WO2006103550A1 - Processes for the preparation of citalopram and its intermediate 5-aminophthalide - Google Patents

Processes for the preparation of citalopram and its intermediate 5-aminophthalide Download PDF

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WO2006103550A1
WO2006103550A1 PCT/IB2006/000752 IB2006000752W WO2006103550A1 WO 2006103550 A1 WO2006103550 A1 WO 2006103550A1 IB 2006000752 W IB2006000752 W IB 2006000752W WO 2006103550 A1 WO2006103550 A1 WO 2006103550A1
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formula
copper
benzofuran
process according
carbonate
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PCT/IB2006/000752
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French (fr)
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Naresh Kumar
Sandeep Nayyar
Mitu Gupta
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Ranbaxy Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3

Definitions

  • the field of the invention relates to processes for the preparation of 5-amino-2- benzofuran-l(3H)-one of Formula I,
  • the invention also relates to a process for the preparation of citalopram or a salt thereof, and pharmaceutical compositions that include the citalopram or a salt thereof.
  • citalopram is a racemic mixture of l-(3-dimethylaminopropyl)-l- (4- fluorophenyl)-l,3-dihydroisobenzofuran -5-carbonitrile of Formula II,
  • Citalopram is commercially available in the form of its hydrochloride or hydrobromide salt which is indicated for the treatment of depression.
  • the antidepressant activity of citalopram is presumed to be linked to potentiation of serotonergic activity in the central nervous system.
  • 5-amino-2-benzofuran-l(3H)-one is a useful intermediate in the preparation of citalopram.
  • U.S. Patent No. 2,130,480 discloses a process for the preparation of 5-amino-2- benzofuran-l(3H)-one by catalytically hydrogenating 5-nitro-2-benzofuran-l(3H)-one of Formula III.
  • a process reported in Zhurnal Obshchei Khimii, 1945, 15, 704-710 involves the conversion of 5-nitro-lH-isoindole-l,3(2H)-dione of Formula V into 5-amino-2- benzofuran-l(3H)-one by using zinc dust, 20% sodium hydroxide and copper sulfate at low temperatures, wherein the ammonia formed in the reaction is removed by steam distillation and the yield of the final product, 5-amino-2-benzofuran-l(3H)-one is reported to be 44%.
  • the process includes: a) treating 5-nitro-lH-isoindole-l,3(2H)-dione of Formula V,
  • the process may include further drying of the product obtained.
  • the process may include further converting the product obtained into citalopram or a salt thereof.
  • the citalopram or a salt thereof may be made into a finished dosage form with one or more pharmaceutically acceptable excipients and administered to a patient in need of a treatment for depression
  • the process includes: a) treating 5-nitro-lH-isoindole-l,3(2H)-dione of Formula V,
  • a pharmaceutical composition that includes a therapeutically effective amount of citalopram or a salt thereof; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the resulting pharmaceutical composition or dosage form may be administered to a patient in need of a treatment for depression.
  • the inventors have developed an efficient process for the preparation of 5-amino- 2-benzofuran-l(3H)-one of Formula I.
  • the process involves treating 5-nitro-l ⁇ -isoindole- l,3(2H)-dione of Formula V with zinc in the presence of a base, and isolating the 5-amino- 2-benzofuran-l(3H)-one of formula I from the reaction mixture thereof.
  • 5-nitro-l ⁇ -isoindole-l,3(2 ⁇ )-dione may be added to water or an organic solvent and an alkali metal salt or an alkaline earth metal salt, or a mixture thereof, at a temperature of from about -1O 0 C to about 25 0 C.
  • the reaction mixture may be stirred at a temperature from about O 0 C to about -10° C for about 0 to about 20 hours.
  • alkali metal salts or alkaline earth metal salts which may be used include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, magnesium hydroxide, magnesium carbonate, magnesium oxide, calcium hydroxide, calcium carbonate, calcium oxide, aluminium hydroxide and ammonia.
  • the 5-nitro-lH-isoindole-l,3(2H)-dione may be treated with zinc containing a catalytic quantity of copper salt.
  • copper salts include copper sulfate, copper nitrate, copper carbonate, copper acetate, copper benzoate, copper chromate, copper oxalate, copper phosphate and copper tetrafluoroborate.
  • the temperature may be reduced below about 25 0 C.
  • the zinc residue may be filtered off and washed with water.
  • 5-amino-2-benzofuran-l(3H)-one of Formula I may be isolated from the reaction mixture after acidification and subsequent basification.
  • the inventors also have developed a process for the preparation of citalopram of Formula II or a salt thereof.
  • the process involves treating 5-nitro-l ⁇ -isoindole-l,3(2 ⁇ )- dione of Formula V with zinc in an alkaline medium to get 5-amino-2-benzofuran-l(3H)- one of Formula I; treating the 5-amino-2-benzofuran-l(3H)-one of Formula I with a source of halogen to get 5-halo-2-benzofuran-l(3 ⁇ )-one of Formula VI; treating 5-halo-2- benzofuran-l(3H)-one of Formula VI with a Grignard solution of l-fluoro-4-halobenzene of Formula VII and N,N-dimethylaminopropyl metal lralide to get 3-[l-(4-fluorophenyl)- 5-halo-l,3-dihydro-2-benzofuran-l-yl]-N,N-
  • 5-amino-2-benzofuran-l(3H)-one of Formula I obtained in the first aspect of the invention may be treated with a source of halogen to get 5-halo-2-benzofuran-l(3 ⁇ )-one of Formula VI.
  • 5-halo-2-benzofuran-l(3H)-one may be further treated with a Grignard solution of 1 -fluoro-4-halobenzene of Formula VII and N,N-dimethylaminopropyl metal halide to get 3-[l-(4-fluorophenyl)-5-halo-l,3-dihydro-2-benzofuran-l-yl]-N,N- dimethylpropan-1 -amine.
  • N,N-dimethylaminopropyl metal halide may be N 5 N- dimethylaminopropyl magnesium chloride.
  • the obtained 5-halo compound may be further treated with a cyanide source to get citalopram.
  • the cyanide source may include one or more of cuprous cyanide, copper potassium cyanide, ferrocyanide, hydrogen cyanide, cadmium cyanide, barium cyanide, and the like.
  • the citalopram may be treated with an acid to get an acid addition salt of citalopram.
  • the 5-amino-2-benzofuran-l(3H)-one may be obtained in a yield of more than 90% by direct conversion of 5-nitro- 1 ⁇ -isoindole- 1 ,3 (2 ⁇ )-dione of Formula V without any necessity to remove the ammonia formed in the reaction.
  • 4-nitrophthalimide (50 g) was added into a pre-cooled mixture of zinc (200 g), copper sulfate pentahydrate (0.846 g) and sodium hydroxide (30 g) in deionised water (200 ml) at -10° to O 0 C. The mixture was stirred at 0° to -5 0 C for 12 h. Deionised water (150 ml) was added to the reaction mixture at 0° to -5 0 C, and then heated to 6O 0 C for 8 to 10 h. The hot zinc residue was filtered off and washed with hot water. The filtrate was acidified with hydrochloric acid to a pH less than 1.0 and then heated to 90° to 95 0 C for 30 minutes.
  • the pH of the reaction mixture was adjusted to 8.0 to 8.5 with 25 % w/v aqueous sodium hydroxide solution. The mixture was stirred for 30 minutes at 0° to 5 0 C and the product was filtered, washed with water and dried to get the title compound.
  • a freshly prepared solution of aqueous sodium iodide (44g) in deionised water (96 ml) was added at -5° to -1O 0 C over a period of 60 minutes.
  • the mixture was stirred for another 2 hours at 0° to 5 0 C, then heated to 45° to 5O 0 C and stirred at this temperature for 60 minutes.
  • the mixture was cooled to 1O 0 C and stirred for another 30 minutes at 5° to 1O 0 C.
  • the reaction mass obtained was filtered and washed with deionised water (80 ml). It was further washed with 5% w/v sodium thiosulfate solution.
  • the crude product obtained was recrystallized from methanol and toluene to get the title compound.
  • reaction mixture was stirred for another 60 minutes at -30° to -35 0 C and then dispersed in an aqueous saturated solution of ammonium chloride (1200 ml).
  • the reaction mass was extracted in ethyl acetate (2 x 500 ml) followed by evaporation of the solvent under reduced pressure to get an oil.
  • Toluene (250 ml), water (25 ml) and othrophosphoric acid (144 g) were added to the oil and stirred at 65° to 7O 0 C for 60 minutes.
  • the reaction mixture was then dispersed in a mixture of toluene (250 ml) and water (1800 ml).
  • Toluene (40 ml) was added to the citalopram free base (6.0 g) as prepared by Example 2 c) and stirred to obtain a homogeneous solution. 48% w/v aqueous hydrobromide solution (3.6g) was added to this solution. The reaction mixture so obtained was stirred for about 4 hours at 5° to 1O 0 C and the toluene layer was removed. Fresh toluene (40 ml) was added to it and further stirred at 5° to 1O 0 C. The separated solid was filtered, washed with toluene and dried to obtain the title compound as a crystalline powder.
  • the compounds described herein can be formulated into dosage forms that are suitable for administering to patients in need of the compound for treating a medical condition for which the compound is indicated, approved, or otherwise beneficial.
  • the citalopram or a salt thereof made according to the above processes can be formulated into a tablet, capsule, injectable solution, etc. along with one or more pharmaceutically acceptable excipients and administered to a patient in need of a treatment for depression.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to processes for the preparation of 5-amino-2-benzofuran- l(3H)-one of Formula (I), and to the use of this compound as an intermediate for the preparation of citalopram. The invention also relates to a process for the preparation of citalopram or a salt thereof, and pharmaceutical compositions that include the citalopram or a salt thereof.

Description

PROCESSES FOR THE PREPARATION OF CITALOPRAM AND ITS INTERMEDIATE 5-AMINOPHTHALIDE
Field of the Invention
The field of the invention relates to processes for the preparation of 5-amino-2- benzofuran-l(3H)-one of Formula I,
Figure imgf000002_0001
Formula I and to the use of this compound as an intermediate for the preparation of citalopram. The invention also relates to a process for the preparation of citalopram or a salt thereof, and pharmaceutical compositions that include the citalopram or a salt thereof.
Background of the Invention
Chemically, citalopram is a racemic mixture of l-(3-dimethylaminopropyl)-l- (4- fluorophenyl)-l,3-dihydroisobenzofuran -5-carbonitrile of Formula II,
Figure imgf000002_0002
Citalopram is commercially available in the form of its hydrochloride or hydrobromide salt which is indicated for the treatment of depression. The antidepressant activity of citalopram is presumed to be linked to potentiation of serotonergic activity in the central nervous system.
5-amino-2-benzofuran-l(3H)-one is a useful intermediate in the preparation of citalopram. There are several methods known for the preparation of this intermediate for example, U.S. Patent No. 2,130,480 discloses a process for the preparation of 5-amino-2- benzofuran-l(3H)-one by catalytically hydrogenating 5-nitro-2-benzofuran-l(3H)-one of Formula III.
Figure imgf000003_0001
Formula III
Bull. Soc. ScL Bretagne Spec, 1951, 26, 35-43 discloses a process for preparing 5- amino-2-benzofuran-l(3H)-one from 5-amino-lΗ-isoindole-l,3(2Η)-dione of Formula IV,
Figure imgf000003_0002
Formula IV using zinc powder, copper sulfate in basic medium.
Ann. Pharm. France, 1958, 16, 21-26 discloses a process for the preparation of 5- amino-2-benzofuran-l(3H)-one by reducing 5-nitro-lΗ-isoindole-l,3(2Η)-dione of Formula V,
Figure imgf000004_0001
Formula V with stannous chloride to get 5-amino-lH-isoindole-l,3(2H)~dione of Formula IV, followed by further reduction with zinc and sodium hydroxide.
A process reported in Zhurnal Obshchei Khimii, 1945, 15, 704-710 involves the conversion of 5-nitro-lH-isoindole-l,3(2H)-dione of Formula V into 5-amino-2- benzofuran-l(3H)-one by using zinc dust, 20% sodium hydroxide and copper sulfate at low temperatures, wherein the ammonia formed in the reaction is removed by steam distillation and the yield of the final product, 5-amino-2-benzofuran-l(3H)-one is reported to be 44%.
Summary of the Invention
In one general aspect there is provided a process for preparing 5-amino-2- benzofuran-l(3H)~one of Formula I.
Figure imgf000004_0002
Formula I
The process includes: a) treating 5-nitro-lH-isoindole-l,3(2H)-dione of Formula V,
Figure imgf000005_0001
Formula V with zinc in the presence of a base; and b) isolating 5-amino-2-benzofuran- 1 (3H)-one of Formula I.
The process may include further drying of the product obtained. The process may include further converting the product obtained into citalopram or a salt thereof. The citalopram or a salt thereof may be made into a finished dosage form with one or more pharmaceutically acceptable excipients and administered to a patient in need of a treatment for depression
In another general aspect there is provided a process for the preparation of citalopram of Formula II or a salt thereof.
Figure imgf000005_0002
Formula II
The process includes: a) treating 5-nitro-lH-isoindole-l,3(2H)-dione of Formula V,
Figure imgf000006_0001
Formula V with zinc in the presence of a base to get 5-amino-2-benzofuran-l(3H)-one of Formula I;
Figure imgf000006_0002
Formula I b) treating the 5-amino-2-benzofuran-l(3H)-one of Formula I with a source of halogen to get 5-halo-2-benzofuran-l(3Η)-one of Formula VI,
Figure imgf000006_0003
Formula VI wherein X is F, Br or I; c) treating the 5-halo-2~benzofuran-l(3H)-one of Formula VI with a Grignard solution of l-fluoro-4-halobenzene of Formula VII,
Figure imgf000007_0001
Formula VII wherein X is Cl, Br or I, and N,N-dimethylaminopropyl metal halide to get 3-[l-(4-fluorophenyl)-5-halo- 1 ,3 -dihydro-2-benzofuran- 1 -yl]-N,N-dimethylpropan- 1 -amine of Formula VIII,
Figure imgf000007_0002
Formula VIII wherein X is Cl, Br or I; d) treating the 3-[l-(4-fluorophenyl)-5-halo-l,3-dihydro-2-benzofuran-l-yl]- N,N-dimethylpropan-l-amine of Formula VIII with a cyanide source to get citalopram of
Formula II; and e) isolating the citalopram or a salt thereof.
In another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of citalopram or a salt thereof; and one or more pharmaceutically acceptable carriers, excipients or diluents. The resulting pharmaceutical composition or dosage form may be administered to a patient in need of a treatment for depression The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.
Detailed Description of the Invention
The inventors have developed an efficient process for the preparation of 5-amino- 2-benzofuran-l(3H)-one of Formula I. The process involves treating 5-nitro-lΗ-isoindole- l,3(2H)-dione of Formula V with zinc in the presence of a base, and isolating the 5-amino- 2-benzofuran-l(3H)-one of formula I from the reaction mixture thereof. In general, 5-nitro-lΗ-isoindole-l,3(2Η)-dione may be added to water or an organic solvent and an alkali metal salt or an alkaline earth metal salt, or a mixture thereof, at a temperature of from about -1O0C to about 250C. The reaction mixture may be stirred at a temperature from about O0C to about -10° C for about 0 to about 20 hours. Examples of alkali metal salts or alkaline earth metal salts which may be used include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, magnesium hydroxide, magnesium carbonate, magnesium oxide, calcium hydroxide, calcium carbonate, calcium oxide, aluminium hydroxide and ammonia.
The 5-nitro-lH-isoindole-l,3(2H)-dione may be treated with zinc containing a catalytic quantity of copper salt. Examples of copper salts include copper sulfate, copper nitrate, copper carbonate, copper acetate, copper benzoate, copper chromate, copper oxalate, copper phosphate and copper tetrafluoroborate. The temperature may be reduced below about 250C. After the completion of the reaction, the zinc residue may be filtered off and washed with water. 5-amino-2-benzofuran-l(3H)-one of Formula I may be isolated from the reaction mixture after acidification and subsequent basification.
The inventors also have developed a process for the preparation of citalopram of Formula II or a salt thereof. The process involves treating 5-nitro-lΗ-isoindole-l,3(2Η)- dione of Formula V with zinc in an alkaline medium to get 5-amino-2-benzofuran-l(3H)- one of Formula I; treating the 5-amino-2-benzofuran-l(3H)-one of Formula I with a source of halogen to get 5-halo-2-benzofuran-l(3Η)-one of Formula VI; treating 5-halo-2- benzofuran-l(3H)-one of Formula VI with a Grignard solution of l-fluoro-4-halobenzene of Formula VII and N,N-dimethylaminopropyl metal lralide to get 3-[l-(4-fluorophenyl)- 5-halo-l,3-dihydro-2-benzofuran-l-yl]-N,N-dimethylpropan-l-amirie of Formula VIII; treating the 3-[l-(4-fluorophenyl)-5-halo-l,3-dihydro-2-benzoruran-l-yl]-N,N- dimethylpropan-1 -amine of Formula VIII with a cyanide source to get citalopram of Formula II, and isolating the citalopram or a salt thereof.
5-amino-2-benzofuran-l(3H)-one of Formula I obtained in the first aspect of the invention may be treated with a source of halogen to get 5-halo-2-benzofuran-l(3Η)-one of Formula VI. 5-halo-2-benzofuran-l(3H)-one may be further treated with a Grignard solution of 1 -fluoro-4-halobenzene of Formula VII and N,N-dimethylaminopropyl metal halide to get 3-[l-(4-fluorophenyl)-5-halo-l,3-dihydro-2-benzofuran-l-yl]-N,N- dimethylpropan-1 -amine. N,N-dimethylaminopropyl metal halide may be N5N- dimethylaminopropyl magnesium chloride. The obtained 5-halo compound may be further treated with a cyanide source to get citalopram. The cyanide source may include one or more of cuprous cyanide, copper potassium cyanide, ferrocyanide, hydrogen cyanide, cadmium cyanide, barium cyanide, and the like. The citalopram may be treated with an acid to get an acid addition salt of citalopram.
As may be seen from the examples that follow, by using or following the processes of the present invention the 5-amino-2-benzofuran-l(3H)-one may be obtained in a yield of more than 90% by direct conversion of 5-nitro- 1 Η-isoindole- 1 ,3 (2Η)-dione of Formula V without any necessity to remove the ammonia formed in the reaction.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and should not be construed in a manner that limits the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1: Preparation of 5-amino-2-benzofuran-l(3H)-one
4-nitrophthalimide (50 g) was added into a pre-cooled mixture of zinc (200 g), copper sulfate pentahydrate (0.846 g) and sodium hydroxide (30 g) in deionised water (200 ml) at -10° to O0C. The mixture was stirred at 0° to -50C for 12 h. Deionised water (150 ml) was added to the reaction mixture at 0° to -50C, and then heated to 6O0C for 8 to 10 h. The hot zinc residue was filtered off and washed with hot water. The filtrate was acidified with hydrochloric acid to a pH less than 1.0 and then heated to 90° to 950C for 30 minutes. After cooling to 0° to 50C, the pH of the reaction mixture was adjusted to 8.0 to 8.5 with 25 % w/v aqueous sodium hydroxide solution. The mixture was stirred for 30 minutes at 0° to 50C and the product was filtered, washed with water and dried to get the title compound.
Yield: 37.0 g Purity (HPLC): 99 %
Example 2: Preparation of Citalopram Hydrobromide a) Preparation of 5-Iodo-2-Benzofuran-l(3H)-One
Freshly prepared sodium nitrite solution (20.4 g) in deionised water (96 ml) was added to a mixture of deionised water (120 ml), concentrated hydrochloric acid (120 ml) and 5- amino-2-benzofuran-l(3H)-one (40 g) as prepared by Example 1, at -5° to -1O0C over a period of 60 minutes. A freshly prepared solution of aqueous sodium iodide (44g) in deionised water (96 ml) was added at -5° to -1O0C over a period of 60 minutes. The mixture was stirred for another 2 hours at 0° to 50C, then heated to 45° to 5O0C and stirred at this temperature for 60 minutes. The mixture was cooled to 1O0C and stirred for another 30 minutes at 5° to 1O0C. The reaction mass obtained was filtered and washed with deionised water (80 ml). It was further washed with 5% w/v sodium thiosulfate solution. The crude product obtained was recrystallized from methanol and toluene to get the title compound. Yield: 29 g b) Preparation of 3-[l-(4-Fluorophenyl)-5-Iodo-l,3-Dihydro-2-Benzofuran-l-yl]-N,N- Dimethylpropan-1-Amine
To a solution of 5-iodo-2-benzofuran-l(3Η)-one (50 g) as prepared by Example 2 a) in tetrahydrofuran (250 ml) was added a Grignard solution of l-bromo-4-fluorobenzene (prepared from p-bromofluorobenzene (77.5 g) and magnesium turnings (10.7 g) in tetrahydrofuran (250 ml)) at -35° to -2O0C over a period of 60 minutes, followed by the addition of N,N- dimethylaminopropyl magnesium chloride (prepared from N9N- dimethylaminopropyl chloride (107 g) and magnesium turnings (21.49 g) in tetrahydrofuran (200 ml)) at - 40° to -350C over a period of 60 minutes. The reaction mixture was stirred for another 60 minutes at -30° to -350C and then dispersed in an aqueous saturated solution of ammonium chloride (1200 ml). The reaction mass was extracted in ethyl acetate (2 x 500 ml) followed by evaporation of the solvent under reduced pressure to get an oil. Toluene (250 ml), water (25 ml) and othrophosphoric acid (144 g) were added to the oil and stirred at 65° to 7O0C for 60 minutes. The reaction mixture was then dispersed in a mixture of toluene (250 ml) and water (1800 ml). The aqueous layer was washed with toluene (500 ml) followed by pH adjustment to 6.5 to 7.0 with ammonia solution. The reaction mass was extracted in toluene (2 x 500ml). The solvent was evaporated under reduced pressure to get the title compound as oil. Yield: 45 g c) Preparation of Citalopram Base
3 -[ 1 -(4-fluorophenyl)-5 -iodo- 1 ,3 -dihydro-2-benzofuran- 1 -yl]-N,N-dimethylpropan- 1 - amine (7.5 g) as prepared by Example 2 b), cuprous cyanide powder (2.4 g) and pyridine (5.6 g) were added to dimethylformamide (40 ml) and the mixture obtained was heated to 140° to 1410C. The reaction mixture was further stirred at 141° to 1450C for about 3 hours. The reaction mixture was then cooled to 350C, and diluted with a cooled mixture of toluene and water. The organic layer was separated, washed with ammonia solution and water. The toluene was recovered under vacuum to get the title compound as a free base in the form of oil. Yield: 6.0 g d) Preparation of Citalopram Hydrobromide
Toluene (40 ml) was added to the citalopram free base (6.0 g) as prepared by Example 2 c) and stirred to obtain a homogeneous solution. 48% w/v aqueous hydrobromide solution (3.6g) was added to this solution. The reaction mixture so obtained was stirred for about 4 hours at 5° to 1O0C and the toluene layer was removed. Fresh toluene (40 ml) was added to it and further stirred at 5° to 1O0C. The separated solid was filtered, washed with toluene and dried to obtain the title compound as a crystalline powder.
Yield: 6.7 g
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. For example, the compounds described herein can be formulated into dosage forms that are suitable for administering to patients in need of the compound for treating a medical condition for which the compound is indicated, approved, or otherwise beneficial. Specifically, the citalopram or a salt thereof made according to the above processes can be formulated into a tablet, capsule, injectable solution, etc. along with one or more pharmaceutically acceptable excipients and administered to a patient in need of a treatment for depression.

Claims

WE CLAIM:
1. A process for the preparation of 5~amino~2-benzofuran- 1 (3H)-one of Formula I,
Figure imgf000013_0001
Formula I the process comprising: a) treating 5-mtro-lΗ-isoindole-l,3(2Η)-dione of Formula V,
Figure imgf000013_0002
Formula V with zinc in the presence of a base; and b) isolating 5-amino-2-benzofuran-l(3H)-one of Formula I.
2. The process according to claim 1 , wherein reaction is carried out at a temperature of from about -10° C to about 25° C.
3. The process according to claim 1, wherein the base comprises one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, magnesium hydroxide, magnesium carbonate, magnesium oxide, calcium hydroxide, calcium carbonate, calcium oxide, aluminium hydroxide and ammonia.
4. The process of claim 1, further comprising adding a catalytic quantity of a copper salt with zinc.
5. The process according to claim 4, wherein the copper salt comprises one or more of copper sulfate, copper nitrate, copper carbonate, copper acetate, copper benzoate, copper chromate, copper oxalate, copper phosphate and copper tetrafluoroborate.
6. The process according to claim 1, wherein the resulting 5-ammo-2-benzofuran- l(3H)-one has a purity of 90% or more by ΗPLC.
7. A process for the preparation of citalopram of Formula II or a salt thereof,
Figure imgf000014_0001
Formula II the process comprising: a) treating 5-nitro-lH-isoindole-l,3(2H)-dione of formula V,
Figure imgf000014_0002
Formula V with zinc in the presence of a base to get 5-ammo-2-benzofuran-l(3H)-one of Formula I;
Figure imgf000015_0001
Formula I b) treating the 5-amino-2-benzofuran-l(3H)-one of Formula I with a source of halogen to get 5-halo-2-benzofuran-l(3Η)-one of Formula VI,
Figure imgf000015_0002
Formula VI wherein X is Cl, Br or I; c) treating the 5-halo-2-benzofuran-l(3H)-one of Formula VI with a Grignard solution of l-fluoro-4-halobenzene of Formula VII,
Figure imgf000015_0003
Formula VII wherein X is Cl, Br or I, and N,N-dimethylaminopropyl metal halide to get 3-[l-(4~fluorophenyl)-5-halo- 1 ,3-dihydro-2-benzofuran- 1 -yl]-N,N-dimethylpropan- 1 -amine of Formula VIII,
Figure imgf000016_0001
Formula VIII wherein X is Cl, Br or I; d) treating the 3-[l-(4-fluorophenyl)-5-halo-l,3-dihydro-2-benzofuran-l-yl]- N,N-dimethylpropan-l -amine of Formula VIII with a cyanide source to get citalopram of Formula II; and e) isolating the citalopram or a salt thereof.
8. The process according to claim 7, wherein the base comprises one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, magnesium hydroxide, magnesium carbonate, magnesium oxide, calcium hydroxide, calcium carbonate, calcium oxide, aluminium hydroxide and ammonia.
9. The process according to claim 7, wherein the N,N-dimethylaminopropyl metal halide of step c) is N,N-dimethylaminopropyl magnesium halide.
10. The process according to claim 7, wherein the cyanide source in step d) comprises one or more of cuprous cyanide, copper potassium cyanide, ferrocyanide, hydrogen cyanide, cadmium cyanide and barium cyanide.
11. The process according to claim 7, further comprising adding a catalytic quantity of a copper salt with zinc.
12. The process according to claim 11, wherein the copper salt comprises one or more of copper sulfate, copper nitrate, copper carbonate, copper acetate, copper benzoate, copper chromate, copper oxalate, copper phosphate and copper tetrafluoroborate.
13. The process according to claim 7, ftirther comprising forming the product into a finished dosage form.
14. The process according to claim 7, ftirther comprising administering the finished dosage form to a patient in need of a treatment for depression.
15. A pharmaceutical composition comprising a therapeutically effective amount of citalopram, or a salt thereof obtained by the process of claim 7; and one or more pharmaceutically acceptable carriers, excipients or diluents.
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