FR2685330A1 - PROCESS FOR THE PREPARATION OF ENANTIOMERS OF AN ISOINDOLINONE DERIVATIVE. - Google Patents

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

qui présente des propriétés anxiolytiques, hypnotiques, anticonvulsivantes, antiépileptiques et myorelaxantes remarquables.PROCESS FOR THE PREPARATION OF ENANTIOMERS
FROM 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.

dans laquelle R1, R2, R3 et R4 constituent les restes d'un diol chiral, séparation de ces diastéréoisomères par chromatographie et hydrolyse de chacun des diastéréoisomères,
Généralement, l'hydrolyse de chacun des diastéréoisomères peut être effectuée au moyen d'un acide minéral tel que l'acide chlorhydrique concentré en opérant dans un solvant organique ou d'un acide organique tel que l'acide acétique ou de leurs mélanges, l'acide organique pouvant jouer le rôle de solvant. I1 est particulièrement avantageux d'opérer à une température voisine de 50"C. I1 has now been found, and this is what is the subject of the present invention, that the enantiomers of the product of formula (I) can be obtained3 after preparation, from the product of racemic formula (I), of diastereoisomeric acetals of general formula:

in which R1, R2, R3 and R4 constitute the residues of a chiral diol, separation of these diastereoisomers by chromatography and hydrolysis of each of the diastereoisomers,
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.

dans laquelle les symboles R représentent chacun un radical allyle contenant 1 à 4 atomes de carbone. Les symboles R sont identiques et représentent, de préférence, chacun un radical méthyle.The diastereoisomeric acetals of the product of general formula (11) 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 allyl radical containing 1 to 4 carbon atoms. The symbols R are identical and preferably represent each a methyl radical.

 Preferably, the choral diols which are particularly suitable are chosen from (-) - pinanediol- (IR, 2R, 3S, 5R) and 1,4-dimethoxy-2,3-butanediol (2S, 3S).

 The racemic acetal of general formula (leak) can be obtained by the action of a triaikyl orthoformate, preferably trimethyl rorthoformate, on the racemic product of formula (I) by operating in an organic solvent such as methanol in the presence of a mineral acid such as sulfuric acid at a temperature between 0 and 500C and preferably close to 20 "C.

 Generally, the action of the chiral diol on the racemic acetal of general formula (yarn) 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.

EXAMPLE 1
To a suspension of 0.6 g of (4 - {(chloro-7 naphthyridine-138 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 in the region of 50 "C., then left for 12 hours at a temperature in the region of 200 C. The reaction mixture is diluted with 250 cm 3 of distilled water and extracted with 3 times 50 cm 3 of ethyl acetate. The combined organic phases are washed with 2 times 50 cm 3 of water, 2 times 5 cm3 of a saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40 "C. 0.26 g is thus obtained, after recrystallization from ethanol of (+) - (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-oxo hexyl) -3 isoindolinone-1 melting at 174 "C whose rotary power is:
[a] 20D = + 1350 + 20 (c = 1.13 to; CHCl3).

A - (+) - [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 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 of 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 400C. 1.0 g of (+) - [(7-chloro-naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-5 hexanone is thus obtained after recrystallization from ethyl acetate -2 pinene-2 acetal- (1R, 2R, 3S, 5R) (form A, first majority eluting diastereoisomer) melting at 2340C whose rotary power is:
[a] 20D +130 "f 20 (c = 1.0%; CHCl3) and 0.6 g of (-) - [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl- 1J-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:
[a] 20D = -1230 + 20 (c = 0.68%; CHCl3).

B - (Chloro-7 naphthyridine-1,8 yl-2) -2 (5-methyl-2,2-dimethoxy-hexyl) -3 isoindolinone-1- (RS) can be prepared in the following way:
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 200C 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 leads to a pasty residue which, by beating in acetonitrile, gives 19 g of (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2,2-dimethoxy-hexyl) -3 isoindolinone-1- (RS) melting at 140 "C.

 (7-Chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-oxo hexyl) -3 isoindolinone-1- (RS) can be prepared according to the method described in American patent US Pat. No. 4,960,779.

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 (-l- (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:
[a] 20D = -1340 + 30 (c = 0.63%; CHCl3).

EXAMPLE 3
The procedure is as in Example 1 but starting with 0.07 g of (+) - [(7-chloro-naphthyridine-1,8 yl-2) -2 3-oxo-isoindolinyl-1] -2 5-methyl hexanone -2 (dimethoxy1,4 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 naphthyridine-1,8 yl-2) -2 (methyl-5 oxo-2 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-1] -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-dimethoxy-hexyl) 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 is thus obtained after recrystallization from diisopropyl ether hexanone-2 (1,4-dimethoxy-2-butene-2) acetal- (2S, 3S) (form A, first elution product) melting at 98 ° C with rotational power:
[α] 20D = +100 3 (c = 0.45%; CHCl3) and 0.35 g of (-) - [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl- 1] -2 5-methyl-hexanone-2 (1,4-dimethoxy-2-butene-2) acetal- (2S, 3S) (form B, second elution product) melting at 115 C whose rotary power is:
[α] 20D = -102 2 (c = 0.66%; CHCl3).

 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 from 0.1 g of (-) - [(7-chloro-naphthyridine-1, 8 yl-2) -2 3-oxo-isoindolinyl-1] -2 5-methyl-2-hexanone (dimethoxy1,4 butene-2) acetal- (2S, 3S) (form B) prepared according to Example 3A, 5 cm3 of acetic acid and 1.0 cm3 of an aqueous solution of 12N hydrochloric acid. This gives 0.06 g of (-) - (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-oxo-hexyl) -3 isoindolinone-1 melting at 172 C and whose rotary power East:
[ocl20D = -1390 +30 (c = 0.73%; CHOl3).

Claims (6)

 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 R1, 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.  5- A method 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.