DESC:FORM 2

THE PATENTS ACT, 1970
[39 of 1970]

&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION

(Section 10; Rule 13)

PROCESS FOR PREPARATION OF Z-7,9-DECADIENYL ACETATE

Barrix Agro Sciences Private Limited

1A-C Block, 2nd Floor, Kushal Garden Arcade,
2nd Phase, Peenya, Bangalore - 560058
India

An Indian Company

The following Specification particularly describes the invention and the manner in which it is to be performed
FIELD OF INVENTION

This present invention relates synthetically preparing semiochemicals of interest. More particularly it relates to synthetic preparation of Z-7,9-decadienyl acetate.

BACKGROUND OF INVENTION

Groundnut (Arachishypogaea L.) is an important oil seed crop of tropical and sub-tropical regions of the world. The groundnut leaf miner (GLM) Aproaeremamodicella Deventer (Lepidoptera: Gelechiidae) is an oligophagous insect pest feeding on leguminous host plants and a serious insect pest of groundnut in rainy and post rainy seasons in India and of groundnut and soybean in south and south east Asia. The damage is characterized by the leaf mining of larva between the upper and lower epidermis and longitudinal folding of individual leaves. Immediately after hatching, the larva burrows in to the leaf and produces blotches by feeding on the green tissue of the leaf. As the larva grows, the tunnel expands; the affected leaves get distorted and finally dry up. Loss of leaves resulted in reduction of the breathing area for the plant and ability to prepare food, which ultimately caused yield loss.

The groundnut leaf miner sex pheromones are effective against only the target pest and closely related organisms in very small quantities, thereby resulting in lower exposures and largely avoiding the pollution problems caused by the conventional pesticides.

Z-7,9-decadienyl acetate is one of the major pheromone attractant used to control groundnut leaf miner. In order to make this compound widely available for use in insect control, economic large scale synthetic conversion processes must be developed. While the known synthetic routes for the preparation of Z-7,9-decadienyl acetate have been fronting the problems which requires multiple reaction steps with consequent low overall product yield, impracticality of large scale production and use of expensive or specialized catalysts.

Therefore, there is a need for an economical process for synthesis of Z-7,9-decadienyl acetate which could abridged steps, use expensive raw materials, easy for the purpose of scaling up and effectively bring down the cost of production.

SUMMARY OF THE INVENTION

In present invention provides a process for the preparation of Z-7,9-decadienyl acetate. In an embodiment of the process for the preparation of Z-7,9-decadienyl acetate, the following steps are included: reacting one of hydroxides of sodium and carbonates of sodium and one of hydroxides of potassium and carbonates of potassium, with aleuritic acid to form respectively, sodium aleuritate and potassium aleuritate, where the reaction being allowed to occur for a duration of 1 hour at temperature ranging from 10 to 15 °C; oxidizing one of the sodium aleuritate and potassium aleuritate with sodium periodate, wherein the oxidization is performed at temperature of 15 °C; extracting the oxidized sodium aleuritate and the oxidized potassium aleuritate in presence of first set of organic solvent(s) to yield 7-hydroxyheptanal, wherein the first set of organic solvents are selected from a group consists of DCM, chloroform, carbon tetrachloride, ethylene dichloride and ethyl acetate; reacting primary halides of allyl with triphenylphosphine in presence of second set of organic solvent(s) to form phosphonium salt, wherein the second set of organic solvent(s) are selected from a group consisting of toluene, benzene, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile and dimethyl sulfoxide (DMSO), and wherein the reaction is carried out at temperature maintained between 50 to 120 °C, more preferably between 82 to 86 °C, for a duration ranging between 12 to 24 hours, more preferably between 16 to 20 hours; reacting the phosphonium salt with the 7-hydroxyheptanal in presence of first set of base(s) and a third set of organic solvent(s), to yield Z-7,9-decadienol; and acylating the Z-7,9-decadienol using acylating agent(s) in the presence of second set of base(s) and fourth set of organic solvent(s) to yield the Z-7,9-decadienyl acetate.

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

The aforementioned aspects and other features of the present invention will be explained in the following description, taken in conjunction with the accompanying drawings, wherein:

Figure 1 is a flow chart illustrating the steps involved in synthetically preparing Z-7,9-decadienyl acetate, according to an embodiment.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular. Generally, nomenclatures used in connection with techniques of chemistry described herein are those well-known and commonly used in the art. In case of conflict, the present specification, including definitions, will control. The materials, methods, and examples are illustrative only and not intended to be limiting.

It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

The term “comprising” as used herein is synonymous with “including” or “containing,” and is inclusive or open-ended and does not exclude additional, unrecited members, elements or process steps.

The present invention discloses a process for the synthesis of Z-7,9-decadienyl acetate.

Structure of Z-7,9-decadienyl acetate

According to an embodiment of the present invention, the process for preparing Z-7,9-decadienyl acetate and its intermediates includes steps of:
a) preparation of 7-hydroxyheptanal: from sodium periodate oxidation of aleuritic acid;
b) preparation of phosphonium salt: reacting primary alkyl halide of allyl with triphenylphosphine in presence of second set of organic solvent(s);
c) wittig reaction: mixing the phosphonium salt with 7-hydroxyheptanal in the presence of first set of base(s) and a third set of organic solvent(s), to form Z-7,9-decadienol; and
d) acetylation of Z-7,9-decadienol: with suitable acetylating agent(s) and a second set of base (s), fourth set of organic solvent(s) to form the desired Z-7,9-decadienyl acetate.
The flow diagram given in Figure 1 provides the detailed steps of the present process (100), according to one embodiment of the present invention.

A. Preparation of 7-hydroxyheptanal

The first stage of the process is preparation of the 7-hydroxyheptanal. The stage includes three steps.

One of hydroxides of sodium and carbonates of sodium and one of hydroxides of potassium and carbonates of potassium is/are allowed to react with aleuritic acid to form respectively, sodium aleuritate and potassium aleuritate at step 102. The reaction being carried out for a duration of 1 hour at temperature ranging from 10 to 15 °C.

The sodium aleuritate and/or the potassium aleuritate is/are oxidised with sodium periodate at step 104. The oxidization is performed at temperature of 15 °C.

The oxidized sodium aleuritate or/and the oxidized potassium aleuritate is/are extracted in presence of first set of one or more organic solvents to yield 7-hydroxyheptanal at step 106. The first set of organic solvents are selected from a group consists of DCM, chloroform, carbon tetrachloride, ethylene dichloride and ethyl acetate.

B. Preparation of phosphonium salt

Second stage of the process is preparation of phosphonium salt. During the stage, primary alkyl halide is allowed to react with triphenylphosphine in presence of second set of organic solvent(s) at step 108.

The present step is performed utilizing reagents and techniques known in the art with suitable sources of alkyl halides. The reaction works well if the alkyl halide is primary group, however it is usually poor with secondary alkyl halide. Tertiary alkyl halide cannot form the phosphonium salt. Presently preferred source of alkyl halide is a primary alkyl halide, where the halide component of the primary alkyl halide can either be chloride or bromide or iodide.

In a preferred embodiment, primary halides of allyl are allowed to react with triphenylphosphine in presence of second set of organic solvent(s) to form the phosphonium salt.

During the formation of the phosphonium salt the second set of organic solvent(s) are selected from a group consisting of toluene, benzene, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile and dimethyl sulfoxide (DMSO). However, the toluene and acetonitrile are preferably used in this process. The reaction of the primary alkyl halide with triphenylphosphine was carried out at a temperature maintained between 50 to 120°C, more preferably between 82 to 86°C, for a duration ranging between 12 to 24 hours, more preferably between 16 to 20 hours. Once the desired phosphonium salt is formed the next set of reactions are performed.

C. Wittig Reaction

The phosphonium salt with the 7-hydroxyheptanal being allowed to react in presence of first set of base(s) and a third set of organic solvent(s), to form a chemical complex having Z-7,9-decadienol at step 110.

The first set base(s) used in the reaction are selected from a group consisting of sodium hydride, sodium methoxide, sodium ethoxide, triethylamine, n-butyllithium, sodium amide, anhydrous potassium carbonate and anhydrous sodium carbonate. More preferably n-butyllithium, sodium hydride and anhydrous potassium carbonate are used. The third set of organic solvents are selected from a group consisting of DMSO, THF, diethyl ether and acetonitrile. The preferred organic solvents are DMSO, THF and acetonitrile.

The mixing of phosphonium salt with a 7-hydroxyheptanal is carried out at a temperature ranging between -30 to 5°C, preferably between -10 to 5°C. The phosphonium salt and 7-hydroxyheptanal are allowed to react during their mixing for a duration of 2 to 4 hours, preferably 2 to 3 hours.

The mineral acid(s) are added to the chemical complex to quench ongoing reaction and yield the Z-7,9-decadienolfrom the chemical complex. The mineral acid(s) used herein are selected from a group consisting of dilute HCl, dilute H2SO4 and ammonium chloride solution. The acid wash which effects a phase separation and causes decomposition of the complex and subsequent yield of the Z-7,9-decadienol, which is further washed with saturated sodium chloride solution and evaporated to remove the organic solvents in excess and obtain residue containing the Z-7,9-decadienol.

D. Preparation of Z-7,9-decadienyl acetate

The Z-7,9-decadienol being acylated using acylating agent(s) in the presence of second set of base(s) and fourth set of organic solvent(s) to yield the Z-7,9-decadienyl acetate at step 112.

The acylating agent(s)are selected from a group consisting of acetic anhydride, acetic acid, sodium acetate, potassium acetate and acetyl chloride. More preferably acetic anhydride and acetyl chloride. The second set of base(s) are selected from a group consisting of sodium hydroxide solution, potassium hydroxide solution, triethylamine, sodium acetate, sodium carbonate, potassium acetate, potassium carbonate and pyridine. The fourth set of organic solvent(s) are selected from a group consisting of chloroform, dichloromethane, carbon tetrachloride, cyclohexane and ethylene dichloride.

The mixing of acylating agent with Z-7,9-decadienol is carried out at a temperature ranging between 10to 20 °C, preferably between 15to 20 °C. The Z-7,9-decadienol and acylating agents are allowed to react during their mixing for a duration of 3to 5 hours, preferably 3to 4 hours.

Reaction schemes for preparation of Z-7,9-decadienyl acetate

Reaction Scheme 1:

In an embodiment where steps 102 to 112 are performed for preparation of Z-7,9-decadienyl acetate.

Reaction Scheme 2:

In another embodiment, the steps of preparation of the 7-hydroxyheptanal are skipped (steps 102-106). Readymade 7-hydroxyheptanal being reacted with the phosphonium salt at step 110.

Reaction Scheme 3:

In a further embodiment, the step 108 for preparation of the phosphonium salt is skipped while rest of the steps are performed as described earlier. Therefore, the phosphonium salt is not prepared and a readymade one is used at the step 110.
Reaction Scheme 4:

In yet another embodiment of the invention, the steps 102 to 106 for preparation of the 7-hydroxyheptanal and the step 108 for preparation of the phosphonium salt is skipped. Therefore, in this scenario the readymade phosphonium salt and readymade 7-hydroxyheptanal are used in step 110.

Reaction Scheme 5:

In a further embodiment of the present invention, the steps for arriving at Z-7,9-decadienol are skipped and directly readymade Z-7,9-decadienol is acylatedat step 112 to yield the Z-7,9-decadienyl acetate.

EXAMPLES

The present invention is explained further in the following specific examples which are only by way of illustration and are not to be construed as limiting the scope of the invention.
Example- I: Preparation of 7-hydroxyheptanal

A ten litres multineck flask equipped with a reflux condenser, mechanical stirrer, thermometer and addition funnel were used. 26.0g of sodium hydroxide in 1600 ml of water was added to the flask, cooled to 10-15 °C followed by addition of 200 g of aleuritic acid and the suspension stirred for 1 hour at same temperature. To the resulting suspension of sodium aleuritate was added 160.0 g of sodium periodate in 1600ml of water over 1 hour without allowing the temperature to raise above 15 °C. 500 ml of dichloromethane (DCM) was then added and the mixture was stirred for further 2 hours 30 minutes at 15 °C. To this, 600 ml of DCM and 200 ml of saturated aqueous sodium bicarbonate were added and the mixture vigorously stirred for half an hour. The precipitated sodium iodate was removed by filtration and the DCM layer was separated. The aqueous phase was further extracted with 2x100ml of DCM and separated. Combined DCM layer was successively washed with 200ml of 5% sodium bicarbonate solution, 200ml of saturated sodium chloride solution and dried over anhydrous sodium sulphate. Removal of the DCM in vacuum below 40 °C to obtain 78.5g of 7-hydroxyheptanal.

Example- II: Synthesis of allyltriphenylphosphonium bromide
A two litres multineck flask equipped with a reflux condenser, mechanical stirrer, thermometer and addition funnel were used. 200g of allyl bromide, 520.3g of triphenylphosphine and 500ml of acetonitrile were added to the flask and reaction mixture refluxed for 12 hours at 82 to 86 °C. Reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, mass was cooled to 10-15 °C and stirred for 2 hours. Solidified mass was filtered and washed with 100ml of hexane. Separated the wet solid, slurried with 500ml of hexane and stirred for 1 hour. Filtered and washed the solid with 100ml of hexane and dried under vacuum at 55 to 65 °C to obtain 576.5g of wittig salt.

Example- III A: Preparation of Z-7,9-decadienol
A two litres multineck flask equipped with a condenser, addition funnel, thermometer, nitrogen inlet and calcium chloride drying tube were used. 18.45g of 60% sodium hydride was added through solid funnel followed by addition of 150ml of DMSO. The reaction mixture was heated for 1 hour at 55 to 60 °C and cooled to room temperature and 600ml of THF was added. The reaction mixture was cooled below 10 °C and 105.96g of allyltriphenylphosphonium bromide was added portion-wise without raising temperature more than 15 °C. The reaction mass was stirred for 1 hour at same temperature. 30.0g of 7-hydroxyheptanaldiluted with 30ml of THF was added drop wise and the temperature was maintained at -30 to-25 °C during the addition. The reaction mixture was allowed to room temperature and stirred for 3 hours. The reaction was monitored by Gas chromatography (GC). The reaction mass was cooled below 15 °C, diluted with 120ml of water and acidified with 60ml of 1:1 HCl to reach pH 1 to 2. Stirred the reaction mass for further 15minutes and separated the THF layer. Re-extracted the aqueous layer with 120ml of ethyl acetate. Combined organic layer was washed with 2x250ml saturated sodium chloride solution and dried over anhydrous sodium sulphate. Removal of organic layer in vacuum below 40 °C obtain crude Z-7,9-decadienol. To this added, 1200ml of hexane, 42.41g of zinc chloride, 316.0g of magnesium chloride hexahydrate and heated to 60-65 °C for 4 hours. Cooled the reaction mass to 25-30 °C and added 250ml of water and stirred for 2 hours. Filtered insoluble on high flow bed, separated the hexane layer and washed with 200ml of water followed by dried with anhydrous sodium sulphate. Concentrated the organic layer under vacuum below 40 °C followed by purification to obtain 10.3g of Z-7,9-decadienol.

Example- III B: Preparation of Z-7,9-decadienol
A four litres multineck flask equipped with a condenser, addition funnel, and thermometer were used.190.8g of anhydrous potassium carbonate and 600ml of acetonitrile followed by 30ml of water were added to the flask at ambient temperature and stirred for 5 minutes. 194.4g of allyltriphenylphosphonium bromide was added lot wise and stirred the reaction mass for further 5 to 10 minutes. 60g of 7-hydroxyheptanal dissolved in 60ml of acetonitrile was added dropwise to the reaction mixture and 1.5g of tetrabutylammonium bromide was added and refluxed the reaction mass for 15 hours. The reaction was monitored by Gas chromatography. Filter the reaction mass using whatman filter paper, dried with anhydrous sodium sulphate and removed the acetonitrile in vacuum below 40 °C to obtain crude Z-7,9-decadienol. To this added, 720ml of hexane, 180ml ethyl acetate, 187.3g of magnesium chloride hexahydrate and heated to 60-65 °C for 5 hours. Cooled the reaction mass to 25-30 °C and filtered insoluble on high flow bed, dried the organic layer with anhydrous sodium sulphate. Concentrated the organic layer under vacuum below 40 °C followed by high vacuum distillation to obtain 12.0g of Z-7,9-decadienol.

Example- IV: Preparation of Z-7,9-decadienyl acetate

One litre multineck flask equipped with a condenser, addition funnel, nitrogen inlet and thermometer were used. 9g of Z-7,9-decadienol, 450ml of dichloromethane (DCM) were added to the flask and 7.07ml of acetylchloride was added drop by drop without raising the temperature more than 15 °C. Stirred the reaction mass for another 15 minutes and 13.98ml of triethylamine was added while maintaining the same temperature. After addition completed, reaction mass was kept at ambient temperature, stirred for 2 hours and monitored using GC. Afterwards, the reaction mass was cooled below 15 °C, quenched with 50ml of water and organic layer formed was separated. Aqueous layer was re-extracted with 50ml of DCM and combined organic layer was successively washed with 50ml of water, 50ml of 3% sodium bicarbonate solution and 50ml of water, and subsequently dried with anhydrous sodium sulphate. The organic solvent was removed by rotary evaporation and the residue was purified with high vacuum distillation to obtain 8.2g of Z-7,9-decadienyl acetate.

The high price of the pheromone has always been a deterrent in the widespread use of the same in agriculture for the purpose of controlling pests and in Integrated Pest Management programs. Present invention makes the Z-7,9-decadienyl acetate readily and cheaply available which helps in overcoming the price barrier. Due to cheaper cost it could be widely used in controlling of groundnut leaf miner (GLM) without harming any other insect and without having any negative effect on the environment.

While the invention has been described with reference to preferred embodiments thereof, it will be apparent to one skilled in the art that various changes can be made, and equivalents employed, without departing from the scope of the invention.

,CLAIMS:
We claim:

1. A process for preparation of the Z-7,9-decadienyl acetate, comprising steps of:
reacting one of hydroxides of sodium and carbonates of sodium and one of hydroxides of potassium and carbonates of potassium, with aleuritic acid to form respectively, sodium aleuritate and potassium aleuritate, where the reaction being allowed to occur for a duration of 1 hour at temperature ranging from 10 to 15 °C;
oxidizing one of the sodium aleuritate and potassium aleuritate with sodium periodate, wherein the oxidization is performed at temperature of 15 °C;
extracting the oxidized sodium aleuritate and theoxidized potassium aleuritate in presence of first set of one or more organic solvents to yield 7-hydroxyheptanal,
wherein the first set of organic solvents are selected from a group consists of DCM, chloroform, carbon tetrachloride, ethylene dichloride and ethyl acetate;
reacting primary halides of allyl with triphenylphosphine in presence of second set of one or more organic solvents to form phosphonium salt,
wherein the second set of one or more organic solvents are selected from a group consisting of toluene, benzene, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile and dimethyl sulfoxide (DMSO), and
wherein the reaction is carried out at temperature maintained between 50 to 120 °C, more preferably between 82 to 86 °C, for a duration ranging between 12 to 24 hours, more preferably between 16 to 20 hours;
reacting the phosphonium salt with the 7-hydroxyheptanal in presence of first set of one or more bases and a third set of one or more organic solvents, to yield Z-7,9-decadienol; and
acylating the Z-7,9-decadienol using one or more acylating agents in the presence of second set of one or more bases and fourth set of one or more organic solvents to yield the Z-7,9-decadienyl acetate.

2. The process as claimed in claim 1, wherein the first set of one or more bases are selected from a group consisting of sodium hydride, sodium methoxide, sodium ethoxide, triethylamine, n-butyllithium, sodium amide, anhydrous potassium carbonate and anhydrous sodium carbonate.

3. The process as claimed in claim 1, wherein the third set of one or more organic solvents are selected from a group consisting of DMSO, THF, diethyl ether and acetonitrile.

4. The process as claimed in claim 1, wherein reacting the phosphonium salt with the 7-hydroxyheptanal being carried out at temperature ranging between -50 °C to 0 °C, preferably between -30 °C to -10 °C, and for duration of 2 to 4 hours, preferably 2 to 3 hours.

5. The process as claimed in claim 1, wherein the one or more acylating agents are selected from a group consisting of acetic anhydride, acetic acid, sodium acetate, potassium acetate and acetyl chloride.

6. The process as claimed in claim 1, wherein the second set of one or more bases are selected from a group consisting of sodium hydroxide solution, potassium hydroxide solution, triethylamine, sodium acetate, sodium carbonate, potassium acetate, potassium carbonate and pyridine.

7. The process as claimed in claim 1, wherein the fourth set of one or more organic solvents are selected from a group consisting of chloroform, dichloromethane, carbon tetrachloride, cyclohexane and ethylene dichloride.

8. The process as claimed in claim 1, wherein the reaction of phosphonium salt with the 7-hydroxyheptanal is quenched by adding one or more mineral acids.

9. The process as claimed in claim 8, wherein the one or more mineral acids are selected from a group consisting of dilute HCl, dilute H2SO4 and ammonium chloride solution.

10. The process as claimed in claim 1, wherein acylating the Z-7,9-decadienol being carried out at a temperature ranging between 10 to 20°C, preferably between 15 to 20 °C, and for a duration of 3 to 5 hours, preferably 3 to 4 hours.

Dated this the 29th day of August 2016
Signature

KEERTHI JS
IN/PA 1729
Agent for the Applicant