Title of Invention	"AN IMPROVED METHOD FOR THE PREPARATION OF 2-CHLORO-5-METHYLPYRIDINE-3-CARBALDEHYDE"
Abstract	An improved process for the preparation of 2-chloro-methylpyridine-3-carbaldehyde by reacting N-benzyl-N-(l-Propenyl) acetamide with Vilsemier reagent in a molar ratio of N-benzyl-N-(l-Propenyl) acetamide to Vilsemier reagent in the range of 0.02:0.35 to 0.07:0.35, at a temperature in the range of 0-10°C for 1-4 hours, heating the above reaction mixture at a temperature ranging between 70-100°C for 4-6 hours to obtain solid mass, pouring the above said mass in cold water and extracting the said mass with methylene chloride followed by remaining methylene chloride by known methods to obtain 2-chloro-5-methyl pyridine-3-carbaldehyde.

Title of Invention

"AN IMPROVED METHOD FOR THE PREPARATION OF 2-CHLORO-5-METHYLPYRIDINE-3-CARBALDEHYDE"

Abstract

An improved process for the preparation of 2-chloro-methylpyridine-3-carbaldehyde by reacting N-benzyl-N-(l-Propenyl) acetamide with Vilsemier reagent in a molar ratio of N-benzyl-N-(l-Propenyl) acetamide to Vilsemier reagent in the range of 0.02:0.35 to 0.07:0.35, at a temperature in the range of 0-10°C for 1-4 hours, heating the above reaction mixture at a temperature ranging between 70-100°C for 4-6 hours to obtain solid mass, pouring the above said mass in cold water and extracting the said mass with methylene chloride followed by remaining methylene chloride by known methods to obtain 2-chloro-5-methyl pyridine-3-carbaldehyde.

Full Text	The present invention relates to an improved process for the preparation of 2-chloro-5-methyl pyridine -3-carbaldehyde an useful intermediate for the variety of pharmaceutical and pesticide products. This study pertains to the preparation of 2-chloro-5-methyl pyridine -3-carbaldehyde having formula 1 as given in the drawing below. (Formula Removed) This study pertains to the preparation of 2-chloro-5-methyl pyridine-3-carbaldehyde with high selectivity. Several pyridine, quinoline, and isoquinoline compounds are important intermediates in that they have been reported as potential anti tumor agents (J.Med.Chem, 19,1209,1976; CA,85:116544q). Carbaldehyde derived products served as ulcer healing agents ( Ger.offen DE 3324034,1984; CA,101:54936g), allergy inhibitors ( EP 120483,1984; CA,102:95649e; EP 120484,1984; CA,102:113500f), antiviral agents ( CA,113:172015b), and useful as intermediates for Pharmaceuticals (Ger.offen DE 4429465,1996,CA, 124:343116u). There is only one method appeared in the literature for the preparation of 2-chloro-5-methylpyridine-3-carbaldehydein 12%yield.(J.C.S.Perkin.Trans 1,1173,1984). The present invention describes an improved process for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde from N-benzyl-N-(l-Propenyl) acetamide using Vilsemier reagent in 64% yield against reported 12% yield. The main objective of the present invention is to provide an improved process for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde which obviates the improvement in the method. The another objective of this present invention is to prepare 2-chloro-5-methylpyridine-3-carbaldehyde in higher yields. Accordingly, the present invention provides an improved process for the preparation of 2-chloro-methylpyridine-3-carbaldehyde which comprises reacting N-benzyl-N-(l-Propenyl) acetamide with Vilsemier reagent in a molar ratio of N-benzyl-N-(l-Propenyl) acetamide to Vilsemier reagent in the range of 0.02:0.35 to 0.07:0.35, at a temperature in the range of 0-10°C for 1-4 hours, heating the above reaction mixture at a temperature ranging between 70-100°C for 4-6 hours to obtain solid mass, pouring the above said mass in cold water and extracting the said mass with methylene chloride followed by remaining methylene chloride by known methods to obtain 2-chloro-5-methyl pyridine-3-carbaldehyde. In an embodiment of the present invention the molar ratio of N-benzyl-N-(1-Propenyl) acetamide to Vilsemier reagent is preferably 0.05 : 0.35. In an another embodiment the reaction time is preferably 2 hours. In yet another embodiment the reaction temperature is preferably in the ange of 75-90°C. In still another embodiment the product yield is 64%. In the improved process for the preparation of the 2-chloro-5-methylpyridine-3-carbaldehyde about 21.93g, 0.3 moles of dimethylformamide is added to a well stirred and cooled 53.65 g, 0.35 moles of phosphorousoxytrichloride material at a temperature range of about 0-20°c for about 25-35 minutes and then adding to it 9.45 g, 0.05 moles of N-benzyl-N-(l-Propenyl) acetamide at the temperature of about 0-20°c . The above reaction mixture is further continued for 2hrs at the room temperature of about 25°c. The ice cold bath is removed and heated to 75-90°c for 4-6hrs. A orange yellow organic mass is produced which is poured over 200 gms of ice cold water with constant stirring. The mass is then extracted with 2x200ml of methylene chloride and the layers are separated which are then dried over sodium sulphate and the solvent is removed under pressure. The residue obtained is subjected to chromatographic purification over silicagel to give a 64% yeild of 2-chloro-5-methylpyridine-3-carbaldehyde.The following examples are given by way of illustration of the present invention and there fore should not be construed to the scope of the present invention. Example 1 : Dimethylformamide (21.93 g, 0.3 moles) was added to a well stirred and cooled material of phosphorousoxytrichloride( 53.65 g, 0.35 moles) at 0°c in 30 minutes and followed by N-benzyl-N-(l-Propenyl) acetamide (9.45g, 0.05 moles) at the same temperature . The reaction mixture was further continued for 2 hours at room temperature of about 25°c. The ice cold bath was removed and heated to 75°c for 5 hours. The orange-yellow coloured organic mass was poured to ice cold water (200g) with stirring .The mass was extracted with methylenechloride (2x 200ml) and the layers were separated. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure . The obtained residue was subjected to chromatographic purification on silicagel to give 2-chloro-5-methylpyridine-3-carbaldehyde in 64% yield . Example 2 : Dimethylformamide (21.93 g, 0.3moles) was added to a well stirred and cooled material of phosphorousoxytrichloride ( 53.65 g, 0.35 moles) at 10 °C in 30 minutes and followed by N-benzyl-N-(l-Propenyl) acetamide ( 9.45g, 0.05 moles) at the same temperature . The reaction mixture was further continued 2 hours at room temperature of about 25°c. The ice cold bath was removed and heated to 90°c for 5 hours. The work up procedure was carried out according to the above mentioned procedure. The obtained residue was subjected to chromatographic purification on silica gel to give 2-chloro-5-methylpyridine-3-carbaldehyde in 64% yield . Advantages : The various advantages of the method are given below. 1. The main advantage of the present invention is that we are reporting the highest yield for the first time . 2. The advantage of the present invention is the employment of controlled time and temperature conditions during the reaction which are critical to the formation of the reagent and the product. 3. The another advantage of the present invention that it doesnot requires any other solvent, longer reaction times and harsh temperatures. 4. The product isolation is very easy. We claim : 1. An improved process for the preparation of 2-chloro-methylpyridine-3- carbaldehyde which comprises reacting N-benzyl-N-(l-Propenyl) acetamide with Vilsemier reagent in a molar ratio of N-benzyl-N-(1- Propenyl) acetamide to Vilsemier reagent in the range of 0.02:0.35 to 0.07:0.35, at a temperature in the range of 0-1 0°C for 1-4 hours, heating the above reaction mixture at a temperature ranging between 70- 100°C for 4-6 hours to obtain solid mass, pouring the above said mass in cold water and extracting the said mass with methylene chloride followed by remaining methylene chloride by known methods to obtain 2-chloro-5- methyl pyridine-3-carbaldehyde. 2. An improved process as claimed in claim 1 wherein the mole ratio of N- benzyl-N-(l-Propenyl) acetamide to Vilsemier reagent is preferably 0.05:0.35. 3. An improved process as claimed in claims 1-2 wherein the reaction time is preferably 2 hours. 4. An improved process as claimed in claims 1-3, wherein the reaction temperature is preferably in the range of 75-90°C. 5. An improved process as claimed in claims 1-4 wherein the product yield is 64%. 6. An improved process for the preparation of 2-chloro-methylpyridine-3- carbaldehyde as substantially herein described with reference to the examples and drawing accompanying this specification.

Full Text

The present invention relates to an improved process for the preparation of 2-chloro-5-methyl pyridine -3-carbaldehyde an useful intermediate for the variety of pharmaceutical and pesticide products. This study pertains to the preparation of 2-chloro-5-methyl pyridine -3-carbaldehyde having formula 1 as given in the drawing below.
(Formula Removed)
This study pertains to the preparation of 2-chloro-5-methyl pyridine-3-carbaldehyde with high selectivity.
Several pyridine, quinoline, and isoquinoline compounds are important intermediates in that they have been reported as potential anti tumor agents (J.Med.Chem, 19,1209,1976; CA,85:116544q). Carbaldehyde derived products served as ulcer healing agents ( Ger.offen DE 3324034,1984; CA,101:54936g), allergy inhibitors ( EP 120483,1984; CA,102:95649e; EP 120484,1984; CA,102:113500f), antiviral agents ( CA,113:172015b), and useful as intermediates for Pharmaceuticals (Ger.offen DE 4429465,1996,CA, 124:343116u).
There is only one method appeared in the literature for the preparation of 2-chloro-5-methylpyridine-3-carbaldehydein 12%yield.(J.C.S.Perkin.Trans 1,1173,1984). The present invention describes an improved process for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde from N-benzyl-N-(l-Propenyl) acetamide using Vilsemier reagent in 64% yield against reported 12% yield.
The main objective of the present invention is to provide an improved process for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde which obviates the improvement in the method.
The another objective of this present invention is to prepare 2-chloro-5-methylpyridine-3-carbaldehyde in higher yields.
Accordingly, the present invention provides an improved process for the preparation of 2-chloro-methylpyridine-3-carbaldehyde which comprises reacting N-benzyl-N-(l-Propenyl) acetamide with Vilsemier reagent in a molar ratio of N-benzyl-N-(l-Propenyl) acetamide to Vilsemier reagent in the range of 0.02:0.35 to 0.07:0.35, at a temperature in the range of 0-10°C for 1-4 hours, heating the above reaction mixture at a temperature ranging between 70-100°C for 4-6 hours to obtain solid mass, pouring the above said mass in cold water and extracting the said mass with methylene chloride followed by remaining methylene chloride by known methods to obtain 2-chloro-5-methyl pyridine-3-carbaldehyde.
In an embodiment of the present invention the molar ratio of N-benzyl-N-(1-Propenyl) acetamide to Vilsemier reagent is preferably 0.05 : 0.35.
In an another embodiment the reaction time is preferably 2 hours.
In yet another embodiment the reaction temperature is preferably in the ange of 75-90°C.
In still another embodiment the product yield is 64%.
In the improved process for the preparation of the 2-chloro-5-methylpyridine-3-carbaldehyde about 21.93g, 0.3 moles of dimethylformamide is added to a well stirred and cooled 53.65 g, 0.35 moles of phosphorousoxytrichloride material at a temperature range of about 0-20°c for about 25-35 minutes and then adding to it 9.45 g, 0.05 moles of N-benzyl-N-(l-Propenyl) acetamide at the temperature of about 0-20°c . The above reaction mixture is further continued for 2hrs at the room temperature of about 25°c. The ice cold bath is removed and heated to 75-90°c for 4-6hrs. A orange yellow organic mass is produced which is poured over 200 gms of ice cold water with constant stirring. The mass is then extracted with 2x200ml of methylene chloride and the layers are separated which are then dried over sodium sulphate and the solvent is removed under pressure.
The residue obtained is subjected to chromatographic purification over silicagel to give a 64% yeild of 2-chloro-5-methylpyridine-3-carbaldehyde.The following examples are given by way of illustration of the present invention and there fore should not be construed to the scope of the present invention.
Example 1 : Dimethylformamide (21.93 g, 0.3 moles) was added to a well stirred and cooled material of phosphorousoxytrichloride( 53.65 g, 0.35 moles) at 0°c in 30 minutes and followed by N-benzyl-N-(l-Propenyl) acetamide (9.45g, 0.05 moles) at the same temperature . The reaction mixture was further continued for 2 hours at room temperature of about 25°c. The ice cold bath was removed and heated to 75°c for 5 hours. The orange-yellow coloured organic mass was poured to ice cold water (200g) with stirring
.The mass was extracted with methylenechloride (2x 200ml) and the layers were separated. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure . The obtained residue was subjected to chromatographic purification on silicagel to give 2-chloro-5-methylpyridine-3-carbaldehyde in 64% yield .
Example 2 : Dimethylformamide (21.93 g, 0.3moles) was added to a well stirred and cooled material of phosphorousoxytrichloride ( 53.65 g, 0.35 moles) at 10 °C in 30 minutes and followed by N-benzyl-N-(l-Propenyl) acetamide ( 9.45g, 0.05 moles) at the same temperature . The reaction mixture was further continued 2 hours at room temperature of about 25°c. The ice cold bath was removed and heated to 90°c for 5 hours. The work up procedure was carried out according to the above mentioned procedure. The obtained residue was subjected to chromatographic purification on silica gel to give 2-chloro-5-methylpyridine-3-carbaldehyde in 64% yield .
Advantages : The various advantages of the method are given below.
1. The main advantage of the present invention is that we are reporting the highest yield
for the first time .
2. The advantage of the present invention is the employment of controlled time and
temperature conditions during the reaction which are critical to the formation of the
reagent and the product.
3. The another advantage of the present invention that it doesnot requires any other
solvent, longer reaction times and harsh temperatures.
4. The product isolation is very easy.

We claim :
1. An improved process for the preparation of 2-chloro-methylpyridine-3-
carbaldehyde which comprises reacting N-benzyl-N-(l-Propenyl)
acetamide with Vilsemier reagent in a molar ratio of N-benzyl-N-(1-
Propenyl) acetamide to Vilsemier reagent in the range of 0.02:0.35 to
0.07:0.35, at a temperature in the range of 0-1 0°C for 1-4 hours, heating
the above reaction mixture at a temperature ranging between 70-
100°C for 4-6 hours to obtain solid mass, pouring the above said mass in
cold water and extracting the said mass with methylene chloride followed
by remaining methylene chloride by known methods to obtain 2-chloro-5-
methyl pyridine-3-carbaldehyde.
2. An improved process as claimed in claim 1 wherein the mole ratio of N-
benzyl-N-(l-Propenyl) acetamide to Vilsemier reagent is preferably
0.05:0.35.
3. An improved process as claimed in claims 1-2 wherein the reaction time
is preferably 2 hours.
4. An improved process as claimed in claims 1-3, wherein the reaction
temperature is preferably in the range of 75-90°C.
5. An improved process as claimed in claims 1-4 wherein the product yield
is 64%.
6. An improved process for the preparation of 2-chloro-methylpyridine-3-
carbaldehyde as substantially herein described with reference to the
examples and drawing accompanying this specification.

Documents:

158-del-2002-abstract.pdf

158-del-2002-claims.pdf

158-del-2002-correspondence-others.pdf

158-del-2002-correspondence-po.pdf

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

158-del-2002-form-1.pdf

158-del-2002-form-2.pdf

158-del-2002-form-3.pdf

158-del-2002-form-4.pdf

158-del-2002-petition-138.pdf

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Patent Number

220778

Indian Patent Application Number

158/DEL/2002

PG Journal Number

30/2008

Publication Date

25-Jul-2008

Grant Date

05-Jun-2008

Date of Filing

28-Feb-2002

Name of Patentee

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI-110 001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	KONDAPURAM VIJAYA RAGHAVAN
2	BHIMAPAKA CHINARAJU
3	VAIDYA JAYATHIRATHA RAO

PCT International Classification Number

C07D 213/24

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA