FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"PROCESS FOR PREPARATION OF ZUCAPSAICIN"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house. Charkop. Kandivali (West)
Mumbai -400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of (Z)-N-[(4-Hydroxy-3-methoxyphenyI) methyl]-8-methylnon-6-enamide of formula (I) or pharmaceutically acceptable salts thereof, commonly known as Zucapsaicin.
The process provides Zucapsaicin in higher yield and purity compared to the previously known processes.

BACKGROUND OF THE INVENTION
Zucapsaicin is cis-isomer of capsaicin. Capsaicin is in the class of medications called TRPV-1 (Transient Receptor Potential Vanilloid-1) channel agonist. Capsaicin and Zucapsaicin are known to be effective pain relievers that are believed to act on peripheral sensory neurons to deplete and prevent reaccumulation of neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP). Zucapsaicin is believed to be more potent as a depleter of neuropeptides from sensory nerves than capsaicin. Therapeutically capsaicin has been used as a topical analgesic. Zucapsaicin is useful in the treatment of painful, inflammatory or allergic disorders, and is effective in such disorders with significantly less of the localized burning and stinging associated with capsaicin's use. Zucapsaicin is prescribed for the treatment of osteoarthritis of the knee and other neuropathic pain.
J. Org. Chem. 1989, 54, 3477-3478 discloses process for preparation of Zucapsaicin by reacting (Z)-8-methyl-6-nonenoic acid of formula (II) with thionyl chloride to give acid

chloride of formula (III), followed by condensation with Vanillylamine hydrochloride of formula (IV), as shown below.

U.S. Patent No. 1,503,631 discloses process of preparation of capsaicin and other pungent compounds by the condensation of guaiacol and an aliphatic acid amide as shown below.

U.S. Patent Publication No. 2005/0085652, U.S. Patent Publication No. 2007/0293703 and Indian Patent No. 233904 disclose process of producing trans-capsaicin by alkylating 3-methyl butyne with halovaleric acid to get 8-methyl-6-nonynoic acid which is then reduced to trans-8-methyl-6-nonenoic acid; followed by activating the obtained product using thionyl chloride to get an acid halide and finally acylating the acid halide with 4-hydroxy-3-methoxybenzylamine hydrochloride to get trans-capsaicin as shown below.


Chinese Publication No. 101717346 discloses process of producing capsaicin homologs by reacting (E)-8-methyl-6-nonenoic acid with thionyl chloride while protecting nitrogen; the reaction product is then reacted with 4-hydroxy-3-methoxy-benzylamine hydrochloride to give capsaicin homologs.



Japanese Publication No. 51113835 discloses process of producing capsaicin and its homologs by electrolytic condensation of 5-methyl-3-hexenoic acid and mono-methyl glutarate in methanol in presence of Pt electrodes to give 8-methyl-6-nonenoic acid which is further converted to the an acid chloride and treated with Vanillylamine in mixture of Et20-C5H5N to form Capsaicin.
However, the above described processes suffer with following drawbacks:
(i) Use of thionylchloride. which is difficult to handle due to its nauseating pungent
odour, for preparation of acid chloride, (ii) High reaction temperature is required for formation of acid chloride; such formation
of acid chloride is moisture sensitive too.
Till date there is no commercially viable process for preparation of Zucapsaicin. Therefore there is a need for a simple, efficient and commercially viable process which does not use excess of reagents like thionylchloride, higher reaction temperature and gives higher yield.
The present invention provides such an alternative process for the preparation of Zucapsaicin.
SUMMARY OF THE INVENTION

The present invention provides an improved process for preparation of Zucapsaicin, represented by formula (1) or a pharmaceutically acceptable salt thereof

comprising,
a) reacting (Z)-8-methyl-6-nonenoic acid with ethyl chloroformate in organic solvent, in presence of base catalyst to form ethyl (6Z)-8-methylnon-6-enoyl carbonate,
b) reacting ethyl (6Z)-8-methylnon-6-enoyl carbonate with vanillylamine or an acid addition salt thereof, in organic solvent to get zucapsaicin
c) optionally, purifying zucapsaicin obtained in step b.
In step a), (Z)-8-methyl-6-nonenoic acid is reacted with ethyl chloroformate in presence of a base catalyst to give ethyl (6Z)-8-methylnon-6-enoyl carbonate.
Ethyl (6Z)-8-methylnon-6-enoyl carbonate obtained in step a) is reacted with vanillylamine or acid addition salt thereof, in presence of organic solvent to give zucapsaicin which can be further purified by recrystallization to get pure zucapsaicin.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for preparation of Zucapsaicin, represented by formula (J) or a pharmaceutically acceptable salt thereof


comprising,
a) reacting (Z)-8-methyl-6-nonenoic acid of formula (II) with ethyl chloroformate of formula (III) in organic solvent, in presence of base catalyst to form ethyl (6Z)-8-methylnon-6-enoyl carbonate of formula (IV)
b) reacting ethyl (6Z)-8-methylnon-6-enoyl carbonate with vanillylamine of formula (V) or an acid addition salt thereof, in organic solvent to get zucapsaicin
c) optionally, purifying zucapsaicin obtained in step b).

In step a), ethyl (6Z)-8-methylnon-6-enoyl carbonate is prepared by reacting (Z)-8-methyl-6-nonenoic acid with ethyl chloroformate in suitable organic solvent, in presence of base catalyst.
In one of the embodiment, suitable organic solvent can be selected from the group consisting of dimethylformamide, dimethylacetamide, N-methylpyrrolidene, dimethylsulfoxide, tetrahydrofuran, toluene, benzene, ethyl acetate, dichloromethane and mixture thereof. More preferably the organic solvent is ethyl acetate.

In another embodiment, the base catalyst is selected from the group consisting of triethylamine, isopropyl ethyl amine, pyridine, lutidine and mixture thereof. More preferably the base catalyst is triethylamine.
In one of the embodiment, the molar ratio of triethylamine to (Z)-8-methyl-6-nonenoic acid is in the range from 1 to 5, more preferably in the range from 2 to 3.
In one of the embodiment, the molar ratio of ethylchloroformate to (Z)-8-methyl-6-nonenoic acid is in the range of 0.8 to 2, more preferably in the range of 0.9 to 1.2.
In one of the embodiment, the reaction temperature for the reaction between (Z)-8-methyI-6-nonenoic acid and ethyl chloroformate is about 0°C to about 20°C. More preferably the reaction temperature is about 0°C to about 5°C. The reaction is completed within 2 to 4 hours.
Ethyl (6Z)-8-methylnon-6-enoyl carbonate obtained after step a), can be isolated and purified or can be used directly without purification for the next step.
In step b), ethyl (6Z)-8-methylnon-6-enoyl carbonate is reacted with Vanillylamine or an acid addition salt thereof in presence of suitable organic solvent to give zucapsaicin.
In one of the embodiment, suitable organic solvent can be selected from dimethyfformamide, dimethylacetamide, N-methylpyrrolidene, dimethylsulfoxide, tetrahydrofuran, toluene, benzene, ethyl acetate, dichloromethane and mixture thereof. More preferably the organic solvent is dimethylformamide.
In one of the embodiment, the molar ratio of Vanillylamine to (Z)-8-methyl-6-nonenoic acid is in the range of 1 to 3, more preferably in the range of 1.2 to 2.0.
In one of the embodiment, ethyl (6Z)-8-methylnon-6-enoyl carbonate is reacted with Vanillylamine or acid addition salt thereof, at about 0°C to about 20°C.

In another embodiment, the obtained zucapsaicin is extracted from the reaction mixture and isolated by recrystallization. More preferably zucapsaicin is extracted from the reaction mixture using ethyl acetate.
]n one of the embodiment, the solvent used for recrystallization is selected from the group consisting of ethyl acetate, dichloromethane, diethyl ether, isopropyl ether, methyl tert-butyl ether, toluene, hexane, heptanes, cyclohexane, petroleum ether or mixture thereof. More preferably the inert solvent is a mixture of isopropyl ether and n-hexane.
The following examples are intended to further illustrate the present invention and are not intended to limit the scope of this invention.
Example-1; Preparation of Zucapsaicin crude
Mixture of (Z)-8-methyl-6-nonenoic acid (110 g, 0.646 moles) and ethyl acetate (715 mL, 6.5 w/w) was stirred at room temperature, cooled to 0-5°C. To the above mixture was added triethylamine (163 g, 1.614 moles) and stirred for 10-15 min. Ethyl chloroformate (70 g, 0.645 moles) diluted with ethyl acetate (55 mL, 0.5w/w) was added within 1-2 h at 0-5°C to the above mixture and stirred for 2-2.5 h. Ethyl (6Z)-8-methylnon-6-enoyl carbonate formation was checked through TLC monitoring. Vanillylamine hydrochloride (190 g, 1.0 mole) was added; followed by dimethylformamide (250 mL, ].3w/w) to reaction mixture at 0-5°C temperature. Reaction mixture was then stirred for 2-3 h at 0-5°C. After completion of reaction, water (500 mL, 4.5w/w) was added and stirred for 10-15 min at 10-20°C. Organic layer was separated and aqueous layer was washed with ethyl acetate (250 mL, 2.3w/w). Organic layers were then combined, washed with water (300 mL), aqueous HC1 (260 mL) and again with water (300 mL). Ethyl acetate layer was dried over sodium sulphate and evaporated under vacuum at 55-60°C to get oily residue. Isopropyl ether (550 mL) was then charged to the residue to get clear solution and further n-hexane (550 mL) was added slowly to the clear solution within 1 h and stirred at room temperature for 1-2 h. The resulted suspension was then cooled, stirred at 15-20°C for 1-2 h and then filtered to get white solid, which was washed with Isopropyl ether (50mL); followed by n-hexane

(1 lOmL x2) and dried at room temperature for 6-7 h to get Zucapsaicin (115g ) (purity 94% with E-isomer 4 %).
Example-2: Purification of Zucapsaicin
Fractional crystallization of zucapsaicin was carried thrice to get pure zucapsaicin (purity=Z-isomer-96% to 98% E-isomer=2% to 4%) as per following method. Zucapsaicin obtained (116 g) was charged in isopropyl ether (696 rnL, 6.0w/w) and heated under stirring at 50-55°C to get clear solution. The clear solution was then cooled at 25-30°C, maintained for 1 h. further cooled to 5-10°c and again maintained for 1 h. The product was then filtered and washed with isopropyl ether. (Yield 90 g, purity 98% with E-isomer 2%).

We claim:
1. A process for preparation of zucapsaicin or pharmaceutical acceptable salt thereof, using ethyl (6Z)-8-methylnon-6-enoyl carbonate of formula (IV).

2. A process according to claim 1, wherein zucapsaicin is obtained by reacting ethyl (6Z)-8-methylnon-6-enoyl carbonate with Vanillylamine of formula (V) or an acid addition salt thereof, in presence of organic solvent.

3. A process according to claim 2, wherein organic solvent used is selected from the group consisting of dimethylformamide, dimethylacetamide, N-methylpyrrolidene? dimethylsulfoxide, tetrahydrofuran, toluene, benzene, ethyl acetate and dichloromethane.
4. A process according to claim 2, wherein organic solvent used is dimethyl formamide.
5. A process according to claim 1, wherein ethyl (6Z)-8-methylnon-6-enoyl carbonate is obtained by reacting (Z)-8-methyl-6-nonenoic acid of formula (II) with ethyl chloroform ate of formula (III) in organic solvent and in presence of base catalyst.


6. A process according to claim 5, wherein organic solvent used is selected from group consisting of dimethylformamide, dimethylacetamide, N-methylpyrrolidene, dimethylsulfoxide, tetrahydrofuran, toluene, benzene, ethyl acetate and dichloromethane.
7. A process according to claim 5, wherein organic solvent used is ethyl acetate.
8. A process according to claim 5, wherein base catalyst used is selected from group consisting oftriethylamine, isopropyl ethyl amine, pyridine and lutidine.
9. A process according to claim 5, wherein base catalyst used is triethylamine.
10. A Process for preparation of Zucapsaicin or a pharmaceutically acceptable salt thereof comprising,

a) reacting (Z)-8-methyl-6-nonenoic acid with ethyl chloroformate in organic solvent in presence of base catalyst to form ethyl (6Z)-8-methylnon-6-enoyl carbonate,
b) reacting ethyl (6Z)-8-methyl non-6-enoyl carbonate with vanillylamine or an acid addition salt thereof, in organic solvent to get zucapsaicin
c) optionally, purifying zucapsaicin obtained in step b).