WO2005049596A1 - A process for the preparation of high purity escitalopram - Google Patents

A process for the preparation of high purity escitalopram Download PDF

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WO2005049596A1
WO2005049596A1 PCT/IN2003/000363 IN0300363W WO2005049596A1 WO 2005049596 A1 WO2005049596 A1 WO 2005049596A1 IN 0300363 W IN0300363 W IN 0300363W WO 2005049596 A1 WO2005049596 A1 WO 2005049596A1
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acid
escitalopram
improved process
formula
base
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PCT/IN2003/000363
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French (fr)
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Muddasani Pullareddy
Talasila Sambasiva Rao
Nekkanti Srinivasa Rao
Nannapaneni Venkaiah Chowdary
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Natco Pharma Limited
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Priority to AU2003282383A priority Critical patent/AU2003282383A1/en
Priority to PCT/IN2003/000363 priority patent/WO2005049596A1/en
Publication of WO2005049596A1 publication Critical patent/WO2005049596A1/en

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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

Definitions

  • the present invention relates to an improved process for the preparation of high purify escitalopram.
  • Escitalopram ((S)- 1 -[3 (dimethylamino)propyl]- 1 -(4-fiuorophenyl)- 1,3- dihydro-5-isobenzofurancarbonitrile) is the S-enantiomer ((+)-isomer) of the well-known antidepressant drug citalopram having the formula-I given below.
  • Escitalopram was found to be more active than the dl-citalopram or the R-citalopram.
  • Citalopram which has been disclosed in DE Patent no. 2,657,013 (1977) corresponding to US Patent no. 4,136,193 (1979) is a well-known antidepressant drug available in the market for some years. It is a selective, centrally acting serotonin (5-HT) reuptake inhibitor, is accordingly having the antidepressant activity.
  • the antidepressant activity of citalopram has been reported in several publications, e.g. J. Hyttel, Prog. Neuro- Psychophannacol. & Biol. Psychiat, 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486.
  • (+)-di-p-toluoyltartaric acid , .. i (likewise A . . . . . V1 1A -*- — - - *- (+)-d ⁇ -p-toluoyltartar ⁇ c acid and (-)-XI salt IPA ⁇
  • (+)- Scheme-5 less than 0.1% level led to very poor yield. Also the yield of escitalopram decreased with increasing scale.
  • the main objective of the present invention is to provide an improved process for the preparation of escitalopram from the corresponding bromo compound of formula-XVTf, which is commercially applicable.
  • Yet another objective of the present invention is to provide an improved process for the preparation of escitalopram by protecting the dimethylamino group present in the bromo intermediate of formula-XVII in its salt form during cyanation step.
  • Still another objective of the present invention is to keep the level of bromo intermediate of formula-XVII at less than 0.1% level in the reaction mass during the cyanation step thereby avoiding the purification step involved during the isolation of escitalopram.
  • the present invention provides improved process for the preparation of escitalopram of formula-I,
  • (+)- and its pharmaceutically acceptable salts which comprises: (i) Conversion of the bromo intermediate of formula-XVII,
  • the step (i) of the process may be carried out preferably in an inert atmosphere for getting better yields.
  • the inert gas which, may be used is selected from nitrogen or argon.
  • the acid used in step (i) is selected from formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, salicylic acid, trifluoro- methanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, or mineral acids like HC1, HBr, H 2 SO 4 , perchloric acid, etc., preferably acetic acid, methanesulfonic acid, oxalic acid, or perchloric acid.
  • the aprotic solvent used step (ii) is selected from N,N-dimethylformamide, N,N-di- methylacetamide, pyridine, N-methylpyrrolidone, etc, preferably N,N-dimethyl- formamide.
  • the amount of copper (I) cyanide used in step (ii) is 1.0-2.5moles per mole of the bromo compound used, preferably 1.5-2.0moles.
  • the amount of copper (I) iodide used in step (ii) is 0.0-1.0moles per mole of bromo compound used, preferably, 0.5moles.
  • the temperature of reaction in step (ii) is preferably, 140-160°C, most preferably 145-150°C.
  • the base used in step (iii) is selected from ammonia, ethylene diamine or, ethanolamine.
  • the solvent used for extraction of crude escitalopram in step (iv) is selected from toluene, ethyl acetate, diisopropyl ether, methylene chloride, etc., preferably, toluene, ethyl acetate or diisopropyl ether.
  • the weak organic acid used in step (v) is selected from acetic acid, propionic acid, formic acid, oxalic acid, preferably acetic acid or oxalic acid.
  • the amount of weak organic acid used in step (v) ranges between 0.8-1.5moles per mole of bromo compound used in the reaction, preferably 1.0-1.2moles
  • the weak base used in step (vi) is selected from ammonia, methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, etc, preferably ammonia.
  • the hydrocarbon solvent which is employed for the extraction of pure escitalopram in step (vii), is selected from toluene, cyclohexane, heptane, etc., preferably, toluene.
  • the ether solvent used during the extraction of pure escitalopram is selected from diethyl ether, diisopropyl ether, methyl t-butyl ether, etc., diisopropyl ether.
  • Escitalopram prepared according to the process disclosed in this application has high yield (>75%) and high purity (>98%) with the bromo impurity level at less than 0.1%.
  • Doing cyanation on the acid addition salt intermediate (formula-XVIII) of escitalopram or citalopram is novel and applied for the first time in making escitalopram or citalopram. Cyanation on the acid addition salt of the intermediate has substantially improved the quality of escitalopram and the yields were consistent during scale up operations.
  • the acid addition salt of compound of formula-XVIII used in the cyanation step can be made in the same solvent used in the cyanation step or can be made separately and isolated.
  • the oxalate salt of bromo compound of formula-XVII was made separately in acetone medium and used in the cyanation step.
  • the molar quantity of acid used during salt formation can be in the range of 0.95-1.05 moles per mole of the bromo compound of formula-XVII.
  • the temperature of the reaction during cyanation is between 120-160°C, preferably between 135-155°C, most preferably between 145-150°C.
  • the amount of copper (I) iodide used in the reaction is in the range of 0.2-2.0 moles per mole of bromo compound, preferably in the range of 0.5-1.0 moles per mole.
  • the amount of copper (I) cyanide used in the reaction can be in the range of 1.0-2.5 moles per mole of bromo compound, preferably 1.5-2.0 moles per mole of bromo compound.
  • the dipolar aprotic solvent used in the reaction is N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, N-methylpyrrolidone, etc, preferably N,N-dimethylformamide.
  • Example 1 Preparation of escitalopram from acetate salt of l-[3-(dimethylamino)propyl] ⁇ l-(4- fluorophenyl)-5-bromo-l,3-dihydroisobenzofuran of formula-XVH
  • acetic acid 15.9gr
  • Copper (I) cyanide 47.4gr
  • copper (I) iodide (25.2gr) were added to the reaction.
  • the reaction mixture was slowly heated under nitrogen atmosphere to 145-150°C.
  • reaction mixture was cooled to 25-30°C and poured into water (3000ml). After stirring for lhr, ethylenediamine (100ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring.
  • Toluene (300ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 200ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (200ml). The combined organic layer was washed with water. The organic layer was extracted with 5% aqueous oxalic acid (800ml and 400ml). The combined oxalic acid layer was treated with charcoal (lOgr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0.
  • Example 2 Preparation of escitalopram from oxalate salt of l-[3-(dimethylamino)propyI]-l-(4- fluorophenyI)-5-bromo-l,3-dihydroisobenzofuran of formuIa-XVH
  • Toluene (300ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 200ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (200ml). The combined organic layer was washed with water. The organic layer was extracted with 5% aqueous oxalic acid (600ml and 400ml). The combined aqueous layer was treated with charcoal (10gr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0.
  • Example 3 Preparation of escitalopram from methanesulfonate salt of l-[3-(dimethylamino)- propyl]-l-(4-fluorophenyI)-5-bromo-l,3-dihydroisobenzofuran of formuIa-XVH
  • Toluene (150ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 100ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (100ml). The combined organic layer was washed with water. The organic layer was extracted with 5% aqueous oxalic acid (400ml and 200ml). The combined aqueous layer was treated with charcoal (5gr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0.
  • the product was extracted into isopropyl ether (1 x 100ml, 2 x 50ml) and the solvent distilled off to get 32.5gr (76%) of escitalopram base as colorless oil. Purity by HPLC was found to be 99%. Bromo compound is less than 0.1%.
  • Example 4 Preparation of escitalopram from benzoate salt of l-[3-(dimethylamino)propyl]-l- (4-fluorophenyl)-5-bromo-l,3-dihydroisobenzofuran of formula-XV ⁇
  • benzoic acid 3.gr
  • Copper (I) cyanide 4.7gr
  • copper (I) iodide 2.5gr
  • reaction mixture was cooled to 25-30°C and poured into water (300ml). After stirring for lhr, ethylenediamine (10ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring.
  • Toluene (50ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 50ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (50ml). The combined organic layer was washed with water. The organic layer was extracted with 5% aqueous oxalic acid (100ml and 50ml). The combined oxalic acid layer was treated with charcoal (l.Ogr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0.
  • Toluene (50ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 50ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (50ml). The combined organic layer was washed with water. The organic layer was extracted with 5% aqueous oxalic acid (100ml and 50ml). The combined oxalic acid layer was treated with charcoal (l.Ogr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0.
  • reaction mixture was cooled to 25-30°C and poured into water (300ml). After stirring for lhr, ethylenediamine (10ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring.
  • Toluene (50ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 50ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (50ml). The combined organic layer was washed with water. The organic layer was extracted with 5% aqueous oxalic acid (100ml and 50ml). The combined oxalic acid layer was treated with charcoal (l.Ogr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0.
  • Example 7 Preparation of dl-citalopram from oxalate salt of dI-l-[3-(dimethylamino)propyl]-l- (4-fluorophenyl)-5-bromo-l,3-dihydroisobenzofuran of formula-XVH
  • oxalate salt of the dl-bromo compound (lOOgr) of formula- XVII in DMF (1000ml) under nitrogen atmosphere was added copper (I) cyanide (38.3gr) and copper (I) iodide (20.2gr). The reaction mixture was slowly heated under nitrogen atmosphere to 145-150°C.
  • reaction mixture was cooled to 25-30°C and poured into water (3000ml). After stirring for lhr, ethylenediamine (100ml) was slowly added to the reaction mixture and maintained for lhr under stirring.
  • Toluene (300ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 200ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (200ml). The combined organic layer was washed with water. The organic layer was extracted with 10% aqueous acetic acid (300ml and 200ml). The combined aqueous acetic acid layer was treated with charcoal (10gr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0.

Abstract

The present invention discloses an improved process for the preparation of high purity escitalopram base of formula (I) by reacting the acid addition salt of formula (XVIII) with copper (I) cyanide and with or without copper (I) iodide in dimethylformamide medium at 145-150 °C. Cyanation on the acid addition salt of formula (XVIII) is found to be superior in yield and quality over the parent base compound of formula (XVII). The process is compatible to scale up operations thereby making the process commercially viable for escitalopram oxalate. Escitalopram oxalate is an antidepressant available in the market.

Description

A PROCESS FOR THE PREPARATION OF HIGH PURITY ESCITALOPRAM
The present invention relates to an improved process for the preparation of high purify escitalopram. Escitalopram ((S)- 1 -[3 (dimethylamino)propyl]- 1 -(4-fiuorophenyl)- 1,3- dihydro-5-isobenzofurancarbonitrile) is the S-enantiomer ((+)-isomer) of the well-known antidepressant drug citalopram having the formula-I given below. Escitalopram was found to be more active than the dl-citalopram or the R-citalopram.
Figure imgf000002_0001
BACKGROUND OF THE INVENTION
Citalopram, which has been disclosed in DE Patent no. 2,657,013 (1977) corresponding to US Patent no. 4,136,193 (1979) is a well-known antidepressant drug available in the market for some years. It is a selective, centrally acting serotonin (5-HT) reuptake inhibitor, is accordingly having the antidepressant activity. The antidepressant activity of citalopram has been reported in several publications, e.g. J. Hyttel, Prog. Neuro- Psychophannacol. & Biol. Psychiat, 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486.
The basic process for the preparation of citalopram described in the above-referred patents involves two major routes illustrated in Scheme- 1 and Scheme-2. Major difference in these two routes is introduction of dimethylaminopropyl side chain at an early stage (Scheme- 1) or at a later stage (Scheme- 2). In the first route, 5-bromophthalide of the formula-II is reacted with p-fluorophenyl- magnesium bromide to get the benzophenone derivative of the formula-Ill. This benzophenone derivative is reacted with 3-(dimethylamino)propylmagnesium chloride to get the dihydroxy intermediate of the formula-IV.
Figure imgf000003_0001
Scheme- 1 Cyclization of the compound of the formula-IV with an acid catalyst resulted in the formation of phthalane derivative of the formula- V. This bromophthalane derivative is reacted with copper (I) cyanide to get the citalopram base of the formula-I. In the second route, 5-bromophthalide of the formula-II is reacted with p-fluorophenyl- magnesium bromide to get the corresponding benzophenone derivative of the formula-Ill
Figure imgf000004_0001
Scheme-2 This compound of the formula-Ill is reduced with lithium aluminum hydride to get the dihydroxy compound of the formula- VI, which is cyclized with an acid catalyst to get the phthalane derivative of the formula- VII. The bromo group is replaced with a cyano group and alkylated with the required side chain to get the citalopram base of the formula-I. Another method for the preparation of citalopram base of the formula-I and a novel intermediate useful for the preparation of citalopram was disclosed in US Pat. No. 4,650,884, according to which 5-cyanophthalide of formula-IX is reacted successively with p-fiuorophenylmagnesium bromide and 3-.(dimethylamino)propylmagnesium chloride to get the compound of the formula-XI which is reacted with 70% sulfuric acid to get the citalopram base (Scheme-3).
Figure imgf000005_0001
Scheme-3
Process for the preparation of escitalopram is disclosed in U. S. Pat. No. 4,943,590. According to this patent, attempts to crystallize the diastereomeric salts of citalopram enantiomers have failed. In this patent a process for the preparation of escitalopram was described by resolving the intermediate (compound of the formula-XI) of citalopram and ring closure of the resolved intermediate in a stereospecific manner to get the escitalopram (Scheme-4).
Figure imgf000006_0001
(+)-di-p-toluoyltartaric acid , .. i ( „ A . . . . . . V1 1A -*- — - - *- (+)-dι-p-toluoyltartarιc acid and (-)-XI salt IPA χ„
Figure imgf000006_0002
Scheme-4 The main drawback in this process is the purity of the intermediate compound of the formula-XI obtained in the Grignard reaction, which is of 80-90% only. The crude compound of formula-XI needs extensive purification before proceeding for resolution. The purification technique given in the above patent process involves repeated charcoal and silica gel treatment to the compound of the formula-XI or its HBr salt. Also, during the HBr salt formation of compound of the formula-XI, the amount of HBr used in the process should be less than the molar quantity to avoid additional impurities formation. As the impurities present in the intermediate compound of the formula-XI have closely related properties such a purification technique is not viable on a commercial scale to make this intermediate and also the escitalopram. Also, the overall yield of escitalopram given in this patent is only 8.8% starting from 5-cyanophthalide of the formula-IX. Therefore such a low yielding process needs to be improved for commercial production of escitalopram. Recently a process for the preparation of escitalopram is disclosed in WO 03/O006449. According to the method given in this patent intermediates of dl-citalopram were separated into the individual enantiomers by chromatographic method and converted to escitalopram. The main drawback in this process is the availability of chiral stationary phase on bulk scale and its implementation on a commercialization. Output from such a process will also be low.
Keeping in view of the difficulties in commercialization of the above-mentioned process for the preparation of escitalopram, we aimed to develop a simple and economical process for commercial production of escitalopram.
DESCRIPTION OF PRESENT INVENTION
We observed that a promising approach for a process for the preparation of escitalopram would be to (a) avoid the usage of 5-cyanophthalide as starting material (b) avoid the purification of intermediates involved in making escitalopram thereby making the process commercially viable and economical (c) develop an efficient method for the conversion of intermediates into escitalopram.
Focusing on these points we developed an improved process for the preparation of escitalopram and filed a patent recently (052 /MAS/ 2003). According to the process
(Scheme-5) disclosed in the said patent application, 5-bromophthalide is subj ected to double Grignard reaction and the resulting dimagnesium salt of formula-XIV is isolated by filtration. By doing so we could remove all the related impurities present in the reaction mass and get the required compound of formula-IV in more than 98% purity after neutralization of salt. The dihydroxy intermediate thus obtained was resolved into its isomers by treating with a resolving agent. The resolved intermediate of forn ula-XVI was cyclized to the bromo derivative of formula-XVH and finally this bromo intermediate was converted to escitalopram base by treating it with copper cyanide. The quality of escitalopram obtained by this procedure was found to be more than 97%. The main impurity present in this compound is the starting bromo compound. Removal of this
Figure imgf000008_0001
XIV (Isolated)
(+)-di-p-toluoyItartaric acid - (+)-di-p-toluoyltartaric acid and (-)-IV salt I PA XV
Figure imgf000008_0002
(+)- Scheme-5 less than 0.1% level led to very poor yield. Also the yield of escitalopram decreased with increasing scale.
During our sustained research to overcome this problem we found that the basicity of dimethylamino group present in bromo compound is the main cause for poor rate of reaction and poor yield in scale up. To reduce the influence of the dimethylamino group present in the bromo compound during cyanation, we aimed to reduce the basicity of the bromo compound of formula-XVLT by converting it into a salt.
Accordingly the main objective of the present invention is to provide an improved process for the preparation of escitalopram from the corresponding bromo compound of formula-XVTf, which is commercially applicable.
Yet another objective of the present invention is to provide an improved process for the preparation of escitalopram by protecting the dimethylamino group present in the bromo intermediate of formula-XVII in its salt form during cyanation step.
Still another objective of the present invention is to keep the level of bromo intermediate of formula-XVII at less than 0.1% level in the reaction mass during the cyanation step thereby avoiding the purification step involved during the isolation of escitalopram.
Accordingly the present invention provides improved process for the preparation of escitalopram of formula-I,
Figure imgf000009_0001
(+)- and its pharmaceutically acceptable salts which comprises: (i) Conversion of the bromo intermediate of formula-XVII,
Figure imgf000010_0001
XVII into the acid addition salt of formula-XVLTI,
Figure imgf000010_0002
using an acid HX where X represents an organic or inorganic moiety . (ii) Reacting the resulting acid addition salt with copper (I) cyanide with or without copper (I) iodide in dipolar aprotic solvent medium at a temperature in the range of 120-200°C. (iii) Quenching the resulting reaction mass into aqueous base . (iv) Extracting the crude escitalopram base into an organic solvent . (v) Extracting the escitalopram base into a weak aqueous organic acid . (vi) Neutralizing the resulting aqueous organic acid layer with a weak organic base . (vii) Extracting the pure escitalopram base into an ether or hydrocarbon solvent. (viii) Removing the solvent to get pure escitalopram and if desired. (ix) Preparing the pharmaceutically acceptable salts by conventional methods. The bromo compound of formula-XVII used in the process can be made according to the process disclosed in our earlier filed application referred to above.
The step (i) of the process may be carried out preferably in an inert atmosphere for getting better yields. The inert gas which, may be used is selected from nitrogen or argon.
The acid used in step (i) is selected from formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, salicylic acid, trifluoro- methanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, or mineral acids like HC1, HBr, H2SO4, perchloric acid, etc., preferably acetic acid, methanesulfonic acid, oxalic acid, or perchloric acid.
The aprotic solvent used step (ii) is selected from N,N-dimethylformamide, N,N-di- methylacetamide, pyridine, N-methylpyrrolidone, etc, preferably N,N-dimethyl- formamide.
The amount of copper (I) cyanide used in step (ii) is 1.0-2.5moles per mole of the bromo compound used, preferably 1.5-2.0moles. The amount of copper (I) iodide used in step (ii) is 0.0-1.0moles per mole of bromo compound used, preferably, 0.5moles. The temperature of reaction in step (ii) is preferably, 140-160°C, most preferably 145-150°C.
The base used in step (iii) is selected from ammonia, ethylene diamine or, ethanolamine. The solvent used for extraction of crude escitalopram in step (iv) is selected from toluene, ethyl acetate, diisopropyl ether, methylene chloride, etc., preferably, toluene, ethyl acetate or diisopropyl ether.
The weak organic acid used in step (v) is selected from acetic acid, propionic acid, formic acid, oxalic acid, preferably acetic acid or oxalic acid. The amount of weak organic acid used in step (v) ranges between 0.8-1.5moles per mole of bromo compound used in the reaction, preferably 1.0-1.2moles The weak base used in step (vi) is selected from ammonia, methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, etc, preferably ammonia. The hydrocarbon solvent, which is employed for the extraction of pure escitalopram in step (vii), is selected from toluene, cyclohexane, heptane, etc., preferably, toluene. The ether solvent used during the extraction of pure escitalopram is selected from diethyl ether, diisopropyl ether, methyl t-butyl ether, etc., diisopropyl ether.
Escitalopram prepared according to the process disclosed in this application has high yield (>75%) and high purity (>98%) with the bromo impurity level at less than 0.1%. Doing cyanation on the acid addition salt intermediate (formula-XVIII) of escitalopram or citalopram is novel and applied for the first time in making escitalopram or citalopram. Cyanation on the acid addition salt of the intermediate has substantially improved the quality of escitalopram and the yields were consistent during scale up operations.
The acid addition salt of compound of formula-XVIII used in the cyanation step can be made in the same solvent used in the cyanation step or can be made separately and isolated. For example, the oxalate salt of bromo compound of formula-XVII was made separately in acetone medium and used in the cyanation step. The molar quantity of acid used during salt formation can be in the range of 0.95-1.05 moles per mole of the bromo compound of formula-XVII. The temperature of the reaction during cyanation is between 120-160°C, preferably between 135-155°C, most preferably between 145-150°C. The amount of copper (I) iodide used in the reaction is in the range of 0.2-2.0 moles per mole of bromo compound, preferably in the range of 0.5-1.0 moles per mole. The amount of copper (I) cyanide used in the reaction can be in the range of 1.0-2.5 moles per mole of bromo compound, preferably 1.5-2.0 moles per mole of bromo compound. The dipolar aprotic solvent used in the reaction is N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, N-methylpyrrolidone, etc, preferably N,N-dimethylformamide.
The pharmaceutically acceptable acid addition salts of escitalopram prepared by the above method can be made by conventional methods. The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1 Preparation of escitalopram from acetate salt of l-[3-(dimethylamino)propyl]~l-(4- fluorophenyl)-5-bromo-l,3-dihydroisobenzofuran of formula-XVH To a solution of the bromo compound (lOOgr) of formula-XVII in DMF (1000ml) under nitrogen atmosphere was added acetic acid (15.9gr) and stirred at RT for 30min. Copper (I) cyanide (47.4gr) and copper (I) iodide (25.2gr) were added to the reaction. The reaction mixture was slowly heated under nitrogen atmosphere to 145-150°C. After maintaining the reaction mixture at this temperature for 24hrs, HPLC of the reaction mixture showed the presence of starting material at <0.1% level. Reaction mixture was cooled to 25-30°C and poured into water (3000ml). After stirring for lhr, ethylenediamine (100ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring.
Toluene (300ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 200ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (200ml). The combined organic layer was washed with water. The organic layer was extracted with 5% aqueous oxalic acid (800ml and 400ml). The combined oxalic acid layer was treated with charcoal (lOgr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (1 x 300ml, 2 x 100ml) and the solvent distilled off to get 60gr (70%) of escitalopram base as colorless to light yellow colored oil. Purity by HPLC was found to be >98%. Bromo compound is less than 0.1%. Example 2 Preparation of escitalopram from oxalate salt of l-[3-(dimethylamino)propyI]-l-(4- fluorophenyI)-5-bromo-l,3-dihydroisobenzofuran of formuIa-XVH
To a stirred suspension of oxalate salt of the bromo compound (lOOgr) of formula-XVII in DMF (1000ml) under nitrogen atmosphere was added copper (I) cyanide (38.3gr) and copper (I) iodide (20.2gr). The reaction mixture was slowly heated under nitrogen atmosphere to I45-150°C. After maintaining the reaction mixture at this temperature for 36hrs, HPLC of the reaction mixture showed the presence of starting material at <0.1% level. Reaction mixture was cooled to 25-30°C and poured into water (3000ml). After stirring for lhr, ethylenediamine (100ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring.
Toluene (300ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 200ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (200ml). The combined organic layer was washed with water. The organic layer was extracted with 5% aqueous oxalic acid (600ml and 400ml). The combined aqueous layer was treated with charcoal (10gr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (1 x 300ml, 2 x 100ml) and the solvent distilled off to get 60gr (87%) of escitalopram base as colorless oil. Purity by HPLC was found to be >99%. Bromo compound is less than 0.1%. Example 3 Preparation of escitalopram from methanesulfonate salt of l-[3-(dimethylamino)- propyl]-l-(4-fluorophenyI)-5-bromo-l,3-dihydroisobenzofuran of formuIa-XVH
To a solution of the bromo compound (50gr) of formula-XVII in DMF (500ml) under nitrogen atmosphere was added methanesulfonic acid (12.7gr) and stirred at RT for 30min. Copper (I) cyanide (23.6gr) was added to the reaction. The reaction mixture was slowly heated under nitrogen atmosphere to 145-150°C. After maintaining the reaction mixture at this temperature for 36hrs, HPLC of the reaction mixture showed the presence of starting material at <0.1% level. Reaction mixture was cooled to 25-30°C and poured into water (1500ml). After stirring for lhr, ethylenediamine (50ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring.
Toluene (150ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 100ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (100ml). The combined organic layer was washed with water. The organic layer was extracted with 5% aqueous oxalic acid (400ml and 200ml). The combined aqueous layer was treated with charcoal (5gr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (1 x 100ml, 2 x 50ml) and the solvent distilled off to get 32.5gr (76%) of escitalopram base as colorless oil. Purity by HPLC was found to be 99%. Bromo compound is less than 0.1%. Example 4 Preparation of escitalopram from benzoate salt of l-[3-(dimethylamino)propyl]-l- (4-fluorophenyl)-5-bromo-l,3-dihydroisobenzofuran of formula-XVπ To a solution of the bromo compound (lOgr) of formula-XVII in DMF (100ml) under nitrogen atmosphere was added benzoic acid (3.2gr) and stirred at RT for 30min. Copper (I) cyanide (4.7gr) and copper (I) iodide (2.5gr) were added to the reaction. The reaction mixture was slowly heated under nitrogen atmosphere to 145-150°C. After maintaining the reaction mixture at this temperature for 33hrs, HPLC of the reaction mixture showed the presence of starting material at <0.1% level. Reaction mixture was cooled to 25-30°C and poured into water (300ml). After stirring for lhr, ethylenediamine (10ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring.
Toluene (50ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 50ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (50ml). The combined organic layer was washed with water. The organic layer was extracted with 5% aqueous oxalic acid (100ml and 50ml). The combined oxalic acid layer was treated with charcoal (l.Ogr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (1 x 50ml, 2 x 25ml) and the solvent distilled off to get 5.0gr (58%) of escitalopram base as colorless oil. Purity by HPLC was found to be >96%. Bromo compound is less than 0.1%. Example 5
Preparation of escitalopram from trifluoromethanesulfonate salt of l-[3-
(dimethylamino)propyl]-l-(4-fluorophenyI)-5-bromo-l,3-dihydroisobenzofuran of formula-XVII
To a solution of the bromo compound (lOgr) of formula-XVII in DMF (100ml) under nitrogen atmosphere was added trifluoromethanesulfonic acid (3.7gr) and stirred at RT for 30min. Copper (I) cyanide (4.8gr) was added to the reaction. The reaction mixture was slowly heated under nitrogen atmosphere to 145-150°C. After maintaining the reaction mixture at this temperature for 33hrs, HPLC of the reaction mixture showed the presence of starting material at <0.1% level. Reaction mixture was cooled to 25-30°C and poured into water (300ml). After stirring for lhr, ethylenediamine (10ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring.
Toluene (50ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 50ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (50ml). The combined organic layer was washed with water. The organic layer was extracted with 5% aqueous oxalic acid (100ml and 50ml). The combined oxalic acid layer was treated with charcoal (l.Ogr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (1 x 50ml, 2 x 25ml) and the solvent distilled off to get 5.0gr (58%) of escitalopram base as colorless oil. Purity by HPLC was found to be >96%. Bromo compound is less than 0.1%. Example 6 Preparation of escitalopram from perchlorate salt of l-[3-(dimethylamino)propyl]- l-(4-fluorophenyl)-5-bromo-l,3-dihydroisobenzofuran of formula-XVH
To a solution of the bromo compound (lOgr) of formula-XVII in toluene (100ml) was added 60% perchloric acid (4gr). The reaction mixture was heated to reflux temperature and water was removed using Dean-Stark apparatus. After the removal of water is over about 70ml of toluene is removed by ordinary distillation and DMF (120ml) added to the reaction mixture. Reaction mass was heated to 145°C while removing the traces of toluene. The reaction mixture was cooled to 30°C and treated with copper (I) cyanide (4.7gr). The reaction mixture was slowly heated under nitrogen atmosphere to 145- 150°C. After maintaining the reaction mixture at this temperature for 33hrs, HPLC of the reaction mixture showed the presence of starting material at <0.1% level. Reaction mixture was cooled to 25-30°C and poured into water (300ml). After stirring for lhr, ethylenediamine (10ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring.
Toluene (50ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 50ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (50ml). The combined organic layer was washed with water. The organic layer was extracted with 5% aqueous oxalic acid (100ml and 50ml). The combined oxalic acid layer was treated with charcoal (l.Ogr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (1 x 50ml, 2 x 25ml) and the solvent distilled off to get 6.0gr (70%) of escitalopram base as colorless oil. Purity by HPLC was found to be >98%. Bromo compound is less than 0.1%. Example 7 Preparation of dl-citalopram from oxalate salt of dI-l-[3-(dimethylamino)propyl]-l- (4-fluorophenyl)-5-bromo-l,3-dihydroisobenzofuran of formula-XVH To a stirred suspension of oxalate salt of the dl-bromo compound (lOOgr) of formula- XVII in DMF (1000ml) under nitrogen atmosphere was added copper (I) cyanide (38.3gr) and copper (I) iodide (20.2gr). The reaction mixture was slowly heated under nitrogen atmosphere to 145-150°C. After maintaining the reaction mixture at this temperature for 28hrs, HPLC of the reaction mixture showed the presence of starting material at <0.1% level. Reaction mixture was cooled to 25-30°C and poured into water (3000ml). After stirring for lhr, ethylenediamine (100ml) was slowly added to the reaction mixture and maintained for lhr under stirring.
Toluene (300ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid of hiflow bed. The hiflow bed was washed with 200ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (200ml). The combined organic layer was washed with water. The organic layer was extracted with 10% aqueous acetic acid (300ml and 200ml). The combined aqueous acetic acid layer was treated with charcoal (10gr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (1 x 300ml, 2 x 100ml) and the solvent distilled off to get 60gr (87%) of dl-citalopram base as white crystalline solid. Melting point is 92-93 °C. Purity by HPLC was found to be >99%. Bromo compound is less than 0.1%. Example 8 Preparation of escitalopram oxalate
Into a 500ml three-necked RB flask was charged 50gr of escitalopram base and 250ml of acetone. The solution was stirred for 5min and treated with 25gr of oxalic acid dihydrate. Crystals began to form soon after the addition of oxalic acid. The reaction mixture was stirred for 3hrs at room temperature and filtered the solid. The wet solid thus obtained was suspended in isopropyl alcohol (1300ml) and heated to reflux temperature. After maintaining for 30min a clear solution formed. Activated carbon (5gr) was added to the reaction mass filtered while hot. The filtrate was slowly allowed to reach 45-50°C and maintained at this temperature for 2hrs. The reaction mass was filtered and the cake washed with 50ml of isopropyl alcohol. Drying of the wet cake at 50°C for 2hrs gave the title compound as white crystalline solid (60gr). HPLC purity of the product is 99.8%. Advantages of the invention
1. The process is commercially applicable.
2. The process is simple and economical.
3. The process avoids purification step. 4. The escitalopram produced of high purity (99.5%) and high yield (75%).

Claims

We Claim:
1. An improved process for the preparation of high purity escitalopram of formula-I,
Figure imgf000020_0001
and its pharmaceutically acceptable salts which comprises: (i) Conversion of the bromo intermediate of formula-XVII
Figure imgf000020_0002
XVII into the acid addition salt of formula-XVIII
Figure imgf000020_0003
using an acid HX where X represents an organic or inorganic moiety (ii) Reacting the resulting acid addition salt with copper (I) cyanide with or without copper (I) iodide in dipolar aprotic solvent medium at a temperature in the range of 120-200°C. (iii) Quenching the resulting reaction mass into aqueous base. (iv) Extracting the crude escitalopram base into an organic solvent. (v) Extracting the escitalopram base into a weak aqueous organic acid . (vi) Neutralizing the resulting aqueous organic acid layer with a weak organic base. (vii) Extracting the pure escitalopram base into an ether or hydrocarbon solvent. (viii) Removing the solvent to get pure escitalopram and if desired . (ix) Preparing the pharmaceutically acceptable salts by conventional methods.
2. An improved process as claimed in claim 1 wherein the acid used in step (i) is selected from formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, salicylic acid, trifluoromethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, or mineral acids like HC1, HBr, H2SO4, perchloric acid, etc., preferably acetic acid, methanesulfonic acid, oxalic acid, or perchloric acid.
3. An improved process as claimed in claims 1 and 2 wherein the aprotic solvent used step (ii) is selected from N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, N- methylpyrrolidone, etc, preferably N,N-dimethylformamide.
4. An improved process as claimed in claims 1 to 3 wherein the amount of copper (I) cyanide used in step (ii) is 1.0-2.5moles per mole of the bromo compound used, preferably 1.5-2.0moles.
5. An improved process as claimed in claims 1 to 4 wherein the amount of copper (I) iodide used in step (ii) is 0.0-1. Omoles per mole of bromo compound used, preferably, 0.5moles.
6. An improved process as claimed in claims 1 to 5 wherein the temperature of reaction in step (ii) is preferably, 140-160°C, most preferably 145-150°C.
7. An improved process as claimed in claims 1 to 6 wherein the reaction in step (i) is carried out in an inert atmosphere, the inert gas used is selected from nitrogen or argon.
8. An improved process as claimed in claims 1 to 7 wherein the base used in step (iii) is selected from ammonia, ethylene diamine or, ethanolamine.
9. An improved process as claimed in claims 1 to 8 wherein the solvent used for extraction of crude escitalopram in step (iv) is selected from toluene, ethyl acetate, diisopropyl ether, methylene chloride, etc., preferably, toluene, ethyl acetate or diisopropyl ether.
10. An improved process as claimed in claims 1 to 9 wherein the weak organic acid used in step (v) is selected from acetic acid, propionic acid, formic acid, oxalic acid, preferably acetic acid or oxalic acid.
11. An improved process as claimed in claim 1 to 10 wherein the amount of weak organic acid used in step (v) ranges between 0.8-1.5moles per mole of bromo compound used in the reaction, preferably 1.0-1.2moles
12. An improved process as claimed in claims 1 to 11 wherein the weak base used in step (vi) is selected from ammonia, methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, etc, preferably ammonia.
13. An improved process as claimed in claims 1 to 12 wherein the hydrocarbon solvent, which is employed for the extraction in step (vii), is selected from toluene, cyclohexane, heptane, preferably, toluene.
14. An improved process as claimed in claim 1 to 13 wherein the ether solvent used during the extraction of pure escitalopram is selected from diethyl ether, diisopropyl ether, methyl t-buty ether, etc., diisopropyl ether.
15. An improved process for the preparation of escitalopram base or dl-citalopram base substantially as described in Examples 1 to 7.
16. An improved process for the preparation of escitalopram oxalate substantially as described in Example 8.
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