Claims:We Claim:

1) A process for the preparation of compound of formula I, comprising:
a) reacting a compound of formula II with an alkylamine solution of formula III to give compound of formula IV

wherein, R1, R2 and R3 are same are different selected from lower alkyl group.
b) reacting the compound of formula IV with a compound of formula V to obtain a compound of formula VI

wherein, R1, R2 and R3 are as defined above.
c) cyclizing and hydrolysing the compound of formula VI gives compound of formula I

2) A process for the preparation of 1,3-dimethylpiperidin-4-one, comprising:
a) reacting methyl 2-methylpropenoate with a solution of methylamine to give methyl 2-methyl-3-(methylamino)propanoate

b) reacting methyl 2-methyl-3-(methylamino)propanoate with methyl prop-2-enoate to obtain methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino]propanoate

c) cyclizing and hydrolysing methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino] propanoate gives 1,3-dimethylpiperidin-4-one

3) The process according to claim 1 or 2, wherein in reactions in steps a), b) and c) are performed in solvents, the same or different for each step, includes but not limited to water, alcohol solvent such as methanol, ethanol, propanol, 2-propanol, n-butanol 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.
3) The process as claimed in claims 1-3, wherein the reactions are carried out at a temperature of about 0 oC to about 100 oC for a period of about 30 minutes to about 36 hours.
4) Use of compound of formula I and 1,3-dimethylpiperidin-4-one in the preparation of Alvimopan. , Description:A PROCESS FOR THE PREPARATION OF 1,3-DIALKYLPIPERIDIN-4-ONE
FIELD OF THE INVENTION
The present application relates to a process for the preparation of 1,3-dialkylpiperidin-4-one.
BACKGROUND OF THE INVENTION
1,3-dialkylpiperidin-4-one of the formula I:

wherein, R1 and R2 are same are different selected from lower alkyl 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 many active pharmaceutical ingredients but not limited to, Alvimopan.
The reported process for the preparation of the above intermediates is very time consuming, which makes it industrially not suitable.
The process of the present invention has advantages of simple, easy handling and increased productivity which afford a significantly greater yield. The process is also industrially scalable; cost effective 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:
a) reacting a compound of formula II with an alkylamine solution of formula III to give compound of formula IV

wherein, R1, R2 and R3 are same are different selected from lower alkyl group.
b) reacting the compound of formula IV with a compound of formula V to obtain a compound of formula VI

wherein, R1, R2 and R3 are as defined above.
c) cyclizing and hydrolysing the compound of formula VI gives compound of formula I

In the second embodiment the present application provides a process for the preparation of 1,3-dimethylpiperidin-4-one, comprising:
a) reacting methyl 2-methylpropenoate with methylamine solution to give methyl 2-methyl-3-(methylamino)propanoate

b) reacting methyl 2-methyl-3-(methylamino)propanoate with methyl prop-2-enoate to obtain methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino]propanoate

c) cyclizing and hydrolysing methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino]propanoate gives 1,3-dimethylpiperidin-4-one

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:
a) reacting a compound of formula II with an alkylamine solution of formula III to give compound of formula IV

wherein, R1, R2 and R3 are same are different selected from lower alkyl group.
b) reacting the compound of formula IV with a compound of formula V to obtain a compound of formula VI

wherein, R1, R2 and R3 are as defined above.
c) cyclizing and hydrolysing the compound of formula VI gives compound of formula I

In aspects, the reaction of compound of formula II with a solution of formula III may be performed in a suitable solvent. The solvents includes but not limited to water, alcohol solvent such as methanol, ethanol, propanol, 2-propanol, n-butanol 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 reaction between compound of formula II and the solution of compound of formula III may be carried out for about 30 minutes to about 36 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction between compound of formula II and the solution of compound of formula III may be carried out for about 1 hour to about 24 hours at about 60 °C to about room temperature. The resulting compound of formula IV may be carried forward to the next step without isolation from the reaction mass or the compound of formula IV may be isolated from the reaction mass by any method known in the art.
In aspects, the compound of formula IV may be reacted with a compound of formula V in a suitable to provide compound of formula VI. The solvents includes but not limited to water, alcohol solvent such as methanol, ethanol, propanol, 2-propanol, n-butanol 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 resulting compound of formula VI may be carried forward to the next step without isolation from the reaction mass or the compound of formula VI may be isolated from the reaction mass by any method known in the art.
In aspects, the compound of formula VI is cyclized to the corresponding ß-ketoester followed by hydrolysis and decarboxylated to give compound of formula I. The cyclization of compound of formula VI may be performed in a suitable solvent optionally in the presence of a suitable base. The solvents includes but not limited to water, 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 mixtures thereof. Specifically, the solvent may be an aromatic solvent. More specifically, the solvent may be toluene. The base includes but not limited to organic base such as triethylamine, diisopropyl ethylamine, sodiummethoxide, sodiumethoxide and the like; inorganic base such as sodium hydroxide, potassium carbonate and the like. Specifically, the base may be an organic base. More specifically, the base may be sodiummethoxide. The resulting ß-ketoester is hydrolysed and decarboxylated to give compound of formula I by known methods in the art or the by the method disclosed in-here.
In the aspects of the second embodiment, the present application provides a process for the preparation of 1,3-dimethylpiperidin-4-one, comprising:
a) reacting methyl 2-methylpropenoate with a solution of methylamine to give methyl 2-methyl-3-(methylamino)propanoate

b) reacting methyl 2-methyl-3-(methylamino)propanoate with methyl prop-2-enoate to obtain methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino]propanoate

c) cyclizing and hydrolysing methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino]propanoate gives 1,3-dimethylpiperidin-4-one

In aspects, the reaction of methyl 2-methylpropenoate with a solution of methylamine may be performed in a suitable solvent. The solvents includes but not limited to water, alcohol solvent such as methanol, ethanol, propanol, 2-propanol, n-butanol 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 solution of methylamine may be prepared by passing methylamine gas into a solvent. The solvents includes but not limited to water, alcohol solvent such as methanol, ethanol, propanol, 2-propanol, n-butanol 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 reaction between methyl 2-methylpropenoate with methylamine may be carried out for about 30 minutes to about 36 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction between methyl 2-methylpropenoate with methylamine may be carried out for about 1 hour to about 24 hours at about 60 °C to about room temperature. The resulting compound methyl 2-methyl-3-(methylamino)propanoate may be carried forward to the next step without isolation from the reaction mass or the compound, methyl 2-methyl-3-(methylamino)propanoate may be isolated from the reaction mass by any method known in the art.
In aspects, the compound methyl 2-methyl-3-(methylamino)propanoate reacted with methyl prop-2-enoate in a suitable solvent to provide methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino]propanoate. The solvents includes but not limited to water, alcohol solvent such as methanol, ethanol, propanol, 2-propanol, n-butanol 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 resulting compound, methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino]propanoate may be carried forward to the next step without isolation from the reaction mass or the compound, methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino]propanoate may be isolated from the reaction mass by any method known in the art.
In aspects, methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino]propanoate is cyclized to the corresponding ß-ketoester followed by hydrolysis and decarboxylated to give 1,3-dimethylpiperdin-4-one. The cyclization of methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino]propanoate may be performed in a suitable solvent optionally in the presence of a suitable base. The solvents includes but not limited to water, 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 mixtures thereof. Specifically, the solvent is an aromatic solvent. More specifically, the solvent may be toluene. The base includes but not limited to organic base such as triethylamine, diisopropyl ethylamine, sodiummethoxide, sodiumethoxide and the like; inorganic base such as sodium hydroxide, potassium carbonate and the like. Specifically, the base may be an organic base. More specifically, the base may be sodiummethoxide. The resulting ß-ketoester is hydrolysed and decarboxylated to give compound of formula I by known methods in the art or the by the method disclosed in-here.
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, Alvimopan.
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.
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.
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 methyl 2-methyl-3-(methylamino) propanoate
A round bottom flask was charged with methyl 2-methylpropenoate (600 gm) and methanol (1500 ml) at room temperature. Cooled the reaction mass to 15-20 oC and added monomethylamine (750 gm) for 2-3 hours. Raised the reaction mass temperature to room temperature and maintained for 12-13 hours. Then the reaction mass was distilled under vacuum at 60 oC to get titled compound.
Example 2: Preparation of methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino]propanoate
A round bottom flask was charged with methyl 2-methyl-3-(methylamino) propanoate (500 gm) and methanol (1000 ml) at room temperature. Cooled the reaction mass to 15-20 oC and added methyl prop-2-enoate (300 gm) for 2-3 hours. Raised the reaction mass temperature to room temperature and maintained for 3-4 hours. Then the reaction mass was distilled under vacuum at 60 oC to get titled compound.
Example 3: Preparation of 1,3-dimethylpiperidin-4-one
A round bottom flask was charged with toluene (4000 ml) and methyl 3-[(3-methoxy-3-oxopropyl)(methyl)amino]propanoate (400 gm) at room temperature. Sodiummethoxide (162.5 gm) was added to the above flask and temperature was raised to 70-75 oC and maintained for 2-3 hours. Cooled the reaction mass to room temperature and potable water (400 ml) was added concentrated hydrochloric acid (481 ml) and stirred for 10 minutes. Separate the layers and toluene layer was taken into a round bottom flask and concentrated hydrochloric acid (81 ml) was added and stirred for 10 minutes at room temperature. Separate the layers and aqueous layer was taken into a round bottom flask and concentrated hydrochloric acid (800 ml) was added and temperature was raised to 100-120 oC. The solvent was distilled out at this temperature and cooled to room temperature and was added liquid ammonia (1600 ml). Chloroform (813 ml) was added and stirred for 30 minutes and layers were separated. Aqueous layer was taken into round bottom flask and liquid ammonia (325 ml) and chloroform (500 ml) were charged and stirred for 30 minutes. Layers were separated and aqueous layer was taken into round bottom flask and chloroform (325 ml) was charged and stirred for 30 minutes. Separate the layers and total chloroform layers were combined and dried over sodium sulphate. Chloroform was distilled out at 75-80 oC to get the titled compound.