FR2860230A1 - NOVEL PROCESS FOR PREPARING CIS-OCTAHYDRO-ISOINDOLE - Google Patents

Abstract

Process for the synthesis of cis-octahydroisoindole from phthalimide.Application to the synthesis of 2- (S) -benzyl-4-oxo-4- (cis-perhydroisoindol-2-yl) -butyric acid, its pharmaceutically acceptable salts and its hydrates.

Description

The present invention relates to a novel process for preparing cis-

octahydroisoindole.

  Cis-octahydroisoindole is a synthetic intermediate widely used, especially in the preparation of active pharmaceutical ingredients.

  In particular, cis-octahydroisoindole is an important intermediate in the synthesis of 2- (S) -benzyl-4-oxo-4- (cis-perhydroisoindol-2-yl) -butyric acid of formula (I): NCO2H

H O (I)

H

  of its pharmaceutically acceptable salts and its hydrates.

  The compound of formula (I), as well as its addition salts and its hydrates, more particularly the dihydrate of its calcium salt, possess particularly advantageous pharmacological properties. They are very powerful insulinosecretors, making them useful in the treatment of non-insulin-dependent diabetes. The compound of formula (I), its preparation and its therapeutic use have been described in patent EP 0 507 534. Its industrial preparation is described in patent WO 99/01430. Given the pharmaceutical interest of this compound, it was important to be able to access intermediate cis-octahydroisoindole with a high-performance industrial synthesis process.

  Several methods for preparing cis-octahydroisoindole are already known.

  Thus, the publication Bull. Soc. Chim. France 1966, 1315-1324, describes the preparation of cis-octahydroisoindole by catalytic hydrogenation, at 120 bars and 200 C, of cistetrahydrophthalimide in the presence of Raney nickel, followed by the chemical reduction by lithium aluminum hydride of the cis-octahydro-isoindol-1-one thus obtained.

  This method has several disadvantages: the first step requires drastic conditions, while the second step requires the use of a large excess of lithium aluminum hydride, which produces aluminum and lithium salts difficult to eliminate.

  The publication Bull. Soc. Chim. France 1956, 906-910, describes the preparation of cis-octahydroisoindole by catalytic hydrogenation, at 140 bar and 160 ° C., of phthalimide in the presence of Raney nickel, followed by catalytic hydrogenation at 250 bar and 300 ° C. in the presence of copper chromite, cis-octahydro-isoindol-1-one thus obtained. This method has the advantage of starting phthalimide, a particularly inexpensive raw material; but it requires, here again, particularly drastic conditions.

  The patent application JP 10218858 describes the preparation of cisoctahydro-isoindol-1-one by catalytic hydrogenation of phthalimide, at 100 bar and 150 C, in the simultaneous presence of the two catalysts Rh6 (CO) 16 and Mo (CO) 6.

  This method gives access to cis-octahydro-isoindol-1-one from phthalimide, a particularly cheap raw material, but the hydrogen pressure remains high. On the other hand, the conversion of cis-octahydro-isoindol-1-one to cis-octahydroisoindole is not described.

  Given the interest of cis-octahydro-isoindole as an intermediate for the synthesis of pharmaceutical active ingredients and in particular 2- (S) -benzyl-4-oxo-4- (cisperhydroisoindol-2-yl) In fact, it was important to find a process that would enable it to be obtained in good yield from inexpensive raw materials and under mild conditions that could easily be transferred to an industrial scale.

  The Applicant has undertaken extensive research which has resulted in the development of a process that meets these conditions.

  More specifically, the present invention relates to a process for preparing cisoctahydroisoindole by hydrogenation of phthalimide, in the presence of a catalyst of formula (Cati): [ArRuX 2] 2 (Cati) in which Ar represents an aromatic ring selected from benzene and naphthalene, optionally substituted by one or more linear or branched (C1-C6) alkyl groups, and X represents a halogen atom, or a catalyst of formula (Cat2): [Ar4Ru4H6] X2 (Cat2) in which Ar represents an aromatic ring selected from benzene and naphthalene, optionally substituted by one or more linear or branched (C1-C6) alkyl groups, and X represents a halogen atom, at a pressure greater than or equal to 1 bar, at a higher temperature or equal to 50 ° C., in water, to yield cis-octahydro-isoindol-1-one, the lactam function of which is then protected, to yield the compound of formula (II) of cis relative configuration:

O N-P H

  in which P represents a protective group chosen from linear or branched (C1-C6) alkoxycarbonyl, aryloxycarbonyl and arylmethyl, it being understood that by aryl group is meant phenyl optionally substituted with one or more groups, which may be identical or different, chosen from halogen, linear or branched (C1-C6) alkyl and linear or branched (C1-C6) alkoxy, which is subjected to a reduction reaction with the compound of formula (III): R1R2SiH2 (III) in which R1 represents an atom or group chosen from hydrogen, phenyl and linear or branched (C1-C6) alkyl, and R2 represents a group chosen from phenyl and linear or branched (C1-C6) alkyl, in the presence of a rhodium (I) or precursor catalyst. rhodium (I) ligand chloride, hydride, carbon monoxide, diene or phosphine, to yield the compound of formula (IV) of cis relative configuration:

H

N-P

H

  wherein P is as defined above, deprotecting the amine function, to yield cis-octahydroisoindole.

  The catalyst of formula (Cati) is preferred [(p-cymene) RuC12] 2.

  The catalyst of formula (Cat2) which is preferred is [(p-cymene) 4Ru4H6] C12.

  The preferred rhodium (I) catalyst is RhC13.H2O. The temperature of the phthalimide hydrogenation reaction is preferably between 50 and 150 C.

  P preferably represents the optionally substituted benzyl group. In this case, the deprotection reaction of the amine function of the compound of formula (IV) is preferably a palladium-carbon-catalyzed hydrogenation reaction, at a temperature above 20 ° C., or a reaction with ammonium formate in the presence of Pd (OH) 2, at reflux of ethanol.

  R1 and R2 each represent preferably the phenyl group.

  The cis-octahydroisoindole thus obtained is particularly useful as an intermediate in the synthesis of active principles such as the compound of formula (I).

  By way of illustration, its reaction with the anhydride of formula (V): O leads to the compound of formula (VI): (V)

H H

  N CO2H (VI) whose catalytic hydrogenation in the presence of an asymmetric catalyst leads to the compound of formula (I).

  EXAMPLE 1: Cis-octahydroisoindole Stage A: [(p-cymene) 4Ru4H6] C12 In an autoclave, 60 mg of (p-cymene) 2Ru2Cl4 and 15 ml of degassed distilled water are introduced under an inert atmosphere. The autoclave is then closed and purged 3 times with hydrogen before being pressurized to 60 bars and heated at 60 ° C. for 20 hours. The water is then evaporated and the residue obtained is dried to yield the expected product in the form of a solid.

  Stage B: cis-octahydro-isoindol-1 -one In an autoclave, 735 mg of phthalimide, 51 mg of the compound obtained in the preceding stage and 10 ml of degassed distilled water are introduced under an inert atmosphere. The autoclave is then closed and purged 3 times with hydrogen before being pressurized to 60 bars and heated at 90 ° C. for 24 hours. After returning to ambient pressure and temperature, the crude product is extracted with ether and the solvent of the organic phase thus obtained is evaporated to yield cisoctahydroisoindol-1-one in the form of a white solid, with a yield of 78%.

  Stage C: Cis-2-benzyl-octahydro-isoindol-1-one In a Schlenk tube 696 mg of the compound obtained in the preceding stage are introduced under an inert atmosphere, 132 mg of sodium hydride and 0.65 ml of bromide. of benzyl and 170 mg of tetrabutylammonium iodide in 20 ml of tetrahydrofuran. The mixture is stirred at room temperature for 15 h and then dichloromethane is added. The organic phase is washed and then dried, filtered and concentrated. Purification on a silica column gives cis-2-benzyl-octahydroisoindol-1-one as a colorless oil, with a yield of 79%.

  Stage D: cis-2-benzyl-octahydroisoindole 330 mg of the compound obtained in the preceding stage, 0.67 ml of diphenylsilane, 3 mg of RhC13.3H2O and 3 ml of tetrahydrofuran are introduced under an inert atmosphere into an inert atmosphere. . The mixture is stirred at ambient temperature for 5 h, then diluted with ether and extracted with a 1M hydrochloric acid solution. The aqueous phase is basified with a 1M sodium hydroxide solution and is extracted with ethyl acetate. The organic phase is then dried, filtered and evaporated to yield cis-2-benzyloctahydroisoindole as a colorless oil with a yield of 90%.

  Stage E: cis-octahydroisoindole In an autoclave, 80 mg of the compound obtained in the preceding stage, 16 mg of Pd on charcoal (20% by weight) and 5 ml of ethanol are introduced under argon. The autoclave is then pressurized with 15 bar of hydrogen and heated at 50 ° C. for 20 hours, then, after returning to ambient pressure and temperature, the contents of the autoclave are filtered and evaporated to yield cis-octahydroisoindole. in the form of a colorless oil, with a quantitative yield.

  EXAMPLE 2: Cis-octahydroisoindole Step A: Cis-octahydro-isoindol-1 -one The process is the same as that described in Step B of Example 1, replacing the [(p-cymene) 4Ru4H6] C12 by 61 mg of [(p-cymene) RuC12] 2.

  Stages B and C: identical to stages C and D of example 1. Stage D: Cisoctahydroisoindole In a Schlenk tube, 100 mg of the compound obtained in the preceding stage, 20 mg of Pd (OH) are introduced under an inert atmosphere. 2.87 mg of ammonium formate and 5 ml of absolute ethanol. The mixture is stirred at reflux for 15 h, then the ethanol is evaporated and the residue is washed, filtered and dried to yield cis-octahydroisoindole in quantitative yield.

Claims (10)

  A process for the preparation of cis-octahydroisoindole by hydrogenation of phthalimide in the presence of a catalyst of formula (Cati): [ArRuX 2] 2 (Cati) in which Ar represents an aromatic ring selected from benzene and naphthalene, optionally substituted by one or more linear or branched (C1-C6) alkyl groups, and X represents a halogen atom, or a catalyst of formula (Cat2): [Ar4Ru4H6] X2 (Cat2) in which Ar represents a chosen aromatic ring among benzene and naphthalene, optionally substituted by one or more linear or branched (C1-C6) alkyl groups, and X represents a halogen atom, under a pressure greater than or equal to 1 bar, at a temperature greater than or equal to 50 C in water, to yield cis-octahydro-isoindol-1-one, which is then protected against the lactam function, to yield the compound of formula (II) of cis-relative configuration: wherein P represents a protective group cho isi among linear or branched (C1-C6) alkoxycarbonyl, aryloxycarbonyl and arylmethyl, it being understood that by aryl group is meant phenyl optionally substituted by one or more groups, identical or different, selected from halogen, linear (C1-C6) alkyl or branched and linear or branched (C1-C6) alkoxy, which is subjected to a reduction reaction with the compound of formula (III): R1R2SiH2 (III) in which R1 represents an atom or group chosen from hydrogen, phenyl and alkyl (C1-C6) linear or branched, and R2 represents a group selected from phenyl and linear or branched (C1-C6) alkyl, in the presence of a rhodium (I) catalyst or chloride-ligand rhodium (I) precursor , hydride, carbon monoxide, diene or phosphine, to yield the compound of formula (IV), of cis relative configuration: H = H   wherein P is as defined above, deprotecting the amine function, to yield cis-octahydroisoindole.   2. Method according to claim 1, characterized in that the catalyst used for the phthalimide hydrogenation reaction is [(p-cymene) RuC12] 2 or [(p-cymene) 4Ru4H6] C12.   3. Method according to claim 1, characterized in that the rhodium catalyst (I) is RhC13.H20.   4. Method according to any one of claims 1 to 3, characterized in that the hydrogenation temperature of the phthalimide is between 50 and 100 C.   5. Process according to any one of claims 1 to 4, characterized in that P represents the optionally substituted benzyl group.   6. Process according to claim 5, characterized in that the deprotection reaction of the amine function of the compound of formula (IV) is a palladium-carbon catalyzed hydrogenation reaction, at a temperature above 20 C, or reaction with ammonium formate in the presence of Pd (OH) 2 at reflux of ethanol.   io 7. Process according to any one of claims 1 to 6, characterized in that R1 and R2 each represent a phenyl group.   8. Process for the preparation of 2- (S) -benzyl-4-oxo-4- (cisperhydroisoindol-2-yl) -butyric acid from cis-octahydroisoindole, characterized in that said cis-octahydroisoindole is prepared according to the process of claim 1.   9. Process for the preparation of the calcium salt of 2- (S) -benzyl-4-oxo4- (cisperhydroisoindol-2-yl) -butyric acid from cis-octahydroisoindole, characterized in that said cis-octahydro- isoindole is prepared according to the process of claim 1.   10. Process for the preparation of calcium bis-2- (S) -benzyl-4-oxo-4- (cisperhydroisoindol-2-yl) -butyrate dihydrate from cis-octahydroisoindole, characterized in that said cis- octahydroisoindole is prepared according to the method of claim 1.