Field of Invention:
The present invention is directed to a process for preparation of difluoromethane sulfonyl
chloride by chlorooxidation of difluoromethylbenzyl sulphide in presence of water and a
water immiscible organic solvent.
Background of Art:
Difluoromethanesulfonyl chlorides which are precursors for fluoroalkyl sulfonamides forms an important class of compound having application in various pharmaceutical segments such as anti-inflammatory, anti convulsant, cardiovascular agents and as an intermediate in herbicidal compounds.
The widely used method of preparation of sulfonyl chlorides involves the reaction of chlorine gas with sulphides in aqueous acidic solutions. The process commonly known as chlorooxidation has been disclosed in the art, for example, in US Patent 5008396, and US patent no 5488109. Such chlorooxidation process gives poor yield when applied to the chlorooxidation of difluormethylbenzyl sulphide.
Although chlorine gas oxidation or chorooxidation in general has some inherent advantage of low cost, it however suffers from the following problems when applied to the reaction of difluoromethyl benzyl sulphide.
a. Poor solubility of the difluormethylbenzyl sulphide, the starting material for this
reaction, hinders the completion of the reaction.
b. The product of the reaction namely difluromethylsulfonyl chloride often gets
hydrolyzed in the aqueous medium into corresponding acid resulting in loss in
yield at the temperature required for smooth chloroxidation
c. Further there is a competing chlorooxidation reaction to form sulfones which
reduce the yield and increases the impurity. The formation of sulfone is through
the hypochlorite generated by the reaction of chlorine gas with water.
Journal of organic chemistry, Vol 44, No -10, 1979, describes the process of synthesis of fluoroalkylsulfonyl chlorides wherein, the author had tried various combination of reactants at different temperature and conditions. Theoretically the chlorooxidation of difluoromethylbenzyl sulfide needs two moles of water per mole of starting material for complete conversion into sulfonyl chloride. However when the same proportion was tried (refer run No-6 in the above paper), the yield of the process was found to be 28 %. Refer run no 7 of the above reference, where the author has claimed a yield of 70 % of difluoromethylsulfonyl chloride with the molar ratio of starting material to that of water at 1: 24. This calls for very huge reactor size and hence makes the process commercially unviable for the scale up.
Organic process Research & development, 1999, 3, 114, describes acetic acid/water as a solvent for the chlorooxidation, complete removal of the acetic acid from the product often meets with difficulties in large scale operation.
Summary of Invention:
An objective of present invention is to provide a process for preparation of
difluoromethane sulphonyl chloride comprising reaction of difluoromethyl benzyl
sulphide with chlorine gas, in presence of water and a water immiscible organic solvent,
which gives a good yield of upto 74.2%.
Another objective of the present invention is to provide a process which can be
conveniently scaled up for use in a commercial plant wherein huge reactor size is not
required.
Yet another objective of the present invention is to provide a process for preparation of
difluoromethane sulphonyl chloride of high purity.
Yet another objective of the present invention is to provide a process for preparation of moisture free difluoromethane sulphonyl chloride, thereby eliminating the need of hydrolysis of the final product.
Detailed Description of Invention:
Present invention discloses a process for preparation of difluoromethane sulphonyl
chloride comprising reaction of difluoromethyl benzyl sulphide with chlorine gas, in
presence of water and organic solvent.
The process of present invention involves use of water immiscible organic solvents that
are unreactive under the reaction conditions of the process in which
difluoromethylsulphonyl chloride are produced. The ratio of solvent to difluoromethyl
benzyl sulfide is 1.5:1 to 1:2.5.
Examples of water immiscible organic solvent include chlorinated hydrocarbon solvents
such as dichloromethane, chloroform, tetrachloromethane, 1,2-dichloroethane, 1,1-
dichloromethane, 1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene,
chlorobenzene, 1,2-dichlorobenzene, preferably dichloromethane.
It is usually advantageous to use sufficient amount of the water immiscible organic
solvent to maintain the difluoromethyl sulfonyl chloride produced in solution at the end
of the reaction.
In an embodiment of the invention water is added in phases, in parts.
In an another embodiment of the invention, the dilute hydrochloric acid is added to
reaction mixture comprising the reactants.
The chlorooxidation reaction produces hydrogen chloride, therefore aqueous phase
medium of reaction mixture goes acidic immediately upon initiation of the chemical
reaction. The amount of water and hydrochloric acid employed in the process can be
adjusted to arrive at the suitable final concentration of hydrochloric acid in the aqueous
phase. Water is taken slightly above the stoichiometric quantity i.e. 2-3 moles, most of the
HC1 is sent out of the system as a gas. Excess water is saturated with HC1 to have a concentration ranging from 33-35 %.
In a preferred embodiment of the invention water is added slowly into the reactor with simultaneous addition of chlorine, so that at any point of time large excess of water is not available for the product sulfonyl chloride to decompose.
Chlorine is generally added to the reaction medium as a gas. It is typically added just on the surface of the reaction medium at a rate which may vary from 2 grams/ minute to 10 grams/minute where the entire absorption of chlorine takes place maintaining the desired reaction temperature. 3 moles of chlorine is needed per mole of difluoromethyl benzyl sulfide, however excess of chlorine ranging from 3.1 to 4 moles of chlorine per mole of difluoromethyl benzyl sulfide is preferred. The water and chlorine is added simultaneously in a manner so that at any given point of time excess water is not available for the hydrolysis of the desired compound.
The reaction is carried out at a temperature at which the chemical reaction of the process proceeds relatively rapidly and at the same time the temperature is low enough that the side reaction is minimized. A temperature of -10 to -30 degree is preferred. The reaction is highly exothermic and efficient cooling is generally required to maintain the temperature. The reaction of the process takes place quickly and normally it takes 6- 8hrs for the completion of the reaction. The solvent methylene chloride has a azeotrope with water and it removes the excess water (0.5 - 1 mole) with it. As a result, the product Difluoromethylsulfonyl chloride is moisture free and hence the hydrolysis of the final product is avoided during the distillation.
The difluoromethanesulfonyl chloride obtained is generally recovered by first separating the organic phase from the aqueous phase of the reaction mixture. From the organic phase, the compound difluormethanesulfonyl chloride can be separated by any conventional distillation process known to a person skilled in the art.
The following examples are presented to illustrate the process of the invention and should not be construed as limitation on the claims .
Example -1
A mixture of 348 gms of (DFMBS) and 500 ml of dichloromethane was placed in round bottom flask of 2 liter capacity fitted with a mechanical stirrer and a glass condenser, having circulation fluid methanol cooled in Julabo system at - 40 degree C to pull back the dichloromethane that may be carried by the hydrogen chloride/unreacted chlorine. The round bottom flask was kept on the cold bath maintained at -30 degree C to maintain the mass temperature between -10 to -20 degree C. Chlorine cylinder kept in weigh balance was used to meter chlorine into the reactor. Simultaneously, 129 gms of water was added with the help of addition funnel to the reactor. The completion of the reaction was monitored by gas chromatographic analysis.
After the completion of the reaction, the aqueous and organic phases are separated. The organic phase was distilled to get 74.2 % yield of difluormethane sulfonyl chloride based on the DFMBS taken for the reaction.
Experiment -2
The experiment was done in the similar set as experiment no-1, 348 grams of DFMBS was taken in the reactor along with 529 grams of methylene chloride. Chlorine 540 grams was purged into the reactor maintaining the temperature of -10 to -20 degree C. Water 87 grams (4.833 moles) was tricked into the reactor through a dropping funnel. At the end of the reaction, the organic phase was distilled to realize a yield of 72.6 % of the difluormethylsulfonyl chloride.

We claim:
1. A process for preparation of difluoromethane sulphonyl chloride comprising chlorooxidation of difluoromethyl benzyl sulphide with chlorine gas in presence of water and a water immiscible organic solvent.
2. The process as claimed in claim 1, wherein the molar ratio of chlorine to difluoromethyl benzyl sulfide ranges from 1 : 3.1 to 1: 4.
3. The process as claimed in claim 1, wherein the molar ratio of water to difluoromethyl benzyl sulfide ranges from 2 to 3 moles of water per mole of difluoromethyl benzyl sulfide.
4. The process as claimed in claim 1, wherein the molar ratio of organic solvent to difluoromethyl benzyl sulfide ranges from 1: 1.5 to 1: 2.5.
5. The process as claimed in claim 1, wherein the solvent in selected from a group consisting of dichloromethane, chloroform, tetrachloromethane, 1,2-dichloroethane, 1,1-dichloromethane, 1,1,1-trichloroethane, trichloroethylene, tertrachloroethylene, chlorobenzene, and 1,2 dichlorobenzene.
6. The process as claimed in claim 1, wherein hydrochloric acid is added alongwith water to form a concentration of 33 to 35%.
7. The process as claimed in claim 1 wherein chlorine is added at a rate that varies from 2 grams/ minute to 10 grams/ minute.
8. The process for preparation of difluoromethane sulphonyl chloride such as herein described with reference to the foregoing examples.