Note: Descriptions are shown in the official language in which they were submitted.
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PROCESSES FOR THE SYNTHESIS OF O-DESMETHYLVENLAFAXINE
CROSS REFERENCE TO RELATED APPLICATIONS
[1] The present application claims the benefit of the following United
States Provisional Patent Application Nos.: 60/833,616, filed July 26, 2006;
60/837,879, filed August 14, 2006; 60/849,216, filed October 3, 2006;
60/843,998,
filed September 11, 2006; 60/849,255, filed October 3, 2006; 60/906,639, filed
March
12, 2007; and 60/906,879, filed 1Vlarch 13, 2007. The contents of these
applications
are incorporated herein by reference.
FIELD OF THE INVENTION
[2] The inverition encompasses processes for the synthesis of O-
desmethylvenlafaxine.
BACKGROUND OF THE INVENTION
[3] Venlafaxine, (t)-1-[2-(Dimethylamino)=1-(4-methoxyphenyl) ethyl]
cyclohexanol is the first of a class of anti-depressants. Venlafaxine acts by
inhibiting
re-uptake of norepinephrine and serotonin, and is an alternative to the
tricyclic anti-
depressants and selective re-uptake inhibitors. Venlafaxine has the following
chemical formula, Formula I:
iH3
H3C'N
OH
H3C-O
Formula I
[4] 0-desmethylvenlafaxine, 4-[2-(dimethylamino)-1-(1-
hydroxycyclohexyl)ethyl]phenol, is reported to be a metabolite of venlafaxine
and has
been reported to inhibit norepinephrine and serotonin uptake. See Klamerus, K.
J. et
al., "Introduction of the Composite Parameter to the Pharmacokinetics of
Venlafaxine
and its Active O-Desmethyl Metabolite," .I. Clzn. Pharmacol. 32:716-724
(1992). 0-
desmethylvenlafaxine has the following chemical formula, Formula II:
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OH
` ~ .
OH
C76Hz5NO2
Mol. Wt-- 263.38
Forrnula II
[51 Processes for the synthesis of 0-desmethylvenlafaxine, comprising a
step of demethylation of the methoxy group of venlafaxine, are described in
U.S.
patent No. 7,026,508 and 6,689,912, and in U.S. publication No. 2005/0197392.
[6] The synthesis disclosed in the above references is performed according
to the following scheme:
O UM:s un!le.
OM:e
~ =~ `.: ;j . . . .
,.~ HO .r ' Reduction
HO
. ,...,CN . .
`= .,~~ .
~...:~.
DOiMV
p"Me OH
Methylation Demethylation
HO ~CH3 HO ~H3
amine 0'LCH3 phenol C N
CH3
Venlefaitine
VNL ONV
Wherein "MBC" refers to methyl benzyl cyanide, "CMBC" refers to cyclohexyl
methylbenzyl cyanide, "DDMV" refers to didesmethyl venlafaxine, and "ODV"
refers to 0-desmethylvenlafaxine.
[7] However, the processes disclosed in the above US patents and US
patent applications all remain problematic when applied to industrial scale
production.
Further, the process disclosed in US Application Publication No. 2005/0197392
uses
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lithiumdiphenyl phosphine, a compound which handling and use in industrial
scale
processes is extremely dangerous. Also, the process disclosed in US Patent No
6,689,912 uses methanol as a solvent, which use is problematic when traces of
methanol remain and in subsequent process steps when high temperatures are
applied.
[8] There is a need in the art for a new synthetic route for obtaining 0-
desmethylvenlafaxine, using a precursor of venlafaxine to obtain 0-
desmethylvenlafaxine rather than by preparing venlafaxine and subsequently
demethylating venlafaxine to obtain 0-desmethyl venlafaxine.
SUMMARY OF THE INVENTION
[9] In one embodiment, there is provided cyclohexylbenzylcyanide
(COBC) of the formula:
OH
OH
CN .
COBC
[10] In another embodiment, the present invention provides a process for
preparing cyclohexy.lbenzylcyanide (COBC) comprising reacting
hydroxybenzylcyanide (OBC) with cyclohexanone, preferably the reaction
comprises
combining OBC, an organic solvent, preferably a dry organic solvent, a base
and
cyclohexanone.
[11] In another embodiment, the present invention provides a process for
obtaining cyclohexylbenzylcyanide (COBC) comprising reacting
hydroxybenzylcyanide (OBC) with cyclohexanone in the presence of a phase
transfer
catalyst and a base_
[12] In another embodiment, the present invention provides a process for
obtaining 0-desmethylvenlafaxine comprising preparing COBC as described above,
and further converting the COBC to O-desmethylvenlafaxine.
[13] In another embodiment, the present invention provides a process for
preparing tridesmethyl venlafaxine (TDMV) comprising: reducing COBC,
preferably
the step of reducing COBC comprises combining COBC, a reducing agent, an
organic
solvent and a Lewis acid catalyst, preferably boron trifluoride (BF3), to
create a
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reaction mixture, optionally followed by recovery of the TDMV from the
reaction
mixture.
[14] In another embodiment, the present invention provides a process for
obtaining 0-desmethylvenlafaxine comprising preparing TDMV as described above,
and further converting the TDMV to 0-desmethylvenlafaxine.
1151 In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: reacting hydroxybenzylcyanide
(OBC) with cyclohexanone, preferably the step of reacting with cyclohexanone
comprises combining OBC, an organic solvent, a base and cyclohexanone;
reducing
COBC, preferably the step of reducing COBC comprises combining a reducing
agent,
an organic solvent and a Lewis acid catalyst, preferably boron trifluoride
(BF3), to
create a reaction mixture; optionally recovering TDMV from the reaction
mixture and
converting the TDMV to 0-desmethylvenlafaxine.
[161 In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: providing a mixture of
hydroxybenzylcyanide (OBC), a phase transfer catalyst, a base and
cyclohexanone, to
obtain COBC; reducing COBC, preferably the step of reducing COBC comprises
combining a reducing agent, an organic solvent and a Lewis acid catalyst,
preferably
boron trifluoride (BF3), to create a reaction mixture; optionally recovering
TDMV
from the reaction mixture and converting the TDMV to 0-desmethylvenlafaxine.
[17] In another embodiment, the present invention provides a process of
preparing 0-desmethyl venlafaxine (ODV) comprising combining
hydroxybenzylcyanid (OBC) with a protecting reagent to obtain a hydroxyl
protected
hydroxybenzylcyanide (POBC), converting POBC to hydroxy protected O-
desmethy.lvenlafaxine (PODV), and deprotecting PODV to form ODV.
[18] In yet another embodiment there is provided a hydroxyl protected
hydroxybenzylcyanide (POBC). Also provided is a process of preparing POBC from
hydroxybenzyl cyanide (OBC).
[19] In another embodiment there is provided a hydroxyl protected
cyclcobexylbenzylcyanide (PCOBC). Also provided is a process of preparing
PCOBC.
[20] In another embodiment there is provided a hydroxyl protected
tridesmethyl venlafaxine (PTDMV). Also provided is a process of preparing
PTDMV).
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[21] In another embodiment there is provided a hydroxyl protected 0-
desmethyl venlafaxine (PODV).
[22] In yet other embodiments of the invention each of the other
embodiments provide one of each of the following compounds in isolated form:
cyclohexylbenzylcyanide (COBC), hydroxyl protected 4-hydroxybenzylcyanide
(POBC), hydroxyl protected cyclohexylbenzylcyanide (PCOBC), hydroxyl protected
tridesmethyl venlafaxine (PTDMV), and hydroxyl protected 0-desmethyl
venlafaxine
(PODV).
DETAILED DESCRIPTION OF THE INVENTION
[23] In one embodiment of the invention there is provided a
cyclohexylbenzylcyanide compound COBC of the following formula
OH
CN
j
COBC
COBC may be obtained by any of the processes described below. Preferably, COBC
is substantially, pure, preferably at least 95% pure, more preferably at least
99% pure.
[24] The invention encompasses a synthetic route for obtaining O-
desmethylvenlafaxine, from hydroxybenzylcyanide (OBC) and
cyclohexylbenzylcyanide (COBC). As used herein, hydroxybenzylcyanide or OBC
refers to the compound 4-hydroxybenzylcyanide and cyclohexylbenzylcyanide or
COBC refers to the compound 4-[1-cyano-l-(1-hydroxycyclohexy.l)methyl]phenol.
[25] As used herein, the term "reduced pressure" refers to a pressure less
than atmospheric pressure. As used. herein, the term "substantially pure"
means a
compound of very high purity as is understood by one of skill in the art, such
as a
purity of about 95%, or greater, as determined, for example, by HPLC area
percent.
As used herein the term "room temperature" or "RT" means the ambient
temperature
of an typical laboratory, which is usually about that of Standard Temperature
and
Pressure (STP). As used herein, an "isolated" compound means the compound has
been separated from the reaction mixture in which it was formed.
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1261 In the process of the invention, the intermediate hydroxybenzylcyanide
(OBC) is condensed with cyclohexanone to form the intermediate
(hydroxy)cyclohexylbenzylcyanide (COBC). Further, the cyano group on the COBC
is subjected to reduction, to form the intermediate tridesmethyl venlafaxine
(TDMV)
which is then subjected to selective alkylation to produce 0-
desmethylvenlafaxine
(ODV).
[27] Alternatively, a protected hydroxy-benzylcyanide (POBC) intermediate
is condensed with cyclohexanone to form the protected intermediate
(hydroxy)cyclohexylbenzylcyanide (PCOBC). Further, the cyano group on the
PCOBC is subjected to reduction, to form the protected intermediate
tridesmethyl
venlafaxine (PTDMV) which is then subjected to selective alkylation to produce
0-
desmethylvenlafaxine (ODV).
1281 The two pathways are as described in the following scheme:
OH o H OH OH
l("v'lJ
Condensation Reduction Methylatfon
OH OH OH i H3
CN CN NHZ N"ICH
3
OBC COBC TDMV ODV
ectI:otb0n0
o)C OX
\ ~ \ \
-' (
Condensation Reduation
OH OH
CN CN NH2
POBC PCOBC PTDMV
wherein X is a hydroxyl protecting group.
[29] In one embodiment, the present invention provides a process for
preparing cyclohexylbenzylcyanide (COBC) comprising reacting
hydroxybenzylcyanide (OBC) with cyclohexanone, preferably in the presence of
an
organic solvent and/or a base. The organic solvent is preferably a "dry
organic
solvent." As used herein the term "dry organic solvent" refers to an organic
solvent
that is essentially free of water such that the amount of residual water, if
detectable,
does not interfere with the reaction (e.g. by destroying catalysts) in a
manner that
prevents the benefits of the present invention from being realized. Such dry
organic
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solvent useful in the process of the present invention preferably comprises
less about
1% by weight, more preferably less than about 0.1 % by weight water, such as
about
0.05% by weight to about 0.1% by weight of water.
1301 A suitable organic solvent is selected from the group consisting of:
ethers, polar aprotic solvents, aromatic hydrocarbons, and alcohols,
acetonitrile, and
mixtures thereof. More preferably, the ethers contain 2-8 carbon atoms, more
.preferably 4-8 carbon atoms, or are selected from the group consisting of:
diisopropyl
ether, diethyl ether, dioxane, tetrahydrofuran (THF); preferably, the polar
aprotic
solvents are selected from the group consisting of dimethyiformamide (DMF),
dimethylacetamide (DMA) and dimethy.lsulfoxide (DMSO); and the aromatic
hydrocarbons are selected from the group consisting of toluene, xylene, and
benzene;
preferably the aromatic hydrocarbons contain 6-14 carbon atoms, more
preferably
from 6-10 carbon atoms, even more preferably toluene, xylene or benzene;
preferably,
the alcohols contain 1-6 carbon atoms, more preferably 1-4 carbon atoms or are
selected from the group consisting of methanol, ethanol,.isopropanol (IPA),
and
butanol. Most preferably, the organic solvent is selected from the group
consisting of:
tetrahydYofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA) and
dimethylsulfoxide (DMSO). Preferably, the organic solvent is a dry organic
solvent.
[311 The organic solvent can be employed as such, or it can be employed in
mixture with another organic solvent such as methanol or toluene.
[32] Preferably, the cyclohexanone is present in an amount of about 1 to
about 2 moles per mole of OBC, more preferably from about 1.1 mole to about
1.5
mole per mole of OBC.
[33] Preferably, the base is an inorganic base.lVlore preferably, the
inorganic base is an alkali metal base. A suitable base for use in the process
of the
present invention is selected from the group consisting of: lithium
diisopropyl amide
(LDA), lithium bis (trimethyl silyl) amide (LiN[(CH3)3Si]2), sodium hydroxide
(NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), cesium hydroxide
(CsOH), sodium hydride (NaH), potassium hydride (KH), cesium hydride (CsH),
potassium tert butoxide (t-BuOK), lithium tert butoxide (t-BuOLi), butyl
lithium
(BuLi) and sodium metoxide (NaOMe). When the organic solvent is
tetrahydrofuran
(THF), the base is preferably lithium diisopropyl amide (LDA), and when the
organic
solvent is a polar aprotic solvent, such as for example DMSO, the base is
preferably
sodium methoxide (NaOMe).
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[34] Preferably, the base is present in an amount of about 1 to about 5
moles per mole of OBC, more preferably in an amount of about 1.5 to about 3.5
moles per mole of OBC, even more preferably the amount is from about 2 to
about 3
moles per mole of OBC.
[35] In one embodiment of the invention, a solution or a slurry of
hydroxybenzylcyanide (OBC) and an organic solvent may be first combined with a
base, followed by combining the obtained reaction mixture with cyclohexanone,
to
obtain COBC. The initial reaction mixture may be cooled prior to adding
cyclohexanone, preferably cooling is to a temperature of about -50 C to about -
80 C,
preferably about -65 C. Preferably, cyclohexanone is added to the reaction
mixture in
a dropwise manner.
[36] After combining the reaction mixture with cyclohexanone, the mixture
may be further maintained, preferably at a constant temperature of about -40 C
to
about 35 C, preferably with stirring, for a sufficient time to obtain a useful
amount of
COBC, which is generally at least 10 minutes, preferably at least 45 min, more
preferably from about 1 hour to an overnight period (about 8 to 18 hours),
even more
preferably from about 2 hours to about 5 hours.
[37] COBC may be further recovered from the reaction mixture by any
method known in the art. In one embodiment, recovery of COBC from the reaction
mixture comprises the steps of extracting COBC from the reaction mixture,
preferably
with ethylacetate, washing the obtained organic layer, preferably with a
saturated
ammonium chloride solution and brine, and evaporating the solvent, preferably
under
reduced pressure, to obtain crude COBC. Such recovery may further comprise the
steps of slurrying the crude COBC in a chlorinated hydrocarbon, preferably
methylene chloride, filtering the slurry, washing the solid with methylene
chloride,
and drying to obtain substantially pure COBC.
[38] In another embodiment, the present invention provides a process for
obtaining cyclohexylbenzylcyanide (COBC) from a mixture of
hydroxybenzylcyanide
(OBC), a phase transfer catalyst, a base and cyclohexanone.
[39] Preferably, the phase transfer catalyst is selected from the group
consisting of: tetrabutylammonium hydrogensulphate; a tetraalkylammonium
halide
wherein the alkyl group can be the same or different and contains from I to 6,
such as
for example tetrabutylammonium bromide, tetrabutylammonium chloride, or
tetrabutylanimonium iodide; benzyltriethyl ammonium chloride; a quaternary
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ammonium salt; a quatemary phosphonium salt and a crown ether. More
preferably,
the phase transfer catalyst is tetrabutylammonium bromide (TBAB).
[40] The base in this embodiment is preferably an inorganic base. Suitable
inorganic bases are, for example, metal oxides and metal carbonates.
Preferably, the
inorganic base is selected from the group consisting of: NaOH, KOH, LiOH,
CsOH,
K2C03, Na2CO3, and Cs2CO3. Other bases suitable for use in the process of the
invention are, for example, metal alkanoxides such as sodium methoxide (NaOMe)
or
sodium ethanoxide (NaOEt). Preferably, the base is present in an amount of
about 0.5
to about 3 mole per mole of OBC, more preferably from about I mole to about 2
mole
per mole of OBC.
[41] Preferably, the cyclohexanone is present in an mnount of about 1 to
about 2 moles per mole of OBC, more preferably from about 1.1 mole to about
1.5
mole per mole of OBC.
[42] The reaction may occur with or without the presence of an organic
solvent or water. Preferably, the reaction occurs in the presence of water.
[43] Preferably, the reaction mixture is maintained, preferably with stirring,
for a sufficient period of time to obtain a useful amount of COBC. A
sufficient period
of tirne may be from about 1 hour to about 24 hours, preferably an overnight
period
(about 8 to about 18 hours). One of ordinary skill in the art could easily
monitor the
reaction to determine whether a sufficient period of time has elapsed.
[44] The present invention also provides hydroxyl protected
hydroxybenzylcyanide (POBC) of the following formula:
x
CN
POBC
wherein X is a hydroxyl protecting group. The hydroxyl protecting group may be
removed by deprotection.
[45] The hydroxyl group on the 4-hydroxybenzylcyanide (OBC) may be
prepared by a process comprising combining OBC with a protecting reagent to
form a
reaction mixture, optionally in an organic solvent and in the presence of a
catalyst, a
base or both, to obtain the hydroxyl protected POBC.
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[46] A suitable protecting agent can be any known hydroxyl protecting
agent. Suitable hydroxyl protecting groups are listed in T.W. Greene,
Protecting
Groups in Organic Synthesis, (2 d Ed.), which is incorporated herein by
reference.
Preferably, the hydroxyl protecting group can be a silyl, acetyl, or 3,4-
dihydro-2H-
puran (DHP). The silyl protecting group is preferably tert-butyldimethylsilyl
(TBDMS). The protection reaction may be carried out at any suitable
temperature
depending on reagent used, preferably the temperature is between about 0 C to
about
100 C, more preferably between about room temperature to about 55 C. A
preferred
base added to the reaction mixture is selected from the group selected from
imidazole,
pyridine, triethylamine, lutidine, and dimethylaminopyridine. A catalyst may
be
added to the mixture, such as for example Pyridinium p-toluene sulfonate
(PPTS).
[47] Preferably, POBC is substantially pure, preferably at least 95% pure,
more preferably at least 99% pure.
[48] The present invention also provides hydroxyl protected
cyclohexylbenzylcyanide (PCOBC). of the following formula:
ox
H
CN
PCOBC
wherein X is as described above. Preferably, PCOBC is substantially pure,
preferably
at least 95% pure, more preferably at least 99% pure.
[491 In another embodiment, the present invention provides a process for
preparing a hydroxyl protected COBC (PCOBC), according to the processes for
preparing COBC, wherein the starting material 4-hydroxybenzylcyanide (OBC) is
a
hydroxyl protected OBC (POBC) as described in the scheme above.
[50] In another embodiment, the present invention provides a process for
obtaining 0-desmethylvenlafaxine comprising preparing COBC or PCOBC in any of
the methods described above, and further converting them to 0-
desmethylvenlafaxine.
[51] In another embodiment of the process of the present invention 0-
desmethyl venlafaxine, salts thereof or hydroxyl protected derivatives thereof
may be
prepared from hydroxybenzylcyanide by first protecting the hydroxyl group on
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hydroxybenzylcyanide (OBC). The hydroxyl protected hydroxybenzylcyanide
(POBC) may then be condensed with cyclohexanone to obtain a hydroxyl protected
cyclohexylbenzylcyanide (PCOBC) which is reduced to form the hydroxyl
protected
tridesmethyl venlafaxine (PTDMV) and methylated to form a hydroxyl protected 0-
desmethyl venlafaxine (PODV) as is shown in the schematic above.
[52] The protected POBC may be converted by any of the above processes
to a hydroxyl protected PCOBC, which can be reduced to a hydroxyl protected
PTDMV by a process described above, and the protected PTDMV may be methylated
to obtain the hydroxyl protected PODV. Subsequently, the PODV is preferably
deprotected with an appropriate deprotecting agent depending on the protecting
group
used. Preferably such deprotection agent can be an acid, such as for example
methanesulfonic acid.
[53] The present invention also provides a process for preparing
tridesmethyl venlafaxine (TDMV). TDMV may be prepared by reducing COBC.
Preferably, COBC is combined with a reducing agent in the presence of an
organic
solvent and/or a Lewis acid catalyst, preferably boron trifluoride (BF3) to
create a
reaction mixture. TDMV may be further recovered from the reaction mixture.
[54] In one embodiment, a solution of COBC, a reducing agent and an
organic solvent are combined with a Lewis acid catalyst to obtain a reaction
mixture,
followed by recovery of the TDMV from the reaction mixture.
[55] Preferably, the solution of COBC, reducing agent and organic solvent
is cooled prior to combining it with a Lewis acid catalyst. A preferred
temperature to
which the mixture is cooled is to a temperature of less than about 10 C, more
preferably from about -10 C to about 10 C.
[56] A preferred Lewis acid catalyst is boron trifluoride (BF3). When BF3
is used, it is preferably added as a complex in ether (BF3Et2O), or else the
complex
may be formed in situ.
[57] In some embodiments, COBC may be prepared by precipitation from a
mixture of hydroxybenzylcyanide (OBC), an organic solvent, a base and
cyclohexanone; or from a mixture of hydroxybenzylcyanide (OBC), a phase
transfer
catalyst, a base and cyclohexanone.
[58] Preferably, the reducing agent is selected from the group consisting of:
sodium borohydride (NaBH4), lithium borohydride (LiBH4), lithium aluminum
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hydride (LiA1H4), L-selectride (lithium tri-sec-butylborohydride), and borane.
More
preferably, the reducing agent is NaBH4.
[59] Alternatively, the reduction can be performed by hydrogenation in the
presence of a catalyst, e.g. Ni, Co, Pd/C, or Pt catalyst.
[60] Preferably, the organic solvent is a dry organic solvent. The organic
solvent is as described above. More preferably, the organic solvent is THF.
[61] Preferably, the reducing agent is present in an amount of about 1 to
about 10 moles per mole of COBC, more preferably in an amount of about 4 to
about
moles per mole of COBC. A preferred amount of the Lewis acid catalyst, such as
BF3, is an amount of about 1 to about 5 moles per mole of COBC, more
preferably
from about 2 to about 3 mole per mole of COBC.
[62] The reaction mixture in the process of the present invention may be
maintained, preferably at a constant temperature, such as at room temperature,
preferably while stirring, for a sufficient period of time to obtain TDMV. A
preferred
period of time is from about 1 hour to about 24 hours, more preferably from
about 3
hours to about 12 hours, even more preferably, from about 8 hours to about 10
hours.
[63] TDMV may then be recovered from the reaction mixture by any
method known in the art. In one embodiment, recovery of TDMV from the reaction
mixture comprises the steps of basifying and optionally extracting TDMV from
the
reaction mixture, preferably with ethylacetate, washing the obtained organic
solution,
preferably with water andlor brine, and drying to obtain= TDMV, preferably by
evaporating the solvent for example under reduced pressure.
[64] The present invention also provides the hydroxyl protected
tridesmethyl venlafaxine (PTDMV) of the following formula:
x
OH
NHa
PTDMV
wherein X is as described above. Preferably, PCOBC is substantially pure,
preferably
at least 95% pure, more preferably at least 99% pure.
[65] In another embodiment, the present invention provides a process for
preparing hydroxyl protected tridesmethyl venlafaxine (PTDMV), according to
the
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preparation of TDMV, wherein the starting material the hydroxyl protected
PCOBC
as described above.
[66] In another embodiment, the present invention provides a process for
preparing O-desmethylvenlafaxine comprising preparing TDMV or PTDMV as
described above, and further converting them to 0-desmethylvenlafaxine.
[67] The conversion of TDMV to 0-desmethylvenlafaxine can be
performed, for example as described in co-pending United States Patent
Application
No. --/-------- filed July 26, 2007, entitled "Processes for the Synthesis of
0-
Desmethylvenlafaxine"(Atty Docket No 1662/03304), which is incorporated herein
by reference. For example, TDMV may be combined with an organic solvent and a
methylating agent to form a mixture, and recovering the 0-desmethylvenlafaxine
from the mixture. Also, TDMV may be subjected to selective reductive amination
to
produce 0-desmethylvenlafaxine ("ODV"). PTDMV is converted to PO-
desmethylvenlafaxine in a similar manner.
[68] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: reacting hydroxybenzylcyanide
(OBC) with cyclohexanone, preferably the step of reacting with cyclohexanone
comprises combining OBC, an organic solvent, a base and cyclohexanone;
reducing
COBC, preferably the step of reducing COBC comprises combining a reducing
agent,
an organic solvent and boron trifluoride (BF3).to create a reaction mixture;
recovering
TDMV from the reaction mixture and converting the TDMV to 0-
desmethylvenlafaxine.
[69] In another embodiment, the present invention provides a process for
preparing O-desmethylvenlafaxine comprising: providing a mixture of
hydroxybenzylcyanide (OBC), a phase transfer catalyst, a base and
cyclohexanone, to
obtain COBC; reducing COBC, preferably the step of reducing COBC comprises
combining a reducing agent, an organic solvent and boron trifluoride (BF3) to
create a
reaction mixture; recovering TDMV from the reaction mixture and converting the
TDMV to 0-desmethylvenlafaxine.
[70] In another embodiment of the present invention a hydroxyl protected
0-desmethyl venlafaxine (PODV) may be prepared by any of the above processes
wherein the starting material is a hydroxyl protected intermediate as
described above.
The present invention also provides the hydroxyl protected 0-desmethyl
venlafaxine
(PODV).
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[71] The 0-desmethyl venlafaxine prepared by any of above process can be
prepared in the form of a salt, preferably a succinate salt.
[72] . Having described the invention with reference to certain preferred
embodiments, other embodiments 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 the synthesis of the compound COBC,
tridesmethyl venlafaxine and further their conversion to 0-
desmethylvenlafaxine. It
will be apparent to those skilled in the art that many modifications, both to
materials
and methods, may. be practiced without departing from the scope of the
invention.
EXAMPLES
HPLC Method:
Column & Packing: Zorbax SB C-18 4.6*250mm Part No.28105-020 or
equivalent column
Column Temperature: 25 C
Buffer Add 4.Oml of trifluoroacetic acid and 7.Oml of
triethylamine to 1L of water adjust the pH to3.0 with
triethylarnine.
Eluent:
ReservoirA 30 JoAcetonitrile and 70% Buffer
Reservoir B To a mixture of 700m1 Acetonitrile and 300m1 buffer
add 1.6m1 of trifluoroacetic acid and 2.9rn1 of
triethylamine measure the pH it should be about 3_0
(correct the pH with triethylamine or trifluoroacetic acid
if necessary).
Gradient Time Reservoir A Reservoir B
0 100% 0%
21 min 100% 0%
55 min 45% 55%
Equilibrium time: 10min
Flow Rate: 1.0 ml/min
Detector: 230 nm
Sample Volume: 10 l
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Diluent: Eluent A
Mobile phase composition and flow rate may be varied in order to achieve the
required system suitability.
Sample Preparation
Weigh accurately about 10 mg of sample in a 20m1 amber volumetric flask.
Dissolve
with eluent A.
Method
Inject the sample solutions into the chromatograph, continuing the
chromatogram of
sample up to the end of the gradient. Determine the areas for each peak in
each
solution using a suitable integrator.
Calculation
Impurity Profile Determination
% impurity _ area impurity in sample x 100
Total area
Preparation of COBC
Example 1:
A 100 ml, three necked flask equipped with Nitrogen inlet, thermometer and
mechanical stirrer was charged with OBC (2g, 15 mmol) and THF (15 ml). This
solution was cooled to -78 C and LDA (2M in THF, 16.5 ml, 33 mmol) was added
slowly, keeping temperature under -65 C. A white solid precipitated during LDA
addition. Afler the end of the addition, the mixture was stirred for 30
minutes.
Cyclohexanone (1.62 g, 16.5 mmol) was then added, and the mixture continued in
the
same conditions for 5 hours. The reaction was quenched by pouring it into 100
ml of a
saturated ammonium chloride solution containing ice.
The product was extracted to EtOAc (3x30 ml). The organic layer was washed
with a saturated ammonium chloride solution and brine. Finally the solvent was
evaporated under reduced pressure to get 3.5 g of a mixture of OBC (30%) and
COBC
(60%) (Yield =60%).
This mixture was suspended in 10 ml methylene chloride, where a solid
precipitated. The slurry was stirred at room temperature-for 2 hours, the
solid filtered,
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washed with methylene chloride and vacuum dried at room temperature, to get
1.9g
COBC (purity 99% by HPLC area, yield=55%).
Examgle 2:
A 100 ml, three necked flask equipped with Nitrogen inlet, thermometer and
magnetic stirrer was charged with OBC (5g, 37.5 mmol) and DMSO (5 ml). The
contents of the flask were stirred to complete dissolving (brown color). KOH
(3.2g,
56 mmol ) was added and the reaction mixture stirred vigorously (exothermic).
Cyclohexanone (5.52 g, 56 mmol) was then added dropwise. The reaction
was quenched with HC1 5% and methylene chloride was added. The layers were
separated and a solid precipitated. The solid was then filtered under reduced
pressure
and washed with a small amount of methylene chloride to yield 3.2g of COBC.
Example 3:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and
mechanical stirrer was charged with OBC (2g, 15 mmol), toluene (15 ml) and DMF
(2ml). The reaction mixture was stirred at about room temperature (RT) until
dissolution was complete and NaH (1.2g, 30 mmol) was added. Cyclohexanone (1.7
g, 17.3 mmol) was then added dropwise. The reaction was stirred at RT for an
additional lhr to get 21% COBC (% area HPLC).
Example 4:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and
mechanical stirrer was charged with OBC (2g, 15 mmol), THF (30 ml) and DMF
(2m1). The reaction mixture was stirred at RT until dissolution was complete
and t-
BuOK (3.3 g, 30 mmol) was added. Cyclohexanone (1.65 g, 16.8 mmol) was then
added dropwise and the reaction was stirred at RT for an additiona13.5hrs to
get
19%COBC (% area HPLC).
Example 5:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and
mechanical stirrer was charged with OBC (2g, 15 mmol), THF (15 ml) and DMF
(2m1). The mixture was stirred at RT until complete dissolution and NaH (1.2g,
30
mmol) was added. Cyclohexanone (1.7 g, 17.3 mmol) was then added dropwise and
the reaction was stirred at RT for and additional 2hrs to get 34%COBC (% area
HPLC).
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Example 6:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and
mechanical stirrer was charged with OBC (2g, 15 mmol) MeOH (15 ml) and DMF
(2ml). The reaction mixture was stirred at RT until complete dissolution and
NaOCH3 (1.7g, 30 mmol) was added. Cyclohexanone (1.7 g, 17.3 mmol) was then
added dropwise and the reaction was stirred at RT overnight to obtain 30% COBC
(%
area HPLC).
Example 7:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and
mechanical stirrer was charged with OBC (2g, 15 mmol), MeOH (10 ml) and DMSO
(lOml). The reaction mixture was stirred at RT until complete dissolution and
NaOCH3 (1.7g, 30 mmol) was added. Cyclohexanone (1.7 g, 17.3 mmol) was added
dropwise. The reaction was stirred at RT overnight to obtain 32% COBC ( 'o
area
HPLC).
Example 8:
A 100 ml, three necked flask equipped with nitrogen inlet, thermometer and
mechanical stirrer was charged with OBC (2g, 15 mmol) and DMSO (l Ornl). The
reaction mixture was stirred at RT until complete dissolution and NaOCH3
(2.65g, 47
mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The
reaction was stirred at RT 10 min to get 43% COBC (% area HPLC).
Example 9:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and
mechanical stirrer was charged with OBC (2g, 15 mmol) and DMSO (10m1). The
reaction mixture was stirred at RT until complete dissolution and NaOCH3 (1 g,
17.6
mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The
reaction was stirred at RT 45 min to get 55% of COBC (% area HPLC).
Example 10:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and
mechanical stirrer was charged with OBC (2g, 15 mmol) and DMSO (lOml). The
reaction mixture was stirred at RT until complete dissolution and LiOH (1g,
23.8
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mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The
reaction was stirred at RT 8.5hrs to get 35% of COBC (% area HPLC).
Example 11:
A 100 ml three necked flask equipped with, thermometer and mechanical
stirrer was charged with OBC (2g, 15 mmol), cyclohexanone (1.7 g, 17.3 mmol),
TBAB (0.26g) and NaOH (6m1 10%). The reaction was stirred at RT overnight to
.get
44% COBC (HPLC).
Example 12:
A 100 ml three necked flask equipped with nitrogen inlet, thennometer and
mechanical stirrer was charged with OBC (2g, 15 mmol) and THF (15m1). The
reaction mixture was stirred at RT until complete dissolution and t-BuOLi (2g,
25
mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The
reaction was stirred at RT 45min to get 19% COBC (% area HPLC).
Example 13:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer,and
mechanical stirrer was charged with OBC (2g, 15 mmol), THF(15m1) and DMF
(1.5m1). The reaction mixture was stiured at RT until complete dissolution and
t-
BuOLi (2.5g, 30 mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then
added dropwise. The reaction was stirred at RT 1.15 hr to get 23.5% COBC (%
area
HPLC).
Example 14:
A 100 ml three necked flask equipped with thermometer and mechanical
stirrer was charged with OBC (2g, 15 mmol) and cyclohexanone (2 g, 20.37
mmol),
TBAB (0.5g) and NaOH (13m1 10%) were added. The reaction was stirred at RT
overnight to get 40%COBC (% area HPLC).
Examule 15:
A 100 ml three necked flask equipped with thermometer and mechanical
stirrer was charged with OBC (2g, 15 mmol) and cyclohexanone (2.2g, 22.4
mmol).
Water (l Oml), TBAB (0.3g) and KOH (1.9g, 30.5 mmol) were then added. The
reaction was stirred at RT overnight to get 39% COBC (% area HPLC).
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Examule 16:
A 100 ml three necked flask equipped with thermometer and mechanical
stirrer was charged with OBC (2g, 15 mmol) and cyclohexanone (2.2g, 22.4
mmol).
Water (10m1), TBAB(0.3gr) and LiOH (2g, 47.6mmo1) were then added. The
reaction
was stirred at RT overnight to get 39% COBC (% area HPLC)_
Example 17:
A 100 ml three necked flask equipped with thermometer and mechanical
stirrer was charged with OBC (2g, 15 mmol), DMA (10m1) and LiOH (2g, 47.7
mmol). Cyclohexanone (2.2g, 22:4 mmol) was then added dropwise. The reaction
mixture was stirred at RT overnight to get 10% COBC (% area HPLC).
Preparation of TDMV
Example 18:
A100 ml three necked flask equipped with nitrogen inlet thenmometer and
mechanical stirrer was charged with COBC (2 g, 8.64 mmol), MeOH (50 ml) and
CoCl anhydrous (2.25 g, 17.32 mmol). The resulting solution was cooled to-10 C
with an ice-bath. NaBH4 (3.35 g, 88.62mmol) was added portionwise at this
temperature. The ice-bath was removed one hour after the end of addition.
The reaction mixture was stirred 3 hours at room temperature and then
quenched with 10%HCI. MeOH was removed under reduced pressure and the
aqueous phase was basified with ammonium hydroxide (25%) and extracted with
EtOAc. The organic phase was washed with water, brine, dried over Na2SO4 and
evaporated under reduced pressure to get 0.4 g of TDMV.
Example 19:
A 100 ml three necked flask equipped with nitrogen inlet thermometer and
mechanical stirrer was charged with NaBH4 (1.2 g, 31.74 mmol) THF (lOml).
This solution was cooled to10 C with an ice-bath. BF3Et2O (3.95g, 27.86mmol)
and
COBC (2 g, 8.64 mmol) were then added. The reaction mixture was stirred at
room
temperature overnight.
The reaction mixture was quenched with formic acid and water. The organic
phase was basified with NaOH (25%), washed with water and evaporated under
reduced pressure to get TDMV.
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Preparation of O-desmethylvenlafaxine
Example 20:
TDMV (0.5 g, 2.12 mmol) was suspended in CH2C12. Methyl iodide (0.26 ml,
4.3 mmol) and triethylamine (0.66 ml, 4.73 mmol) were added. The reaction
mixture
was stirred under nitrogen atmosphere at room temperature for 6 hours. At this
stage
methyl iodide (0.5 ml) and NEt3 (1.2 ml) were added. The addition caused the
temperature to rise. After 16 hours, BPLC analysis indicated the presence of
ODV.
Preparation of POBC
Example 21: Preparation of OBC-DHP
OBC (0.5g, 3.7 mmol) was dissolved at room temperature in 3,4-dihydro-2H-
pyran (DHP) (approx. 2 ml) under N2. Pyridinium p-toluene sulfonate (PPTS,
catalytic amount) was added and heated to 55 C for 45 min. The end of reaction
was
determined by TLC (eluent EtOAc:Hex 1:1). The product was extracted in EtOAc,
washed with brine and dried over MgSO4. A pale yellow powder was obtained
(0.74g,
purity= 98% by area % of HPLC, yield= 91%)
Example 22: Preparation of OBC-TBDMS
OBC (5g, 37 mmol), 11 g of TBDMS-Cl, 12g of imidazole and 25m1 of
CH2Cla were stirred together for 2 hours at ambient temperature under N2
atmosphere.
The product was washed with brine, a 10% aqueous solution of citric acid,
brine and
dried over MgSO4. After removal of the solvent 4g of product was obtained.
Preparation of PCOBC
Example 23: Preparation of COBC-DHP
OBC-DHP (0.74g, 3.4 mmol), cyclohexanone (0.5 g), TBAB (0.15g) and a
10% aqueous solution of NaOH (4 ml) were mixed and stirred at room
temperature,
forming two phases. After 30 minutes of stirring, the organic phase was
analyzed by
HPLC, containing 46% COBC-DHP and 48% unreacted OBC-DHP.
Example 24:
OBC-DHP (3.25g, 15 mmol) was dissolved in dry THF under N2 and cooled
to -80 C. LDA 2M in THF/heptane/ethyl benzene (8 ml, 16 mmol) was added
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dropwise, keeping the temperature under -60 C. The mixture was stirred at -80
C for
30 minutes. Cyclohexanone (1.65g, 16.5 mmol) was added dropwise. After 1 hour
stirring a sample was analyzed by HPLC, containing 41% COBC-DHP and 42%
unreacted OBC-DHP.
Preparation of PTDMV
Example 25:
A 100 ml three necked flask equipped with nitrogen inlet thermometer and
mechanical stirrer is charged with PCOBC (8.64 mmol), MeOH (50 ml) and CoCI
anhydrous (17.32 mmol). The resulting solution is cooled to-10 C with an ice-
bath.
NaBH4 (88.62mmol) is added portionwise at this temperature. The ice-bath is
removed one hour after the end of addition.
The reaction mixture is stirred 3 hours at room temperature and then quenched
with 10%HCI. MeOH is removed under reduced pressure and the aqueous phase is
basified with ammonium hydroxide (25%) and extracted with EtOAc. The organic
phase is washed with water, brine, dried over Na2SO4 and evaporated under
reduced
pressure to get PTDMV.
Example 26:
A 100 ml three necked flask-equipped with nitrogen inlet thermometer and
mechanical stirrer is charged with NaBH4 (31.74 mmol) and THF (lOml).
This solution is cooled to10 C with an ice-bath. BF3Et2O (27.86nunol) and
PCOBC
(8.64 mmol) are then added. The reaction mixture is stirred at room
temperature
overnight.
The reaction mixture is quenched with formic acid and water. The organic
phase is basified with NaOH (25 Jo), washed with water and evaporated under
reduced
pressure to get PTDMV.
Preparation of PODV
Exarnple 27:
P-TDMV (2.12 mmol) is suspended in CH2Cl2. Methyl iodide (4.3 mmol) and
triethylamine (4.73 mmol) are added. The reaction mixture is stirred under
nitrogen
atmosphere at room temperature for 6 hours. At this stage methyl iodide (0.5
ml) and
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NEt3 (1.2 ml) are added. After 16 hours, HPLC analysis indicated the presence
of
PODV.
Preparation of 0-desmethylvenlafaxine
Example 28:
PODV (2.12 mmol) is suspended in THF in presence of methanesulfonic acid
(6 mmol).The reaction is stirred at ambient temperature overnight. To the
mixture so-
obtained is first added EtOAc and the organic phase is washed with brine,
Na2CO3
saturated and water. The organic phase is then concentrated under reduced
pressure to
get ODV.
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