Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF -(2-METHYLAMINOETHYL)-4-FLUOROPHEYLMETHANOL

Abstract

Present invention discloses an improved process for the preparation of -(2-methylaminoethyl)-4-fluorophenylmethanol of formula-I by N-debenzylating the acid addition salt of 3-(benzyl(methyl)amino)-l-(4-fluorophenyl)propan-l-ol of formula-V under heterogeneous hydrogenation conditions. Hydrogenation of acid addition salt has minimized the formation of des-fluoro impurity to below 0.1%. Hydrogenation of free base by earlier known method would normally give more than 1% of des-fluoro Impurity, which is very difficult to remove by purification techniques. Compound of formula-V is prepared from 3-chloro-l-(4-fluorophenyl)propan-l-one of formula-X by conventional chemistry.

Full Text

FIELD OF INVENTION The present invention relates to an improved process for the preparation of ¥-(2-methyi-aminoethyl)-4-fluorophenylmethanol. The ¥-(2-methylaminoethyi)-4-fluorophenyl-methanol prepared by the process of the present invention has the formula-I given below, is an important intermediate in the synthesis of (±)-trans-4-(4-fluorophenyl)-3-hyroxymethyl-1-methylpiperidine of the formula-II. The Compound of formula-II is an advanced intermediate widely used in the synthesis of antidepressant drug paroxetine hydrochloride of the formula-Ill. Paroxetine hydrochloride of the formula-Ill is commercially available in the market as an anti-depressant, which inhibits 5-hydroxytryptamine (5-HT) reuptake. IT IT BACKGROUND OF INVENTION The compound of the formula-I was prepared for the first time by us and effectively used in constructing the piperidine ring of paroxetine. Details of this invention are disclosed in our co-pending Indian Patent application no 830 / MAS / 2002. In that co-pending application for patent, we have described two routes for the preparation of the compound of formula-I. In the first route (Scheme-I) the Mannich salt of the formula-IV is reduced with a reducing agent to get the hydroxy compound of the formula-V. This hydroxy compound of the formula-V is debenzylated under hydrogenation conditions to get the required compound of the formula-I. Although this process is attractive for a commercial scale one major drawback in this process is the formation of desfluoro impurity during debenzylation step. Although the formation is not very high ( In the second route for the preparation of compound of the formula-I, we started with a different Mannich salt and completed the synthesis of compound of the formula-I (Scheme-II). In this process the compound of formula-VI is reacted with a reducing agent to get the known hydroxy compound of the formula-VII. This compound of the formula-VII is reacted with a chlorofomate derivative to get the urethane derivative of the formula-VIII. The urethane derivative of the formula-VIII is hydrolyzed with alkali to get the required compound of formula-I. One major drawback in this process is a large excess (at least 4-6 molar equivalents) of chloroformate is required to make the urethane derivative of the formula-VII. Also, the hydrolysis step is slow and requiring high temperature (100-140°C) to get the required compound of formula-I. Also, the yield of the compound of formula-I is not satisfactory ( Keeping in view of the difficulties in the above processes we looked for the improvements over these routes. During our sustained research on the hydrogenation of the compound of the formula-V, we found that the hydrogenation on salts of compound of the formula-V was found to be faster and cleaner than the hydrogenation of free base. Accordingly, we proceeded on this basis and developed an improved process for the preparation of the compound of the formula I. Therefore the main objective of the present invention is to provide an improved process for the preparation of compound of formula-I which is simple & economical Another objective of the present invention is to provide an improved process for the preparation of compound of the formula-I in more than 90% yield compared to 70-75% obtained by the processes earlier reported. Yet another objective of the present invention is to provide an improved process for the preparation of compound of formula-I wherein the formation of des-fluoro impurity is less than 0.02% compared to more than 0.5% by the earlier reported hydrogenation process. Still another objective of the present invention is to provide an improved process for the preparation of compound of the formula-I which is useful for the production on commercial scale. Accordingly, the present invention provides an improved process for the preparation of the compound of the formula-I, which comprises: (i) Reducing the compound of the formula-X with sodium borohydride in alcoholic solvent medium to obtain a compound of the formula XI (ii) Aminating the resulting compound of the formula-XI with N- methylbenzylamine to get the compound of the formula-V (iii) N-Debenzylating the compound of the formula-V under heterogeneous hydrogenation condition by adding one equivalent of an acid to the compound of the formula-V (iv) Neutralizing the resultant salt of the compound of formula-I with a base to get the compound of formula-I In a preferred embodiment of the invention the compound of the formula-X is prepared according to the procedure given in J. Chem. Soc, Chem. Commun., 1986, (13), p1018-19 starting from fluorobenzene and 3-chloropropionyl chloride under Friedel-Crafts acylation conditions. The carbonyl group present in the compound of the formula-X is reduced with sodium borohydride in an alcoholic solvent medium to get the known hydroxy compound of the formula-XI as syrup. The compound of the formula-XI is reacted with N-benzylmethylamine to get the crystalline N-benzyl compound of formula-V. This on mild hydrogenation in the presence of an acid gave the required compound of formula-I in its salt form. The acid used in hydrogenation can be acetic acid, oxalic acid, propionic acid, methanesulfonic acid, benzoic acid, mandelic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc. After the hydrogenation is over salts of the compound of formula-I can be isolated by crystallization or can be directly neutralized and the resultant base can be crystallized. The N-debenzylation was found to be much faster than the one on free base. Reaction was over in 3-4 hr compared to 10-12 hr on free base. Also, the desfluoro impurity was less than 0.02% compared to more than 0.5% when the reaction was done on free base. The neutralization of the salt with a weak base gave the required secondary amine of formula-I as crystalline solid. The invention is described in detail in the Example given below which are provided only by way of illustration and therefore should not be construed to limit the scope of the invention further illustrated by the following examples. Example 1 Preparation of (±)-¥-(2-methylaminoethyl)-4-fluorophenylinethanol (i) Preparation of (±)-4-fluoro-¥-(2-chloroethyl)phenyImethanol Into a IL three-necked RB flask was charged 500 mL of isopropanol and 100 g of 4-fluoro-p-chloropropiophenone. The reaction mass was cooled to 10-15 °C. Sodium borohydride (7.0 g) was added to the reaction mass in lots keeping the temperature below 20 °C. The reaction mixture was stirred at 20-25 °C for 2-3 hr and quenched by adding 10 mL of acetic acid. Isopropanol was distilled off from the reaction mass below 40 °C. The residue was partitioned between water and toluene. Toluene layer was separated, dried, and evaporated to get 95 g of crude product. Crystallization from a mixture of hexane and diisopropyl ether gave the title compound as white solid. (ii) Preparation of (±)-¥-(2-N-benzylmethylaminoethyI)-4-fluorophenylmethanoI Into a 1-L, three-necked RB flask was charged 300 mL of methanol and 67.2 g of N-benzyl-N-methylamine. The resulting solution was cooled to 10-15 °C and added a solution of above prepared (=t)-4-fluoro-¥-(2-chloroethyl)phenylmethanol (50 g) in methanol (100 mL). After stirring for 1 hr at same temperature the reaction mass allowed to reach 25-30 °C. The reaction mass was transferred into a stainless steel kettle, added 10 g of potassium iodide, and heated to 60-70 °C under pressure. After maintaining at same condition for 36 hr reaction mass was cooled to 25-30 °C and distilled off solvent under vaccum. The residue was suspended in isopropyl ether (200 mL) and filtered the solids. To the filtrate water (200 mL) and acetic acid (20 mL) were added. pH was adjusted to 7.5 using ammonia. After separation of isoporpyl ether layer pH of aqueous layer was adjusted to 8.5-9.0 with ammonia and extracted product into isopropyl ether. Isopropyl ether layer was distilled off to get 50 g of crude compound. The crude product was crystallized from hexane to get 41 g of the title compound as white crystalline solid. M. P. is 65.5-66.0 °C. (iii) Preparation of (±)-¥-(2-methyIaininoethyl)-4-fluoroplienylmethanoI acetate salt Into a 1-L stainless steel kettle are charged 50 g of above prepared (±)-¥-(2-N-benzylmethylaminoethyl)-4-fluorophenylmethanol, 500 mL of isopropanol, 11 g of acetic acid, and 2.5 g of 5% palladium-on-carbon (50% wet). After evacuating the kettle it was filled with hydrogen and shaken under hydrogen pressure of 40-60psi at room temperature. After maintaining under hydrogen pressure for 6 hr reaction mass was filtered and the filtrate distilled under vaccum to get 43 g of crude acetate salt of (±)-N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]propylamine. The crude salt was suspended in diisopropyl ether (40 mL) and filtered to get 40 g of pure white crystalline acetate salt. Melting point is 83-84 °C. Purity by HPLC is 99.3% and the des-fluoro impurity is 0.07%. (iv) Preparation of (±)-¥-(2-inethylaminoethyl)-4-fluorophenylmethanol The above step (iii) salt was suspended in 250 mL of water and neutralized with 7.5 g of sodium hydroxide. The resultant base was extracted into toluene, and distilled off solvent under vaccum to get 30 g of crude base. Crystallization of this base from hexane/isopropyl ether gave 27 g of title compound as white crystalline solid. Melting point is 68.6 °C. Example 2 Preparation of (+)-¥-(2-methylaminoethyl)-4-fluorophenylmethanol (i) Preparation of (+)-N-benzyl-N-methyl-N-[3-hydroxy-3-(4-fluorophenyI)]propyl-amine (+)-mandeIic acid salt Into a 2-L, three-necked RB flask was charged 200 g of (±)-N-benzyl-N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]propyl-amine prepared by the process described in step (ii) of Example 1, 650 mL of isopropanol, and 110 g of (+)-mandelic acid. The reaction mass was heated to 50-55 °C and maintained for 1 hr to get a clear solution. The reaction mass was allowed to cool to 25-30 °C and filtered and the wet solid washed with 50 mL of isopropanol to get 140 g of (+)-N-benzyl-N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]propyl-amine (+)-mandelic acid salt. Optical rotation is +54.44 (c =1, MeOH). The above crude mandelate salt was taken into a 2-L, three-necked, RB flask and added 600 mL of isopropanol. After heating to 70 °C a clear solution formed. The resultant solution was allowed to cool to 25-30 °C and maintained for 1 hr. The reaction mass was filtered and the solid washed with 100 mL of isopropanol to get 125 g of pure mandelate salt. Optical rotation is +62.7 (c = 1, MeOH). Melting point is 110-111 °C. Chiral purity by HPLC is 100%. (ii) Preparation of (+)-N-benzyi-N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]propyl-amine Into a 1-L, three-necked, RB flask were charged 450 mL of isopropanol and 11.5 g of sodium hydroxide. After stirring the reaction mass for 20 min, 125 g of (+)-N-benzyl-N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]propyl-amine (+)-mandelic acid salt prepared by the process described in step (i) was added to the reaction mass and kept under stirring for 6 hr. The reaction mass was filtered and the cake washed with 100 mL of isopropanol and dried to get 40 g of sodium mandelate. The isopropanol filtrate was taken into a RB flask and distilled off solvent under vaccum. The residue was suspended in water (150 mL) and extracted with toluene (2 x 300 mL). The toluene layer was washed with water, dried and evaporated under vaccum to get 82 g of (+)-N-benzyl-N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]propyl-amine as liquid. Optical rotation is +22.36 (c=l,MeOH). (iii) Preparation of (+)-¥-(2-methylaminoethyl)-4-fluorophenyImethanol acetate salt Into a 1-L stainless steel kettle are charged 50 g of (+)-¥-(2-N-benzylmethylaminoethyl)-4-fluorophenylmethanol (above step (ii) material), 500 mL of isopropanol, 11 g of acetic acid, and 2.5 g of 5% palladium-on-carbon (50% wet). After evacuating the kettle it was filled with hydrogen and shaken under hydrogen pressure of 40-60psi at room temperature. After maintaining under hydrogen pressure for 6 hr reaction mass was filtered and the filtrate distilled under vaccum to get 43 g of crude acetate salt of (+)-N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]propylamine. The crude salt was suspended in toluene (40 mL) and filtered to get 40 g of pure white crystalline acetate salt. Melting point is 127 °C. Optical rotation is +41.4 (c = 1, MeOH). Purity by HPLC is 99,3% and the des-fluoro impurity is 0.07%. (iv) Preparation of (+)-¥-(2-methyiaminoethyl)-4-fluorophenylmethanol The (+)-¥-(2-methylaminoethyl)-4-fluorophenylmethanol acetate salt prepared by the process described in step (iii) above was suspended in 250 mL of water and neutralized with 8 g of sodium hydroxide. The resultant base was extracted into toluene, dried the toluene layer with sodium sulfate, and distilled off solvent under vaccum to get 30 g of title compound as liquid. Optical rotation is +32.3 (c = 1, MeOH). HPLC purity is 99.9%. Example 3 Preparation of (+)-¥-(2-niethylaminoethyI)-4-fluorophenyImethanol (i) Preparation of (+)-¥-(2-methyIaminoethyl)-4-fluorophenylmethanoI oxalate salt Into a 1-L stainless steel kettle are charged 50 g of (+)-¥-(2-N-benzylmethylaminoethyl)-4-fluorophenylmethanol prepared by the process described in step (ii) of Example 2, 500 mL of isopropanol, 23 g of oxalic acid dihydrate, and 2.5 g of 5% palladium-on-carbon (50% wet). After evacuating the kettle it was filled with hydrogen and shaken under hydrogen pressure of 40-60psi at room temperature. After maintaining under hydrogen pressure for 6 hr reaction mass was filtered and the filtrate distilled under vaccum to get 48 g of crude oxalate salt of (+)-N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]-propylamine. The crude salt was suspended in acetone (40 mL) and filtered to get 44 g of pure white crystalline oxalate salt. Melting point is 195 °C. Optical rotation is +35.95 (c = 1, MeOH). Purity by HPLC is 99.5% and the des-fluoro impurity is 0.07%. (ii) Preparation of (+)-¥-(2-methylaminoethyI)-4-fluorophenyImethanol The (+)-¥-(2-methylaminoethyl)-4-fluorophenylmethanol oxalate salt prepared by the process described in step (i) was suspended in 250 mL of water and neutralized with 10 g of sodium hydroxide. The resultant base was extracted into toluene, dried the toluene layer with sodium sulfate, and distilled off solvent under vaccum to get 28 g of title compound as liquid. Optical rotation is +32.1 (c = 1, MeOH). HPLC purity is 99.8%. Example 4 Preparation of (+)-¥-(2-methylaininoethyl)-4-fluorophenylmethanoI (i) Preparation of (+)--(2-methylaminoethyl)-4-fluorophenylmethanol (+)-mandelic acid salt Into a 1-L stainless steel kettle are charged 50 g of (+)-¥ -(2-N-benzylmethylaminoethyl)-4-fluorophenylmethanol (+)-mandelate salt prepared by the process described in step (i) of Example 2, 500 mL of methanol, and 2.5 g of 5% palladium-on-carbon (50% wet). After evacuating the kettle it was filled with hydrogen and shaken under hydrogen pressure of 40-60psi at room temperature. After maintaining under hydrogen pressure for 20 hr reaction mass was filtered and the filtrate distilled under vaccum to get 44 g of crude mandelate salt of (+)-N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]propylamine. The crude salt was recrystallized from isopropanol (120 mL) to get 34 g of pure white crystalline mandelate salt. Melting point is 93.4 °C. Optical rotation is -^-12,61 (c = 1, MeOH). Purity by HPLC is 99.5% and the des-fluoro impurity is 0.06%. (ii) Preparation of (+)-¥-(2-methyIaminoethyl)-4-fluorophenylmethanoI The (+)-¥-(2-methylaminoethyl)-4-fluorophenylmethanol (+)-mandelic acid salt prepared by the process described in step (i) was suspended in 250 mL of water and basified to pH 8.5-9.0 with sodium carbonate. The resultant base was extracted into toluene, and distilled off solvent under vaccum to get 18 g of title compound as liquid. Optical rotation is +32.1 (c = 1, MeOH). HPLC purity is 99.8%. • Advantages of the Present Invention 1. The compound of the formula-I is obtained in more than 90% yield compared to 70-75%) obtained by the processes earlier reported. 2. Formation of des-fluoro impurity by the process of the present invention is less than 0.02% compared to more than 0.5% by the earlier reported hydrogenation process. 3. Process is suitable for the production of compound of the formula-I on commercial scale. WE CLAIM 1. An improved process for the preparation of -(2-methylaminoethyl)-4-fluorophenylmethanol of formula-I, Which comprises: (i) Reducing 3-chloro-l-(4-fluorophenyl)propan-l-one of the formula-X, with sodium borohydride in alcohoHc solvent medium at a temperature of 0-40°C to yield 3-chloro-l-(4-fluorophenyl)propan-l-ol of formula-XI, (ii) Aminating the resulting 3-chloro-l-(4-fluorophenyl)propan-l-ol of the formula-XI with N-methylbenzylamine in an alcoholic solvent medium by maintaining the pressure in the range of 0-lOOpsi, and the temperature in the range of 25-100°C to get 3-(benzyl(methyl)amino)-l-(4-fluorophenyl)propan-l-ol of the formula-V, (iii) N-Debenzylating 3-(benzyl(methyl)amino)-l-(4-fluorophenyl)propan-l-ol of the formula-V under metal catalyzed hydrogenation conditions by using one equivalent of an acid to the compound of the formula-V to get the compound of formula I in its salt form (iv) Neutralizing the resultant salt of the compound of formula-I with a base and extracting the pure base into an organic solvent to get the compound of formula-I 2. A process as claimed in claim 1 wherein the alcoholic solvent used in step (i) is selected from methanol, ethanol, isopropanol, or isomers of butanol, preferably, methanol or isopropanol. 3. A process as claimed in claims 1 & 2 wherein the alcoholic solvent used in step (ii) is selected from methanol, ethanol, isopropanol, preferably methanol or isopropanol. 4. A process as claimed in claims 1-3 wherein a pressure in the range of 0-100psi of inert gas is used in the reaction in step (ii). 5. A process as claimed in claims 1-4 wherein the temperature in the range of 25-100°C is used in the reaction in step (ii). 6. A process as claimed in claims 1-5 wherein a metal catalyst used in hydrogenation step (iii) which is selected from Raney nickel, palladium-on-carbon, platinum-on-carbon, rhodium-on-alumina. 7. A process as claimed in claims 1-6 wherein the acid used in step (iii) is selected from acetic acid, propionic acid, mandelic acid, oxalic acid, succinic acid, benzoic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid. 8. A process as claimed in claims 1-7 wherein the base used in step (iv) is selected from ammonia, sodium or potassium bicarbonate, carbonate or hydroxide. 9. A process as claimed in claims 1-8 wherein the solvent used in step (iv) is selected from ethers such as diethyl ether, diisorpopyl ether, esters like ethyl acetate halogenated solvents such as methylene chloride, ethylene dichloride, hydrocarbon solvents such as toluene, cyclohexane, heptane. 10. An improved process for the preparation of compound of formula-I substantially as described in Examples 1 to 4. Dated this 04th October 2004

Documents:

858-CHE-2003 CORRESPONDENCE-OTHERS 03-11-2009.pdf

858-che-2003-abstract.pdf

858-che-2003-claims.pdf

858-che-2003-correspondnece-others.pdf

858-che-2003-correspondnece-po.pdf

858-che-2003-description(complete).pdf

858-che-2003-description(provisional).pdf

858-che-2003-form 1.pdf

858-che-2003-form 19.pdf

858-che-2003-form 5.pdf

abs-858-che-2003.jpg