EP0643711A1

EP0643711A1 - Method for preparing enantiomers of an isoindolinone derivative

Info

Publication number: EP0643711A1
Application number: EP93902350A
Authority: EP
Inventors: Michel Barreau; Claude Cotrel; Marie-Christine Dubroeucq; Franco Manfre
Original assignee: Rhone Poulenc Rorer SA
Current assignee: Aventis Pharma SA
Priority date: 1991-12-20
Filing date: 1992-12-18
Publication date: 1995-03-22
Also published as: CA2122025A1; FR2685330B1; JPH07502282A; FR2685330A1; WO1993013098A1

Abstract

A method for preparing enantiomers of the product of formula (I) by hydrolyzing a diastereoisomeric acetal of general formula (II), wherein R1?, R2?, R3? and R4? are chiral diol residues. The dextrorotatory isomer of the product of formula (I) has anxiety-relieving, hypnotic, anticonvulsant, antiepileptic and muscle relaxant properties.

Description

PROCESS FOR THE PREPARATION OF ENANTIOMERS OF AN ISOINDOLINONE DERIVATIVE

The present invention relates to a process for the preparation of enantiomers of the isoindolinone derivative of formula:

which has remarkable anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle relaxant properties.

According to American patent US 4,960,779, the enantiomers of the isoindolinone derivative of formula (I) can be obtained from the corresponding racemic by chromatography on chiral phase. However, the industrial implementation of this process is not always easy to carry out.

It has now been found, and this is the subject of the present invention, that the enantiomers of the product of formula (I) can be obtained, after preparation, from the product of racemic formula (I), d diastereoisomeric acetals of general formula:

in which R ^, R2, R3 and R4 constitute the residues of a chiral diol, separation of these diastereoisomers by chromatography and hydrolysis of each of the diastereoisomers.

REPLACEMENT SHEET Generally, the hydrolysis of each of the diastereoisomers can be carried out using a mineral acid such as concentrated hydrochloric acid by operating in an organic solvent or an organic acid such as acetic acid or their mixtures, l organic acid which can act as a solvent. It is particularly advantageous to operate at a temperature in the region of 50 ° C.

The diastereoisomeric acetals of the product of general formula (H) can be obtained by the action of a chiral diol on a racemic acetal of general formula:

in which the symbols R each represent an alkyl radical containing 1 to 4 carbon atoms. The symbols R are identical and preferably represent each a methyl radical.

Preferably, the chiral diols which are particularly suitable are chosen from (-) - pinanediol- (1R, 2R, 3S, 5R) and 1,4-dimethoxy-2,3-butanediol (2S.3S). The racemic acetal of general formula (lu) can be obtained by the action of a trialkyl orthoformate, preferably trimethyl orthoformate, on the racemic product of formula (I) by operating in an organic solvent such as methanol in presence of a mineral acid such as sulfuric acid at a temperature between 0 and 50 ° C and preferably close to 20 ° C. Generally, the action of the chiral diol on the racemic acetal of general formula (lu) is carried out in an inert organic solvent such as an aromatic hydrocarbon such as toluene or a halogenated aliphatic hydrocarbon such as 1,2-dichloroethane. presence of an agent such as pyridinium tosylate or p.toluenesulfonic acid by operating at the reflux temperature of the reaction mixture. Depending on the nature of the diol used, the number of diastereoisomeric acetals obtained varies. For example, it is 4 in the case of (-) - pinanediol- (1R, 2R, 3S, 5R) and it is 2 in the case of 1,4-dimethoxy-2,3-butanediol (2S, 3S ).

The following examples illustrate the present invention.

REPLACEMENT SHEET EXAMPLE 1

To a suspension of 0.6 g of (+) - [(7-chloro-naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-5 hexanone-2 pinene-2 acetal- ( 1R, 2R, 3S, 5R) (form A) in 50 cm3 of acetic acid, 5 cm3 of an aqueous solution of 12N hydrochloric acid are added. The solution obtained is stirred for 6 hours at a temperature close to 50 ° C., then left for 12 hours at a temperature close to 20 ° C. The reaction mixture is diluted with 250 cm3 of distilled water and extracted with 3 times 50 cm3 of ethyl acetate. The combined organic phases are washed with 2 times 50 cm3 of water, 2 times 5 cm3 of a saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate and concentrated to dryness under reduced pressure at 40 ° C. 0.26 g of (+) - (7-chloro-naρhtyridine-1,8 yl-2) -2 (5-methyl-2-oxo-hexyl) -3 isoindolinone-1 is thus obtained, after recrystallization from ethanol at 174 ° C whose rotary power is:

[α] ²⁰ _D = + 135 ° ± 2 ° (c = 1.13%; CHC1 ₃ ).

A - (+) - [chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-l] -2 methyl-5 hexanone-2 pinene-2 acetal- (1R, 2R, 3S, 5R ) (form A) can be prepared as follows:

To a mixture containing 7 g of (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2,2-dimethoxy-hexyl) -3 isoindolinone-1- (RS) and 0.97 g of tosylate pyridinium dissolved in 100 cm3 of 1,2-dichloroethane, 0.84 g of (-) - pinanediol- (1R, 2R, 3S, 5R) is added. The mixture is heated at reflux for 3 hours then is concentrated to dryness under reduced pressure. The residue obtained is taken up in 100 cm3 of an ethyl acetate-cyclohexane mixture (30-70 by volume). The solid is separated by filtration and the filtrate is concentrated to dryness under reduced pressure. After a first filtration on silica (eluent: ethyl acetate-cyclohexane (30-70 by volume) and evaporation of the solvents under reduced pressure, the mixture of diastereoisomers obtained is purified by chromatography on silica (methylene chloride-methanol (99- 1 by volume)). The fractions containing the two majority diastereoisomers are collected and concentrated to dryness under reduced pressure at 40 ° C. 1.0 g of (+) - [[]] is thus obtained after recrystallization from ethyl acetate. (chloro-7 naρhtyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-5 hexanone-2 pinene-2 acetal- (1R, 2R, 3S, 5R) (form A, first diastereoisomer elution majority) melting at 234 ° C whose rotary power is:

[α] ²⁰ D = + 130 ° ± 2 ° (c = 1.0%; CHCI3)

REPLACEMENT SHEET and 0.6 g of (-) - [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-5 hexanone-2 pinene-2 acetal- (1R, 2R , 3S, 5R) (form B, second majority eluting diastereoisomer) melting at 197 ° C whose rotary power is: [c] ²⁰ D ≈ -123 ° ± 2 ° (c = 0.68%; CHC1 ₃ ) .

B - (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2,2-dimethoxy hexyl) -3 isoindolinone-1- (RS) can be prepared in the following manner:

To a suspension of 25 g of (chloro-7 naphthyridine-1,8 yl-2) -2 (methyl-5 oxo-2 hexyl) -3 isoindolinone-1 - (RS) in 600 cm3 of methanol, 27 is added, 5 cm3 (28 g) of trimethyl orthoformate and 1.5 cm3 of concentrated sulfuric acid. The reaction mixture is stirred for 12 hours at a temperature in the region of 20 ° C and is then diluted with 200 cm3 of dichloromethane and brought to a pH in the region of 7 by addition of triethylamine. Evaporation of the solvents under reduced pressure results in a pasty residue which, by threshing in acetonitrile, gives 19 g of (chloro-7 naphth ridine-1,8 yl-2) -2 (methyl-5 dimethoxy-2,2 hexyl ) -3 isoindolinone-1- (RS) melting at 140 ° C.

(7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-oxo hexyl) -3 isoindoIinone-1- (RS) can be prepared according to the method described in American patent US Pat.

EXAMPLE 2 The procedure is as in Example 1 but starting with 0.1 g of (-) - [(7-chloro-naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl- 5 hexanone-2 pinene-2 acetal- (1R, 2R, 3S, 5R) (form B) prepared according to Example 1A, 10 cm3 of acetic acid and 1 cm3 of an aqueous solution of 12N hydrochloric acid . 0.03 g of (-) - (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-oxo-hexyl) -3 isoindolinone-1 is thus obtained, after recrystallization from ethanol at 171 ° C whose rotary power is:

M ²⁰ D = -134 ° ± 3 ° (c = 0.63%; CHCI3).

EXAMPLE 3

The procedure is as in Example 1 but starting from 0.07 g of (+) - [(7-chloro-naphthyridine-1,8 yl-2) -2 oxo-3 isoindoϋnyl-l] -2 methyl-5 hexanone -2 (dimethoxy-

1,4 butene-2 acetal- (2S, 3S) (form A), 3 cm3 of acetic acid and 0.5 cm3 of an aqueous solution of 12N hydrochloric acid. This gives 0.02 g of (+) - (chloro-7

F _β WLUB DE Be PLACEMEMT naphthyridine-1,8 yl-2) -2 (5-methyl-2 oxo-hexyl) -3 isoindolinone-1 melting at 172 ° C and having an enantiomeric excess greater than 99%.

(+) - [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-l] -2 methyl-5 hexanone-2 (1,4-dimethoxy-2-butene-2) acetal- (2S , 3S) (form A) can be prepared by operating in a manner analogous to that described in Example 1A but from 3.2 g of (7-chloro-naphthyridine-1,8 yl-2) -2 ( 5-methyl-2,2-dimethoxyhexyl) -3 isoindolinone-1- (RS) prepared according to Example 3, 0.7 g of 1,4-dimethoxy butanediol- (2S, 3S) and 0.3 g of pyridinium tosylate. 0.45 g of (+) - [(7-chloro-naphthyridine-1.8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-5 hexanone- is thus obtained after recrystallization from diisopropyl ether 2 (1,4-dimethoxy-2-butene-2) acetal- (2S, 3S) (form A, first elution product) melting at 98 ° C. whose rotary power is:

[α] 20 _D = + 100 ° ± 3 ° (c = 0.45%; CHC1 ₃ ) and 0.35 g of (-) - [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo -3 isoindolinyl-1] -2 methyl-5 hexanone-2 (1,4-dimethoxy-2-butene-2) acetal- (2S, 3S) (form B, second elution product) melting at 115 ° C including rotational power is: [α] ² 0 _D = -102 ° ± 2 ° (c = 0.66%; CHCI3).

Dimethoxy-1,4-butanediol- (2S, 3S) can be prepared according to the method described by H. FUJIOKA et al., Chem. Pharm. Bull., 37, 1488-1492 (1989).

EXAMPLE 4

The procedure is as in Example 1, but starting with 0.1 g of (-) - [(7-chloro-naphthyridine-1,8 yl-2) -2 3-oxo-isoindolinyl-1] -2 5-methyl-hexanone -2 (dimethoxy-1,4 butene-2) acetal- (2S, 3S) (form B) prepared according to Example 3A, of 5 cm3 of acetic acid and 1.0 cm3 of an aqueous solution of hydrochloric acid 12N. We thus obtain 0.06 g of (-) - (chloro-7 naρhtyridine-1,8 yl-2) -2 (methyl-5 oxo-2 hexyl) -3 isoindolinone-1 melting at 172 ° C and whose power rotary is: [] 20 _D = -139 ° ± 3 ° (c = 0.73%; CHCI3).

REPLACEMENT TENSION

Claims

REVENPICAπQNS

1 - Process for the preparation of the enantiomers of the isoindolinone product of general formula:

characterized in that, after preparation, from the racemic product of formula (I), diastereoisomeric acetals of general formula:

in which R] _, R2, R3 and R4 constitute the residues of a chiral diol and separation of these diastereoisomers by chromatography, each of these diastereoisomers is hydrolyzed.

2 - Process according to claim 1 characterized in that the chiral diol is chosen from (-) - pinanediol- (1R, 2R, 3S, 5R) and 1,4-dimethoxy-2,3-butanediol (2S.3S ).

3 - Process according to claim 1 characterized in that the hydrolysis is carried out by means of a mineral acid in an organic solvent or an organic acid or their mixtures.

4 - Process according to claim 3 characterized in that the mineral acid is hydrochloric acid.

^. E FROM BEMPLACHMHNT 5 - Process according to claim 3 characterized in that the organic solvent is acetic acid.

6 - Process according to claim 1 characterized in that the hydrolysis is carried out at a temperature between 20 ° C and the reflux temperature of the reaction mixture.

REPLACEMENT SHEET