HK1053300B - 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 use thereof for 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 in the industrial synthesis of perindopril and its pharmaceutically acceptable salts.

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

wherein R represents linear or branched (C)₁-C₆) The alkyl group, preferably the ethyl 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 its pharmaceutically acceptable salts.

Perindopril and its salts have valuable pharmacological properties. Their essential properties are the inhibition of the enzyme (or kininase) which converts angiotensin, thus preventing the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (vasoconstrictor) on the one hand, and the decay of bradykinin (vasodilator) to the inactive peptide on the other hand. These two effects have a positive effect on perindopril in the treatment of cardiovascular diseases, in particular arterial hypertension and cardiac insufficiency.

The preparation and therapeutic use of perindopril is described in european patent specification EP 0049658.

To obtain a compound of pharmaceutical value, it is important to be able to obtain the intermediate of formula (I) by an efficient industrial synthesis process which, in particular, enables the selective production of the (S, S) diastereoisomer in good yields and excellent purity.

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

the journal Tet.Lett.1982,23(16) 1677-80 describes the production 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 agents are particularly toxic, very hygroscopic and difficult to handle on an industrial scale.

Patent specifications EP 0308340 and EP 0308341 describe the preparation of compounds of formula (I) (R ═ ethyl) by reaction of norvaline ethyl ester hydrochloride with pyruvic acid in the presence of hydrogen, palladium on carbon and sodium hydroxide in water. The crude product was isolated by evaporation of water and then ethanol was added to precipitate the sodium chloride formed during the reaction. After filtration, the resulting ethanol solution was evaporated and the residue was recrystallized from acetonitrile.

These methods have a number of disadvantages:

its use generates impurities in the reaction mixture due to the instability of pyruvic acid.

The reaction proceeds at a pH near neutral. Thus, the use of norvaline ethyl ester hydrochloride necessitates the addition of significant amounts of sodium hydroxide (1.1-1.2 moles per mole of norvaline ester hydrochloride salt), which produces significant amounts of sodium chloride, which is laborious to remove in commercial scale separations.

The separation process comprises a step of removing water from the reaction mixture by evaporation, which takes a particularly long time on an industrial scale.

-patent specification EP 0309324 describes the reaction of benzyl alaninate with ethyl α -bromovalerate in dimethylformamide in the presence of triethylamine to give the compound of formula (I) (R ═ ethyl). The main disadvantage of this process is that it comprises a large number of steps and the yield of the (S, S) isomer is low. In fact, since the reaction is not diastereoselective, an additional purification step is required to obtain the pure (S, S) isomer, which involves fractional crystallization in the presence of maleic acid.

The applicant has developed a process for the industrial synthesis of the compounds of formula (I) with great economic benefits, firstly because it allows to obtain the (S, S) diastereoisomers directly in good purity and yield, secondly because it allows a rapid and simple separation on an industrial scale, and finally because it uses the natural starting alanine as chiral source, with low costs.

More precisely, the invention relates to a method for the industrial synthesis of a compound of formula (I), characterized in that alanine of formula (III)

Condensing with a compound of formula (IV),

wherein R is defined as formula (I),

then using 5 percent palladium on carbon for catalytic hydrogenation,

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

at a pressure of 1-30 bar, preferably 1-5 bar,

at a temperature of 10-60 deg.C, preferably 10-40 deg.C,

in the presence of from 0 to 0.5 mol, preferably from 0.1 to 0.2 mol, of sodium hydroxide per mole of compound of the formula (IV); the reaction mixture is acidified to pH3-3.5, filtered, and the resulting precipitate is recrystallized from acetonitrile to obtain the compound of formula (I) in optically pure form.

The process uses small amounts of sodium hydroxide, thus limiting the formation of sodium chloride during the acidification of the reaction mixture, facilitating the subsequent recrystallization.

The separation process avoids the total removal of water by evaporation from the reaction mixture and is therefore particularly rapid and simple to carry out on an industrial scale.

The following examples are intended to illustrate the invention without, however, having any limiting meaning.

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

Into a vessel equipped with a stirrer were introduced 25kg of L-alanine dissolved in water, 1.1kg of sodium hydroxide and 36kg of ethyl 2-oxopentanoate. The reaction mixture was stirred for 30 minutes. The hydrogenation apparatus was charged with 5% palladium on carbon suspended in water and then the mixture obtained above. Hydrogenation was carried out at ambient temperature and 1 bar pressure until the theoretical amount of hydrogen was absorbed. The catalyst was removed by filtration, and concentrated hydrochloric acid was added to the filtrate until the pH was 3. Filtering, absorbing the filter cake with acetonitrile under reflux, filtering while hot and then crystallizing to finally obtain a solid product.

Claims (5)

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

wherein R represents linear or branched (C)₁-C₆) An alkyl group, a carboxyl group,

which is characterized by alanine of the formula (III)

Condensing with a compound of formula (IV),

wherein R is defined as formula (I),

then using 5 percent palladium on carbon for catalytic hydrogenation,

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

at a pressure of between 1 and 30 bar,

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

in the presence of 0-0.5 mole of sodium hydroxide per mole of compound of formula (IV), acidifying the reaction mixture to pH3-3.5, filtering, and recrystallizing the resulting precipitate from acetonitrile to obtain the compound of formula (I) in optically pure form.

2. The synthesis process according to claim 1, obtaining a compound of formula (I) wherein R represents ethyl.

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

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

5. A synthesis according to any one of claims 1 to 4, characterized in that from 0.1 to 0.2 mol of sodium hydroxide are added per mol of compound of formula (IV).