DESC:FORM 2

THE PATENTS ACT, 1970
[39 of 1970]

&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION

(Section 10 and Rule 13)

A PROCESS FOR SYNTHESIS OF Z-9-HENICOSENE

Barrix Agro Sciences Private Limited

An Indian Company

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

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 semio-chemicals. More particularly, it relates to preparing Z-9-henicosene, a sex pheromone component for common house fly Musca domestica. L.
BACKGROUND OF THE INVENTION
The pheromones are substances which servers in general to stimulate chemically mediated behavior of interactions of organisms with one another.

Among the pheromones are counted primary sex attractions, as well as substances causing the expressions of alarm, aggregation, attack, defense, etc., of the insects. These pheromones are generally effective even in minute quantities.

Sex pheromones have been employed in a variety of ways for control of insect population. For examples, traps baited with appropriate pheromone compounds or mixtures can be employed to monitor for the presence of particular insects in the field. In this way, most efficient use of pesticides or other conventional means of insect control can be applied.

The common housefly Musca domestica lives in close association with people all over the world. The insects feed on human food stuffs and wastes were they can pick up and transport various disease agents.

The hydrocarbons sex pheromones of the female housefly Musca domestica was isolated by Carlson et al. (Sciences, 174, 76-78, 1971) and was identified as Z-9-tricosene, which is also known under the name of muscular. It has been discovered that, in addition to Z-9-tricosene, several other Z-olefins with a double bond in the 9-position are effective as sex pheromones. In particular, a mixture of Z-9-tricosene and Z-9-henicosene in a weight ratio of 7:3 is said to process optimum effectiveness, as has been reported by Man Singh et al. (Can. Entomol. 104, 1963-65, 1972).
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-henicosene 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 pheromone very expensive to be used as pesticide.

Therefore, there is an urgent need for a process for the synthesis of Z-9-henicosene which could easily scale-up reactions and which did not require multiple reaction vessels hence simple and cost-effective.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing pheromone namely Z-9-henicosene.

An embodiment of the present invention describes a process for preparing pheromone, where the pheromone Z-9-henicosene. The process begins with reacting primary halide of dodecane with triphenylphosphine in presence of first set of organic solvent(s) to form phosphonium salt. The reaction is allowed to occur for a duration of 12 hours to 24 hours, while stoichiometric ratio of the primary alkyl halide to the triphenylphosphine range between 1:1 to 1:1.3. The phosphonium salt obtained in the previous step is mixed with nonanal, in the presence of base(s) and a second set of organic solvent(s). Finally, to quench the ongoing reaction of phosphonium salt with nonanal the mineral acid(s) added, which yields the Z-9-henicosene.
In a further embodiment of the present invention, the yielded Z-9-henicosene is further purified by removing the second set of organic solvent(s) present in excess to obtain residue containing the Z-9-henicosene and subsequently purifying the residue to obtain the Z-9-henicosene.

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 the preparation of pheromone, Z-9-henicosene, according to one embodiment.

Figure 2 is a flow chart illustrating the steps involved in purification of the Z-9-henicosene, according to another 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 provides a process for synthesis of Z-9-henicosene, a pheromone sex component of common housefly Musca domestica, which is efficient, involving mineral reaction conditions and cost effective for using readily available inexpensive starting materials.
Structure of (Z)-9-Henicosene:

The process includes broadly two consecutive steps:

(a) Preparation of phosphonium salt: from primary halides of dodecane reacting with triphenylphosphine form a first reaction product in suitable organic solvent(s); and

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

Reaction Scheme:

The flow diagram given in Figure1 provides the detailed steps of the present process (100), according to one embodiment of the present invention.
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 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.

Further, where the desired end product of the process (100) is Z-9-henicosene, then primary halide of dodecane is used as the primary alkyl halide.
The phosphonium salt formed by reacting the primary halide of dodecane with triphenylphosphine is (1-dodecyl)triphenylphosphonium halide. For example, (1-dodecyl)triphenylphosphonium bromide

During the formation of the phosphonium salt the first set of organic solvent(s) 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 base(s) and a second set of organic solvent(s), to form Z-9-henicosene at step 104.

The base(s) 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 sodium hydride and n-butyllithium is/are 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 reaction of the phosphonium salt with a nonanal is carried out at a predetermined temperature and duration. The phosphonium salt and nonanal are allowed to react during their mixing for a duration of 2 hours to 4 hours, preferably 2 hours to 3 hours, while maintaining temperature ranging between -30 °C and 5 °C, preferably between -10 °C and 5 °C.

The mineral acid(s) are added to the chemical complex to quench ongoing reaction and yield the Z-9-henicosene from the chemical complex at step 106. 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 Z-9-henicosene.

Purification of the Z-9-Henicosene

In a further embodiment of the present invention, purification of the Z-9-henicosene so yielded is also performed.

The flow diagram given in Figure 2 provides the detailed steps of the present process (200), according to one embodiment of the present invention.

The Z-9-henicosene yielded at the step 106 is rotary evaporated to remove the organic solvent(s) present in excess in the yield in order to obtain residue containing the pheromone, at step 202.

At step 204 the residue is purified to obtain the pheromone, Z-9-henicosene. In an embodiment of the present invention, the purification is performed by (a) adding zinc chloride and toluene to the residue containing Z-9-henicosene, and heating to 65 °C to 75 °C for a duration of 5 hours, and (b) performing vacuum distillation at temperature ranging between 160-165 °C and pressure of 650 mmHg to obtain the Z-9-henicosene

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 1: Synthesis of Dodecyltriphenylphosphonium bromide
A three liter multineck flask equipped with a reflux condenser, mechanical stirrer, thermometer and addition funnel was selected. 200g of 1-bromododecane, 231.51g of triphenylphosphine and 400ml of acetonitrile was added to the flask and the reaction mixture was refluxed for 15 hours at temperature ranging between 82 °C to 86 °C. Reaction was monitored by TLC, and after completion of the reaction the excess solvent was removed by distillation under reduced pressure. The crude product was slurried in hexane to obtain 281.33g of the dodecyltriphenylphosphonium bromide (phosphonium salt).
EXAMPLE 2: Synthesis of Z-9-henicosene
A three liter multineck flask equipped with a condenser, addition funnel, thermometer, nitrogen inlet and calcium chloride drying tube was selected. 20.21g of 60% sodium hydride was added through the solid funnel and further to that 250ml of dimethyl sulphoxide 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 400ml of tetrahydrofuran. The reaction mixture was cooled below 10 °C and 238g of dodecyltriphenylphosphonium 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, 44.27g of nonanal in 100 ml 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 100ml 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, 65.6g 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 74.84g of the Z-9-henicosene.

,CLAIMS:We Claim:
1. A process for preparing Z-9-henicosene, comprising steps of:
reacting primary halide of dodecane with triphenylphosphine in presence of first set of one or more organic solvents to form phosphonium salt,
wherein stoichiometric ratio of the primary alkyl halide to the triphenylphosphine ranges between 1:1 to 1:1.3, and the reaction is allowed to occur for a duration of 12 hours to 24 hours;
mixing phosphonium salt with nonanal, in the presence of one or more bases and a second set of one or more organic solvents; and
adding one or more mineral acids to quench the ongoing reaction of phosphonium salt with nonanal to yield the Z-9-henicosene.

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 reacting the primary halide of dodecane with the triphenylphosphine being performed at temperature ranging between 50 °C to 120 °C, preferably 82 °C to 86 °C.

4. 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.

5. The process as claimed in claim 1, wherein the second set of one or more organic solvents are selected from a group consisting of DMSO, tetrahydrofuran (THF) and diethyl ether.

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

7. 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.

8. 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-henicosene; and
purifying the residue to obtain the Z-9-henicosene.

9. The process as claimed in claim 8, wherein purifying the residue comprises:
adding zinc chloride and toluene to the residue containing Z-9-henicosene, and heating to 65 °C to 75 °C for a duration of 5 hours; and
performing vacuum distillation at temperature ranging between 160-165 °C and pressure of 650 mmHg to obtain the Z-9-henicosene.

dated this the 18th day of May 2016
Signature

KEERTHI JS
Patent Agent
Agent for Applicant