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-11-HEXADECENOL

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 chemicals of interest. More particularly it relates to process for preparation of Z-11-hexadecenol, which is one of the pheromone component for Lepidopteran species.

BACK GROUND OF INVENTION
The pests are control by conventional methods such as spraying pesticides and bio-pesticides, this will lead to more burden to farmers in terms of money, time and labor. Even though, they were not controllable by pesticides, instead they are resist and develop a variety of species of same and are again uncontrollable and pathetic to farmers.
Insects may also be controlled by chemical mediators which regulate insect-insect relationships or plant-insect relationships. Among such chemical mediators are pheromones, kairomones, and allomones. Pheromones are chemical substances that are used for communication between individual organisms of the same species, which can be used against pest insect species to help prevent pesticide misuse, spraying the wrong type or too much or spraying in the wrong place or at the wrong time. During the past 40 years, pheromones of hundreds of insect species have been chemically elucidated. Generally, they are classified as hydrocarbons, epoxides, acetates, aldehydes, ketones, alcohols and carboxylic acids.
Lepidopteran species such as Helicoverpa armigera (American boll warm), Plutella xylostella (Diamondback moth), Pseudaletia unipuncta (Armyworm), Chilo suppressalis (Striped rice stem borer), Chilo infuscatellus (Shoot borer), Leucania separata, Mamestra brassicae (Cabbage moth) are more economic and sever damaging pests to the crops. Z-11-hexadecenol is one of sex pheromone naturally secreting by Lepidopteran species.
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-11-hexadecenol 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 making the pheromones very expensive to be used as an alternative to pesticides for controlling insects in the field.

SUMMARY OF THE INVENTION

The present disclosure provides a process for preparation of Z-11-hexadecenol.

In an embodiment of the present invention, the process for preparation of Z-11-hexadecenol includes following steps: (a) reacting primary alkyl halide of undecenoic acid with triphenylphosphine in presence of first set of organic solvent(s) to produce phosphonium salt; (b) reacting the phosphonium salt with pentanal, in the presence of base(s) and a second set of organic solvent(s), to form a first chemical complex; (c) adding mineral acid(s) to the chemical complex to quench the ongoing reaction to yield the Z-11-hexadecenoic acid from the chemical complex; (d) reacting the Z-11-hexadecenoic acid with reducing agent(s) in the presence of third set organic solvent(s) to form a second chemical complex; and (e) finally adding the mineral acid(s) to the second chemical complex mixture to quench the ongoing reaction to yield Z-11-hexadecenol.

In a further embodiment of the present invention, first round of purification of the so yielded of the Z-11-hexadecenoic acid is additionally performed before performing the second chemical complex. The steps of the purification process include following: (a) reacting toluene and zinc chloride with the Z-11-hexadecenoic acid yielded from the chemical complex for a duration of 5 hours at a temperature of 65-70o C; (b) filtering outcome of the previous step at a lower temperature of 25-30o C; (c) washing the filtrate with water; (d) drying the washed filtrate over anhydrous sodium sulphate; and (e) removing solvent under vacuum below 50 °C.

In a further embodiment of the present invention, a second round of purification of Z-11-hexadecenoic acid is performed. The steps of purification process include following: adding methanol and sodium methoxide to the purified Z-11-hexadecenoic acid at a cooled temperature of 10-15o C to obtain a precipitate; performing distillation of the precipitate to remove excess methanol at a temperature of 25-30 °C; acidifying the precipitate; and extracting the Z-11-hexadecenoic acid with organic solvent(s).

BRIEF DISCUSSION OF ACCOMPANYING DRAWINGS
Figure 1 is a flow chart depicting the steps included in the process for preparing Z-11-hexadecenol, according to one embodiment.
Figure 2 is a flow chart depicting the steps of purification protocol for the Z-11-hexadecenoic acid, according to one embodiment.

DETAILED DISCUSSION 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 Z-11-hexadecenol, which is one of sex pheromone naturally secreting by Lepidopteran species. The same could be used individually or in combination with other pheromones as a lure for attracting insects in the insect traps for catching insects of the aforementioned species. The use of pheromones to control insect is an eco-friendly way as compared to the present methods of using chemical pesticides. Further, the use of pheromones also allows selective controlling of the insect(s) damaging the crop instead of indiscriminately killing all types of insects present in the crop field.

The present invention provides for an easy to implement protocol while using easily available raw materials/ingredients. Therefore, overall cost of the production of Z-11-hexadecenol remains under check, at the same time this process also enhances yield significantly thereby bringing down the overall cost of production.

Structure of Z-11-Hexadecenol:

In one of the embodiments of the present invention, the process broadly includes following steps:
a) preparation of phosphonium salt: reacting primary alkyl halide of undecenoic acid with triphenylphosphine in presence of first set of organic solvent(s);
b) Wittig reaction: mixing the phosphonium salt with pentanal in the presence of base(s) and a second set of organic solvent(s), to form Z-11-hexadecenoic acid; and
c) reduction of Z-11-hexadecenoic acid: with suitable reducing agent(s) and a third set of organic solvent(s) to form the desired Z-11-hexadecenol.
Figure 1 illustrates one of embodiments of the process for producing hexadecenol. As mentioned above the process uses easily available raw materials such as primary alkyl halide of undecenoic acid, triphenylphosphine, phosphonium salt and pentanal.
A. Preparation of phosphonium salt
During the formation of phosphonium salt, primary alkyl halide is allowed to react with triphenylphosphine in presence of first set of organic solvent(s). 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.
The primary alkyl halide of undecenoic acid is allowed to react with triphenylphosphine in presence of first set of organic solvent(s) to produce phosphonium salt, at step 102. The first set of organic solvent(s) are selected from a group consisting of toluene, benzene, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile and dimethyl sulfoxide (DMSO). The reaction is carried out for a specific pre-set duration and temperature. The pre-set temperature maintained during the reaction ranges between 50°C to 120°C, however the best result is achieved at 82°C to 86°C. The pre-set duration for which the reaction is carried out is for 12 to 24 hours, more preferably between 16 to 20 hours.
B. Wittig Reaction

The phosphonium salt is allowed to react with pentanal, in the presence of base(s) and a second set of organic solvent(s), to form a first chemical complex, at step 104.

In an alternative embodiment of the present invention, the phosphonium salt is directly used without preparing the same, while skipping the step 102.

The base(s) used in reaction 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, THF and diethyl ether. The preferred organic solvents are DMSO and THF.

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

The mineral acid(s) are added to the chemical complex to quench ongoing reaction and to yield the Z-11-hexadecenoic acid 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 the Z-11-hexadecenoic acid.

C. Preparation of Z-11-hexadecenol
The Z-11-hexadecenoic acid is allowed to react with reducing agent(s) in the presence of third set of organic solvent(s) to form a second chemical complex, at step 108.

The one or more reducing agents are selected from a group consisting of lithium aluminium hydride (LAH), borane dimethylsulfide (BMS), mixture of sodium borohydride and boron trifluoride diethyl etherate. More preferably LAH and BMS are used.

The third set of organic solvent(s) are selected from a group consisting of THF and diethyl ether.

The reaction of Z-11-hexadecenoic acid with reducing agent is carried out at a temperature ranging between 0°C to 10°C. Preferably between 5°C to 10°C. The Z-11-hexadecenoic acids and reducing agents are allowed to react during their mixing for a duration of 2 hours to 5 hours, preferably 2 hours to 3 hours.

The mineral acid(s) are added to the second chemical complex mixture to quench ongoing reaction to yield Z-11-hexadecenol, at step 110. The mineral acid(s) used herein are selected from a group consisting of dilute HCl and dilute H2SO4. The acid wash which effects a phase separation of organic solvent containing Z-11-hexadecenol and evaporated to remove the organic solvents in excess and obtain residue containing the Z-11-hexadecenol.

Reaction scheme for Z-11-Hexadecenol

Purification of the Z-11-hexadecenoic acid
In a further embodiment of the present invention, the Z-11-hexadecenoic acid produced at step 106 is purified before being used in the step 108. This step provides a suitable alternative for purifying large quantities of the chemicals for bulk production of the same, as opposed to the column chromatography being used in the present state of the art which can be used for purification of only few milligrams of a given chemical.
Figure 2 illustrates the steps included in the purification protocol as per one of the embodiment.
Toluene and zinc chloride are reacted with the Z-11-hexadecenoic acid yielded from the chemical complex (at step 106), at step 202. The reaction is allowed to occur for a duration of 5 hours at a temperature of 65-70o C.
The outcome of the step 202 is filtered at a lower temperature of 25-30o C, at step 204.
Further to this, the filtrate is washed with water and dried over anhydrous sodium sulphate, at step 206.
The solvent is removed from the dried filtrate under vacuum below 50 °C, at step 208.
In another further embodiment of the present invention, the Z-11-hexadecenoic acid yielded at step 208 is further purified.
The process starts with adding methanol and sodium methoxide to Z-11-hexadecenoic acid at a cooled temperature of 10-15o C to obtain a precipitate. The precipitate is distilled to remove excess methanol at a temperature of 25-30 °C. Next to this, the precipitate is acidified by adding suitable acids to the same. The Z-11-hexadecenoic acid is extracted with one or more organic solvents. Finally, carrying out distillation of the extracted Z-11-hexadecenoic acid to produce the purified Z-11-hexadecenoic acid.

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: Synthesis of 11-(triphenylphosphonium)undecanoic acid bromide
A Three litre multineck flask equipped with a reflux condenser, mechanical stirrer, thermometer and addition funnel is used. 300g of 11-bromoundecanoic acid, 296.7g of triphenylphosphine and 1200ml of acetonitrile were added to the multineck flask and reaction mixture was refluxed for 24 hours at 82-86 °C. Reaction was monitored by thin layer chromatography (TLC), once reaction completed, the mass was cooled to 50-55 °C and distilled out under vacuum to remove excess acetonitrile. 300ml of toluene was added to the mass and stirred for 5min at 60-65 °C. Slowly, 1500ml of hexane was added to the mass having toluene, the same was cooled to 25-30 °C and stirred for 3 hours. Solidified mass was filtered and washed with 300ml of fresh hexane. Separated the wet solid, slurried with1500ml of hexane and stirred for 1 hour. Filtered and washed the solid with 300ml of hexane and dried under vacuum at 40-45 °C to obtain 540g of desired compound.
Example- II: Preparation of Z-11-hexadecenoic acid
A five litre multineck flask equipped with a condenser, addition funnel, thermometer, nitrogen inlet and calcium chloride drying tube were used. 40.86g of 60% sodium hydride was added through solid funnel and 400ml of DMSO was added further to it. The reaction mixture was heated at 60-65 °C for 1 hour and cooled to ambient temperature, followed by addition of 1000ml of THF. The reaction mixture was cooled below 10°C and 257.22g of 11-(triphenylphosphonium)undecanoic acid bromide was added portion wise without raising temperature more than 15 °C. The reaction mass was stirred for 1 hour at same temperature and added 1000ml of THF. To this, 40g of pentanal diluted with 80ml of THF was added drop wise and maintained the temperature at 0-5 °C. The reaction mass was maintained at 10-20 °C and stirred for 3 hours. The reaction was monitored by Gas chromatography (GC). The Reaction mass was cooled below 15 °C, diluted with 700ml of water and acidified with 250ml of dilute HCl to obtain pH 1 to 2. Stirred the reaction mass for further 15minutes and separated the THF layer. Re-extracted the aqueous layer with 240ml of ethyl acetate and combined organic layer washed with 2x400ml of saturated sodium chloride solution, followed by drying over anhydrous sodium sulphate. Removal of solvent under vacuum below 50 °C yielded crude Z-11-hexadecenoic acid. To this added, 1080ml of toluene, 158.24g of zinc chloride were added and heated to 65-70 °C for 5 hours. Cooled the reaction mass to 25-30 °C and filtered insoluble on high flow bed. Filtrate was washed with 2x400ml of water and dried over anhydrous sodium sulphate. The solvent was removed under vacuum below 50 °C to obtain 108.5g of Z-11-hexadecenoic acid. To this, 296ml of methanol was added and cooled to 10-15 °C. Further to this, 76.42g of 25% sodium methoxide was added and stirred for 1 hour at 10-15 °C. Distilled the excess methanol under vacuum, cooled to 25-30 °C. Next to this, added 267ml of hexane and stirred for 1 hour. Precipitate formed was filtered, washed with fresh hexane and dried under vacuum. Added 180ml of methanol and water in ratio of 7:3, adjusted pH 1 to 2 using conc.HCl and extracted with 280ml of ethyl acetate which resulted in forming of organic layer. The organic layer was washed with 120ml of water. Followed by washing with 120ml of saturated sodium chloride solution. Further, the organic layer is dried over anhydrous sodium sulphate. The solvent was removed under vacuum below 40 °C to obtain 65g of Z-11-hexadecenoic acid.
Example- III: Preparation of Z-11-hexadecenol
A two litre multineck flask equipped with a condenser, addition funnel, thermometer, nitrogen inlet and calcium chloride drying tube were used. 43g of Z-11-hexadecenoic acid and 430ml of THF was added to the multineck flask. Reaction mixture was cooled to 10-15 °C and 7.71g of lithium aluminium hydride pellets was added portion wise without allowing the temperature to raise above 15 °C. The reaction mixture was stirred for 3 hours at the same temperature and progress of the reaction was monitored by GC. The reaction mass cooled 0-5°C, quenched with 130ml of water, acidified with 80ml of conc.HCl to adjust pH 1 to 2 and further stirred the mass for 1 hour. Separated the organic layer, re-extracted aqueous layer with 170ml of ethyl acetate. Combined organic layer successively washed with 170ml of saturated sodium chloride, 170ml of 3% sodium bicarbonate, 170ml of saturated sodium chloride, and dried over anhydrous sodium sulphate. Concentrated the organic layer under vacuum below 40°C followed by high vacuum distillation to obtain 35.2g of Z-11-hexadecenol.

,CLAIMS:We Claim:

1. A process for preparing Z-11-hexadecenol, comprising:
reacting primary alkyl halide of undecenoic acid with triphenylphosphine in presence of first set of one of more organic solvents to produce phosphonium salt,
wherein the first 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),
wherein the reaction is carried out at temperature maintained between 50°C to 120°C, more preferably between 82°C to 86°C for a duration of 12 hours to 24 hours, more preferably between 16 hours to 20 hours;

reacting the phosphonium salt with pentanal, in the presence of one or more bases and a second set of one or more organic solvents, to form a first chemical complex;

adding one or more mineral acids to the chemical complex to quench the ongoing reaction to yield the Z-11-hexadecenoic acid from the chemical complex;

reacting the Z-11-hexadecenoic acid with one or more reducing agents in the presence of third set of one or more organic solvents to form a second chemical complex; and

adding the one or more mineral acids to the second chemical complex mixture to quench the ongoing reaction to yield Z-11-hexadecenol.

2. 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.

3. 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, THF and diethyl ether.

4. The process as claimed in claim 1, wherein the phosphonium salt and the pentanal are allowed to react for a duration of 2 hours to 4 hours, preferably 2 hours to 3 hours at temperature ranging between -30°C to 5°C, preferably between -10°C to 5°C.

5. 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.

6. The process as claimed in claim 1, wherein the one or more reducing agents are selected from a group consisting of lithium aluminium hydride (LAH), borane dimethylsulfide (BMS), mixture of sodium borohydride and boron trifluoride diethyl etherate.

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

8. The process as claimed in claim 1, further comprises purification of the Z-11-hexadecenoic acid yielded:

reacting toluene and zinc chloride with the Z-11-hexadecenoic acid yielded from the chemical complex for a duration of 5 hours at a temperature of 65-70o C;
filtering outcome of the previous step at a lower temperature of 25-30o C;
washing the filtrate with water;
drying the washed filtrate over anhydrous sodium sulphate;
removing solvent under vacuum below 50 °C to produce Z-11-hexadecenoic acid.

9. The process as claimed in claim 8, further comprises second round of purification of Z-11-hexadecenoic acid:
adding methanol and sodium methoxide to the Z-11-hexadecenoic acid at a cooled temperature of 10-15o C to obtain a precipitate;
performing distillation of the precipitate to remove excess methanol at a temperature of 25-30 °C;
acidifying the precipitate; and
extracting the Z-11-hexadecenoic acid with one or more organic solvents.

Dated this the 23rd day of May 2016 Signature
KEERTHI JS
Patent Agent
Agent for the Applicant