Title of Invention

A PROCESS FOR THE PREPARATION OF 4-FLUORO-α- (2-MONO- OR DISUBSTITUTED-AMINOETHYL) PHENYLMETHANOLS

Abstract An improved and general process for the 4-fluoro-α -(2-dialkylaminoethyl)- phenylmethanols of formula-I is disclosed in the present invention. Compound of the formula-I (R' = H, R" = Me) is an important intermediate for the synthesis of (+)-trans- 4-( 4-fluorophenyl)-3-hyroxymethyl-l-methylpiperidine of the formula-II. The compound of the formula-II is an advanced intermediate widely used for the synthesis of antidepressant drug, paroxetine hydrochloride of the formula-III. According to the process of present invention iodo compound of formula-XIII is reacted with various primary or secondary amines to get the compounds of formula-I. Compound of formula- XIII is made from the readily available known chloro analogue.
Full Text INTRODUCTION:
The present invention relates to an improved process for the preparation of 4-fluoro-oc-(2-mono- or disubstituted-aminoethyl)phenylmethanols. The 4-fluoro-oc-(2-mono- or di-substitutedaminoethyl)phenylmethanols prepared by the process of the present invention have the general formula-I given below:

wherein, R" = H, R" = methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenylmethyl, etc.; R" & R" may also be methyl, ethyl, propyl, phenylmethyl, etc.; and R" and R" together may form piperidino, morpholino, pyrrolidino, N-methylpiperazino, N-ethylpiperazino, etc.
Compounds of the formula-I where R" = H, R" = Me is an important intermediate for the synthesis of (±)-trans-4-(4-fluorophenyl)-3-hyroxymethyl-l-methylpiperidine of the formula-II given below. The compound of the formula-II is an advanced intermediate widely used for the synthesis of antidepressant drug, paroxetine hydrochloride of the formula-Ill. Paroxetine hydrochloride is commercially available in the market as an anti¬depressant, which inhibits 5-hydroxytryptamine (5-HT) reuptake.


8ACKGROUND OF INVENTION:
Compound of the formula-I where R" = H, R" = Me, (4-fluoro-x-(2-methylamino-ethyl)phenylmethanol) is 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 pending Indian Patent application no 830/MAS/2002. In that patent application we have described two routes for the preparation of compound of the formula-I.
In the first route (Scheme-I shown below) the Mannich salt of the formula-IV is reduced with a reducing agent to get the hydroxy compound of the formula-V. The resulting 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, we have observed that one major drawback of this process is that defluorination is also possible during debenzylation step resulting in x-(2-methyl-aminoethyl)phenylmethanol of the formula-VI. Removal of this impurity of the formula-VI to an acceptable level (

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 the compound of the formula-I (Scheme-II shown below). The compound of the formula-VIII is reacted with a reducing agent to get the hydroxy compound of the formula-IX. This compound of the formula-IX is reacted with a chlorofomate derivative to get the urethane derivative of the formula-X. The urethane derivative of the formula-X is hydrolyzed with alkali to get the compound of the formula-I, free from the impurity of the formula-VI.
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-X which leads to the cost escalation of the process and also creating environmental pollution problems. Also, the hydrolysis step is slow and requiring high temperature (100-140°C) causing slow rate of reaction leading to less production. Further, prolonged heating at higher temperature (in the plant scale) may lead to color and quality problems of the final compound of the formula-I.

Scheme-II Keeping in view of the difficulties in the above-mentioned processes we continued our R & D for developing an alternative, simple, economical and commercially applicable process for the preparation of compound of the formula-I. Our efforts were successful and an improved, simple, economical and commercially applicable process could be

developed Also, this process is general and applicable to make various 4-fluoro-oc-(2-mono- or disubstituted-aminoethyl)phenyl-methanols of the formula-I.
Accordingly the present invention provides an improved process for the preparation of compound of formula-I,

wherein, R" = H, R" = methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenylmethyl; R" & R" may also represent methyl, ethyl, propyl, phenylmethyl; R" & R" together may form piperidino, morpholino, pyrrolidino, N-methylpiperidino, N-ethylpiperidino or its acid addition sahs which comprises: (i) Reacting the chloro compound of the formula-XII

with sodium iodide in acetone medium at reflux temperature to get the iodo compound of formula-XIII,

(ii) Reacting the resulting compound of the formula-XIII with the amine of formula-XIV,
R"R"NH XIV

Wherein,
R" = H, R" = methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenylmethyl; R" &R" represent methyl, ethyl, propyl, phenylmethyl; R" & R" together may form piperidino, morpholino, pyrrolidino, N-methylpiperidino, N-ethylpiperidino in alcoholic or aqueous or both at a temperatutre in the range of ambient to 200°C.
(iii) Isolating the resulting compound of the formula-I by removal of the alcoholic
solvent by distillation under reduced pressure (iv) Suspending the residue in water and extracting the compound of the formula-I
into non-polar solvent (v) Distilling the solvent and isolating the compound of the formula-I by
distillation or crystallization and if required (vi) Purifying the compound of the formula I by crystallization and (vii) Preparing the acid addition salts thereof by conventional methods
The above process is shown in the reaction Scheme-Ill indicated below:

The starting material, P-chloro-4-fluoropropiophenone of the formula-XI is prepared by following the Friedel-Crafts acylation method on fluorobenzene given in J. Chem. Soc, Chem. Commun., 1986, (13), pl018-19. The known compound of the formula-XII may

be prepared by the process described in Suom. Kemistilehti B 1970, 43(12), 512-16; CA; 74, 63686b.
In a preferred embodiment of the invention the alcoholic solvent used in reaction of step (iii) may be selected from methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol, preferably methano, ethanol or isopropanol.
The temperateure which may be employed in the reaction of step (ii) may be between 20-120°C, more preferably 20-80°C and the pressure preferably atmospheric to 6kg, preferably atmospheric to 3kg.
The solvent used for extraction of the crude compound of formula-I may be selected from methylene chloride, chloroform, ethyl acetate, toluene, cyclohexane, ether, isopropyl ether, preferably ethyl acetate, cyclohexane, isopropyl ether or toluene. The solvent used for re-crystallization of compound of the formula-I may be is selected from hexane, cyclohexane, ethyl acetate, isopropyl ether, isopropanol or a mixture there of
The acid addition salts of the compound of the formula-I may be prepared by treating the compound of the formula-I with acids selected from oxalic acid, acetic acid, benzoic acid, succinic acid, maleic acid, p-toluenesulfonic acid, preferably oxalic acid
In a preferred embodiment of the present invention compound of formula-XIII is reacted with a primary amine or secondary amine in alcoholic medium or aqueous alcoholic medium at a temperature of 20-100°C with or without pressure. In case of reaction under pressure the pressure is in the range of l-5kg. The alcoholic solvent used in the reaction is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, sec-butanol, t-butanol, etc.
The product formed in the reaction is isolated by distillation of the alcoholic solvent; suspension of the residue in water and extraction of product into a non-polar solvent, and distillation of solvent to get the crude compound of the formula-I. The crude compound

of the formula-I can be purified by simple crystallization, via acid addition salt or by column chromatography. The organic solvent used for extraction of compound of formula-I is selected from methylene chloride, chloroform, ethyl acetate, toluene, cyclohexane, ether, isopropyl ether, etc.
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.
Preparation 1
Preparation of 4-fluoro-oc-(2-iodoethyl)phenyiniethanol
Into a 2 L, three-necked, RB flask was charged 930 mL of acetone, 93 g of 4-fluoro-oc-(2-chloroethyl)phenylmethanol, and 93 g of sodium iodide. The reaction mixture was slowly heated to reflux temperature and maintained at reflux for 36hr. The reaction mixture was cooled to 25-30 °C, filtered the inorganic solids and the solvent distilled off from the filtrate under vaccum. The residue was dissolved in 500 mL of IPE, added 15 g of carbon, heated to 40-45 °C, and filtered on a hiflow bed. IPE was distilled off from the filtrate under vaccum to get 120 g of crude solid. To the crude added 100 mL of IPE and 600 mL of hexane. After stirring and maintaining at 25-30 °C for 1 hr solids were filtered and dried at 25-30 °C to get 100 g of title compound as white solid. Purity by HPLC was found to be >97%. M. P. is 46.2 °C. IR (KBr): 3224, 2949, 2894, 1603, 1510, 1448, 1422, 1350, 1328, 1296, 1224, 1203, 1172, 1156, 1123, 1094, 1029, 1009, 838, 702, 573, and 542cm-1 1H-NMR (300MHz, CDCI3): 7.26-7.38 (m, 2H, Ar. H); 7.00-7.09 (m, 2H, AT. H); 4.78-4.86 (m, IH, -CH(OH)); 3.10-3.37 (m, 2H, -CH2I); 2.03-2.33 (m, 2H, -CH2CH2I); 1.99 (d, J = 3.3Hz, exch. with D2O, IH, -CH(OH)).
Example 1
Preparation of 4-fluoro-cx:-(2-propylaniinoethyI)phenylniethanol
Into a 250mL, three-necked, RB flask was charged 30 mL of methanol and 10 g of propylamine. The solution was cooled to 10-15 °C and added a solution of 4-fluoro-oc-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL) over a period of 15 min. The

reaction temperature was raised to 25-30 °C and maintained for 12-13 hr. Methanol was distilled off from reaction mass. The residue was dissolved in toluene (100 mL) and washed with water (50 mL). Water layer was extracted with 50 mL of toluene and the combined toluene layer washed with 50ml of water. Toluene was distilled off under vaccum to get 6 g of crude compound.
The above crude compound was dissolved in 4 mL of IPE and 10 mL of hexane at 50 °C. The reaction mass was cooled to 0-5 °C, maintained for 1 hr and filtered. The solid was washed with 10 mL of cold hexane and air dried to get 5 g of title compound as white solid. M. P. is 63 °C. IR(KBr): 3278, 3072, 2963, 2882, 2820, 2762, 1606, 1508, 1475, 1233, 1114, 1078, 942, 875, 831, 578, 554, and 530cm-1 "H-NMR (300MHz, CDCI3): 7.26-7.37 (m, 2H, Ar. H); 6.97-7.06 (m, 2H, Ar. H); 4.93 (dd, J = 3.3Hz, 8.8Hz, IH, -CH(OH)-); 3.76 (br. s, exch. with D2O, IH, -NH); 2.80-3.03 (m, 2H, -NCH2); 2.50-2.72 (m, 2H, -NCH2); 1.66-1.91 (m, 2H, -CH(0H)CH2); 1.44-1.63 (m, 2H, -CH2CH3); 0.95 (t, J = 7.3Hz, 3H,-CH2CH3).
Example 2
Preparation of 4-fluoro-K-(2-diisopropylaininoethyl)phenyImethanol
Into a 500 mL stainless steel kettle was taken 200 mL of methanol, 60 g of diisopropylamine, and 20 g of 4-fluoro-Qc-(2-iodoethyl)phenylmethanol. The kettle was filled with nitrogen (40 psi pressure) and heated to 60-65 °C. The reaction mass was maintained for 22-23 hr and cooled to 25-30 °C. Nitrogen pressure was released, transferred the mass into a single-necked RB flask, and distilled off methanol under vaccum. To the residue 100 mL of toluene and 50 mL of water were added. After stirring for 10 min separated the layers and water layer extracted with 50 mL of toluene. Combined toluene layer was washed with 50 mL of water, dried over sodium sulfate and distilled off solvent below 60 °C to get 15 g of crude compound. The crude compound was purified over a column of silica gel by first eluting with ethyl acetate/hexane (1:1) and then with methanol/ethyl acetate (3:7) to get 10 g of title compound as syrup. IR (neat): 3179, 2969, 1604, 1510, 147, 1391, 1369, 1220, 1200, 1168, 1058, 835, 816, and 774cm•^ "H-NMR (300MHZ, CDCI3): 7.31-7.38 (m, 2H, Ar. H); 6.95-7.04 (m, 2H, Ar.

H); 4.86 (dd, J = 2.6Hz, 9.9Hz, IH, -CH(OH)-); 3.11-3.25 (m, 2H, -NCH2); 2.76-2.85 (m, 4H, 2 X -NCH2); 1.54-1.94 (m, 2H, -CH2CH2N); 1.15 (d, J = 7.0Hz, -CH(CH3)2); 1.03 (d, J = 6.6Hz, -CH(CH3)2).
Example 3
Preparation of 4-fluoro-oc-(2-cyclohexylaminoethyl)phenylinethanol
A 250 mL, three-necked, RB flask was charged with 13 g of cyclohexylamine and 30 ml of methanol. To the reaction mixture a solution of 4-fluoro-Qc-(2-iodoethyl)-phenylmethanol (5 g) in methanol (10 mL) is added over a period of 20 min. The reaction mass was heated to reflux temperature and maintained at reflux for 3 hr. Methanol was distilled off from reaction mass. Water (50 mL) and toluene (100 mL) were added to the residue and stirred for 15 min. Layers were separated and the aqueous layer extracted with 50 mL of toluene. Combined toluene layer was washed with 50 mL of water, dried with sodium sulfate and distilled off solvent under vaccum.
The above residue (3 g) was dissolved in acetone (18 mL) and added 2 g of oxalic acid dihydrate. The resulting slurry was heated to 50 °C, cooled to 25-30°C. After maintaining for 1 hr, filtered the mass and the solid washed with 5 mL of acetone, dried at 50 °C to get 3.5 g of solid oxalate salt. M. P. is 156.6 °C.
Neutralization of above salt with sodium hydroxide, extraction into toluene, and distillation of solvent gave 2.5 g of white solid. M. P. is 71.9 °C. IR (KBr): 3262, 3164, 2928, 2851, 2799, 1603, 1508, 1450, 1370, 1218, 1178, 1154, 1114, 1074, 908, 832, 571, and 541cm-\ "H-NMR (300MHz, CDCI3): 7.26-7.37 (m, 2H, Ar. H); 6.97-7.10 (m, 2H, Ar. H); 4.93 (dd, J = 2.9Hz, 8.4Hz, IH, -CH(OH)); 2.79-3.49 (m, 2H, -NCH2); 2.37-2.51 (m, IH, -NCH); 1.58-1.93 (m, 7H); 0.99-1.37 (m, 5H).
Example 4
Preparation of 4-fluoro-oc-(2-(4-methylpiperazinyl)aminoethyl)phenylmethanol
Into a 250 mL, three-necked RB flask was charged 30 mL of methanol and 5 g of N-methylpiperazine. The solution was cooled to 10-15 °C and added a solution of 4-fluoro-

x-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL). The reaction temperature was raised to 25-30 °C and maintained for 12-13 hr. Methanol was distilled off from reaction mass under vaccum. The residue was dissolved in toluene (100 mL) and washed with water (50 mL). Separated the layers and water layer extracted with 50 mL of toluene. Combined toluene layer was washed with 50 mL of water, dried over sodium sulfate, and distilled off toluene below 60 °C to get 7 g of crude compound.
The crude compound obtained above was dissolved in 5 mL of IPE and 10 mL of hexane at 40 °C. The solution was cooled to 25-30 °C, maintained for 1 hr and filtered. The wet cake was washed with 5 mL of hexane and air dried to get 5 g of tile compound as white solid. M. P. is 107.9 °C. IR (KBr): 3071, 2942, 2803, 2693, 1601, 1506, 1457, 1297, 1283, 1216, 1161, 1138, 1052, 1010, 940, 845, 818, 740, 560, and 544cm-". "H-NMR (300MHz, CDCI3): 7.26-7.38 (m, 2h, Ar. H); 6.97-7.08 (m, 2H, Ar. H); 6.80 (br. s, IH, -CH(OH)); 4.91 (t, J = 5.5Hz, IH, -CH(OH)); 2.39-2.78 (m, lOH, 5 x -NCH2); 2.30 (s, 3H, -NCH3); 1.77-1.86 (m, 2H, -CH2CH2N).
Example 5
Preparation of 4-fluoro-oc-(2-ethylaininoethyl)phenylinethanol
Into a 250 mL, three-necked, RB flask was charged 10 g of aqueous ethylamine and 30 mL of methanol. The solution was cooled to 10-15 °C. A solution of 4-fluoro-oc-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL) was added to the reaction mass. The temperature of reaction mass was raised to 25-30 °C and maintained for 12-13 hr. Methanol was distilled off from the reaction mass below 40 °C. The residue was dissolved in toluene (75 mL) and washed with water (50 mL). Water layer was extracted with 50 mL of toluene. Combined toluene layer was washed with 50 mL of water, dried over sodium sulfate and distilled off toluene below 60 °C to get 5 g crude compound.
The above crude compound was dissolved in 10 mL of acetone and added 2 g of oxalic acid dihydrate. The reaction mass (thick slurry) was heated to 40 °C (clear solution) and cooled to 25-30 °C. IPE (30 mL) was added to the reaction mass, stirred for 1 hr and

filtered. Wet cake was washed with 10 mL of IPE, dried the solid at 25-30 °C to get 5 g of white oxalate salt of title compound. M. P. is 139-142 °C.
The above salt was neutralized using aqueous sodium hydroxide, extracted the liberated base into toluene, and distilled off solvent below 60 °C to get title compound as syrup. Oxalate salt IR (KBr): 3384, 2983, 2800, 1709, 1702, 1606, 1511, 1404, 1279, 1222, 1159, 1118, 1061, 839, and 720cm-1. "H-NMR (300MHZ, CDCI3): 7.27-7.37 (m, 2H, Ar. H); 6.97-7.07 (m, 2H, Ar. H); 4.89-4.95 (dd, J= 3.3Hz, 8.4Hz, IH, -CH(OH); 4.10 (br. s, IH, -NH), 2.81-3.02 (m, 2H, -NCH2); 2.56-2.79 (m, 2H, -NCH2); 1.65-1.90 (m, 2H, -CH(OH)CH2CH2); 1.13 (t, J = 7.2Hz, 3H, -CH2CH3).
Example 6
Preparation of 4-fluoro-Qc-(2-isopropyIaminoethyI)phenylinethanol
A 250 mL, three-necked, RB flask was charged with 9 g of isopropylamine and 30 mL of methanol. To the reaction mixture was added a solution of 4-fluoro-oc-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL) over a period of 20 min. The reaction mass was stirred at room temperature for 3 days. Methanol was distilled off from reaction mass. Water (50 mL) and toluene (100 mL) were added to the residue and stirred for 15 min. Layers were separated and the aqueous layer extracted with 50 mL of toluene. Combined toluene layer was washed with 50 mL of water, dried and distilled off solvent under vaccum.
The residue (4 g) was dissolved in acetone (10 mL) and added 2.5 g of oxalic acid dihydrate. The resulting slurry was heated to 50 °C, cooled to 25-30 °C. After maintaining for 1 hr, fihered the mass and the solid washed with 5 mL of acetone, dried at 50 °C to get 4 g of white oxalate saU of title compound. M. P. is 160.4°C.
Neutralization of the above salt with aqueous sodium hydroxide, extraction into toluene, and distillation of solvent under vaccum gave 2.5 g of white solid. M. P. is 60.3°C. IR (KBr): 3263, 3103, 2975, 2925, 2816, 1607, 1509, 1475, 1383, 1344, 1229, 1154, 1079, 1064, 1049, 928, 900, 836, 720, 578, and 552cm-\ "H-NMR (300MHz, CDCI3): 7.26-

7.39 (m, 2H, Ar. H); 6.97-7.07 (m, 2H, Ar. H); 4.93 (dd, J = 2.9Hz, 8.4Hz, IH, -CH(OH)); 3.80 (br. s, IH, NH); 2.74-3.03 (m, 3H, -NCHj, -NCH); 1.65-1.92 (m, 2H, -CH2CH2N); 1.11 (d, J = 1.8Hz, 3H, -CHCH3); 1.08 (d, J= 1.9Hz, 3H, -CHCH3).
Example 7
Preparation of 4-fluoro-a:-(2-cyclopropylaininoethyl)phenyImethanoI
A 250 mL, three-necked, RB flask was charged with 5 g of cyclopropylamine and 30 ml of methanol. To the reaction mixture was added a solution of 4-fluoro-oc-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL) over a period of 20 min. The reaction mass was heated to reflux temperature and maintained at reflux for 5 hr. Methanol was distilled off from reaction mass. Water (50 mL) and toluene (100 mL) were added to the residue and stirred for 15 min. Layers were separated and the aqueous layer extracted with 50 mL of toluene. Combined toluene layer was washed with 50 mL of water, dried over sodium sulfate and distilled off toluene under vaccum.
The residue (3 g) was dissolved in acetone (8 mL) and added 2 g of oxalic acid dihydrate. The resulting solution was cooled to 0-5°C, added 10 mL of diisopropyl ether, and maintained for 1 hr. Solid was fihered, washed with 5 ml of chilled acetone, dried at 50 °C to get 3 g of white crystalline oxalate salt of title compound. M. P. is 143.4°C. Oxalate salt IR (KBr): 3398, 2950, 2768, 1719, 1702, 1512, 1279, 1221, 1157, 1081, 830, and 720cm-\ "H-NMR (300MHz, CDCI3): 7.22-7.48 (m, 2H, Ar. H); 6.85-7.19 (m, 2H, Ar. H); 6.75 (br. s, IH, -NH); 4.82 (t, J = 7.3Hz, IH, -CH(OH)); 3.25 (br. s, 2H, -NCH2); 2.55-2.62 (m, IH, -NCH); 2.04-2.17 (m, 2H, -CH2CH2N); 1.02-1.03 (m, 2H, -cycloprpyl-CH2); 0.68-0.77 (m, 2H, -cyclopropyl-CH2).
Example 8
Preparation of 4-fluoro-a:-(2-t-butyIaminoethyl)phenylmethanol
Into a 250 mL, three-necked, RB flask was charged 8 g of t-butylamine and 30 mL of methanol. The reaction mixture was cooled to 15-20 °C and added a solution of 4-fluoro-oc-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL). After allowing to rise the temperature to 25-30 °C, the reaction mass was stirred for 10 hr. The reaction mass was

heated to reflux and maintained for 4 hr. Methanol was distilled off from the reaction mass under vaccum. The residue was diluted with toluene (75 mL) and water (50 mL) added. After stirring for 20 min, layers were separated, aqueous layer extracted with toluene (50 mL). Combined toluene layer was washed with water (50 mL), dried with sodium sulfate, and evaporated to get 6 g of crude compound. The crude compound was dissolved in acetone (10 mL), treated with 4 g of oxalic acid dihydrate. After stirring for 1 hr at 25-30 °C, 40 mL of IPE was added, maintained for 1 hr, filtered, and dried at 50-60 °C to get 5 g of white oxalate salt of title compound. M. P. is 123.7°C.
The above sah was dissolved in water, neutralized with sodium hydroxide, extracted with toluene. Toluene layer was dried, and distilled off under vaccum to get 4 g of title compound as white solid. M. P. is 79.6°C. IR (KBr): 3263, 3088, 2940, 2849, 2685, 1604, 1507, 1494, 1364, 1310, 1222, 1116, 1080, 874, 847, 821, 788, and 755cm-1 "H-NMR (300MHz, CDCI3): 7.26-7.38 (m, 2H, Ar. H); 6.97-7.05 (m, 2H, Ar. H); 4.93 (dd, J = 2.6Hz, 8.8Hz, IH, -CH(OH)); 2.74-3.00 (m, 2H, -NCH2); 1.83-1.94 (m, IH, -CH2CH2N); 1.63-1.74 (m, IH, -CH2CH2N); 1.13 (s, 9H, 3 x CH3).
Example 9
Preparation of 4-fluoro-Qc-(2-diethylaminoethyl)phenylmethanol
Into a 250 mL, three-necked RB flask was charged 30 mL of methanol and 13 g of aqueous diethylamine. The resulting solution was cooled to 10-15 °C and added a solution of 4-fluoro-x-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL). After stirring for 1 hr at same temperature the reaction mass allowed to reach 25-30 °C and maintained for 12-13 hr. Methanol was distilled off" from reaction mass and the residue dissolved in toluene (100 mL) and washed with water (50 mL). Water layer was extracted with toluene (50 mL) and the combined toluene layer was washed with water (50 mL). Toluene was distilled off below 60 °C to get 3.5 g of title compound as oil. IR (neat): 3178, 2975, 2931, 2827, 1605, 1508, 1471, 1385, 1220, 1197, 1155, 1065, 836, 819, and 774cm-\ ^H-NMR (300MHz, CDCI3): 7.26-7.39 (m, 2H, Ar. H); 6.97-7.05 (m, 2H, Ar. H); 4.89 (dd, J = 4.4Hz, 7.3Hz, IH, -CH(OH)); 2.41-2.79 (m, 6H, 3 x -CH2)); 1.73-1.81(m, 2H, -CH2CH2N); 1.09 (t, J = 7.0Hz, 6H, 2 x -CH3).

Example 10
Preparation of 4-fluoro-oc-(2-inethylaminoethyl)phenylmethanoI
Into a 250 mL, three-necked RB flask was charged 30 mL of methanol and 13 g of aqueous methylamine. The resulting solution was cooled to 10-15 °C and added a solution of 4-fluoro-x-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL). After stirring for 1 hr at same temperature the reaction mass allowed to reach 25-30 °C and maintained for 12-13 hr. Methanol was distilled off from reaction mass and the residue dissolved in toluene (100 mL) and washed with water (50 mL). Water layer was extracted with toluene (50 mL) and the combined toluene layer was washed with water (50 mL). Toluene was distilled off below 60 °C to get 5 g crude compound.
The above crude compound was dissolved in acetone (10 mL) and added oxalic acid dihydrate (0.8 g). The reaction mass was heated to 40 °C, maintained for 30 min and cooled to 25-30 °C and filtered. Wet cake was washed with 5 mL of acetone, dried at 50-60 °C to get 4 g of white crystalline sohd of title compound. M. P. is 139 °C.
The above salt was neutralized with aqueous sodium hydroxide, extracted into toluene and distilled off toluene below 60 °C to get the base. The resulting base was suspended in hexane and fihered to get 2.5 g of title compound as white crystalline solid. M. P. is 68.6 °C. IR(KBr): 3288, 3054, 2936, 2800, 1602, 1506, 1479, 1421, 1359, 1337, 1220, 1154, 1112, 1077, 1014, 986, 855, 824, 572, and 529cm-\ ^H-NMR (300MHz, CDCI3): 7.26-7.37 (m, 2H, Ar. H); 6.95-7.07 (m, 2H, Ar. H); 4.92 (dd, J = 3.3Hz, 8.4Hz, IH, -CH(OH)); 3.77 (br. s, IH, -NH); 2.78-2.95 (m, 2H, -CH2N); 2.45 (s, 3H, -NCH3); 1.67-1.89(m, 2H,-CH2CH2N).
Example 11
Preparation of (+)-4-fluoro-oc-(2-dimethylaminoethyl)phenylmethanol
Into a IL, three-necked RB flask was charged 300 mL of methanol and 150 g of aqueous dimethylamine. The resuhing solution was cooled to 10-15 °C and added a solution of 4-fluoro-oc-(2-iodoethyl)phenylmethanol (50 g) in methanol (100 mL). After stirring for 1

hr at same temperature the reaction mass allowed to reach 25-30 °C and maintained for 12-13 hr. Methanol was distilled off from reaction mass and the residue dissolved in toluene (150 mL) and washed with water (100 mL). Water layer was extracted with toluene (100 mL) and the combined toluene layer was washed with water (100 mL). Toluene was distilled off below 60 °C to get 50 g of crude compound.
The above crude compound was taken into a 500 mL three-necked RB flask and added 250 mL of IP A. (+)-Mandelic acid (38 g) was added to the reaction mass and heated to 45-50 °C. After maintaining at same temperature for 1 hr, reaction mass was slowly cooled to 40 °C, fihered, and dried to get 36.5 g of salt. This salt was once recrystallized from IPA to get 32.5 g of salt. M. P. of this salt is 130-133 °C and OR is (+) 15.83° (c = L0,MeOH)
The above salt (32 g) was neutralized with aqueous sodium hydroxide and extracted the liberated base into toluene, distilled off toluene below 60 °C to get 18 g crude compound. To the crude 40 mL of hexane added and stirred for 1 hr at 15-20 °C, filtered and dried to get 12 g of title compound as white solid. M. P, is 44.7 °C and OR is (-) 3L75° (c = 1.0, MeOH).
Example 12
Preparation of (-)-4-fluoro-oc-(2-dimethylaminoethyl)phenylmethanol
The crude Mandelate salt mother liquors and RC mother liquors of above experiment were combined, distilled of IP under vacuum to get crude compound. The crude compound was suspended in water and neutralized with aqueous sodium hydroxide, extracted the liberated base into toluene, and distilled off toluene below 60 °C to get 28 g of base. This was dissolved in 150 mL of IPA and added (-)-Mandelic acid (18.7 g). After heating to 60 °C and maintaining for 1 hr, reaction mass was cooled to 40 °C and filtered the solid. The resulting solid was once recrystallized from IPA to get pure Mandelate salt.

The above Mandelate salt was dissolved in water, neutralized with aqueous sodium hydroxide, extracted the liberated base into toluene, and distilled off toluene below 60 °C to get 16.5 g of the crude base. The crude base was suspended in hexane, filtered, and dried at 25-30 °C to get 15 g of title compound as white sohd. M. P. is 44 °C and OR is (+) 31.5° (c = 1.0, MeOH). IR (KBr): 3357, 2950, 2864, 2826, 2763, 1604, 1509, 1466, 1220, 1156, 1078, 1052, 1014, 838, 773, 581, and 559cm-". "H-NMR (300MHZ, CDCI3): 7.26-7.42 (m, 2H, Ar. H); 6.93-7.15 (m, 2H, Ar. H); 4.91 (t, J = 6.0 Hz, IH, -CH(OH)); 2.61-2.74 (m, IH, -CH2N); 2.39-2.51 (m, IH, -CH2N); 2.30 (s, 6H, 2 x -NCH3); 1.73-1.96(m,2H,-CH2CH2N).
Example 13
Preparation of 4-fluoro-ac-(2-dibenzyiaininoethyl)phenylmethanoI
Into a 250 mL, three-necked ElB flask was charged 30 mL of methanol and 7.5 g of dibenzylamine. The resulting solution was cooled to 10-15 °C and added a solution of 4-fluoro-oc-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL). After stirring for 1 hr at same temperature the reaction mass allowed to reach 25-30 °C and maintained for 12-13 hr. Methanol was distilled off from reaction mass and the residue dissolved in toluene (100 mL) and washed with water (50 mL). Water layer was extracted with toluene (50 mL) and the combined toluene layer was washed with water (50 mL). Toluene was distilled off below 60 °C to get 5 g of title compound as syrup. IR (neat): 3252, 3086, 3062, 3029, 2945, 2823, 1604, 1509, 1496, 1453, 1374, 1221, 1155, 1106, 1074, 1028, 1014, 882, 836, 750, 733, and 699cm-\ "H-NMR (300MHz, CDCI3): 7.21-7.44 (m, lOH, Ar. H); 7.11-7.19 (m, 2H, Ar. H); 6.86-6.96 (m, 2H, Ar. H); 4.65 (dd, J = 2.3Hz, 8.0Hz, IH, -CH(OH)); 3.79 (d, J = 14.3Hz, 2H, PhCH2-); 3.37 (d, J = 13.2Hz, 2H, PhCH2-); 2.73-2.86 (m, IH, -CH2CH2N); 2.53-2.64 (m, IH, -CH2CH2N); 1.42-1.90 (m, 2H, -CH2CH2N).
Example 14
Preparation of 4-fluoro-oc-(2-prrolidinylaminoethyl)phenylmethanol
Into a 250 mL, three-necked RB flask was charged 30 mL of methanol and 5 g of pyrrolidine. The resulting solution was cooled to 10-15 °C and added a solution of 4-

fluoro-oc-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL). After stirring for 1 hr at same temperature the reaction mass allowed to reach 25-30 °C and maintained for 12-13 hr. Methanol was distilled off from reaction mass and the residue dissolved in toluene (100 mL) and washed with water (50 mL). Water layer was extracted with toluene (50 mL) and the combined toluene layer was washed with water (50 mL). Toluene was distilled off below 60 °C to get 4 g crude compound. Recrystallization from hexane afforded 3 g of title compound as white crystalline soUd. M. P. is 79-81 °C. ER. (KBr); 3094, 2970, 2942, 2819, 1603, 1506, 1315, 1222, 1130, 1096, 1083, 1056, 880, 832, 579, and 547cm"\ ^H-NMR (300MHz, CDCI3): 7.31-7.42 (m, 2H, Ar. H); 6.93-7.10 (m, 2H, Ar. H); 4.95 (dd, J = 2.0Hz, 7.5Hz, IH, -CH(OH)); 2.80-3.00 (m, IH); 2.48-2.78 (m, 6H); 1.68-1.87 (m,6H).
Example IS
Preparation of 4-fluoro-x-(2-piperidinylaminoethyl)phenyImethanoi
Into a 250 mL, three-necked RB flask was charged 30 mL of methanol and 5 g of piperidine. The resulting solution was cooled to 10-15 °C and added a solution of 4-fluoro-a:-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL). After stirring for 1 hr at same temperature the reaction mass allowed to reach 25-30 °C and maintained for 12-13 hr. Methanol was distilled off from reaction mass and the residue dissolved in toluene (100 mL) and washed with water (50 mL). Water layer was extracted with toluene (50 mL) and the combined toluene layer was washed with water (50 mL). Toluene was distilled off below 60 °C to get 5 g crude compound. Recrystallization from IPE gave 3.8 g of title compound as white crystalline solid. M. P. is 64-65 °C. IR (KBr): 3112, 2944, 2925, 2856, 2815, 2784, 1603, 1508, 1475, 1440, 1317, 1293, 1222, 1185, 1153, 1117, 1094, 1080, 1053, 872, 832, 765, 578, and 550cm-". "H-NMR (300MHZ, CDCI3): 7.22-7.42 (m, 2H, Ar. H); 6.93-7.15 (m, 2H, Ar. H); 4.91 (t, J = 4.0Hz, IH, -CH(OH)); 2.43-2.71 (m, 6H, 3 X-NCH2); 1.47-1.91 (m, 8H, 4 X-CH2).

Example 16
Preparation of 4-fluoro-oc-(2-inorpholinylaiminoethyl)phenylinethanol
Into a 250 mL, three-necked RB flask was charged 30 mL of methanol and 3.5 g of morpholine. The resulting solution was cooled to 10-15 °C and added a solution of 4-fluoro-oc-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL). After stirring for 1 hr at same temperature the reaction mass allowed to reach 25-30 °C and maintained for 12-13 hr. Methanol was distilled off from reaction mass and the residue dissolved in toluene (100 mL) and washed with water (50 mL). Water layer was extracted with toluene (50 mL) and the combined toluene layer was washed with water (50 mL). Toluene was distilled off below 60 °C to get 5 g crude compound. Recrystallization from a mixture of hexane/IPE afforded 3.5 g of title compound as white crystalline solid. M. P. is 54-55 °C. IR (KBr): 3512, 3356, 3219, 3070, 2962, 2935, 2871, 2831, 1602, 1508, 1451, 1269, 1214, 1159, 1134, 1118, 1073, 1007, 870, 842, 766, 580, and 551cm-1 1H-NMR (300MHz, CDCI3): 7.27-7.39 (m, 2H, Ar. H); 6.98-7.08 (m, 2H, Ar. H); 6.56 (br. s, IH, -CH(OH)); 3.76 (t, J = 4.4Hz, IH, -CH(OH)); 3.76 (t, J = 4.4Hz, 4H, -CH2OCH2-); 2.46-2.78 (m, 6H, 3 x -NCH2); 1.79-1.88 (m, 2H, -CH2CH2N).
Example 17
Preparation of 4-fluoro-oc-(2-(N-benzyl-N-methylamino)ethyl)phenylmethanol
Into a 250 mL, three-necked RB flask was charged 300 mL of methanol and 47.5 g of N-benzyl-N-methylamine. The resulting solution was cooled to 10-15 °C and added a solution of 4-fluoro-oc-(2-iodoethyl)phenylmethanol (50 g) in methanol (100 mL). After stirring for 1 hr at same temperature the reaction mass allowed to reach 25-30 °C and maintained for 12-13 hr. Methanol was distilled off from reaction mass and the residue dissolved in toluene (300 mL) and washed with water (150 mL). Water layer was extracted with toluene (100 mL) and the combined toluene layer was washed with water (100 mL). Toluene was distilled off below 60 °C to get 50 g crude compound. The crude product was crystallized from hexane to get 40 g of the title compound as white crystalline solid. M. P. is 65.5-66.0 °C. IR (KBr): 3063, 2826, 1603, 1509, 1465, 1219, 1078, 1027, 832, 740, and 697 cm-1 "H-NMR (300MHz, CDCI3): 7.25-7.37 (m, 6H,

ar.H); 6.94-7.05 (m, 3H, ar.H); 4.87 (dd, J = 4.IH2, 7.IH2, IH, -CH(OH)-); 3.65 (d, J = 2.8Hz, IH, PhCH2); 3.46 (d, J = 2.8Hz, IH, PhCHj); 2.75-2.90 (m, IH); 2.52-2.64 (m, IH); 2.27 (s, 3H, -NCH3); 1.79-1.89 (m, 2H, -NCH2CH2-).
Example 18
Preparation of 4-fluoro-oc-(2-benzylaminoethyl)phenylmethanol
Into a 250 mL, three-necked RB flask was charged 30 mL of methanol and 10 g of benzylamine. The resuhing solution was cooled to 10-15 °C and added a solution of 4-fluoro-x-(2-iodoethyl)phenyImethanoI (5 g) in methanol (10 mL). After stirring for 1 hr at same temperature the reaction mass allowed to reach 25-30 °C and maintained for 12-13 hr. Methanol was distilled off from reaction mass and the residue dissolved in toluene (100 mL) and washed with water (50 mL). Water layer was extracted with toluene (50 mL) and the combined toluene layer was washed with water (50 mL). Toluene was distilled off below 60 °C to get 4 g of crude compound. This was purified over a column of silica gel (initially eluted with hexane and then with ethyl acetate/methanol) to get 3 g of title compound as syrup. IR (neat): 3298, 3064, 3030, 2918, 2844, 1604, 1510, 1454, 1338, 1220, 1156, 1104, 1078, 1029, 1014, 837, 745, and 699cm"\ "H-NMR (300MHZ, CDCI3): 7.23-7.40 (m, 2H, Ar. H); 6.94-7.03 (m, 2H, Ar. H); 4.91 (dd, J = 2.9Hz, 8.1Hz, IH, -CH(OH)); 4.04 (br. s, IH, exch. with D2O, -NH), 3.79 (d, J = 0.9Hz, 2H, PhCHa-); 2.80-3.00 (m, 2H, -CH2N); 1.70-1.92 (m, 2H, -CH2CH2N).
Example 19
Preparation of 4-fluoro-cx:-(2-(4-ethylpiperazinyl)aminoethyl)phenylmethanol
Into a 250 mL, three-necked RB flask was charged 30 mL of methanol and 6 g of N-ethylpiperazine. The resulting solution was cooled to 10-15 °C and added a solution of 4-fluoro-oc-(2-iodoethyl)phenylmethanol (5 g) in methanol (10 mL). After stirring for 1 hr at same temperature the reaction mass allowed to reach 25-30 "C and maintained for 12-13 hr. Methanol was distilled off from reaction mass and the residue dissolved in toluene (100 mL) and washed with water (50 mL). Water layer was extracted with toluene (50 mL) and the combined toluene layer was washed with water (50 mL). Toluene was distilled off below 60 °C to get 4.1 g crude compound. Recrystallization of the crude

from hexane (10 mL) and isolation at 5-10 °C gave 3.8 g of title compound as white solid. M. P. is 77.2°C. IR (KBr); 3158, 2938, 2814, 2769, 1605, 1510, 1468, 1448, 1349, 1308, 1270, 1222, 1161, 1130, 1070, 1008, 942, 856, 837, 764, 575, and 554cm-". "H-NMR (300MHz, CDCl3): 7.27-7.37 (m, 2H, Ar. H); 6.93-7,01 (m, 2H, Ar. H); 4.90 (t, J = 5.9Hz, IH, -CH(OH)); 2.32-2.78 (m, lOH, 5 x -CH2N); 2.43 (q, J = 7.3Hz, 2H, -NCH2CH3); 1.72-1.93 (m, 2H, -CH2CH2N); 1.09 (t, J = 7.3Hz, 3H, -NCH2CH3).
Advantages of present invention:
1) The process is simple reaction, economical and commercially applicable.
2) The process is general and can be applied to various secondary or tertiary amine derivatives of formula-I.
3) Since the present process does not require hydrogenation, the problem of removing desfluoro impurity of the formula-VI is avoided thereby making the process simple and economical.
4) Purity (desfluoro impurity is nil) of the compound of the formula-I (R" = H, R" = Me) is better than the earlier process disclosed in our pending patent application no. 830/MAS/2002 for the preparation of compound of the formula-I (R" = H, R" = Me).

We Claim:
1. A process for the preparation of 4-fluoro-oc-(2-dialkylaminoethyl)-phenyImethanols of formula-I,

wherein, R" = H, R" = methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenylmethyl; R" & R" represent methyl, ethyl, propyl, phenylmethyl; R" & R" together form piperidino, morpholino, pyrrolidine, N-methylpiperidino, N-ethylpiperidino or its acid addition salts which comprises:
(i) Reacting 4-fluoro-oc-(2-chloroethyl)-phenylmethanol of formula-XII,

with sodium iodide in acetone medium at reflux temperature to get 4-fluoro-Qc-(2-iodoethyl)-phenylmethanol of formula-XIII,

(ii) Reacting the resulting compound of the formula-XIII with dialkylamine of formula-XIV,
R"R"NH XIV

Wherein,
R" = H, R" represents methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenylmethyl; R" & R" represent methyl, ethyl, isopropyl, phenylmethyl; R" & R" represent piperidino, morpholino, pyrrolidino, N-methylpiperidino, N-ethylpiperidino in alcoholic or aqueous or both at 20 to 200 °C and at pressure of 1-l00psi of nitrogen
(iii) Isolating the compound of the formula-I by removing the alcoholic solvent by
distillation under reduced pressure (iv) Suspending the residue in water and extracting the compound of formula-1
into non-polar solvent (v) Distilling the solvent and isolating the compound of the formula-I by
chromatographic purification or crystallization, if required (vi) Further purifying the compound of the formula-I by crystallization and (vii) If required preparing the acid addition salts of the compound of the formula-I
by known methods
2. An improved process as claimed in claim 1 wherein the alcoholic solvent used in reaction of step (ii) is selected from methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol, preferably methano, ethanol or isopropanol.
3. An improved process as claimed in claims 1 & 2 wherein the temperature of reaction of step (ii) is between 20-120°C, preferably 20-80°C.
4. An improved process as claimed in claims 1 to 3 wherein the pressure of reaction is atmospheric to 6kg, preferably atmospheric to 3kg.
5. An improved process as claimed in claims 1 to 4 wherein the solvent used for extraction of crude compound of formula-I is selected from methylene chloride, chloroform, ethyl acetate, toluene, cyclohexane, ether, isopropyl ether, preferably ethyl acetate, cyclohexane, isopropyl ether or toluene.
6. An improved process according to claim 1 to 5 wherein solvent used for crystallization of compound of formula-I is selected from hexane, cyclohexane, ethyl acetate, isopropyl ether, isopropanol or a mixture there of.

7. The process as claimed in claims 1-6 wherein the acid used for formation of salts of compound of formula-! is selected from oxalic acid, acetic acid, benzoic acid, succinic acid, maleic acid, p-toluenesulfonic acid, preferably oxalic acid
8. A process for the preparation of 4-fluoro-oc-(2-dialkylaminoethyl)-phenylmethanols of the formula-I herein described with reference to the Examples 1 to 19.

Documents:

461-mas-2003 abstract-duplicate.pdf

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461-mas-2003 abstract.pdf

461-mas-2003 claims-duplicate.pdf

461-mas-2003 claims.pdf

461-mas-2003 correspondence-others.pdf

461-mas-2003 correspondence-po.pdf

461-mas-2003 description (complete)-duplicate.pdf

461-mas-2003 description (complete).pdf

461-mas-2003 description (provisional).pdf

461-mas-2003 form-1.pdf

461-mas-2003 form-19.pdf

461-mas-2003 form-5.pdf

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Patent Number 215910
Indian Patent Application Number 461/MAS/2003
PG Journal Number 13/2008
Publication Date 31-Mar-2008
Grant Date 05-Mar-2008
Date of Filing 06-Jun-2003
Name of Patentee NATCO PHARMA LIMITED
Applicant Address NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD - 500 033
Inventors:
# Inventor's Name Inventor's Address
1 PULLA REDDY MUDDASANI NATCO PHARMA LTD, NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD 500 033,
2 RAJASHEKHARA REDDY PEDDI NATCO PHARMA LTD, NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD 500 033,
3 RADHARANI KAGITHA NATCO PHARMA LTD, NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD 500 033,
4 VENKAIAH CHOWDARY NANNAPANENI NATCO PHARMA LTD, NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD 500 033,
PCT International Classification Number A61K 31/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA