Claims:1. A Novel process for preparation of a sex attractant pheromone (Z, Z)-11,13-Hexadecadien-1-al (18) using 11-Dodecyn-1-ol (5) comprising the steps of:
a. reacting a starting material, 11-Dodecyn-1-ol with 3,4-dihydro-2H-pyran (10) in the presence of PTSA and dichloromethane;
b. coupling of reagent with 2-(dodec-11-ynyloxy)-tetrahydro-2H-pyran (11) in presence of n-BuLi;
c. coupling of 13-(tetrahydro-2H-pyran-2-yloxy) tridec-2-ynal (13) via a Wittig reaction with Triphenyl(propyl)phosphonium bromide (14);
d. deprotecting C-16 Enyne intermediate (15) using PTSA and methanol;
e. converting C-16 Enyne alcohol (16) using zinc & ammonium chloride and methanol; and
f. oxidizing the hydroxyl group of C-16 dienol (17) using by PCC and in presence of solvent dichloromethane and hexane or Stahl oxidation using copper (I) catalyst in presence of acetonitrile.

2. The process for preparation as claimed in claim 1, wherein the preparation of starting material 11-Dodecyn-1-ol (5) comprising the steps of:
a. reacting 1-Bromononane (7) with 3-tertiary butoxy prop-1-yne in the presence of sodamide and ammonia;
b. deprotecting 1-tertiary butoxydodec 2-yne (9) in the presence of sulphuric acid and methanol; and
c. reacting 2-Dodecynol (1) with Sodium hydride in the presence of ethylenediamine and MTBE under heating conditions.

3. The process for preparation as claimed in claim 1, wherein the preparation of starting material 11-Dodecyn-1-ol (5) comprising the steps of:
a. reacting 1-decyne reacts with ethylene oxide in the presence of methyl magnesium chloride and THF as a solvent; and
b. reacting 3-Dodecynol (2) with Sodium hydride in the presence of ethylenediamine and MTBE under heating conditions.

4. The process for preparation as claimed in claim 1, wherein the step c, coupling reaction of 2-(dodec-11-ynyloxy)-tetrahydro-2H-pyran is carried out with a reagent of N, N-dimethylformamide with in presence of n-BuLi.

5. The process for preparation as claimed in claim 1, wherein the step f, is carried out with copper (I) catalyst in presence of THF as a solvent.

6. The process for preparation as claimed in claim 1, wherein the (Z, Z)-11,13-Hexadecadien-1-al is sex attractant insect pheromone.
, Description:Technical Field of the Invention
The present invention relates to a process for the preparation of Navel Orange worm (NOW) Pheromone, (Z, Z)-11,13-Hexadecadienal starting from 11-Dodecyn-1-ol.

Background of the Invention
According to the recent studies, Insect pheromones can be used in a variety of insect control strategies that include mating disruption and attract-and-kill, as well as mass trapping. These strategies have proven to be effective, selective (e.g., they do not harm beneficial insects, such as bees and lady bugs), and safe (e.g., the compounds are generally biodegradable and do not accumulate in the food chain). Even the very stringent USDA Organic Program lists insect pheromones as one of the few synthetic organic compounds allowed in organic crop production, another important recognition of the high safety of these products. Accordingly, pheromones already form the basis of integrated pest management (IPM) practices in fruit production on the U.S. west coast, and their use in organic farming is growing worldwide.

Sex pheromones are used in the chemical communication of many insects for attracting the species of the opposite sex to engage in reproduction. Pheromones are useful for pest control largely through four means: monitoring, mass trappings, attract and kill, and disruption of communication or confusion. “Monitoring” methodology attracts the pests to a central area, which allows the grower to obtain precise information on the size of the pest population in order to make informed decisions on pesticide use or non-use. “Mass trappings” brings the pest to a common area and physically trap them, which hinder production of new generations of pests. “Attract and kill” allows the pests to be drawn into a centrally located container and killed in the container by the pesticide reducing the need to spread pesticides in broad areas. “Disruption of communication” can occur in that a large concentration of sex pheromone can mask naturally occurring pheromones or saturate the receptors in the insect causing confusion and disruption of natural reproductive means (Shani, 1998). For each one of these means, each individual species of pest needs to be treated with a tailor-made composition which can add substantially to the cost in creating a bulk amount.

One of the major sex pheromone of the navel orangeworm has been isolated and analyzed is (Z,Z)-11,13-hexadecadienal (HDAL). This pheromone and others have been described in studies and belongs in the Ando type I pheromones (Ando T. et al., “Lepidopteran sex pheromones,” Top Curr Chem 239: 51-96, 2004). HDAL has been shown in other studies to have a high affinity for binding to a major pheromone binding protein (AtraPBP) which can correlate to having some effect on the mating disruption and monitoring of the adult moths (Leal et al., “Unusual pheromone chemistry in the navel orangeworm: novel sex attractants and a behavioral antagonist,” Nature wissenshaften 92:139-146 (2005)).

A method of synthesis for HDAL was described in a 1980 publication that described an at least seven step method (Sonnett, P. E. and R. R. Heath, “Stereospecific synthesis of (Z,Z)-11,13-hexadienal, a Female Sex Pheromone of the Navel Orangeworm, Amyelosis transitella, (Lepidoptera:Pyralidae)” Journal of Chemical Ecology, 6,221-228, 1980). U.S. Pat. Nos. 4,198,533 and 4,228,093 describe similar seven or more reaction step methods. Some of the problems faced by industry in the process of making pheromones, include use of toxic reagents, lack of available refined starting materials in the market, and inefficiencies in the processes. Therefore there remains a need in the art for new and better methods for synthesizing the navel orange worm pheromones.

To the best of knowledge known at the time of this patent application, the improved methods herein for creating a synthetic composition of the navel orange worm pheromone for use in pest management have not been described.

Brief Summary of the Invention
Accordingly, the exemplary embodiments of the invention provide for methods of forming the (Z,Z)-11,13-hexadecadienal, utilizing intermediate products in less than six steps. The starting material in this embodiment utilizes 11-dodecynol. Initial step in NOW synthesis involves the protection of the hydroxyl functionality in 11-dodecynol using 3,4 dihydro pyran in the presence of PTSA to yield 2-(dodec-11-ynyloxy) tetrahydro-2H-pyran. Further the resultant intermediate is coupled with N, N-dimethylformamide in the presence of n-BuLi to form the 13- (tetrahydro-2H-pyranyloxy) tridec-2-ynal. Followed by the transformation of C-13 Aldehyde Intermediate into the C-16 Enyne Intermediate via a Wittig reaction using Triphenyl(propyl)phosphonium bromide. Deprotection of C-16 Enyne intermediate using PTSA and methanol to yield C-16 Enyne alcohol, which is further converted into C-16 dienol intermediate using zinc & ammonium chloride and methanol as a solvent media. In the final step, the hydroxyl group in the C-16 dienol intermediate is oxidized by using PCC and MDC as a solvent to obtain Z11, Z13-Hexadecadienal or Stahl oxidation of C-16 Dienol intermediate using copper catalyzed air oxidation process in presence of Acetonitrile at ambient temperature to yield (Z,Z)-11, 13-hexadecadienal.

Other embodiments of the invention provide for methods of forming the (Z, Z)-11,13-hexadecadienal utilizing various reagents. Accordingly, these reagents are selected from N,N-dimethylformamide, NaH, EDA, PTSA, n-BuLi, propyl triphenyl phosphonium bromide, zinc dust and ammonium chloride and Pyridinium chloro chromate (PCC), Celite wherein the solvents used in all the steps are methanol, MTBE, THF, DCM, Hexane and water respectively.

Other embodiments of the invention provide for forming the stable version of the navel orange worm pheromone (Z,Z)-11,13-hexadecadienal by utilizing a method of less than six synthetic steps.

Another embodiment of the invention provide for a synthesis that utilizes all synthetic reagents, starting materials, methods, and apparatuses for forming the (Z,Z)-11,13-hexadecadienal, navel orange worm sex pheromone.

Brief Description of the Drawings
The present invention will be more readily understood from the detailed description of embodiments thereof made in conjunction with the accompanying drawings of which:

Fig. 1 shows step wise synthetic scheme 1 for preparation of (Z,Z)-11,13-hexadecadienal.
Fig. 2 shows step wise synthetic schemes (schemes 2 to 4) for preparation of 11-Dodecyn-1-ol

Detailed Description of the invention
Main object of the present invention to provide a novel process for preparation of a sex attractant the navel orange worm pheromone, namely (Z, Z)-11,13-Hexadecadien-1-al using 11-Dodecyn-1-ol wherein the process comprises the following steps;
1. reacting a starting material 11-Dodecyn-1-ol with 3,4-dihydro-2H-pyran in the presence of PTSA and dichloromethane;
2. coupling of N, N-dimethylformamide with 2-(dodec-11-ynyloxy)-tetrahydro-2H-pyran in presence of n-BuLi;
3. coupling of 13-(tetrahydro-2H-pyran-2-yloxy) tridec-2-ynal via a Wittig reaction with Triphenyl(propyl)phosphonium bromide;
4. deprotecting C-16 Enyne intermediate using PTSA and methanol;
5. converting C-16 Enyne alcohol using zinc & ammonium chloride and methanol; and
6. oxidizing the hydroxyl group of C-16 dienol using by PCC and in presence of solvent dichloromethane and hexane or Stahl oxidation using copper (I) catalyst in presence of acetonitrile.
Another object of the present invention to provide a process for preparation of starting material 11-Dodecyn-1-ol wherein the process comprises the steps of;
1. reacting 1-Bromononane with 3-tertiary butoxy prop-1-yne in the presence of sodamide and ammonia;
2. deprotecting 1-tertiary butoxydodec 2-yne in the presence of sulphuric acid and methanol; and
3. reacting 2-Dodecynol with Sodium hydride in the presence of ethylenediamine and MTBE under heating conditions.

The above process for preparation of starting material 11-Dodecyn-1-ol is depicted in Scheme 2 and scheme 4.

Another object of the present invention to provide a process for preparation of starting material 11-Dodecyn-1-ol wherein the process comprises the steps of;
1. reacting 1-decyne with ethylene oxide in the presence of methyl magnesium chloride and THF as a solvent;and
2. reacting 3-Dodecynol with Sodium hydride in the presence of ethylenediamine and MTBE under heating conditions.

The above process for preparation of starting material 11-Dodecyn-1-ol is depicted in Scheme 3 and scheme 4.
Accordingly, the exemplary embodiments of the invention provide for methods of forming the (Z,Z)-11,13-hexadecadienal, utilizing intermediate products in less than six steps. The starting material in this embodiment utilizes 11-dodecynol. Initial step in NOW synthesis involves the protection of the hydroxyl functionality in 11-dodecynol using 3,4 dihydro pyran in the presence of PTSA to yield 2-(dodec-11-ynyloxy) tetrahydro-2H-pyran. Further the resultant intermediate is coupled with N,N-dimethylformamide in the presence of n-BuLi to form the 13- (tetrahydro-2H-pyranyloxy)tridec-2-ynal. Followed by the transformation of C-13 Aldehyde Intermediate into the C-16 Enyne Intermediate via a Wittig reaction uisng Triphenyl(propyl)phosphonium bromide. Deprotection of C-16 Enyne intermediate using PTSA and methanol to yield C-16 Enyne alcohol, which is further converted into C-16 dienol intermediate using zinc & ammonium chloride and methanol as a solvent media. In the final step the hydroxyl group of C-16 dienol intermediate is oxidized by using PCC and MDC as a solvent to obtain Z11, Z13-Hexadecadienal or Stahl oxidation of C-16 Dienol intermediate using copper catalyzed air oxidation process in presence of Acetonitrile at ambient temperature to yield (Z,Z)-11, 13-hexadecadienal. The synthesis is depicted in scheme 1 below.

Other embodiments of the invention provide for forming the stable version of the navel orange worm pheromone (Z,Z)-11,13-hexadecadienal by utilizing a method of less than six synthetic steps.

Scheme 1: illustrates the synthesis of (Z,Z)-11, 13-hexadecadienal (HDAL):

Scheme 2:

Scheme 3:

Scheme 4:

EXPERIMENTAL DETAILS:
Example 1. Synthesis of 11-Dodecynol (5):
In RBF charge NaH under Nitrogen, slowly added EDA under the temperature of the reaction mixture at 60 - 65°C, and maintained the mixture at 60 – 65 °C for 1hr, further cooled the mixture, followed by the addition of 2-Dodecynol or 3-Dodecynol at the mixture at 45°C, stirred the reaction mixture at 70 - 75°C and cooled the mixture to 40 - 45°C. Pour the mixture into ice cold water slowly, under stirring for 30 mins, added MTBE, stirred and separated both MTBE and aqueous layers followed by extraction of the aqueous layer twice with MTBE and adjusted the pH to 6.5 – 7.0, washed the MTBE layer with brine solution, concentrated the MTBE layer to obtain11-Dodecynol, analyzed by GC, with Percent Yield - 70.0 to 73.0 % and Purity of 98.0 %.
Example 2. Synthesis of 2-Dodecynol (1):
Condensed the ammonia into RBF at -60°C, in the presence of sodamide added 3-tertiary butoxy propyne for 1 hour, followed by the addition of 1-Bromo nonane, stirred for 2 hrs, evaporated ammonia and quenched the reaction mass with ammonium chloride solution, extracted 1-tertiary butoxy 2-dodecyne with hexane, which was further deprotected in the presence of Sulphuric acid and methanol as a solvent to obtain 2-Dodecynol, analyzed by GC, with Percent Yield - 60.0 to 65.0 % and Purity of 95.0 %.
Example 3. Synthesis of 3-Dodecynol (2):
Charged methyl magnesium chloride in RBF, slowly added 1-decyne, stirred for 2 hrs at reflux temperature, cooled to 0°C, followed by addition of ethylene oxide and THF mixture as a solvent, stirred for 6 hrs and quenched with sulphuric acid solution, extracted 3-Dodecynol with hexane, to obtain 3-Dodecynol, analyzed by GC, with Percent Yield - 80.0 to 85.0 % and Purity of 95.0 %.
Example 4. Synthesis of 2-(dodec-11-ynyloxy)-tetrahydro-2H-pyran (11):
Charged DCM and 11-Dodecynol into the RBF at room temperature, and Cooled the reaction mixture to 0-5°C, added PTSA, slow addition of 3,4-dihydro-2H-pyran (DHP) (10), stirred the mixture at RT, charged water to the mixture, separated the DCM layer, washed the DCM layer with 10% sodium bicarbonate solution, concentrated the DCM to obtain2-(dodec-11-ynyloxy)-tetrahydro-2H-pyran, analyzed by GC, with Percent Yield - 95.8 % and Purity of 93.0 %.
Example 5. Synthesis of 13-(tetrahydro-2H-pyran-2-yloxy) tridec-2-ynal (13):
Charged THF to the RBF at RT under nitrogen atmosphere, with addition of 2-(dodec-11-ynyloxy)-tetrahydro-2H-pyran, cooled to -5°C followed by the addition of n-BuLi drop wise at -5°C to +4°C, after completion of the addition of n-BuLi; stirred for 30 min, coupling with N, N-dimethylformamide (12), quenched the reaction mixture with sodium di-hydrogen phosphate solution, extracted the compound with MTBE, and distilled off MTBE under vacuum to obtain13-(tetrahydro-2H-pyran-2-yloxy) tridec-2-ynal , analyzed by GC, with Percent Yield - 96.0 % and Purity of 92.0 %.
Example 6. Synthesis of C-16 Enyne Intermediate (15):
Charged THF and propyl triphenyl phosphonium bromide (14) in RBF at room temperature, under N2 atmosphere, cooled to 10°C, added potassium tert. butoxide to the reaction mixture, stirred the reaction mixture for 1 hour, then cooled to -5°C. Further slowly added 13-(tetrahydro-2H-pyrynyl oxy) tridec-2ynal at -5 to 0°C, Stirred for 2 hrs, charged water, separated the THF layer, distilled THF under vacuum added hexane, filtered the mass, concentrated to obtain C-16 Enyne Intermediate analyzed by GC, with Percent Yield - 93.5 % and Purity of 90.0 %.
Example 7. Synthesis of C-16 Enyne alcohol Intermediate (16):
Deprotection of C-16 Enyne intermediate was carried out by charging methanol in RBF at 25-30?, added PTSA, increased the temperature to 60-65?, stirred the mixture, cooled the mass to 25-30?, slowly added Sodium bicarbonate, distilled off the methanol under vacuum, cooled it to 25-30?, charged water and MTBE, extracted the compound with MTBE, distill off MTBE under vacuum, to obtain C-16 Enyne alcohol Intermediate, analyzed by GC, with Percent Yield - 72.6 % and Purity of 94.0 %.

Example 8. Synthesis of C-16 dienol intermediate (17):
Charged methanol and C-16 Enyne alcohol intermediate in RBF, added Zinc & ammonium chloride to the mass at 25-30°C, refluxed at ~65°C, stirred the mixture for 24 hours, filtered off solid mass and washed with methanol, distilled off the methanol under vacuum, added water & hexane, stirred for 10 mins, separated both layers, washed the hexane layer with brine solution and driedover anhydrous sodium sulphate, concentrated the hexane layer to obtain C-16 dienol intermediate, analyzed by GC, with Percent Yield – 70.1 % and Purity of 94.0 %.
Example 9. Synthesis of (Z, Z)-11, 13-hexadecadienal (18):
Charged DCM in RBF under nitrogen atmosphere at RT, added PCC and celite, slowly added C-16 dienol intermediate stirred the mixture for 3 hrs, added MTBE & stirred the mixture for 30 mins, filtered the reaction mixture and washed with MTBE, distillled off the combined DCM and MTBE layer under vacuum below 35°C, charged Hexane and filtered through celite bed, washed with hexane, followed by distillation of Hexane layer under vacuum to obtain(Z, Z)-11, 13-hexadecadienal, analyzed by GC, with Percent Yield – 76.7 % and Purity of 90.0%.
Example 10. Synthesis of (Z, Z)-11, 13-hexadecadienal (18):
Charged acetonitrile and C-16 Dienol intermediate material in RBF at 25-30?, added Tetrakis acetonitrile copper triflate CuOTf (ACN)4, followed by 2,2’bipyridine to the reaction mass at 25-30?, stirred for 5 minutes, added TEMPO, followed by N-Methyl imidazole, stirred the reaction mass at 25-30?, distilled off 80% of the acetonitrile under vacuum, added water, extracted the compound with hexane, washed hexane layer with disodium EDTA solution, distilled off the solvent under vacuum, cooled to 25-30? to obtain (Z, Z)-11, 13-hexadecadienal, analyzed by GC, with Percent Yield –90.0 % and Purity of 90.0%.