IE60995B1 - Process for the synthesis of alpha N alkylated amino acids and esters thereof. Application to the synthesis of carboxyalkyl dipeptides. - Google Patents

Abstract

Process for industrial synthesis of the derivative of formula (I): <IMAGE> and their addition salts with an inorganic or organic acid or base, in which: R1 is linear or branched lower alkyl (of 1 to 6 carbon atoms), R2 is hydrogen or a linear or branched lower alkyl group (of 1 to 4 carbon atoms). Application to the industrial synthesis of carboxyalkyl dipeptides.

Description

The present invention relates to a process for the industrial synthesis of N-alkylated, optionally esterified, a-amino diacids and their application in the industrial synthesis of carboxyalkyl dipeptides.

More specifically, the present invention relates to a new process for the industrial synthesis of derivatives of the general formula (I)s (S) HO - OC - CH - NH CH - CO - 0¾ (S) (I) and their addition salts with a mineral or organic acid or base, in which formula: Ri is linear or branched lower alkyl (having from 1 to 6 carbon atoms), R2 is hydrogen or a linear or branched lower alkyl group (having from 1 to 4 carbon atoms), and the two asymmetric carbon atoms have the (£) configuration.

The derivatives of formula (I) which are obtained, according to the process of the invention can be used in the synthesis of carboxyalkyl dipeptid.es of formula (II): Pi R30 - OC - CH - N - CO - CH - NH - CH - CO - OR2 (II) A | CH3 as well as in the synthesis of their pharmaceutically acceptable salts, in which formula: Ri and R2 have th® same meaning as in formula (I) iR3 is a hydrogen atom or a lower alkyl group having from 1 to 4 carbon atoms, - the structure CH - N denotes indoline, isoindoline, tetrahydroquinoline, tetrahydroisoquinoline, perhydroindole, perhydroisoindole, perhydroisoquinoline , perhydroquinoline, perhydrocyclopenta(b]pyrrole, 2azabicyclo(2,2,2]-octane or 2 azabicyclo [ 2,, 2,1 ] heptane.

The preferred compound of formula (XI) is perindopril of formula (III) (S) - CH - CCOC2H5 s (ill) or (2&, 3afi, 7a£i)~l-<2-( 1-(ethoxycarbonyl)-(&)-butylamino](S)-propionyl}-octahydroindole-2-carboxylic acid, as well as ! addition salts with, a pharmaceutically acceptable acid or base, for which the process of the invention may be more particularly applied. a The compounds of formula (II) as well as their salts hav© interesting pharmacological properties. In particular, they exert an inhibiting activity on certain enzymes, such as carboxypolypeptidases, encephalinases or kininase XX. in particular, they inhibit the conversion of angiotensin I decapeptide to angiotensin II- octapeptide, which are responsible in certain cases for arterial hypertension, by acting on the conversion enzyme.

Th® therapeutic use of these compounds makes it possible, therefore, to reduce or even to suppress the activity of these IS enzymes, which are responsible for hypertension or cardiac insufficiency. The action ot kininase II results in an increase in circulating bradykinin and also in a reduction in blood pressure via this route.

Compounds of formula (II) and, more particularly, the compound. of formula (III), its preparation and its therapeutic use have been described in European Patent Ko- 0 049 658.

The compounds of formula (I) can be employed for the preparation of compounds ox formula (II).

The compounds of formula (I) comprise two so-called asymmetric carbon atoms, each being capable of having two configurations Β or (Rt,S) (R,S) * * * Rx HO ~ OC - CH - NH - CH - CO - OR2 (I) CH3 Ths compounds of formula (I) exist, therefore, in the form of four stereoisomers which may be denoted by (&,&), (R,£), (£,B) and (£,H), according to the configuration of the two so-called asymmetric carbons.

The most active compounds of formula (II) are those where the two carbon atoms in the side chain both have the £ configuration.

This is the reason why the process according to the present invention is concerned more particularly with the industrial synthesis of compounds of formula (I) in which the two asymmetric carbon atoms both have the £ configuration.

Few specific processes for the industrial synthesis of the derivatives of formula (I) have been described. European Patent Application No. 0 117 488 is known, which is very general and which employs α-carboxylated trifluoromethanesulphonates. However, the stereochemistry of both starting materials must be strictly chosen in order to obtain the desired diastereoisomer of the product of formula (I). It is possible by preparations 6 to 8 of EP 0095163 to obtain compounds that are structurally similar to the derivatives of -- formula (I)- However, the operating conditions described in that Application are not compatible with obtaining large » quantities of the derivatives of formula (I). Finally, us Patent 4296110 gives general conditions for the synthesis of derivatives of formula I without either indicating the stereochemistry of the asymmetric carbon atoms or providing a solution to the problems encountered by the person skilled in the art in obtaining a specific diastereo-isomer in a high yield.

The Applicants have now found a process for the industrial synthesis of derivatives of formula (I) which is of great interest, because, on the one hand, it is very simple to implement and, on the other hand, it employs a natural and therefore inexpensive starting material, alanine, which thus introduces a chain member that already possesses th© £ configuration.

When the synthesis is complete, the (£.,£) and {£,£) isomers obtained are separated by a simple fractional crystallisation in the presence of maleic acid.

The combination of these choices, which are made in accordance with a strict selection, makes if possible to obtain a synthesis of the compounds of fomula (I) which is especially advantageous for industrial scale application. More especially, the process according to the invention consists in employing as a starting material L-alanine of formula (IV, s (S) - CH - COOK (IV) CK3 in which: the asymmetric carbon has the £ configuration In which the carboxyl group is protected by esterification with bensyl alcohol, in the presence of para-toluenesulphonic acid, with the water formed being progressively distilled off, to obtain a derivative of formula (V,s ΗΖΝ - CH - COOCK2CsH3 ch3 (V) in the form of its para-tolunenesulphonate which is converted, by rendering alkaline with ammonium hydroxide, into the corresponding base which, after extraction, is condensed, with the application of heat in the presence of a tertiary amine, with a brominated derivative of formula (Vl)s Br - CH - COOR2 (VI) Ri in which Ri and R2 have the same xmeaning as in formula (I), to obtain a derivative of formula (Vli)~ (S) (R,S) C6H3CH2OCO -CH - NH - CH - COOR2 (VII) CH3 Ri in which Rx and R, have the same meaning as in formula (I), the (£,£) isomer of which is isolated by bringing into organic solution and adding maleic acid, the precipitate obtained being filtered off, dried and recrystallised to give a maleate of the (£,£) isomer of the derivative of formula (VII), the latter being liberated from its salt by rendering an aqueous solution alkaline, followed by extraction and evaporation of the solvent, I the (£,£) isomer thus obtained being subjected to hydrogenolysis in the presence of palladium/earfoon to give the compound of formula (I).

The invention also extends to the novel products obtained during the implementation of the process according to the invention and, more particularly, to salts of polycarboxylic acids with the derivatives of formula (VII).

The following Example illustrates the invention, but does not limit it in any way.

EXAMPLES Η-[(£)-1-ΕΤΗΟΧΤΟϋΚΒΟΪϊΤ^ΒΐΓΓΥΙ,)-(£)-ΑΙ«ΑΗΙΗΕ STAGE As Benzyl ester of (£)-alanine, para-toluene-sulphonate Heat to reflux, with stirring, a suspension of 8.2 kg of (£)alanine, 1.78 kg of para-toluenesulphonic acid and 2 kg of benzyl alcohol in 3.30 litres of toluene, and distill off the water as it is formed.

Refluxing is continued until the theoretical quantity of water is obtained.

Cool the reaction mixture to 70°C and evaporate it under vacuum. Into the pasty residue obtained, pour 12.30 litres of diisopropyl ether and stir for 5 hours at 20-22°C.

The suspension obtained is suctioned off and the precipitate is washed with two 1.50 litre portions of diisopropy! ether.

After drying, 32 kg of the para-toluenesulphonate of (£)alanine benzyl ester are obtained.

Xi£ld= 99.0 % Rotatory..powers [«]d° ~ -3° .7 (c = 1/MeOH) Melting points 90°C JA£xaxed_SDecrs2ffier£2: (Nu j ο 1) s 5 Bands at 1760, 1730 era'1 m£l^XLJ»aaagtiq_^^sonanee_si2e£i£prae££v ‘h -SO MHs: solvents methanol-d4 δ = 1.41 ppm, doublet, 3H, CH-CH,. J=6.9 Hs δ = 2.29 ppm, singlet, 3H, CH3-C6Ha δ - 4.02 ppm, quadruplet, IH, CH-CH,, J=6.9 Hz S = 4.85 ppm, broad signal, 3H, ΜΗ?, S03fi S = 5.21 ppm, singlet, 2H, COO-CH? δ = 7.0 to 7.8 ppm, unresolved peaks, 9K, aromatics.

STAGE Bs Benzyl ester of 5,-alanine To a solution of 3.14 kg of the para-toluene-sulphonate of (£,) -alanine benzyl ester in 9.30 litres of water add ammonium hydroxide until alkaline.

Keep stirring for thirty minutes, then extract with 1.25 litres of methylene chloride. Separate off the organic phase and counterextract the aqueous phase with two 1-litre portions of methylene chloride.

Combine the methylene chloride phases, wash them with water and then dry over magnesium sulphate.

After evaporating off th© methylene chloride, 1.5 kg of the benzyl ester of (£)-alanine are obtained in the form of a yellow oily liquid.

Helds 95% ln£xa£ed_spacxro®etrv (Nuj ο1)s Sands at 1750 and 1730 csn'1 MucIgax,magjieHS_XSafiE^O££-^S£tXQmet£y ‘h - 60 MHz: δ = 1.39 ppm, doublet, 3H, CH-CH^,. J=6.9 Hs δ = 3.98ppm, quadruplet, IH, CH-CH?.» J=5.9 Hs δ = 4.90 ppm, broad signal, 2H, NH2 δ = 5.23 ppm, singlet, 2H, COO-OJj δ = 7.10 ppm, unresolved peaks, 5H, aromatics.

STAGS C: Benzyl ester of N-[ 1-ethoxycarbonylbutyl]-(£)*alanine Heat gradually to 90eC, with stirring, a mixture of 1.43 kg of the benzyl ester of (£)-alanine, 1.84 kg of ethyl abromovalerate and 8.9 kg of triethylamine in 12 litres of N,N15 dimethylformamide. Keep stirring for three hours at 90°C before cooling the reaction mixture to 70°C.

Evaporate off the Ν,Ν-dimethylformamide under vacuum, then take up the oily residue in 7 litres of diisopropyl ©ther. Add 7 litres of water and keep stirring for half an hour.

Separate off the organic phase and extract the agueous phase with 3.5 litres of diisopropyl ether. Combine the organic phases and extract them with 9 litres of a molar solution of hydrochloric acid. Render alkaline the aqueous phase thus obtained using sodium carbonate, then extract with diisopropyl ether. Combine the organic phases and wash them with water; dry over magnesium sulphate and then evaporate under vacuum. 2.11 kg of the benzyl ester of N-(l-ethoxycarbonylbutyl]-(£,alanine are obtained in the form of a lightly coloured oil. - il Xifilxb S6% Infrared...aagct£QSiQtX3i (Hu j ο 1) s Bands at 1760 and 1730 cm1 Nuclear magnetic resonance apgcxrpmetrv lH - 60 hffizs 5 solvent CC14 = 0.65 - 1.60 pom, unresolved peaks 13 H (2 x CH3 + ) β - 2.11 ppm, singlet, IS δ = 2.95 to 3.49 ppm, multiplet, 2 x CS S = 3.99 ppm, quadruplet, 2H, Cfii-CHj, J~6.6 Hz = 5.02 ppm, singlet, 2H, CH2-0 δ = 7.20 ppm, unresolved peaks, 5H, aromatics.

STAGE D; Maleate of Nl·-[ (£)-1-ethoxycarbonylbutyl J ~ (£) -alanine bensyl ester Add 376 g of maleic acid to a solution of 1.9 kg of th© benzyl ester of M-[l~ethoxycarbonylbutyl]-(£)-alanine in a mixture of 10.44 litres of cyclohexane and 5.22 litres of acetone. The mixture is then heated to 80°C with stirring and the solution obtained Is kept at reflux for one hour. Allow to cool to room temperature and keep stirring for twelve hours before ice-cooling for two hours to 0.5°C.

Suction off the precipitate and wash it with cyclohexane on the filter.

After drying, 1070 g of crude salt ar® obtained and are recrystallised from a mixture of cyclohexane and acetone.

In this manner 955 g of the maleate of N-[(£)~lethoxycarbonylbutyl)-(£)-alanine benzyl ester are obtained in the form of a white crystalline powder.

BQtatO£y_gowg£s [a]2D° = -19.0° (c = 1/EtOH) gaining aaia&s io2°c iategd,. -goe.c_txommar: (Nu j o 1) : a band at 1740 cm-1 Nuclear.magnetic. re.sonanGg_gpectroinekcy- *H - SO MHz: solvents COC13 δ = 0.80 - 2.10 ppm, unresolved, peaks 13 H (2 x CH3 + C3H7) 3.89 ppm, unresolved peaks, 2.H, 2CH δ » 4.19 ppm, quadruplet, 2H, £Si-CH3, J=6.8 H2 δ - 5.15 ppm. singlet, 2JL 15 δ = 5.89 ppm. singlet. 2 x COOH + Ng δ = 6-15 ppm. singlet, 2H, CH^CB δ » 7.31 ppm. singlet, 5H, aromatics.

STAGE Es Benzyl ester of N-[ (£)- 1-ethoxycarbony Ibutyl ]-(£.)alanine Ammonium hydroxide is added dropwise to a suspension of 0.72 kg of the maleate of N-[ (£)-1-ethoxycarbonyl.butyl ]-(£)-alanine benzyl ester in 13.50 litres of water, until alkaline, while the temperature is kept below 20°C Separate off the oil formed, extract the aqueous phase with four 2.25 litre portions of diisopropyl ether. Combine the organic phases and dry them over magnesium sulphate before evaporating them under vacuum. 500 g of the benzyl ester of N~((£)-1-ethoxycarbonyIbutyl](£) -alanine ©re obtained in the form of a slightly yellow liquid.

Xiaisb 95.5% Rotatory power; [cs]o° = -48°.2 (c = 1/EtOH) Infrayed spectrometry; (Nujol): a band at 1730 cm1 Nuclear magnetic resonance spectrometry - 60 MHz: solvents CC1« = 0,,65 - 1.60 ppm, unresolved peaks 13 H (2 x CHJ + C3H7) = 2.11 ppm, singlet, NH = 2.95 - 3.49 ppm, multiplet, 2 x CH = 3-99 ppm, quadruplet, 2Ja, CH2-CH?, J=S.6 Hz = 5.02 ppm, singlet, (2H), CHj-O = 7.2 ppm, unresolved peaks, 5H, aromatics.

STAGE Fs N-[(£)-1-ethoxycarbonylbutyl]-(£)-alanine Dissolve 4.5 kg of the benzyl ester of N-[(£)-lethoxycarbonylbutyl]-(£.)-alanine in 75 litres of ethanol, add 5% palladium-on-carbon catalyst, then hydrogenate at atmospheric pressure at 20~22°C.

Then dilute the mixture with ethanol and heat to 70°C to produce a solution. Filter the solution hot and rinse the catalyst with 10 litres of hot ethanol.

Evaporate off the solvent under vacuum and crystallise from acetonitrile th® residue obtained. <9 2.61 kg of N-[ (£)-l~ethoxycarbonylbutyi )-(£,) -alanine obtained in the form of a white powder.

XieJ^s 82% ict)o° = +4°. 7 (c - 1/H20) M&XtiQS_E2ija£.s 149°c BiSiBsatajLAs&teis.; c 10h 19no* are Element Theory Result C 55.28 55.28 H 8.81 8.97 N 6.45 6.35 ^M^-X®HS^_£taiffiSLtoSXaahx S Solvent: chloroform: 70 methanol: 30 acetic acid: 1 Rf : 0.45 XaXsaxari_ Sands at 3050, 2250, 1740, 1620 and 1205 cm'1 Bi£lej&X^ 1H - 200 MHzs solvent DMSO"d6 S ~ 0.86 ppm, triplet, 3H, (C£22) - 1.17 ppm, doublet, 3H, CH-C& ~ 1.18 ppm, triplet, 3H, CGQ-CH2-£g3 1.30 ppm, multiplet ( 1.50 ppra, multiplets ο s δ δ -=· *5 1 *—· *!» S 3.17 ppm, quadruplet 3.26 pp®., 4 . ; Pfr ppm, 2g, CK2, CEfe-CHj H, £jS2~CH2"CH3 IH, CE, CHj :iplet, IH, £H-C3H7, quadruplet, 2H, COO-£Jg2-CH3 .6 to 7.7 ppm, unresolved peaks, exchangeabl· and NH 2H, COOH Mmcleay magnetic resonance _ spectrometry l3C - 50 MHss DMSO-ds 17 3. S and 175.4 signals corresponding to the carboxyls Solvent

Claims (7)

1. Process for the industrial synthesis of N-alkylated alpha-amino diacids or their esters of formula (I); HO - OC - CH - HH - CH — CO * 0¾ L· ch 3 (I) in whichs 10 denotes a having from linear 1 to S or branched carbon atoms lower alkyl group a 2 denotes a linear or branched lower alkyl group having froa 1 to 4 carbon atoms, exhibiting the characteristic of having the two 15 asymmetric carbon atoms both having th© £ configuration (referred to as derivatives of formula (l£)), characterised in that L-alanine of formula (IV) 5 (S) H 2 N - CH - COOH (IV) 20 CH 3 in which the asymmetric carbon has the £ configuration, is protected by esterification with benzyl alcohol, in th® presence of para-toluenesulphonic acid, with the water formed being 25 progressively distilled off, to obtain, a derivative of formula (V)s Η Ζ Ν CH - COOCH 2 C 6 H 3 (V) ch 3 in the form of its para-toluenesulphonate which is converted, by rendering alkaline with ammonium hydroxide, into the corresponding base which, after extraction, is condensed, in the presence of a tertiary amine, with a brominated derivative of formula (VI); Br - CH - COOR 2 (VI) Hi In which R x and R 2 have the same meaning as in formula (I), to obtain a derivative of formula (VII): (S) (R,S) C s H 5 CH 2 OCO - CH - NH - CH - COOR, (VII) CH 3 R x in which R 3 and R 2 have the same meaning as in formula (I)r the (£,£) isomer of which Is isolated by bringing into organic solution and adding maleic acid, the precipitate obtained being filtered off, dried and, if desired, recrystallised, to give a salt of the chosen maleate and of the (£,£) isomer of the derivative of formula (VII), th© latter being liberated free its salt by rendering an aqueous solution alkaline, followed by extraction and evaporation of the solvent, the (&/SL) isomer thus obtained being subjected to , hydrogenation in the presence of palladiura/carbon to give the compound of formula (I). t Industrial process according to claim 1 for the industrial synthesis of a compound of formula (I), characterised in that the separation of the (£,£) isomer frown the mixture of the two isomers (£,3) and (£,£) of the derivative of formula (VII) obtained by condensing the derivative of formula (V) with a derivative of formula (VI) is effected by adding maleic acid to an organic solution of the mixture of the two isomers (£,3) and (£,£). Industrial process for the separation of the (£,£) isomer from a mixture of th® two isomers (3,£) and (£.,5.) of derivatives of formula (VII) according to claim 1, characterised in that maleic acid is added to an organic solution of a mixture of the two isomers (£,£) and (S.»B), th® precipitate obtained being filtered, off, dried and recrystallised to give a salt of the chosen acid and of the (£,£) isomer of the derivative of formula (VIII), th® latter being liberated from its salt by rendering alkaline its aqueous solution, followed by extraction with a suitable solvent and separation of th® solvent. Industrial synthesis process according to any one of claims 1 to 3 of a derivative of formula (la), that is in particular of a derivative of formula (1)= in which R. is a propyl group, R 2 is aa ethyl group KQOC - CH - NE - CH - COOC 2 H 3 (la) CH a CE 2 CH 2 CH 3 exhibiting the characteristic of having the two asymmetric carbons in the £ configuration (±a£,)u

2. 5 characterised in that the derivative of formula (IV) according to claim 1 is condensed, after protection of the carboxylic acid function by esterification with benzyl alcohol in the presence of para-toluenesulphonic acid, with ethyl o-bromovalerate of formula (Via): 10 Br - CH - COOC 2 H 3 (Via) CH 2 CH 2 CH 3 to obtain the derivative of formula (Vila): (S) (R,S) C s H 3 CH 2 OCO ~ CH - NH - CH - COOC 2 H 3 (Vila) 15 CH 3 CH 2 CH 2 CH 3 the (£,£) isomer of which is isolated by bringing into organic solution, followed by the addition of maleic acid, th® precipitate obtained being filtered off, dried and 20 recrystal Used to give a salt of the maleate and of the (£,£.) isomer of the derivative of formula (Vila), the latter being liberated from its salt by rendering an agueous solution alkaline followed by extraction with a suitable organic solvent and evaporation of the solvent, the (.5.,H) isomer thus obtained being subjected to catalytic hydrogenation to give the compound of formula (la). 5. Salt of the (5.,5.) isomer of the derivative of formula (Vila) with maleic acid.

3. 6. The use of a derivative of formula (I) or (la) obtained according to any one of claims 1 to 4 for the synthesis of derivatives of formula (II): R 3 0 - OC - CH - N - CO - CH - NH - CH - CO - OR Z and their pharmaceutically acceptable salts in which Rx and R 2 have the same meaning as in formula (I) or (la), R 3 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms the structure CH - N denotes indoline i so in d ο 1ine , tetra hydroquinoline, tetrahydroisoquinoline, perhydroindole, perhydroisoindole , perhydroisoquinoline , perhydroquinoline, perhydrocyclopenta[b]pyrrole, 2azabicyclo[2,2,2]~octane or 2 ~ asabicyclo[2,2,1]heptane.

4. 7. use according to claim a of the derivative of formula (la) obtained according to claim 4 in the synthesis of derivatives of formula (II).

5. 8. Use according to either of claims δ and 7 of the derivative of formula (la) in the synthesis of derivatives of formula (II) in which - N - CH 5 denotes perhydroindole. Use according to any one of claims 6 to 8 of the derivative of formula (la) in the synthesis of ( 2£, 3a£, 7 a£) -1-(2-( 1-( ethoxycarbonvl) - (£) -butylamino ] - (£) propionyl J.-octahydroindole-2-carboxylic acid, or perindopril.

6. 10. A process substantially as hereinbefore described with reference to the accompanying Example. A use substantially as hereinbefore described with reference to the accompanying Example.

7. 15 12. A compound of Formula I as defined in claim 1 whenever prepared by a process as claimed in any of claims 1 to 4 or 10.