MXPA99011657A - Method for preparing a substituted perhydroisoindole - Google Patents

Abstract

The invention concerns a method for the industrial synthesis of a substituted perhydroisoindole of formula (I) and its pharmaceutically acceptable salts.

Description

METHOD FOR PREPARING A SUBSTITUTED PERHIDROISOINDOL DESCRIPTION OF THE INVENTION The present invention relates to a process for the industrial synthesis of a substituted perhydroisoindole of formula (I): and pharmaceutically acceptable salts thereof. The compound of formula (I) and its addition salts have especially valuable pharmacological properties. It is a very powerful insulin secretor, which becomes useful in the treatment of non-insulin-dependent diabetes. The compound of formula (I), its preparation and its therapeutically use have been described in the European patent specification EP 0 507 534. However, the industrial preparation of a compound such as the compound of formula (I), requires an investigation deep of all the reaction stages, of the selection of the initial materials and of the reagents and solvents that make it possible to obtain optimal performance. The process for the synthesis of the compound of formula (I) described in patent specification EP 0 507 534 no. 5 allows the compound to be obtained in optimum yield. In fact, obtaining the isomer of interest by the synthesis method described does not allow the desired regioselectivity to be obtained. Therefore, it is necessary to carry out many purification operations in order to obtain the "klO pharmaceutical grade" isomer. Given the pharmaceutical value of the compound and given the absence of a process that allows it to be obtained with good yield, with satisfactory purity and, if possible, from cheap starting materials that are commercially available, it has been carried out a deeper investigation which has resulted in the development of a new and especially useful synthesis process. The invention relates more specifically to a process for the preparation of the compound of formula (I), characterized in that the dimethyl succinate is reacted with benzaldehyde in a methanolic medium, to provide the diacid of formula (II): which, after heating in an aprotic solvent, such as tetrahydrofuran or isopropyl ether, in the presence of acetic anhydride, provides the anhydride of formula (III) which is reacted with the perhydroisoindole of formula (IV) in an aprotic solvent, such as toluene, acetonitrile, ethyl acetate, methyl tertiary butyl ether or tetrahydrofuran, or in a tetrahydrofuran / toluene mixture, to provide the compound of formula (V) which is subjected to catalytic hydrogenation using as the asymmetric hydrogenation catalyst the rhodium complex / (2S, 4S) -N-butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphino-methylpyrrolidine or Rh / (S, S) BPPM, in methanolic medium or methylene chloride, followed by conversion to a salt in the presence of an amine A to provide a compound of formula (VI): which: in a basic medium in the presence of a mineral salt, provides an addition salt of the compound of formula (I) which is converted, if desired, into the corresponding acid, or in an acidic medium provides the compound of formula (I), which is converted, if desired, into a pharmaceutically acceptable addition salt. Among the pharmaceutically acceptable addition salts, there may be mentioned as non-limiting examples the sodium and calcium salts in hydrated or unhydrated form. The preferred addition salt is the calcium salt. The process is especially useful for the following reasons; The opening of the anhydride of formula (III) by the perhydroisondol of formula (IV) allows a high regioselectivity to be obtained. In fact, the compound of formula (V) is isolated with a regioselectivity of more than 99.5%.

The enantioselective reduction of the compound of formula (V) by the Rh / (S, S) complex BPPM provides an enantiomeric excess of more than 92%. The molar ratio of complex / substrate in this step is from 1/2000 to 1 / 10,000, and preferably from 1/2000 to 1 / -4000. The rhodium complex Rh (S, S) BPPM is known from the literature as an enantiospecific hydrogenation catalyst. However, in methanol or methylene chloride (reaction solvent), the acid of formula (I / a) has a tendency to generate a mixture of regioisomers (I / a) (I / b): (I / a) '.I / b) A kinetic study has made it possible to show that the regioisomer percentage (I / b) increases rapidly as a function of time and temperature. It has been shown that when the compound (I) is in the presence of an amine A, the formation of the compound of the formula (1 / b) is considerably slowed down.

By way of example, at 65 ° C after 12 hours of methanol solution, the percentage of the compound (I / b) is about 9% when the compound is in the form of the free acid, while the percentage of the compound (I / b) is about 1% when the compound is in the form of a salt of an amine A. This constitutes a considerable advantage in the development of this industrial process. In addition, the crystallization of the resulting salt is easily applicable on an industrial scale and allows an excellent enantiomeric and chemical purification of the expected product. It also allows all traces of catalyst to be removed. Among the amines A which can be used in this step of the reaction, there can be mentioned (R) -1-phenylethylamine, orpholine, N-methylmorpholine and cyclohexylamine. Preferred amines are (R) -1-phenylethylamine and morpholine. The following examples illustrate the invention but do not limit it in any way.

EXAMPLE 1: B-s-2- (S) -benzyl-4-oxo-4- (cis-pexrhydroisoindol-2-yl) butyrate dihydrate Step A: Benzylideneuccinic acid 700 mmoles of dimethyl succinate and then 20 ml of methanol are added to 290 mmoles of sodium methylate dissolved in 80 ml of methanol. The mixture is brought to reflux, and 236 mmoles of benzaldehyde are added slowly, followed by 20 ml of methanol. The mixture is refluxed, with stirring, for one hour, and then 100 ml of methanol are distilled off. 120 ml of water and 120 ml of an ION sodium hydroxide solution are added to the concentrated reaction mixture. The methanol removal is continued by distillation. The residue is (10 dilute with 150 ml of water) After the addition of dichloromethane, the diacid is precipitated by slow addition of 12N hydrochloric acid.The diacid is filtered and washed with dichloromethane and then with water, drying gives the expected product. Melting point: 199 ° C 15 Stage B: Benzylideneuccinic anhydride 291 mmoles of the compound obtained in the preceding step are suspended in 180 ml of isopropyl ether. Add to 320 mmoles of acetic anhydride and the suspension is refluxed for 3h30. Cooling to 4 ° C, filtering the resulting anhydride and washing with isopropyl ether gives the expected product. Melting point: 168 ° C 25 Stage C: 2- [(cis-Perhydroisoindol-2-yl) carbonylmethyl] -3-phenylacrylic acid A solution of 175 mmoles of perhydroisoindoline in 32 ml of toluene is added very slowly to 165 mmoles of the anhydride obtained in the preceding step, suspended in 250 ml of toluene. The mixture is cooled to -5 ° C. The resulting monoamide precipitate is filtered off and washed with ice-cold toluene. Drying provides the expected product.

Melting point: 162 ° C.

Step D: 2 - (S) -ben ci 1 - 4-ox or -4- (ci s -perh i dro i s or indole-2-yl) butyrate of 1 - (R) -phenylethylamine 80 mmoles of the amide obtained in the preceding step are dissolved in 75 ml of methanol. 40 micromoles of (S, S) BPPM are dissolved in 15 ml of methanol and 20 micromoles of [Rh (COD) Cl] 2 are dissolved in 15 ml of methanol. The solutions are degassed, placed in the hydrogenation reactor and hydrogenated at 20 ° C under 5 bar. 250 ml of toluene are added to the methanolic hydrogenation solution and, at 5 ° C, a solution of 82.5 mmoles of (R) -1-phenylethylamine in 100 ml of toluene. The methanol is expelled under reduced pressure at room temperature, and 300 ml of toluene are added. The resulting precipitate is filtered off at 20 ° C and washed twice with 20 ml of toluene each time. After drying, the resulting crude salt is recrystallized from acetone, separated by filtration and dried to provide the expected product.

Melting point: 144 ° C Stage E: Di h i dra to bi s -2 - (S) -ben ci l - 4 -oxo - 4 - (ci s -perhidroisoindol-2-yl) butyral to calcium 13 ml of an aqueous solution containing 9 mmoles of calcium chloride dihydrate to 9 mmoles of the above purified salt of 1- (R) -phenylethylamine in 80 ml of an aqueous ammonia solution of 1.8% are added. The resulting precipitate is separated by filtration, washed with water and dried to provide the expected product.

Melting point: 214 ° C [a] 36520 = +32.4 (c = 5%, MeOH) EXAMPLE 2: Calcium bis-2- (S) -benzyl-4-oxo-4- (cis-perhydroisoindol-2-yl) butyrate dihydrate Stages A, B and C: These three steps are identical to the steps A, B and C of example 1.

Stage D: 2- (S) -benzyl-4-oxo-4- (cis-perhydroisoindol-2-yl) -5 morpholine butyrate The hydrogenation is carried out as in the above. 69 g of morpholine are added to the methanolic hydrogenation solution cooled with ice, and the concentration is carried out ^ 10 in vacuo at a temperature below 25 ° C to remove methanol. The concentrate is adjusted to a weight of 115 g by adding morpholine and then 250 ml of methylterbutyl ether is added and the mixture is stirred at room temperature for 20 hours. The amine salt that precipitates is filtered off and washed with a mixture of methylterbutyl ether / morpholine and then with methylterbutyl ether. Drying provides the expected product i.

Melting point: 110 ° C. Step E: Bis-2 - (S) -benzyl-4-oxo-4 - (cis-perhydroi-S? Indol-2-yl) calcium di-chloride. ml of a 1N sodium hydroxide solution and then 28 ml of an aqueous solution containing 12.5 mmoles of calcium chloride dihydrate are added to 25 mmoles of the above purified morpholine salt dissolved in 75 ml of ethanol and my water The resulting precipitate is filtered off, washed and dried to provide the expected product. Melting point: 214 ° C [a] 36520 = +32.4 (c = 5%, MeOH).

Claims (7)

1. A method for the industrial preparation of a substituted perhydroisoindole of formula (I): and pharmaceutically acceptable salts thereof, characterized in that dimethyl succinate is reacted with benzaldehyde in a methanolic medium, to provide the diacid of formula (II): which, after heating in an aprotic medium in the presence of acetic anhydride, provides the anhydride of formula (III): which is reacted with the perhydroisoindole of formula (IV) in an aprotic solvent to provide the compound of formula (V) which is subjected to catalytic hydrogenation using as the asymmetric hydrogenation catalyst the complex of rhodium / (2S, 4S) -N-butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphino-methylpyrrolidine or Rh / (S, S) BPPM, in medium methanolic or methylene chloride, followed by conversion to a salt in the presence of an amine A to provide a compound of formula (VI): Which: in a basic medium in the presence of a mineral salt, provides an addition salt of the compound of formula (1) which is converted, if desired, into the corresponding acid, or in an acidic medium provides the compound of formula (I), Which becomes, if desired, in a pharmaceutically acceptable addition salt.

2. The method of preparation, as described in claim 1, characterized in that the amine A used is 25 (R) -1-phenylethylamine.

3. The method of preparation, as described in claim 1, characterized in that the amine A is morpholine.

4. The method of preparation, as described in claim 1, characterized in that the amine A is N-methylmorpholine.

5. The method of preparation, as described in claim 1, characterized in that the amine A is thiocyclohexylamine.

6. The method as described in claim 1, for the preparation of the calcium salt of bis (S) -2-benzyl-4-oxo-4- (cis-perhydroisoindol-2-yl) butyric acid. The method as described in claim 1, for the preparation of calcium bis (2- (S) -benzyl-4-oxo-4- (cis-perhydroisoindol-2-yl) butyrate dihydrate.