Title of Invention

"PROCESS FOR PRODUCING 2-CYANO-5-HALOPYRIDINE"

Abstract The present invention relates to a novel process for producing 2-cyano-5-halopyridine of formula (I) by nucleophilic dehalo-cyanation. The process includes diazotization and bromination reaction -of 2-amino-5-halopyridine, followed by cyanation of 2-bromo-5-halopyridine with alkali cyanide along with copper cyanide in the presence of solvent to obtain 2-cyano-5-halopyridine of formula (I). Recovery and reuse of the solvents is also disclosed in the present invention.
Full Text FIELD OF THE INVENTION
This invention, in general relates to a process for producing substituted halo derivative of pyridine. More particularly, but without restriction to the particular embodiments hereinafter described in accordance with the best mode of practice, this invention relates to a novel process for producing 2-cyano-5-halopyridine by nucleophilic dehalo-cyanation.
BACKGROUND OF THE INVENTION
2-Cyano-5-halopyridine is widely used as an intermediate in the preparation of agricultural chemicals, drugs which act as metabotropic glutamate receptor antagonists and are useful for treating neurological diseases and disorders.
Few processes are reported in the known arts for the cyanation of pyridine derivatives.
JP 60185764 discloses a process for the preparation of compounds of formula (II) and
formula (III)
(Formula Removed)
where X1-X4 and Y1-Y4 are H, alkyl, aryl, alkoxy, aryloxy, etc.; at least one of X1-X4 and at least one of Y1-Y4 are halogen. The process comprises reacting 2-(or 6-) or-4-substituted sulfonyl-halopyridine derivatives with alkali metal cyanide as a nucleophilic agent.
Also, W.K. Fife reported a process in Heterocycles, 22 (1), 93-96 (1984) in which when the 3-substituted pyridine-N-oxide derivatives were treated with trimethyl silyl cyanide and (CH3)2NCOC1, a mixture of products is obtained viz., 90% of 2-cyano-3-halo-pyridine and 10% of 2-cyano-5-halo-pyridine.
S. Takao et al. in Chem. & Pharma. Bull. 33(2), 565-71 (1985) has discussed the site selectivity in the cyanation of 3-substiuted pyridine-1-oxide with trimethyl silane carbonitrile. It has been found that among the 3-halo substituted pyridine-1-oxide, 2-cyano-5-halopyridine
is obtained along with 2-cyano-3-halopyridine with chloro and bromo derivatives, but with fluoro, only 2-cyano-3-fluoro is obtained.
The major disadvantage of the processes disclosed in the prior art is the use of costly raw materials thereby resulting into much costlier process along with low yield of desired product.
It is, therefore, an object of the present invention to improve upon limitations in the prior art. These and other objects are attained in accordance with the present invention wherein there is provided a simple, efficient and commercially suitable process for producing 2-cyano-5-halo pyridine by utilizing commercially viable raw materials.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a novel process for producing substituted halo pyridine derivatives of formula (I) in a high purity and yield. The process disclosed herein is the two-step process, which is simple, efficient and commercially feasible.
It is a principal aspect of the present invention to provide for a novel, commercially feasible process for producing 2-cyano-5-halopyridine of formula (I) from corresponding 2-amino-5-halopyridine of formula (IV) comprising the steps of diazotization of 2-amino-5-halopyridine with brominating agent to form 2-bromo-5-halo pyridine of formula (V) followed by cyanation of 2-bromo-5-halopyridine with alkali cyanide along with copper cyanide and further followed by isolation and purification in organic solvent.
hi accordance with another aspect of the present invention, there is provided a novel process for producing 2-cyano-5-halo pyridine of formula (I), wherein the cynation process is carried out in the presence of dimethyl formamide.
Furthermore, the present invention is also directed to the process for recovery of the solvent used in the purification and isolation, and reusing the same into the process.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the disclosed process steps of the present invention have advantages over prior art due to the utilization of industrially suitable solvents and commercially viable raw materials and elimination of undesired processing steps to make it comparatively safe and more cost effective.
The present invention provides a two-steps process for the preparation of 2-cyano-5-halo pyridine from corresponding 2-amino-5-halo pyridine as described in Scheme I. The said process comprising diazotization of 2-amino-5-halopyridine of formula (IV) followed by bromination and then the substitution of compounds of formula (V) employing an alkali cyanide along with copper cyanide.
(Scheme Removed)
Scheme-I
Where,
R1 is H or a C1 to C4 straight chain or branched group; R2 is H or a C1 to C4 straight chain or branched group; R3 is H or a C1 to C4 straight chain or branched group; and X is Cl, Br or I.
According to the process of the present invention, step I, is carried out by reacting 2-amino-5-halo pyridine with bromine, hydrobromic acid and alkali nitrite at 0-30°C.
In the process of the present invention, the compound of formula (IV) is reacted preferably with bromine and hydrobromic acid preferably at a temperature between 0-20°C followed by
the addition of aqueous solution of alkali nitrite to give 2-bromo-5-halopyridine. The preferred alkali nitrite for the reaction is sodium nitrite or potassium nitrite.
In step II, 2-bromo-5-halopyridine and its derivatives of formula (IV) is reacted with alkali cyanide in the presence of dimethyl formamide at a temperature of 120 - 155°C. The alkalicyanides that are particularly preferred are sodium cyanide and potassium cyanide. The reaction mass is treated with alkali dihydrogen phosphates (monobasic alkali phosphates) preferably potassium or sodium dihydrogen phosphate to bring pH range between 3.0 - 6.0 and isolated from the aqueous mass by using organic solvent preferably ethyl acetate or diisopropyl acetate. The organic layer was concentrated and purified using organic solvent to obtain 2-cyano-5-halo-pyridine with high purity and yield. The organic solvent used in purification is selected preferably from dichloromethane, dichloroethane, ethyl acetate, methanol or isopropyl alcohol. The organic solvent used in isolation and purification are distilled off and reused in subsequent batches.
The present invention is further illustrated below with reference to the following examples without intending to limit the scope of the present invention in any manner.
Example 1
Preparation of 2-Bromo-5-Chloropyridine
Hydrobromic acid (217.8 ml) was charged in a R.B. flask and cooled to 10-15°C. To this was charged 2-amino-5-chloropyridine (55.0 gm) while maintaining temperature at 10-15°C. The reaction mass was then slowly cooled to 0-5°C. To this reaction solution bromine (58.1 ml) was added dropwise in 60-90 minutes. The resulting mixture was stirred for 10-15 minutes. After that, sodium nitrite solution (74.13 gm sodium nitrite in 175 ml of water) was added in two hours at 0-5°C. The reaction mass was stirred for one hour and then heated up to 20°C and maintained for 90 minutes. Sodium bisulphate (118.4 gm) was added slowly to the reaction mass and pH was adjusted to 8.5-9.0 with 42% sodium hydroxide solution.
The reaction mass was filtered and the cake was washed with water till neutral pH is achieved. The wet cake was dissolved in concentrated sulphuric acid (50 ml) at a temperature 0-10°C then quenched over ice (250 gm). The pH of the solution was adjusted to 7.5-8.0 with 25% liquor ammonia (170.0 ml). The resulting precipitate was filtered and washed with water (2 x 100 ml). The wet cake was dried at 35-40°C till the moisture content to give 2-bromo-5-chloropyridine (65.0 gm). The yield of 2-bromo-5-chloropyridine was 78% and product was confirmed by mass spectroscopy and melting point (109°C).
Preparation of 5-Chloro-2-Cyano pyridine
A round bottom flask fitted with a condenser was charged with 2-bromo-5-chloropyridine (50 gm) obtained in step 1. Thereafter sodium cyanide (12.21 gm) along with copper cyanide (22.31 gm) was added to the flask. To this was charged dimethyl formamide (100 ml) at room temperature. Reaction mixture was then heated to 130°C - 140°C for 5 - 6 hrs. The TLC is used to test the end of the reaction using solvent system (Toluene : Methanol : : 9 : 1). The reaction mass was then cooled to room temperature followed by addition of ethyl acetate (400 ml). 10% Solution of monobasic potassium phosphate (300 ml) was added to bring the pH of reaction mixture between 4 to 6. After 30 minutes, the reaction mass was filtered through hyflobed and washed with 25 ml of water. Organic layer was then separated. Aqueous layer was extracted again with (1 x 250 ml + 1 x 100 ml) ethyl acetate. All the organic layer were then combined and washed with 500 ml of water. Resultant emulsion was filtered through hyflobed followed by washing with ethyl acetate (1 x 25 ml). Organic layer was then dried over anhydrous sodium sulphate (25 gm). Organic layer was then distilled under reduced pressure to get the product. Distilled ethyl acetate was kept aside for recycling in next batch. The crude product was then charged with 90.0 ml of isopropyl alcohol. The reaction mixture was then heated up to 75 - 80°C to get a clear solution. The activated charcoal (1.5 gm) was charged in homogeneous solution and the reflux was maintained for 1.0 hr. The reaction mass was filtered while hot through hyflobed which was then washed with hot isopropyl alcohol (10 ml). The filtrate was gradually cooled. The cake was filtered and washed with 2 x 10 ml of chilled isopropyl alcohol. The mother liquor was distilled. The distillate isopropyl alcohol was kept aside for reuse in next batch for purification. Wet cake was dried at 55 - 60°C u/v for 8 - 10 hrs to give 5-chloro-2-cyanopyridine (25.0 gm). The yield of the 5-chloro-2-cyanopyridine was 70% and the GC purity was ~ 99%. Product was confirmed by mass spectroscopy and melting point (106 - 108°C).
Example 2
Preparation of 5-chloro-2-cyano pyridine by using recovered solvents: A round bottom flask fitted with a condenser was charged with 2-bromo-5-chloropyridine (50 gm) as obtained as in step 1 of Example 1. Thereafter sodium cyanide (12.21 gm) along with copper cyanide (22.31 gm) was added to the flask. To this was charged dimethyl formamide
(100 ml) at a temperature between 25 - 30°C. Reaction mixture was then heated to 130°C -140°C for 5 - 6 hrs. The TLC is used to test the end of the reaction using solvent system Toluene : Methanol : : 9 : 1. The reaction mass was then cooled to room temperature followed by addition of ethyl acetate (400 ml) recovered in step 2 of Example 1. 10% Solution of monobasic potassium phosphate (300 ml) was added to bring the pH of reaction mixture between 4 to 6. After 30 minutes, the reaction mass was filtered through hyflobed and washed with 25 ml of water. Organic layer was then separated. Aqueous layer was extracted again with (1 x 250 ml + 1 x 100 ml) ethyl acetate recovered in step 2 of Example 1. The entire organic layer were then combined and washed with 500 ml of water. Resultant emulsion was filtered through hyflobed followed by washing with ethyl acetate (1 x 25 ml). Organic layer was then dried over anhydrous sodium sulphate (25 gm). Organic layer was then distilled under reduced pressure to get the product. Distilled ethyl acetate was kept aside for further recycling in next batch. The crude product was then charged with 90.0 ml of isopropyl alcohol recovered in step 2 of Example 1. The reaction mixture was then heated up to 75 - 80°C to get a clear solution. The activated charcoal (1.5 gm) was charged in homogeneous solution and the reflux was maintained for 1.0 hr. The reaction mass was filtered while hot through hyflobed which was then washed with hot isopropyl alcohol (10 ml) recovered in step 2 of Example 1. The filtrate was gradually cooled. The cake was filtered and washed with 2 x 10 ml of chilled isopropyl alcohol. The mother liquor was distilled. The distillate isopropyl alcohol was kept aside for reuse in next batch for purification. Wet cake was dried at 55 - 60°C u/v for 8 - 10 hrs to give 5-chloro-2-cyanopyridine (25.0 gm). The yield of the 5-chloro-2-cyanopyridine was 70% and the GC purity was ~ 99%. Product was confirmed by mass spectroscopy and melting point (106 -108°C).
Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.









We Claim:
1. A process for producing 2-cyano-5-halopyridine of formula (I) comprising;
(a) reacting 2-amino-5-halopyridine of formula (IV) with alkali nitrite and brominating agent to prepare 2-bromo-5-halopyridine of formula (V);
(b) reacting the 2-bromo-5-halopyridine of formula (V) with an alkali cyanide along with copper cyanide at 100-160°C;
(c) isolating crude 2-cyano-5-halopyridine from reaction mass obtained in step (b) employing an organic solvent; and
(d) purifying isolated crude 2-cyano-5-halopyridine in organic solvent to obtain final product of formula (I)
(Formula Removed)
where,
R1 is H or a C1 to C4 straight chain or branched group; R2 is H or a C1 to C4 straight chain or branched group; R3 is H or a C1 to C4 straight chain or branched group; X is Cl, Br or I; and wherein, in the 2-amino-5-halopyridine of formula (IV) and 2-bromo-5-halopyridine of formula (V):
(Formula Removed)
R1 is H or a C1 to C4 straight chain or branched group; R2 is H or a C1 to C4 straight chain or branched group; R3 is H or a C1 to C4 straight chain or branched group; and X is C1, Br or I.
2. The process as claimed in claim 1, wherein the alkali nitrite is sodium nitrite or potassium nitrite.
3. The process as claimed in claim 1, wherein the brominating agent is hydrobromic acid and bromine.
4. The process as claimed in claim 1, wherein the alkali cyanide is sodium cyanide or potassium cyanide.
5. The process as claimed in claim 1, wherein the temperature of the reaction is in the range of 130-140°C.
6. The process as claimed in claim 1, wherein an organic solvent used in the isolation is selected from ethyl acetate or diisopropyl acetate.
7. The process as claimed in claim 1, wherein an organic solvent used in the purification is selected from the group comprising dichloromethane, dichloroethane, isopropyl alcohol, methanol or ethyl acetate.
8. The process as claimed in claim 1, wherein the organic solvent is recyclable.
9. A process for producing 2-cyano-5-halopyridine of formula (I) as substantially herein described with reference to examples.



Documents:

2465-del-2004-abstract.pdf

2465-DEL-2004-Claims (04-11-2009).pdf

2465-del-2004-claims.pdf

2465-DEL-2004-Correspondence-Others (04-11-2009).pdf

2465-DEL-2004-Correspondence-Others-(28-06-2010).pdf

2465-del-2004-correspondence-others.pdf

2465-del-2004-description (complete).pdf

2465-del-2004-form-1.pdf

2465-del-2004-form-18.pdf

2465-del-2004-form-2.pdf

2465-DEL-2004-Form-26 (04-11-2009).pdf

2465-del-2004-form-3.pdf

2465-del-2004-form-5.pdf


Patent Number 243368
Indian Patent Application Number 2465/DEL/2004
PG Journal Number 42/2010
Publication Date 15-Oct-2010
Grant Date 07-Oct-2010
Date of Filing 10-Dec-2004
Name of Patentee JUBILANT ORGANOSYS LIMITED
Applicant Address PLOT 1A, SECTOR 16 A, NOIDA-201 301, UP, INDIA
Inventors:
# Inventor's Name Inventor's Address
1 PRAKASH ANAND JUBILANT ORGANOSYS LTD, C-26, SECTOR-59, NOIDA (UP)INDIA.
2 TYAGI ANIL KUMAR JUBILANT ORGANOSYS LTD, C-26, SECTOR-59, NOIDA (U.P.)INDIA.
3 AGARWAL ASHUTOSH JUBILANT ORGANOSYS LTD, BHARTIAGRAM, GAJRAULA, JYOTIBA PHULEY NAGAR DISTRICDT MORADABAD 244 223, UTTAR PRADESH, INDIA.
PCT International Classification Number A61K31/277
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA