HK1053301B - Novel method for synthesis of n-[(s)-1-carboxybutyl]-(s)-alanine esters and use in synthesis of perindopril - Google Patents

Description

Process for the synthesis of N- [ (S) -1-carboxybutyl ] - (S) -alanine esters and their use in the synthesis of perindopril

The present invention relates to a process for the industrial synthesis of N- [ (S) -1-carboxybutyl ] - (S) -alanine esters and their use for the supply of synthetic perindopril and its pharmaceutically acceptable salts.

More specifically, the present invention relates to a new process for the industrial synthesis of compounds of formula (I) and their addition salts with inorganic or organic acids or bases:

wherein R represents linear and branched (C)₁-C₆) An alkyl group.

The compound of formula (I) obtained according to the process of the present invention is used for the synthesis of perindopril of formula (II) and for the synthesis of its pharmaceutically acceptable salts:

perindopril and its salts have valuable pharmaceutical properties. Their main property lies in the inhibitory action on the enzyme that converts angiotensin I (or myopeptidase II), which on the one hand prevents the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (vasoconstrictor) and on the other hand prevents the degradation of bradykinin (vasodilator) to an inactive peptide.

These two effects are responsible for the beneficial effects of perindopril on cardiovascular diseases, in particular arterial hypertension and cardiac insufficiency.

Perindopril, its preparation and its therapeutic use have been described in european patent specification EP 0049658.

Due to the favorable pharmaceutical properties of this compound, it is important to be able to obtain the intermediates of formula (I) by an efficient industrial synthesis process which enables the selective preparation of the (S, S) diastereoisomer in good yields and excellent purity and which can be carried out equally easily on an industrial scale.

Several processes for the preparation of compounds of formula (I) are known, but these have significant disadvantages on an industrial scale:

tet.lett.1982, 23(16), 1677-80 describes the preparation of compounds of formula (I) (R ═ ethyl) by reaction of ethyl 2-oxopentanoate with tert-butyl alanine in ethanol in the presence of sodium cyanoborohydride, but the reducing agent is highly toxic, hygroscopic and difficult to handle on an industrial scale.

Patent specification EP0309324 describes the obtaining of compounds of formula (I) (R ═ ethyl) by reaction of benzyl alaninate with ethyl α -bromovalerate in dimethylformamide in the presence of triethylamine. The main disadvantages of this process are the multiple reaction steps and the low yield of the (S, S) isomer. In fact, since the reaction is not diastereoselective, in order to obtain the pure (S, S) isomer, it is necessary to add a purification step comprising fractional crystallization in the presence of maleic acid.

Patent specifications EP0308340 and EP0308341 describe the preparation of compounds of formula (I) (═ ethyl) by reaction of norvaline ethyl ester hydrochloride with pyruvic acid in water in the presence of hydrogen and palladium on carbon and sodium hydroxide. The crude product is then isolated by evaporation of water and ethanol is added to precipitate the sodium chloride formed during the reaction. After filtration, the resulting ethanolic solution was evaporated and the residue was recrystallized from acetonitrile.

The advantage of this process is that compounds of formula (I) are obtained with excellent optical purity: only the (S, S) diastereomer crystallizes under those conditions. Furthermore, the low-cost, industrially available natural product pyruvic acid as reagent and water as reaction solvent are particularly advantageous.

On the other hand, however, the disadvantage of this process is that its application on an industrial scale is particularly laborious: in order to obtain this product in chemically and optically pure form, the isolation of the reaction product requires, in practice, the evaporation of a large amount of water and then a series of operating steps (addition of a first organic solvent, filtration, evaporation and recrystallization from a second organic solvent).

The applicant has now developed a new process for the industrial synthesis of the compounds of formula (I) which combines the advantages of hydrogenation in aqueous medium and of a particularly rapid and simple separation process for industrial production.

More specifically, the present invention relates to a process for the industrial synthesis of compounds of formula (I), characterized by sodium pyruvate of formula (III):

with a compound of formula (IV):

wherein R is defined as formula (I),

the reaction is carried out in water, and the reaction solution is,

at a pressure of 1 to 20 bar, preferably 1 to 5 bar,

at 10-60 deg.C, preferably 10-40 deg.C,

in the presence of 0.1 to 0.2 mol of sodium hydroxide per mol of compound of the formula (IV) used,

catalytic hydrogenation was carried out with 5% palladium on carbon,

so that after acidifying the reaction mixture to a pH of 2.8 to 4.5, preferably 3 to 3.5, and filtering,

the compound of formula (I) is directly obtained in optically pure form.

Lower hydrogen pressure unexpectedly results in yields and chemical and enantiomeric purities as good as when the reaction is carried out at higher pressure.

Surprisingly, simple precipitation after acidification of the aqueous reaction mixture gives the single (S, S) isomer with good chemical purity and excellent enantiomeric purity.

Thus, the recrystallization step can be omitted, making the separation process particularly fast and simple, suitable for industrial production.

The following examples illustrate the invention but do not limit it in any way.

Example (b): n- [ (S) -ethoxycarbonyl-1-butyl ] - (S) -alanine

Into a reactor equipped with a stirrer were charged 3kg of S-norvaline ethyl ester hydrochloride dissolved in water, 0.6 liter of 4N aqueous sodium hydroxide solution and 2kg of sodium pyruvate. To the hydrogenation apparatus was added 5% palladium on carbon suspended in water, followed by the addition of the above solution. Hydrogenation was carried out at 35 ℃ and a pressure of 1.2 bar until the theoretical amount of hydrogen had been absorbed. The catalyst was removed by filtration, and then concentrated hydrochloric acid was added to the filtrate until the pH was 3.1. Cooled to 0-5 ℃ and the resulting solid was collected by filtration. The filter cake was washed with ice cold acetonitrile and dried to constant weight in a vented oven at 40 ℃.

Thus, N- [ (S) -ethoxycarbonyl-1-butyl ] - (S) -alanine was obtained in a yield of 62%, with a chemical purity of 95% and an enantiomeric purity of over 99%.

Claims (6)

1. A process for the industrial synthesis of a compound of formula (I),

wherein R represents a linear or branched chain (C)₁-C₆) An alkyl group characterized by sodium pyruvate of formula (III):

with a compound of formula (IV):

wherein R is defined as formula (I), the reaction is carried out in water,

at a pressure of between 1 and 20 bar,

at the temperature of 10-60 ℃, the temperature of the mixture is controlled,

in the presence of 0.1 to 0.2 mol of sodium hydroxide per mol of compound of the formula (IV) used,

catalytic hydrogenation was carried out with 5% palladium on carbon,

so that after acidifying the reaction mixture to a pH of 2.8-4.5 and filtering,

the compound of formula (I) is directly obtained in optically pure form.

2. The synthesis according to claim 1, which gives compounds of formula (I) in which R represents ethyl.

3. The synthesis process according to claim 1 or 2, characterized in that the hydrogen pressure is between 1 and 5 bar.

4. A synthesis process according to any one of claims 1 to 3, characterised in that the hydrogenation reaction temperature is between 10 and 40 ℃.

5. The synthesis process according to any one of claims 1 to 4, characterized in that the pH after acidification is between 3 and 3.5.

6. Use of a compound of formula (I) obtained according to any one of claims 1 to 5 for the synthesis of perindopril or a pharmaceutically acceptable salt thereof.