DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of intermediate for paroxetine and pharmaceutically acceptable salts thereof which are suitable for large scale commercial operation. The present invention further relates to a process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I.

BACKGROUND OF THE INVENTION

Pharmaceutical product paroxetine is useful as an antidepressant and anti-Parkinson. The process for preparation of paroxetine are described in US3912743A and US4007196A. An especially important intermediated compound among those disclosed is ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol.

Various processes have been described for the preparation of paroxetine, for example in US 4,007,196, EP 0219,934, EP 0223,334, EP 223,403, EP 0300,617 and Acta Chemica Scandinavica (1996) volume 50 page 164. A particularly useful starting material employed in processes described therein is (-) trans 4-(4 -fluorophenyl)-3- hydroxymethyl-1-methylpiperidine, which is the (-) form of the tra/js-piperidine carbinol.

In the process described in US4902801A, a racemic trarcs-piperidine carbinol of structure (1) is resolved by conversion to a salt with a chiral acid. In one of the example of US4902801A (+)-2 '-nitrotartranilic acid is used, and in another Example the resolving agent is (-)-di-p-toluoyltartaric acid. The (-) trans carbinol is subsequently liberated from the chiral acid salt and may then be coupled with sesamol, then deprotected, to give paroxetine.

However, above processes have the drawback that, upon deprotection of N-methyl group, complicated procedures such as hydrolysis after the transformation of N-methyl group to carbamate group are required.

The chiral acid resolving agent specified in Example of US4902801A, (+)-2 - nitrotartranilic acid, is not commercially available, and the synthesis of this acid requires a number of steps. The process of Example is therefore not suited to large scale manufacture.

An object of the present invention is to provide a compound useful as an intermediate for preparing paroxetine and a process for simply and industrially preparing the compound.

Thus, the present invention provides an efficient and industrially advantageous process for the preparation of highly pure ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I in high yields. The preparation method of the present invention has the advantages of moderate reaction condition, strong exclusivity for generating byproduct, high yield, low cost of raw materials, etc. The present invention is a new method for large-scale industrial production.

SUMMARY OF THE INVENTION

Accordingly, in one aspect, present invention provides an improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I

Comprises:
a) Prepare a mixture of Ethyl acetate and Sodium tert-butoxide 1 to 1.5 mole equivalent by addition of Sodium tert-butoxide in 2 to 4 lots at -5°C to 30°C temperature;
b) addition of 4-fluorobenzaldehyde to reaction mass in between 10 to 120 minutes;
c) addition of Ethyl 3-(methylamino)-3-oxopropanoate of compound of formula III in in presence of Sodium methoxide with mole ratio 1 to 2 mole further acidified the reaction mass with acetic acid at 0 to -5°C and followed by addition of process water at same temperature to obtain ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV;

d) prepare a complexing agent of Sodium borohydride in 2 to 3 mole equivalent and BF3.OEt2 in 2.5 to 3.5 mole equivalent in THF wherein temperature of reaction mass during diborane complex formation is between 5°C to -15 °C;
e) addition of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV in 2 to 15 lots at 5°C to -15 °C temperature in complexing agent in presence of solvent to obtain (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V;

f) reacting (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V with D-(-) Tartaric acid 1 to 2 mole equivalent in Methanol;
g) addition of Ethanol at temperature 60°C to 70 °C to filter ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI at temperature 0°C to 10 °C;

h) treatment of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI with base and solvent to obtain ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol compound of formula I.

Accordingly, in one aspect, present invention provides an improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I

Comprises:
a) Reacting 4-fluorobenzaldehyde of compound of formula II with Ethyl acetate in presences of Sodium tert-butoxide and further reacted with Ethyl 3-(methylamino)-3-oxopropanoate of compound of formula III in presences of Sodium methoxide to obtain ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV;

b) reacting of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV with complexing agent Sodium borohydride/ BF3.OEt2 in presence of solvent to obtain (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V;

c) reacting (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V with D-(-) Tartaric acid in presence of alcoholic solvent to obtain ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI;

d) treatment of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI with base and solvent to obtain ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol compound of formula I.

In another aspect, of the present invention reacting (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V with D-(-) Tartaric acid in presence of alcoholic solvent to obtain ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI.

Accordingly, an object of the present invention is to provide a method of producing ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol compound of formula I with high efficiency.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms below have the meanings indicated.

The singular forms "a," "an," and "the" may refer to plural articles unless specifically stated otherwise.

The term "about," as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

In the first embodiment the present invention provides an improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I

Comprises:
a) Prepare a mixture of Ethyl acetate and Sodium tert-butoxide 1 to 1.5 mole equivalent by addition of Sodium tert-butoxide in 2 to 4 lots at -5°C to 30°C temperature;
b) addition of 4-fluorobenzaldehyde to reaction mass in between 10 to 120 minutes;
c) addition of Ethyl 3-(methylamino)-3-oxopropanoate of compound of formula III in in presence of Sodium methoxide with mole ratio 1 to 2 mole further acidified the reaction mass with acetic acid at 0 to -5°C and followed by addition of process water at same temperature to obtain ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV;

d) prepare a complexing agent of Sodium borohydride in 2 to 3 mole equivalent and BF3.OEt2 in 2.5 to 3.5 mole equivalent in THF wherein temperature of reaction mass during diborane complex formation is between 5°C to -15 °C;
e) addition of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV in 2 to 15 lots at 5°C to -15 °C temperature in complexing agent in presence of solvent to obtain (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V;

f) reacting (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V with D-(-) Tartaric acid 1 to 2 mole equivalent in Methanol;
g) addition of Ethanol at temperature 60°C to 70 °C to filter ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI at temperature 0°C to 10 °C;

h) treatment of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI with base and solvent to obtain ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol compound of formula I.

In the another embodiment the present invention provides an improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I

Comprises:
a) Reacting 4-fluorobenzaldehyde of compound of formula II with Ethyl acetate in presences of Sodium tert-butoxide and further reacted with Ethyl 3-(methylamino)-3-oxopropanoate of compound of formula III in presences of Sodium methoxide to obtain ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV;

b) Reduction of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV with Sodium borohydride/ BF3.OEt2 in presence of solvent to obtain (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V;

c) reacting (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V with D-(-) Tartaric acid in presence of alcoholic solvent to obtain ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI;

d) treatment of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI with base and solvent to obtain ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol compound of formula I.

According to the embodiment of the present invention, there is provided a process for the preparation of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV by reacting 4-fluorobenzaldehyde of compound of formula II with Ethyl acetate in presences of Sodium tert-butoxide and further reacted with Ethyl 3-(methylamino)-3-oxopropanoate of compound of formula III in presences of Sodium methoxide to obtain ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV.

The reaction of 4-fluorobenzaldehyde of compound of formula II with Ethyl acetate in presences of Sodium tert-butoxide, at 5°C to 30°C temperature. The reaction mass is further reacted with Ethyl 3-(methylamino)-3-oxopropanoate of compound of formula III in presences of Sodium methoxide.

The reaction is preferably conducted in presence of mixture of bases such as Sodium hydride, Sodium tert-butoxide, Potassium tert-butoxide, Sodium methoxide etc. The detailed process for preparation of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate with mixture of base Sodium tert-butoxide and Sodium methoxide which provide (88 - 93%) yield and purity (91 – 95%).

Prepare a mixture of Ethyl acetate and Sodium tert-butoxide 1 to 1.5 mole equivalent by addition of Sodium tert-butoxide in 2 to 4 lots at -5°C to 30°C temperature; addition of 4-fluorobenzaldehyde to reaction mass in between 10 to 120 minutes; addition of Ethyl 3-(methylamino)-3-oxopropanoate of compound of formula III in in presence of Sodium methoxide with mole ratio 1 to 2 mole further acidified the reaction mass with acetic acid at 0 to -5°C and followed by addition of process water at same temperature to obtain ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV.

The reaction is preferably conducted in solvent or a mixture of solvents selected from the dimethylsulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, chloroform, dichloromethane, carbon tetrachloride, n-hexane, benzene, toluene, ethyl acetate, methanol, ethanol, tetrahydrofuran or dioxane or mixtures thereof.

According to the embodiment of the present invention, there is provided a process for the preparation of (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V by reaction of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV with Sodium borohydride/ BF3.OEt2 in presence of solvent to obtain (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V.

The reaction is preferably conducted in presence of complexing agent selected from the Sodium borohydride/ BF3.OEt2. Prepare a complexing agent of Sodium borohydride in 2 to 3 mole equivalent and BF3.OEt2 in 2.5 to 3.5 mole equivalent in THF wherein temperature of reaction mass during diborane complex formation is between 5°C to -15 °C.

The reaction is preferably conducted in presence Sodium borohydride/ BF3.OEt2 is used in an amount of 2 to 8 moles, preferably 3 to 6 moles, of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate. When the amount of Sodium borohydride/ BF3.OEt2 is less than 2 moles by-product is generated as an undesirable yield and when Sodium borohydride/ BF3.OEt2 is greater than 8 mol a large amount of Sodium borohydride/ BF3.OEt2 must be distilled off during a purification step, leading to a disadvantage with respect to energy consumption.

Further the complexing agent selected from Raney nickel or nickel nanoparticles on zeolite, palladium-on-carbon, platinum(IV) oxide, or Urushibara nickel, Sodium hydrosulfite, Sodium sulfide (or hydrogen sulfide and base), Tin(II) chloride, Titanium(III) chloride, Zinc, Samarium, Raney nickel, platinum-on-carbon, or zinc dust and formic acid or ammonium formate, Decaborane in presence of palladium-on-carbon and acetic acid, Hydroiodic acid.

The reaction is by addition of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV in 2 to 15 lots at 5°C to -15 °C temperature in complexing agent in presence of solvent to obtain (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V.

The reaction is preferably conducted in solvent or a mixture of solvents selected from the group consisting dimethylsulfoxide (DMSO), sulfolane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), benzene, toluene, xylene, Methanol, Ethanol, Isopropyl alcohol or mixtures thereof.

The reaction temperature is not particularly limited. However, a temperature not higher than 0? to 100?. Specifically, reaction temperature of 0? to 10? or lower is appropriate because the rate of reaction is excessively low, whereas when the temperature is 70? or higher, the amount of required heat increases due to boiling the solvent, leading to a disadvantage with respect to energy consumption.

The reaction time, which varies depending on reaction conditions and the type and amount of the catalyst employed, is typically 2-30 hours.

According to the embodiment of the present invention, there is provided a process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI by reacting (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V with D-(-) Tartaric acid in presence of alcoholic solvent to obtain ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI.

The (4-(4-fluorophenyl)-1- methylpiperidin-3-yl) methanol compound of formula V is reacted with D-(-) Tartaric acid, a solvent can be used. The solvent includes, for instance, alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, isopropanol; ketones, such as acetone and methyl ethyl ketone, and the like. Those solvents can be used alone or in an admixture thereof. Further most preferable solvents are methanol or ethanol or mixture thereof in obtaining ((3S, 4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl) methanol (2S, 3S)-2, 3-dihydroxysuccinic acid compound of formula VI having high optical purity.

According to the embodiment of the present invention, the solvent comprising methanol or ethanol or mixture thereof refers to a solvent containing at least 50% by volume of methanol or ethanol. Among the solvents comprising methanol or ethanol as a main component, methanol or a mixed solvent of methanol and at least one compound of isopropyl alcohol and acetone is desirable from the viewpoint of obtaining ((3S,4S)-4-(4-fluorophenyl) -1-methylpiperidin-3-yl) methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI having higher optical purity. Also, the mixed solvent of methanol and at least one compound of ethanol and 1%Toluene: Ethanol or isopropyl alcohol and acetone is also desirable from the viewpoint of obtaining ethanol in high yields. It is desired that the ratio of methanol to at least one compound of ethanol is such that the amount of at least one compound of ethanol is at least 10 parts by volume, preferably at least 20 parts by volume, more preferably at least 30 parts by volume, and 1%Toluene:Ethanol, based on 100 parts by volume of methanol; from the viewpoint of obtaining the ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl) methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI in high yields. In addition, the ratio of methanol to at least one compound of ethanol cannot be absolutely determined, because the optical purity of the resulting ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl) methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI may differ depending upon several factors such as amount of the solvent, temperatures during the formation of a salt, and period of time required for the formation of a salt as well as the ratio of methanol to at least one compound of isopropyl alcohol and acetone. Generally, in accordance with the increase of the ratio of methanol to at least one compound of isopropyl alcohol and acetone, its optical purity tends to be lowered. Accordingly, it is desired that the amount of at least one compound of ethanol is usually at most 500 parts by volume, preferably at most 200 parts by volume, more preferably at most 100 parts by volume, further preferably at most 60 parts by volume, particularly preferably at most 40 parts by volume, based on 100 parts by volume of methanol, from the viewpoint of improvement in optical purity.

It is desired that the amount of the solvent is at least 200 parts by weight, preferably at least 500 parts by weight, based on 100 parts by weight of the ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI with high optical purity, and that the amount of the solvent is at most 2000 parts by weight, preferably at most 700 parts by weight, based on 100 parts by weight of the ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl) methanol (2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI, from the viewpoint of improvement in yields.

When the (4-(4-fluorophenyl)-1- methylpiperidin-3-yl) methanol compound of formula V is reacted with D-(-) Tartaric acid to form a salt in a solvent, any of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S) -2,3-dihydroxysuccinic acid compound of formula VI can be firstly dissolved in the solvent.

It is desired that the amount of D-(-) Tartaric acid is at least 1.0 mol, preferably at least 1.01 mol, per one mol of the (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V compound, giving a compound with high optical purity, and that the amount of D-(-) Tartaric acid is at most 2 mol, preferably at most 1.0 mol, per one mol of the (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V compound of suppression of the residual D-(-) Tartaric acid and economic advantages.

It is desired that the temperature during the formation of a salt is at least 0° C., preferably at least 10° C., more preferably at least 20° C., from the viewpoint of acceleration of the formation of a salt, and that the temperature is at most a boiling point of the solvent used, preferably at most 40° C. Particularly, it is desired that the temperature during the formation of a salt is 20° to 35° C., and obtain ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI having high optical purity in high yields.

The atmosphere the formation of a salt is not limited to specified ones, and it may be air, or an inert gas such as nitrogen gas.

The time period required for the formation of a salt cannot be absolutely determined, because it may differ depending upon the conditions for the formation of a salt. Usually, the time period for the reaction is 1 to 24 hours or so. However, since the time period for the reaction is longer, the optical purity of the resulting ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI tends to be lowered, it is desired that the time period is as short as possible, for instance, at most 5 hours, preferably at most 3 hours.

Thus, the ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl) methanol (2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI can be precipitated as crystals by reacting the (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V with D-(-) Tartaric acid to form a salt. The resulting ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl) methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI was isolated and purified by, for instance, separating by such means as filtration, and as occasion demands, washing with the solvent and drying.

According to the embodiment of the present invention, there is provided a process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol compound of formula I by treatment of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI with base and solvent to obtain ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol compound of formula I

In the present invention, ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI is neutralized first, preferably with a base. The base is preferably selected so that the base forms a water soluble. As the base, inexpensive and readily available bases containing alkali metals are preferred, and particularly preferred are sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate and the like. Sodium hydroxide is extremely particularly preferable because it is available with high purity. It is preferred to use at least equal moles of a base, particularly from 1 to 10 times as many moles of a base, as the ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI.

EXAMPLES
Now, the present invention will be described in further details by reference to specific Examples, but the present invention is by no means restricted thereto.

Example 1: Process for preparation of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV.

A solution of p-fluorobenzaldehyde (100 g) in ethyl acetate (50 ml) was added slowly to a mixture of Sodium tert-butoxide (85.17 g) in ethyl acetate (1000 ml), maintaining the temperature at 10°-20°C. and stirring for a further 10-30 minutes at -5°C, raise reaction mass temperature to 10 - 15°C, and was maintained for 60 minutes. Sodium tert-butoxide (7.74 g) was added and reaction mass was maintained 90 minutes at 10 - 15°C. Then a solution of Ethyl 3-(methylamino)-3-oxopropanoate (128.73 g) in ethyl acetate (50 ml) was added over in 20 to 45 min whilst maintaining the temperature at 10 - 15°C. and stirring for a further 5 - 10 minutes. Sodium methoxide (78.34 g) was added over 1 – 2 hour whilst maintaining the temperature at 10°-15° C. and stirring for a further 5 to 10 hours. The resulting mixture was added to a solution of acetic acid (120 g) in water (475 ml) and stirred for 30 minutes. The lower aqueous layer was then separated and discarded. The rich solvent was washed with 10% brine solution (200 ml). The solvent was removed by vacuum distillation and replaced with Di-isopropyl ether (50 ml) then cooled with stirring to obtain the crystalline title compound. Water (600 ml) was added over 30 minutes and the mixture stirred for 1-2 hours at 15°-25° C. The product was filtered and washed with water then isopropyl ether before drying. % Yield: 93.22 %.
Wet cake : 225
Dry Wt. : 214
Practical Yield (w/w) : 2.1
Theoretical Yield : 2.36
% Yield : 93.22 %

Example 2: Process for preparation of (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V
Charged THF (200 ml) and sodium borohydride (29 gm) at 25 to 35°C. Cool reaction mass 0 to -10 °C, added BF3.OEt2 (130 gm) within 60 to 90 minutes and stirred reaction mass for 30 minutes. Charged ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV (100 gm) in 10 to 12 lot wise in 10 to 12 minutes at intervals within 120 minutes at 0 to -10 °C. Stirred reaction mass for 30 minutes, raise reaction mass temperature 25 to 35 °C and stirred reaction mass temperature for 120 minutes. Raised reaction mass temperature 40 to 45 °C and stirred reaction mass for 240 minutes. Cool reaction mass 0 to -5 °C. Sideways arranged another RBF having water: HCl solution (500 ml: 120 ml) and cool reaction mass 0 to -10 °C. Added reaction mass to water: HCl solution at 0 to -10 °C and stirred reaction mass for 30 minutes. Raise reaction mass temperature 25 to 35 °C and stirred reaction mass for 60 minutes. Cool reaction mass 0 to -5 °C and filter the reaction mass with chilled THF (50 ml). Raised reaction mass temperature 65 to 70 °C and distilled out THF atmospherically. Cool reaction mass 0 to 5 °C, adjust pH of reaction mass to 12 to 13 using caustic lye charged Toluene (300 ml). Raised reaction mass temperature 60 to 70 °C, stirred and separated organic layer. Aqueous layer further extracted with Toluene (150 ml X 2), combined organic layer washed with water (200 ml). Distilled out reaction mass under vacuum, Charged Toluene (40 ml) and n-Heptane (160 ml) at 40 to 45 °C and cool reaction mass 0 to 10 °C. Stirred reaction mass for 30 minutes, filter reaction mass and washed w/c with n-Heptane (50 ml X 2). Dry w/c for 8 hours at 50 to 60 °C to obtain (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V.
Results:
Weight of wet cake : 71 g
Weight of dried product : 67 g
Yield ratio (w/w) : 0.67
Theoretical Yield ratio : 0.76
% Yield : 88.15%

Example 3: Process for preparation of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI
Arranged 1.0 liter four neck RBF fitted with thermo pocket condenser and stopper in water tub charge Methanol (350 ml) and D-(-) Tartaric acid (67.88 g) at 25 - 35°C. Add (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V (100 g) in Ethanol (50 ml) heat reaction mass temperature to clear solution at 60°C. Stir reaction mass for 30 minute at temperature range of 5 C ranges. Wash the wet cake with chilled Ethanol. The solids were collected by filtration, washed with Ethanol, and dried.
Results:
Weight of wet cake : 80 to 90 g
Weight of dried product : 70 to 80 g
Yield ratio (w/w) : 0.7 to 0.8
Theoretical Yield ratio : 0.84
% Yield : 83 to 95.23

Example 4 : Process for preparation of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol compound of formula I.
Solid ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol (2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI (100 g) in Water (100 ml) and was added to toluene (400 mL), and aqueous sodium hydroxide (to Adjust pH of reaction mass to 11.25 to 11.75) was added with stirring. The resulting solution was stirred for 50 minutes and then allowed to stand. After separation of the toluene layer, the remaining aqueous layer was extracted with toluene (930 mL), and the toluene extract was combined with the previously separated toluene layer. Then, the toluene layer was distil out under vacuum. Reaction mass was washed with n-Heptane (100 ml), dried to give paroxetine free base.
Results:
Weight of wet cake : 60 to 55 g
Weight of dried product : 59 to 50 g
Yield ratio (w/w) : 0.59 to 0.50
Theoretical Yield ratio : 0.60
% Yield : 98.33 to 84.74

Example 5 : Process for preparation of of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol compound of formula I
Stage-01:
1. Providing a mixture comprising of formula II with Ethyl acetate in presence of Sodium tert-butoxide 1 to 1.5 mole equivalent having respectively.
2. The addition of Sodium tert-butoxide added in 2 to 4 lots during preparation of Step-I at -5°C to 30°C temperature preferably.
3. The addition of 4-fluorobenzaldehyde to reaction mass in between 10 to 120 minutes.
4. During preparation of formula IV step-I reaction carried out between temperature ranges at -5°C to 30°C.
5. The step-I of formula IV further reaction with Ethyl 3-(methylamino)-3-oxopropanoate in presence of Sodium methoxide with mole ratio 1 to 2 mole equivalent respectively.
6. The addition of Sodium methoxide in 2 to 6 lots during preparation of formula IV at -5°C to 30°C temperature preferably.
7. The addition of Ethyl 3-(methylamino)-3-oxopropanoate to reaction mass in between 10 to 120 minutes.
8. During preparation of formula IV reaction carried out between temperature ranges at -5°C to 30°C.
9. Preparation of Formula IV by using mixture of bases such as Sodium methoxide and Sodium tert-butoxide to minimise the formation intermediate impurity.
10. Before quenching acidified the reaction mass with acetic acid at 0 to -5°C and followed by addition of process water at same temperature.
11. Formula IV is prepared by using mixture of Sodium tertiary butoxide: sodium methoxide with mole ratio 0.66.
Stage-02:
1. Solvent includes, for instance, such as THF, Isopropanol; ketones, such as acetone, 1,4-dioxane and ethereal solvents.
2. Providing a mixture of comprising Formula IV, Sodium borohydride 2 to 3, BF3.OEt2 2.5 to 3.5 mole equivalent respectively in THF.
3. Temperature of reaction mass during diborane complex formation between 5°C to -15 °C.
4. Addition of BF3.OEt2 to reaction mass in between 30 to 150 minutes at 5°C to -15 °C preferably.
5. Charging of PXN-01 in reaction mass in 2 to 15 lots at 5°C to -15 °C temperature preferably.
6. Formula V is prepared firstly by formation of complex of Sodium borohydride with BF3.OEt2 in THF solvent then lot wise addition of Formula IV. Complex formation in initial stage is preferred.
Stage-03:
1. Solvent includes, for instance, alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, isopropanol; ketones, such as acetone and methyl ethyl ketone.
2. Providing a mixture of comprising Formula V, D-(-) Tartaric acid 1 to 2 mole equivalent in Methanol and Ethanol and mixture of there of.
3. Preparation of formula VI using formula V and D-(-) Tartaric acid in Methanol at temperature 60°C to 70 °C.
4. Filtration temperature of formula VI at temperature 0°C to 10 °C.
5. Purification of formula VI using Ethanol solvent or mixture of Methanol and Ethanol.
Stage-04:
1. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, base selected from sodium hydroxide, potassium hydroxide and dibasic metal carbonates.

Result & Discussion:

Preparation of Ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate (Formula IV) :

Reaction of 4-fluorobenzaldehyde with Ethyl acetate in presence of base and further reaction of in-situ intermediate with Ethyl 3-(methylamino)-3-oxopropanoate in presence of base to form ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate which provides 75% yields and purity 90%. The details of lab experimental batches are as below,

Sr. No. Batch No. Input (gm) Output (gm) Yield (%) Purity
1. 21/PXN-01/004/010 20 30 63.55 89.58
2. 21/PXN-01/004/012 50 80 67.79 83.44
3. 21/PXN-01/012/003 20 35 74.15 88.50

To improve yield and quality we did the reaction in presence of mixture of bases such as Sodium hydride, Sodium tert-butoxide, Potassium tert-butoxide, Sodium methoxide etc. The detailed process for preparation of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate with mixture of base Sodium tert-butoxide and Sodium methoxide is described in Example 1 which provide (88 - 93%) yield and purity (91 – 95%). The details of lab validation batches are as below,

Sr. No. Batch No. Input (gm) Output (gm) Yield (%) Purity
1. 21/PXN-01/012/001 160 338.1 89.53 94.24
2. 21/PXN-01/012/002 160 338.6 89.67 93.64
3. 21/PXN-01/012/003 160 336.5 89.11 92.90

Preparation of (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol (Formula V):
Reaction of Ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate with sodium borohydride in tetrahydrofuran at 0 to -10°C. Addition of BF3.OET2 in tetrahydrofuran at 0 to -10°C to obtained (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol which provides 65 to 72% yield and 95 to 98% purity. The details of lab experimental batches are as below,

Sr. No. Batch No. Input (gm) Output (gm) Yield (%) Purity
1. 21/PXN-02/004/020 50 20 52.63 99.33
2. 21/PXN-02/004/021 50 24.8 65.26 99.20
3. 21/PXN-02/004/023 50 14.1 37.10 77.62

To improve yield and quality we changed the addition pattern by forming first the complex of Sodium borohydride with BF3.OET2 in tetrahydrofuran at 0 to -5°C. To this complex was added Ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate in lots 10 to 12 lots to give (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol with 87 to 93% yield and purity above 99%. The details of lab validation batches are as below,

Sr. No. Batch No. Input (gm) Output (gm) Yield (%) Purity
1. 21/PXN-02/012/004 300 207.5 91.00 99.49
2. 21/PXN-02/012/005 300 207.7 91.09 99.39
3. 21/PXN-02/012/006 300 208.3 91.30 99.60

,CLAIMS:We Claim,
1. An improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I

Comprises:
a) Prepare a mixture of Ethyl acetate and Sodium tert-butoxide 1 to 1.5 mole equivalent by addition of Sodium tert-butoxide in 2 to 4 lots at -5°C to 30°C temperature;
b) addition of 4-fluorobenzaldehyde to reaction mass in between 10 to 120 minutes;
c) addition of Ethyl 3-(methylamino)-3-oxopropanoate of compound of formula III in in presence of Sodium methoxide with mole ratio 1 to 2 mole further acidified the reaction mass with acetic acid at 0°C to -5°C and followed by addition of process water at 0°C to -5°C temperature to obtain ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV;

d) prepare a complexing agent of Sodium borohydride in 2 to 3 mole equivalent and BF3.OEt2 in 2.5 to 3.5 mole equivalent in THF wherein temperature of reaction mass during diborane complex formation is between 5°C to -15 °C;
e) addition of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate compound of formula IV in 2 to 15 lots at 5°C to -15 °C temperature in complexing agent in presence of solvent to obtain (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V;

f) reacting (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V with D-(-) Tartaric acid 1 to 2 mole equivalent in Methanol;
g) addition of Ethanol at temperature 60°C to 70°C to filter ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI at temperature 0°C to 10 °C;

h) treatment of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI with base and solvent to obtain ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol compound of formula I.

2. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, process of preparation of Formula IV is prepared by using mixture of Sodium tertiary butoxide: sodium methoxide with mole ratio 0.66, at 5°C to 30°C temperature.

3. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, process of step (a) reaction is preferably conducted in solvent or a mixture of solvents selected from the dimethylsulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, chloroform, dichloromethane, carbon tetrachloride, n-hexane, benzene, toluene, ethyl acetate, methanol, ethanol, tetrahydrofuran or dioxane or mixtures thereof.

4. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, process of step (d) addition of BF3.OEt2 to reaction mass in between 30 to 150 minutes at 5°C to -15 °C,

5. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, process of step (e) complexing agent selected from, Sodium borohydride/ BF3.OEt2, Raney nickel or nickel nanoparticles on zeolite, palladium-on-carbon, platinum(IV) oxide, or Urushibara nickel, Sodium hydrosulfite, Sodium sulfide (or hydrogen sulfide and base), Tin(II) chloride, Titanium(III) chloride, Zinc, Samarium, Raney nickel, platinum-on-carbon, or zinc dust and formic acid or ammonium formate, Decaborane in presence of palladium-on-carbon and acetic acid, Hydroiodic acid.

6. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, process of step (e) firstly formation of complex of Sodium borohydride with BF3.OEt2 in THF solvent then lot wise addition of Formula IV, wherein complex formation in initial stage is preferred.

7. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, process of step (e) complexing agent is Sodium borohydride/ BF3.OEt2.

8. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, process of step (e) Sodium borohydride/ BF3.OEt2 is used in an amount of 2 to 8 moles, preferably 2.5 to 3.5 moles, of ethyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate.

9. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, process of step (c) solvent is selected from the group consisting dimethylsulfoxide (DMSO), sulfolane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), benzene, toluene, xylene, Methanol, Ethanol, Isopropyl alcohol, acetone, 1,4-dioxane and ethereal solvents or mixtures thereof.

10. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, wherein, process of step (f) solvent is selected from methanol, ethanol, Toluene, isopropyl alcohol and acetone mixture thereof.

11. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, solvent includes, for instance, alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, isopropanol; ketones, such as acetone and methyl ethyl ketone.

12. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, base selected from sodium hydroxide and potassium hydroxide

13. The improved process for the preparation of ((3S,4S)-4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol of formula I as claimed in claim 1 wherein, process for preparation of ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI comprises of reacting (4-(4-fluorophenyl)-1- methylpiperidin-3-yl)methanol compound of formula V with D-(-) Tartaric acid in presence of alcoholic solvent to obtain ((3S,4S)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol(2S,3S)-2,3-dihydroxysuccinic acid compound of formula VI.

Dated this 25th Day of June, 2022