DESC:FORM 2

THE PATENTS ACT, 1970
[39 of 1970]
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION

(Section 10; Rule 13)

A PROCESS FOR SYNTHESIS OF Z-9-TRICOSENE

Barrix Agro Sciences Private Limited
1A-C Block, 2nd Floor, Kushal Garden Arcade,
2nd Phase, Peenya, Bangalore - 560068
India
[An Indian Company]

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

The present invention relates to a process of synthetically preparing semiochemicals. More particularly, it relates to preparing Z-9-tricosene, a major pheromone sex component of common house fly Musca domestica L.

BACKGROUND OF THE INVENTION

We are facing the menace of insects and pests on a daily basis, be it agricultural land or houses or factories. This problem is conventionally tackled by copious use of pesticides or insecticides, which are often toxic in nature and have serious side effects not only on person consuming those fruits/vegetables exposed to the pesticides/insecticides, but also on the person spraying those pesticides/insecticides. The prolonged use of the pesticides/insecticides deteriorates the soil quality and contaminates the water.

However, there are some other ways of controlling the insects and pests, such as non-toxic botanical pesticides which are naturally occurring substances that control pests by non-toxic mechanisms and can substantially decrease the use of conventional pesticides. The semiochemicals such as insect 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.

The common housefly M. domestica is generally counted among the destructive insects, since it can transmit numerous diseases and deposits eggs in food stuffs which are rendered unfit for consumption due to the growing maggots.

Z-9-tricosene is a major pheromone attractants used to control common house flies. It can be found in the cuticle and feces of the female housefly and it attracts the male fly, thus facilitating sexual reproduction.

To make these pheromones readily available for use in insect control, a variety of chemical syntheses have been developed. These syntheses involve classical types of organic synthesis utilizing alkynes, phosphonium salts, ketone reductions with hydrazine (Huang-Minlon type reductions), ozonolysis of 1,5-cyclooctadiene, sulfone coupling, or borane coupling, synthesis utilizing metathesis chemistry, synthesis using electrochemical coupling of carboxylic acids, and synthesis utilizing Grignard coupling of various erucyl and oleyl derivatives with the appropriate Grignard reagents.

In order to make this compound widely available for use in insect control, economic large scale synthetic conversion processes are required. The presently known synthetic routes for the preparation of Z-9-tricosene have been facing the hurdle of requirement of multiple reaction steps and consequent low overall product yield. This renders the known processes impractical for large scale production and consequently makes the pheromones very expensive to be used as pesticide.

Therefore, there is an urgent need for a process for the synthesis of Z-9-tricosene which could easily scale-up reactions and did not require multiple reaction vessels hence simple and cost-effective.

SUMMARY OF THE INVENTION

The various embodiments of the present invention disclose a process for preparing Z-9-tricosene.

In an embodiment of the present invention, the process for preparing Z-9-tricosene is disclosed.

The first step in the process is reacting one of a primary halide of tetradecane and primary halide of nonane with triphenylphosphine in presence of first set of one or more organic solvents to form phosphonium salt. Stoichiometric ratio of the one of the primary halide of tetradecane and the primary halide of nonane to the triphenylphosphine ranges between 1:1 to 1:1.3, preferably between 1:1.1 to 1: 1.2. The reaction is allowed to occur for a duration of 12 hours to 24 hours, preferably 16 hours to 20 hours, at temperature maintained between 50 °C to 120 °C, preferably between 82 °C to 86 °C. The next step is mixing the phosphonium salt with one of a nonanal and tetradecanal in the presence of one or more bases and a second set of one or more organic solvents, to form a chemical complex. Finally, adding one or more mineral acids to the chemical complex to quench ongoing reaction thereby yielding Z-9-tricosene.

In a further embodiment of the process a purification protocol has been added. The process includes removing the second set of one or more organic solvents present in excess to obtain residue containing the Z-9-tricosene; and purifying the residue to obtain the Z-9-tricosene.

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 preparing a pheromone of Z-9-tricosene, 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 preparing pheromone of Z-9-tricosene which is the sex pheromone of the house fly (M. domestica L).

Structure of (Z)-9-Tricosene:

The process includes broadly two consecutive steps:
(a) Preparation of phosphonium salt: reacting a primary halide of tetradecane or primary halide of nonane with triphenylphosphine in presence of first set of one or more organic solvents to form phosphonium salt; and

(b) Wittig reaction: combining the first reaction product with nonanal or tetradecanal to form a corresponding Z-9-tricosene, wherein said steps are carried out in a suitable base medium and organic solvent.

Reaction Scheme 1:

Reaction Scheme 2:

The flow diagram given in Figure 1 provides the detailed steps of the present process (100), according to one embodiment.

A. Preparation of Phosphonium Salt

The process starts with formation of phosphonium salt where primary alkyl halide is allowed to react with triphenylphosphine in presence of first set of one or more organic solvents to form phosphonium salt at step 102. 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 group cannot form the ylide. 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 one of the embodiments of the present invention, the phosphonium salt formed by reacting the primary halide of tetradecane with triphenylphosphine is (1-tetradecyl)triphenylphosphonium halide. For example, (1-tetradecyl)triphenylphosphonium bromide

In another embodiment of the present invention, the phosphonium salt formed by reacting the primary halide of nonane with triphenylphosphine is (1-nonyl)triphenylphosphonium halide. For example, (1-nonyl)triphenylphosphonium bromide.

During the formation of the phosphonium salt the first set of one or more organic solvents are selected from a group consisting of toluene, benzene, THF, DMF, acetonitrile and DMSO. However, the toluene and acetonitrile are preferably used in this process.

The other parameters observed during the formation of phosphonium salt are: (1) temperature is maintained between 50 °C to 120 °C, more preferably between 82 °C to 86 °C;
(2) stoichiometric ratio of the primary alkyl halide to the triphenylphosphine ranges between 1:1 to 1: 1.3, more preferably between 1:1.1 to 1: 1.2; and

(3) the primary alkyl halide is allowed to react with the triphenylphosphine for a duration ranging between 12 hours to 24 hours, more preferably between 16 hours to 20 hours.

Once the desired phosphonium salt is formed the next set of reactions are performed.

B. Wittig Reaction

The phosphonium salt is mixed with nonanal, in the presence of one or more bases and a second set of one or more organic solvents, to form a chemical complex at step 104. In an alternative embodiment, the phosphonium salt is mixed with tetradecanal, in the presence of one or more bases and a second set of one or more organic solvents, to form a chemical complex.

The one or more bases used in step 104 are selected from a group consisting of sodium hydride, sodium methoxide, sodium ethoxide, triethylamine, n-butyllithium and sodium amide. More preferably n-butyllithium and sodium hydride is used. The second set of organic solvents are selected from a group consisting of DMSO, tetrahydrofuran (THF) and diethyl ether. The preferred organic solvents are DMSO and THF.

The mixing of the phosphonium salt with nonanal or tetradecanal is carried out at a temperature ranging between -30 °C and 5 °C, preferably between -10 °C and 5 °C.

The phosphonium salt and nonanal or tetradecanal are allowed to react during their mixing for a duration of 2 hours to 4 hours, preferably 2 hours to 3 hours.
The one or more mineral acids are added to the chemical complex to quench ongoing reaction and yield Z-9-tricosene from the chemical complex at step 106. The one or more mineral acids 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 Z-9-tricosene.

In a further embodiment of the present invention, a purification protocol has been added. The purification includes removing the second set of one or more organic solvents present in excess to obtain residue containing the Z-9-tricosene, and subsequently purifying the said residue to obtain the Z-9-tricosene.

The purification of the residue is performed by adding zinc chloride and toluene to the residue containing Z-9-tricosene, and heating it to 65 °C to 75 °C for a duration of 5 hours, and performing high vacuum distillation to obtain the Z-9-tricosene.

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 1A: Synthesis of Tetradecyltriphenylphosphonium bromide
A three liter multineck flask equipped with a reflux condenser, mechanical stirrer, thermometer and addition funnel was used. 200g of 1-bromotetradecane, 189.2g of triphenylphosphine and 400 ml of acetonitrile were added to the flask and the reaction mixture was refluxed for 15 hours at 82 °C to 86 °C. Reaction was monitored by TLC, once completion of the reaction the excess solvent was removed by distillation under reduced pressure. The crude product was slurried in hexane to obtain 297.82g of phosphonium salt.

EXAMPLE 1B: Synthesis of Z-9-tricosene
A three liter multineck flask equipped with a condenser, addition funnel, thermometer, nitrogen inlet and calcium chloride drying tube was used. 21.1g of 60% sodium hydride was added through solid funnel and 220ml of dimethyl sulfoxide was added. The reaction mixture was heated for 1 hour at 55 °C to 60 °C and cooled to room temperature followed by addition of 650ml of tetrahydrofuran. The reaction mixture was cooled below 10 °C and 227.6g of tetradecyltriphenylphosphonium bromide was added portion wise without raising temperature more than 20 °C and stirred the reaction mass for 1 hour at the same temperature. To this, 50.0g of nonanal in 100ml of tetrahydrofuran was added drop wise over the period of 1 hour at -5 °C to 5 °C. The reaction mixture was stirred for 3 hours at room temperature, cooled below 20 °C and 250ml of 10% ammonium chloride solution was added followed by phase separation. The aqueous layer was re-extracted with 200ml of tetrahydrofuran and the combined organic phase was washed with 2x250ml of saturated sodium chloride solution, followed by dry over anhydrous sodium sulphate and the organic solvent was removed under reduced pressure to obtain crude residue. To this residue, 71.9g of zinc chloride was added along with 500ml of toluene and maintained temperature for 5hours at 65 °C to 75 °C. The reaction mass was cooled to room temperature and filtered through celite. The organic solvent was removed under reduced pressure and purified through high vacuum distillation to obtain 93.8g of Z-9-tricosene.

EXAMPLE 2A: Synthesis of Nonyltriphenylphosphonium bromide

A one liter multineck flask equipped with a reflux condenser, mechanical stirrer, thermometer and addition funnel was used. 20g of 1-bromononane, 30.2g of triphenylphosphine and 80ml of acetonitrile were added to the flask and the reaction mixture was refluxed for 15 hours at 82 °C to 86 °C. Reaction was monitored by TLC, once completion of the reaction the excess solvent was removed by distillation under reduced pressure. The crude product was slurried in hexane to obtain 35.8g of phosphonium salt.

EXAMPLE 2B: Synthesis of Z-9-tricosene

A one liter multineck flask equipped with a condenser, addition funnel, thermometer, nitrogen inlet and calcium chloride drying tube was used. 6.35g of 60% sodium hydride was added through solid funnel and 120ml of dimethyl sulfoxide was added. The reaction mixture was heated for 1 hour at 55 °C to 60 °C and cooled to room temperature followed by addition of 320ml of tetrahydrofuran. The reaction mixture was cooled below 10 °C and 35.8g of nonyltriphenylphosphonium bromide was added portion wise without raising temperature more than 20 °C and stirred the reaction mass for 1 hour at the same temperature. To this, 13.5g of tetradecanal in 20ml of tetrahydrofuran was added drop wise over the period of 1 hour at -5 °C to 5 °C. The reaction mixture was stirred for 3 hours at room temperature, cooled below 20 °C and 50ml of 10% ammonium chloride solution was added followed by phase separation. The aqueous layer was re-extracted with 75ml of tetrahydrofuran and the combined organic phase was washed with 2X50ml of saturated sodium chloride solution, followed by dry over anhydrous sodium sulphate and the organic solvent was removed under reduced pressure to obtain crude residue. To this residue, 19.4g of zinc chloride was added along with 100ml of toluene and maintained temperature for 5h at 65 °C to 75 °C. The reaction mass was cooled to room temperature and filtered through celite. The organic solvent was removed under reduced pressure and purified through high vacuum distillation to obtain 25.6g of Z-9-tricosene.

,CLAIMS:
WE CLAIM:

1. A process for preparing Z-9-tricosene, comprising:

reacting one of a primary halide of tetradecane and primary halide of nonane with triphenylphosphine in presence of first set of one or more organic solvents to form phosphonium salt,
wherein stoichiometric ratio of the one of the primary halide of tetradecane and the primary halide of nonane to the triphenylphosphine ranges between 1:1 to 1:1.3, preferably between 1:1.1 to 1: 1.2, and
the reaction is allowed to occur for a duration of 12 hours to 24 hours, preferably 16 hours to 20 hours, at temperature maintained between 50 °C to 120 °C, preferably between 82 °C to 86 °C;

mixing the phosphonium salt with one of a nonanal and tetradecanal in the presence of one or more bases and a second set of one or more organic solvents, to form a chemical complex; and

adding one or more mineral acids to the chemical complex to quench ongoing reaction thereby yielding Z-9-tricosene.

2. The process as claimed in claim 1, wherein the first set of one or more organic solvents are selected from a group consisting of toluene, benzene, THF, DMF, acetonitrile and DMSO.

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

4. The process as claimed in claim 1, wherein the second set of organic solvents are selected from a group consisting of DMSO, THF and diethyl ether.

5. The process as claimed in claim 1, wherein the mixing of the phosphonium salt with the one of the nonanal and the tetradecanal is carried out at a temperature ranging between -30 °C to 5 °C, preferably between -10 °C to 5 °C, for a duration of 2 hours to 4 hours, preferably 2 hours to 3 hours.

6. The process as claimed in claim 1, wherein the one or more mineral acids are selected from a group consisting of dilute HCl, dilute H2SO4 and ammonium chloride solution.

7. The process as claimed in claim 1, further comprising the steps of:

removing the second set of one or more organic solvents present in excess to obtain residue containing the Z-9-tricosene; and

purifying the residue to obtain the Z-9-tricosene.

8. The process as claimed in claim 7, wherein purifying the residue comprises:

adding zinc chloride and toluene to the residue containing Z-9-tricosene, and heating to 65 °C to 75 °C for a duration of 5 hours; and

performing high vacuum distillation to obtain the Z-9-tricosene.

dated this the 20th day of June 2016

Signature

SANTOSH VIKRAM SINGH
Patent Agent (IN/PA-414)
Agent for the Applicant