Title of Invention	AN IMPROVED GREEN PROCESS FOR THE PREPARATION OF 14-HYDROXYCODEINONE FROM THEBAINE
Abstract	This present invention provides an improved green process for the preparation of 14-hydroxycodeinone from thebaine. This invention particularly provides an efficient, improved and green method for the production of 14-hydroxycodeinone (2) (Scheme 1), which is a crucial intermediate for the synthesis of a strong analgesic agent Oxycodone (3). More particularly, the present invention an improved green process for the preparation of 14-hydroxycodeinone from readily available starting material thebaine (1) which on oxidation produces 14-hydroxycodeinone (2) in excellent yield (92-81%).

Title of Invention

AN IMPROVED GREEN PROCESS FOR THE PREPARATION OF 14-HYDROXYCODEINONE FROM THEBAINE

Abstract

This present invention provides an improved green process for the preparation of 14-hydroxycodeinone from thebaine. This invention particularly provides an efficient, improved and green method for the production of 14-hydroxycodeinone (2) (Scheme 1), which is a crucial intermediate for the synthesis of a strong analgesic agent Oxycodone (3). More particularly, the present invention an improved green process for the preparation of 14-hydroxycodeinone from readily available starting material thebaine (1) which on oxidation produces 14-hydroxycodeinone (2) in excellent yield (92-81%).

Full Text	Field of the invention This present invention relates to an improved green process for the preparation of 14-hydroxycodeinone from thebaine. This invention particularly relates to an efficient, improved and green method for the production of 14-hydroxycodeinone (2) (Scheme 1), which is a crucial intermediate for the synthesis of a strong analgesic agent Oxycodone (3). More particularly, the present invention relates to an improved green process for the preparation of 14-hydroxycodeinone from readily available starting material thebaine (1) which on oxidation produces 14-hydroxycodeinone (2) in excellent yield (92-81%). Background of the invention Reference may be made to J. Am. Chem. Soc. 1955, 77, 6359-6361 for the production of 14-hydroxycodeinone.In this paper cold Chromic acid was applied for the oxidation of thebaine to 14-hydroxycodeinone. A solution of Chromic acid in 10 N sulphuric acid was added to a solution of thebaine in 1 N sulphuric acid maintained at 3-5 °C over 6-8 hours period. One hour after completion of addition, Na2SO3 was added to destroy any oxidant left and after work-up it produced of 14-hydroxycodeinone in 25% yield. Drawbacks: In this method, toxic Chromic acid and strong acidic reaction medium was used. The yield was very poor (25%). Another reference may be made to J. Med. Chem. 1974, 17, 1117. In this research paper, Thebaine was oxidized to 14-hydroxycodeinone by m-Chloroperbenzoic acid in a mixture of acetic acid and trifluoroacetic acid which produced 14-hydroxycodeinone in 74% yield. Here, thebaine in a mixture of acetic acid and trifluoroacetic acid was treated with m-chloroperbenzoic acid over 12 minute. The reaction mixture was then placed in a preheated (95 °C) stirring wax bath for 15 minutes and after removing from preheated bath, additional amount m-chloroperbenzoic acid was added. The reaction mixture was again placed in a heating bath for 20 minute and after removing it was again stirred for 10 minute and cooled in an ice bath. After work-up, it produced 14-hydroxycodeinone in 74% yield. Drawbacks: This method involved expensive m-chloroperbenzoic acid and very strong trifluoroacetic acid which are not cost effective and environment friendly. The procedure is a tedious one. More importantly, Ijima et al. reported that this reaction did not give reproducible yield (about 24.3%) and many undesirable products were formed (Helv. Chim. Acta. 1977, 60, 2135). Yet another reference may be made to Helv. Chim. Acta. 1977, 60, 2135.In this method, Thebaine was oxidized to 14-hydroxycodeinone by m-chloroperbenzoic acid in a mixture of acetic acid and trifluoroacetic acid in 24% yield. Here, thebaine in a mixture of acetic acid and trifluoroacetic acid was treated with m-chloroperbenzoic acid over 5 min. After heating for 5 min. at 95 °C (bath temperature) additional amount of m-chloroperbenzoic acid was added over 5 min. The reaction mixture was again heated for 10 min at 90 °C and then stirred for 10 min at RT, cooled and poured in ice water. After work-up it produced 14-hydroxycodeinone in 24.3% yield. Apart from this, 8-acetoxy-14-hydroxydihydrothebaine was also formed in 36.5% yield as undesired product. Drawbacks: It involved expensive m-chloroperbenzoic acid and very strong trifluoroacetic acid. The procedure was also a complex one. Above all, the yield is very poor (24.3%). Yet another reference may be made to Indian J. Chem. 1998, 37B, 749-753.In this procedure, microbial transformation of thebaine to 14-hydroxycodeinone was carried out by employing Bacillus sp which was isolated from soil using morphine as the sole source of carbon. The yield of 14-hydroxycodeinone by this method was 53%. Drawbacks: It produced poor yield (53%) of 14-hydroxycodeinone from thebaine accompanying 14-hydroxycodeine as the side product (yield 9%). Yet another reference may be made to Tetrahedron 1999, 55, 11429-11436. Rice et al. developed a method for the oxidation of codeinone to 14-hydroxycodeinone by employing different oxidizing agents. Among them stoichiometric amount of Co(OAc)3 furnished maximum yield (51%) of 14-hydroxycodeinone. Drawbacks: The yield of the method is poor and many side products are formed. Additionally, stoichiometric amount of toxic metal catalyst was required. Yet another reference may be made to US Patent, 2005, 6,864,370. Here, thebaine bitartrate monohydrate was used for the preparation of 14-hydroxycodeinone. 30% Hydrogen peroxide was added to a solution of thebaine bitartrate monohydrate in a mixture of water, isopropanol and formic acid at 0-5 °C. The reaction mixture was stirred at the same temperature for 1-2 hours followed by heating at 40- 45 °C for 2-3 hours. After work-up, yield of 14-hydroxycodeinone was 90%. Drawbacks: Though the yield was excellent, the preparation of starting material thebaine bitartrate monohydrate was a laborious process and involved several steps such as thebaine bitartrate monohydrate was prepared from N-carboethoxynorthebaine, which itself was produced from N-carboethoxynorcodeinone. Additionally, it involved acidic reaction media. Yet another reference may be made to US Patent, 2006, 7,071,336. Francis et al. used concentrate poppy straw as the source of thebaine. Poppy straw was treated with water, dilute H2SO4, formic acid and 30% H2O2. After 30 min stirring the solution was heated in an oil bath to 50 °C for 20-24 hours to furnish 14-hydroxycodeinone in 74% yield. Drawbacks: The required time for the completion of the reaction was very long and the yield was not also very good. Additionally the method involved acidic reaction media. Yet another reference may be made to U.S. patent application, 2006, 20060111383 A1. Oxidation of thebaine was carried out by adding 30% hydrogen peroxide in 85% formic acid over a period of two hours followed by stirring for additional 3 hours. The corresponding yield of 14-hydroxycodeinone is 75%. Drawbacks: The method involved acidic reaction media and the yield was also not References may be made to 1. J. Org. Chem. 1957, 22, 1505-1508 2. J. Org. Chem. 1958, 23,1247-1251 3. J. Org. Chem. 1960, 25, 987 - 990 4. Tetrahedron Lett. 1969, 22, 1805-1808 5. J. Med. Chem. 1978, 21, 398-400 6. J. Org. Chem. 1981,46, 4012-4014 7. Acta Pharm. Sin. 1983, 18, 475-477 8. US Patent, 1987, 4,639,520 9. US Patent, 1999, 6,008,355 10. US Patent, 2001,6,262,266 11. US Patent, 2001,6,177,567 12. US Patent, 2002, 6,403,798 13. US Patent, 2002, 6,469,170 14. US Patent, 2006, 7,129,248 15. US Patent, 2006, 7,153,966 16. Heterocycles 1998, 49, 43 and references cited therein. Oxidation of thebaine to 14-hydroxycodeinone is a very important transformation because 14-hydroxycodeinone is a crucial intermediate for the synthesis of a strong analgesic agent oxycodone. It is therefore desirable to develop an efficient, environmentally benign and catalytic method to produce 14-hydroxycodeinone eliminating the drawbacks stated above. Objectives of the Invention The main objectives of the present invention is to provide an improved, environmentally benign and a catalytic process for the preparation of 14-hydroxycodeinone (2) from thebaine (1). Another objective of the present invention is to provide oxidation of thebaine (1) to 14-hydroxycodeinone (2) by V2O5 along with co-oxidant H2O2. Yet, another objective of the present invention is to carry out the oxidation with catalytic (20 mol %) amount of V2O5. Still, another objective of the present invention is to carry out the reaction with recyclable and reusable V2O5 with much shorter time of 30-45minutes in excellent yield. Summary of the Invention Accordingly the present invention provides an improved green process for the preparation of 14-hydroxycodeinone from thebaine which comprises refluxing thebaine and H2O2 in molar ratio of 1:1-1:2, in the presence of 5-25 mol% V2O5, in a mixture of H2O and organic solvent, for a period of 30-45 minutes, neutralising the above said reaction mixture with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate, washing the resultant organic layer with brine solution and drying it over sodium sulphate, followed by removal of solvent, under reduced pressure, to obtain the desired product of 14-hydroxycodeinone. In an embodiment of the present invention the amount of oxidising agent V2O5 used is preferably in the range of 15-20mol% In yet another embodiment the molar ratio of thebaine and H2O2 used preferably is 1:1.5 1:2.0. In yet another embodiment the concentration of H2O2 used is preferably 30%. In yet another embodiment the organic solvent used is selected from the group consists of THF, acetonitrile, methanol and ethanol. In yet another embodiment the organic solvent used is preferably THF. In yet another embodiment the ratio of water to THF used is preferably 1:2. In yet another embodiment the yield of 14-hydroxycodeinone obtained is in the range of 90-95%. In still another embodiment the catalyst V2O5 used is recyclable and can be reused for consecutive five times to conduct fresh reactions. Detailed Description of the Invention The present invention provides an improved and green method for the production of 14-hydroxycodeinone, which is a crucial intermediate for the synthesis of a strong analgesic agent oxycodone. This invention provides an improved, environmentally benign and catalytic process comprises refluxing of thebaine in H2O and organic solvents THF, methanol, acetonitrile and ethanol in range of 5-25 mol% V2O5 and equiv. of H2O2 for a period of 30-45 minutes, neutralizing the reaction mixture with saturated sodium bicarbonate solution and washing the separated organic layer with brine solution (5%), drying over sodium sulphate, removing the solvent under reduced pressure to get 14-hydroxycodeinone in 92% yield which on hydrogenation with Pd/C in aqueous acetic acid furnished oxycodone in 85% yield. V2O5 can be reused for consecutive five times to conduct fresh reactions without any loss in activity. Also, it does not produce chemical waste to the environment. Thus the whole process is simple, green and economically more viable. Maximum yield was obtained with H20/THF mixture in the ratio of 1:2, with 20 mol% V2O5and 30 mol% of H2O2. V2O5 can be reused for consecutive five times to conduct fresh reactions without any loss in activity. Also, it does not produce chemical waste to the environment. Thus the whole process is simple, green and economically more viable. The process for the production of (2) by oxidation of (1) of formula (1) isshown in Scheme 1 SYNTHESIS OF 14-HYDROXYCODEINONE (Scheme Removed) Scheme 1 The details of the method disclosed in this invention have been described in the following specific examples, which are provided to illustrate the invention only and therefore, these should not be construed to limit the scope of the present invention. Oxidation of thebaine to 14-hydroxycodeinone by V2O5 in presence of 30% H2O2 in water/THF mixture and followed by hydrogenation by Pd/C in aqueous acetic acid to produce oxycodone Example (1A): Preparation of 14-hydroxycodeinone: In a 100 ml two-necked round bottom flask, thebaine (1) (0.311 g, 1 mmol) was mixed with 30% H2O2 (1.5 equiv.) and 20 mol% of vanadium pentoxide (0.036 g) in a 10 ml mixture of H20/THF (1:1). The reaction mixture was then refluxed for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was neutralised with saturated sodium bicarbonate solution and was extracted with ethyl acetate (3x10 ml). The organic layer was washed with brine (1x10 ml), dried over Na2SO4 and concentrated under vacuum to give the crude product which was recrystallized from methanol to afford pure 14-hydrxycodeinone (2) in 92% yield (0.287 g). The aqueous phase was reused for the subsequent fresh reactions for the five times without any loss of activity. Characterization data of 14-hydrxycodeinone m.p. 274-275 °C [Lit. m.p. 274-275 °C (Helv. Chim. Acta. 1977, 60, 2135)]; 1H NMR (CDCI3, 300MHz): δ 1.67-1.71 (m, 2H), 2.23-2.42 (m, 2H), 2.44 (s, 3H), 3.03 (m, 2H), 3.20-3.26 (m,1H), 3.84 (s, 3H), 4.71 (s, 1H), 5.14 (brs, 1H), 6.17 (d, J= 9.96 Hz, 1H), 6.47-6.70 (m, 3H); FT-IR (KBr, cm-1): 1674.3, 3423.9; ESI-MS (m/z): 314.3 (M++1). Anal. Calcd. for C18H19O4N: C, 69.00; H, 6.11; N, 4.47. Found: C, 69.08; H, 6.17; N, 4.40. Preparation of oxycodone from 14-hydroxycodeinone by Pd/C in aqueous acetic acid: The 14-hydroxycodeinone (0.287 g) was dissolved in a mixture of water (5 ml) and acetic acid (5 ml). 10% Pd/C (0.200 g) was added to it in one portion. The system was then evacuated, filled with hydrogen gas and shaken at an initial pressure of 40 psi for about 5 hours at room temperature. The mixture was filtered to remove the catalyst. The residue was washed with 5 ml of acetic acid. The filtrate was concentrated in vacuum to dryness at 50 °C. The filtrate was treated with concentrated ammonium hydroxide solution to pH 10. The mixture was then extracted with ethyl acetate (3 x 10ml), washed with water, dried over Na2SO4 and concentrated under vacuum. The corresponding yield of oxycodone is 0.244 g (85%). Characterization data of oxycodone m.p. 217-218 °C [Lit. m.p. 218 °C (J. Med. Chem. 1978, 21, 398)]; 1H NMR (CDCI3, 300MHz): δ 1.55-1.61 (m, 2H), 1.83 (d, J= 12.1 Hz, 1H), 2.16 (t, J= 12.1 Hz, 1H), 2.29 (m, 2H), 2.40 (s, 3H), 2.44 (m, 1H), 2.57 (m, 1H), 2.83 (d, J= 4.2 Hz, 1H), 2.98 (t, J= 12.1 Hz, 1H), 3.12 (d, J= 16.1 Hz, 1H), 3.87 (s, 3H), 4.68 (s, 1H), 5.05 (s 1H), 6.62 (d, J= 8.2 Hz, 1H), 6.68 (d, J= 8.2 Hz, 1H); FT-IR (KBr, cm"1): 1720.1, 3422.6; ESI-MS (m/z): 316.4 (M++1). Anal. Calcd. for C18H21O4N: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.59; H, 6.79; N, 4.38. Example (1 B): Preparation of 14-hydroxycodeinone: Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30 % H2O2 (1.5 equiv.), V2O5: 0.045 g (25 mol%), Solvent: 10 ml H2O/THF (1:1), time: 30 min, yield: 0.287 g (92%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.281 g, yield: 0.244 g (85%). Example (1C): Preparation of 14-hydroxycodeinone: Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30% H2O2 (1.5 equiv.), V2O5: 0.027 g (15 mol%), Solvent: 10 ml H2O/THF (1:1), time: 40 min, yield: 0.281 g (90%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.272 g, yield: 0.236 g (84%). Example (1D): Preparation of 14-hydroxycodeinone: Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30% H202 (1.5 equiv.), V2Os: 0.018 g (10 mol%), Solvent: 10 ml H20/THF (1:1), time: 45 min, yield: 0.272 g (87%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.253 g, yield: 0.232 g (85%). Example (1E): Preparation of 14-hydroxycodeinone: Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30 % H2O2 (1.5 equiv.), V2O5: 0.009 g (5 mol%), Solvent: 10 ml H2O/THF (1:1), time: 1.0 hour, yield: 0.253 g (81%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.234 g, yield: 0.215 g (85%). Example (1F): Preparation of 14-hydroxycodeinone: Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30% H2O2 (1.5 equiv.), V2O5: 0.036 g (20 mol%), Solvent: 10 ml H2O/THF (1:2), time: 30 min, yield: 0.287 g (92%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.281 g, yield: 0.239 g (83%). Example (1G): Preparation of 14-hydroxycodeinone: Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30% H2O2 (1.5 equiv.), V2O5: 0.036 g (20 mol%), Solvent: 10 ml H2O/THF (2:1), time: 30 min, yield: 0.275 g (88%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.275 g, yield: 0.234 g (85%). Example (1H): Preparation of 14-hydroxycodeinone: Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30% H2O2 (1.5 equiv.), V2O5: 0.036 g (20 mol%), Solvent: 10 ml H2O/MeCN (1:1), time: 40 min, yield: 0.275 g (88%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.275 g, yield: 0.225 g (82%). Example (11): Preparation of 14-hydroxycodeinone: Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30% H2O2 (1.5 equiv.), V2O5: 0.036 g (20 mol%), Solvent: 10 ml H2O/MeOH (1:1), time: 40 min, yield: 0.262 g (84%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.262 g, yield: 0.220 g (84%). Example (1J): Preparation of 14-hydroxycodeinone: Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30% H2O2 (1.5 equiv.), V2O5: 0.036 g (20 mol%), Solvent: 10 ml H2O/EtOH (1:1), time: 35 min, yield: 0.266 g (85%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.266 g, yield: 0.226 g (85%). Example (1K): Preparation of 14-hydroxycodeinone: Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30% H2O2 (1.0 equiv.), V2O5: 0.036 g (20 mol%), Solvent: 10 ml H2O/THF (1:1), time: 45 min, yield: 0.262 g (84%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.262 g, yield: 0.217 g (83%). Example (1L): Preparation of 14-hydroxycodeinone: Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30% H2O2 (1.2 equiv.), V2O5: 0.036 g (20 mol%), Solvent: 10 ml H2O/THF(1:1), time: 45 min, yield: 0.266 g (85%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.266 g, yield: 0.224 g (84%). Example (1M): Preparation of 14-hydroxycodeinone: Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30% H2O2 (2.0 equiv.), V2O5: 0.036 g (20 mol %), Solvent: 10 ml H2O/THF (1:1), time: 30 min, yield: 0.287 g (92%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.281 g, yield: 0.241 g (84%). Table 1. Recycling of the catalyst (Table Removed) Isolated yield. The Main Advantages of the Present Invention are : 1 The method is very simple and environmentally benign. 2 The product can be obtained in excellent yield (81-92%). 3 Catalytic amount of V2O5 (20 mol%) is sufficient to carry out the reaction effectively. 4 H2O2 is used as a green co-oxidant. 5 The catalyst is recyclable and can be reused for consecutive five times to conduct fresh reactions without any loss in activity. Also, it does not produce chemical waste to the environment. Thus the whole process is simple, green and economically more viable. We Claim 1. An improved green process for the preparation of 14-hydroxycodeinone from thebaine which comprises refluxing thebaine and H2O2 in molar ratio of 1:1-1:2, in the presence of 5-25 mol% V2O5, in a mixture of H2O and organic solvent, for a period of 30-45 minutes, neutralising the above said reaction mixture with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate, washing the resultant organic layer with brine solution and drying it over sodium sulphate, followed by removal of solvent, under reduced pressure, to obtain the desired product of 14-hydroxycodeinone. 2. An improved process as claimed in claim 1, wherein the amount of oxidising agent V2O5 used is preferably in the range of 15-20mol% 3. An improved process as claimed in claims 1 & 2, wherein the molar ratio of thebaine to H2O2 used is preferably in the range of 1:1.5 1:2.0. 4. An improved process as claimed in claims 1-3, wherein the concentration of H2O2 used is preferably 30%. 5. An improved process as claimed in claims 1-4, wherein the organic solvent used is selected from the group consisting of THF, acetonitrile, methanol and ethanol. 6. An improved process as claimed in claims 1-5, wherein the organic solvent used is preferably THF. 7. An improved process as claimed in claims 1-6, wherein the ratio of water to THF used is preferably 1:2. 8. An improved process as claimed in claims 1-7, wherein the yield of 14-hydroxycodeinone obtained is in the range of 90-95%. 9. An improved process as claimed in claims 1-8, wherein the catalyst V2I5 used is recyclable and can be reused for consecutive five times to conduct fresh reactions 10. An improved green process for the preparation of 14-hydroxycodeinone from thebaine, substantially as herein described with reference to the examples

Full Text

Field of the invention
This present invention relates to an improved green process for the preparation of 14-hydroxycodeinone from thebaine. This invention particularly relates to an efficient, improved and green method for the production of 14-hydroxycodeinone (2) (Scheme 1), which is a crucial intermediate for the synthesis of a strong analgesic agent Oxycodone (3). More particularly, the present invention relates to an improved green process for the preparation of 14-hydroxycodeinone from readily available starting material thebaine (1) which on oxidation produces 14-hydroxycodeinone (2) in excellent yield (92-81%).
Background of the invention
Reference may be made to J. Am. Chem. Soc. 1955, 77, 6359-6361 for the production of 14-hydroxycodeinone.In this paper cold Chromic acid was applied for the oxidation of thebaine to 14-hydroxycodeinone. A solution of Chromic acid in 10 N sulphuric acid was added to a solution of thebaine in 1 N sulphuric acid maintained at 3-5 °C over 6-8 hours period. One hour after completion of addition, Na2SO3 was added to destroy any oxidant left and after work-up it produced of 14-hydroxycodeinone in 25% yield.
Drawbacks: In this method, toxic Chromic acid and strong acidic reaction medium was used. The yield was very poor (25%).
Another reference may be made to J. Med. Chem. 1974, 17, 1117. In this research paper, Thebaine was oxidized to 14-hydroxycodeinone by m-Chloroperbenzoic acid in a mixture of acetic acid and trifluoroacetic acid which produced 14-hydroxycodeinone in 74% yield. Here, thebaine in a mixture of acetic acid and trifluoroacetic acid was treated with m-chloroperbenzoic acid over 12 minute. The reaction mixture was then placed in a preheated (95 °C) stirring wax bath for 15 minutes and after removing from preheated bath, additional amount m-chloroperbenzoic acid was added. The reaction mixture was again placed in a heating bath for 20 minute and after removing it was again stirred for 10 minute and cooled in an ice bath. After work-up, it produced 14-hydroxycodeinone in 74% yield.
Drawbacks: This method involved expensive m-chloroperbenzoic acid and very strong trifluoroacetic acid which are not cost effective and environment friendly. The procedure is a tedious one. More importantly, Ijima et al. reported that this reaction
did not give reproducible yield (about 24.3%) and many undesirable products were formed (Helv. Chim. Acta. 1977, 60, 2135).
Yet another reference may be made to Helv. Chim. Acta. 1977, 60, 2135.In this method, Thebaine was oxidized to 14-hydroxycodeinone by m-chloroperbenzoic acid in a mixture of acetic acid and trifluoroacetic acid in 24% yield. Here, thebaine in a mixture of acetic acid and trifluoroacetic acid was treated with m-chloroperbenzoic acid over 5 min. After heating for 5 min. at 95 °C (bath temperature) additional amount of m-chloroperbenzoic acid was added over 5 min. The reaction mixture was again heated for 10 min at 90 °C and then stirred for 10 min at RT, cooled and poured in ice water. After work-up it produced 14-hydroxycodeinone in 24.3% yield. Apart from this, 8-acetoxy-14-hydroxydihydrothebaine was also formed in 36.5% yield as undesired product. Drawbacks: It involved expensive m-chloroperbenzoic acid and very strong trifluoroacetic acid. The procedure was also a complex one. Above all, the yield is very poor (24.3%).
Yet another reference may be made to Indian J. Chem. 1998, 37B, 749-753.In this procedure, microbial transformation of thebaine to 14-hydroxycodeinone was carried out by employing Bacillus sp which was isolated from soil using morphine as the sole source of carbon. The yield of 14-hydroxycodeinone by this method was 53%.
Drawbacks: It produced poor yield (53%) of 14-hydroxycodeinone from thebaine accompanying 14-hydroxycodeine as the side product (yield 9%).
Yet another reference may be made to Tetrahedron 1999, 55, 11429-11436. Rice et al. developed a method for the oxidation of codeinone to 14-hydroxycodeinone by employing different oxidizing agents. Among them stoichiometric amount of Co(OAc)3 furnished maximum yield (51%) of 14-hydroxycodeinone.
Drawbacks: The yield of the method is poor and many side products are formed. Additionally, stoichiometric amount of toxic metal catalyst was required.
Yet another reference may be made to US Patent, 2005, 6,864,370. Here, thebaine bitartrate monohydrate was used for the preparation of 14-hydroxycodeinone. 30% Hydrogen peroxide was added to a solution of thebaine bitartrate monohydrate in a mixture of water, isopropanol and formic acid at 0-5 °C.
The reaction mixture was stirred at the same temperature for 1-2 hours followed by heating at 40- 45 °C for 2-3 hours. After work-up, yield of 14-hydroxycodeinone was 90%.
Drawbacks: Though the yield was excellent, the preparation of starting material thebaine bitartrate monohydrate was a laborious process and involved several steps such as thebaine bitartrate monohydrate was prepared from N-carboethoxynorthebaine, which itself was produced from N-carboethoxynorcodeinone. Additionally, it involved acidic reaction media.
Yet another reference may be made to US Patent, 2006, 7,071,336. Francis et al. used concentrate poppy straw as the source of thebaine. Poppy straw was treated with water, dilute H2SO4, formic acid and 30% H2O2. After 30 min stirring the solution was heated in an oil bath to 50 °C for 20-24 hours to furnish 14-hydroxycodeinone in 74% yield.
Drawbacks: The required time for the completion of the reaction was very long and the yield was not also very good. Additionally the method involved acidic reaction media.
Yet another reference may be made to U.S. patent application, 2006, 20060111383 A1. Oxidation of thebaine was carried out by adding 30% hydrogen peroxide in 85% formic acid over a period of two hours followed by stirring for additional 3 hours. The corresponding yield of 14-hydroxycodeinone is 75%.
Drawbacks: The method involved acidic reaction media and the yield was also not References may be made to
1. J. Org. Chem. 1957, 22, 1505-1508
2. J. Org. Chem. 1958, 23,1247-1251
3. J. Org. Chem. 1960, 25, 987 - 990
4. Tetrahedron Lett. 1969, 22, 1805-1808
5. J. Med. Chem. 1978, 21, 398-400
6. J. Org. Chem. 1981,46, 4012-4014
7. Acta Pharm. Sin. 1983, 18, 475-477
8. US Patent, 1987, 4,639,520
9. US Patent, 1999, 6,008,355

10. US Patent, 2001,6,262,266
11. US Patent, 2001,6,177,567
12. US Patent, 2002, 6,403,798
13. US Patent, 2002, 6,469,170
14. US Patent, 2006, 7,129,248
15. US Patent, 2006, 7,153,966
16. Heterocycles 1998, 49, 43 and references cited therein.
Oxidation of thebaine to 14-hydroxycodeinone is a very important transformation because 14-hydroxycodeinone is a crucial intermediate for the synthesis of a strong analgesic agent oxycodone. It is therefore desirable to develop an efficient, environmentally benign and catalytic method to produce 14-hydroxycodeinone eliminating the drawbacks stated above.
Objectives of the Invention
The main objectives of the present invention is to provide an improved, environmentally benign and a catalytic process for the preparation of 14-hydroxycodeinone (2) from thebaine (1).
Another objective of the present invention is to provide oxidation of thebaine (1) to 14-hydroxycodeinone (2) by V2O5 along with co-oxidant H2O2.
Yet, another objective of the present invention is to carry out the oxidation with catalytic (20 mol %) amount of V2O5.
Still, another objective of the present invention is to carry out the reaction with recyclable and reusable V2O5 with much shorter time of 30-45minutes in excellent yield.
Summary of the Invention
Accordingly the present invention provides an improved green process for the preparation of 14-hydroxycodeinone from thebaine which comprises refluxing thebaine and H2O2 in molar ratio of 1:1-1:2, in the presence of 5-25 mol% V2O5, in a mixture of H2O and organic solvent, for a period of 30-45 minutes, neutralising the above said reaction mixture with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate, washing the resultant organic layer with brine solution and drying it over sodium sulphate, followed by removal of solvent, under reduced pressure, to obtain the desired product of 14-hydroxycodeinone.
In an embodiment of the present invention the amount of oxidising agent V2O5 used is preferably in the range of 15-20mol%
In yet another embodiment the molar ratio of thebaine and H2O2 used
preferably is 1:1.5 1:2.0.
In yet another embodiment the concentration of H2O2 used is preferably 30%.
In yet another embodiment the organic solvent used is selected from the group consists of THF, acetonitrile, methanol and ethanol.
In yet another embodiment the organic solvent used is preferably THF.
In yet another embodiment the ratio of water to THF used is preferably 1:2.
In yet another embodiment the yield of 14-hydroxycodeinone obtained is in the range of 90-95%.
In still another embodiment the catalyst V2O5 used is recyclable and can be reused for consecutive five times to conduct fresh reactions.
Detailed Description of the Invention
The present invention provides an improved and green method for the production of 14-hydroxycodeinone, which is a crucial intermediate for the synthesis of a strong analgesic agent oxycodone.
This invention provides an improved, environmentally benign and catalytic process comprises refluxing of thebaine in H2O and organic solvents THF, methanol, acetonitrile and ethanol in range of 5-25 mol% V2O5 and equiv. of H2O2 for a period of 30-45 minutes, neutralizing the reaction mixture with saturated sodium bicarbonate solution and washing the separated organic layer with brine solution (5%), drying over sodium sulphate, removing the solvent under reduced pressure to get 14-hydroxycodeinone in 92% yield which on hydrogenation with Pd/C in aqueous acetic acid furnished oxycodone in 85% yield. V2O5 can be reused for consecutive five times to conduct fresh reactions without any loss in activity. Also, it does not produce chemical waste to the environment. Thus the whole process is simple, green and economically more viable. Maximum yield was obtained with H20/THF mixture in the ratio of 1:2, with 20 mol% V2O5and 30 mol% of H2O2.
V2O5 can be reused for consecutive five times to conduct fresh reactions without any loss in activity. Also, it does not produce chemical waste to the environment. Thus the whole process is simple, green and economically more viable.
The process for the production of (2) by oxidation of (1) of formula (1) isshown in Scheme 1 SYNTHESIS OF 14-HYDROXYCODEINONE

(Scheme Removed)
Scheme 1
The details of the method disclosed in this invention have been described in the following specific examples, which are provided to illustrate the invention only and therefore, these should not be construed to limit the scope of the present invention.
Oxidation of thebaine to 14-hydroxycodeinone by V2O5 in presence of 30% H2O2 in water/THF mixture and followed by hydrogenation by Pd/C in aqueous acetic acid to produce oxycodone
Example (1A):
Preparation of 14-hydroxycodeinone:
In a 100 ml two-necked round bottom flask, thebaine (1) (0.311 g, 1 mmol) was mixed with 30% H2O2 (1.5 equiv.) and 20 mol% of vanadium pentoxide (0.036 g) in a 10 ml mixture of H20/THF (1:1). The reaction mixture was then refluxed for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was neutralised with saturated sodium bicarbonate solution and was extracted with ethyl acetate (3x10 ml). The organic layer was washed with brine (1x10 ml), dried over Na2SO4 and concentrated under vacuum to give the crude product which was recrystallized from methanol to afford
pure 14-hydrxycodeinone (2) in 92% yield (0.287 g). The aqueous phase was
reused for the subsequent fresh reactions for the five times without any loss of
activity.
Characterization data of 14-hydrxycodeinone
m.p. 274-275 °C [Lit. m.p. 274-275 °C (Helv. Chim. Acta. 1977, 60, 2135)]; 1H NMR (CDCI3, 300MHz): δ 1.67-1.71 (m, 2H), 2.23-2.42 (m, 2H), 2.44 (s, 3H), 3.03 (m, 2H), 3.20-3.26 (m,1H), 3.84 (s, 3H), 4.71 (s, 1H), 5.14 (brs, 1H), 6.17 (d, J= 9.96 Hz, 1H), 6.47-6.70 (m, 3H); FT-IR (KBr, cm-1): 1674.3, 3423.9; ESI-MS (m/z): 314.3 (M++1). Anal. Calcd. for C18H19O4N: C, 69.00; H, 6.11; N, 4.47. Found: C, 69.08; H, 6.17; N, 4.40.
Preparation of oxycodone from 14-hydroxycodeinone by Pd/C in aqueous acetic acid:
The 14-hydroxycodeinone (0.287 g) was dissolved in a mixture of water (5 ml) and acetic acid (5 ml). 10% Pd/C (0.200 g) was added to it in one portion. The system was then evacuated, filled with hydrogen gas and shaken at an initial pressure of 40 psi for about 5 hours at room temperature. The mixture was filtered to remove the catalyst. The residue was washed with 5 ml of acetic acid. The filtrate was concentrated in vacuum to dryness at 50 °C. The filtrate was treated with concentrated ammonium hydroxide solution to pH 10. The mixture was then extracted with ethyl acetate (3 x 10ml), washed with water, dried over Na2SO4 and concentrated under vacuum. The corresponding yield of oxycodone is 0.244 g (85%).
Characterization data of oxycodone
m.p. 217-218 °C [Lit. m.p. 218 °C (J. Med. Chem. 1978, 21, 398)]; 1H NMR (CDCI3, 300MHz): δ 1.55-1.61 (m, 2H), 1.83 (d, J= 12.1 Hz, 1H), 2.16 (t, J= 12.1 Hz, 1H), 2.29 (m, 2H), 2.40 (s, 3H), 2.44 (m, 1H), 2.57 (m, 1H), 2.83 (d, J= 4.2 Hz, 1H), 2.98 (t, J= 12.1 Hz, 1H), 3.12 (d, J= 16.1 Hz, 1H), 3.87 (s, 3H), 4.68 (s, 1H), 5.05 (s 1H), 6.62 (d, J= 8.2 Hz, 1H), 6.68 (d, J= 8.2 Hz, 1H); FT-IR (KBr, cm"1): 1720.1, 3422.6; ESI-MS (m/z): 316.4 (M++1). Anal. Calcd. for C18H21O4N: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.59; H, 6.79; N, 4.38.
Example (1 B): Preparation of 14-hydroxycodeinone:
Same procedure was followed as described in example 1 (A) with
thebaine: 0.311 g (1 mmol), 30 % H2O2 (1.5 equiv.), V2O5: 0.045 g (25 mol%),
Solvent: 10 ml H2O/THF (1:1), time: 30 min, yield: 0.287 g (92%).
Preparation of oxycodone from 14-hydroxycodeinone by catalytic
hydrogenation:
Same procedure was followed as described in example 1 (A) with
14-hydroxycodeinone: 0.281 g, yield: 0.244 g (85%).
Example (1C):
Preparation of 14-hydroxycodeinone:
Same procedure was followed as described in example 1 (A) with
thebaine: 0.311 g (1 mmol), 30% H2O2 (1.5 equiv.), V2O5: 0.027 g (15 mol%),
Solvent: 10 ml H2O/THF (1:1), time: 40 min, yield: 0.281 g (90%).
Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation:
Same procedure was followed as described in example 1 (A) with
14-hydroxycodeinone: 0.272 g, yield: 0.236 g (84%).
Example (1D):
Preparation of 14-hydroxycodeinone:
Same procedure was followed as described in example 1 (A) with
thebaine: 0.311 g (1 mmol), 30% H202 (1.5 equiv.), V2Os: 0.018 g (10 mol%),
Solvent: 10 ml H20/THF (1:1), time: 45 min, yield: 0.272 g (87%).
Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation:
Same procedure was followed as described in example 1 (A) with
14-hydroxycodeinone: 0.253 g, yield: 0.232 g (85%).
Example (1E):
Preparation of 14-hydroxycodeinone:
Same procedure was followed as described in example 1 (A) with
thebaine: 0.311 g (1 mmol), 30 % H2O2 (1.5 equiv.), V2O5: 0.009 g (5 mol%),
Solvent: 10 ml H2O/THF (1:1), time: 1.0 hour, yield: 0.253 g (81%).
Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation:
Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.234 g, yield: 0.215 g (85%).
Example (1F):
Preparation of 14-hydroxycodeinone:
Same procedure was followed as described in example 1 (A) with
thebaine: 0.311 g (1 mmol), 30% H2O2 (1.5 equiv.), V2O5: 0.036 g (20 mol%),
Solvent: 10 ml H2O/THF (1:2), time: 30 min, yield: 0.287 g (92%).
Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation:
Same procedure was followed as described in example 1 (A) with
14-hydroxycodeinone: 0.281 g, yield: 0.239 g (83%).
Example (1G):
Preparation of 14-hydroxycodeinone:
Same procedure was followed as described in example 1 (A) with
thebaine: 0.311 g (1 mmol), 30% H2O2 (1.5 equiv.), V2O5: 0.036 g (20 mol%),
Solvent: 10 ml H2O/THF (2:1), time: 30 min, yield: 0.275 g (88%).
Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.275 g, yield: 0.234 g (85%).
Example (1H):
Preparation of 14-hydroxycodeinone:
Same procedure was followed as described in example 1 (A) with
thebaine: 0.311 g (1 mmol), 30% H2O2 (1.5 equiv.), V2O5: 0.036 g (20 mol%),
Solvent: 10 ml H2O/MeCN (1:1), time: 40 min, yield: 0.275 g (88%).
Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation:
Same procedure was followed as described in example 1 (A) with
14-hydroxycodeinone: 0.275 g, yield: 0.225 g (82%).
Example (11):
Preparation of 14-hydroxycodeinone:
Same procedure was followed as described in example 1 (A) with
thebaine: 0.311 g (1 mmol), 30% H2O2 (1.5 equiv.), V2O5: 0.036 g (20 mol%),
Solvent: 10 ml H2O/MeOH (1:1), time: 40 min, yield: 0.262 g (84%).
Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation:
Same procedure was followed as described in example 1 (A) with
14-hydroxycodeinone: 0.262 g, yield: 0.220 g (84%).
Example (1J):
Preparation of 14-hydroxycodeinone:
Same procedure was followed as described in example 1 (A) with
thebaine: 0.311 g (1 mmol), 30% H2O2 (1.5 equiv.), V2O5: 0.036 g (20 mol%),
Solvent: 10 ml H2O/EtOH (1:1), time: 35 min, yield: 0.266 g (85%).
Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation:
Same procedure was followed as described in example 1 (A) with
14-hydroxycodeinone: 0.266 g, yield: 0.226 g (85%).
Example (1K):
Preparation of 14-hydroxycodeinone:
Same procedure was followed as described in example 1 (A) with
thebaine: 0.311 g (1 mmol), 30% H2O2 (1.0 equiv.), V2O5: 0.036 g (20 mol%),
Solvent: 10 ml H2O/THF (1:1), time: 45 min, yield: 0.262 g (84%).
Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation:
Same procedure was followed as described in example 1 (A) with
14-hydroxycodeinone: 0.262 g, yield: 0.217 g (83%).
Example (1L):
Preparation of 14-hydroxycodeinone:
Same procedure was followed as described in example 1 (A) with
thebaine: 0.311 g (1 mmol), 30% H2O2 (1.2 equiv.), V2O5: 0.036 g (20 mol%),
Solvent: 10 ml H2O/THF(1:1), time: 45 min, yield: 0.266 g (85%).
Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.266 g, yield: 0.224 g (84%).
Example (1M):
Preparation of 14-hydroxycodeinone:
Same procedure was followed as described in example 1 (A) with thebaine: 0.311 g (1 mmol), 30% H2O2 (2.0 equiv.), V2O5: 0.036 g (20 mol %), Solvent: 10 ml H2O/THF (1:1), time: 30 min, yield: 0.287 g (92%). Preparation of oxycodone from 14-hydroxycodeinone by catalytic hydrogenation: Same procedure was followed as described in example 1 (A) with 14-hydroxycodeinone: 0.281 g, yield: 0.241 g (84%). Table 1. Recycling of the catalyst

(Table Removed)
Isolated yield. The Main Advantages of the Present Invention are :
1 The method is very simple and environmentally benign.
2 The product can be obtained in excellent yield (81-92%).
3 Catalytic amount of V2O5 (20 mol%) is sufficient to carry out the reaction
effectively.
4 H2O2 is used as a green co-oxidant.
5 The catalyst is recyclable and can be reused for consecutive five times to conduct fresh reactions without any loss in activity. Also, it does not produce chemical waste to the environment. Thus the whole process is simple, green and economically more viable.

We Claim
1. An improved green process for the preparation of 14-hydroxycodeinone from thebaine which comprises refluxing thebaine and H2O2 in molar ratio of 1:1-1:2, in the presence of 5-25 mol% V2O5, in a mixture of H2O and organic solvent, for a period of 30-45 minutes, neutralising the above said reaction mixture with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate, washing the resultant organic layer with brine solution and drying it over sodium sulphate, followed by removal of solvent, under reduced pressure, to obtain the desired product of 14-hydroxycodeinone.
2. An improved process as claimed in claim 1, wherein the amount of oxidising agent V2O5 used is preferably in the range of 15-20mol%
3. An improved process as claimed in claims 1 & 2, wherein the molar ratio of
thebaine to H2O2 used is preferably in the range of 1:1.5 1:2.0.
4. An improved process as claimed in claims 1-3, wherein the concentration of H2O2 used is preferably 30%.
5. An improved process as claimed in claims 1-4, wherein the organic solvent used is selected from the group consisting of THF, acetonitrile, methanol and ethanol.
6. An improved process as claimed in claims 1-5, wherein the organic solvent
used is preferably THF.
7. An improved process as claimed in claims 1-6, wherein the ratio of water to THF used is preferably 1:2.
8. An improved process as claimed in claims 1-7, wherein the yield of 14-hydroxycodeinone obtained is in the range of 90-95%.
9. An improved process as claimed in claims 1-8, wherein the catalyst V2I5 used
is recyclable and can be reused for consecutive five times to conduct fresh reactions
10. An improved green process for the preparation of 14-hydroxycodeinone from
thebaine, substantially as herein described with reference to the examples

Documents:

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Patent Number

269936

Indian Patent Application Number

1804/DEL/2008

PG Journal Number

47/2015

Publication Date

20-Nov-2015

Grant Date

19-Nov-2015

Date of Filing

30-Jul-2008

Name of Patentee

COUNCIL OF SCIENTEFIC AND INDUSTRIAL RESEARCH

Applicant Address

ANUSANDHAN BHAWAN, RAFI MARG, NEW DELHI-110 001,INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	DILIP KONWAR	CHEMICAL SCIENCE BLOCK, NORTH EAST INSTITUTE OF SCIENCE AND TECHNOLOGY (NEIST), JORHAT-785006, ASSAM.
2	SAIKAT DAS SHARMA	CHEMICAL SCIENCE BLOCK, NORTH EAST INSTITUTE OF SCIENCE AND TECHNOLOGY (NEIST), JORHAT-785006, ASSAM

PCT International Classification Number

C07D

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA