Title of Invention	"A PROCESS FOR THE MANUFACTURE OF ISONICOTINIC ACID HYDRAZIDE (INH) USEFUL IN THE TREATMENT OF TUBERCULOSIS"
Abstract	A process for the manufacture of isonicotinic acid hydrazide (INH) useful in the treatment of tuberculosis by dissolving isonicotinamide in alcohol containing C1 to C3 carbon atoms in a ratio in the range of 1:1 to 1:8; adding hydrazine hydrate in a ratio in the range of 0.4 to 2 of isonicotinamide; refluxing the resultant mixture at a temperature in the range of 100 to 120 degree Celsius for a time period in the range of 3-5 hours and distilling off the alcohol to obtain isonicotinic acid hydrazide (INH).

Title of Invention

"A PROCESS FOR THE MANUFACTURE OF ISONICOTINIC ACID HYDRAZIDE (INH) USEFUL IN THE TREATMENT OF TUBERCULOSIS"

Abstract

A process for the manufacture of isonicotinic acid hydrazide (INH) useful in the treatment of tuberculosis by dissolving isonicotinamide in alcohol containing C1 to C3 carbon atoms in a ratio in the range of 1:1 to 1:8; adding hydrazine hydrate in a ratio in the range of 0.4 to 2 of isonicotinamide; refluxing the resultant mixture at a temperature in the range of 100 to 120 degree Celsius for a time period in the range of 3-5 hours and distilling off the alcohol to obtain isonicotinic acid hydrazide (INH).

Full Text	The present invention relates to a process for the manufacture of isoaicotinic acid hydrazide (INH) useful in the treatment of tuberculosis. The present invention particularly relates to a process for the manufacture of isonicotinic acid hydrazide{INH) from isonicotinamide. Isonicotinic acid hydrazide( INH) is used in the treatment of tuberculosis. Pyridine carboxylic acid hydrazide is prepared by the reaction of an ester or an acid chloride with hydrazine or substituted hydrazines. For the preparation of unsubstituted pyridine carbohydrazide, reaction between an ester and hydrazine gives good yield. If the acid chloride is used, a dipyridoyl hydrazine may be formed, but replacement of active halogen in 2- & 4- hydrazides is difficult. Acid hydrazides are generally prepared by the reaction of hydrazine with an ester or an acyl chloride. Amides and acids can also be converted to the respective hydrazides by treatment with hydrazine hydrate, but, in general, amides appear to be more sluggish than ester in the reaction with hydrazine hydrate. The overall yield of acid hydrazide is not satisfactory. Reference may be made to Indian Patent No. 100112 wherein the process steps comprise of oxidation of 4-pieoline by nitric acid to isonicotinic acid; esterification of isonicotinic acid and treatment of the resulting ester with hydrazine hydrate. The drawback of the process is that it causes corrosion of the reactor and separation of the ester is very cumbersome. Reference may also be made to Indian Patent No: 107934 wherein the process steps comprises of oxidation of 4-picoline by potassium permanganate to isonicotinic acid; esterification of isonicotinic acid and treatment of resulting ester by hydrazine hydrate. The drawback of the process is that the overall yield is very poor and separation of ester is very difficult. Prior art search for synthesis of isonicotinic acid hydrazide from isomcotinamide was made based on literature survey and patent databases, which did not yield any relevant references. The main object of the present invention is to provide a process for the manufacture of isonicotinic acid hydrazide (INH) from isonicotinamide which obviates the drawbacks as detailed above. Another object of the present invention is to provide a process for the conversion of isonicotinamide to isonicotinic acid hydrazide( INH) by hydrazine hydrate. Yet another object of the present invention is to convert isonicotinamide to obtain yield greater than 95 % (w/w) of isonicotinic acid having more than 99 % purity. Still another object of the present invention is to provide a simple and single step process, avoiding harmful chemicals and saving energy. The invention provides a process for the manufacture of isonicotinic acid hydrazide (INH) useful in the treatment of tuberculosis. The invention relates to the single step conversion of isonicotinamide by hydrazine hydrate to isonicotinic acid hydrazide (INH) of yield greater than 95 % (w/w) and purity more than 99 %. Accordingly, the present invention provides a process for the manufacture of isonicotinic acid hydrazide (INH) useful in the treatment of tuberculosis which comprises dissolving isonicotinamide in alcohol containing C1 to C3 carbon atoms in a ratio in the range of 1:1 to 1:8; adding hydrazine hydrate in a ratio in the range of 0.4 to 2 of isonicotinamide; refluxing the resultant mixture at a temperature in the range of 100 to 120 degree Celsius for a time period in the range of 3-5 hours and distilling off the alcohol to obtain isonicotinic acid hydrazide (INH). In an embodiment of the present invention hydrazine hydrate (100%) may be used to obtain yield of isonicotinic acid hydrazide (INH) greater than 95% (w/w%). In another embodiment of the present invention the hydrazine hydrate used is preferably in a ratio in the range of 0.7 to 1.1 to obtain yield of isonicotinic acid hydrazide (INH) greater than 97% (w/w%). In yet another embodiment of the present invention the purity of isonicotinic acid hydrazide (INH) obtained may be more than 99%. The novelty of the process of the present invention resides in converting an amide (isonicotinamide) to isonicotinic acid hydrazide (INH) in a single step reaction in comparison to multi-step prior art processes and recovering the alcohol added after the reaction in full. The above said novelty and usefulness has been achieved by the non-obvious single Inventive step of the process of the present invention. The following examples are given by way of illustration of the present invention and should not be construed to limit the scope of the present invention. Example-1 9.9918 gms of isonicotinamide was dissolved in 77.97 gms of absolute alcohol and 10.1 gms of hydrazine hydrate(100%) was added to it. The reaction mixture was refluxed in glycerine bath for 4 hours at 115 degree Celsius; after which alcohol was distilled off and solid mass, Isonicotinic acid hydrazide( INH) was taken out in hot condition. Recovered Isonicotinic acid hydrazide was 9.727 gms i.e. 97.34 wt% and the melting point obtained was 170 degree Celsius against 169.9 degree Celsius actual. Example-2 19.3989 gms of isonicotinamide was dissolved in 39.488 gms of methyl alcohol and 14.14 gms of hydrazine hydrate(100%) was added to it. The reaction mixture was refluxed in glycerine bath for 4 hours at 110 degree Celsius; after which alcohol was distilled off and solid mass, Isonicotinic acid hydrazide( INH) was taken out in hot condition. Recovered Isonicotinic acid hydrazide was 19.3 gms i.e. 99.49 wt% and the melting point obtained was 169.9 degree Celsius against 169.9 degree Celsius actual. Example-3 24.99 gms of isonicotinamide was dissolved in 39.48 gms of methyl alcohol and 20.20 gms of hydrazine hydrate(100%) was added to it. The reaction mixture was refluxed in glycerine bath for 4 hours at 110 degree Celsius; after which alcohol was distilled off and solid mass, Isonicotinic acid hydrazide( INH) was taken out in hot condition. Recovered Isonicotinic acid hydrazide was 24.0 gms i.e. 96.03 wt% and the melting point obtained was 169.9 degree Celsius against 169.9 degree Celsius actual. The main advantages of the present invention are: 1. It is a simple and single step process, avoiding handling of harmful chemicals and saving energy. 2. The average yield is greater than 95 % (w/w). 3. Purity of the product achieved is more than 99% as evidenced by melting point determination and through FTIR Spectroscopy. We claim : 1. A process for the manufacture of isonicotinic acid hydrazide (INH) useful in the treatment of tuberculosis which comprises dissolving isonicotinamide in alcohol containing C1 to C3 carbon atoms in a ratio in the range of 1:1 to 1:8; adding hydrazine hydrate in a ratio in the range of 0.4 to 2 of isonicotinamide; refluxing the resultant mixture at a temperature in the range of 100 to 120 degree Celsius for a time period in the range of 3-5 hours and distilling off the alcohol to obtain isonicotinic acid hydrazide (INH). 2. A process as claimed in claim 1 wherein the hydrazine hydrate used is preferably in a ratio in the range of 0.7 to 1.1 to obtain yield of isonicotinic acid hydrazide (INH) greater than 96% (w/w). 3. A process for the manufacture of isonicotinic acid hydrazide (INH) useful in the treatment of tuberculosis substantially as herein described with reference to the examples.

Full Text

The present invention relates to a process for the manufacture of isoaicotinic acid hydrazide (INH) useful in the treatment of tuberculosis.
The present invention particularly relates to a process for the manufacture of isonicotinic acid hydrazide{INH) from isonicotinamide.
Isonicotinic acid hydrazide( INH) is used in the treatment of tuberculosis. Pyridine carboxylic acid hydrazide is prepared by the reaction of an ester or an acid chloride with hydrazine or substituted hydrazines. For the preparation of unsubstituted pyridine carbohydrazide, reaction between an ester and hydrazine gives good yield. If the acid chloride is used, a dipyridoyl hydrazine may be formed, but replacement of active halogen in 2- & 4- hydrazides is difficult.
Acid hydrazides are generally prepared by the reaction of hydrazine with an ester or an acyl chloride. Amides and acids can also be converted to the respective hydrazides by treatment with hydrazine hydrate, but, in general, amides appear to be more sluggish than ester in the reaction with hydrazine hydrate. The overall yield of acid hydrazide is not satisfactory.
Reference may be made to Indian Patent No. 100112 wherein the process steps comprise of oxidation of 4-pieoline by nitric acid to isonicotinic acid; esterification of isonicotinic acid and treatment of the resulting ester with hydrazine hydrate. The drawback of the process is that it causes corrosion of the reactor and separation of the ester is very cumbersome.
Reference may also be made to Indian Patent No: 107934 wherein the process steps comprises of oxidation of 4-picoline by potassium permanganate to isonicotinic acid; esterification of isonicotinic acid and treatment of resulting ester by hydrazine hydrate. The drawback of the process is that the overall yield is very poor and separation of ester is very difficult.
Prior art search for synthesis of isonicotinic acid hydrazide from isomcotinamide was
made based on literature survey and patent databases, which did not yield any relevant
references.
The main object of the present invention is to provide a process for the manufacture of
isonicotinic acid hydrazide (INH) from isonicotinamide which obviates the drawbacks as
detailed above.
Another object of the present invention is to provide a process for the conversion of
isonicotinamide to isonicotinic acid hydrazide( INH) by hydrazine hydrate.
Yet another object of the present invention is to convert isonicotinamide to obtain yield
greater than 95 % (w/w) of isonicotinic acid having more than 99 % purity.
Still another object of the present invention is to provide a simple and single step process,
avoiding harmful chemicals and saving energy.
The invention provides a process for the manufacture of isonicotinic acid hydrazide
(INH) useful in the treatment of tuberculosis. The invention relates to the single step
conversion of isonicotinamide by hydrazine hydrate to isonicotinic acid hydrazide (INH)
of yield greater than 95 % (w/w) and purity more than 99 %.
Accordingly, the present invention provides a process for the manufacture of isonicotinic acid hydrazide (INH) useful in the treatment of tuberculosis which comprises dissolving isonicotinamide in alcohol containing C1 to C3 carbon atoms in a ratio in the range of 1:1 to 1:8; adding hydrazine hydrate in a ratio in the range of 0.4 to 2 of isonicotinamide; refluxing the resultant mixture at a temperature in the range of 100 to 120 degree Celsius for a time period in the range of 3-5 hours and distilling off the alcohol to obtain isonicotinic acid hydrazide (INH).
In an embodiment of the present invention hydrazine hydrate (100%) may be used to obtain yield of isonicotinic acid hydrazide (INH) greater than 95% (w/w%).
In another embodiment of the present invention the hydrazine hydrate used is preferably in a ratio in the range of 0.7 to 1.1 to obtain yield of isonicotinic acid hydrazide (INH) greater than 97% (w/w%).
In yet another embodiment of the present invention the purity of isonicotinic acid hydrazide (INH) obtained may be more than 99%.
The novelty of the process of the present invention resides in converting an amide (isonicotinamide) to isonicotinic acid hydrazide (INH) in a single step reaction in comparison to multi-step prior art processes and recovering the alcohol added after the reaction in full.
The above said novelty and usefulness has been achieved by the non-obvious single Inventive step of the process of the present invention.
The following examples are given by way of illustration of the present invention and should not be construed to limit the scope of the present invention.
Example-1 9.9918 gms of isonicotinamide was dissolved in 77.97 gms of absolute alcohol and 10.1 gms of hydrazine hydrate(100%) was added to it. The reaction mixture was refluxed in glycerine bath for 4 hours at 115 degree Celsius; after which alcohol was distilled off and solid mass, Isonicotinic acid hydrazide( INH) was taken out in hot condition. Recovered Isonicotinic acid hydrazide was 9.727 gms i.e. 97.34 wt% and the melting point obtained was 170 degree Celsius against 169.9 degree Celsius actual.
Example-2 19.3989 gms of isonicotinamide was dissolved in 39.488 gms of methyl alcohol and 14.14 gms of hydrazine hydrate(100%) was added to it. The reaction mixture was refluxed in glycerine bath for 4 hours at 110 degree Celsius; after which alcohol was distilled off and solid mass, Isonicotinic acid hydrazide( INH) was taken out in hot condition. Recovered Isonicotinic acid hydrazide was 19.3 gms i.e. 99.49 wt% and the melting point obtained was 169.9 degree Celsius against 169.9 degree Celsius actual.
Example-3 24.99 gms of isonicotinamide was dissolved in 39.48 gms of methyl alcohol and 20.20
gms of hydrazine hydrate(100%) was added to it. The reaction mixture was refluxed in
glycerine bath for 4 hours at 110 degree Celsius; after which alcohol was distilled off
and solid mass, Isonicotinic acid hydrazide( INH) was taken out in hot condition.
Recovered Isonicotinic acid hydrazide was 24.0 gms i.e. 96.03 wt% and the melting
point obtained was 169.9 degree Celsius against 169.9 degree Celsius actual.
The main advantages of the present invention are:
1. It is a simple and single step process, avoiding handling of harmful chemicals and saving energy.
2. The average yield is greater than 95 % (w/w).
3. Purity of the product achieved is more than 99% as evidenced by melting point determination and through FTIR Spectroscopy.

We claim :
1. A process for the manufacture of isonicotinic acid hydrazide (INH) useful in the treatment of tuberculosis which comprises dissolving isonicotinamide in alcohol containing C1 to C3 carbon atoms in a ratio in the range of 1:1 to 1:8; adding hydrazine hydrate in a ratio in the range of 0.4 to 2 of isonicotinamide; refluxing the resultant mixture at a temperature in the range of 100 to 120 degree Celsius for a time period in the range of 3-5 hours and distilling off the alcohol to obtain isonicotinic acid hydrazide (INH).
2. A process as claimed in claim 1 wherein the hydrazine hydrate used is preferably in a ratio in the range of 0.7 to 1.1 to obtain yield of isonicotinic acid hydrazide (INH) greater than 96% (w/w).
3. A process for the manufacture of isonicotinic acid hydrazide (INH) useful in the treatment of tuberculosis substantially as herein described with reference to the examples.

Documents:

335-del-2002-abstract.pdf

335-del-2002-claims(cancelled).pdf

335-del-2002-claims.pdf

335-del-2002-complete specification (granted).pdf

335-del-2002-correspondence-others.pdf

335-del-2002-correspondence-po.pdf

335-del-2002-description (complete).pdf

335-del-2002-form-1.pdf

335-del-2002-form-2.pdf

335-del-2002-form-3.pdf

335-del-2002-form-4.pdf

335-del-2002-petition-138.pdf

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Patent Number

195686

Indian Patent Application Number

335/DEL/2002

PG Journal Number

31/2009

Publication Date

31-Jul-2009

Grant Date

21-Apr-2006

Date of Filing

27-Mar-2002

Name of Patentee

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI-110001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SUBHASH CHANDRA RAY	CENTRAL FUEL RESEARCH INSTITUTE, P.O.F.R.I.-828108,DHANBAD, INDIA.
2	LAKSHMI NARAYAN NANDI	CENTRAL FUEL RESEARCH INSTITUTE, P.O.F.R.I.-828108,DHANBAD, INDIA.
3	BALDEV SINGH	CENTRAL FUEL RESEARCH INSTITUTE, P.O.F.R.I.-828108,DHANBAD, INDIA.
4	HIRALAL PRASAD	CENTRAL FUEL RESEARCH INSTITUTE, P.O.F.R.I.-828108,DHANBAD, INDIA.
5	SUMANT MAHARAJ	CENTRAL FUEL RESEARCH INSTITUTE, P.O.F.R.I.-828108,DHANBAD, INDIA.
6	SATYA NIKETAN YADAV	CENTRAL FUEL RESEARCH INSTITUTE, P.O.F.R.I.-828108,DHANBAD, INDIA.
7	PRODYOT KUMAR SARKAR	CENTRAL FUEL RESEARCH INSTITUTE, P.O.F.R.I.-828108,DHANBAD, INDIA.
8	PASHUPATI DUTTA	CENTRAL FUEL RESEARCH INSTITUTE, P.O.F.R.I.-828108,DHANBAD, INDIA.
9	SHYAM KISHORE ROY	CENTRAL FUEL RESEARCH INSTITUTE, P.O.F.R.I.-828108,DHANBAD, INDIA.
10	ANUP KUMAR BANDOPADHYAY	CENTRAL FUEL RESEARCH INSTITUTE, P.O.F.R.I.-828108,DHANBAD, INDIA.

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA