Claims:1. A novel synthetic process for preparation of a sex attractant pheromone, (E, Z)-7,9-dodecadien-1-yl acetate using a novel intermediate, 9-Tert-butoxy-1,1-diethoxynon-2-yne comprising the steps of:
a. reacting 6-bromohexan-1-ol with 2-methyl prop-1-ene in presence of sulphuric acid to give 1-Tert-butoxy 6-bromohexane,
b. coupling the 1-Tert-butoxy 6-bromohexane with 3,3-diethoxy prop-1-yne in presence of sodium hydride to give 9-Tert-butoxy-1,1-diethoxynon-2-yne,
c. reducing the 9-Tert-butoxy-1,1-diethoxynon-2-yne in presence of H2, Nickle acetate and sodium borohydride to give (E)-9-tert-butoxynon-2-enal,
d. propylating the (E)-9-tert-butoxynon-2-enal using propyl triphenyl phosphonium bromide in presence of Potassium tertiary butoxide to give (3Z, 5E)-12-tert-butoxy dodeca-3, 5- diene, and
e. acetylating (3Z, 5E)-12-tert-butoxydodeca-3,5-diene in presence of acetylating agent and Ferric chloride to give (E, Z)-7,9-dodecadien-1-yl acetate.

2. The synthetic process for preparation of (E, Z)-7,9-dodecadien-1-yl acetate as claimed in claim 1, wherein the preparation of a novel intermediate 9-Tert-butoxy-1,1-diethoxynon-2-yne for the synthesis of (E,Z)–7,9–dodecadien-1-yl acetate is carried out by coupling of 1-Tert-butoxy 6-bromohexane with 3,3-diethoxy prop-1-yne in presence of sodium hydride, in toluene as a solvent.

3. The synthetic process for preparation of (E, Z)-7,9-dodecadien-1-yl acetate as claimed in claim 1 or claim 2, wherein the coupling reaction in step b) is carried out at a temperature of 110°C.

4. A process for preparation of (E,Z) 7,9–dodecadien-1-yl acetate, from 9-Tert-butoxy-1,1-diethoxynon-2-yne, which process comprises ;
a) reducing the 9-Tert-butoxy-1, 1-diethoxynon-2-yne in presence of H2 using Nickle acetate and sodium borohydride to give (E)-9-tert-butoxynon-2-enal,
b) propylating the (E)-9-tert-butoxynon-2-enal using propyl triphenyl phosphonium bromide in presence of Potassium tertiary butoxide to give (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene, and
c) acetylating the (3Z, 5E)-12-tert-butoxydodeca-3,5-diene in presence of acetic anhydride and Ferric chloride to give (E,Z)-7,9-dodecadien-1-yl acetate.

5. The synthetic process for preparation of (E, Z)-7,9-dodecadien-1-yl acetate as claimed in claim 1 or claim 4, wherein the acylating agent is selected from the group consisting of acetyl halides, acetic anhydride and alkyl acetates such as acetic anhydride.

6. The synthetic process for preparation of (E, Z)-7,9-dodecadien-1-yl acetate as claimed in claim 1 or claim 4, wherein the acetylation reaction in step e) is carried out at room temperature.

7. The synthetic process for preparation of (E, Z)-7,9-dodecadien-1-yl acetate as claimed in claim 1, wherein the synthesis of (E,Z)–7,9–dodecadien-1-yl acetate proceeds via novel intermediates viz., 9-Tert-butoxy-1,1-diethoxynon-2-yne;(E)-9-tert-butoxynon-2-enal; and (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene.

8. A novel intermediate compound, 9-Tert-butoxy-1,1-diethoxynon-2-yne, having the following structure.

9. A novel intermediate compound, (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene, having the following formula,

10. A novel intermediate compound, (E)-9-tert-butoxynon-2-enal, having the following formula,

11. The synthetic process for preparation of (E, Z)-7,9-dodecadien-1-yl acetate as claimed in claim 1, wherein the (E,Z)-7,9-dodecadien-1-yl acetate is sex attractant insect pheromone of Lobesia botrana.
, Description:Technical Field of the Invention
The present invention relates to a novel process for the preparation of (E,Z)-7,9-dodecadien-1-yl acetate with excellent yields using novel intermediates, viz., 9-Tert-butoxy-1,1-diethoxynon-2-yne (E)-9-tert-butoxynon-2-enal and (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene. The present invention further relates to novel intermediate compounds viz., 9-Tert-butoxy-1,1-diethoxynon-2-yne (E)-9-tert-butoxynon-2-enal and (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene useful for the synthesis of (E,Z)-7,9-dodecadien-1-yl acetate with excellent yields and purity.

Background of the Invention
Pheromones are very promising for the eco-friendly protection of a wide range of crops such as grape, banana, apple, etc. Contrary to classical pesticides, pheromones are specific to one species of pest; however, other insects and especially pollinator insects, are unaffected. Furthermore, pheromones are biodegradable and have no effect upon human health. Those properties make pheromones ideal candidates for modern eco-friendly crop protection. In our continued effort to develop efficient and large-scale procedures, we became interested in developing a new industrial access to the sex pheromone of grapevine moth Lobesia botrana.
The major sex pheromone of the female grape vine moth has been identified as trans-7, cis-9-dodecadienyl acetate by Roelofs et al, Mitteilunger Der Schweizerischen Entomologoschen Gesellschaft, Band 46, p. 71-73 (1973).
The (E,Z)–7,9 dodecadienyl–1–acetate compound can be used as an attractant for monitoring, through selective trapping, thereby controlling the population of Lobesia botrana. Population counts thus obtained are used in determining the frequency and quantity of spray of insecticide or another insect control agent. The (E,Z)–7,9 dodecadienyl–1–acetate compound can also be used for the direct control of Lobesia botrana by mass trapping or mating disruption (confusion).

Since, 7,9–dodecadien-1-yl acetate as molecule carries 2 double bonds and thus has 4 possible geometric isomers recalled in the following are recovered in the form of a mixture of two isomers in the following ratio:
Z,Z–7,9– dodecadien-1-yl acetate: <1%
Z,E–7,9– dodecadien-1-yl acetate: <1%
E,Z–7,9– dodecadien-1-yl acetate: 78%
E,E–7,9– dodecadien-1-yl acetate: 21%
To effectively respond to the economic problem posed by the synthesis of this pheromone, the following items should be considered: only the (E, Z) isomer is active. It is therefore essential to be able to prepare the (E, Z) isomer predominantly. Among all these isomers, the thermodynamically most stable isomer is the (E,E) isomer. It has been shown that when (E,Z)–7,9 dodecadienyl–1–acetate is subjected to light exposure or free radical generators, the molecule rearranges into a mixture of these isomers in the proportions of 14/70/14/2 which reflect the equilibrium between these different isomers. (Ideses & al. Journal of Chemical Ecology, Vol. 8, No. 1, 1982, p. 973). It should nevertheless be noted that the three isomers other than (E,Z) are known as not hindering the attractiveness of the pheromone (Ideses & al. Journal of Chemical Ecology, Vol. 8, No. 1, 1982, p. 195). The (E,E) isomer is the most stable isomer and is the main inactive impurity in all known synthesis.
In order to determine the economic efficiency of a synthesis, it is necessary to consider not only the overall yield of the synthesis which reflects savings in terms of raw material, but also the number of synthetic steps, which governs the cost of implementing said synthesis. By synthetic step, the applicant means any chemistry operation leading to isolating an intermediate. The fewer the number of steps, the more economical the synthesis pathway.

In US3954818 the authors describe a synthesis in more than 9 steps with an unspecified yield and a pheromone purity close to 99%. However, it is necessary to note that this method is difficult to envisage industrially due to the reactants used (lithium wire, butyl lithium, disiamylborane, etc.). The key intermediate of this synthesis is methyl non–4–en–6–ynoate.
In EP3845108, the method consists of 8 synthetic steps with an overall yield of 30% from the fourth step and a final purity of only 70% is disclosed. The method is characterized by an iminophosphonate intermediate and the use of industrially unusable reagents (mercury oxide).
In EP0241335, the authors describe a method in 5 synthetic steps with an overall yield of approximately 10%. The purity of the pheromone is at least 75%. The key intermediate is a 1–halo–(E,Z)–7,9–dodecadiene. This expensive method requires equipment for hydrogenation under pressure. It also uses a Wittig reaction that generates large quantities of triphenyl phosphine oxide and which is expensive to eliminate.

Patent US4912253 describes the synthesis of the European grapevine moth pheromone by a coupling catalyzed with copper between a magnesium (chloropentanol derivative) and (E,Z)–2,4–heptadienyl acetate. The preparation of the acetate derivative is difficult, however, and this access pathway, while convergent remains expensive.
In FR2609868, the authors report two synthetic methods for a precursor of a pheromone analog (Z–9–dodecen–9–ynol) via a method characterized in that the key intermediate is an alkynol protected by a tetrahydropyranyl function. The yields are similar to those of EP0241335.

In US 7932410, a general method for forming dienes conjugated to a long fatty chain is described, and is characterized by the use of esters with a double bond in the alpha position, such as 1–penten–3–yl isobutyrate which is coupled to a Grignard reagent via a catalyst based on copper complexes. This method is not applicable industrially to the synthesis of (E,Z)–7,9 dodecadien-1-yl acetate since the 1,3–hept–dien–3–yl isobutyrate necessary for this synthesis is very difficult to access industrially.
The conventional methodologies known in the literature for the synthesis of European grapevine moth pheromone are therefore involve acetylene intermediates (coupling via acetylides), coupling reactions between aldehyde and phosphorus ylides called Wittig reactions.
Thus, there is a need in the art for economical and an industrially practicable synthesis of the original pheromone, i.e., (E,Z)-7,9-dodecadien-1-yl acetate.
Accordingly, the objective of the present invention is to provide a stereoselective synthesis for preparation of a sex attractant pheromone, (E,Z)-7,9-dodecadien-1-yl acetate using a novel intermediate, 9-Tert-butoxy1,1-diethoxynon-2-yne; which uses readily available starting material and is economical to practice on industrial scale.

Brief Summary of the Invention
This invention discloses synthesis of the sex pheromone (7E, 9Z)-7,9-dodecadien-1-yl acetate of the grape vine moth Lobesia botrana and novel intermediates thereof.

According to a particular embodiment, the invention concerns with process for the synthesis of (7E, 9Z)-7,9-dodecadien-1-yl acetate with excellent yields and purity with greater stereo chemistry involving 9-Tert-butoxy-1,1-diethoxynon-2-yne; (E)-9-tert-butoxynon-2-enal; and (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene, as novel intermediates.

Detailed Description of the invention
In accordance with the above objective, the present invention provides a novel process for preparation of a sex attractant pheromone (E,Z)-7,9-dodecadien-1-yl acetate using a novel intermediate, 9-Tert-butoxy1,1-diethoxynon-2-yne, which process comprising the steps of:
a. reacting 6-bromohexan-1-ol with 2-methyl prop-1-ene in presence of sulphuric acid to give 1-Tert-butoxy 6-bromohexane,
b. coupling the 1-Tert-butoxy 6-bromohexane with 3,3-diethoxy prop-1-yne in presence of sodium hydride to give 9-Tert-butoxy-1,1-diethoxynon-2-yne,
c. reducing the 9-Tert-butoxy-1, 1-diethoxynon-2-yne in presence of H2 using a reducing agent, to give (E)-9-tert-butoxynon-2-enal,
d. propylating the (E)-9-tert-butoxynon-2-enal using propyl triphenyl phosphonium bromide in presence of Potassium tertiary butoxide to give (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene, and
e. acetylating the (3Z, 5E)-12-tert-butoxydodeca-3,5-diene in presence of acetylating agent and Ferric chloride to give (E,Z)-7,9-dodecadien-1-yl acetate.

In an embodiment, the coupling reaction in step b) may be carried out in toluene at reflux temperature.
In a preferred embodiment, the acetylating agent is selected from the group consisting of acetyl halides, mixture of acetic acid and acetic anhydride or acetic anhydride. Acetylation is a reaction that introduces an acetyl functional group into an organic compound. The acetylation reaction may be carried out at room temperature.

According to the present invention, the synthesis of (E,Z)-7,9-dodecadien-1-yl acetate involves five steps, as discussed above. First of all, the synthesis of 1-Tert-butoxy-6-bromohexane includes purging of isobutylene gas into the reaction mass consisting of 6-Bromo hexanol in sulphuric acid. After the competition of the reaction (by TLC), the reaction mixture is quenched in potassium hydroxide solution to yield 1-Tert-butoxy-6-bromohexane with an yield of more than 80% and purity of more than 95%.

1-Tert-butoxy-6-bromohexane thus obtained is reacted with 3,3-diethoxyprop-1-yne in presence of sodium hydride in toluene under nitrogen atmosphere. The reaction mass is refluxed at 110°C for 24 hrs and cooled to 20-25 °C, quenched the mass with ammonium chloride solution. The layers are separated and extracted the aqueous layer with toluene and distilled off the combined organic layer under vacuum to yield 9-Ter-butoxy-1,1-diethoxynon-2-yne with an yield of more than 80% and purity of more than 95%.

9-Ter-butoxy-1,1-diethoxynon-2-yne thus obtained in EDA is subjected to reduction with sodium borohydride, nickel acetate in methanol at room temperature under hydrogen gas pressure at 5kg/cm2 into the reaction mass under stirring. After completion of the reaction, the mass was filtered, washed with Methanol, distilled off the methanol layer under vacuum, and charged water and Dichloromethane (DCM) and separated the layers. To the DCM layer, added HCl and water, stirred, washed the DCM layer with sodium bicarbonate solution, adjusted pH to 6.5 to7.0, filtered, dried, and distilled off the DCM to yield 9E-tert-butoxynon-2-enal with an yield and purity of more than 90%.

Synthesis of (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene includes the reaction of 9E-tert-butoxynon-2-enal with potassium tertiary butoxide in THF in presence of propyl triphenyl phosphonium bromide under N2 atmosphere, under stirring at -10°C. After the completion of reaction(by TLC), the THF and aqueous layers were separated, dried and distilled off the THF layer under vacuum, to yield (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene with an yield of more than 72% and purity of more than 84 %.

Finally the synthesis of (E,Z) 7,9–dodecadien-1-yl acetate is conducted by acylating the (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene with acetic anhydride in presence of ferric chloride by maintaining temperature at 70 - 75°C for 2 to 3 hrs, under stirring. After the completion of reaction, the reaction mass is cooled, charged water and Hexane and separated both layers. The organic phase is recovered and then concentrated under vacuum to recover (E,Z) 7,9–dodecadien-1-yl acetate with an yield of 85% and a purity of more than 84 % purity

However, depending on the purity required, the (E,Z) 7,9–dodecadien-1-yl acetate can be subjected to urea purification..

In another embodiment, the present invention encompasses novel intermediate compounds viz., 9-Tert-butoxy-1,1-diethoxynon-2-yne; (E)-9-tert-butoxynon-2-enal and (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene.

An embodiment of the invention also involves a preparation method for (E,Z) 7,9–dodecadien-1-yl acetate, from 9-Tert-butoxy-1,1-diethoxynon-2-yne, which method comprises;
a) reducing the 9-Tert-butoxy-1, 1-diethoxynon-2-yne in presence of H2 using Nickel acetate and sodium borohydride to give (E)-9-tert-butoxynon-2-enal,
b) propylating the (E)-9-tert-butoxynon-2-enal using propyl triphenyl phosphonium bromide in presence of Potassium tertiary butoxide to give (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene, and
c) acetylating the (3Z, 5E)-12-tert-butoxydodeca-3,5-diene in presence of acetic anhydride and Ferric chloride to give (E,Z)-7,9-dodecadien-1-yl acetate.

In another embodiment, the invention encompasses a novel intermediate compound, 9-Tert-butoxy-1,1-diethoxynon-2-yne having the following structure.

In yet another embodiment, the invention encompasses a novel intermediate compound, (E)-9-tert-butoxynon-2-enal, having the following formula.

In a further another embodiment, the invention encompasses a novel intermediate compound, (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene, having the following formula.

The aforementioned intermediates are hither to unreported in the prior art documents and not described in any literature prior to the current invention.

The synthetic method reported in the present invention via aforementioned novel intermediates enables the synthesis of (E,Z) 7,9–dodecadien-1-yl acetate using less number of synthetic steps, with a greater stereo selectivity of 84% and with an yield of 85% or more and with a purity of more than 84 % purity and cost effective.

Thus the claimed process is industrially scalable as it not only provides the desired isomer with high stereo selectivity, yield and purity over the processes reported in the prior art documents but also economically viable.

Although the molecular structure of the main component, (E,Z)-7,9-dodecadien-l-yl acetate (E7,Z9-12Ac), is not too complicated and in spite of the numerous synthetic routes described in the literature there has been to date no industrially practicable way of synthesizing it on a large scale. In order to avoid this problem, we looked for a suitable mimic.

The main component of the sexual pheromone of grape eudemis is (E, Z)-7,9-dodecadien-1-yl acetate. Whereas the product is isolated by evaporation of the solvents under partial vacuum. 7,9–dodecadien-1-yl acetate as molecule carries 2 double bonds and thus has 4 possible geometric isomers recalled in the following are recovered in the form of a mixture of two isomers in the following ratio:
Z,Z–7,9– dodecadien-1-yl acetate: <1%
Z,E–7,9– dodecadien-1-yl acetate: <1%
E,Z–7,9– dodecadien-1-yl acetate: 78%
E,E–7,9– dodecadien-1-yl acetate: 21%

Characterization by retention time using gas chromatography:

To respond effectively to the economic problem posed by the synthesis of this pheromone, the following elements should be considered, only the isomer (?, ?) is active. It is therefore essential to be able to prepare it for the most part. Of all these isomers, the thermodynamically most stable isomer is the (E, E) isomer. It is important to note that the 3 isomers other than (E, Z) are known as not impeding the attractiveness of the pheromone. Accordingly, the process disclosed in the present invention is aimed at improving the yields and purity of the (?, ?) isomer in the overall product yield.

In general, in the present invention, the proportions of the different isomers and the isomeric purities can be determined by any suitable quantitative technique by NMR, MASS, and in particular by GC.

Scheme 1, shown below illustrates the synthetic scheme of (E,Z) 7,9–dodecadien-1-yl acetate

Experimental details:
Example 1. Synthesis of 1-Tert-butoxy-6-bromohexane:
Charged 6-Bromo hexanol (100 g) into the RBF and added sulphuric acid (1.6 ml) and passed isobutylene gas (34 g). After the competition of the reaction quenched the reaction mixture in potassium hydroxide solution (30 ml in 300ml water), separated and dried the organic layer with sodium sulphate (20 g) to yield 1-Tert-butoxy-6-bromohexane (110 g), analyzed by GC, with Yield: 84.6% and > 95% purity.

Example 2. Synthesis of 9-Ter-butoxy-1, 1-diethoxynon-2-yne:
Charged Sodium hydride (62.5 g) into the RBF under nitrogen atmosphere and added Toluene (500 g) and slowly added 3,3-diethoxyprop-1-yne (100 g) to the mixture, stirred and slowly added 1-Tert-butoxy-6-bromohexane (185 g). Refluxed the mixture at 110°C for 24 hrs and cooled to 20-25 °C, quenched the mass with ammonium chloride water (500ml), separated both the aqueous and organic layers, and extracted the aqueous layer with toluene (100ml) and distilled off the organic layer under vacuum to yield 9-Ter-butoxy-1,1-diethoxynon-2-yne (180 g), analyzed by GC, with Yield: 81.4% and > 95% purity.

Example 3. Synthesis of 9E-tert-butoxynon-2-enal:
Charged Methanol (200 ml) and Nickel Acetate (13 g) in RBF under nitrogen atmosphere at RT, followed by addition of sodium borohydride (2.8 g) portion wise, and charged EDA (8.8 g) along with 9-Ter-butoxy1, 1-diethoxynon-2-yne (100 g) and flushed out with nitrogen, passed hydrogen gas pressure at 5kg/cm2 in to the reaction mass, stirred, filtered, washed with Methanol, distilled off the methanol layer under vacuum, and charged water and DCM (200 ml), separated aqueous and organic layers. To DCM layer added HCl (58 ml) and water (42 ml), stirred, washed the DCM layer with sodium bicarbonate solution, adjusted pH to 6.5 to7.0, dried, filtered and distilled off the DCM to yield 9E-tert-butoxynon-2-enal (70 g), analyzed by GC, with Yield: 93.0% and >90% purity.

Example 4. Synthesis of (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene:
Charged THF (450 ml) under N2 atmosphere and added propyl triphenyl phosphonium bromide (220 g), stirred, followed by the addition of potassium tertiary but oxide (65 g) in portion wise to the mixture, stirred and cooled the mixture to -10°C and slowly added 9E-tert-butoxynon-2-enal (100 g), stirred for 1 hr charged water and separated aqueous and THF layer, extracted the aqueous layer with hexane (400 ml), dried, filtered and distilled off the THF layer under vacuum, to yield (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene (80 g), analyzed by GC, with Yield: 72% and > 84 % purity.

Example 5. Synthesis of (E,Z) 7,9–dodecadien-1-yl acetate:
Charged acetic anhydride (165 ml) and ferric chloride (15 g) into the RBF and added (3Z, 5E)-12-tert-butoxydodeca-3, 5- diene (100 g) and maintained the reaction mass at temperature up to 70 - 75°C for -2 to 3 hrs, stirred, cooled, charged water and Hexane (400 ml) and separated both organic and aqueous layers, washed with water, dried, filtered and distilled off the hexane layer under vacuum to yield (E,Z) 7,9–dodecadien-1-yl acetate (80 g), analyzed by GC, with Yield: 85% and >84 % purity.