Method for preparing citalopram diol intermediate

Abstract

The present invention relates to a method for preparing a citalopram diol represented by formula IV, comprising the following steps: in the existence of an auxiliary reagent of metal salt, allowing 5-cyanophthalide to sequentially subjected to Grignard addition reactions with p-fluorophenyl magnesium halide and N, N-dimethylaminopropyl magnesium halide in an organic solvent; and after the reactions are completed, performing hydrolysis and separation to obtain citalopram diol represented by formula IV. In the present invention, by adding an auxiliary reagent of metal salt, the activity and the selectivity of the Grignard reactions are remarkably improved, and the reaction yield is obviously enhanced. ##STR00001##

Claims

1. A method for preparing citalopram diol represented by formula IV, comprising the following steps: ##STR00007## performing Grignard addition reactions of 5-cyanophthalide successively with p-fluorophenyl magnesium halide and N,N-dimethylaminopropyl magnesium halide in an organic solvent; after the reaction, hydrolyzing and separating to obtain free base of citalopram diol represented by formula IV; optionally, further converting the compound of formula IV into its acid salt; characterized in that the Grignard reaction is carried out in the presence of an auxiliary reagent of metal salt M.sub.AX.sub.B, wherein M is selected from the group consisting of Mn, Cu, Zn, Li, or Cs, X is selected from the group consisting of Cl, Br, or I, A is 1, and B is 1 or 2.

2. The method according to claim 1, wherein the auxiliary reagent of metal salt M.sub.AX.sub.B is MnCl.sub.2, CuI, ZnCl.sub.2, LiCl, and LiBr.

3. The method according to claim 1, wherein the molar ratio of the auxiliary reagent of metal salt M.sub.AX.sub.B to 5-cyanophthalide is 0.2.

4. The method according to claim 3, wherein the molar ratio of the auxiliary reagent of metal salt M.sub.AX.sub.B to 5-cyanophthalide is from 0.5 to 1.0.

5. The method according to claim 1, wherein the p-fluorophenyl magnesium halide is p-fluorophenyl magnesium bromide.

6. The method according to claim 1, wherein N,N-dimethylaminopropyl magnesium halide is N,N-dimethylaminopropyl magnesium chloride.

7. The method according to claim 1, wherein the organic solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, isopropyl ether, or diethyl ether.

8. The method according to claim 7, wherein the organic solvent is tetrahydrofuran.

9. A method for preparing citalopram or S-citalopram, characterized in further converting the citalopram diol represented by formula IV obtained according to the method of claim 1 into citalopram or S-citalopram, wherein the citalopram is obtained by cyclizing the citalopram diol, and the S-citalopram is obtained by cyclizing S-citalopram diol prepared by chiral resolution of the citalopram diol.

Description

DETAILED DESCRIPTION

(1) The present invention will now be described in more detail by way of example so that the object, technical solutions, and advantages of the invention are more clear. Obviously, the described examples are only part of the examples of the present invention, rather than all of the examples. Based on the examples of the present invention, all the other examples obtained by those skilled in the art without creative efforts are within the protection scope of the present invention.

EXAMPLES 1-15

(2) ##STR00006##

(3) 5-cyanophthalide (31.8 g, 1.0 equiv.), tetrahydrofuran (300 ml), and a certain amount of metal salt M.sub.AX.sub.B were added. The reactants were cooled to 5 C., and the reaction was carried out under stirring for 0.5 hour. At a temperature controlled at 5 to 0 C., 300 ml of a solution of p-fluorophenyl magnesium bromide in tetrahydrofuran (0.8 mmol/ml, 1.2 equiv.) was slowly added dropwise. After the addition, the reaction was carried out under stirring for 1 hour while maintaining the temperature. The temperature was raised to 5 C. and controlled between 5 to 10 C. 260 ml solution of N,N-dimethylaminopropyl magnesium chloride in tetrahydrofuran (1.0 mmol/ml, 1.3 equivalent) was slowly added dropwise. After the addition, the reaction was carried out under stirring for 0.5 hour while maintaining the temperature. The reaction solution was added into 500 mL of saturated aqueous solution of ammonium chloride, and stirred for 2 hours. The organic layer was separated. The aqueous layer was extracted twice with toluene 200 ml2. The organic layers were combined, washed twice with water 200 ml2, and concentrated to dry. A sample was taken and tested with HPLC for the conversion rate of the reaction and the purity of the main product in the reaction solution. 400 ml of toluene was added to the dry product. The mixture was heated to 50 C., and stirred till clear. 100 ml of water was added to the mixture. The aqueous layer was adjusted with concentrated hydrochloric acid to a pH of 4.0-5.0, and separated. The toluene layer was further extracted once with 50 ml of water. The aqueous layers were combined, and cooled to 5 C. A large amount of solid was precipitated. The mixture was stirred for 60 minutes while maintaining the temperature, and filtered. The filter cake was dried under vacuum at 50 C. to give citalopram diol hydrochloride. The yield was calculated. Different equivalents and types of metal salt M.sub.AX.sub.B, and different organic solvents are used for performing the above experiment. The results are shown in the following table:

(4) TABLE-US-00001 Equivalent weight of Conversion Purity of main Example Metal salt metal salt, M.sub.AX.sub.B, relative rate of product in reaction No. M.sub.AX.sub.B to 5-cyano-phthalide Organic solvent reaction liquid Yield 1 MnCl.sub.2 1.0 tetrahydrofuran 97% 86% 84% 2 MnBr.sub.2 0.5 2-methyl- 98% 81% 75% tetrahydrofuran 3 MnI.sub.2 0.5 cyclopentyl 97% 83% 72% methyl ether 4 LiCl 2.0 methyl tert- 98% 87% 83% butyl ether 5 LiCl 0.5 isopropyl ether 98% 87% 82% 6 LiCl 0.2 tetrahydrofuran 95% 82% 76% 7 LiBr 1.0 tetrahydrofuran 98% 82% 77% 8 LiI 1.0 2-methyl- 97% 81% 72% tetrahydrofuran 9 CsI 0.5 cyclopentyl 92% 84% 70% methyl ether 10 ZnCl.sub.2 1.0 methyl tert-butyl 98% 85% 80% ether 11 CuCl.sub.2 1.0 isopropyl ether 96% 81% 70% 12 CuBr 0.5 tetrahydrofuran 95% 85% 73% 13 CuI 0.5 tetrahydrofuran 97% 87% 76% 14 MnCl.sub.2 0.7 2-methyl- 96% 87% 83% tetrahydrofuran 15 CuBr.sub.2 0.8 cyclopentyl 97% 86% 82% methyl ether

Comparative Example 1 (without Metal Salt)

(5) 5-cyanophthalide (31.8 g, 1.0 equiv.) and tetrahydrofuran (300 ml) were added. The reactants were cooled to 5 C., and the reaction was carried out under stirring for 0.5 hour. At a temperature controlled at 5 to 0 C., 300 ml of a solution of p-fluorophenyl magnesium bromide in tetrahydrofuran (0.8 mmol/ml, 1.2 equiv.) was slowly added dropwise. After the addition, the reaction was carried out under stirring for 1 hour while maintaining the temperature. The temperature was raised to 5 C., and controlled between 5 to 10 C. 260 ml of a solution of N,N-dimethylaminopropyl magnesium chloride in tetrahydrofuran (1.0 mmol/ml, 1.3 equiv.) was slowly added dropwise. After the addition, the reaction was carried out under stirring for 0.5 hour while maintaining the temperature. The Grignard reaction solution was added to 500 mL of saturated aqueous solution of ammonium chloride, and stirred for 2 hours. The organic layer was separated. The aqueous layer was extracted twice with toluene 200 ml2. The organic layers were combined, washed twice with water 200 ml2, and concentrated to dry. A sample was taken and tested with HPLC. The conversion rate of the reaction was 77% and the purity of the main product in the reaction solution was 69%. 400 ml of toluene was added to the dry product. The mixture was heated to 50 C., and stirred till clear. 100 ml of water was added to the mixture. The aqueous layer was adjusted with concentrated hydrochloric acid to a pH of 4.0-5.0, and separated. The toluene layer was further extracted once with 50 ml of water. The aqueous layers were combined, and cooled to 5 C. A large amount of solid was precipitated. The mixture was stirred for 60 minutes while maintaining the temperature, and filtered. The filter cake was dried under vacuum at 50 C. to give citalopram diol hydrochloride. The yield was 61%.

Comparative Example II (U.S. Pat. No. 4,650,884)

(6) 5-cyanophthalide (31.8 g, 1.0 equiv.) and tetrahydrofuran (300 ml) were added. The reactants were cooled to 3 C., and the reaction was carried out under stirring for 0.5 hour. At a temperature controlled at 3 to 0 C., 300 ml of a solution of p-fluorophenyl magnesium bromide in tetrahydrofuran (0.8 mmol/ml, 1.3 equiv.) was slowly added dropwise. After the addition, the reaction was carried out under stirring for 0.5 hour while maintaining the temperature. The cold bath was removed. The mixture was stirred overnight. The temperature was controlled between 10 to 12 C. 200 ml of a solution of N,N-dimethylaminopropyl magnesium chloride in tetrahydrofuran (1.0 mmol/ml, 1.0 equiv.) was slowly added dropwise. After the addition, the cold bath was removed. The mixture was stirred overnight at room temperature. The Grignard reaction solution was added to ice water, and adjusted with acetic acid to a pH of 6.5-7.0. Tetrahydrofuran was distilled off. 300 mL of toluene was added. The reaction solution was adjusted with saturated aqueous solution of ammonium chloride to a pH of 9.0. The toluene layer was separated. The aqueous layer was further extracted once with 200 ml of toluene. The toluene layers were combined, and washed once with 200 ml of hot water at 50 C. A sample of toluene layer was taken and tested with HPLC. The conversion rate of the reaction was 75%, and the purity of the main product in the reaction solution was 65%. The toluene layer was further extracted once with aqueous solution of acetic acid. 300 ml of toluene was added. The mixture was adjusted with aqueous ammonia to pH>9.0. The aqueous layer was extracted once with 200 ml of toluene. The toluene layers were combined, and concentrated to dry. The concentrate was absorbed with active carbon and silica gel, and purified. The purified product was salified with HBr to give 38.1 g of citalopram diol hydrochloride. The yield was 45%.

(7) By comparing the above examples with the comparative examples, it can be seen that during the Grignard addition reactions of 5-cyanophthalide successively with p-fluorophenyl magnesium halide and N, N-dimethylaminopropyl magnesium halide in an organic solvent, the activity and selectivity of the specific Grignard addition reactions can be significantly improved by the addition of an auxiliary reagent of metal salt (M.sub.AX.sub.B). For example, in the case that the auxiliary reagent of metal salt (M.sub.AX.sub.B) according to the present invention is not added, the conversion rate of the reaction is only 77%, and the yield is only 61%, according to Comparative Example 1; the conversion rate of the reaction is only 75%, and the yield is only 45%, according to Comparative Example 2. However, in the case that the auxiliary reagent of metal salt (M.sub.AX.sub.B) according to the present invention is added, the conversion rate of the reaction was remarkably increased to 92% or above, even up to 98%, and the yield was remarkably increased to 70% or above, even up to 84%. Such results are completely unexpectable by those skilled in the art.

(8) The foregoing are only preferred examples of the invention, and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention are within the protection scope of the present invention.