FIELD OF THE INVENTION
The present invention provides a process for preparation of a compound of formula 1,

wherein, R is C1-10 alkyl, halo C1-10 alkyl, aryl, substituted aryl, hetero aryl or substituted hetero aryl; and Xa is Cl, Br, I or F.

BACKGROUND OF THE INVENTION
Halo substituted sulfonyl halides are important intermediates in the preparation of various pharmaceuticals e.g., 2,6-difluorobenzenesulfonyl chloride is used in the preparation of Dabrafenib which is a drug for the treatment of cancers associated with a mutated version of the gene BRAF and it is also a biochemical for proteomics research. Very few methods are known in the art for the preparation of these intermediates e.g., PCT Publication Number WO/2002/079122 discloses the preparation of 2,6-difluorobenzenesulfonyl chloride by reacting 2,6-dichlorobenzenethiol with N-chlorosuccinimide in presence of acetic acid, water and potassium acetate.
The main disadvantage of using N-chlorosuccinimide is that it undergoes decomposition to emit toxic fumes of chloride and nitrogen oxides.
Thus there is a need to develop an alternative and industrially safe process for the preparation of halo substituted sulfonyl halides.
Surprisingly, the inventors of the present invention found that the halo substituted sulfonyl halides can be prepared in very efficient and cheaper manner.

OBJECT OF THE INVENTION
The object of the present invention is to provide an alternative and cost effective process for the preparation of a compound of formula 1,

wherein, R is C1-10 alkyl, halo C1-10 alkyl, aryl, substituted aryl, hetero aryl or substituted hetero aryl; and Xa is Cl, Br, I or F.

SUMMARY OF THE INVENTION
The present invention provides a process for preparation of a compound of formula 1,

wherein, R is C1-10 alkyl, halo C1-10 alkyl, aryl, substituted aryl, hetero aryl or substituted hetero aryl; and Xa is Cl, Br, I or F,
comprising the steps of:
a) diazotizing a compound of formula 3 to produce a compound of formula 2; and

wherein, R is C1-10 alkyl, halo C1-10 alkyl, aryl, substituted aryl, hetero aryl or substituted hetero aryl; and Xa is Cl, Br, I or F
b) contacting the compound of formula 2 with a protic acid and a sulphur dioxide source to obtain the compound of formula 1.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparation of a compound of formula 1,

wherein, R is C1-10 alkyl, halo C1-10 alkyl, aryl, substituted aryl, hetero aryl or substituted hetero aryl; and Xa is Cl, Br, I or F,
comprising the steps of:
a) diazotizing a compound of formula 3 to produce a compound of formula 2; and

wherein, R is C1-10 alkyl, halo C1-10 alkyl, aryl, substituted aryl, hetero aryl or substituted hetero aryl; and Xa is Cl, Br, I or F.
b) contacting compound of formula 2 with a protic acid and a sulphur dioxide source to obtain the compound of formula 1.
As used herein, aryl, hetero aryl are substituted with at least one of the group selected from alkyl, halo alkyl, nitro, halogen, carboxyl, alkoxy, formyl and sulfonyl group.
As used herein, the protic acid is selected from a group consisting of hydrochloric acid, hydroiodic acid, hydrobromic acid and hydrofluoric acid.
The diazotizing agent used for diazotization of the compound of formula 3 is nitrous acid formed in-situ using a protic acid and nitrites.
The nitrites used to prepare diazotizing agent can be selected from a group consisting of sodium nitrite, potassium nitrite, and lower alkyl nitrites mainly methyl nitrite, ethyl nitrite, propyl nitrite and butyl nitrites.
In a preferred embodiment, diazotizing agent is prepared using hydrochloric acid and sodium nitrite. In another preferred embodiment, diazotizing agent is prepared using hydrochloric acid and potassium nitrite.
The process of step a) i.e., diazotization is carried out at a temperature of -5 to 0°C
As used herein, the sulphur dioxide source is selected from a group of consisting of bisulphites, sulphites and metabisulfites such as alkali metal bisulfites, alkaline earth metal bisulfites, alkali metal metabisulfites, alkaline earth metal metabisulfites, alkali metal sulphites and alkaline earth metal sulphites or a mixture thereof.
The preferred source for sulphur dioxide as used in the present invention is sodium bisulfite, potassium bisulfite, sodium metabisulfite, potassium metabisulfite, sodium sulphite and potassium sulphite or a mixture thereof.
In an embodiment, the reaction of the compound of formula 2 with a sulphur dioxide source is carried out in presence of a catalyst. The catalyst used is selected from a group consisting of copper halides and copper sulphates or hydrates thereof.
The preferred catalyst used is selected from a group consisting of CuCl, CuCl2, CuI, CuI2, CuBr, CuBr2, CuCl2.H2O and CuCl2.2H2O or a mixture thereof.
The process of step b) i.e., the preparation of compound of formula 1 from compound of formula 2 is carried out at a temperature of 0 to 5°C.
The solvent used for the process of the present invention is selected from a group consisting of acetic acid; water; chlorinated hydrocarbons e.g., dichloromethane, chloroform; ethers e.g., di-isopropypl ether; aromatic hydrocarbons e.g., toluene, m-xylene, p-xylene; acetone, methyl isobutyl ketone and acetonitrile or a mixture thereof.
In an embodiment, the solvent used is acetic acid. In another embodiment, the solvent used is water. In still another embodiment, the solvent used is toluene.
In a specific embodiment, the present invention provides a process for preparation of a compound of formula 1a,

comprising the steps of:
a) diazotizing a compound of formula 3a using sodium nitrite and hydrogen chloride to produce a compound of formula 2a; and

b) contacting compound of formula 2a with sodium bisulfite and hydrogen chloride to obtain the compound of formula 1a.
The sodium nitrite used for preparing diazotizing agent is mainly in the form of a solution in water.
In a preferred embodiment, the compound of formula 1 is prepared from compound of formula 2 in presence of CuCl catalyst.
In a preferred embodiment, the diazotized intermediate i.e., the compound of formula 2 is converted in-situ to compound of formula 1 without isolating from the reaction mass.

The conversion of compound of formula 2 into compound of formula 1 was analysed by making the morpholine derivative of the sample of compound of formula 2 withdrawn during reaction monitoring and monitoring it by LC till it ceases below 0.5%.
As used herein, the term “isolating” refers to the method used to isolate the compound from the reaction mixture. The isolation is carried out using any of the process consisting of extraction, distillation, filtration, decantation, washing, dryings or combination thereof.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), gas chromatography (GC), liquid chromatography (LC) and a like.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The compound of formula 3 which is used herein as starting material can be prepared by any of the methods known in the art i.e., or can be obtained commercially.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLES
EXAMPLE-1
Step-1A: Preparation of 2,6-dichlorobenzenediazonium chloride
Acetic acid (67.7g) was taken in 1000 mL round bottom flask (RBF 1) and added 2, 6-dichloroaniline (100g) and then added conc. hydrochloric acid (268g). The reaction mass was cooled to 0°C. Added aqueous sodium nitrite solution (45.17g in 100 ml water) to the above suspension. The reaction mass was stirred at -5 to 0°C for 30 minutes and was monitored by LC analysis till reaction completion to obtain diazotized reaction mass.
Step-1B: Preparation of 2,6-dichlorobenzenesulfonyl chloride
Acetic acid (838g) was taken in RBF 2 and added sodium bisulfite (178g) and conc. HCl (23.6g). Cooled mass to 5°C. Added conc. hydrochloric acid (188g) to the above suspension and then added CuCl (3.69g), toluene (8.7g) at same temperature to obtain bisulfite mixture. Added diazotized reaction mass to the bisulfite mixture and maintained reaction for 30 minutes at 0 to 5°C. The reaction was monitored by LC analysis under cooling till diazo morpholine derivative ceases to 0.5%. Added toluene (250ml) and deionized water (500mL). Separated the layers. Washed organic layers with water (2×100mL) and dried organic layer with dry Na2SO4. The solvent was removed under vacuum to get crude product. The crude product thus obtained was crystallized using isopropyl alcohol (650ml) to obtain the pure 2,6-dichlorobenzenesulfonyl chloride.
Yield: 64.02%
Purity: 99.5%
EXAMPLE-2
Step-1A: Preparation of 2, 6-dichloropyridine-4-diazonium chloride
Toluene (67.7g) was taken in 1000 mL round bottom flask (RBF 1) and added 2, 6-dichloro-4-amino-pyridine (100g) and then added conc. hydrochloric acid (268g). The reaction mass was cooled to 0°C. Added aqueous potassium nitrite solution (45.17g in 100 ml water) to the above suspension. The reaction mass was stirred at -5 to 0°C for 30 minutes and was monitored by LC analysis till reaction completion to obtain diazotized reaction mass.
Step-1B: Preparation of 2, 6-dichloropyridine-4-sulfonyl chloride
Toluene (838g) was taken in RBF 2 and added sodium bisulfite (178g) and conc. HCl (23.6g). Cooled mass to 5°C. Added conc. hydrochloric acid (188g) to the above suspension and then added CuCl2 (3.69g), toluene (8.7g) at same temperature to obtain bisulfite mixture. Added diazotized reaction mass to the bisulfite mixture and maintained reaction for 30 min at 0 to 5°C. The reaction was monitored by LC analysis under cooling till diazo morpholine derivative ceases to 0.5%. Added toluene (250ml) and deionized water (500ml). Separated the layers. Washed organic layers with water (2×100ml) and dried organic layer with dry Na2SO4. The solvent was removed under vacuum to get crude product. The crude product thus obtained was crystallized using isopropyl alcohol (650 mL) to obtain the pure 2, 6-dichloropyridine-4-sulfonyl chloride.
Yield: 62.02%
Purity: 98.5%

CLAIMS:WE CLAIM:
1. A process for preparation of a compound of formula 1,

wherein, R is C1-10 alkyl, halo C1-10 alkyl, aryl, substituted aryl, hetero aryl or substituted hetero aryl; and Xa is Cl, Br, I or F,
comprising the steps of:
a) diazotizing a compound of formula 3 to produce a compound of formula 2; and

wherein, R is C1-10 alkyl, halo C1-10 alkyl, aryl, substituted aryl, hetero aryl or substituted hetero aryl; and Xa is Cl, Br, I or F
b) contacting compound of formula 2 with a protic acid and a sulphur dioxide source to obtain the compound of formula 1.
2. The process as claimed in claim 1, wherein the diazotizing agent used for diazotizing the compound of formula 3 is nitrous acid which is formed in-situ using a protic acid and nitrites.
3. The process as claimed in claim 1 and claim 2, wherein the protic acid is selected from a group consisting of hydrochloric acid, hydroiodic acid, hydrobromic acid and hydrofluoric acid.
4. The process as claimed in claim 2, wherein the nitrite is selected from a group consisting of sodium nitrite, potassium nitrite, and lower alkyl nitrites selected from methyl nitrite, ethyl nitrite, propyl nitrite and butyl nitrites.
5. The process as claimed in claim 1, wherein the reactions of step a) and step b) are carried out at a temperature of -5 to 5°C.
6. The process as claimed in claim 1, wherein the sulphur dioxide source is selected from a group of consisting of alkali metal bisulfites, alkaline earth metal bisulfites, alkali metal metabisulfites, alkaline earth metal metabisulfites, alkali metal sulphites and alkaline earth metal sulphites or a mixture thereof.
7. The process as claimed in claim 1, wherein step b) is carried out using a catalyst selected from a group consisting of copper halides and copper sulphates or hydrates thereof.
8. The process as claimed in claim 8, wherein the catalyst is selected from a group consisting of CuCl, CuCl2, CuI, CuI2, CuBr, CuBr2, CuCl2.H2O and CuCl2.2H2O or a mixture thereof.
9. The process as claimed in claim 1, wherein the reaction is carried out in presence of a solvent selected from the group consisting of acetic acid, water, chlorinated hydrocarbons, ethers, aromatic hydrocarbons, ketones and nitriles or a mixture thereof.