FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
A PROCESS FOR PREPARING BUPRENORPHINE HYDROCHLORIDE AND ITS INTERMEDIATE.
2. APPLICANT (S)
(a) NAME: BABASAHEB PANDURANG BANDGAR,SANJAY SURESH
SAWANT, S. M. SALMAN JAWEED MUKARRAM
(b) NATIONALITY: INDIAN
(c) ADDRESS: SCHOOL OF CHEMICAL SCIENCES
SOLAPUR UNIVERSITY SOLAPUR, SOLAPUR - PUNE HIGHWAY,KEGAON SOLAPUR-413255, MAHARASHTRA, INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for the preparation of Buprenorphine
hydrochloride, and it's intermediate.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides a process for preparation of Buprenorphine or its hydrochloride salt. The invention further relates to process for the preparation of intermediate of Buprenorphine, which involves condensation of thebaine with methyl venyl ketone in presence of hydroquinone to obtain thebaine adduct and its conversion to Buprenorphine or its hydrochloride salt.Chemically, Buprenorphine is 17-(cyclopropylmethyl)-a-(l, 1 -dimethylethyl)-4, 5-epoxy-18, 19-dihydro-3-hydroxy-6-methoxy-α-methyl-6, 14- ethenomorphinan-7-methanol, hydrochloride [5α, 7a(S)]. Buprenorphine having the structural formula-l.

Formula I Buprenorphine is a synthetic thebaine congener, highly lipid soluble and 25 times more potent than a morpholine. Buprenorphine is an opioid partial agonist. The agonist effects of buprenorphine increase linearly with increasing doses of the drug until at moderate doses they reach a plateau and no longer continue to increase with further increases in dose-the "ceiling effect". Thus, buprenorphine carries a lower risk of abuse, addiction, and side effects compared to full opioid agonists.
Buprenorphine is indicated for the treatment of moderate to severe pain, peri-operative analgesia, and opioid dependence. It has a longer duration of action than morphine, and sublingual tablet offer an analgesic effect for 6 to 8 hours.
A clinical trial conducted that a majority of unipolor non-psychotic patients with major depression refractory to conventional thymolepticanti depressants could be successfully treated with buprenorphine.

United States patent US 3,433,791 discloses the preparation of Thebaine and oripavine derivatives particularly buprenorphine base. J.Am.Chem.Soc.3281-3292 (89:13): 1967 discloses the preparation of 7α-acetyl-6,14-endoethano-6, and 7, 8, 14-tetrahydro-thebaine from thebaine.
J.Am.Chem.Soc.3281-3292 (89:13) 1967 discloses preparation of dihydrothevinone (7 a -acetyl-6, 14-endoethano-6,7,8,14-tetrahydrothebaine) by reduction of 7α-acetyl-6,14-endoethano-6, 7, 8, 14-tetrahydro thebaine with 10 % Pd/C, H2 in acetic acid at 50°C for 10 h.
Preparation of N-cyano-7a-acetyl-6,14-endoethano-6,7,14-tetrahydrothebaine is disclosed in Magnetic Resonance in Chemistry 454 - 459, 23, (6) 1985.
Various other prior art references, US20090156817; EP 2222679; WO2009078986; US20080125592; US20100274019; EP2076131 and EP2332409 applications disclose process for preparing oxymorphone, naltrexone, and buprenorphine.
US 20100081813 and WO/2010/039217 applications disclose condensation of thebaine with methyl vinyl ketone in presence of isopropanol and water mixture to produce 6,14-endo-etheno-7.alpha.-acetyltetrahydro-thebaine.
The above prior art references faces one or the other problems, for example, low yield and formation of by-products, which requires further purification. Therefore, the present inventors developed a novel alternate process for preparing Buprenorphine or its salt, which is an industrially applicable, commercially feasible and provides high yield.
In an aspect of the present invention provides a process for the preparation of intermediate of Buprenorphine, thebaine adduct of formula II, which comprises reaction of compound of formula (I) with methyl venyl ketone in presence of reagent and solvent, to obtain a compound of formula (II);


The reaction of a compound of formula-l with methyl venyl ketone is performed in presence of reagent such as hydroquinone, trimethylhydroquinone and the like. The suitable temperature for conducting the reaction is about room temperature to reflux temperature as per the solvent used. Suitable solvent used for the reaction includes but are not limited to hydrocarbon such as toluene, n-hexane, benzene, heptane and the like; halogenated solvent such as chloroform, dichloromethane, and the like; ether such as tetrahydrofuran, diisopropyl ether and the like. The reaction may be carried out for a period of about 1 hour to 3 hour or more.
After completion of reaction, reaction mixture may be concentrated and subjected to the precipitation of solid by using suitable techniques such as recrystallization, anti-solvent technique and the like.
The yield of thebaine adduct obtained from the present invention is more than or equal to 97%.
The resultant compound of formula II is further converted to Buprenorphine hydrochloride or its intermediates as the process disclosed in the prior art or as per the examples of the present invention.
The resultant compound is converted to an intermediate of Buprenorphine, 7a-(1- (s)-hydroxy-1, 2,2-trimethylpropyl)-6, 14- endo-ethano tetrahydronorthebaine of Formula VI, as per the process disclosed in the prior art, for example, Faming Zhuanli Shenqing Gongkai Shuomingshu, 1939920; Guangxi Daxue Xuebao, Ziran Kexueban, 29(3), 265-268; WO 2010039220; and WO 2009122436 or the process disclosed in example No II to IV, which involves reduction, grignard reaction, cyanation, and then hydrolysis to provide the compound of formula VI. The general process is represented for the compound of Formula VI in the following Scheme I:


In another aspect of the present invention provides a process for the preparation of
Buprenorphine or its hydrochloric acid salt, which comprises:
a) Condensation of the compound of formula (VI) with cyclopropyl methyl bromide in presence of base and solvent to provide N-cyclopropyl methyl-7a- (1- (s)-hydroxy-l, 2, 2-trime-thylpropyl)-6, 14-endoethanotetrahydronorthebaine of Formula VII; and


(b) hydrolysis of the compound of formula (VII) with base in presence of diethylene glycol to obtain 21-cyclopropyl-7a-(2-hydroxy-3,3-dimethyt-2-butyl)-6, 14-endoethano -6, 7, 8, 14-tetrahydrooripavine of formula (VIII);

The condensation reaction of a compound of formula VI with cyclopropyl methyl bromide is performed in presence of solvent such as nitrile, for example, acetonitrile and the like; amide such as dimethyl formamide (DMF) and dimethyl acetamide (DMA) and the like; DMSO or combination of water thereof. The suitable base includes but are not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like. The condensation reaction may be performed at about room temperature to about reflux condition for sufficient period of time, for example, 1 hour to 4 hour or more.
The hydrolysis reaction of step b) involves reaction of compound of formula VII with base may be carried out in presence of solvent such as diethylene glycol at about room temperature to reflux temperature or about 150 °C. The suitable base includes but are not limited to inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like; organic base such as triethyl amine, pyridine and the like. The reaction may be performed in presence of inert atmosphere for about 30 minutes to 1 hour or more to obtain Buprenorphine base.

The resultant Buprenophine is further treated with concentrated hydrochloric acid (HCI) or aqueous or organic solution of hydrochloric acid such as aqueous HCI, alcoholic HCI, ketonic HCI and the like. The reaction is performed in presence of solvent such as ketone, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone and the like. The reaction may be maintained for a period of about 30 minutes to about 1 hour. After completion of reaction, the reaction mixture may be filtered and recrystallized with methanol to obtain Buprenophine hydrochloride.
The yield of Buprenophine hydrochloride obtained from the present invention is more than or equal to 96%.
The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.
EXPERIMENTAL Example No- 1
Synthesis of 7a -acetyl-6,14-endoethano-6, 7, 8,14-tetrahydrothebaine (II):
To a solution of thebaine (25 g, 0.080 mole) in toluene and n-hexane mixture (150 ml), was added a catalytic amount of hydroquinone (8 mg, 7.5 m mole), methylvinylketone (20 g, 0.286 mole). The reaction mixture was heated under reflux at 80 - 85°C for 3 h. After completion of reaction, reaction mixture was concentrated under vacuum and recrystllise from ethyl alcohol to yield 7a acetyl-6, 14-endoethano-6, 7, 8, 14-tetrahydrothebaine (II).
Yield = 29.7 g, 97%
MP = 116-123 °C

IR cm'1 (KBr): 459.1, 467.3, 490.52, 520.68, 555.14, 585.3, 597.37, 638.45,647.62, 688.74, 699.51, 728.58, 746.56, 766.78, 776.17, 791.07, 817.33, 858.09879.10, 910.35, 926.00, 939.67,950.75, 959.26, 977.04, 991.61, 1009.73, 1050.91, 1064.61, 1084.72, 1107.13, 1129.94, 1149.46, 1164.38, 1211.44, 1252.50, 1274.94, 1298.06, 1320.23, 1336.50, 1347.28, 1378,84, 1444.57, 1453.80,1471.91,1601.99, 1628.30, 1821.35, 2696.08, 2769.94, 2798.21, 2835.20, 2875.36, 2897.84, 3022.33, 3054.53, 3413.84, 3697.02,3839.16.
Example No -2
Synthesis of 7 a -acetyl-6,14-endoethano-6, 7, 8, 14-tetrahydro-thebaine (Dihydrothevinone) (III):
To a solution of 7-acetyl-6, 14-endoethano-6, 7, 8, 14-tetrahydrothebaine (25 g, 0.066 mole) in ethyl alcohol (125 ml) in under nitrogen atmosphere, a catalytic amount of palladium on carbon 5 % (1.5 g, 0.014 mole) in water (5 ml) was added. Connect the hydrogen gas inlet tube and maintain reaction mixture at 30 - 35 °C under 2 kg /cm"3 pressures for 2 h. After completion of reaction, allow the reaction mixture cooled to room temperature and collect the palladium 5 % on carbon by filtration at suction. The organic layer was concentrated and recrystallized from ethyl alcohol to furnish 7a -acetyl-6, 14-endoethano-6, 7, 8, 14-tetrahydro-thebaine (Dihydrothevinone) (III).
Yield = 24g, 96%
MP=134-138°C
IR cm'1 (KBr): 457.78, 473.07, 489.43, 508.03, 533.81, 558,60, 574.80,590.46, 642.12, 692.91, 757.29, 771.34, 794.69, 821.57, 856.91, 880.54,900.99, 940.65, 960.39, 992.83, 1013.20, 1051.17, 1097.90, 1128.21, 1145.67,1167.31, 1209.99, 1280.23, 1257.64, 1319.17, 1355.40, 1450.61, 1501.94, 1597.53, 1625.23, 2348.41, 2785.87, 2841.52, 2882.22, 2944.99, 2972.92, 3397.55.

Example No - 3
Synthesis of 7α-(1-(s)-hydroxy-1, 2, 2-trimethylpropyJ-6,14-endoetha-no tetrahydrothebaine (IV):
To a suspension of magnesium metal (6 g, 0.25 mole) in dry ether (150 ml) was added a catalytic amount of iodine (1 g, 0.004 mole or 0.4 % mmole) and t-butyl chloride (28 g, 0.3. mole). The resulting solution was heated under reflux for 1 h to the reaction mixture 7 a -acetyl-6, 14-endoethano-6, 7, 8, 14-tetrahydrothebaine (dihydrothevinone) (25 g, 0.065 mole) in toluene was added at reflux temperature and continue the reaction mixture at same temperature for 6 h. After completion of reaction, allow the reaction mixture cooled to room temperature, the reaction mixture was filtered and washed with saturated solution of ammonium chloride (175 ml) and then washed with water (125 ml). The organic layer was dried with anhydrous Na2SO4, concentrated and re crystallized in methanol to furnish the yield of 7α-(1-(s)-hydroxy-1, 2, 2-trimethylpropyl~6, 14-endoethano tetrahydrothebaine (IV). Yield = 13 g, 45%; MP =184-188 °C
IR cm-1(KBr): 457.00, 472.7, 517.85, 556.45, 572.64, 622.49, 637.49, 655.02, 685.12, 741.10, 754.22, 771.18, 784.66, 801.32, 819.72, 852.05, 87191,884.33, 908.84, 918.06, 926.87, 944.54, 960.64, 989.29, 1006.13, 1033.11, 1050.13, 1080.05, 1091.78, 1150.43, 1208.23, 1241.68, 1258.84, 1281.35, 1313.40, 1337.23, 1354.91, 1360.63, 1407.82, 1446.27, 1474.95, 1598.79, 1626.55, 1836.80, 2298.19, 2343.15, 2711.73, 2769.00, 2839.63, 2792.04, 2896.71, 2921.21, 2974.24, 2989.13, 3420.58.
Example No -4
Synthesis of N-cyano-7a- (1, (s)-hydroxy-l, 2,2-trimethylpropyl)-6,14- endoethano
tetrahydrothebaine (V):
To a solution of 7a- (1- (s)-hydroxy-l, 2, 2-trimethylpropyl-6, 14-endoethano tetrahydrothebaine (25 g, 0.055 mole) in chloroform (75 ml) was added a cyanogen bromide (9 g, 0.086 mole). The resulting solution is heated at reflux temperature for 5 h. After completion of reaction, concentrate reaction mixture and recrystallised from methanol to yield N-cyano -7a-(1- (s)-hydroxy-l, 2, 2-trimethy!propyJ)-6, 14- endoethano tetrahydrothebaine (V). Yield = 24 g, 95 %

MP = 205-210 °C
IRcm-3(KBr): 473.55, 460.07, 489.76, 507.64, 520.92, 560.43, 593.15, 632.35, 650.62,
689.76, 754.95, 784.69, 792.64, 804.92, 823.42, 850.55, 874.60, 887.45, 900.73,
927.76, 944.54, 958.81, 990.88, 1014.70, 1034.96, 1054.76, 1099.33, 125.76, 158.18, 1186.61, 1216.61, 1267.65, 1279.52, 1292.23, 1317.39, 1339.95, 1366.33, 1387.08, 1401.32,1450.51, 503.92, 1628.02, 1596.98, 2100.01, 2836.17, 2906.98, 2979.56, 3460.87.
Example No - 5:
Synthesis of 7a-(1- (s)-hydroxy-l, 2,2-trimethylpropyl)-6,14- endo-ethano tetrahydronorthebaine (VI):
To a suspension of N-cyano -7a-(1- (s)-hydroxy-l, 2, 2-trimethylpropyl)-6, 14-endoethano tetrahydrothebaine (25 g, 0.055 mole), in diethylene glycol (200 ml), was added a potassium hydroxide (18 g 0.32 mole) in inert atmosphere. The resulting solution was heated at reflux temperature for 4 h. After completion of reaction, allowed the reaction mixture to cool to room temperature and the reaction mixture was quenched with water (1800 ml). The reaction mixture was filtered and washed with water (25 ml) and recrystallised from methanol to obtain 7a-(1- (s)-hydroxy-l, 2, 2-trimethylpropyl)-6, 14- endoethano tetrahydronorthebaine (VI). Yield = 22 g, 94 %; MP = 165-169 °C
IR cm"1 (KBr): 458.01, 472.80, 490.11, 509.42, 552.23, 568.69, 631.50, 655.29, 692.77, 713.71, 751.35, 783.79, 808.79, 846.80, 861.76, 916.43, 944.62, 961.20, 987.82, 1012.12 ,1039.92, 1058.84, 1072.44, 1089.88, 1164.21, 1188.63, 1207.12, 1239.50, 1241.60, 1263.08, 1281.00, 1304.05, 1316.87, 1329.01,1341.60, 1360.00, 1368.98, 1387.57, 1415.90, 1452.37, 1468.61, 1568.73,1598.98, 1629.83, 1830.83, 2208.08, 2672.11, 2740.59, 2844.82, 2868.20, 2985.63, 316.09, 3362.39 .

Example No-6
Synthesis of N-cyclopropyl methyl-7α- (1- (s)-hydroxy-1, 2,2-trime-thylpropyJ)-6, 14- endoethano tetrahydronorthebaine (VII):
To a solution of 7a-(1-(s)-hydroxy-1, 2,2-trimethylpropyl)-6, 14- endoethano tetrahydronorthebaine (25 g, 0.058 mole) in acetonitrile (200 ml) was added potassium carbonate (22.5 g, 0.163 mole), cyclopropyl methyl bromide (9.5 g, 0.070 mole). The resulting solution is heated at reflux temperature for 4 hours. Aftercompletion of reaction (TLC), allowed the reaction mixture to cool to 0-5 °C. The reaction mixture was filtered to give N-cyclopropylmethyl-7α-(1-(s)-hydroxy-1, 2, 2-thmethylpropyl)-6, 14-endoethano tetrahydro northebaine (VII). Yield = 27 g, 97 % MP = 106-112 °C
IR cm-1 (KBr): 457.10, 481.03, 508.71, 523.63, 558.09, 577.86, 597.87, 627.52, 639.52, 653.57, 691.33, 740.59, 752.11, 777.49, 820.87, 852.32, 880.77,910.21, 921.77, 937.20, 957.83, 969.97, 988.08, 1007.42, 1018.10, 1057.57, 1076.45, 1098.22, 1110.36, 1129.60, 1164.99, 1205.96, 1219.82, 1241.50, 1263.50, 1281.08, 1283.40, 1322.26, 1334.06, 1369.23, 1380.17, 1401.46, 1442.25, 1452.24, 1598.40, 1628.25, 1801.04, 2064.08, 2295.51, 2673.70, 2775.47,2813.01, 2835.64, 2927.87, 2948.87, 3036.11,3077,81,3 448.29.
Example No - 7
Synthesis of 21-cyclopropyl -7a- (2-hydroxy-3, 3-dimethyl -2-butyl)-6, 14-endoethano -6, 7, 8,14-tetrahydrooripavine (VIII):
To a suspension of N-cyclopropyl methyl-7a- (1-(s)-hydroxy-1,2,2-trimethylpropyl)-6, 14-endoethano tetrahydro northebaine (25 g, 0.052 mole) in diethylene glycol (500 ml) was added potassium hydroxide (50 g, 0.893 mole) under inert atmosphere .The resulting solution was heated at 200 - 210 °C for 1 h. After completion of reaction (TLC), allowed the reaction mixture cool to room temperature and the reaction mixture was quenched with water (225 ml) at 5 -10 °C and extracted with chloroform (600 ml) with continues stirring, was separated organic layer and washed with saturated solution of ammonium chloride (225 ml) and then washed with water (225 ml). The organic layer was

concentrated and recrystalized in cyclohexane to furnish the yield of 21-cyclopropyl-7a-(2-hydroxy-3, 3-dimethyl-2-butyl)-6, 14-endoethano -6, 7, 8, 14-tetrahydrooripavine (VIII).
Yield = 23g, 97%
MP = 202-210 °C
IR cm-1 (KBr): 459.10, 470.60, 506.73, 524.60, 560.44, 573.40, 597.80, 637.59, 654.39, 700.41, 724.87, 745.03, 788.23, 823.55, 851.03, 885.05, 903.68, 932.05, 945.83, 963.27, 995.00, 1022.95, 1075.08, 1106.96, 1160.23, 1196.87, 1217.43, 1238.55, 1280.68, 1299.25, 1310.94, 1326.25, 1352.15, 1371.13, 1388.09, 1409.27, 1428.28, 1507.57, 1606.82, 1630.23, 1828.73, 2042.55, 2363.14, 2715.44, 2746.38, 2809.39, 2911.91, 2955.23, 3051.27, 3080.94, 3237.92, 3401.22.
Example No-8
Synthesis of 21-cyclopropyl -7a- (2-hydroxy-3, 3-dimethyl -2-butyl)-6,14-endoethano -6,7,8,14-tetrahydrooripavine hydrochlo-ride (IX)
To a solution of 21-cyclopropyl -7a- (2-hydroxy-3, 3-dimethyl -2-butyl)-6, 14-endoethano - 6,7,8,14-tetrahydrooripavine (10 g, 0.021 mole) in acetone (140 ml) was added a small amount of concentrated hydrochloric acid (3 g, 0.10 mole) and stirring was continued for 1h r.t. After completion of reaction (TLC), reaction mixture was filtered and recrystallized with methanol to give 21-cyclopropyl -7a- (2-hydroxy-3, 3-dimethyl -2-butyl)-6, 14- endoethano -6, 7, 8, 14-tetrahydrooripavine hydrochloride (IX). Yield = 10g, 95% MP = 260°C
IR cm'1 (KBr): 474.10, 488.79, 507.46, 5 25.27, 534.95, 557.38, 649.91, 674.76,744.54, 754.66, 771.76, 795.35, 818.61, 840.82, 856.64, 872.96, 888.01,904.64,925.77, 972.03, 989.80, 997.55, 1029.60, 1043.71, 1098.36, 1121.41,1156.37, 170.86, 1212.25,
1241.12, 1269.76, 1321.28, 1337.88, 1371.29, 1399.29, 1436.63, 1504.70, 1615.36,
1639.12, 1828.11, 2342.02, 2362.03, 2349.17, 2760.80, 2829.06, 3027.23, 3142.48, 3363.10.

We Claim:
1. A process for the preparation of thebaine adduct of formula II,

which comprises:
treating a compound of formula (I) with methylvenylketone in presence of reagent and
solvent, to obtain a compound of formula (II);

2. The process of claim 1, wherein said reagent is hydroquinone.
3. The process of claim 1, wherein said solvent is selected from toluene, chloroform, benzene, ether, n-hexane.
4. A process for the preparation of Buprenorphine or its hydrochloric acid salt,
which comprises:
a) condensation of the compound of formula (VI) with cyclopropyl methyl bromide in presence of base and solvent to provide N-cyclopropyl methyl-7a- (1- (s)-hydroxy-1,2,2-trime-thylpropyl)-6, 14-endoethanotetrahydronorthebaine of Formula VII; and


(b) hydrolysis of the compound of formula (VII) with base in presence of diethylene glycol to obtain 21-cyclopropyl-7α-(2-hydroxy-3, 3-dimethyl-2-butyl)-6, 14-endoethano -6, 7, 8, 14-tetrahydrooripavine of formula (VIII);

5. The process according to claim 4, wherein the solvent nitrite, for example, acetonitrile and the like; amide such as dimethyl formamide (DMF) and dimethyl acetamide (DMA) and the like; DMSO or combination of water thereof.
6. The process according to claim 4, wherein the said base of step a) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.

7. The process according to claim 4, wherein the hydrolysis reaction of step b) is performed at inert atmosphere.
8. The process according to claim 4, wherein the base is selected from inorganic base and organic base.