Title of Invention

NOVEL PROCES FOR THE PREPARATION OF CITALOPRAM INTERMEDIATE

Abstract ABSTRACT NOVEL PROCESS FOR THE PREPARATION OF CITALOPRAM INTERMEDIATE The present invention discloses a simple, economical, and improved process for the preparation of compound of formula-I from the compound of formula-XV using NiCl2/PPh3/Zn(CN)2. The compound of formula-XV is prepared by a sequence of reactions on compound of formula-X (displacement of bromo with cyano, hydrolysis of cyano to acid, esterfication of acid to its alkyl ester, reduction of both keto and ester groups with sodium borohydride to the dihydroxy compound of formula-XIV, and cyclization using p-TsOH). The starting benzophenone derivative of formula-X is prepared by a Friedel-Crafts reaction between 2-bromo-4-chlorobenzoyl chloride and fluorobenzene.
Full Text

INTRODUCTION
The present invention relates to a novel process for the preparation of l-(4-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile of the formula-I. Compound of the formula-I is a key intermediate used in the synthesis of citalopram hydrobromide of formula-II, an antidepressant drug available in the market.

BACKGROUND OF THE INVENTION
Compound of the formula-I, a key intermediate in the synthesis of citalopram is disclosed in the patent DE 2,657,013 (1977). Only one process is reported for the synthesis of this compound in the above-mentioned patent. According to the process disclosed, 5-bromophthalide of the formula-Ill is reacted with p-fluorophenylmagnesium bromide to get the benzophenone derivative of the formula-IV. The benzophenone derivative of the formula-IV is reduced with lithium aluminum hydride and the resulting dihydroxy compound of the formula-V is cyclized using ortho-phosphoric acid to get the phthalane derivative of the formula-VI. The compound of the formula-VI is reacted with copper cyanide in DMF medium to get the cyano derivative of the formula-I. This process is illustrated in the Scheme


Scheme-I The main drawback in this process is a Grignard reaction and the lithium aluminum hydride reduction is involved in making the compound of the formula-I. These two reactions are not easily adaptable for commercial scale due to the risk involved in handling such chemistry/ process. Also, Grignard reaction is known to be a low yielding step often associated with impurities. In this particular Grignard reaction, one major impurity (a bis- Grignard product, compound of the formula-VII) is formed along with the required product of formula-IV


Scheme-II (Scheme-II). In addition, handling of lithium aluminum hydride on a commercial scale is always risky and is a very expensive reagent. As both the steps involved in making the intermediate of formula-I are very expensive the process is not an economically viable.
Keeping in view of the diflficuhies in commercialization of the above-mentioned process for citalopram intermediate of the formula-I, we aimed to develop a simple and economical process for the preparation of compound of the formula-I. We observed that a promising approach for such a process is to avoid the Grignard reaction involved in making the compound of the formula-IV and avoid lithium aluminum hydride for making the compound of the formula-V.
The present invention is based on our finding that an equivalent of the benzophenone derivative of the formula-IV can be prepared by a simple Friedel-Crafts benzoylation reaction. The resulting benzophenone derivative can be suitably manipulated to get the analogous dihydroxy compound of the formula-V.
Accordingly, the main objective of the present invention is to provide a novel improved process for the preparation of compound of the formula I avoiding the usage of Grignard reagent and develop a Friedel-Crafts reaction to prepare an analogous benzophenone derivative of formula-V.
Still another objective of the present invention is to provide a novel improved process for the preparation of compound of the formula I by replacing the costly and hazardous lithium aluminum hydride used in the preparation of the compound of formula-V with simple sodium borohydride.
Yet another objective of the present invention is to provide a novel improved process for the preparation of compound of the formula I by avoiding / replacing the large quantity of ortho-phosphoric acid used in the preparation of compound of formula-VI to avoid the effluents problem.

Another objective of the present invention is to provide novel intermediates of the formulae X, XI, Xn, XIII, XIV, and XV defined hereinafter.
Yet another objective of the present invention is to provide processes for the preparation of novel intermediates of the formulae X, XI, XII, XIII, XIV, and XV defined hereinafter.
Accordingly the process of the present invention is shown in Scheme-Ill below:


Accordingly, the present invention provides a novel and improved process for the preparation of the compound of formula-I, which comprises:
i) Reacting 2-bromo-4-chlorobenzoyl chloride of formula-VIII,

with fluorobenzene in the presence of aluminum chloride to get the benzophenone derivative of the formula-X,

ii) Cyanating the resulting benzophenone derivative of formula-X with copper(I)cyanide in a polar solvent medium to get the cyano derivative of the formula-XI,
iii) Hydrolysing the cyano derivative of the formula-XI to get the benzoic acid of the formula-XII,


iv) Esterifying the benzoic acid of the formula-XII to its alkyl ester of formula-XIII,

wherein, R = C1-C4-alkyl v) Reducing the compound of the formula-XIII with sodium borohydride to get the dihydroxy compound of the formula-XIV,

vi) CycHzing the diol compound of the formula-XIV with an acid catalyst to get the phthalane derivative of formula-XV,


vii) Cyanating the chloro group present in compound of the formula-XV to the cyano compound of formula-I by known methods.

According to the preferred embodiment of the present invention, the Friedel-Crafts reaction on fluorobenzene with 2-bromo-4-chlorobenzoyl chloride of the formula-VIII can be carried out in a halogenated solvent like methylene chloride, ethylene dichloride, or neat with fluorobenzene as a solvent-cum-reagent. The temperature of the reaction can be in the range of20-80°C.
The cyanation of compound of the formula-X can be effected using copper(I)cyanide in a polar solvent like pyridine, dimethylformamide, dimethylacetamide, etc. The hydrolysis of cyano compound of formula-XI can be done under basic or acidic condition using alkali as a reagent for basic condition and sulfuric acid for acidic condition. The esterification of the acid compound of the formula-XII can be done in alcoholic solvent (C1-C4-alkanol) medium using sulfuric acid as a catalyst. The reduction of the keto-ester of the formula-XII can be carried out in t-butanol/methanol medium.

The cyclization of the dihydroxy compound of the formula-XIII can be carried out by using catalytic amount of p-toluenesulphonic acid under azeotropic conditions in an aromatic solvent like benzene, toluene, at its reflux temperature. The chloro group present in compound of the formula-XIV can be displaced with a cyanide source (NiCl2/PPh3/Zn(CN)2) according to the procedure given for a similar compound in the patent WO 00/11926.
The invention also provides novel compound of the formula-X and a novel process for its preparation. The process comprises:
(i) Reacting the benzoyl chloride of the formula-VIII,

with fluorobenzene in the presence of aluminum chloride to get the benzophenone derivative of the formula-X,

The present invention also provides a novel compound of the formula-XI and a process for its preparation. The process comprises:
(i) Reacting the benzoyl chloride of the formula-VIII,


with fluorobenzene in the presence of aluminum chloride to get the benzophenone derivative of the formula-X,

(ii) Cyanating the benzophenone derivative of the formula-X with copper(I)cyanide in a polar solvent medium to get the cyano derivative of formula-XI,
The present invention also provides a novel compound of the formula-XII and a process for its preparation. The process comprises:
(i) Reacting the benzoyl chloride of the formula-VIII,

with fluorobenzene in the presence of aluminum chloride to get the benzophenone derivative of the formula-X,


(ii) Cyanating the benzophenone derivative of the formula-X with copper(I)cyanide in a polar solvent medium to get the cyano derivative of the formula-XI,
(iii) Hydrolyzing the cyano derivative of the formula-XI to get the benzoic acid of the formula-XII,
The present invention also provides a novel compound of the formuIa-XIII and a process for its preparation. The process comprises:
(i) Reacting the benzoyl chloride of the formula-VIII,

with fluorobenzene in the presence of aluminum chloride to get the benzophenone derivative of the formula-X,


(ii) Cyanating the benzophenone derivative of the formula-X with copper(I)cyanide in a polar solvent medium to get the cyano derivative of the formula-XI,

(iii) Hydrolyzing the cyano derivative of the formula-XI to get the benzoic acid of the formula-XII,
(iv) Esterifying the benzoic acid of the formula-XII to its alkyl ester of the formula-XIII,


wherein, R = C1-C4-aIkyl The present invention also provides a novel compound of the formula-XIV and a process for its preparation. The process comprises:
a) Reacting the benzoyl chloride of the formula-VIII,

with fluorobenzene in the presence of aluminum chloride to get the benzophenone derivative of the formula-X,

b) Cyanating the benzophenone derivative of the formula-X with
copper(I)cyanide in a polar solvent medium to get the cyano derivative of the
formula-XI,


(ii) Hydrolyzing the cyano derivative of the formula-XI to get the benzoic acid of the formula-XII,

(iv) Esterifying the benzoic acid of the formula-XII to its alkyl ester of the formula-XIII,
wherein, R = Ci-C4-alkyl (v) Reducing the compound of the formula-XIII with sodium borohydride to get the dihydroxy compound of the formula-XIV,


The present invention also provides a novel compound of the formula-XV and a process for its preparation. The process comprises:
(i) Reacting the benzoyl chloride of the formula-VIII,

with fluorobenzene in the presence of aluminum chloride to get the benzophenone derivative of the formula-X,

(ii) Cyanating the benzophenone derivative of the formula-X with copper(I)cyanide in a polar solvent medium to get the cyano derivative of the formula-XI,


(iii) Hydrolyzing the cyano derivative of formula-XI to get the benzoic acid of the formula-XII,

(iv) Esterifying the benzoic acid of the formula-XII to its alkyl ester of the formula-XIII,
wherein, R = C1-C4-alkyl (v) Reducing the compound of the formula-XIII with sodium borohydride to get the dihydroxy compound of the formula-XIV,


(vi) Cyclizing the diol compound of the formula-XIV with an acid catalyst to get the phthalane derivative of the formula-XV,

The invention is described in detail in the Examples given below which are provided only by way of illustration and therefore should not be construed to limit the scope of the invention.
Example 1
Preparation of l-(4-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile: i) Preparation of 2-bromo-4-chlorobenzoyl chloride:
Into a 500ml three-necked RB was charged 45gr (0.2mol) of 2-bromo-4-chlorobenzoic acid and 225ml of dry benzene. Thionyl chloride (28gr, 0.24mol) was added to the reaction mixture at room temperature. The reaction mixture was slowly heated to reflux temperature and maintained at reflux temperature for 4hr. Benzene and excess thionyl chloride were distilled off from the reaction mixture and finally applied vaccum to get the required 2-bromo-4-chlorobenzoyl chloride as a residue.

ii) Preparation of 2-bromo-4-chloro-4'-fluorobenzophenone:
Into a clean and dry 500ml three-necked RB flask was added 22ml of fluorobenzene and 14gr (O.lSmol) anhydrous aluminum chloride. The reaction mixture was cooled to 0-5°C. A solution of 2-bromo-4-chlorobenzoyl chloride (22.6gr, 0.09mol) in 22ml of fluorobenzene was added to the reaction mixture at 0-5°C. The reaction temperature was slowly raised to 50-60°C and maintained at this temperature for 3hr. The reaction mixture was cooled to RT and poured into ice-water (200ml) containing 20ml of cone, hydrochloric acid. The reaction mixture was extracted with methylene chloride and the organic layer washed with aqueous sodium bicarbonate. Drying and distillation of solvent gave crude product. The crude compound was distilled under vaccum (200°C at 3/mm Hg) to get the required 2-broino-4-chloro-4'-fluorobenzophenone (20.0gr, 71.5% yield). A small sample was recrystallized from isopropanol to get the crystalline compound. Melting point is 80-81°C. IR (KBr): 3081, 1673, 1597, 1582, 1504, 1283, 1243, 1149, 1180, 1044, and 929 cm-1 ^H-NMR (200MHz, CDCI3): 7.77-7.87 (m, IH), 7.68 (d, J = 1.8Hz, IH), 7.40-7.44 (m, IH), 7.29 (d, J = 8.4Hz, IH), and 7.09-7.21 (m,2H).
iii) Preparation of 2-cyano-4-chIoro-4'-fluorobenzophenone:
Into a clean and dry 500ml three-necked RB flask was charged 39gr (0.12mol) of 2-bromo-4-chloro-4'-fluorobenzophenone and 11.7gr (0.13mol) of copper (I) cyanide, and 200ml of dry DMF. The reaction mixture was slowly heated to 110°C and maintained at this temperature for 7hr. TLC of the reaction mixture showed the absence of starting bromo compound. The reaction mixture was cooled to RT and poured into 500ml of water. Product was extracted into benzene and the solvent distilled off to get crude compound (35.0gr). The crude product thus obtained was recrystallized from 100ml of isopropanol to get 25gr (78% yield) of 2-cyano-4-chloro-4'-fluorobenzophenone as ofF-white crystalline solid. Melting point is 114-5°C. IR(KBr): 3075, 2234, 1661, 1599, 1558, 1502, 1286, 1273, 1236, 1153, 932, 854, 842, and 774 cm-1. 'H-NMR (200MHz, CDCI3): 7.79-7.89 (m, 3H), 7.58-7.72 (m, 2H), and 7.13-7.28 (m, 3H).

iv) Preparation of 2-(4-fluorobenzoyl)-4-chlorobenzoic acid:
Aqueous sulfuric acid (22.5gr, 75% w/w) and 2-cyano-4-chloro-4'-fluorobenzophenone (lOgr, 0.04mol) were charged into a 100ml three-necked RB flask and the contents were heated to 160°C and maintained at this temperature for 3hr. TLC of the reaction mixture showed the absence of starting material and the reaction mixture was cooled to RT before pouring into ice-water (100ml). Product was extracted into methylene chloride and the organic layer extracted with 30ml of 10% aqueous sodium hydroxide solution. The aqueous layer was treated with carbon and filtered. The filtrate was acidified with cone, hydrochloric acid to get the precipitate. Product was isolated by filtration and dried at 60-70°C to get 9.7gr (90% yield) of off-white crystalline solid of 2-(4-fluorobenzoyl)-4-chlorobenzoic acid. A small sample was recrystallized from toluene to get white crystalline solid. Melting point is 144-146°C. IR(KBr): 3288, 3114, 1721, 1660, 1598, 1564, 1505, 1288, 1262, 1230, 1199, 1152, 1109, 936, 852, and 763 cm'^ 'H-NMR (200MHz, CDCI3): 10.23 (br. s., IH, -COOH), 8.05 (d, J = 1.8Hz, IH, aromatic), 7.68-7.77 (m, 2H, aromatic), 7.62-7.67 (m, IH, aromatic), 7.26-7.15 (m, IH, aromatic), and 7.04-7.15 (m, 2H, aromatic).
v) Preparation of methyl 2-(4-fluorobenzoyl)-4-chlorobenzoate:
Into a 250ml three-necked RB flask was charged 100ml of dry benzene, lOgr (0.036mol) of 2-(4-fluorobenzoyl)-4-chlorobenzoic acid, and 7.0ml of thionyl chloride. The reaction mixture was heated to reflux temperature and maintained for 3hr. Excess thionyl chloride and benzene were removed from the reaction mass under vaccum and to the crude compound was added 30ml of methanol and stirred for 2hr at RT. Methanol was distilled off from the reaction mixture under vaccum and the residue was recrystallized from ethyl acetate-hexane to get 9.0gr (85.6% yield) of white crystalline solid, methyl 2-(4-fluorobenzoyl)-4-chlorobenzoate. Melting point is 78-80°C. IR (KBr): 3074, 2956, 1724, 1671, 1599, 1298, 1258, 1147, 931, 823, and 756 cm"'. 'H-NMR (200MHZ, CDCI3): 8.02 (d, J = 1.8Hz, IH, aromatic), 7.71-7.81 (m, 2H, aromatic), 7.61 (dd, J= 1.8Hz, 8.1Hz, IH, aromatic), 7.26-7.34 (m, IH), 7.05-7.17 (m, 2H, aromatic), and 3.67 (s, 3H, COOCH3).
vi) Preparation of l-(4-chloro-2-hydroxymethylphenyl)-l-(4-fluorophenyI)methanol:

Into a 250ml three-necked RB flask was charged 5.0gr (0.01TmoI) methyl 2-(4-fluorobenzoyl)-4-chlorobenzoate, 50ml of t-butanol, and 3.0gr (0.05mol) of sodium borohydride. The reaction mixture was heated to reflux temperature and 10ml of methanol was added in 4 lots over a period of 8hr. After maintaining for 2hr at reflux temperature after the last lot addition, reaction was found to be complete by TLC. The reaction mixture was quenched by adding 4ml of acetic acid and the solvents distilled off under vaccum. To the residue, water (50ml) was added and the product extracted into methylene chloride (3 x 50ml). Methylene chloride layer was dried over sodium sulfate, and the solvent distilled off to get 4.0gr (88% yield) of the crude dihydroxy compound, l-(4-chloro-2-hydroxymethylphenyl)-l-(4-fluorophenyl)-methanoI as syrup. This was directly used in the next step after checking its IR and 'H-NMR spectra. IR (neat): 3319, 1603, 1508, 1405, 1224, 1158, 1095, 1021, and 830 cm-1 ^H-NMR (200MHz, CDCI3): 6.95-7.24 (m, 7H, aromatic), 5.83 (s, IH, -CHOH-), 4.27-4.50 (m, 2H, -CH2OH), and 3.72 (br. s, 2H, -CHOH-, CH2OH).
vii) Preparation of l-(4-flourophenyI)-l,3-dihydro-5-chloro-isobenzofuran:
Into a 250ml three-necked RB flask was charged benzene (25ml), 2.4gr (O.Olmol) of l-(4-chloro-2-hydroxymethylphenyl)-l-(4-fluorophenyl)methanol, and p-toluene-sulfonic acid (0.63gr, 0.004mol). The reaction mixture was heated to reflux temperature under azeotropic conditions using Dean-Stark apparatus to remove the water formed in the reaction. After refluxing for 2hr reaction was found to be complete by TLC. The reaction mixture was cooled to RT. Water (100ml) was added to the reaction mixture and the product extracted into benzene. Benzene layer was washed with 5% sodium bicarbonate and water (50ml) and dried over sodium sulfate. Solvent was removed on rotavapor to get 2.0gr (89% yield) of crude l-(4-flourophenyl)-l,3-dihydro-5-chloro-isobenzofuran as oil. Purity by HPLC was found to be >96%. Chromatographic purification over a column of silica gel gave the title compound pure. IR (neat); 3072, 2923, 2855, 1605, 1509, 1476, 1419, 1341, 1225, 1156, 1039, 1015, 828, 813, 782, and 699 cm"'. 'H-NMR (200MHZ, CDCI3): 7.17-7.30 (m, 4H, aromatic), 6.08-7.08 (m, 3H, aromatic), 5.30 (s, IH, -CHO-), and 5.20 (ddd, J = 1.8Hz, 12.8Hz, and 28. 6Hz, 2H, -CH2O-).

viii) Preparation of l-(4-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile:
Into a 250ml three-necked flask was charged nickel(II)chloride (0.031gr, 0.003mol), triphenylphosphine (0.25gr, 0.0012mol), acetonitrile (25ml). The reaction mixture was heated to reflux temperature and after maintaining for 2hr, it was cooled to RT and treated with 0.2gr of zinc powder. After stirring for 30min at RT, a solution of l-(4-flourophenyl)-l,3-dihydro-5-chloro-isobenzofuran (1.5gr, 0.006mol) in 25ml of acetonitrile was added to the reaction mixture. After stirring for 30min at RT, potassium cyanide (0.22gr, 0.003mol) was added to the reaction mixture and heated the contents to reflux temperature. After maintaining for 8hr at reflux, reaction mixture was diluted with diisopropyl ether (200ml) and filtered on hi-flow bed. The filtrate was distilled off on rotavapor and the residue chromatographed over a silica gel column to get 0.86gr (60% yield) of l-(4-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile as off-white crystalline solid. Melting point is 94-95°C. HPLC purity of this material was found to be 98.5%. This compound was found to be matching in respects with the compound prepared by the known patent (DE 2,657,013) process.
Example 2 Preparation of l-(4-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile: i) Preparation of 2-bromo-4-chloro-4'-fluorobenzophenone:
Into a clean and dry 500ml three-necked RB flask was added 75ml of methylene chloride and 26.0gr (0.15mol) anhydrous aluminum chloride. The reaction mixture was cooled to 10-55°C. A solution of 2-bromo-4-chlorobenzoyl chloride (30.0gr, 0.12mol) in 50ml of methylene chloride was added to the reaction mixture at 10-15°C. The reaction temperature was slowly raised to 25-30°C and maintained at this temperature for overnight. The reaction mixture was cooled to 15-20°C and poured into ice-water (200ml) containing 30ml of cone, hydrochloric acid. The reaction mixture was extracted with 100ml of methylene chloride and the organic layer washed with aqueous sodium bicarbonate. Drying with sodium sulfate and distillation of solvent gave crude product. The crude compound was distilled under vaccum (200°C at 3/mm Hg) to get the required 2-bronio-4-chloro-4'-fluorobenzophenone (25.0gr, 67.6% yield). Melting point is 80-81°C. Neutralization of the sodium bicarbonate layer gave 5.0gr of 2-bromo-4-chlorobenzoic acid.

ii) Preparation of 2-cyano-4-chloro-4'-fluorobenzophenone;
Into a clean and dry 500ml three-necked RB flask was charged 25gr (0.08mol) of 2-bromo-4-chloro-4'-fluorobenzophenone and l0.8gr (0.12mol) of copper (I) cyanide, and 50ml of dry pyridine. The reaction mixture was slowly heated to reflux temperature and maintained at this temperature for 7hr. TLC of the reaction mixture showed the absence of starting bromo compound. The reaction mixture was cooled to RT and poured into 500ml of water. Product was extracted into isopropyl ether and the organic layer washed with 2% HCl. Isopropyl ether was distilled off to get the crude compound. The crude product thus obtained was recrystallized from 100ml of isopropanol to get 15.6gr (75% yield) of 2-cyano-4-chloro-4'-fluorobenzophenone as off-white crystalline solid. Melting point is 114-5°C.
iii) Preparation of 2-(4-fluorobenzoyl)-4-chlorobenzoic acid:
Aqueous sulfuric acid (22.5gr, 75% w/w) and 2-cyano-4-chloro-4'-fluorobenzophenone (15gr, 0.06mol) and acetic acid (25ml) were charged into a 100ml three-necked RB flask and the contents were heated to reflux temperature and maintained for 4hr. TLC of the reaction mixture showed the absence of starting material and the reaction mixture was cooled to RT before pouring into ice-water (100ml). Product was extracted into methylene chloride and the organic layer extracted with 30ml of 10% aqueous sodium hydroxide solution. The aqueous alkali layer was treated with carbon (Igr) and filtered. The filtrate was acidified with cone, hydrochloric acid. The precipitate was filtered and dried at 60-70°C to get 15.5gr (90% yield) of off-white crystalline solid of 2-(4-fluorobenzoyl)-4-chlorobenzoic acid. Melting point is 144-146°C.
iv) Preparation of ethyl 2-(4-fluorobenzoyl)-4-chIorobenzoate:
Into a 250ml three-necked RB flask was charged 50ml of dry toluene, 15gr (0.054mol) of 2-(4-fluorobenzoyl)-4-chlorobenzoic acid, and 10.0ml of thionyl chloride. The reaction mixture was heated to reflux temperature and maintained for 3hr. Excess thionyl chloride and toluene were removed from the reaction mass under vaccum and to the crude compound was added 30ml of anhydrous ethanol and stirred for 2hr at RT. Ethanol was distilled off from the reaction mixture under vaccum and the residue was recrystallized from ethyl

acetate-hexane to get 14.0gr (85% yield) of white crystalline solid, ethyl 2-(4-fluorobenzoyl)-4-chlorobenzoate.
v) Preparation of l-(4-chloro-2-hydroxymethylphenyl)-l-(4-fluorophenyl)methanol:
Into a 250ml three-necked RB flask was charged lO.Ogr (0.033mol) of ethyl 2-(4-fluorobenzoyl)-4-chlorobenzoate, 50ml of t-butanol, and 2.5gr (0.07mol) of sodium borohydride. The reaction mixture was heated to reflux temperature and 10ml of methanol was added in 4 lots over a period of 8hr. After maintaining for 2hr at reflux temperature after the last lot addition, reaction was found to be complete by TLC. The reaction mixture was quenched by adding 4ml of acetic acid and the solvents distilled off under vaccum. To the residue, water (50ml) was added and the product extracted into methylene chloride (3 x 50ml). Methylene chloride layer was dried over sodium sulfate, and the solvent distilled off to get 7.8gr (90% yield) of the crude dihydroxy compound, l-(4-chloro-2-hydroxymethylphenyl)-l-(4-fluorophenyl)-methanol as syrup. This was directly used in the next step after checking its IR and 'H-NMR spectra.
vi) Preparation of l-(4-fIourophenyl)-l,3-dihydro-5-chloro-isobenzofuran:
Into a 250ml three-necked RB flask was charged toluene (25ml), l-(4-chloro-2-hydroxymethylphenyl)-l-(4-fluorophenyl)methanol (5.0gr, 0.02mol), and p-toluenesulfonic acid (0.63gr, 0.004mol), The reaction mixture was heated to reflux temperature under mild vaccum at 65-70°C. The reflux system was connected to Dean-Stark apparatus to remove the water formed in the reaction. After refluxing for 3hr reaction was found to be complete by TLC. The reaction mixture was cooled to RT. Water (100ml) was added to the reaction mixture and the product extracted into toluene. Toluene layer was washed with 50ml of 5.0% sodium bicarbonate solution and dried the organic layer over sodium sulfate. Toluene was removed on rotavapor at reduced temperature to get 4,0gr (85% yield) of crude l-(4-fIourophenyl)-l,3-dihydro-5-chIoro-isobenzofuran as oil.
vii) Preparation of l-(4-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitriIe:
Into a 250ml three-necked flask was charged nickel(Il)chloride (0.062gr, 0.006mol), triphenylphosphine (O.SOgr, 0.003mol), acetonitrile (25ml). The reaction mixture was heated

to reflux temperature and after maintaining for 2hr, it was cooled to RT and treated with 0.4gr of zinc powder. After stirring for 30min at RT, a solution of l-(4-flourophenyl)-l,3-dihydro-5-chloro-isobenzofuran (3.0gr, 0.012mol) in 25ml of acetonitrile was added to the reaction mixture. After stirring for 30min at RT, potassium cyanide (0.44gr, 0.006mol) was added to the reaction mixture and heated the contents to reflux temperature. After maintaining for 8hr at reflux, reaction mixture was diluted with diisopropyl ether (200ml) and filtered on hi-flow bed. The filtrate was distilled off on rotavapor and the residue chromatographed over a silica gel column to get 1.8gr (60% yield) of l-(4-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile as off-white crystalline solid. Melting point is 94-95°C. HPLC purity of this material was found to be 98.6%.
Advantages of the present invention:
1. The process is economical and simple for the preparation of the compound of formula-I, an intermediate used in the preparation of citalopram.
2. No Grignard reaction is involved in making the compound of the formula I.
3. No lithium aluminum hydride is involved in the preparation of compound of the formula-I.
4. The process produces novel intermediates of the formulae X, XI, XII, XIII, XIV, and XV.


We Claim:
1. An improved process for the preparation of compound of formula-I,

wherein, the preparation of compound of formula-I involves: (i) Reacting the benzoyl chloride of the formula-VIII,

with fluorobenzene in the presence of aluminum chloride to get the benzophenone derivative of the formula-X,

(ii) Cyanating the benzophenone derivative of the formula-X with copper(I)cyanide in a polar solvent medium to get the cyano derivative of the formula-XI,


(iii) Hydrolyzing the cyano derivative of the formula-XI to get the benzoic acid of the formula-XII,
(iv) Esterifying the benzoic acid of the formula-XII to its alkyl ester of the formula-XIII,

wherein, R = Ci-C4-alkyl
(v) Reducing the compound of the formula-XIII with sodium borohydride to get the dihydroxy compound of the formula-XIV,

(vi) Cyclizing the diol compound of the formula-XIV with an acid catalyst to get the phthalane derivative of the formula-XV,


(vii) Displacing the chloro group present in compound of the formula-XV with a cyanide source (NiCl2/PPh3/Zn(CN)2)) to get the compound of the formula-I
2. A process as claimed in claim 1 wherein the step (i) namely the Friedel-Crafts reaction is carried out in a halogenated solvent selected from methylene chloride, ethylene dichloride, or neat with fluorobenzene as a solvent-cum-reagent.
3. A process as claimed in claims 1 & 2 wherein the step (i) the temperature of the Friedel-Crafts reaction used is in the range of 20-80°C.
4. A process as claimed in claim 1 to 3 wherein the step (ii) the bromo displacement reaction with copper(I)cyanide is carried out in the presence of pyridine, dimethylformamide, dimethylacetamide, etc.
5. A process as claimed in claims 1 to 4 wherein in step (iii) the hydrolysis of nitrile group is effected under acidic or basic condition using alkali as a reagent for basic condition and sulfuric acid for acidic condition.
6. A process as claimed in claim 1 to 5 wherein the step (iv) the esterification is effected in alcohol medium using sulfuric acid as a catalyst.
7. A process as claimed in claims 1 to 6 wherein step (v) the sodium borohydride reduction of the keto-ester group is done in t-butanol/methanol medium.

8. A process as claimed in claims 1 to 7 wherein step (vi) the phthalane ring formation is done by using catalytic amount of p-toluenesulphonic acid under azeotropic reflux conditions in an aromatic solvent like benzene, toluene, xylene, etc. at reflux temperature.
9. A process as claimed in claims 1 to 8 wherein in the step (vii), the replacement of chloro group is carried out by using NiCl2/PPhs/metal cyanide.

10. A process as claimed in claim 1 and 9 wherein the metal cyanide used is selected from sodium cyanide, potassium cyanide, zinc cyanide.
11. An improved process for the preparation of compound of the formula-I substantially as herein described with reference to the Examples.


Documents:

0049-che-2003 abstract duplicate.pdf

0049-che-2003 abstract.jpg

0049-che-2003 abstract.pdf

0049-che-2003 claims duplicate.pdf

0049-che-2003 claims.pdf

0049-che-2003 correspondence others.pdf

0049-che-2003 correspondence po.pdf

0049-che-2003 description (complete) duplicate.pdf

0049-che-2003 description (complete).pdf

0049-che-2003 form-1.pdf

0049-che-2003 form-19.pdf

0049-che-2003 form-5.pdf


Patent Number 207524
Indian Patent Application Number 49/CHE/2003
PG Journal Number 30/2009
Publication Date 24-Jul-2009
Grant Date 14-Jun-2007
Date of Filing 17-Jan-2003
Name of Patentee M/S. NATCO PHARAMA LIMITED
Applicant Address NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD 500 033
Inventors:
# Inventor's Name Inventor's Address
1 NE NE
PCT International Classification Number N/A
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA