FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PROCESS FOR CONVERSION OF ORIPAVINE TO THEBAINE"
2. APPLICANT:
(a) NAME: RUSAN PHARMA LIMITED
(b) NATIONALITY: Indian Company incorporated under the Companies
Act, 1956
(c) ADDRESS: 58-D, Government Industrial Estate, Charkop, Kandivali (West),
Mumbai - 400 067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of invention:
The present invention relates to an improved process for conversion of Oripavine to Thebaine in good yield and purity.
Background of the invention:
Thebaine an N-methylmorphinan having the structure;

is an opiate alkaloid and a minor constituent of opium. Chemically thebaine is similar to both morphine and codeine, and has stimulatory rather than depressant effects causing convulsions at higher doses.
The supply of thebaine is limited, and the demand is increasing; therefore, the price of thebaine is high. Thebaine and analogous compounds containing dienol ether or a dienol ester are useful intermediates in the preparation of 14-hydroxymorphinans, such as oxycodone, naltrexone, nalbuphine and naloxone.
Various processes are described for the preparation of thebaine.
U.S.Pat. No. 3894026 disclose a method for producing thebaine from salutaridinol, but
the starting material is however not readily available.
U.S.Pat. No. 4045440 provides a method for producing thebaine from codeine via the
intermediate codeine methyl ether.
U.S.Pat. No. 6090943 describes a method for making thebaine by reacting codeinone with
a metal alkoxide, such as potassium tert-butoxide, in a solvent followed by treating the
resultant product with a methylating agent, such as dimethylsulfate.
H. Rapoport et al., J. Amer. Chem. Soc. 89(8): 1942-1947 (1967) describes a method for
making thebaine by reacting codeinone dimethyl ketal with phosphorous oxychloride in
pyridine.

The prior art methods for preparing thebaine from codeine or a salt thereof are not commercially viable in several respects, such as, the methods require the use of costly reagents, reactions are time-consuming, sensitive to reaction conditions and most importantly purity of thebaine obtained is relatively low, thereby requiring considerable additional costly purification steps thus resulting in poor yields.
Oripavine is an opiate and a major metabolite of thebaine. Oripavine is very similar to codeine and is the parent compound from which a series of semi-synthetic opioids can be derived. Structurally oripavine and thebaine differ in the C-3 position. In thebaine the C-3 hydroxy group is methylated whereas, in oripavine there is a free phenolic hydroxy group. The development of poppy strain with enriched oripavine content in Australia/Europe & it's commercial availability at competitive prices, from these sources, made oripavine an important starting material for synthesis of opiates of commercial value, including synthesis of Thebaine.
It has now been thought that the phenolic hydroxy group at C-3 in Oripavine may be methylated to obtain Thebaine. Methylation of the phenolic groups in opioids has been reported in literature.
A number of methylating agents have been employed in the prior art methods. Methyl iodide was the most commonly known methylating agent (M. Grimaux, C. R. Acad. Sci.; 1881, vol. 92, p. 1140). Alkylating agents such as methyl chloride (M. A. Phillips, Chetuist Druggist, 1965, vol. 183, pp. 661 and 4454), dimethyl sulfate (M. A Phillips, Ibid, and German Patent 418,391), diazomethane ( H. von Pechmann, Bar., 1894, vol. 27, p. 1888; Ibid. 1895, vol. 28, p. 1624 and other reagents as disclosed in German Patent 39,887; However, the use of the above mentioned methylating agents are accompanied with undesirable side reactions, affecting the yield and purity, thereby rendering them of limited value from a commercial standpoint.
The use of quaternary ammonium bases in the form of halides or alkoxides are considered to optimize the methylation process. Omethylation of phenols with phenyl trimethyl ammonium chloride has been reported by Carlsen etal .in Acta Chemica Scandinavica, 1997,51, pp.343-344.

US4764615 discloses the preparation of codeine which comprises reacting morphine with trimethyl phenyl ammonium chloride in the presence of an alkali metal carbonate and a hydrocarbon solvent and recovering codeine from the reaction mixture.
US6579985 discloses preparation of codeine from morphine, wherein, methylating slurry of phenyl trimethyl ammonium chloride in sodium ethoxide in ethanol followed by addition of excess of ethanol is added to the dehydrated morphine slurry in toluene at a temperature of 90-105°C in about 0.5-3 hours. The reaction is completed in 2-6 hours. After completion of the reaction, water is added to the reaction mixture and the pH is adjusted to 11-12. The toluene layer containing codeine and dimethylaniline(DMA) is further neutralized with addition of dilute mineral or organic acid. Codeine is selectively precipitated as salt & DMA separated by filtration followed by repeated washing with hydrocarbon solvent. Codiene is regenerated from salt by basification, filtration & drying.
US6972332 discloses the process for preparation of codeine comprising methylating the solution of morphine with phenyl trimethylammonium chloride (0.8-2.5eq) in presence of potassium hydrogen carbonate and recovering codeine as phosphate from DMA. The isolated codeine salt is then purified by washing with hot toluene followed by 95% aq.ethanol. Purified codeine phosphate on basification yields codeine, however, the procedure is lengthy.
Thus there remains a need to develop a process that overcomes the drawbacks of the prior art processes for the preparation of thebaine from oripavine.
It is therefore the object of the instant invention to obtain thebaine from oripavine which employs methylation of the phenolic hydroxy group using quaternary ammonium reagent in absence of alcohol. A further object is to provide a simple and efficient separation of diethylaniline impurity from thebaine, thus improving the yield of the desired product.
Summmary of the invention:
In accordance with the objective, the present invention relates to an improved and efficient process for the preparation of thebaine from oripavine. Accordingly, the process includes adding alkoxide prior to methylation of oripavine slurry in an organic solvent, the methylating agent selected from trimethyl phenyl ammonium halide (TMPAX)

wherein X is chloride, bromide, iodide, alkoxide (OR) where R is C1 to C10 alkyl group, followed by recovery and purification thebaine from solvent mixture.
In a preferred aspect of the invention, in order to effect the separation of thebaine and dimethylaniline (DMA), the residue obtained after methylation is washed with solvent and the filtrate is successively washed with water till neutral pH. The organic layer is then distilled out completely under vacuum for removal of solvent and DMA.
Detailed description of 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.
In accordance with the present invention, there is provided an efficient process for the preparation and purification of thebaine from oripavine. The process according to the present invention improves the yield and purity of the desired product.
In an embodiment, the process of preparation includes; (a) adding an alkoxide prior to methylation of oripavine solution in inert solvent with a suitable methylating agent,(b) extracting the reaction mass in said inert solvent and washing the filtrate repetitively with water till neutral pH; (c) distilling the organic layer under vacuum at 40-60°C and maintaining for 2hours to effect complete removal of the solvent and DMA; and (f) purifiying thebaine from solvent mixture to obtain good quality of the product.
The solvents are selected from aliphatic and aromatic hydrocarbons such as petroleum ether, n-pentane, n-hexane, n-heptane, toluene, xylene etc, chlorinated hydrocarbons such as methylene dichoride, chloroform, ethylene dichloride, etc either alone or mixtures thereof; the methylating agent is selected from the group consisting of trimethyl phenyl ammonium halide (TMPAX) wherein X is chloride, bromide, iodide, alkoxide (OR) where R is C1 to C10 alkyl group.
The methylation step is carried out at the reflux temperature and the methylating agent is utilized in an amount of 1.5-3.5 moles per mole of oripavine used.


Accordingly, oripavine is mixed with toluene at 30-35°C and the resulting oripavine-toluene slurry is heated to a reflux temperature with azeotropic removal of the contained water under reflux conditions. The reaction mass is further heated with addition of toluene, and then cooled till 60-65°C. The methylation is carried out by addition of sodiumt mehoxide followed by addition of trimethyl phenyl ammonium chloride at a reflux temperature (60-120°C) for about 8hours. After completion of the methylation reaction, the reaction mass is cooled to a temperature of approximately 60-70°C, filtered and washed the residue with hot toluene. The residue obtained is isolated as the inorganic salt, a by product of methylating agent used.
The toluene filtrate consists of thebaine and dimethylaniline (DMA). In accordance with the invention, in order to effect the separation of thebaine and dimethylaniline, the filtrate is subjected to successive washings with water till pH is neutral. The organic layer is distilled out completely under vacuum at 40-60°C to distill off toluene and maintained under vacuum for about 2 hours at 40-60°C ,for removal of maximum DMA(Complete solvent & DMA removal is essential for high yield of product).
The purification is carried out by dissolving the dried reaction mass obtained above with toluene and heated till reflux to obtain the clear solution. It is then cooled to 0-5°C and stirred for another 2 hours at the same temperature; filtered and washed with chilled toluene, followed by repeated washing with hexane to remove traces of DMA. The residual solvent is removed by drying the product under vacuum at 50-60°C for 6 hours.

Further purification and crystallization to obtain second crop involves concentrating the filtrate obtained above under vacuum at 50-55°C till toluene is completely distilled off. To the residual oil so obtained is added methylene dichloride (MDC) followed by addition of 10% sulphuric acid till pH 4.5-5 is attained. The reaction mass is stirred and the separated aqueous layer obtained after further washing with MDC is neutralized to pH 10 by adding liq. ammonia followed by addition of MDC. The organic layer separated. Washed the organic layer till neutral with water. MDC distilled off & last traces of MDC removed under vacuum. The residue is treated with toluene -hexane to remove traces of DMA as described above.
In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.
Further details of the process of the present invention will be apparent from the example presented below. The example presented is purely illustrative and not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.
Example: Preparation of thebaine from oripavine
To a clean dry 5 lit RBF with TP, dean stark, OHS and condenser in oil bath was charged Oripavine (78%; 128.2g ) and toluene (2000ml). The reaction mass was stirred at 30-35°C and further heated till reflux temperature of 110°C with azeotropic distillation for 2 hours, whereby 180ml toluene and 27ml water was collected. To the brown black solid in solution was charged 200ml toluene to maintain the volume. Heating was discontinued and the reaction mass was cooled till temperature of 60-65°C. The sample was detected for KF(<1%). This was followed by addition of sodium methoxide (54.5g) and phenyltrimethylammonium chloride (174g). A slight exotherm was seen and the heating was further continued upto 110°C for about 8 hours till completion of the reaction. (TLC was observed every 60min for sodium methoxide content which should be less than 1 %.) The reaction mass changed its color from light brown to dark brown and the sample was submitted for HPLC analysis for completion of the reaction (SM NMT1%). After completion of reaction, heating was discontinued and the reaction mass cooled till temperature was 60-70°C. Filtered the reaction mass and washed the residue with

(2><150ml) hot toluene. The brown solid residue obtained was isolated as the inorganic salt, a byproduct of methylating agent, and weighed 86g.
The filtrate obtained above was charged into RBF and added 150ml water, stirred for 15min, settled, separated the organic layer. The separated organic layer was subsequently charged into RBF and washed with (2><150ml) water till pH was 7(neutral).The organic layer collected, after washings with water, was distilled out completely under vacuum at 40-60°C and maintained under vacuum for another 2hours. The reaction mass so obtained is completely dried with no traces of the solvent.(l700ml of toluene was recovered)
The solid residue obtained above was charged into RBF and added 200ml toluene.
The reaction mixture was refluxed till clear solution, cooled at 0-5°C, stirred and
maintained at 0-5°C for 2hours. Filtered, washed with chilled toluene (35ml; 0-5°C). The
solid mass was then unloaded into 500ml RBF followed by addition of hexane (200ml)
stirred for l0min, filtered and further washed with 20ml hexane. The wet product was
dried under vacuum at 50-60°C for 6hours.
Wt of the 1st crop (dry product): 86g
Yield : 82.68%, HPLC : > 99% ,M.P. : 190-193°C {lit. 193°C, (rapid heating), THE
MERCK INDEX},
[α]D at 23°c = - 233.98°(C = 5 in CHC13) [ lit.[α]D at 23°c = - 230oo(C = 5 in
CHC13),THE MERCK INDEX] & [α]D at 15°c = - 217.10°(C = 2 in alcohol) [ lit.[α]D at 15°c = - 219°(C = 2 in alcohol, THE MERCK INDEX].
Recovery of the IInd Crop:
The filtrate obtained after washing with chilled toluene was concentrated under vacuum at 40-60°C till complete distillation of toluene. Wt of oil: 16g; toluene recovered: 140ml.
To the concentrate was charged MDC (50ml) followed by addition of 10% sulphuric acid (30ml) dropwise till pH 4.5-5, stirred the reaction mixture for 30min and separated the aqueous layer. The separated aqueous layer was again washed with MDC (20ml) for 15min and to the separated aqueous layer was charged liq ammonia till pH 10 followed by addition of addition of MDC (30ml) and stirred for 15min. This was followed by separation of the aqueous layer and organic layer. The aqueous layer was washed with MDC (30ml), stirred for 15min and separated the organic layer. The

collected organic layers were washed with water (20ml), stirred for I5min and the separated organic layer was concentrated till complete removal of MDC. Wt. of llnd Crop:l lg; MDC recovered: 55ml
To the concentrated organic layer obtained above was charged toluene (11ml) and refluxed till clear solution. The solution was cooled to 0-5°C, stirred the reaction mass for 2hours at 0-5°C, filtered, and washed with chilled hexane (20ml). The wet product obtained was dried under vacuum at 50-60°C for 6 hours. wt of IIndcrop(dry product): 2.64g Yield : 3.85%, HPLC : > 99% ,M.P.: 191-193°C {lit. 193°C, (rapid heating), THE
MERCK INDEX}, Crop I+II Composite sample: 88.64 g, Yield : 86.53%, HPLC : > 99% ,M.P. : 190-192°C {lit. 193°C, (rapid heating), THE MERCK INDEX}.

We claim,
1. A process for the preparation of thebaine from oripavine including the steps of; (a) adding an alkoxide prior to methylation of oripavine solution in inert organic solvent with a suitable methylating agent, (b) extracting the reaction mass in said inert organic solvent and washing the filtrate repetitively with water till neutral pH; (c) distilling the organic layer under vacuum at 40-60°C and maintaining for 2 hours to effect complete removal of the solvent and DMA; and (d) purifiying thebaine from solvent mixture to obtain good quality of the product.
2. The process according to claim 1, wherein, the solvent is selected from aliphatic and aromatic hydrocarbons such as, petroleum ether, n-pentane, n-hexane, n-heptane, toluene, xylene etc; halogenated hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride, either alone or mixtures thereof.
3. The process according to claim 1, wherein, the methylating agent is selected from the group consisting of trimethyl phenyl ammonium halide (TMPAX) wherein X is chloride, bromide, iodide, alkoxide (OR) where R is C1 to C10 agent is utilized in an amount of 1.5-3.5 moles per mole of oripavine used.

5. The process according to claim 1, wherein, the methylation of oripavine solution is conducted at 60-120°C temperature.
6. The process according to claim 1, wherein, the purification of thebaine comprises the steps of;
a. dissolving the solid residue, obtained after distillation of the solvent and
DMA, in inert solvent and heated at 60-120°C to obtain clear solution,
cooled, filtered;
b. extracting the solid residue in chilled solvent and further washing with the
solvent, filtering, drying the wet product under vacuum to obtain the 1st
crop;
c. concentrating the filtrate of step (b) under vacuum at 40-60°C, adding
organic solvent to the residual oil followed by addition of mineral acid till
pH 4.5-5, stirred, separated the aqueous layer;

d. raising the pH with liq. NH3 and washing the aqueous layer repeatedly
with the organic solvent and further washing with water, concentrating the
collected organic layer;
e. adding solvent to the concentrated organic layer, heated at reflux, cooled,
filtered;
f. washing the residual mass with chilled hydrocarbon solvent and drying the
wet product under vacuum to obtain the 2nd crop.
7. The process according to claim 1, wherein, the solvent is selected from aliphatic and aromatic hydrocarbons such as, petroleum ether, n-pentane, n-hexane, n-heptane, toluene, xylene etc; halogenated hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride, either alone or mixtures thereof.
8. The process according to any of the preceding claims as exemplified in the example above.