Field of the invention
The present invention relates to an improved process for the preparation of (E)-ll-hexadecen-1-ol (STR-I) and (E)-ll-hexadecenyl acetate (STR-II). More particularly, the present invention relates to a process for the preparation of (E)-ll-hexadecen-l-ol (STR-I) and (E)-l 1-hexadecenyl acetate (STR-II) in multi-gram batch scale against the reported milligram batch size.
Background of the invention
A blend of (E)-ll-hexadecen-l-ol (STR-I) and (E)-l 1-hexadecenyl acetate (STR-II), respectively in 1:100 blend ratio, constitute the female released sex pheromone system of brinjal shoot and fruit borer (Leucinodes orbonalis) insect pest. Sex pheromone mediated mass trapping of brinjal shoot and fruit borer is one of the latest Integrated Pest Management (IPM) tools developed to protect the brinjal crop from economic loses caused by brinjal shoot and fruit borer insect pest. Improved process technology for large-scale preparation of STR-I and STR-II involving two new chemical transformations, is of commercial significance and import substitution.
Reference may be made to 'Convenient synthesis of (E)-l 1-hexadecenyl acetate, the female sex pheromone of the brinjal moth Leucinodes orbonalis Guenee' (Neelakanthi E Gunawardena, J. Natn. Sci. Coun. Sri Lanka, 1992, 20(1): 71-80), where in synthesis of STR-I and STR-II was reported for the first time. The draw backs are (i) overall yield of the synthesis is 27% (ii) synthetic process is reported for milli-gram scale preparation of the final products and the process technology is not optimized for large scale production of the pheromone components (iii) one of the synthetic steps involves highly sensitive and expensive reagents and solvents viz., n-butyl lithium and HMPA (iv) another transformation in the synthetic sequence i.e. Trans-reduction of triple bond by Birch reduction involves handling of high volumes of liquid ammonia, expensive ether solvents and longer reaction times (16-18 hours) (v) finally trans-reduction of triple bond using Na/liquid ammonia could not be reproduced for large scale preparation of STR-I and STR-II by following the reported experimental protocols.
Reference may also be made to 'Synthesis of insect sex pheromones' (Clive A. Henrick, Tetrahedron, 1977, 33: 1845-1889), where in synthesis of long chain trans- alkenes

(C10-C16) alcohols, acetates and aldehydes were reported using excess of lithium amide in tetrahydrofuran or n-butyl lithium in hexane for alkylation reactions and sodium in large quantities of liquid ammonia and ether or lithium aluminium hydride in diglyme for selective trans reduction of triple bonds. Again drawbacks being-(i) non-reproducibility of the reaction conditions with high reaction yields and product purities, (ii) solvents and reagents are expensive and sensitive and hence, are not suitable for large scale preparation of STR-I and STR-II.
Reference may also be made to 'Monitoring Pickleworm (Lepidoptera : Pyralidae) moths with pheromone baited traps (D Michael Jackson et al., J Economic Entomology, 91(4), 950-963, 1998) where in synthesis of STR-I and STR-II was reported starting from another pheromone compound viz., (Z)-l 1-hexadecenyl acetate. The drawbacks are (i) this is not a straightforward direct process for obtaining STR-I and STR-II as it involves a three stage chemical inversion of the Cll-double bond configuration from cis-(Z) to trans-(E), which makes the process lengthy, (ii) products obtained by this method will always have cis-(Z)-isomer along with the required trans-(E)-isomer thereby bringing down the isomeric purity of the required compounds, (iii) generally purification of compounds for removal of the isomeric contamination by physical separation methods is very difficult and ineffective, which makes the process less suitable for up-scaling purposes.
Objectives of the invention
The main objective of the present invention is to provide an improved process for the preparation of (E)-l 1-hexadecen-l-ol (STR-I) and (E)-l 1-hexadecenyl acetate (STR-II) which obviates the drawbacks as detailed above.
Another objective of the present invention is to provide an improved process for the preparation of (E)-l 1-hexadecen-l-ol (STR-I) and (E)-l 1-hexadecenyl acetate (STR-II) in multi-gram batch scale.
Yet another object of the present invention is to produce (E)-l 1-hexadecen-l-ol (STR-I) and (E)-l 1-hexadecenyl acetate (STR-II) with >95 % product and isomeric purities.
Yet another objective of the present invention is to replace some sensitive and expensive chemicals like butyl lithium-HMPA with less expensive reagents like lithium-liquid ammonia.

Yet another objective of the present invention is to find substitute chemical transformations for replacing longer reaction times of triple bond reduction to trans-double bond without compromising the reaction yield as well as product and isomeric purities.
In the drawing accompanying this specification (Scheme-1):
Figure I: represents (E)-11 -hexadecen-1 -ol (STR-I)
Figure II: represents (E)-l 1-hexadecenyl acetate (STR-II)
Figure III: represents 1,10-decandiol (STR-III)
Figure IV: represents 10-bronio-l-decanol (STR-IV)
Figure V: represents 10-bromo-l-(tetrahydropyran-2-yloxy)decane (STR-V)
Figure VI: represents 1-hexyne (STR-VI)
Figure VII: represents 10-(tetrahydropyran-2-yloxy)hexadeca-5-yne (STR-VII)
Figure VIII: represents (E)-10-(tetrahydropyran-2-yloxy)hexadeca-5-en (STR-VIII)
Summary of the invention
Accordingly the present invention provides an improved process for the preparation of (E)-11-hexadecen-l-ol (STR-I) and (E)-l 1-hexadecenyl acetate (STR-II), the said process comprising the steps of:
a) brominating 1,10-decanediol by reacting it with hydrobromic acid, in an organic
solvent, under reflux, for a period of 24-36 hrs with continuous azeotropic removal
water, separating the organic layer from the reaction mixture, followed by
washing with NaHCOs and water and drying it over NaiSO^ to obtain 10-bromo-
1-decanol (STR-IV),
b) reacting 10-bromo-l-decanol obtained in step (a) with 3,4-dihydropyran in an
organic solvent, in the presence of para toluene sulphonic acid , at a temperature of
20-40°C, for a period of 6-10 hrs, followed by vacuum distillation to obtain the 10-
bromo-1 -(tetrahydropyran-2-yloxy)decane,
c) coupling 10-bromo-l-(tetrahydropyran-2-yloxy)decane with 1-hexyne by using
lithium/liquid ammonia in an organic solvent, at a temperature in the range of -25
to -80°C, for a period of 10-12 hrs, under stirring to obtain the C-16 carbon chain
compound of 10-(tetrahydropyran-2-yloxy)hexadeca-5-yne (STR-VII) with a triple

bond at Cl 1, followed by stereospecific trans-reduction of the triple bond by using lithium and ethyl amine to obtain (E)-10-(tetrahydropyran-2-yloxy)hexadeca-5-en (STR-VIII),
d) deprotecting (E)-10-(tetrahydropyran-2-yloxy)hexadeca-5-en (STR-VIII) obtained
in step (c) by removing tatrahydropyranyl ether group in methanol and HC1, under
stirring, at a temperature of 25-40°C, for a period of 6-12 hrs to obtain the desired
(E)-ll-hexadecen-l-ol (STR-I),
e) acetylating the above said (E)-l 1-hexadecen-l-ol (STR-I) by reacting it with acetic
anhydride in pyridine, at a temperature of 20-40°C, for a period of 10-12 hrs to
obtain the desired (E)-l 1-hexadecenyl acetate (STR-II).
In an embodiment of the present invention the organic solvent used hi step (a) is selected from haptane and toluene.
In yet another embodiment the HBr used in step (a) is 48% HBr.
In yet another embodiment the molar ratio of 1,10-decandiol (STR-III) to HBr used hi step(a) is in the range of in 1:1.2 to 1:2.
In yet another embodiment the organic solvent used in step(b) is selected from dichloromethane and chloroform.
In yet another embodiment the molar ratio of 10-bromo-l-decanol to 3,4-dihydropyran used is in the range of 1:1.2 to 1:2.3.
In yet another embodiment the organic solvent used in step (c) is selected from. Tetrahydrofuran (THF) and diethyl ether.
In yet another embodiment the molar ratio of 10-bromo-l-(tetrahydropyran-2-yloxy)decane : 1-hexyne : lithium/liquid ammonia used is in the range of 1: 1.5 : 6 to 1 : 2 : 8.
In yet another embodiment the molar ratio of 10-(tetrahydropyran-2-yloxy) hexadeca-5-yne (STR-VII) to lithium taken in ethyl amine used is in the range of 1:1 to 1:5.
In yet another embodiment the temperature used in step (c ) is in the range of-40° to -70° C.
In yet another embodiment the molar ratio of (E)-l 1-hexadecen-l-ol (I) to acetic anhydride used in step (e) is in the range of 1: 1.1 to 1 : 1.5.
In yet another embodiment the purity of (E)-l 1-hexadecen-l-ol obtained is > 99.5%.

In yet another embodiment the purity of (E)-l 1-hexadecenyl acetate obtained is in the range of 96-98%.
The following examples are given by the way of illustration and therefore should not be construed to limit the scope of the invention.
Example 1.
1,10-Decanediol (STR-III, lOOg) taken in heptane was refluxed with 48% hydrobromic acid (85ml) for 24 hours with continuous azeotropic removal of water using a Dean-Stark apparatus. The organic layer was separated from the aqueous layer and washed with NaHCO3 , water, dried over anhydrous Na2SC»4 and the solvent was evaporated under vacuum (100 mm/ 45 ° C). Purification of the obtained residue by vacuum distillation (130°C / 0.5-1.0 mmHg) afforded 10-bromo-l-decanol (STR-IV, 85g, 65%). Structure confirmation was done by NMR, MS and purity was assessed to be 99 % by GC.
10-bromo-l-(tetrahydropyran-2-yloxy)decane (STR-V, lOOg, 90% ) was prepared from 10-bromo-l-decanol (STR-IV, 82g) by treating with 3,4-dihydropyran (45ml) in dichloromethane or chloroform and paratoluenesulphonicacid (PTSA) at room temperature (20-40 ° C) for 6 hours. Usual work-up followed by purification by vacuum distillation (125 ° C/O.lmm Hg) yielded the product with 99.6 % purity as assessed by GC and structure confirmation was done by NMR & MS.
Lithium metal mediated coupling of 10-bromo-l-(tetrahydropyran-2-yloxy)decane (STR-V, 60.0g) with 1-hexyne (STR-VI, 22.5g) in a mixture of liquid ammonia (800 ml) and THF (100 ml) at -78° C over 10 hours stirring, afforded the required sixteen carbon chain compound, 10-(tetrahydropyran-2-yloxy)hexadeca-5-yne, with a triple bond at C-l 1. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with NtiiCl and the resultant organic reaction mixture was extracted with ether. The organic layer was washed with water, dried over Na2SC»4 and concentrated on the rotaevaporator. The product 60.0 g (>90% purity on GC), was carried over to the next step without any purification. However, when the coupling reaction was carried out on unprotected 11 -hexadecyne-1 -ol compound, reaction did not give the required coupling product.

10-(tetrahydropyran-2-yloxy)hexadeca-5-yne (60.0 g) was subjected to trans reduction under controlled conditions using lithium (6g) and ethyl amine (500ml) at -78° C over 2 hours duration. Reaction was- carefully monitored by TLC/GC and terminated with NUtCl when all the starting material disappeared. Obtained crude (E)-10-(tetrahydropyran-2-yloxy) hexadeca-5-en (58.0g) was taken to deprotection step without any purification. However, structure confirmation for the product was done by NMR and GC for isomeric purity
Tetrahydropyran ether protection group from crude (E)-10-(tetrahydropyran-2-yloxy)hexadeca-5-en (58. Og) was removed by stirring the compound in methanol (120 ml) and concentrated Hydrochloric acid for 6 hours at 25-40 ° C. Usual work afforded 43.0 g of crude (E)-ll-Hexadecen-l-ol (II) having >99.5% purity (GC) and was taken to the final acetylation step without purification to obtain the other pheromone component.
(E)-ll-Hexadecen-l-ol (40.0 g) was acetylated with freshly distilled acetic anhydride (30ml) in pyridine at room temperature (20-40 ° C) over 10-12 hours period. Crude product obtained after usual work up was purified by short column vacuum distillation (110-113 ° C/0.05 mmHg) to afford (E)-ll-hexadecenyl acetate (STR-II, 34.0g, 90%) with >97.5% product purity (GC). Structure confirmation of the final products was done by NMR. IR and MS and overall synthetic yield was 40 %.
Confirmation for the trans-(E)-disposition about the double between C11-C12 was arrived at by comparing the NMR & IR spectrum of (E)-ll-hexadecenyl acetate with the NMR and IR of authentic (Z)-ll-hexadecenyl acetate. Coupling constants (J Hz values) for the double protons, in the NMR are expected to be different for trans (E)- and cis(Z)- isomers; J-value for cis (Z)-isomer should be more than that of trans(E)-isomer. NMR spectrum of (E)-11-hexadecenyl acetate (STR-II), indicated coupling for the olefinic protons at PPM: 5.331, 5.340, 5.349 with J = 3.6Hz. On the other the cis-isomer ie. (Z)-ll-hexadecenyl acetate indicated coupling of olefinic protons at PPM: 5.3001, 5.3165, 5.3323 with J = 4.8 Hz. IR Spectra of both (E)- and (Z)-ll-hexadedcenyl acetates revealed distinct differences in the finger print region (1800-600 cm"1). Non-superimposability of the finger print region and presence of a strong bending frequency of the double bond hydrogen at 967.7 cm"' in the trans-(E)- isomer and its absence in the cis-(Z)-isomer is the final proof for the isomeric specificity of the (E)-l 1-hexadecenyl systems. Notable improvement in the present invention

with respect to the prior art is, the replacement of highly sensitive & expensive reagent and solvent with less cumbersome reagents in one of the most important chemical transformations in the synthetic route, for the coupling of C-6 unit with C-10 to obtain the basic C-16 carbon chain skeleton and subsequent reduction of the triple bond to trans double bond.
The main advantages of the present invention are:
1. Improved process for the large-scale preparation of (E)-ll-hexadecen-l-ol (STR-I) and
(E)-l 1-hexadecenyl acetate (STR-II) with 95 % product and 99.5% isomeric purity.
2. Higher overall synthetic yield (40 %) of (E)-ll-hexadecen-l-ol (STR-I) and (E)-ll-
hexadecenyl acetate (STR-II) has been obtained.
3. Replacement of some sensitive and expensive chemicals like n-butyl lithium-HMPA,
lithium amide-tetrahydrofuran and lithium aluminium hydride-diglyme, with less
expensive reagents like lithium-liquid ammonia.
4. The trans reduction of 10-(tetrahydropyran-2-yloxy)hexadeca-5-yne (STR-VII) to obtain
(E)-ll-hexadecen-l-ol (STR-I) by lithium / ethyl amine method is reported for the first
time with drastic reduction in the reaction time and the reaction conditions are suitable for
scale - up process as ethyl amine is easier to handle compared to liquid ammonia and
ether solvents.
5. Reduction of triple bond to trans - double bond using lithium / ethyl amine is reported for
the first time on a C-16 carbon chain compound.
6. Easy work-up procedures while eliminating purification steps by vacuum distillations, for
three out of six chemical transformations, with out compromising the product as well as
isomeric purities.

We claim
1. An improved process for the preparation of (E)-ll-hexadecen-l-ol (STR-I) and (E)-ll-
hexadecenyl acetate (STR-H), the said process comprising the steps of:
a) brominating 1,10-decanediol by reacting it with hydrobromic acid, in an organic
solvent, under reflux, for a period of 24-36 hrs with continuous azeotropic removal
water, separating the organic layer from the reaction mixture, followed by
washing with NaHCOs and water and drying it over Na2SC4, to obtain 10-bromo-
l-decanol(STR-IV),
b) reacting 10-bromo-l-decanol obtained in step (a) with 3,4-dihydropyran in an
organic solvent, in the presence of para toluene sulphonic acid , at a temperature of
20-40°C, for a period of 6-10 hrs, followed by vacuum distillation to obtain the 10-
bromo-1 -(tetrahydropyran-2-yloxy)decane,

c) coupling 10-bromo-l-(tetrahydropyran-2-yloxy)decane with 1-hexyne by using
lithium/liquid ammonia in an organic solvent, at a temperature in the range of -25
to -80°C, for a period of 10-12 hrs, under stirring to obtain the C-16 carbon chain
compound of 10-(tetrahydropyran-2-yloxy)hexadeca-5-yne (STR-VII) with a triple
bond at Cl 1, followed by stereo specific trans-reduction of the triple bond by using
lithium and ethyl amine to obtain (E)-10-(tetrahydropyran-2-yloxy)hexadeca-5-en
(STR-VIII),
d) deprotecting (E)-10-(tetrahydropyran-2-yloxy)hexadeca-5-en (STR-VIII) obtained
in step (c) by removing tatrahydropyranyl ether group in methanol and HC1, under
stirring, at a temperature of 25-40°C, for a period of 6-12 hrs to obtain the desired
(E)-ll-hexadecen-l-ol (STR-I),
e) acetylating the above said (E)-l 1-hexadecen-l-ol (STR-I) by reacting it with acetic
anhydride in pyridine, at a temperature of 20-40°C, for a period of 10-12 hrs to
obtain the desired (E)-l 1-hexadecenyl acetate (STR-II).

2. An improved process as claimed in claim 1 wherein the organic solvent used in step (a) is
selected from haptane and toluene.
3. An improved process as claimed in claim 1 wherein the HBr used in step (a) is 48% HBr.
4. An improved process as claimed in claim 1 wherein the molar ratio of 1,10-decandiol
(STR-III) to HBr used in step(a) is in the range of in 1:1.2 to 1:2.

5. An improved process as claimed in claim 1 wherein the organic solvent used in step(b) is
selected from dichloromethane and chloroform.
6. An improved process as claimed in claim 1 wherein the molar ratio of 10-bromo-l-
decanol to 3,4-dihydropyran used is in the range of hi.2 to 1:2.3.
7. An improved process as claimed in claim 1 wherein the organic solvent used in step (c) is
selected from, Tetrahydrofuran (THF) and diethyl ether.
8. An improved process as claimed in claim 1, wherein the molar ratio of 10-bromo-l-
(tetrahydropyran-2-yloxy)decane : 1 -hexyne : lithium/liquid ammonia used is in the range
ofl: 1.5 : 6 to 1 : 2 : 8.
9. An improved process as claimed in claim 1, wherein the molar ratio of 10-
(tetrahydropyran-2-yloxy) hexadeca-5-yne (STR-VII) to lithium taken in ethyl amine used
is in the range of 1:1 to 1:5.
10. An improved process as claimed in claim 1, wherein the temperature used in step (c ) is in
the range of ^0°to-70° C.
11. An improved process as claimed in claim 1, wherein the molar ratio of (E)-l 1-hexadecen-
l-ol (I) to acetic anhydride used in step (e) is in the range of 1: 1.1 to 1 : 1.5.
12. An improved process as claimed in claim 1, wherein the purity of (E)-ll-hexadecen-l-ol
obtained is 99.5%.
13. An improved process as claimed in claim 1, wherein the purity of (E)-ll-hexadecenyl
acetate obtained is in the range of 96-98%.
14. An improved process for the preparation of (E)-ll-hexadecen-l-ol (STR-I) and (E)-ll-
hexadecenyl acetate (STR-II), substantially as herein described with reference to the
examples and drawings accompanying this specification.