FORM 2
THE PATENT ACT 1970
&
The Patents Rules, 2003
PROVISIONAL / COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION:
'A Novel Process for preparation of 2-Methyl Pyrazine 5- Carboxylic Acid and 2-Methyl Pyrazine 5- Carboxylic Acid obtained thereof.'
2. APPLICANT(S)
(a) NAME: SUDARSHAN CHEMICAL INDUSTRIES LTD.
(b) NATIONALITY: Indian Company registered under the provisions
of the Companies Act, 1956
(c) ADDRESS: 162, Wellesley road,
PUNE-411001, Maharashtra State, India
3. PREAMBLE TO THE DESCRIPTION
PROVISIONAL COMPLETE
The following specification describes the The following specification
invention. particularly describes the invention
and the manner in which it is to be
performed.
4. DESCRIPTION (Description starts from page 2)
5. CLAIMS: Given on a separate sheet
6. DATE AND SIGNATURE: Given at the end of last page of specification.
7. ABSTRACT OF THE INVENTION: Given on a separate sheet
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Title: A Novel process for preparation of 2-Methyl Pyrazine 5- Carboxyic acid and 2-Methyl Pyrazine 5- Carboxyic acid obtained thereof.
Technical field
The present invention relates to a process for preparation of 2-Methyl Pyrazine 5-Carboxyic acid by using acetone aldoxime as a key raw material. More particularly, the present invention relates to the process for the preparation and isolation of 2-Methyl Pyrazine 5- Carboxyic acid. The process for the preparation and isolation of 2-Methyl Pyrazine 5- Carboxyic acid comprises of three steps, (i) Reaction of isopropyl nitrite with Acetone in presence of concentrated Hydrochloric acid, (ii) reaction of Diaminomalenonitrile with Acetone aldoxime in presence of dilute inorganic acid and (iii) hydrolysis followed by selective insitu decarboxylation of 2, 3-dicyano 5-methyl pyrazine in aqueous sulphuric acid.
The expression MPCA used in the specification means the compound of the present invention.
The main object of the present invention is to provide new process for the preparation of 2-Methyl Pyrazine 5- Carboxyic acid.
Another object of the present invention is to provide simple process.
Further object of the present invention is to improve yield of 2-Methyl Pyrazine 5- Carboxyic acid with purity to make it suitable for pharmaceutical intermediate
Background and Prior art:
2-Methyl Pyrazine 5- Carboxyic acid (MPCA) is a pyrazine derivative used as an intermediate for Glipizide (Compare patent - EP0149592). The N - Oxide derivative of
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MPCA is Acipimox, a valuable compound used as Antilipemic and Hypolipidemic agent (Compare patent - US2005261312, US2005239803).
The MPCA has been prepared by several known methods. One such known method is described by Chinese patent no. CN 1392143 (2003), wherein o -Phenylenediamine condensed with pyruvic aldehyde in presence of Sodium hydrogensulfite, oxidized by KMn04 / K2Cr207 and decarboxylated with H2S04 to give MPCA.
US patent 5091066 (1992) disclosed electrochemical oxidation of 2 - methyl 5 -oxomethylpyrazine using NiO (OH) with 74 - 93 % yield of MPCA
Another method described by G.B.Barlin in "The Pyrazines" John Wiley Ed. Page 79 (1982), wherein, 2 - Methyl-pyrazine 5 - carboxylic acid prepared by direct oxidation of 2, 5 - dimethyl pyrazine. In this reaction pyrazine-2, 5 - dicarboxylic acid is also being formed as by products.
E.Felder et al, in Chem Ber, 100, 555-559 (1967), have disclosed method which gives mixture of 2 - methylpyrazine-5 - carboxylic acid and 2 - methylpyrazine- 6 -carboxylic acid when 2, 3 - diamino propionic acid reacted with methyl glyoxal.
Process for preparation of MPCA is disclosed in GB2099820 A (1982) that involves condensation of diamino malenonitrile with pyruvic aldehyde in aqueous ethyl alcohol and acetic acid to gives 2,3- dicyano-5-methyl pyrazine which is hydrolyzed in dilute suphuric acid and decarboxylated insitu at 100 °C, to obtain desired product with 40 -45 % yield. In this process, pyruvic aldehyde used as starting material, which is not easily accessible.
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Deficiencies of prior art:
The prior art processes either involves starting materials, which are not easily accessible commercially or provide very low yield.
Description of the present invention:
Detailed description of the present invention is provided herein: however, it is to be understood that the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in virtually any appropriately detailed system, structure or matter.
The present invention relates to the simple process for the preparation of pure MPCA. The present invention relates to the process for the preparation of pure MPCA of formula (I) of good purity.
The present invention relates to the process for the preparation of MPCA comprises of following steps: (a) Preparation of acetone aldoxime by reaction of isopropyl nitrite with acetone of formula (V) in presence of concentrated hydrochloric acid at 0-30 °C, (b) condensation of Acetone aldoxime of formula (III) with diaminomalenonitrile of formula (IV) in presence of dilute sulphuric acid at 50 - 80 °C to give 2, 3 - dicyano 5 - methyl pyrazine of formula (II) and (c) Hydrolysis of 2, 3 -dicyano 5 - methyl pyrazine in 50 % v/v aqueous sulphuric acid and decarboxylation insitu at 80-100 °C to obtain 2 - methyl Pyrazine 5 - Carboxylic acid of formula (I) shown in scheme as follows,
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H3CT

^CH,

Isopropyl nitrite

Na ,NH-

(V)

(III)

(II)

(I)

Example:
1. Preparation of Acetone aldoxime:
In a 4 necked round bottom flask equipped with dropping funnel and over head stirrer were placed 4.0 moles of acetone and chilled it to + 5 °C. 3 gm of cone, hydrochloric acid was added at 0°C - 10 °C. In to reaction mass, 1 mole of isopropyl nitrite solution was added drop wise through dropping funnel at 10 to 15°C. The reaction mass was stirred further at 10 - 30 °C for 1-2 hour. The excess acetone and isopropyl alcohol were distilled out under vacuum 30- 60 °C to get crystalline mass of Acetone aldoxime with 83 - 88 % yield and 98% purity by GLC.
2. Preparation of 2,3- dicyano 5 - methyl pyrazine:
In a 4 necked round bottom flask equipped with dropping funnel and over head stirrer reflux condenser and thermowell were placed 4 to 5 ml of water per lgm DAMN and 0.926 moles of diaminomalenonitrile (DAMN) at 30°C. In to mixture, 92 ml 50 % sulphuric acid (v/v) was added drop wise through dropping funnel at 30°C. The reaction mass was heated to 50 - 80°C. Then 1.1-1.2 moles of acetone aldoxime preheated for 0.5 hr in 5 ml water per gm of acetone aldoxime and 0.86 moles sulphuric acid at 50-70 °C was added drop wise during 0.5-1 hour maintaining reaction temperature 80°C. The reaction mass was maintained at same temperature for 1 -2 hours. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of reaction, reaction mass was cooled to 25 °C and extracted with toluene. The combine
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extracts were washed with water and distilled off toluene under reduced pressure to give solid product in 75 % yield with 98 % purity. (M.P = 98-100 °C.)
3. Preparation of 2 - Methyl Pyrazine 5 - carboxylic acid (MPCA):
In a 4 necked round bottom flask equipped with dropping funnel and over head stirrer were placed 8-10 ml of 50 % v/v sulphuric acid per 1 gm of 2, 3 - dicyano 5 - methyl pyrazine and 0.694 moles 2, 3 - dicyano 5 - methyl pyrazine at 30 °C. The reaction mass was heated to 70-100 °C and maintained for 3-5 hours. The progress of the reaction was monitored by HPLC/TLC. After completion of reaction, reaction mass was cooled to 5 to 10 °C and 40 % caustic lye solution was added to adjust pH 2 - 3 and extracted with methyl ethyl ketone. The combined extracts were washed with saturated sodium chloride solution and distilled off methyl ethyl ketone under reduced pressure to give crude solid product weighed 55-60 gm which was crystallized by water to obtain pure product weighed 45-50 gm (46 - 52% yield). It was analyzed by High Performance Liquid Chromatography (HPLC) for its purity (m.p = 163 -165°C.) The product obtained was characterized by elementary analysis, IR and NMR.
The embodiments of the invention as described above and the method disclosed of the present invention will suggest further modification and alterations to those skilled in the art. Such further modifications and alterations may be made without departing from the spirit and scope of the invention, which is defined, by the scope of the following claims.
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We claim:
1. A novel process for the preparation of 2-Methyl Pyrazine 5-Carboxyllic acid comprising of the following steps:
(a) Preparation of acetone aldoxime by reaction of isopropyl nitrite with acetone of formula (V) in presence of concentrated hydrochloric acid at 0-3 0°C
(b) Condensation of Acetone aldoxime of formula (III) with diaminomalenonitrile of formula (IV) in presence of dilute sulphuric acid at 50-80 °C to give 2,3-dicyano 5-methyl pyrazine of formula (II) and
(c) hydrolysis of 2,3-dicyano 5-methyl pyrazine in 50% v/v aqueous sulphuric acid and decarboxylation insitu at 80-100 °C to obtain 2-Methyl Pyrazine 5-Carboxyllic acid of formula (I) as shown in the following scheme:

H,C
(V)

Isopropyl nitrite
>.

I OH
(III)

NC^ ,NH.

2. A process as claimed in claim 1, wherein the solvent is selected for purification from the group comprising of acetone, methanol, Ethanol, IP A, and water.
3. A process as claimed in claim 1, wherein the condensing agent is selected from the group comprising of HC1, H2S04, acetic acid and oxalic acid.
4. A process as claimed in claim 1, wherein, acetone aldoxime used in 1.1 to 1.3-mole equivalent.
5. A process as claimed in claim 1, wherein, 50 % v/v aqueous. Sulphuric acid used in 8 to 10 volume per 1 gm of 2, 3 - dicyano 5 - methyl pyrazine.
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6. A process of as claimed in claim 1 substantially as herein described with reference to the examples.
7. MPCA prepared by the process as claimed in claims 1 to 6 above.

»th
Dated this 28m day of May, 2007


CHETAN GUNDECHA (AGENT FOR THE APPLICANT)

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Abstract
The present invention relates to the process for the preparation of the 2 - methyl Pyrazine 5 - Carboxylic acid using the Acetone aldoxime as a key raw material comprising of the following steps:
(a) Preparation of acetone aldoxime by reaction of isopropyl nitrite with acetone (of formula (V) in presence of concentrated hydrochloric acid at 0-30 °C,
(b) condensation of Acetone aldoxime of formula (III) with diaminomalenonitrile of formula (IV) in presence of dilute sulphuric acid at 50 - 80 °C to give 2, 3 -dicyano 5 - methyl pyrazine of formula (II) and
(c) Hydrolysis of 2, 3 - dicyano 5 - methyl pyrazine in 50 % v/v aqueous sulphuric acid and decarboxylation insitu at 80-100 °C to obtain 2 - methyl Pyrazine 5 -Carboxylic acid of formula (I) shown in scheme as follows,

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