Claims:1. A process for preparation of Thebaine of formula I from Oripavine of formula II comprising;

a) O-methylating oripavine of formula (II) in an inert reaction solvent in presence of sodium hydride as a base and dimethyl sulphate as a methylating agent wherein the dimethyl sulfate present in an amount ranging from 1.0-3.0 mol per mole of oripavine; and
b) Isolating thebaine from the reaction mass by extracting into suitable organic solvent.

2. The process as claimed in claim 1, wherein, the inert reaction solvent is selected from the group consisting of dimethylformaamide and dichloromethane.

3. The process as claimed in claim 1, wherein, the methylation reaction is conducted at a temperature range of room temperature to 55°C, more preferably in the range of 30 to 55°C.

4. The process as claimed in claim 1, wherein, the base is present in an amount ranging from 1.0-5.0 mol per mole of oripavine.
5. The process as claimed in claim 1, wherein, the process provides higher conversions up to 99% and purity upto 99% of the desired product, i.e., thebaine.

6. The process as claimed in claim 1, wherein, the suitable solvent used in isolating thebaine is Cyclopentyl methyl ether (CPME).
, Description:Field of invention:
The present invention relates to an improved process for conversion of Oripavine to Thebaine in good yield and purity. More particularly, the present invention relates to process for conversion of Oripavine into Thebaine in presence of dimethyl sulphate as methylating agent and sodium hydride as a base with good yield and purity in shorter reaction time.

Background of the invention:
Thebaine (paramorphine), also known as codeine methyl enol ether, having the following structure of formula I;

Formula I
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. Although, thebaine is not used therapeutically, however, it is the main alkaloid extracted from Papaver bracteatum and can be converted industrially into a variety of opiate compounds, including oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine, Butorphanol and etorphine. Further, the synthetic enantiomer (+)-thebaine shows analgesic effects apparently mediated through opioid receptors.

The supply of thebaine is limited, and the demand is increasing; therefore, the price of thebaine is very 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, as reported herein below.

US3894026 disclose a method for producing thebaine from salutaridinol, but the starting material is however not readily available.

US4045440 provides a method for producing thebaine from codeine via the intermediate codeine methyl ether.

US6090943 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.

Generally, the Methylation reaction of the phenolic groups in opioids has been reported in literature using a number of methylating agents such as methyl iodide (most commonly used methylating agent); alkylating agents such as methyl chloride, diazomethane etc.; however, the use of the each of the above mentioned methylating agents has its own effects and side effects on the phenolic group in the reacting molecule that influences the yields and the purity of the methylated molecule. Many of these methylating agents are accompanied with undesirable side reactions, affecting the yield and purity, thereby rendering them of limited value from a commercial standpoint for the production of thebaine from oripavine.

In this context, it has been reported for the first time by the present inventors in their earlier Indian Patent Application No. 160/MUM/2011 that the phenolic hydroxy group at C-3 in Oripavine may be methylated to obtain Thebaine. The methylation was reported with trimethyl phenyl ammonium halide (TMPAX) in presence of a base; however, this reaction results in thebaine with 82% yields only. TMPAX reagents are also expensive and therefore not commercially-viable.
In the light of the only report available by the present inventors in 160/MUM/2011, for the conversion of oripavine to thebaine; there remains a need to improve the performance of the methylation reaction of oripavine to obtain thebaine with good yields and purity. Moreover, there is also a need to provide a cost-effective and an efficient industrial process that is easier to scale up.

Therefore, it is an objective of the present invention to provide an efficient and cost-effective preparation of thebaine from oripavine with higher conversation rates and purity in shorter time periods and thus the process can be scaled up for industrial production.

Summary of the invention:
In line with the above objective, the present invention provides a process for preparation of Thebaine from Oripavine in good yield and purity.

Accordingly, in an aspect, the present invention provides a process for preparation of Thebaine of formula I from Oripavine of formula II, which process comprises;

a) O-methylating oripavine of formula (II) in an inert reaction solvent using a base and dimethyl sulphate a methylating agent wherein the dimethyl sulfate present in an amount ranging from 1.0-3.0 mol per mole of oripavine to obtain thebaine; and
b) Isolating the thebaine from the reaction mass by extracting into suitable organic solvent.

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.

In meeting with the above objective, the present invention provides a process for conversion of Oripavine into Thebaine in good yield and purity.

Accordingly, oripavine was subjected to O-methylation using variety of methylating agents at various molar ratios; various inert organic solvents; various bases and at various reaction temperatures to assess the reactivity and ability of the oripavine to convert into thebaine.

Although, O-methylation reaction of Oripavine to obtain Thebaine appears simple, however, the complexity of the O-methylation reaction involved in the conversion of Oripavine to Thebaine can be envisaged from the yields, purity and the time period involved from various experiments reported in table 1.

Table 1:
S. No Reagent Base Solvent Temp (°C) Time (h) HPLC purity
1 MeI
(5.0 equiv) K2CO3
(2 equiv) DMF 80 4 Impurities formation only
2 MeI
(5.0 equiv) Cs2CO3
(2 equiv) ACN 80 4 Impurities formation only
3 DMS
(1.2 equiv) NaOMe
(3 equiv) Toluene 110 15 Impurities formation only
4 DMS
(1.0 equiv) NaH
(10 equiv) THF 30 8 THB: 40.0%
ORP: 28.3%
IMP: 31.7%
5 DMS
(1.5 equiv) NaH
(3 equiv) CPME 30 8 THB: 50.0% IMP: 50.0%
6 DMS
(1.0 equiv) NaH
(3 equiv) 1,2-DCE 80 16 THB: 41.0%
ORP: 36.9%
IMP: 22.1%
7 DMS
(1.2 equiv) NaH
(3 equiv) DCM 30 7 THB: 98.0% IMP: 2.0%
8 DMS
(1.8 equiv) NaH
(3 equiv) DMF 90 8 THB: 91.0%
ORP: 1.7%
IMP: 7.3%
9 DMS
(1.0 equiv)
NaH
(3 equiv) DMF 80 8
THB: 86.0%
ORP:13.0%
IMP: 1.0%
10 DMS
(1.5 equiv) NaH
(3 equiv) DMF 90 7 THB: 98.0%
ORP: 1.2%
IMP: 0.8%
11 DMS
(1.3 equiv) NaH
(3 equiv) DMF 50 3 THB: 99.2%
IMP: 0.8%

DMS: dimethyl sulfate; THF: tetrahydrofuran; CPME: cyclopentylmethyl ether; 1,2-DCE: 1,2-dichloroethane; DCM: dichloromethane; DMF: dimethylformamide; THB: thebaine; ORP: oripavine; IMP: impurities
As is evident from table 1, methylation of oripavine using 5 equivalents of methyl iodide as methylating agent in presence of potassium carbonate in DMF or caesium carbonate in acetonitrile (Sr. No. 1 and 2) at a temperature of 80°C results in large number of impurities. These experiments clearly conclude that methyl iodide is definitely not a choice of methylating agent for oripavine to thebaine.

In another experiment the methylation of oripavine is conducted with dimethyl sulphate as methylating agent (SR. No. 3 and 4) in presence of various bases such as sodium methothoxide in toluene and sodium hydride in THF at a temperature of 110°C and 30°C, respectively. These reactions also results in large number of impurities.

It can be further noted from the experiments (Sr. No 5 to 8) of table 1, wherein the dimethyl sulphate as a methylating agent in variable molar equivalents along with sodium hydride as a base, but, in various solvents such as CPME, 1,2-DCE; DCM and DMF. However, these experiments also results in higher amounts of impurities. Although the solvents DCM and DMF (Sr. No. 7 and 8) provides higher conversion rates of oripavine to thebaine with the yields of 98 and 91% respectively; however, the reaction mixture contains unreacted oripavine and the impurities in relatively higher amounts which necessitates additional purification steps to obtain pure compound. These experiments prove that DCM and DMF are the best suitable solvents for methylation of oripavine when conducted in presence of dimethylsulphate and sodium hydride as a base. These experiments further prove that the 1 to 2 equivalents of dimethyl sulphate and 1 to 3 equivalents of sodium hydride is sufficient to obtain optimum results.

Therefore, in yet another experiment (SR. No. 9, 10 and 11) the methylation reaction of oripavine was studied with 1 to 2 equivalents of dimethyl sulphate to oripavine and 1 to 3 equivalents of sodium hydride as a base to oripavine in DMF as a solvent however, at variable reaction temperatures of 50 to 90°C. The results of these experiments conclude that the methylation reaction at 50°C results in the reaction mixture with more than 99% of thebaine along with impurities in minor amounts, viz., 0.8%.

In the light of the above results demonstrated in table 1, the present inventors have realized that in addition to type of methylating agent, base, solvent and reaction temperature; the molar ratio of the methylating agent to the oripavine and the base to oripavine, has a direct impact on the formation of impurities and the rate of conversion of oripavine into thebaine.

Accordingly, in an embodiment, the present invention provides a process for preparation of Thebaine of formula I from Oripavine of formula II which process comprises;

a) O-methylating oripavine of formula (II) in an inert reaction solvent in presence of sodium hydride as a base and dimethyl sulphate a methylating agent wherein the dimethyl sulfate present in an amount ranging from 1.0-3.0 mol per mole of oripavine to obtain thebaine; and
b) Isolating the thebaine from the reaction mass by extracting into suitable organic solvent.

According to another embodiment, the inert reaction solvent is selected from the group consisting of dimethylformaamide, and dichloromethane.

According to another embodiment, the methylation reaction is conducted at a temperature range of room temperature to 55°C, more preferably in the range of 30 to 55°C.

According to yet another embodiment, the reaction is accomplished within 3 to 7 hrs, thereby reduces the impurity formation.

According to further embodiment, the molar ratio of the base is present in an amount ranging from 1.0-5.0 mol per mole of oripavine.

The process according to the present invention provides higher conversion of oripavine up to 99% and purity upto 99% (by HPLC) of the desired product, i.e., thebaine.

According to another embodiment, the isolation of the thebaine comprises a step of extracting the same into suitable organic solvent. One such solvent is Cyclopentylmethyl ether (CPME) solvent among other solvents such as diethyl ether, tert-butylmethyl ether, tetrahydrofuran, ethyl acetate, dichloromethane, and chloroform. CPME is the preferred organic solvent as it offers higher resistance to peroxide formation, and is also a more environmentally-benign and “greener” solvent.
Accordingly, in a preferred embodiment, oripavine was dissolved in dimethyl formaamide (DMF) followed by portionwise addition of NaH (60% suspension in mineral oil) and further added additional amounts of DMF and stirred sufficient period of time. During the addition of NaH, the temperature rises to 40°C to 45°C and maintained the reaction mass at this temperature for about 1 h. To this reaction mixture, dimethyl sulphate was added over the period of 10 minutes and heated the mass at 50-55° C for about 2 hrs till the reaction mass is clear. After completion of the reaction (by TLC), the mass was cooled to room temperature and triturated with ice and water mixture. To the reaction mass, Cyclopentyl methyl ether (CPME) was added and separated the organic layer. The aq. Layer was further extracted with additional CPME. The combined organic layers were washed with water and concentrated the organic layers in vacuo to obtain yellowish sticky solid. To this solid, hexane was added and concentrated to obtain Thebaine with a purity of 99%.

Those of ordinary skilled in the art will appreciate that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments or examples disclosed herein, but is intended to cover modifications within the objectives and scope of the present invention as defined in the specification. The presented examples illustrate the invention, but they should not be considered to limit the scope of the invention in any way.

Example 1
Charged 50 g Oripavine into a four neck 2 l round bottom flask equipped with condenser, nitrogen, overhead stirrer. Added DMF (1 litre) to it to obtain the reaction mass as a clear solution. Added NaH (20 g, 60% suspension in mineral oil) portionwise to the reaction mass and added additional 250 mL DMF to the mass and stirred for 1 hr. The temperature of the reaction mass rises to 40°C; maintained the temperature at 40-45° for 1 hr. Added 20 mL DMS dropwise using additional funnel over the period of 10 minutes. Continued the heating at 50-55° C for 1.5 h till reaction mass becomes clear. After completion of the reaction (checked by TLC); cooled the reaction mass to room temperature. Added 1 kg ice and 200 mL water mixture to the reaction mass slowly. Added 1200 mL CPME and separated the layers. The aq. layer was extracted with 4 x 1100 mL CPME. Combined the organic layers and washed with 1200 mL water. The combined organic layer was concentrated in vacuo to obtain a wet sticky solid. Added 100 mL hexane to the solid and concentrated in vacuo; dried at 60° C for 2 h, to obtain 46.4 g of thebaine. Yield: 88%. Purity by HPLC: 99%.