CS219862B2 - Process for preparing N - [(2S) -3-mercapto-2-methylpropionyl] -L-proline - Google Patents

Abstract

The invention relates to a method for producing N-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, which consists in reacting the trimethylsilyl ester of L-proline with a derivative of (2S)-3-mercapto-2-methylpropionic acid in the presence of a tertiary organic base, after which the trimethylsilyl group and the sulfur-bound protective group present in the resulting intermediate are hydrolytically cleaved in an aqueous medium at room temperature.

Description

The present invention relates to a process for the preparation of N- [(2S) -3-mercapto-2-methylpropionyl] -L-proline by reacting L-proline trimethylsilyl ester with a (2S) -3-mercapto-2 acid derivative. methylpropionic in the presence of a tertiary organic base, whereupon the trimethylsilyl group and the sulfur-bonded protecting group present in the resulting intermediate are hydrolytically hydrolysed in aqueous medium at room temperature.

The present invention relates to a novel process for the preparation of N- [(2S) -3-mercapto-2-methylpropionyl] -L-proline of the formula I

COOH

WHAT

CH-CH $

CH, -SH!)

The compound of formula (I) is a widely used anti-high pressure agent for which a number of processes have been proposed (cf. French Patent No. 7,704,122).

Of the proposed processes, the only one that is of industrial importance and has hitherto been operated on a technical scale is the process that involves

a) reacting L-proline tert-butyl ester with 3-acetylthio-2-methylpropionic acid in the presence of a condensing agent followed by purification of 1- (3-acetylthio-2-methylpropionyl) -L-proline tert-butyl ester thus obtained,

b) hydrolysis of the resulting 1- (3-acetylthio-2-methylpropionyl) -L-proline tert-butyl ester using trifluoroacetic acid and anisole to remove the tert-butyl group, wherein a mixture of the 1- (3-acetylthio-2- diastereoisomers) thus obtained L-proline methylpropionyl must undergo a number of complicated treatments to separate and purify N- [(2S) -3-acetylthio-2-methylpropionyl] -L-proline, and to hydrolyze N- [(2S) -3-acetylthio] 2-methylpropionyl] -L-proline by methanolic ammonia solution to give N - [(2S, 3-mercapto-2-methylproplonyl) -L-proline, which is purified on an ion exchange resin column.

We have now found a new process for the preparation of N- [(2S) -3-mercapto-2-methylpropionyl] -L-proline of formula I which is much simpler and more economical than the best processes described hitherto; this new process makes it possible to produce a compound of formula I at many lower costs than hitherto possible.

Process according to the invention for the preparation of N - [(2S, 3-mercapto-2-methylpropionyl) -L-proline of formula I

is characterized in that the trimethylsilyl ester of L-proline of formula II

Cl

COOSUCH 2 (II) is reacted with a (2S) -3-mercapto-2-methylpropionic acid derivative of the formula III

CH3

I (2S) CHa-CH-COX

SR (ΠΙ), where

X is halogen or a diphenylphosphinite group [(C 6 H 5 Z 2 O-O-) a

O

R is R ¹ —C—

O or group

Ri —O — C—,

Wherein R ¹ represents an alkyl group, an aralkyl group or an aryl group, preferably a methyl, ethyl, benzyl or phenyl group, in the presence of a tertiary organic base, whereupon the resulting intermediate of formula IV is formed

and.

^^ COOSidCH ^ CO

CH-CH.

CLh-SR ¹

CO ch-ch ₃

CH 2 SH (I) wherein

R is as defined above, hydrolysis is in an aqueous medium at room temperature to remove the trimethylsilyl and R groups.

This new process of performing the two reactions described above can be illustrated by the following reaction scheme:

1.

^ N ^ COOSLlCHI Η ³ (II)

CH.

I ^p

- (2S) CH.-CH-COX I *

SR (III) principle cx.

'N COOSES ^ CO

CH-CH.

i ^ύ

CH-SR (IV)

Hydrolysis of COOSL (CH3)

WHAT

CH- CH, i $

CHf SR (IV) o

what

CH ~ CH.

i ⁵

CH-SH

COOH

The starting compound of formula (II) for the process according to the invention, i.e. L-proline trimethylsilyl ester, is a novel product which is obtained very simply by reacting L-proline with a suitable trimethylsilyl derivative, preferably with trimethylsilyl chloride or hexamethyldisilazane in an organic aprotic solvent.

The trimethylsilyl derivative is added to the proline solution in a stoichiometric amount and reacts quantitatively to convert any L-proline present into the L-proline trimethylsilyl ester. Therefore, it is not necessary to isolate the resulting product of formula II from solution; the solution containing this compound is used directly in the reaction step (1j after addition of a suitable solvent).

The compound of formula III, i.e. (2S) -3-mercapto-2-methylpropionic acid, is obtained by a known method by adding anions RS 'or thiols of formula RSH, where R is as defined above, to methacrylic acid according to of the reaction scheme

_CH2 = C-COOH + RSH CH-CH-COOH

I I I

CH3 SR CH3 whereupon the two optical antipodes contained in the racemic product are separated by conversion into an optically active base salt and isolated by traction crystallization from suitable solvents.

The optically active bases used may preferably be alkaloid series bases.

It has proven to be more advantageous to react the compound of formula II with (2S) -3-mercapto-2-methylpropionic acid instead of the corresponding racemic product because - while 3-mercapto-2-methylpropionic acid readily dissolves in the high yield and high purity - the mixture of diastereoisomers resulting from the reaction of a compound of formula II with racy-3-mercapto-2-methylpropionic acid is difficult to separate into individual components, requiring a greater number of steps and reduces yield.

The reaction of the compound of formula (II) with the compound of formula (III) is carried out in a non-aqueous aprotic organic solvent, preferably ethyl ether, tetrahydrofuran, acetonitrile, ethyl acetate, methylene chloride or chloroform. As mentioned above, the solvent in the reaction of a compound of formula II with a compound of formula III may be the same as that used to prepare L-proline trimethylsilyl ester, allowing, as a preferred solution, to obtain a new starting compound of formula II and react with the compound of formula III in a single reaction medium without the need to isolate and purify the resulting intermediates.

The reaction is carried out in the presence of a tertiary base which neutralizes the HX acid formed, wherein X is a halogen or a diphenylphosphinite group, as mentioned above. Preferably, the base is selected from the group consisting of triethylamine, N-methylmorpholine, N-methylpiperidine and N-methylpyrrolidine.

The intermediate of formula (IV) can be hydrolyzed by two alternative processes, namely

(a) in two consecutive steps, the first being simple hydrolysis using water to remove the trimethylsilyl group and the second being hydrolysis with an organic or inorganic base to remove the protecting group R; or

b) in a single stage of action of aqueous organic or inorganic bases which simultaneously hydrolyze the trimethylsilyl group and the R group.

It should be noted that reaction (2) of the novel process of the invention does not require isolation and purification of the intermediate compound (IV). Conversely, step (2) is preferably carried out by directly treating the reaction mixture of step (1) with water or aqueous bases.

The resulting product of formula I, i.e. N- [(2S) -3H-mercapto-2-methylpropionyl] -L-proline, can be obtained from its salts in the pure state by eluting with dilute organic or inorganic acids using a basic resin column, or eluting with water using acid resin columns.

In this way, a product of pharmaceutical purity is obtained in high yield.

A simple comparison with the best methods so far described reveals the extent to which the new method of the invention is simpler and more economical:

The three steps of the prior art process are separated from one another and provide for the isolation and purification of the intermediates formed. On the other hand, the novel process of the invention, which is also a preferred solution, can be carried out in a single reaction medium from which only the resulting product is isolated and purified;

- step (b) of the known process involves in fact a large number of separation and purification operations and is particularly complicated, firstly because the hydrolysis with trifluoroacetic acid and anisole (the only one which is industrially feasible with tert-butyl ester) is very drastic and therefore leads to formation numerous by-products, partly because the two diastereoisomers formed are difficult to separate from one another. Conversely, the respective process step of the invention is very simple and, as already mentioned, is not separated from the other process steps, since the use of the optically pure derivative of the general formula III results in the formation of a single product instead of a mixture of products. Moreover, since the hydrolysis of the trimethylsilyl group is carried out with water at room temperature, this hydrolysis is very mild and does not lead to secondary reactions and consequently to the formation of by-products;

In the prior art process, the two protecting groups on the carboxyl group of the proline and the thio group have completely different characteristics and therefore require two completely separate hydrolytic steps which must not interfere with one another. Conversely, in the process of the invention, the trimethylsilyl group and the R group can be hydrolyzed under the same conditions, quantitatively and without the formation of by-products. As already mentioned, the use of the process according to the invention in all cases yields a pharmaceutical grade product.

The following examples illustrate the invention in greater detail without limiting its scope. Example 1

1 mol of (2S) -3-acetylthio-2-methylpropionic acid in 5 ml of anhydrous ethyl acetate is treated with 1 mmol of chlorodiphenylphosphine (prepared from chlorodiphenylphosphine by air oxidation) in the presence of 1 mmol of N-methylmorpholine. The solution was stirred at room temperature for 2 hours. A solution of 1 mmol of trimethylsilyl ester L-proline and 1 mmol of N-methylmorpholine in 5 mL of anhydrous ethyl acetate was added.

Stirring of the solution was continued at room temperature for 5 hours, water was added and the mixture was stirred again for 30 minutes. The organic layer was separated and the aqueous layer was extracted several times with ethyl acetate. The organic layer was then washed with a small amount of saturated aqueous sodium chloride solution, dried and evaporated to dryness.

The N - ((2S) -3-acetylthio-2-methylpropionyl) -L-proline thus obtained is hydrolysed with aqueous ammonia solution at room temperature, if the hydrolysis is carried out with aqueous sodium carbonate solutions or aqueous organic base solutions at room temperature, the result is always same

The solution obtained by hydrolysis is allowed to soak through a bed of acidic resin to remove cations. The product containing fractions containing N - [(2S) -3-mercapto-2-methylpropionyl] -L-proline were combined, evaporated under reduced pressure and the residue was recrystallized from ethyl acetate-hexane.

Mp 103-104 ° C; [α] D = -131 °

Example 2

1 mmol of (2S) -3-methoxydithiocarbonyl-2-methylpropionic acid in 8 ml of anhydrous methylene chloride CH2Cl2 was treated with 1 mmol of chlorodiphenyl phosphite in the presence of 2 mmol of triethylamine.

After stirring at room temperature for 2 hours, a solution of 1 mmol of L-proline trimethylsilyl ester in 10 mL of CH 3 CN was added. The proline ester was prepared directly in solution without isolation from 1 mmol of L-proline suspended in 10 mL of acetonitrile by treatment with 1 mmol of (CH 3) 3 SiCl and 1 mmol of tributylamine, or 1 mmol of L-proline and 1 mmol of hexamethyldisilazane in the same solvent.

The reaction mixture containing the (2S) -3-methoxydithiocarbonyl-2-ethyl-propionic acid diphenylphosphite derivative and the L-proline trimethylsilyl ester was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure, the residue was dissolved in ammonium hydroxide and the solution was stirred for 3 hours, then added to a column of basic (quaternary ammonium) resin.

The column was then washed with water and eluted with dilute formic acid. Fractions containing N - [(2S) -3-mercapto-2-methylpropionyl) -L-proline as a product were combined and evaporated to dryness under reduced pressure. The residue, recrystallized from ethyl acetate-hexane, affords pure N - [(2S, 3-mercapto-2-methylpropionyl) -L-proline.

Claims (4)

SUBJECT VYNALEZU Process for the preparation of N - [(2S) -3-mercapto-2-methylpropionyl] -L-proline of the formula I M COOH CO CH-CH _a CH 2 SH (I) characterized in that the L-proline trimethylsilyl ester of formula (II) is used COOSIA (II) is reacted with a (2S) -3-mercapto-2-methylpropionic acid derivative of formula III CH 2 (2S) CH 2 —CH-COX AND SR (ΠΙ), where X is halogen or diphenylphosphinite; and R is one of the groups of formulas R 1-C a and O Rl__O-C-, wherein R ¹ represents an alkyl, aralkyl or aryl group, preferably a methyl, ethyl, benzyl or phenyl, in the presence of a tertiary organic base, and then from the resulting ester of formula IV ΓΊ tf ^ COOSUCH) WHAT CH-CH, ¹³ Z Ct-i-SR ^L (IV) where R is as defined above, hydrolytically cleaves the trimethylsilyl group and the R group in an aqueous medium at room temperature. 2. The process of claim 1 wherein the reaction of the trimethylsilyl L-proline ester with the (2S) -3-mercapto-2-methylpropionic acid derivative is carried out in an aprotic anhydrous organic solvent. 3. The process of claim 1 wherein the protecting groups in the compound of formula (IV) are hydrolytically cleaved in two consecutive steps, wherein the trimethylsilyl group is first cleaved in the first step with water at room temperature, followed by the second step. R is treated with an aqueous organic or inorganic base at room temperature. 4. The process of claim 1 wherein the two protecting groups in the compound of formula (IV) are removed hydrolytically in a single step by direct treatment with an aqueous organic or inorganic base at room temperature.