Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF CITALOPRAM

Abstract

'..- The present invention discloses an improved process for the preparation of citalopram hydrobromide of formula-I from citalopram base of formula-III without isolating and crystallizing the latter. The citalopram base of formula-III is prepared according to earlier known method from the isobenzofuran of formula-II. Accordingly, the organic layer containing citalopram base is directly treated with aqueous hydrobromic acid to get the citalopram hydrobromide.

Full Text

INTRODUCTION: The present invention relates to an improved process for the preparation of citalopram hydrobromide. Citalopram hydrobromide [l-(3«dimethylaminopropyl)-l-(41-fluoro-phenyl)-l,3-dihydro~isobenzoiuran-5-carbonitrile] is having the formula-I given below is prepared from citalopram base of formula-Ill without isolating and crystallizing the latter. Organic layer containing citalopram base is directly converted into its hydrobromide salt by treating with hydrobromic acid. Citalopram base of formula-Ill is prepared from the Citalopram hydrobromide is a well-known antidepressant drug available in the market. It is a selective, centrally active serotonine (5-hydroxytrypamine, 5-HT) re-uptake inhibitor, accordingly having antidepressant activity. BACKGROUND OF THE INVENTION: The antidepressant activity of citalopram has been reported in several publications, eg. H. Dufour, et al, Int. Clin. Psychopharmacol. 2, 225 (1987), L, Timmerman, et al, ibid, 239, and A. Gravem, Acta Psychiatr, Scand., 75, 478 (1987). The process for the preparation of antidepressant citalopram hydrobromide and its pharmaceutical properties were first disclosed in DE Patent no. 2, 657, 013 (1977) corresponding to US Patent no. 4, 136, 193 (1979). Subsequently it was also disclosed in GB patent no.l, 526, 331 (1978). The basic process for the preparation of citalopram hydrobromide 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 formula-IV is reacted with p-fluorophenyl-magnesium bromide to get a benzophenone derivative of formula-V. This benzophenone derivative is reacted with 3-(dimethylamino)propylmagnesium chloride to get the dihydroxy compound of formula-VI. Cyclization with an acid catalyst resulted in the formation of phthalane derivative of formula-VTL This bromophthalane derivative is reacted with copper cyanide to get the citalopram base of formula-Ill. This base was converted to its HBr salt of formula-I by conventional methods. In the second route, 5-bromophthalide of formula-IV is reacted with p-fluorophenyl-magnesium bromide to get the corresponding benzophenone derivative of formula-V. This compound is reduced with lithium aluminum hydride to get the dihydroxy compound of formula-VIII, which is cyclized with an acid catalyst to get the phthalane derivative of formula-! The bromo group is replaced with a cyano group and alkylated with the required side chain to get the citalopram base. This base was converted to its HBr salt by conventional methods. Bogeso (EP patent no 171, 943, corresponding to US patent no 4, 650, 884) has indicated that the methods described in the above patents for the preparation of citalopram hydrobromide possess some problems in the scale-up to commercial production. In an attempt to develop a shorter route for the preparation of citalopram hydrobromide and to avoid the risk involved in the metalation step used previously, Bogeso started with 5-cyanophthalide of formula-IX and surprisingly found that cyano group survived the cyclization step where 70% sulfuric acid was used at 80°C temperature (Scheme-3). The citalopram base thus obtained was converted to its HBr salt in acetone medium by Further processes have been disclosed in international patent application nos. WO 98/019511, WO 98/019512, WO 98/019513, WO 99/030548, WO 00/011926, WO 00/013648, and WO 00/023431. International patent application no WO 98/019511 discloses a process for the manufacture of citalopram hydrobromide wherein a compound of formula-X was reduced with sodium borohydride to get a compound of the formula-XII. However, yield is only 40% and large quantity (-50 times) of alcohol was used. This compound of formula-XII is subjected to ring closure and the resulting 5-substituted dihydroisobenzofuran derivative is converted to the corresponding 5-cyano derivative and alkylated with (3-dimethylamino)propyl chloride to obtain citalopram base. WO 98/019512 and WO 98/019513 relate to methods wherein a 5-amino-, 5-carboxy-? or 5-(sec-aminocarbonyl)phthalide is subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e. citalopram base. International patent application no 99/030548 discloses a process for the preparation of citalopram wherein cyano group was introduced from the corresponding 5-aldehyde analogue of citalopram. International patent application no WO 00/011926 and WO 00/013648 disclose an improved process for the preparation of citalopram hydrobromide wherein 5-halogen (CI or Br) analogue of citalopram is activated by using palladium or nickel complex catalyst to introduce the corresponding cyano group present in citalopram. International patent application no WO 00/023431 discloses a process for introduction of cyano group present in citalopram via the corresponding 5-oxazolyl analogue of citalopram. A major drawback in the scale up for the commercial production of citalopram hydrobromide by following the original patent process (disclosed in US patent no.4, 136, 193) is removal of impurities present in citalopram hydrobromide to an acceptable level of pharmaceutical quality. Methods followed to improve the quality of citalopram hydrobromide are either by chemical purification (via acid addition salt wherever applicable) or by high vacuum distillation. Chemical method does not seem to remove the impurities up to the acceptable level because some of the impurities like compound of formula-VI, formula-VII or formula-XIII have similar salt formation properties with an acid. All the intermediates involved in the original patent for the preparation of citalopram hydrobromide have very high boiling point (~200°C at Second route of the original patent for preparation of citalopram hydrobromide involves purification of intermediate compounds of the formulae-I and II by high vacuum distillation (180-200°C at commercial production. Also, this route involves handling of a costly and hazardous reagent, lithium aluminum hydride. Third and simplified route (disclosed in EP Patent no 171,943) for the preparation of citalopram hydrobromide involves the introduction of 5-cyano group present in citalopram hydrobromide at the beginning itself The citalopram base prepared by this method is extracted into toluene at pH 10.0 and the extracted product was twice passed through a bed of silica gel (weight equal to product). After treatment with charcoal, hydrogen bromide gas is introduced into the acetone - toluene solution of citalopram base and made acidic until pH 3.0. pH is raised to 7.0 by adding some of the above citalopram base containing solution. The crude citalopram hydrobromide thus obtained was recrystallized from water after charcoal treatment. The crystals from the first recrystallization were dissolved in methanol/sopropyl alcohol medium and recrystallized after charcoal treatment. The material from this 2nd recrystallization is dissolved in a mixture of methanol and acetone and filtered with charcoal and recrystallized to get the pure citalopram hydrobromide with a melting point of 185-186°C. After three recrystallizations a loss of 23-26% was reported in this process. Also, the chemical purity of the final crystallization material is not mentioned. Six solvents (a total of 46-47 liters per kg of citalopram hydrobromide) were used involving three recrystallizations and it took more than four days time. In the above said process, controlling the molar quantity of HBr gas seems to be difficult. So readjusting of pH with spare citalopram base solution is not an appropriate method for commercial scale operations. Also, filtering citalopram base through silica gel column and three recrystallization techniques for purification of the hydrobromide salt with six solvents over a period of 4 - 5 days is not an economically viable process for plant scale operations. As a mixture of solvents were used in recrystallization technique, their reuse is again a tedious and difficult process. Such a process needs to be improved or modified before using it for commercial production of citalopram hydrobromide for operational feasibility. The process for citalopram hydrobromide salt described in EP Patent no 171, 943 is not suitable for commercial scale as mentioned above. Citalopram hydrobromide has become a well-known antidepressant drug that has been now in the market for a considerable amount of time and has proved to be a valuable antidepressant drug with few side effects. Therefore there is a need to develop an improved process for its production that can be employed commercially. Especially such an improved process would be welcome considering the difficulties associated with the commercial application of the above-mentioned processes for the preparation of citalopram hydrobromide. Keeping this aspect into consideration, we aimed to develop a simple and economical process for commercial production of citalopram hydrobromide. Recently we have filed an application for patent in India (Application No 162/MAS/2001) describing an improved process for the preparation of pure citalopram base and its hydrobromide salt. This process is the improvement of the process shown in scheme-II above. In this patent application crude citalopram base obtained from the reaction was extracted into an aqueous organic acid and treated with a weak organic base and the citalopram base is isolated at controlled pH. By this process we could get citalopram base of >99% purity. A detailed process for converting this base into its hydrobromide salt was also described in this patent application. In that process the base was converted to its hydrobromide salt in aqueous medium using aqueous hydrobromic acid as a source of hydrogen bromide. This is a major improvement if one considers the earlier known process using molar and controlled quantity of hydrogren bromide gas, which is difficult to get commercially. Statement of invention: During our sustained research to develop a simpler and cheaper process for the preparation of citalopram hydrobromide of pharmaceutical grade which can also applicable for its commercial production, we observed that pure citalopram base present in organic solvent (prepared according to the process described and claimed in our above said co-pending Indian patent application) has some impurities such as amide impurity, acid impurity, acetyl. Normally these impurities can be eliminated if one isolates citalopram base by crystallization technique (this technique is described in our above said co-pending Indian patent application). However, we observed that due to their good solubility in aqueous hydrobromic acid medium they could also be eliminated during citalopratn hydrobromide formation. By doing so one can avoid the crystallization and isolation of pure citalopratn base. Also, during the crystallization and isolation process some of the citalopram base is lost due to its solubility in the medium of crystallization. This loss is much less during the crystallization of citalopram hydrobromide from aqueous hydrobromic acid medium. Therefore, the overall yield of citalopram hydrobromide has increased and the process became simpler. Identification of the solubility of impurities in aqueous hydrobromic acid medium during the formation of citalopram hydrobromide is our inventive step and has commercial value. Accordingly the main objective of the present invention is to provide an improved process for the preparation of citalopram hydrobromide of formula-I, which is useful for commercial application. Another objective of the present invention is to provide an improved process for the preparation of citalopram hydrobromide of formula-I, which is useful for commercial application which avoids the isolation of citalopram base of formula-Ill from the organic solvent in the process shown in scheme-II. Yet another objective of the present invention is to provide an improved process for the preparation of citalopram hydrobromide of formula-I, which is useful for commercial application, which is simple and economical. Accordingly the present invention provides an improved process for the preparation of which comprises: (ii) Extracting the crude citalopram base of formula-Ill into an organic solvent (iii) Extracting the crude citalopram base from the organic solvent obtained in step (ii) into dilute aqueous organic acid thereby forming an organic layer and an aqueous organic acid layer and separating the layers by known methods, (iv) Adjusting the pH of the resulting aqueous organic acid layer to 8.0 to 9.0 using aqueous organic base to liberate pure citalopram base (v) Extracting the liberated pure citalopram base into ether or an aromatic solvent (vi) Extracting the pure citalopram base into aqueous hydrobromic acid to yield citalopram hydrobromide (vii) Isolating the citalopram hydrobromide from water and (viii) Recrystallizing the citalopram hydrobromide from aqueous isopropanol or methanol to get pharmaceutical^ acceptable grade citalopram hydrobromide. The strong base used in step (i) may be sodium hydride or potassium t-butoxide, preferably sodium hydride. The aromatic solvent used in step (ii) may be selected from benzene, toluene, xylene, etc., preferably toluene. The organic acid used in step (iii) may be selected from acetic acid, propionic acid, succinic acid, oxalic acid, etc., preferably acetic acid or oxalic acid. The organic base used in step (iv) may be selected from ammonia, monomethyl amine, dimethylamine, triethylamine, etc., preferably ammonia. The ether solvent used in step (v) may be selected from diethyl ether, di-isoporpyl ether, t-butyl methyl ether, etc.; preferably, diethyl ether or di-isopropyl ether and the aromatic solvent may be selected from, benzene, toluene, xylene, etc., preferably toluene. The aqueous solvent used in step (viii) is selected from methanol or isopropanol, preferably isopropanol may have water in 5-50%, preferably 5-15%. 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 l-(3-DimethyIaminopropyl)-l-(4,-fluorophenyI)-l,3-dihydroiso-benzofuran-5-carbonitrile hydrobromide (citalopram hydrobromide) of formula-I: A solution of dimsyl sodium in DMSO was prepared by adding 22gr of 50% sodium hydride in paraffin oil to DMSO (1000ml) at 20-25°C and slowly heating to 60-65°C under nitrogen. To this solution kept at a temperature in the range of 20-25°C, was added a solution of l-(4-fluorophenyl)-5-cyanophthalan (lOOgr) in DMSO (200ml) slowly in 2-3hrs. After maintaining for 15-20min, a solution of 3-(dimethylamino)propyl chloride (56gr) in toluene (120ml) was slowly added keeping the temperature between 25-30°C. After the addition is over, reaction mixture was maintained at this temperature for 30min and decomposed by adding 50ml of methanol. The reaction mixture was poured into 3000ml of water and extracted with 1000ml of toluene. Aqueous layer was again extracted with 500ml of toluene to obtain crude citalopram base. The combined organic layer containing crude citalopram base was extracted with 2 x 1000ml of 20% aqueous acetic acid. The combined aqueous acetic acid layer was treated with 20gr of active carbgj^fiKered and the filtrate neutralized with aqueous ammonia (25%) to get the pH 6r8.5-9.0. -^fter the pH adjustment, 500ml of toluene was added and stirred for 15min. Toluene layer was separated and the aqueous layer extracted with 2 x 200ml of toluene. The combined toluene layer was treated with carbon (lOgr) and filtered. The toluene solution was treated with aqueous hydrobromic acid (60ml of cone. HBr dissolved in 200ml of water) and kept under stirring for Ihr. Aqueous layer was separated and kept under stirring for lOhrs. The crystalline citalopram hydrobromide thus formed was isolated by filtration and dried at 60°C to get dry citalopram hydrobromide. This material was recrystallized from aqueous isopropyl alcohol (300ml isopropyl alcohol and 30ml water) to get pure citalopram hydrobromide (115gr). Purity by HPLC is 99.9%. Example 2 Preparation of l-(3-Dimethylaminopropyl)-l-(4,-fluorophenyI)-l,3-dihydroiso-benzofuran-5-carbonitriIe hydrobromide (citalopram hydrobromide) of formula-l To a stirred suspension of 22gr of sodium hydride (50-55% in paraffin oil) in 1000ml of dimethyl sulfoxide at 20-25°C was added a solution of l-(4-fluorophenyl)~5-cyanophthalan (lOOgr) in dimethyl sulfoxide (200ml) slowly in 2-3 hrs. After maintaining for 15-20min, a solution of 3-(dimethylamino)propylchloride (56gr) in toluene (120ml) was slowly added keeping the temperature between 25-3 0°C. After the addition is over, reaction mixture was maintained at this temperature for 30min and decomposed by adding 50ml of methanol. The reaction mixture was poured into 3000ml of water and extracted with 1000ml of toluene. Aqueous layer was again extracted with 500ml of toluene to obtain crude citalopram base. The combined toluene layer was washed with water (500ml) to get crude citalopram base. The above toluene layer containing crude citalopram was extracted with 2 x 1000ml of 20% aqueous acetic acid. The combined aqueous acetic acid layer was treated with carbon (lOgr) and neutralized with aqueous ammonia (25% w/v) to get the pH of 8.5-9.0. After the pH adjustment, product was extracted into 3 x 500ml of toluene. The combined toluene layer was treated with carbon (lOgr) and filtered. The filtrate was taken into a 3L three-necked RB flask and added dilute hydrobromic acid (90ml of cone, hydrobromic acid dissolved in 250ml water) keeping the temperature 25-30°C. After stirring for lhr toluene layer was separated from the reaction mixture and the aqueous layer kept under stirring for lOhr. The reaction mixture was cooled to 10°C and maintained for 2hr before filtration. The wet cake of citalopram hydrobromide thus obtained was recrystallized from aqueous isopropanol (350ml isopropanol and 35ml water) to get pure citalopram hydrobromide (135gr). Purity by HPLC is 99.9%. Advantages of the invention: 1. In the present process of invention citalopram base is not isolated & dried and is used directly thereby making the process simpler and economical. 2. The process avoids the wastage of about 5-7% citalopram base (according to our earlier isolation process) which results in higher yields of citalopram hydrobromide. with a strong base in dimethyl sulfoxide medium followed by the addition of 3-(dimethylamino)propyl chloride at 20°-25°C to form the crude Citalopram base of formula-Ill, (ii) Extracting the crude citalopram base of formula-Ill from reaction mass into aromatic solvent (iii) Extracting the crude citalopram base from aromatic solvent medium into dilute aqueous organic acid medium (iv) Adjusting the pH of the resulting aqueous organic acid layer to 8.0 to 9.0 using aqueous organic base to liberate pure citalopram base (v) Extracting the liberated pure citalopram base into ether or an aromatic solvent (vi) Extracting the pure citalopram base present in ether or aromatic solvent into dilute hydrobromic acid medium (vii) Isolating the citalopram hydrobromide by Alteration after crystallization from aqueous hydrobromic acid ^———-^^ (viii) Recrystallizing the citalopram base intc/aqueous alcoholic medium. 2. A process as claimed in claim 1 wherein the strong base used in step (i) is selected from sodium hydride, potassium t-butoxide, preferably sodium hydride. 5. A process as claimed in claims 1 & 2 wherein the aromatic solvent used in the step (ii) s selected from benzene, toluene, xylene etc., preferably toluene. k A process as claimed in claims 1 to 3 wherein the organic acid used in step (iii) is selected from acetic acid, propionic acid, succinic acid or oxalic acid, preferably acetic icid or oxalic acid. 5. A process as claimed in claims 1 to 4 wherein the organic base used in step (iv) is selected from ammonia, monomethyl amine, dimethylamine, triethylamine, preferably ammonia. 6. A process as claimed in claims 1 to 5 wherein the ether solvent used in step (v) is selected from diethyl ether, di-isoporpyl ether, t-butyl methyl ether, etc., preferably, diethyl ether or isopropyl ether. 7. A process as claimed in claims 1 to 6 wherein the aromatic solvent used in step (v) is selected from, benzene, toluene, xylene, etc., preferably toluene. 8. A process as claimed in claims 1 to 7 wherein the alcoholic solvent used in step (viii) is selected from methanol or isopropanol, preferably isopropanol. 9. A process for the preparation of citalopram hydrobromide of formula-I substantially as described in Examples 1 and 2.

Documents:

331-mas-2003- abstract.pdf

331-mas-2003- claims duplicate.pdf

331-mas-2003- claims original.pdf

331-mas-2003- correspondence others.pdf

331-mas-2003- correspondence po.pdf

331-mas-2003- description complete duplicate.pdf

331-mas-2003- description complete original.pdf

331-mas-2003- form 1.pdf

331-mas-2003- form 19.pdf

331-mas-2003- form 3.pdf

331-mas-2003- form 5.pdf

331.jpg

abs-331-mas-2003.jpg