DE3721430A1 - Process for the preparation of 1-[3'-{mercapto}-(2')-{methyl}-propionyl]pyrrolidine-(2S)-carboxylic acid or its salts - Google Patents

Abstract

The invention relates to a process for the preparation of 1-[3'-{mercapto}-(2'S)-{methyl}-propionyl]-pyrrolidine-(2S)-carboxylic acid of the formula <IMAGE> or its salts by reacting compounds of the general formula <IMAGE> in which X stands for a halogen atom, or their salts with thiourea and subsequent hydrolysis, in which the reaction of the compounds of the general formula III or their salts with the thiourea is carried out in organic dipolar aprotic solvents and the resulting isothiuronium compound of the formula <IMAGE> if appropriate in the form of its internal salt, or resulting acid addition salts thereof with hydrohalic acids, are hydrolysed, if appropriate after their isolation, and the resulting compound of the formula I is optionally converted in a manner known per se into acid addition salts and/or the resulting acid addition salts of the compound of the formula I are converted into the free 1-[3'-{mercapto}-(2'S)-{methyl}-propionyl]-pyrrolidine-(2S)-carboxylic acid of the formula I and/or into other acid addition salts.

Description

The invention relates to a new method of manufacture of 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] - pyrrolidine (2S) -carboxylic acid <briefly also 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] - (2S) -proline called <of the formula

or their salts.

The 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] pyrrolidine (2S) -carboxylic acid of formula I is under the name Captopril is known and has a valuable hypotensive Effect.

According to UK Pat. No. 1,576,161, the halogen atom of l - (halogen) -acylprolinen can be converted into a mercapto group using various reactants. The reaction is carried out with the anion RS ^- , in which R is a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, a phenylalkyl radical with 1 to 4 carbon atoms in the alkyl part, a triphenylalkyl radical with 1 or 2 carbon atoms in the alkyl part or an acyl radical of the general formula

in which latter R₁ for one Alkyl radical with 1 to 4 carbon atoms or one Phenyl radical means.  

Only those RS ^- anions are suitable for the production of 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl-pyrrolidin- (2S) - carboxylic acid, in which the substituent of the sulfur atom from the the substitution reaction of the halogen atom can be removed, that is, how a protective group acts.

About the simplest case in which R is a hydrogen atom means, was in the UK-PS 15 76 161 none Given teaching.

If R is a tert-butyl radical, a benzyl radical or means a trityl residue, would be the reagent used tert .- (butyl) mercaptan, benzyl mercaptan respectively Trityl mercaptan. These are reactants dangerous, carcinogenic or toxic compounds. For Carrying out the substitution of the halogen atom must Proline 's carboxyl group temporarily with a Protection group are provided. Furthermore, the yield is unacceptable low. By K. Hofmann and co-workers [J. At the. Chem. Soc., 71 [1949], 1253 was an analogous method described with benzyl mercaptan: A 4- (chloro) butyl derivative is reacted with the sodium salt of benzyl mercaptan, and from that in a yield of 66% of theory S- (Benzyl) -4- (mercapto) butyl derivative obtained is the Protecting group, i.e. the benzyl group, with sodium in Ethanol removed. The total yield is only 34% of the Theory.

Even worse results are when used expected from tert-butyl mercaptan and trityl mercaptan, because the spatial disability in the two connections is much higher. The protection groups of this kind are in the molecules generally in reverse order introduced, namely that which has already been formed Mercapto compound with isobutylene or thionyl chloride  implemented (T. W. Greene, Protective Groups in Organic Synthesis, p. 193, 1981).

If R is an acyl radical of the formula

stands, the 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] pyrrolidine (2S) -carboxylic acid produced extremely uneconomical will. According to an example of UK-PS 15 76 161 that Analog 1- [2 ′ - (mercapto) acetyl] proline using thiobenzoic acid produced. The yield based on the proline is only 15% of theory.

The case where R represents a hydrogen atom was described in UK-PS 20 65 643. N- [3- {halogen} - (2S) - {methyl} -propionyl] - (S) -proline is mixed with an aqueous Solution of sodium hydrosulfide implemented. For implementation long-lasting heating is required, and also the corresponding disulfide is used in an amount of 5 mol% educated. This by-product is then said to be in a special Level in the presence of an acid can be reduced with zinc. The yield of the reduction is 71% of theory. If the sodium hydrosulfide is in N, N-di (methyl) formamide is solved, the yield decreases to 65% of theory. Apparently the best result is when using a receive aqueous solution of ammonium hydrosulfide, the reaction product and the by-products formed can but can only be isolated chromatographically. This too A mixture of 92% by weight 1- [3 ′ - {Mercapto} - (2′S) - {methyl} propionyl] pyrrolidine (2S) carboxylic acid <Captopril <, 6 wt .-% corresponding disulfide and 0.5 wt .-% corresponding symmetrical sulfide obtained. The formation of the latter impurity is irreversible, this means that they are never in 1- [3 ′ - {Mercapto} - (2′S) - {methyl} propionyl] pyrrolidine (2S) carboxylic acid can be. Furthermore, the sulfide and the 1- [3 ′ - {Mercapto} - (2′S) - {methyl} propionyl] pyrrolidine (2S) carboxylic acid  such a similar solubility that it simply does not can be separated. What has been said above is through an article by M. Shiwazaki and co-workers (Chem. Pharm. Bull., 30 [1982], 3129). That's how it is the latter process for the production of 1- [3 ′ - {Mercapto} - (2′S) - {methyl} propionyl] pyrrolidine (2S) carboxylic acid not suitable on a technical scale.

According to US-PS 43 32 725, the halogen atom is by means of Sodium thiosulfate transferred to the mercapto group. In this Case a so-called Buntesch salt is formed, the heated with concentrated hydrochloric acid and on this Manner in 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] - pyrrolidine (2S) carboxylic acid is transferred. The yield is 70% of theory.

According to DE-OS 35 26 023 N- [3- {halogen} - (2S) - {methyl} -propionyl] - (S) -proline with thiourea in water, an alcohol or an aqueous alcohol at 60 to 100 ° C implemented. It becomes a compound of the formula

wherein X represents a halogen atom, obtained without Isolate in the reaction mixture with an alkali metal hydroxide or carbonate is hydrolyzed. But it was practically impossible to rework this known method.

The invention has for its object a new Process for the preparation of 1- [3 ′ - {Mercapto} - (2′S) -  {methyl} propionyl] pyrrolidine (2S) carboxylic acid or their salts, through which these in higher yield and purity obtained from easily accessible starting materials can be create.

The above was surprisingly accomplished by the invention reached.

The invention relates to a method for manufacturing of 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] - pyrrolidine (2S) carboxylic acid of the formula

or their salts by reacting 1- [3 ′ - {halogen} - (2′S) - {methyl} propionyl] pyrrolidine (2S) carboxylic acids <1- [3 ′ - {Halogen} - (2′S) - {methyl} -propionyl] - (2S) -prolinen < the general formula

wherein

X represents a halogen atom,

or their salts with thiourea and subsequent ones Hydrolysis, which is characterized is that the implementation of 1- [2 ′ - {halogen} - (2′S) -  {methyl} propionyl] pyrrolidine (2S) carboxylic acids of general formula III or its salts with the thiourea in organic dipolar aprotic solvents is carried out and the isothiuronium compound obtained 1 - [(2′S) - {methyl} -3 ′ - {isothiuronium} propionyl] - pyrrolidine (2S) carboxylic acid (or with other designation <2 - [(2′S) - {carboxyl-pyrrolidin-1′- ylcarbonyl] - (2S) - [methyl] -S- {äth-1-yl}] - thiourea) of the formula

optionally in the form of their inner salt, or obtained acid addition salts thereof with hydrogen halides, optionally after their isolation, hydrolyzed as well as, if necessary, in a known manner Way the obtained 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] - pyrrolidine (2S) -carboxylic acid of the formula I in acid addition salts is transferred and / or the received Acid addition salts of 1- [3 ′ - {Mercapto} - (2′S) - {methyl} - propionyl] pyrrolidine (2S) carboxylic acid of the formula I in the free 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] - pyrrolidine (2S) carboxylic acid of the formula I and / or in other acid addition salts are transferred.

Be advantageous as serving as starting substances 1- [3 ′ - {halogen} - (2′S) - {methyl} propionyl] pyrrolidine (2S) -carboxylic acids of the general formula III, such which X stands for a bromine atom is used. The 1- [3′- {Halogen} - (2′S) - {methyl} -propionyl] pyrrolidine (2S) -carboxylic acids of the general formula III can in addition to anhydrous form also advantageous in the hydrate form, in particular in the monohydrate form.

The implementation of 1- [3 ′ - {halogen} - (2′S) - {methyl} -propionyl] -  pyrrolidine (2S) carboxylic acids of the general Formula III or salts thereof with thiourea runs only in organic dipolar aprotic Solvents.

It is preferred to use organic dipolar [s] aprotic [s] solvents N, N-di- (methyl) formamide, N, N-di (methyl) acetamide and / or Dimethyl sulfoxide used.

The implementation of the 1- [3 ′ - {halogen} - (2′S) - {methyl} propionyl] pyrrolidine (2S) carboxylic acids of the general formula III or its salts with the thiourea at temperatures of 20 to 80 ° C, in particular 50 to 70 ° C performed. It is also preferred under Atmospheric pressure to work. In general, the implementation finished after 15 to 25 hours.

According to an expedient embodiment of the invention The procedure is the implementation of 1- [3′- {Halogen} - (2′S) - {methyl} -propionyl] pyrrolidine (2S) - carboxylic acids of the general formula III or their salts with the thiourea in the presence of acid-binding Funds carried out. Be advantageous as acid-binding agents organic bases used. In this case, that is, if one acid-binding agent is present in the reaction mixture, the isothiuronium compound of formula II in solid Condition preserved. It is preferably in the form of a inner salt (carboxylates) isolated and further implemented.

In the presence of acid-binding agents Acid addition salt with that of the isothiuronium compound 1 - [(2′S- {methyl} -3 ′ - {isothiuronium} propionyl] pyrrolidine (2S) -carboxylic acid of the formula II split off during the reaction receive corresponding hydrogen halide. In general, this remains in the solution, which is why it is expediently hydrolyzed without isolation, it can  but can also be isolated before hydrolysis.

The hydrolysis of the isothiuronium compound 1 - [(2′S) - {methyl} -3 ′ - {isothiuronium} -propionyl] - is advantageous
pyrrolidine (2S) -carboxylic acid of the formula II or acid addition salts thereof in the presence of bases, in particular hydrazine.

The hydrolysis of the isothiuronium compound is expedient 1 - [(2′S) - {methyl} -3 ′ - {isothiuronium} propionyl] - pyrrolidine (2S) carboxylic acid of the formula II or Acid addition salts thereof at temperatures of 0 to 30 ° C, in particular 10 to 15 ° C, performed. It is also preferred to work under atmospheric pressure. The product 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] - pyrrolidine (2S) carboxylic acid of the formula I or their acid addition salt can from the reaction mixture in known way, for example by extracting and Evaporation can be isolated.

Conversion of the free carboxyl group of 1- [3′- {Mercapto} - (2′S) - {methyl} -propionyl] -pyrrolidine (2S) -carboxylic acid of the formula I in salts can with inorganic or organic bases are made.

The isothiuronium compound is obtained by the process according to the invention 1 - [(2′S) - {methyl} -3 ′ - {isothiuronium} - propionyl] pyrrolidine (2S) carboxylic acid of the formula II in almost theoretical yield obtained and by hydrolysis also in almost theoretical yield in the 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] pyrrolidine (2S) -carboxylic acid of formula I <Capropril <transferred. Even if the end product is recrystallized, a Overall yield of over 80% of theory can be achieved. The 1- [3′- {Mercapto} - (2′S) - {methyl} -propionyl] -pyrrolidine (2S) -carboxylic acid  of formula I does not contain the corresponding disulfide nor the symmetrical sulfide as an impurity, which is why their iodometric purity is 99.5%.

The invention is illustrated by the following examples explained in more detail.

example 1 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] pyrrolidine (2S) -carboxylic acid

10.56 g (0.0374 mol) 1- [3 ′ - {bromine} - (2′S) - {methyl} -propionyl] - pyrrolidine (2S) carboxylic acid monohydrate and 3.04 g (0.040 mol) of thiourea are dissolved in 30 ml of N, N, dimethyl acetamide dissolved under nitrogen, and the reaction mixture is at 60 ° C under nitrogen for 15 to 20 hours long stirred. The solvent is reduced Pressure evaporated and the residue distilled in 50 ml Water dissolved. 6.00 g are obtained to the solution obtained (0.12 mol) hydrazine hydrate while cooling with ice water and added under nitrogen, and the reaction mixture is stirred at room temperature for 30 minutes. The The reaction mixture is 100 ml of 5 wt .-% sulfuric acid solution added and the white precipitate is filtered off, washed with water and then with dichloromethane. The filtrate is four times with 30 ml of dichloromethane extracted, the combined organic solutions washed twice with 20 ml of water, and the organic Phase is extracted twice with 15 ml dichloromethane each. The organic phases are combined, over anhydrous Magnesium sulfate dried, filtered and under evaporated under reduced pressure. 7.54 g (99% of theory) Oil remains, which recrystallizes from 25 ml of trichlorethylene becomes.

6.10 g of title product are thus obtained, which at 104 to 106 ° C melts. The yield is 80% of the Theory.  

The 1- [3 ′ - {bromine} - (2′S) - {methyl} propionyl] pyrrolidine (2S) carboxylic acid monohydrate has been obtained as follows.

3.34 g (0.02 mol) of 3-bromo-2-methylpropionic acid and 4.60 g (0.02 mol) of (S) -proline benzyl ester hydrochloride are dissolved in 50 ml of anhydrous dichloromethane, and the resulting solution becomes the mixture of 1.9 g Triethylamine and 5 ml of anhydrous dichloromethane and then 3.92 g (0.019 mol) dissolved in 20 ml dichloromethane N, N'-dicyclohexyl-carbodiimide at 0 ° C with stirring and Cooling added. The reaction mixture becomes more 2 hours at 0 ° C and then another 12 hours long at room temperature. The reaction mixture is filtered, and the filtrate with 20 ml of 9% by weight hydrochloric acid solution, 20 ml of water, 5% by weight sodium bicarbonate solution and finally extracted 20 ml of water. The organic phase is over anhydrous magnesium sulfate dried and evaporated. 6.40 g (95% of theory) 1- [3 ′ - {bromine} - (2′S) - {methyl} -propionyl] pyrrolidine (2S) - carboxylic acid benzyl esters are in the form of a light yellow Get oil.

Thin layer chromatography (silica gel, 3 parts benzene, 1 part glacial acetic acid): R _f = 0.44 and 0.48, which correspond to a diastereomer ratio of 1: 1.

The oil obtained is dissolved in 60 ml of ethyl acetate, and the solution are 0.6 g of 10 wt .-% palladium / carbon catalyst added. The suspension is at room temperature and hydrogenated under atmospheric pressure. If the starting compound by thin layer chromatography can no longer be proven, the Filtered catalyst, washed with ethyl acetate, the evaporated organic solvent and the residue recrystallized from water. So 2.00 g  1- (3 ′ - {bromine} - (2′S) - {methyl} propionyl] pyrrolidine (2S) - carboxylic acid monohydrate obtained at 69 to 72 ° C. melts. The yield is 42.5% of theory.

Example 2 1- [3 ′ - {Mercapto} - (2S) - {methyl} -propionyl] pyrrolidine (2S) -carboxylic acid

2.64 g (0.01 mol) 1- [3 ′ - {bromine} - (2′S) - {methyl} -propionyl] - pyrrolidine (2S) carboxylic acid and 0.76 g (0.01 mol) Thiourea are dissolved in 10 ml of dimethyl sulfoxide, and the solution obtained is at 60 to 70 ° C for 24 hours stirred for a long time, then with 30 ml of 10% by weight sodium hydroxide solution treated and stirred for an additional hour. The pH is lowered with 20% by weight hydrochloric acid solution Cooling with ice water is set to 1, and the solution is extracted four times with 20 ml of dichloromethane, over dried anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The leftover Oil is recrystallized from trichlorethylene.  

So 1.64 g of title compound are obtained, which at 104 to 106 ° C melts. The yield is 81% of the Theory.

The 1- [3 ′ - {bromine} - (2′S) - {methyl} propionyl] pyrrolidine (2S) carboxylic acid monohydrate is like in the production of the starting substance of Example 1 have been described.

Example 3 1- [3 ′ - {Mercapto} - (2S) - {methyl} -propionyl] pyrrolidine (2S) -carboxylic acid

5.28 g (0.02 mol) of 1- [3- {bromo} - (2′S) - {methyl} propionyl] - pyrrolidine (2S) carboxylic acid and 1.67 g (0.022 mol) Thiourea are dissolved in 15 ml of N, N-dimethylformamide, and the solution obtained is at 60 ° C for 24 hours long stirred. The solvent is reduced The pressure was evaporated and the residue was distilled in 30 ml Dissolved water, the solution obtained with 6.00 g 50 wt .-% Hydrazine solution treated with cooling with ice water and stirred for an additional hour with cooling. The The reaction mixture is 50 ml of 5 wt .-% sulfuric acid solution added, the precipitate which has separated out is filtered off, washed with water and then with dichloromethane. 10 g of sodium chloride are added to the aqueous phase added, and the mixture is mixed with 30 ml dichloromethane extracted four times. The united organic Solutions are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The remaining oil is made from 20 ml of trichlorethylene recrystallized.  

This gives 3.33 g of the title compound, which at 104 to 106 ° C melts. The yield is 82% of the Theory.

The 1- [3 ′ - {bromine} - (2′S) - {methyl} propionyl] pyrrolidine (2S) carboxylic acid monohydrate is like in the production of the starting substance of Example 1 have been described.

Example 4 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] -pyrrolidine (2S) -carboxylic acid A. 1 - [(2′S) - {Methyl} -3 ′ - {isothiuronium } -propionyl] - pyrrolidine (2S) carboxylate (inner salt of 1 - [(2′S) - {methyl} -3 ′ - {isothiuronium} - propionyl] -pyrrolidine (2S) -carboxylic acid) The by dissolving of 5.64 g (0.02 mol) of 1- [3 ′ - {bromine} - (2′S) - {methyl} -propionyl] pyrrolidine (2S) -carboxylic acid monohydrate in 50 ml of dichloromethane and stirring for 1 hour the solution obtained with 5 g of anhydrous magnesium sulfate and filtering off the drying agent, washing with 10 ml of dichloromethane, combining the organic solutions and evaporation under reduced pressure, the residue obtained is dissolved in 15 ml of anhydrous N, N-dimethylacetamide, with 1.52 g (0.05 02 moles) of anhydrous triourea and stirred under nitrogen for 24 hours. During the reaction, the flask containing the reaction mixture is kept in an oil bath at 70 ° C. Then the mixture is cooled with ice water and diluted with 150 ml of acetonitrile. 2.8 ml (0.02 mol) of triethylamine in 20 ml of acetonitrile are added dropwise to the mixture obtained within 30 to 40 minutes with stirring. The reaction mixture is stirred for a further 2 hours, the precipitate is filtered off, suspended in 20 ml of acetonitrile, filtered, resuspended in 20 ml of acetonitrile, filtered and dried. 4.2 g of the title compound are obtained, which melts at 187 to 189 ° C. The yield is 81% of theory. Thin layer chromatography: R _f value = 0.41 (6 parts by volume of a mixture of pyridine, water and glacial acetic acid in a volume ratio of 20: 11: 6 and 4 parts by volume of ethyl acetate); R _f value = 0.2 (mixture of butanol, glacial acetic acid and water in a volume ratio of 7: 1: 3). B. 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] pyrrolidine (2S) -carboxylic acid 2 ml (0.02 mol) 50% by weight hydrazine are the stirred and with ice-water-cooled solution of 2.59 g (0.01 mol) 1 - [(2′S) - {methyl} -3 ′ - {isothiuronium} - propionyl] pyrrolidine (2S) -carboxylic acid methyl ester in 25 ml water Dropped nitrogen. The reaction mixture is stirred for a further 30 minutes with cooling, then the cooling bath is removed and the mixture is stirred for a further 30 minutes. The reaction mixture is cooled again to a temperature below 10 ° C., treated with the mixture of 2 ml of concentrated hydrochloric acid and 2 ml of water and stirred for 30 minutes. After the addition of 6 to 10 g of sodium chloride, the product is extracted three times with 20 ml of dichloromethane. The organic solutions are combined, washed with 15 ml of water and the aqueous phase is extracted with 5 ml of dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The 2.03 g of oily residue is recrystallized from 10 ml of trichlorethylene, the crystals are washed with n-hexane and dried. This gives 1.62 g of the title compound which melts at 103 to 104 ° C. The yield is 80% of theory.

Claims (6)

1. Process for the preparation of 1- [3 ′ - {Mercapto} - (2′S) - {methyl} -propionyl] pyrrolidine (2S) -carboxylic acid of the formula or their salts by reacting 1- [3 ′ - {halogen} - (2′S) - {methyl} -propionyl] pyrrolidine (2S) -carboxylic acids of the general formula whereinX stands for a halogen atom, or its salts with thiourea and subsequent hydrolysis, characterized in that the reaction of 1- [3 ′ - {halogen} - (2′S) - {methyl} -propionyl] pyrrolidine (2S ) -carboxylic acids of the general formula III or their salts with the thiourea in organic dipolar aprotic solvents and the isothiuronium compound 1 - [(2′S) - {methyl} - -3 ′ - {isothiuronium} -propionyl] -pyrrolodine ( 2S) -carboxylic acid of the formula optionally in the form of their inner salt, or acid addition salts obtained with hydrogen halides, if appropriate after their isolation, hydrolyzed and, if appropriate, in a manner known per se, the 1- [3 ′ - {mercapto} - (2′S) - {methyl} -propionyl obtained ] -pyrrolidine (2S) -carboxylic acid of the formula I converted into acid addition salts and / or the acid addition salts obtained of the 1- [3 ′ - {mercapto} - (2′S) - {methyl} -propionyl] -pyrrolidine (2S) -carboxylic acid of the formula I into the free 1- [3 ′ - {mercapto} - (2′S) - {methyl} -propionyl] pyrrolidine (2S) -carboxylic acid of the formula I and / or converted into other acid addition salts. 2. The method according to claim 1, characterized in that that as organic [s] dipolar [s] aprotic [s] Solvent N, N-di- (methyl) -formamide, N, N-di- (methyl) acetamide and / or dimethyl sulfoxide used. 3. The method according to claim 1 or 2, characterized in that the implementation of 1- [3 ′ - {halogen} - (2′S) - {methyl} propionyl] pyrrolidine (2S) carboxylic acids of the general formula III or its salts with the thiourea at temperatures from 20 to 80 ° C, in particular 50 to 70 ° C, is carried out. 4. The method according to claim 1 to 3, characterized in that the implementation of 1- [3 ′ - {halogen} - (2′S) - {methyl} propionyl] pyrrolidine (2S) carboxylic acids  of the general formula III or its salts with the thiourea in the presence of acid-binding Funds. 5. The method according to claim 1 to 4, characterized in that the hydrolysis of the isothiuronium compound 1 - [(2′S) - {methyl} -3 ′ - {isothiuronium} - propionyl] pyrrolidine (2S) carboxylic acid of the formula II or acid addition salts thereof in the presence carried out by hydrazine. 6. The method according to claim 1 to 5, characterized in that that the hydrolysis of the isothiuronium compound 1 - [(2′S) - {methyl} -3 ′ - {isothiuronium} propionyl] - pyrrolidine (2S) carboxylic acid of the formula II or acid addition salts thereof Temperatures from 0 to 30 ° C, especially 10 to 15 ° C.