Claims:We claim:

1. A process for preparation of N-benzyl-3-hydroxy piperidine of Formula 1

comprising the steps of:
a) reacting 3-hydroxy pyridine of Formula 2 with benzyl halide of Formula 3 in the presence of hydrocarbon solvents to form 1-benzyl-3-hydroxypyridinium chloride of Formula 4;

wherein, X is selected from chloro, bromo and iodo

b) de-aromatizating 1-benzyl-3-hydroxypyridinium chloride of Formula 4 with sodium borohydride in presence of a solvent and suitable base to form N-benzyl-3-hydroxy piperidine of Formula 1.

2. The process as claimed in claim 1, wherein the hydrocarbon solvents are selected from cyclohexane, toluene and xylene.

3. The process as claimed in claim 1, wherein the ratio of 1-benzyl-3-hydroxypyridinium chloride of Formula 4 to sodium borohydride is 1:1-1:2.

4. The process as claimed in claim 1, wherein the base used in step b) is selected from alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide and alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate.

5. The process as claimed in claim 1, wherein the ratio of 1-benzyl-3-hydroxypyridinium chloride of Formula 4 to the base is 1:1 to 1:1.5.

6. The process as claimed in claim 1, wherein the solvent used in step b) is selected from C1-4 alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol and ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methylether, dioxane, 2-methyl tetrahydrofuran.

7. The process as claimed in claim 1, wherein the temperature in step b) is maintained in a range of 40-60 0C.

8. The process as claimed in claim 1 further comprising resolving N-benzyl-3-hydroxy piperidine of Formula 1 using (-)-camphor sulfonic acid in the presence of acetone to form camphor sulfonic acid salt of (3R)-diastereomer of Formula 5 and camphor sulfonic acid salt of (3S)-diastereomer of Formula 6.

9. The process as claimed in claim 8, wherein the camphor sulfonic acid salt of (3R)-diastereomer of Formula 5 is treated with suitable alkali to break the salt thereby forming compound of Formula 5A.

10. The process as claimed in claim 9, wherein the alkali is bicarbonate selected from sodium bicarbonate and potassium bicarbonate.

11. The process as claimed in claim 9, wherein the compound of Formula 5A is racemized using a suitable base and recycled back in the resolution of N-benzyl-3-hydroxy piperidine of Formula 1.

12. The process as claimed in claim 11, wherein the base is selected from alkali metal alkoxide such as sodium alkoxide, potassium alkoxide and alkali metal carbonates such as sodium carbonate, calcium carbonate, cesium carbonate.

13. The process as claimed in claim 8, wherein the camphor sulfonic acid salt of (3S)-diastereomer of Formula 6 is treated with a suitable alkali to break the salt thereby forming (3S)-isomer of Formula 6A.

14. The process as claimed in claim 13, wherein the alkali is bicarbonate selected from sodium bicarbonate and potassium bicarbonate.

15. The process as claimed in claim 13 further comprising debenzylating (3S)-isomer of Formula 6A using suitable catalyst in the presence of a first solvent to form (3S)-piperidine-3-ol of Formula 7 followed by reacting (3S)-piperidine-3-ol of Formula 7 with di-t-butyl-dicarbonate in the presence of a base and a second solvent to form (3S)-1-tert-butyloxycarbonyl-piperidine-3-ol of Formula 8.

16. The process as claimed in claim 15, wherein the catalyst used is selected from Pd/C, Pd(OH)2 and Raney nickel.

17. The process as claimed in claim 15, wherein the first solvent used in debenzylation is selected from tetrahydrofuran, methylene dichloride and alcoholic solvent such as methanol, ethanol, propanol, iso-propanol.

18. The process as claimed in claim 15, wherein the second solvent used is selected from dioxane, methylene dichloride, chloroform, tetrahydrofuran, acetonitrile, methanol, ethanol, iso-propanol and mixtures thereof.

19. The process as claimed in claim 15, wherein the base used is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and triethylamine.

Dated this 27th day of May, 2016

For Aarti Industries Limited,
By their Agent

(ANAND MAHURKAR)
Patent Agent No.: IN/PA- 1862
KRISHNA & SAURASTRI ASSOCIATES
, Description:FORM 2
THE PATENT ACT 1970
(39 OF 1970)
&
THE PATENT RULES, 2005
COMPLETE SPECIFICATION
[SEE SECTION 10 AND RULE 13]

PROCESS FOR PREPARATION OF N-BENZYL-3-HYDROXY PIPERIDINE

AARTI INDUSTRIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ADDRESS, 71, UDYOG KSHETRA, 2ND FLOOR, MULUND GOREGAON LINK ROAD, MULUND (W) MUMBAI, 400080, MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

Field of the invention

The present invention relates to a process for preparation of N-substituted-3-hydroxypiperidine and more particularly, to an improved process for preparation of N-benzyl-3-hydroxy piperidine.

Background of the invention

N-substituted-3-hydroxypiperidine of Formula (A) is well-known in the art as an important intermediate in the manufacturing of Ibrutinib, an anti-cancer drug and Benidipine hydrochloride, a calcium channel blocker.

P is protecting group selected from benzyl and t-butyloxycarbonyl (BOC) and represent bonds.

In the preparation of both these drugs (R)-isomer of N-substituted-3-hydroxy piperidine is required. The purity and cost of this intermediate affects the purity and cost of final active pharmaceutical ingredient.

Advanced Synthesis & Catalysis (2013), 355(1), 35-40 reports hydrogenation of various quaternary ammonium salt by using iodide anion promoted rhodium catalyst dimer [Cp*RhCl2]2. The yield obtained is 63% using 0.005mol% catalyst. However, the rhodium catalyst is very costly and hence the process is not financially feasible.

CN101817779 reports preparation of N-benzyl substituted-3-piperidinol by reacting 3-hydroxypyridine with benzyl chloride to give n-benzyl-3-hydroxypyridine, a quaternary ammonium salt followed by catalytic reduction using nickel to give N-benzyl-3-piperidinol.

Use of metal catalysts like rhodium or nickel for reduction of N-benzyl pyridine hydrochloride quaternary ammonium salt to N-benzyl-3-hydroxy piperidine is costly due to high cost of the metal thereby increasing overall cost of the synthesis.

CN102351783 reports synthesis of 1-benzyl-piperidone hydrochloride. The process comprises adding 3-hydroxypyridine to an organic solvent and refluxing under a temperature of 100 to 110 DEG C followed by addition of benzyl halide. The product obtained is treated with sodium borohydride in an alcoholic solvent. The application reports reaction time of 10-12 hours. Sodium borohydride required is around 2 moles with respect to N-benzyl pyridine hydrochloride quaternary ammonium salt. The patent further reports preparation of N-benzyl piperidone hydrochloride by Swern oxidation of 3-hydroxy piperidine.

CN103204801 reports synthesis of N-Boc-3-piperidone by reacting 3-hydroxyl pyridine with benzyl bromide in an organic solvent to obtain N-benzyl-3-hydroxyl pyridine quaternary ammonium salt followed by reduction with sodium borohydride to obtain N-benzyl-3-hydroxyl piperidine. Sodium borohydride required is around two moles with respect to N-benzyl 3-hydroxy pyridine hydrochloride quaternary ammonium salt.

As the number of moles of sodium borohydride used in prior art processes is higher (1:2 - 1:2.5) thereby affecting the overall costing of the process. Also, the prior art processes require much higher reaction time.
Accordingly, there is a need of a cost effective and industrially feasible process for preparation of N-benzyl-3-hydroxy piperidine that overcomes the above mentioned drawbacks of the prior art.

Objects of the invention

An object of the present invention is to provide an improved process for preparation of N-benzyl-3-hydroxy piperidine that consumes less moles of sodium borohydride.

Another object of the present invention is to provide the improved process for preparation of N-benzyl-3-hydroxy piperidine that reduces reaction time.

Yet another object of the present invention is to provide the improved process for preparation of N-benzyl-3-hydroxy piperidine that provides higher yield and better purity.

Another object of the present invention is to provide a cost effective and industrially feasible process for preparation of N-benzyl-3-hydroxy piperidine.

Yet another object of the present invention is to provide the improved process for preparation of N-benzyl-3-hydroxy piperidine and use thereof in preparation of (3S)-1-tert-butyloxycarbonyl-piperidine-3-ol.

Summary of the invention

Accordingly, in one aspect, the present invention teaches an improved process for preparation of N-benzyl-3-hydroxy piperidine of Formula 1. The process comprises reacting 3-hydroxy pyridine of Formula 2 with benzyl halide of Formula 3 in the presence of hydrocarbon solvents to form 1-benzyl-3-hydroxypyridinium chloride of Formula 4. Further, 1-benzyl-3-hydroxypyridinium chloride of Formula 4 is de-aromatizated with sodium borohydride in presence of a solvent and suitable base to form N-benzyl-3-hydroxy piperidine of Formula 1. The temperature of the reaction is maintained in a range of 40-60 0C. More preferably the temperature is 50-55 0C.

The ratio of 1-benzyl-3-hydroxypyridinium chloride of Formula 4 to sodium borohydride is 1:1-1:2, preferably 1:1-1:1.5. The ratio of 1-benzyl-3-hydroxypyridinium chloride to base is 1:1 to 1:1.5, preferably 1:1.

Further, the present invention teaches resolution of compound of Formula 1. N-benzyl-3-hydroxy piperidine of Formula 1 is resolved using (-)-camphor sulfonic acid (hereinafter "CSA") in the presence of acetone to form CSA salt of (3R)-diastereomer of Formula 5 and CSA salt of (3S)-diastereomer of Formula 6. The CSA salt of (3R)-diastereomer of Formula 5 is treated with suitable alkali to break the salt thereby forming compound of Formula 5A. The compound of Formula 5A is racemized using a suitable base and recycled back in the resolution of N-benzyl-3-hydroxy piperidine of Formula 1. The compound of Formula 6 is treated with a suitable alkali to break the salt thereby forming (3S)-isomer of Formula 6A.

In another aspect, the present invention provides a process for preparation of (3S)-1-tert-butyloxycarbonyl-piperidine-3-ol of Formula 8. The process comprises debenzylating compound of Formula 6A prepared by process of the present invention using suitable catalyst in the presence of a first solvent to form (3S)-piperidine-3-ol of Formula 7. Further, compound of Formula 7 is reacted with di-t-butyl-dicarbonate in the presence of a base and a second solvent to form compound of Formula 8.

Detailed description of the invention

The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.
In one aspect, the present invention relates to a process for preparation of N-benzyl-3-hydroxy piperidine of Formula 1. The process comprises reacting 3-hydroxy pyridine of Formula 2 with benzyl halide of Formula 3 in the presence of hydrocarbon solvents to form 1-benzyl-3-hydroxypyridinium chloride of Formula 4. The hydrocarbon solvents are selected from cyclohexane, toluene and xylene. Preferably, the solvent is toluene.

Further, compound of Formula 4 is de-aromatizated with sodium borohydride in presence of a solvent and suitable base to form compound of Formula 1. The temperature of the reaction is maintained in a range of 40-60 0C. More preferably the temperature is 50-55 0C.
The ratio of 1-benzyl-3-hydroxypyridinium chloride of Formula 4 to sodium borohydride is 1:1-1:2, preferably 1:1-1:1.5.

The solvent is selected from C1-4 alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol and ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methylether, dioxane, 2-methyl tetrahydrofuran.

The base is selected from alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium isopropoxide, potasium methoxide, potassium ethoxide, potassium isopropoxide, alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate.

The ratio of 1-benzyl-3-hydroxypyridinium chloride to base is 1:1 to 1:1.5, preferably 1:1.

The reaction scheme of preparing compound of Formula 1 is represented below:

X is selected from chloro, bromo and iodo.

Further, N-benzyl-3-hydroxy piperidine of Formula 1 is resolved using suitable resolving agent, preferably (-)-camphor sulfonic acid (hereinafter "CSA"). The reaction is carried out in presence of acetone. The temperature of the reaction is maintained in a range of 70-75 0C. After completion of the reaction, a reaction mass is cooled to 20-25 0C to form CSA salt of (3R)-diastereomer of Formula 5 and CSA salt of (3S)-diastereomer of Formula 6.

The compound of Formula 5 is recovered from an organic layer. Further, the compound of Formula 5 is treated with suitable alkali to break the salt thereby forming compound of Formula 5A. The alkali is bicarbonate selected from sodium bicarbonate and potassium bicarbonate. The compound of Formula 5A is racemized and recycled back in the resolution of N-benzyl-3-hydroxy piperidine of Formula 1. The racemization is achieved by treating the organic layer with a suitable base. The base is selected from alkali metal alkoxide such as sodium alkoxide, potassium alkoxide and alkali metal carbonates such as sodium carbonate, calcium carbonate and cesium carbonate. However, it is understood here that the racemization may be achieved by using resins in other alternative embodiments of the present invention.

The compound of Formula 6 is purified by isopropyl alcohol. The pure salt of compound of Formula 6 is dissolved in water and treated with a suitable alkali to break the salt thereby forming (3S)-isomer of Formula 6A. The alkali is bicarbonate selected from sodium bicarbonate and potassium bicarbonate. The process of the present invention provides 70-75% yield of (3S)-isomer of Formula 6A.

The reaction scheme of resolving compound of Formula 1 is represented below:

In another aspect, the present invention relates to a process for preparation of (3S)-1-tert-butyloxycarbonyl-piperidine-3-ol of Formula 8. The compound of Formula 6A prepared by the process of the present invention is debenzylated using a suitable catalyst in the presence of a first solvent to form (3S)-piperidine-3-ol of Formula 7. The reaction is carried out by hydrogenation in presence of suitable catalyst selected from Pd/C, Pd(OH)2 and Raney nickel.

The first solvent is selected from tetrahydrofuran, methylene dichloride and alcoholic solvent such as methanol, ethanol, propanol, iso-propanol. The temperature of the reaction is maintained in a range of 0-40 0C. Preferably, the reaction is carried out using 10% pd/C in ethanol at room temperature.

Further, compound of Formula 7 is reacted with di-t-butyl-dicarbonate in the presence of a base and a second solvent to form 3(S)-1-tert-butyloxycarbonyl-piperidine-3-ol of Formula 8. The base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and triethylamine.

The second solvent is selected from dioxane, methylene dichloride, chloroform, tetrahydrofuran, acetonitrile, methanol, ethanol, iso-propanol and mixtures thereof. The reaction is carried out at room temperature.

The reaction scheme of preparing compound of Formula 8 is represented below:

EXAMPLES
The following examples illustrate the invention, but are not limiting thereof.
Example 1
Preparation of 1-benzyl-3-hydroxy pyridinium chloride

3-hydroxy pyridine (100 g) was added to toluene (500 ml) at 25-30 0C. The mixture was stirred and heated to 75-80 0C. Benzyl chloride (162 ml) was added gradually over the period of 3-4 hours. After complete addition of benzyl chloride, the reaction mass was stirred for 2-3 hours at 75-80 0C. Gradually the mixture was cooled to 25-30 0C and stirred for 1-2 hours. The solid obtained was filtered and washed with toluene (100 ml). The solid obtained was suck dried and washed with acetone (100 ml) at 25-30 0C. The solid obtained was suck dried under vacuum at 60-65 0C for 4-5 hours to obtain quaternary ammonium salt of 1-benzyl-3-hydroxy pyridinium chloride (225 g).

Example 2
Preparation of 1-benzyl-3-hydroxy pyridinium chloride

3-hydroxy pyridine (1 kg) was added to toluene (5 L) at 25-30 0C. The mixture was stirred and heated to 75-80 0C. Benzyl chloride (1.62 L) was added gradually over the period of 3-4 hours. After complete of addition of benzyl chloride, the reaction mass was stirred for 2-3 hours at 75-80 0C. Gradually the mixture was cooled to 25-30 0C and stirred for 1-2 hours. The solid obtained was filtered and washed with toluene (1 L). The solid obtained was suck dried and washed with acetone (1 L) at 25-30 0C. The solid obtained was suck dried under vacuum at 60-65 0C for 4-5 hours to obtain quaternary ammonium salt of 1-benzyl-3-hydroxy pyridinium chloride (2.1 kg).

Example 3
Preparation of 1-benzyl piperidine-3-ol

1-benzyl-3-hydroxy pyridinium chloride (100 g) obtained in example 1 was charged in isoppropyl alcohol (500 ml). Sodium methoxide (25 g) was added lot wise to the reaction mixture at 25-30 0C. The reaction mixture was stirred for 30 minutes. Sodium borohydride (26 g) was added lot wise at 25-55 0C. After complete addition of sodium borohydride, the reaction mixture was stirred for 15 minutes at 40-45 0C. The reaction mixture was warmed to 50-55 0C and maintained for 2-3 hours. After completion of the reaction, the reaction mass was cooled to 10-15 0C and quenched with 25% HCl Solution (400 ml) at 10-15 0C. The reaction mass was stirred for 45-60 minutes at 25-30 0C. To the cooled reaction mass at 10-15 0C, sodium hydroxide (50% solution) (8 ml) was added. The aqueous layer was extracted with chloroform. The organic layer was distilled at 70-80 0C and cooled to 25-30 0C. The organic layer was separated and distilled out under vacuum to remove solvent at 45-50 0C to obtain 1-benzyl piperidine-3-ol as oil (80 g).

Example 4
Preparation of 1-benzyl piperidine-3-ol

1-benzyl-3-hydroxy pyridinium chloride (1 kg) obtained in example 1 or 2 was charged in isoppropyl alcohol (5 L). Sodium methoxide (250 g) was added lot wise to the reaction mixture at 25-30 0C. The reaction mixture was stirred for 30 minutes. Sodium borohydride (260 g) was added lot wise at 25-55°C. After complete addition of sodium borohydride, the reaction mixture was stirred for 15 minutes at 40-45 0C. The reaction mixture was warmed to 50-55 0C and maintained for 2-3 hours. After completion of the reaction, the reaction mass was cooled to 10-15 0C and quenched with 25% HCl Solution (4 L) at 10-15 0C. The reaction mass was stirred for 45-60 minutes at 25-30 0C. To the cooled reaction mass at 10-15 0C, sodium hydroxide (50% solution) (80 ml) was added. The aqueous layer was extracted with chloroform. The organic layer was distilled at 70-80 0C and cooled to 25-30 0C. The organic layer was separated and distilled out under vacuum to remove solvent at 45-50 0C to obtain 1-benzyl piperidine-3-ol as crude oil (780 g). The crude oil was purified by high vacuum distillation to yield 1-benzyl piperidine-3-ol (purity 98.5%).

Example 5
Preparation of (3S)-1-benzyl-piperidine-3-ol

1-benzyl piperidine-3-ol (100 g) obtained in example 3 was charged in acetone (200 ml). The mixture was slowly warmed to reflux conditions. (-)-Camphor sulfonic acid (73 g) in acetone (300 ml) was added to the reaction mixture at reflux conditions. The reaction mass was stirred for 1-2 hours at 70-75 0C. The mass was cooled to 25-30 0C and filtered. The compound obtained was washed with acetone (100 ml) and solid obtained was suck dried. The wet cake was added to isopropyl alcohol (300 ml) at 25-30 0C. The mixture was warmed to 60-70 0C, stirred, was gradually cooled to 25-30 0C, filtered and washed with isopropyl alcohol (50 ml). The solid (3S)-1-benzyl piperidine-3-ol Camphor sulfonic acid salt thus obtained was suck dried.

The purification by isopropyl alcohol was repeated till the achievement of chiral purity of 99.99%. The salt (100 g) was charged in water (50 ml) and pH was adjusted to 8.5-9 using sodium bicarbonate solution (prepared by 40 g NaHCO3 in 150 ml water). The reaction mixture was allowed to stir at 25-30 0C for 30 minutes. The mass was extracted with ethyl acetate (200 ml). The organic layer was separated and washed with water (100 ml). The organic layer was distilled off at 75-80 0C. (3S)-1-benzyl-piperidine-3-ol was obtained as oil (yield - 30 g).
Chiral purity: 99.99%

Example 6
Preparation of (3S)-1-benzyl-piperidine-3-ol

1-benzyl piperidine-3-ol (1 kg) obtained in example 3 was charged in acetone (2 L). The mixture was slowly warmed to reflux conditions. (-)-Camphor sulfonic acid (730 g) in acetone (3 L) was added to the reaction mixture at reflux conditions. After completion of the reaction, the reaction mass was stirred for 1-2 hours at 70-75 0C. The mass was cooled to 25-30 0C and filtered. The compound obtained was washed with acetone (1 L) and solid obtained was suck dried. The wet cake was added to isopropyl alcohol (3 L) at 25-30 0C. The mixture was warmed to 60-70 0C and stirred. The mixture was gradually cooled to 25-30 0C, filtered and washed with isopropyl alcohol (500 ml). The solid (3S)-1-benzyl piperidine-3-ol Camphor sulfonic acid salt thus obtained was suck dried.

The purification by isopropyl alcohol is repeated till the achievement of chiral purity of 99.99%. The salt (1 Kg) was charged in water (500 ml) and pH was adjusted to 8.5-9 using sodium bicarbonate solution (prepared by 40 g NaHCO3 in 150 ml water). The reaction mixture was allowed to stir at 25-30 0C for 30 minutes. The mass was extracted with ethyl acetate (2 L). The organic layer was separated and washed with water (1 L). The organic layer was distilled off at 75-80°C. (3S)-1-benzyl-piperidine-3-ol was obtained as oil (300 g)
Chiral purity 99.99%

Example 7
Preparation of (3S)-1-tertbutyloxy carbonyl piperidine-3-ol

(3S)-1-benzyl-piperidine-3-ol (100 g) obtained in example 5 was charged in methanol (300 ml). DiBOC (120 g) was added at 25-30 0C. Pd/C 5% (Wet) (5 g) was added to the reaction mixture at 25-30 0C. The reaction was carried out under inert atmosphere by flushing nitrogen and hydrogen and at 5-6 kg/cm2 H2 pressure. The reaction mixture was heated to 45-50 0C. The reaction was maintained at 45-50 0C and 6 kg/cm2 H2 pressure for 3-4 hrs. Cooling was applied and the temperature was brought to 25-30 0C. The reaction mass was filtered through hyflo bed and washed with methanol (50 ml). The filtrate was concentrated under vacuum at 60 0C and degas well. N-Heptane (200 ml) was added to the oil (150 ml) obtained and stirred for 30 minutes to get a clear solution. The mass was allowed to chill to 0-5 0C. The turbid reaction mass was allowed to stir for 2-3hrs at 0-5 0C. The (3S)-1-tertbutyloxy carbonyl piperidine-3-ol precipitated as solid was filtered and washed with n-heptane (50 ml). It was suck dried well under vacuum at 25-30 0C to get free dry solid (98 gm).
Chiral purity 99.99%

Example 8
Preparation of (3S)-1-tertbutyloxy carbonyl piperidine-3-ol

(3S)-1-benzyl-piperidine-3-ol (1 kg) obtained in example 5 was charged in methanol (3 L). DiBOC (1.2 kg) was added at 25-30 0C. Pd/C 5% (Wet) (50 g) was added to the reaction mixture at 25-30 0C. The reaction was carried out under inert atmosphere by flushing nitrogen and hydrogen and at 5-6 kg/cm2 H2 pressure. The reaction mixture was heated to 45-50°C. The reaction was maintained at 45-50°C and 6 kg/cm2 H2 pressure for 3-4 hrs. Cooling was applied and the temperature was brought to 25-30 0C. The reaction mass was filtered through hyflo bed and washed with methanol (500 ml). The filtrate was concentrated under vacuum at 60 0C and degas well. N-Heptane (2 L) was added to the oil (1.5 L) obtained and stirred for 30 minutes to get a clear solution. The mass was allowed to chill to 0-5 0C. The turbid reaction mass was allowed to stir for 2-3hrs at 0-5 0C. The (3S)-1-tertbutyloxy carbonyl piperidine-3-ol precipitated as solid was filtered and washed with n-heptane (50 ml). It was suck dried well under vacuum at 25-30 0C to get free dry solid (980 gm).
Chiral purity 99.99%

Example 9
Racemization of (3R)-1-benzyl piperidine-3-ol

After separating isomer (3S)-1-benzyl piperidine-3-ol of Camphor sulfonic acid salt from example 5, the organic layer obtained was distilled to get thick mass (315 g). Water (630 ml) was added to the mass and stirred for 15 minutes. Sodium bicarbonate (20 g) was added and stirred for 30 minutes. To the concentrated mass, methylene dichloride (1000 ml) was charged and stirred for 1 hour. Both the layers were settled and separated. The organic layer was washed with brine solution (300 ml) and concentrated under vacuum to obtain (3R)-1-benzyl piperidine-3-ol (289 g) which was further used for racemization.

Sodium methoxide (10.47 g) were added to (3R)-1-benzyl piperidine-3-ol (100 g) and heated to 180 0C and maintained for 2 hours. Water (200 ml) was added at 50 0C and stirred for 30 minutes. Chloroform (500 ml) was added and stirred for 10 minutes and the layers were settled and separated. The organic layer was washed with saturated brine solution (200 ml) and concentrated under vacuum to get racemized 1-benzyl piperidine-3-ol (87.5 g) which is recycled back to the resolution process as described in example 3.