Filed of the invention:

The present invention relates to a process for sulfinylation of heterocyclic compounds. More particularly the present invention relates to preparation of sulfinyl heterocyclic compounds with high degree of purity thereby making it suitable for therapeutic applications.

Background of the invention and prior art.

Fipronil is a broad use insecticide that belongs to the phenylpyrazole chemical family. Fipronil is used to control ants, beetles, cockroaches, fleas, ticks, termites, mole crickets, thrips, rootworms, weevils, and other insects. Fipronil is a white powder with a moldy odor.

Various processes for the preparation of fipronil has been reported in the literature. The process involves sulfinylation of N-phenyl pyrazole.

In one of the method reported for sulfinylation of heterocyclic compounds involve two stage. First stage is formation of aryl/ alkyl thio heterocyclic compounds and the second stage is oxidation of the aryl/ alkyl thio heterocyclic compounds to form sulfinyl heterocyclic compounds.
Various processes are known in the literature for preparation of aryl/ alkyl thio pyrazoles. For example J.Org Chem. 1964, 29, 895 describes the condensation of trifluoromethanesulfenyl chloride CF3SCI with organo magnesium compounds to obtain the -SCF3 pyrazole derivatives. Similarly Tetrahedron Letters 1981,22, 323 described a method of preparation of SCF3Br derivatives by the action of CF2Br2 or CF2BrCI on thiophenates in liquid liquid phase transfer condition at the presence of a phase transfer catalyst. Various oxidizing agents such as TFA/H2O2, trichloroacetic acid/ H2O2 can be used for the oxidation of aryl/ alkyl thio heterocyclic compounds to form sulphynyl heterocyclic compounds. But this method of preparing sulfinyl heterocyclic compounds suffers various drawbacks such as usage of toxic reactant for example SCF3Br, SCF3CI and oxidation with TFA/H2O2 leads to corrosion of the glass linings of industrial reaction vessels.

Another method for sulfinylation reported in the prior art involves direct sulfinylation. For example EP 0 668 269 describes a one step sulfinylation process involving the reaction of a reagent RS(=O)X with the heterocyclic compound to form the desired sulfinylated compound. However, the reaction does not always proceed as desired, particularly when the reagent CF3SO2H or CF3SO2Na is used to carry out the sulfinylation process, further SOCI2 or phosgene, potentially hazardous reagents, must be used in addition in this case.

Another method involves reaction of RX with the S—S bond of a disulfide intermediate, to yield the corresponding sulfide, which is subsequently oxidized to form sulfinyl heterocyclic compound. For example US 6,881,848 disclose a process for the preparation of a sulfinyl heterocyclic compound comprises of preparing alkyl thio heterocyclic compound followed by oxidizing with trifluoroperacetic acid in the presence boric acid. The process for preparing alkyl thio heterocyclic compound comprises of adding sulfur dioxide to a mixture of the corresponding disulfide, a formate salt, trifluoromethyl bromide and a polar solvent; and a process for preparing the disulfide comprising adding S2CI2 to a solution, in an organic solvent, of the corresponding 4-unsubstituted pyrazole. Eventhough the process overcomes the usage of toxic reactant it does not avoid the subsequent oxidation step.

Further US application number 20100004307 disclose a process for the sulfinylation of a pyrazole derivative, characterized in that 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonitrile (II) is reacted with a sulfinylating agent S in the presence of at least one amine acid complex wherein the amine(s) are selected from secondary and/or tertiary amines and the acid(s) are selected from hydrofluoric, hydrochloric, hydrobromic and hydroiodic acid and sulfonic acid derivatives, and with the addition of a halogenating agent, wherein S is [CF3S(0)]20; or

CF3S(0)X wherein X means fluoro, chloro, bromo, iodo, a hydroxy group, or an alkaline or alkaline earth metal salt of the hydroxy group; or mixtures thereof, wherein the temperature of the reaction mixture at no time exceeds 39° C. However this process utilizes the usage of corrosive reagents. Moreover major drawback of this process is formation of one impurity [10-15%] which is very much unwanted and this impurity lowers the purity & yield of the final of the product.
Further US application number 20110034530 discloses a process for preparing 5-amino-1-(2,6-dichloro-4-(trifluo-romethyl)phenyl)-4-(trifluoromethylthi- o)-IH-pyrazole-3-carbonitrile, which is useful as an intermediate for the antiparasitic agent fipronil, and a process for preparing 5-amino-3-cyano-1-(2,6-dichloro-4-tri-fluoromethylphenyl)-4-trifluorometh- yl sulfinylpyrazole.

The process for preparing fipronil comprising: a first step of reacting CF3S(=O)ONa with a derivative of N-phenyl pyrazole in the presence of a reducing/halogenating agent; and a second step of oxidizing the compound of formula thioalkylated N-phenyl pyrazole obtained in first step in the presence of a selective oxidizing agent, under suitable conditions. However this process suffers drawbacks because of oxidation step and yield is also very much low which leads this process commercially unviable.

Further EP 0295117 discloses a process for the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulfinylpyrazole by the oxidation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole with 3-chloroperbenzoic acid. However in this process the co-formation of the corresponding sulfone compound 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulfonylpyrazole is obtained , which is difficult to remove from the sulfoxide. Furthermore this process requires trifluoro acetic acid & 3-chloroperbenzoic acid. Both of these reagents are costly and process is not commercially viable.

Further US application number 20090030211 discloses a process for the preparation of fipronil, an insecticide, and related pyrazoles. The preparation involves process of oxidation of corresponding thioalkyl pyrazoles using an oxidizing agent, preferably hydrogen peroxide, in a medium comprising trichloro acetic acid and at least one melting point depressant. However this process also suffers limitation because of oxidation step.

Further US 5,618,945 discloses a novel process for the sulfinylation of heterocyclic compounds, which comprises reacting: a compound of the formula RS(O)X, with an heterocyclic compound in the presence of phosgene or SOCI2, or CICOOC2H5. However this process demands high reaction temperature and requires special filtration equipment. Moreover formation of one impurity in stated reaction condition is very high. So commercially this process does not have any importance.

Thus the cited patents discussed above suffer severe disadvantages such as usage of toxic reactant such as RSX, usage of corrosive acids in the oxidation step, unnecessary formation of sulfones during oxidation step which are difficult to separate from the main product, usage of potentially hazardous chemicals such as phosgene or SOCI2 or requires high temperature for the reaction thereby making the process not prone to industrial application. Further the yield and purity of the prepared compounds are also less.

Hence there exists a need to develop a simple process for sulfinylation of heterocyclic compounds which is devoid of toxic or hazardous or corrosive reagents to prepare sulfinyl heterocyclic compound at room temperature with high purity.

Object of the invention:

The main object of the present invention is to develop a novel and safe process for sulfinylation of heterocyclic compound.

Another object of the present invention is to develop a process for sulfinylation of heterocyclic compound to prepare sulfinyl heterocyclic compound with high degree of purity thereby making it suitable for therapeutic applications.

Yet another object of the present invention is to develop a process for sulfinylation of heterocyclic compound comprises of reacting RSOX with the reaction mixture containing heterocyclic compound, tosyl acid and aliphatic amine in the presence of SO2 atmosphere.
Yet another object of the present invention is to develop a novel sulfinylation process which may be carried out in room temperature.

Yet another object of the present invention is to develop a novel sulfinylation process in which the catalyst dimethyl tosylate may be generated insitu by the reaction of tosylacid and dialkyl amines.

Yet another object of the present invention is to develop a novel sulfinylation process which is devoid of usage of toxic or hazardous or corrosive reagents and subsequent oxidation step for the sulfinylation reaction.

Further objective of the present invention is to develop a single step process for the preparation of sulfinyl heterocyclic compound with a better yield.

Summery of the invention:

The present invention relates to a process of sulfinylation of heterocyclic compounds to prepare sulfinyl heterocyclic compounds with high degree of purity. The process comprises of adding a compound of the formula RS(0)X to a reaction mixture containing heterocyclic compound, tosyl acid and an secondary amine for a period of 10-15 minutes at a temperature of 15-20°C in the presence of SO2 atmosphere. Then the reaction is maintained for a period of 16 hours at the temperature of 24-25°C. After

the period of 16 hours the reaction mixture is neutralized with a base followed by filtration to obtain the precipitated sulfinyl heterocyclic compound.

Description of the invention:

The present invention relates to a process of sulfinylation of heterocyclic compounds to prepare sulfinyl heterocyclic compounds with high degree of purity. The process comprises of adding a compound of the formula RS(O)X, in which R is a linear or branched alkyl group having from 1 to 4 carbon atoms, which is substituted with one or more identical or different halogen atoms and X is a halogen atom, the hydroxyl group or one of the salts thereof, a group -NR2R3, R2 and R3 being alkyl or haloalkyl groups of 1 to 4 carbon atoms, or an aryloxy or aralkoxy group, in which the aryl part preferably corresponds to a phenyl group, which is optionally substituted with one or more halogen atoms or alkyl or haloalkyl groups of 1 to 4 carbon atoms, to a reaction mixture containing heterocyclic compound, tosylacid and an amine for a first period of time at a first temperature. The heterocyclic compound is selected from the group consisting of pyrroles, pyrazoles, imidazoles, oxazoles, isoxazoles, thiazoles, isothiazoles and triazoles, all of these heterocyclic compounds may optionally being substituted with one or more atoms or groups chosen from halogen, amine, alkylamine, dialkylamine, nitrile, aryl, and aryl substituted with one or more halogen atoms and/or one or more alkyl, haloalkyl or SF5 groups. The above sulfinylation reaction is carried out in the presence of SO2 atmosphere. Then the reaction is maintained for a second period of time at a second temperature. After the second period of time water is added to the reaction mixture and neutralized with a base. Then the reaction mixture is filtered to obtain the precipitated sulfinyl heterocyclic compound.

In accordance with the invention the catalyst dimethyl tosylate is generated insitu by the reaction of p-toluene sulfonic acid and dimethyl amine in the sulfinylation reaction.

As per the invention the first period of time ranges from 0-5 hours and more preferably 10-15 minutes and the first temperature ranges from 0 to 50C and more preferably 10-20°C.
According to the invention the second period of time ranges from 3- 24 hours and more preferably 12-17 hours and the second temperature ranges from 10- 110C and more preferably 20-30°C.

As per the invention the ratio of heterocyclic compound and trifluoromethylsulfinyl chloride ranges from 1: 1 to 1: 2 and more preferably 1: 1.2 to 1:1.5 and the ratio of heterocyclic compound and dimethyltosylate ranges from 1: 1 to 1:2 and more preferably 1:1.2 to 1:1.8.
In accordance with the invention the yield of synthesized sulfinyl heterocyclic compound is 80-90% and the purity of the synthesized sulfinyl heterocyclic compound is 94-97%.
The invention also relates to a process for the preparation of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)-1 H-pyrazole-3-carbonitrile of formula I. (fipronil).

Formula I

The process of preparing compound of formula I comprises of adding CF3SOCI to a reaction mixture containing heterocyclic compound of formula II, tosylate for a period of 10-15 minutes at a temperature of 10-20°C in the presence of SO2 atmosphere. Then the reaction is maintained for a period of 12-15 hours at the temperature of 20-30°C. After the period of 15 hours the reaction mixture is neutralized with a base followed by filtration to obtain the precipitated sulfinyl heterocyclic compound yield. The catalyst dimethyl tosylate is generated in situ by the reaction of tosyl acid and dimethyl amine in the sulfinylation reaction.

Formula II

The ratio of compound of formula II and trifluoromethylsulfinyl chloride is 1:1.5 and the ratio of compound of formula II and dimethyltosylate is 1:1.2. The yield of is 85- 90% and the purity was found to be 95-97%.

Examples: #01.

Take 80 gms of hydrated p toluene sulfonic acid (0.421 moles) and 300 ml of toluene in a reactor fitted with a overhead stirrer condenser & dean stark apparatus to remove azeotropic water. To this 40% aqueous solution of dimethyl amine [ 71.2 gms; 0.631 moles] was added slowly and then mixture was refluxed for 3-4 hours to remove the water. Afterwards mixture was allowed to cool to 30C and 112.6 gms [ 0.351 moles] of 5-Amino-3-cyano-N- (2,6 Dichloro-4- trifluoro methyl phenyl) pyrazole was added under S02 atmosphere. To the reaction mass then Trifluoromethyl sulfenyl chloride 80.3 gms [ 0.526 moles] was added at 15-20C under SO 2 atmosphere. The reaction mass was then stirred for 12 hours at 20-30C under SO2 atmosphere and finlly neutralized with caustic solution. Solid product thus precipitated is filtered & washed with water and toluene. Dry product [135 gms] is obtained and purity is 95.8% by HPLC and impurity Sulfone is 2.8%.

Example : # 02

Experiment No #01 was repeated without S02 atmosphere. Dry product obtained is 122 gms; Purity of Fipronil is 89.4 % by HPLC and formation of Sulfone is 15.5% by HPLC.
Although certain embodiments and examples have been used to describe the present invention, it will be apparent to those skilled in the art that changes to the embodiments and examples shown may be made without departing from the scope and spirit of this invention.

WE CLAIM:

1. A process of synthesis of sulfinyl heterocyclic compound by sulfinylation reaction of heterocyclic compound comprises of

a. adding a compound of the formula RS(0)X over a first period of time at a first temperature to a reaction mixture containing heterocyclic compound, & a tosylate prepared from tosyl acid and secondary amine for sulfinylation of heterocyclic compound

b. characterized in carrying out the said sulfinylation in the presence of S02 atmosphere

c. Continuing the reaction for a second period of time

d. characterized in maintaining the reaction at a second temperature

e. adding a base to the said reaction mixture for neutralization and

f. filtering the reaction mixture of step (e) to obtain the precipitated sulfinyl heterocyclic compound yield.

wherein

R is a linear or branched alkyl group having from 1 to 4 carbon atoms, which is substituted with one or more identical or different halogen atoms and X is a halogen atom, the hydroxyl group or one of the salts thereof, a group -NR2R3, R2 and R3 being alkyl or haloalkyl groups of 1 to 4 carbon atoms, or an aryloxy or aralkoxy group, in which the aryl part preferably corresponds to a phenyl group, which is optionally substituted with one or more halogen atoms or alkyl or haloalkyl groups of 1 to 4 carbon atoms the heterocyclic compound is selected from the group consisting of pyrroles, pyrazoles, imidazoles, oxazoles, isoxazoles, thiazoles, isothiazoles and triazoles, all of these heterocyclic compounds may optionally being substituted with one or more atoms or groups chosen from halogen, amine, alkylamine, dialkylamine, nitrile, aryl, and aryl substituted with one or more halogen atoms and/or one or more alkyl, haloalkyl or SF5 groups.

2. The process as claimed in claim 1 further includes insitu generation of the catalyst dimethyl tosylate in the step 1(a) of claim 1 by the reaction of tosylacid and an secondary amine for increasing the rate of the reaction.

3. The process as claimed in claim 1 wherein the said first period of time ranges from 0- 5 hours and more preferably 10-15min.

4. The process as claimed in claim 1 wherein the said first temperature ranges from 0 - 100C and more preferably 10-20°C.

5. The process as claimed in claim 1 wherein the said second period of time ranges from 3 to 24 hrs and more preferably 12-18 hours.

6. The process as claimed in claim 1 wherein the said second temperature ranges from 10 - 110C and more preferably 20-30°C.

7. The process as claimed in claim 1 wherein the ratio of heterocyclic compound and RSOX ranges from 1:1 to 1: 2 more preferably 1:1.2 to 1:1.5.

8. The process as claimed in claim 1 wherein the yield of the synthesized sulfinyl heterocyclic compound is 80-90% based on pyrazole intermediate.

9. The process as claimed in claim 1 wherein the purity of the synthesized sulfinyl heterocyclic compound is 94-97%.

10. A process of synthesis of compound of formula I

Formula I by sulfinylation reaction of compound of formula II

Formula II comprises of

a. adding trifluoromethylsulfinyl chloride for a period of 10-15minutes at 15-20°C to a reaction mixture containing compound of formula II, tosylate prepared from tosyl acid & amine for sulfinylation of compound of formula II, wherein the ratio of compound of formula II and trifluoromethylsulfinyl chloride is 1:1.5.

b. characterized in carrying out the said sulfinylation in the presence of SO2 atmosphere

c. Continuing the reaction for a period of 15 hours

d. characterized in maintaining the reaction at a temperature of 20-30°C

e. adding a base to the said reaction mixture for neutralization and

f. filtering the reaction mixture of step (e) to obtain the precipitated compound of formula I.