DK173730B1 - Process for the synthesis of Alpha-N-alkylated amino acids and esters thereof and intermediate by the process - 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

in DK 173730 B1

The present invention relates to a process for the industrial synthesis of N-alkylated, optionally esterified α-amino-d in acids.

More particularly, the invention relates to a novel process for the industrial synthesis of derivatives of the general formula (I): II - OC - CH - NH - CH - CO - OR2 (I) CH3 and their addition salts with a mineral acid or organic acid or a base in which formula:

R 1 is linear or branched lower alkyl of 1 to 6 carbon atoms, R 2 is hydrogen or a linear or branched lower alkyl group of 1 to 4 carbon atoms.

The derivatives of formula (I) obtained by the process of the invention can be used for the synthesis of carboxyalkyl dipeptides of formula (II) 25 R 30 - OC - CH - N - OC - CH - NH - CH - CO - OR 2 (II )

^ A J I

ch3 30 and their pharmaceutically acceptable salts, in which formula:

R 1 and R 2 have the same meaning as in formula (I), R 3 is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, the structure CH - N represents indoline, isoindoline, tetrahydroquin (A) noline, tetrahydro isoqui no 1 in, perhydro 1ndoΊ, perhydro 1 so i ndo 1, perhydroisoquinoline, perhydroquinol in, perhydrocyclopenta [b) -5 pyrrole, 2-azabicyclo [2,2,2] octane and 2-azabicyclo [2.2, 1] heptane.

The preferred compound of formula (II) is perindopril of formula (III) 10 (S) 1 L (S) + - COOH (III) I (S) (S) .C - CH - NH - CH COOC2H.

15 O * I I

CH, CH2CMjCH, or (2S, 3aS, 7aS) -1- {2- [1- (ethoxycarbonyl) - (S) -butylamino] - (S) -propionyl) octahydroindole-2-carboxylic acid and its addition - 20 salts with a pharmaceutically acceptable acid or base, in which case the process according to the invention can be especially used.

The compounds of formula (II) and their salts have interesting pharmacological properties. In particular, they exert an inhibitory effect on certain enzymes, such as carboxypolypepti dases, monkey phalinases or kininase II. In particular, they inhibit the conversion of angiotensin I decapeptide to angiotensin II octapeptide, which in some cases is responsible for arterial hypertension, by acting on the conversion enzyme.

Therefore, the use of these compounds in therapeutic agents makes it possible to reduce or even suppress the activity of these enzymes, which are responsible for hypertensive disorder or cardiac failure. The effect on kininase II results in an increase in circulating bradykinin and also in the reduction of arterial pressure along this route.

3 DK 173730 B1

Compounds of formula (II) and in particular the compound of formula (III), its preparation and use in therapeutic agents are disclosed in European Patent No. 0.049,658.

The compounds of formula (I) can be used to prepare compounds of formula (II).

The compounds of formula (II) comprise two so-called asymmetric carbon atoms, each capable of having two conjugates in ones R or S: (R, S) (R, S) # # Ri HO - OC - CH - NH - CH - CO - OR 2 (I) CH 3

The compounds of formula (I) therefore exist in the form of four stereoisomers which may be designated (R, R), (R, S), (S, R) or (S, S), depending on the configuration of the two so-called asymmetries. 2 0 tri carbon atoms.

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

In particular, the process of the invention relates to the industrial synthesis of compounds of formula (I), wherein the two asymmetric carbon atoms both have S configuration.

Only a few methods for industrial synthesis of the derivatives of formula (I) have been described. European Patent Application No. 0,117,488, which is very general, is known and according to this cc-carboxylated trifluoromethanesulfonates are used. However, the stereochemistry of both starting materials must be carefully selected to obtain the desired di-astereo isomer of the product of formula (I).

Applicants have now found a process for industrial synthesis of derivatives of formula (I) which is of great interest, on the one hand, it is very simple to perform and on the other hand uses a natural starting material alanine and is therefore cheap and thus introduces a chain link which has S configuration in advance.

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

The combination of these choices, made after rigorous selection, makes it possible to obtain a synthesis of the compounds of formula (I) which is particularly advantageous to use on an industrial scale. More particularly, the process of the invention consists in L-alanine of formula (IV): 15 '(S) H2N - CH - C00H (IV) ch3 wherein the asymmetric carbon atom has S configuration is protected by esterification with 20 benzyl alcohol in the presence of para-toluenesulfonic acid and, under distillation of water formed during the course of the reaction, to give a para-toluenesulfonate salt of the compound of formula (V): H; N - Cl I - COOCHAH5 (V)

25 I

CII3 which, by alkalization with ammonia, is converted to the corresponding base of formula (V), which in the presence of a tertiary amine is condensed with a bromine derivative of formula (VI):

Br - CH - COOR, (VI) R, wherein R, and R, have the same meaning as in Formula (I) to form a mixture of (S, R) -3 and (SS) isomers of formula (VTT): 5 DK 173730 B1 (S) (R, S) C6H5CH2OCO - CH - NH - CH - COOR2 (VII)

I I

wherein R 1 and R 2 have the same meaning as in formula (I) from which the (SS) isomer is isolated in the form of its maleic acid by dissolving in an organic solvent and adding maleic acid, after which the precipitate formed is filtered off, dried and refined the salt is converted to the (S, S) isomer of formula (VII) by alkalizing an aqueous solution followed by extraction and evaporation of the solvent and then the resulting (S, S) isomer is subjected to hydrogenation in the presence of palladium-on-carbon to form a compound of formula (I).

The invention also relates to the maleic acid salt of the (S, S) isomer of the compound of formula (Vila).

(S) (R, S) C6H5CH2OCO-CH-NH-CH-COOC2H5 (Viruses) ch3 ch2ch2ch3

The following example illustrates the invention.

EXAMPLE I N - [(S) -1-Carbathoxybutyl] - (S) -alanine STEP A: Benzyl ester of (S) -alanine, para-toluenesulfonate.

A suspension of 8.2 kg of (S) -alanine, 1.78 kg of para - two 1U of sulfonic acid and 2 kg of benzyl of 1ChoI 1 of 3.30 liters of toluene is heated under ten liters of reflux and stirring, and the water formed is distilled off as the is formed.

T in 1 baking soda Things continued until the theoretical amount of water was obtained.

6 DK 173730 B1

The reaction mixture is cooled to 70 ° C and evaporated in vacuo. Into the resulting paste-like residue is poured 12.30 liters of isopropyl ether and stirred for 5 hours at 20-22 ° C.

The resulting suspension is filtered off and the precipitate is washed with two portions of 1.50 liters of isopropyl ether.

After drying, 32 g of the para-toluene sulfonate of the benzyl ester of (S) -alanine is obtained.

10

Yield: 99.0%.

Turning Capability: [α] 20 = -3.7 ° (c »1 / MeOH)

D

15

Melting point: 98 ° C.

Spectrometry in the infrared (nujol): bands at 1760, 1730 cm

20

Nuclear Magnetic Resonance Spectrometry Ih - 60 MHz:

Solvent: methanol-d 6 = 1.41 ppm, doublet, 3H, CH-CH 3, J = 6.9 Hz δ = 2.29 ppm, singlet, 3H, CH 3 -CgH, j δ = 4.02 ppm, quadrupled, 1H, CH-CH3, J = 6.9 Hz 2 δ = 4.85 ppm, broad signal, 3H, NH2, SO3H δ * 5.21 ppm, singlet, 2H, COO-CH2 6 = 7.0 to 7.8 ppm, unresolved peaks, 9H, aromatic.

STEP B; Benzyl ester of S-alanine 30

To a solution of 3.14 kg of para-two 1ensu 1 phonate of the benzyl ester of (S) -alanine in 9.30 liters of water is added ammonia until a 1-ka1 i n i te t.

35

Stir for 30 minutes, then extract with 1.25 liters of methylene chloride. The organic phase is separated and the aqueous phase is extracted with two 1 liter portions of methylene chloride or d.

7 DK 173730 B1

The methylene or id phases are combined, washed with water and dried over magnesium sulfate.

After evaporation of the methylene chloride, 1.5 kg of benzyl ester 5 of (S) -alanine is obtained in the form of a yellow oily bag.

Yield: 95%.

Spectrometry in the infrared (nujol): 10 bands at 1760 and 1730 cm -1.

Nuclear Magnetic Resonance Spectrometry Ih - 60 MHz: δ 1.39 ppm, doublet, 3H, CH-CH3, J + 6.9 Hz δ * 3.98 ppm, quadruplet, IH, CH-CH3, J »4.90 ppm, broad signal, 2H, NH2 δ * 5.23 ppm, singlet, 2H, COO-CH2 δ * 7.10 unresolved peaks, 5H, aromatic.

STEP C: Benzyl ester of N- [1-carbethoxybutyl] - (S) -alanine

A mixture of 1.43 kg of the benzyl ester of (S) -alanine, 1.84 kg of ethyl α-bromovalerate and 8.9 kg of triethyl amine in 12 liters of N, N-dimethyl formamide is gradually heated under stirring to 90®C. Stir for 3 hours at 90 ° C before the reaction mixture is cooled to 70 ° C.

The Ν, Ν-dimethylformamide is evaporated in vacuo and the oily residue is taken up in 7 liters in sump ropy 1 ether. 7 liters of water were added and kept stirring for half an hour. The organic phase is separated and the aqueous phase is extracted with 3.5 liters of isopropyl ether. The organic phases are combined and extracted with 9 liters of a molar solution of hydrochloric acid. The resulting aqueous phase is made alkaline using sodium carbonate and then extracted with isopropyl ether. The organic phases 35 are combined and washed with water. Dry over magnesium sulfate and then evaporate in vacuo.

2.11 kg of the benzyl ester of N- [1-carbethoxybuty 1] - (S) -alanine is obtained in the form of a slightly colored oil.

DK 173730 B1 e

Yield: 86%

Spectrometry 1 the infrared: bands at 1760 and 1730 c »1.

5

Nuclear Magnetic Resonance Spectrometry 1H - 60 MHz ·.

Solvent: CC14

δ 0.65-1.60 ppm, unresolved peaks 13H (2 x CH3 + C3H7) δ »2.11 ppm, singlet, NH 10 δ 2.95 to 3.49 ppm, multiplet, 2 x CH

δ »3.99 ppm, quadruplet, 2H, CH 2 -CH 3, J = 6.6 Hz δ s 5.02 ppm, singlet, 2H, CH 2-0 6 7.20 ppm, unresolved peaks, 5H, aromatic.

STEP D: Maleate of the benzyl ester of N - [(S) -1-carbethoxybutyl] - (S) -alan in 376 g of maleic acid is added to a solution of 1.9 kg of the benzyl ester of N - [1- carbethoxybutyl] - (S) -α1 an into a mixture of 10.44 liters of cyclohexane and 5.22 liters of acetone. The mixture is then heated to 80 ° C with stirring and the resulting solution is refluxed for 1 hour. Cool to ambient temperature and keep stirring for 12 hours before cooling for 2 hours to 0-5ftC.

25

The precipitate is filtered off and washed with cyclohexane on the filter.

After drying, 1070 g of crude salt is obtained, which is recrystallized from a mixture of cyclohexane and acetone.

In this way, 955 g of maleate of the benzyl ester of N - [(S) -1-carbethoxybutyl] - (S) -alanine is obtained in the form of a white crystalline powder.

Rotation: [α] 20 = -19.0 ° (c - 1 / EtOH) 0

Spectrometry in the infrared (nujol):

A band at 1740 cu'l.

9 DK 173730 B1

Nuclear Magnetic Resonance - 60 MHz:

Solvent: CC13 6 »0.80-2.10 ppm, unresolved peaks 13H (2 x CH3 + C3H7) δ 3.89 ppm, unresolved peaks, 2H, 2CH 5 6» 4.19 ppm, quadruplet, 2H, CH2 CH3.0 = 6.8 Hz H2 δ 5.02 ppm, singlet, 2H, C6H5-CH2

δ 5.89 ppm, singlet, 3H, 2 x COOH + NH

δ 6.15 ppm, singlet, 2H, CH = CH

δ * 7.31 ppm, singlet, 5H, aromatic.

TRIM E: Benzyl Ester of N - [(S) -1-Carbethoxybutyl 1] - (S) -α 1 an

Aqueous ammonia is added dropwise to a suspension of 0.72 kg of maleate of the benzyl ester of N- [(S) -1-carbethoxybutyl] - (S) -alanine in 13.50 liters of water until alkalinity while keeping the temperature below 20 ° C.

The oil formed is separated and the aqueous phase is extracted with four portions of 2.25 liters of isopropyl ether. The combined organic phases are dried over magnesium sulfate until evaporated in vacuo.

500 g of benzyl ester of N - [(S) -1-carbethoxybutyl] - (S) -alanine is obtained in the form of a pale yellow liquid.

25

Yield: 95.5%

Rotation: [α] 2 ° = -48.2 ° (c + 1 / EtOH) 30

Spectrometry in the infrared (nujol):

A band at 1730 cm ~ l.

Nuclear Magnetic Resonance Spectrometry Ih - 60 MHz:

Solvent: CCI4 3 5

δ = 0.65-1.60 ppm, unresolved peaks 13H (2 χ CH3 + C3H7) δ * 2.11 ppm, singlet, NH δ * 5.89 ppm, singlet, 3H, 2 x C00H + NH

DK 173730 B1 <5 2.95-3.49 ppm, multiplet, 2 * CH δ »3.99 ppm, quadruplet, 2H, CH2" CH3 'Hz <5 * 5.02 ppm, singlet, 2H, CH2 " 0 δ «7.2 ppm, unresolved peaks, 5H, aromatic, STEP F: N - [(S) -1-carbethoxybutyl] - (S) -α 1 an in 4.5 kg of the benzyl ester of N - [( S) -1-Carbethoxybutyl] - (S) -α1α-nine is dissolved in 75 liters of ethanol and a catalyst containing 5% palladium on charcoal is added and then hydrogenated at atmospheric pressure at 20-22 ° C.

The mixture is then diluted with ethanol and heated to 70 ° C to form a solution. The solution is filtered hot and the catalyst is rinsed with 10 ml of warm ethanol.

The solvent is evaporated in vacuo and the residue is crystallized by acetone tril.

2.61 kg of N - [(S) -1-carbethoxybutyl] - (S) -alanine is obtained in the form of a white powder.

Yield: 82% 25 Turning capacity: [a] 20 ° + 4.7 ° (c = 1 / H2 O)

Melting point: 149 ° C

Elemental Analysis: C10H19NO4 3 0 3 5 11 DK 173730 B1

Element Theoretical Result C 55.28 55.28 5 ---------- H 8.81 8.97 N 6.45 6.35 10

Thin Layer Chromatography:

Solvent: chloroform: 70 methanol: 30 acetic acid: 1 Rf: 0.45

Spectrometry in the in red: Bands at 3050, 2250, 1740, 1620 and 1205 cm "*.

20

Nuclear Magnetic Resonance Spectrometry * H - 200 MHz:

Solvent: DMSO-d6 6 * 0.86 ppm, triplet 3H, (CH2) 2 "CH3 δ = 1.17 ppm, doublet, 3H, CH-CH3 + <5 = 1.18 ppm, triplet, 3H, COO CH2 "OH3 6 = 1.30 ppm, multiplet, 2H, CH2'C ^ 2" ^^ 3 δ * 1.50 ppm, multiplet, 2H, CH2 '^ H2-C ^ 3 δ = 3.17 ppm, quadrupled = 3.26 ppm, triplet IH, CH-C3H7 30 δ «4.10 ppm, quadruplet, 2H, C00-CH2-CH3 δ - 5.6 to 7.7 ppm, unresolved peaks, interchangeable 2H, C00H and NH.

Nuclear Magnetic Resonance Spectrometry 13C - 50 MHz:

Solvent DMSO-d6 173.9 and 175.4 signals corresponding to the carboxyls.

35

Claims (3)

A process for the industrial synthesis of N-alkylated <x-amino acids and their esters of formula (I): Wherein R 1 represents a straight or branched lower alkyl group having 1 to 6 carbon atoms, R 2 represents hydrogen or a linear or branched lower alkyl group having R 1 to 4 carbon atoms, characterized in that the two asymmetric carbon atoms are always present in the S-15 configuration (referred to as (S, S) isomers), characterized in that L-alanine of formula (IV): (S) H2N - CH - COOH (IV) CH3 wherein the asymmetric carbon atom has S configuration is protected by esterification with benzyl alcohol in the presence of para-toluenesulfonic acid and distilling off water formed during the reaction to give a para-toluenesulfonate salt of the compound of formula (V): DK 173730 B1 H2N - CH - COOCH 2 C 6 H 5 (V) ch 3 which, by ammonia alkalinity, is converted to the corresponding base of formula (V), which in the presence of a tertiary amine is condensed with a bromine derivative of formula (VI): Br - CH - COOR 2 ( WE) Wherein R [and R2 are as defined in formula (I) to form a mixture of (S, R) ~ and (S, S) isomers of formula (VII): (S) (RS) C6H5CH2OCO - CH - NH - CH - COOR2 (VII) 15. In ch 3 wherein R 1 and R 2 have the same meaning as in formula (I), from which the (S, S) isomer is isolated in the form of its maleic acid salt by dissolving in an organic solvent and adding maleic acid, after which the precipitate obtained from filter, filtered, dried and, if desired, recrystallized, which salt is converted to the (S, S) isomer of formula (VII), by making an aqueous solution alkaline followed by extraction and evaporation of the solvent, whereupon it is obtained (S Isomer is subjected to hydrogenation in the presence of palladium-on-carbon to form the compound of formula (I). DK 173730 B1 A process according to claim 1 for the preparation of a compound of formula (Ia) wherein R 1 is a propyl group and R 2 is an ethyl group HOOC - CH - NH - CH - COOC 2 H 5 (Ia) I in CH3 CH2CH2CH3 characterized in that the bromine derivative of formula (VI) is ethyl α-bromo valerate. 3. The maleic acid salt of the (S, S) isomer of the compound of formula (Vila) (S) (R, S) CbH5CH2OCO - CH - NH - CH - COOC2H5 (Vila) iolο in I ch3 ch2ch2ch3