FIELD OF THE INVENTION
The present invention relates to a commercially viable and improved process for
preparation of tapentadol of formula I and its pharmaceutically acceptable salts
via novel intermediate.
OH
(R)
(R)
N
Formula I
5 BACKGROUND OF THE INVENTION
Tapentadol of formula I, a centrally-acting analgesic compound, is chemically
known as 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol and
marketed in the form of hydrochloride salt under the trade name Nucynta.
OH
(R)
(R)
N
Formula I
Tapentadol and its analogues were first disclosed in US patent USRE 39,593
10 herein referred as US ‘593 (reissue of US patent 6,248,737). According to the
process disclosed in this patent, tapentadol is prepared as shown in below scheme:
OCH3
Br
O
N
Mg
THF
OCH3
OH
N
.HCl
(2RS,3RS)
+
OCH3
OH
N
.HCl
(2R,3R)
Chiral separation
by HPLC
OCH3
Cl
N
.HCl
(2R,3R)
SOCl2
anhy.ZnCl2
NaBH4
OCH3
N
.HCl
(2R,3R)
HBr
T
OH
N
.HCl
(2R,3R)
3
Process involves reacting 3-bromoanisole with l-dimethylamino-2-methylpentan-
3-one to form racemic tertiary alcohol intermediate, which is then resolved by
chiral HPLC. The resolved intermediate is then converted into corresponding
chloride compound using excess of thionyl chloride, followed by reduction with
5 zinc borohydride, zinc cyanoborohydride or tin cyanoborohydride and then finally
transformed into tapentadol by demethylation using hydrobromic acid. The main
disadvantage of this process is that resolution is performed by using chiral
HPLC, chloro compound is prepared by using excess amount of thionyl chloride,
which is considered to be a violent agent. Further reducing agents zinc
10 borohydride, zinc cyanoborohydride or tin cyanoborohydride pose considerable
fire and health hazards, so not amenable for industrial level synthesis.
US patent 7,417,170 herein referred as US ‘170 discloses a process for the
preparation of racemic 3-(3-methoxyphenyl)-N,N-2-trimethylpentenamine, an
intermediate of tapentadol by the reaction of (2S,3S)-l-(dimethylamino)-3-(3-
15 methoxyphenyl)-2-methyl-3-pentanol with an acid to form a mixture of cis and
trans isomer of alkene intermediate, the resulting mixture is then hydrogenated to
form a mixture of (2R,3R) (2R,3S)-3-(3-methoxyphenyl)-N,N-2-
trimethylpentanamine as outlined below:
N
OCH3
(2S,3S) (Z)-(2R)+(E)-(2R)
OH
N
OCH3
Catalyst
H2
N
OCH3
+
N
OCH3
(2R,3R) (2R,3S)
20 US patent publication 2006/0167318 herein referred as US ‘318 discloses a
process for preparation of racemic 3-(3-methoxyphenyI)-N,N-2-trimethylpentenamine,
an intermediate of tapentadol, by dehydrating corresponding (2S,3S)
tertiary alcohol intermediate, followed by reduction of resulting alkene
intermediate using heterogeneous catalyst to form a mixture of (2R,3R) and
25 (2R,3S)-3-(3-methoxyphenyl-N,N-2-trimethylpentanamine as outlined below:
4
OCH3
OH
N
(2S,3S)
OCH3
N
(Z)-(2R)+(E)-(2R)
Catalyst H2
OCH3
N
(2R,3R) (2R,3S)
OCH3
N
Heterogeneous catalyst
1) Heterogeneous catalyst
2) catalyst/H2/ one pot synthesis
T/ P
T/ P
 
 
In both the above disclosures [US‘170 and US‘318], the undesired (2R,3S)
stereoisomer forms in substantial amount and has to be separated from mixture
of two isomers to obtain pure desired (2R,3R) stereoisomer. Further undesired
5 isomer has to be disposed of as chemical waste, resulting in low yields, which is
economically undesirable for any industrial scale production.
US patent 8,138,376 discloses a process for the preparation of (2R,3R)-3-(3-
methoxyphenyl)-N,N-2-trimethylpentenamine, an intermediate of tapentadol, by
treating corresponding tertiary alcohol intermediate with ethyl oxalyl chloride or
10 trifluoro acetic acid anhydride, then converted to (2R,3R)-3-(3-methoxyphenyl)-
N,N,2-trimethylpentanamine or its acid addition salts as outlined below:
OCH3
O N
(s)
EtMgCl
THF
OCH3
N
OH
1) (CF3CO)2O
or Acetyl chloride
or ethyl oxalyl chloride
2-Methyl-THF
2)Pd/C 10%, H2
OCH3
N
This patent is silent about further conversion to tapentadol, may be converted by
known processes.
15 US patent 8,263,809 discloses a process for preparation of (2R,3R)- [3-acyl-3-(3-
hydroxy protected-phenyl)-2-methyl-pentyl]-dimethyl-amine, an intermediate of
tapentadol, by treating tertiary alcohol intermediate with acylating agent, then
5
converted the resulting compound into tapentadol free base or its acid addition
salts as outlined below:
Acylating
agent
OR1
(R)
(R)
N
Catalyst, Deprotection
inert solvent
OH
(R)
(R)
N
OR
(R)
(S)
OH
N
OR
(R)
(S)
O
N
acyl R' = H
R1 represents H, C3-8 cycloalkyl, C1-6 alkylcarbonyl,
tetrahydropyranyl, or C1-3 alkyl substituted with
phenyl or naphthyl
US patent publication 2009/0043132 discloses a process for preparation of (E/Z)-
5 [3-(3-substituted-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine, an intermediate
of tapentadol, by dehydrating tertiary alcohol intermediate, followed by reduction
of (E/Z) alkene intermediate, using homogeneous catalyst and chiral ligand. This
process yield product in which undesired compound is present in higher ratio.
US patent publication 2010/0099916 discloses a process for the preparation of
10 tapentadol hydrochloride comprising racemic 3-(3-methoxyphenyI)-N,N-2-
trimethylpentenamine, an intermediate of tapentadol, prepared by dehydrating
corresponding (2S,3R) tertiary alcohol intermediate, followed by hydrogenation
of alkene intermediate and finally it converts into tapentadol hydrochloride by
demethylation using methanesulfonic acid and methionine as outlined below:
OCH3
(R) N
(R)
OH
(R) N
(R)
OCH3
N
Hydrogenation
i) MSA
ii)CH3COCH3,
HCl, IPA
.HCl
OCH3
(R)
(S)
OH
N
Dehydration
.HCl
15
This process may generate methylmethanesulfonate using methanesulfonic acid
during demethylation, reaction, which is carcinogenic and its formation should
be avoided. Therefore, above process is not an attractive option for industrial
scale synthesis.
20 PCT publication WO 2011/107876 discloses preparation of tapentadol through
racemic [3-(3-methoxy-phenyl)-2-methyl-pentyl]-dimethyl-amine, an
intermediate of tapentadol, prepared by acylating corresponding racemic tertiary
6
alcohol intermediate, followed by hydrogenation and then resolution of resulting
compound to achieve desired isomer and finally demethylation to give tapentadol
as outlined below:
OCH3
N
OH
(2R,3R)/(2S,3S)
ii) Hydrogenation
catalyst
OCH3
N
(2R,3R)/(2S,3S)
OCH3
N
Demethylating
agent
Resolution
OH
N
(2R,3R) (2R,3R)
i) Trifluoroacetic
anhydride,
5 In this process, chances of complete conversion of undesired isomer into desired
isomer are less because of non-availability of acidic protons on carbon and hence
undesired isomer remains in higher amounts.
PCT publication WO2011/128784 discloses a preparation of tapentadol
comprising resolution of tertiary alcohol tapentadol derivative followed by
10 separation of desired isomer and converting desired (2R,3R) tertiary alcohol
tapentadol derivative into tapentadol or its salt thereof as shown below:
OH
(R)
(R)
N
Trifluoroacetic
anhydride
Hydrogenation
catalyst
Optionally
OH
N
OH
(2R,3S) / (2S,3R)
OH
(R)
(S)
N
OH
OH
(R)
(R)
N
(2S,3R) (2R,3R) (2R,3R)
.Salt
Major drawback of above process is that it involves resolution step after Grignard
reaction. If resolution is carried out at dihydroxy compound as in above scheme,
15 then desired isomer is obtained in very low yield because undesired isomer
cannot be converted into desired isomer completely because of non-availability
of acidic protons and hence yields are less. Further two free hydroxy groups are
available at acylation stage and it is very difficult to acylate selectively only one
hydroxy group, so this may require double amount or excess of acylating agent,
20 which is additional burden and hence amounts to more cost.
PCT publication WO2012/023147 discloses a process of preparation of tapentadol
comprising of activating hydroxyl group of 1-dimethylamino-3-(3-methoxyphenyl)-
2-methyl-pentan-3-ol by using methanesulfonic acid or methylbenzene
7
sulfonic acid in the presence of mineral acid, followed by reductive
deoxygenation of resulting compound to afford [3-(3-methoxy-phenyl)-2-methylpentyl]-
dimethyl-amine and converting it into tapentadol by demethylating using
methanesulfonic acid and dimethyl sulfide as outlined below:
OCH3
N
OH
OCH3
N
OR
R= -SO2CH3; -SO2-C6H4.CH3
Reductive
deoxygenation,
Catalyst
OCH3
N
OH
N
DMS, MSA
5
This disclosure is silent about purity/chiral purity, no where it is mentioned, how
much undesired isomer is present is not clear, therefore to achieve desired purity,
additional purification steps are required. Further chances of formation of carcino
genic impurities makes the process unappealing as per regulatory requirements.
10 PCT publication WO2012/038974 discloses a process of preparation of tapentadol
comprising racemic 3-(3-methoxyphenyI)-N,N-2-trimethylpentenamine, an
intermediate of tapentadol, prepared by dehydrating corresponding (2S,3R)-
tertiary alcohol intermediate, followed by hydrogenation of resulting alkene
intermediate and finally converting into tapentadol hydrochloride salt.
15 In view of the above, most of the disclosures use hydrobromic acid or
methanesulfonic acid for demethylation. Hydrobromic acid is a corrosive liquid
and can cause irritation to body tissues, respiratory tract and eyes; and methane
sulfonic acid may generate carcinogenic impurities. So, there is an urgent need to
develop a cost effective, commercially viable and improved process for synthesis
20 of tapentadol, wherein use of corrosive reagents has been avoided. Thus, present
invention provides an industrially advantageous process for preparing tapentadol
of formula I and its pharmaceutically acceptable salts using novel intermediates.
OBJECT OF THE INVENTION
The main object of the present invention is to provide a commercially viable and
25 improved process for the preparation of tapentadol and pharmaceutically
acceptable salts thereof using novel intermediate.
8
Another object of the present invention is to provide novel intermediate including
its isomers, stereoisomers, enantiomers, diastereomers, racemates, solvates,
hydrates or pharmaceutically acceptable salts thereof
Yet another object of the present invention is to provide a process for preparation
5 of novel intermediate which is useful in the preparation of tapentadol and
pharmaceutically acceptable salts thereof.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a commercially viable and improved
process for preparation of tapentadol of formula I and pharmaceutically
10 acceptable salts thereof
OH
(R) N
(R)
Formula I
from tertiary hydroxy sulfonyl compound of formula II or its salts,
OSO2R1
(R)
(S)
N
OH
Formula II
wherein R1 represents hydrogen, straight chain or branched alkyl, aryl, aralkyl,
alkaryl, heteroalkyl, heteroaryl and the like which can be substituted or
unsubstituted
15 via tertiary hydroxy protected sulfonyl compound of formula III.
OSO2R1
(R)
(S)
N
OR2
Formula III
wherein R1 is same as above and R2 represents CH3-CO-, CF3-CO-, CH2ClCO-,
CHCl2-CO-, CCl3-CO-, CH3O-CO-CO-, CH3O-CO-, CH3CH2O-CO-, CH3CH2OCO-
CO, phenyl-CO-, or meta-CH3COO-phenyl- CO- or –SO2R’; wherein R’ can
9
be selected from hydrogen, straight chain or branched alkyl, aryl, aralkyl,
alkaryl, heteroalkyl, heteroaryl; which can be substituted or unsubstituted and
like.
According to one other embodiment, the present invention provides a process for
5 converting tertiary hydroxy protected sulfonyl compound of formula III or its
salts into sulfonyl protected compound of formula IV or its salts,
OSO2R1
(R) N
(R)
Formula IV
wherein R1 is same as above
According to one other embodiment, the present invention provides a process for
converting tertiary hydroxy protected sulfonyl compound of formula III into
10 tapentadol compound of formula I or pharmaceutically acceptable salt thereof.
According to one another embodiment, the present invention provides a process
for the preparation of tapentadol compound of formula I or pharmaceutically
acceptable salt thereof comprises:
a) activating tertiary hydroxy sulfonyl compound of formula II,
OSO2R1
(R)
(S)
N
OH
Formula II
wherein R1 is same as above
15 using a suitable activating agent in an organic solvent to give a tertiary hydroxy
protected sulfonyl compound of formula III,
OSO2R1
(R)
(S)
N
OR2
Formula III
wherein R1 and R2 are same as above
10
b.) hydrogenating the tertiary hydroxy protected sulfonyl compound of formula
III in the presence of a suitable hydrogenating catalyst and suitable solvents or
mixture of solvents to give a sulfonyl protected compound of formula IV,
OSO2R1
(R) N
(R)
Formula IV
c.) deprotecting the resulting sulfonyl protected compound of formula IV using a
5 suitable deprotecting reagent to give tapentadol of formula I,
d.) optionally converting tapentadol into its pharmaceutically acceptable salts.
According to one another embodiment, the present invention provides a novel
intermediate, tertiary hydroxy protected sulfonyl compound of formula III
OSO2R1
(R)
(S)
N
OR2
Formula III
wherein R1 and R2 are same as above.
10 including its isomers, stereoisomers, enantiomers, diastereomers, racemates,
solvates, hydrates or pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a commercially viable and improved process for
the preparation of tapentadol and pharmaceutically acceptable salts thereof.
15 According to one embodiment, the present invention provides a process for the
preparation of tapentadol or pharmaceutically acceptable salts thereof via a novel
intermediate, tertiary hydroxy protected sulfonyl compound of formula III. The
tertiary hydroxy protected sulfonyl compound of formula III is prepared starting
from the corresponding tertiary hydroxy sulfonyl compound of formula II,
20 wherein R1 can be selected from hydrogen, straight chain or branched alkyl, aryl,
aralkyl, alkaryl, heteroalkyl, heteroaryl and the like which can be substituted or
unsubstituted. The tertiary hydroxy sulfonyl compound of formula II, as used
11
herein includes its pure stereoisomers, enantiomers, diastereomers, or racemates,
or mixture of stereoisomers, mixture of enantiomers, and mixture of
diastereomers in any ratio, as salts, as solvates and as hydrates thereof. The
tertiary hydroxy sulfonyl compound of formula II can be prepared by methods
5 known in the art or by following the process as disclosed in PCT publication
WO2012/038974. Typically, the process involves reaction of starting material,1-
(3-hydroxy-phenyl)-propan-1-one with a suitable sulfonyl compound in the
presence of base to protect hydroxy group with suitable substituted sulfonyl
group. Thereafter, the resulting substituted sulfonyl compound undergoes amino
10 methylation using a suitable amino methylating reagent which includes, but is not
limited to formaldehyde and dimethyl amine or N-methyl-N-methylenemethane
ammonium halide and acetyl halide. The resulting compound can be used as such
for further reaction or can be first resolved to form a specific desired enantiomer
by using a suitable resolving reagent, preferably L-dibenzoyl tartaric acid. The
15 chiral salt is optionally purified and hydrolyzed using a base to give the
corresponding pure desired diastereomer of corresponding sulfonyl amino
compound, followed by reaction with an ethyl anion under strictly anhydrous
reaction conditions to provide desired corresponding tertiary hydroxy sulfonyl
compound of formula II. The ethyl anion can be added via an ethyllithium or
20 ethylmagnesium halide, diethylzinc or any other organometallic reagent
equivalent to EtMX, wherein M is a suitable metal and X is a suitable ligand.
The addition of the ethyl anion in this reaction introduces a second asymmetric
carbon atom, so tertiary hydroxy sulfonyl compound of formula II prepared by the
process may be contaminated with specific diastereomers such as (R)(R), (R)(S),
25 (S)(S), (S)(R) or mixture of two or more in any proportion.
According to one another embodiment of the present invention, tertiary hydroxy
sulfonyl compound of formula II can be activated by converting tertiary hydroxy
group to better leaving group and thus forming tertiary hydroxy protected
sulfonyl compound of formula III. The activation can be executed via
12
acylation or sulfonylation reaction. Generally, tertiary hydroxy sulfonyl
compound of formula II is treated with a suitable activating agent in a suitable
solvent at suitable temperature ranging from 00C to reflux temperature of solvent,
preferably at 0-65 0C, more preferably at 0-500C for sufficient time, selected from
5 for few minutes to few hours, preferably till the completion of the reaction. A
suitable activating agent can be an acylating agent or a sulfonylating agent. The
acylating reagent used for the reaction can be selected from acetic anhydride,
acetyl chloride, trifluoroacetic anhydride, pentafluoropropionic anhydride,
heptafluorobutyric anhydride, chloroacetic anhydride, chloroacetylchloride,
10 dichloroaceticanhydride, trichloroacetic anhydride, methyloxalyl chloride, ethyl
oxalyl chloride, methylchloroformate, ethyl chloroformate, benzoicanhydride,
benzoylanhydride, benzoyl chloride, or acetylsalicyloyl chloride or any other
suitable acylating agent which subsequently introduces the acyl group at position
of tertiary hydroxy group of compound of formula II thereby activating the
15 tertiary hydroxy group of compound of formula II. Particularly, acylating reagent
used for reaction can be selected from acetic anhydride, acetyl chloride,
trifluoroacetic anhydride and alike. The sulfonylating reagent used for the
reaction can be selected from alkyl or arylsulfonyl halides or anhydrides and
includes but not limited to methane sulfonyl chloride, p-toluene sulfonyl
20 chloride, methane sulfonic anhydride, toluene sulfonic anhydride etc.
The solvent used in the reaction can be selected from solvents such as C4-12 ethers,
C5-10 aliphatic hydrocarbons, C6-10 aromatic hydrocarbons, halogenated hydrocarbons,
C3-7 ketones, C3-10 ester aliphatic nitrile, polar aprotic solvent and mixture
thereof. Particularly, solvent can be selected from tetrahydrofuran, 2-methyl
25 tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1,4-
dioxane, methyl cyclopentyl ether, acetonitrile, dichloromethane, dimethylaceta
mide, dimethylformamide, dimethylsulfoxide or mixtures thereof. Optionally the
reaction can be carried out with or without base. if desired base is selected from
organic base having general formula NR1R2R3, wherein R1, R2 and R3 can be
13
independently selected from hydrogen, alkyl, alkaryl or arylalkyl. Particularly
organic base can be trialkyl amine such as triethylamine and etc.
In other embodiment, the tertiary hydroxy protected sulfonyl compound of
formula III can optionally be isolated or can be proceeded further without
5 isolation for next reaction. Preferably, the tertiary hydroxy protected sulfonyl
compound of formula III may be isolated by aqueous or non-aqueous workup.
The tertiary hydroxy protected sulfonyl compound of formula III forms a
inventive part of present invention wherein R1 can be selected from hydrogen,
straight chain or branched alkyl, aryl, aralkyl, alkaryl, heteroalkyl, heteroaryl and
10 the like which can be substituted or unsubstituted preferably sulfonyl group
substituents. R2 represents CH3-CO-, CF3-CO-, CH2ClCO-, CHCl2-CO-, CCl3-
CO-, CH3O-CO-CO-, CH3O-CO-, CH3CH2O -CO-, CH3CH2O-CO-CO, phenyl-
CO-, or meta-CH3COO-phenyl-CO- or –SO2R’; wherein R’ can be selected from
hydrogen, straight chain or branched alkyl, aryl, aralkyl, alkaryl, heteroalkyl,
15 heteroaryl and like which can be substituted or unsubstituted. when R1 is paramethyl
phenyl group and R2 is trifluoromethyl; then it forms the preferred
embodiment of invention and represents the tertiary hydroxy protected sulfonyl
compound of formula IIIa.
O
(R)
(S)
N
OCOCF3
S
O
O
Formula IIIa
14
The tertiary hydroxy protected sulfonyl compound of formula III or IIIa as
prepared herein, includes its pure stereoisomer, enantiomer, diastereomer, or
racemates, or mixture of stereoisomer, mixture of enantiomer, and mixture of
diastereomer in any ratio, as salts, as solvates, and as hydrates thereof.
5 In one another embodiment the tertiary hydroxy protected sulfonyl compound of
formula III as obtained above, is converted into compound of formula I or its
pharmaceutically acceptable salt thereof.
In one other embodiment the tertiary hydroxy protected sulfonyl compound of
formula III is converted to sulfonyl protected compound of formula IV by
10 hydrogenolysis or its salts followed by deprotection of sulfonyl group substituents
resulting in preparation of tapentadol of formula I or its pharmaceutically
acceptable salt thereof. Generally hydrogenolysis can be carried out using a
suitable catalyst in the presence of an inert solvent under hydrogen pressure or in
the presence of hydrogen transfer reagent.
15 The suitable catalyst used for hydrogenolysis includes but is not limited to
palladium, Raney nickel, platinum, ruthenium or rhodium catalysts. The preferred
catalyst can be palladium catalyst which may be selected from homogenous
catalyst such as Pd(OAc)2, PdCl2, Pd(PPh3)4, Pd(PPh3J2CI2, Pd2(dba)3
(tris(dibenzylidene acetone) dipalladium), palladium thiomethylphenyl20
glutaramide metallacycle and the like, or a heterogeneous catalyst like palladium,
palladium on charcoal, palladium hydroxides on charcoal, palladium on metal
oxides, palladium on zeolites, palladium on alumina,; or platinium catalyst like
platinum on carbon and platinum on alumina or lithium aluminium hydride,
sodium borohydride or like and with or without additives. Percentage of
25 palladium metal in the catalyst can vary from 0.1%-50%, preferably it can be
between 2-30%. Further the catalyst can be wet or dry and water content can vary
between 0.05% to 75%w/w, preferably it is desired between 0.05% to 60%w/w.
The solvent used for hydrogenolysis reaction can be selected from C4-12 ethers
such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethyl ether, 1,2-diethyl
15
ether or C3-12 ester such as ethyl acetate; C3-10 aliphatic ketone such as acetone,
methyl ethyl ketone; C6-12 hydrocarbon such as toluene, xylene, hexane, heptane,
cyclohexane and the like; halogenated solvent such as dichloromethane, 1,2-
dichloroethane; aliphatic nitriles such as acetonitrile, propionitrile and the like or
5 mixture thereof. Particularly, solvent can be selected from tetrahydrofuran, 2-
methyl tetrahydrofuran 1,2-dimethyl ether, 1,2-diethyl ether or mixtures thereof.
The hydrogenolysis can be accomplished at a temperature of 0 ºC to reflux
temperature of solvent for few minutes to few hours, preferably till the complete
hydrogenolysis takes place. Preferably hydrogenolysis reaction can be carried out
at a temperature of 30-70 010 C for 8-16 hours. The sulfonyl protected compound of
formula IV, can be isolated by aqueous or non-aqueous workup and if desired,
can be purified by using suitable solvents or mixture of solvents or by forming
acid addition salt of sulfonyl protected compound of formula IV or by using
extraction method comprising suitable solvent and aqueous carbonate or any
15 other purification method can be employed to enhance the purity or to reduce the
amount of impurity in the product. The suitable solvents used in extraction can be
selected from C4-12 ether, C6-12 aromatic or aliphatic hydrocarbon or halogenated
hydrocarbon and alike or mixture thereof. Particularly solvent can be selected
from tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, isopropyl ether,
20 methyl tert-butyl ether, 1,4-dioxane, methyl cyclopentyl ether or mixtures thereof
and the aqueous carbonate can be selected from sodium bicarbonate, sodium
carbonate, potassium carbonate, potassium bicarbonate or alike.
The sulfonyl protected compound of formula IV can be reacted with a suitable
acid to form a salt, which upon filteration followed by neutralization to obtain a
25 purified sulfonyl protected compound of formula IV or its salt can be directly
used for further reaction. The acids used for the salt formation can be selected
from achiral acids which includes inorganic acids such as hydrochloric acid,
sulfuric acid, nitric acid, phosphoric acid, perchloric acid; organic acids such as
formic acid, acetic acid, oxalic acid and the like or chiral acids such as camphor
16
sulfonic acid, mandelic acid, substituted or unsubstituted tartaric acid, Ldibenzoyl
tartaric and the like. Solvent for salt formation can be selected from
water, aliphatic alcohols, aliphatic ethers, aliphatic esters, nitriles, aliphatic or
aromatic hydrocarbon, ketones, halogenated solvent and or mixture thereof. The
5 sulfonyl protected compound of formula IV as prepared herein includes its pure
stereoisomer, enantiomer, diastereomer, or racemates, or mixture of
stereoisomers, mixture of enantiomers, and mixture of diastereomers in any ratio,
as salts, as solvates, and as hydrates thereof. Alternatively, the sulfonyl protected
compound of formula IV or salts thereof can be purified by crystallization or
10 stirring in a suitable solvent.
In one another embodiment the sulfonyl protected compound of formula IV is
converted into tapentadol of compound of formula I via deprotection of sulfonyl
group substituents such hydrogen, straight chain or branched alkyl, aryl, aralkyl,
alkaryl, heteroalkyl, heteroaryl and the like which can be substituted or
15 unsubstituted and thus obtained the tapentadol of formula I.
The deprotection of sulfonyl group can be proceeded using methods known in the
art or by following the process as disclosed in PCT publication WO2012/038974.
Generally, the process involves reaction of sulfonyl protected compound of
formula IV with a suitable deprotecting reagent at a temperature of -10 to 180 ºC
20 for 48 hours. Deprotection reaction involves the removal of -SO2R1 group by any
suitable reagent known for the deprotection of hydroxyl protecting group
depending upon the nature of protecting group that effectively serves the purpose
and are well known in the field of organic synthesis. Preferably deprotection
reaction can be carried in the presence of a suitable base. Suitable bases employed
25 for the reaction can be organic or inorganic base. Organic base used for the
reaction can be selected from amine such as triethylamine, diisopropylethylamine,
and the like. Inorganic base that can be selected from alkali or alkaline metal
hydroxide, carbonates, bicarbonates, hydrides or alkoxides thereof such as sodium
carbonate, lithium carbonate, potassium carbonate, lithium hydroxide, potassium
17
hydroxide, sodium hydroxide, sodium bicarbonate, potassium bicarbonate,
lithium bicarbonate and the like or combination thereof. The reaction can be
carried out using a suitable solvent which includes water, C1-8 alcohols such as
methanol, ethanol, propanol, isopropanol; aliphatic or aromatic hydrocarbon
5 solvent, C4-10 ethers, nitriles, C3-12 ketones, C3-12 esters, halogenated solvents, polar
aprotic solvents and the like or mixture thereof. The reaction can take place over a
wide range of temperature depending upon the nature of -SO2R1 group as well as
on deprotecting reagent employed for the reaction. Usually reaction can be carried
out at 0 ºC to 180ºC for 1 to 48 hours, till the completion of the reaction. In a
10 preferred embodiment, sulfonyl protected compound of formula IV is treated with
a suitable base such as sodium hydroxide in presence of a suitable solvent such as
alcohol or ether to deprotect phenol functionality and forms tapentadol free base.
The reaction completion at any stage can be monitored by suitable techniques
such as HPLC, TLC, GC or UPLC and the like. After completion of the reaction,
15 the desired product can be isolated from the reaction mixture using suitable
conventional methods or can be converted in situ to the next step. The resulting
compound can be isolated by aqueous or non-aqueous workup.
Specifically, tapentadol of formula I can be converted to tapentadol hydrochloride
using a suitable source of hydrochloric acid. The process involves the reaction of
20 tapentadol in a suitable solvent with a source of hydrochloric acid at a
temperature of -20 to 80 ºC for 15 minutes to several hours, preferably till the salt
formation. The source of hydrochloric acid employed for the reaction can be
aqueous, concentrated hydrochloric acid, gaseous hydrogen chloride, solvent
purged with hydrogen chloride gas or hydrochloric acid in a solution with a
25 solvent or hydrochloride salts of amines. Solvent used for the generation of source
of hydrochloric acid can be selected from water or C1-10 alcohol such as methanol;
C4-10 ethers such as diethylether, isopropyl ether; C3-10 esters such as ethyl acetate;
aliphatic nitriles such as acetonitrile and the like or mixture thereof. Solvents
employed for the salt formation reaction can be selected from halogenated solvent
18
such as dichloromethane; aliphatic nitriles such as acetonitrile; ethers such as
tetrahydrofuran; alcohols such as methanol; aliphatic ketones such as acetone and
the like or mixture thereof. After completion of the salt formation, tapentadol
hydrochloride can be isolated from reaction mixture by the suitable techniques
5 such as solvent removal by evaporation, distillation, filtration and the like.
Compound of formula I or tapentadol or pharmaceutically acceptable salt thereof
thus isolated can be purified using a suitable purification method such as
crystallization, sublimation, extraction, chromatography, slurry wash, refluxing,
washing, acid base treatment, carbon treatment, silica or alumina treatment.
10 Suitable solvents employed for the purification includes but are not limited to
water, alcohols such as methanol, ethanol and isopropanol, aliphatic ester such as
ethyl acetate; aliphatic nitriles such as acetonitrile, aliphatic ethers such as
isopropyl ether, aliphatic ketones such as acetone, aliphatic or aromatic
hydrocarbon solvents, halogenated solvents and the like or mixture thereof.
15 Specifically, tapentadol free base can be purified to enhance the enantiomeric
purity or to minimize the other impurities in final product. It can be purified by
crystallization, sublimation, chromatography, extraction using suitable solvents,
refluxing, slurry wash, acid base treatment, carbon treatment, silica or alumina
treatment. Suitable solvents for purification includes but are not limited to water;
20 hydrocarbons such as n-hexane, n-heptane, cyclohexane; alcohols such as
methanol, ethanol and isopropanol; aliphatic ester such as ethyl acetate; aliphatic
ketone such as acetone, methyl ethyl ketone; ether such as diisopropylether,
methyl tert-butyl ether, tetrahydrofuran, isopropyl ether, 2-methyltetrahydrofuran,
1,4-dioxane; halogenated solvent such as dichloromethane; nitriles acetonitrile,
25 propionitrile and the like or mixture thereof. Specifically, tapentadol
hydrochloride can be purified to enhance the enantiomeric purity or to minimize
the other impurities in final product. It can be purified by crystallization,
extraction, slurry wash in a suitable solvent. Preferably, tapentadol hydrochloride
can be stirred in a suitable solvent at a temperature of -10 to 80ºC for 15 minutes
19
to several hours. Suitable solvent for purification includes but not limited to
alcohols such as methanol, ethanol and isopropanol; aliphatic ester such as ethyl
acetate; aliphatic ketone such as acetone, methyl ethyl ketone; ether such as
diisopropylether, methyl tert-butyl ether, tetrahydrofuran, isopropyl ether, 2-
5 methyl tetrahydrofuran, 1,4-dioxane; hydrocarbons such as n-hexane, n-heptane,
cyclohexane and the like; halogenated solvent such as dichloromethane; nitriles
such as acetonitrile, propionitrile and the like or mixture thereof. Particularly,
solvents used for purification of tapentadol hydrochloride to enhance the
enantiomeric purity or to minimize the other impurities in final product are
10 selected from alcohols such as methanol, ethanol and nitriles such as acetonitrile,
propionitrile or mixture thereof. Thereafter, the mixture can be cooled to a
temperature of -30 ºC to ambient temperature.
Tapentadol hydrochloride obtained by the process of present invention having
high enantiomeric excess, preferably more than 99 %, more preferably 100 % e.e.
15 Major advantages of present invention is to provide an industrially advantageous
and efficient process for preparation of highly enantiomerically pure tapentadol
hydrochloride and avoiding the use of corrosive acids in the final deprotecting
step to prepare tapentadol from protected tapentadol. The process of present
invention is efficient, reproducible as well as industrially advantageous.
20 Having described the invention with reference to certain preferred aspects, other
aspects will become apparent to one skilled in the art from consideration of the
specification. The invention is further defined by reference to the following
examples describing in detail by the preparation of compounds of the invention.
EXAMPLE 1: Preparation of (1R,2R)-toluene-4-sulfonic acid 3-(3-
25 dimethylamino-1-ethyl-2-methyl-propyl)-phenyl ester
Method A: To a cooled solution of (1R,2S)-toluene-4-sulfonic acid 3-(3-
dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl)-phenyl ester (200g) in
tetrahydrofuran (100 ml), trifluoroacetic anhydride (200g) was slowly added at 0-
5 °C and the reaction mixture was stirred at 20-25 °C for 15 hours. After
20
completion of the reaction, reaction mass was transferred to an autoclave under
nitrogen gas atmosphere. A suspension of 20% of palladium/carbon (20g) and
tetrahydrofuran (3.0 L) were added to the reaction mass. Hydrogen gas pressure
of 5-6kg was applied to the reaction mass and the temperature was slowly raised
5 to 50-55 °C and stirred the reaction mass at same temperature. After completion
of the reaction, the mass was cooled to 20-25 °C and filtered. The filtrate was
concentrated under reduced pressure at 45-50 °C to give an residue. The resulting
residue was dissolved in methyl tert-butyl ether (1.0 L) and the reaction mixture
was washed with aqueous sodium bicarbonate (12%, 700 ml). The layers were
10 separated and the aqueous layer was extracted with methyl tert-butyl ether (2 x
250 ml). The combined organic layer was dried, filtered and then distilled under
reduced pressure at 35-40°C to obtain 170g of title compound.
Method B: To a cooled solution of (1R,2S)-toluene-4-sulfonic acid 3-(3-
dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl)-phenyl ester (200g) in
15 tetrahydrofuran (100 ml), trifluoroacetic anhydride (200g) was slowly added at 0-
5°C and the reaction mixture was stirred at 20-25°C for 15 hours. After
completion of the reaction, the mass was transferred to an autoclave under
nitrogen gas atmosphere. A suspension of 20% of palladium hydroxide/carbon
(40g, 50% water) and tetrahydrofuran (3.0L) was added to the reaction mass and
20 hydrogen gas pressure of 5-6 kg was applied to the reaction mass. Temperature of
the reaction was slowly raised to 50-55°C and further stirred till completion of
the reaction. Thereafter, the reaction mass was cooled to 20-25°C and filtered.
The filterate was concentrated under reduced pressure at 45- 50°C to give an
oily residue. The resulting residue was dissolved in methyl tert-butyl ether (1.0
25 L) and washed with aqueous sodium bicarbonate solution (12%, 700ml). The
layers were separated and aqueous layer was extracted with methyl tert-butyl
ether (2x250 ml). The combined organic layer was dried over sodium sulfate (50
g), filtered and the organic solvent was distilled off under reduced pressure at
21
35-40°C to give (1R,2R)-toluene-4-sulfonic acid 3-(3-dimethylamino-1-ethyl-2-
methyl-propyl)-phenyl ester (175g).
Example 2: Preparation of Tapentadol hydrochloride
Method A: Step 1- Preparation of Tapentadol:
5 To a solution of (1R,2R)-toluene-4-sulfonic acid 3- (3-dimethylamino-1-ethyl-2-
methyl-propyl)-phenyl ester (35g) in methanol (280ml), a solution of sodium
hydroxide (19g, in 70ml water) was added at 5-10°C. The temperature of reaction
mixture was raised to 30-35°C and stirred for further 20 hours. After completion
of reaction [checked by TLC], solvent was distilled off at 45-50°C, the resulting
10 residue was washed with cyclohexane (70ml) and then extracted with ethyl
acetate (350 ml). The reaction mass was cooled to 0-5°C, filtered over hyflo to
remove any suspended material. The hyflo bed was washed with ethyl acetate (50
ml) and the combined filtrate was concentrated under vacuum to give an oily
residue. The resulting oily residue was dissolved in ethyl acetate (350 ml) and
15 washed with water (3 x 50 ml). The organic layer was dried over sodium sulfate,
filtered and solvent was distilled off to afford tapentadol as a viscous oil (20.5g).
Step 2- Preparation of Tapentadol hydrochloride:
Tapentadol (20g) was dissolved in ethyl acetate (20ml), cooled and mixed with
a solution of ethyl acetate-hydrochloride (35 ml, 12%) at 0-5 oC. The resulting
20 mixture was stirred for 1hour, filtered and dried to give a crude tapentadol
hydrochloride (15g). The resulting solid was stirred in acetonitrile (75 ml) at
reflux temperature for 1 hour. The suspension was cooled to 20-25°C , stirred for
30 minutes, filtered and suck dried to give tapentadol hydrochloride (13.5g,
98.5%). The resulting tapentadol hydrochloride was further refluxed in a mixture
25 of acetonitrile (64ml) and methanol (3.4ml) for 60 minutes. The suspension was
cooled to 20-25°C , further stirred for 30 minutes, filtered and suck dried under
vacuum at 75-90 oC for 24 hours to afford pure tapentadol hydrochloride as a
white crystalline solid (12.7g, 99.91%, diastereomeric impurity 0.03%).
Method B Step 1- Preparation of Tapentadol:
22
To a solution of (1R,2R)-toluene-4-sulfonic acid 3-(3-dimethylamino-1-ethyl-2-
methyl-propyl)-phenyl ester (9g) in methanol (72ml), a solution of sodium
hydroxide (4g) in water (18ml) was added at 20-25°C. The temperature of the
reaction mixture was raised to 35-45°C, stirred further for 20 hours. After
5 completion of the reaction, the solvent was distilled off to give a residue. Water
(45 ml) was added to the resulting residue followed by extraction with
dichloromethane (2 x 27ml). Layers were separated and dichloromethane layer
was dried over molecular sieves, filtered through hyflo and concentrated to
afford 4.24g ( yield- 80%) of title compound as a viscous oil.
10 Step 2- Preparation of Tapentadol hydrochloride:
The resulting tapentadol was dissolved in ethylacetate (10ml) and cooled to 0-
5oC and mixed with a solution of ethyl acetate-hydrochloride (1.7ml, 12%) at 0-
5oC and stirred for further 1 hour. Thereafter reaction mixture was filtered to
obtain tapentadol hydrochloride (3.0g). A slurry of tapentadol hydrochloride
15 (3.0g) in acetonitrile (15ml) was refluxed at 75-80 ºC for 1hour, cooled to 20-
25oC and stirred for 30 minutes, filtered and dried to afford tapentadol
hydrochloride (2.7g, 98.7% by HPLC). Again a slurry of crude tapentadol
hydrochloride (2.7g) in acetonitrile (12.8ml) was refluxed for 1hour. The
suspension was cooled to 20-25oC, stirred for 30 minutes, filtered and dried under
vacuum at 75-90 o20 C for 24 hours to afford pure tapentadol hydrochloride as a
solid (2.5g, 99.84%, diastereomeric impurity 0.10%).
EXAMPLE 03: Preparation of highly pure Tapentadol hydrochloride
Method A: Step 1: Preparation of (1R,2R)-toluene-4-sulfonic acid 3-(3-
dimethylamino-1-ethyl-2-methyl-propyl)-phenyl ester :
25 Trifluoroacetic anhydride (200g) was slowly added to a cooled solution of
(1R,2S)-toluene-4-sulfonic acid 3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-
phenyl ester (200g) in tetrahydrofuran (100 ml) and the reaction mass was
stirred for 15 hours at 20-25°C. After completion of reaction, reaction mass was
transferred to an autoclave under nitrogen gas atmosphere. A suspension of 20%
23
palladium hydroxide/carbon (40g, 50% water) and tetrahydrofuran (3.0 L) was
added to the reaction mass and hydrogen gas pressure of 5-6 kg was applied. The
temperature of reaction mixture was raised to 50-55 °C, after completion of the
reaction, the mass was cooled to 20-25 °C and filtered. The filtrate was
5 concentrated and resulting residue was dissolved in methyl tert-butyl ether (1.0L)
and treated with aqueous sodium carbonate (10%, 300 ml). The layers were
separated, the aqueous layer was extracted with methyl tert-butyl ether (2 x 250
ml) and the combined organic layer was dried over molecular sieve (20 g),
filtered and distilled at 35-40 °C to give188g of title compound.
10 Step 2- Preparation of Tapentadol hydrochloride :
To the above compound (188g) in methanol (1.5L), a solution of sodium
hydroxide (100g) and water (376 ml) was added at 5-10 oC and temperature of
reaction mass was slowly raised to 30-35oC. After completion of reaction, solvent
was distilled off at 45-50oC and the resulting residue was dissolved in ethyl
acetate (1.9L) and then slowly cooled the reaction mass to 0-5o15 C and stirred it for
30 minutes. The reaction mass was filtered over hyflo and the filtrate was washed
with water (3 x 270 ml), stirred with activated charcoal (10g), dried over
molecular sieves (3A, 30g) and filtered. Then approx 50% of ethyl acetate was
distilled off and the reaction mixture was cooled to 5-10 oC and mixed with a
solution of ethyl acetate-hydrochloride (198 ml, 12%) at 0-5 o20 C, stirred for 1 hour
and filtered to give tapentadol hydrochloride (86g, 93.3% by HPLC). The
resulting tapentadol hydrochloride (81g) was suspended in acetonitrile (405 ml)
and the suspension was refluxed for 90 minutes. The suspension was then cooled
to 25-30 oC, stirred for 60 minutes, filtered, washed with acetonitrile ( 40 ml) and
25 dried to obtain title compound (30g , 99.88%, diastereomeric impurity 0.08%).
Step 3- Preparation of highly pure Tapentadol hydrochloride:
Tapentadol hydrochloride (30g, 99.88%, diastereomeric impurity 0.08%)
obtained above, was suspended in acetonitrile (150 ml) and methanol (7 ml) and
suspension was refluxed for 1 hour. The suspension was then cooled to 25-30°C,
24
stirred for 60 minutes, filtered and dried. The solid was then refluxed in ethyl
acetate (120 ml) for 30 minutes and cooled to 0-5°C, stirred for further 30
minutes, filtered and dried at 75-90°C for 48 hours to afford pure tapentadol
hydrochloride as solid (26.4g, 99.96%, diastereomeric impurity 0.02%).
5 Method B: Step 1-Preparation of (1R,2R)-toluene-4-sulfonic acid 3-(3-
dimethylamino-1-ethyl-2-methyl-propyl)-phenyl ester :
To a cooled solution of (1R,2S)-toluene-4-sulfonic acid 3-(3-dimethylamino-1-
ethyl-1-hydroxy-2-methyl-propyl)-phenyl ester (100g) in trifluoroacetic
anhydride (150g) was slowly added at 0-5°C and the reaction mass was stirred
10 for 18 hours at 20-25 °C. After completion of the reaction the reaction mass was
then subjected to heating under vacuum for 4 hours till most of the volatiles was
evaporated [removal of in-situ generated triflouroacetic acid and excess of
unreacted trifluoroacetic anhydride]. The reaction mass was then diluted with
tetrahydrofuran (500ml) and after complete dissolution, the reaction mass was
15 transferred to an autoclave, under inert atmosphere and 20% palladium
hydroxide/carbon (20g, 50% water) and tetrahydrofuran (1L) were successively
added to the reaction mass. Nitrogen was replaced by hydrogen gas and pressure
of 5-6 Kg was applied to the reaction mass. The temperature was slowly raised
to 50-55°C and stirred the reaction mass at same temperature. After completion
20 of reaction, the reaction mass was cooled to 20-25°C, filtered and the filtered
catalyst was washed with tetrahydrofuran (100ml). Solvent was then distilled off
at 45-50°C to produce an oily residue and dissolved in methyl tertiary-butyl
ether (500ml) and washed with aqueous sodium carbonate (20%, 250ml). The
layers were separated, the aqueous layer was extracted with methyl tertiary-butyl
25 ether ( 300ml) and the combined organic layer was dried over molecular sieve,
filtered and then distilled at 35-40°C to give 82g of title compound.
Step 2- Preparation of Tapentadol hydrochloride :
To the above compound (82g ) in methanol (820 ml), a solution of sodium
hydroxide (43.7g) and water (164ml) was added at 5-10oC and the temperature of
25
the reaction mass was slowly raised to 30-35oC. The reaction mass was stirred at
that temperature for 20 hours and then at 45-50oC for 6 hours. After completion
of the reaction, the solvent was distilled off under vacuum at 45-50oC and the
resulting residue was then dissolved in ethyl acetate (300 ml) and then distilled
and degas at 50-60o5 C . Ethyl acetate (820ml) was then added and the reaction
mass was washed with demineralized water (164ml), the layers were separated
and the aqueous layer was washed with ethyl acetate (2 x 246 ml) and the
combined organic layer was again washed with demineralized water (3 x 164ml)
and filtered. The solvent was then distilled under vacuum at 50-60oC to give 45g
10 of tapentadol free base as an oil. Tapentadol was dissolved in acetonitrile (54ml)
and cooled to 0-5oC and stirred. acetonitrile-hydrochloride (68.6ml, 12%) was
then added to the reaction mass at 0-5oC. The temperature of the reaction was
slowly raised to 25-30oC and then reaction mass was stirred for 2 hrs at 25-30 oC.
The reaction mass was then cooled to 0-5 oC, stirred for 1 hour. The resulting
15 solid was filtered, washed with acetonitrile (10ml) and resulting compound was
suspended in acetonitrile (225 ml) and heated at reflux temperature for 60
minutes. The suspension was then cooled to 25-30oC, stirred for 60 minutes,
filtered, washed with acetonitrile (45ml) and suck dried for 60 minutes to give
title compound (40g).
20 Step 3- Preparation of highly pure Tapentadol hydrochloride:
Tapentadol hydrochloride (45g) obtained above, was suspended in mixture of
acetonitrile (190ml) and methanol (10ml), the suspension was refluxed for 1hour
and cooled to 25-30oC, stirred for 60 min, filtered washed with acetonitrile
(40ml) to give 37g of solid tapentadol hydrochloride. The resulting tapentadol
25 hydrochloride (37g) again purified in acetonitrile (175.75 ml ) and methanol
(9.25 ml), the suspension was refluxed for 1hour, cooled to 25-30oC, stirred for
60 minutes, filtered and washed with acetonitrile (37ml) and dried under vacuum
at 65-70 oC for 24 hours to afford pure tapentadol hydrochloride as a white to off
white crystalline solid (32g , 99.9%, diastereomeric impurity 0.04%).

WE CLAIM:
1. A process for the preparation of tapentadol of formula I and pharmaceutically
acceptable salts thereof comprising the steps of :
a.) activating tertiary hydroxy sulfonyl compound of formula II,
OSO2R1
(R)
(S)
N
OH
Formula II
5 wherein R1 represents hydrogen, straight chain or branched alkyl, aryl,
aralkyl, alkaryl, which is substituted or unsubstituted;
using a suitable activating agent in an organic solvent, optionally in the
presence of a base to give a tertiary hydroxy protected sulfonyl compound of
formula III,
OSO2R1
(R)
(S)
N
OR2
Formula III
10 wherein R1 is same as defined above and R2 represents CH3-CO-, CF3-CO-,
CH2ClCO-, CHCl2-CO-, CCl3-CO-, CH3O-CO-CO-, CH3O-CO-, CH3CH2OCO-,
CH3CH2O-CO-CO, phenyl-CO-, or meta-CH3COO-phenyl- CO- or –
SO2R’; wherein R’ is selected from hydrogen, straight chain or branched
alkyl, aryl, aralkyl, alkaryl and like; which is substituted or unsubstituted
15 b.) hydrogenating tertiary hydroxy protected sulfonyl compound of formula
III in the presence of a suitable hydrogenating catalyst in a suitable solvent to
prepare sulfonyl protected compound of formula IV,
27
OSO2R1
(R) N
(R)
Formula IV
wherein R1 is same as defined above
c.) deprotecting the resulting sulfonyl protected compound of formula IV
using a suitable deprotecting reagent to give tapentadol of formula I,
d.) optionally converting tapentadol into its pharmaceutically acceptable salt.
5 2. The process as claimed in claim 1, wherein in step a.) activating agent is an
acylating agent or a sulfonylating agent selected from acetic anhydride, acetyl
chloride, trifluoroacetic anhydride, pentafluoropropionic anhydride,
heptafluorobutyric anhydride, chloroacetic anhydride, chloroacetylchloride,
dichloroaceticanhydride, trichloroacetic anhydride, methyloxalyl chloride,
10 ethyl oxalyl chloride, methylchloroformate, ethyl chloroformate,
benzoicanhydride, benzoylanhydride, benzoyl chloride, or acetylsalicyloyl
chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride,
methanesulfonic anhydride, toluenesulfonic anhydride.
3. The process as claimed in claim 1, wherein in step a.) organic solvent is
15 selected from C4-12 ethers, C5-10 aliphatic hydrocarbons, C6-10 aromatic
hydrocarbons, halogenated hydrocarbons, C3-7 ketones, C3-10 ester aliphatic
nitrile, polar aprotic solvent and mixture thereof.
4. The process as claimed in claim 1, wherein in step a.) base is organic base.
5. The process as claimed in claim 1, wherein in step b.) suitable hydrogenating
20 catalyst used for hydrogenation is selected from palladium, Raney nickel,
platinum, ruthenium or rhodium catalysts; lithium aluminium hydride,
sodium borohydride or like and with or without additives; solvent used for
hydrogenolysis reaction is selected from C4-12 ethers, C3-12 ester, C3-10
aliphatic ketone, C6-12 hydrocarbon, halogenated solvent, aliphatic nitriles and
25 the like or mixture thereof.
28
6. The process as claimed in claim 1, wherein in step c.) suitable deprotecting
reagent is selected from an organic base or an inorganic base.
7. A tertiary hydroxy protected sulfonyl compound of formula III,
OSO2R1
(R)
(S)
N
OR2
Formula III
wherein R1 represents hydrogen, straight chain or branched alkyl, aryl,
5 aralkyl, alkaryl, which is substituted or unsubstituted; and R2 represents CH3-
CO-, CF3-CO-, CH2ClCO-, CHCl2-CO-, CCl3-CO-, CH3O-CO-CO-, CH3OCO-,
CH3CH2O-CO-, CH3CH2O-CO-CO, phenyl-CO-, or meta-CH3COOphenyl-
CO- or –SO2R’; wherein R’ is selected from hydrogen, straight chain
or branched alkyl, aryl, aralkyl, alkaryl, heteroalkyl, heteroaryl and like;
10 which is substituted or unsubstituted.
8. The tertiary hydroxy protected sulfonyl compound of formula III as claimed
in claim 7, is IIIa,
O
(R)
(S)
N
OCOCF3
S
O
O
Formula IIIa
9. A process for the preparation of tapentadol of formula I or pharmaceutically.
acceptable salts thereof, comprising the step of
15 a.) hydrogenating the tertiary hydroxy protected sulfonyl compound of
formula III
OSO2R1
(R)
(S)
N
OR2
Formula III
wherein R1 represents hydrogen, straight chain or branched alkyl, aryl,
aralkyl, alkaryl, which is substituted or unsubstituted; and R2 represents CH3-
29
CO-, CF3-CO-, CH2ClCO-, CHCl2-CO-, CCl3-CO-, CH3O-CO-CO-, CH3OCO-,
CH3CH2O-CO-, CH3CH2O-CO-CO, phenyl-CO-, or meta-CH3COOphenyl-
CO- or –SO2R’; wherein R’ is selected from hydrogen, straight chain
or branched alkyl, aryl, aralkyl, alkaryl, heteroalkyl, heteroaryl and like;
5 which is substituted or unsubstituted
in the presence of a suitable hydrogenating catalyst in a suitable solvent to
prepare sulfonyl protected compound of formula IV,
OSO2R1
(R) N
(R)
Formula IV
wherein R1 is same as above
b.) deprotecting the resulting sulfonyl protected compound of formula IV
10 using a suitable deprotecting reagent to give tapentadol of formula I,
c.) optionally converting tapentadol into its pharmaceutically acceptable salt.
10. The process as claimed in claim 9, wherein in step a.) a suitable
hydrogenating catalyst is selected from palladium, Raney nickel, platinum,
ruthenium or rhodium catalyst; lithium aluminium hydride, sodium
15 borohydride or like and with or without additives; solvent used for
hydrogenolysis reaction is selected from C4-12 ethers, C3-12 ester, C3-10
aliphatic ketone, C6-12 hydrocarbon, halogenated solvent, aliphatic nitriles and
the like or mixture thereof; a suitable deprotecting reagent in step b.) is
selected from an organic base or an inorganic base.