Title of Invention

"PROCESS FOR THE ISOLATION OF HIGH PURITY CRYSTALLINE CITALOPRAM BASE"

Abstract

A method is provided for the isolation of high purity crystalline citalopram (l-[3-dimethylamino) propyl]- l-(4-fluorophenyl )-1,3-dihydro-5-isobenzofurancarbonitrile) base directly from the alkylation reaction mixture of 5-cyanophthalane with N,N-dimethylaminopropylchloride in a polar aprotic solvent using a strong base. The method comprises: (a) diluting the reaction mixture with ice cold water and extracting the resulting mixture with a water-immiscible organic solvent; (b) re-extracting the water-immiscible organic solvent extract with an aqueous acid; (c) diluting the aqueous acid extract with a substantially equal volume of a water miscible organic solvent, based on the volume of water in the aqueous acid extract; (d) adjusting the pH to basic with an inorganic base to precipitate free crystalline base, and (e) further isolating the precipitated free crystalline base by filtration.

Full Text

PROCESS FOR THE ISOLATION OF HIGH PURITY CRYSTALLINE CITALOPRAM BASE This invention relates to a process for preparing citalopram (1-[3-dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-/sobenzofurancarbonitrile), in particular to the isolation of high purity crystalline citalopram base directly from the alkylation reaction mixture of 5-cyanophthalane (1 -(4'-fluorophenyl)-1,3-dihydro/sobenzofuran-5-carbonitrile) with N,N-dimethylaminopropylchloride in a polar aprotic solvent using a strong base. Background of the Invention: Citalopram and its pharmaceutically acceptable acid addition salts, such as its hydrogen bromide salt (Formula (i)) as described in US-A-4,-135,193,-are anti- depressant drugs with few side effects. (Formula Removed) Various processes for the preparation of citalopram have been described in the prior art. For example, US-A-4,136,193 describes the alkylation of cyanophthalane with 3-dimethylaminopropylchloride, using sodium hydride as a base in a dimethylsulphoxide (DMSO) medium (Scheme - 1). The reaction mixture is poured into ice water and extracted with ether. Then, after standard acid-base work-up, crude citalopram base is isolated as an oil. The isolated oil is purified by high vacuum distillation, (0.03 mm at 175-180°C) and then converted to the hydrobromide salt. Scheme -1 (Scheme Removed) Another process, as described in WO-A-98/19511, is the alkylation of cyanophthalane with 3-dimethylaminopropylchloride in the presence of a strong base (such as n-butyl lithium) and diisopropylamine in a dimethoxyethane medium at -50°C (Scheme - 2). After completion of the reaction, the reaction mixture is poured into ice water and extracted with toluene. After standard acid-base work-up using toluene as solvent, citalopram base is isolated as an oil. The oily base is then converted to acid addition salts such as citalopram hydrobromide and hydrochloride by conventional methods. Scheme - 2 (Scheme Removed) A drawback of the above two processes is that the citalopram base is isolated as an oil. Purification of citalopram oily base is carried out by high vacuum distillation (0.03mm) at 175-181 °C. Achieving such a very high vacuum at plant level is difficult and hence the process described is not easily transferable to the commercial scale. Apart from these constraints, citalopram base having a cyano group at the 5th position of the bicyclic ring system may decompose during high vacuum distillation at high temperature to form citalopram carboxamide as an impurity, resulting in poor quality and yield. In yet another process, citalopram is made as described in US-A-4,650,884. The process involves the successive Grignard reaction of 5-cyanophthalide with 4-fluorophenylmagnesiumbromide and N.N-dimethylaminopropylmagnesiumchloride and the cyclisation of the resulting diol to obtain citalopram base as an oil (Scheme-3). The oily base is converted to the hydrobromide salt using anhydrous hydrogen bromide gas in acetone medium. Due to the poor quality of the oily base, repeated crystallization of the hydrobromide was necessary to obtain a pharmaceutically acceptable quality of citalopram hydrobromide. Scheme-3 (Scheme Removed) Using the sane strategy, citalopram base may be made as described in CA-A-1,339,452 lequivalent to US-A-4,943,590, EP-A-347066 & GB-A-8,814,057 Scheme-3]. The racemic diol base, as described in the patent, is dissolved in dichloromethane. Triethylamine and methane sulphonyl chloride are added over a period of 1 hour. The reaction mixture is then washed twice with 0.1M sodium hydroxide solution, the organic phase is separated and dried over anhydrous magnesium sulphate followed by solvent concentration under reduced pressure, and the citalopram base is isolated as a crystalline solid. For the first time, citalopram base has been reported as a crystalline solid. However, no physical data are described here [EP-A-347066]. The solid base is converted to the hydrobromide salt using anhydrous hydrogen bromide gas in acetone medium. DE-A-20 007 303 discloses yet another process for the isolation of citalopram base, as a solid, from citalopram hydrobromide. However, the process for making citalopram hydrobromide is not described. The isolated crystalline base is then converted into the desired salt. According to the process described here, pure citalopram hydrobromide is dissolved in 5 volumes of water and the pH is adjusted to about 10 with 6N sodium hydroxide. Citalopram base is then extracted into a non-polar organic solvent, such as toluene. The toluene is distilled off under reduced pressure and the resulting residue is triturated with n-heptane to precipitate citalopram base as a solid. The solid is then filtered to produce crystalline citalopram base. The main disadvantage of this process is that citalopram hydrobromide has to be made first from the crude oily base isolated from the prior art process and then converted back to solid citalopram base. Then, the solid base is again converted to its corresponding hydrobromide salt Thus, the process involves multiple operations which are tedious and time consuming. In addition, prolonged heating of citalopram base may increase the carboxamide imparity; resulting in poor quality citaiopram. Summary of the Invention: The present invention provides a process for the isolation of crystalline citalopram base of formula (1) from the alkylation reaction mixture of 1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (5-cyanophthalane) with N,N-dimethylaminopropylchloride in a polar aprotic solvent medium, such as dimethylsulfoxide (DMSO), in the presence of a strong base, such as potassium tert-butoxide or sodium hydride, which comprises: a) diluting the reaction mixture with ice cold water and extracting the resulting mixture with a water-immiscible organic solvent; b) re-extracting the water-immiscible organic solvent extract with an aqueous acid; c) diluting the aqueous acid extract with a substantially equal volume of a water miscible organic solvent, based on the volume of water in the aqueous acid extract; d) adjusting the pH to basic with an inorganic base to precipitate free crystalline base, and e) further isolating the precipitated free crystalline base by filtration. Detailed Description of the Invention: The invention provides a simple and efficient process for the isolation of highly pure crystalline citalopram base directly from the alkylation reaction mixture of 5-cyanophthalane with N,N-dimethylaminopropylchloride in a polar aprotic solvent, preferably DMSO, using a strong base. According to the present invention, the alkylation of 1-(4-fluorophenyl)-1,3- dihydroisobenzofuran-5-carbonitrile (5-cyanophthalane) with N,N- dimethylaminopropylchloride may be carried out following prior art procedure, and preferably as described in US-A-4,136,193. However, according to the process described in US-A-4,136,193, after the completion of the alkylating reaction, the reaction mass is diluted with ice cold water and the aqueous layer is extracted into ether. The ether layer is then extracted with 20% aqueous acetic acid. The pH of the aqueous acidic layer is then adjusted to alkaline, e.g. pH 10-11, with sodium hydroxide and the citalopram base extracted into ether. The ether layer is then concentrated under reduced pressure to obtain citalopram base oil. Scheme - 4 (Scheme Removed) By contrast, according to the present invention (Scheme-4), after the completion of the alkylating reaction, the reaction mass is diluted with ice cold water and extracted with a suitable water immiscible organic solvent, such as toluene, methylenedichloride, chloroform, ethylacetate and diethyl ether, but most preferred is toluene. The toluene layer is then taken for an acid - base work up, as follows. The acid work-up comprises extracting the organic (preferably, toluene) layer with an aqueous acid, for example a mineral acid such as hydrochloric or hydrobromic acid, or, preferably, a weak organic acid such as formic, oxalic or acetic acid. Most preferred is to use 20% aqueous acetic acid. To the above aqueous acidic extract, is added a substantially equal volume of a water-miscibie solvent, based on the volume of water in the aqueous acid extract. By substantialiy equat in this context is meant that the water miscible solvent is added in a ratio (v/v), to water in the aqueous acid extract, in the range from 0.8:1 to 1.2:1, preferably in the range from 0.9:1 to 1.1:1, most preferably 1:1. Suitable water-miscible solvents comprise: alcohols such as methanol, ethanol and isopropanol; ketones such as acetone; dimethylformamide (DMF); and/or dimethylsulphoxide (DMSO), especially isopropyialcohol (IPA)). Then, the pH of the mixture is carefully adjusted in order to precipitate the crystalline free base. Preferably, the pH is adjusted to about 8.0 - 9.5, more preferably to about 8.5 - 9.0, since, at higher pH, impurities start precipitating and, at lower pH, the yield is lower. Suitable bases for adjusting the pH include aqueous ammonia, sodium hydroxide, potassium hydroxide and sodium or potassium carbonates, but preferably a mild base such as aqueous ammonia is used. The precipitation reaction is preferably carried out at below ambient temperature (i.e. below about 25 °C), more preferably between 10-15 °C; at higher temperatures, yield is reduced because of the higher solubility and, at lower temperatures, impurities also precipitate. Preferably, the mixture is then stirred, for example for additional 3-5 hours, to precipitate citalopram completely. The crystalline citalopram base is then preferably filtered, and preferably also washed with a cold aqueous water-miscible solvent, preferably IPA, and optionally may be washed with a washing agent to remove the water-miscible solvent, such as with a hydrocarbon, e.g. a C5-7 alkane or cycloalkane, preferably hexane. By this method, high purity crystalline citalopram base can be isolated in a single step directly from the alkylation reaction mixture, i.e. the citalopram base can be isolated in crystalline form without prior isolation of crude oily base or crude hydrobromide salt. The crystalline citalopram base can then be converted to corresponding acid addition salts such as citalopram hydrobromide and citalopram hydrochloride by conventional prior art procedure, preferably using aqueous hydrobromic acid or hydrochloric acid in a alcoholic solvent medium. The present invention is further illustrated by the following non-limiting examples. In each, the citalopram base was characterized by IR, 1H-NMR, HPLC and melting point. Purity was determined by HPLC and found to be in excess of 98%. EXAMPLES In the Examples, 1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (5-cyanophthalane) is prepared by using commercially available 5-bromophthalide as per the process described in US-A-4,136,193. However, it will be appreciated that commercially available 5-cyanophthalide could instead be used, as per the process described in WOA-98/19511. Example 1: Isolation of High Purity Crystalline R.S-Citalopram using Potassium tertiary Butoxide as a Base (a) 72 grams of potassium tertiary butoxide are dissolved in 575ml of dimethylsulphoxide at 60-70°C under a nitrogen atmosphere. To the resulting solution of potassium salt of dimethylsulphoxide, 96 g of 1-(4'-fluorophenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile, dissolved in 150ml of dimethylsulphoxide, is added dropwise over a period of 10 min at 25-30°C. The mixture is then stirred for an additional 10 min at 25-30°C. 53 g of 3-dimethylaminopropylchloride in 25 ml of dimethylsulphoxide are added quickly and the reaction mixture is then heated to 40°C and maintained for 50 min. The reaction mixture is then poured into ice-water and extracted with toluene. The toluene phase is extracted with 200ml of 20% aqueous acetic acid {40ml acetic acid and 160ml water). (b) Then, the acetic acid solution is diluted with 160ml of isopropyl alcohol, cooled to 5-10°C and the pH is then adjusted to 8.5-9.0 using aqueous ammonia (85ml) whilst maintaining the temperature between 5-10°C for 4 hours. The crystalline citalopram base thus produced is men filtered and washed with cold aqueous /sopropyl alcohol (20%, 100ml) followed by washing with 100ml hexane. The filtrate is dried at 40°C under a vacuum of 500-600mm Hg until at constant weight. Yield: 95-97g Purity by HPLC: 99.5% Highest single impurity: 0.08% Melting point: 89-91 °C As shown by the experimental data, a water: isopropyl alcohol ratio of 1:1 has given very good yield and purity of citalopram base. The details of experimental data with solvents other than isopropyl alcohol/water are given in Table -1 Table -1 (Table Removed) The salient feature of the process of Example 1 is the isolation of high purity crystalline citalopram base directly from the reaction mixture. Example 2: Isolation of High Purity Crystalline R,S-Citalopram using Sodium Hydride as a Base. The procedure of Example 1 is followed, except 72g of potassium t-butoxide in 575ml. DMSO is replaced by 21 grams of sodium hydride (60% in mineral oil) dissolved in 900ml of dimethyl sulphoxide. Yield: 92-94g HPLC purity: 99.32% Highest single impurity: 0.12% Melting point: 89-91 °C The details of experimental data with solvents other than /sopropyl alcohol/water are given in the Table - 2 Table - 2 (Table Removed) The above data show improved yield and purity over corresponding prior art processes. We Claim: 1. A process for the isolation of crystalline citalopram (l-[3-dimethylamino)propyl]-l-(4-fluorophenyl)-l,3-dihydro-5-isobenzofurancarbonitrile) base of formula (1) (Formula Removed) characterised in that the isolation is from the alkylation reaction mixture of l-(4'-fluorophenyl)-l,3- dihydroisobenzofuran-5-carbonitrile (cyanophthalane) of formula (2) (Formula Removed) with N,N-dimethylaminopropylchloride in a polar aprotic solvent medium in the presence of a strong base, which comprises: a) diluting the reaction mixture with ice cold water and extracting the resulting mixture with a water-immiscible organic solvent; b) re-extracting the water-immiscible organic solvent extract with an aqueous acid; c) diluting the aqueous acid extract with a substantially equal volume of a water miscible organic solvent, based on the volume of water in the aqueous acid extract; d) adjusting the pH to basic with an inorganic base to precipitate free crystalline base, and e) further isolating the precipitated free crystalline base by filtration. 2. The process as claimed in claim 1, wherein, the water-immiscible organic solvent is selected from methylenedichloride (MDC), chloroform (CHCl3), toluene, diethyl ether, ethyl acetate, and mixtures thereof. 3. The process as claimed in claim 2, wherein, the water-immiscible organic solvent is toluene. 4. The process as claimed in claim 1, wherein, the aqueous acid is a mineral acid selected from hydrochloric acid and hydrobromic acid, or a weak organic acid selected from formic acid, acetic acid and oxalic acid, or a mixture thereof. 5. The process as claimed in claim 4, wherein, the aqueous acid is acetic acid. 6. The process as claimed in claim 5, wherein, the acetic acid is 20% v/v in water. 7. The process as claimed in claim 1, wherein, the water miscible organic solvent is selected from methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, dimethylformamide (DMF) and dimethylsulphoxide (DMSO), and mixtures thereof. 8. The process as claimed in claim 7, wherein, the water miscible organic solvent is isopropyl alcohol. 9. The process as claimed in claim 1, wherein, the inorganic base is selected from sodium carbonate or hydroxide, potassium carbonate or hydroxide, and liquor ammonia. 10. The process as claimed in claim 1, wherein, the inorganic base is liquor ammonia. 11. The process as claimed in claim 1, wherein, the pH is adjusted to 8.5-9.5 preferably at a temperature between 10-15°C. 12. The process as claimed in claim 1, wherein, if desired (g) the isolated free crystalline base is washed with cold aqueous isopropyl alcohol. 13. The process as claimed in claim 13, wherein if desired (h) the isolated free crystalline base is washed with hexane to remove the isopropyl alcohol. 14. The process as claimed in claim 13 or claim 14, wherein if desired (i) the washed isolated free crystalline base is dried.

Documents:

2876-DEL-2004-Correspondence Others-(29-08-2011).pdf

2876-DELNP-2004-Abstract-(09-12-2010).pdf

2876-delnp-2004-abstract.pdf

2876-delnp-2004-assignment.pdf

2876-DELNP-2004-Claims-(08-11-2011).pdf

2876-DELNP-2004-Claims-(09-12-2010).pdf

2876-delnp-2004-claims.pdf

2876-DELNP-2004-Correspondence Others-(04-07-2011).pdf

2876-DELNP-2004-Correspondence Others-(08-11-2011).pdf

2876-delnp-2004-Correspondence Others-(20-06-2011).pdf

2876-delnp-2004-Correspondence Others-(23-06-2011).pdf

2876-DELNP-2004-Correspondence Others-(31-05-2011).pdf

2876-DELNP-2004-Correspondence-Others-(09-12-2010)-.pdf

2876-delnp-2004-Correspondence-Others-(09-12-2010).pdf

2876-delnp-2004-correspondence-others.pdf

2876-DELNP-2004-Description (Complete)-(09-12-2010).pdf

2876-delnp-2004-description (complete).pdf

2876-delnp-2004-form-1.pdf

2876-delnp-2004-form-18.pdf

2876-DELNP-2004-Form-2-(09-12-2010).pdf

2876-delnp-2004-form-2.pdf

2876-delnp-2004-form-26.pdf

2876-delnp-2004-Form-3-(09-12-2010)-.pdf

2876-DELNP-2004-Form-3-(09-12-2010).pdf

2876-delnp-2004-form-3.pdf

2876-delnp-2004-form-5.pdf

2876-delnp-2004-pct-306.pdf

2876-delnp-2004-pct-409.pdf

2876-delnp-2004-pct-416.pdf

2876-delnp-2004-Petition 137-(09-12-2010).pdf