DESC:Brief Description of the Drawings
(Figure 1): HPLC Chromatogram showing highly pure (S)-methoprenewith cis- isomer less than 0.1 %, which comes at around 20.347 RT.

The details of the HPLC are as follows:
Column: Agilent C18 Flow rate: 1.5 ml/min Wavelength: 254 nm Inj volume: 10 µl
Column oven temperature: Ambient Run time: 50 min
Solution A: Acetonitrile Solution B: Water

Detailed Description of the Invention

As used herein the following definitions apply unless clearly indicated otherwise. It should be noted that the singular forms “a” “an” and “the” include plural reference unless the context clearly dictates otherwise.

The term “base” as used herein refers to tertiary amines such as trimethylamine, triethylamine, triisopropylamine, diisopropylethylamine, N- methylpiperidine, imidazole, pyridine, substituted pyridines, such as collidine, lutidineor 4-dimethylaminopyridine, and also polycyclic amides and amidines, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane (DABCO).

The term “solvent” as used herein refers towater, aliphatic hydrocarbon, such as pentane, hexane or cyclohexane; aromatic hydrocarbon, such as benzene, toluene, o-, m-, and p-xylene; halogenated aromatic or aliphatic hydrocarbon, such as dichloromethane, chloroform, carbon tetrachloride or chlorobenzene; alcohols, such as methanol, ethanol, propanol, isopropanol or n-butanol; ethers, such as dimethyl ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, dioxane or tetrahydrofuran; nitriles, such as acetonitrile; ketones, such as acetone or methyl isobutyl ketone; acetates, such as ethyl acetate; amides and urea derivatives, such as dimethylformamide, N-methyl-2-pyrrolidone or dimethyl acetamide; dimethyl sulfoxide, and mixture thereof.

The term “alkyl” as used herein refers to straight or branched chain hydrocarbon, for example, methyl, ethyl, propyl, isopropyl or tert-butyl.

The term “aryl” as used herein refers to aromatic hydrocarbon such as phenyl or naphthyl.

According to a first aspect of the present invention, there is provided a process for the preparation of highly pure (S)-methoprene, having formula

comprising converting a mixed anhydride of formula

to (S)-methoprene having purity of more than 99% with cis-isomer being less than 0.4%, using titanium isopropoxide as converting agent, wherein R is selected from C1-C6 alkyl, aryl or -COCl
According to a second aspect of the present invention, there is provided a process for the preparation of highly pure (S)-methoprene, having formula

comprising:
a) reacting (2E,4E)-11-methoxy-3,7,11-trimethyldodeca-2,4-dienoic acid of formula

with acid chloride in a solvent to form mixed anhydride of formula

whereinR is selected from C1-C6 alkyl, aryl or –COCl,

b) reacting mixed anhydride with titanium isopropoxide to form methoprene.

According to one embodiment thereaction is carried out in the presence of a base, preferably in tertiary amines such as trimethylamine, triethylamine, triisopropylamine, diisopropylethylamine, N-methylpiperidine, imidazole, pyridine, substituted pyridines, such as collidine, lutidine or 4-dimethylaminopyridine, and also polycyclic amides and amidines, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane (DABCO). In a preferred embodiment, the present invention envisages triethyl amine, diisopropylethyl amine, pyridine or 1,8- Diazabicyclo[5.4.0]undec-7-ene as the preferred base. According to another embodiment, the base is trimethylamine or triethylamine.

According to another embodiment the reaction is carried out ina solvent, preferably in water, pentane, hexane, cyclohexane, benzene, toluene, o-xylene, m-

xylene, p-xylene, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, methanol, ethanol, propanol, isopropanol, n-butanol, dimethyl ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, dioxane, tetrahydrofuran, acetonitrile, acetone, methyl isobutyl ketone, ethyl acetate, dimethylformamide, N-methyl-2-pyrrolidone, dimethyl acetamide, dimethyl sulfoxide or mixture thereof. In a preferred embodiment, the solvent is selected from pentane, hexane, cyclohexane, benzene, toluene, o-xylene, m-xylene or p-xylene. In yet another preferred embodiment, the solvent is toluene.

According to another embodiment, the reaction in step (a) is carried out at a temperature ranges from about 0 to 30 0C, preferably about 10 to 15 0C.

According to another aspect, the highly pure (S)-methoprene is having purity of more than 99% with cis-isomer being less than 0.4%.

In another embodiment of the present invention, there is provided a process for the preparation of highly pure (S)-methoprene, comprises of
a) adding an organic solvent, (2E,4E)-11-methoxy-3,7,11-trimethyldodeca- 2,4-dienoic acid, a base and acid chloride;
b) maintaining the temperature at 0 to 30 0C, preferably 10-15 0C;
c) adding titanium tetraisoproppoxide;
d) isolating the pure (S)-methoprene.

In a preferred embodiment of the present invention the acid chloride is selected from acetyl chloride, oxalyl chloride, benzoyl chloride or pivaloyl chloride, the base is selected from trimethylamine, triethylamine, triisopropylamine or diisopropylethylamine and the solvent is selected from pentane, hexane, cyclohexane, benzene, toluene, o-xylene, m-xylene, p-xylene or mixture thereof.

In yet another embodiment there is provided high purity (S)-methoprene having purity of more than 99%, preferably more than 99.5%by HPLC.

In yet another embodiment there is provided high purity (S)-methoprene having cis-isomer less than 0.5%, preferably cis-isomer less than 0.4%.

High purity (S)-methoprene is useful for the control of insects, preferably applied to the immature insect, namely during the embryo, larvae or pupae stage in view of their effect on metamorphosis and otherwise cause abnormal development leading to death or inability to reproduce. High purity (S)-methoprene is effective control agents for Hemipteransuch as Lygaedae, Miridaeor Pyrrhocoridae; Lepidopteran such as Pyralidae, NoctuidaeorGelechiidae; Coleopteran such as Tenebrionidae,Crysomelidaeor Dermestidae; Dipteran such as mosquitos, flies; Homopteran such as aphids; and other insects.

Thus, another aspect of the present invention provides the use of high purity (S)-methoprene having purity of more than 99%, preferably more than 99.5%by HPLC with cis-isomer less than 0.5%, preferably 0.4% in the control of insects.

The use of the compound of the present invention can be accomplished by spraying, dusting or exposing the insects to the vapour of the said compound. The dosages form can be prepared in a suitable formulation, which can include insect attractants, emulsifying agents or wetting agents to assist in the application and effectiveness of the active ingredient.In one embodiment, the formulation of the present invention comprises high purity (S)-methoprene having purity of more than 99%, preferably more than 99.5% by HPLC with cis-isomer less than 0.5%and one or more excipients selected fromfillers, extenders, binders, humectants, disintegrants, plasticizers, stabilizers, solution retarding agents, wetting agents, suspending agents, thickening agents, absorbents, lubricants, surfactants, buffering agents, diluents, solvents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, separating agents, coating permeability adjusters, and combinations thereof, wherein the one or more excipients are known and are easily available in the market, for example,suitable insect attractants include any type of insect food and/or attractant which will lure the insect to the bait to ingest the bait. Exemplary insect foods or attractants include, but are not limited to, any type of insect food, including various sugars, proteins, carbohydrates, yeast, fats, and/or oils.

Thus, the present invention further provide a pharmaceutical composition comprising high purity (S)-methoprene having purity of more than 99%, preferably

99.5%by HPLC with cis-isomer less than 0.5%, preferably 0.4%, useful for the control of insects.

The pharmaceutical compositions as discussed hereinbefore can be prepared by following the methods well known to a person of ordinary skill in the art.

Experimental Procedures

Hereinafter, the present invention is described in details with reference to example(s) such as Example 1 below. It should be noted that the starting materials for the synthetic methods are commercially available and/or have been reported widely in scientific documents or can be formed from commercially available products by appropriately using synthetic methods reported in scientific documents. As a general guide to reaction conditions or reagents, see Advanced Organic Chemistry, Vol. 4 (Jerry March, ed., published by John Willey and Sons, 1992)

(Example 1) Charged toluene (50 mL) and (2E,4E,7S)-11-Methoxy-3,7,11- trimethyl-2,4-dodecadienoic acid (SMP-acid, 43 g, 0.16 moles) in a 4 neck flask. Charged triethyl amine (22 g, 0.22 moles) at about 10-15 0C, followed by addition of pivaloyl chloride (23.5g, 0.19 moles) over a period of 30 min to reaction mixture at about 10-15 0C. Upon completion of the reaction, the reaction mixture was filtered, and washed the precipitate with toluene (25 mL).

The filtrate was then transferred to 4-neck flask, and added titanium tetraisopropoxide (51.0 g, 0.18 moles) over a period of 30 minutes at 10-15 0C. The reaction mixture was added to cold water (100 mL), maintained at 0-5 0C over a period of 30 minutes, stirred for 15 minutes at the same temperature. The organic layer was separated, washedthe aqueous layer with toluene (50 mL). The combine organic layer was washed with brine (50 mL), followed by separation of the organic layer, which was washed with sodium hydroxide solution (25 mL) twice and with brine solution (25 mL) twice.

The organic layer was then dried using sodium sulfate, treated with charcoal, and filtered. The filtrate was distilled under vacuum to obtain the desired (S)- methoprene (45 g), more than 99%purity by HPLC withcis impurity less than 0.1%.
,CLAIMS:We Claim

(Claim 1) A process for preparing highly pure (S)-methoprene,

comprising:
c) reacting (2E,4E)-11-methoxy-3,7,11-trimethyldodeca-2,4-dienoic acid of formula

with acid chloride in a solvent to form mixed anhydride of formula

whereinR is selected from C1-C6 alkyl, aryl or –COCl,
d) reacting mixed anhydride with titanium isopropoxide to form methoprene.

(Claim 2) The process according to claim 1 wherein acid chloride is selected from acetyl chloride, oxalyl chloride, benzoyl chloride or pivaloyl chloride.

(Claim 3) The process according to claim 1, wherein the base is selected from trimethylamine, triethylamine, triisopropylamine or diisopropylethylamine.

(Claim 4) The process according to claim 1, wherein the solvent is selected from pentane, hexane, cyclohexane, benzene, toluene, o-xylene, m-xylene, p- xylene or mixture thereof.

(Claim 5) A process for the preparation of highly pure (S)-methoprene, comprises of
a. adding an organic solvent, (2E,4E)-11-methoxy-3,7,11-trimethyldodeca- 2,4-dienoic acid, a base and acid chloride;
b. maintaining the temperature at 10-15 0C;
c. adding titanium tetraisoproppoxide;

d. isolating the pure (S)-methoprene.

(Claim 6) The process according to claim 5, wherein the solvent is selected from pentane, hexane, cyclohexane, benzene, toluene, o-xylene, m-xylene, p- xylene or mixture thereof; base is selected from trimethylamine, triethylamine, triisopropylamine or diisopropylethylamine; and acid chloride is selected from acetyl chloride, oxalyl chloride, benzoyl chloride or pivaloyl chloride.

(Claim 7) (S)-methoprene obtained following the process according to claim 1 to 6 has purity of more than 99% by HPLC with cis-isomer less than 0.4%.

(Claim 8)A process for the preparation of highly pure (S)-methoprene, of formula

comprising converting a mixed anhydride of formula

to (S)-methoprene having purity of more than 99% with cis-isomer being less than 0.4%, using titanium isopropoxide as converting agent; wherein R is selected from C1-C6 alkyl, aryl or -COCl
(Claim 9) A pharmaceutical composition comprising high purity (S)- methoprene having purity of more than 99%by HPLC with cis-isomer less than 0.4% useful for the control of insects.

(Claim 10) Use of high purity (S)-methoprene having purity of more than 99%by HPLC with cis-isomer less than 0.4%, in the control of insects.