JP2013216655A - Improved preparation method of blonanserin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an improved preparation method of 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine-(1H)-ketone, a further conversion of the same into blonanserin, a preparation of blonanserin hydrochloride, and a method of further converting the blonanserin hydrochloride into pure blonanserin.SOLUTION: An improved preparation method of 4-(4-fluorophenyl)-5,6,7,8,9,10-hexanydrocyclooctane[b]pyridine-(1H)-ketone comprises a step of hydrolyzing 4-fluorobenzoyl acetonitrile in the presence of an acid, a step of reacting the intermediate with cyclooctanone, and a step of isolating 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine-(1H)-ketone.

Description

  The present invention relates to an improved method for the preparation of a blonanserin intermediate and further conversion to blonanserin. The invention further relates to the purification of blonanserin.

  Blonanserin, ie 2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine having the formula -I is Used as an antipsychotic. Blonanserin is marketed in Japan as Lonacene (registered trademark) by Dainippon Pharmaceutical Co., Ltd.

Patent Document 1 discloses blonanserin and related compounds together with the synthesis of blonanserin. U.S. Patent No. 6,057,034 discloses 4- (4-fluorophenyl) of formula II by hydrolysis of 4-fluorobenzoylacetonitrile in the presence of polyphosphoric acid and further reaction with cyclooctanone and condensation with N-ethylpiperazine. A process for the preparation of 5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone is disclosed.

  U.S. Patent No. 6,057,034 discloses 4- (4-fluorophenyl) of formula II by hydrolyzing 4-fluorobenzoylacetonitrile with sulfuric acid to give the intermediate compound 3- (4-fluorophenyl) -3-oxopropanamide. Disclosed is a process for preparing -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone. This compound gives 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone in reaction with cyclooctanone. U.S. Patent No. 6,099,088 also discloses a similar method for preparing 4- (4-fluorophenyl) 5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone. .

  In Patent Document 1 of the prior art, hydrolysis of 4-fluorobenzoylacetonitrile is performed in the presence of polyphosphoric acid. The handling of polyphosphoric acid is very difficult in large scale synthesis and the color of the reaction mass will change to black at the reaction temperature. The yield obtained by the prior art method is low. There is a need in the art to prepare blonanserin with improved yield and quality.

  Non-Patent Document 1 discloses blonanserin hydrochloride monohydrate and a method of preparing blonanserin by dissolving blonanserin hydrochloride in hot nitromethane. Isolation of blonanserin hydrochloride monohydrate in the preparation of blonanserin will increase the purity of blonanserin. The present invention thus provides an improved industrially feasible method for the preparation of blonanserin hydrochloride and further conversion to blonanserin.

US Pat. No. 5,021,421 Chinese Patent Application No. 1020307707 Chinese Patent Application No. 102093289

CrystEngCom, 2012, 14th volume, 2367-2372

The basic object of the present invention is to provide an improved process for the preparation of blonanserin.
Another object of the present invention is 2-halo-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine of formula III which is an intermediate of blonanserin. It is to provide an improved preparation method.

  Another object of the present invention is to provide an improved industrially feasible method for the preparation of blonanserin hydrochloride.

One aspect of the present invention is to provide a method for preparing 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone. And the method is
a) hydrolyzing 4-fluorobenzoylacetonitrile in the presence of an acid to give 3- (4-fluorophenyl) -3-oxopropanamide;
b) reacting with cyclooctanone;
c) isolating 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone;
The acid is selected from methane sulfonic acid, Eaton's reagent, or an organic acid.

  Another aspect of the invention provides an improved process for preparing 2-halo-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine. The method comprises reacting 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone with a halogenating agent. Providing the corresponding halide compound.

  Another aspect of the invention is to provide an improved process for the preparation of blonanserin, which process comprises 2-halo-4- (4-fluorophenyl) -5,6,7,8,9, Reacting 10-hexahydrocyclooctane [b] pyridine with N-ethylpiperazine in an organic solvent.

Another aspect of the present invention is to provide a process for preparing blonanserin hydrochloride, said process comprising:
a) dissolving blonanserin in water, a water-miscible organic solvent or a mixture thereof;
b) adding an HCl source;
c) isolating blonanserin hydrochloride.

Another aspect of the present invention is:
a) placing blonanserin hydrochloride in a solvent or mixture of solvents;
b) adjusting the pH to basic with a base;
c) isolating blonanserin;
d) providing pure blonanserin from blonanserin hydrochloride, optionally comprising converting it to its pharmaceutically acceptable salt.

Another aspect of the present invention is:
a) placing blonanserin hydrochloride into a mixture of water and a water-immiscible organic solvent;
b) adjusting the pH to basic with a base;
c) separating the organic layer;
d) optionally extracting blonanserin from the aqueous layer;
e) providing pure blonanserin from blonanserin hydrochloride, comprising isolating pure blonanserin from the organic layer.

  The present invention relates to an improved process for the preparation of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone. The method includes hydrolyzing 4-fluorobenzoylacetonitrile in the presence of an acid, reacting with cyclooctanone, and 4- (4-fluorophenyl) -5,6,7,8,9,10. Isolating hexahydrocyclooctane [b] pyridine- (1H) -ketone. The invention also relates to further conversion of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone to blonanserin. The present invention also provides methods for the preparation of blonanserin hydrochloride and further conversion of blonanserin hydrochloride to pure blonanserin.

The main aspect of the present invention is an improved process for the preparation of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone. And the method comprises:
a) hydrolyzing 4-fluorobenzoylacetonitrile in the presence of an acid to give 3- (4-fluorophenyl) -3-oxopropanamide, wherein the acid is methanesulfonic acid, Eaton's reagent, or organic acid Being selected from
b) reacting with cyclooctanone;
c) isolating 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone.

In one embodiment of the present invention, the Eaton reagent is a solution of 5.3-9.5 wt% phosphorous pentoxide in methanesulfonic acid.
In another embodiment of the invention, the organic acid is selected from trifluoroacetic acid and trichloroacetic acid, preferably from trifluoroacetic acid.

  In Patent Document 1 of the prior art, hydrolysis of 4-fluorobenzoylacetonitrile is performed in the presence of polyphosphoric acid. The handling of polyphosphoric acid is very difficult in large scale synthesis and the color of the reactant will change to black at the reaction temperature. The yield obtained by the prior art method is low. The handling of methanesulfonic acid or Eaton reagent is easy in large scale synthesis and the amount of methanesulfonic acid and Eaton reagent used in the reaction is very small compared to polyphosphoric acid.

  According to the invention, 4-fluorobenzoylacetonitrile is placed in the acid. The acid is selected from methanesulfonic acid, Eaton reagent, or organic acid, preferably selected from methanesulfonic acid or Eaton reagent. The reaction temperature is raised to 50-90 ° C, preferably 65-75 ° C and maintained for 1-5 hours, preferably 2-3 hours. Next, cyclooctanone is added and the temperature is raised to 90-120 ° C, preferably 110 ° C, and maintained for 1-4 hours, preferably 2-4 hours. A water immiscible organic solvent is added to the reactants. The water-immiscible organic solvent is selected from ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, halogenated solvents such as dichloromethane, chloroform, preferably dichloromethane. To this is added water and the layers are separated.

  The organic layer is washed with water and distilled out. The product is crystallized from a solvent selected from acetone, IPA, ethyl acetate or cyclohexane.

Another embodiment of the present invention is a 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone as shown in Scheme I Further provided is the conversion of to blonanserin. The transformation is
a) 4- (4-Fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone to 2-halo-4- (4-fluorophenyl) Converting to 5,6,7,8,9,10 hexahydrocyclooctane [b] pyridine;
b) 2-halo-4- (4-fluorophenyl) 5,6,7,8,9,10 hexahydrocyclooctane [b] pyridine is condensed with N-ethylpiperazine to obtain blonanserin. .

According to the present invention, 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone reacts with a halogenating agent to respond. Is converted to 2-halo-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine.

  In one embodiment, the halogenating agent used for the halogenation is selected from phenylphosphonic dichloride in the presence of a polar aprotic solvent such as N-methylpyrrolidone.

  Prior art methods do not involve the use of solvents in the preparation of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine. The handling of neat reactions is very difficult in large scale synthesis and the reactions are exothermic. Sampling and in-process analysis do not match the neat reaction. Thus, the use of organic solvents is easy in large scale synthesis.

  In one embodiment of the invention, 2-halo-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine is reacted with N-ethylpiperazine. To obtain blonanserin.

  According to the invention, 2-halo-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine compound, preferably 2-chloro-4- ( 4-Fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine is reacted with N-ethylpiperazine in the absence / presence of a suitable solvent. A suitable solvent used in this reaction is selected from N-methylpyrrolidone and dimethyl sulfoxide (DMSO), preferably N-methylpyrrolidone.

  Prior art methods do not involve the use of solvents in the preparation of blonanserin. The handling of the neat reaction is very difficult in large scale synthesis and the reaction is exothermic. Sampling and in-process analysis do not match the neat reaction. Thus, the use of organic solvents is easy in large scale synthesis.

Another aspect of the present invention is to provide an improved method of preparing blonanserin hydrochloride, which method comprises:
a) dissolving blonanserin in water, a water-miscible organic solvent, or a mixture thereof;
b) adding an HCl source;
c) isolating blonanserin hydrochloride.

  According to the present invention, blonanserin is dissolved in water, a water-miscible organic solvent, or a mixture thereof. The water miscible organic solvent is selected from alcohol solvents such as methanol, ethanol and isopropanol, preferably selected from methanol and ethanol, more preferably methanol. The most desirable solvent mixture used to dissolve blonanserin is a mixture of methanol and water. To this is added an HCl source. The HCl source is selected from HCl gas, concentrated HCl, alcoholic HCl, preferably from concentrated HCl. The reactants are optionally heated to 70-100 ° C, preferably 80-85 ° C. The reactants are cooled to 20-40 ° C, preferably 25-30 ° C. The resulting solid is filtered and crystallized in a mixture of methanol and purified water to give pure blonanserin hydrochloride. The resulting blonanserin hydrochloride can be in the form of a hydrate, preferably in the form of blonanserin hydrochloride monohydrate.

Another aspect of the present invention is:
a) placing blonanserin hydrochloride in a solvent or mixture of solvents;
b) adjusting the pH to basic with a base;
c) isolating blonanserin;
d) providing pure blonanserin from blonanserin hydrochloride, optionally comprising converting it to its pharmaceutically acceptable salt.

  In one embodiment, the solvent used in this reaction is selected from water miscible solvents, water immiscible solvents, or mixtures thereof. The water miscible solvent is selected from alcohol solvents such as methanol, ethanol and isopropanol. The water immiscible solvent is selected from halogenated solvents such as chloroform and dichloromethane, and alkyl acetates such as ethyl acetate and isopropyl acetate. A suitable solvent mixture is methanol and water, or ethyl acetate and water.

  In another embodiment, the base used to adjust the pH to basic is an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, and an alkali metal carbonate such as potassium carbonate, sodium carbonate, And selected from alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, preferably sodium hydroxide.

  According to the invention, blonanserin hydrochloride, preferably blonanserin hydrochloride monohydrate, is placed in a solvent or a mixture of solvents. Solvents are water miscible solvents that are alcoholic solvents such as methanol, ethanol and isopropanol, halogenated solvents such as chloroform and dichloromethane, and water immiscible solvents that are alkyl acetates such as ethyl acetate and isopropyl acetate, The solvent mixture is selected from methanol and water, or ethyl acetate and water, preferably selected from methanol and water. The reaction temperature is raised to 40-70 ° C., preferably 50-60 ° C., the pH is a base such as sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, preferably water. It is adjusted to 7.5 to 11, preferably 8 to 8.5 with sodium oxide. The reactants are cooled to 20-40 ° C, preferably 25-30 ° C. The resulting solid is filtered and optionally crystallized in a mixture of water and methanol to give pure blonanserin.

Another aspect of the present invention is:
a) placing blonanserin hydrochloride in a mixture of water and a water-immiscible organic solvent;
b) adjusting the pH to basic with a base;
c) separating the organic layer;
d) optionally extracting blonanserin from the aqueous layer;
e) providing pure blonanserin from blonanserin hydrochloride, comprising isolating pure blonanserin from the organic layer.

  In one embodiment, the water-immiscible organic solvent used in the reaction is selected from halogenated solvents such as chloroform and dichloromethane, and alkyl acetates such as ethyl acetate and isopropyl acetate, preferably ethyl acetate.

  In another embodiment, the base used to adjust the pH to basic is an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, an alkali metal carbonate such as potassium carbonate, sodium carbonate, and It is selected from alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, preferably sodium hydroxide.

  According to the present invention, blonanserin hydrochloride, preferably blonanserin hydrochloride monohydrate, is placed in a mixture of water and a water-immiscible organic solvent. Water-immiscible organic solvents are halogenated solvents such as chloroform and dichloromethane, and alkyl acetates such as ethyl acetate and isopropyl acetate, preferably ethyl acetate. The pH of the reactants is 7.5-11, preferably 8. with bases such as sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide. It is adjusted to 5-9. The layers are separated and the aqueous layer is extracted with a water immiscible organic solvent. The combined organic layers are removed by distillation at 30-50 ° C., preferably 40-45 ° C. under vacuum to obtain a residue. This residue is dissolved in an alcohol solvent such as isopropyl alcohol. The reactants are cooled to 0-10 ° C, preferably 0-5 ° C. The resulting solid is filtered and dried to give pure blonanserin.

  The following examples are provided to illustrate the method of the present invention. However, these examples are in no way intended to limit the scope of the present invention, and several other examples of these examples will be apparent to those skilled in the art.

  Experimental procedure:

Preparation of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone 4-Fluorobenzoylacetonitrile (10 g), methanesulfonic acid A mixture of (23.6 g) and water (1.42 mL) was placed in a round bottom flask and heated at a temperature of 70 ° C. for 3 hours. Methanesulfonic acid (0.7 g) and water (0.042 mL) were added and maintained at 70 ° C. for 2-4 hours. To this was added cyclooctanone (8.5 g) and the temperature was raised to 110 ° C. The reaction mass was maintained at 110 ° C. for 2 hours. The reaction mass was cooled to 30 ° C. and dichloromethane was added. The reaction mixture was poured into cold water and the layers were separated. The aqueous layer was extracted with dichloromethane, and the organic layers were combined. The combined organic layers were washed with saturated sodium bicarbonate solution followed by water. The organic layer was dried over sodium sulfate and dichloromethane was distilled out completely at 40 ° C. under vacuum. The product was crystallized from acetone to give the title compound (10-11 g).

Preparation of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone 4-Fluorobenzoylacetonitrile (10 g) and Eaton's reagent ( 18 mL) was placed in a round bottom flask and heated at a temperature of 70 ° C. for 4 hours. To this was added cyclooctanone (8.5 g) and the temperature was raised to 110 ° C. The reaction mass was maintained at 110 ° C. for 2-4 hours. The reaction mass was cooled to 30 ° C. and dichloromethane was added. The reaction mixture was poured into cold water and the layers were separated. The aqueous layer was extracted with dichloromethane, and the organic layers were combined. The combined organic layers were washed with saturated sodium bicarbonate solution followed by water. The organic layer was dried over sodium sulfate and dichloromethane was removed by complete distillation at 40 ° C. under vacuum. The product was crystallized from acetone to give the title compound (10-11 g).

Method for preparing 3- (4-fluorophenyl) -3-oxopropanamide A mixture of trifluoroacetic acid (20 mL) and 4-fluorobenzoylacetonitrile (5 g) was placed in a round bottom flask and the temperature was raised to 75 ° C. The reactants were maintained at the same temperature as above for 4 hours. After completion of the reaction, the reaction mass was cooled to 35 ° C. and poured into cold water. The solid was collected by filtration and washed with water. The residue was dried to give the title compound (14-16 g).

Method for preparing 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine 4- (4-fluorophenyl) -5,6,7 , 8,9,10-Hexahydrocyclooctane [b] pyridine- (1H) -ketone (10 g) and N-methylpyrrolidone (10 mL) were placed in a round bottom flask to which phenylphosphonic dichloride (14. 32 g) was added. The temperature of the reactants was raised to 170 ° C. and maintained for 4 hours. The reaction mass was cooled to 30 ° C. and dichloromethane was added. The reaction mixture was poured into cold water and the pH of the reactants was adjusted to 8-8.5 with ammonia solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layer was dried over sodium sulfate and half of the dichloromethane was removed by distillation under vacuum. To this was added ethanol and the solvent was distilled off completely. The residue was crystallized from acetonitrile to give the title compound. Instead, the product was crystallized from ethanol to give the title compound (8.5-9.2 g).

Method for preparing 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine 4- (4-fluorophenyl) -5,6,7 , 8,9,10-Hexahydrocyclooctane [b] pyridine- (1H) -ketone (100 g) was placed in a round bottom flask and phenylphosphonic dichloride (144.4 g) was added thereto. The temperature of the reactants was raised to 165 ° C. and maintained for 2 hours. The reaction mass was cooled to 30 ° C. and dichloromethane was added. The reaction mixture was poured into cold water and the pH of the reactants was adjusted to 8-8.5 with ammonia solution. The layers were separated and the aqueous layer was extracted with dichloromethane. Activated carbon was added to the organic layer and maintained at room temperature for 20-30 minutes. The reaction mass was filtered and washed with dichloromethane. Dichloromethane was removed by distillation under vacuum to give a residue. To this, acetone (200 mL) was added to remove traces of dichloromethane and removed by distillation under vacuum. The residue was crystallized from acetone to give the title compound (80-90 g).

Preparation method of blonanserin 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine (10 g), N-methylpyrrolidone (10 mL), iodine A mixture of potassium halide (5.5 g) and N-ethylpiperazine (12.36 g) was placed in a round bottom flask and the temperature was raised to 170 ° C. The reactants were maintained at the same temperature as above for 14 hours. The reaction mass was cooled to 30 ° C. and a mixture of ethyl acetate and water was added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and hydrochloric acid was added. The organic layer was extracted with hydrochloric acid, the aqueous layers were combined, and ethyl acetate was added. The pH of the reactants was adjusted to 8 with ammonia solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and ethyl acetate was removed by complete distillation under vacuum. The residue was crystallized from ethanol to give the title compound (8.5-9.5 g).

Preparation of blonanserin hydrochloride monohydrate 2-Chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine (50 g, 0.173 mol) , Potassium iodide (27.5 g, 0.165 mol), and N-ethylpiperazine (60.1 g, 0.52 mol) were placed in a round bottom flask at ambient temperature. The temperature of the reactants was raised to 170 ° C. and maintained for 16 hours. The reaction mass was cooled to 55-60 ° C. and a mixture of ethyl acetate (1000 mL) and purified water (200 mL) was added and maintained for 20 minutes and slowly cooled to 25-30 ° C. The organic layer was separated. The aqueous layer was extracted with ethyl acetate (250 mL). The combined ethyl acetate layer was washed with purified water (250 mL × 2 times). To the organic layer was added dilute hydrochloric acid solution (55 mL concentrated HCl and 250 mL water) and maintained for 20 minutes. The layers were separated. The organic layer was extracted with dilute hydrochloric acid solution (55 mL concentrated HCl and 250 mL water). The combined aqueous layer was washed with ethyl acetate (250 mL). Ethyl acetate was added to the aqueous layer and the pH was adjusted to 8-8.5 with 30% sodium hydroxide solution. The layers were separated. The aqueous layer was extracted with ethyl acetate (250 mL). Both ethyl acetate layers were combined and washed with purified water (250 mL). The combined organic layers were removed by complete distillation at 45 ° C. under vacuum. To the remaining residue was added a mixture of methanol (125 mL) and purified water (375 mL). To this was added concentrated hydrochloric acid solution (17 g) and the temperature was raised to 80-85 ° C. to obtain a homogeneous solution, which was maintained at the same temperature as above for 30 minutes. The reactants were cooled to 25-30 ° C. and maintained at 25-30 ° C. for 2 hours. The solid was filtered and washed with a mixture of methanol (12.5 mL) and purified water (37.5 mL). The resulting solid was crystallized in a mixture of methanol (125 mL) and purified water (375 mL). The resulting solid was dried at 40-45 ° C. for 10 hours to give the title compound (42-50 g) with HPLC purity> 99.8%.

Preparation of blonanserin A mixture of methanol (75 mL) and purified water (225 mL) was added to blonanserin hydrochloride monohydrate (30 g). The temperature of the reactants was raised to 80-85 ° C. and maintained for 15-20 minutes. If the reactants are not clear, add 0.5 mL of concentrated hydrochloric acid to obtain a clear solution. The hot reactant was filtered and the filtrate was added to raise the temperature to 50-55 ° C. The pH was adjusted to 8-8.5 with 30% sodium hydroxide solution. The reactants were cooled to 25-30 ° C. and maintained at 25-30 ° C. for 2 hours. The solid was filtered and washed with purified water until the filtrate showed a negative test for chloride. The reaction mass was washed again with a mixture of methanol (7.5 mL) and purified water (22.5 mL). The resulting solid was dried at 40-45 ° C. for 10 hours to give blonanserin (20-23 g) with HPLC purity> 99.9%.

Preparation of blonanserin A mixture of purified water (150 mL) and ethyl acetate (300 mL) was added to blonanserin hydrochloride monohydrate (30 g). The pH was adjusted to 8.5-9 with 30% sodium hydroxide solution at 25-30 ° C. The layers were separated and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed with purified water (150 mL). The organic layer was filtered so that the organic layer did not contain particles. Ethyl acetate was removed by complete distillation at 40-45 ° C. under vacuum. Isopropyl alcohol (150 mL) was added to the residue and the temperature was raised to 80-85 ° C. and maintained for 15-20 minutes to give a clear solution. The reaction mass was cooled to 0-5 ° C. The solid was filtered and washed with isopropyl alcohol. The resulting solid was dried at 40-45 ° C. for 10 hours to give blonanserin (20-25 g) with HPLC purity> 99.8%.

Claims (15)

In an improved process for preparing 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone, the process comprises:
a) hydrolysis of 4-fluorobenzoylacetonitrile in the presence of an acid to give 3- (4-fluorophenyl) -3-oxopropanamide, wherein the acid is methanesulfonic acid, Eaton's reagent, or A process selected from among organic acids;
b) reacting with cyclooctanone;
c) isolating 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone.   The resulting 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone is further converted to blonanserin. The method described. A further method for preparing blonanserin from 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine- (1H) -ketone is:
a) converting a compound of formula II to a compound of formula III comprising:
Wherein X is halogen, and
b) condensing the compound of formula III with N-ethylpiperazine;
c) isolating blonanserin.   4. The method of claim 3, wherein the compound of formula II is converted to a compound of formula III in the presence of a halogenating agent.   The method of claim 4, wherein the halogenating agent is phenylphosphonic dichloride.   4. The method of claim 3, wherein the compound of formula III is condensed with N-ethylpiperazine in the presence of an organic solvent such as N-methylpyrrolidone and dimethyl sulfoxide (DMSO). A method of preparing blonanserin hydrochloride, the method comprising:
a) dissolving blonanserin in water, a water-miscible organic solvent, or a mixture thereof;
b) adding an HCl source;
c) isolating blonanserin hydrochloride.   The method of claim 7, wherein blonanserin is dissolved in a mixture of water and a water-miscible organic solvent selected from alcoholic solvents.   9. The method of claim 8, wherein blonanserin is dissolved in a mixture of water and methanol. A method for preparing pure blonanserin from blonanserin hydrochloride, the method comprising:
a) placing blonanserin hydrochloride in a solvent or mixture of solvents;
b) adjusting the pH to basic with a base;
c) isolating blonanserin.   The method of claim 10, wherein the blonanserin hydrochloride is placed in a solvent selected from methanol, ethanol, isopropanol, and water, or mixtures thereof.   11. A process according to claim 10, wherein the solvent mixture is selected from methanol and water. A method for preparing pure blonanserin from blonanserin hydrochloride, the method comprising:
a) placing blonanserin hydrochloride into a mixture of water and a water-immiscible organic solvent;
b) adjusting the pH to basic with a base;
c) separating the organic layer;
d) optionally extracting blonanserin from the aqueous layer;
e) isolating pure blonanserin from the organic layer.   14. The method of claim 13, wherein the water immiscible organic solvent is selected from chloroform, dichloromethane, ethyl acetate, or isopropyl acetate.   14. A process according to any one of claims 10 and 13, wherein the base is selected from sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide.