HK1118285B - Intermediate for synthesizing esters of n-[(s)-1-carboxybutyl]-(s)-alanine and use thereof for synthesizing perindopril - Google Patents

Description

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

A divisional application of PCT application PCT/FR2004/002213 entitled "new method for the synthesis of N- [ (S) -1-carboxybutyl ] - (S) -alanine esters and use of this compound in the synthesis of perindopril", filed on 8/31/2004, said PCT application having a date of entry into the national phase of china of 2006, 16/2/200480023534.0.

Technical Field

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

More specifically, the present invention relates to a novel process for the synthesis of derivatives of formula (I) below and their addition salts with one or more inorganic or organic acids or bases:

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

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

perindopril and its salts have important pharmacological properties.

Background

Their main property is to inhibit angiotensin I converting enzyme (or kininase II), so on the one hand they are able to prevent the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (vasoconstrictor) and on the other hand they are able to prevent the degradation of bradykinin (vasodilator) to inactive peptides.

Both effects contribute to the beneficial effects of perindopril in cardiovascular diseases, especially arterial hypertension and insufficient blood supply to the heart.

Perindopril, its preparation process and its use in therapy are described in european patent EP 0049658.

In view of the pharmaceutical value of this compound, it is important to be able to obtain the intermediate of formula (I) by a competitive synthesis method, in particular to be able to obtain selectively the diastereoisomers (S, S), in high yields and with excellent purity, and also to be easily transferable to industrial scale.

Several processes for the preparation of compounds of formula (I) are known.

Journal of tet.lett, 1982, 23(16), 1677-80 describes the reaction of ethyl 2-oxopentanoate with tert-butyl alanine in ethanol in the presence of sodium cyanoborohydride to give the compound of formula (I) (R ═ ethyl).

Patent 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).

Patents EP 0308340 and EP 0308341 describe the reaction of ethyl glutarate hydrochloride with pyruvic acid in water in the presence of hydrogen, palladium on charcoal and sodium hydroxide to give the compound of formula (I) (R ═ ethyl).

Disclosure of Invention

The applicant has now developed a new industrial synthesis of the derivatives of formula (I).

More specifically, the present invention relates to a process for the synthesis of a compound of formula (I), characterized in that a morpholinone of formula (III):

wherein P represents an amino-functional protecting group,

or with bromide or allyl triflate in the presence of a base to give a compound of formula (IV) having the (3S, 5S) configuration:

wherein P is as defined above, and wherein,

the compound is hydrogenated in the presence of palladium on carbon,

or with iodopropane to give a compound of formula (V) having the (3S, 5S) configuration:

wherein P is as defined above, and wherein,

the compound is reacted with LiOH and then an esterification reagent to obtain a compound shown in the following formula (VI):

wherein R and P are as defined above,

the compound reacts with an oxidant to obtain the compound of formula (I) after the amino functional group is deprotected.

Among the amino-functional protecting groups which can be used according to the invention, mention may be made, as non-limiting examples, of tert-butoxycarbonyl and benzyloxycarbonyl groups. A preferred P group is tert-butoxycarbonyl.

Among the bases which can be used for the reaction of the compound of formula (III) with bromide or allyl triflate, Lithium Diisopropylamide (LDA), sodium bis (trimethylsilyl) amide (NaHMDS) and potassium tert-butoxide may be mentioned as non-limiting examples.

Among the esterification reagents which can be used for the preparation of the compound of formula (VI), mention may be made, as preferred, of the compounds of formula (VII):

R-X (VII)

wherein R is as defined for formula (I) and X represents a triflate, p-toluenesulfonate or methanesulfonate group or a halogen atom, preferably an iodine atom.

When it is desired to obtain a compound of formula (I) in which R represents a methyl group, the esterifying reagent may also be diazomethane.

Among the oxidizing agents which can be used in the oxidation reaction of the compound of formula (VI), mention may be made, as a non-limiting example, of RuCl₃NaIO in the Presence₄。

This oxidation can also be carried out in two steps, the first step, for example by converting the compound of formula (VI) under Swern conditions to the corresponding aldehyde, the second step, for example with KMnO₄This aldehyde is oxidized to the corresponding carboxylic acid.

The compounds of formulae (V) and (VI) are novel products useful as intermediates in the synthesis and are therefore part of the present invention in the chemical or pharmaceutical industry, in particular in the synthesis of perindopril.

The preferred R group is ethyl.

The compound of formula (III) can be obtained by using (S) -N-benzylalaninol, reacting (S) -N-benzylalaninol with ethyl bromoacetate in the presence of triethylamine, obtaining, after cleavage of the benzyl group, (S) -N- (ethoxycarbonylmethyl) alaninol, which is protected again with a P group as defined above, and then cyclized by reaction with P-toluenesulfonic acid.

Detailed Description

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

Step A: (3S, 5S) -3-allyl-5-methyl-2-oxo-4-morpholinecarboxylic acid tert-butyl ester:

the reactor was charged with 200g of tert-butyl (5S) -5-methyl-2-oxo-4-morpholinecarboxylate and 700ml of tetrahydrofuran, this solution was then cooled to-60 ℃ and 700ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran and heptane were added while the temperature of the reaction medium was kept below-40 ℃. After 1 hour of reaction, 225g of allyl bromide are added, while the temperature of the reaction medium is kept below-30 ℃ and stirring is carried out for 3 hours.

The reaction mixture is then allowed to warm to room temperature, hydrolyzed with aqueous ammonium chloride solution, extracted with diethyl ether and the ether phase washed with water.

The ether phase is dried and isolated to give tert-butyl (3S, 5S) -3-allyl-5-methyl-2-oxo-4-morpholinecarboxylate, which is used as such in the subsequent step.

Step B: (3S, 5S) -5-methyl-3-propyl-2-oxo-4-morpholinecarboxylic acid tert-butyl ester:

the hydrogenator was charged with 200g of the compound obtained in the previous step in ethanol, followed by 5g of 10% Pd/C. The hydrogenation is carried out at atmospheric pressure and room temperature until the theoretical amount of hydrogen is absorbed.

The catalyst was removed by filtration and tert-butyl (3S, 5S) -5-methyl-3-propyl-2-oxo-4-morpholinecarboxylate was isolated by drying.

Step C: (2S) -2- { (tert-Butoxycarbonyl) [ (1S) -2-hydroxy-1-methylethyl]-amino } -pentanoic acid ethyl ester

A reactor was charged with 200g of the compound obtained in the previous step, 500ml of acetonitrile, 500ml of water and 500ml of hexane, and then 33g of lithium hydroxide hydrate was added and stirred at 0 ℃ for 3 hours.

The reaction mixture was dried, and the resulting lithium salt was dissolved in 1.5 liters of dimethylformamide and then treated with 122g of iodoethane at room temperature.

After evaporation of dimethylformamide, the dried residue was treated with ethanol and filtered over silica to give (2S) -2- { (tert-butoxycarbonyl) [ (1S) -2-hydroxy-1-methylethyl ] -amino } -pentanoic acid ethyl ester in 60% yield.

Step D: n- [ (S) -ethoxycarbonyl-1-butyl]-N- (tert-butoxycarbonyl) - (S) -alanine

The reactor was charged with 500ml of dichloromethane, 500ml of water and 500ml of acetonitrile, and then 141g of sodium periodate and 1.35g of ruthenium trichloride hydrate were added. After stirring for 1h, 200g of the compound obtained in the previous step were added rapidly. After the reaction was completed, the organic phase was filtered through celite, washed and evaporated to dryness to obtain N- [ (S) -ethoxycarbonyl-1-butyl ] -N- (tert-butoxycarbonyl) - (S) -alanine.

Step E: n- [ (S) -ethoxycarbonyl-1-butyl]- (S) -alanine, hydrochloride salt:

the reactor was charged with 200g of the compound obtained in the preceding step and 1.5 l of ethyl acetate, the temperature of the reaction medium was then adjusted to 0 ℃ and a stream of hydrochloric acid was passed in for 30 minutes. After stirring overnight at room temperature, the resulting precipitate was filtered, rinsed and dried to give N- [ (S) -ethoxycarbonyl-1-butyl ] - (S) -alanine hydrochloride in quantitative yield.

Claims (2)

1. A compound of formula (V):

wherein P represents a tert-butoxycarbonyl group.

2. A compound of formula (VI):

wherein P represents a tert-butoxycarbonyl group and R represents an ethyl group.