Claims:1. A synthetic method for preparation of (E, Z, Z)- tetradeca-3,8,11-trienyl acetate, which is characterized by:
a) Coupling of 6-heptynol with 1-bromo-2-pentyn in presence of copper iodide, potassium carbonate and in presence of a phase transfer catalyst in a solvent to obtain dodeca-6,9-diyn-1-ol;
b) Hydrogenating the dodeca-6,9-diyn-1-ol using sodium borohydride-reduced nickel (P-2 Ni), with ethylenediamine in a solvent system to obtain (6Z, 9Z)-dodeca-6,9-dien-1-ol;
c) Oxidizing the (6Z, 9Z)-dodeca-6,9-dien-1-ol with an oxidising agent in a solvent system to obtain (6Z, 9Z)-dodeca-6,9-dienal;
d) coupling the (6Z, 9Z)-dodeca-6,9-dienal with malonic acid in presence of piperidine, acetic acid to obtain (3E, 8Z, 11Z)-tetradeca-3,8,11-trienoic acid;
e) Reducing the (3E, 8Z, 11Z)-tetradeca-3,8,11-trienoic acid in presence of Red-Al in a solvent to obtain the corresponding alcohol; and
f) Acetylating the alcohol in presence of acetyl chloride and acetic acid to obtain (E, Z, Z)- tetradeca-3,8,11-trienyl acetate.
2. The synthetic method for preparation of (E, Z, Z)- tetradeca-3,8,11-trienyl acetate as claimed in claim 1, characterized in that the solvent is selected from the group consisting of THF, DCM, MTBE, methanol, hexane water and mixtures thereof.

3. The synthetic method for preparation of (E, Z, Z)- tetradeca-3,8,11-trienyl acetate as claimed in claim 1, characterized in that the oxidization of (6Z, 9Z)-dodeca-6,9-dien-1-ol is carried out by using PCC in DCM or Stahl oxidation using copper (I) catalyst in presence of acetonitrile.

4. The synthetic method for preparation of (E, Z, Z)- tetradeca-3,8,11-trienyl acetate as claimed in claim 1, characterized in that the synthesis is conducted at a temperature between 0°C and 60°C and under nitrogen atmosphere.

5. The synthetic method for preparation of (E, Z, Z)- tetradeca-3,8,11-trienyl acetate as claimed in claim 1, characterized in that the phase transfer catalyst is selected from tetrabutylammonium halides.

6. The synthetic method for preparation of (E, Z, Z)- tetradeca-3,8,11-trienyl acetate as claimed in claim 1, characterized in that the phase transfer catalyst is tetrabutylammonium bromide.

7. The synthetic method for preparation of (E, Z, Z)- tetradeca-3,8,11-trienyl acetate as claimed in claim 1, characterized in that the (E, Z, Z)- tetradeca-3,8,11-trienyl acetate is sex attractant insect pheromone of TUTA absoluta.
, Description:Technical filed:
The present invention relates to synthetic method for the preparation of (E,Z,Z)-3,8,11-Tetradecatrienyl acetate, with high yields in a cost-effective manner.

Background and prior art:
Tomato (Lycopersicon esculentum) is an economically important plant, cultivated extensively all over the world. However, tomato is extremely susceptible to insect attack by Tuta absoluta Meyrick. Tuta absoluta Meyrick (Lepidoptera: Gelechiidae), although originates from South America; however, is now considered to be one of the most damaging invasive pests of tomatoes in the Mediterranean Basin countries of Europe and North Africa. This insect causes severe damage to the crops. Blanket spraying of conventional insecticides and pesticides not only upsets delicate natural balances by eliminating non-targeted species, including natural predators of the pest and pollinators but also lead to the emergence of insect strains which show resistance to the chemicals being applied, thereby making subsequent insect control more difficult.

In recent years, pheromones have been recognized as useful alternate components in successful pest control programs. A pheromone is generally defined as a chemical substance secreted by living organisms, including insects, to convey information or produce a specific response in other individuals of the same species. Thus, the sex pheromones attracts insects of the same species to the location of the pheromone emission.

Tuta absoluta virgin females release a sex pheromone that strongly attracts conspecific males. The main pheromone component was reported to be identified as (3E,8Z,11Z)-tetradeca-3,8,11-trienyl acetate and a minor component (10%) was identified as (3E,8Z)-tetradeca-3,8-dienyl acetate. These synthetic pheromones were highly attractive and useful in pest monitoring and mating disruption.
One of the main drawbacks of the use of these pheromones is its cumbersome multistep synthesis that results in lower yields and thus associated with higher costs, which limits its production and utilization in large scale. Therefore, a very efficient and economical synthesis of (3E,8Z,11Z)-tetradeca-3,8,11-trienyl acetate is desirable to control the menace of Tuta absoluta Meyrick and to safe guard the produce of Tomato (Lycopersicon esculentum) crop in terms of its quality as well as quantity.

There is limited literature available on the synthesis of (3E, 8Z, 11Z)-tetradeca-3,8,11-trienyl acetate which is discussed herein below.
US5728376 first reported the isolated (3E,8Z,11Z)-tetradeca-3,8,11-trienyl acetate and a method of synthesizing (3E,8Z,11Z)-3,8,11-tetradecatrienyl acetate. The synthesis reported in this patent includes preparation of 1-(tetrahydropyran-2-yloxy)-4,7- decadiyne by reacting 1-(tetrahydropyran-2-yloxy)-4-pentyne with CH3MgBr in THF, followed by treatment with 2-pentyn-1-yl p-toluenesulfonate in presence of Cu(I)Br. MeS complex, followed by quenching the reaction with aqueous ammonia and saturated NHCl solution. The 1-(tetrahydropyran-2-yloxy)-4,7- decadiyne thus obtained is reacted with dicyclohexylborane followed by oxidation with H2O2 to obtain a mixture of (4Z,7Z)-1-(tetrahydropyran-2-yloxy)- 4,7-decadiene and (4Z,7Z)-4,7-decadien-1-ol. This mixture is reacted with triphenylphosphine bromide to obtain (4Z,7Z)-1-bromo-4,7-decadiene. This compound dissolved in 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidine (DMPU) is reacted with a mixture containing 1-(tetrahydropyran-2-yloxy)-3-butyne and n-butyllithium hexane solution to obtain (8Z,11Z)-1-(tetrahydropyran-2- yloxy)-8.11-tetradecadien-3-yne, which is treated with ion exchange resin to obtain (8 Z,11Z)-8, 11-tetradecadien-3-yn-1-ol.

The (8 Z,11Z)-8, 11-tetradecadien-3-yn-1-ol thus obtained is converted into (3E,8Z,11Z)-3,8,11-tetradecatrien-1-y1 acetate by reduction with LiAlH4 to obtain the corresponding alcohol which is further subjected to acetylation to obtain (3E,8Z,11Z)-tetradeca-3,8,11-trienyl acetate. The reaction is shown below in scheme 1.
Scheme 1:


Another synthetic route for the preparation of (3E,8Z,11Z)-tetradeca-3,8,11-trienyl acetate, was reported by Jorge A. Cabezas (Tetrahedron Letters 60 (2019) 407–410). According to this article, but-3-yn-1-ol, 17, which was treated with 3,4-dihydro-2H-pyran in presence of catalytic amounts of p-TSA to obtain the corresponding THP-protected alcohol, 18. A one-carbon homologation of 18 was performed by reaction with n-BuLi at 78° C and addition of paraformaldehyde. This reaction mixture was allowed to warm to room temperature and, after the usual aqueous work-up, the propargyl alcohol 19 obtained was purified and isolated by high vacuum distillation. Reduction of the propargyl alcohol, 19, was carried out with LiAlH4 to obtain the corresponding E-allylic alcohol 20, which was acetylated with acetic anhydride without any further purification to obtain Allylic acetate, 21. Bromide 23, was treated with magnesium in ether, to form the corresponding Grignard reagent. This Grignard reagent was coupled with allylic acetate 21, assisted by catalytic amounts of lithium tetrachlorocuprate, Li2CuCl4. The crude reaction was purified by column chromatography to obtain triene, 16. Deprotection of 16, was performed under very mild conditions, with PPTS in ethanol 95%, to obtain alcohol 11. Alcohol 11 was purified by column chromatography and acetylation of 11 was accomplished using acetic anhydride, triethylamine and 4-dimethylaminopyridine as a catalyst to obtain acetate, 1 with an overall yield of 41%.
The reaction is shown in below scheme 2.
Scheme 2:

Another article by M. Puigmartí et al. reported the synthesis of the Pheromone Components of the Tomato Leafminer Tuta absoluta (synthesis 2015, 47, 961–968). According to the synthesis reported in this article, Coupling reaction of the Grignard derivative of 1-bromopent-2-yne with 1-(methoxymethyloxy)pent-4-yne 3 was conducted with Me2S·CuBr as catalyst in THF to provide 4. The compound 4 was reacted with Lindlar catalyst in the presence of 1.5 equivalents of quinoline in EtOAc, to obtain compound 5. Acid hydrolysis of diene 5 followed by reaction with NBS/Ph3P in CH2Cl2 afforded bromo derivative 7. Alkylation of 7 with the lithium salt of 1-(tetrahydropyran-2-yloxy)but-3-yne 8 in THF–HMPA (10:1) to afford THP-protected alcohol 9. Reduction of the acetylenic bond in 9 with Na/NH3 in THF for two hours provided triene 10a. Acid hydrolysis of 10a followed by acetylation under standard conditions provided major pheromone compound 1 in 29.7% overall yield from 3 and 97% E,Z,Z-stereo selectivity by 13C NMR spectroscopy.
The reaction is shown below in scheme 3.
Scheme 3

As is evident from the foregoing, highly selective methods must be employed for constructing the (E,Z,Z)-conjugated triene system in (E, Z. Z)- tetradeca-3,8,11-trienyl acetate. Moreover, overall yield of the final product, viz., (E, Z. Z)- tetradeca-3,8,11-trienyl acetate never exceeded 41% in the multistep synthetic methods reported in prior arts, despite using costly and stereo selective reagents.
Therefore, it is important to provide an efficient synthetic route to produce (E, Z. Z)- tetradeca-3,8,11-trienyl acetate with improved yields in cost effective manner so that same can be scaled up for industrial production.
Accordingly, it is an objective of the present invention to provide an efficient synthetic route for preparation of (E, Z. Z)- tetradeca-3,8,11-trienyl acetate by employing easily available starting material, i.e., 6-heptynol.

Summary of the invention:
In accordance with the above, the present invention provides an efficient alternate synthetic method for preparation of (E, Z, Z)- tetradeca-3,8,11-trienyl acetate, which comprises;
a) Copper mediated coupling of 6-heptynol with 1-bromo-2-pentyn in presence of copper iodide, potassium carbonate and in presence of a phase transfer catalyst to obtain dodeca-6,9-diyn-1-ol;
b) Hydrogenating the dodeca-6,9-diyn-1-ol using Sodium Borohydride-reduced nickel (P-2 Ni), with ethylenediamine in a solvent system to obtain (6Z, 9Z) dodeca 6,9-dien-1-ol;
c) Oxidizing the (6Z, 9Z)-dodeca-6,9-dien-1-ol with an oxidising agent to obtain (6Z, 9Z)-dodeca-6,9-dienal;
d) Reacting the (6Z, 9Z)-dodeca-6,9-dienal with malonic acid in presence of piperidine, acetic acid to obtain (3E, 8Z, 11Z)-tetradeca-3,8,11-trienoic acid;
e) Reducing the (3E, 8Z, 11Z)-tetradeca-3,8,11-trienoic acid in presence of Red-Al to obtain the corresponding alcohol; and
f) Acetylating the alcohol in presence of acetyl chloride and acetic acid to obtain (E, Z, Z)- tetradeca-3,8,11-trienyl acetate.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention provides an efficient alternate synthetic route for preparation of (E, Z. Z)- tetradeca-3,8,11-trienyl acetate, which comprises;
a) Copper mediated coupling of 6-heptynol with 1-bromo-2-pentyn in presence of copper iodide, potassium carbonate and in presence of a phase transfer catalyst to obtain dodeca-6,9-diyn-1-ol;
b) Hydrogenating the dodeca-6,9-diyn-1-ol using sodium borohydride-reduced nickel (P-2 Nickel), with ethylenediamine in a solvent system to obtain (6Z, 9Z)-dodeca-6,9-dien-1-ol;
c) Oxidizing the (6Z, 9Z)-dodeca-6,9-dien-1-ol with PCC in DCM as solvent to obtain (6Z, 9Z)-dodeca-6,9-dienal;
d) Reacting the (6Z, 9Z)-dodeca-6,9-dienal with malonic acid in presence of piperidine, acetic acid to obtain (3E, 8Z, 11Z)-tetradeca-3,8,11-trienoic acid;
e) Reducing the (3E, 8Z, 11Z)-tetradeca-3,8,11-trienoic acid in presence of Red-Al to obtain the corresponding alcohol; and
f) Acetylating the alcohol in presence of acetyl chloride and acetic acid to obtain (E, Z, Z)- tetradeca-3,8,11-trienyl acetate.
Accordingly, in an embodiment, 6-heptynol is subjected to coupling reaction with 1-bromo-2-pentyn in presence of copper iodide, potassium carbonate and a phase transfer catalyst in a DMF as solvent at room temperature to obtain dodeca-6,9-diyn-1-ol. The phase transfer catalyst may be selected from tetrabutylammonium halides. In a preferred embodiment, the phase transfer catalyst is tetrabutylammonium bromide.

The dodeca-6,9-diyn-1-ol thus obtained is subjected to stereospecific hydrogenation using Borohydride-reduced nickel (P-2 Nickel) (prepared by borohydride reduction of Nickel acetate with ethylenediamine in methanol as solvent system at room temperature) to obtain (6Z, 9Z) dodeca 6,9-dien-1-ol. The compound, (6Z, 9Z) dodeca 6,9-dien-1-ol thus obtained is oxidized using oxidising agent selected from Pyridinium chlorochromate (PCC) in dichloromethane as solvent system or Stahl oxidation using copper (I) catalyst in presence of acetonitrile at room temperature to obtain the corresponding aldehyde, viz., (6Z, 9Z) dodeca 6,9-dienal.

The construction of the (E,Z,Z)-conjugated triene system in (E, Z. Z)- tetradeca-3,8,11-trienyl acetate is easily performed by reacting the (6Z, 9Z) dodeca 6,9-dienal thus obtained with malonic acid in presence of piperidine and acetic acid to obtain (3E, 8Z, 11Z) tetradeca 3,8,11 trienoic acid in high yields with high purity. This acid is selectively reduced with Red-Al(Sodium bis(2-methoxyethoxy)aluminium hydride), in ether as a solvent system to obtain the corresponding alcohol. Finally, this alcohol is converted into (E, Z, Z)- tetradeca-3,8,11-trienyl acetate by treating with acetyl chloride and acetic acid in high yield and high purity. The overall yield of the process of the present invention is more than 85% with a purity greater than 75% and with stereo selectivity of more than 75%.
The entire process for the preparation of (E, Z, Z)- tetradeca-3,8,11-trienyl acetate is operated at a temperature ranging from 0°C to 60°C and under nitrogen atmosphere.

The solvents which can be successfully employed in the synthetic method for the preparation of (E, Z, Z)- tetradeca-3,8,11-trienyl acetate, according to the invention is selected from the group consisting of THF, DCM, MTBE, methanol, hexane water and mixtures thereof.

The reaction scheme is shown below under scheme 4.
Scheme 4:

The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.

EXAMPLES:
Example 1: Synthesis of dodeca-6,9-diyn-1-ol
Charged DMF (800 ml) in RBF under nitrogen atmosphere at RT, along with Copper Iodide (125 g), TBAB (200 g) and Potassium carbonate (120 g), under stirring followed by addition of 6-Heptyn-1-ol (100 g) and 1-Bromo-2-pentyn (137 g) slowly and dissolve 75 g of ammonium chloride in 500 ml of water, and added ammonia (500 ml), added MTBE (200 ml), separated both the aqueous and organic layers, extracted the aqueous layer with MTBE, dried the organic layer over anhydrous sodium sulphate and distilled off the organic layer under vacuum to yield dodeca-6,9-diyn-1-ol, (140 g) analysed by GC, with purity >90% and yield 84%.

Example 2: Synthesis of (6Z, 9Z)-dodeca-6,9-dien-1-ol
Charged Methanol (500 ml) in RBF under nitrogen atmosphere at RT and added nickel acetate (34 g), stirred, and slowly added sodium borohydride (6 g) followed by the addition of ethylene diamine (EDA) (17 g), stirred under hydrogen gas pressure below 0.5kg/cm2 for 3 to-4hrs, filtered and distilled off excess methanol and added HCl solution (200 ml), further added MTBE (200 ml) and separated the organic layer & extracted the aqueous layer with MTBE, dried the organic layer and distilled off the organic layer under vacuum to yield (6Z, 9Z)-dodeca-6,9-dien-1-ol (90 g), analysed by GC, with purity >85% and yield >90%.

Example 3: Synthesis of (6Z, 9Z)-dodeca-6,9-dienal
Charged DCM (1 lt) into the RBF under nitrogen atmosphere at RT and added celite (177gr) and PCC (177 g) to the DCM, followed by addition of (6Z, 9Z)-dodeca-6,9-dien-1-ol (100 g), stirred and filtered the reaction mixture and washed with MTBE(200ml), distilled off the combined DCM and MTBE layer under vacuum followed by addition of hexane (300 ml), stirred, filtered and washed with hexane(100ml), distilled off the hexane layer under vacuum to yield (6Z, 9Z)-dodeca-6,9-dienal (75 g), analysed by GC, with purity >82% and yield >75.7%.

Example 4: Synthesis of (3E, 8Z, 11Z)-tetradeca-3,8,11-trienoic acid
Charged DMF (800 ml) & Malonic acid (115 g) in RBF under nitrogen atmosphere at RT, and then charged piperidine acetate (1.7 g) followed by addition of (6Z, 9Z)-dodeca-6,9-dienal (100 g), stirred, raised the temperature of the mixture to 100°C, stirred the mixture for 4 hrs, cooled the mixture and added water(1.6Lt) and MTBE (200 ml), stirred and separated both organic and aqueous layers, extracted aqueous layer with MTBE(200ml), dried and distilled off the organic layer under vacuum to yield (3E, 8Z, 11Z)-tetradeca-3,8,11-trienoic acid (85 g), analysed by GC, with purity >80% and yield >85%.

Example 5: Synthesis of (3E, 8Z, 11Z)-tetradeca-3,8,11-trienol
Charged Red-AL (370 g) in RBF under nitrogen atmosphere at RT, charged THF (500 ml), stirred, cooled to 10 °C, slowly added(3E, 8Z, 11Z)-tetradeca-3,8,11-trienoic acid (100 g) at 10°-15°C, stirred, added HCl solution (400 ml) and MTBE (200 ml), stirred and separated the MTBE layer, dried the MTBE layer with sodium sulphate(20gm). Filtered the sodium sulphate and distilled off the MTBE layer under vacuum to yield (3E, 8Z, 11Z)-tetradeca-3,8,11-trienol (60 g), analysed by GC, with isomeric purity >75.0% and yield >60%.

Example 6: Synthesis of (E, Z, Z)- tetradeca-3,8,11-trienyl acetate
Charged acetic acid (300 ml) under nitrogen atmosphere at RT and added (3E, 8Z, 11Z)-tetradeca-3,8,11-trienol (100 g) and cooled to 10°C, slowly added acetyl chloride (120 ml), stirred and added water(900ml) and MTBE (400 ml), stirred, and separated both organic and aqueous layers, extracted MTBE, dried, and distilled off organic layer under vacuum to yield (E, Z, Z)- tetradeca-3,8,11-trienyl acetate (90 g), analysed by GC with isomeric purity >75.0% and yield >85.0%.