FIELD OF INVENTION:

The present invention relates to a process of preparing alkyl/aryl thiopyrazole . and alkyl/aryl sulfinylpyrazole. More particularly the invention relates to a novel process for manufacturing of 5-Amino 4-alkyl/aryl thiopyrazole derivatives and 5-Amino 4- alkyl/aryl sulfynylpyrazole derivatives.

PRIOR ART: |

The state of art is represented by US 6015910, US 5283337, US 5232940, US5814652, US 6881848, US 6531501, US 4804675 US 6160002 and WO 97/22593.
Preparation and uses of 5- amino-4 ethyl sulfur containing pyrazoles are known in the literature. European Patent Publication numbers 0295117 discloses 5-amino-3- cyano -1-(2,6-dichloro -4-trifluoromethylphenyl]-4- ethylsulfenylpyrazole and 5- amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl]-4-ethanesulfonyl pyrazole. These compounds are described as having generally good pesticidal properties and in particular as effective against Plutella xylostella in a contact spray test.

Various processes are known in the literature for preparation of these 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.

Patent FR 2540108 describes mainly the preparation of phenyl perfluoroalkyl sulfides by reaction of thiophenates with perfluoroalkyl halides.

EuropeanPatents 201852 and 234119 described the reaction of disulfides with alkyl halides in presence of alkali metal dithionite in an inert organic or aqueous-organic solvent. However this method has a disadvantage and requires the preliminary preparation of the thiolate.

EP 0295117 discloses a process for preparing 5-amino-3-cyano-1-(2,6-dichloro-4- trifluoromethylpheny1)-4-methylthiopyrazole. The process consist of two stage, 1®' stage involves preparation of 5-Amino-3-cyano-1-(2,6-dichloro-4- trifluoromethylphenyl)-4-thiocyanatopyrazole by reacting 5-amino-3-cyano-1-(2,6- dichloro-4-trifluoromethylphenyl)pyrazole with potassium thiocyanate and liquid bromine at -78°C. Subsequently in the second stage the formed thiocyanate pyrazole is reacted with alkyl iodide at -7°C to get the required alkyl thiopyrazoles.
US 5,637,607 disclose two methods for the preparation of alkyl thiopyrazoles. The first method involves reduction of corresponding pyrazoledisulphide with an appropriate reducing agent such as sodium borohydride, to form intermediate sulfide or thiolate, followed by reacting the intermediate with an appropriate alkylating agent, such as an alkyl halide or a dialkyl sulfate, in a suitable solvent such as alcohol, water or ether or a mixture thereof. The reaction can be carried out at a temperature of from about -20° C. to about 150° C., preferably at room temperature.

The second method involves preparation of alkyl thiopyrazole prepared by direct alkylation of the 4-unsubstituted corresponding pyrazole with appropriate alkylsulfenyl halides (also known as alkylthio halides), such as methylsulfenyl chloride or ethylsulfenyl chloride. The reaction can be conducted in the presence of a catalyst such as a basic catalyst, for example a metal carbonate, a metal hydride, such as sodium hydride, or a metal hydroxide, such as sodium hydroxide. The reaction can be carried out at a temperature of from about -20°C. to about 150°C., preferably at a temperature of from about 0°C. to about 100°C.

US 6518266 disclose synthesis of 1-aryl-4-cyanopyrazoles. The method involves reaction of substituted phenylhydrazine with 3,3-(bismethylthio)-2-cyanoacrylonitrile in isopropyl alcohol (15 mL). The reactant mixture was heated at reflux for 16 h. The solvent was removed under reduced pressure and the desired product alkyl thiopyrazole obtained after chromatographic separation (silica gel) using ethyl acetate:hexanes (Y=50-90%).
The cited prior art discloses various methods for the preparation of alkyl or haloalkyl thiopyrazole and sulfynylpyrazole. In particular the preparation of alkyl thiopyrazole suffers drawbacks such as the process demands hazardous chemicals as referred in EP0295117, very low temperature reaction condition as referred in BP 0295117, prolonged reaction time as referred in US 6518266, catalyst or atleast require two steps to prepare the final product as referred in EP0295117, US 5,637,607 which are not viable for industrial manufacturing. Thus a simple single step process which is relatively inexpensive involving non hazardous reactants with out any catalyst and can be carried out at room temperature is an important need in the state of art.

OBJECTS OF THE INVENTION

The objective of the present invention is to provide a simple one step process for the preparation of alkyl/aryl thio pyrazoles with a better yield.

Another objective of the present invention is to prepare alkyl/aryl thio pyrazoles by reacting pyrazole disulfides with a reducing agent sulfur dioxide in the presence of a formate ion and an alkyl / aryl halides in particular bromide or iodide.
Another objective of the present invention is to avoid the use of hazardous chemicals like bromine or chlorine and use simple alkyl/aryl halides in the preparation of alkyl/aryl thio pyrazoles.

Another objective of the present invention is to prepare alkyl/aryl thio pyrazoles with very good yield and conversion.

Another objective of the present invention is to prepare alkyl/aryl thio pyrazoles with high purity..

Another objective of the present invention is to provide a simple industrially viable method for large scale production of alkyl/aryl thio pyrazoles.

Another objective of the present invention is to provide a process for the preparation of alkyl/aryl sulfinylpyrazoles with a better yield.

Another objective of the present invention is to prepare alkyl/aryl sulfinylpyrazoles by reacting pyrazole disulfides with a reducing agent sulfur dioxide in the presence of a formate ion and an alkyl / aryl halides followed by subsequent oxidation with sulphuric acid and hydrogen peroxide.

Another objective of the present invention is to prepare alkyl/aryl sulfinylpyrazoles with very good yield and conversion.

Another objective of the present invention is to prepare alkyl/aryl sulfinylpyrazoles with high purity.

Another objective of the present invention is to provide a simple industrially viable method for large scale production of alkyl/aryl sulfinylpyrazoles.

These and other objects of the invention are met in whole and in part by the present invention. They shall become readily apparent from the description of the present invention which follows.

SUMMARY OF THE INVENTION

The present invention relates to a simple one step process for 5-Amino-4-thioalkyl pyrazoles of the formula (I).

where A is chloride or bromide or iodide, B is -CF3 or -OCF3, X is hydrogen or - CH3 or -C2H5, and Y is -CH3 or -C2H5, or -nC3H7

The process of preparing the compound of formula (I) comprises of reacting a compound of formula (II) with alkyl halide AY in presence of SO2 and formate anion.

(II)
where A is chloride or bromide or iodide, B is -CF3 or -OCF3, X is hydrogen or - CH3 or -C2H5, Y is -CH3, or -C2H5, or -nC3H7 and all substituent's are independent to each other.

The invention also relates to a process of preparing compound of formula (III)

(III)
The process of preparing compound of formula (III) comprises of preparing compound of formula (I) as above and oxidizing the compound of formula (I) with sulphuric acid and hydrogen peroxide.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In one of the preferred embodiment the present invention shall disclose a simple one step process for the preparation of compound of formula (I)

wherein A is chloride or bromide or iodide, B is -CF3 or -OCF3, X is hydrogen or - CH3 or -C2H5, and Y is -CH3, or -C2H5, or -nC3H7

The process of preparing the compound of formula (I) comprises of reacting a compound of formula (II) with alkyl halide AY in presence of SO2 and formate anion.

where A is chloride or bromide or iodide, B is -CF3 or -OCF3, X is hydrogen or - CH3 or -C2H5, Y is -CH3. or -C2H5, or -nC3H7 and all substituent's are independent to each other.

Details method for synthesis of starting disulfide compounds for this invention is described in European Patent application number 88/3053068 filled in 10th june 1988.
Pyrazole disulfides are taken in a polar solvents where this disulfide has a good solubility; among those solvents preferred solvents are DMF, Formamide, dimethyl
acetamide ( DMA) , N-methyl pyrolidone( NMP) ; Dimethyl sulfoxde (DMSO) ; hexamethyl phosphoramide (HMPA); Sulfolane etc.

Along with the disulfide molar quantity of formate is employed; however use of more quantity is also possible. Optimized mole ratio of disulfide to formate is 1:1 to 1: 5, however mole ratio of 1:1 to 1: 3 is preferred one. Use of excess has no additional advantage.

Sulfur dioxide is required in catalytic quantity for this reaction. The molar proportion of sulfur dioxide to the formate ion is generally between 0.01 to 4 moles/mole, although the upper limit is not critical.

Since one mole of disulfide yields two moles of thio pyrazoles, molar ratio of alkyl halides with respect to disulfide should be at least 2:1. However for complete conversion preferred mole ratio is 2.5:1 to10:1. Excess alkyl halide used in the reaction can be recovered after the reaction is completed and it can be recycled back.

Reaction can be carried out from 20°C to 120°C , however the optimum range is 45- 85°C. alkyl halides with low boiling points requires slight higher pressure [autogeneous] for smooth reaction[ 0.5 kg/ cm - 5 kg/cm].

More preferably list of compounds which can be prepared by this novel method includes the following compounds:

5 -Amino-3-cyano -1-(2,6 dichloro-4-trifluoromethylphenyl) -4-ethylthio pyrazole:
5 -Amino-3-cyano -1-(2,6 dichloro-4-trifluoromethylphenyl) -4-methylthio pyrazole
5 -Amino-3-cyano -1-(2,6 dichloro-4-trifluoromethylphenyl) -4-propyl(n)thio pyrazole
5-Amino-3-cyano -1-(2,6 dichloro -4-trifluoromethoxyphenyl)-4-ethylthio pyrazole.
5-methylamino-3-cyano -1-(2,6 dichloro -4-trifluoromethylphenyl)-4-ethylthio pyrazole.
5-ethylamino-3-cyano -1-(2,6 dichloro -4-trifluoromethylphenyl)-4-ethylthio pyrazole.
5 -Amino- -1-(2- bromo -6-chloro-4-trifluoromethylphenyl) -4-ethylthio pyrazole:

EXAMPLE 1: [Preparation of 5-Amino -3-cyano -1-(2,6 dicfiloro -4- trifluoromethylphenyl) -4-etliyl thio pyrazole.]

Into a thick 3 liters glass autoclave following chemicals are introduced sequentially as follows: i) Dimethyl formamide =643 gm, ii) 5 -Amino -3-cyano -1-(2,6 dichloro -4- trifluoromethy phenyl) pyrazole -4yl disulfide =157.6 gm [0.224 moles] ill) Sodium formate = 38 gm [ 0.56 moles] iv) Ethyl bromide = 190 gm [1.17 moles]. Total reaction mass is then allow to stir at room temperature. Gaseous sulfur dioxide [ 20 gm; 0.31 moles] is then slowly purged into this reaction mass under agitation. Temperature is then slowly increased up to 45-75C by external heating. Autogenous pressure increases up to 2-3 kg. Subsequently reaction is maintained for another 4-5 hour at 45-75C for completion of reaction. Reaction is monitored by HPLC. After five hours maintaining conversion of disulfide is more than 98%. Area % of the titled product is about 97%. After the unreacted disulfide is < 1%, reaction is allowed to cool down to room temperature and pressure is released through a caustic trap.

Reaction mass is then slowly dumped/quinched into ice water [1200 gm] and solid product is digested for 2 hours. Subsequently solid powder is filtered and washed with chilled water. Wt of the dry product is 157 gm.

Yield of light yellow product is > 90% . Melting point of the dried product is 157- 159°C The Purity of the product by HPLC is >97 %. Identity of the product was confirmed by GC Mass & NMR Spectra.

NMR (DMSO-D6) δ 1.12 (t, 3H); 2.49 (q, 2H), 6.52 (s,2H) 8.23(s,2H)
Following compounds can be prepared by same method by using respective disulfides & appropriate alkyl halides.

5-Amino-3-cyano -1-(2,6 dichloro -4-trifluoromethoxyphenyl)-4-ethylthio pyrazole. 5-Amino-3-cyano -1 -(2,6 dichloro -4-trifluoromethoxyphenyl)-4-methylthio pyrazole 5-Amino-3-cyano -1-(2,6 dichloro -4-trifluoromethoxyphenyl)-4-n-propylthio pyrazole
if
5-methylamino-3-cyano -1-(2,6 dichloro -4-trifluoromethylphenyl)-4-ethylthio pyrazole.
5-ethylamino-3-cyano -1-(2,6 dichloro -4-trifluoromethylphenyl)-4-ethylthio pyrazole. 5 -Amino- -1-(2- bromo -6-chloro-4-trifluoromethylphenyl) -4-ethylthio pyrazole.

In another preferred embodiment the present invention shall disclose a process of preparing compound of formula (III)

wherein
A is chloride or bromide or iodide,
Y is -CH3, or -C2H5, or -nC3H7
B is -CF3 or -OCF3 ,
X is hydrogen or -CH3 or -C2H5,
and all substituent's are independent to each other.

The process of preparing compound of formula (III) comprises of
a. purging sulphur dioxide to a mixture comprising of compound of formula(ll).

along with alkylhalide AY, fonnate anion and a polar solvent to form compound of formula (I)

b. oxidizing the obtained formula (I) with hydrogen peroxide under acidic condition using methanol as a solvent to form compound of formula (III)

wherein
A is chloride or bromide or iodide, Y is -CH3. or -C2H5, or -nC3H7 B is -CF3 or -OCF3 , X is hydrogen or -CH3 or -C2H5, and all substituent's are independent to each other.
According to the present invention, compound of formula (III) also can be prepared by oxidation of a compound of formula (I) wherein the A.B X, Y are as defined above by some other oxidizing agents normally used in the industry with some special solvents. Fluorinated acetic acids are used in the prior art as a solvent for these oxidation reactions and is normally reaction is carried out at very lower temperature like -30°C to a temperature of boiling point of the solvent used. Hydrogen peroxide or metachloroperbenzoic acid, per acetic acid etc are used as oxidizing agents. More economical process is oxidation in methanol by hydrogen peroxide both of which is much cheaper and does not require recovery and recycling to make the process commercially viable.

A major problem for preparation of 5-Amino-1-(2,6 dichloro-4-trifluoromethyl phenyl) -3-cyano-4-ethyl sulfinylpyrazole by oxidation of 5-Amino-1-(2,6 dichloro-4- trifluoromethyl phenyl) -3-cyano-4-ethyl thiopyrazole is the co formation of the corresponding sulfone compound which is difficult to remove from the main product. So a number of oxidants like sodium vanadate , peracetic acid, sodium tungstate , performic acid, pertrichloro acetic, metachloro perbenzoic acid etc have been used for selective and efficient oxidation which will only give the controlled oxidation product of good purity and yield. Moreover this process should be industrially viable. Customarily a mixture of fluorinated acetic acid and hydrogen peroxide gives excellent results in terms of selectivity and yields; however a major deficiency of this process for commercial application is rapid corrosion of glass line reactor in industrial manufacturing. Even at room temperature rate of corrosion is about 285 micrometer / year. Whenever fiuorinated acetic acids are used as a solvent it produces hydrogen fiuoride as a side product which is mainly responsible for this rapid corrosion in the glass lining reactors , making this process unviable for commercial application.

So one main objective of the inventive process is to use a simple, cheap & easily available solvent like methanol or isopropanol or mixture of both as a solvent and use of commercially abundant and cheap oxidizing agent like hydrogen peroxide for selective oxidation, to get a good purity and satisfactory yield for this process.

Another objective of this invention was to render a commercially viable process with minimum corrosion problem by using methanol as solvent and hydrogen peroxide as oxidizing agent, thereby making the corrosion problem to a minimum.

Amount of solvent is not very critical and quantity sufficient to dissolve the starting thiopyrazole like 5-Amino-1-(2,6 dichloro-4-trifluoromethyl phenyl) -3-cyano-4-ethyl sulfinylpyrazole is required for this process.

Normally equimolar quantity of hydrogen peroxide is used for this oxidation step to avoid the formation of unwanted sulfone impurity, however 10-15% molar excess does not affect the purity of final product. So mole ratio of 5-Amino-1-(2,6 dichloro-4- trifluoromethyl phenyl) -3-cyano-4-ethyl thiopyrazole to Hydrogen peroxide is 1: 0.5 to 1: 1.2 ; However more preferable is 1: 0.9 to 1:1.1 for an excellent yield and purity.
Oxidation is carried out under acidic condition using sulphuric acid. Nitric acid, acetic acid or combinations thereof.

Mole ratio of conc sulfuric acid with respect to 5-Amino-1-(2,6 dichloro-4- j
trifluoromethyl phenyl) -3-cyano-4-ethyl thiopyrazole (compound of formula (I) is 0.1 : 1 to 1 :1 , more preferably mole ratio is 0.4 : 1 to 0.8 :1 .

Oxidation can be carried out from -10°C to 100°C, however temperature from 25°- 80°C is preferred one.

Following non limiting example illustrate the invention for better understanding and application.

EXAMPLE 2 : [ Preparation of 5- Amino-1-[2,6 dichloro -4-trifluoromethyl phenyl) -4- (ethylsulfinyl) 1-H pyrazole-3-carbonitrile]

5 -Amino-3-cyano -1-(2,6 dichloro-4-trifluoromethylphenyl ) -4-ethylthio pyrazole prepared by above method is taken 20 gm (0.0226 moles) in methanol (65 gm). To the mixture 1.5 gm con sulfuric acid is added. Subsequently 50% hydrogen peroxide 8 gm (0.0706 moles) was added drop wise to the mixture under agitation at temperature (40-70°C). Total reaction mass is then allowed to stir for 2-4 hours and finally it is cooled down to 10°C temperature. At this temperature, slowly 150 gm of chilled water was added to the mass. Solid product precipitated is digested for half an hour at 20 -25°C & then filtered and washed with water. Wt of dried product is 17 gm. This off white colour powder has a melting point = 175°C. The product structure has been identified/confirmed by GC Mass & NMR Spectra. The purity of the product analysed by HPLC is about 96%. The product was analyzed against analytical standard from Sigma-Aldrich.
NMR (DMSO-D6) δ 1.12 (t, 3H); 2.48 (q, 2H), 6.91 (s,2H) 8.27(s,2H)

The examples which are discussed above, illustrate the inventions and show how it may be implemented and are not limitations. Any alteration/ modifications of the described parameters by a person skilled in the art is possible, which does not affect the novelty of this invention.

WE CLAIM

1. A process of preparing a compound having formula (I)

(1)
the said process comprising of purging sulphur dioxide to a mixture comprising of compound of formula(ll),

II
along with alkylhalide AY, formate anion and a polar solvent

wherein
A is selected from the group comprising of chloride, bromide or iodide,
Y is selected from the group comprising of -CH3, or -C2H5, or -nC3H7
B is selected from the group comprising of -CF3 or -OCF3 ,
X is selected from the group comprising of hydrogen or -CH3 or -C2H5,

2. The process as claimed in claim 1 wherein the said polar solvent is selected from the group comprising of DMF, Formamide, dimethyl acetamide ( DMA), N-methyl pyrolidone( NMP) ; Dimethyl sulfoxde (DMSO) ; hexamethyl phosphoramide (HMPA); Sulfolane or combination thereof.

3. The process as claimed in claim 1 wherein the molar ratio of the compound of formula (II) to alkyl halide AY is from 1: 0.5 to 1:10 and more preferably 1: 8.

4. The process as claimed in claim 1 wherein the molar ratio of the compound of formula (II) to formate ion is from 1:1 to 1:5 and more preferable range is 1: 2to1:3

5. The process as claimed in claim 1 wherein the molar proportion of sulfur dioxide relative to formate ion is from 0.01 to 4 moles/ mole

6. The process as claimed in claim 1 wherein process temperature is between 20°C to 120°C and more preferably 45 to 85°C

7. A process of preparing a compound having formula (III) the said process comprising of

a. purging sulphur dioxide to a mixture comprising of compound of formula(ll),

along with alkylhalide AY, formate anion and a polar solvent to form compound of formula (I)

b. oxidizing the obtained formula (I) of step (a) with hydrogen peroxide and methanol under acidic condition to form compound of formula (III)

wherein
A is selected from the group comprising of chloride, bromide or iodide, Y is selected from the group comprising of -CH3, or -C2H5, or -nC3H7 B is selected from the group comprising of -CF3 or -OCF3, X is selected from the group comprising of hydrogen or -CH3 or -C2H5,

8. The process as claimed in claim 7, wherein the said polar solvent of step (a) is selected from the group comprising of DMF, Formamide, dimethyl acetamide ( DMA) , N-methyl pyrolidone( NMP) ; Dimethyl sulfoxde (DMSO) ; hexamethyl phosphoramide (HMPA); Sulfolane or combination thereof.

9. The process as claimed in claim 7, wherein the molar ratio of the compound of formula (II) to alkyl halide AY in step (a) is from 1: 0.5 to 1:10 and more preferably 1: 8.

10. The process as claimed In claim 7, wherein the molar ratio of the compound of formula (II) to formate ion in step (a) is from 1:1 to 1:5 and more preferable range is1:2to1:3

11. The process as claimed in claim 7, wherein the molar proportion of sulfur dioxide relative to formate ion in step (a) is from 0.01 to 4 moles/mole.

12. The process as claimed in claim 7, wherein the process temperature of step (a) is between 20°C to 120°C and more preferably 45 to 85°C.

13. The process as claimed in claim 7 , wherein the molar ratio of the compound of formula (I) to hydrogen peroxide in step (b) is from 1: 0.5 to 1: 1.2 and more preferable range is 1: 0.9 to 1:1.1

14. The process as claimed in claim 7, wherein the process temperature of step (b) is between -10°C to 100°C and more preferably 25° to 80°C.

15. The process as claimed in claim 7, wherein the acidic condition in step (b) means addition of acid selected from the group comprising of sulphuric acid, Nitric acid, acetic acid or combinations thereof.

16. The process as claimed in claim 7 wherein the mole ratio of sulfuric acid to compound of formula (I) in step(b) is 0.1 : 1 to 1.0 : 1 and more preferably 0.4 : 1 to 0.8:1.