US008981097B2

(12) United States Patent

Saxena et a].
(54)

INDUSTRIAL PROCESS FOR THE

(56)

PREPARATION OF BUPRENORPHINE AND

ITS INTERMEDIATES

U.S. PATENT DOCUMENTS

3/1969 Bentley

2011/0152527 A1

6/2011 Patel et al.

2011/0313163 A1 *

(72) Inventors: Navin Satyapal Saxena, Mumbai (IN);

Kunal Saxena, Mumbai (IN); Kaushik
Babubhai Sata, Mumbai (IN)

Mar. 17, 2015

References Cited

3,433,791 A

(71) Applicant: Rusan Pharma Limited, Mumbai (IN)

US 8,981,097 B2

(10) Patent N0.:

(45) Date of Patent:

12/2011

Hudlicky et a1. ............. .. 546/39

FOREIGN PATENT DOCUMENTS

WO

2013050748

4/2013

* cited by examiner

(73) Assignee: Rusan Pharma Limited, Mumbai (IN)

(*)

Notice:

Primary Examiner * Charanjit Aulakh

(74) Attorney, Agent, or Firm * Kramer Amado, RC.

Subject to any disclaimer, the term of this

patent is extended or adjusted under 35

(57)

U.S.C. 154(b) by 0 days.

There is provided an ef?cient industrial process for the prepa

ABSTRACT

ration of 21 -cyclopropyl-701-(2-hydroxy-3,3-dimethyl-2-bu

(21) Appl.No.: 14/302,159

tyl)-6,l4-endo-ethano-6,7,8,l4-tetrahydro-oripavine,
i.e.
buprenorphine of Formula-l in high yield and purity, With

(22) Filed:

enhanced safety and eco-friendly norms. The invention fur

ther relates to an improved process for preparation of inter

Jun. 11, 2014

(65)

mediates thereof in high yield and purity.

Prior Publication Data

US 2014/0364612 A1

Dec. 11,2014

Formulal
HO

(30)

Foreign Application Priority Data

Jun. 11,2013

(IN) ....................... .. l988/MUM/2013

(51) 1111.0.
C07D 489/12
C07D 489/02

(52)

(2006.01)
(2006.01)

vs. C].

MeO
HO

CPC .................................. .. C07D 489/12 (2013.01)

USPC

(58)

............................................. .. 546/39; 546/44

l Bu

Buprenorphine

Field of Classi?cation Search

USPC

.................................................... .. 546/39, 44

See application ?le for complete search history.

17 Claims, No Drawings

US 8,981,097 B2
1

INDUSTRIAL PROCESS FOR THE

PREPARATION OF BUPRENORPHINE AND
ITS INTERMEDIATES

invention further relates to an improved process for the prepa

ration of intermediates thereof in a high yield and purity.

BACKGROUND OF THE INVENTION

Buprenorphine, chemically known as 21 -cyclopropyl-70t

FIELD OF INVENTION

(2-hydroxy-3,3-dimethyl-2-b 1)-6,14-endo-ethano-6,7,8,14

The present invention relates to an e?icient industrial pro

cess for the preparation of 21 -cyclopropyl-70t-(2-hydroxy-3,

3 -dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydro
oripavine, i.e. buprenorphine of Formula-I, in a high yield and
purity With enhanced safety and eco-friendly norms. The

tetrahydrooripavine, is a semi-synthetic opiate used as a pow

erful analgesic and is indicated for the treatment of moderate

to severe pain and opioid dependence. The compound was

?rst reported by K. W. Bentley in US. Pat. No. 3,433,791.

This patent reports the semi-synthesis of buprenorphine from

thebaine as depicted in Scheme-1.

Scheme- 1:

MeO

MeO

MVK

>

MeO

N/

Hydrogenation

>

N/

MeO

Theb aine
O

F ormula II

O
FormulaIII

FormulaIV

grignard reaction l tBuMgCl

MeO

MeO

O
NH

DEG/KOH
165 o C -

MeO

MeO

CNBr
O

\CN

MeO
HO

MeO
HO

tBu

HO

tBu

FormulaVII

Formul aVI

Formula V

OMe

MeO

LiAlH4
N

HO

DEG/KOH

>

>

210 c.

MeO

MeO
HO

MeO
HO

HO
t Bu

FormulaVIII

FormulaIX

F ormulaI

US 8,981,097 B2
4

3
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

methods for preparing buprenorphine wherein thebaine is

thebaine. In addition, the workup procedure for O-demethy

used as a key starting material.

US 2011/0152527A1 discloses a process for the prepara
tion of buprenorphine as depicted in Scheme-2. The process
up to Formula-V is similar to the Bentley process reported in

hazardous, highly ?ammable and peroxide forming solvents,

unsuitable at an industrial scale. Finally, the process requires
an extra step for puri?cation, resulting in a low yield of the

Us. Pat. No. 3,433,791. However, major modi?cations

?nal product.

lation is tedious and there is no mention of the purity of the

product and intermediates. Furthermore, the process uses

for example diethyl ether and THF, which makes the process

Scheme2:

MeO

MeO

0 N

MVK

>

MeO

MeO

0 N

MeO

Hydrogenation

>

MeO

Thebaine
FormulaH

O
FormulaHI

FormulaIV

grignard reaction i tBuMgCl

MeO

MeO

MeO
Chlorobenzene

NaUEthyl
O

DEG/KOH
NH

chloroformate

130-1400 C.

OC H

\H/ 2 5

O
MeO

MeO
HO

MeO
HO

tBu

HO

tBu

FormulaVII

tBu

FormulaX

FormulaV

MsCl\ 5 OH
MeO

HO

Thio phenol
N

>

Chlorobenzene

MeO

MeO
HO

HO

FormulaIX

FormulaI

include the use of ethyl chloroformate and then heating at

130 C. to 140 C. with KOH and diethylene glycol for

N-demethylation of the compound of Formula-V to get the

compound of Formula-VII; the subsequent reaction with

WO 2013/050748 of Johnson Matthey PTC discloses a

process for the preparation of buprenorphine or its deriva
tives, as shown in Scheme-3 below. The preparation of the

compound of Formula-VI is performed by known processes.

cyclopropyl methyl alcohol with mesyl chloride for N-alky 65 However, major modi?cations include N-demethylation,

lation; and ?nally the use of thiophenol for O-demethylation

to get buprenorphine base of Formula-l. The overall reported

which is carried out at lower temperatures using NaOH, water

and ethylene glycol or methoxy ethanol and then sub sequent

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
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
intermediate. The ?rst reaction is N-demethylation, which is
followed by 3-O-demethylation to get the compound of For
mula-XI which is further converted to buprenorphine. A dis
advantage associated with this process is the formation of

MeO

Demethylation

MeO

impurities which arises during the ?nal step of N-alkylation,

as alkylation can occur on both the NH group and 3-phenolic

HO

group. Thus, additional steps for puri?cation may be

required, which lead to poor yield and lower quality of the
?nal product. It is further mentioned that 3-O-demethylation

tBu

3OMethylbuprenorphine
HO

cannot happen on the N-alkylcycloalkylated intermediate.

For that reason, both N-demethylation and O-demethylation
are carried out prior to the N-alkylation step.
O
N

20

Scheme3:
MeO
MeO
HO

25

Ethylene glycol
O

tBu

NaOH, H20

\CN

Buprenorphine

115-12500.
One drawback associated with the prior art processes is an

MeO

overall low yield of product buprenorphine. Another draw

back associated with the prior art processes is the use of toxic,

HO

highly ?ammable and hazardous solvents in the Grignard

reaction step, for example benzene, diethyl ether and THF,

tBu
FormulaVI

35

MeO

HO

making the process unsuitable for scaling-up to industrial

scale due to safety and environmental concerns. Additionally,
the prior art processes are prone to the formation of by

products/impurities and thus, require extra steps for puri?ca

tion at intermediate stages as well as at the ?nal product stage.
O

thiols

40

NH >

NH

Base

MeO

e?iciently. The attempted O-demethylation of 3-O-methyl

MeO
HO

45

HO

Bu

buprenorphine (N-alkylated) gives a conversion to buprenor

phine of no more than 2.1% using potassium tert.butoxide and
l-dodecanethiol. The same reaction when attempted using

tBu

FormulaVII

This leads to poor yield and inferior quality at intermediate

stages as well as at the ?nal product stage. It is clearly men
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

sodium propane thiolate was unsuccessful and no product

FormulaXI

was detected.
50

Thus, there remains a need in the art to provide an e?icient,

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

O
N

number of solvents used in the process for preparing

buprenorphine and the intermediates thereof, in order to ren
der the process economically viable.
SUMMARY OF THE INVENTION

60

MeO

The present invention provides technical solutions to over

come the drawbacks of the prior art processes for the prepa

HO

ration of buprenorphine and its intermediates, in particular

tBu
Formulal

65

those disclosed above in Scheme-2 and 3.

According to a ?rst aspect of the present invention, there is
provided a process for the preparation of a compound of

Formula-l, comprising:

US 8,981,097 B2
-continued
MeO

Formulal
HO

O
O

N\

Nk

MeO

MeO
HO

O
TAR
FormulaIV

l Bu

Buprenorphine

c) contacting the compound of Formula-IV obtained in

a) contacting thebaine of Formula-ll, (5a)-6,7,8,14-tet

rahydro -4, 5 -epoxy-3, 6-dimethoxy- 1 7 -methylmorphi

step (b) With tertiary butyl metal halide in a solvent to

obtain a compound of Formula-V, 70t-(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-Ill, 70t-acetyl-6,14-endo-etheno- 20

drothebaine (TARG);

6,7,8, 1 4-tetrahydrothebaine (TA);

MeO

MeO

25

>

N\

0 N\

MeO

Thebaine
Formulall

30

MeO

M60

MeO
TAR
FormulaIV

C,

35

N\

r N\
MeO

MeO

40

HO
0
TA
FormulaIll

tBu
TARG
FormulaV

45

b) reducing the compound of Formula-Ill 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-70t-(2-hydroxy-3,3

Formula-IV, 70t-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

13'

N\
>

60

MeO
HO
tBu

TA
FormulaIll

65

TARG
FormulaV

US 8,981,097 B2
-continued
MeO
MeO

O
NH

>

N\CN
10 MeO

MeO

HO
tBu

HO

MeO

tBu
TARG-NCN
FormulaVI

TARG-NH
FormulaVII

O
N
20

e) contacting the compound of Formula-VI obtained in

MeO

step (d) With alkali metal hydroxide in a solvent to obtain

a compound of Formula-VII, 70t-(2-hydroxy-3,3-dim

l
HO

ethyl-2 -butyl)-6, l 4-endo -ethano-6,7, 8, l 4-tetrahy

dronorthebaine (TARG-NH);

25

tBu
TARG-NCP
FormulaIX

MeO

g) contacting the compound of Formula-IX obtained in

step (l) with an alkane thiol and a base in a solvent to

produce a compound of Formula-l

O
MeO

N\ CN
35

MeO
O

>

HO

tBu
TARG-NCN

40

MeO

F ormula Vl

HO
MeO

tBu
45

HO
TARG-NCP
Formula-IX

O
NH

O
N
50

MeO

MeO

HO
t Bu

l_
HO

55

TARG-NH

tBu

FormulaVII

Buprenorphine
Formulal

The invention provides an e?icient, economical and indus

l) contacting the compound of Formula-VII obtained in

trially viable process for the preparation of 2l-cyclopropyl

70t- (2 -hydroxy-3 ,3 -dimethyl-2-butyl)-6, l 4-endo -ethano-6,

step (e) With cyclopropyl methyl-L in a solvent to pro

duce a compound of Formula-IX, N-cyclopropylm

ethyl-70t- (2 -hydroxy-3 ,3-dimethyl-2 -butyl)-6, l 4-endo

ethano-6,7,8, l 4-tetrahydronorthebaine (TARG-NCP),
Wherein L-is a leaving group selected from halides, tosyl
and mesyl; and

7,8,14-tetrahydrooripavine i.e. buprenorphine of Formula-l,

in a high yield and purity. Additionally, the invention provides
65

an in-situ process for the preparation of buprenorphine (For

mula-l) and its intermediate compound of Formula-VI, thus
reducing the number of operational steps.

US 8,981,097 B2
11

12

According to a second aspect of the present invention, there

is provided a process for the preparation of a compound of

-continued

Formula-V, comprising contacting a compound of Formula

IV with tertiary butyl metal halide in CPME.

MeO
01

MeO
N

CNBr
CPME

N\

_>
n

MeO
TARG
FormulaV

(OPTIONALLY ISOLATING)

O
TAR

20

MeO

Formul a lV

MeO

25

CN.

O
N
\I

MeO
HO

30

MeO

t Bu

HO

TARG-N CN
F orrnula Vl

tBu
TARG
F orrnula V

Advantageously, the process results in the formation of the

compound of Formula-V in a higher yield and purity com
pared to the prior art processes. Additionally, the process uses
a safe and eco-friendly solvent, namely CPME.
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
mula-IV With tertiary butyl metal halide in CPME to obtain a
compound of Formula-V, followed by reaction With cyanogen
bromide to obtain a compound of Formula-VI, Without iso

35

40

45

Advantageously, the process results in the formation of the

compound of Formula-VI in a higher yield and purity com
pared to the prior art processes. Additionally, the process uses
a safe and eco-friendly solvent. Furthermore, due to the in
situ nature of the process, fewer operational steps are required
to form the compound of Formula-VI.
According to a fourth aspect of the present invention, there
is provided a process for the preparation of a compound of

Formula-IX, comprising contacting a compound of Formula

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:

lating the compound of Formula-V:

50

MeO
MeO

t. BuM gCl

55

>

CPME
N

NH

\
60

MeO

MeO

O
TAR
Formul a IV

65

TARG-NH
F orrnula Vll

US 8,981,097 B2
13

14

-continued

According, to a ?rst aspect of the present invention, there is

provided a process for the preparation of buprenorphine of

MeO

Formula-I, comprising:

FormulaI
HO

MeO
HO
tBu
TARG-NC P
F ormula IX

Advantageously, the process results in the formation of the

compound of Formula-IX in a higher yield and purity com
pared to the prior art processes. Additionally, the process uses
a safe and eco-friendly solvent.

k
MeO
HO
20
1 Bu

Buprenorphine

DEFINITIONS

Thebaine:
(5a)-6,7,8,l4-Tetrahydro-4,5-epoxy-3,6
dimethoxy- l 7-methylmorphinan.
TA: 70t-Acetyl-6, l 4-endo -etheno-6,7, 8, l4-tetrahydrothe

25

a) contacting thebaine of Formula-II, (5a)-6,7,8,l4-tet

baine

TAR: 70t-Acetyl-6, l 4-endo -ethano-6,7, 8, l4-tetrahydrothe

baine

TARG: 70t-(2-Hydroxy-3,3-dimethyl-2-butyl)-6,l4-endo
ethano-6,7, 8, l 4-tetrahydrothebaine
TARG-NCN: N-Cyano-70t-(2-hydroxy-3,3-dimethyl-2-b

30

rahydro -4 , 5 -epoxy-3, 6-dimethoxy- l 7 -methylmorphi

nan, With methyl vinyl ketone (MVK) in a solvent to
obtain a compound of Formula-III, 70t-acetyl-6,l4

endo -etheno-6,7,8, l 4-tetrahydrothebaine (TA);

l)-6, l 4 -endo -ethano -6 , 7, 8, l4 -tetrahydronorthebaine

TARG-NH:

70t-(2 -Hydroxy-3,3-dimethyl-2 -butyl)-6, l 4

endo-ethano- 6 ,7 , 8, l 4 -tetrahydronorthebaine.

TARG-NCP:
N-Cyclopropylmethyl-70t-(2-hydroxy-3,3
dimethyl-2-butyl)-6, l 4-endo -ethano-6,7, 8, l4-tetrahy
dronorthebaie.

DMF: dimethyl formamide

DMSO: dimethyl sulfoxide
THF: tetrahydrofuran

CPME: cyclopentyl methyl ether

DMPU: dimethyl propylene urea
DMA: dimethyl acetamide
NMP: N-methylpyrrolidinone
DEA: diethyl acetamide

45

Theb aine
Formula II

MVK: methyl vinyl ketone

DEF: diethyl formamide

DEG: diethylene glycol

MtBE: methyl tertiary butyl ether

. 9%
'3 \

50

MsCl: mesyl chloride

ACN: acetonitrile

PSI: pounds per square inch

DETAILED DESCRIPTION OF THE INVENTION

55

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.

FormulaIII
60

The term contacting as used herein refers to mixing,

b) reducing 70t-acetyl-6, l4-endo-etheno-6,7,8,l4-tetrahy

heating, stirring, re?uxing or combinations thereof.

drothebaine (TA) of Formula-III obtained in step (a) by

catalytic hydrogenation or by catalytic transfer hydro

The present invention discloses an ef?cient, economical

and industrially viable process for the preparation of

buprenorphine of Formula-I. The present invention further
discloses processes for the preparation of its intermediates of
Formula-V, VI and IX.

65

gen reaction in a solvent to obtain a compound of For

mula-IV, 70t-acetyl-6, l4-endo-ethano-6,7,8,l4-tetrahy

drothebaine (TAR);

US 8,981,097 B2
15

16
pound of Formula-V1, N-cyano-70t-(2-hydroxy-3,3

dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahy

MeO

dronorthebaine (TARG-CN);
O

up

_>

o N \

MeO J

10

o
M O

TA
FormulaIll

>

\
15

MeO
O
N

HO

\
20

tBu

TARG
FormulaV

M60
O
25

TAR
FormulaIV

M60

c) contacting the compound of Formula-1V obtained in

step (b) With a tertiary butyl metal halide (t-BuMX) in a 30
solvent to obtain a compound of Formula-V, 70t-(2-hy-

droxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,

\CN

1 4-tetrahydrothebaine (TARG);
35

MeO

MeO

HO
tBu

TARGNCN
Formula-VI

40

N
\

_>

MeO

45

e) contacting the compound of Formula-VI obtained in

step (d) With alkali metal hydroxide in a solvent to obtain

a compound of Formula-V11 70t-(2-hydroxy-3,3-dim
ethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahy

TAR
Formula-IV
MeO

dronorthebaine (TARG NH);

50

MeO

MeO

CN
H0

60

MeO

t Bu

HO

TARG
FormulaV
65

d) contacting the compound of Formula-V obtained in step

(c) With cyanogen bromide in a solvent to yield a com

TARG-NCN
F ormula Vl

US 8,981,097 B2
-continued
MeO
MeO
5

>

O
N
O
NH
1 0 MeO

MeO

HO
HO

tBu

PBU

TARG-NCP
Formula-IX

15

TARG-NH
FormulaVII

HO

20

i) 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-70t- (2 -hydroxy-3 ,3-dimethyl-2 -butyl)-6, l 4-endo- 25

M60

ethano-6,7,8,l4-tetrahydronorthebaine (TARG NCP),

HO

Wherein L is a leaving group selected from halides, tosyl

and mesyl; and

PBH
Buprenorphine
Formulal
30

MeO

Detailed Process Steps are Outlined Below:

Step (a): Preparation of TA (Formula-Ill) from Thebaine:

O

35
NH

Thebaine of Formula-ll is contacted With methyl vinyl

ketone (MVK) in the presence of a solvent to produce the

compound of Formula-Ill.
M60

40

HO

HO
tBu
O

TARG-NH

45

FormulaVII
MeO

>

0 N

M60

50

Thebaine
Formulall

MeO

0 N \

HO

TARG-NCP
FormulaIX

60

M60

J
O

g) contact1ng
.
the compound of Formula-IX obtained
~
in
~
65

step (f) With an alkanethiol and a base in a solvent to

produce a compound of Formula-l (buprenorphine)

Fonnulaqn

US 8,981,097 B2
19

20
Step (c): Grignard Reaction for Preparation of TARG (For

Preferably methyl vinyl ketone is used in the ratio of 0.5

volume to Thebaine. The solvent used in this step may be

mula-V):

selected from inert organic solvents, including aromatic

hydrocarbons, for example toluene and xylene, and ethereal

Step (c) involves the preparation of the buprenorphine

intermediate of Formula-V, comprising reacting a Grignard
reagent With the compound of Formula-IV (TAR) to produce
the compound of Formula-V (TARG). The Grignard reagent
may be prepared by the reaction of magnesium, lithium, Zinc,

solvents, for example THF, Me-THF, methyl tert.butyl ether

and cyclopentyl methyl ether. Preferably the solvent is cyclo

pentyl methyl ether.

Step (h): Hydrogenation to Prepare TAR (Formula-IV):

cadmium metal or derivatives thereof, With a tertiary butyl

halide, Where the halide may be selected from chloride, bro
mide or iodide. Preferably the Grignard reagent is t-BuMgCl,
t-BuMgBr or t-BuMgl.

Step (b) involves the preparation of the intermediate of

Formula-IV (TAR) by reducing the double bond of the the
baine adduct (TA) of Formula-Ill. Preferably this step is
carried out in the presence of a protic or aprotic solvent at a
temperature in the range of from 80 C. to 85 C. and a

pressure of 100 PSI. Under these conditions, the yield and

purity of the compound of Formula-IV is enhanced.

MeO I

MeO

20

O
N
\

>

MeO

25

MeO

TAR
Formula-IV

0
30

MeO

TA
FormulaIll
MeO
O
35

O
N

MeO
HO

40

MeO
tBu
TARG
FormulaV

O
TAR
FormulaIV

The reduction is carried out by catalytic transfer hydrogen

reaction or by catalytic hydrogenation.
The catalytic hydrogen transfer reaction preferably takes

45

Step (c) is carried out in the presence of a solvent.

Examples of suitable solvents include, but are not limited to,

ethereal solvents, for example dialkyl ether, Wherein the alkyl

50

butyl ether, dimethoxy ethane, cyclopentyl methyl ether and

diisopropyl ether; dioxanes; dialkoxy ethanes; and aliphatic

place in the presence of ammonium forrnate, formic acid or

hydraZine hydrate in the presence of a protic or aprotic sol
vent at atmospheric pressure. This is advantageous since it
avoids using an external source of hydrogen gas and increased
pressure.

is selected from C1 to C4 straight or branched chain alkyl

groups e.g. diethyl ether, THF, 2-methyl THF, methyl tert

or aromatic hydrocarbons, for example toluene, hexane, hep

55

tane, cyclohexane or mixtures thereof. Preferably the solvent

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

tion may be selected from metals such as Palladium and

Step (d) and Step (e): N-demethylation to Prepare TARG-NH

60

Platinum, loaded onto carbon, barium sulphate, PtZO or

mula-V With cyanogen bromide in a solvent to produce the

lyst is 10% palladium loaded onto carbon. The reaction is

compound of Formula-VI (TARG-NCN). Step (e) involves

preferably carried out at a temperature of from 80 C. to 85

C. and under hydrogen pressure of 100 PS1. The protic or

aprotic solvent may be selected from C1 to C5 alcohols,

organic acids, esters, ethers and mixtures thereof.

(Formula-VII):
Step (d) involves the reaction of the compound of For

Raney nickel for example. Preferably the heterogeneous cata

65

the compound of Formula-VI being reacted With a base in a

solvent to yield the buprenorphine intermediate of Formula

VII.

US 8,981,097 B2
MeO

MeO

O
N

'

\
MeO

MeO

HO
tBu

TAR
F ormula lV

TARG
Formula V

_ MeO

MeO

20

O
N

>

\CN

MeO
25

MeO
HO

HO
_

tBu
TARG-NCN
Formula Vl

30

t Bu

Y1

TARG
FormulaV
MeO

MeO
O
N
35

\CN

O
NH

MeO
HO
40

MeO

tBu
TARG-NCN
F ormula VI

HO
t Bu

TARG-NH

The subsequent reaction for the preparation of the

buprenorphine intermediate of Formula-VII (step (e)) com
prises the reaction of the compound of Formula-VI (TARG

Formul a Vll

NCN) With a base Which may be selected from alkali metal

There is no particular restriction on the nature of the sol

50

hydroxides, for example NaOH, KOH and LiOH, to produce

the compound of Formula-VII (TARG-NH).

55

vent to be employed for the formation of the compound of

Formula-VII, provided that it has no adverse effect on the
reaction or the reagents involved. Examples of suitable sol
vents include, but are not limited to, high boiling solvents for

vent to be employed for the formation of the compound of

Formula-VI in step (d), provided that it has no adverse effect
on the reaction or the reagents involved. Examples of suitable
solvents include, but are not limited to, ethereal solvents for

example diethyl ether, THF, 2-Methyl THF, methyl tert.bu

tylether, dimethoxy ethane, cyclopentyl methyl ether and

There is no particular restriction on the nature of the sol

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)

has advantages over the hazardous, non-ecofriendly chlori
nated solvents of the prior art, and results in a high yield and

DEA, water, n-butanol, ethanol and IPA. Preferably the sol

vent is diethylene glycol. It should be appreciated that the
same reaction may be carried out in a biphasic mixture of an

organic solvent With water, and a phase transfer catalyst.

high product purity.

Step (e) may be carried out at a temperature of from 160 C.

to 170 C. Preferably step (e) is carried out at a temperature of
165 C.

Another advantage of using CPME as the solvent for this

reaction is that this reaction can be performed in-situ from the

previous Grignard reaction step (step (c)). Thus, the cyanogen

bromide reaction (step (d)) can be carried out Without isolat

Step (f): N-alkylation to Prepare TARG-NCP (Formula-IX):

Step (f) involves the preparation of the buprenorphine

ing the Grignard product of Formula-V.

intermediate of Formula-IX, comprising the reaction of the

65

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

>

O
NH

MeO

>

HO
t Bu

MeO

TARG-NC P
FormulaIX

HO
tBu
TARG-NH
FormulaVII

HO
20

MeO
O
N
O

25

N
MeO
HO

MeO
30

t Bu

HO

Buprenorphine
tBu

F orrnulal
TARG-NCP
FormulaIX
35

The L group in cyclopropyl methyl-L may be a leaving

group selected from halides, tosyl and mesyl. The halide
leaving group may be chloride, bromide or iodide. Preferably

The alkane thiols selected for this reaction may be straight

chain n-alkanethiols, branched chain alkanethiols, alkanethi
ols containing cyclic rings or dithiols and combinations
40

the cyclopropyl methyl-L compound is cyclopropyl methyl

bromide.
There is no particular restriction on the nature of the sol
vent to be employed for the formation of the compound of
Formula-IX, provided that it has no adverse effect on the
reaction or the reagents involved. Examples of suitable sol
vents include, but are not limited to, polar aprotic solvents, for

example acetonitrile, DMF, DEF, DMSO, N-methylpyrroli

dinone, DMPU, DMA, DEA, sulpholane, acetone, methyl
ethyl ketone, methyl iso-butyl ketone, THF, Me-THF, CPME,

ethanethiol, pentanethiol, heptanethiol and dodecanethiol.

45

50

55

for example triethylamine, diisopropyl ethyl amine, pyridine,

dimethyl amino pyridine, imidazole, ethylene diamine, N,N
60

Step (g): O-Demethylation for Preparation of Buprenorphine

(Formula-l):

Step (g) involves the preparation of buprenorphine of For

mula-l, comprising contacting the compound of Formula-IX
(TARG-NCP) with an alkane thiol in the presence of a base

product buprenorphine.

Examples of suitable solvents for step (g) include, but are

not limited to, DMF, DEF, DMSO, toluene and cyclopentyl
methyl ether (CPME). Preferably the solvent is DMF or
CPME.

dimethyl aniline and colidine. Additionally, Kl or Nal may be

and a suitable solvent that enhances the yield and purity of the

The reaction may be carried out at a temperature in the

range of from 80 C. to 150 C. Preferably the reaction is
carried out at a temperature in the range of from 100 C. to
130 C., more preferably from 110 C. to 115 C.

of a base or acid scavenger. The base or acid scavenger may be

added in this reaction as a catalyst.

The base employed in this reaction may be selected from

sodium hydride, sodamide and alkali metal C1 to C4 straight
chain or branched chain alkoxides. Preferably the base is
selected from alkali metal tertiary butoxides. More preferably

the base is potassium tertiary butoxide.

MtBE and DME. Preferably the solvent is acetonitrile or

CPME.
The reaction in step (f) may be carried out in the presence

selected from inorganic bases for example alkali and alkaline

earth metal carbonates and bicarbonates; and organic bases

thereof. The alkanethiols may contain from 5 to 12 carbon

atoms. The preferred alkanethiols for this reaction are

65

Step (g) enables the isolation of the desired product of

Formula-l (buprenorphine) in a higher yield and greater
purity than the prior art processes, as the reaction is carried
out at a comparatively lower temperature with simple work
up and without any extra steps for puri?cation and crystalli
zation.

One speci?c embodiment of the process of the present

invention is shown below in Scheme-4.

US 8,98l,097 B2
25

26

Scheme4:

MeO

MVK

10% PdC, H2

>

4>

MeO
Thebaine
FormulaH

O
TAR
Formula-IV

FormulaHI

CPMEl t-BuMgCl
M60

M60

NH

DEG/KOH

_ M60

165 c.

MeO

CNBr

\ CN

MeO
HO

tBu

CPME

MeO
HO

HO

tBu

TARG-NH
FormulaVII

TARG-NCN
FormulaVI

tBu

TARG
FormulaV

Optionally isolating

Br

MeO

HO

Pentane thiol/K tBuO

MeO

DMF, 110-115 C.

MeO
HO

HO

tBu

t'Bu

TARG'NCP
FormulaIX

Buprenorphine
Formulal

Although the Pmsemt invention has been described in terms

According to a second aspect of the present invention, there
of an 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
Formula-V,
comprising contacting a compound of Formula
processes outlined in steps (a) to (g), and to any combination

thereof.

IV With tertiary butyl metal halide in CPME:

US 8,981,097 B2
-continued
MeO

MeO

N
\

_>

\CN.

MeO

MeO

HO
O
tBu

TAR
F ormula IV

TARGNCN
FormulaVI

MeO

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
\ I

20

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
F ormula V
O
NH

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
mula-IV With tertiary butyl metal halide in CPME to obtain a
compound of Formula-V, followed by reaction With cyanogen

>

MeO
HO
35

bromide to obtain a compound of Formula-VI, Without iso

t Bu

lating the compound of Formula-V:

TARG-NH
F ormula VII
MeO

MeO

40

O
N

N\

_>

45

MeO
MeO
HO
O
t Bu

50

TARG-NCP

TAR
Formula-IV

Formul a IX

_ MeO

It should be appreciated that the preferred features of the

?rst aspect of the present invention can also relate to the

second, third and fourth aspects of the invention.

O

N\

INDUSTRIAL ADVANTAGES

,
60

MeO
HO
_

tBu

TARG
FormulaV

1. The present invention provides an ef?cient industrial pro

cess Which may provide buprenorphine from thebaine in an
overall yield of from about 30% to about 50%, more spe
ci?cally from about 40% to about 42%. This is substan

tially higher than the prior art yield of 26% to 28% dis

_ n

65

closed in US 2011/0152527A1.

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

the prior art process disclosed in US2011/0152527. Addi

mula-IX (the N-methylcyclopropyl substituted intermedi

ate), with high yield and purity. The chance of impurity

tionally, the improved process may produce the thebaine

adduct of Formula-Ill (TA) in a yield of greater than 90%,

formation which arises when the intermediate of formula

IX is alkylated (as alkylation may occur on both the amine

more speci?cally from about 91% to about 95%.

3. The present invention may allow for the elimination of
diethyl ether, benzene and THE as the reaction media for

and 3-phenolic position), is reduced in the present process.

Thus, the process results in a higher yield and better quality
of the ?nal product.

the Grignard reaction step (step (c)). The use of these

The invention will now be more speci?cally described by

the following examples, so that various aspects thereof may
be more fully understood and appreciated.

solvents is not viable on an industrial scale due to the

carcinogenic nature of benzene and the highly ?ammable

and hazardous nature of solvents such as diethyl ether and

THF. The inventors of the present invention have surpris

ingly found that cyclopentyl methyl ether (CPME) can be

Example 1

used as an alternative solvent for this step. CPME has now

Preparation of TA of Formula-Ill

become available in commercial quantities with approval

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 Noti?ed 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

under reduced pressure and the residual mass was stripped off

acidic and basic conditions, high hydrophobicity and for

20

mation of azeotropes with water, coupled with a narrow

explosion range render CPME a favourable alternative to

with isopropyl alcohol, cooled to room temperature and

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

genic), and 1,2-dimethoxyethane (DME). The desired

99%).
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
gen bromide is preferably carried out in cyclopentyl
methyl ether (CPME) rather than the chlorinated solvents
used in the prior art processes. An advantage of using

Preparation of TAR of Formula-IV

30

CPME as a solvent in this step is that it enables the reaction

to be performed in-situ from the previous step without

having to isolate the Grignard reaction product. Thus, the
number of operational steps may be reduced.
5. The yield of the compound of Formula-VII from step (d)

35

and step (e) may be as much as 87.4% with HPLC purity

above 99%.

6. In the present process, the N-alkylcycloalkylated interme

diate of formula-IX is produced in a one-step reaction (step

99.5%).
Example 3
40

f) of cyclopropyl methyl-L with the compound of Formula

VII (TARG-NH) in the presence of a solvent, for example
CPME or acetonitrile, preferably under re?ux conditions.
Using this process, a yield of 92.9% of the compound of
Formula-IX with 99.5% HPLC purity, may be realised.

Preparation of TARG of Formula-V

Under an inert atmosphere and anhydrous conditions, 1 kg

of magnesium turnings and iodine was charged into a vessel.
45

7. The O-demethylation of step (g) is preferably performed

with alkane thiol and potassium tert.
butoxide in DMF at a comparatively lower temperature
than the prior art processes. The lower temperature reduces
the formation of undesirable impurities, which tend to form
when the reaction is performed at a higher temperature, for

CPME was added to the reaction mixture at such a rate that

50

example between 210 C. and 220 C. Consequently, a higher

55

61.18%; HPLC purity: 98.74%).

60

tallization is required. The process provides a simpler

work-up procedure and results in a substantially higher

yield and better quality of the ?nal buprenorphine prod

uct than the prior art processes.

8. Contrary to the reports published in WO 2013/050748, the

inventors of the present invention have successfully per
formed the 3-O-demethylation on the compound of For

reaction did not subside. After the addition was completed,

the reaction mixture was stirred for 12 hours at 35 C. to 40
C. 1 kg of TAR in CPME was added to the reaction mixture
and stirred at 35 C. to 40 C. for 10 hours. The reaction
mixture was cooled and quenched with ammonium chloride
in 70 L of water. Suitable work up gave 710 g TARG (Yield:

Same Reaction Scaled-Up to 10 Kg:

10 kg of magnesium tumings and iodine was charged into

cible solvent, for example chloroform, MDC or ethyl

acetate. The product buprenorphine base may be
obtained in a 91% yield with over 99% HPLC purity.
Advantageously, no extra step for puri?cation or crys

To this was added 3.5 L of CPME. 1 L of t-butyl chloride was

added to the mixture under stirring. The mixture was heated

slowly and maintained below re?ux temperature, until the

reaction started. A further 5 L of t-butyl chloride and 30 L of

yield and purity of the ?nal product is achieved.

After completion of the reaction, the reaction mass may be
quenched in water and the desired product may be iso
lated by extraction with CPME or another water immis

60 L ofisopropanol, 6 kg of TA and 250 g of 10% Pd4C

catalyst were charged into a 100 L autoclave and hydroge
nated at 100 PS1 for 3 to 4 hours at 80 C. to 85 C. The
charcoal was ?ltered off under hot conditions and the solvent
was partially removed, the remaining mixture was cooled to
room temperature and stirred for 2 hours. Finally, the product
was ?ltered to get 5 .58 kg TAR (Yield: 92.53%; HPLC purity:

65

a 1000 L vessel under an inert atmosphere and anhydrous

conditions. To this was added 35 L of CPME. 1 L of t-butyl
chloride was added to the mixture under stirring. The mixture
was heated slowly and maintained below re?ux temperature,
until the reaction started. A further 50 L of t-butyl chloride
and 300 L of CPME was added to the reaction mixture at such
a rate that the reaction did not subside. After the addition was

completed, the reaction mixture was stirred for 12 hours at

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.

The reaction mixture was cooled and quenched with ammo

Example 8

nium chloride in 700 L of water. Suitable work-up gave 7.5 kg

(a) Preparation of Buprenorphine (BPN) using

Pentanethiol*

TARG (Yield: 65.16%; HPLC purity: 99.09%).

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
in batches. 3 kg of TARG-NCP was added to the mixture and
subsequently the reaction mixture was stirred at 100 C. to
130 C. for 18 hours. The reaction mixture was cooled and

5 kg of TARG was dissolved in 15 L CPME. To this was

added 1.4 kg of cyanogen bromide. The reaction mixture was
stirred under re?ux conditions until completion of the reac
tion. The solvent was removed under reduced pressure,

stripped off with methanol, cooled and then ?ltered to obtain

placed in water containing ammonium chloride. The aqueous

layer was extracted with CPME/chloroform to give 2.654 kg

4.815 kg of product TARG-NCN (Yield: 93.95%; HPLC

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 ln-Situ

20

(b) Preparation of Buprenorphine (BPN) Using

Heptanethiol

25

atmosphere. To this was added 10 ml heptanethiol. The mix

Under an inert atmosphere and anhydrous conditions, 1 kg

of magnesium turnings and iodine was charged into a vessel.
To this was added 10 L of CPME. 0.1 L of t-butyl chloride was

added to the reaction mixture under stirring until the reaction

started. A further 0.5 L of t-butyl chloride and 30 L of CPME

100 ml DMF was charged into a vessel under an inert

ture was stirred and then 10 g potassium t-butoxide was

added. 5 g TARG-NCP was further added to the mixture and
subsequently the reaction mixture was stirred at 100 C. to
130 C. for 16 hours. The reaction mixture was cooled and

was added to the reaction mixture at such a rate that the

reaction did not subside. After the addition was completed,

the reaction mixture was stirred at 35 C. to 40 C. until

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

this was added 0.2 kg cyanogen bromide and the reaction
mixture was stirred under re?ux conditions until completion
of reaction. The solvent was removed under reduced pressure,

99%).
35

(c) Preparation of Buprenorphine (BPN) Using

stripped off with methanol, cooled and ?ltered to get 0.72 kg

of product TARG-NCN.

Example 6

Ethanethiol

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

glycol and 4.8 kg potassium hydroxide. The reaction mixture

for 18 hours. The reaction mixture was placed into water

45

was stirred at 165 C. until completion of the reaction. The

reaction mass was cooled and placed in water. This mixture

containing ammonium chloride and extracted with chloro

form/CPME to get 20.31 g buprenorphine (Yield: 83.68%;

HPLC purity: 98.92%).

was stirred at 15 C. to 20 C. for 2 to 3 hours. The solid was

(d) Preparation of Buprenorphine (BPN) using

?ltered off and dried to obtain 5.24 kg of product TARG-NH

(Yield: 92.94%; HPLC purity: 99%)

50

Example 7

Dodacanethiol
200 ml of DMF was charged into a vessel under an inert

atmosphere. To this was added 80 ml of dodacanethiol. The

mixture was stirred followed by addition of 80 g of potassium

Preparation of TARG-NCP of Formula-IX

5 kg TARG-NH was taken in 35 L acetonitrile and the
reaction mass cooled. To this was added 4.54 kg anhydrous

t-butoxide. 10 g TARG-NCP was added to the mixture and

subsequently the reaction mixture was stirred at 100 C. to
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

55

cyclopropyl methyl bromide. The reaction mixture was

stirred under re?ux conditions until completion of the reac

layer was extracted with CPME/chloroform to obtain

60

buprenorphine (HPLC purity: 77%).

tion. The unwanted material was ?ltered off and the ?ltrate
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

solvent to get the product (TARG-NCP) in an equivalent yield

and purity.

65

The potassium salt of pentanethiol (6.61 g; prepared from

pentanethiol & potassium t-butoxide) was charged into a
vessel containing 75 ml DMF under inert atmosphere. To this

US 8,981,097 B2
33
solution was added 5 g TARG-NCP. The reaction mixture was
stirred at 100-1300 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

98.57%).

(f) Preparation of Buprenorphine (BPN) Using

>

10 MeO

Sodium t-Butoxide
HO
t Bu

TARG-NC P
Formula IX

DMF (150 ml) was charged under inert atmosphere into a

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 10 g TARG-NCP, and the reaction mixture
was stirred at 100-1300 C. for 6 hours. The reaction mixture
was cooled andplaced in 600 ml water containing ammonium
chloride. The aqueous layer was extracted with CPME/chlo

20

roform to obtain 7.08 g buprenorphine (Yield: 72.9%; HPLC

purity 98.05%).

MeO
25

HO
t Bu

(g) Preparation of Buprenorphine (BPN) Using

Buprenorphine

N,N-Dimethyl Acetamide as Solvent

30

N,N-dimethyl acetamide (150 ml) was charged under inert

atmosphere into a vessel. To this vessel was added 12 g

potassium t-butoxide. The resulting solution was stirred, fol

lowed by addition of 12 mL pentanethiol. To the resulting
mixture was further added 10 g TARG-NCP, and the reaction
mixture was stirred at 100-1300 C. for 6 hours. The reaction
mixture was cooled and placed in 600 ml water containing
ammonium chloride. The aqueous layer was extracted with

35

CPME/chloroform to obtain 7 g buprenorphine (Yield:

40

said contacting being carried out at a temperature between

about 80 C. and about 150 C.
2. The process according to claim 1, wherein the
alkanethiol is selected from the group consisting of straight

chain n-alkanethiols, branched chain alkanethiols, cyclic

alkanethiols, dithiols, alkali metal salts thereof, and mixtures
thereof.
3. The process according to claim 1, wherein the
alkanethiol is at least one alkanethiol selected from the group

consisting of straight chain n-alkanethiols containing from 5

72.1%; HPLC purity 98.22%)

to 7 carbon atoms.

The invention claimed is:

1. A process for the preparation of a compound of For
mula-l in a purity of at least 98%, comprising:

4. The process according to claim 1, wherein the

alkanethiol is selected from the group consisting of
45

ethanethiol, pentanethiol, heptanethiol, and mixtures thereof.

5. The process according to claim 1, wherein the compound
of Formula-IX is obtained by contacting a compound of For

Formulal
HO
50

mula-VII with a cyclopropyl methyl halide, cyclopropyl

methyl tosylate, or cyclopropyl methyl mesylate in a second
solvent to produce the compound of Formula-IX:
MeO

55

MeO
NH
HO
l Bu

Buprenorphine

60

MeO
HO

contacting a compound of Formula-IX with a C2-C7

alkanethiol and a base in a ?rst solvent to produce a

compound of Formula-l, wherein said ?rst solvent is

DMF:

tBu
TARG-NH
F ormula Vll

US 8,981,097 B2
35
-continued
MeO

MeO

\CN

>

10 MeO

MeO

HO

HO

tBll

tBu
TARGNCP
FormulaIX

M60
TARG-NCN
FormulaVI

15

6. The process according claim 5, wherein said second

solvent is a polar aprotic solvent.
7. The process according to claim 6, Wherein the polar 20
aprotic solvent is selected from the group consisting of aceto

NH.

MeO

nitrile, DMF, DEF, DMSO, N-methylpyrrolidinone, DMPU,

DMA, DEA, sulpholane, acetone, methyl ethyl ketone,
methyl isobutyl ketone, THF, Me-THF, dioxane, CPME, 25

HO
tBu
TARG-NH
FormulaVII

MtBE, and DME.

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

MeO

35

diisopropyl ether.
11. The process according to claim 8, Wherein the com

pound of Formula-V is obtained by contacting a compound of

Formula-IV With a tertiary butyl metal halide in a ?fth solvent
to obtain the compound of Formula-V:
O

>NBI
Solvent

40
MeO

MeO
H0

45

tBu
TARG
FormulaV

>

MeO
MeO
50

MeO
TAR
Formula-IV

O
N

CN 55

O
N

MeO
HO

MeO

tBu

60

TARGNCN
FormulaVI

HO
tBu
TARG
FormulaV

b) contacting the compound of Formula-VI With an alkali 65

metal hydroxide in a fourth solvent to obtain the com

pound of Formula-VII:

12. The process according to claim 11, Wherein the tertiary

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-Ill 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 ?fth

reaction in a seventh solvent to obtain the compound of

Formula-IV:

solvent is selected from the group consisting of dialkyl ether,

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;

dioxanes; dialkoxyethane; hydrocarbons selected from the
group consisting of toluene, hexane, and heptane; and mix
tures thereof.

14. The process according to claim 11, Wherein the ?fth

I
I

solvent comprises cyclopentyl methyl ether.

15. The process according to claim 11, Wherein the com

pound of Formula-IV is obtained by:

c) reacting thebaine of Formula-ll With methyl vinyl

N
\ >

MeO

ketone in a sixth solvent to obtain a compound of For

0

mula-Ill; and

TA
FormulaIll
20

MeO

MeO

"

25

>

MeO

\_

MeO

Theb aine

30

Formul a ll

TAR
Formula-IV

16. The process according to claim 15, Wherein 0.5 liters

methyl vinyl ketone are used per kg thebaine in step (c).

17. The process according to claim 15, Wherein the sixth
and seventh solvents are the same or different; and

Wherein the sixth and seventh solvents are each selected

FormulaIll

from the group consisting of toluene, IPA, cyclopentyl

methyl ether, and mixtures thereof.
*