Claims:We Claim:
1. An improved process for the preparation of compound of Formula (I)

Formula (I)
wherein the process comprises reacting oxirane compound of Formula II

Formula (II)
with 1,2,4 triazole using a base in a polar solvent to produce Cyproconazole, wherein the 1,2,4-triazole used in 1.0 to 2.0 molar equivalents of oxirane; the base used in 1.0 to 2.0 molar equivalents of oxirane.

2. The process of claim 1, wherein the molar equivalent of oxirane : triazole : base used in the present invention is preferably in the range of 1.0 : 1.0 : 1.0 to 1.0: 2.0: 2.0.

3. The process of claim 1, wherein solvent is selected from N,N-dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide.

4. The process of claim 3 wherein the solvent is preferably N-methylpyrrolidone.

5. The process of claim 1, wherein the base is selected from potassium hydroxide, sodium hydroxide, sodium methoxide or sodium ethoxide.

6. The process of claim 5 wherein the base is preferably potassium hydroxide.

7. The process of claim 1, wherein the reaction is carried out at a temperature of 125 - 200 °C.

8. The process of claim 1, wherein cyproconazole is obtained with a purity of 98% with isomeric impurity below 2%.

9. The process of claim 1, wherein the process comprises:

(a) reacting oxirane compound of Formula II

Formula (II)

with 1,2,4- triazole using a base in a polar solvent controlling the temperature between 125 to 200 °C, wherein the triazole is used in 1.0 to 2.0 molar equivalents of oxirane; the base is used in 1.0 to 2.0 molar equivalents of oxirane, wherein the reaction condition results in Cyproconazole with 93-95% purity, and

(b) followed by purification process to obtain in Cyproconazole having 98% purity with isomeric impurity below 2%.

Dated this Sixteenth (16th) day of December, 2019

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883 , Description:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR PREPARATION OF AN AZOLE FUNGICIDE

We, COROMANDEL INTERNATIONAL LIMITED, a company incorporated under the companies act, 1956 having address at Coromandel House, Sardar Patel Road, Secunderabad, Telangana-500003, India

The following specification describes and ascertains the nature of this invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an improved processes for the preparation of a fungicide of the class of azoles.

The present invention specifically relates to an improved process for the preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol having the following Formula I.

Formula I

BACKGROUND OF THE INVENTION
Cyproconazole is an agricultural fungicide of the class of azoles. The chemical name for Cyproconazole is (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol. The molecular formula is C15H18ClN3O and the molecular weight is 291.779 g/mol. The chemical structure of Cyproconazole is

Cyproconazole is claimed as product in US 4,664,696 A. The process disclosed in this patent for the preparation of Cyproconazole involves reaction of oxirane compound with triazole using potassium carbonate in a solvent which is shown below:

CN 101565406 B discloses a process for the preparation of Cyproconazole which involves condensation of oxirane compound with 1,2,4-triazole in a polar solvent at a controlled temperature of 70 to 120 °C in the presence of a base to obtain crude Cyproconazole of formula I; wherein the polar solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide ; the base is selected from the group consisting of potassium hydroxide, sodium hydroxide, sodium methoxide or sodium ethoxide in an amount of 0.05 to 0.3 molar equivalent of 2-(4-chlorophenyl)-2-(1-cyclopropylethyl) ethylene oxide and the 1,2,4-triazole is 1.0 to 3.5 molar equivalents of 2-(4-chlorophenyl)-2-(1-cyclopropylethyl) ethylene oxide. The process is shown in the scheme given below:

The process specifically disclosed in this patent for the preparation of Cyproconazole comprises 126 g of 2-(4-chlorophenyl)-2-(1-cyclopropylethyl) oxirane was dissolved to 373 g of dry N, N-dimethylformamide (abbreviated as DMF) in the solvent, add 49 g of 1,2,4-triazole and 7 g of potassium hydroxide powder, and then maintain it at about 90°C for 4 hours. The mole ratio of oxirane: triazole: base used in CN ‘406 is 1: 1.25: 0.22.
The coupling reaction for the preparation of cyproconazole in the above documents, could not produce desired isomeric purity of Cyproconazole, therefore post this coupling reaction there are multiple process operations (including repeated crystallization) involved to get the desired purity of Cyproconazole, which results in lower yields of Cyproconazole. This process is not only time consuming, but also limits the scale of production of the product.

Further, the prior art processes failed to achieve the maximum conversion of Cyproconazole with isomer ratio less than 2% and involves purification steps by making Cyproconazole hydrochloride salt, deacidification of salt, higher reaction times, repeated crystallizations, silica gel column chromatography, lower yields and generating higher amounts of effluent and process is tedious.

Accordingly, there is a need for a process for the preparation of cyproconazole which overcomes the drawbacks of the technical problem of the prior art, to provide a product of high purity, high yield, low cost, simple operation and secure unit cyproconazole industrial preparation process.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol having the following Formula I.

Formula I

It is therefore an object of the present invention to provide a simple, economical and commercially feasible process for the preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol with a high yield and high purity.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Cyproconazole ) having the following Formula I.

Formula (I)
wherein the process comprises reacting oxirane compound of Formula II

Formula (II)
with 1,2,4- triazole using a base in a polar solvent to produce Cyproconazole, wherein the triazole is used in 1.0 to 2.0 molar equivalents of oxirane; the base is used in 1.0 to 2.0 molar equivalents of oxirane.

In another embodiment, the present invention provides an improved process for the preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Cyproconazole ) having the following Formula I.

Formula (I)
wherein the process comprises reacting oxirane compound of Formula II

Formula (II)
with 1,2,4-triazole using a base in a polar solvent controlling the temperature between 125 to 200 °C, wherein the 1.2.4-triazole is used in 1.0 to 2.0 molar equivalents of oxirane; the base is used in 1.0 to 2.0 molar equivalents of oxirane, wherein the process results in Cyproconazole in 98% purity and below 2% of undesired diastereoisomers.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol by reacting compound of Formula (II) with triazole in a polar solvent and using a base.

The process of the present invention for the preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol wherein the triazole used in 1.0 to 2.0 molar equivalents of oxirane; the base used in 1.0 to 2.0 molar equivalents of oxirane. Further, the molar equivalent of oxirane: triazole: base used in the present invention is preferably in the range of 1.0: 1.0: 1.0 to 1: 2.0: 2.0.

When carrying out the process of the invention, the reaction temperature can be varied within a relatively wide range. The temperature chosen will depend on the nature of the solvent or diluent, for example on its boiling point and/or its effectiveness for promoting the desired reaction, and on the speed at which the reaction is to be carried out. In any given solvent or diluent, the reaction will tend to progress more slowly at lower temperatures. In general, the reaction may be carried out at a temperature of from 100 to 200 °C.

The reaction of 2-(4-chlorophenyl)-2-(1-cyclopropylethyl)oxirane in a polar solvent with 1,2,4-triazole is carried out by controlling the temperature between 125 - 200 °C, in the presence of a base results in cyproconazole with purity of 98% with isomeric ratio below 2%.

The polar solvent used herein is selected from N,N- dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide, and preferably N-methylpyrrolidone.

The base used herein is selected from potassium hydroxide, sodium hydroxide, sodium methoxide or sodium ethoxide and preferably potassium hydroxide.

The process of the present invention is more economical, produces less by-products and impurities and further generates considerably less effluents as a result of the improved yield as given in the table below:

Table 1:

CN 101565406
Our process
Example Oxirane Cyproconazole Yield Example Oxirane Cyproconazole Yield
1 82g 82g 76% 1 50g 55.7g 85%
2 126g 125g 75.6% 2 100g 112g 85.5%
3 50g 54.3g 82.9%
4 50g 54g 82.4%
5 50g 55.8g 85.2%
6 50g 55g 84%
7 50g 55.8g 85.2%
8 50g 55g 84%

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example-1:
Preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Cyproconazole )

1H-1,2,4-Triazole (20.2 g, 0.292 moles, 1.3eq) potassium hydroxide (12.6g, 0.224 moles, 1.0eq) was dissolved in N-methylpyrrolidone (200ml) wherein the triazole was converted to potassium salt of triazole at 145 -150°C. Thereafter, oxirane (50g, 0.224 moles, 1.0eq) solution dissolved in 50 ml of NMP was added dropwise and stirred for 2 hrs. at 145 – 150 °C, and the reaction was monitored by HPLC, the in-process analysis result was as below
Cyproconazole : 95.7%
Undesired Isomers: 1.7%.
Unreacted Oxirane: 0.8%
After completion of the reaction, N-Methyl Pyrrolidone (NMP) was distilled off completely under reduced pressure at 130°C. Cooled to 50°C and toluene was added and stir for 30 mins, washed with water. The toluene layer was concentrated under reduced pressure and crude product is taken in cyclohexane and heat to 50-55 °C for 30 mins and then cooled to 25°C. Stir for 2 hrs at 25°C and then filter the obtained solid, the product obtained is 55.7g which is having purity of 98% cyproconazole and the undesired isomers below 2% (by HPLC).

Example-2:
Preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Cyproconazole )

1H-1,2,4-Triazole (40.4 g, 0.585 moles, 1.3eq) potassium hydroxide (25.2g, 0.45 moles, 1.0eq) was dissolved in N-methylpyrrolidone (400ml) and was converted to potassium salt of triazole at 145-150°C. The reaction mass was maintained for 1hr at 145-150°C and then slowly the solution of 2-(4-chlorophenyl)-2-(1-cyclopropylethyl)-oxirane (100g, 0.45 moles, 1.0eq) dissolved in 100ml N-Methyl Pyrrolidone (NMP) was added at 145-150°C in 30mins. The reaction mixture was stirred for 2hrs at 145-150°C and the reaction was monitored by HPLC, the in-process analysis result was as below
Cyproconazole : 95.7%
Undesired Isomers: 1.7%.
Unreacted Oxirane: 0.8%
After completion of the reaction, N-Methyl Pyrrolidone (NMP) was distilled off completely under reduced pressure at 130°C. Cooled to 50°C and toluene was added and stir for 30 mins, washed with water. The toluene layer was concentrated under reduced pressure and crude product is taken in cyclohexane and heat to 50-55°C for 30 mins and then cooled to 25°C. Stir for 2 hrs at 25°C and then filter the obtained solid, the product obtained is 112g which is having purity of 98% cyproconazole and the undesired isomers below 2% (by HPLC).

Example-3:
Preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Cyproconazole )

1H-1,2,4-Triazole (20.2 g, 0.292 moles, 1.3eq) potassium hydroxide (7.5g, 0.134moles, 0.6eq) was dissolved in N-methylpyrrolidone (200ml) and was converted to potassium salt of triazole at 145-150°C. The reaction mass was maintained for 1hr at 145-150°C and then slowly the solution of 2-(4-chlorophenyl)-2-(1-cyclopropylethyl)-oxirane (50g, 0.224 moles, 1.0eq) dissolved in 50ml N-Methyl Pyrrolidone (NMP) was added at 145-150°C in 30mins. The reaction mixture was stirred for 2hrs at 145-150°C and the reaction was monitored by HPLC, the in- process analysis results was as below
% Cyproconazole : 95.2%
Undesired isomers:2.8%.
Unreacted oxirane : 1.0%
After completion of the reaction, N-Methyl Pyrrolidone (NMP) was distilled off completely under reduced pressure at 130°C. Cooled to 50°C and toluene was added and stir for 30 mins, washed with water. The toluene layer was concentrated under reduced pressure and crude product is taken in cyclohexane and heat to 50-55 °C for 30 mins and then cooled to 25°C. Stir for 2 hrs at 25°C and then filter the obtained solid, the product obtained is 54.3g which is having purity of 98% cyproconazole and the undesired isomers below 2% (by HPLC).

Example-4:
Preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Cyproconazole )

1H-1,2,4-Triazole (20.2 g, 0.292 moles, 1.3eq) potassium hydroxide (15g, 0.268moles, 1.2 eq) was dissolved in N-methylpyrrolidone (200ml) and was converted to potassium salt of triazole at 145-150°C. The reaction mass was maintained for 1hr at 145-150°C and then slowly the solution of 2-(4-chlorophenyl)-2-(1-cyclopropylethyl)-oxirane (50g, 0.224 moles, 1.0eq) dissolved in 50ml N-Methyl Pyrrolidone (NMP) was added at 145-150°C in 30mins. The reaction mixture was stirred for 2hrs at 145-150°C and the reaction was monitored by HPLC, the in-process analysis result was as below
Cyproconazole: 94.5%
Undesired Isomers: 2.7%.
Unreacted Oxirane: 0.9%
After completion of the reaction, N-Methyl Pyrrolidone (NMP) was distilled off completely under reduced pressure at 130°C. Cooled to 50°C and toluene was added and stir for 30 mins, washed with water. The toluene layer was concentrated under reduced pressure and crude product is taken in cyclohexane and heat to 50-55°C for 30 mins and then cooled to 25°C. Stir for 2 hrs at 25°C and then filter the obtained solid, the product obtained is 54.0g which is having purity of 98% cyproconazole and the undesired isomers below 2% (by HPLC).

Example-5:
Preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Cyproconazole )

1H-1,2,4-Triazole (20.2g,0.292moles,1.3eq) and potassium hydroxide(12.6g, 0.224moles, 1.0eq) was taken in 200 ml N-Methyl Pyrrolidone (NMP) and was converted to potassium salt of triazole at 145-150°C. The reaction mass was maintained for 1hr at 145-150°C and then slowly the solution of 2-(4-chlorophenyl)-2-(1-cyclopropylethyl)-oxirane (50g, 0.224 moles, 1.0eq) dissolved in 50ml N-Methyl Pyrrolidone (NMP) was added at 145-150°C in 30mins. The reaction mixture was stirred for 2hrs at 145-150°C and the reaction was monitored by HPLC and in-process results are as below
Cyproconazole : 94.7%
Undesired isomers:1.53%.
Unreacted oxirane : 0.9%
After completion of the reaction, N-Methyl Pyrrolidone (NMP) was distilled off completely under reduced pressure at 130°C. Cool to 50°C and 1,2-dichloroethane (EDC) was added and stir for 30mins and washed with water . The EDC layer was concentrated under reduced pressure and crude is dissolved in toluene at 50-55°C and cooled to 25°C. Stir for 2hrs and filter the solids and the product obtained is 55.8g which is having purity of 98% cyproconazole and the undesired isomers below 2% (by HPLC).

Example-6:
Preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Cyproconazole )

1H-1,2,4-Triazole (20.2g, 0.292moles, 1.3eq) and potassium hydroxide(10g, 0.178moles, 0.8eq) was taken in 200 ml N-Methyl Pyrrolidone (NMP) and was converted to potassium salt of triazole at 145-150°C. The reaction mass was maintained for 1hr at 145-150°C and then slowly the solution of 2-(4-chlorophenyl)-2-(1-cyclopropylethyl)-oxirane (50g, 0.224 moles, 1.0eq) dissolved in 50ml N-Methyl Pyrrolidone (NMP) was added at 145-150°C in 30mins. The reaction mixture was stirred for 2hrs at 145-150°C and the reaction was monitored by HPLC and in-process results are as below
Cyproconazole : 94.7%
Undesired isomers:1.53%.
Unreacted oxirane : 0.9%
After completion of the reaction, N-Methyl Pyrrolidone (NMP) was distilled off completely under reduced pressure at 130°C. Cool to 50°C and 1,2-dichloroethane (EDC) was added and stir for 30mins and washed with water . The EDC layer was concentrated under reduced pressure and crude is dissolved in toluene at 50-55°C and cooled to 25°C. Stir for 2hrs and filter the solids .The product obtained is 55.0g which is having purity of 98% cyproconazole and the undesired isomers below 2% (by HPLC).

Example-7:
Preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Cyproconazole )

1H-1,2,4-Triazole (20.2g,0.292moles,1.3eq) and potassium hydroxide (12.6g, 0.224moles, 1.0eq) was taken in 200 ml N,N-Dimethyl Acetamide (DMA) and was converted to potassium salt of triazole at 145-150°C. The reaction mass was maintained for 1hr at 145-150°C and then slowly the solution of 2-(4-chlorophenyl)-2-(1-cyclopropylethyl)-oxirane (50g, 0.224 moles, 1.0eq) dissolved in 50ml DMA was added at 145-150°C in 30mins. The reaction mixture was stirred for 2hrs at 145-150°C and the reaction was monitored by HPLC and in-process results are as below
% Cyproconazole : 92.9%
Undesired isomers:1.89%.
Unreacted Oxirane : 0.67%
After completion of the reaction, DMA was distilled off completely under reduced pressure at 130°C. Cool to 50°C and toluene was added and stir for 30mins and washed with water . The toluene layer was concentrated under reduced pressure and crude is taken in cyclohexane at 50-55°C and cooled to 25°C. Stir for 2hrs and filter the solids. The product obtained is 55.8g which is having purity of 98% cyproconazole and the undesired isomers below 2% (by HPLC).

Example-8:
Preparation of (2RS,3RS;2SR,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Cyproconazole )

1H-1,2,4-Triazole (20.2g,0.292moles,1.3eq) and potassium hydroxide (12.6g, 0.224moles, 1.0eq) was taken in 200 ml Dimethyl sulfoxide (DMSO) and was converted to potassium salt of triazole at 145-150°C. The reaction mass was maintained for 1hr at 145-150°C and then slowly the solution of 2-(4-chlorophenyl)-2-(1-cyclopropylethyl)-oxirane (50g, 0.224 moles, 1.0eq) dissolved in 50ml DMSO was added at 145-150°C in 30mins. The reaction mixture was stirred for 2hrs at 145-150°C and the reaction was monitored by HPLC and in-process results are as below
% Cyproconazole : 93.9%
Undesired isomers:1.89%.
Unreacted oxirane : 0.8%
After completion of the reaction, DMSO was distilled off completely under reduced pressure at 130°C. Cool to 50°C and toluene was added and stir for 30 mins and washed with water . The toluene layer was concentrated under reduced pressure and crude is taken in cyclohexane at 50-55°C and cooled to 25°C. Stir for 2hrs and filter the solids. The product obtained is 55.0g which is having purity of 98% cyproconazole and the undesired isomers below 2% (by HPLC).