(12) United States Patent (10) Patent No.: US 8,981,097 B2 Saxena Et Al

US008981097B2

(12) United States Patent (10) Patent No.: US 8,981,097 B2 Saxena et al. (45) Date of Patent: Mar. 17, 2015

(54) INDUSTRIAL PROCESS FOR THE (56) References Cited PREPARATION OF BUPRENORPHINE AND ITS INTERMEDIATES U.S. PATENT DOCUMENTS 3.433,791 A 3/1969 Bentley (71) Applicant: Rusan Pharma Limited, Mumbai (IN) 2011/O152527 A1 6, 2011 Patel et al. 2011/0313163 A1* 12/2011 Hudlicky et al...... 546,39 (72) Inventors: Navin Satyapal Saxena, Mumbai (IN); FOREIGN PATENT DOCUMENTS Kunal Saxena, Mumbai (IN); Kaushik Babubhai Sata, Mumbai (IN) WO 2013050748 4/2013 * cited by examiner (73) Assignee: Rusan Pharma Limited, Mumbai (IN) Primary Examiner — Charanjit Aulakh (74) Attorney, Agent, or Firm — Kramer Amado, P.C. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 (57) ABSTRACT U.S.C. 154(b) by 0 days. There is provided an efficient industrial process for the prepa ration of 21-cyclopropyl-7C-(2-hydroxy-3,3-dimethyl-2-bu tyl)-6, 14-endo-ethano-6,7,8,14-tetrahydro-oripavine, i.e. (21) Appl. No.: 14/302,159 buprenorphine of Formula-I in high yield and purity, with enhanced safety and eco-friendly norms. The invention fur (22) Filed: Jun. 11, 2014 ther relates to an improved process for preparation of inter mediates thereof in high yield and purity. (65) Prior Publication Data US 2014/0364612 A1 Dec. 11, 2014 Formula-I HO (30) Foreign Application Priority Data Jun. 11, 2013 (IN) ...... 1988/MUMA2013

(51) Int. Cl. CO7D 489/2 (2006.01) N CO7D 489/02 (2006.01) MeO (52) U.S. Cl. HO CPC ...... C07D489/12 (2013.01) i-Bu USPC ...... 54.6/39: 546/44 Buprenorphine (58) Field of Classification Search USPC ...... 546/39, 44 See application file for complete search history. 17 Claims, No Drawings US 8,981,097 B2 1. 2 INDUSTRAL PROCESS FOR THE invention further relates to an improved process for the prepa PREPARATION OF BUPRENORPHINE AND ration of intermediates thereof in a high yield and purity. ITS INTERMEDIATES BACKGROUND OF THE INVENTION Buprenorphine, chemically known as 21-cyclopropyl-7.C.- FIELD OF INVENTION (2-hydroxy-3,3-dimethyl-2-b 1)-6, 14-endo-ethano-6,7,8,14 tetrahydrooripavine, is a semi-synthetic opiate used as a pow The present invention relates to an efficient industrial pro erful analgesic and is indicated for the treatment of moderate cess for the preparation of 21-cyclopropyl-7C.-(2-hydroxy-3, to severe pain and opioid dependence. The compound was 3-dimethyl-2-butyl)-6, 14-endo-ethano-6,7,8,14-tetrahydro- 10 first reported by K. W. Bentley in U.S. Pat. No. 3.433,791. oripavine, i.e. buprenorphine of Formula-I, in a highyield and This patent reports the semi-synthesis of buprenorphine from purity with enhanced safety and eco-friendly norms. The thebaine as depicted in Scheme-1.

Scheme-1:

MeO MeO

HerMVK O CN N Hydrogenation O N

MeO MeO Thebaine Formula-II O O Formula-III Formula-IV

grignard reaction t-BuMgCl

MeO MeO MeO

DEGfKOH O CNBr. O O a 1659 C. NH N NON N N

MeO MeO MeO

HO HO HO t-Bu t-Bu Formula-VII Formula-VI Formula-V

OMe MeO HO

O LiAlH4 O DEGfKOH O O --> N 210° C. N

MeO MeO MeO

HO HO HO t-Bu t-Bu t-Bu Formula-VIII Formula-IX Formula-I US 8,981,097 B2 3 4 Various methods for the preparation of buprenorphine are yield of the process is only 27% of buprenorphine base from reported in the prior art. The following documents disclose thebaine. In addition, the workup procedure for O-demethy methods for preparing buprenorphine wherein thebaine is lation is tedious and there is no mention of the purity of the product and intermediates. Furthermore, the process uses used as a key starting material. hazardous, highly flammable and peroxide forming solvents, US 2011/0152527A1 discloses a process for the prepara for example diethyl ether and THF, which makes the process tion of buprenorphine as depicted in Scheme-2. The process unsuitable at an industrial scale. Finally, the process requires up to Formula-V is similar to the Bentley process reported in an extra step for purification, resulting in a low yield of the U.S. Pat. No. 3,433,791. However, major modifications final product.

Scheme-2: MeO MeO MeO

O CN N --MVK O CN N Hydrogenation O N

MeO MeO MeO Thebaine Formula-II O O Formula-III Formula-IV grignard reaction | t-BuMgCl MeO MeO MeO

Chlorobenzene NaI/Ethyl O DEG, KOH O chloroformate O NH 130-140° C. N r OCH215 N N O MeO MeO MeO

HO HO HO t-Bu t-Bu t-Bu Formula-VII Formula-X Formula-V s s OH MeO HO

O Thio phenol O N -e- N Chlorobenzene

MeO MeO

HO HO t-Bu t-Bu Formula-IX Formula-I

60 include the use of ethyl chloroformate and then heating at WO 2013/050748 of Johnson Matthey PTC discloses a 130° C. to 140° C. with KOH and diethylene glycol for process for the preparation of buprenorphine or its deriva N-demethylation of the compound of Formula-V to get the tives, as shown in Scheme-3 below. The preparation of the compound of Formula-VII; the subsequent reaction with compound of Formula-VI is performed by known processes. cyclopropyl methyl alcohol with mesyl chloride for N-alky 65 However, major modifications include N-demethylation, lation; and finally the use of thiophenol for O-demethylation which is carried out at lower temperatures using NaOH, water to get buprenorphine base of Formula-I. The overall reported and ethylene glycol or methoxy ethanol and then Subsequent US 8,981,097 B2 5 O-demethylation using a different combination of thiols and bases to get the compound of Formula-XI. This compound is MeO further converted to buprenorphine using methods known in the prior art. The publication does not disclose the formation of compound of Formula-VI and starts with this advance 5 intermediate. The first reaction is N-demethylation, which is O Demethylation followed by 3-O-demethylation to get the compound of For N - X mula-XI which is further converted to buprenorphine. A dis advantage associated with this process is the formation of impurities which arises during the final step of N-alkylation, 10 MeO as alkylation can occur on both the NH group and 3-phenolic HO group. Thus, additional steps for purification may be required, which lead to poor yield and lower quality of the t-Bu final product. It is further mentioned that 3-O-demethylation 3-O-Methylbuprenorphine cannot happen on the N-alkylcycloalkylated intermediate. 15 HO For that reason, both N-demethylation and O-demethylation are carried out prior to the N-alkylation step. O N Scheme-3: MeO MeO

25 HO Ethylene glycol t-Bu O N NaOH, H2O -e- Buprenorphine NON 115-125° C. One drawback associated with the prior art processes is an MeO 30 overall low yield of product buprenorphine. Another draw back associated with the prior art processes is the use of toxic, HO highly flammable and hazardous solvents in the Grignard t-Bu reaction step, for example benzene, diethyl ether and THF, making the process unsuitable for Scaling-up to industrial Formula-VI 35 scale due to safety and environmental concerns. Additionally, MeO HO the prior art processes are prone to the formation of by products/impurities and thus, require extra steps for purifica tion at intermediate stages as well as at the final product stage. This leads to poor yield and inferior quality at intermediate O thiols O 40 stages as well as at the final product stage. It is clearly men NH - - NH Base tioned in WO 2013/050748 that when the amino group is Substituted with an -alkylcycloalkyl group, such as methyl cyclopropane, the 3-O-demethylation reaction does not work MeO MeO efficiently. The attempted O-demethylation of 3-O-methyl 45 buprenorphine (N-alkylated) gives a conversion to buprenor HO HO phine of no more than 2.1% using potassium tert.butoxide and t-Bu t-Bu 1-dodecanethiol. The same reaction when attempted using Formula-VII Formula-XI Sodium propane thiolate was unsuccessful and no product was detected. 50 Thus, there remains a need in the art to provide an efficient, industrially scalable process for the conversion of thebaine to buprenorphine and the intermediates thereof, in a high yield HO and purity. Further to this, there remains a need in the art to reduce the 55 number of solvents used in the process for preparing O buprenorphine and the intermediates thereof, in order to ren N der the process economically viable. SUMMARY OF THE INVENTION 60 MeO The present invention provides technical solutions to over HO come the drawbacks of the prior art processes for the prepa t-Bu ration of buprenorphine and its intermediates, in particular those disclosed above in Scheme-2 and 3. Formula-I 65 According to a first aspect of the present invention, there is provided a process for the preparation of a compound of Formula-I, comprising: US 8,981,097 B2

-continued Formula-I MeO HO

O NN

N MeO 10 MeO

HO O TAR i-Bu Formula-IV Buprenorphine 15 c) contacting the compound of Formula-IV obtained in a) contacting thebaine of Formula-II, (5O)-6,7,8,14-tet step (b) with tertiary butyl metal halide in a solvent to rahydro-4,5-epoxy-3,6-dimethoxy-17-methylmorphi obtain a compound of Formula-V. 7O-(2-hydroxy-3.3- nan, with methyl vinyl ketone in a solvent to obtain a dimethyl-2-butyl)-6, 14-endo-ethano-6,7,8,14-tetrahy compound of Formula-III, 7C.-acetyl-6, 14-endo-etheno drothebaine (TARG): 6,7,8,14-tetrahydrothebaine (TA); MeO MeO

25 O Her NN

MeO 3- NN 30 MeO Thebaine O MeO Formula-II TAR Formula-IV 35 O (e. N-N- IC 40 MeO HO

t-Bu TA Formula-III TARG 45 Formula-V b) reducing the compound of Formula-III obtained in step d) contacting the compound of Formula-V obtained in step (a) by catalytic hydrogenation or by catalytic transfer (c) with cyanogen bromide in a solvent to yield a com hydrogen reaction in a solvent to obtain a compound of pound of Formula-VI, N-cyano-7C.-(2-hydroxy-3.3- Formula-IV. 7C.-acetyl-6,14-endo-ethano-6,7,8,14-tet 50 dimethyl-2-butyl)-6, 14-endo-ethano-6,7,8,14-tetrahy rahydrothebaine (TAR): dronorthebaine (TARG-NCN); MeO MeO 55

-es (l- N NN 60 MeO 6 HO t-Bl TA 65 TARG Formula-III Formula-V US 8,981,097 B2 9 10 -continued MeO

MeO

O NH -b-

10 MeO MeO HO

HO t-Bu MeO t-Bu 15 TARG-NH TARG-NCN Formula-VII Formula-VI O N e) contacting the compound of Formula-VI obtained in step (d) with alkalimetal hydroxide in a solvent to obtain a compound of Formula-VII, 7c.-(2-hydroxy-3,3-dim MeO ethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahy HO dronorthebaine (TARG-NH); 25 t-Bu TARG-NCP Formula-IX MeO g) contacting the compound of Formula-IX obtained in 30 step (f) with an alkane thiol and a base in a solvent to produce a compound of Formula-I O NN CN MeO He 35 MeO O -o- HO N t-Bu TARG-NCN 40 Formula-VI MeO HO MeO t-Bu HO 45 TARG-NCP Formula-IX O NH O N 50 MeO MeO HO t-Bui HO 55 TARG-NH t-Bu Formula-VII Buprenorphine Formula-I The invention provides an efficient, economical and indus f) contacting the compound of Formula-VII obtained in 60 trially viable process for the preparation of 21-cyclopropyl step (e) with cyclopropyl methyl-L in a solvent to pro 7c-(2-hydroxy-3,3-dimethyl-2-butyl)-6, 14-endo-ethano-6, duce a compound of Formula-IX, N-cyclopropylm 7,8,14-tetrahydrooripavine i.e. buprenorphine of Formula-I, ethyl-7c-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo in a high yield and purity. Additionally, the invention provides ethano-6,7,8,14-tetrahydronorthebaine (TARG-NCP), 65 an in-situ process for the preparation of buprenorphine (For wherein L-is a leaving group selected from halides, tosyl mula-I) and its intermediate compound of Formula-VI, thus and mesyl; and reducing the number of operational steps. US 8,981,097 B2 11 12 According to a second aspect of the present invention, there -continued is provided a process for the preparation of a compound of Formula-V, comprising contacting a compound of Formula IV with tertiary butyl metal halide in CPME. MeO

MeO N CNBr. CPME 10

O MeO N -e- HO t-Bu MeO 15 TARG Formula-V O (OPTIONALLY ISOLATING)

TAR MeO Formula-IV MeO

25 O CN. N N MeO

MeO 30 HO t-Bu HO TARG-N CN t-Bu Formula-VI TARG Formula-V 35 Advantageously, the process results in the formation of the compound of Formula-VI in a higher yield and purity com Advantageously, the process results in the formation of the pared to the prior art processes. Additionally, the process uses compound of Formula-V in a higher yield and purity com a safe and eco-friendly solvent. Furthermore, due to the in pared to the prior art processes. Additionally, the process uses 40 situ nature of the process, fewer operational steps are required a safe and eco-friendly solvent, namely CPME. to form the compound of Formula-VI. According to a third aspect of the present invention, there is According to a fourth aspect of the present invention, there provided an in-situ process for the preparation of a compound is provided a process for the preparation of a compound of of Formula-VI, comprising contacting a compound of For 45 Formula-IX, comprising contacting a compound of Formula mula-IV with tertiary butyl metal halide in CPME to obtain a VII with cyclopropyl methyl halide in the presence of an acid compound of Formula-V, followed by reaction with cyanogen scavenger in a solvent selected from acetonitrile and CPME, bromide to obtain a compound of Formula-VI, without iso to obtain a compound of Formula-IX: lating the compound of Formula-V: 50

MeO MeO

t. BuMgCl 55 Hs O CPME NH N N

MeO MeO 60 HO t-Bu

TARG-NH TAR 65 Formula-IV Formula-VII US 8,981,097 B2 13 14 -continued According, to a first aspect of the present invention, there is MeO provided a process for the preparation of buprenorphine of Formula-I, comprising:

Formula-I

MeO ... 10 HO HO t-Bu TARG-NCP Formula-IX 15 N Advantageously, the process results in the formation of the MeO compound of Formula-IX in a higher yield and purity com pared to the prior art processes. Additionally, the process uses HO a safe and eco-friendly solvent. i-Bu Buprenorphine DEFINITIONS Thebaine: (5C.)-6,7,8,14-Tetrahydro-4,5-epoxy-3,6- dimethoxy-17-methylmorphinan. 25 TA: 7C-Acetyl-6, 14-endo-etheno-6,7,8,14-tetrahydrothe baine a) contacting thebaine of Formula-II, (5C)-6,7,8,14-tet TAR: 7C-Acetyl-6, 14-endo-ethano-6,7,8,14-tetrahydrothe rahydro-4,5-epoxy-3,6-dimethoxy-17-methylmorphi baine nan, with methyl vinyl ketone (MVK) in a solvent to TARG: 7C.-(2-Hydroxy-3.3-dimethyl-2-butyl)-6, 14-endo 30 obtain a compound of Formula-III, 7C.-acetyl-6, 14 ethano-6,7,8,14-tetrahydrothebaine endo-etheno-6,7,8,14-tetrahydrothebaine (TA); TARG-NCN: N-Cyano-7c-(2-hydroxy-3,3-dimethyl-2-b 1)-6, 14-endo-ethano-6,7,8,14-tetrahydronorthebaine TARG-NH: 7C.-(2-Hydroxy-3,3-dimethyl-2-butyl)-6, 14 endo-ethano-6,7,8,14-tetrahydronorthebaine. TARG-NCP: N-Cyclopropylmethyl-7C.-(2-hydroxy-3.3- dimethyl-2-butyl)-6, 14-endo-ethano-6,7,8,14-tetrahy dronorthebaie. DMF: dimethyl formamide DMSO: dimethyl sulfoxide THF: tetrahydrofuran CPME: cyclopentyl methyl ether DMPU: dimethyl propylene urea DMA: dimethyl acetamide Thebaine NMP: N-methylpyrrolidinone 45 Formula-II DEA: diethyl acetamide MVK: methyl vinyl ketone DEF: diethyl formamide DEG: diethylene glycol MtBE: methyl tertiary butyl ether 50 MsCl: mesyl chloride ACN: acetonitrile a PSI: pounds per square inch C DETAILED DESCRIPTION OF THE INVENTION 55

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that TA various aspects thereof may be more fully understood and Formula-III appreciated. 60 The term contacting as used herein refers to mixing, heating, stirring, refluxing or combinations thereof. b) reducing 7O-acetyl-6, 14-endo-etheno-6,7,8,14-tetrahy The present invention discloses an efficient, economical drothebaine (TA) of Formula-III obtained in step (a) by and industrially viable process for the preparation of catalytic hydrogenation or by catalytic transfer hydro buprenorphine of Formula-I. The present invention further 65 gen reaction in a solvent to obtain a compound of For discloses processes for the preparation of its intermediates of mula-IV. 7O-acetyl-6, 14-endo-ethano-6,7,8,14-tetrahy Formula-V, VI and IX. drothebaine (TAR): US 8,981,097 B2 16 pound of Formula-VI, N-cyano-7C.-(2-hydroxy-3.3- MeO dimethyl-2-butyl)-6, 14-endo-ethano-6,7,8,14-tetrahy dronorthebaine (TARG-CN);

O C. He (uN N (C N MeO MeO 10

O O MeO TA Formula-III 15

MeO O HO N N t-Bu TARG MeO Formula-V

O 25 TAR Formula-IV MeO c) contacting the compound of Formula-IV obtained in step (b) with a tertiary butyl metal halide (t-BuMX) in a 30 solvent to obtain a compound of Formula-V. 7O-(2-hy droxy-3,3-dimethyl-2-butyl)-6, 14-endo-ethano-6,7,8, CN 14-tetrahydrothebaine (TARG);

35 MeO MeO HO t-Bu TARG-NCN O 40 Formula-VI N N Her

MeO 45 e) contacting the compound of Formula-VI obtained in O step (d) with alkali metal hydroxide in a solvent to obtain a compound of Formula-VII 7C.-(2-hydroxy-3,3-dim TAR ethyl-2-butyl)-6, 14-endo-ethano-6,7,8,14-tetrahy Formula-IV dronorthebaine (TARG NH); MeO 50

MeO O N N 55 O Her

MeO CN

HO 60 MeO t-Bu TARG HO Formula-V t-Bu 65 TARG-NCN d) contacting the compound of Formula-V obtained in step Formula-VI (c) with cyanogen bromide in a solvent to yield a com US 8,981,097 B2 18 -continued MeO

MeO

O N O NH

10 MeO

MeO HO

HO t-Bu t-Bu TARG-NCP 15 Formula-IX TARG-NH HO Formula-VII

f) contacting the compound of Formula-VII obtained in step (e) with cyclopropyl methyl-L in a solvent to pro duce a compound of Formula-IX, N-cyclopropylm ethyl-7C-(2-hydroxy-3,3-dimethyl-2-butyl)-6, 14-endo MeO 25 ethano-6,7,8,14-tetrahydronorthebaine (TARG NCP), HO wherein L is a leaving group selected fromhalides, tosyl and mesyl; and t-Bu Buprenorphine Formula-I 30

MeO Detailed Process Steps are Outlined Below: Step (a): Preparation of TA (Formula-III) from Thebaine: 35 Thebaine of Formula-II is contacted with methyl vinyl O NH Her ketone (MVK) in the presence of a solvent to produce the compound of Formula-III.

MeO 40 HO HO t-Bu -e- TARG-NH Formula-VII 45 O CN.

MeO MeO Crs

50 Thebaine Formula-II O N

MeO HO (e. t-Bu TARG-NCP 60 C Formula-IX

TA g) contacting the compound of Formula-IX obtained in 65 Formula-III step (f) with an alkanethiol and a base in a solvent to produce a compound of Formula-I (buprenorphine) US 8,981,097 B2 19 20 Preferably methyl vinyl ketone is used in the ratio of 0.5 Step (c): Grignard Reaction for Preparation of TARG (For volume to Thebaine. The solvent used in this step may be mula-V): selected from inert organic solvents, including aromatic Step (c) involves the preparation of the buprenorphine hydrocarbons, for example toluene and Xylene, and ethereal intermediate of Formula-V, comprising reacting a Grignard solvents, for example THF, Me-THF, methyl tert.butyl ether 5 and cyclopentyl methyl ether. Preferably the solvent is cyclo reagent with the compound of Formula-IV (TAR) to produce pentyl methyl ether. the compound of Formula-V (TARG). The Grignard reagent Step (h): Hydrogenation to Prepare TAR (Formula-IV): may be prepared by the reaction of magnesium, lithium, Zinc, Step (b) involves the preparation of the intermediate of cadmium metal or derivatives thereof, with a tertiary butyl Formula-IV (TAR) by reducing the double bond of the the 10 halide, where the halide may be selected from chloride, bro baine adduct (TA) of Formula-III. Preferably this step is mide or iodide. Preferably the Grignard reagentist-BuMgCl, carried out in the presence of a protic or aprotic solvent at a t-BuMgBr ort-BuMgI. temperature in the range of from 80° C. to 85° C. and a pressure of 100 PSI. Under these conditions, the yield and 15 purity of the compound of Formula-IV is enhanced. MeO

MeO O N N Her O 1 N N MeO 6 N 25 O MeO

TAR O Formula-IV 30 MeO TA Formula-III MeO

O 35 N N O N N MeO

40 HO MeO t-Bu TARG O Formula-V

TAR 45 Formula-IV Step (c) is carried out in the presence of a solvent. Examples of suitable solvents include, but are not limited to, The reduction is carried out by catalytic transfer hydrogen ethereal solvents, for example dialkyl ether, wherein the alkyl reaction or by catalytic hydrogenation. 50 is selected from C to C straight or branched chain alkyl The catalytic hydrogen transfer reaction preferably takes groups e.g. diethyl ether, THF, 2-methyl THF, methyl tert place in the presence of ammonium formate, formic acid or butyl ether, dimethoxyethane, cyclopentyl methyl ether and hydrazine hydrate in the presence of a protic or aprotic Sol diisopropyl ether, dioxanes; dialkoxy ethanes; and aliphatic vent at atmospheric pressure. This is advantageous since it or aromatic hydrocarbons, for example toluene, hexane, hep avoids using an external source of hydrogen gas and increased 55 tane, cyclohexane or mixtures thereof. Preferably the solvent pressure. is cyclopentyl methyl ether. The particular use of an eco The catalytic hydrogenation reaction may take place in the friendly solvent such as cyclopentyl methyl ether in this step presence of a heterogeneous catalyst and a protic or aprotic makes the process commercially viable on an industrial scale. Solvent. The heterogeneous catalyst for catalytic hydrogena Step (d) and Step (e): N-demethylation to Prepare TARG-NH tion may be selected from metals such as Palladium and 60 Platinum, loaded onto carbon, barium sulphate, Pt.O or (Formula-VII): Raney nickel for example. Preferably the heterogeneous cata Step (d) involves the reaction of the compound of For lyst is 10% palladium loaded onto carbon. The reaction is mula-V with cyanogen bromide in a solvent to produce the preferably carried out at a temperature of from 80°C. to 85° compound of Formula-VI (TARG-NCN). Step (e) involves C. and under hydrogen pressure of 100 PSI. The protic or 65 the compound of Formula-VI being reacted with a base in a aprotic solvent may be selected from C to Cs alcohols, solvent to yield the buprenorphine intermediate of Formula organic acids, esters, ethers and mixtures thereof. VII. US 8,981,097 B2

MeO MeO

5 O O N N N N

MeO 10 MeO

HO O

t-Bl TAR TARG Formula-IV Formula-V 15 MeO

MeO

O N O N NYCN -e- MeO

MeO 25 HO

HO t-Bu pi TARG t-Bl Formula-V TARG-NCN MeO Formula-VI 30

MeO O N 35 NCN O NH MeO

HO 40 MeO t-Bl HO TARG-NCN Formula-VI t-Bu TARG-NH 45 The subsequent reaction for the preparation of the Formula-VII buprenorphine intermediate of Formula-VII (step (e)) com prises the reaction of the compound of Formula-VI (TARG NCN) with a base which may be selected from alkali metal hydroxides, for example NaOH, KOH and LiOH, to produce There is no particular restriction on the nature of the Sol- 50 the compound of Formula-VII (TARG-NH). vent to be employed for the formation of the compound of There is no particular restriction on the nature of the sol Formula-VI in step (d), provided that it has no adverse effect vent to be employed for the formation of the compound of on the reaction or the reagents involved. Examples of suitable Formula-VII, provided that it has no adverse effect on the solvents include, but are not limited to, ethereal solvents for reaction or the reagents involved. Examples of Suitable sol example diethyl ether, THF, 2-Methyl THF, methyl tert.bu- 55 vents include, but are not limited to, high boiling solvents for tylether, dimethoxy ethane, cyclopentyl methyl ether and example diethylene glycol, triethylene glycol, ethylene gly diisopropyl ether. Preferably the solvent is cyclopentyl meth col, N-methylpyrrolidinone, DMF, DMSO, DMPU, DMA, ylether (CPME). The use of CPME as the solvent in step (d) DEA, water, n-butanol, ethanol and IPA. Preferably the sol has advantages over the hazardous, non-ecofriendly chlori vent is diethylene glycol. It should be appreciated that the nated Solvents of the prior art, and results in a high yield and 60 same reaction may be carried out in a biphasic mixture of an high product purity. organic solvent with water, and a phase transfer catalyst. Step (e) may be carried out at a temperature of from 160° C. Another advantage of using CPME as the solvent for this to 170° C. Preferably step (e) is carried out at a temperature of reaction is that this reaction can be performed in-situ from the 1650 C. previous Grignard reaction step (step (c)). Thus, the cyanogen 65 Step (f): N-alkylation to Prepare TARG-NCP (Formula-IX): bromide reaction (step (d)) can be carried out without isolat Step (f) involves the preparation of the buprenorphine ing the Grignard product of Formula-V. intermediate of Formula-IX, comprising the reaction of the US 8,981,097 B2 23 compound of Formula-VII (TARG-NH) with cyclopropyl methyl-L in the presence of a solvent, to produce the com MeO pound of Formula-IX (TARG-NCP).

MeO O N Her

O 10 NH He MeO HO

MeO t-Bl TARG-NCP HO 15 Formula-IX t-Bl TARG-NH Formula-VII HO 2O MeO

O N O 25 N MeO

MeO HO 30 t-Bu HO Buprenorphine t-Bl Formula-I TARG-NCP Formula-IX 35 The alkane thiols selected for this reaction may be straight The L. group in cyclopropyl methyl-L may be a leaving chain n-alkanethiols, branched chain alkanethiols, alkanethi group selected from halides, tosyl and mesyl. The halide ols containing cyclic rings or dithiols and combinations leaving group may be chloride, bromide or iodide. Preferably 40 thereof. The alkanethiols may contain from 5 to 12 carbon the cyclopropyl methyl-L compound is cyclopropyl methyl atoms. The preferred alkanethiols for this reaction are bromide. ethanethiol, pentanethiol, heptanethiol and dodecanethiol. There is no particular restriction on the nature of the sol vent to be employed for the formation of the compound of The base employed in this reaction may be selected from Formula-IX, provided that it has no adverse effect on the 45 sodium hydride, sodamide and alkali metal C1 to C4 straight reaction or the reagents involved. Examples of Suitable sol chain or branched chain alkoxides. Preferably the base is vents include, but are not limited to, polar aprotic solvents, for selected from alkali metal tertiary butoxides. More preferably example acetonitrile, DMF, DEF, DMSO, N-methylpyrroli the base is potassium tertiary butoxide. dinone, DMPU, DMA, DEA, sulpholane, acetone, methyl ethylketone, methyl iso-butylketone, THF, Me-THF, CPME, 50 The reaction may be carried out at a temperature in the MtBE and DME. Preferably the solvent is acetonitrile or range of from 80° C. to 150° C. Preferably the reaction is CPME. carried out at a temperature in the range of from 100° C. to The reaction in step (f) may be carried out in the presence 130° C., more preferably from 110° C. to 115° C. ofa base or acid Scavenger. The base or acid Scavenger may be Examples of suitable solvents for step (g) include, but are selected from inorganic bases for example alkali and alkaline 55 not limited to, DMF, DEF, DMSO, toluene and cyclopentyl earth metal carbonates and bicarbonates; and organic bases for example triethylamine, diisopropyl ethylamine, pyridine, methyl ether (CPME). Preferably the solvent is DMF or dimethylamino pyridine, imidazole, ethylene diamine, N.N- CPME. dimethyl aniline and colidine. Additionally, KI or NaI may be Step (g) enables the isolation of the desired product of added in this reaction as a catalyst. 60 Formula-I (buprenorphine) in a higher yield and greater Step (g): O-Demethylation for Preparation of Buprenorphine purity than the prior art processes, as the reaction is carried (Formula-I): out at a comparatively lower temperature with simple work Step (g) involves the preparation of buprenorphine of For up and without any extra steps for purification and crystalli mula-I, comprising contacting the compound of Formula-IX (TARG-NCP) with an alkane thiol in the presence of a base 65 Zation. and a suitable solvent that enhances the yield and purity of the One specific embodiment of the process of the present product buprenorphine. invention is shown below in Scheme-4. US 8,981,097 B2 25 26

Scheme-4:

MeO

10% Pd-C, H, -e- O N N

MeO Thebaine Formula-II O TAR Formula-III Formula-IV cru t-BuMgCl

MeO MeO MeO

O DEG, KOH O N CNBr. O N 1659 C. n CN CPME N

MeO MeO MeO

HO HO HO

t-Bu t-Bl t-Bu TARG-NH TARG-NCN TARG Formula-VII Formula-VI Formula-V Optionally isolating s Br

MeO HO

O Pentane thiol K tBuO O N DMF, 110-1159 C. N

MeO MeO

HO HO

t-Bu t-Bl TARG-NCP Buprenorphine Formula-IX Formula-I

Although the present invention has been described in terms According to a second aspect of the present invention, there ofan overall process for the formation of buprenorphine from is provided a process for the preparation of a compound of thebaine, the invention also relates to each of the individual 65 processes outlined in steps (a) to (g), and to any combination Formula-V, comprising contacting a compound of Formula thereof. IV with tertiary butyl metal halide in CPME: US 8,981,097 B2

-continued MeO MeO

O O N N N -e- NCN.

MeO 10 MeO HO O TAR t-Bu Formula-IV TARG-NCN MeO 15 Formula-VI According to a fourth aspect of the present invention, there is provided a process for the preparation of a compound of O Formula-IX, comprising contacting a compound of Formula N N VII with cyclopropyl methyl halide in the presence of an acid scavenger in a solvent selected from acetonitrile and CPME, to obtain a compound of Formula-IX: MeO

HO 25 MeO t-Bu TARG Formula-V O NH -e- 30 According to a third aspect of the present invention, there is provided an in-situ process for the preparation of a compound of Formula-VI, comprising contacting a compound of For MeO mula-IV with tertiary butyl metal halide in CPME to obtain a HO compound of Formula-V, followed by reaction with cyanogen 35 bromide to obtain a compound of Formula-VI, without iso t-Bl lating the compound of Formula-V: TARG-NH Formula-VII MeO MeO 40

O O N

N He 45

MeO MeO HO O 50 t-Bu TAR TARG-NCP Formula-IV Formula-IX MeO It should be appreciated that the preferred features of the 55 first aspect of the present invention can also relate to the second, third and fourth aspects of the invention. O N INDUSTRIAL ADVANTAGES 60 1. The present invention provides an efficient industrial pro MeO cess which may provide buprenorphine from thebaine in an overall yield of from about 30% to about 50%, more spe HO cifically from about 40% to about 42%. This is substan t-Bl pi tially higher than the prior art yield of 26% to 28% dis TARG 65 closed in US 2011/0152527A1. Formula-V 2. The loading quantity in step (a) of the hazardous, lachry matic, toxic and expensive raw material, methyl vinyl US 8,981,097 B2 29 30 ketone, may be reduced to half of its quantity as reported in mula-IX (the N-methylcyclopropyl substituted intermedi the prior art process disclosed in US2011/0152527. Addi ate), with high yield and purity. The chance of impurity tionally, the improved process may produce the thebaine formation which arises when the intermediate of formula adduct of Formula-III (TA) in a yield of greater than 90%, IX is alkylated (as alkylation may occur on both the amine more specifically from about 91% to about 95%. 5 and 3-phenolic position), is reduced in the present process. 3. The present invention may allow for the elimination of Thus, the process results in a higher yield and better quality diethyl ether, benzene and THF as the reaction media for of the final product. the Grignard reaction step (step (c)). The use of these The invention will now be more specifically described by solvents is not viable on an industrial scale due to the the following examples, so that various aspects thereof may carcinogenic nature of benzene and the highly flammable 10 be more fully understood and appreciated. and hazardous nature of solvents such as diethyl ether and THF. The inventors of the present invention have surpris Example 1 ingly found that cyclopentyl methyl ether (CPME) can be used as an alternative solvent for this step. CPME has now Preparation of TA of Formula-III become available in commercial quantities with approval 15 by the Toxic Substances Control Act (TSCA) and the Euro 50 kg of thebaine was added to 100 L dry toluene, and the pean List of Notified Chemical Substances (ELINCS). A mixture was cooled to 15° C. 25 L of MVK was added to the high boiling point (106° C.) and preferable characteristics cooled mixture and stirred for 30 minutes, followed by stir such as low formation of peroxides, relative stability under ring at 80°C. to 85°C. for 18 hours. The solvent was removed acidic and basic conditions, high hydrophobicity and for under reduced pressure and the residual mass was stripped off mation of azeotropes with water, coupled with a narrow with isopropyl alcohol, cooled to room temperature and explosion range render CPME a favourable alternative to stirred for 1 hour. The resultant product was isolated and dried other ethereal solvents such as tetrahydrofuran (THF), to get 57.01 kg product TA (Yield: 93.28%; HPLC purity: 2-methyl tetrahydrofuran (2-MeTHF), dioxane (carcino 99%). genic), and 1,2-dimethoxyethane (DME). The desired 25 product of Formula-V may be obtained with above 99% Example 2 HPLC purity. 4. In step (d) of the present invention, the reaction of cyano Preparation of TAR of Formula-IV gen bromide is preferably carried out in cyclopentyl methyl ether (CPME) rather than the chlorinated solvents 30 60 L of isopropanol, 6 kg of TA and 250 g of 10% Pd C used in the prior art processes. An advantage of using catalyst were charged into a 100 L autoclave and hydroge CPME as a solvent in this step is that it enables the reaction nated at 100 PSI for 3 to 4 hours at 80° C. to 859 C. The to be performed in-situ from the previous step without charcoal was filtered off under hot conditions and the solvent having to isolate the Grignard reaction product. Thus, the was partially removed, the remaining mixture was cooled to number of operational steps may be reduced. 35 room temperature and stirred for 2 hours. Finally, the product 5. The yield of the compound of Formula-VII from step (d) was filtered to get 5.58 kgTAR (Yield: 92.53%; HPLC purity: and step (e) may be as much as 87.4% with HPLC purity 99.5%). above 99%. 6. In the present process, the N-alkylcycloalkylated interme Example 3 diate of formula-IX is produced in a one-step reaction (step 40 f) of cyclopropyl methyl-L with the compound of Formula Preparation of TARG of Formula-V VII (TARG-NH) in the presence of a solvent, for example CPME or acetonitrile, preferably under reflux conditions. Under an inert atmosphere and anhydrous conditions, 1 kg Using this process, a yield of 92.9% of the compound of of magnesium turnings and iodine was charged into a vessel. Formula-IX with 99.5% HPLC purity, may be realised. 45 To this was added 3.5 L of CPME. 1 Loft-butyl chloride was 7. The O-demethylation of step (g) is preferably performed added to the mixture under stirring. The mixture was heated with alkane thiol and potassium tert. slowly and maintained below reflux temperature, until the butoxide in DMF at a comparatively lower temperature reaction started. A further 5 L oft-butyl chloride and 30 L of than the prior art processes. The lower temperature reduces CPME was added to the reaction mixture at such a rate that the formation of undesirable impurities, which tend to form 50 reaction did not subside. After the addition was completed, when the reaction is performed at a higher temperature, for the reaction mixture was stirred for 12 hours at 35° C. to 40° example between 210°C. and 220°C. Consequently, a higher C. 1 kg of TAR in CPME was added to the reaction mixture yield and purity of the final product is achieved. and stirred at 35° C. to 40° C. for 10 hours. The reaction After completion of the reaction, the reaction mass may be mixture was cooled and quenched with ammonium chloride quenched in water and the desired product may be iso 55 in 70 L of water. Suitable work up gave 710 g TARG (Yield: lated by extraction with CPME or another water immis 61.18%; HPLC purity: 98.74%). cible solvent, for example chloroform, MDC or ethyl Same Reaction Scaled-Up to 10 Kg: acetate. The product buprenorphine base may be 10 kg of magnesium turnings and iodine was charged into obtained in a 91% yield with over 99% HPLC purity. a 1000 L vessel under an inert atmosphere and anhydrous Advantageously, no extra step for purification or crys 60 conditions. To this was added 35 L of CPME. 1 L oft-butyl tallization is required. The process provides a simpler chloride was added to the mixture under stirring. The mixture work-up procedure and results in a Substantially higher was heated slowly and maintained below reflux temperature, yield and better quality of the final buprenorphine prod until the reaction started. A further 50 L of t-butyl chloride uct than the prior art processes. and 300 L of CPME was added to the reaction mixture at such 8. Contrary to the reports published in WO 2013/050748, the 65 a rate that the reaction did not subside. After the addition was inventors of the present invention have successfully per completed, the reaction mixture was stirred for 12 hours at formed the 3-O-demethylation on the compound of For 35° C. to 40° C. 10 kg of TAR in CPME was added to the US 8,981,097 B2 31 32 reaction mixture and stirred at 35° C. to 40°C. for 10 hours. Example 8 The reaction mixture was cooled and quenched with ammo nium chloride in 700 L of water. Suitable work-up gave 7.5 kg (a) Preparation of Buprenorphine (BPN) using TARG (Yield: 65.16%; HPLC purity: 99.09%). Pentanethiol Example 4 100 L DMF was charged into a vessel under an inert atmo Preparation of TARG-NCN of Formula-VI sphere. To this was added 3.6 L pentane thiol. The mixture was stirred and then 3.6 kg of potassium t-butoxide was added 5 kg of TARG was dissolved in 15 L CPME. To this was 10 in batches. 3 kg of TARG-NCP was added to the mixture and added 1.4kg of cyanogen bromide. The reaction mixture was subsequently the reaction mixture was stirred at 100° C. to stirred under reflux conditions until completion of the reac 130° C. for 18 hours. The reaction mixture was cooled and tion. The solvent was removed under reduced pressure, placed in water containing ammonium chloride. The aqueous stripped off with methanol, cooled and then filtered to obtain layer was extracted with CPME/chloroform to give 2.654 kg 4.815 kg of product TARG-NCN (Yield: 93.95%; HPLC 15 buprenorphine (Yield: 91%; HPLC purity: 99.22%). purity: 99.5%). * This reaction is also carried out on 14 kg input scale, by changing sequence of addition, giving satisfactory yield. Example 5 Preparation of TARG-NCN from TAR In-Situ (b) Preparation of Buprenorphine (BPN) Using Heptanethiol Under an inert atmosphere and anhydrous conditions, 1 kg of magnesium turnings and iodine was charged into a vessel. To this was added 10L of CPME.0.1 Loft-butylchloride was 100 ml DMF was charged into a vessel under an inert added to the reaction mixture under stirring until the reaction 25 atmosphere. To this was added 10 ml heptanethiol. The mix started. A further 0.5 L oft-butyl chloride and 30 L of CPME ture was stirred and then 10 g potassium t-butoxide was was added to the reaction mixture at Such a rate that the added. 5 g TARG-NCP was further added to the mixture and reaction did not subside. After the addition was completed, subsequently the reaction mixture was stirred at 100° C. to the reaction mixture was stirred at 35° C. to 40° C. until 130° C. for 16 hours. The reaction mixture was cooled and completion of the reaction. 1 kg of TAR in CPME was added 30 placed in 750 ml water containing ammonium chloride. The to the reaction mixture and stirred at 35° C. to 40° C. until aqueous layer was extracted with CPME/chloroform to completion of the reaction. The reaction mixture was cooled obtain 3.806 g buprenorphine (Yield: 78.40%; HPLC purity and worked up as in Example 3 to obtain TARG in CPME. To 99%). this was added 0.2 kg cyanogen bromide and the reaction mixture was stirred under reflux conditions until completion 35 ofreaction. The solvent was removed under reduced pressure, (c) Preparation of Buprenorphine (BPN) Using stripped off with methanol, cooled and filtered to get 0.72 kg Ethanethiol of product TARG-NCN. Example 6 40 1 L of DMF was added to 50 ml of ethanethiol under an inert atmosphere and stirred. To this was added 51 g of potas Preparation of TARG-NH of Formula-VII sium t-butoxide. 25 g of TARG-NCP was added to the mix ture and the reaction mixture was stirred at 100° C. to 13°C. 6.0 kg of TARG-NCN was taken in 52 L of diethylene for 18 hours. The reaction mixture was placed into water glycol and 4.8kg potassium hydroxide. The reaction mixture 45 containing ammonium chloride and extracted with chloro was stirred at 165° C. until completion of the reaction. The form/CPME to get 20.31 g buprenorphine (Yield: 83.68%; reaction mass was cooled and placed in water. This mixture HPLC purity: 98.92%). was stirred at 15° C. to 20° C. for 2 to 3 hours. The Solid was filtered off and dried to obtain 5.24 kg of product TARG-NH (d) Preparation of Buprenorphine (BPN) using (Yield: 92.94%; HPLC purity: 99%) 50 Dodacanethiol Example 7 200 ml of DMF was charged into a vessel under an inert atmosphere. To this was added 80 ml of dodacanethiol. The Preparation of TARG-NCP of Formula-IX mixture was stirred followed by addition of 80 g of potassium 55 t-butoxide. 10 g TARG-NCP was added to the mixture and 5 kg TARG-NH was taken in 35 L acetonitrile and the subsequently the reaction mixture was stirred at 100° C. to reaction mass cooled. To this was added 4.54 kg anhydrous 130° C. for 16 hours. The reaction mixture was cooled and potassium carbonate, followed by the addition of 1.775 kg placed in water containing ammonium chloride. The aqueous cyclopropyl methyl bromide. The reaction mixture was layer was extracted with CPME/chloroform to obtain stirred under reflux conditions until completion of the reac 60 buprenorphine (HPLC purity: 77%). tion. The unwanted material was filtered off and the filtrate was distilled to reduce the quantity and cooled to obtain 5.23 (e) Preparation of Buprenorphine (BPN) Using kg of product TARG-NCP; (Yield: 92.89%; HPLC purity: Sodium t-Butoxide 99.5%). The same reaction was performed using CPME as the 65 The potassium salt of pentanethiol (6.61 g; prepared from solvent to get the product (TARG-NCP) in an equivalent yield pentanethiol & potassium t-butoxide) was charged into a and purity. vessel containing 75 ml DMF underinert atmosphere. To this US 8,981,097 B2 33 solution was added 5 gTARG-NCP. The reaction mixture was stirred at 100-130° C. for 4 hours. The reaction mixture was MeO cooled and placed in 225 ml water containing ammonium chloride. The aqueous layer was extracted with CPME to obtain 2.98 g buprenorphine (Yield: 61%; HPLC purity O 98.57%). N -e-

(f) Preparation of Buprenorphine (BPN) Using 10 MeO Sodium t-Butoxide HO

t-Bl DMF (150 ml) was charged under inert atmosphere into a TARG-NCP 15 Formula-IX vessel. To this vessel was added 12 g sodium t-butoxide. The HO resulting solution was stirred, followed by addition of 12 mL pentanethiol to the stirred solution. To the resulting mixture was further added 10g TARG-NCP, and the reaction mixture O was stirred at 100-130° C. for 6 hours. The reaction mixture N was cooled and placed in 600 ml water containing ammonium chloride. The aqueous layer was extracted with CPME/chlo roform to obtain 7.08 g buprenorphine (Yield: 72.9%; HPLC MeO purity 98.05%). 25 HO (g) Preparation of Buprenorphine (BPN) Using t-Bu Buprenorphine N,N-Dimethyl Acetamide as Solvent Formula-I 30 N,N-dimethyl acetamide (150 ml) was charged under inert atmosphere into a vessel. To this vessel was added 12 g said contacting being carried out at a temperature between potassium t-butoxide. The resulting solution was stirred, fol about 80° C. and about 150° C. lowed by addition of 12 mL pentanethiol. To the resulting 2. The process according to claim 1, wherein the 35 alkanethiol is selected from the group consisting of straight mixture was further added 10 g TARG-NCP, and the reaction chain n-alkanethiols, branched chain alkanethiols, cyclic mixture was stirred at 100-130° C. for 6 hours. The reaction alkanethiols, dithiols, alkali metal salts thereof, and mixtures mixture was cooled and placed in 600 ml water containing thereof. ammonium chloride. The aqueous layer was extracted with 3. The process according to claim 1, wherein the CPME/chloroform to obtain 7 g buprenorphine (Yield: 40 alkanethiol is at least one alkanethiol selected from the group 72.1%; HPLC purity 98.22%) consisting of straight chain n-alkanethiols containing from 5 to 7 carbon atoms. The invention claimed is: 4. The process according to claim 1, wherein the 1. A process for the preparation of a compound of For alkanethiol is selected from the group consisting of 45 ethanethiol, pentanethiol, heptanethiol, and mixtures thereof. mula-I in a purity of at least 98%, comprising: 5. The process according to claim 1, wherein the compound of Formula-IX is obtained by contacting a compound of For Formula-I mula-VII with a cyclopropyl methyl halide, cyclopropyl HO methyl tosylate, or cyclopropyl methyl mesylate in a second 50 solvent to produce the compound of Formula-IX:

MeO N 55 MeO NH HO

i-Bll 60 Buprenorphine MeO HO contacting a compound of Formula-IX with a C-C, t-Bl alkanethiol and a base in a first solvent to produce a 65 TARG-NH compound of Formula-I, wherein said first solvent is Formula-VII DMF: US 8,981,097 B2 35 -continued MeO MeO

O N NoN Hip

MeO 10 MeO

HO HO

t-Bu t-Bl MeO TARG-NCP TARG-NCN Formula-IX 15 Formula-VI

O 6. The process according claim 5, wherein said second NH. Solvent is a polar aprotic Solvent. 7. The process according to claim 6, wherein the polar 2O aprotic solvent is selected from the group consisting of aceto MeO nitrile, DMF, DEF, DMSO, N-methylpyrrolidinone, DMPU, HO

DMA, DEA, sulpholane, acetone, methyl ethyl ketone, t-Bl methyl isobutyl ketone, THF, Me-THF, dioxane, CPME, 25 TARG-NH MtBE, and DME. Formula-VII 8. The process according to claim 5, wherein the compound 9. The process according to claim 8, wherein the third of Formula-VII is obtained by solvent is an ethereal solvent. a) contacting a compound of Formula-V with cyanogen 30 10. The process according to claim 9, wherein the ethereal bromide in a third solvent to yield a compound of For solvent is selected from the group consisting of diethyl ether, mula-VI; and tetrahydrofuran: 2-methyl tetrahydrofuran, methyl tert-bu tylether, dimethoxyethane, cyclopentyl methyl ether and diisopropyl ether. MeO 35 11. The process according to claim 8, wherein the com pound of Formula-Vis obtained by contacting a compound of Formula-IV with a tertiary butyl metal halide in a fifth solvent to obtain the compound of Formula-V: NBir N 40 N Solvent MeO

MeO

O He HO 45 N N t-Bl TARG Formula-V MeO MeO 50 O MeO TAR Formula-IV

CN ss O N N MeO

HO MeO t-Bl 60 HO TARG-NCN Formula-VI t-Bl TARG Formula-V b) contacting the compound of Formula-VI with an alkali 65 metal hydroxide in a fourth solvent to obtain the com 12. The process according to claim 11, wherein the tertiary pound of Formula-VII: butyl metal halide is selected from the group consisting of US 8,981,097 B2 37 38 tertiary butyl magnesium halide, tertiary butyl lithium halide, d) reducing the compound of Formula-III by catalytic tertiary butyl Zinc halide, and tertiary butyl cadmium halide. hydrogenation or by a catalytic transfer hydrogenation 13. The process according to claim 11, wherein the fifth reaction in a seventh solvent to obtain the compound of Solvent is selected from the group consisting of dialkyl ether, Formula-IV: wherein alkyl is selected from the group consisting of C1 to C4 straight chain or branched chain alkyl groups; tetrahydro furan: 2-methyl tetrahydrofuran; cyclopentyl methyl ether; MeO dioxanes; dialkoxyethane: hydrocarbons selected from the group consisting of toluene, hexane, and heptane; and mix tures thereof. 10 14. The process according to claim 11, wherein the fifth O 1 NN Solvent comprises cyclopentyl methyl ether. 15. The process according to claim 11, wherein the com (C N -- pound of Formula-IV is obtained by: 15 c) reacting thebaine of Formula-II with methyl vinyl MeO ketone in a sixth solvent to obtain a compound of For O mula-III; and TA Formula-III MeO MeO

O 25 N He N (uN N N.

MeO MeO Thebaine 30 Formula-II O TAR Formula-IV

35 16. The process according to claim 15, wherein 0.5 liters (e. methyl vinyl ketone are used per kg thebaine in step (c). 17. The process according to claim 15, wherein the sixth C and seventh solvents are the same or different; and 40 wherein the sixth and seventh solvents are each selected TA from the group consisting of toluene, IPA, cyclopentyl Formula-III methyl ether, and mixtures thereof. k k k k k