ACID AND ESTERS FIELD OF INVENTION

The present invention relates to a method for producing (lR,3R)-2,2-dimethyl-3- (Z)-prop-l-en-l-yl)cyclopropane carboxylic acid [I]and its salts and esters, shown as figure I from easily available(lR,3S)-3-(2,2-dihaloethenyl)-2,2-dimethyl- cyclopropanecarboxylic acid of structural formula II, and the salts and esters derived from formula II

R=H, metal, alkyl, arylalkyl, cycloalkyl groups R=H, metal, alkyl, arylalkyl, cycloalkyl groups X1=X2=CI, Br

II

Figure I

BACKGROUND ART Metofluthrin is one of the favoured synthetic pyrethroids for use in household applications, to control disease carrying vectors among insects. Metofluthrin dimethyl-3-prop-l-enylcyclopropanecarboxylate] consists of 2,3,5,6-tetrafluoro-4- (methoxymethyl)benzyl-(Z)-(lR,3R)-2,2-dimethyl-3-prop-l- enylcyclopropanecarboxylate as the major component [More than 97%]

(lR,3R)-2,2-dimethyl-3-(Z)-prop-l-en-l-yl) cyclopropane carboxylic acid [I] serves as an important intermediate for the production of Metofluthrin. US patent No 6225495 describes the synthesis using 2,3,5,6-tetrafluoro-4- (methoxymethyl)benzyl alcohol III and acid chloride IV derived from (lR,3R)-2,2- dimethyl-3-(2-methylprop-l-enyl)cyclopropane-l-carboxylicaci d[chrysanthemic acid] followed by ozonolysis of the resulting ester V to provide the aldehyde which through reaction with ethyl triphenyl phosphorane provided Metofluthrin VII as depicted in Scheme 1

Schemel

US6225495 process suffers from usage of expensive reactants as also involves the hazardous step of ozonolysis and the Wittig reaction involved in the last step generation waste products.

An article entitled “ Syntheses of ¹⁴ C -labelled ( + )-trans-chrysanthemum mono- and di- carboxylic acids, and of related compounds’ ’ published in J. Chem. Soc. C, 1970, 1076- 1080 byL. Crombie, Christine F. Doherty and G. Pattenden discloses stereospecific syntheses of ¹⁴ C -labelled (+)-trans-chrysanthemum mono- and di-carboxylic acids wherein the methyl esters of the acids are obtained by Wittig condensation between the (+)-trans-cyclopropane aldehyde (VIII) and the appropriate ¹⁴ C -labelled phosphoranes. The conversion of methyl chrysanthemate into chrysanthemum dicarboxylic acid via aldehyde (VIII) proceeds in an overall yield of 39%. Methyl nor-(9) and bisnor- (8)(±)-trans-chrysanthemates are synthesised from (VIII) by condensation with appropriate alkylidene pho sphoranes .

IN191230 (35/MAS/2001) reports a method for producing 2,2-dimethyl-3-(l- propenyl) cyclopropane carboxylate ester of structural formula I, which is depicted in Scheme 2

Scheme 2

IN191230 process suffers from use of hazardous ozonolysis step and waste 5 generating Wittig reaction. Also the E, Z isomer ratio (10:90) is not as good as required commercially.

US Patent 6072074 describes synthesis of 2,2-dimethyl-3-(l-propenyl) cyclopropane carboxylate ester by cyclisation of open chain precursors as shown in0 Scheme 3

Scheme 3

US6072074 process leads to formation of a racemic mixture which needs to be resolved in the last step incurring a loss of at least 50 % material.

US7393971 describes a method for producing 2,2-dimethyl-3-(l-propenyl) cyclopropane carboxylate ester, wherein pyrethrinic acid is decarboxylated with copper oxide or copper powder in presence of quinoline at an elevated temperature which is depicted in scheme 4 below.

Scheme 4

Pyrethrinic acid used in Scheme 4 is not easily available from natural sources. US Patent 7985872 describes a process for producing 2,2-dimethyl-3-(l-propenyl) cyclopropane carboxylate ester I by Aldol condensation to give compound XVI and deformylation of Compound XVI to give Compound I, as shown in scheme 5

VIII XV XVI

Scheme 5

US7985872 also suffers from poor availability of chrysanthemic acid and ozonolysis reaction step.

An article entitled “ Studies on Chrysanthemate Drivatives. VI. A Stereoselective synthesis of trans-3 -(2, 2-Dichloroethenyl)-2,2-dimethyl-l -cyclopropane carboxylic Acid and related compounds’ ’ published in Bull. Chem Soc.52, 1511- 1514 (1979) describes stereoselective synthesis of trans-3-(2,2-dichloroethenyl)- 2, 2-dimethyl- 1 -cyclopropane carboxylic acid II which was obtained by dehydrochlorination and hydrolysis of XX using potassium hydroxide in ethanol. Further treatment of II with potassium t-butoxide in THF gave ethyl trans-3-(2- chloroethynyl)-2,2-dimethyl-l-cyclopropanecarboxylate XVII. (Scheme 6)

Thus, there exists a distinct need to develop a new and practical method to prepare formula I as intermediates for preparation of Metofluthrin VII. OBJECT OF INVENTION

According to one object of the invention there is provided a short and efficient process for the preparation of (lR,3R)-2,2-dimethyl-3-(Z)-prop-l-en-l-yl) cyclopropane carboxylic acid [I], an advanced intermediate for Metofluthrin VII with high yield and purity

According to another object of the invention there is provided a short and efficient method for producing 2,2-dimethyl-3-(l-propenyl) cyclopropane carboxylic acid, I (R=H) and its metal salts (R=M+) and esters (R= alkyl, aralkyl, cycloalkyl) with high yield and purity.

According to another object of the invention, there is provided a process for preparation of Formula [I] which avoids the use of hazardous/toxic chemicals as also avoids generation of unwanted polluting side products. According to another object of the invention, there is provided a process for preparation of Formula [I] which will enable a skilled person to prepare intermediate of formula [I] more efficiently and cost effectively.

SUMMARY OF THE INVENTION

According to one embodiment of the present invention, there is provided a process for preparation of (lR,3R)-2,2-dimethyl-3-(Z)-prop-l-en-l-yl) cyclopropane carboxylic acid, and its salts or esters of the general formula I

R=H, metal, alkyl, arylalkyl, cycloalkyl group

I is depicted in Scheme 7 and comprises the steps of: a. Reacting(lR,3S)-3-(2,2-dihaloethenyl)-2, 2-dimethyl-cyclopropane carboxylic acid, or their salts and esters of the general formula II with a strong base in a polar solvent to obtain (lR,3S)-3-(haloethynyl)-2,2- dimethylcyclopropanecarboxylic acid, salts and esters of the general formula XVII;

R=H, metal, alkyl, arylalkyl, cycloalkyl groups R=H, metal, alkyl, arylalkyl, cycloalkyl groups X1=X2=CI, Br X1=X2=CI, Br XVII b. Converting (lR,3S)-3-(haloethynyl)-2,2-dimethylcyclopropanecarboxylic acid, salts and esters of the general formula XVII to obtain general formula XVIII by reacting formula XVII with butyl lithium to obtain lithium acetylide followed by methylation step as mentioned in step (C); or by Reacting Formula XVII with methyl Grignard reagent, in presence of a metal salt and a ligand to obtain a mixture of methyl acetylene of the general formula XVIII and a small percentage of metal acetylide of the general formula XIX.

R=H, metal, alkyl, arylalkyl, cycloalkyl groups R=H, metal, alkyl, arylalkyl, cycloalkyl groups

XVIII XIX c. Insitu conversion of metal acetylide XIX to methyl acetylene XVIII by

5 adding a methylating agent the reaction mixture obtained in step (b); d. Semi-hydrogenation/ partial reduction of the triple bond in the methyl acetylene XVIII to obtain compound of formula I, wherein in the semi -hydrogenation in step (d) is achieved through catalytic hydrogenation in presence of low percentage heterogeneous catalysts on

10 different supports or transfer hydrogenation with a hydrogen donor in presence of a catalyst based on palladium, nickel, cobalt, manganese, iron or a combination of metals in the presence of a hydrogen donor such as water, formic acid, ammonium formate, hydrazinium formate.

15 According to another embodiment of the present invention, the semi-hydrogenation of the methyl acetylene XVIII to I is carried out through any of the following two procedures:

(i) Partial reduction of the triple bond in XVIII to double bond by catalytic hydrogenation in presence of a suitable metal catalyst. The resulting olefin I has

20 predominantly Z-geometry;

(ii) Alternatively, semi-hydrogenation of the triple bond of XVIII by transfer hydrogenation with a hydrogen donor in presence of a suitable catalyst. The resulting product I is predominantly the desired Z-isomer.

25 DESCRIPTION OF THE INVENTION

The present invention provides a process for preparation of (lR,3R)-2,2-dimethyl- 3-(Z)-prop-l-en-l-yl) cyclopropane carboxylic acid, and its salts or esters of the general formula I

R=H, metal, alkyl, arylalkyl, cycloalkyl group

I comprising the steps of: a. Reacting(lR,3S)-3-(2,2-dihaloethenyl)-2, 2-dimethyl-cyclopropane carboxylic acid, or their salts and esters of the general formula II with a strong base in a polar solvent to obtain (lR,3S)-3-(haloethynyl)-2,2- dimethylcyclopropanecarboxylic salts and esters of the general formula XVII;

R=H, metal, alkyl, arylalkyl, cycloalkyl groups R=H, metal, alkyl, arylalkyl, cycloalkyl groups X1=X2=CI, Br X1=X2=CI, Br XVII b. Converting (lR,3S)-3-(haloethynyl)-2,2-dimethylcyclopropanecarboxylic acid, salts and esters of the general formula XVII to obtain general formula XVIII by reacting formula XVII with butyl lithium to obtain lithium acetylide followed by methylation step as mentioned in step (C); or by Reacting Formula XVII with methyl Grignard reagent, in presence of a metal salt and a ligand to obtain a mixture of methyl acetylene of the general formula XVIII and a small percentage of metal acetylide of the general formula XIX.

R=H, metal, alkyl, arylalkyl, cycloalkyl groups R=H, metal, alkyl, arylalkyl, cycloalkyl groups

XVIII XIX c. Insitu conversion of metal acetylide XIX to methyl acetylene XVIII by adding a methylating agent the reaction mixture obtained in step (b); d. Semi-hydrogenation/ partial reduction of the triple bond in the methyl acetylene XVIII to obtain compound of formula I, wherein in the semi-hydrogenation in step (d) is achieved through catalytic hydrogenation in presence of low percentage heterogeneous catalysts on different supports or transfer hydrogenation with a hydrogen donor in presence of a catalyst based on palladium, nickel, cobalt, manganese, iron or a combination of metals in the presence of a hydrogen donor such as water, formic acid, ammonium formate, hydrazinium formate.

R= H, metal, alkyl, aralkyl, cycloalkyl groups R= H, metal, alkyl, aralkyl, cycloalkyl groups X1=X2= Cl, Br X= Cl, Br

II XVII

R= H, metal, alkyl, aralkyl, cycloalkyl groups

R= H, metal, alkyl, aralkyl, cycloalkyl groups

I

R= H, metal, alkyl, aralkyl, cycloalkyl groups

XIX

Scheme 7 The steps are described in detail hereinafter.

Step 1.

In the first step geminal dihalo alkenyl compound [Formula II; (R=H, Metal, alkyl, aralkyl, cycloalkyl; X1=X2=C1, Br)] are treated with a strong base in an inert organic solvent. Preferably 3-(2,2-dichlroroethenyl)-2,2-dimethylcyclopropane carboxylic acid or their esters were dehydrochlorinated to chloroacetylene XVII by treating with a strong base without effecting the acid/ester group.

The strong base is preferably selected from bases such as alkali and alkaline earth metal hydroxide or alkoxide such as but not limited to potassium hydroxide, potassium tertiary butoxide, sodium hydroxide and other strong bases such as sodium hydride, tertiary amines and sodamide.

When R=H, X1=X2=C1, the dehydrochlorination was carried out in solvent selected from polar solvents but not limited to tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethylformamide, N,N-dimethylacetamide and N-methyl pyrrolidone, sulpholane.

When R=H, X1=X2=C1, the dehydrochlorination is preferably carried out in potassium hydroxide in dimethyl sulphoxide.

The amount of base used is usually 2.0 mole equivalents to 3.0 mole equivalents. The temperature for performing the reaction is usually 10-35°C, preferably 30- 35°C. The reaction timing for the step is from 2-8 hours, preferably 4-5 hours.

Step 2.

The halo-acetylenes of formula XVII on treatment with butyl lithium or with methyl Grignard reagent, in presence of metal salts and some ligands gives predominantly methyl acetylene of the formula XVIII along with some metal acetylide XIX. The halo-acetylene of the formula XVII (R=alkyl, aralkyl, cycloalkyl or lithium metal) is treated with methyl Grignard reagent such as methyl magnesium halide wherein methyl magnesium halide is selected from among methyl magnesium iodide, methyl magnesium bromide and methyl magnesium chloride.

The metal salt is selected from among cupric chloride, nickel chloride, ferric acetylacetonate but preferably cupric chloride.

The ligand is selected from among N-methyl pyrrolidine, N,N-tetramethylethylene diamine, triethyl phosphite, triphenylphosphine, tritoluyl phosphine but preferably N-methyl pyrrolidone.

A practical procedure for this coupling involved using methyl magnesium iodide, bromide or chloride, in conjunction with cupric chloride and N-methyl pyrrolidone. Thus the second step involves the treatment of mono-halo alkynyl compound (Formula XVII, R=alkyl, aralkyl, cycloalkyl or metal) with a copper (II) halide and a ligand like N-methyl pyrrolidone in an organic inert solvent at a temperature range of 10-35°C, preferably 20-35°C and most preferably 25-30°C for a time period of 10-90 minutes, preferably 30-90 minutes and most preferably 45-60 minutes.

The copper (II) halide can be copper (II) chloride, copper (II) bromide, copper (II) iodide, most preferably copper (II) chloride. The quantity of copper (II) halide can be 2 mole % to 50 mole %, preferably 5 mole % to 15 mole % and most preferably 4 mole % to 8 mole %.

The quantity of ligand can be from 2 mole% to 20 mole %, preferably 5-10 mole

%.

The reaction in step (b) is carried out in solvent selected from diethyl ether, tetrahydrofuran, dioxane or anisole either alone or in combination with hydrocarbon solvents such hexane, toluene, xylene. The next part of reaction is reacting this mixture with a methyl magnesium halide in the same inert solvent. The methyl magnesium halide can be methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide. The addition time of methyl magnesium halide can be from 30 minutes to 180 minutes, preferably 60-120, most preferably 60-90 minutes.

The temperature of the reaction can be 0-25°C, most preferably 0-10°C and the quantity of methyl magnesium halide can be 1.0-2.0 mole equivalents, most preferably 1.2- 1.5 mole equivalents.

Step 3.

Metal acetylide XIX is converted to methyl acetylene XVIII by adding a methylating agent such as methyl iodide, methyl chloride, methyl bromide, dimethyl carbonate and dimethyl sulphate preferably dimethyl carbonate to the reaction mixture, in situ. The quantity of methylating agent can vary from 0.1 -0.5 mole equivalents, most preferably 0.2-0.3 mole equivalents.

The reaction mixture is then allowed to react with a methylating agent at same temperature as mentioned above viz. 0-25°C, most preferably 0-10°C.

When the substrate is a carboxylic acid of formula XVII (R=H, X=C1), it is converted to a metal carboxylate salt, to save on the quantity of methyl magnesium halide used in this step. The carboxylic acid of the formula XVII (R=H, X=C1) is treated with alkali metal base in an inert organic solvent.

The alkali metal base can be sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium carbonate, lithium methoxide, or alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide or alkaline earth metal oxides/ alkoxides such as magnesium oxide, magnesium methoxide. The inert solvent can be non-polar solvents such as toluene, xylene, acetone, methyl isobutyl ketone, tetrahydrofuran, dichloromethane, chloroform, methyl tertiary butyl ether (MTBE).

The temperature for the reaction can be 110 to 140°C under optional nitrogen pressure.

The resulting water or methanol is distilled off along with the inert solvent.

The metal carboxylate salt is then diluted with an inert solvent and used in next step. The inert solvent used is tetrahydrofuran. The amount of inert solvent used is usually 10-30 parts by weight, preferably 10 parts by weight. The amount of inorganic base used is usually 1.0 to 1.5 mole equivalents, most preferably 1.05 mole equivalents.

Step 4.

Semi-hydrogenation of methyl acetylenes XVIII (R=H, alkyl, aralkyl or cycloalkyl) provides the desired (lR,3R)-2,2-dimethyl-3-(Z)-prop-l-en-l-yl) cyclopropane carboxylic acid or its esters of formula I, where R= H, alkyl, aralkyl or cycloalkyl groups. Semi-hydrogenation of the methyl acetylene of the formula XVIII is accomplished by (i) catalytic hydrogenation in presence of a suitable catalyst (ii) semi-hydrogenation with hydrogen donor in presence of a suitable catalyst.

Semi-hydrogenation of acetylenes has been conventionally, carried out in presence of Lindlar catalyst [US 6072074] though it suffers from the following shortcomings: a) It contains 5% palladium poisoned with lead acetate while low percentage of palladium catalysts can accomplish the same conversion without the use of poisoning with lead. b) Stereoselectivity of hydrogenation with Lindlar catalyst is poor and needs to be improved by addition a secondary poison like quinoline. The present inventors have found that following two procedures gave good results in the conversion of XVIII to the desired Z-alkene of the formula I:

(I) The triple bond in XVIII is partially reduced to double bond by catalytic hydrogenation in presence of a suitable metal catalyst.

(il) Alternatively, the triple bond in XVIII is semi-hydrogenated by transfer hydrogenation with a hydrogen donor in presence of a suitable catalyst.

The semi-hydrogenation is carried out either by catalytic hydrogenation in presence of low percentage heterogeneous palladium catalysts on different supports or transfer hydrogenation in presence of palladium or other mixed metal catalysts and hydrogen donors.

The conversion of methyl acetylene XVIII to the desired Z-alkene of the formula I is preferably carried out as follows: a) Methyl acetylene XVIII was hydrogenated in presence of 0.5% palladium on carbon or titanium dioxide b) Methyl acetylene XVIII was reduced through transfer hydrogenation in dimethylformamide and water in presence of palladium acetate.

The semi-hydrogenation of methyl acetylene of the formula XVIII is achieved through catalytic hydrogenation in presence of low percentage heterogeneous catalysts on different supports or transfer hydrogenation with a hydrogen donor in presence of a catalyst based on palladium, nickel, cobalt, manganese, iron or a combination of metals in the presence of a hydrogen donor such as water, formic acid, ammonium formate, hydrazinium formate.

The semi-hydrogenation of methyl acetylene of the formula XVIII is preferably carried out in presence of 0.5 to 1.0% palladium on carbon or titanium dioxide and gaseous hydrogen in as solvent selected from among hydrocarbons such as hexane or alcohols such as methanol, ethanol, isopropanol, 2-methoxyethanol etc. In step (d) the semi-hydrogenation/partial reduction of formula (VIII) to formula (I) is preferably achieved through transfer hydrogenation in presence of palladium acetate and base such as sodium hydroxide, lithium hydroxide, potassium hydroxide or alkaline earth metal hydroxide such as magnesium hydroxide and suitable solvents selected from dimethylformamide, water and alcohols such as methanol, ethanol.

The transfer hydrogenation is carried out in a suitable solvent selected from among, alcohols such as methanol, ethanol or polar solvent such dimethylformamide. The reaction is carried out at elevated temperatures of 50 to 150°C, preferably 130 to 150°C.

The process steps for preparation of formula I are illustrated, but not limited, by the following examples.

1. Preparation of (l/?,3S)-3-(chloroethynyl)-2, 2-dimethyl cyclopropane carboxylic acid (XVII) from (l/f,35)-3-(2,2-dichloroethenyl)-2,2- dimethylcyclopropanecarboxylic acid (II) using a strong base.

To a mixture of dimethyl sulphoxide (30 ml) and (lR,3S)-3-(2,2-dichloroethenyl)- 2,2-dimethylcyclopropanecarboxylic acid (10 g, 0.047 moles); potassium hydroxide (5.33 g, 0.095 moles) was added and stirred at room temperature for 4 hours. Reaction mixture was quenched with water and the pH of the reaction mixture was adjusted to acidic with dilute aqueous HC1 solution. The resulting product was extracted into toluene. Toluene layer was distilled under vacuum to afford (lR,3S)-3-(chloroethynyl)-2,2-dimethylcyclopropanecarboxylic acid as pale yellow oil with a yield of 97% and GC purity of 99.8%.

H^MR (CDCh, internal standard-TMS, 400 MHZ), d value (ppm): 1.27 (S, 3H), 1.32 (S, 3H), 1.70 (d, 1H), 1.96 (dd, 1H). 2. Preparation of t-butyl (l/?,3S)-3-(chloroethynyl)-2, 2-dimethyl cyclopropane carboxylate (XVII) from t-butyl (l/?,35)-3-(2,2- dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate (II) using a strong base.

To a mixture of dimethyl sulphoxide (30 ml) and t-butyl (lR,3S)-3-(2,2- dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate (10 g, 0.037 moles); potassium hydroxide (4.22 g, 0.075 moles) was added and stirred at room temperature for 4 hours. Reaction mixture was quenched with water and the pH of the reaction mixture was adjusted to acidic with dilute aqueous HC1 solution. The resulting product was extracted into toluene. Toluene layer was distilled under vacuum to afford t-butyl (lR,3S)-3-(chloroethynyl)-2,2- dimethylcyclopropanecarboxylate as pale yellow oil with a yield of 97% and GC purity of 99.8%.

H^MR (CDCb, internal standard-TMS, 400 MHZ), d value (ppm): 1.20 (S, 3H), 1.27 (S, 3H), 1.44 (S, 9H), 1.61 (d, 1H), 1.84 (dd, 1H).

3. Preparation of (l/?,3/?)-2,2-dimethyl-3-(prop-l-yn-l-yl) cyclopropane carboxylic acid (XVIII) from (l/?,35)-3-(chloroethynyl)-2, 2-dimethyl cyclopropane carboxylic acid (XVII).

A mixture of (lR,3S)-3-(chloroethynyl)-2,2-dimethylcyclopropanecarboxylic acid (10 g, 0.058 moles), L1OH.H2O lithium hydroxide monohydrate (2.45 g, 0.058 moles) and toluene (200 ml) was allowed to heat to 110-112°C and an azeotrope of toluene and water was allowed to distill out via Dean-Stark apparatus completely. The resulting solid was diluted with THF (100 ml). CuCh (4 mole %) and N-methyl pyrrolidone (5 mole %) was added to the reaction mixture and stirred for 60 minutes at room temperature. The reaction mixture was cooled to 0-5°C and methyl magnesium iodide (3.0 M in diethyl ether, 24 ml, 0.071 moles) was added to it under stirring in 60 minutes at 0-5 °C and allowed to stir at 0-5 °C for another 60 minutes. Methyl iodide (2.1 g, 0.014 moles) was added to the reaction mixture and stirred at room temperature for 15 hours. Water was added to the reaction mixture and stirred for 3minutes. Layers were separated and the aqueous phase was acidified with dilute HC1 solution followed by addition of toluene to the reaction mass. Toluene layer was distilled under vacuum to afford crude (lR,3R)-2,2-dimethyl-3- (prop-l-yn-l-yl) cyclopropane carboxylic acid as brown viscous oil with a yield of 85% and GC purity of 95%. f^NMR (CDCh, internal standard-TMS, 400 MHZ), d value (ppm): 1.24 (S, 3H), 1.27 (S, 3H), 1.60 (d, 1H), 1.79 (d, 3H), 1.90 (dd, 1H).

4. Preparation of ethyl (l/?,3/?)-2,2-dimethyl-3-(prop-l-yn-l-yl) cyclopropane carboxylate (XVIII) from ethyl (l/f,35)-3-(chloroethynyl)-2,2- dimethylcyclopropanecarboxylate (XVII).

A mixture of ethyl (lR,3S)-3-(chloroethynyl)-2,2-dimethylcyclopropane carboxylate (10 g, 0.05 moles), L1OH.H2O lithium hydroxide monohydrate (2.1 g, 0.05 moles) and toluene (200 ml) was allowed to heat to 110-112°C and an azeotrope of toluene and water was allowed to distill out via Dean-Stark apparatus completely. The resulting solid was diluted with THF (100 ml). CuCh (4 mole %) and N-methyl pyrrolidone (5 mole %) was added to the reaction mixture and stirred for 60 minutes at room temperature. The reaction mixture was cooled to 0-5°C and methyl magnesium iodide (3.0 M in diethyl ether, 20 ml, 0.06 moles) was added to it under stirring in 60 minutes at 0-5°C. The reaction mixture was allowed to stir at 0-5°C for 60 minutes. Methyl iodide (2.1 g, 0.014 moles) was added to the reaction mixture and stirred at room temperature for 15 hours. Water was added to the reaction mixture and stirred for 3minutes. Layers were separated and the aqueous phase was acidified with dilute HC1 solution followed by addition of to the reaction mass. Toluene layer was distilled under vacuum to afford crude ethyl (lR,3R)-2,2- dimethyl-3-(prop-l-yn-l-yl) cyclopropane carboxylate as brown viscous oil with a yield of 85% and GC purity of 95%.

H^MR (CDCh, internal standard-TMS, 400 MHZ), d value (ppm): 1.12 (S, 3H), 1.22 (S, 6H), 1.57 (d, 1H) 1.73 (S, 3H), 1.85 (d, 1H), 4.11 (q, 2H) 5. Preparation of t-butyl (l/?,3/?)-2,2-dimethyl-3-(prop-l-yn-l-yl) cyclopropane carboxylate (XVIII)from t-butyl (l/?,35)-3-(chloroethynyl)- 2, 2-dime thylcyclopropanecarboxylate (XVII) .

A mixture of t-butyl (lR,3S)-3-(chloroethynyl)-2,2-dimethylcyclopropane carboxylate (10 g, 0.043 moles), LiOH.f O lithium hydroxide monohydrate (1.83 g, 0.043 moles) and toluene (200 ml) was allowed to heat to 110-112°C and an azeotrope of toluene and water was allowed to distill out via Dean-Stark apparatus completely. The resulting solid was diluted with THF (100 ml). CuCh (4 mole %) and N-methyl pyrrolidone (7 mole %) was added to the reaction mixture and stirred for 60 minutes at room temperature. The reaction mixture was cooled to 0-5°C and methyl magnesium iodide (3.0 M in diethyl ether, 17 ml, 0.051 moles) was added to it under stirring in 60 minutes at 0-5 °C. The reaction mixture was allowed to stir at 0-5°C for 60 minutes. Methyl iodide (2.1 g, 0.014 moles) was added to the reaction mixture and stirred at room temperature for 15 hours. Water (200 ml) was added to the reaction mixture and stirred for 3minutes. Layers were separated and the aqueous phase was acidified with dilute HC1 solution followed by addition of toluene to the reaction mass. Toluene layer was distilled under vacuum to afford crude t-butyl (lR,3R)-2,2-dimethyl-3-(prop-l-yn-l-yl) cyclopropane carboxylate as brown viscous oil with a yield of 85% and GC purity of 95%. f^NMR (CDCh, internal standard-TMS, 400 MHZ), d value (ppm): 1.20 (S, 3H), 1.26 (S, 3H), 1.44 (S, 9H), 1.52 (d, 1H), 1.80 (d, 1H), 1.81 (S, 3H).

6. Selective semi-hydrogenation of (l/?,3/?)-2,2-dimethyl-3-(prop-l-yn-l-yl) cyclopropane carboxylic acid (XVIII) using palladium acetate with dimethylformamide/KOH.

A mixture of (li?,3R)-2,2-dimethyl-3-(prop-l-yn-l-yl) cyclopropane carboxylic acid (0.76 g, 0.0050 moles), dimethylformamide (10 ml), KOH (0.42 g, 0.0075 moles) and palladium acetate (0.0245 g, 0.000109 moles) was heated in a sealed tube at 145°C and kept at same temperature for 4 hours. The reaction mixture was cooled to room temperature. The catalyst was filtered and washed with dimethylformamide. To the filtrate mother was added water (10 ml) and toluene (10 ml) and stirred at room temperature. The layers were separated and the aqueous layer acidified with dilute aqueous HC1 solution and the product was extracted into toluene (10 ml). Toluene layer was distilled under vacuum to afford 0.72 g of (lR,3R)-2,2-dimethyl-3-[(lZ)-prop-l-en-l-yl] cyclopropane carboxylic acid with Z/E isomer ratio of 97.5/2.5. f^NMR (CDCb, internal standard-TMS, 400 MHZ), d value (ppm): 1.20 (S, 3H), 1.32(S,3H), 1.47 (d, 1H),1.71 (d, 3H), 2.19 (d, 1H), 5.15 (d, 1H), 5.61 (d, 1H).

7. Selective semi-hydrogenation of ethyl (l/?,3/?)-2,2-dimethyl-3-(prop-l-yn-l- yl) cyclopropane carboxylate (XVIII) using palladium acetate with dimethylformamide/KOH.

A mixture of ethyl (lR,3R)-2,2-dimethyl-3-(prop-l-yn-l-yl) cyclopropane carboxylate (0.90 g, 0.0050 moles), dimethylformamide (10 ml), KOH (0.42 g, 0.0075 moles) and palladium acetate (0.0245 g, 0.000109 moles) was heated in a sealed tube at 145°C and kept at same temperature for 4 hours. The reaction mixture was cooled to room temperature. The catalyst was filtered and washed with dimethylformamide. To the filtrate was added water and toluene and stirred at room temperature. The layers were separated and the aqueous layer acidified with dilute aqueous HC1 solution and the product was extracted into toluene. Toluene layer was distilled under vacuum to afford 0.85 g (93.4%) of ethyl (lR,3R)-2,2-dimethyl-3- [(lZ)-prop-l-en-l-yl] cyclopropane carboxylate with Z/E isomer ratio of 97.5/2.5. (by gas liquid chromatography)

H^MR (CDCb, internal standard-TMS, 400 MHZ), d value (ppm): 1.20 (S, 3H), 1.32(S,3H), 1.47 (d, 1H),1.71 (d, 3H), 2.19 (d, 1H), 5.15 (d, 1H), 5.61 (d, 1H).

8. Selective semi-hydrogenation of t-butyl (l/?,3/?)-2,2-dimethyl-3-(prop-l-yn- 1-yl) cyclopropane carboxylate (XVIII) using palladium acetate with dimethylformamide/KOH.

A mixture of t-butyl (lR,3R)-2,2-dimethyl-3-(prop-l-yn-l-yl) cyclopropane carboxylate (1.04 g, 0.0050 moles), dimethylformamide (10 ml), KOH (0.42 g, 0.0075 moles) and palladium acetate (0.0245 g, 0.000109 moles) was heated in a sealed tube at 145°C and kept at same temperature for 4 hours. The reaction mixture was cooled to room temperature. The catalyst was filtered and washed with dimethylformamide. To the filtrate was added water and toluene and stirred at room temperature. The layers were separated and the aqueous layer acidified with dilute aqueous HC1 solution and the product was extracted into toluene. Toluene layer was distilled under vacuum to afford 0.95 g (93.4%) of t-butyl (lR,3R)-2,2-dimethyl-3- [(lZ)-prop-l-en-l-yl] cyclopropane carboxylate with Z/E isomer ratio of 97.5/2.5. (by gas liquid chromatography) 9a. Selective semi-hydrogenation of ethyl (l/?,3/?)-2,2-dimethyl-3-(prop-l-yn-

1-yl) cyclopropane carboxylate (XVIII) using 0.5% palladium on carbon

A mixture of ethyl ( 1 /,3 /)-2,2-dimcthyl-3-(prop- 1 -yn- 1 -yl) cyclopropane carboxylate (0.90 g, 0.0050 moles), hexanes (10 ml), 0.5% palladium on carbon (0.45 g) was charged. Nitrogen gas was purged for 30 minutes and evacuated by hydrogen gas purging. Hydrogen gas was purged to intake ceased. The catalyst was filtered and washed with hexanes under nitrogen atmosphere. Hexanes layer was distilled under vacuum to afford 0.85 g of ethyl (lR,3R)-2,2-dimethyl-3-[(lZ)-prop- 1-en-l-yl] cyclopropane carboxylate with Z/E isomer ratio of 98/2.0.

H^MR (CDCb, internal standard-TMS, 400 MHZ), d value (ppm): 1.20 (S, 3H), 1.32(S,3H), 1.47 (d, 1H),1.71 (d, 3H), 2.19 (d, 1H), 5.15 (d, 1H), 5.61 (d, 1H).

9b. Selective semi-hydrogenation of ethyl (l/?,3/?)-2,2-dimethyl-3-(prop-l-yn- 1-yl) cyclopropane carboxylate (XVIII) using 0.5% palladium on Titanium silicate The procedure in 9a was repeated by replacing 0.5% palladium on carbon by 0.5% palladium on titanium sulphate. The final product, ethyl (lR,3R)-2,2-dimethyl-3- [(lZ)-prop-l-en-l-yl] cyclopropane carboxylate with Z/E isomer ratio of 98.5/1.5. (0.85 g) was obtained.