PL118386B1 - Process for preparing novel derivatives of mercaptoacyl substituted prolines zamehhennykh prolinov - Google Patents

Description

The present invention relates to a process for the preparation of new proline-substituted mercaptoacyl derivatives, namely new ether- and thioether-mercaptoacyl-prolines of the formula I in which the X — Rt group is in the 3- or 4-position of the ring; X is oxygen or sulfur; R represents a hydrogen atom or a lower alkyl radical; R is a lower alkyl radical, a lower alkenyl radical, a lower alkynyl radical, a phenyl radical, a substituted phenyl radical, a phenyl- (lower) alkyl radical or a (substituted) phenyl- (lower) alkyl radical; Rj, R "are each independently hydrogen, loweralkyl and trifluoromethyl, R4 is hydrogen, the group R5 — CO— in which R5 is loweralkyl, phenyl or phenyl- (lower) -alkyl radical; n is a number with the value 0, 1 or 2; and their salts. In its broadest aspect, the process of the invention relates to the preparation of ether- and thioether-mercaptoacylproline of the formula I above for use as active ingredients in pharmaceuticals against hypertension. The term "lower alkyl radical" as used in the definition of the symbols R, Rlf, R * and R3, denote straight-chain or branched hydrocarbon radicals containing up to seven carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl- pentyl, isopentyl, etc. Preferred lower alkyl radicals are those containing up to four carbon atoms, and most preferably methyl and ethyl radicals. The term "lower alkenyl", as used to denote the rhymbol of Ri, denotes carbon radicals. Hydrogen with one unsaturated bond and straight or branched chain containing 2 to 7 carbon atoms, such as ethenyl, propenyl, isopropenyl, butenyl and and the like. Lower alkynyl radicals are straight or branched chain hydrocarbyl groups containing 2 to 7 carbon atoms, having one triple bond, for example a propargyl radical. Preferred lower alkenyl radicals are groups with 2 to 5 carbon atoms, and preferred lower alkynyl radicals are groups with 3 to 4 carbon atoms. The term "substituted phenyl" and "(substituted) phenyl- ( lower) alkyl "as used in the definition of the symbol R 1, means that there is one or two, preferably one, substituent in the phenyl ring. The substituents that can be used in the compounds according to the invention are lower alkyl radicals with 1 to 4 carbon atoms, especially the methyl radical, lower alkoxy radicals with 1 to 4 carbon atoms 118 3863 118 386 4 carbon, especially methoxy, lower alkylthio radicals with 1 to 4 carbon atoms, especially methylthio, halogen atoms, especially chlorine or fluorine, trifluoromethyl, acetyloxy and hydroxy radicals. Phenyl radical, substituted hydroxy group and phenyl radicals hydrolyze the corresponding phenyl compound, the acetyloxy group at the last stage of the synthesis process. The term "halogen" includes four known elements, i.e. chlorine, bromine, fluorine and iodine, with chlorine, bromine and fluorine being preferred. The term "phenyl- (lower) radical" "alkyl" as used in the definition of the symbols R 1 and R 5 includes groups such as the group of formula 12 where n is an integer from 1 to 4. Preferred phenyl- (lower) alkylene radicals These are phenylmethyl and phenylethyl radicals, especially phenylmethyl. The lower alkanoyl groups, defined by the formula R5 — CO—, are the groups having acid radicals of lower fatty acids with 2 to 7 carbon atoms, for example acetates - lyl, propionyl, butyryl, isobutyryl and the like. Lower alkanoyl groups containing up to four carbon atoms are preferred, and an acetyl group is particularly preferred. Likewise, when R5 in the R5 — CO— group is phenyl- (lower) alkyl, benzoyl is particularly preferred. The asterisk in Formula 1 is the asymmetric center found in the proline ring. Of course, an additional asymmetric center may be present in the mercaptan. side chain depending on R3 and Rj. The products of the formula I therefore exist in stereoisomeric forms or in their racemic mixtures. All of them are prepared according to the invention. The synthesis described below, carried out according to the invention, may use the racemate or one of the enantiomorphic forms as starting materials. If the racemic starting material is used in the synthesis, the steroisomers obtained in the final product can be separated by conventional chromatography or fractional crystallization methods. The presence of the X-Ri group also leads to cis-trans isomerism. The center of asymmetry in the proline ring is preferably L-configuration, and if the asymmetry center is present in the mercaptoacyl side chain, it preferably has the D-configuration. According to the invention, there are those compounds of formula I in which R is hydrogen; R 1 is a lower alkyl radical of 1 to 3 carbon atoms or a radical of formula 13 in which p is zero, 1 or 2, and R 1 is hydrogen, methyl, methoxy, methylthio, chlorine, fluorine, trifluoromethyl or a hydroxy group; R * is hydrogen, methyl or trifluoromethyl; R9 is hydrogen; n is a number with value zero or one; and R4 is hydrogen. Preferred intermediates are the above compounds in which R4 is an acetyl or benzoyl radical, especially acetyl. The most preferred compounds of the above compounds, prepared by the process according to the invention, of formula I, in which X is tq. ¬ nu; R x is a methyl or ethyl radical, especially methyl; n is 1; Rg represents a hydrogen atom or a methyl radical, especially a methyl radical; Rs is hydrogen; Ra is hydrogen; and the group -XRi is in the 4-position of the proline ring, especially where the -XRi group is in the cis configuration. According to the invention, ethers and thioethers of formula I are prepared by coupling an ether- and thioetherproline of formula II with an acid or its a chemical equivalent of formula III to give the product of formula I, where in the formulas all substituents have the meaning given above. These reactions may be carried out in the presence of a binder such as dicyclohexylcarbodiimide or the like, or the acid may be activated by preparing its mixtures of anhydride, symmetric anhydride, acid halide, active ester, or by using Woodward's reagent K, N-ethoxycarbonyl -2-ethoxy-1,2-dihydroxyquinoline or similar compounds. An overview of acylation methods is can be found in "Methoden der Organischen Chemie" (Haouben-Weyl), Vol. XV, Part II, p. 1 et seq. (1974). An acid halide, especially an acid chloride of formula 3k The ester compounds of the formula I, ie the compounds in which R is an alkyl radical, are preferably reacted with the acid of the formula II, and optionally converted by known methods into the free acid, that is, the compounds in which R is hydrogen. For example, if R is a tert -butyl radical, the free acid is obtained by treatment with trifluoroacetic acid and anisole. The product of formula I is preferably isolated and purified by crystallization, e.g. by preparation of the dicycohexylamine salt and subsequent processing salt to the free acid by treatment with an aqueous acid such as acid potassium sulfate. The product of formula I having the acyl group Rb — CO— is optionally converted to the product of formula I, wherein R4 is hydrogen by conventional hydrolysis or The esters of formula I, in which R is a lower alkyl radical, are prepared from compounds of the carboxylic acid nature, that is to say, where R is hydrogen, by known esterification methods, for example by esterification by with the aid of a diazoalkane such as diazomethane, 1-alkyl-3-p-tolyl-triazene, such as ln-butyl-3-p-tolyl-triazene, and the like. ymi ways. For example, hydroxy or mercapto-proline IV is acylated with an acylating agent such as acetic acid anhydride, acetyl chloride, propionic acid anhydride, acid anhydride, or a hydroxy or 10 15 20 25 30 35 40 50 55. butyric acid, benzyl chloroformate etc. as needed for nitrogen protection. The group R 1 is then introduced by reacting a compound of formula IV in N-protected form with a halide of the formula Ri-hal in which hal is a halogen atom, preferably iodine, in the presence of silver oxide, sodium hydride, sodium hydroxide or others to form the intermediate of formula 5. Alkaline hydrolysis of a compound of formula 5, a base such as barium hydroxide, sodium hydroxide, potassium hydroxide or the like, produces free acid (COOH), followed by hydrolysis with an inorganic acid such as like sulfuric acid gives the starting compound of formula 2. Another method for preparing the proline starting materials of formula II is that the N-protected toluene-4-sulfonyloxy ester of proline, preferably the methyl ester of formula 6, is treated with sodium salt of formula 7 to form the intermediate of formula 8. In formula 6, Ts represents the tosyl group of formula 14 and a benzyloxycarbonyl group is used as a preferred protecting group for nitrogen protection. or other commonly used acyl protecting groups. If in this reaction the tosyloxy group is in the cis configuration, then the XRi group will be in the trans configuration, and if the tosyloxy group is in the trans configuration, then the XRi group will be in the cis configuration yew. The intermediate compound of formula 8 is then subjected to removal of the alkyl ester group and then reacted with hydrogen bromide to give the HBr salt of the proline substrate of formula II, which can then be coupled with an acid, preferably an acid chloride of formula 3. Formula II starting materials in which X is sulfur and the XRi group is in the -3-position of proline can also be prepared by treating 1,2-dehydroproline, preferably tert-butyl ester of formula 9 with with acylating agents such as benzyl chloroformate, acetyl chloride, etc., to obtain a 4,5-dehydro compound of formula 10, which is then reacted to give a compound of formula 11 in which -S-Rx is in the configuration trance. The N-protecting groups and the alkyl groups are then removed to give the desired starting material. Proline starting materials of formula II, in which R 1 is phenyl, substituted phenyl, phenyl (lower) alkyl or (substituted) Phenyl (lower) alkyl can also be prepared by treating the N-protected proline benzyl ester of Formula 4 with the R 1 —OH alcohol in the presence of triphenylphosphine and diethyl azocarboxylate, according to the procedure of Bittner et al., Chemistry and Industry, March 15 1975, p. 281. By removal of the N-protecting group and the benzyl ester group, the starting material of Formula 2 is obtained. Additional explanations on how to prepare the starting materials and intermediates can be found in the following publications: Ondetti et al., U.S. Patent Nos. 4,046,889, 4,105,776, and 4,154,935; Neuberger, J. Chem. Soc, 1945, pp. 429-432; Patchett et al., J. Amer. Chem. Soc. 79, pp. 185-192 (1957); Baer et al., Can J. Biochem. and Phys. 37, pp 583-587 (1959); Sheehan et al., J. Amer. Chem. Soc. 85, pp. 3863-3865 (1963); Magerlein, J. Med. Chem. 10, pp. 1161-1163 (1967). The procedures illustrated therein may be used as general methods for the synthesis and spatial conversion of compounds used in the process of the invention. Additional experimental details are provided in the Examples that describe the preferred compounds. They also serve as models for the preparation of other compounds of this group. The compounds of the present invention form basic salts with numerous inorganic or organic bases. The salt-forming ions derived from such bases may be metal ions, e.g. aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as sodium or potassium, alkaline earth metal ions, such as calcium or magnesium, or an amine salt ion, many of which may be used for this purpose, for example, arylalkylamines such as dubenzylamine, N, N-dubenzylethyleneamine, lower alkylamines such as methylamine, T-butylamine, procaine, (lower) alkyl-piperidines such as N-ethylpiperidine, cycloalkylamines such as cyclohexylamine or dicyclohexylamine, 1-adamantanamine, benzathine or amino acid derivatives such as arginine, lysine or the like. physiologically, salts, such as sodium or potassium, the therapeutic use of which is described below. These and other non-physiologically acceptable salts are used to isolate or purify an acceptable product for the purposes described above, as is illustrated in the dicyclohexylamine and cyclohexylamine salts in the Examples. it is prepared by reacting the acid form of the compound with an equivalent amount of base to provide the desired base ion in a saline or aqueous medium and then freeze-drying. The free acid form can be obtained from the salt by known methods of neutralization, e.g. with acid calcium sulfate, hydrochloric acid, etc. The compounds according to the invention inhibit the conversion of angiotensin I decapeptide into angiotensin II and thus find application in lowering or alleviating hypertension. The compounds produced according to the invention interact in the process of successive transformations: rhenium -? angiotensinogen -? angiotensin I -? angiotensin II by inhibiting the action of the angiotensin converting enzyme and reducing the intensity or inhibition of the formation of the pressure-lifting substance angiotensin II. Thus, by administering an effective blood pressure lowering amount of an agent containing one or more of the compounds of formula I or their physiologically acceptable blood pressure, blood pressure is reduced or attenuated in naïve mammals. To reduce blood pressure. as stated in described by SL Engel T.R.Schaeffer, M.H.Waugh and B. Rubin in Proc. Soc.Exp.Biol.Med. 143, 483 (1973) in animal experiments, the compound according to the invention should be administered in a single dose or preferably in two to four divided daily doses based on a baseline value from about 0.1 to about 100 mg per day. kilogram per day, preferably about 1 to 50 mg per kilogram per day. The active ingredient is preferably administered orally, but parenteral routes of administration, for example, subcutaneously, intramuscularly or intraperitoneally, may also be applicable. The compounds of the invention may also be used. can be used to reduce blood pressure as the active ingredient of oral tablets, capsules or elixirs or parenteral canned solutions or suspensions. About 10 to about 500 mg of a compound or mixture of compounds of formula (I) or a physiologically usable salt is processed with a physiologically acceptable excipient, carrier, diluent, binder, preservative, stabilizer, fragrance. etc., in a unit dose corresponding to those used in pharmaceuticals. The amount of active substance in these agents or preparations is selected in such a way as to obtain the appropriate dose within the above-mentioned range of values. Typical auxiliaries that can be used in tablets, capsules and the like are the following substances: binder, such as gum tragacanth, acacia, corn starch or gelatin; a diluent such as dicalcium phosphate or microcrystalline cellulose; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetener such as sucrose, lactose or saccharin; a flavoring agent such as peppermint oil, aged oil or cherry oil. Where the unit dose is in the form of capsules, it may contain, in addition to materials of the above type, also a liquid carrier such as fatty oil. The compositions may also include various other materials, for example as a coating layer, or as a substance used to modify the physical form of the dosage unit. Tablets may, for example, be coated with hexacetate, sugar or both. substances at the same time. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye, and a flavoring such as cherry or orange. De-lined injectables may be prepared by methods known in the art. pharmaceutical formulation by dissolving or suspending the active ingredient in an excipient such as water for injection, natural vegetable oil such as sesame oil, coconut oil, orange oil, cottonseed oil. The following examples illustrate the preferred embodiments of the process of invention. They also serve as models for the production of other compounds from a given group which may be produced when given reactants are replaced with appropriately substituted analogs. All temperatures are given in degrees Celsius. Example I. Synthesis of 1- (3-acetylthio-1-ketopropyl) -trans-4-methoxy-Li-proline a) N-acetyl-trans-4-hydroxy -L-proline A suspension of 26.2 g (0.2 mol) of trans-4-hydroxy-L-proline in 400 ml of acetic acid is mixed and treated with 26 ml of acetic anhydride. The solid dissolves gradually over the two-hour stirring period at room temperature. The solution is transferred to a 2 liter flask and the solvent is removed on a rotary evaporator at a bath temperature of 45 °. A syrupy residue (57.5 g) is diluted with 100 ml of ether to give a crystalline solid. After cooling and keeping it for the next day, the solids are filtered off, washed with cooled ether and dried in a desiccator. This material (35.7 g) is pulverized and suspended in 100 ml of ether, cooled and filtered, yielding 33.8 g (98%) of N-acetyl-trans-4-hydroxy-L-proline. melting point 128-131 °. Recrystallization of 0.5 g of this material with 5 ml of tf acetonitrile yields 0.45 g of a colorless solid at 130-132 °; [a] g-92 ° (c, 1% in EtOH). b) N-acetyl-trans-4-methoxy-L-proline methyl ester M A mixture of 30.0 g (0.17 mol) N-acetyl-trans- -4-hydroxy-L-proline and 130 g of silver oxide in a mortar, and this homogeneous mixture is added to a 1 liter flask containing 300 ml of acetone. The suspension is stirred, a total of 130 ml of methyl iodide are added in portions, and the temperature is kept below 40 ° C by cooling in a bath with cold water. The mixture was stirred for 7 hours and left until the next day. The solids are filtered off, rinsed thoroughly with acetone, and the filtrate is concentrated on a rotary evaporator to give 38.3 g of a syrup-like residue. The latter is redissolved in 350 ml of acetone and treated again with 130 g of silver oxide and 130 ml of methyl iodide, leaving 118 386 9 10 41 g of a residue. This residue is distilled to obtain 32.2 g of distillate with a boiling point of 130-140 ° under 39.99 Pa. After dissolving in 30 ml of cyclohexane and cooling, an almost colorless solid is obtained, which is the methyl ester N -acetyl-trans-4-methoxy-L-proline, 31.4 g, mp 71 ° -75 °. After recrystallization from 31 ml of methyl acetate, 25.1 g (66%) of a colorless solid are obtained, 76 ° -77 °; [a] g-83 ° (c, 1% in EtOH). c) trans-4-methoxy-L-proline To a solution of 27.0 g (0.085 mol) of barium hydroxide in 525 ml of water (about 3.3 N) 11.0 g (0.05 mol) of methyl ester is added with stirring. Yellow N-acetyl-trans-4-methoxy-L-proline. The resulting solution is stirred at 18-20 ° C for 3 hours, cooled and treated with dilute sulfuric acid (8.8 g of conc. H * SO 4 in 20 ml of water). The acidic slurry is left to stand overnight. The mixture is passed through a thick layer of celite, obtaining a "milky" effluent. The latter is concentrated on a rotary evaporator at 50 °, using a high-vacuum pump and yields 121 g of milky residue. This material is treated. with dilute sulfuric acid (19.0 g of concentrated H 2 SO 4 in 75 ml of water) and the resulting mixture is stirred and refluxed for 3 hours. After cooling to 30 °, the mixture is gradually added to the mixture. 48 g of barium hydroxide octahydrate and then the pH is adjusted to 6.0 to 4.0 with dilute sulfuric acid. The next day the mixture is passed through a thick layer of celite. The "milky" permeate is concentrated as described above, giving 50 g of colorless dry residue is dissolved in 200 ml of hot chloroform and filtered through a celite bed to remove barium sulphate. the filtrate is concentrated on a rotary evaporator to obtain 17.7 g of gelatinous material, which is suspended in 100 ml of ether and filtered to obtain 7.5 g (94%) of an almost colorless solid, mp 185 - - 190 ° (with distribution). This material is suspended in 30 ml of warm acenitrile, cooled and filtered to obtain 4.0 g (50%) of a colorless solid, i.e. trans-4-methoxy-L-proline, mp 209-211 ° ( with distribution); [a] g-75 ° (c, 1% in EtOH). d) 1- (acetylthio-1-ketopropyl) -trans-4-methoxy-L-proline. A solution of 3.5 g (0.024 mol) of trans-4-methoxy-L-proline in 50 ml of water is stirred and cooled to 5 ° and 3 g of sodium carbonate are added. The mixture is treated with a solution of 4.0 g (0.024 mole) of 3-acetylthiopropionyl chloride in 5 ml of ether over 10 minutes, while adding 3 g of sodium carbonate in the meantime to maintain the pH at around 8.0. the mixture is stirred in an ice bath for the next 1 hour, 25 ml of water are added followed by a solution of 5 ml of concentrated hydrochloric acid in 25 ml of water (evolution of CO2). The strongly acidic solution is saturated with sodium chloride and extracted with 50 ml of ethyl acetate (four times). The organic phases are combined, dried (MgSO 4), filtered and the solvent is evaporated off to give 6.0 g (90%) of a colorless, syrupy 1- (3-acetylthio-1-ketopropyl) -trans-4-methoxy- L-proline. This acid was dissolved in 25 ml of ethyl acetate and treated with 4.7 g of dicyclohexylamine to give a 1 solution which solidified in a short time. A further 15 ml of ethyl acetate was added and the mixture was digested in a steam bath, cooled and filtered to give 8.7 g of the dicyclohexylamine salt, mp 170-172 °. After recrystallization from 60 ml of acetonitrile, 8.3 g (75%) of a colorless solid are obtained, mp 171-173 °; [a] "-35 ° (c, 1% in EtOH). The dicyclohexylamine salt is converted to 1- (3-acetylthio-1-ketopropyl) -trans-4-methoxy-L-proline by slurrying from 8, 0 g of this compound in 60 ml of ethyl acetate cooled in an ice bath and treatment in successive portions with a total of 60 ml of 10% acid potassium sulfate The clear layers are separated and the aqueous portion is extracted with ethyl acetate (2X). Organic phases it is combined, dried (MgSO 4), filtered and the solvent is evaporated off, giving 4.6 g (80%) of a colorless syrup. Example II. 1- (3-mercapto-1-ketopropyl) -trans-4 -methoxy-L-proline. To 1- (3-acetylthio-1-ketopropyl) -trans-4-methoxy-L-proline obtained in example I (4.6 g; J5 0.017 mol), add a cooled solution of concentrated ammonia in 22 ml of water The base dissolves in about 30 minutes and the product obtained is left for 2 hours in an argon atmosphere at room temperature. This solution is cooled and extracted with acetate. (2X) and the acetate extract is discarded. The solution is again covered with a layer of 25 ml of ethyl acetate and acidified with 17 ml of hydrochloric acid, diluted 1: 1. The mixture is shaken, separated, and the aqueous phase is extracted with 25 mL of ethyl acetate (3X). The organic phases are combined, dried (MgSO 4), filtered and the solvent is removed on a rotary evaporator to give 2.3 g (59%) of a colorless 1- (3-mercapto-1-keto-propyl) -trans-syrup. 4-methoxy-L-proline; [1% in EtOH); Rf 0.49 (MeOH on silica gel, visualized with a nitroproxide reagent). Chemical composition for C9H15NO4S-1 / 4HaO: M Calculated C, 45.46; H, 6.57; N, 5, 87; S, 13.48. Found C, 45, 42; H, 6.78; N, 5.96; S, 13, 27. An additional 1.1 g of product (3.4 g - 87% in total) is obtained by saturating the aqueous phase with sodium chloride and extracting with 25 ml of ethyl acetate (2X). Sodium salt is formed by treatment of syrup with an aqueous solution of sodium acid carbonate and freeze-drying. Example III. (trans) -1- [D-3- (acetylthio) -2-methyl- 6 * yl-1-ketopropyl] -4-methoxy-L-proline11 118 38S 12 Solution 4.3 g (0.029 mol) trans-4 -methoxy-L-proline in 50 ml of water is stirred, cooled to 5 ° and 3 g of sodium carbonate are added. This solution is treated with 5.2 g (0.029 mol) of D-3- (acetylthio) -2-methylpropionyl chloride in 5 ml of ether over a period of 10 minutes, during which time 3 g of sodium carbonate are added in small portions to maintain the pH value is about 8.0. The mixture is stirred in an ice bath for 1.5 hours, 25 ml of water are added, followed by 6 ml of a solution of concentrated hydrochloric acid in 25 ml of water (CO is released). The resulting strongly acid solution is extracted with 50 ml of ethyl acetate (four times). The organic phases are combined, dried (MgSO 4), filtered and the solvent is evaporated to give 6.1 g (73%) of (trans) -1- [D -3- (acetylthi) -2-methyl-1-ketopropyl] -4-methoxy-L-proline as a residue with a light yellow color and a syrup-like consistency. This acid is dissolved in 50 ml of ethyl acetate and treated with a solution of 4.0 g of dicyclohexylamine in 20 ml of ethyl acetate. Within about 1 minute, the product begins to crystallize out of the solution. After cooling overnight, the resulting almost colorless solid is filtered off and dried; yield 6.7 g, m.p. 175 ° -177 °; [a] 2 * -55 ° (c, 1% in EtOH). After recrystallization from 60 ml of acetonitrile, 5.6 g (41%) of an almost colorless solid dicyclohexylamine salt were obtained, mp 179-181 °; [a] ≤ -62 ° (c, 1% in EtOH). The dicyclohexylamine salt is converted to acid by slurrying 5.5 g of the salt in 50 ml of ethyl acetate, cooling in an ice bath and treating with 50 ml of a 10% sulfuric acid solution Potassium ¬ate. The layers are separated and the aqueous portion is extracted with 50 mL of ethyl acetate (2X). The organic phases are combined, dried over MgSO 4, filtered and the solvent evaporated to give 3.4 g (41%) of almost colorless (trans) -1- [D-3- (acetylthio) -2-methyl-1- ketopropyl] -4-methoxy-L-proline in the form of a syrup. Example IV. (trans) -4-methoxy-1- (D-3-mercapto-2-methyl-1-ketopropyl) -L-proline Up to 3.4 g (trans) -1- [D-3- (acetylthio) A cooled solution of 8 ml of concentrated ammonia in 20 ml of water is added to -2-methyl-l-ketropyl] -4-methoxy-L-proline. The base dissolves in about 10 minutes and the resulting solution is allowed to stand for 2 hours (under argon) at room temperature. This solution is cooled, extracted with 20 ml of ethyl acetate (2X), covered with a layer of 20 ml of ethyl acetate and acidified with 15 ml of diluted hydrochloric acid 1: 1, the mixture is saturated with sodium chloride, the layers are separated and the aqueous phase it is extracted with 20 ml of ethyl acetate (3 ×). The organic phases are combined, dried (MgSO 4), filtered and the solvent is evaporated to give 2.9 g (100%) of almost colorless (trans) -4-methoxy-1- (D-3-mercapto-2-methyl). - 1-l-ketopropyl) -L-proline; [a] * ≤ —80 ° (C, 1% in EtOH); Rf 0.53 (MeOH on silica gel, visualized with nitroprusside reagent). Chemical composition for C10H17NO4S-1/411 * 0: Calculated C, 47.69; H, 6.83; N, 5, 56; S, 12, 73. Found C, 47, 90; H, 6, 84; N, 5, 85; S, 12, 76. Example V. (trans) -1- [D-3- (acetylthio) -2-methyl- * yl-1-ketopropyl] -4-ethoxy-L-proline Using the procedure described in example III but replacing (trans) -4-methoxy-L-proline with an equivalent amount of trans-4-ethoxy-L-proline (J.Med.Chem., 10, 1161 (1967)) gives (trans) -1 - [D- and 3- (acetylthio) -2-methyl-1-ketopropyl] -4-ethoxy-L-proline. The product is purified as the dicyclohexylamine salt, mp 170-172 ° (crystallization from isopropyl alcohol); [α] 25 -64 ° (c, 1% in EtOH). 15 This salt (7.75 g) is converted to the free acid by treatment with a solution of acid potassium sulfate as described in Example 4 to obtain 4.85 g of an almost colorless (trans) -1- [D-3- (ace - tylthio) -2-methyl-1-ketopropyl] -4-ethoxy-L-proline 20 in the form of a syrup. Example VI (trans) -4-ethoxy-1- (D-3-mercapto-2-methyl- l-ketopropyl-L-proline To 4.85 g of the material obtained in example V is added a cold solution of 9 ml of concentrated ammonia in 22 ml of water under argon. The mixture is processed in the same way as described in example IV, obtaining 4, 2 g (100%) almost colorless (trans) -4-ethoxy-1- (D-3-mercapto-2-methyl-1-ketopropyl) -L-proline in the form of a syrup; [a] ≤ -80 ° (c, 1% in EtOH); Rf 0.64 (MeOH on silica gel, visualization with nitroprusside reagent) Chemical composition for CnHuNOiS: 35 Calculated: C, 50, 55; H, 7, 33; N, 5, 36; S, 12, 27. Found: C, 50, 34; H, 7, 34; N, 5, 39; S, 12, 11. Example VII. (Cis) -1- [D-3- (acetylthio ) -2-methyl-1-ketopro pyl] -4-methoxy-L-proline a) N-carbobenzyloxy-cis-4-hydroxy-L-proline 40 10 g (0.038 mol) N-carbobenzyloxy-4-keto-L-proline are dissolved in 300 ml of methanol and reduced with 5.8 g (0.15 mol) of sodium borohydride in 200 ml of water as described in JACS, 79, 189 (1957) to give 8.7 g of foam product. This material is dissolved in 30 ml of ethanol, treated with 3.5 g of cyclohexylamine in a little ethanol and diluted to 500 ml with ether. After the introduction of the nuclei and friction, the crystalline cyclohexylamine salt is rapidly separated and 10 is obtained. 8 g of salt, m.p. 163-165 °. This cyclohexylamine salt was then treated with 30 ml of 2N HCl and extracted with ethyl acetate (4 × 50 ml) to give 8 g of N-carbobenzyloxy-cis-4-hydroxy-L-proline as a glassy substance. b) N-carbobenzyloxy-cis-4-methoxy-L-proline methyl ester 60 13.9 g (0.052 mol) of N-carbobenzyloxy-cis-4-hydroxy-L-proline is treated with 40 g of silver oxide and 40 ml of methyl iodide (2X) in acetone (first 100 ml, then 120 ml) as described in the second step of the process illustrated in Example 65 I, yielding 17.5 g (100%) of N-kar methyl ester -118 386 13 14 bobenzyloxy-cis-4-methoxy-L-proline in the form of a yellow oil. c) N-carbobenzyloxy-cis-4-methoxy-L-proline 17.5 g (approximately 0.052 mol) of N-carbobenzyloxy-cis-4-methoxy-L-proline methyl ester is dissolved in 135 ml of methanol, droplets at -1 ° to 4 ° 32 milliliters (0.064 moles) of 2N sodium hydroxide solution, then kept at 0 ° for one hour and at room temperature until the next day. After removing about half of the solvent on an evaporator rotating, the solution is diluted with 300 ml of water, washed with ether (the purge is discarded), acidified, cooled with 12.5 ml of 1: 1 hydrochloric acid to pH 2 and extracted with ethyl acetate (4 × 150 ml). The extracts are combined, dried (MgSO 4), filtered and the solvent evaporated to give 15 g of an orange-yellow syrup. The latter is dissolved in 60 ml of ethanol, treated with 6 g of cyclohexylamine in 10 ml of ethanol and diluted to 900 ml with ether. After introducing the nuclei and friction, the crystalline N-carbobenzyloxy-cis-4 cyclohexylamine salt is separated. -methoxy-L-prolines; after being kept at low temperature until the next day, it weighs 10.2 g and has a melting point of 148-150 ° (s. 144 °); [a]% -35 ° (c, 1% in ethanol). After recrystallization from 40 ml of acetonitrile, 8.8 g of an almost colorless solid are obtained; mp 150-152 ° (pp. 145 °); [a] * £ -34 ° (c, 1% in ethanol). The cyclohexylamine salt is treated with hydrochloric acid to obtain 6.9 g (48%) of N-carbobenzyloxy-cis-4-methoxy-L-proline as a thick syrup light yellow in color; [a] ^ —32 ° (c »** in ethanol). d) cis-4-methoxy-L-proline. A mixture of 6.8 g of N-carbobenzyloxy-cis-4-methoxy-L-proline, 210 ml of a 2: 1 mixture of methanol and water and 2.3 g of 5% Pd-C is placed in the hydrogenator under 2 atmospheres of hydrogen for four hours. The mixture is filtered to remove the catalyst and the filtrate is evaporated to give 3.15 g of a grayish solid; mp 218-220 ° (dec.). The sample was recrystallized from a mixture of methanol and ether to give a colorless cis-4-methoxy-L-proline, mp 224 ° -226 ° (dec.); [α] JJ -42 ° (c, 1% in methanol). Chemical composition for CjHuNOj: Calculated: C, 49.64; H, 7, 64; N, 9, 65; Found C, 49.63; H, 7.71; N, 9, 54. e) (cis) -1- [D-3- (acetylthio) -2-methyl-1-ketopropyl] -4-methoxy-L-proline 3 g (0.021 mol) cis-4-methoxy -L-proline and 4.2 g (0.023 mol) of D-3-acetylthio-2-methylpropionyl chloride in 5 ml of ether are reacted in 60 ml of water in the presence of acidic sodium carbonate as described in Example III. About 20 ml of 25% by weight sodium carbonate solution is needed to bring the pH value initially to 8.5 and to maintain the pH value in the range 7.5 to 8.4 during the acylation reaction. , 4 g) was dissolved in 50 ml of ethyl acetate and treated with 3.9 g of dicyclohexylamine in 20 ml of ethyl acetate. The product that crystallizes out of the solution is filtered and dried to give 6.6 g of the dicyclohexylamine salt, mp 172-174 ° (170 ° s.), [Α] * -60 ° (c, 1% in ethanol). ). 6.5 g of this material was crystallized with 35 ml of acetonitrile to give 6 g of a colorless solid dicyclohexylamine salt; mp 173-175 ° (s 170 °). [α] g -60 ° (c, 1% in ethanol). Chemical composition for CH 2 NO 2 S-CuI 4 N: Calculated C, 61.24; H, 9.00; N, 5.95; S, 6.81. Found C, 61.16; H, 8.81; N, 5.95; S, 6.67 Using the procedure illustrated in Example 3, the dicyclohexylamine salt is converted to acid by suspending 5.9 g of this salt in 60 ml of ethyl acetate, which is then chilled in an ice bath and treated with 60 ml of a 10% acid solution. potassium sulfate. The layers are separated and the aqueous phase is extracted with 50 ml of ethyl acetate (4 ×). The organic phases are combined, dried (MgSO 4), filtered and the solvent evaporated to give 3.5 g (60%) of a colorless (cis) -1- [D-3- (acetylthio) -2-methyl-1-ketopropyl] -4-methoxy-L-proline; mp 90-92 ° (triturated with ether); 30 [«] d ~ 139 ° silica gel). Chemical composition for C12H19NO5S; Calculated: C, 49.81; H, 6.62; N, 4.84; Found: C, 49.85; H, 6.66; N, 4.97. Example VIII. a) (cis) -4-methoxy-1- (D-3-mercapto-2-methyl-1-ketopropyl) -L-proline 2.9 g (0.01 mol) (cis) -1- [ D-3- (acetylthio) -2-methyl-1-ketopropyl] -4-methoxy-L-proline is hydrolyzed in 15 ml of water containing 6.5 ml of concentrated ammonia as described in example IV , yielding 2.3 g (93%) of a very thick liquid (cis) -4-methoxy-1- (D-3-mercapto-2-methyl-1-ketopropyl) -L-proline, which during storage becomes wax consistency; [a] g —88 ° (c, 1% in ethanol). b) adamantanamine salt (cis) -4-methoxy-1- (D-3-mercapto-2-methyl-1-ketopropyl) -L-proline. Solution 0.55 g (0.0022 mol) cis-4-methoxy- 1- (D-3-mercapto-2-methyl-1-ketopropyl) -L-proline in 50 ml of ethyl acetate is treated under a protective atmosphere of argon with a heated solution of 0.34 g (0.0022 mol) of 1-adamantanamine. in 10 ml of ethyl acetate to precipitate the salt. After the mixture is kept for 3 hours at low temperature, the solid which is lost is filtered off under a protective argon atmosphere (adhesively retained solvent), washed with a little amount of chilled ethyl acetate and dried for 20 hours in vacuo to give 0. 7 g (79%) of M (cis) -4-methoxy-1- (D-3-mercapto-2-methyl-1-ketopropyl) -L-proline as 1-adamantanamine salt, m.p. 215-217 ° (sublimes 210 °, spreads 220 °); [a] g -60 ° (c, 1% in methanol). Example IX. (cis) -4-methoxy-1- (3-mercapto-2- 68 methyl-1-ketopTopyl) -L-proline 15 118 386 16 a) (cis) -4-methoxy-1- [3- (benzylthio) - 2-Methketopropyl] -L-proline. Reaction of 3-benzoylthio-2-methylpropanoic acid chloride (obtained by treating 3-benzoylthio-2-methylpropionic acid with thionyl chloride) with cis-4-methoxy-L-proline according to The general procedure as illustrated in Example III gives the product (cis) -4-methoxy-1- [3- (benzoylthio) -2-methyl-1-ketopropyl] -L-proline. b) (cis) -4-methoxy-1- (3-mercapto-2-methyl-1-ktopropyl) -L-proline Hydrolysis of (cis) -2-methoxy-1- [3- (benzoyoltio) -2 -methyl-1-ketopropyl] -2-proline with an aqueous ammonia solution, according to the general procedure illustrated in Example IV, gives (cis) -4-methoxy-1- (3-mercapto-2 -methyl-1-ketopropyl) -L-proline. Example X. (trans) -1- [D-3- (acetylthio) -2-methyl-1-ketopropyl] -4-propoxy-L-proline (propyl ester) a) N-acetyl-trans-4-propoxy-L-proline. The reaction between 30 g of N-acetyl-trans-4-hydroxy-L-proline obtained in the first step of the procedure illustrated in Example I, and 110 g of silver oxide and 110 ml of propyl iodide in 300 ml of acetone following the procedure illustrated in the second step of Example II yield 19.6 g (41%) of N-acetyl-trans propyl ester. 4-propoxy-L-proline having a light yellow-orange color; bp 155-165 ° (26.664 Pa). b) N-acetyl-trans-4-propoxy-L-proline. A solution of 6 g (0.15 mol) sodium hydroxide in 150 ml of water is added to 19.4 g (0.075 mol) of N-acetyl-trans-4 propyl ester -propoxy-L-proline to give a light orange colored solution. The solution is kept overnight at room temperature and extracted with 60 ml of ethyl acetate (rejecting the flow) and then acidified with 1: 1 diluted hydrochloric acid, saturated with sodium chloride and extracted with 50 ml of chloroform (3x). the organics were combined, dried (MgSO 4), filtered and the solvent was evaporated to give 12.6 g of a brown oil. The latter is dissolved in 80 ml of ethyl acetate and combined with a solution of 10.7 g of dicyclohexylamine in 20 ml of ethyl acetate. The salt crystallizes out at room temperature. The dicyclohexylamine salt is kept overnight in a cold room, filtered and washed with cold ethyl acetate, yielding 17.3 g of a nearly colorless solid dicyclohexylamine salt; mp 148-153 °. Recrystallization of this material from 125 ml of ethyl acetate gave 14.5 g of a colorless dicyclohexylamine salt; mp 157-159 °; [a] g -30 ° (c, 1% in ethanol). Chemical composition for C10Hi7N (VCitHi3N: Calculated: C, 66.63; H, 10.17; N, 7.07 Found: C, 66.47; H, 10.22; N, 7.06 g. Dicyclohexylamine salt (14.4 g) is converted to the free acid by dusting, slurrying in 100 ml of ethyl acetate and treating the suspension in small portions, totaling 100 ml of 10% acid potassium sulfate solution. The organic phase is separated and the aqueous phase is extracted with 100 ml of ethyl acetate (2x). The organic phases are combined and the solvent is evaporated to give 6.7 g (41%) of N-acetyl-trans-4-propoxy -L-proline in the form of a liquid with a pale brown color. C) (trans) -1- [D-3- (acetylthio) -2-methyl-1-ketopropyl] -4-propoxy-L-proline 10 6, 4 g (0.03 mole) of N-acetyl-trans-4-propoxy-L-proline are treated with a solution of 10 g of concentrated sulfuric acid in 100 ml of water, and the resulting solution is stirred and refluxed under reflux. 3 hours. The solution is gradually cooled to 15 °, 12 g of sodium carbonate are gradually added, adjusting the pH to 8.0 and then treated with a solution of 5.4 g (0.03 mol) of D-3-acetylthio-2 chloride. -methylpropionyl in 5 ml of ether over 10 minutes, adding 7 g of sodium carbonate during this time, in order to maintain the pH value at about 8.0. The mixture is then stirred in an ice bath for 30 minutes and at room temperature in one hour. The product was then isolated and purified as the dicyclohexylamine salt following the procedure illustrated in Example III, yielding 6.3 g of the dicyclohexylamine salt; mp 165—167 ° (from acetonitrile), [α] -56 ° (c, 1% in ethanol.) Chemical composition for C14HzsNO5S * Ci * H23N: Calculated C, 62.62; H, 9.30; N, 5.61; S, 6.43. Found C, 62.35; H, 9.48; N, 5.88; S, 6.45. Dicyclohexylamine salt (6.1 g) is converted to the free acid by suspending in 60 ml of ethyl acetate, chilled in an ice bath and treated with 60 ml of 10% acid potassium sulfate solution. The layers are separated and the aqueous phase is extracted with 60 ml of ethyl acetate (2 ×). The organic phases are combined, dried (MgSO 4), filtered and the solvent is evaporated off, yielding 4.0 g (42%) of (trans) -1- [D-3- (acetylthio) -2-methyl-1-ketopropyl] - -4-propoxy-L-proline in the form of an almost colorless syrup. Example XI. 1- (D-3-mercapto-2-methyl-1-ketopropyl) -trans-4-propoxy-L-proline Hydrolysis 4.0 g (trans) -1D-3- (acetylthio) -2-methyl- 1-1-ketopropyl-4-propoxy-L-proline with 8 ml of concentrated ammonia in 20 ml of water under argon, according to the procedure illustrated in example IV, gives 3.42 g (97%) 1- (D-3-mercapto-2-methyl-1-ketopropyl) -trans-4-propoxy-L-proline in the form of an almost colorless syrup; [a] "-72 ° (c, 1% in ethanol). Chemical composition for CuHjNO3S • 1 / 4HaO: Calculated: C, 51.49; H, 7.74; N, 5.05; S, 11 , 46 Found: C, 51.66; H, 7.76; N, 5.94; S, 10.51. Example XII. 1- (3-mercapto-1-ketopropyl) -60-cis-4-methoxy -L-proline a) 1- (3-acetylthio-1-ketopropyl) -cis-4-methoxy-L-proline According to the procedure illustrated in the example Id, cis-4-methoxy-L-proline is treated with a solution • 5 3-acetylthiopropyl chloride in the presence of sodium i-1T 118 386 18 carbonate to give 1- (3-acetylthio-1-ketopropyl) -cis-4-methoxy-L-proline.b) 1- (3-mercapto-1 -ketopropyl) -cis-4-methoxy-L-proKna-1- <3-acetylthio-1-ketopropyl) -cis-4-methoxy-L-proline is hydrolyzed with aqueous ammonia according to the procedure illustrated in Example II to give 1- (3-mercapto-1-ketopropyl) -cis-4-methoxy-L-proline. Example XIII. (cis) -4- (4-fluorophenoxy) -1- (D- -3 -merkapto-2-methyl-1-ketopropyl) -L-proline a) (cis) -4- (4-fluorophenoxy) -L-proline For a solution of 8.4 g (0.024 mol) of benzyl N -carbobenzyloxy-trans-4-hydroxy-L-proline (Baer et al., Can. J. Biochem. Phys., 37, 583, (1959)), 4.0 g (0.036 mol) of 4-fluorophenol and 9.27 g (0.036 mol) of triphenylphosphine in 75 ml of anhydrous tetrahydrofuran are added dropwise over 1 hour to 6.2 g. (0.036 mole) of diethyl azodicarboxylate in 25 ml of tetrahydrofuran. The solution is stirred overnight at room temperature. The mixture is evaporated and 100 ml of ether are added to the residue. The precipitate consisting of triphenylphosphine and diethyl azodicarboxylate is filtered off. By column chromatography (silica gel) 8.1 g of a mixture containing about 70% of the benzyl N-carbobenzoxy-cis-4- (4-fluorophenoxy) -L-proline benzyl ester is separated. A solution of 7.5 g of the above mixture, containing benzyl ester, it is hydrated at a pressure of 1 atmosphere (room temperature) with 0.8 g of 10% Pd / C. A white precipitate forms during the reaction. After the reaction with hydrogen has ended, the mixture is filtered and the filter cake is digested with three 125 ml portions of hot methanol. The methanol solution was evaporated to dryness to give 3.2 g of cis-4 (4-fluorophenoxy) -L-proline, mp 235-236 °. Chemical composition for CnHuFNO 3. 3HjO: Calculated: C, 57.14; H, 5.48; N, 6.06; F, 8.22 Found: C, 56.94; H, 5.19; N, 5.94; F, 7.97 b) 1- [D-3- (acetylthio) -2-methyl-1-ketopropyl] -cis- -4 (4-fluorophenoxy) -L-proline For suspension 2.25 g (0.01 mol) cis-4- (4-fluorophenoxy) -L-proline in 125 ml of anhydrous pyridine are added at room temperature 1.0 g (0.01 mol) triethylamine and 2 g (0.11 mol) D- chloride 3 - it is stirred at room temperature overnight and then evaporated to dryness. The residue is taken up in water, covered with ether and acidified with 10% hydrochloric acid. The aqueous layer is re-extracted with ether, the ethereal layers are combined, washed with water, dried (NaSOi) and evaporated to dryness, leaving 3.9 g of residue. The residue is chromatographed on 250 ml of silica gel with ether to give a fraction containing the desired product. The column is washed with methanol and pass through methanol again through a short chromatographic column containing silica gel to obtain more product. The procedure was repeated one more time, giving a total of 1.2 g of pure Id-3 * (acetylthio) -2-methyl-1-rketopropyl-4- (4-fluorophenoxy) -L-proline. C) (cis ) -4- (4-fluorophenoxy) -1- (D-3-mercapto-2-methyl-1-ketopropyIo) -L-proline 1.2 g 1- [D-3- (acetylthio) -2- methyl-1-ketopropyl] * -cis-4- (4-fluorophenoxy) -L-proline is dissolved in 25 ml of ethanol and treated with 5 ml of concentrated ammonia under argon for 40 m inut. Volatiles are stripped off and the residue is covered with ethyl acetate. The aqueous layer is acidified with 10% hydrochloric acid. The layers are separated and the acidic layer is washed with ethyl acetate. The combined ethereal layers are stripped with water (2x), saturated with saturated sodium chloride solution (2x) and dried (Na * SO 4). The solvent is stripped off to give 1.1 g of a solid, foamed substance in the form of cis-4- (4-fluorophenoxy) -1- (D-3-mercap-to-2-methyl-1-ketopropyl) -L »-proline Chemical composition for OsHi8FN (V1 / 3HaO: Calculated: C, 54.05; H, 5.70; N, 4.20; F, 5.70; S, 9.60 Found: C, 54.04; H , 5.71; N, 4.05; F, 5.40; S, 9.61 Thin Layer Chromatography confirms the identity of the product, at Rf 0.30, by detection in ultraviolet light with SH reagent ( yellow spot) and vanilla (yellow spot); [a] * -80 ° (c, 1% in chloroform). 25 Example XIV Using the procedure illustrated in example XIII, with the difference that instead of 4-fluorophenol in step the first, an equivalent amount of 4-fluorophenyl mercaptan is used, it is (cis) -4- (4-fluorophenylthio) -1- (D-3-mer-80-capto-2-methyl-1-ketopropyl) -L -proline The melting point of this product, in the form of a salt with adamanthylamine, is 242-243 ° C. Example XV. 1- (D-3-mercapto-2-methyl-1-ketopropyl) -cic-4- phenylthio-L-proline A) N-carbobenzyloxy-cis-4-phenyl-thio-L-proline methyl ester 0.85 g (0.037 mol) of sodium metal is dissolved in 40 ml of absolute ethanol. 3.7 ml (0.036 mole) of thiophenol 48 and then 7.5 g (0.017 mole) of N-carbobenzyloxy-trans-4-toluene-4-sulfonyloxy-L-proline methyl ester (J) are added to the solution while stirring. Amer. Chem. Soc., 79, 191, (1957). The latter compound gradually dissolves, but solid product precipitates shortly thereafter. The mixture is stirred for 4 hours and kept at room temperature until the next day, the ethanol evaporates. on a rotary evaporator. For the most part, the solid residue is mixed with 120 ml of dichloromethane and 60 ml of water. The layers are separated (some methanol is added to facilitate separation of the emulsion) and the aqueous phase is extracted with additional dichloromethane (2 × 60 ml The organic layers are combined, washed with 100 ml of a saturated sodium chloride solution, dried (MgSO 4), the solvent is evaporated to give 6.5 g (100%) of N-carbobenzyloxy-cis-4-phenyl-thio-L-proline methyl ester in the form of a slightly liquid oil with a light yellow color. in b) N-carbobenzyloxy-cis-4-phenylthio-L-proline. The methyl ester product obtained in the previous step (6.5 g, 0.017 mol) is dissolved in 55 ml of ethanol *; treat at ~ 16 to 4 ° 13 ml (0.026 mol) divided into smaller portions of 2N sodium hydroxide solution, stirred at 0 ° for 1 hour and kept at room temperature for about 16 hours. gin. After about half of the solvent has been removed on a rotary evaporator, the cooled solution is diluted with 100 ml of water, washed with 60 ml of ether (the purge is discarded), covered with 70 ml of ethyl acetate, stirred, cooled and acidified with 4.8 ml of hydrochloric acid, diluted in a proportion of 1 : 1. After separation, the aqueous phase was extracted with additional ethyl acetate (3.times.40 ml) and the combined organic layers were dried (MgSO4) and evaporated to give a 5.9 thick liquid oil with a light yellow color. The latter compound dissolved. in 30 ml of ethanol, treated with 1.9 g of cyclohexylamine in 3 ml of ethanol and diluted to 330 ml with ether. Upon the introduction of seed crystals, the crystalline cyclohexylamine salt is separated. After standing for about 16 hours at low temperature, the amount of salt obtained was 5.3 g; mp 148-151 ° (subl. 135 °). This material is combined with 1.5 g of the identical product of the previous experiment, mixed with 200 ml of boiling acetonitrile and chilled to give 6.3 g of colorless cyclohexylamine salt; mp 152-155 ° (subl. 137 °); [a] -24 ° (c, 1% in ethanol). The above cyclohexylamine salt is suspended in 25 ml of ethyl acetate, stirred and treated with 25 ml of a 1N hydrochloric acid solution. After separating into two transparent layers, their separation is performed and the aqueous phase is extracted with additional ethyl acetate (3 × 25 ml). The combined organic layers were dried (MgSO 4) and the organic solvent was evaporated to give 5.0 g (65%) of N-carbobenzyloxy-cis-4-phenylthio-L-proline as an almost colorless, very thick liquid syrup. c) (cis) -4-phenylthio-L-proline hydrobromide 4.9 g (0.014 mol) N-carbobenzyloxy-cis-4-phenylthio-L-proline are treated with 25 ml of hydrobromide in acetic acid (30-32% ), loosely closed with a stopper and mixed with a magnetic stirrer. After one hour, the orange-yellow solution is diluted to 250 ml with ether, whereby the product is precipitated as a high-viscosity oil, which gradually crystallizes upon introduction of seed crystals, rubbing and cooling. The material was stirred in an ice bath for one hour, filtered under nitrogen, washed with ether, suspended in fresh ether, cooled for about 16 hours and drained again to give 3.2 g (77% ) (cis) -4-phenylthio-L-proline hydrobromide, m.p. 106-109 ° (subl. 99 °); [α] JJ -3 ° (c, 1% in methanol). d) 1- [D-3- (acetylthio) -2-methyl-1-ketopropyl] -cis- -4-phenylthio-tr-pholine Reaction between 3.0 g (0.0094 mbla) of hydrobromide (cis) -4-phenylthio-L-prolyri and 2.0 g (0.0011 mol) of D-3-acetylthio-2-methylpropionyl chloride in 25 ml of water, under the conditions described in example I, step IV (using about 15 ml 20% sodium carbonate solution to maintain the pH value in the range 8.0 to 8.4), leads to 3.8 g of a dense liquid funnel with a pale yellow * color. In two crops a total of 2.9 g of dicyclohexylamine salt (prepared in 30 ml of ethyl acetate using 1.8 g of dicyclohexylamine (mp 184-188 ° (subl. 180 °)) are obtained. 15 ml of acetonitrile yield 2.4 g of a colorless solid dicyclohexylamine salt, mp 184-186 ° (subl. 180 °); [α] 75 ° (c, 1% in ethanol). The above dicyclohexylamine salt is treated with 30 ml. 10% potassium sulfate acid solution and extracted with ethyl acetate as described in Example 2 to obtain 2.0 g (59%) of [1D-3- (acetylthio) -2-methyl-1-ketopropyl] -cis-4-phenyl-thio-L-proline, with a glass appearance. 10 e) 1 - (. D-3-mercapto-2-methyl-1-ketopropyl) -cis- -4-phenylthio-1-proline 2 .0 g (0.0042 mol) 1- [D-3- (acetylthio) -2-methyl-1-ketopropyl] -cis-4-phenylthio-L-proline is treated with 3.5 g of concentrated ammonia in 8.5 ml water according to the procedure illustrated in example II (sta) and the ammonium salt is separated from the mixture of rea %) to obtain 1.35 g (100%) of 1- (D-3-mercapto-2-methyl-1-ketopropyl) -cis-4-phenylthio-L-proline jjj with the consistency of a thick liquid syrup; [a] JJ —43 ° (c, 1% in ethanol). Example XVI. Using the procedure illustrated in Example XV, with the difference that in the first step thiophenol is replaced with 4-chlorophene-methyl mercaptan, one obtains 1- (D-3-mercapto--2-methyl-1-ketopropyl) -cis- 4- (chlorophenylthio) -L--proline. The melting point of this product, in the form of an adamantylamine salt, is 240 ° -241 ° C. 40 Example XVII. (trans) -1- (3-mercapto-1-ketopropyl) -3-methylthio-D, L-proline a) 1,2 tert-butyl ester 1,2-dehydroproline Solution 34.2 g (0, 20 moles) of the tert-butyl proline ester in 600 ml of the ester is mixed and added dropwise at -5 ° to 0 ° over 10 minutes, 21.7 g (23.9 ml, 0.20 moles) freshly prepared tert-butyl hypochlorite (Org. Syn., Coli. Vol. V, 184 (1973)). During the instillation, the temperature remains within the range of -5 ° to 0 °. After the addition of the reagent is complete, the solution is stirred at this temperature for an additional 5 minutes. The vigorously stirred solution is added quickly (about 3-5 minutes) with a solution of 7.8 g (0.20 mol) of fresh potassium. distilled anhydrous (CaHs) tert-butanol. Upon completion of this operation, the temperature of the reaction mixture was approximately 18 °. The reaction vessel was removed from the bath, and the reaction mixture was stirred for 30 minutes while cooling. The reaction mixture is passed through the celite (diatomaceous earth) and the filtrate is concentrated under reduced pressure. The residue is suspended in ether and washed with several portions of water. The ethereal solution is dried and concentrated under reduced pressure to give 31.6 g of a yellow-colored liquid. A trace amount of hydroquinone is added and the crude product is distilled to give 22.4 g of 1,2-dehydroproline tert-butyl ester (66%), boiling point 60-62 ° (13.332 mbar). b) 1-benzyloxycarbonyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid tert-butyl ester. Solution of 16.9 g (0.1 mol) of 1,2-dehydroproline tert-butyl ester in 70 ml of dichloromethane is cooled to -10 ° in an argon atmosphere. A solution of freshly distilled benzyl chloroformate (14.2 ml, 0.1 mol), bp 62-64 ° (53.328 Pa) (in 70 ml of dichloroethane) is added dropwise over 30 minutes. The mixture is stirred at low temperature for a further 30 minutes, and over a period of 20 minutes, treated with a solution of 15.22 g (0.1 mol) of 1,5-diazabicyclo [5.4.0] undecene in 70 ml of dichloromethane. The cooling bath then removes are mixed and stirred for one hour at room temperature. After washing twice with cooled dilute hydrochloric acid and a single wash with saturated sodium carbonate solution, the solution is dried in vacuo to give 18.2 g (60%) of l-benzyloxycarbonyl-4-tert-4-butyl ester. , 5-dihydro-1H-pyrrole-2-carboxylic acid as a pale yellow oil. c) Tert-butyl (trans) -1-benzyloxycarbonyl-3-methylthio-D, L-proline. Solution of 18.2 g (0.06 mol) of tert-butyl ester of l-benzyloxycarbonyl-4 acid The 5-dihydro-1H-pyrrole-2-carboxylic acid in 180 ml of anhydrous methanol is treated with 3.24 g (0.06 mol) of sodium methoxide and cooled in an ice bath. Methanethiol is bubbled through the solution at low speed for 30 minutes. The mixture is stirred overnight under argon at room temperature. Dilute acetic acid is then added to the mixture until it is slightly acidic. Argon is then bubbled through the solution for one hour, and the solution is then evaporated to almost dry under reduced pressure. Ethyl acetate is added to the residue and the solution is washed twice with saturated sodium carbonate solution, dried and freed from the solvent under reduced pressure to give 17 g of oil with a yellow color. This oil is separated by chromatography using 300 g of silica gel and a mixture of petroleum ether and ether (4: 1) to give 11.1 g of (trans) -1-benzyloxycarbonyl-3-methylthio-D, L-proline as an oil colorless. d) (trans) -3-methylthio-D, L-proline 8.4 g (0.024 mol of (trans) -1-benzyloxycarbonyl -3-methylthio-D, L-proline are treated with 45 ml of 4N hydrobromic acid in acetic acid The solution is stirred for one hour at room temperature and dried in vacuo. A little water is added to the residue and washed twice with ether. The aqueous solution is poured onto a column containing 300 ml of ion exchange resin and water is passed through until the eluate ceases to show signs. strongly acidic reaction. The product is then eluted with a buffer solution of pH 6.5 (aqueous pyridine acetate solution). Fractions showing a positive reaction to ninhydrin are pooled and lyophilized to give 3.4 g ( 88%) of the product in the form of a white fluff A small sample of this material is recrystallized from ethanol to give (trans) -3-methylthio-D, L-proline, mp 196-200 ° (dec.) (sub. 192 °). Chemical composition for CeHuOiNS: Calculated: C, 4 4.70; H, 6.88; N, 8.69; S, 19.89. Found: C, 44.53; H, 7.10; N, 8.61; S, 19.95. a) (trans) -1- [3- (acetylthio) - 1-ketopropyl] -3-methylthio-D, L-proline 3.05 g (0.019 mol) (trans) -3-methylthio-D, The L-prolines are dissolved in 19 ml of 1N sodium carbonate solution 80 and diluted with 10 ml of water. The solution is cooled in an ice bath and, with vigorous stirring, a solution of 3-acetylthiopropionyl chloride in 20 ml of ether is added. The pH value is maintained by the addition of a 1N sodium carbonate solution equal to S. After 2 30 minutes the pH value does not change anymore and a total of 45 ml of sodium carbonate solution is added to the solution for this purpose. The layers of the mixture were separated and the aqueous layer was washed once with ether. The aqueous layer is then acidified with a 10% solution of acid potassium sulfate and the product is extracted with ethyl acetate, dried and freed from the solvent under reduced pressure to give 5.2 g of an oil. The material is separated by chromatography on 150 g silica gel, elution with ethyl acetate. 3.85 g of the (trans) -1-3- (acetylthio) -1-ketopropyl-3-methylthio-D, L-proline impurity are obtained. 40 A small sample is dissolved in ether and converted to the dicyclohexylamine salt to give the dicyclohexylamine salt (trans) -1- [3-acetylthio) -1-ketopropyl] -3-methylthio-D, L-proline at the temperature of mp 153-157 °. 45 Chemical composition for CuH13NS-fCeHnJHN: Calculated: C, 58.55; H, 8.53; N, 5.83; S, 13.57 Found: C, 58.77; H, a, 57; N, 5.68; S, 13.74. f) trans (-1-) 3-mercapto-1-ketopropyl) -3-methylthio-D, L-proline 50 2.05 g (0.007 mol) (trans) -1- [3- (acetylthio) - 1-Capropyl] -3-methylthio-D, L-proline is cooled in an ice bath under argon with a mixture of 7 ml of water and 7 ml of concentrated ammonia. The solution is stirred for 30 minutes at 0 ° C and then acidified with hydrochloric acid. The product is extracted with ethyl acetate, dried and freed from the solvent under reduced pressure to give 1.85 g of a material, which crystallizes partially on standing. By triturating with ether, 1.0 g (57%) of a white crystalline product is obtained. By recrystallization with ethyl acetate (5 ml), 0.85 g of (trans) -1- (3-mercapto-1 * ketopropyl) -3-methylthio-D, L-proline is obtained, m.p. 89-93 ° .23 118 38 * 24 Chemical composition for CfHisOjNSt: Calculated: C, 43.35; H, 6.06; N, 5.62; S, 25.72 Found: C, 43.35; H, 5.54; S, 25.91. Example XVHI. (cisH ^ 3-mercapto-2D-methyl-1-ketopropyl) -4-phenoxy-L-proline Using the procedure described in Examples and IV but replacing 4-methoxy-L-proline with an equivalent amount of cis-4-phenoxy-L -proline gives the title compound in crystalline form. The melting point of this product is 125-135 ° C. Example XIX. (cis) -l- (3-mercapto-2D-methyl-1-ketopropyl) -4-tert-butyloxy-L-proline Using the procedure described in examples 3 and 4 but using an equivalent amount of cis-4-tert. - butyloxy-L-rtoline instead of 4-methoxy-L-proline, the title compound is obtained in the form of a colorless solid, mp 106-108 ° C (sintering 103 ° C). Example XX. (cis) -1- (3-mercapto-2D-methyl-1-ketopropyl) -3-phenoxy-D, L-proline Using the procedure described in Examples III and IV but substituting 4-methoxy-L-proline equates to With the amount of (cis) -3-phenoxy-D, L-proline the title compound is obtained in the form of a colorless solid, mp 134-155 ° C. (mixture of diastereoisomers). Example XXI. (cis) -1- (3-mercapto-2D-methyl-1-ketopropyl) -4- (4-methylphenyl) thio-L-proline Using the procedure described in example III and IV but replacing 4-methoxy-L- proline, equal to the amount of Eis-4- (4-methylphenyl) -thio-L-proline, the title compound is obtained, the adamanthylamine salt of which has a melting point of 240 ° -241 ° C. Example XXII. (cis) -1- (3-mercapto-2D-methyl-1-ketopropyl) -4- (4-methoxyphenyl) thio-L-proline Using the procedure described in example III and IV but replacing 4-methoxy-L -proline, an equivalent amount of 4- (4-methoxyphenyl) thio-L-proline, is the title compound, the adamanthylamine salt of which has a melting point of 237-239 ° C. Patent claims 1. Method for the preparation of new derivatives of - #captoacyl substituted prolines of formula I in which Rupa X-Rt is attached to the 3- or 4-position of the proline ring; X is oxygen or sulfur; R is hydrogen or a lower alkyl radical; Ri is lower alkyl, lower alkenyl, lower alkenyl, phenyl (lower) alkyl, R * and Rs each independently represent hydrogen, lower alkyl, R4 is hydrogen or R * - CO- where R 'is a lower alkyl, phenyl or phenyl- (lower) alkyl radical; and n is a number with the value 0, 1 or 2 and their salts with bases, characterized in that the proline compound of formula 2, wherein X and R 1 are as defined above, are combined with an acid or its chemical equivalent of formula 3, wherein R 1, R j, R 4 and n are as defined above, and the optionally produced product in which R 4 is R 5 —CO — is hydrolyzed to give a product in which R 4 is hydrogen. '* 2. The method for the preparation of new mercaptoacyl derivatives of the substituted prolines of formula I, in which the group X-Ri is attached to the 3- or 4 * position of the proline ring, X is an oxygen or sulfur atom, R is a hydrogen atom or lower 15 alkyl radical, Ri is a lower alkyl radical, a lower alkenyl radical, a lower alkenyl radical, a phenyl radical, a substituted phenyl radical, a phenyl (lower) alkyl radical or a substituted phenyl (lower) alkyl radical. , R * and R 'each independently represent a hydrogen atom, a lower alkyl radical or a trifluoromethyl radical, R4 is a hydrogen atom, a group of the formula R5-CO-, where R9 is a lower alkyl, phenyl or phenyl- (lower) alkyl radical and n is a number of 0, 1 or 2, where when Ri is a lower alkyl radical, a lower alkenyl radical, a lower alkynyl radical, a phenyl- (lower) -alkyl radical, then at least one of Ra and Rj represents the trifluoromethyl group, and their * • salts with base I, characterized in that the proline compound of formula II, in which X and R 1 have the above meanings, are combined with an acid or its chemical equivalent of formula III, in which Rt, Rj, R4 and n are as defined in above, "* and the optionally formed product in which R4 is R5-CO- is hydrolyzed to form a product in which R4 is hydrogen. 118 386 Ra R z1H X-R1 R4 - S- (CH)) n- CH-CO-NC- COOR H W20R 1 H. rf XR1 HN-C-COOR PATTERN 2 ^ 3 ^ 2 R4-S- (CH) n-CH-C00H PATTERN 3118 386 HN-C-COOH oKna-NC -COORi HH MODEL 4 MODEL 5 H2C ^ f0Ts & «- NC-COOa / MR! -X-Na MODEL 6 MODEL 7 -NCC 1 W * - NC-COO protective alkyl, N ^ MODEL 8118 386 ..a MODEL9 DESIGN 10 SR, Q9ZL "^^ - COO alkyl FORMULA 11 (CH2) w ^ O - (CH2) P- MODEL12 FORMULA 13 6 - S02 -®- CH3 FORMULA 14 PL

Claims (1)

Claims 1. A process for the preparation of novel substituted mercaptoacyl proline derivatives of formula 1, wherein Rupa X-Rt is attached to the 3- or 4-position of the proline ring; X is oxygen or sulfur; R is hydrogen or a lower alkyl radical; Ri is lower alkyl, lower alkenyl, lower alkenyl, phenyl (lower) alkyl, R * and Rs each independently represent hydrogen, lower alkyl, R4 is hydrogen or R * - CO- where R 'is a lower alkyl, phenyl or phenyl- (lower) alkyl radical; and n is a number with the value 0, 1 or 2 and their salts with bases, characterized in that the proline compound of formula 2, wherein X and R 1 are as defined above, are combined with an acid or its chemical equivalent of formula 3, wherein R 1, R j, R 4 and n are as defined above, and the optionally produced product in which R 4 is R 5 —CO — is hydrolyzed to give a product in which R 4 is hydrogen. '* 2. A method for the preparation of the new mercaptoacyl derivatives of the formula I substituted with X-Ri is attached to the 3- or 4-position of the proline ring, X is oxygen or sulfur, R is hydrogen or lower alkyl radical, Ri is a lower alkyl radical, a lower alkenyl radical, a lower alkenyl radical, a phenyl radical, a substituted phenyl radical, a phenyl (lower) alkyl radical or a substituted phenyl- (lower) radical alkyl, R * and R 'each independently represent a hydrogen atom, a lower alkyl radical or a trifluoromethyl radical, R4 is a hydrogen atom, a group of the formula R5-CO-, where R9 is a lower alkyl, phenyl or phenyl- (lower) radical alkyl, and n is a number of 0, 1 or 2, provided that when Ri is a lower alkyl radical, a lower alkenyl radical, a lower alkynyl radical, a phenyl- (lower) -alkyl radical, then at least one of Ra and Rj is the trifluoromethyl group, and their * • salts from base A compound of formula II, in which X and Ri have the above meanings, are combined with an acid or its chemical equivalent of formula III, in which Rt, Ri, R4 and n are as defined in above, "* and the optionally formed product in which R4 is R5-CO- is hydrolyzed to form a product in which R4 is hydrogen. 118 386 Ra R z1H X-R1 R4 - S- (CH)) n- CH-CO-NC- COOR H W20R 1 H. rf XR1 HN-C-COOR PATTERN 2 ^ 3 ^ 2 R4-S- (CH) n-CH-C00H PATTERN 3118 386 HN-C-COOH oKna-NC -COORi HH MODEL 4 MODEL 5 H2C ^ f0Ts & «- NC-COOa / MR! -X-Na MODEL 6 MODEL 7 -NCC 1 W * - NC-COO protective alkyl, N ^ MODEL 8118 386 ..a MODEL9 DESIGN 10 SR, Q9ZL "^^ - COO alkyl FORMULA 11 (CH2) w ^ O - (CH2) P- MODEL12 FORMULA 13 6 - S02 -®- CH3 FORMULA 14 PL