Process for the synthesis of isonicotinic acid hydrazide

Details Process for the synthesis of isonicotinic acid hydrazide Process for the synthesis of isonicotinic acid hydrazide

2003-03-20

2004-05-11

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06734309

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the synthesis of isonicotinic acid hydrazide. More particularly, the present invention relates to a process for the synthesis of isonicotinic acid hydrazide(INH) from isonicotinamide. Isonicotinic acid hydrazide (INH) is used in the treatment of tuberculosis.
BACKGROUND OF THE INVENTION
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 appears to be more sluggish than ester in the reaction with hydrazine hydrate. The overall yield of acid hydrazide is not satisfactory.
Reference is made to Indian Patent No. 100112 wherein the process steps comprise of oxidation of 4-picoline 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 a very cumbersome.
Reference is 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 isoniconitinamide was made based on literature survey and patent databases, which did not yield any relevant references.
OBJECTS OF THE INVENTION
The main object of the invention is to provide a process for the conversion of isonicotinamide to isonicotinic acid hydrazide (INH) by hydrazine hydrate which obviates the drawbacks as detailed above.
Another object of the invention is to provide a process for the conversion of isonicotinamide to isonicotinic acid hydrazide (INH) by hydrazine hydrate.
Yet another object of the invention is to convert isonicotinamide to obtain yield greater than 95% (w/w) of isonicotinic acid hydrazide 99% purity.
Still another object of the invention is to provide a simple and single step process avoiding harmful chemicals and saving energy.
SUMMARY OF THE INVENTION
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 preparation of isonicotinic acid hydrazide which comprises dissolving isonicotinamide in C1 to C3 alcohol, adding hydrazine hydrate to the isonicotinamide solution, refluxing the resultant mixture and distilling off alcohol to obtain isonicotinic acid hydrazide.
In one embodiment of the invention, the reaction is carried out in a single step.
In another embodiment of the invention, the isonicotinamide to alcohol ratio is in the range of 1:1 to 1:8.
In yet another embodiment of the invention, the hydrazine hydrate is added to the solution of isonicotinamide in a ratio in the range of 0.4 to 2 of hydrazine hydrate to isonicotinamide.
In yet another embodiment of the invention, the mixture of hydrazine hydrate and isonicotinamide solution is refluxed at a temperature in the range of 100 to 120° C. for a time period in the range of 3-5 hours.
In another embodiment of the invention the yield of isonicotinic acid hydrazide is greater than 95% (w/w) when hydrazine hydrate (100%) is used.
In another embodiment of the invention hydrazine hydrate used is in ratio in the range of 0.7 to 1.1 to obtain yield of isonicotinic acid hydrazide(INH) greater than 97% (w/w).
In another embodiment of the invention the purity of isonicotinic acid hydrazide(INH) obtained is greater than 99%.
DETAILED DESCRIPTION OF THE INVENTION
The novelty 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.


REFERENCES:
patent: 2891067 (1959-06-01), Lal Mukherjee
patent: 11 16 667 (1961-11-01), None
Database CrossFire Beilstein 'Online! Beilstein Institut zur Forderung der Chemischen Wissenschaften, Frankfurt am Main, DE; Database accession No. Reaction ID: 329566 XP002237627. Abstract & Dzhumaulleva, S.A., et al Russ. J. Phys. Chem. vol. 67, No. 5 (1993) pp 976-977.
Database WPI Section Ch, Week 199627 Derwent Publications Ltd., London, GB; Class BO3, AN 1996-266597 XP002237628 & SU 1197396 (Orozhonikidze Chem Pharm Inst) (1995) col. 1, line 52-67, Ex. 2.

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