DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)

A PROCESS FOR THE PREPARATION OF 4-BENZAMIDO PIPERIDINE

Vasudha Pharma Chem Limited
An Indian company having its registered office at
78/A, Vengalrao Nagar,
Hyderabad – 500038,
Telangana
India

The following specification particularly describes the nature of this invention and the manner in which it is to be performed:
A PROCESS FOR THE PREPARATION OF 4-BENZAMIDO PIPERIDINE
FIELD OF THE INVENTION
The present invention relates to a novel process for the synthesis of 4-benzamido piperidine.
BACKGROUND OF THE INVENTION
Indoramin (trade names Baratol and Doralese) is a piperidine antiadrenergic agent. It is an alpha-1 selective adrenoceptor antagonist with direct myocardial depression action; therefore, it results in no reflex tachycardia. It is also used in benign prostatic hyperplasia (BPH).
Indoramin is chemically known as N-[1-[2-(1H-Indol-3-yl)ethyl]-4-piperidinyl] benzamide, having the structure as shown below:

I
4-Benzamido piperidine or N-(Piperidin-4-yl)benzamide of formula A

Formula A
is an important intermediate in the synthesis of Indoramin.
J. Med. Chem. 2010, 53, 6386–6397 disclosed preparation of 4-Benzamido piperidine as shown below:

Wherein, (a) TBD-methylpolystyrene, 1,2-dichloroethane; (b) Tris-(2-aminoethyl)amine polystyrene resin; (c) TFA; (d) SCX resin; (e) NH3/MeOH (4 M). The above route uses different kinds of resins and the process is tedious and expensive.
Archives of Pharmacal Research (2018), 41(12), 1149-1161 disclosed the following scheme for the preparation of 4-Benzamido piperidine:

Wherein, (a) 4-amino-1-Boc-piperidine, EDCl, HOBt, CH2Cl2, 0oC 20 min then to rt 12 h; 2 M HCl, EtOAc, 2 h, 73–86% for 2 steps. The reaction requires reagents such as EDCl, HOBt with a maximum yield of 86%.
Therefore, there is still a need in the art for an improved low-cost process for the preparation of compound of formula A, which will be suitable for large-scale preparation, in terms of simplicity, chemical yield and purity of the product.
SUMMARY OF THE INVENTION
In the first embodiment the present application provides a process for the preparation of compound of formula A, comprising:
reacting benzoic acid of formula II with a compound of formula III in the presence of thionyl chloride to give compound of formula IV and then hydrolysing compound of formula IV:

Wherein R is a C1-3 alkyl group.
In the second embodiment the present application provides a process for the preparation of compound of formula A, comprising:
reacting benzoic acid of formula II with a compound of formula V in the presence of thionyl chloride to give compound of formula VI and then hydrolysing compound of formula VI:

DETAILED DESCRIPTION OF THE INVENTION
In the aspects, the present application provides a process for the preparation of compound of formula A, comprising:
reacting benzoic acid of formula II with a compound of formula III in the presence of thionyl chloride to give compound of formula IV and then hydrolysing compound of formula IV:

Wherein R is a C1-3 alkyl group.
In aspects, the compound of formula II is first reacted with thionyl chloride and then the intermediate chloride compound formed is reacted with ester compound of formula III to produce compound of formula IV. The resulting compound of formula IV may be isolated or it can be carried to the next step without isolation.
In aspects, the reaction may be performed in a suitable solvent. The solvents include but not limited to water, alcohol solvents such as methanol, ethanol, propanol, iso-propanol; ether solvent such as, 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.
The reaction 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 reaction may be carried out for about 8 hours to about 12 hours at about 60 °C to about 75 °C. The resulting compound of formula IV may be isolated or it can be carried to the next step without isolation.
In aspects, the hydrolysis of compound of formula IV is carried in the presence of a base. The base includes but not limited to inorganic base such as sodium hydroxide, potassium hydroxide, Lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like. Specifically, the base may be an inorganic base. More specifically, the base may be potassium hydroxide.
The hydrolysis compound of formula IV 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 reaction may be carried out for about 20 hours to about 24 hours at about 75 °C to about 80 °C. The resulting compound of formula A is isolated from the reaction mass by any method known in the art.
In aspects, the hydrolysis of compound of formula IV may be performed in a suitable solvent. The solvents include but not limited to water, alcohol solvents such as methanol, ethanol, propanol, iso-propanol; ether solvent such as, 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.
In the aspects, the present application provides a process for the preparation of compound of formula A, comprising:
reacting benzoic acid of formula II with a compound of formula V in the presence of thionyl chloride to give compound of formula VI and then hydrolysing compound of formula VI:

In aspects, the compound of formula II is first reacted with thionyl chloride and then the intermediate chloride compound formed is reacted with ethyl ester compound of formula V to produce compound of formula VI. The resulting compound of formula VI may be isolated or it can be carried to the next step without isolation.
In aspects, the reaction may be performed in a suitable solvent. The solvents include but not limited to water, alcohol solvents such as methanol, ethanol, propanol, iso-propanol; ether solvent such as, 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.
The reaction 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 reaction may be carried out for about 8 hours to about 12 hours at about 60 °C to about 75 °C. The resulting compound of formula VI may be isolated or it can be carried to the next step without isolation.
In aspects, the hydrolysis of compound of formula VI is carried in the presence of a base. The base includes but not limited to inorganic base such as sodium hydroxide, potassium hydroxide, Lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like. Specifically, the base may be an inorganic base. More specifically, the base may be potassium hydroxide.
The hydrolysis compound of formula VI 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 reaction may be carried out for about 20 hours to about 24 hours at about 75 °C to about 80 °C. The resulting compound of formula A is isolated from the reaction mass by any method known in the art.
In aspects, the hydrolysis of compound of formula VI may be performed in a suitable solvent. The solvents include but not limited to water, alcohol solvents such as methanol, ethanol, propanol, iso-propanol; ether solvent such as, 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.
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.
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.
The term "optional" or "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
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.
The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the person skilled in art.
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 4-benzamido piperidine
To a round bottom flask toluene (375 ml), benzoic acid (187.5 g) and thionyl chloride (250g) are added at room temperature. The temperature was raised to 100 oC and maintained for 6 hours and cooled down to 80 oC. Toluene and thionyl chloride were distilled out and toluene (187.5 ml) was added to the mass. Distil out toluene under vacuum and the mass was cooled down to room temperature. Charged toluene (500 ml) into the mass. Prepare a solution of toluene (500 ml) and ethyl 4-aminopiperidine-1-carboxylate (250 g). Slowly add this solution to the above toluene solution for 5 hours. The reaction mass was maintained for 3 hours at 20 oC and water (750 ml) was added to this. pH was adjusted to 10 by adding sodium hydroxide (100 ml) and maintained for 3 hours. The material was filtered and washed with water (125 ml).
In another round bottom flask methanol (1250 ml) and potassium hydroxide (300 g) were charged. The above wet material was added to this and temperature was raised to 75 oC for 20 hours, cool the reaction mass to room temperature and filtered and washed with methanol (125 ml). The filtrate was taken and solvent was distilled under vacuum. The reaction mass was washed with acetone (125 ml) and dried under vacuum to give the titled compound.

Dated this on 1st day of April, 2025

Signature: ___________________
Name: Dr. Phani Kumar Balusu
Vasudha Pharma Chem Limited
,CLAIMS:We Claim:

1) A process for the preparation of compound of formula A, comprising: reacting benzoic acid of formula II with a compound of formula III in the presence of thionyl chloride to give compound of formula IV and then hydrolysing compound of formula IV:

Wherein R is a C1-3 alkyl group.

2) A process for the preparation of compound of formula A, comprising:
reacting benzoic acid of formula II with a compound of formula V in the presence of thionyl chloride to give compound of formula VI and then hydrolysing compound of formula VI:

3) The process as claimed in claim 1 or 2, wherein the hydrolysis of compounds of formula IV or VI conducted in the presence of a base.

4) The process as claimed in claim 3, wherein the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and mixtures thereof.

Dated this on 1st day of April, 2025

Signature: ___________________
Name: Dr. Phani Kumar Balusu
Vasudha Pharma Chem Limited