TECHNICAL FIELD:
The invention described herein relates to a process for preparing certain cyclopropane derivatives useful as chemical intermediates in the preparation of agricultural products, particularly alpha-aryl-alpha-cyclopropylalkyl-lH-azolyl ethanols including the imidazolyl and 1,2,4-triazolyI ethanols known to be useful as fungicides.
BACKGROUND OF THE INVENTION:
GB 2136423 discloses fungicidal alpha-aryl-alpha-cyclopropylalkyl-IH-azolyl ethanols. One process described for making them involves starting with an aryl cyclopropylalkyl methanol. Unfortunately, such compounds are not readily prepared by conventional methods.
l-(4-chIorophenyl)-2-cyclopropyl-I-propanone is very important intermediate of triazole fungicides Cyproconazole. It is conventionally prepared by using chlorobenzaldehyde as raw material by reacting with Grignard reagent which is simple but yield may affected. Further, it uses 1,2-dibromomethane as cyclizing agent which is expensive and increases production cost.

Also in Grignard reaction route methyl iodide is used to increase yield but methyl iodide is expensive and highly toxic reagents, thus making the process costly and hazardous.
Another route is DARSEN synthetic method by using, chlorobenzene and cyclopropyl methyl ketone as a starting material. The first step reaction is conducted by using a weight DARSEN row to prepare cyclopropyl propionaldehyde, this step requires at low -10-0 ° C under the conditions, the experimental conditions are harsh, the equipment in the industry requirements, require costly investment, and in the vacuum distillation black process prone to coke-like substances, it is affecting the yield of the end and therefore not conducive to industrial production.

CN102584558 discloses another route for the preparation of l-(4-chlorophenyl)-2-cyclopropyl-1-propanone. The cyclopropyl methyl ketone is epoxidised by using dimethyl sulfate, dimethyl sulfide and sodium hydroxide to obtain 2-cyclopropyl-2-methyl ethylene oxide. The oxide is catalyzed and re-ranged by anhydrous zinc chloride at the room temperature to obtain 2-cyclopropyl propionaldehyde. This aldehyde is oxidized by 50 percent oxydol at the room temperature to obtain 2-cyclopropyl monopropanol which is further treated with thionyl chloride to obtain 2-cyclopropyl propionyl chloride. The 2-cyclopropyl propionyl chloride reacted with chlorobenzene in presence of anhydrous aluminum trichloride to obtain the l-(4-chlorphenyI)-2-cyclopropyl-1 -acetone. However, the sulfide is highly volatile, at atmospheric pressure distillation process will lose a lot of sulfide, condensation effect of the equipment is highly demanding on the industrial production increased costs. Further, the rearrangement step required distilled water for the processing. The oxidation reaction used hydrogen peroxide which is relatively high cost. This method has multi-step operation, thus the production cyde is long, the cost consumption is large.
CN 103113203 discloses another route for the synthesis of l-(4-chlorophenyl)-2-cyclopropyl-l-propanone. The cyclopropyl methyl ketone is epoxidised by using sulfur ylide reagent in toluene to obtain 2-cyc!opropyl-2-methyloxirane which is catalyzed and re-ranged to obtain 2-cyclopropyl propionaldehyde. This aldehyde is oxidized to obtain corresponding acid. This acid is condensed with chloro benzene in the presence of polyphosphoric acid to obtain l-(4-ch!orophenyl)-2-cyclopropyl-l-propanone.
US5770741 and US4973767 claimed 1 -(4-chlorophenyl)-2-cyclopropylpropan-1 -of having formula (I);

US5770741discloses process for cylopropane derivatives, particularly l-(4-chlorophenyl)-2-cyclopropylpropan-1-one. It discloses two routes. In one route, Crotyl chloride is converted into Grignard reagent and further treated with 4-Chlorobenzaldehyde to obtain 3-methyl-4-(4-chlorophenyl)-but-l-en-4-ol. This was treated with dibromomethane, zinc dust and copper(I)

chloride in dry ether under reflux in a sonic bath to obtain l-(4-chlorophenyl)-2-cyclopropylpropan-l-ol which is further converted into l-(4-chlorophenyi)-2-cyclopropy!propan-1-one by treatment with Oxalyl chloride in dimethylsulphoxide and dry dichloromethane under nitrogen.
The second route disclosed in this patent where Grignard reagent of Ally! chloride is prepared by treating it with magnesium turnings in dry tetrahydrofuran (50 ml) at reflux. The Grignard reagent of Ally! chloride was then heated under reflux and treated with 4-Chlorobenzaldehyde in dry tetrahydrofuran to obtain crude 4-(4-chlorophenyl)but-l-en-4-ol. It is converted into l-(4-chlorophenyl)-2-cyclopropyIethanol by treating it with zinc dust, copper(l) chloride and dibromomethane in dry ether under reflux followed by acid treatment. l-(4-chlorophenyl)-2-cyclopropylethanol is treated with Oxalyl chloride in dimethylsulphoxide and dry dichloromethane to obtain l-(4-chlorophenyl)-2-cyclopropylethanone.
It further states that a common method for preparing secondary and tertiary alcohols is to treat a Grignard reagent with an aldehyde or a ketone. In applying this method to the compounds of interest difficulties arise with the cyclopropylalkyl Grignard reagent. For example. 1-cyclopropylethyl bromide rearranges to the homoallylic bromide making it difficult to prepare the Grignard reagent required for the cylclopropylethyl compound. Further, it has been found that when the cyclopropylethyl Grignard reagent is reacted with an alpha-aryl-lH-1.2,4-triazole ethanone, the unsaturated alcohol is formed in admixture with the desired product.

CN 102249882 discloses process for the preparation of l-(4-chlorophenyl)-2-cyclopropyl-l-acetone in which 4-(chloromethyl) chlorobenzene is treated with triethyl phosphite at 120-200° C
CN 102675050 discloses method for the preparation of l-(4-chlorphenyl)-2-cyclopropyl-l-propanol. l-(4-chlorphenyl)-2-cyclopropyl-propylene (III) is hydrogenated using alkali metal hydroborate/boron trifluoride ether solution/aluminum trichloride mixture and further oxidized with oxydol in the presence of alkali to obtain the l-(4-chlorphenyl)-2-cyclopropyl-propanol (I).

to give the compound (I). The compound (I) is treated with cyclopropylmethyl ketone and strong base to give the compound (II). The compound (II) is teated with sodium borohydride, alkali solution and hydrogen peroxide to give the compound (III). The compound (III) is converted into l-(4-chlorophenyl)-2-cyclopropyl-l-acetone (IV) on treatment of aqueous sodium hypochlorite solution.

CN 102675074 discloses process for the preparation of l-(4-chlorophenyl)-2-cyclopropyl-l-acetone in which 2-(4-chIorophenyl)-3-cyclopropyl-2-butene grades Dad carbonitrile was hydrogenated under pressure, a solvent and palladium on carbon catalyst to obtain the compound (II). The compound (II) was oxidized in presence of bases, catalysts and uniform flow of oxygen to obtain I-(4-chlorophenyl)-2-cyclopropyl-l -acetone.


Process research and development in the companies aim to produce a process for the manufacture of a intermediate and fungicidal or bactericidal thereof at minimal cost with high yield and better quality.
Hence, there is an urgent need for a solution that overcomes these limitations stated above. Thus there is need to invent economic and simple to method with great practical significance for the preparation of cyclopropane derivatives useful as chemical intermediates in the preparation of agricultural products.
OBJECTS OF THE PRESENT INVENTION:
An object of the present invention is to provide a process for preparation of cyclopropane derivatives useful as chemical intermediates in the preparation of agricultural products, particularly alpha-aryl-alpha-cyclopropylalkyl-IH-azolyl ethanols including the imidazolyl and 1,2,4-triazoIyl ethanols known to be useful as fungicides.
Another object of the present invention is to provide a process for preparation of cyclopropane derivatives useful as chemical intermediates in the preparation of agricultural products, wherein the yield is improved to 75% thereby making the process efficient, high throughput and cost-effective.
Still another object of the present invention is to provide a process for preparation of cyclopropane derivatives useful as chemical intermediates in the preparation of agricultural products, wherein the said process eliminates laborious workup, extensive purifications, and avoids the exposure of production personnel to industrial operations. Hence, makes the process simple and easy and user friendly.
Yet another object of the present invention is to provide a process for preparation of cyclopropane derivatives useful as chemical intermediates in the preparation of agricultural products, wherein the cylopropane derivatives obtained is substantially free from impurities and thereby substantially eliminating the purification steps required and further making process cost effective and efficient.

DETAILED DESCRIPTION OF THE INVENTION:
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only, and is not intended to limit the scope of the present invention.
Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "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 St. 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 the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
The term "substantially free of in reference to a composition, as used herein, means that an absent substance cannot be detected in the composition by methods known to those skilled in the art at the time of the filing of this application.
According to the invention there is provided a process for the preparation of cyclopropane derivatives useful as chemical intermediates in the preparation of agricultural products, said process comprising
a. preparing Grignard reagent by treating the compound of formula (I) with Magnesium turning in dry solvent under in an inert atmosphere at reflux temperature;

b. preparing compound of formula (III) by treating the Grignard reagent with aldehyde of
formula (II) in presence of dry solvent at reflux temperature to obtain the compound of
formula (III); and
c. preparing compound of formula (IV) by subjecting the compound of formula (III) to
oxidation in presence of catalyst and solvent to obtain the compound of formula (IV);

Wherein X : -C1 (Chloro), Br (Bromo), I (Iodo), etc and R1 is C\ to C5 straight or branched chain aliphatic alkyl group,
Preferably, step (a) comprising treating the compound of formula (I) with Magnesium turning in the ratio of 1.05 to 2.0 in dry solvent under in an inert atmosphere at reflux temperature followed by refluxing the reaction mixture for at least 1.5 hour and cooling down the reaction mixture.
The solvent used in step (a) is selected from dry tetrahydrofiiran, toluene, xylene, Cyclopentyl methyl ether, diisopropyl ether, dibutyl ether, diethyl ether and the like
The compound (I) used in step (a) is para chloro halo benzene, where halo is Chloro, bromo, iodo.

Preferably, step (b) comprising adding solution of aldehyde of formula (II) in dry solvent to the reaction mixture containing the Grignard reagent obtained from step (a) at reflux temperature to obtain the compound of formula (III).
The solvent used in step (b) is selected from dry tetrahydrofuran, toluene, xylene, Cyclopentyl methyl ether, diisopropyl ether, dibutyl ether, diethyl ether and the like.
The aldehyde of formula (II) used in step (b) is selected from 2-cyclopropyI propanal, 2-cyclopropyl butanal, 2-cyclopropyl pentanal, 2-cyclopropyl hexanal, 2-cyclopropyl heptanal and the like.
The compound of formula (III) obtained in step (b) is either l-(4-chlorophenyl)-2-cyclopropyl propan-1 -ol, 1 -(4-chlorophenyl)-2-cyclopropyl butan-1 -ol, 1 -(4-chlorophenyl)-2-cyclopropyl pentan-1-ol, l-(4-chlorophenyl)-2-cyclopropyl hexan-l-ol or I-(4-chlorophenyl)-2-cyclopropyl heptan-1-ol.
The step (b) further comprises isolation of compound of formula (III) by quenching the reaction mass of step (b) with water and acid to obtain biphasic mixture; extracting the aqueous phase with organic solvent followed by combining the organic phases; washing it with brine followed by drying it over magnesium sulfate and distilling out the solvent under vacuum to isolate the compound of formula (III).
The organic solvent used in the isolation of the compound of formula (III) is selected from dry tetrahydrofuran, toluene, xylene, Cyclopentyl methyl ether, diisopropyl ether, dibutyl ether and diethyl ether the like.
The acid used in the isolation of the compound of formula (III) is selected from hydrochloric acid, sulfuric acid, acetic acid or mixture thereof.
The catalyst used in step (c) is selected from sodium hypochlorite / chromic acid / calcium hypochlorite.
The solvent used in step (C) is selected from water, acetic acid, acetonitrile, ethyl acetate, dioxane, methylene dichloride and the like.

The step (c) further comprising cooling the reaction mass to 10° - 40°C with stirring followed by separation of organic layer; extracting the aqueous layer with organic solvent followed by combining the extracted organic layer with previous organic layer; washing it with brine followed by drying it over magnesium sulfate and distilling out the solvent under vacuum to isolate the compound of formula (IV).
The organic solvent used in the isolation of the compound of formula (IV) is selected from ethyl acetate, acetonitrile, dioxane, methylene dichloride and the like.
The compound of formula (IV) obtained in step (c) is either l-(4-chlorophenyl)-2-cyclopropyl propan-1-one, l-(4-chlorophenyI)-2-cyclopropyl butan-1-one. I-(4-chlorophenyl)-2-cyclopropyl pentan-1 -one, 1 -(4-chlorophenyl)-2-cyclopropyl hexan-1 -one or 1 -(4-chlorophenyl)-2-cyclopropyl heptan-1-one.
The yield of the compound of formula (III) and (IV) is 80% and 95% respectively. The present process reduces impurities. The present invention eliminates laborious work up.
BEST MODE OR EXAMPLES FOR WORKING OF THE INVENTION:
The present invention is described in the examples given below;.further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.
EXAMPLE 1
a) Preparation of Grignard reagent
4-Bromo Chlorobenzene ( 106 gm, 0.56 mole ) was added into Tetrahydrofuron ( 200 gm) in an inert atmosphere to prepare the solution. This solution was added drop wise into a mixture comprising Mg turnings ( 14.75 gm, 0.61 mole ) and Tetrahydrofuron (180 gm) in an inert atmosphere under reflux for about 1 hour. The reaction mixture was maintained for 1.5 hr. under reflux condition. Then the reaction mass was cooled to room temperature to obtained the reaction mixture containing Grignard reagent.

b) Preparation of l-(4-chlorophenyl)-2-cyclopropyl propan-1-ol
2-cyclopropyl propanal (57 gm, 0.51 mole ) was added in Tetrahydrofuron (150 gm) with stirring for 1 hr. to obtain solution. This solution was added to the reaction mixture obtained from step (a). The reaction mixture was maintained for 1.5 hr at reflux condition. The reaction mixture was quenched with water ( 120 gm ) and HC1 ( 70 gm ). The organic layer was separated from the aqueous layer. The aqueous layer was extracted with tetrahydrofuran (300 ml). The extract was mixed with the previously separated organic layer. The organic layer was washed with brine and dried over Magnesium Sulphate. The solvent was removed by distilling out under vacuum to obtain l-(4-chlorophenyl)-2-cyclopropyl propan-1-ol (122 gm, 80% purity).
c) Preparation of l-(4-chlorophenyl)-2-cyclopropyl propan-1-one.
l-(4-chlorophenyl)-2-cyclopropyI propan-1-ol ( 122 gm, 0.54 mole) was subjected to oxidation using solution of sodium hypochlorite ( 37 gm, 0.27 mole)/chromic acid, Water (617 gm ), and acetic acid ( 264 gm, 4.40 mole) in acetonitrile ( 350 gm ). The reaction mass was cooled to 10°C and stirred for 5 hr. The organic layer was separated from the aqueous layer. The aqueous layer was extracted with ethylacetate (300 ml). The extract was mixed with the previously separated organic layer. The organic layer was washed with brine and dried over Magnesium Sulphate. The solvent was removed by distilling out under vacuum to obtain l-(4-chlorophenyl)-2-cyclopropyl propan-1-one (90 gm, 91% purity).

We claim:
1. A process for the preparation of cyclopropane derivatives useful as chemical intermediates in the preparation of agricultural products, said process comprising
a. preparing Grignard reagent by treating the compound of formula (I) with Magnesium
turning in dry solvent under in an inert atmosphere at reflux temperature;
b. preparing compound of formula (III) by treating the Grignard reagent with aldehyde
of formula (II) in presence of dry solvent at reflux temperature to obtain the
compound of formula (III); and
c. preparing compound of formula (IV) by subjecting the compound of formula (III) to
oxidation in presence of catalyst and solvent to obtain the compound of formula (III);

Wherein X : -CI (Chloro), Br (Bromo), I (Iodo), etc and R1 is C1 to C5 straight or branched chain aliphatic alkyl group.
2. The process as claimed in claim 1, wherein the step (a) comprising treating the compound
of formula (I) with Magnesium turning in the ratio of 1.05 to 2.0 in dry solvent under in an inert atmosphere at reflux temperature followed by retluxing the reaction mixture for at least 1.5 hour and cooling down the reaction mixture.

3. The process as claimed in claim 2, wherein the solvent used in step (a) is selected from dry tetrahydrofuran, toluene, xylene, Cyclopentyl methyl ether, diisopropyl ether, diethyl ether or dibutyl ether.
4. The process as claimed in claim 1, wherein the compound (I) used in step (a) is para chloro halo benzene, where halo is Chloro, bromo, iodto.
5. The process as claimed in claim 1, wherein the step (b) comprising adding solution of aldehyde of formula (II) in dry solvent to the reaction mixture containing the Grignard reagent obtained from step (a) at reflux temperature to obtain the compound of formula (III).
6. The process as claimed in claim 5, wherein the solvent used in step (b) is selected from ether or diethyl ether.
7. The process as claimed in claim 5, wherein the aldehyde of formula (II) used in step (b) is selected from 2-cyclopropyl propanal, 2-cyclopropyl butanal, 2-cyclopropyl pentanai, 2-cyclopropyl hexanal, or 2-cyclopropyl heptanal.
8. The process as claimed in claim 5, wherein the step (b) further comprises isolation of compound of formula (III) by quenching the reaction mass of step (b) with water and acid to obtain biphasic mixture; extracting the aqueous phase with organic solvent followed by combining the organic phases; washing it with brine followed by drying it over magnesium sulfate and distilling out the solvent under vacuum to isolate the compound of formula (III).
9. The process as claimed in claim 8, wherein the organic solvent used in the isolation of the compound of formula (III) is selected from dry tetrahydrofuran, toluene, xylene, cyclopentyl methyl ether, diisopropyl ether, dibutyl ether or diethyl ether.
10. The process as claimed in claim 8, wherein the acid used in the isolation of the compound of formula (III) is selected from hydrochloric acid, sulfuric acid, acetic acid or mixture thereof.

11. The process as claimed in claim 1. wherein the compound of formula (III) obtained in step (b) is either l-(4-chlorophenyl)-2-cyclopropyl propan-1-ol, l-(4-chlorophenyl)-2-cyclopropyl butan-1 -ol, l-(4-chlorophenyl)-2-cyclopropyl pentan-1 -ol, 1 -(4-chlorophenyl)-2-cyclopropyl hexan-1-ol or l-(4-chlorophenyl)-2-cyclopropyl heptan-1-ol.
12. The process as claimed in claim 1, wherein the catalyst used in step (c) is selected from sodium hypochlorite / chromic acid / calcium hypochlorite.
13. The process as claimed in claim 1, wherein the solvent used in step (C) water, acetic acid, acetonitrile, ethyl acetate, methylene dichloride or dioxane.
14. The process as claimed in claim 1, wherein the step (c) further comprising cooling the reaction mass to 10° - 40°C with stirring followed by separation of organic layer; extracting the aqueous layer with organic solvent followed by combining the extracted organic layer with previous organic layer; washing it with brine followed by drying it over magnesium sulfate and distilling out the solvent under vacuum to isolate the compound of formula (IV).
15. The process as claimed in claim 14, wherein the organic solvent used in the isolation of the compound of formula (IV) is ethyl acetate, acetonitrile, methylene dichloride or dioxane.
16. The process as claimed in claim 1, wherein the compound of formula (IV) obtained in step (c) is either I-(4-chlorophenyl)-2-cyclopropyl propan-1-one, l-(4-chlorophenyl)-2-cyclopropyl butan-1-one, l-(4-chlorophenyl)-2-cyclopropyl pentan-1-one, l-(4-chlorophenyl)-2-cyclopropyl hexan-1-one or l-(4-chlorophenyl)-2-cyclopropyl heptan-1-one.