U.S. patent application number 11/881825 was filed with the patent office on 2008-07-24 for processes for the synthesis of o-desmethylvenlafaxine.
Invention is credited to Tamar Nidam, Valerie Niddam-Hildesheim.
Application Number | 20080177110 11/881825 |
Document ID | / |
Family ID | 38924359 |
Filed Date | 2008-07-24 |
United States Patent
Application |
20080177110 |
Kind Code |
A1 |
Niddam-Hildesheim; Valerie ;
et al. |
July 24, 2008 |
Processes for the synthesis of O-desmethylvenlafaxine
Abstract
Provides are intermediates and processes for preparation of
o-desmethylvenlafaxine.
Inventors: |
Niddam-Hildesheim; Valerie;
(Kadima, IL) ; Nidam; Tamar; (Yehud, IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
38924359 |
Appl. No.: |
11/881825 |
Filed: |
July 26, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60833616 |
Jul 26, 2006 |
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60837879 |
Aug 14, 2006 |
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60849216 |
Oct 3, 2006 |
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60843998 |
Sep 11, 2006 |
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60849255 |
Oct 3, 2006 |
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60906639 |
Mar 12, 2007 |
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60906879 |
Mar 13, 2007 |
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Current U.S.
Class: |
564/316 ;
568/705 |
Current CPC
Class: |
A61P 25/24 20180101;
C07C 235/34 20130101; C07C 2601/14 20170501 |
Class at
Publication: |
564/316 ;
568/705 |
International
Class: |
C07C 209/00 20060101
C07C209/00; C07C 255/35 20060101 C07C255/35 |
Claims
1. (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC).
2-3. (canceled)
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: C.sub.2-8 ethers, polar aprotic
solvents (Polarity Index of greater than about 2.0),
C.sub.1-C.sub.8 chlorinated aliphatic and aromatic,
C.sub.6-C.sub.12 aromatic hydrocarbons, and C.sub.1-6 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 claim 5, wherein the organic solvent contains
less than 1% water by volume.
10. The process of claim 5, wherein the base is an alkali metal or
alkaline earth metal.
11. The process of claim 5, wherein the base is selected from the
group consisting of: lithium diisopropyl amide (LDA), lithium
bis(trimethyl silyl) amide (LiN[(CH.sub.3).sub.3Si].sub.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
(NaOCH.sub.3).
12. The process of claim 5, wherein the process is 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.
13. The process of claim 5, further comprising recovering CBBC.
14. The process of claim 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 claim 13, further comprising crystallizing CBBC
from the residue.
16. The process of claim 4, 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 claim 16, 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 claim 16, wherein the phase transfer catalyst is
selected from the group consisting of: tetrabutylammonium
hydrogensulphate, tetrabutylammonium bromide, tetrabutylammonium
chloride, tetrabutylammonium iodide, benzyltriethyl ammonium
chloride, aliquot, quaternary ammonium salt, quaternary phosphonium
salt and crown ether.
20. The process of claim 16, wherein the phase transfer catalyst is
tetra butyl ammonium bromide (TBAB).
21. The process of claim 5, wherein the base is an alkali metal or
alkaline earth metal hydroxide or carbonate.
22. The process of claim 16, wherein the base is NaOH, KOH, LiOH,
CsOH, K.sub.2CO.sub.3, NaCO.sub.3 or Cs.sub.2CO.sub.3
23. A process for preparing O-desmethylvenlafaxine comprising
preparing CBBC as described in claim 4, and further converting the
CBBC to O-desmethylvenlafaxine.
24. 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV).
25-26. (canceled)
27. A process for preparing a compound according to claim 24
comprising reacting CBBC with a reducing agent.
28-37. (canceled)
38. 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol
(BODV).
39-40. (canceled)
41. A process for preparing the compound of claim 38 comprising
combining BDDMV, formaldehyde and a reducing agent.
42-46. (canceled)
47. A process for preparing the compound of claim 38 comprising
combining BDDMV, an organic solvent, and a methylating agent.
48-55. (canceled)
56. A process for preparing O-desmethylvenlafaxine comprising
preparing BODV according to claim 47, and further converting the
BODV to O-desmethylvenlafaxine.
57. A process for preparing O-desmethylvenlafaxine comprising
hydrolyzing BODV of claim 38.
58. A process for preparing O-desmethylvenlafaxine comprising:
combining BODV of claim 38, a hydroxide donor base and a metal salt
to obtain a reaction mixture, followed by recovery of the
O-desmethylvenlafaxine from the reaction mixture.
59-65. (canceled)
66. A process for preparing O-desmethylvenlafaxine comprising
combining BODV of claim 38 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.
67-72. (canceled)
73. The process of any of claims 56-58 and 66 which synthesize
O-desmethylvenlafaxine, wherein a hydroxyl protected BODV is used
to synthesize O-desmethylvenlafaxine.
74-75. (canceled)
76.
Hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohex-
anol (BODV-P).
77-80. (canceled)
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.
82-85. (canceled)
86. A process for preparing O-desmethylvenlafaxine comprising
preparing BODV according to claim 41, and further converting the
BODV to O-desmethylvenlafaxine
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of the following
U.S. Provisional Patent Application Nos. 60/833,616, filed Jul. 26,
2006; 60/837,879, filed Aug. 14, 2006; 60/849,216, filed Oct. 3,
2006; 60/843,998, filed Sep. 11, 2006; 60/849,255, filed Oct. 3,
2006; 60/906,639, filed Mar. 12, 2007; and 60/906,879, filed Mar.
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
O-desmethylvenlafaxine.
BACKGROUND OF THE INVENTION
[0003] Venlafaxine,
(.+-.)-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:
##STR00001##
[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).
O-desmethylvenlafaxine has the following chemical formula, Formula
II:
##STR00002##
[0005] Processes for the synthesis of O-desmethylvenlafaxine,
comprising a step of demethylation of the methoxy group of
venlafaxine, are described in U.S. Pat. Nos. 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:
##STR00003##
Wherein "MBC" refers to methyl benzyl cyanide, "CMBC" refers to
cyclohexyl methylbenzyl cyanide, "DDMV" refers to didesmethyl
venlafaxine, and "ODV" refers to O-desmethylvenlafaxine.
[0007] However, the processes disclosed in the above U.S. patents
and U.S. patent applications all remain problematic when applied to
industrial scale production. The process in U.S. Pat. No. 7,026,508
uses L-selectride, a compound which is very 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 U.S. Pat. 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 O-desmethylvenlafaxine.
SUMMARY OF THE INVENTION
[0009] In one embodiment, the invention encompasses
(4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC).
[0010] In one embodiment the present invention provides a process
for preparing CBBC comprising reacting BBC with cyclohexanone.
[0011] 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.
[0012] 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.
[0013] 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 O-desmethylvenlafaxine.
[0014] In another embodiment, the invention encompasses
1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV).
[0015] In another embodiment, the present invention provides a
process for preparing
1-[2-amino-1-(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.
[0016] In another embodiment, the present invention provides a
process for obtaining O-desmethylvenlafaxine comprising preparing
BDDMV as described above, and further converting the BDDMV to
O-desmethylvenlafaxine.
[0017] In another embodiment, the invention encompasses
1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol
(BODV).
[0018] In another embodiment, the present invention provides a
process for preparing
1-[1-(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.
[0019] 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.
[0020] In another embodiment, the present invention provides a
process for obtaining O-desmethylvenlafaxine comprising preparing
BODV in any of the methods described above, and further converting
the BODV to O-desmethylvenlafaxine.
[0021] In another embodiment, the present invention provides a
process for preparing O-desmethylvenlafaxine comprising: combining
BODV, a hydroxide donor base and a metal salt to create a reaction
mixture, followed by recovery of the O-desmethylvenlafaxine from
the reaction mixture.
[0022] In another embodiment, the present invention provides a
process for converting BODV to O-desmethylvenlafaxine, using a
Grignard reaction or organocuprate reaction.
[0023] In one embodiment the present invention provides a process
for preparing O-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-desmethylvenlafaxine.
[0024] In another embodiment, the invention encompasses
hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol
(BODV-P).
[0025] In another embodiment, the present invention provides a
process for preparing
hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cy-
clohexanol (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.
[0026] In another embodiment, the present invention provides a
process for obtaining O-desmethylvenlafaxine comprising preparing
BODV-P as described above, and further converting the BODV-P to
O-desmethylvenlafaxine.
[0027] In another embodiment, the present invention provides a
process for converting BODV-P to O-desmethylvenlafaxine, using a
Grignard reaction or organocuprate reaction.
[0028] In another embodiment, the present invention provides a
process for preparing O-desmethylvenlafaxine comprising: combining
BODV-P, hydroxide donor base and a metal salt to create a reaction
mixture, followed by recovery of the O-desmethylvenlafaxine from
the reaction mixture.
[0029] The present invention further provides processes for
preparing O-desmethylvenlafaxine via the intermediates described
above.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The invention encompasses a new synthetic route for
obtaining O-desmethylvenlafaxine, from 4-bromophenylacetonitrile
(BBC), (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC),
1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV),
1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV) and
hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol
(BODV-P).
[0031] 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-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV)
which is then subjected to selective alkylation to produce
1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV),
which is finally converted to O-desmethylvenlafaxine (ODV), by
performing halide exchange (optionally, the final conversion step
can go via a protected BODV intermediate) as described in the
following scheme:
##STR00004##
where x is a suitable hydroxy protecting group.
[0032] The use of precursors of venlafaxine which contain a halogen
group, in the new synthetic route for obtaining
O-desmethylvenlafaxine, highly improves the yield of the
reaction.
[0033] 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 NMR .sup.1H (DMSO-d.sub.6)
.delta.: 1.56 (4H, H cyclohexyl), 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.).
[0034] The present invention also provides a process for preparing
(4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) by reacting
BBC with cyclohexanone
[0035] 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.
[0036] Preferably, the dry organic solvent is selected from the
group consisting of: C.sub.4-8 ethers, polar aprotic solvents
(Polarity Index of greater than about 2.0), C.sub.1-C.sub.8
chlorinated aliphatic, C.sub.6-C.sub.12 aromatic hydrocarbons, and
C.sub.1-6 alcohols. More preferably, the ethers are selected from
the group consisting of: diisopropyl ether, diethyl ether, dioxane,
tetrahydrofuran (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.
[0037] 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[(CH.sub.3).sub.3Si].sub.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 (NaOCH.sub.3).
The base is preferably present in an amount of about 1 to about 5
moles per mole of BBC.
[0038] 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 the reaction
mixture with cyclohexanone, the mixture is further maintained,
until completion of the reaction.
[0039] 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), CH.sub.2Cl.sub.2, 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.
[0040] 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 water allows for obtaining a product that otherwise would be
contaminated with residual organic solvent.
[0041] The phase transfer catalyst can be a tetraalkylammonium,
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.
[0042] The phase transfer catalyst can be a tetraalkylammonium
halide, preferably wherein the alkyl group can be the same or
different and contains from 1 to 6, preferably from 1 to 4 carbon
atoms, and the halide is fluoride, chloride, bromide or iodide,
preferably chloride, bromide or iodide.
[0043] Preferably, the phase transfer catalyst is selected from the
group consisting of: tetrabutylammonium hydrogensulphate,
tetrabutylammonium bromide, tetrabutylammonium chloride,
tetrabutylammonium iodide, benzyltriethyl ammonium chloride,
aliquot, quaternary ammonium salt, quaternary phosphonium salt and
crown ether. More preferably, the phase transfer catalyst is tetra
butyl ammonium bromide (TBAB).
[0044] The base may be an inorganic base, such as an alkali metal
or alkaline earth metal hydroxide or carbonate, preferably, NaOH,
KOH, LiOH, CsOH, K.sub.2CO.sub.3 or NaCO.sub.3, Cs.sub.2CO.sub.3,
KHCO.sub.3 or NaHCO.sub.3
[0045] BBC, cyclohexanone, the phase transfer catalyst such as TBAB
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 added 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.
[0046] 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 O-desmethylvenlafaxine.
[0047] In another embodiment, the invention encompasses
1-[2-amino-1-(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.
[0048] 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 C.sub.1-C.sub.8 chlorinated hydrocarbons and
C.sub.4-C.sub.8 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 present in an amount of about 1 to about 3 moles per mole
of CBBC. Alternatively, the reducing agent may be H.sub.2 in
presence of catalyst such as Ni or Co or Pt. The resulting reaction
mixture can then be maintained, preferably for about 1 hr to about
48 hrs, such as about 12 hours. This mixture can then be quenched
such as by adding NH.sub.4Cl and hydrogen peroxide.
[0049] 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
NH.sub.4OH 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 Na.sub.2SO.sub.4 or under a pressure of less than
one atmosphere, or both.
[0050] In another embodiment, the present invention provides a
process for obtaining O-desmethylvenlafaxine comprising preparing
BDDMV as described above, and further converting the BDDMV to
O-desmethylvenlafaxine.
[0051] In another embodiment, the invention encompasses
1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV).
Also provided is BODV in isolated or purified form. 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.
[0052] 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.
[0053] BDDMV, such as that prepared above, can be dissolved or
suspended (preferably dissolved) in a C.sub.1-4 alcohol such as
MeOH. Formaldehyde, 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 NaBH.sub.4 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.degree. 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.
[0054] 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 HCl 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.
NH.sub.4OH 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.
[0055] 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.
[0056] 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 C.sub.3-C.sub.9 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 C.sub.5-C.sub.12 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 for
about 30 minutes to about 16 hours to obtain BODV. The BODV can
then be recovered.
[0057] In another embodiment, the present invention provides a
process for obtaining O-desmethylvenlafaxine comprising preparing
BODV in any of the methods described above, and further converting
the BODV to O-desmethylvenlafaxine.
[0058] In another embodiment, the present invention provides a
process for preparing O-desmethylvenlafaxine comprising: combining
BODV, a hydroxide donor base and a metal salt to create a reaction
mixture, followed by recovery of the O-desmethylvenlafaxine from
the reaction mixture.
[0059] 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
(AgNO.sub.3). Optionally, the AgNO.sub.3 is employed into the
reaction mixture, as a supported AgNO.sub.3. The term "supported
AgNO.sub.3" 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 1 to about 20 moles per mole of BODV.
Preferably, the metal salt is present in an amount of about 1 to
about 20 by weight of BODV.
[0060] As exemplified, to a solution of AgNO.sub.3 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.degree. C., such as about 100.degree. 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 AgNO.sub.3 are combined. Preferably,
the reaction mixture is heated to a temperature of above 20.degree.
C.; more preferably, the reaction mixture is heated to about
100.degree. 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.
[0061] The present invention further provides a process for
converting BODV to O-desmethylvenlafaxine, using a Grignard
reaction or a organocuprate reaction. In one embodiment, BODV is
combined with Mg, a halogen (only Mg or 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 O-desmethylvenlafaxine.
[0062] In one embodiment, Mg and a halogen such as I.sub.2 are
combined with BODV in an inert solvents organic solvent such as
THF, CH.sub.2Cl.sub.2, ACN, ethers. The BODV can be added dropwise.
The mixture can then be heated, such as to a temperature of about
30 to about reflux, more preferably about reflux. Before adding
borate, the mixture is preferably cooled, such as to about -20 C,
to about 10 C, preferably about -10 C. 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 removed such as by reducing the pressure to
less than one atmosphere.
[0063] Optionally, the new synthetic route for obtaining
O-desmethylvenlafaxine can go via a protected intermediate of
BODV.
[0064] The protected intermediate of BODV may contain any suitable
hydroxyl protecting group, such as silyl, acetyl and dihydropyran
(DHP).
[0065] In another embodiment, the invention encompasses
hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol
(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.
[0066] In another embodiment, the present invention provides a
process for preparing
hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cy-
clohexanol (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.
[0067] Typically, the solvent used can be any organic solvent.
Preferably, the organic solvent is ethyl acetate. Other organic
solvents such as CH.sub.2Cl.sub.2, ethers such THF, toluene, hexane
or ACN can also be used.
[0068] Preferably, the process is performed under basic conditions.
Typically, the basic source is organic or inorganic base.
Preferably, the basic source is a C.sub.3-C.sub.9 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 K.sub.2CO.sub.3 can also be used,
[0069] 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 or 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.
[0070] 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 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.
[0071] In another embodiment, the present invention provides a
process for obtaining O-desmethylvenlafaxine comprising preparing
BODV-P as described above, and further converting the BODV-P to
O-desmethylvenlafaxine.
[0072] In another embodiment, the present invention provides a
process for converting BODV-P to O-desmethylvenlafaxine, using a
Grignard reaction.
[0073] The conversion can be performed as described above for
BODV.
[0074] In another embodiment, the present invention provides a
process for preparing O-desmethylvenlafaxine comprising: combining
BODV-P, a hydroxide donor base and a metal salt.
O-desmethylvenlafaxine is then be recovered from the reaction
mixture.
[0075] The hydroxide donor base and a metal salt used in the
reaction are as described above.
[0076] 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 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.
[0077] In 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, a hydroxide donor base and a
metal salt to create a reaction mixture and recovering
O-desmethylvenlafaxine from the reaction mixture.
[0078] In 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; combining BODV-P, a hydroxide donor base
and a metal salt to create a reaction mixture and recovering
O-desmethylvenlafaxine from the reaction mixture.
[0079] In 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 and converting BODV to O-desmethylvenlafaxine,
using a Grignard reaction or organocuprate reaction.
[0080] In 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
O-desmethylvenlafaxine, using a Grignard reaction or organocuprate
reaction.
[0081] In 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, 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 O-desmethylvenlafaxine
from the reaction mixture.
[0082] In 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, 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
O-desmethylvenlafaxine from the reaction mixture.
[0083] In 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, an organic solvent, and a
methylating agent to form a mixture; recovering the BODV from the
mixture and converting BODV to O-desmethylvenlafaxine, using a
Grignard reaction.
[0084] In 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, 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 O-desmethylvenlafaxine,
using a Grignard reaction.
[0085] 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, a hydroxide donor base and a metal salt to
create a reaction mixture and recovering O-desmethylvenlafaxine
from the reaction mixture.
[0086] 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
O-desmethylvenlafaxine from the reaction mixture.
[0087] 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 and converting BODV to O-desmethylvenlafaxine, using a
Grignard reaction or organocuprate reaction.
[0088] 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 and converting BODV-P to O-desmethylvenlafaxine,
using a Grignard reaction or organocuprate reaction.
[0089] 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, 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 O-desmethylvenlafaxine from the
reaction mixture.
[0090] 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, 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 O-desmethylvenlafaxine
from the reaction mixture.
[0091] 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, an organic solvent, and a methylating
agent to form a mixture; recovering the BODV from the mixture and
converting BODV to O-desmethylvenlafaxine, using a Grignard
reaction or organocuprate reaction.
[0092] 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, 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 O-desmethylvenlafaxine, using a
Grignard reaction or organocuprate reaction.
[0093] The invention in certain of its embodiments is illustrated
by the following non-limiting examples.
EXAMPLES
Preparation of CBBC
Example 1
[0094] A 250 ml three necked flask equipped with nitrogen inlet,
thermometer and mechanical stirrer was charged slowly with MeOH (50
ml) and NaOCH.sub.3 (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
[0095] A 100 ml three necked flask equipped with, thermometer and
mechanical stirrer is charged with BBC (2 g, 10 mmol),
cyclohexanone (2 g, 20.3 mmol), TBAB (0.2 g) and NaOH (6 ml 10%).
The reaction is stirred at RT overnight to get CBBC.
Preparation of BDDMV
Example 3
[0096] A 250 ml 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, 39.89 mmol) was added dropwise. This mixture was
stirred overnight at ambient temperature and poured into saturated
solution of NH.sub.4Cl. A 30% solution of hydrogen peroxide was
then added. The layers were separated and the organic layer was
acidified with citric acid.
[0097] The aqueous phase was basified with NH.sub.4OH and extracted
with diethylether. The organic layer was then washed with brine,
dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure
to get BDDMV.
Preparation of BODV
Example 4
[0098] BDDMV (0.81 g, 2.72 mmol) was dissolved in MeOH (20 ml). A
formalin solution (1.3 ml, 16.25 mmol) was added and the solution
was cooled with an ice bath. To the cold solution NaBH.sub.4 (0.25
g, 6.5 mmol) 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% HCl. The aqueous phase was basified with
NH.sub.4OH and extracted with methylene chloride. The organic phase
was then evaporated under reduced pressure to get BODV.
Example 5
[0099] BDDMV (0.2 g, 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 MeI (0.25 mmol) is
added. The reaction mixture is stirred until we get BODV (HPLC
monitoring).
Example 6
[0100] BDDMV (0.5 g, 1.67 mmol) is suspended in CH.sub.2Cl.sub.2.
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 mmol) and NEt.sub.3
(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 AgNO.sub.3
[0101] To a solution of AgNO.sub.3 (3.38 g in 100 ml H.sub.2O),
montmorillonite K10 (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.degree. C. for 1 hour.
[0102] 0.4 g of BODV (1.26 mmol), 0.2 g of NaOH (5 mmol) and 2 g of
supported AgNO.sub.3 were mixed thoroughly in a mortar. The mixture
was heated to 100.degree. C. overnight under mechanical stirring.
The mixture was then extracted with chloroform and with methanol to
get ODV.
Example 8
[0103] A 100 ml three-necked flask equipped with nitrogen inlet,
thermometer, mechanical stirrer and condenser was charged with Mg
(0.2 g, 8.23 mmol) and 12 (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.degree. C. and
trimethylborate (1 ml, 8.8 mmol) was added. After stirring for 30
min glacial acetic acid (2 ml, 34.9 mmol) was added. Then a cold
solution of 30% hydrogen peroxide (2 ml 19.64 mmol) was also added.
Diethylether was added and the organic phase was filtered to get
ODV.
Preparation of BODV-P
Example 9
[0104] A 100 ml three-necked flask equipped with Nitrogen inlet,
thermometer, mechanical stirred and condenser was charged with BODV
(0.37 g 1.13 mmol), EtOAc (20 ml) and Et.sub.3N (1 ml 7.16 mmol).
Acetylchloride (1 ml 14 mmol) 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
Example 10
[0105] A 250 ml three-necked flask equipped with Nitrogen inlet,
thermometer, mechanical stirred and condenser was charged with Mg
(0.7 g, 28.80 mmol) and 12 (0.2 g 0.78 mmol). BODV-P (1 g, 2.71
mmol) in THF (30 ml) was added dropwise and the mixture was heated
to reflux for 2 hours. The mixture was then cooled to -10.degree.
C. and trimethylborate (20 ml, 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.
Example 11
Preparation of Supported AgNO.sub.3
[0106] To a solution of AgNO.sub.3 (3.38 g in 100 ml H.sub.2O),
montmorillonite 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.degree. C. for 1
hour.
[0107] 0.4 g of P-BODV, 0.2 g of NaOH (5 mmol) and 2 g of supported
AgNO.sub.3 are mixed thoroughly in a mortar. The mixture is heated
to 100.degree. C. overnight under mechanical stirring. The mixture
is then extracted with chloroform and with methanol to get ODV.
* * * * *