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

Technical Field of Invention:
The present invention relates to an efficient industrial process for the preparation of 21-cyclopropyl-7a-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydro-oripavine, i.e Buprenorphine of Formula-1 in high yield and purity with enhanced safety and eco-friendly norms. The invention further relates to an improved process for preparation of intermediates thereof in high yield and purity.
Background of the invention:
Buprenorphine, chemically known as 21-cyclopropyl-7a-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydrooripavine is a semi-synthetic opiate used as a powerful analgesic indicated for the treatment of moderate to severe pain and opioid dependence. The compound was first reported by K. W. Bentley in US 3433791. This patent reported its semi-synthesis from thebaine as depicted in Scheme-1.


There are many reported literature for the preparation of buprenorphine by different methods, of those, few are cited herein where thebaine is used as key starting material and chosen for the improvement to those reported process.
US 2011/0152527A1 discloses the process for preparation of buprenorphine by the process depicted in Scheme- 2. The process up to Formula-V is similar to the Bentley process reported in US 3433791. The major modification is done by the use of ethyl chloroformate and then heating at 130-140°C with KOH and diethylene glycol for N-demethylation of compound of Formula- V to get compound of Formula- VII followed by reaction with cyclopropyl methyl alcohol with mesyl chloride for N-alkylation and finally the use of thiophenol for O-demethylation to get buprenorphine base of Formula-1. The overall reported yield of the process is 27% up to buprenorphine base from thebaine, more over the workup procedure for O-demethylation is tedious and there is no mention of purity of product and intermediates. The process uses hazardous, highly inflammable and peroxide forming solvents like diethyl ether, THF etc, which makes the process non-suitable at industrial scale. The process requires extra step for purification resulting to the lower yield of final product.
Scheme-2:


PCT Publication No. WO 2013/050748 of Johnson Matthey PLC discloses the following Scheme-3 for the preparation of buprenorphine or its derivatives. The preparation of compound of formula- VI is performed by known process. The major modifications are in N-demethylation, which is done at lower temperature using NaOH, water and ethylene glycol or methoxy ethanol and then subsequent O-demethylation by using different combination of thiols and bases to get the compound of formula- XI. This compound is further converted to buprenorphine by the methods known in prior arts. The said publication does not disclose the formation of compound of formula-VI and starts with this advance intermediate. The first reaction is N-demethylation, which is followed by 3-O-demethylation to get the compound of formula-XI which is further converted to buprenorphine. The disadvantage associated with this process is formation of impurity

which arises during final step of N-alkylation as alkylation can occur on both NH and 3-phenolic group. Thus this may require additional steps for purifications and lead to poor yield and lower quality of final product. It is further mentioned that 3-O-demethylation cannot happen on N-alkylcycloalkylated intermediate (page no. 17; Example-15, page no. 34) for that reason t both N-demethylation and O-demethylation are carried out prior to N-alkylation step.
Scheme-3:

The common drawbacks associated with prior art processes is overall low yield of product buprenorphine. The second drawback associated with prior art processes is use of toxic, highly inflammable and hazardous solvent in Grignard reaction step like benzene, diethyl ether and THF, which make the process unsuitable to scale-up to plant scale due to

safety and environmental concerns. The prior art processes are prone to formation of by-products/ impurities, which require extra steps for purification at intermediate stages as well as at final product stage which leads to poor yield and inferior quality at intermediate stages as well as at final product buprenorphine. It is clearly mentioned in WO 2013/050748 that when amino group is substituted with -alkylcycloalkyl group such as methyl cyclopropane, the 3-O-demethylation reaction does not work efficiently. The attempted O-demethylation of 3-O-methyl buprenorphine (N-alkylated) does not give conversion to buprenorphine more than 2.1% using potassium tert. butoxide and 1-dodecanethiol. The same reaction when attempted using sodium propane thiolate was unsuccessful and no product was detected.
There, therefore, 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 high yield and purity.
The further object of the invention is to reduce the number of solvents in the process of preparation buprenorphine and the intermediates thereof thus rendering the process economically viable.
Summary of the invention:
In accordance with the above objectives, the present invention provides technical solutions to overcome the drawbacks of prior art processes disclosed hereinabove in Scheme-2 and 3 for the preparation of buprenorphine and'its intermediates thereof.
Accordingly, in the first aspect, the present invention provides an efficient, economical and industrially viable process for the preparation of 21-cyclopropyl-7a-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydrooripavine i.e Buprenorphine of Formula-I in high yield and purity.


In the second aspect, the present invention provide a novel process for the preparation of buprenorphine (formula I) intermediates of, formula- V (TARG), formula- VI (TARG-NCN) and formula- IX (TARG-NCP) in higher/ equivalent yield and purity using safe and eco-friendly solvent.
In the third aspect, the invention provides an in-situ process for the preparation of buprenorphine (formula I)and its intermediate compounds of formula- VI (TARG-NCN) thus reducing the operational steps.
Detailed meaning of terms used hereinabove and hereinbelow:
Thebaine: (5α)-6,7,8,14-Tetrahydro-4,5-epoxy-3,6-dimethoxy-17-methylmorphinan.
TA: 7α-Acetyl-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine.
TAR: 7α-Acetyl-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine.
TARG: 7α-(2-Hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-
tetrahydrothebaine.
TARGNCN:N-Cyano-7a-(2-hydroxy-3,3-dimethyl-2-butyI)-6,14-endo-ethano-6,7,8,14-
tetra hydronorthebaine.
TARG-NH: 7α-(2-Hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-
tetrahydronorthebaine.
TARG-NCP: N-Cyclopropylmethyl-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-
ethano-6,7,8,14-tetrahydronorthebaie.
DMF is dimethyl formamide, DMSO, is dimethyl sulfoxide, THF is tetrahydrofuran,
CPME is cyclopentyl methyl ether, DMPU is dimethyl propylene urea, DMA is dimethyl
acetamide, NMP is N-methyl pyrrolidinone, DEA is diethyl acetamide, MVK is methyl
vinyl ketone, DEF is diethyl formamide; DEG is diethylene glycol, MtBE is methyl

tertiary butyl ether, MsCl is mesyl chloride, ACN is acetonitrile, PSI is pound per square inch.
Detailed description of the Invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The term 'Contacting' as mentioned herein in the specification refers and means to mixing, heating, stirring, refluxing or combination thereof.
The present invention discloses an efficient, economical and industrially viable process for the preparation of buprenorphine of formula-1. The present invention further discloses the process for preparation of its intermediates of formula- V, VI and IX.
In an embodiment, the process for the preparation of buprenorphine of formula (I) comprises;

a) contacting thebaine of formula- II (5α)-6,7,8,14-tetrahydro-4,5-epoxy-3,6-dimethoxy-17-methylmorphinan with methyl vinyl ketone (MVK) in a solvent to produce the compound of formula- III (TA) 7α-acetyl-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine;


b) reducing 7α-acetyl-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine of formula-III (TA) of step (a) by catalytic hydrogenation or by catalytic transfer hydrogen reaction in a solvent to produce the compound of formula- IV (TAR) 7α-acetyl-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine;

c) contacting compound of formula- IV of step (b) with tertiary butyl metal halide (t-BuMX) in a solvent to produce compound of formula- V (TARG) 7a-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,l 4-tetrahydrothebaine;


d) contacting compound of formula- V (TARG) of step (c) with cyanogen bromide in a solvent to produce compound of formula- VI (TARG-NCN), N-cyano-7a-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine;

e) contacting compound of formula- VI (TARG-NCN) of step (d) with alkali metal hydroxide in a solvent to produce compound of formula- VII (TARG-NH) 7a-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine;

f) contacting compound of formula- VII (TARG-NH) of step (e) with cyclopropyl methyl-L in a solvent to produce compound of formula- IX (TARG-NCP) N-cyclopropylmethyl-7a-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine;


wherein, L-is a leaving group selected from halides, tosyl, mesyl etc. g) contacting compound of formula- IX (TARG-NCP) of step (f) with alkanethiol and base in a solvent to produce compound of formula-1 (Buprenorphine).

The process is depicted below in Scheme 4:


Scheme 4
Detailed process steps are as below:
Step a: Preparation of TA from Thebaine:
Thebaine of Formula (II) is contacted with methyl vinyl ketone (MVK) in presence of a solvent to produce the compound of Formula (III).


wherein, methyl vinyl ketone is taken in the ratio of 0.5 volume to Thebaine. Solvent is selected from inert organic solvents, but not limited to aromatic hydrocarbons like toluene, xylene, and ethereal solvents like T'HF, Me-THF, methyl tert.butyl ether, cyclopentyl methyl ether etc.
Step b: Hydrogenation to prepare TAR:
In the second aspect, the present invention discloses a process for the preparation of intermediate of formula-IV (TAR) comprising reduction of double bond of Thebaine adduct (TA) of formula-Ill) in presence of protic or aprotic solvents at a temperature in the range of 80-85°C and 100 PSI pressure that enhances the yield and purity.

The reduction is carried out by catalytic hydrogenation or by catalytic transfer hydrogen reaction. The catalytic hydrogen transfer reaction takes place in presence of ammonium formate, formic acid or hydrazine hydrate in presence of protic or aprotic solvent at atmospheric pressure thus avoiding external source of hydrogen gas and pressure reaction. The heterogeneous catalyst for catalytic hydrogenation is selected from metals like Pd, Pt, loaded on carbon/ barium sulphate, Pt20 and Raney nickel etc. Reaction is

carried out at 80-85 C and under hydrogen pressure of 100 PSI. The protic or aprotic solvents are selected from the group of C1 to C5 alcohols, organic acids, esters, ethers either alone or mixtures thereof.
Step c: Grignard Reaction for preparation of TARG (V):
Referring to third aspect, the present invention discloses a process for the preparation of buprenorphine intermediate of formula-V comprising reacting with Grignard reagent compound of formula-IV (TAR) to produce the compound of formula- V (TARG). The Grignard reagent is prepared by reaction of magnesium, lithium, zinc or cadmium metal or its derivatives with tertiary butyl halide, where the halide is selected from chloride, bromide or iodide.

Examples of suitable solvents are selected from but not limited to etheral solvents like diethyl ether, THF, 2-Methyl THF, methyl tert butylether, dimethoxy ethane, cyclopentyl methylether, diisopropyl ether and aliphatic or aromatic hydrocarbons like toluene, hexane, heptane, cyclohexane etc or mixtures thereof. Preferable solvent is cyclopentyl methyl ether (CPME). The particular use of eco-friendly solvent like cyclopentyl methyl ether (CPME) as an alternative for this step makes the process commercially viable at plant scale.
Step d: N-demethylation to prepare TARG-NH (VII):
Referring to fourth aspect, the present invention discloses a process for the preparation of buprenorphine intermediate of formula- VII comprising reaction of compound of

formula- V with cyanogen bromide to produce the compound of formula- VI (TARG-NCN), which is further reacted with base in diethylene glycol at 160-170 C temperature to produce the compound of formula- VII (TARG-NH).

There is no particular restriction on the nature of the solvent to be employed for the formation of compound of formula-VI, provided that it has no adverse effect on the reaction or the reagents involved. Examples of suitable solvents include but not limited to ethereal solvents like diethyl ether, THF, 2-Methyl THF, methyl tert.butylether, dimethoxy ethane, cyclopentyl methyl ether, diisopropyl ether. Preferable solvent is cyclopentyl methylether (CPME). The use of said solvent in the said step is advantageous over the use of hazardous, non-eco-friendly chlorinated solvents of the prior art, yet resulting in high yield and purity.
Another advantage of using CPME as preferred solvent for this reaction is that this reaction is performed in-situ from previous Grignard's step, where cyanogen bromide reaction can be carried out without isolating the Grignard product of formula- V.


The subsequent reaction for the preparation of buprenorphine intermediate of formula-VII comprises reaction of compound of formula- VI (TARG-NCN) with a base selected from alkali metal hydroxide such as NaOH, KOH, LiOH etc. to produce the compound of formula-VII (TARG-NH).
There is no particular restriction on the nature of the solvent to be employed for the formation of compound of formula-VII, provided that it has no adverse effect on the reaction or the reagents involved. Examples of suitable solvents, but not limited to, are high boiling solvents like diethylene glycol, triethylene glycol, ethylene glycol, N-methyl pyrrolidinone, DMF, DMSO, DMPU, DMA, DEA, water, n-butanol, ethanol, IPA etc. Preferable solvent is diethylene glycol. The same reaction can be carried out in biphasic mixture of organic solvent with water using phase transfer catalyst.
Step e: N-alkylation to prepare TARG-NCP (IX):
Referring to fifth aspect, the present invention discloses a process for the preparation of buprenorphine intermediate of formula- IX comprising reaction of compound of formula-VII (TARG-NH) with cyclopropyl methyl halide in presence of base and preferably polar aprotic solvent to produce the compound of formula- IX (TARG-NCP).

There is no particular restriction on the nature of the solvent to be employed for the formation of compound of formula-IX, provided that it has no adverse effect on the reaction or the reagents involved. Examples of suitable solvents include but not limited to polar aprotic solvents like acetonitrile, DMF, DEF, DMSO, N-methyl pyrrolidinone, DMPU, DMA, DEA, sulpholane, acetone, methyl ethyl ketone, methyl iso- butyl ketone,

THF, Me-THF, CPME, MtBE, DME etc. Preferable solvent is acetonitrile or CPME. KI or Nal can be added in this reaction as catalyst. Base or acid excavengers are selected from inorganic bases like alkali and alkaline earth metal carbonates and bicarbonates and organic bases like triethylamine, diisopropyl ethyl amine, pyridine, dimethyl amino pyridine, imidazole, ethylene diamine, N,N-dimethyl aniline, colidine etc.
Step f: O-Demethylation for preparation of buprenorphine:
Referring to sixth aspect, the present invention discloses a novel process for the preparation of buprenorphine of formula-I, comprising contacting the compound of formula-IX (TARG-NCP) with alkylthiol in presence of base like potassium tertiary butoxide in a suitable solvent that enhances the yield and purity of the product buprenorphine.

The alkylthiols selected for this reaction are straight chain n-alkylthiols, branched chain alkyl thiols containing carbon atoms C-5 to C-12, or containing cyclic rings or dithiols and combination of these thiols thereof. The preferred thiols for this reaction are pentanethiol, heptanethiol and dodecanethiol. The base employed in this reaction is selected from sodium hydride, sodamide, alkali metal C1 to C4 straight chain or branched chain alkoxides, preferably the base is selected from alkali metal tertiary butoxide, more preferably potassium tertiary butoxide. The reaction is carried at temperature in the range of 80-150°C, preferably at a temperature 100-130C. Examples of suitable solvents include, but not limited to, DMF, DEF, DMSO, toluene and cyclopentyl methyl ether (CPME).

Another preferred embodiment of this reaction is the isolation of desired product of formula-1 (buprenorphine) in higher yield and greater purity, as reaction is at comparatively lower temperature with simple work-up and without any extra step for purification and crystallization.
Industrial Adavntages:
1. The present invention provides an efficient industrial process which provides buprenorphine from thebaine in overall yield of 40-42%, which is substantially higher than the prior art yield of 26-28% disclosed in US 2011/0152527A1.
2. The loading quantity of hazardous, lacrymatic, toxic and expensive raw material methyl vinyl ketone is reduced to the half of its quantity as reported in the prior art process US2011/0152527 for the formation of compound of formula-Ill, thebaine adduct (TA). The improved process produces the thebaine adduct (TA) in 91-95% yield.
3. The present improved process eliminates the use of diethyl ether/ benzene and THF as reaction media for Grignard reaction. As use of these solvents are not industrially viable due to the carcinogenic nature of benzene and highly flammable and hazardous nature of solvents like diethyl ether and THF. The inventors of the present invention have used cyclopentyl methyl ether (CPME) as an alternative solvent for this step which has now become available in commercial quantities with approval by the Toxic Substances Control Act (TSCA) and the European List of Notified Chemical Substances (ELINCS) have high boiling point (106°C) and preferable characteristics such as low formation of peroxides, relative stability under acidic and basic conditions, high hydrophobicity and formation of azeotropes with water coupled with a narrow explosion range render CPME an alternative to other ethereal solvents such as tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-MeTHF), dioxane (carcinogenic), and 1,2-dimethoxyethane (DME). The desired product is obtained with above 99% HPLC purity.
4. In the present improved process the reaction of cyanogen bromide is carried out in cyclopentyl methyl ether (CPME) instead of using chlorinated solvent as used in

prior art processes. Another advantage of using CPME as a solvent in this step is that this reaction is also performed in-situ from previous step without/ optionally isolating the Grignard product. Thus, reducing the operational step.
5. The combined yield of cyanogen bromide reaction and diethylene glycol/ KOH step leading to N-demethylation is 87.4% (from compound of formula-V) with HPLC purity above 99%.
6. In the present process the N-alkylcycloalkylated intermediate of formula- IX is produced in one step by the reaction of cyclopropyl methyl bromide with compound of formula-VII (TARG-NH) under reflux conditions in polar aprotic solvent like acetonitrile giving 92.9% yield and 99.5% HPLC purity. CPME as solvent produces the product of formula- IX (TARG-NCP) in equivalent yield and purity.
7. In the present improved process the O-demethylation is performed with alkanethiol/ potassium tert. butoxide/ in DMF at comparatively lower temperature thereby reducing the chances of formation of undesired products as impurities, which may form when reaction is performed at high temperature (210-220°C). Thus results in higher yield and purity of the final product. After completion of reaction, reaction mass is quenched in water and isolated the desired product by extraction with CPME or other water immiscible solvent like chloroform, MDC or ethyl acetate and the product Buprenorphine base is isolated in 91% yield and above 99% HPLC purity without any extra step for purification or crystallization. The process provides rather simpler work-up procedure with substantial higher yield and better quality of final product buprenorphine.
8. Contrary to the reports published in WO 2013/050748, the inventors of the present invention have successfully performed the 3-O-demethylation on compound of formula-IX (the N-methylcyclopropyl substituted intermediate) with high yield and quality. Thus reduces the chances of formation of impurity which may arise when the intermediate of formula-XI is alkylated, as alkylation may occur on both amine and 3-phenolic position. Thus the improved process gives higher yield and better quality.

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. However, any skilled person will appreciate the extent to which such embodiments could be extrapolated in practice.
Example 1: Preparation of (TA) of formula III:
Added 50 kg thebaine into 100 liter dry toluene. Cooled the mixture to 15 C. To this was added 25 litre MVK and stirred the reaction mixture for 14 hour, followed by stirring at 80-85 C for 18 hours. Solvent was removed under reduced pressure and residual mass was stripped off with isopropyl alcohol, cooled to room temperature, stirred for 1 hour. Resultant product was isolated and dried to get 57.01 kg product TA. (Yield: 93.28%, HPLC purity: 99%)
Example 2: Preparation of (TAR) of formula IV:
Charged 60 liter isopropanol, 6 kg TA and 250 g 10% Pd-C in 100 litre autoclave and hydrogenated at 100 PSI for 3-4 hours at 80- 85 C. Filtered out the charcoal under hot conditions and the solvent was removed partially, cooled to room temperature, stirred for 2 hour. Filtered the product to get 5.58 kg TAR (Yield: 92.53 %, HPLC purity: 99.5 %).
Example 3: Preparation of TARG of formula V
Under inert atmosphere and anhydrous conditions, was charged 1 kg magnesium turning and iodine in vessel. To this was added 3.5 liter CPME. To the mixture was further added 1 liter /-butyl chloride, under stirring. The mixture was heated slowly and maintained below reflux temperature, till the reaction initiated. Added rest of 5 liter /-butyl chloride to 30 liters CPME at such rate that reaction did not subside. After addition was over, reaction mixture was stirred for 12 hour at 35-40 C. To this was added 1 kg TAR in CPME and stirred at 35-40 C for 10 hours. Cooled the reaction mixture and quenched with ammonium chloride in 70 liter water. Suitable work up gave 710 g TARG (Yield: 61.18 %; HPLC purity: 98.74 %).
Same reaction scaled-up to 10 Kg:
In 1000 liter vessel under inert atmosphere and anhydrous conditions was charged 10 kg magnesium turning and iodine. To this was added 35 liter CPME. To the mixture was

further added 1 liter t-butyl chloride (10% of total requirement), under stirring. The mixture was heated slowly and maintained below reflux temperature, till the reaction initiated. Added rest of 50 liter t-butyl chloride to 300 liter CPME, at such rate that the reaction did not subside. After addition was over, reaction mixture was stirred for 12 hour at 35-40° C hr. To this was added 10 kg TAR in CPME and stirred at 35-40° C for 10 hour. Cooled the reaction mixture and quenched with ammonium chloride in 700 liter water. Suitable work-up gave 7.5 kg TARG (Yield: 65.16%; HPLC purity: 99.09%).
Example 4: Preparation of TARG-NCN of formula VI
5 kg TARG was dissolved in 15 liter CPME. To this was added 1.4 kg cyanogen bromide and reaction mixture stirred under reflux condition until completion of reaction. The solvent was removed under reduced pressure, stripped of with methanol, cooled and filtered to obtain 4.815 kg of product TARG-NCN (Yield: 93.95 %; HPLC purity: 99.5 %).
Example 5: Preparation of TARG-NCN from TAR in-situ
In a vessel under inert atmosphere and anhydrous conditions was charged 1 kg magnesium turning and iodine. To this was added 10 liter CPME. To this mixture was further added 0.1 liter t-butyl chloride under stirring till the reaction initiated. Added rest of 0.5 liter /-butyl chloride to 30 liter CPME at such rate that the reaction did not subside. After addition was over, reaction mixture was stirred at 35-40°C until completion of the reaction. To this was added 1kg TAR in CPME and stirred at 35-40°C until completion of the reaction. Cooled the reaction mixture and worked up as in example 3 to obtain TARG in CPME. To this was added 0.2 kg cyanogen bromide and reaction mixture was stirred under reflux condition until completion of reaction. The solvent was removed under reduced pressure, stripped of with methanol, cooled and filtered to get 0.72 kg of product TARG-NCN
Example 6: Preparation of TARG-NH of formula VII:
6.0 kg TARG-NCN was taken in 52 liter diethylene glycol and 4.8 kg potassium hydroxide. Reaction mixture was stirred at 165 C until completion of reaction. Reaction mass was cooled and dumped in water. This mixture was stirred at 15-20°C for 2-3 hour.

Filtered the solid and dried to get 5.24 kg product TARG-NH (Yield: 92.94 %; HPLC purity: 99%)
Example 7: Preparation of TARG-NCP of formula IX
5 kg TARG-NH was taken in 35 liter acetonitrile and cooled the reaction mass, to this was added 4.54 kg anhydrous potassium carbonate, followed by addition of 1.775 kg cyclopropyl methyl bromide. Reaction mixture was stirred under reflux until completion of reaction. Filtered the unwanted material and filtrate was distilled to reduce the quantity and cooled to obtain 5.23 kg product TARG-NCP; (Yield: 92.89 %; HPLC purity: 99.5 %).
Same reaction was performed using CPME as solvent to get the product (TARG-NCP) in equivalent yield and purity.
Example 7: (a). Preparation of Buprenorphine (BPN) using Pentanethiol
Charged 100 liter DMF under inert atmosphere in a vessel. To this was added 3.6 L propanethiol and stirred followed by addition of 3.6 kg potassium t-butoxide in lots. To this was added 3 kg TARG-NCP and stirred the reaction mixture at 100-130°C for 18 hours. Reaction mixture was cooled and dumped in water containing ammonium chloride. Extracted the aqueous layer with CPME / chloroform to give 2.6540 kg buprenorphine (Yield: 91 %; HPLC purity: 99.22%).
(b) Preparation of Buprenorphine (BPN) using Heptanethiol
Charged 100 ml DMF under inert atmosphere in a vessel. To this was added 10 ml heptanethiol and stirred followed by addition of 10 g potassium t-butoxide. To the mixture was further added 5 g TARG-NCP and stirred reaction mixture at 100-130° C for 16 hours. Reaction mixture was cooled and dumped in 750 ml water containing ammonium chloride. Extracted the aqueous layer with CPME / chloroform to obtain 3.806 g buprenorphine (Yield: 78.40 %; HPLC purity 99 %)
(c ) Preparation of BPN using Ethanethiol
To 1 liter DMF under inert atmosphere was added 50 ml ethanethiol and stirred. To this was added 51 g potassium t-butoxide. To the mixture was added 25 g TARG-NCP and

stirred reaction mixture at 100-130o C for 18 hours. Reaction mixture was dumped into water containing ammonium chloride and extracted with chloroform / CPME to get 20.31 g buprenorphine (Yield: 83.68 %; HPLC purity: 98.92%).
(d) Preparation of BPN using dodacanethiol
Charged 200 ml DMF under inert atmosphere in a vessel. To this was added 80 ml dodacanethiol and stirred followed by addition of 80 g potassium t-butoxide. To this was added 10 g TARG-NCP and stirred the reaction mixture at 100-130°C for 16 hours. Reaction mixture was cooled and dumped in water containing ammonium chloride. Extracted the aqueous layer with CPME / chloroform to obtain buprenorphine (HPLC purity: 77 %)

WE CLAIM:
1. A process for the preparation of compound of formula (I);

comprising;
a) contacting thebaine of formula- II (5a)-6,7,8,14-tetrahydro-4,5-epoxy-3,6-
dimethoxy-17-methylrnorphinan with methyl vinyl ketone (MVK) in a solvent to
obtain compound of formula- III (TA) 7a-acetyl-6,14-endo-etheno-6,7,8,14-
tetrahydrothebaine;

b) reducing 7α-acetyl-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine; of formula-Ill of step (a) by catalytic hydrogenation or by catalytic transfer hydrogen reaction in a solvent to obtain compound of formula- IV (TAR) 7a-acetyl-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine;


c) contacting compound of formula- IV of step (b) with tertiary butyl metal halide in a solvent to obtain compound of formula- V (TARG) 7a-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine;

d) contacting compound of formula- V (TARG) of step (c) with cynogen bromide in a solvent to yield compound of formula- VI (TARG-NCN) N-cyano-7a-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine;


e) contacting compound of formula- VI (TARG-NCN) of step (d) with alkali metal hydroxide in a solvent to obtain compound of formula- VII (TARG-NH) 7a-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine;

f) contacting compound of formula- VII (TARG-NH) obtained above in step (e) with cyclopropyl methyl-L in a solvent to produce compound of formula- IX (TARG-NCP) N-cyclopropylmethyl-7a-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine;

wherein L-is a leaving group selected from halides, tosyl, mesyl etc. g) contacting compound of formula- IX (TARG-NCP) obtained above in step (f) with alkanethiol and base in a solvent to produce compound of formula-1.


2. The process according to claim 1, wherein the ratio of methyl vinyl ketone of step (a) with respect to thebaine is 0.5 volume.
3. The process according to claim 1(c), wherein the metal for tertiary butyl metal halide is selected from magnesium, lithium, zinc or cadmium.
4. The process according to claim 1( c), wherein the solvent is selected from ethers like dialkyl ether, where alkyl is selected from CI to C4 straight chain or branched chain alkyl group, cyclic ethers like tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, dioxanes and dialkoxy ethane and hydrocarbons selected from toluene, or mixtures thereof.
5. The process according to claim 1(d), wherein the solvent is selected from ethereal solvents like diethyl ether, THF, 2-Methyl THF, methyl tert.butylether, dimethoxy ethane, cyclopentyl methyl ether and diisopropyl ether .
6. The process according to claim 1 (f), wherein the solvent is selected from polar aprotic solvents such as acetonitrile, DMF, DEF, DMSO, N-methyl pyrrolidinone, DMPU, DMA, DEA, sulpholane, acetone, methyl ethyl ketone, methyl isobutyl ketone, THF, Me-THF, dioxane, CPME, MtBE, and DME.
7. The process according to claim 1(g), wherein alkanethiol is selected from C5 to C12 straight chain, branched chain or containing cyclic ring alkanethiol or dithiol.

10. An in-situ process for the preparation of compound of formula - VI
8. The process according to any of the preceding claims, wherein the solvent is CPME.
9. A process for the preparation of compound of formula-V comprising contacting compound of formula- IV of claim 1 with tertiary butyl metal halide in CPME;


comprising contacting the compound of formula- IV (TAR) of claim lwith tertiary butyl metal halide in CPME to obtain compound of formula-V (TARG) followed by reaction with cyanogen bromide to obtain compound of formula- VI (TARG-NCN) without isolating compound V.
11. A process for the preparation of the compound of formula - IX comprising contacting the compound of formula- VII (TARG-NH) of claim 1 with cyclopropyl methyl halide in the presence of acid excavenger in solvent selected

from acetonitrile (ACN) or CPME to obtain compound of formula-IX (TARG-NCP).