AU607260B2

AU607260B2 - Process for the synthesis of alpha n alkylated amino acids and esters thereof. application to the synthesis of carboxyalkyl dipeptides.

Info

Publication number: AU607260B2
Application number: AU22356/88A
Authority: AU
Inventors: Jean Baliarda; Bernard Marchand; Georges Remond; Michel Vincent
Original assignee: ADIR SARL
Current assignee: Laboratoires Servier SAS
Priority date: 1987-09-17
Filing date: 1988-09-16
Publication date: 1991-02-28
Anticipated expiration: 2008-09-16
Also published as: JP2524489B2; AU2235688A; HK55196A; EP0309324B1; FR2620700B1; IE882807L; NZ226222A; DK173730B1; DK515288D0; ATE61567T1; IE60995B1; CA1341380C; FR2620700A1; OA08941A; JPH0725723B2; GR3001874T3; DE3862006D1; PT88530A; ES2034324T3; EP0309324A1

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

4 ApplicaV~on COMMONWEALTH OF AUV PATENTS ACT 19521 90O726 CO__''MPLETE SPECIFICATION Form Number: Lodged: IORIGINAL I Class Int. Class 4 4t I I t I Complete Specification Lodged: Priority Acceupted: Published: Related Art

IC

*4

~II

II

9 9* **.Name of Applicant: Address of Applicant: *Actual Inventor: ADIR ET CIE 22 rue Garnier, F-92201 Neuilly Sur Seine, France MICHEL VINCENT, GEORGES REMOND JEAN BALIARDA, BERNARD MARCHAND and Address for Servki, EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: PROCESS FOR THE SYNTHESIS OF ALPHA N ALKYLATED AMINO ACIDS AND ESTERS THEREOF. APPLICATION TO THE SYNTHESIS OF CARBOXYALKYL DIPEPTIDES The following statement Is a full description of this Invention, Including the best method of performing It known to -la- T;e present invention relates to a process for the industrial synthesis of N-alkylated, optionally esterified, a-amino diacids and their application to the industrial synthesis of carboxyalkyl dipeptides.

More specifically, the present invention relates to a new process for the industrial synthesis of derivatives of general formula R1 HO OC C NH CH CO OR 2 (I) CH3 and their addition salts with a mineral or organic acid or 10 base, in which formula: t #1 RI is linear or branched lower alkyl (with 1 to 6 carbon atoms), R2 is hydrogen or a linear or branched lower aLkyL group (with 1 to 4 carbon atoms).

The derivatives of formula which are obtained according to the process of the invention can be used in the synthesis of carboxyalkyl dipeptides of formula

(II):

20 i SR0 OC- CH- N OC CH-H CH- CO -O4R 2 A

CH

3 as well as in that of their pharmaceutically acceptable sco salts, in which formula;

R

1 and R 2 have the same meaning as in formula R3 is a hydrogen atom or a lower aLkyL group with 1 to 4 carbon atoms the structure CH N denotes indoline, isoindoline,

KA)

tetrahydroquinoine, tetrahydroisoquinoline, perhydroindole, perhydroisoindole, perhydroisoquino- Line, perhydroquinoline, perhydrocycopentaCbJpyrrole, 2-azabicycoC2,2,2Joctane and 2-azabicycLoC2,2,1lheptane.

The preferred compound of formula (It) is perindopril of formula (III) 2 i (S <s) -COOH (II) I(S) (S) C- CH- NH- CH COOC 2

H

s 0 I CHa CH 2

CH

2

CH

3 or (2S,3aS,7aS)-1-{2-E1-(ethoxycarbonyyL)-(S)-butylamino]- (S,-propionyl}octahydroindole-2-carboxylic acid, as well as its addition salts with a phartnaceutically acceptable 5 acid or base, in the case of which the process of the present invention may be applied more particularly.

The compounds of formula (II) as well as their salts have interesting pharmacological properties. In particular, they exert an inhibiting activity on certain enzymes, such as carboxypolypeptidases, enkephalinases or S. kininase II. In particular, they inhibit the conversion S of angiotensin I decapeptide to angiotensin II octapeptide, which are responsible in certain cases for arterial hypertension by acting on the conversion enzyme.

The use of these compounds in therapeutics makes it possible, therefore, to reduce or even to suppress the activity of these enzymes, which are responsible for the hypertensive disorder or for cardiac insufficiency. The action on kininase II results in an increase in circulating bradykinin and also in a lowering of the arterial pressure via thia route.

Compounds of formula (II) and, more particularly, the compound of formula (III), its preparation and its use in therapeutics have been described in European Patent No. 0,049,658.

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

The compounds of formula comprise two iocalled asymmetric carbons, each being capable of having two configurations R or S:

(R,S)

SR(I)

HO OC CH NH CH CO OR2

I

The compounds of formula exist, therefore, in the form of four stereoiscmers which may be denoted by or according to the configuration of the two so-called asymmetric carbons.

Now, the most active compounds of formuLa (II) are those in the case of which the two carbons in the side chain both have the S configuration.

This is the reason why the process according to 10 the present invention is concerned more particularly with the industrial synthesis of the compounds of formula (I) in which the two asymmetric carbon atoms both have the S *9 configuration.

Few specific processes for the industrial synthe- 15 sis of the derivatives of formula have been described.

European Patent Application No. 0,117,488, which is very general and which employs a-carboxylated trifLuoromethanesulfonates, is known. However, the stereochemistry of both starting materials must be strictly chosen in order to obtain the desired diastereoisomer of the product of formula .The Applicant Company has now found a process for the industrial synthesis of derivatives of formula (I) which is of great interest, being, on the one hand, very simple to implement and, on the other hand, employing a natural starting material, alanine, which is therefore inexpensive, and thus introducing a chain member possessing the S configuration beforehand.

When the synthesis is complete, the and (R,S) isomers obtained are separated by a single fractional crystallization in the presence of an acid chosen preferably from maleic, tartaric and citric acids.

The combination of these choices which are made after a strict selection, makes it possible to obtain a synthesis of the compounds' of formula which is

(C

4 especially advantageous to apply on industrial scale.

More particularly, the process according to the invention consists in employing as a starting material L-alanine of formula (IV):

(IV)

H2N CH COOH

I

CH3 in which: the asymmetric carbon has the S configuration, in which the carboxylic group is protected by esterification with benzyl alcohol in the presence of ar esterification catat. 10 lyst to obtain a derivative of formula H2N CH COOCH2C6H5 4. (V) CH3 which is condensed, in the presence of a hydracid scavenger, with a halogenated derivative of formula (VI): SX -H COC3 (VI)

I

Ri in which X denotes a halogen atom, and preferably a bromine atom, and RI and R2 have the same meaning as in formula to obtain a derivative of formula (VII):

(R,S)

C6H5CH20CO CH NH CH CGOR2 CH3 Ri in which RI and R 2 have the same meaning as in formula whose isomer is isolated by forming an organic solution and adding to a polyacid preferably chosen from acetic, tartaric and maleic acids, the precipitate obtained being filtered off, driel and recrystallized to give a salt of the chosen acid and of the isomer of the derivative of formula (VII), the latter being liberated from its salt by alkalifying an aqueous solution followed by extraction and evaporation of the solvent, the isomer thus obtained being subjected to hydrogenolysis in the presence of a catalyst chosen preferably from nickel, palladium, platinum or rhodium, mixed with a support such as charcoal, to give the compound of formula The invention also extends to the original products obtained during the performance of the process according to the invention, and more particularly to salts of carboxylic polyacids with the derivatives of formula (VII).

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

EXAMPLE: N-[(S)-1-CARBETHOXYBUTYL)(S)-ALANINE S STAGE A: Benzyl ester of,(S)-alanine, para-toluenesulfonate S* Heat to reflux, with stirring, a suspension of S 8.2 kg of (S)-alanine, 1.78 kg of para-toluenesulfonic acid and 2 kg of benzyl alcohol in 3.30 Liters of toluene, and distill off the water as it is formed.

25 Refluxing is continued until the theoretical quan- Stity of water is obtained.

Cool the reaction mixture to 70°C and evaporate it down under vacuum. Into the pasty residue obtained, pour 12.30 liters of isopropyl ether and stir for 5 hours at 20 22 0

C.

The suspension obtained is filtered off and the prsc pitate is washed with two 1.50 liter portions of isopropyl ether.

After drying, 32 g of the para-toluenesulfonate of the benzyL ester of (S)-alanine are obtained.

Yield: 99.0% Rotatory power: aa -3.7(c I/MeOH

D

I"-

6 Melting point: 98 0

C.

Spectrometry in the infrared (nujol): -1 Bands at 1760, 1730 cm 1 Nuclear magnetic resonance spectrometry H 60 MHz: Solvent: methanol-d 4 6 1.41 ppm, doublet, 3H, CH-CH 3 J=6.9 Hz 6 2.29 ppm, singlet, 3H, CH 3

-CH

4 6 4.02 ppm, quadruplet, 1H, CH-CH 3 J=6.9 Hz 6 4.85 ppm, broad signal, 3H, NH 2

S

0 3H 6 5.21 ppm, singlet, 2H, COO-CH2 7.0 to 7.8 ppm, unresolved peaks, 9H, aromatics.

STAGE B: Benzyl ester of S-alanine To a solution of 3.14 kg of para-toluenesulfonate of the benzyl ester of (S)-alanine in 9.30 liters of t .water, aou aqueous ammonia until alkaline.

20 Keep stirring for thirty minutes, then extract with 1.25 Liters of methylene chloride. Ser rate off the r" organic phase and counterextract the aqueous phase with two 1-Liter portions of methylene chloride.

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

After evaporating off the methylene chLoride, 1.5 kg of benzyl ester of (S)-alanine are obtained in the form of a yeLLow oily liquid.

Yield: Spectrometry in the infrared (nujol): Bands at 1760 and 1730 cm Nuclear magnetic resonance spectrometry 1 H 60 MHz: 6 1.39 ppm, doublet, 3H, CH-CH 3 J=6.9 Hz 6 3.98 ppm, quadruplet, 1H, CH-CH 3 J=6.9 Hz 4.90 ppm, broad signal, 2H, NH 2 6 5.23 ppm, singlet, 2H, COO-CH 2 -7- 7.10 ppm, unresolved peaks, 5H, aromatics.

STAGE C: Benzyl ester of N-C1-carbethoxybutyl](S)a an i ne Heat gradually to 90 0 C, with stirring, a mixture of 1.43 kg of the benzyl ester of (S)-alanine, 1.84 kg of ethyl c-bromovaLerate and 8.9 kg of triethylamine in 12 liters of N,N-dimethylformamide. Keep stirred for three hours at 90 0 C before cooling the reaction mixture to 700C.

Evaporate off N,N-dimethylformamide under vacuum, then take up the oily residue in 7 liters of isopropyl t ether. Add 7 liters of water and keep stirred for half j 15 an hour. Separate off the organic phase and extract the Saqueous phase with 3.5 Liters of isopropyl ether. Combine the organic phases and extract them with 9 Liters of a molar solution of hydrochloric acid. Alkalify the S1t* aqueous phase thus obtained using sodium carbonate, then t 20 extract with isopropyl ether. Combine the organic phases and wash them with water; dry over magnesium sulfate and then evaporate down under vacuum.

2.11 kg of the benzyl ester of N-C1-carbethoxybutyll(S)-alanine are obtained in the form of a slightly colored oil.

Yield: 86% Spectrometry in the infrared: Bands at 1760 and 1730 cm 1 Nuclear magnetic resonance H 60 MHz: Solvent

CCL

4 6 0.65 1.60 ppm, unresolved peaks 13 H (2 x

CH

3

C

3

H

7 6 2.11 ppm, singlet, NH 6 2.95 to 3.49 ppm, multiplet, 2 x CH 6 3.99 ppm, quadruplet, 2H, CH 2

-CH

3 J=6.6 Hz 6 5.02 ppm, singlet, 2H, CH2-O -8- 7.20 ppm, unresolved peaks, 5H, aromnatics.

STAGE D: MaLeate of the benzyL ester of N-C(S)-1--carbethoxybutyLJ(S)-aLanine Add 376 g of maLeic acid to a solution of 1.9 kg of the benzyL ester of N-E1-carbethoxybutyL](S)-aLanire in a mixture of 10.44 Liters of cycLohexane and 5.22 Liters of acetone. The mixture is then heated to 80 0 C with stirring and the solution obtaiined is kept at reflux for orre hour. Allow to cooL to ambient temperature and keep stirred for twelve hours before ice-cooling for two hours to 0 510C.

Filter off the precipitate and wash it with cycLohexane on the filter.

After drying, 1070 g of crude salt are obtained and are recrysta(Llzed from a mixture of cycLohexane and acetone.

In this manner 955 g of maLeate of the benzyL es- 20 ter of N-[($)-1-carbethoxybutyLJ(S)-aLanine are obtained in the form of a white crystalline powder.

Rotatory power: D 1 %0,0(C I Melting point: 102 0

C

spe .rometry in the infrared (nujoL): a band at 1740 cm- 1 Nuclear magnetic resonance 1H 60 MHz-.

Solvent CDCI 3 6=0.80 2.10 ppm, unresolved peaks 13 H (2 x

CH

3

C

3

H

7 6=3.89 ppm, unresolved peaks, 2H, 2CH s=4.19 ppm, quadruplet, 2H4, CH 2

-CH

3 J-6.8 H42 6=5.15 ppm, singlet, 2H4, C6H5-CH 2 6 =5.89 ppol, singlet, 314, 2 x COOH NH 9- 6 6.15 ppm, singlet, 2H, CH,.-CH 6 7.31 ppm, singlet, 5H, aromatics.

STAGE E: Benzy ester of N-[(S)-l-carbethoxybutylJ- (s)-alanine Aqueous ammonia is added dropwise to a suspension of 0.72 kg of mal.eate of the benzyL ester of N-E(S)-l-carbethoxybutylJ(S)-alanine in 13.50 liters of water, until alkaline, while the temperature is kept beLow 20 0

C.

Separate off the oil formed, extract the aqueous phase with four 2.25-liter portiros of isopropyl ether.

Combine the organic phases and dry them rver magnesium sulfate before evaporating them down undei' vacuum.

500 g of benzyL ester of N-C(S)-l-carbethoxybutyL]- (S)-alanine are obtained in the form of a slightly yellow qliquid.

Yield, .95,5% Rotatory power: 2W 48*.2 (c I Ei)R Srectrometry in the infrared (nujo): A band at 1730 cm- 1 Nuclear magnetic resonance spectrometry 1 H -60 MHz Solvent: CdL 4 6 0,65 1.60 ppm, unresolved peaks 13 H (2 x CH3 C3H7) 4 2.11 ppm, singlet, Nl 6 2.95 3.49 ppm, multiplet, 2 x CH 3.99 ppm,. quadruplet, 2H, H 2

-CH

3 J=6.6 Hz S 5.02 ppm, singlet, CH 2

-O

6 7.2 ppm unresolved peaks, 5H, aromatics.

STAGE P: carbethoxybutyL 1(S)-alanine Dissolve 4.5 kg of the benzyl ester of N-C(S)PU 10 carbethoxybutyLJ(S)-aLanine in 75 L iters of ethanol, add the catalyst containing 5% paLLadium on charco~aL, then hydrogenate at atmospheric pressure at 20-22O 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 Liters of hot ethanol.

Evaporate off the solvent under vacuum and crystaL ize the residue obtained from acetonitriLe.

2.61 kq of N-C(S)-1-carbethoxybutylJ(S)-aLanine are obtained in the form of a white powder.

Y ie Ld: 82% Rotatory power: a~a D2 4.7 (c i Melting point: 1490C 0 Vs Elemental analysis: C 10

H

19 N0 4 Element Theory Result C 55.28 55.28 H8.81 8.97 N6.45 6.35 rhirv Layer chromatography: Solvent: chloroform methanol acetic acid:1 R f :0.45 Spectrom-etry in the infrared:, Bands at 3050, 2250, 1740,. 1620 and 1205 dMK 1 Nuclear magnetic resonance spectrometry H -200 MHz: Solvent DMS0-d 6 a 0.86 ppm, triplet 3H, (CH 2 2

-CH

3 6 1.1? ppm, dloublet, 3H, CH-CH 3 6=1.18 ppm, triplet, 3H, COO-CH 2

-CH

3 6 1.30 ppm, muLtipLet, 2H, CH 2

,CH

2

-CH

3 ppm, muLtipLet, 2H, cH 2

-CH

2

-CH

3 6 =3.17 ppm, quadruplet, 1H, CH, CH 3 6 =3.26 ppm, triplet 1H, CH-C 3

H

7 6 =4.10 ppm, quadruplet, 2H, COO-CH 2

-CH

3 6 =5.6 to 7.7 ppm, unresolved peaks, exchangeabL~e 2H, COOH and NH Nuclear magnetic resonance spectrometry C 50 MHz:- S 15 Solvent DMSO-d 6 173.9 and 175.4 signals corresponding to the carboxyLs.

Claims

1. A process for the industrial synthesis of N-alky- Lated alpha-amino diacids or of their esters of formuLa Ri HO OC CH dH CH CO OR2 I S S 64 I St C Ir SII in which: R 1 denotes a Linear or branched lower aLkyl group with 1 to 6 carbon atoms, R 2 denotes a Linear or branched Lower aLkyL group with 1 to 4 carbon atoms, exhibiting the particularity of having the two asymmetric carbons both having the S configuration (which are called derivatives of formula wherein L-alanine of for- mula (IV): H2N CH COOH CH CH3 (IV) in which the asymmetric carbon has the S configuration, is protected by esterification with benzyl alcohol in the presence of an esterification catalyst to obtain a derivative of for- mula H2N CH COOCH2C6H5 CH 3 which is condensed, in the presence of a hydracid scaven- ger, with a halogenated derivative of formula (VI): X CH COOR2 I R1 (VI) in which X denotes a halogen atom, and Ri and R2 have the same meaning as in formula to obtain a derivative of formula (VII): r 13 (R,S) (VII) C6H5CH20CO CH NH CH COOR2 CH3 R1 in which R 1 and R 2 have the sdme meaning as in formula whose isomer is isolated by pLacing in an organic solution and adding to a polyacid, the precipitate obtained being filtered of', dried and, if desired, recrystallized, to give a salt of the chosen acid and of the isomer, of the derivative of formula (VII), P the latter being liberated from its salt by alkalifying t an aqueous solution followed by extraction and evapora- tion of the solvent, the isomer thus obtained being subjected to hydrogen- ation in the presence of a catalyst preferably chosen from U 15 nickel, palladium, platinum or rhodium, mixed with a support such as charcoal, to give the compound of formula

2. The process of industrial synthesis of derivatives of formula as claimed in claim 1, wherein the catalyst chosen for the reaction of esterification of alanine with benzyl alcohol is para-toluenesulfonic acid.

3. The industrial synthesis process as claimed in either of claims 1 and 2, wherein the catalytic hydrogen- ation permitting the liberation of the carboxylic acid group is performed using palladized charcoal as cata- lyst.

4. The industrial process as claimed in any one of claims 1 to 3, wherein the derivative of formula (VI) is a bromo derivative.

The industrial process as claimed in any one of claims 1 to 4, for the industrial synthesis of a compound of formula wherein the separation of the iso- mer from the mixture of the two and isomers of the derivative of formula (VII) obtained after conden- sation of the derivative of formula with a derivative of formula (VI), is effected by adding a polyacid chosen from maLeic, 14 citric or tartaric acids to an organic solution of the mixture of the two and isomers.

6. The industrial process for the separation of the isomer from a mixture of two and iso- mers of derivatives of formula (VII) as claimed in claim 1, wherein a polyacid chosen from maleic, citric and tar- taric acids is added to an organic solution of a mixture of the two and isomers, the precipitate ob- tained being filtered off, dried and recrystallized to give a salt of the chosen acid and of the isomer of the derivative of formula (VII), the Latter being Liberated from its salt by alkalifying its aqueous solution, followed by extraction with a suitable solvent and by separation of the solvent. i

7. The industrial process as claimed in any one of claims 1 to 6, wherein the isomer of the derivative of formula (VII) is separated from the mixture of the two and isomers by using maleic acid.

8. The industrial synthesis process as claimed in any f one of claims 1 to 7, of a derivative of formula in the particular case of a derivative of formula I in which R 1 is a propyl group, R 2 is an ethyl group HOOC CH NH CH H COOC2H 5 I ia CH 3 CH2CH2CH 3 exhibiting the particularity of having the two asymmetric carbons of S configuration (laS), wherein the derivative of formula (IV) as claimed in claim 1 is condensed, after protection of the carboxylic acid group by esterification with benzyl alcohol in the presence of para-toluenesul- fonic acid, with ethyl a-bromovalerate of formula (VIa): Br CH I (VIa) CH2CH2CH 3 to obtain the derivative of formula (VIIla): 3) C6H 5 CH20CO CH NH CH COOC2H5 (VIla) CH3 CH2CH2CH3 whose isomer is isolated by placing in an organic solution, followed by the addition of a polyacid chosen from citric, tartaric and maleic acids, the precipitate obtained being filtered off, dried and recrystallized by means of a suitable organic solvent tco give a salt of the chosen acid and of the isomer of the derivative of formula (Vila), the latter being liberated from its salt by alkalifying an aqueous solution followed by extraction and f *4 evaporation of the solvent, t *the isomer thus obtained being subjected to catalytic hydrogenation to give the compound of formula I o a)

9. The industrial process as claimed in claim 8, wherein the separation of the isomer from the mixture of the two and isomers of the derivative of formula (Vila) is effected by using maleic acid. 0 0 o o

10. The salts of the derivatives of formula (VII) as claimed in calimn 1, with a polyacid chosen from citric, S maleic and tartaric acids. 0 0 S0

11. The salts of the isomers of derivatives of I formula (VII), as claimed in calim 1, with a polyacid chosen from citric, maleic and tartaric acids.

12. The salts of compounds of formula (Vila) as claimed in claim 8, with a polyacid chosen from citric, maleic and tartaric acids.

13. The salt of the isomer of the derivative of formula (VII) as claimed in claim I, wherein R i CH 2 CH 2 CH 3 R 2 C 2 with maleic acid. 11% L i, uu- ;Il i 15a

14. The use of a derivative of formula obtained as claimed in any of claims 1 to 9, for the synthesis of derivatives of formula (II): Rl R0 OC CH -N CO -CH NH CH CO OR A C" 3 and their pharmaceutically acceptable salts, in which S, formula: R1 and R 2 have the same meaning as in formula S- R 3 is a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, 9 4 r **1 -16 -the structure CH N denotes indol ine, isoindoL ine, K'A> tetrahydroquinoline, tetrahydroisoquinoLine, per-hydra- indole, perhydroisoindoLe, perhydroisoquinoLine, per- hydroquinolime, perhydrocyclopenta~bJpyrroLe, 2-azabi- cycLoE2,2,2]octane and 2-azabicyclo[2,2,1 Jheptane.

The use as claimed in claim 14 of the derivative of formuLa (Ia) in the synthesis of derivatives of for- mul a (I I).

16. The use as cLaimed in either of claims 14 a-,d Ao o f the~ derivative of forrrujla (1a) in the synthesis of dt de rivatives of formula (II) in which N CH denotes perhydroindoLe.

17. The use as claimed in either of claims 15 and 16 of the derivative of formula (1a) in the synthe~sis of the derivative of (2S,3aS,7aS)-1-{C2-1-ethoycarbori'L butyL aminoJ (S)-prop ionyL) oc tahydro indloLe-2-carboxyL ic ac id, or perindlopriL. DATED this 15th day of September 1988. ADIR ET CIE EDWD. WATERS SONS PATENT ATTORNEYS QUEEN STREE~T ii MELBOURNE. VIC. 3000.