyclohexyl-carbamyl) -amide of the formula
EMI19.1
 which melts at 145 - 146.50; [a] = +280 + 10 (c = 1.049 in chloroform); Infrared absorption bands (in methylene chloride) at 3.05, 5.86, 6.02, 7.2 eleven,
7.58, 8.27 Il, 8.63 and 9.20; Final absorption in the U1 traviolet spectrum (in ethanol).



   Example XIX
To a solution of 0.523 g of L-2,2-dimethyl-3-tert. butyloxycarbonyl-thiazolidine-4-carboxylic acid in 25 ml of dry acetone are added at - 90 0.28 ml of triethylamine and then 0.195 ml of ethyl chloroformate in 15 mol of acetone with stirring. After 15 minutes, the precipitate formed is filtered off, the filtrate is evaporated to dryness and then dissolved twice in benzene and in each case evaporated and then dissolved twice in benzene and evaporated in each case to remove the acetone. The residue is dissolved in 200 ml of chloroform, cooled to -50 and treated dropwise with a solution of 20 mmol of hydroxylamine (freshly prepared from 1.39 g of finely powdered hydroxyamine hydrochloride and 2.8 ml of triethylamine) in 12 ml of methanol within 15 minutes and below added vigorous stirring.

  After cooling for 30 minutes at -30, the cooling bath is removed, the solution is stirred for 4 hours at room temperature and diluted with 150 ml of methylene chloride and washed twice with ice-cold 1N aqueous sodium hydrogen carbonate solution and then with water. After drying, the organic solution is evaporated and the semicrystalline yellow oil is crystallized from benzene.

  The L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid - N - hydroxy-amide of the formula
EMI19.2
 after two recrystallizations from a mixture of methylene chloride and hexane, it melts at 136.5 to 137.50; [CC] D = 1050 + 10 (c = 1.05 in chloroform); Infrared absorption bands (in methylene chloride) at 2.94, 3.05-3.15, 5.99, p, 7.24, 7.35, 7.49, 8.10, 9.23, 9.40, 10.33 u and 11.70.



      Example XX
A mixture of 0.377 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid - N - hydroxy-amide in 30 ml of methylene chloride is mixed with 0.21 ml of triethylamine and then dropwise at 00 with 0.256 g of anisoyl chloride added in 20 ml of methylene chloride. After stirring for 30 minutes at 0 and a further 30 minutes at room temperature, the solution is washed twice with aqueous sodium hydrogen carbonate solution and with water, dried and evaporated.

  The glassy L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid-N- (4-methoxy-benzoyloxy) -amide of the formula is obtained in this way
EMI19.3
   [X] D = -1000 + 10 (c = 1.55 in chloroform); Infrared absorption bands (in methylene chloride) at 3.1 lot (weak), 5.68, 5.85, 6.05 lt '6.22u. 6.62, 7.21, 7.32, 7'43lt '8.55, 9.35, u "9.73 lt and 11.80 lt; ultraviolet absorption bands) max 210 m, (° = 17 400) and 262 m (# = 18,300).



   Example XXI
A solution of 2.936 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid in 22.5 ml of methylene chloride is mixed with 1.55 ml of triethylamine, cooled to 100 and then with 1.08 ml Treated ethyl chloroformate in 22.5 ml of methylene chloride dropwise with stirring. The mixture is stirred at 100 for one hour and then 1.5 g of N-tert-butyloxycarbonylhydrazine are added all at once. The cooling bath is removed; stirring is continued and then left to stand overnight. After extraction with 40 ml of 5% strength aqueous sodium hydrogen carbonate solution and washing neutral with water, the organic solution is dried over sodium sulfate and evaporated and the crystalline residue is recrystallized from a mixture of methylene chloride and hexane.

  The L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine- -4-carboxylic acid-N '- tert thus obtained. butyloxycarbonyl - hydrazide of the formula
EMI19.4
  after recrystallization from an acetone-hexane mixture, it melts at 135-136.50; iCc], 20 = 840 (c = 1.25 in chloroform); Infrared absorption bands (in methylene chloride) at 2.94, 5.75y (shoulder), 5.9 (broad), 6.78 tl, 7.35 lt, 8.20 lt and 8.65 p.



   Example XXII
A solution of 0.378 g of L-2,2-dimethyl-3-tert-butyl oxycarbonyl-thiazolidine-4-carboxylic acid - N - tert-butyloxycarbonyl hydrazide in 6 ml of anhydrous acetonitrile is treated with 0.58 g of lead tetraacetate while stirring The mixture was stirred for a further 15 minutes. The suspension obtained is evaporated to a volume of 2-3 ml without heating, then diluted with 2 ml of ether and 20 ml of hexane, stirred and, after 5 minutes, filtered. The filtrate is almost completely evaporated at room temperature under reduced pressure, the semi-solid residue is extracted with 20 ml of hexane and the organic extract is dried over sodium sulfate and evaporated under reduced pressure.

  The red, very viscous oil is dried at a pressure of 0.05 mm Hg at room temperature and provides LN- (2, - -dimethyl-3-tert. Butyloxycarbonyl-4-thiazolidinyl-carbonyl) -N'-tert-butyloxycarbonyl -diimine of the formula
EMI20.1
 dar, ia] D = 210 + 10 (c = 1.20 in chloroform); Infrared absorption bands (methylene chloride) at 5.65u, 5.86u, 7.33, 7.40, 9.35 and 12.00 Lt. Ultraviolet absorption bands (in ethanol): final absorption Xmax at 440 ifllt.



   Example XXIII
A solution of 2.615 g of L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid in 200 ml of methylene chloride is cooled to -90 and mixed with 1.4 ml of triethylamine and then dropwise with 0.96 ml of ethyl chloroacetate added in 50 ml of methylene chloride.



  After stirring for one hour at 0, the mixture is cooled to 100, a solution of N, N-dimethylhydrazine in 50 ml of methylene chloride is slowly added and the mixture is stirred for 7 hours, the cooling bath being removed after 2 hours. After dilution with 200 ml of methylene chloride, the reaction mixture is extracted 3 times with 50 ml of saturated aqueous sodium hydrogen carbonate solution and then washed neutral with water, dried over magnesium sulfate and evaporated at room temperature or a little above in a high vacuum (about 0.01 mm Hg). The crystalline residue is purified by sublimation at 1000 / 0.001 mm Hg or by recrystallization from a methylene chloride-hexane mixture.

  The L-2,2-dimethyl -3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid N ', N- dimethyl hydrazide of the formula obtained in this way
EMI20.2
 melts at 153-153.5; [] D = 850 + 10 (c = 1.236 in chloroform); Infrared absorption bands (in methylene chloride) at 3.1 p (weak), 5.95, 7.25, 7.45, 8.60, 11, 9.25 and 9.40 p.



   Example XXIV
1.01 g of triethylamine in 3 ml of methylene chloride and then 1.08 g of ethyl chloroformate in 3 are added to a solution of 2.6 g of L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid in 20 ml of methylene chloride ml of methylene chloride was added at 5 and the mixture was stirred at this temperature for 45 minutes. At 0 a solution of 1.09 g of p-aminophenol in 10 ml of dimethylformamide is added. After stirring for 16 hours at room temperature, the solvents are evaporated at 400/10 mm Hg, the residue is extracted with ethyl acetate and the organic solution is washed with aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate and evaporated under reduced pressure.



  The semi-solid residue is crystallized from an ethyl acetate-heptane mixture and L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid-N-4-hydroxy-anilide of the formula is obtained
EMI20.3
 F. 205-2070; Infrared absorption bands (in methylene chloride) at 2.75 l, 3.00 l and 5.95 l and in potassium bromide at 3.0, 5.95, 6.24, a, 6.35 l and 6.60 l; Ultraviolet absorption bands (in methanol) max 208 mm (± = 12,500) and 253 ml (± = 15,000).

 

   Example XXV
A solution of 0.78 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid in 20 mol of acetonitrile, containing 0.42 ml of triethylamine, is converted into a suspension of 0.76 with stirring g of 3- (2-ethyl-5-isoxazolinium) benzene sulfonate (Woodward reagent K) added to 20 ml of acetonitrile and the mixture was stirred at 00 for one hour and then 0.282 g of 4-aminopyridine in 20 ml of acetonitrile were added. After stirring for 16 hours at room temperature, the solvent is evaporated under reduced pressure, ethyl acetate is added and the organic extract is washed with water, aqueous sodium hydrogen carbonate solution and again with water, dried over magnesium sulfate and evaporated under reduced pressure.

  The residue is chromatographed on aluminum oxide (activity III) and the L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid -N-4-pyridyl amide of the formula
EMI21.1
 eluted with a 7: 3 mixture of benzene and ethyl acetate. The product is crystallized from a mixture of acetone and cyclohexane, F. 195-1970; [a] D = 1430 (c = 0.99 in chloroform); Infrared absorption bands (in methylene chloride) at 2.90 lt, 5.90 lt and 6.0; Ultraviolet absorption bands (in methanol) m3x 246 mlt (± = 16,850) and protonated (mineral acid) max 272 m.



   A solution of 0.185 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid-N-4-pyridyl-amide in 3 ml of acetone, containing an excess of methyl iodide, is left to stand for 16 hours and then evaporated under reduced pressure. The residue gives the amorphous L-2,2-dimethyl-3-tert.butyloxycarbo nyl-thiazolidine-4-carboxylic acid-N- (1-methyl-4-pyridinium) amide iodide, mp 1200; Infrared absorption bands in methylene chloride at 5.80, 5.60 and 6.09 liters and in potassium bromide at 5.82, 6.01 and 6.13; Ultraviolet absorption bands (in methanol) #max 277 m (= 29,300) and basic #max 324 ml (± = 24,600).



   Example XXVI
A solution of 2.615 g of L-2,2-dimethyl-3-tert.butyloxycarbonyl-thiazolidine-4-carboxylic acid in 100 ml of methylene chloride is cooled to -70 and treated with 1.4 ml of triethylamine and then dropwise with 0.96 ml of ethyl chloroformate added in 60 ml of methylene chloride. The reaction mixture is stirred for one hour at -5 to 00 and then 1.9 g of benzophenone hydrazone in 50 ml of methylene chloride is slowly added at -70 and stirred for 30 minutes at this temperature. The cooling bath is removed and, after stirring for a further 3 hours, the colorless solution is diluted with 100 ml of methylene chloride, washed with 80 ml of ice-cold 1 -N aqueous sodium hydrogen carbonate solution, and with water, dried over magnesium sulfate and evaporated.

  The residue is chromatographed on 210 g of a diatomaceous earth preparation (Florisil). The forerun with a 95: 5 mixture of benzene and ethyl acetate is discarded and that with this solution.



  Medium-mixed eluted main product crystallized from a mixture of ether and hexane. The L-2,2-dimethyl- -3-tert. butyloxycarbonyl-thiazolidine-4-carboxylic acid N'-diphenylmethylene hydrazide of the formula
EMI21.2
 After recrystallization from methylene chloride, hexane melts at 134.1350; [α] D = 930 + 10 (c = 1.063 in chloroform); Infrared absorption bands (in methylene chloride) at 3.04,, 5.93, 6.25, 7.35-7.50 u, 8.60 u and 9.37; Ultraviolet absorption bands (in ethanol); imax 220 times (± = 20 750) and about 290 mlt (s = 22 150).



   Example XX VII
A solution of 0.2763 g of L-2,2-dimethyl-3-tert-butyloxycarbonyl-thiazolidine-4-carboxylic acid-N-hydroxy-amide in 2 ml of acetic anhydride and 2 ml of pyridine is allowed to stand at room temperature overnight and is diluted then with benzene and heptane and evaporated them to dryness; The dilution and evaporation are repeated several times to completely remove the pyridine and acetic acid. The viscous oil obtained is dissolved in 200 ml of methylene chloride, stirred with 5 g of silica gel, filtered and evaporated.

  The residue is distilled and the desired L-2,2-dimethyl-3-tert-butyl oxycarbonyl-thiazolidine-4-carboxylic acid-N-acetyl-N-acetyl-oxy-amide of the formula
EMI21.3
 recovered at 1350 / 0.001 mm Hg; [o = -830 + 0.40 (c = 2.665 in chloroform); Infrared absorption bands (in methylene chloride) at 5.58, 5.80 - lt '7.43, 8.28p, 8.60 lt' 9.24, 9.37, 9.82 u, 10.28, 10, 47, 11.00, 11.20, 11.65 p and 11.85, u.



   Example XXVIII
0.834 ml of triethylamine is added to a solution of 1.382 g of L-2,2-dimethyl-3-tert.bu tyloxycarbonyl-thiazolidine-4-carboxylic acid-N-hydroxy-amide in 75 ml of methylene chloride, the mixture is cooled to 00 and with 0.4265 ml of acetyl chloride in 75 ml of methylene chloride are added dropwise with stirring. The mixture is stirred for 50 minutes at 0 and overnight at room temperature, then diluted with 200 ml of methylene chloride and extracted twice with 50 ml of ice-cold saturated aqueous sodium hydrogen carbonate solution and washed with 50 ml of cold water.

  After drying over magnesium sulfate, the organic solution is evaporated and the crystalline residue is recrystallized from methylene chloride hexane. The L-2,2-dimethyl-3-tert-butyl oxycarbonyl-thiazolidine-4-carboxylic acid-N-acetyloxy-amide of the formula
EMI22.1
 melts at 128-1290; [OC] D = -1050 + 10 (c = 1.186 in chloroform);

  Infrared absorption bands (in methylene chloride) at 5.58 u, 5.86 u, 6.02, u, 7.22 u, 7.35>, 7.46>, 8.58 lt '8.95>, 9 , 20p, 9.36 lt, 9.54 lt and 11.67, u.

 

   Compounds obtained according to the invention can, as shown in the equation, be converted into 7-amino-cephalosporanic acid and its derivatives; this conversion can e.g. according to the patent specifications nos. 497445 (Wo 3), 497 450 (Wo 4), 497447 (Wo 5), 497 448 (Wo 6), 497451 (Wo 7), 497 456 (Wo 8), 497371 (Wo 9 ), 497 369 (Wo 10), 497 457 (Wo 11), 497460 (Wo 12), 497 379 (Wo 13) and 497 461 (Wo 14).

 

Claims (1)

PATENT CLAIM Process for the preparation of hydrazinothiazolidine compounds of the formula EMI22.2 wherein Ac stands for an acyl group, X stands for the disubstituted carbon atom of the thiazolidine ring, R1 stands for a functionally modified carboxyl group and each of the groups Ra and Rb stands for the remainder of an alcohol, characterized in that a compound of the formula EMI22.3 with an azodicarboxylic acid ester of the formula RaOOC- -N = N-COORb. SUBCLAIMS 1. The method according to claim, characterized in that the reaction is carried out at an elevated temperature. 2. The method according to claim, characterized in that the reaction is carried out at an elevated temperature but below the decomposition temperature of the azodicarboxylic acid ester. 3. The method according to claim, characterized in that in a compound of formula IVa obtained, a functionally modified carboxyl group R1 is converted into a free or another functionally modified carboxyl group. 4. The method according to claim or one of the dependent claims 1-3, characterized in that compounds of the formula IVa according to claim are prepared, wherein Ac represents an acyl radical occurring in a pharmacologically active N-acyl derivative of a 7-aminocephalosporanic acid or an easily cleavable acyl radical X stands for the group of the formula EMI22.4 in which each of the groups R3 and R4 is an aliphatic, an aromatic or an araliphatic hydrocarbon radical or, if taken together, a divalent aliphatic hydrocarbon radical or an oxo or thiono group, R1 is a free or esterified carboxyl, a carbamyl or a nitrile -, an azidocarbonyl, a hydrazinocarbonyl or an azocarbonyl group, each of the groups Ra and Rb is the residue of an aliphatic alcohol. 5. The method according to claim or one of the subclaims 1-3, characterized in that compounds of the formula IVa according to claim are prepared, in which Ac is the thienylacetyl, chloroethylcarbamyl or phenylacetyl radical or the radical of a half-ester of carbonic acid, X the formula EMI22.5 R1 represents a carboxyl group which is free or esterified with a lower alkanol or halogenated lower alkanol, each of the groups Ra and Rb represents the remainder of a lower alkanol or halogenated lower alkanol and R represents a hydrogen atom. 6. The method according to claim or one of the dependent claims 1 and 2, characterized in that L-2,2-dimethyl-3-tert.butyloxycarbonyl-58- (N, N'-dicarbomethoxy-hydrazino) thiazolidine - 4 - produces carboxylic acid methyl ester. 7. The method according to claim or one of the dependent claims 1 and 2, characterized in that L-2,2-dimethyl-3-tertbutyloxycarbonyl-5f3- (N, N'-di-carbethoxy-hydrazino) -thiazolidine-4-carboxylic acid methyl ester manufactures 8. The method according to claim or one of the dependent claims 1 and 2, characterized in that L-2,2-dimethyl-3-tert.butyloxycarbonyl-5p .- (N, N'-di-carbomethoxy-hydrazino) - thiazolidine 4-carboxylic acid-2,2, - 2-trichloroethyl ester produces.