CS230562B2 - Production method of halogen n-/mepkaptoacyl/proline derivatives - Google Patents

Abstract

Compounds which have the general formula (I> <IMAGE> wherein R is hydrogen, lower alkanoyl or <IMAGE> m is 1 or 2; n is 0 or 1; R1 is hydrogen or lower alkyl; R2 and R'2 each is hydrogen or halogen; R3 is hydrogen, lower alkyl or CF3, and also halogen when n is 1; R4 is hydrogen, lower alkyl or trifluoromethyl; R6 is hydrogen, and also halogen when m is 1; at least one of R2, R'2, R3, R4 and R6 being halogen or CF3 as represented by the symbols and only R2 and R'2 can both be halogen at the same time, and basic salts thereof may be used as hypotensive agents.

Description

Particularly preferred are those compounds of formula I in which the hydrogen or C 2 -C 4 alkanoyl group, in particular hydrogen or acetyl, represents a hydrogen atom or a C 1 -C 4 alkyl group, in particular a hydrogen atom. .

in each case hydrogen or halogen, in particular hydrogen or fluorine, in each case represents a hydrogen atom, a trifluoromethyl group or an alkyl group. . C 1 -C 4 carbon atoms, wherein in the case of. and R8 is a hydrogen atom, one of R1 and R1 is trifluoromethyl and the other of which is hydrogen, and has a value of 0 or 1, in particular 1.

Managed by the preferred configuration for the above prines is the L-configuration ·

The above-defined alkyl groups are straight or branched chain hydrocarbon radicals, from methyl to ethyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. Preferred are those groups mentioned above containing 1 or 2 carbon atoms.

The aforementioned alkanoyl groups are to be understood as meaning the acyl radicals of lower C 2 -C 4 fatty acids, such as, for example, acetyl, propionyl, bityrole, isobutyryl and the like. Acetyl is particularly preferred.

By halogen atoms is meant all four conventional halogens, of which chlorine, bromine and fluorine, especially fluorine, are preferred.

Compounds of formula (X) above may be prepared by a variety of synthetic procedures.

In general, these compounds can be prepared by reacting the compounds of formula XX

RS- (CH) _n -CH-COOH (XX) is condensed with aminotyyslinou formula XXX ^H 2 \ / ^2/4

И ₂ with CH ₂

HN-CHCCOC4 (III) by any method that can be used to form amide bonds [see, for example, der Organischen Chemie (Houbsn-Weyl), part X,. 376 et seq., part Ш, page 1 and later (1974)).

The acids of formula H in which n has a value of 1 can be obtained by addition of a thiocyanate of formula

R-SH to a suitably substituted acrylic acid. For the temporary protection of the mercaptoacin in the compounds of the formula (I), a p-methenoxybutyl radical R may be used. This group is then removed by treatment with trifluoroacetic acid and mercuric acetate. The gels of the general formula H1. wherein δ is 0 to be prepared by an exchange reaction using an acid of the formula R-SH and 2-halo-methyl.

When R in the starting material of the formula XI is an alkanoyl group having 2 to 4 carbon atoms, they are obtained by the above reaction of a compound of the formula V

COOR, (V), wherein alk is a (C 1 -C 3) alkyl group which can then be converted by conventional alkaline hydrolysis or anonolysis. can be converted to the corresponding compounds of formula VI

COOR, (VI).

In the case where R 1 represents an ester residue (i.e., when R represents a C 1 -C 4 alkyl group which is present in the product when the starting acid of the formula III is used in the ester form), it is possible to this ester residue is cleaved in a conventional manner. Thus, for example, when R 1 is a tert-butyl group, it is obtained by reacting an ester of formula (V) or (VI) with trifluoroacetic acid and an anisole in addition to the free acid. In the case of other alkoryl groups, the corresponding acid is obtained by basic hydrolysis.

When the starting material is an acid of formula (III) or the resulting product in the form of free carboztylic acid, it can be converted to the ester, for example by esterification with diazoalkane, such as diazomethane, 1-alkyl 1-3. - .beta.-trichloro-azene, such as 1-o-tert-butyl-3-ylglyltrezeoe, and the like;

According to a variant of the invention the ester of formula III, preferably tert-butyl or meetyl- operate in anhydrous prootředí such as dichloromethane, tetrahydrofuran, dioxane, etc., Acylthioakkanvvvu acid of formula VII and ^{4 - | 3} -alk-CO -S- (CH) n-CH-COOH (VII) in the presence of dicyclic hexyltrimide, N, N'-carbonylbisimidazole, ethorylacetyl, diphenylphosphorycaside or the like condensation agent, at a temperature in the range of about 0 to 10 ° C. The ester group can then be removed, for example by treatment with trifluoroacetic acid and anisone at a temperature around room temperature, to give the corresponding free acid (R1 = hydrogen).

In accordance with a further moodfication, preferably when n is 1, R1 is a trifluoromethyl group and R1 is a hydrogen atom, the acid of the formula akk-CO-SH is reacted with an acrylic acid derivative of the formula VIII.

(VVII), - COOR, _{^η н о с} i J Uι

I liI

CH = C-C -N and then proceed as described above.

Compounds of formula VIII are prepared from 3-trifluoroethylacrylic acid and an ester of formula III as described in Example 1 below.

Halogen compounds of formula (III) which are used as starting materials can be prepared by known methods [see, for example, Biochemistry 6, 2509 (1965), Amt. J. Chem., £ 0, 1493 (1967), J. Arner, Chem., Soc. 6, 4709 (1964); J. Med. Chem. 20, 1176 (1977)].

The products of formula I produced contain one or more centers of asymmetry. Accordingly, the compounds of formula I may exist in stereoisomeric forms or in recombinant mixtures thereof. All of the above forms are within the scope of the invention. In the synthetic procedures described above, the racemate or one of the enantiomers may be used as the starting material. When the racemate is used as the starting material for the synthesis, the resulting product can be resolved into stereoisomers by conventional chromatographic techniques or by freeze-drying. The preferred isomeric form is generally the L-isomer (with respect to the basic center of the asylene).

The compounds produced by the process of the invention form salts with various inorganic and organic bases, which salts are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts such as sodium and potassium salts (these salts are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohenyrlamine, benzathine, N-mmt I-D-glucamine and hydrabamine, salts with amino acids such as arginine, lysine and the like. Preferred salts are non-toxic, physiologically acceptable salts, but other salts are also useful, for example, to isolate or purify products.

Solve the said salts are prepared in a conventional manner by the reaction product as the free acid with one · or more equivalents of the appropriate base poskytujcí desired cation in extended ^p ou ^by adding an organic solvent or prootředí in which the salt is insoluble not ^b o in a ^ga with follow-íÍrodstměním water By non-ironization of the salt with an insoluble acid, such as an β-cycle ion exchanger (for example with polystyrenesulphonic acid such as Dowex 50) or with an aqueous acid, with extraction with an organic solvent such as ethyl acetate, dichloromethane and the like can be again, the free acid can be recovered and optionally converted to another salt.

Further experimental details are set forth in the Examples, which are preferred embodiments and also serve as modal processes for preparing other compounds of the invention.

The compounds of the invention are useful as typotensive agents. These compounds inhibit the conversion of the decapeptide α-β-β-I to engiotenein II and are therefore useful for suppressing or alleviating hypertension caused by anglotensin. Angiotensin I is produced by the action of the enzyme renin, not angiotheresis, which is pseudoglottinHn in blood plasma.

Angiotensin I is converted to angiotensin II by the action of the angiotensin converting enzyme (ACE). The latter compound is an active hypertension which causes various forms of hypertension in various mammalian species, such as rats and dogs.

The compounds of the invention interfere with the angiotensinogen process, -> (renin) -> angiotensin I -> (АСЕ) - ^ angiotensin II by inhibiting the enzyme АСЕ and suppressing or eliminating the formation of the angiotensin II pressor. Administration of compositions comprising one or more compounds of Formula I, or physiologically acceptable salts thereof, ameliorates angiotensin-induced hypertension in a mammal suffering from the disease.

The result of the modeled animal tests described by S. L. Engel, T. R. Schaeffer, Μ. H. Waugh and B. Rubin [Proc. Soc. Exp. Biol. Copper. 143. 483 (1973)], a single dose, or preferably two to four sub-daily doses, in an amount of 0.1 to 100 mg of active ingredient per kilogram of body weight per day, preferably about 1 to 50 mg, is suitable for lowering blood pressure. kg / day ^

The active compounds according to the invention are preferably administered orally, but can also be administered parenterally, such as subcutaneously, intramuscularly, intrevenously or intraperitoneally.

The compounds of the invention may be used to lower blood pressure in the form of compositions, such as tablets, capsules or elixirs for oral administration, or sterile solutions or suspensions for parenteral administration.

Tzv. A unit dose, commonly known in pharmaceutical practice, comprises about 10 to 500 mg of a compound or mixture of compounds of Formula I, or a physiologically acceptable salt thereof, in combination with a physiologically acceptable carrier, binder, preservative, stabilizer, flavoring, or other auxiliary substance. Said compositions contain an amount of active ingredient such that a suitable dosage will be obtained within the above range when administered.

Examples of excipients which may be used in the preparation of tablets, capsules and the like include binders such as trangant, acacia, corn starch or gelatin, diluents such as calcium phosphate or microcrystalline cellulose, disintegrating agents such as corn starch , potato starch, alginic acid and the like, glidants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint oil, wintergreen oil or cherry flavoring.

When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various longer materials may be used to coat or otherwise modify the physical form of the unit dose.

For example, tablets may be coated with shellac, sugar, or both. Syrups or elixirs may contain the active ingredient, sucrose as a sweetener, methyl and propylparabens as preservatives, coloring and flavoring agents such as cherry or orange flavor.

Sterile injectables may be prepared by conventional pharmaceutical procedures by dissolving or suspending the active ingredient in a vehicle such as water for injection, natural vegetable oils such as sesame oil, cocoa oil, peanut oil, cottonseed oil and the like.

The invention is illustrated by the following non-limiting examples. These examples describe particularly preferred embodiments.

Example 1

1- (4,4,4-Trifluoro-2-butenoyl) -L-proline

In a 50 ml flask equipped with a Dean-Stark trap, 7.0 g (0.1 mol) of boric anhydride (prepared by melting boric acid in a platinum crucible and comminuting under nitrogen) was mixed with 32.2 g (0.173 mol). of ethyl 3-hydro-3,4,4-trifluorobutenoate and the mixture was heated in a salt bath until all the anthrydride had dissolved (6 hours). The temperature is raised to 350 ° C, 23 ml of distillate are collected in the well. The dessilate is returned to the reaction flask and the aforementioned gaze - repetition. This procedure was repeated four times to ensure complete dehydration with the hydrosulfate.

The dilatate is pelletized in petooletheum, dried over phosphorous phosphate and distilled. Yield - 10 g ethylesteou 4.4 | ^ 4 ^ * ^ ^{<^} ril ^] ^ ^ 22 ^ oox buien ^ o ^ ve - ester (b.p. 115-120 ° C) and 650 mg of 4,4,4 trifluoro-lenoic acid (van 150 ° C, melting point 53-55 ° C from pentane crystallization).

The ester was mixed with 24 ml of -0% aqueous sodium hydroxide, stirred at 25 ° C for 6 hours, then diluted with water and extracted with ether to remove unreacted material. Aqueous layer with concentrated hydrochloric acid. The mixture was extracted three times with 50 ml of methylene chloride each time.

The organic layers were combined, dried over sodium sulfate, concentrated and distilled. Crystalline 4,4,4-trifluoro-2-lueic acid having a van temperature of 145-153 ° C is obtained. After recrystallization from pentane, the acid melts at 54-55 ° C. Yield 4.6 g.

A mixture of 4.91 g (35 mmol) of 4,4,4-trifluoro-2-lysinic acid, 4.73 g (35 mo) of hydroxybenzotriazole, 6.00 g (35 mmol) of L-proline tert -butylssteol and 7. 22 g (35 ml) of dicyclohexylcarbodiioid are stirred in 200 ml of ethyl phosphate overnight under nitrogen at room temperature. '

The resulting mixture is filtered, the filtrate is washed twice with 50 ml each of 5% sodium hydrogen sulphate and twice with 50 ml each of saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated. The oily residue is taken up in ether, the solution is cooled and the precipitate formed is filtered off.

Concentration of the IR gives 8.7 g of a solid, m.p. 95 DEG-100 DEG C. which gave a single spot with a Rf value of 0.85 when thin-layer chromatography on a thin layer of silica gel in an ethyl acetate-dichloromethane (1: 1) solvent system.

4.0 g (13.6%) of the above-prepared 1- (4,4,4-trifluoromethyl-2-butynoyl) -L-proline tert -butylettene with 60 ml of trifluoroacetic acid and 13 ml of enol The mixture was stirred under nitrogen for 1 hour. The roasters were evaporated at age, the residue was dissolved in 10 ml of ether and poured into 500 ml of foam. ,

This precipitation is repeated and the residue is allowed to stand at 0 ° C for 72 hours while undergoing step-thylation. After recrystallization from a mixture of stylyl acetate and hexane, 1- (4,4,4-oxo-22-biphenyl) -L-ol is obtained, m.p. 119-120 ° C. Siní extract 2,4β g.

Example 2

- (- mercapto-1,4,4-trifluoromethyl) -L-proline

1.5 ml of acetic acid was added to -20 mg ((3 mol of 1 - ((, 4,4-trifluoro-2-lutengyl)) in an atmospheric atmosphere. The mixture was stirred overnight at room temperature, and the excess acetic acid was evaporated in vacuo and the remaining 1- (3-methylthio-4,4,4-trichloro-thiotlotnoyl) (-L-prolonged with ethyl acetate). Aqueous ammonia (15 ml concentrated ammonia + 15 ml water).

The mixture was stirred at room temperature for 2 hours, then diluted with ice and washed with concentrated hydrochloric acid. The acidic mixture was extracted with ethyl acetate (3 x 50 ml), dried over sodium sulfate and concentrated. The oily residue was dissolved by dissolving in water (used - osdestigative water), clarifying the solution with activated charcoal and filtering through a millipore filter (0.4 β then 0.08 m). 3-mercapt-3-mercapto-trifluorobutanoyl-L-proline in the form of a glassy product · Rf = 0.24 [benzene-acetic acid (7: 1)] ·

Example 3 cis-1- [D-3- (acetylthio) -2-methylpropanoyl] -4-flbor-L-proline

4.5 g (0 '; 021 ' eol) of cis [beta] - [beta] - [beta] -L-proline hydrobromide and 4.2 g (0.023 mol) of D-3-acetylthi) 22 ' 20 minutes of reaction in 50 ml of water in the presence of sodium carbonate to maintain a pH of 8.0 to 8.2 during the acylation. After a further hour, the mixture is washed twice with 50 ml of ethyl acetate, overlaid with ethyl acetate, propyl and hydrochloric acid to pH 2, saturated with sodium chloride and the layers are separated.

The aqueous phase was not extracted with further ethyl acetate, the organic layers were combined and evaporated to dryness. The solid residue after evaporation of ethyl acetate and under ether was triturated and evaporated again. 5.4 g (93%) of a colorless product, m.p. 146 DEG-148 DEG C. (sintered at 133 DEG C.) and optical rotation [.alpha.] @ -132 DEG (c = 1; methane).

Adding dicyclohexylamine to the cis-1- [D-3). (Acetylthi)) - 2mnehyrlpripanoiOl242flцo _{Γ), Γ} .L2p I.2 isoquinoline in 70 ml of ethyl acetate was prepared dicyclohexylammonium salt · 8.1 g salts which from ethyl vyknytmluje and has a melting point of 202 to 204 ° C (sinters at 187 ° C) and an optical rotation of ^[α] ρ ⁶ - ⁷² ° ⁽ c = ^1; methtno ⁱ ).

After krytel-ISATIO i80pripolalkihilb of 90 ml, 7.0 g of product, mp 205-207 DEG C. @ ¹ Linum 9 at ⁰ ° ^C) and TLCK rotocifa ^] ^ = - ⁷ ° · 4 patterns ^to exhibit the ^d uktu ^e after překxrrstalování from ethanol, no change in melting point ENI neither optical rotation ·

16.9 g of the cyclotexylammonium salt are converted back to the free acid by shaking between 10% potassium borohydride and ethyl acetate (60 ml of a 10% potassium hydrogen chloride solution and four extractions each with 50 ml of ethyl acetate). The organic layers were combined and evaporated to dryness · 4.1 g (71%) of colorless free acid, mp 154-156 ° C (sintered at ¹ 40 ° ^C), and ^P ^ ⁱ cal rotaaiCfo] ^ = -142 ^(c = 1, methyl htao ^{e i).}

EXAMPLE 4 • C24-C24ffboo211- (2-2-methyl-2-methylpropanoyl) -L-propanol

3> 9 g (0.014 mol) of IIS-1- [D-'3-aacetytthO)) ^p 22maetlorPpro eooyO] 242fbucπ2L2prilinb hydrolysed in 22 ml of water contains! 9 ml of concentrated ammonium hydroxide. The reaction mixture was crystallized with hydrochloric acid and extracted with ethyl acetate. Concentration of the organic layer to dryness yielded 3.3 g of a glassy product which, when dried at 50 DEG C. under a pressure of 27 Pa, slowly melted to the cover. triturated with 20 ml of ethyl acetate under gentle heating under argon, diluted with 25 ml of hexane and, after trituration, cooled to room temperature overnight. argon ·

Filtration under argon, washing with hexane and drying in vacuo afforded 2.8 g (85%) of a colorless solid cis-4-fluoro-1- (D) -3-eecappi22-metholpripano [2H] -proline with a melting point of 135-137 °. C (sinters at 129 ° C) e optical rotation '' = -116 ° (c = 1; ι ^^ οΌ ·

Example 5

1- (2-Isopropylthyl) -12-ylpropapanoy-L-L-proline (Isomer A).

1.44 g of L-proline and 667 mg of sodium carbonate were dissolved in 17 ml of water and dissolved. After stirring, it is cooled in ice, and then a solution of 2 g of sodium carbonate in 8.5 ml of water is added, followed immediately by 2.5 g of 3-acetyl-h-o-2-h-halo-o-propanoic acid chloride. Remove the cooling bath. After 30 minutes, a precipitate formed which was dissolved by adding 17 ml of water. After a total of 1.5 hours, the reaction mixture was extracted twice with ethyl acetate, the aqueous layer was cooled, acidified with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. After drying over magnesium sulfate and concentration in vacuo to dryness,

3.3 g of crude product as an oil.

The oil was applied to a 100 g @ 1 H @ 2 gel column and eluted with 7: 1 benzene / acetic acid. 2 g of product are obtained which, after taryalization from water, yields 450 mg of 1- [3- (acetylhydroxy) -2-trifluoromethyl-4-ol] m.p. 111 DEG-113 DEG C. and an optical rotation of [.alpha.] D = 170. ° (c = 1; ethane).

Example 6 _:

- [Зз (acetylthiu) -2-chloropoupanooSl-LpгoUio (isomer · B)

The aqueous mother liquors of Example 5 were lyophilized and purified by chromatography using a 7: 1 mixture of benzene and acetic acid as eluent. The fraction containing the material 10002010, UV light, which, according to the crystallography, is not a thin layer of homunene, was started, concentrated to dryness and the residue crystallized from water. 800 m of compound are obtained at a melting point of 90 to 109 ° C and an optical rotation of -44 ° (c = 2,1-ethhenol). The mother liquors were concentrated to dryness by lyophilization and the residue formed by 1- [3- (acatylhhlo) -2-chloroPOPOPlonoyl] -L-propyl (isomer

B) is crystallized from a mixture of ether and hexane. 380 mg of the product is obtained at a melting point of 108 DEG-110 DEG C. and an optical rotation of +17.6 DEG (c = 1.25; ethanol).

Example 1 a d 7

1- [3- (ajcetythho) -2-Oromppoopnonyl-11 Lpollin

Substitution of 3-pentylhhlo-β-hlopropanic acid chloride by the procedure of Example 5 with 3pecetylhlo-O-bromopropinic acid chloride yields 1-b- (ietetylthiophthalmol)] - β-γ-11 at a melting point of 109-110 ° C and an optical rotation of [i]. [.alpha.] D = -162 DEG (c = 1.39, Et2O).

Example

3p (Meihosophobonyl) tU-o-t-trSOOmorphetylmorpholonate acid

A mixture of 3.9 g of 1-trifluoromethyl-acrylic acid and 4.3 g of 4-methyl-4-carbonyloylthols was stirred at 100 DEG to 110 DEG C. for 1 hour, then left to cool to room temperature and solid maltrial. recrystallizes from cyclohexin. The desired product melting at 72-74 ° C is obtained.

EXAMPLE 9 teoc.Oul ^; ^] Lesteo 1- (3- (4-methophpboaoyllthiop2ptrifSuomyl) yrlpropeooyhJpL (prolins)

To a solution of 6.5 g of 3- (4-pmtho) β-carbonyoyl-thiOp 2 -ptrifluoro-pentane and 3.76 g of taoc.Ostyl.asteou proline in 500 ml of dichloromethane is added 4.53 g of dicyclohexylchloride while stirring at 0 ° C. 30 minutes at 0 ° C, then overnight at lithium temperature, filtered and the filtrate was neutralized. The organic layer was dried and concentrated to dryness in vacuo. The ttlikagahs thin-layer residue chromatograph in the methylene chloride-ethyl acetate (95: 5) solvent system contains two major spots of 0.46 and 0.51 Rg, respectively, corresponding to two iilseoaooi8Paorom ·

Example 1 a d 10 *

- (3-menrkatOv22 · lrlfllVImβt ^ hrlpropotnvlL) -L · ppoVio

A solution of 4.47 g of tert-butyl ester 1- [3- (methylmethoxybenzyl) -2-trifluoromethylchloroethyl] -L-proline prepared in Example 9 and cooled to 0 DEG C. with 10 ml of anisol, and then firstly 100 ml. acid and then 3.18 g of mercuric acetate.

·. The cooling bath was removed, the reaction mixture was stirred for 1 hour at room temperature, then snapped to dryness in vacuo and the residue triturated with ether / hexane. The insoluble material was suspended in water and hydrogen sulfide was suspended for 10 minutes. The precipitate was filtered off and the filtrate was collected. 1- (Zmerkepto-2-trifluoromethyl-chloroethyl) -L-prolio was obtained as a dark solid, which had a silica gel gel thin layer in a 7: 1 benzene-acetic acid solvent system (7: 1) Rf 0.29- 0.31.

Example tunes 1

Chloride D · 3ltcetyllhVl2l-meUyL0pvopanvové keliny

A suspension of 1 50 g (690 mam) of 1 · 1 (D-3-methyl-2-methyl-2-methylpyrrolidin-1-one) in 1,274 ml of water and 426 ml (5,526 mol) of concentrated hydrochloric acid was heated under stirring to reflux for 8 hours. reflux condensers *. The resulting solution was allowed to stand overnight at room temperature and then extracted ten times with 400 ml of chloroform.

The combined chloroform extracts were dried under nitrogen over sodium sulfate and evaporated. 176 ml (1.809 mol) of cethanhydride and 180 ml of pyridine are added to the residue of 81.2 g and the mixture is left to react at 20 DEG C. for 20 hours and then evaporated.

The oily residue is dissolved in 1000 ml of ethyl acetate, the solution is treated with 200 ml of a saturated sodium chloride solution containing 5% hydrochloric acid (pH 2 of the liquids), twice with a saturated sodium chloride solution (second with a pH of 7). ) and then the solvent is evaporated

96.9 g (86.5%) of a clear, oily residue having an optical rotation of -61.8 DEG (chloroform) are obtained. To this residue was added 83 ml (1.173 mol) of freshly-treated citric acid and the solution was stirred at room temperature for 18 hours while gas evolution occurred.

The supernatant was removed in vacuo at a bath temperature of 50 ° C and distilled under reduced pressure. 55.9 g of D13-tert-ethylthio-1-methylpropionic acid chloride, boiling at 40 DEG-44 DEG C./23 to 27 Pa, are obtained, and the optical rotation is -42.5 DEG (c = 2; methanol).

Example 12

Tr8aos1 - ['D-1-Lacetylthio) -2-methyl-11-propyl] -4-fluoro-L-orolLo

A) Tran8-1lbosyl · vylcycloool·L - fllvrlL-orolio

11.5 ml of 2N sodium hydroxide solution are added dropwise at a temperature of 0-5 ° C to a solution of 6.2 g of tert-butylbenzylcarbonyl-oxylcarbonyl ester in 50 ml of methanol at 0-5 ° C, the mixture is cooled at 0 ° C for 1 hour and then is allowed to warm to room temperature overnight. The mixture was quenched from reduced pressure to half its original volume, diluted with 100 mL of water, extracted with ether and the ether extracts discarded.

The aqueous solution was acidified to pH 2 with hydrochloric acid while cooling. - the lever is extracted four times with 50 ml of ethyl acetate each time. The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

230 562

194 DEG-196 DEG C. and an optical rotation of -44 DEG (c @ + - .delta.);

The free acid is obtained by passing the cyclohexilammonium salt in 25 ml of ethyl acetate with 22 ml of 1 N hydrochloric acid and extracting the aqueous layer four times with 35 ml of ethyl acetate each time. The combined ethyl acetate extracts were without ^^ c ^ smoke sulfurizing sulfate - rozpooutědlo and evaporated under reduced pressure to give the desired trsn8-1- ^<banzylo: χУcceЪooyl'4 - luoχr> -L-proline.

B) trans-4-fluoro-L-proline tydrobromide

A mixture of 3 g of trana-1-benzlloxycarbonyl-4-fluoro-L-proline and 15 ml of 30-32% hydrogen bromide in acetic acid was stirred for 1 hour, after which 150 ml of anhydrous ether was added. The solvent is decanted from the precipitate and the precipitate is triturated first with - fresh ether and then with mottylethylketone. There was obtained trans-4-fluoro-L-proline hydrobromide, m.p. 162-164 ° C - (decomposition) and optical rotation [α] -30 ° (c 1 ann methanone).

C) Trans-1- [D-3- (Acatylthio) -2-methyl-1-oxopropyl] -4-fluoro-L-proline

To a solution of 1.9 g of trena-.alpha.-fluoro-L-proline hydrobromide in 25 ml of cold water was added 1 g of sodium carbonate with stirring to adjust the pH to 8.2. 1.8 g of D-3-acetylthio-2-methylpropionyl chloride in 2.5 ml of ether are then added dropwise to the mixture, while cooling at 5 [deg.] C. and stirring, while maintaining the pH at about 8 by dropping a 25% aqueous solution of sodium carbonate. 2 ei 8.3. After the addition was complete, the reaction mixture was stirred with cooling for 1 hour, then extracted twice with 25 ml of ethyl acetate each time, and the extracts were washed with ethyl acetate.

50 ml of ethyl acetate were added to the aqueous layer, and concentrated hydrochloric acid was added dropwise to the mixture with stirring and cooling until pH 2.0. The aqueous layer was saturated with sodium chloride and the ethyl acetate layer was separated. The aqueous layer was extracted three times with 25 ml of ethyl acetate each time, the combined ethyl acetate extracts were taken up in anhydrous magnesium sulfate and concentrated under reduced pressure. The desired product is obtained, which is converted into the dichloro-hexylammonium salt by dissolving in 25 ml of ethyl acetate and adding a solution of 1.8 g of dioiclohexilamine in 35 ml of ethyl acetate.

The precipitated salt was filtered off and recrystallized from isopropyl alcohol. The disidohexylemmonium salt of tris-1- [D-3- (soothyl) -2-methyl-1-oxo-propyl] -4-fluoro-L-proline melting at 209 DEG -211 DEG C., optical rotation [.alpha.] -85 DEG (.delta.

The free acid was regenerated by dissolving the dicidohexylammonium salt in 5% aqueous potassium bisulfate solution and extracting the solution with ethyl acetate. The ethyl acetate extract was extracted with anhydrous magnesium sulfate and concentrated under reduced pressure. The desired product is obtained

1- [D-3- (acetylthio) -2-methyl-1H-1-oxopropyl] -4-fluoro-L-pgoline

Example 13

Traa8s4-fluoro-1- (D-3-marcapto-2-methyl-1-oxoproppУ) -L-proline

To a cold solution of 4.2 ml of concentrated ammonium hydroxide in 16 ml of water and introduce a stream of argon, and then, under argon atmosphere, add 1.8 < trans-1- [D-3- (α * tlthio)] stirring. 2-Methyl-1-oxopropyl-4-fluoro-L-proline. The reaction mixture was stirred for 2 hours then extracted with ethyl acetate.

The ethyl acetate extract is discarded, 30 ml of ethyl acetate are added to the aqueous layer, the aqueous layer is treated with concentrated hydrochloric acid, saturated with sodium chloride, and the ethyl acetate layer is separated. The aqueous layer is extracted three times with EA modes 30 ml ethyl acetate, the combined ethyl acetate extracts were vy® ¹ ^ anhydrous magnesium hořečiutým and sahuuaí SS shí1 1 weight limit pressure. The desired trns-4-fluoro-1- [D-3-mercapto-2-methyl-1-oxopropyl] -L-proline is obtained with an optical yield of [α] = -112 ° (c »1%; methanol) .

Example 14

1- [D-3- (acetylthio) 22-methyl-1-oxopropyl] -4,4-difluoro-L-prolio

A) 1-Benzyl-p-β-γ-cyclo-1,4-difluoro-L-pooline

To a cooled solution of 3.3 g of 1-benzyloxleabonol-4-keto-L-proline meecyl ester in 80 ml of n-trichlorodichloride was added dropwise 3.3 ml of methylamifluorofluorifluoride in 80 ml. The reaction mixture is allowed to stand overnight at room temperature, about 100 g of crushed ice are added while stirring, and the resulting mixture is stirred for 45 minutes. The organic layer was separated and the aqueous layer was extracted twice with 40 ml of meetylene chloride. The combined extract was dried over anhydrous magnesium sulfate and reduced under reduced pressure. There was thus obtained 1-benzyl-1,4-dioxo-1,4-dihydro-1,4-difluoro-L-methyl-methyl alcohol.

B) 1-Benzyloxycarbonyl-4,44-difluoro-L-proline

11.5 ml of 2 N sodium hydroxide solution are added dropwise at a temperature of 0-5 ° C to a solution of 5.6 g of 1-benzyl-hexyl-1,4-difluoro-L-proline meethyl ester in 50 ml of methanol. The reaction mixture was allowed to react at 0 ° C for 1 hour and allowed to warm to room temperature overnight. The resulting mixture was turned to about half its original volume under reduced pressure, diluted with 100 mL of water, extracted with ether, and the ether extract was discarded. The aqueous solution was acidified with dilute hydrochloric acid to pH 2 from cooling and extracted three times with 50 ml of ethyl acetate each time.

The bitylacetate extract was combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then bent. The desired 1-beozyloxycarbonyl-4,4-difluoro-L-prolio is obtained, which salt is converted to the cyclohexylemmonium salt. The product has a melting point of 180-185 ° C and an optical rotation of = -24 ° (c = 1%; ethanol).

The free acid is obtained by adding hydrochloric acid to the aqueous solution of the cyclohexylsonic acid salt and extracting the mixture four times with 30 ml of haloacetate. The ethyl acetate extract was dried over anhydrous magnesium sulphate and bent under reduced pressure. The desired t-beosyl-4-cyclooyl-4,44 difluoro-L-prolio is obtained.

C) 4,4-difloo-L-pouline hydrobromide

A mixture of 2.4 g of 1-benzylcarbonyl-4,44-fluoro-L-prulia and 12 ml of 30 to 32% hydrogen bromide in acetic acid was stirred at room temperature for 30 minutes and then 300 ml of anhydrous ether was added. The resulting mixture was cooled, the precipitate formed was decanted and dried under reduced printing. The desired 4,4-difluoro-L-poolin hydrobromide melts with decomposition at 163-165 ° C, with an optical rotation of [α] = -14 ° (c = 1%; methanoo).

D) 1-D-3- (acetyl, hio) 22-ultlyl-1-oxuprupyl-4-di-1H-l-prolio

To a solution of 2.7 g of 4,4-fluoro-L-poolin hydrobromide in 30 ml of water cooled to 5 ° C was added solid sodium carbonate up to a pH of 8.4 and then mixed under constant cooling. and stirring dropwise 2.4 g of D-3-acetyl-thio-2-methylpiperfooyl chloride in 3 ml of anhydrous ether, maintaining the pH of the solution at 8.1 to 8.3 by adding 25% aqueous sodium carbonate solution. After the addition was complete, the reaction mixture was stirred under cooling for an hour, then extracted twice with 25 ml of ethyl acetate and the extract. is postponed. Ethyl acetate (50 ml) was added to the aqueous layer, and concentrated hydrochloric acid was added dropwise with stirring and cooling to pH 2.0.

0 562

The aqueous layer was saturated with sodium chloride and the ethyl acetate layer was separated. The aqueous layer was extracted three more times with 25 ml of ethyl acetate each time, the combined ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The desired product is obtained, which is converted into the dicyclohexylammonium salt by dissolving in 40 ml of ethyl acetate and adding a solution of 2.3 g of dicyclohexylamine in 5 ml of ethyl acetate.

The precipitated salt is filtered off and recrystallized from ethanol. The dicyclohexylammonium salt of 1- [D-33 (ethylthio) -2-methyl-1-oxoppropl] -4,4-difluoro-L-proline melts at 225-227 ° C and has an optical rotation of [α] = -70 ° (c = 0.5%;

The free acid is regenerated by dissolving the dicyclohexylammonium salt in 5% aqueous potassium bisulfate and extracting with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulphate and curved under reduced pressure. The desired 1- [D334 (acetylthoo (22-methyl-1-isoxropropS) -3,4-difluoro-L-proline) was obtained.

Example 1 d 1 1

4,4-Difluoro-1- (D-3-mercapto323methyl-1-oxopropyl) -L-proline

To a cold solution of concentrated ammonium hydroxide (4.6 ml) in water (11 ml) was added a stream of argon, and 2.1 g of 1-fD-1- (4-acetylthio) 2-methoxys-1-oxoopooylS-3,443ffluprзL was added under stirring in an argon atmosphere. The reaction mixture was stirred for a further 2 hours and then extracted with ethyl acetate.

The extract was discarded, 30 ml of ethyl acetate were added from the aqueous layer with stirring, the aqueous layer was acidified with concentrated hydrochloric acid, saturated with sodium chloride, and the ethyl acetate layer was separated. The aqueous phase is extracted three times with 25 ml of ethyl acetate each time, the combined ethyl acetate extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The desired 4,4зfifSuoз - (- (DзЗ-mercaptpз2зmethylз1зpχoprooyS) -L-proline in the form of a syrup is obtained, with an optical rotation of [α] = -85 ° ( _c = 1 ·· methane!).

Example 16

Ciu-4зchlprз1- (3-aceSythiPз23-D-methylprppanopS) -L-prolio

3.15 g of cis-4-chloro-4-chlorophenol bromide are treated with 2.8 g of D-3-acetylthiP-2-methylpropionyl chloride in 40 ml of water containing 2.3 g of sodium carbonate (the acid chloride is first dissolved in 4 ml of ether) . The mixture was maintained for 10 minutes by the addition of 8 ml of 25% sodium carbonate solution at pH 8.2 to 8.4.

VVsledná mixture was stirred for another hour, then the product extracted into ethyl acetate from which 3.6 g · maateiálu viscous oil which was converted into ethyl n ^e salt dicyklohexyleminem, Tojice ¹⁸⁹ and ^{from 192} ° C ^(sinters at, ¹⁸⁵ ° C). After recrystallization from isopropyl alcohol, the melting point was increased to 190-192 ° C (sintered at 188 ° C).

Example 17

Ci8з4зchlpr41 4 (3-merkeptoз2зD-meethSpгooeeopSl-LLзroPlo

1.6 g of the product of Example 16 ee by hydrolysis in 9 ml of water containing 4 ml of concentrated ammonium hydroxide are converted to 1.2 g of the desired product which, after trituration with hexane, gives 1.1 g of a colorless solid, m.p. and the optical rotation Mj ⁶ = -79 ° (c = »1%; ethane!) ·

Claims (2)

SUBJECT OF THE INVENTION Process for the preparation of halogenated N- (mercaptoacyl) proline derivatives of the general formula X (I) RS- (CH) _n -CH-CO-N ------------ CH-COOR in which R represents a hydrogen atom or an alkanoyl group having 2 to 4 carbon atoms, n being 0 or 1, R is hydrogen or alkyl having 1 to 4 carbon atoms, each of R ₂ and R represents a hydrogen or halogen atom, n 3 represents a hydrogen atom, a (C1-C4) alkyl group or a trifluoromethyl group, provided that when D is 1, R ^ is also a halogen atom and / or R is hydrogen, alkyl having 1 to 4 carbon atoms, or trifluoromethyl, with the proviso that at least one of R _2, R _2, and R represents a halogen atom or trifluoromethyl group, in accordance with the above meanings of these symbols wherein only R 8 and R ₂ can both simultaneously represent a halogen atom and their base salts, characterized in that the acid of the general formula II (II) in which: R, ^R 3, ^R 4 ^and - as defined above, condense with the amino acid of formula III h ₂ c ch ₂ (III), HN ----------- CH-COOR ₁ wherein R @ ₁ , R @ ₂ and R @ 2 are as defined above, the resulting product of formula (I) wherein R is C2 -C4 alkanoyl and the remaining radicals are as defined above, optionally hydrolyzed to the corresponding product wherein R @ 2 represents a hydrogen atom and / or the resulting compound is optionally converted by treatment with a base into its base salt. 2. The process of item 1 for producing compounds of formula Ia wherein (Ia), R, R and n are as defined in point 1, each of R2a and R2a being hydrogen or fluorine » When n is 0, trilomethyl is 1, and when n is 1, R 1 and R 6 are both trifluoromethyl and the other is hydrogen, and their salts with oases, The compounds of the formulas IIa and IIIa can be used as starting materials R-S- (CH) n-CH-COOH; H _O C CH, (Ia) (IKe), HN ---------- CHcOOJRj of which R, R, о ^»К 21 '* RJA 2a' and ^R ga mmaí here of limbs herein defined.