PROCESSES FOR THE SYNTHESIS OF O-DESMETHYLVENLAFAXINE

PROCEDE POUR SYNTHETISER LE COMPOSE O-DESMETHYLVENLAFAXINE

English Abstract

Provides are intermediates and processes for preparation of o- desmethylvenlafaxine.

French Abstract

L'invention concerne des produits intermédiaires et des procédés pour préparer le composé O-desméthylvenlafaxine.

Claims

What is claimed is:
1. (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC).
2. The compound of claim 1, wherein the compound is in isolated or purified
form.
3. The compound of any one of claims 1 or 2, wherein the compound has a purity
of at least about 50% as measured by HPLC.
4. A process for preparing compound of claim 1, 2 or 3 comprising reacting BBC
with cyclohexanone.
5. The process of claim 4, wherein the process comprises combining
bromophenylacetonitrile (BBC), an organic solvent, a base and cyclohexanone
to precipitating CBBC.
6. The process of claim 5, wherein the organic solvent is selected from the
group
consisting of: C2-8 ethers, polar aprotic solvents (Polarity Index of greater
than
about 2.0), C1-C8 chlorinated aliphatic and aromatic, C6-C12 aromatic
hydrocarbons, and C1-6 alcohols.
7. The process of claim 5, wherein the organic solvent is selected from the
group
consisting of diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran
(THF),
dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide
(DMSO), methylene chloride, chlorobenzene, toluene and benzene.
8. The process of claim 5, wherein the organic solvent is selected from the
group
consisting of tetrahydrofuran (THF), methanol, methylene chloride and
toluene.
9. The process of any one of claims 5-8, wherein the organic solvent contains
less than 1% water by volume.
10. The process of any one of claims 5-9, wherein the base is an alkali metal
or
alkaline earth metal.
11. The process of any one of claims 5-10, wherein the base is selected from
the
group consisting of: lithium diisopropyl amide (LDA), lithium bis (trimethyl
silyl) amide (LiN[(CH3)3Si]2), potassium hydroxide (KOH), lithium hydroxide
(LiOH), sodium hydride (NaH), potassium tert butoxide (t-BuOK), lithium tert
butoxide (t-BuOLi), butyl lithium (BuLi) and sodium methoxide (NaOCH3).
12. The process of any one of claims 5-11, wherein the process is carried out
by
combining a solution or a slurry of BBC and a dry organic solvent with a base
22

to obtain a reaction mixture, followed by combining the reaction mixture with
cyclohexanone, to obtain CBBC.
13. The process of any one of claims 5-12, further comprising recovering CBBC.
14. The process of any one of claims 13, wherein recovery comprises
evaporating
the solvent, dissolving the residue in a water immiscible solvent such as
toluene, washing with water or brine, and evaporated to get a residue.
15. The process of any one of claims 13-14, further comprising crystallizing
CBBC from the residue.
16. The process of any one of claims 4-15, wherein the process comprises
combining bromophenylacetonitrile (BBC), a phase transfer catalyst,
optionally a base and cyclohexanone.
17. The process of claim 16, wherein the reaction occurs in the presence of
water.
18. The process of any one of claims 16-17, wherein the phase transfer
catalyst is
a tetraalkylammonium, tetraalkylphosphonium, tetraarylammonium or
tetraarylphosphonium, wherein the alkyl group can be the same or different
and contains from 1 to 10 carbons, and wherein the aryl group can be the same
or different and contains from 6 to 8 carbons
19. The process of any one of claims 16-17, wherein the phase transfer
catalyst is
selected from the group consisting of: tetrabutylammonium hydrogensulphate,
tetrabutylammonium bromide, tetrabutylammonium chloride,
tetrabutylammonium iodide, benzyltriethyl ammonium chloride, aliquot,
quaternay ammonium salt, quaternary phosphonium salt and crown ether.
20. The process of any one of claims 16-18, wherein the phase transfer
catalyst is
tetra butyl ammonium bromide (TBAB).
21. The process of any one of claims 5-20, wherein the base is an alkali metal
or
alkaline earth metal hydroxide or carbonate.
22. The process of any one of claims 16-21, wherein the base is NaOH, KOH,
LiOH, CsOH, K2CO3, NaCO3 or Cs2CO3
23. A process for preparing O-desmethylvenlafaxine comprising preparing CBBC
as described in any one of claims 4-22, and further converting the CBBC to O-
desmethylvenlafaxine.
24. 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV).
25. The compound of claim 24, wherein the compound is in isolated or purified
form.
23

26. The compound of any one of claims 24-25, wherein the compound has a purity
of at least about 50% as measured by HPLC.
27. A process for preparing a compound according to any of claims 24 to 26
comprising reacting CBBC with a reducing agent.
28. The process of claim 27, comprising combining CBBC and an organic solvent
to obtain a solution, and adding a reducing agent to the solution.
29. The process of claim 28, wherein the solvent is a dry organic solvent.
30. The process of any one of claims 28-29, wherein the reducing agent is
Borane
or hydride.
31. The process of claim 30, wherein the reducing agent is Borane
dimethylsulfide.
32. The process of any one of claims 28-29, wherein the reducing agent is H2
in
presence of catalyst such as Ni, Co or Pt.
33. The process of any one of claims 27-32, wherein the solvent is
tetrahydrofuran
(THF).
34. The process of claim 31, wherein the borane is present in an amount of
about 1
to about 3- moles per mole of CBBC.
35. The process of any one of claims 27-34, further comprising quenching,
acidifying resulting organic layer, and extracting CBBC from the organic
layer.
36. The process of any one of claims 27-35, further comprising drying the
organic
layer over Na2SO4 or under a pressure of less than one atmosphere, or both.
37. A process for preparing O-desmethylvenlafaxine, comprising preparing
BDDMV as described in any one of claims 27-36, and further converting the
BDDMV to O-desmethylvenlafaxine.
38. 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV).
39. The compound of claim 38, wherein BODV is in isolated or purified form.
40. The compound of any one of claims 38-39, wherein BODV has a purity of at
least about 50% as measured by HPLC.
41. A process for preparing the compound of any one of claims 38-40 comprising
combining BDDMV, formaldehyde and a reducing agent.
42. The process of claim 41, wherein BDDMV is dissolved or suspended in an
organic solvent, preferably a C1-4 alcohol such as MeOH, followed by addition
of formaldehyde and the reducing agent.
24

43. The process of any one of claims 41-42, wherein the reducing agent is
NaBH4.
44. The process of any one of claims 41-42, wherein the reducing agent is
formic
acid.
45. The process of any one of claims 41-44, further comprising recovering BODV
from an organic solvent.
46. The process of any one of claims 41-45, wherein recovery comprises
evaporating the organic solvent to obtain a residue, optionally dissolving the
residue in a second organic solvent, acidifying, evaporating the second
organic
solvent.
47. A process for preparing the compound of claim 38 comprising combining
BDDMV, an organic solvent, and a methylating agent.
48. The process of claim 47 wherein the process comprises optionally
dissolving
BDDMV in an organic solvent to obtain a solution, adding a base and a
methylating agent to the solution to obtain BODV.
49. The process of any one of claims 47-48, wherein the solvent is
dichloromethane or dimethylsulfoxide, THF, ACN or toluene.
50. The process of any one of claims 48-49 wherein the base is BuLi or a C3-C9
trialkylamine.
51. The process of claim 50, wherein the base is triethylamine.
52. The process of any one of claims 43-51 wherein the methylating agent is a
methyl halide or dimethylsulfate.
53. The process of claim 52 wherein the methylating agent is methyl iodide.
54. The process of claim 53, wherein the NaI is a neat reagent.
55. The process of any one of claims 41-54 further comprising recovering BODV
from the obtained reaction mixture.
56. A process for preparing O-desmethylvenlafaxine comprising preparing BODV
according to any one of claims 41-55, and further converting the BODV to O-
desmethylvenlafaxine.
57. A process for preparing O-desmethylvenlafaxine comprising hydrolyzing
BODV of any one of claims 38-40.
58. A process for preparing O-desmethylvenlafaxine comprising: combining
BODV of any one of claims 38-40, a hydroxide donor base and a metal salt to
obtain a reaction mixture, followed by recovery of the O-
desmethylvenlafaxine from the reaction mixture.

59. The process of claim 58, wherein the hydroxide donor base is an alkali
metal
or alkaline earth metal hydroxide.
60. The process of claim 59, wherein the base is a potassium hydroxide (KOH),
lithium hydroxide (LiOH) or sodium hydroxide (NaOH), CsOH.
61. The process of any one of claims 58-60, wherein the metal salt is silver
nitrate
(AgNO3).
62. The process of claim 61, wherein the metal salt is AgNO3 optionally on a
support.
63. The process of any one of claims 56-62, wherein the process comprises
combining AgNO3 in water with solid support (montmorillonite or silica) to
obtain a reaction mixture, heating the mixture, removing the water to obtain a
residue, combining BODV, a base and the residue to obtain ODV.
64. The process of claim 63, further comprising recovering ODV by extracting
ODV with an organic solvent.
65. The process of claim 64, wherein the solvent is a mixture of chloroform
and
methanol.
66. A process for preparing O-desmethylvenlafaxine comprising combining
BODV of any one of claims 38-40 with Mg or Cu, and an organic solvent to
obtain a grignard reagent or an organocuprate reagent, and combining the
reagent with borate and an acid to provide O-desmethylvenlafaxine.
67. The process of claim 66, wherein the process comprises combining Mg or Cu
and a halogen when Cu is not used with BODV in an organic solvent such as
THF.
68. The process of claim 67, wherein the halogen is 12.
69. The process of any one of claims 66-68, wherein the borate is
trimethylborate.
70. The process of any one of claims 66-69, wherein the acid is glacial acetic
acid.
71. The process of any one of claims 66-70, further comprising quenching with
hydrogen peroxide.
72. The process of claim 66-71, further comprising adding a water immiscible
organic solvent in which O-desmethylvenlafaxine is soluble in, preferably
diethylether, to recover O-desmethylvenlafaxine.
73. The process of any of the preceding claims which synthesize O-
desmethylvenlafaxine, wherein a hydroxyl protected BODV is used to
synthesize O-desmethylvenlafaxine.
26

74. The process of claim 73, wherein the protected intermediate of BODV has a
suitable hydroxyl protecting group selected from the group consisting of
silyl,
acetyl and dihydropyran (DHP).
75. The process of claim 74, wherein the BODV is protected with an acetyl
group.
76. Hydroxyprotected-1-[1-(4-bromophenyl)-2-
(dimethylamino)ethyl]cyclohexanol (BODV-P).
77. The BODV-P of claim 76 in isolated or purified form.
78. The BODV-P of claim 76 or 77, wherein the protecting group is acetyl
group.
79. The BODV-P of claim 76 or 77, wherein the protecting group is silyl,
acetyl or
dihydropyran (DHP).
80. The BODV-P of claim 76-79 having a purity of at least about 50% as
measured by HPLC.
81. A process for preparing the hydroxyprotected-1-[1-(4-bromophenyl)-2-
(dimethylamino)ethyl]cyclohexanol (BODV-P) of claim 76 comprising
combining BODV an organic solvent, a base and a protecting agent to create a
reaction mixture, and recovering the BODV-P from the reaction mixture.
82. The process of claim 81 wherein the organic solvent is ethyl acetate.
83. The process of claim 81 -82 wherein the process is performed under basic
conditions.
84. The process of claim 81-83 wherein the base is a C3-C9 trialkyl amine such
as
triethylamine, or imidazole or lutidine or pyridine or inorganic base such
K2CO3.
85. The process of claim 81-84 wherein the protecting agent is selected from
the
group consisting of: silyl, acetyl, DHP and derivatives thereof.
27

Description

CA 02656167 2008-12-22
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PROCESSES FOR THE SYNTHESIS OF O-DESMETHYLVENLAFAXINE
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] 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 March 13, 2007. The contents of these
applications
are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention encompasses a process for the synthesis of 0-
desmethylvenlafaxine.
BACKGROUND OF THE INVENTION
[0003] Venlafaxine, (f)-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:
CH3
N
HsC"
OH
H3C-O
Formula I
[0004] O-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," J. Clin. Pharmacol. 32:716-724 (1992).
0-
desmethylvenlafaxine has the following chemical formula, Formula II:
1

CA 02656167 2008-12-22
WO 2008/013994 PCT/US2007/017010
I
= N~
OH
I \
OH
C1eH25NOZ
Mol. Wt:263.38
Formula II
[0005] 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.
[0006] The synthesis disclosed in the above references is performed
according to the following scheme:
=. ~
. = =~- .
:. .= . . . .
. .. . . ;~; . .
.... . ...- . . = . .
. ,.
OMe .: . . : _ ; . =
= = ~ . ~
' ~; . .., ..... . . . . . , .
=.. .,=.
'.. ''~~ .:, : : = j .. = . : = I ;;;.~ '= ' ' . ~. = = ;;.==.
H~.=
e'= ue ian
. . ~
.
o = ==. . .
: =.
= / ` =' =CN = =. .
--_~
, ,.. = = ~ . = H
= ~ . . = = =
. ,,, = .. ~ . .
. . . . GN.
~. ,,. ' , . . .. . . ~ .
.~ :. .
_ , .= , .
MBtiC ~ _=... = ;GMBC': : . ; '. UDIMIT
OH<
..,....
..: .., , .,. ~. ~ . ~= .
~:'= -
=-. = . . .
~ =, ..=
. =.,
.. = .
.. . . r
..-= r = . = .. .
:{= -L -!. .= . ;:i% , ' ~ ' '~r ~a .
Met~h',lation ` ' =: ~' ~` -r`
De thylation'
! ~ .. ..,; t~ ,! _.;:;=~ , me -- =. 'y. ,~ ~ r
õy~G =
~ t ~ z .h h . H:O ;sHp ,
,> YHs N~C
. ~amine = , '= '=:; <; ' , p~henol '. ~ s~ = cIkNcH .. .. =~ii:.': . .. ;.
,Sy$ " . ~,~..:a, _ . .= - ' 1 = . ' =r` '
= . _ _ r~~ i..,:~a,~r,+.=' ~.. ; . t,;: :,; '
= ^ ' ~fV'enlsfa~on~e~='' :~:: == . . . . = : ===- - :. ~ :. =, _~=; =
= .. =.
. .. = =. . .,.
.. ~
y:.i: ^ ;=*: , _ , ~qr.5,.:,~.: r3~';~'~.. =r' ';. .. = ' = ~ = .
. . ,.. ... .
. ... .. = . ,
' ~:=, '~ :
Wherein "MBC" refers to methyl benzyl cyanide, "CMBC" refers to cyclohexyl
methylbenzyl cyanide, "DDMV' refers to didesmethyl venlafaxine, and "ODV"
refers to 0-desmethylvenlafaxine.
[0007] However, the processes disclosed in the above US patents and US
patent applications all remain problematic when applied to industrial scale
production.
The process in US Patent No. 7,026,508 uses L-selectride, a compound which is
very
2

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WO 2008/013994 PCT/US2007/017010
problematic when scaling up the process for industrial application. Further,
the
process disclosed in US Application Publication No. 2005/0197392 uses
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.
[0008] There is a need in the art for a new synthetic route for obtaining sO-
desmethylvenlafaxine, using a precursor of venlafaxine to directly obtain 0-
desmethylvenlafaxine.
SUMMARY OF THE INVENTION
[0009] In one embodiment, the invention encompasses (4-bromophenyl)(1-
hydroxycyclohexyl)acetonitrile (CBBC).
[00010] In one embodiment the present invention provides a process for
preparing CBBC comprising reacting BBC with cyclohexanone.
[00011] In another embodiment, the present invention provides a process for
preparing (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) comprising
precipitating CBBC from a mixture of: bromophenylacetonitrile (BBC), a dry
organic
solvent, a base and cyclohexanone.
[00012] ' In another embodiment, the present invention provides a process for
obtaining (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) from a
mixture
of bromophenylacetonitrile (BBC), a phase transfer catalyst, a base and
cyclohexanone.
[00013] In another embodiment, the present invention provides a process for
obtaining 0-desmethylvenlafaxine comprising preparing CBBC in any of the
methods
described above, and further converting the CBBC to 0-desmethylvenlafaxine.
[00014] -In another embodiment, the invention encompasses 1-[2-amino-l-(4-
bromophenyl)ethyl]cyclohexanol (BDDMV).
[00015] In another embodiment, the present invention provides a process for
preparing 1-[2-amino- I -(4-bromophenyl) ethyl] cyclohexanol (BDDMV)
comprising:
combining CBBC, an organic solvent and borane to create a reaction mixture,
followed by recovery of the BDDMV from the reaction mixture.
3

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[00016] In another embodiment, the present invention provides a process for
obtaining 0-desmethylvenlafaxine comprising preparing BDDMV as described
above, and further converting the BDDMV to 0-desmethylvenlafaxine.
[00017] In another embodiment, the invention encompasses
bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV).
[00018] In another embodiment, the present invention provides a process for
preparing 1-[l-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV)
comprising: combining BDDMV, formaldehyde and a reducing agent to create a
reaction mixture, followed by recovery of the BODV from the reaction mixture.
[00019] In another embodiment, the present invention provides a process for
preparing 1-[ 1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV)
comprising: combining BDDMV, an organic solvent, and a methylating agent to
form
a mixture, and recovering the BODV from the mixture.
[00020] In another embodiment, the present invention provides a process for
obtaining 0-desmethylvenlafaxine comprising preparing BODV in any of the
methods described above, and further converting the BODV to 0-
desmethylvenlafaxine.
[00021] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: combining BODV, a hydroxide donor
base and a metal salt to create a reaction mixture, followed by recovery of
the 0-
desmethylvenlafaxine from the reaction mixture.
[00022] In another embodiment, the present invention provides a process for
converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or
organocuprate reaction.
[00023] In one embodiment the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising combining BODV with Mg or Cu, and
an organic solvent to obtain a grignard reagent or an organocuprate reagent,
and
combining the reagent with borate and an acid to provide O-
desmethylventafaxine.
[00024] In another embodiment, the invention encompasses
hydroxyprotected-l-[ 1-(4-bromophenyl)-2-(dimethylarnino)ethyl]cyclohexanol
(BODV-P).
[00025] In another embodiment, the present invention provides a process for
preparing hydroxyprotected-l-[1-(4-bromophenyl)-2-
(dimethylamino)ethyl]cyclohexanol (BODV-P) comprising: combining BODV an
4

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organic solvent, a base and a protecting agent to create a reaction mixture,
and
recovering the BODV-P from the reaction mixture.
[00026] In another embodiment, the present invention provides a process for
obtaining 0-desmethylvenlafaxine comprising preparing BODV-P as described
above, and further converting the BODV-P to 0-desmethylvenlafaxine.
[00027] In another embodiment, the present invention provides a process for
converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or
organocuprate reaction. '
[00028] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: combining BODV-P, hydroxide donor
base and a metal salt to create a reaction mixture, followed by recovery of
the 0-
desmethylvenlafaxine from the reaction mixture.
[00029] The present invention further provides processes for preparing 0-
desmethylvenlafaxine via the intermediates described above.
DETAILED DESCRIPTION OF THE INVENTION
[00030] The invention encompasses a new synthetic route for obtaining 0-
desmethylvenlafaxine, from 4-bromophenylacetonitrile (BBC), (4-bromophenyl)(1-
hydroxycyclohexyl)acetonitrile (CBBC), 1-[2-amino-l-(4-
bromophenyl)ethyl]cyclohexanol (BDDMV), 1-[ 1-(4-bromophenyl)-2-
(dimethylamino)ethyl]cyclohexanol (BODV) and hydroxyprotected-1-[1-(4-
bromophenyi)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P).
[00031] In the process of the invention, the intermediate
bromophenylacetonitrile (BBC) is condensed with cyclohexanone to form the
intermediate (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile .(CBBC).
Further,
the cyano group on the CBBC is subjected to reduction, to form the
intermediate 1-[2-
amino-l-(4-bromophenyl)ethyl]cyclohexanol (BDDMV) which is then subjected to
selective alkylation to produce 1-[i-(4-bromophenyl)-2-
(dimethylamino)ethyl]cyclohexanol (BODV), which is finally converted to 0-
desmethylvenlafaxine (ODV), by performing halide exchange (optionally, the
final
conversion step can go via a protected BODV intermediate) as described in the
following scheme:

CA 02656167 2008-12-22
WO 2008/013994 PCT/US2007/017010
{F' r OH
' 'x~'`';. . ~';. ;~ ,F ==. .. ' ~~>'~ i: _ '=~
`.: "` ~ .;' _ : j ~ ~~ ~'. ~'' . ' ,'*', '' ` ' = ~' ` . .
= '~ =~ . . r Y~.~ ,''='_=~~~ ~~~' =~' :,>=! =' }'i ~ ~ ' TT. . ;Cu
.^.'~ ' _ T' ~ : ~CFi = ~ õ~07 ,
= er .~ =:, ' = . t rH_ ; s==:.K4:""~=; y '~'' N:' = = = ` = i, N~~
.. . .
. . õ .
~ c'0 ^.CN , :a:+ = `.,' ~}j~.,:
~CN. ~' ~'= s - =; ` '= =
~ ~ ~~= ' N~a - = ~~,: ~- ,:
ggC c~,gBC BODMV r BODV = > ~Oils~wnMtaxlna
i. ' .~;,...'!.+ '=.=. a?-?;',¾.:r' .;~-r+=.
; .= ~,=,.=: } sODV
!'=.'.l.' f e'~'~' = N:- ~ =.r . ,~~: .= S.=.~.}~,n.., =
= ;~: _ . :ik=.~. ;~~~ .¾.:.,.;~ ..
__ ..} ~,, . Fi' :F':+'..aFq , y=: i~.7 )L~` ~ ,/~ : . . ' . . = ~'' ~
'.' =s = :=. ''=?;a : #' \ . .,~.: "
.=
,e-.. , , =_ . . .r..p: 'i...=.....,.,. ~.:t:o:1= ,;: = + = .
.. .
,=.,. .
. . . .;~
< =
r . = . _
.. . .. '~
. . , . _. . .= i + .
=n ~ . =
= . . . 1..}+. ,.'- r~ ~ .
. . . .., .
.. + . =;; , . r r .a. . . (. . . . .. , . . ~, =
. . . . . . . . = ~, - . :; ?' =
. . ., .. = ,=%; .
., _ . = i. , ,n. 7 ~ x ~i ~ `'~i 9 .,i ~ {u _~~CM~ 'S~' .
. t. = .. '. ~ ~.~ t_,,~f.: _ .!{. r.y, = :.= ~ , ~.. _ '~' . ,; . , = = .
V~ = ' . .. ='.
' ~ r . ' ' '. ' . = ....... ..... . . . . . Ji.. ~. . . , . =, , . ,
where x is a suitable hydroxy protecting group.
[00032] The use of precursors of venlafaxine which contain a halogen
group, in the new synthetic route for obtaining 0-desmethylvenlafaxine, highly
improves the yield of the reaction.
[00033] In one embodiment, the invention encompasses (4-bromophenyl)(1-
hydroxycyclohexyl)acetonitrile (CBBC). Also provided is CBBC in isolated or
purified form. Isolated refers to being separated from the reaction mixture in
which it
forms. The CBBC may have a purity of at least about 50% as measured by HPLC.
The compound is characterized by N=1VIl2 'H (DMSO-d6) 8: 1.56 (4H, H
cycloheyl),
1.71 (2H, H cyclohexyl), 2.25 (2H, H cyclohexyl), 2.61 (2H, H cyclohexyl),
3.32 (1H,
CHCN), 7.27 (2H, H arom.), 7.65 (2H, H arom.).
[00034] The present invention also provides a process for preparing (4-
bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) by reacting BBC with
cyclohexanone
[00035] This process can comprise precipitating CBBC from a mixture of:
bromophenylacetonitrile (BBC), organic solvent, a base and cyclohexanone.
Preferably the organic solvent is dry. An organic solvent is dry if it 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 or reagents) in a manner that
prevents the
benefits of the present invention from being realized. Typically an organic
solvent
having less than 1% by water is considered to be dry by one of ordinary skill
of art.
[00036] Preferably, the dry organic solvent is selected from the group
consisting of: C4-8 ethers, polar aprotic solvents (Polarity Index of greater
than about
2.0), Cj-C8 chlorinated aliphatic, C6-'12 aromatic hydrocarbons, and C1_6
alcohols.
6

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More preferably, the ethers are selected from the group consisting of
diisopropyl
ether, diethyl ether, dioxane, tetrahydrofizran (THF), the polar aprotic
solvents are
selected from the group consisting of dimethylformamide (DMF),
dimethylacetamide
(DMA) and dimethylsulfoxide (DMSO), the chlorinated organic solvents are
selected
from the group consisting of methylene chloride and chlorobenzene or
chloroform
and the aromatic hydrocarbons are selected from the group consisting of
toluene and
benzene. Most preferably, the dry organic solvent is selected from the group
consisting of: tetrahydrofuran (THF), methanol, methylene chloride and
toluene. The
organic solvent can be used individually, or in a mixture with another
solvent,
particularly methanol_
[00037] . The base can be an inorganic base, such as an alkali metal or
alkaline
earth metal. More preferably, the base is selected from the group consisting
of:
lithium diisopropyl amide (LDA), lithium bis (trimethyl silyl) amide
(LiN[(CH3)3Si]2), potassium hydroxide (KOH), lithium hydroxide (LiOH), sodium
hydride (NaH), potassium tert butoxide (t-BuOK), lithium tert butoxide (t-
BuOLi),
butyl lithium (BuLi) and sodium methoxide (NaOCH3). The 'base is preferably
present in an amount of about 1 to about 5 moles per mole of BBC.
[00038] The process can be carried out by combining a solution or a slurry of
BBC and a dry organic solvent with a base to obtain a reaction mixture,
followed by
combining the reaction mixture with cyclohexanone, to obtain CBBC.
Cyclohexanone
can be added to the reaction mixture in a dropwise manner. After combining'rhe
reaction mixture with cyclohexanone, the mixture is further maintained, until
completion of the reaction.
[00039] CBBC may then be recovered. The solvent can be evaporated and
the residue dissolved in a water immiscible solvent such as toluene, EtOAc
(ethyl
acetate), CH2C12, diethyl ether, MTBE (methyl-t-butyl ether), MEK (methyl
ethyl
ketone) washed with water or brine, and evaporated to get an oil. The oil can
then be
added to an organic solvent such as methanol to obtain a solution and
crystallize
CBBC.
[00040] In another embodiment, the present invention provides a process for
obtaining (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) from a
mixture
of bromophenylacetonitrile (BBC), optionally a phase transfer catalyst, a base
and
cyclohexanone. The reaction may occur with or without the presence of an
organic
solvent or water. Preferably, the reaction occurs in the presence of water.
The use of
7

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water allows for obtaining a product that otherwise would be contaminated with
residual organic solvent.
[00041] The phase transfer catalyst can be a tetraalkylarnmonium,
tetraalkylphosphonium, tetraarylammonium or tetraarylphosphonium, preferably
wherein the alkyl group can be the same or different and contains from 1 to 10
carbons, and wherein the aryl group can be the same or different and contains
from 6
to 8 carbons.
[00042] The phase transfer catalyst can be a tetraalkylammonium halide,
preferably wherein the alkyl group can be the same or different and contains
from I to
6, preferably from 1 to 4 carbon atoms, and the halide is fluoride, chloride,
bromide or
iodide, preferably chloride, bromide or iodide.
[00043] Preferably, the phase transfer catalyst is selected from the group
consisting of: tetrabutylammonium hydrogensulphate, tetrabutylammonium
bromide,
tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltriethyl
ammonium
chloride, aliquot, quatemary ammonium salt, quaternary phosphonium salt and
crown
ether. More preferably, the phase transfer catalyst is tetra butyl anunonium
bromide
(TBAB).
[00044] The base may be an inorganic base, such as an alkali metal or
alkaline earth metal' hydroxide or carbonate, preferably, NaOH, KOH, LiOH,
CsOH,
K2C03 or NaCO3, Cs2CO3, KHCO3 or NaHCO3
[00045] BBC, cyclohexanone, the phase transfer catalyst such as TBr'1.B and
the base such as NaOH are combined. Preferably, the base is added in an amount
of
about 0.5 to about 1 mole per mole of BBC. The cyclohexanone is dded in an
amount
of about 1 to about 1.15 moles per mole of BBC. The reaction is then
maintained to
get CBBC. The reaction can be maintained from about 1 to about 24 hours. It
can
also be stirred while maintained.
[00046] In another embodiment, the present invention provides a process for
obtaining O-desmethylvenlafaxine comprising preparing CBBC in any of the
methods
described above, and further converting the CBBC to 0-desmethylvenlafaxine.
[00047] In another embodiment, the invention encompasses 1-[2-amino-l-(4-
bromophenyl)ethyl]cyclohexanol (BDDMV). Also provided is BDDMV in isolated
or purified form. Isolated refers to being separated from the reaction mixture
in
which it forms. The BDDMV may have a purity of at least about 50% as measured
by HPLC.
8

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[00048] BDDMV can be prepared by reacting CBBC with a reducing agent.
More specifically, BDDMV can be prepared by combining CBBC an organic solvent
such as THF to obtain a solution, to which a reducing agent is added.
Preferably the
solvent is a dry organic solvent, as described above, more preferably THF.
Chlorinated solvents, such as Cj-Cg chlorinated hydrocarbons and C4-C8 ethers
can
also be used. Preferably the reducing agent is borane or a hydride, more
preferably a
Borane dimethylsulfide complex, which is added dropwise. Preferably, the
borane is
piresent in an amount of about 1 to about 3 moles per mole of CBBC.
Alternatively,
the reducing agent may be H2 in presence of catalyst such as Ni or Co or Pt.
The
resulting reaction mixture can then be maintained, preferably for about lhr to
about
48 hrs, such as about 12 hours. This mixture can then be quenched such as by
adding
NH4C1 and hydrogen peroxide.
[00049] The BDDMV can then be recovered. The resulting layers may be
separated and the organic layer acidified, such as with citric acid.
Optionally, the
aqueous phase can be basified such as with NHaOH and extracted with
diethylether to
recover more of the product. The organic layer can then be washed with brine
or
water to remove water soluble impurities, and dried. Drying can be carried out
over
Na2SOa or under a pressure of less than one atmosphere, or both.
[00050] In another embodiment, the present invention provides a process for
obtaining 0-desmethylvenlafaxine comprising preparing BDDMV as described
above, and further converting the BDDMV to 0-desmethylvenlafaxine.
[00051] In another embodiment, the invention encompasses 1-[1-(4-
bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV). Also provided is
BODV in isolated or purified fonn. Isolated refers to being separated from the
reaction mixture in which it forms. The BODV may have a purity of at least
about
50% as measured by HPLC.
[00052] The present invention also provides a process for preparing 1-[1-(4-
bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV). BODV may be
prepared by reductive amination reaction of BDDMV and a formaldehyde source in
the presence of a reducing agent. In one embodiment this process comprises
combining BDDMV, formaldehyde and a reducing agent. BODV is then recovered
from the obtained reaction mixture.
[00053] BDDMV, such as that prepared above, can be dissolved or
suspended (preferably dissolved) in a C,-s alcohol such as MeOH. Formaldehyde,
9

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preferably in the form of a formalin solution is then added to obtain a
solution.
Formaldehyde in water can also be used as a solvent. A reducing agent,
preferably
NaBH4 or formic acid is then added. The reaction is an exothermic reaction, so
prior
to combining the sodium borohydride with the formaldehyde solution,
formaldehyde
solution is preferably cooled to a temperature of less than about 10 C.
Preferably, the
reaction mixture is maintained, while stirring, for about 1 to about 24 hours,
such as
about 12 hours. Preferably, the formaldehyde is present in an amount of from
about 1
mole per mole of BDDMV, to an excess amount, such as about 50 moles.
Preferably,
the sodium borohydride is present in an amount of about 1 mole per mole of
BDDMV.
[00054] The BODV can= then be recovered. Recovery can be carried out by
evaporating the organic solvent, such as under reduced pressure, to obtain a
residue.
The residue can then be dissolved in a water immiscible organic solvent such
as
methylene chloride EtOAc, toluene, MEK, TBME, diethyl ether and acidified to a
pH
of about 2 to about 6. An inorganic acid such as HC1 or H2SO4 can be used.
Optionally the aqueous phase is basified to a pH of about 8 to about 10 to
facilitate
extraction of additional amounts of BODC. NH4OH can be used as a base and
methylene chloride as a solvent for extraction. The organic phase can then be
evaporated, such as under a pressure of less than about one atmosphere, to
obtain
BODV.
[00055] BODV can also be prepared by a process which comprises
combining BDDMV, an organic solvent, and a methylating agent. BODV is then
recovered from the obtained reaction mixture.
[00056] BDDMV, such as that prepared above, is dissolved in an organic
solvent, preferably dichloromethane or dimethylsulfoxide. Optionally a base is
added
to the solution. The base can be BuLi or a C3-C9 trialkylamine such as
triethylamine.
Alkali metal or alkaline earth metal hydrides or hydroxides such as NaH and
NaOH
can also be used. If an inorganic base is used, an inert organic solvent may
also be
added. For example, with BuLi can be added as a solution in a C5-C12 saturated
(aliphatic) or aromatic hydrocarbon, such as hexane. A methylating agent is
added.
Preferably the methylating agent is a methyl halide, preferably, methyl
iodide.
Dimethylsulfate can also be used. The reaction can be done as neat reaction,
methyliodide being the solvent and the reagent. Preferably, the organic
solvent is
dichloromethane or dimethylsulfoxide or THF. The mixture can then be
maintained

CA 02656167 2008-12-22
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for about 30 minutes to about 16 hours to obtain BODV. The BODV can then be
recovered.
[00057] In another embodiment, the present invention provides a process for
obtaining 0-desmethylvenlafaxine comprising preparing BODV in any of the
methods described above, and further converting the BODV to 0-
desmethylvenlafaxine.
[00058] ' In another embodiment, the present invention provides a process for
prepariiig 0-desmethylvenlafaxine comprising: combining BODV, a hydroxide
donor
base and a metal salt to create a reaction mixture, followed by recovery of
the 0-
desmethylvenlafaxine from the reaction mixture.
[00059] Preferably, the hydroxide donor base is an alkali metal or alkaline
earth metal hydroxide, such as potassium hydroxide (KOH), lithium hydroxide
(LiOH), sodium hydroxide (NaOH), cesium hydroxide. Preferably, the metal salt
is
silver nitrate (AgNO3). Optionally, the AgNO3 is employed into the reaction
mixture,
as a. supported AgNO3. The term "supported AgNO3" as used herein refers to
Montmorillonite. Silica can also be used as support. Montmorillonite is a very
soft
phyllosilicate mineral that typically forms in microscopic crystals, forming a
clay.
Preferably, the hydroxide donor base is present in an amount of about i to
about 20
moles per mole of BODV. Preferably, the metal salt is present in an amount of
about
I to about 20 by weight of BODV.
[00060] As exemplified, to a solution of AgNO3 in water montmorillonite is
added and the resulting mixture is heated. Heating is preferably carried out
to a
temperature of about 40 to about 150 C, such as about 100 C for 1 hour. The
solution can then be dried, such as by heating, or reducing the.pressure to
less than
about one atmosphere. Then, BODV, and a base such as NaOH and the supported
AgNO3 are combined. Preferably, the reaction mixture is heated to a
temperature of
above 20 C; more preferably, the reaction mixture is heated to about 100 C.
Preferably, the obtained reaction mixture is maintained, while stirring, for
about 18
hours. ODV can then be extracted from the reaction mixture with an organic
solvent,
such as with a mixture of chloroform and methanol. Other solvents such as
EtOAc,
THF, or acetone can also be used.
[00061] The present invention further provides a process for converting
BODV to 0-desmethylvenlafaxine, using a Grignard reaction or a organocuprate
reaction. In one embodiment, BODV is combined with Mg, a halogen (only Mg or
11

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Cu in case of organo cuprate reaction) and a dry organic solvent to provide a
Grignard
reagent. Such synthetic step is known by one skilled in the art as Grignard
reaction.
The Grignard reagent is then combined with borate and an acid to provide 0-
desmethylvenlafaxine.
[00062] In one embodiment,_Mg and a halogen such as I2 are combined with
BODV in an inert solvents organic solvent such as THF, CH2Cla, ACN, ethers.
The
BODV can be added dropwise. The mixture can then be heated, such as to a
temnerature of about 30 to about reflux, more preferably about reflux. Before
adding
borate, the mixture is preferably cooled, such as to about -20C to about IOC,
pref~rably about -lOC. Trimethylborate is then added. After stirring an
organic or
inorganic acid, such as glacial acetic acid is added. The reaction mixture can
then be
quenched, such as by adding hydrogen peroxide. For recovery, a water
immiscible
solvents organic solvent, such as Diethylether, EtOAc, TBME, toluene, MEK, is
added to the reaction mixture to obtain ODV. The solvent can then be rmoved
such
as by reducing the pressure to less than one atmosphere.
[00063] Optionally, the new synthetic route for obtaining O-
-desmethylvenlafaxine can go via a protected intermediate of BODV.
[00064] The protected intermediate of BODV may contain any suitable
hydroxyl protecting group, such as silyl, acetyl and dihydropyran (DHP).
[00065] In another embodiment, the invention encompasses
hydroxyprotected-l-[1-(4-bromophenyl)-2-(dimethylamino)ethyljcyclohexanol
(BODV-P). Preferably, the BODV is protected with an acetyl. Also provided is
BODV-P, particularly acetyl protected, in isolated or purified form. Isolated
refers to
being separated from the reaction mixture in which it forms. The BODV-P
including
acetyl- protected may have a purity of at least about 50% as measured by HPLC.
[00066] In another embodiment, the present invention provides a process for
preparing hydroxyprotected-l-[ 1-(4-bromophenyl)-2-
(dimethylamino)ethyl]cyclohexanol (BODV-P) comprising: combining BODV an
organic solvent, a base and a protecting agent to create a reaction mixture,
and
recovering the BODV-P from the reaction mixture.
[00067] Typically, the solvent used can be any organic solvent. Preferably,
the organic solvent is ethyl acetate. Other organic solvents such as CH2C12,
ethers
such THF, toluene, hexane or ACN can also be used.
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[00068] Preferably, the process is performed under basic conditions.
Typically, the basic source is organic or inorganic base. Preferably, the
basic source is
a C3-C9 trialkyl amine such as triethylamine or imidazole or lutidine or
pyridine. An
inorganic base such as an alkali metal or alkaline earth metal carbonate such
as
K2C03 can also be used,
[00069] Preferably, the protecting= agent is selected from the group
consisting
of: silyl, acetyl, DHP and derivatives thereof. More preferably, the
protecting agent is
acetyl chloride oir acetic anhydride. The reaction mixture is optionally
maintained for
about 30 minutes to about 24 hours to obtain BODV-P. BODV-P may then be
recovered from the reaction mixture by any method known in the art.
[00070] One of ordinary skill of art would appreciate that each of the above
processes described for preparation of CBBC, BDDMV, BODV, BODV-P and ODV
can be combined. Such combination can be combining the process of of CBBC,
with
BDDMV to prepare BODV, and further to prepare BODV-P if desired, and further
to
prepare ODV. Such process can also start with BDDMV, BODV or BODV-P. Such
combinations are provided in further detail below.
[00071] In another embodiment, the present invention provides a process for
obtaining 0-desmethylvenlafaxine comprising preparing BODV-P as described
above, and further converting the BODV-P to 0-desmethylvenlafaxine.
[00072] In another embodiment, the present invention provides a process for
converting BODV-P to 0-desmethylvenlafaxine, using a Grignard reaction.
[00073] The conversion can be performed as described above for BODV.
[00074] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: combining BODV-P, a hydroxide
donor base and a metal salt. 0-desmethylvenlafaxine is then be recovered from
the
reaction mixture.
[00075] The hydroxide donor base and a metal salt used in the reaction are as
described above.
[00076] One of ordinary skill of art would appreciate that each of the above
processes described for preparation of CBBC, BDDMV, BODV, BODV-P and ODV
can be combined. Such combination can be combining the process of of CBBC,
with
BDDMV to prepare BODV, and further to prepare BODV-P if desired, and further
to
prepare ODV. Such process can also start with BDDMV, BODV or BODV-P. Such
combinations are provided in further detail below.
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[00077] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: precipitating CBBC from a mixture
of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create
a
reaction mixture, recovering BODV from the reaction mixture; combining BODV, a
hydroxide donor base and a metal salt to create a reaction mixture and
recovering 0-
desmethylvenlafaxine from the reaction mixture.
[00078] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: precipitating CBBC from a mixture
of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create
a
reaction mixture, recovering BODV from the reaction mixture; combining BODV.an
organic solvent, a base and a protecting agent to create a reaction mixture;
recovering
BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and
a metal salt to create a reaction mixture and recovering 0-
desmethylvenlafaxine from
the reaction mixture.
[00079] In another embodinient, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: precipitating CBBC from a mixture
o.f BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create
a
reaction mixture, recovering BODV from the reaction mixture and converting
BODV
to 0-desmethylvenlafaxine, using a Grignard reaction or organocuprate
reaction.
[00080] Tn another embodiment, the present invention provides a process for
preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture
of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create
a
reaction mixture, recovering BODV from the reaction mixture; combining BODV an
organic solvent, a base and a protecting agent to create a reaction mixture;
recovering
BODV-P from the reaction mixture and converting BODV-P to 0-
desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
14

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[00081] - In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: precipitating CBBC from a mixture
of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, an organic solvent, and a methylating agent
to
form a niixture; recovering the BODV from the mixture; combining BODV, a
hydroxide donor base and a metal salt to create a reaction mixture and
recovering O-
desmethylvenlafaxirie from the reaction mixture.
[00082] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: precipitating CBBC from a mixture
of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, an organic solvent, and a methylating agent
to
form a mixture; recovering the BODV from the mixture; combining BODV an
organic solvent, a base and a protecting agent to create a reaction mixture;
recovering
BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and
a metal salt to create a reaction mixture and recovering 0-
desmethylvenlafaxine from
the reaction mixture.
[00083] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: precipitating CBBC from a mixture
of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, an organic solvent, and a methylating agent
to
form a mixture; recovering the BODV from the mixture and converting BODV to 0-
desmethylvenlafaxine, using a Grignard reaction.
[00084] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: precipitating CBBC from a mixture
of: BBC, a. dry organic solvent, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, an organic solvent, and a methylating agent
to
form a mixture; recovering the BODV from the mixture; combining BODV an
organic solvent, a base and a protecting agent to create a reaction mixture;
recovering
BODV-P from the reaction mixture and converting BODV-P to 0-
desmethylvenlafaxine, using a Grignard reaction.

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[00085] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of
BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create
a
reaction mixture, recovering BODV from the reaction mixture; combining BODV, a
hydroxide donor base and a metal salt to create a reaction mixture and
recovering 0-
desmethylvenlafaxine frum the reaction mixture.
[00086] In another embodiment, the present invention provides a process for
preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of
BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create
a
reaction mixture, recovering BODV from the reaction mixture; combining BODV an
organic solvent, a base and a protecting agent to create a reaction mixture;
recovering
BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and
a metal salt to create a reaction mixture and recovering 0-
desmethylvenlafaxine from
the reaction mixture.
[00087] In another embodiment, the present invention provides a process for
preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of
BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction rriixture, recovering BDDMV
from the
reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create
a
reaction mixture, recovering BODV from the reaction mixture and converting
BODV
to 0-desmethylvenlafaxine, using a Grignard reaction or organocuprate
reaction_
[00088] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of
BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create
a
reaction mixture, recovering BODV from the reaction mixture; combining BODV an
organic solvent, a base and a protecting agent to create a reaction mixture;
recovering
BODV-P from the reaction mixture and converting BODV-P to 0-
desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction..
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[00089] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of
BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, an organic solvent, and a methylating agent
to
form a mixture; recovering the BODV from the mixture; combining BODV, a
hydroxide donor base and a metal salt to create a reaction mixture and
recovering 0-
desmethylvenlafaxine frorii the reaction mixture.
[00090] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of
BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, an organic solvent, and a methylating agent
to
form a mixture; recovering the BODV from the mixture; combining BODV an
organic solvent, a base and a protecting agent to create a reaction mixture;
recovering
BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and
a metal salt to create a reaction mixture and recovering 0-
desmethylvenlafaxine from
the reaction mixture.
[00091] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of
BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, an organic solvent, and a methylating agent
to
form a mixture; recovering the BODV from the mixture and converting BODV to 0-
desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction..
[00092] In another embodiment, the present invention provides a process for
preparing 0-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of
BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an
organic solvent and borane to create a reaction mixture, recovering BDDMV from
the
reaction mixture; combining BDDMV, an organic solvent, and a methylating agent
to
form a mixture; recovering the BODV from the mixture; combining BODV an
organic solvent, a base and a protecting agent to create a reaction mixture;
recovering
BODV-P from the reaction mixture and converting BODV-P to 0-
desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction..
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[00093] The invention in certain of its embodiments is illustrated by the
following non-limiting examples.
EXAMPLES
Preparation of CBBC
Example I
A 250 ml three necked flask equipped with nitrogen inlet, thermometer and
mechanical stirrer was charged slowly with MeOH (50 ml) and NaOCH3(10 g, 185
mmol) at ambient temperature. DMF (4 ml) and Bromophenylacetonitrile (20 g,
102
mmol) were added. The reaction mixture was stirred at ambient temperature
until
complete dissolution. Cyclohexanone (20 g, 203 mmol) was then added dropwise
and
the reaction was stirred at ambient temperature overnight. The solvent was
evaporated
and the residue was dissolved in toluene, washed with brine and evaporated to
get an
oil which on crystallization from MeOH yielded CBBC.
Example 2
A 100 ml three necked flask equipped with, thermometer and mechanical stirrer
is
charged with BBC (2g, 10 mmol), cyclohexanone (2 g, 20.3 mmol), TBAB (0.2g)
and
NaOH (6ml 10%). The reaction is stirred at RT overnight to get CBBC.
Preparation of BDDMV
Example 3
A 250m1 three necked flask equipped with nitrogen inlet, thermometer and
mechanical stirrer was charged with CBBC (7 g, 23.79 mmol) and THF (100 ml).
This solution was stirred at ambient temperature. Then a solution of Borane
dimethylsulfide complex (20 ml 2M in THF, 39.89mmol) was added dropwise. This
mixture was stirred overnight at ambient temperature and poured into saturated
solution of NH4Cl. A 30% solution of hydrogen peroxide was then added. The
layers
were separated and the organic layer was acidified with citric acid.
The aqueous phase was basified with NH4OH and extracted with diethylether. The
organic layer was then washed with brine, dried over Na2SO4 and evaporated
under
reduced pressure to get BDDMV.
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Preparation of BODV
Example 4
BDDMV (0.81 g, 2.72 mmol) was dissolved in MeOH (20m1). A formalin solution
(1.3 ml, 16.25 mmol) was added and the solution was cooled with an ice bath.
To the
cold solution NaBH4 (0.25 g, 6.5mmol) was added. The reaction mixture was
stirred
at ambient temperature overnight and the solvent was then evaporated under
reduced
pressure. The residue was dissolved in methylene chloride and acidified with
10%
HCI. The aqueous phase was basifie5d with NH4OH and extracted with methylene
chloride. The organic phase was then evaporated under reduced pressure to get
BODV.
Example 5
BDDMV (0.2g, 0.68 mmol) is dissolved in DMSO (2.5 ml). The solution is cooled
into an ice bath causing its solidification. 1.6 M BuLi solution in hexane
(0.4 mmol) is
added, and the temperature is allowed to heat to room temperature. Then Mel
(0.25
mmol) is added. The reaction mixture is stirred until we get BODV (HPLC
monitoring).
Example 6
BDDMV (0.5 g, 1.67 mmol) is suspended in CH2C12. Methyl Iodide (2.65 mmol) and
Triethylamine (2.9 mmol) are added. The reaction mixture is stirred under
nitrogen
atmosphere at room temperature for 6 hours. At this stage MeI (5 nunol) and
NEt3 (3
ml) are added. The addition caused the temperature to rise. After 16 hours,
the
analysis shows the presence of BODV.
Preparation of ODV from BODV
Example 7
Preparation of supported AgNO3:
To a solution of AgNO3 (3.38g in 100 ml H20), montmorillonite Kl0 (15 g) was
added and the mixture was stirred for 30 min. at ambient temperature. The
solution
was then evaporated to dryness and the residue was dried in an oven at 100 C
for 1
hour.
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0.4 g of BODV (1.26 mmol), 0.2g of NaOH (5 mmol) and 2 g of supported AgNO3
were mixed thoroughly in a mortar. The mixture was heated to 100 C overnight
under
mechanical stirring. The mixture was then extracted with chloroform and with
methanol to get ODV.
Example 8
A 100ml three-necked flask equipped with nitrogen inlet, thermometer,
mechanical
stirrer and condenser was charged with Mg (0.2 g, 8.23 mmol) and I2 (0.1 g
0.39
mmol). BODV (0.3 g, 0.92 mmol) in THF (30 ml) was added dropwise and the
mixture was heated to reflux for 1 hour. The mixture was cooled to -10 C and
trimethylborate (1 ml, 8.8 mmol) was added. After stirring for 30 min glacial
acetic
acid (2m1, 34.9 mmol) was added. Then a cold solution of 30% hydrogen peroxide
(2ml 19.64nunol) was also added. Diethylether was added and the organic phase
was
filtered to get ODV.
Preparation of BODV-P
Example 9
A 100ml three-necked flask equipped with Nitrogen inlet, thermometer,
mechanical
stirred and condenser was charged with BODV (0.37g 1.1.3mmo1), EtOAc (20m1)
and
Et3N (lml 7.16mmol). Acetylchioride (lmi 14mmo1) was added slowly. The
reaction
mixture was stirred 1 hour at ambient temperature and the organic phase was
washed
with water, dried over magnesium sulfate and evaporated to get BODV-P.
Preparation of ODV from BODV-P
Examnle 10
A 250ml three-necked flask equipped with Nitrogen inlet, thermometer,
mechanical
stirred and condenser was charged with Mg (0.7g, 28.80 mmol) and 12 (0.2 g
0.78
mmol). BODV-P (1g, 2.71 mmol) in THF (30m1) was added dropwise and the
mixture was heated to reflux for 2hours. The mixture was then cooled to -10 C
and
trimethylborate (20m1, 176 mmol) was added. After stirring for 30 min at this
temperature glacial acetic acid (15 ml, 261.75 mmol) was added. Then a cold
solution
of 30%hydrogen peroxide (20 ml 196.4 mmol) was added. The organic phase was
washed with saturated ferrous ammonium sulfate, dried over magnesium sulfate
and
concentrated to get ODV.

CA 02656167 2008-12-22
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Example 11 Preparation of supported AgNO3:
To a solution of AgNO3 (3.38g in 100 ml H20), mdntmorillonite K10 (15 g) is
added
and the mixture is stirred for 30 min. at ambient temperature. The solution is
then
evaporated to dryness and the residue is dried in an oven at 100 C for 1 hour_
0.4 g of P-BODV, 0.2g of NaOH (5 mmol) anci 2 g of supported AgNO3 are mixed
thoroughly in a mortar. The mixture is heated to 100 C ovemight under
mechanical
stirring. The mixture is then extracted with chloroform and with methanol to
get
ODV.
21