U.S. patent application number 11/881826 was filed with the patent office on 2008-07-31 for process for the synthesis of o-desmethylvenlafaxine.
Invention is credited to Tamar Nidam, Valerie Niddam-Hildesheim.
Application Number | 20080183016 11/881826 |
Document ID | / |
Family ID | 38924359 |
Filed Date | 2008-07-31 |
United States Patent
Application |
20080183016 |
Kind Code |
A1 |
Niddam-Hildesheim; Valerie ;
et al. |
July 31, 2008 |
Process for the synthesis of O-desmethylvenlafaxine
Abstract
Provided are processes and intermediates for the synthesis 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.: |
11/881826 |
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 ;
564/443 |
Current CPC
Class: |
A61P 25/24 20180101;
C07C 235/34 20130101; C07C 2601/14 20170501 |
Class at
Publication: |
564/316 ;
564/443 |
International
Class: |
C07C 211/27 20060101
C07C211/27; C07C 215/46 20060101 C07C215/46 |
Claims
1. 2-(4-hydroxyphenyl)-N,N-dimethylacetamide having the structure:
##STR00013##
2-3. (canceled)
4. A process for preparing the
2-(4-hydroxyphenyl)-N,N-dimethylacetamide of claim 1 comprising
forming an acid-activated derivative of 4-hydroxyphenylacetic acid
(4-hydroxyphenyl)acetic acid), and reacting the activated acid with
dimethylamine.
5. A process according to claim 4 wherein the acid-activated
derivative of 4-hydroxyphenylacetic acid is prepared by combining
4-hydroxyphenylacetic acid with an acid activating agent and a
catalyst, and optionally recovering the activated acid.
6. A process according to claim 4 wherein the activated acid is
combined with an amine to obtain OBA, and optionally recovering the
OBA.
7. The process of claim 5, wherein the catalyst is an organic
catalyst.
8. The process of claim 5, wherein the catalyst is dimethyl
formamide (DMF) or Pyridinium p-toluene sulfonate (PPTS).
9. The process of claim 4, wherein the acid is activated in the
presence of a solvent.
10. The process of claim 9, wherein the solvent is selected from a
group consisting of C.sub.6-12 aromatic hydrocarbon, a C.sub.1-4
halogenated hydrocarbon, a C.sub.4-8 ether and mixtures
thereof.
11. The process of claim 9, wherein the solvent is selected from a
group consisting of toluene, CH.sub.2Cl.sub.2 and THF.
12. The process of claim 9, wherein the solvent is
CH.sub.2Cl.sub.2.
13. The process of claim 9, wherein the solvent is cooled to a
temperature of about -40.degree. C. to about 70.degree. C.
14. The process of claim 13, wherein the solvent is cooled to a
temperature of about -10.degree. C. to about 10.degree. C.
15. The process of claim 5, wherein the activating agent is
SOCl.sub.2, CoCl.sub.2, DCC(N'-dicyclohexyl carbodiimide) or
analogs, HOBT or analogs, or FMOC or analogs.
16. The process of claim 15, wherein the activating agent is
SOCl.sub.2.
17. The process of claim 5, wherein the activated acid is recovered
by removing the solvent.
18. The process of claim 5, wherein the dimethylamine is a salt,
and subsequent to its reaction with the activated acid, a second
amine is added.
19. The process of claim 18, wherein the amine salt is
dimethylamine HCl.
20. The process of claim 19, wherein the second amine is a
C.sub.3-C.sub.9 tertiary amine.
21. The process of claim 20, wherein the second amine is
diisopropylamine.
22. The process of claim 17, wherein recovery is done by quenching;
washing, filtering, and drying.
23. The process of claim 5, further comprising converting OBA to
O-desmethylvenlafaxine or a salt thereof.
24. Protected hydroxyphenyl dimethylamide of the following
structure: ##STR00014## wherein x is a hydroxy protecting
group.
25-30. (canceled)
31. A process for preparing compound of claim 24 comprising
combining OBA with a suitable hydroxyl protecting agent and
optionally a base.
32-39. (canceled)
40.
2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)-N,N-dimethylacetamide
(COBA) having the following structure: ##STR00015##
41. (canceled)
42. A process for preparing the compound of claim 40 comprising
reacting OBA with cyclohexanone and a base able to form a carbanion
and recovering the obtained COBA.
45-53. (canceled)
54. Hydroxyl protected
2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)-N,N-dimethylacetamide
(PCOBA) having the following structure: ##STR00016## wherein x is a
hydroxy protecting group.
55. (canceled)
56. A process for preparing the hydroxyl protected
2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)-N,N-dimethylacetamide
of claim 54 comprising reacting a hydroxy protected OBA (POBA) with
cyclohexanone and a base able to form a carbanion and recovering
the obtained PCOBA.
57. A process for preparing ODV (O-desmethylvenlafaxine) comprising
converting the COBA of claim 40 or the PCOBA of claim 54 to ODV or
a salt thereof.
58-66. (canceled)
67. A process for preparing ODV (O-desmethylvenlafaxine) or salts
thereof comprising the steps of: combining OBCarboxy, a catalyst
and an acid activating agent to obtain an activated acid;
recovering the activated acid, combining it with dimethylamine or a
salt thereof and an amine to obtain OBA; reacting the obtained OBA
with cyclohexanone and a base able to form a carbanion; recovering
the obtained COBA; reacting the obtained COBA, and a reducing
agent; and recovering the obtained ODV or a salt thereof.
68. (canceled)
69. A process for preparing ODV (O-desmethylvenlafaxine) or salts
thereof comprising the steps of: (i) preparing OBA from
4-hydroxyphenylacetic acid by a process according to claim 4; (ii)
optionally preparing POBA from OBA by a process according to claim
31; (iii) preparing COBA from OBA by a process according to claim
42; (iv) optionally preparing PCOBA from POBA according to claim
56; (v) converting the COBA or PCOBA to ODV by a process according
to claim 57.
70-71. (canceled)
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,
of the following formula,
##STR00001##
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.
[0004] O-desmethylvenlafaxine,
4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol, of the
following formula,
##STR00002##
is reported to be a metabolite of venlafaxine, which is known also
as an inhibitor of norepiniphrine 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," and J. Clin. Pharmacol. 32:716-724 (1992).
[0005] Processes for the synthesis of O-desmethylvenlafaxine by
demethylation of the methoxy group of venlafaxine are described in
U.S. Pat. Nos. 7,026,508 and in 6,689,912.
[0006] The synthesis disclosed in the above patents 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] The demethylation process disclosed in U.S. Pat. No.
7,026,508 provides ODV succinate salt by using L-selectride, which
is an alkali metal salt of trialkyl borohydride; where hydrogen gas
is formed during the reaction. Hence, the process isn't suitable
for industrial scale manufacture.
[0008] US application No. 2005/0197392 describes a method for
preparing (.+-.)O-desmethylvenlafaxine hydrochloride salt by
reacting venlafaxine with lithium diphenyl phosphide.
[0009] U.S. Pat. No. 6,689,912 describes demethylation process
performed by using a salt of high molecular weight alkane, arene,
or arylalkyl thiolate anion in the presence of protic or aprotic
solvent. The salt can be prepared separately and then react with
venlafaxine, or can react in-situ with venlafaxine. When prepared
separately, the solvent, methanol should be removed. This operation
is very complicated because the mixture containing the salt is
highly viscous, hence the operation necessitate long time even
under high vacuum. When the reaction is performed in-situ via
removal of methanol in situ, this operation is still tedious and
only partially successful, since it is difficult to reach the high
temperature that the reaction necessitate to advance.
[0010] The described ODV synthesis processes are all indirect, i.e;
performed via Venlafaxine. The present invention provides a direct
synthesis of O-desmethylvenlafaxine; i.e.; without passing through
venlafaxine as an intermediate.
SUMMARY OF THE INVENTION
[0011] In one embodiment, the invention encompasses hydroxyphenyl
dimethylamide (OBA), having the following formula,
##STR00004##
[0012] In another embodiment, the present invention provides a
process for preparing hydroxyphenyl dimethylamide (OBA) comprising
combining hydroxybenzyl carboxy (OBCarboxy), a catalyst and an acid
activating agent to obtain an activated acid; recovering the
activated acid, and combining it with a dimethylamine to obtain
OBA.
[0013] Preferably, the process for preparing OBA is done in the
presence of an organic solvent.
[0014] In yet another embodiment, the present invention provides a
process for preparing ODV by preparing OBA as described above, and
converting it to ODV. OBA can be transformed to ODV via another
intermediated such as COBA.
[0015] In yet another embodiment, the present invention encompasses
hydroxy protected OBA (POBA), having the following formula,
##STR00005##
[0016] In another embodiment, the present invention encompasses a
process for preparing POBA comprising; combining OBA with a
hydroxyl protecting agent and a base.
[0017] In yet another embodiment, the present invention provides a
process for preparing ODV by preparing POBA as described above, and
converting it to ODV. POBA can be transformed to ODV via another
intermediated such as PCOBA.
[0018] In yet another embodiment, the present invention encompasses
cyclohexylOBA (COBA), having the following formula,
##STR00006##
[0019] In one embodiment the process for the preparation of
cyclohexylOBA (COBA) comprising: reacting OBA with cyclohexanone
and a base able to form a carbanion; and recovering the obtained
COBA.
[0020] In yet another embodiment, the present invention provides a
process for preparing ODV by preparing COBA as described above, and
converting it to ODV, by any method known in the art, i.e: the
method described above.
[0021] In yet another embodiment, the present invention encompasses
a hydroxyl protected COBA (PCOBA), having the following
formula,
##STR00007##
PCOBA
[0022] In another embodiment the process for preparing PCOBA
comprising; combining POBA with cyclohexanone and a base able to
form a carbanion; and recovering the obtained PCOBA.
[0023] In yet another embodiment, the present invention provides a
process for preparing ODV by preparing PCOBA as described above and
converting it to ODV, by any method known in the art, i.e: the
method described above.
[0024] In another embodiment, the present invention encompasses a
process for preparing ODV from COBA comprising: reacting COBA and a
reducing agent to obtain ODV, where optionally, PCOBA can be used
as a starting material.
[0025] In another embodiment, the present invention encompasses a
process for preparing ODV comprising the steps of: combining
OBCarboxy, a catalyst and an acid activating agent to obtain an
activated acid; recovering the activated acid and combining it with
an amine to obtain OBA; reacting the obtained OBA with
cyclohexanone and a base able to form a carbanion; recovering the
obtained COBA and reacting the obtained COBA; a reducing agent; and
recovering the obtained ODV, wherein, optionally, a protected
derivative of OBA (POBA) can be used as a starting material and
PCOBA is obtained, which is then reacted with the reducing agent to
obtain ODV.
DETAILED DESCRIPTION OF THE INVENTION
[0026] As used herein, the term "ambient temperature" refers to a
temperature of about 18.degree. C. to about 25.degree. C.
[0027] As used herein, the term "OBA" refers to hydroxyphenyl
dimethylamide (IUPAC name
2-(4-hydroxyphenyl)-N,N-dimethylacetamide) of the following
structure:
##STR00008##
[0028] As used herein, the term "POBA" refers to protected
hydroxyphenyl dimethylamide (IUPAC name: protected
2-(4-hydroxyphenyl)-N,N-dimethylacetamide) of the following
structure:
##STR00009##
wherein x is a hydroxy protecting group.
[0029] As used herein, the term "COBA" refers to cyclohexyl
hydroxyphenyl dimethylamide (IUPAC name
2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)-N,N-dimethylacetamide)
of the following structure;
##STR00010##
[0030] As used herein, the term "PCOBA" refers to protected
cyclohexyl hydroxyphenyl dimethylamide (IUPAC name: protected:
2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)-N,N-dimethylacetamide)
of the following structure;
##STR00011##
wherein x is a hydroxy protecting group.
[0031] As used herein, the term "ODV" refers to
O-desmethylvenlafaxine.
[0032] The present invention provides a direct synthesis of ODV via
novel intermediates. This process produces ODV and its
intermediates in high yields and purity. In the process of the
present invention ODV is synthesized without going through
venlafaxine, leading to elimination of a demethylation step.
[0033] In the process of the invention, the intermediate OBA is
condensed with cyclohexanone to form the intermediate COBA.
Further, the carboxylic group of COBA is reduced, and the reduced
product is converted to ODV. The process can be performed via the
protected intermediates POBA and PCOBA, in order to increase the
yield, due to avoidance of side-reactions. The process is described
in the following scheme.
##STR00012##
[0034] In one embodiment, the invention encompasses hydroxyphenyl
dimethylamide (OBA) (IUPAC name
2-(4-hydroxyphenyl)-N,N-dimethylacetamide). OBA is characterized by
.sup.1HNMR (Bruker DPX-300 (DMSO-d6)) with .delta.: 2.80 (s,
CH.sub.3--N), 2.96 (s, CH.sub.3N), 3.53 (s, CH.sub.2), 6.70 (m, H
atom), 6.98 (m, H atom), 9.24 (s, OH). OBA has a mass of 180 (MS
(CI+)=180).
[0035] In one embodiment the present invention provides isolated or
purified OBA. Isolated refers to being separated from the reaction
mixture in which it forms. Preferably the OBA is at least about 50%
pure as measured by HPLC.
[0036] OBA is prepared by a process comprising combining
hydroxybenzyl carboxy OBCarboxy (IUPAC name:
(4-hydroxyphenyl)acetic acid)) catalyst and an acid activating
agent to obtain an activated acid; recovering the activated acid,
and combining it with an amine to obtain OBA.
[0037] Preferably, the catalyst is an organic catalyst. Most
preferably, the catalyst is dimethyl formamide DMF or Pyridinium
p-toluene sulfonate (PPTS). Typically, the reaction is done in the
presence of a solvent. The solvent is an organic solvent that does
not react with the acid activating agent. More preferably, the
solvent is selected from a group consisting of C.sub.6-12 aromatic
hydrocarbon, preferably C.sub.6 to C.sub.8, a C.sub.1-4 halogenated
hydrocarbon, preferably chloroform, dichloromethane, a C.sub.4-8
ether preferably C.sub.4 to C.sub.6 ether, more preferably
tetrahydrofuran, diethylether, methyltert-butyl ether and mixtures
thereof. Even more preferably, the solvent is selected from a group
consisting of toluene, CH.sub.2Cl.sub.2 and THF. Most preferably,
the solvent is CH.sub.2Cl.sub.2.
[0038] Usually, the reaction with the acid activating agent is
exothermic; hence the mixture is cooled prior to combining it with
the acid activating agent. Preferably, the mixture is cooled to a
temperature of about -10.degree. C. to about 10.degree. C.,
preferably -5.degree. C. to about 5.degree. C., more preferably, to
a temperature of about 0.degree. C.
[0039] In order to decrease the exothermic effect of the reaction,
the acid activating agent is added dropwise, preferably during 30
minutes to about 3 hours. Preferably, the acid activating agent is
an agent that activates carboxylic acids, i.e., converts the "OH"
to a suitable leaving group. The activating agent may be
SOCl.sub.2, COCl.sub.2, DCC (N'-dicyclohexyl carbodiimide) or
analogs, HOBT (N-Hydroxybenzotriazole), FMOC
(fluorenylmethoxycarbonyl) or analogs (and other analogs used in
peptide chemistry) or PC15 or (COCl).sub.2. Most preferably, the
activating agent is SOCl.sub.2.
[0040] Following to the addition of the activating agent, the
obtained mixture is heated, preferably to a temperature of about
0.degree. C. to about 30.degree. C., preferably about 15.degree. C.
to about 28.degree.. More preferably the heating is to a
temperature of about ambient temperature.
[0041] The heated mixture is stirred for a sufficient time to
obtain the activated acid, preferably for a period of time of about
0.5 to about 3 hours, preferably for about 1 to about 2.5 hours.
More preferably, the stirring is for about 2 hours.
[0042] The activated acid is optionally recovered by any method
known in the art. Preferably, it is recovered by removing the
solvent and providing a residue comprising of the activated acid.
One of ordinary skill of art can also devise a one pot process
which skips recovery of the intermediate in the synthetic
scheme.
[0043] Preferably the solvent is removed by evaporation under
reduced pressure (pressure of below one atmosphere).
[0044] Then, the residue is optionally dissolved in another organic
solvent; wherein the solvent is described above. Subsequently, the
solution is combined with dimethylamine to provide a mixture. This
reaction is more facile if a dimethylamine salt is used, and then
the salt is removed with another amine. Preferably the amine salt
is dimethylamine-HCl and the second amine is a C.sub.3-C.sub.9
trialkylamine, where each alkyl chain is independently selected
from C.sub.1-C.sub.7 carbons. Example of such amine includes
diisopropylethylamine. A gaseous amine can also be used.
Preferably, the second amine is added dropwise, more preferably,
during about 1 hour.
[0045] The mixture is then stirred for a sufficient time to obtain
OBA. Preferably, the stirring is done over a period of time of
about 1 hour to about 24 hours more preferably about 4 hours to
about 16 hours. More preferably, the stirring is performed
overnight.
[0046] OBA can be recovered. The recovery is preferably done by
quenching the new mixture providing a precipitate; washing,
filtering, and drying. Preferably, the quenching is done by adding
a saturated solution of a base. More preferably, the base is an
inorganic base, such as an alkali metal or alkaline earth metal
carbonate/bicarbonate. Most preferably, the base is
NaHCO.sub.3.
[0047] Preferably, the precipitate is filtered under a reduced
pressure. Preferably, the washing is done with methylene chloride,
and the drying, under vacuum (pressure of less than about 100
mmHg). Preferably, the drying is at a temperature of about
20.degree. C. to about 80.degree. C. More preferably, the drying is
done at room temperature.
[0048] The process for preparing OBA can further comprise a process
for converting OBA to ODV. OBA can be transformed to ODV via
another intermediated such as COBA.
[0049] In another embodiment, the present invention encompasses
hydroxy protected OBA (POBA). Suitable hydroxy protected groups are
listed in T. W. Greene, Protective Groups in Organic Synthesis,
(2.sup.nd ed.), which is incorporated herein by reference. Most
preferably, POBA is a silyl-protected POBA, such as a tri(C.sub.1-6
alkyl)silyl-protected POBA, wherein the alkyl groups can be the
same or different, preferably t-butyldimethylsilyl ether
(TBDMS)-protected OBA, or trimethylsilyl (TMS), with TBDMS being
preferred, or DHP-protected OBA.
[0050] In one embodiment the present invention provides isolated or
purified POBA, including TBDMS-OBA. Isolated refers to being
separated from the reaction mixture in which it forms. Preferably
the POBA is at least about 50% pure as measured by HPLC.
[0051] TBDMS-OBA is characterized by .sup.1HNMR (Bruker DPX-300
(DMSO-d6)) with .delta.: 0.20 (s, Me2Si), 0.99 (s, tBuSi), 2.85 (s,
CH.sub.3--N), 2.99 (s, CH.sub.3N), 3.62 (s, CH.sub.2), 6.77 (m, H
atom), 7.10 (m, H atom).
[0052] POBA, including TBDMS-OBA, can be prepared by combining OBA
with a suitable hydroxyl protecting agent and a base. An acid may
also be used instead of a base.
[0053] Usually, the reaction is done in the presence of a solvent.
Preferably, the solvent is an organic solvent. Preferably the
solvent is a non-protic solvent. The organic solvent can be a
C.sub.6 to C.sub.12 aromatic hydrocarbon or a C.sub.1-C.sub.6
chlorinated hydrocarbon or C.sub.4-6 ether. More preferably, the
solvent is selected from the group consisting of toluene,
CH.sub.2Cl.sub.2 and THF. Most preferably, the solvent is
CH.sub.2Cl.sub.2.
[0054] Preferably, the hydroxyl protecting agent is a trialkylsilyl
halide, preferably a tri(C.sub.1-6 alkyl)silyl halide, wherein the
alkyl may be the same or different, preferably the trialkylsilyl
halide is a trimethylsilyl halide or a tert-butyldimethylsilyl
halide, wherein the halide is chloride or bromide or DHP
(dihydropyran). Preferably, the hydroxyl protecting agent is a
silyl protecting group or DHP (dihydropyran). More preferably, the
hydroxyl protecting agent is TBDMS-Cl, acetylchloride or acetic
anhydride.
[0055] Preferably, the base is imidazole. Other bases such as
pyridine, triethylamine, lutidine, dimethylaminopyridine may also
be used.
[0056] The obtained combination is stirred at a temperature of
about 0.degree. C. to about 100.degree. C., preferably about
40.degree. C. to about 70.degree. C. Preferably, the stirring is
done at a temperature of about 55.degree. C.
[0057] Preferably the above combination is maintained, while
stirring, for about 0.5 hour to about 24 hours, preferably about 1
hour to about 4 hours, more preferably for about two hours, during
which POBA is formed.
[0058] The process for preparing POBA can further comprise a
recovery process. The recovery is, preferably done by quenching the
combination providing a two-phase system; separating the obtained
two phases, washing and drying the organic phase, followed by
filtering and solvent evaporation under reduced pressure (pressure
of less than one atmosphere). Preferably, the combination is
quenched with brine and 10% aqueous solution of citric acid.
[0059] The process for preparing POBA can further comprise a
process for converting POBA to ODV. POBA can be converted to ODV
via COBA or PCOBA.
[0060] In another embodiment, the present invention encompasses
cyclohexylOBA (COBA). Also provided is isolated or purified COBA.
Isolated refers to being separated from the reaction mixture in
which it forms. Preferably the COBA is at least about 50% pure as
measured by HPLC.
[0061] COBA can be prepared by reacting OBA with cyclohexanone and
a base able to form a carbanion; and recovering the obtained COBA.
Optionally, a protected derivative of OBA can be used as a starting
material, to obtain PCOBA.
[0062] Usually, the reaction is done in the presence of a solvent.
Preferably, the solvent is as described above. More preferably, the
solvent is THF.
[0063] Initially, OBA or POBA is combined with the solvent to
obtain a mixture. Then a base able to form a carbanion is added,
providing a new mixture.
[0064] Preferably, the base is able to form a carbanion. More
preferably, the base is LDA; or alkali metal or alkaline earth
metal (such as lithium) diisopropylamide; or BuLi. The base may
also be Sodium hydride (NaH); or alkali metal or alkaline earth
metal (such as sodium or potassium or lithium) salts of bis
trimethylsilylamide {MN(SiMe.sub.3).sub.2}; or metal salt of
tert-butoxide (MOtBu)
[0065] The reaction of the base with the reagent is exothermic.
Preferably, the base is added at a temperature of about 80.degree.
C. to about 25.degree. C. For example, when the base is LDA, the
addition can be done at ambient temperature, and when the base is
BuLi, the addition can be done at a temperature of about
-80.degree. C.
[0066] Usually, the base is added dropwise. Preferably, the
dropwise addition is done during a period of time of about 30
minutes. The new mixture is then stirred. Preferably, the stirring
is for about 10 minutes to about 2 hours. More preferably, the new
mixture is stirred for about 30 minutes.
[0067] Cyclohexanone is then added to the mixture. Preferably
cyclohexanone is added dropwise, more preferably, during a period
of time of 30 minutes.
[0068] Preferably, the obtained mixture is maintained, while being
stirred, for about 30 minutes to about 24 hours, more preferably,
the stirring is done overnight.
[0069] The reaction mixture can then be quenched, by reacting the
reaction mixture with a proton donor, such as NH.sub.4Cl. The
recovery provides COBA or PCOBA, depending on the starting
material.
[0070] PCOBA and COBA can then be recovered. Preferably, the
recovery stage includes: separating the layers obtained after
quenching, washing the organic layer obtained after quenching with
brine, and further evaporating the residual organic solvent under
reduced pressure (pressure of less than one atmosphere) to obtain
COBA or PCOBA.
[0071] In another embodiment, the present invention encompasses a
hydroxyl protected cyclohexylOBA (PCOBA). Preferably, PCOBA is
TBDMS-protected COBA.
[0072] The process for preparing COBA or PCOBA can further comprise
a process for converting COBA or PCOBA to ODV. COBA and PCOBA can
be converted to ODV by reacting COBA or PCOBA with a reducing
agent, and recovering to obtain ODV.
[0073] Usually, COBA or PCOBA are combined with a solvent to obtain
a solution. Solvents that are inert to the reducing agent can be
used. Preferably the solvent is THF. Subsequently, a reducing agent
is added, preferably, the reducing agent is a metal hydride
complex. More preferably, the metal hydride complex is selected
from a group consisting of BH.sub.3 derivatives or aluminum hydride
derivatives. Most preferably, the reducing agent is LiAlH.sub.4,
NaBH.sub.4, NaBH3CN: sodium cyanoborohydride Instead of using metal
hydride complex, the hydrogenation may be performed under H.sub.2
pressure in presence of catalyst such Ni or Co.
[0074] Usually, the reducing agent is added dropwise to avoid heat
accumulation. The addition can be done during a period of time of
about 30 min. The addition can preferably be done at a temperature
of about -50.degree. C. to about RT. Preferably, the temperature is
ambient temperature.
[0075] The addition of the reducing agent provides a mixture.
Preferably, the mixture is stirred for about 1 hour to about 24
hours. More preferably, the stirring is stirred for over night.
[0076] Preferably, the recovery of ODV is done by quenching. More
preferably the quenching is done by acidification of the mixture.
Acidification is done for example by adding aqueous solution of HCl
or NH.sub.4Cl. The quenching, typically, provides a two-phase
system, comprising of an aqueous phase and of an organic phase. The
phases are separated, and the aqueous phase is neutralized
preferably, by adding a base. The neutralization is done by adding
a base such as an alkali or alkaline earth metal
carbonate/bicarbonate. Preferably, the base is a saturated solution
of NaHCO.sub.3.
[0077] The process for preparing ODV can further comprise a
recovery process. The recovery can be done by extracting ODV from
the aqueous layer, such as by adding a water immiscible organic
solvent. Preferably, the water immiscible organic solvent is
CH.sub.2Cl.sub.2, EtOAc, hexanes or toluene
[0078] The extract may then be dried, filtered and evaporated under
reduced pressure (pressure of less than one atmosphere). The drying
is preferably over Na.sub.2SO.sub.4.
[0079] One of ordinary skill of art would appreciate that each
above described process can be combined into one continuous process
for synthesis of ODV. In such process ODV can be synthesized by
combining OBCarboxy, a catalyst and an acid activating agent to
obtain an activated acid; recovering the activated acid, combining
it with an amine to obtain OBA; reacting the obtained OBA with
cyclohexanone and a base able to form a carbanion; recovering the
obtained COBA; reacting the obtained COBA, and a reducing agent;
and recovering the obtained ODV. Optionally, a protected derivative
of OBA (POBA) can be used as a starting material for the process
for preparing PCOBA, and wherein, optionally, a protected
derivative of COBA (PCOBA) can be used as a starting material for
the preparation of ODV.
[0080] Having described the invention with reference to certain
preferred embodiments, other embodiments will become apparent to
one skilled in the art from consideration of the specification. The
invention is further defined by reference to the following examples
describing in detail the synthesis of the compound OBA, COBA, their
protected forms and further their conversion to
O-desmethylvenlafaxine. It will be apparent to those skilled in the
art that many modifications, both to materials and methods, may be
practiced without departing from the scope of the invention.
EXAMPLES
Preparation of OBA
Example 1
[0081] A 500 ml three-neck flask equipped with nitrogen inlet,
thermometer and mechanical stirrer was charged with OBcarboxy (10
g, 65.72 mmol), DMF (1 ml) and CH.sub.2Cl.sub.2 (50 ml). The
reaction mixture was stirred at 0.degree. C. and SOCl.sub.2 was
added dropwise.
[0082] The reaction was stirred at ambient temperature for 2 hours
and then the solvent was evaporated under reduced pressure. The
residue was dissolved in CH.sub.2Cl.sub.2 (50 ml) and
dimethylamine-HCl (100 g, 1.22 mol) was added. Then
diisopropylethylamine (150 ml, 0.882 mol) was added dropwise. The
mixture was stirred at ambient temperature overnight and then
washed with a saturated solution of NaHCO.sub.3; a precipitate
appeared. The precipitate was filtered under reduced pressure and
washed with methylene chloride. The solid so-obtained was dried in
a vacuum oven at room temperature to get 5.55 g of OBA (purity
99.45%).
[0083] The organic layer was washed with brine and evaporated to
dryness yielding crystals 5.84 g OBA (purity 96.57%). Total
yield=97.85%.
Preparation of Protected OBA (POBA)
Example 2
[0084] A 100 ml three-neck flask equipped with nitrogen inlet,
thermometer and mechanical stirrer was charged with OBA (2.4 g,
13.39 mmol) TBDMS-Cl (4.5 g, 29.9 mmol), imidazole (5.5 g, 80.78
mmol) and CH.sub.2Cl.sub.2 (20 ml). The reaction mixture was
stirred at ambient temperature for 2 hours. The reaction was
quenched with brine and a 10% aqueous solution of citric acid The
organic phase was then washed with brine and dried over
Na.sub.2SO.sub.4. After filtration the solvent was evaporated under
reduced pressure to get 3.82 g OBA-P (purity: 99.34%, yield:
97.45%).
Example 3
[0085] In a 50 ml flask equipped with a mechanical stirrer, OBA
(1.45 g, 8.09 mmol) was dissolved at room temperature in DHP (8 ml)
under nitrogen. Pyridinium p-toluene sulfonate (PPTS, catalytic
amount) was added and the reaction mixture was heated to 55.degree.
C. for 5 hours. The reaction was monitored by HPLC. EtOAc was added
and the organic layer was washed with brine, dried over MgSO.sub.4
and filtered under reduced pressure to get OBA-DHP.
Preparation of Protected COBA (PCOBA)
Example 4
[0086] A 100 ml three-neck flask equipped with nitrogen inlet,
thermometer and mechanical stirrer was charged with OBA-TBDMS (3.8
g 12.95 mmol) and THF (50 ml). The solution was cooled to
-80.degree. C. and n-BuLi (1M in Hexane 8.5 ml 13.6 mmol) was added
dropwise. The reaction was stirred at -80.degree. C. for 45 min and
cyclohexanone (1.7 g, 17.32 mmol) was added dropwise. This mixture
was stirred for 3 hours at this temperature and poured into a
saturated solution of NH.sub.4Cl. The layers were separated.
[0087] The organic layer was washed with brine and dried over
Na.sub.2SO.sub.4. After filtration the solvent was evaporated under
reduced pressure to get 4.85 g of COBA-P (purity: 79.63%, yield:
95.65%)
Preparation of COBA Via OBA
Example 5
[0088] A 100 ml three-neck flask equipped with nitrogen inlet,
thermometer and mechanical stirrer was charged with OBA (1.2 g,
6.69 mmol) and THF (10 ml). The mixture was stirred at ambient
temperature and LDA (2M in THF 7 ml, 14.02 mmol) was added
dropwise. The mixture was stirred at this temperature for 30 min
and cyclohexanone (1.4 g, 14.26 mmol) was added dropwise. This
mixture was stirred overnight at ambient temperature and then
poured into a NH.sub.4Cl aqueous saturated solution. The layers
were separated and the organic phase was washed with brine dried
over Na.sub.2SO.sub.4 and evaporated under reduced pressure to get
COBA.
Preparation of ODV Via PCOBA
Example 6
[0089] A 100 ml three-neck flask equipped with nitrogen inlet,
thermometer and mechanical stirrer was charged with PCOBA-TBDMS
(2.2 g, 5.6 mmol) and THF (30 ml). This solution was stirred at
ambient temperature and LiAlH.sub.4 (1M in THF10 ml, 10 mmol) was
added dropwise. The mixture was stirred at ambient temperature
overnight. This mixture was then acidified with a 10% aqueous
solution of HCl. The layers were separated and the aqueous phase
was basified with a NaHCO.sub.3 saturated solution. The aqueous
layer was extracted with CH.sub.2Cl.sub.2, dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
get 0.43 g of ODV (purity=100%).
Preparation of ODV Via COBA
Example 7
[0090] A 100 ml three-neck flask equipped with nitrogen inlet,
thermometer and mechanical stirrer is charged with COBA-TBDMS (2.2
g, 5.6 mmol) and THF (30 ml). This solution is stirred at ambient
temperature and LiAlH.sub.4 (1M in THF10 ml, 10 mmol) is added
dropwise. The mixture is stirred at ambient temperature overnight.
This mixture is then acidified with a 10% aqueous solution of HCl.
The layers are separated and the aqueous phase is basified with a
NaHCO.sub.3 saturated solution. The aqueous layer is extracted with
CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4, filtered and
evaporated under reduced pressure to obtain ODV.
* * * * *