METHOD FOR RESOLUTION OF CITALOPRAM INTERMEDIATE 5-CYANO DIOL

Abstract

Provided is a method for resolution of formula 4-[4-dimethylamino-1-(4-fluorophenyl)-1-hydroxylbutyl]-3-hydroxy-methyl benzonitrile as an enantiomer thereof, comprising the following steps: a salt of (S)-4-[4-dimethylamino-1-(4-fluorophenyl)-1-hydroxylbutyl]-3-hydroxymethyl benzonitrile with a resolving agent D-(+)di-p-toluoyl tartaric acid was crystallized in a resolving solvent; the method is characterized in that the resolving solvent is an ether solvent. Also provided is a new crystal form of the resolved intermediate.

Claims

1. A method for resolution of 4-[4-dimethylamino-1-(4-fluorophenyl)-1-hydroxylbutyl]-3-hydroxymethyl benzonitrile of formula I as an enantiomer thereof, comprising the following steps: a salt of (S)-4-[4-dimethylamino-1-(4-fluorophenyl)-1-hydroxylbutyl]-3-hydroxymethyl benzonitrile of formula with a resolving agent D-(+)di-p-toluoyl tartaric acid of formula II was crystallized in a resolving solvent, characterized in that the resolving solvent is an ether solvent, ##STR00008##

2. The method according to claim 1, wherein the ether solvent is selected from: tetrahydrofuran, methyltetrahydrofuran, cyclopentyl methyl ether, isopropyl ether, dioxane, ethylene glycol monornethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, diethylene glycol dimethyl ether, propylene glycol dimethyl ether and propylene glycol diethyl ether.

3. The method according to claim 1, characterized in that the volume percentage of water in the ether solvent is 0.2%-10%.

4. The method according to claim 3, characterized in that the volume percentage of water in the ether solvent is 0.2%-5%.

5. A crystal form of the resolved intermediate of formula III, ##STR00009## characterized in that the DSC thermogram obtained from differential scanning calorimetry (heating rate 10° C./minute) shows an endothermic peak, which is onset 135.20° C., peak 150.85° C.

6. A crystal form of the resolved intermediate of formula III′, ##STR00010## characterized in that the DSC thermogram obtained from differential scanning calorimetry (heating rate 10° C./minute) shows two endothermic peaks, which are onset 107.40° C., peak 114.11° C., and onset 144.44° C., peak 154.55° C. respectively.

7. The crystal form according to claim 6, characterized in that the thermogravimetric. analysis thermogram is shown in FIG. 4.

8. The crystal form according to claim 6, characterized in that the powder X-ray diffraction pattern is shown in FIG. 5.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 is the DSC thermogram of form A of (S)-5-cyano did resolved intermediate (III).

[0022] FIG. 2 is the DSC thermogram of form B of (S)-5-cyano diol resolved intermediate (III).

[0023] FIG. 3 is the DSC thermogram of form C of (S)-5-cyano diol resolved intermediate dihydrate (III′).

[0024] FIG. 4 is the TGA thermogram of form C of (S)-5-cyano diol resolved intermediate dihydrate (III′).

[0025] FIG. 5 is the PXRD pattern of form C of (S)-5-cyano diol resolved intermediate dihydrate (III′).

EMBODIMENTS

EXAMPLE 1

[0026] ##STR00006##

[0027] Racemic 5-cyano diol (34.2g, 1.0 equivalent), D-(+)di-p-toluoyl tartaric acid (20.1 g, 0.52 equivalent) were added, an ether solvent (513 mL) was added, the temperature was increased to 50˜60° C., the reaction was stirred for 2 hours. The temperature was decreased slowly to 30° C., a large amount of solids were precipitated, stirred for 60 minutes with the temperature kept. Filtered, the filter cake was washed by 30 mL ether solvent once. The filter cake was vacuum dried at 50° C. to obtain the resolved intermediate (III).

[0028] The results with different ether solvents are shown in table 2:

TABLE-US-00002 TABLE 2 Solvent Yield Chiral purity Tetrahydrofuran 48.5% 99.8% Methyltetrahydrofuran 47.3% 99.7% Cyclopentyl methyl ether 48.2% 99.2% Diethyl ether 44.7% 98.7% Isopropyl ether 45.5% 99.1% Dioxane 45.1% 99.5% Diethylene glycol dimethyl ether 46.0% 99.3% Ethylene glycol monomethyl ether 42.5% 98.4% Ethylene glycol dimethyl ether 45.7% 99.2% Ethylene glycol diethyl ether 46.1% 99.1% Ethylene glycol dibutyl ether 45.8% 99.4% Propylene glycol dimethyl ether 45.1% 99.0% Propylene glycol diethyl ether 46.2% 99.2%

EXAMPLE 2

[0029] ##STR00007##

[0030] Racemic 5-cyano diol (34.2 g, 1.0 equivalent), D-(+)di-p-toluoyl tartaric add (20.1 g, 0.52 equivalent) were added, an ether solvent (513 mL) and a certain amount of water were added, the temperature was increased to 5060° C., the reaction was carried out under stirring for 2 hours. The temperature was decreased slowly to 30° C., a large amount of solids were precipitated, stirred for 60 minutes with the temperature kept. Filtered, the filter cake was washed by 30 mL ether solvent once. The filter cake was vacuum dried at 50° C. to obtain the resolved intermediate (III′).

[0031] The results with different volume ratios of ether solvent to water are shown in table 3:

TABLE-US-00003 TABLE 3 Solvent(V/V) Yield Chiral purity Tetrahydrofuran/Water 48.2% 99.5% (99.8:0.2) Tetrahydrofuran/Water 47.5% 99.7% (99.5:0.5) Tetrahydrofuran/Water 41.5% 99.4% (95.0:5.0) Tetrahydrofuran/Water 38.5% 99.5% (90.0:10.0) Methyltetrahydrofuran/Water 46.3% 99.3% (99.0:1.0) Cyclopentyl methyl 46.0% 99.1% ether/Water (99.0:1.0) Isopropyl ether/Water 45.1% 99.0% (99.0:1.0) Dioxane/Water (99.0:1.0) 46.2% 99.6% Dioxane/Water (90:10) 36.2% 99.6% Diethylene glycol dimethyl 46.0% 99.5% ether/Water (99.0:1.0) Ethylene glycol monomethyl 40.0% 97.9% ether/Water (99.0:1.0) Ethylene glycol dimethyl 44.7% 99.0% ether/Water (99.0:1.0) Ethylene glycol dibutyl 46.5% 99.3% ether/Water (99.0:1.0) Propylene glycol dimethyl 45.0% 99.5% ether/Water (99.0:1.0) Propylene glycol diethyl 46.1% 99.4% ether/Water (99.0:1.0)

COMPARATIVE EXAMPLE 1

US2009/0069582 EXAMPLE 1

[0032] D-(+)di-p-toluoyl tartaric acid (15.0 g) was added, then n-propyl alcohol (118 mL) was added, the temperature was increased to 40° C., stirred for a complete dissolution, acetic acid (1.2 g) was added. Within 1 hour, the above solution of the resolving agent was added to the solution of racemic 5-cyano diol base (34.2 g) and n-propyl alcohol (32 mL), the temperature was kept at 40° C., the reaction was carried out under stirring for 2 hours. The temperature was decreased to 20-25° C., stirred crystallized for 2 hours with the temperature kept. Filtered, the filter cake was washed with n-propyl alcoholtwice, crude resolved intermediate was obtained, chiral purity: S-5-cyano diol 91%-98%.

[0033] The crude product was added to a flask, n-propyl alcohol (86 mL) was added, the temperature was increased to 50° C., stirred for 2 hours, then cooled to 20-25° C., stirred and crystallized for 2 hours with the temperature kept. Filtered, the filter cake was washed with n-propyl alcohol, the filter cake was vacuum dried at 50° C., 18.5g resolved intermediate was obtained, yield: 34.5%. The chiral purity of the resolved intermediate was: S-5-cyano did 99.3%.

COMPARATIVE EXAMPLE 2

WO2007/012954 EXAMPLE 5

[0034] Isopropanol (1125 ml) was added to racemic S-5-cyano diol (178.1 g), the temperature was increased to 50˜55° C., stirred for a complete dissolution. D-(+)di-p-toluoyl tartaric acid (105 g) was added when the temperature was kept at 50˜55° C., the temperature was decreased slowly to 25˜30° C., stirred for 10 hours with the temperature kept, Filtered, the filter cake was washed with isopropanol twice, 110 ml for each time. The filter cake was vacuum dried at 50° C., 185 g crude resolved intermediate was obtained, chiral purity was: S-5-cyano diol 96:1%.

[0035] The crude product was added to a flask, isopropanol (1500 mL) was added, the temperature was increased to 80° C., stirred for a complete dissolution, then cooled to 20˜25° C., stirred and crystallized for 1 hours with the temperature kept. Filtered, the filter cake was washed with isopropanol twice, 50 ml for each time, the filter cake was vacuum dried at 50° C., 101.2 g resolved intermediate was obtained, yield: 36.3%, the chiral purity was: S-5-cyano diol 99.1%.