FIELD OF THE INVENTION
The present application relates to a process for the preparation of 4-hydroxypiperidines.
BACKGROUND OF THE INVENTION
4-hydroxypiperidines of the formula I:

wherein, R is H, a lower alkyl group or an N-protecting group, are important pharmaceutical intermediates, used for synthesis many active pharmaceutical ingredients. For example the compound of formula I may be used for the synthesis of but not limited to, Bepotastine, Cyproheptadine, Loratadine, desloratadine, Rupatadine, Ebastine, Domperidone, Pentanyl, Alcaftadine, Crizotinib and Ketotifen.
The reported process for the preparation of the above intermediates is reduction of the corresponding piperidin-4-one using sodiumborohydride in an organic solvent like methanol or ethanol. In metal hydrides reduction the resulting alkoxide salts are insoluble and need to be hydrolysed (with care) before the alcohol product can be isolated. Reduction using sodium borohydride, is extremely exothermic. The reaction has therefore been characterised using a heat flow calorimeter to determine whether reaction occurs readily or if accumulation could lead to a

potential hazard. Further sodiumborohydride reacts with water or moist air to produce flammable and explosive hydrogen gas, which makes it industrially not suitable.
The process of the present invention has advantages of improved yield, simple, easy handling, not formation alkoxides and increased productivity which afford a significantly greater yield. The process is also industrially scalable, cost effective and the reducing agent may be used with water which makes it highly suitable for industrial scale.
SUMMARY OF THE INVENTION
In the first embodiment the present application provides a process for the preparation of compound of formula I, comprising: reducing a compound of formula II with Raney Ni in the presence of hydrogen,

wherein, R is H, a lower alkyl group or an N-protecting group.
In the second embodiment the present application provides a process for the preparation of compound of formula I, comprising: reducing a compound of formula II with Raney Ni in the presence of hydrogen in water,


wherein, R is H, a lower alkyl group or an N-protecting group.
In the third embodiment the present application provides a process for the preparation of 1-methylpiperidin-4-ol, comprising: reducing 1-methylperidin-4-one with Raney Ni in the presence of hydrogen in water.
In the fourth embodiment the present application provides a process for the preparation of 1-(ethoxycarbonyl) piperidin-4-ol, comprising: reducing 1-(ethoxycarbonyl) piperidin-4-one with Raney Ni in the presence of hydrogen in water.
In the fifth embodiment the present application provides a process for the preparation of 1-(t-butoxycarbonyl) piperidin-4-ol, comprising: reducing 1-(t-butoxycarbonyl) piperidin-4-one with Raney Ni in the presence of hydrogen in methanol.
In the sixth embodiment the present application provides a process for the preparation of 1-benzylpiperidin-4-ol, comprising: reducing 1-benzylpiperidin-4-one with Raney Ni in the presence of hydrogen in methanol.
DETAILED DESCRIPTION OF THE INVENTION
In the aspects of the first embodiment, the present application provides a process for the preparation of compound of formula I, comprising: reducing a compound of formula II with Raney Ni in the presence of hydrogen,


wherein, R is H, a lower alkyl group or an N-protecting group.
In aspects, the reduction of compound of formula II with Raney Ni may be performed in a suitable solvent under hydrogen atmosphere. The solvents includes but not limited to water; alcohol solvents such as methanol, ethanol and the like; ester solvents like ethylacetate, Ethyl acetoacetate and the like; ether solvent such as tetrahydrofuran, diethyl ether and the like; aromatic hydrocarbon solvent such as benzene, toluene and the like; aliphatic hydrocarbon solvent such as heptane, hexane and the like; chlorinated hydrocarbon solvent such as dichloromethane and the like and the mixtures thereof. Specifically, the solvent is an alcoholic solvent. More specifically, the solvent may be methanol.
The reduction of compound of formula II may be carried out for about 30 minutes to about 24 hours at about 0 °C to about boiling point of the solvent. Specifically, the reduction compound of formula II may be carried out for about 1 hour to about 12 hours at about 60 °C to about 75 °C under hydrogen pressure.
In the aspects of the second embodiment, the present application provides a process for the preparation of compound of formula I, comprising: reducing a compound of formula II with Raney Ni in the presence of hydrogen in water,


wherein, R is H, a lower alkyl group or an N-protecting group.
In aspects, the reduction of compound of formula II with Raney Ni in the presence of hydrogen is performed in water.
The reduction of compound of formula II may be carried out for about 30 minutes to about 24 hours at about 0 °C to about 100 oC. Specifically, the reduction compound of formula II may be carried out for about 1 hour to about 12 hours at about 60 °C to about 75°C under hydrogen pressure.
In the aspects of the third embodiment the present application provides a process for the preparation of 1-methylpiperidin-4-ol, comprising: reducing 1-methylpiperidin-4-one with Raney Ni in the presence of hydrogen in water.
In aspects, the reduction of 1-methylpiperidin-4-one with Raney Ni in the presence of hydrogen is performed in water.
The reduction of 1-methyl-4-piperidinone may be carried out for about 30 minutes to about 24 hours at about 0 °C to about 100 oC. Specifically, the reduction of 1-methyl-4-piperidinone may be carried out for about 10 hours to about 12 hours at about 60 °C to about 75°C under hydrogen pressure.
In the aspects of the fourth embodiment the present application provides a process for the preparation of 1-(ethoxycarbonyl) piperidin-4-ol, comprising: reducing 1-(ethoxycarbonyl) piperidine-4-one with Raney Ni in the presence of hydrogen in water.

In aspects, the reduction of 1-(ethoxycarbonyl) piperidin-4-one with Raney Ni in the presence of hydrogen is performed in water.
The reduction of 1-(ethoxycarbonyl) piperidin-4-one may be carried out for about 30 minutes to about 24 hours at about 0 °C to about 100 oC. Specifically, the reduction of N-carboethoxypiperid-4-one may be carried out for about 1 hour to about 3 hours at about 60 °C to about 75°C under hydrogen pressure.
In the aspects of the fifth embodiment the present application provides a process for the preparation of 1-(t-butoxycarbonyl) piperidin-4-ol, comprising: reducing 1-(t-butoxycarbonyl) piperidin-4-one with Raney Ni in the presence of hydrogen in methanol.
In aspects, the reduction of 1-(t-butoxycarbonyl) piperidin-4-one with Raney Ni in the presence of hydrogen is performed in methanol.
The reduction of may be carried out for about 30 minutes to about 24 hours at about 0 °C to about 100 oC. Specifically, the reduction of 1-(t-butoxycarbonyl) piperidin-4-one may be carried out for about 1 hour to about 3 hours at about 60 °C to about 75 °C under hydrogen pressure.
In the aspects of the sixth embodiment the present application provides a process for the preparation of 1-benzylpiperidin-4-ol, comprising: reducing 1-benzylpiperidin-4-one with Raney Ni in the presence of hydrogen in methanol.
In aspects, the reduction of 1-benzylpiperidin-4-one with Raney Ni in the presence of hydrogen is performed in methanol.
The reduction of 1-benzylpiperidin-4-one may be carried out for about 30 minutes to about 24 hours at about 0 °C to about 100 oC. Specifically, the reduction of 1-benzylpiperidin-4-one may be carried out for about 6 hours to about 12 hours at about 60 °C to about 75 °C under hydrogen pressure.
The compound of formula I may be used for the synthesis of many active pharmaceutical ingredients. For example the compound of formula I may be used

for the synthesis of but not limited to, Bepotastine, Cyproheptadine, Loratadine, desloratadine, Rupatadine, Ebastine, Domperidone, Pentanyl, Alcaftadine, Crizotinib and Ketotifen.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, "generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
As used herein, “lower alkyl group” means an alkyl group having 1 to 6 carbon atoms. This alkyl group may be branched. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, pentyl and hexyl.
The conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
As used herein, "N-protecting group" is a functional group that protects the N-
group from participating in reactions that are occurring in other parts of the
molecule. Suitable N-protecting groups that are used above include, acetyl,
alkoxycarbonyl, benzoyl, benzyl, β-methoxyethoxymethyl ether, methoxymethyl
ether, dimethoxytrityl, p-methoxybenzyl ether, methylthiomethyl ether, allyl
ether, t-butyl ether, pivaloyl, trityl, silyl ether (e.g., trimethylsilyl (TMS), t-
butyldimethylsilyl (TBMDS), t-butyldiphenylsilyl (TBDPS), i-
butyldimethylsilyloxymethyl (TOM) or triisopropylsilyl (TIPS) ether),

tetrahydropyranyl (THP), methyl ether and ethoxyethyl ether (EE) or any suitable N-protecting group known in the art.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located’. Typically, room temperature can be from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.
The reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art. Typically, the reaction time can vary from about few minutes to several hours. For example the reaction time can be from about 10 minutes to about 24 hours, or any other suitable time period. The reaction time normally depends on the amount of Hydrogen pressure applied. The hydrogen pressure applied may vary from 1 kg/cm2 to 30 kg/cm2. Preferably 5 to 10 kg/cm2.
The isolation may be effected by methods such as, removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, freeze drying, or any other suitable fast evaporation technique.

Suitable temperatures for isolation may be less than about 120 °C, less than about 80 °C, less than about 60 °C, less than about 40 °C, less than about 30 °C, less than about 20 °C, less than about 10°C, less than about 0 °C, less than about -10 °C, less than about -40 °C or any other suitable temperatures.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.
EXAMPLES
Example 1: Preparation of 1-methylperidin-4-ol
Charge water (10 ml), 1-methylpiperidin-4-one (5 gm) and Raney Nickel (0.04 gm) into an autoclave at room temperature. Pass Hydrogen gas into the autoclave then raise the temperature to 50-55 oC and maintain the reaction mass for 10 to 12 hours. Cool the reaction mass to 45 oC and filter the Raney Nickel. Water is evaporated from the reaction mass at 110 oC under vacuum to get the titled compound of 4.72 gm.
Example 2: Preparation of 1-(ethoxycarbonyl) piperidin-4-ol
Charge water (1.8 ml), 1-(ethoxycarbonyl) piperidin-4-one (4.5 gm) and Raney Nickel (0.05 gm) into an autoclave at room temperature. Pass Hydrogen gas into the reactor then raise the temperature to 70-75 oC and maintain the reaction mass for 1 to 2 hours. Cool the reaction mass to 55 oC and filter the Raney Nickel. Water is evaporated from the reaction mass at 110 oC under vacuum to get the titled compound of 4.05 gm
Example 3: Preparation of 1-(t-butoxycarbonyl) piperidin-4-ol
Charge methanol (1000 L), 1-(t-butoxycarbonyl) piperidin-4-one (100 KG) and Raney Nickel (1 KG) into an autoclave at room temperature. Pass Hydrogen gas

into the reactor then raise the temperature to 35-40 oC and maintain the reaction mass for 1 to 2 hours. Cool the reaction mass to 20-25 oC and filter the Raney Nickel. Methanol is evaporated from the reaction mass at 70 oC under vacuum and dried at 40 oC to get the titled compound of 92 KG.
Example 4: Preparation of 1-benzylpiperidin-4-ol
Charge methanol (300 L), 1-benzylpiperidin-4-one (100 KG) and Raney Nickel (5 KG) into an autoclave at room temperature. Pass Hydrogen gas into the autoclave then raise the temperature to 60-65 oC and maintain the reaction mass for 6 to 7 hours. Cool the reaction mass to 35 oC and filter the Raney Nickel. Methanol is evaporated from the reaction mass at 80 oC under vacuum and dried at 40 oC to get the titled compound of 77 KG.

We Claim:
1) A process for the preparation of compound of formula I, comprising: reducing
a compound of formula II with Raney Ni in the presence of hydrogen,

wherein, R is H, a lower alkyl group or an N-protecting group.
2) A process for the preparation of compound of formula I, comprising: reducing
a compound of formula II with Raney Ni in the presence of hydrogen in water,

Wherein, R is H, a lower alkyl group or an N-protecting group.
3) A process for the preparation of 1-methylpiperidin-4-ol, comprising: reducing
1-methylpiperidin-4-one with Raney Ni in the presence of hydrogen in water.

4) A process for the preparation of 1-(ethoxycarbonyl) piperidin-4-ol, comprising:
reducing 1-(ethoxycarbonyl) piperidin-4-one with Raney Ni in the presence of
hydrogen in water.
5) A process for the preparation of 1-(t-butoxycarbonyl) piperidin-4-ol,
comprising: reducing 1-(t-butoxycarbonyl)piperidin-4-one with Raney Ni in the
presence of hydrogen in methanol.
6) A process for the preparation of 1-benzylpiperidin-4-ol, comprising: reducing 1-benzylpiperidin-4-one with Raney Ni in the presence of hydrogen in methanol.
7) The process as claimed in claim1, wherein the reduction is carried out in a solvent selected from the group comprising water; alcohol solvents such as methanol, ethanol and the like; ester solvents like ethylacetate, Ethyl acetoacetate and the like; ether solvent such as tetrahydrofuran, diethyl ether and the like; aromatic hydrocarbon solvent such as benzene, toluene and the like; aliphatic hydrocarbon solvent such as heptane, hexane and the like; chlorinated hydrocarbon solvent such as dichloromethane and the like and the mixtures thereof.
8) The process as claimed in claims 1-7, wherein the reduction is carried out in the presence hydrogen pressure.
9) The process as claimed in claims 1-8, wherein the reduction is carried out at a temperature of about 0 oC to about 100 oC for a period of about 30 minutes to about 24 hours.

10) Use of compound of formula I in the preparation of Bepotastine, Cyproheptadine, Loratadine, desloratadine, Rupatadine, Ebastine, Domperidone, Pentanyl, Alcaftadine, Crizotinib and Ketotifen.