U.S. patent application number 13/956765 was filed with the patent office on 2014-02-27 for preparation of chiral amides and amines.
This patent application is currently assigned to SUNOVION PHARMACEUTICALS INC.. The applicant listed for this patent is SUNOVION PHARMACEUTICALS INC.. Invention is credited to Roger P. Bakale, Stefan G. Koenig, Surendra Singh, Charles P. Vandenbossche, Harold Scott Wilkinson, Hang Zhao.
Application Number | 20140057990 13/956765 |
Document ID | / |
Family ID | 38564252 |
Filed Date | 2014-02-27 |
United States Patent
Application |
20140057990 |
Kind Code |
A1 |
Zhao; Hang ; et al. |
February 27, 2014 |
PREPARATION OF CHIRAL AMIDES AND AMINES
Abstract
This invention provides a convenient method for converting
oximes into enamides. The process does not require the use of
metallic reagents. Accordingly, it produces the desired compounds
without the concomitant production of a large volume of metallic
waste. The enamides are useful precursors to amides and amines. The
invention provides a process to convert a prochiral enamide into
the corresponding chiral amide. In an exemplary process, a chiral
amino center is introduced during hydrogenation through the use of
a chiral hydrogenation catalyst. In selected embodiments, the
invention provides methods of preparing amides and amines that
include the 1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine substructure.
Inventors: |
Zhao; Hang; (Westborough,
MA) ; Koenig; Stefan G.; (Shrewsbury, MA) ;
Vandenbossche; Charles P.; (Waltham, MA) ; Singh;
Surendra; (Shrewsbury, MA) ; Wilkinson; Harold
Scott; (Westborough, MA) ; Bakale; Roger P.;
(Malverne, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SUNOVION PHARMACEUTICALS INC. |
Marlborough |
MA |
US |
|
|
Assignee: |
SUNOVION PHARMACEUTICALS
INC.
Marlborough
MA
|
Family ID: |
38564252 |
Appl. No.: |
13/956765 |
Filed: |
August 1, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13333616 |
Dec 21, 2011 |
8524950 |
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13956765 |
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12281819 |
Jan 30, 2009 |
8097760 |
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PCT/US2007/065659 |
Mar 30, 2007 |
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13333616 |
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60787837 |
Mar 31, 2006 |
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Current U.S.
Class: |
514/657 ;
435/128; 564/222; 564/414; 564/428 |
Current CPC
Class: |
A61P 25/14 20180101;
A61P 25/30 20180101; A61P 29/00 20180101; A61P 19/02 20180101; C07B
43/06 20130101; C07C 209/62 20130101; C07C 211/42 20130101; C07C
231/12 20130101; C07C 249/08 20130101; A61P 25/08 20180101; A61P
17/06 20180101; A61P 25/22 20180101; C07C 209/50 20130101; A61P
25/28 20180101; C07C 231/14 20130101; C07C 2602/10 20170501; A61P
25/24 20180101; A61P 25/18 20180101; A61P 25/04 20180101; A61P
25/00 20180101 |
Class at
Publication: |
514/657 ;
564/222; 564/414; 564/428; 435/128 |
International
Class: |
C07C 231/14 20060101
C07C231/14; C07C 209/50 20060101 C07C209/50; C07C 211/42 20060101
C07C211/42; C07C 231/12 20060101 C07C231/12 |
Claims
1. A method for converting an oxime into an enamide, said method
comprising: (a) contacting said oxime with a phosphine and an acyl
donor, under conditions appropriate to convert said oxime into said
enamide.
2. The method according to claim 1 wherein said oxime has the
formula: ##STR00071## wherein R.sup.1, R.sup.2 and R.sup.3 are
members independently selected from H, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocycloalkyl, and at least two of
R.sup.1, R.sup.2 and R.sup.3 are optionally joined to form a ring
system selected from substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl.
3. The method according to claim 1, wherein said oxime has the
formula: ##STR00072## wherein Ar is a member selected from
substituted or unsubstituted aryl and substituted or unsubstituted
heteroaryl; R.sup.4 is a member selected from H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl; and a
is selected from the integers from 1 to 4.
4. The method according to claim 3 wherein R.sup.4 is substituted
or unsubstituted aryl.
5. The method according to claim 4 wherein R.sup.4 is substituted
or unsubstituted phenyl.
6. The method according to claim 5 wherein R.sup.4 is phenyl
substituted with at least one halogen.
7. The method according to claim 6 wherein R.sup.4 has the formula:
##STR00073## wherein X.sup.1 and X.sup.2 are independently selected
halo moieties.
8. The method according to claim 7 wherein X.sup.1 and X.sup.2 are
each chloro.
9. The method according to claim 3 wherein Ar is substituted or
unsubstituted phenyl.
10. The method according to claim 9, said oxime having the formula:
##STR00074##
11. The method according to claim 1 wherein said acyl donor has the
formula: Z--C(O)--R.sup.5 wherein Z is a leaving group; and R.sup.5
is a member selected from H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocycloalkyl.
12. The method according to claim 11 wherein Z has the formula:
R.sup.6--C(O)--O-- wherein R.sup.6 is a member selected from
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl.
13. The method according to claim 12 wherein both R.sup.5 and
R.sup.6 are independently selected substituted or unsubstituted
C.sub.1-C.sub.4 moieties.
14. The method according to claim 1 wherein said phosphine has the
formula: P(Q).sub.3 wherein each Q is a member independently
selected from H, substituted or unsubstituted alkyl and substituted
or unsubstituted aryl.
15. The method according to claim 14 wherein each Q is a member
independently selected from substituted or unsubstituted
C.sub.1-C.sub.6 alkyl.
16. The method according to claim 1 wherein said contacting is in
solution with an aprotic solvent.
17. The method according to claim 16 wherein said aprotic solvent
is an aromatic solvent.
18. The method according to claim 17 wherein said aprotic aromatic
solvent is selected from toluene, xylene and combinations
thereof.
19. The method according to claim 15 wherein said enamide has the
formula: ##STR00075##
20. The method according to claim 19 wherein C-4 has a
configuration selected from R, S and mixtures thereof.
21. The method according to claim 20 wherein C-4 is of S
configuration.
22. The method according to claim 1, said method further
comprising: (b) contacting said enamide formed in step (a) with a
hydrogenation catalyst and hydrogen or hydrogen transfer reagent
under conditions appropriate to hydrogenate a carbon-carbon double
bond of said enamide, thereby converting said enamide to an
amide.
23. The method according to claim 22 wherein said catalyst is a
chiral catalyst.
24. The method according to claim 23 wherein said chiral catalyst
is a complex of a transition metal with a chiral phosphine
ligand.
25. The method according to claim 22 wherein said amide is a
racemic or chiral amide.
26. The method according to claim 22 wherein said amide has the
formula: ##STR00076##
27. The method according to claim 26 wherein C-1 and C-4 have a
configuration independently selected from R and S.
28. The method according to claim 27 wherein C-1 is of R
configuration; and C-4 is of S configuration.
29. The method according to claim 22, further comprising: (c)
contacting said amide with a deacylating reagent under conditions
appropriate to deacylate --HNC(O)R.sup.5 of said amide, thereby
forming an amine.
30. The method according to claim 29, further comprising: (d)
isolating said amine.
31. The method according to claim 30, wherein said isolating
comprises selective crystallization.
32. The method according to claim 29 wherein said amine has the
formula: ##STR00077## wherein Q.sup.- is an anion; and e is 0 to
1.
33. The method according to claim 32 wherein C-1 and C-4 have a
configuration independently selected from R and S.
34. The method according to claim 33 wherein C-1 is of R
configuration; and C-4 is of S configuration.
35. A method of converting an oxime having the formula ##STR00078##
into an enamide having the formula: ##STR00079## wherein R.sup.4 is
selected from substituted or unsubstituted awl and substituted or
unsubstituted heteroaryl; and R.sup.5 is selected from H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl, said method comprising: (a) contacting said oxime
with a phosphine and an acyl donor under conditions appropriate to
convert said oxime to said enamide.
36. The method according to claim 35 wherein C-4 is of S
configuration.
37. The method according to claim 34 wherein said phosphine is a
trialkylphosphine.
38. The method according to claim 35 wherein said oxime, said acyl
donor and said phosphine are dissolved in an aromatic solvent.
39. The method according to claim 35 wherein said acyl donor is an
alkyl anhydride.
40. The method according to claim 35, said method further
comprising: (b) contacting said enamide formed in step (a) with a
chiral hydrogenation catalyst and hydrogen under conditions
appropriate to hydrogenate a carbon-carbon double bond conjugated
to C(O) of said enamide, thereby converting said enamide to an
amide having the formula: ##STR00080## wherein C-1 has a
configuration selected from R and S.
41. The method according to claim 40 wherein said chiral catalyst
comprises rhodium complexed to a chiral phosphine ligand.
42. The method according to claim 40, further comprising: (c)
contacting said amide with a deacylating reagent under conditions
appropriate to deacylate --HNC(O)R.sup.5 of said amide, thereby
forming an amine having the formula: ##STR00081## wherein Q.sup.-
is an anion; and e is 0 or 1.
43. The method according to claim 42 wherein said deacylating
reagent is an enzyme.
44. The method according to claim 42 wherein said deacylating
reagent is an acid.
45. A mixture comprising: ##STR00082## wherein R.sup.4 is a member
selected from substituted or unsubstituted aryl and substituted or
unsubstituted heteroaryl; Q.sup.- is an anion; e and f are
independently selected numbers from 0 to 1; and x and y are
selected from R and S, such that when x is R, y is R, and when x is
S, y is S.
46. The mixture according to claim 45 wherein A is present in said
mixture in a diastereomeric excess of at least 90% relative to
B.
47. The mixture according to claim 46 wherein A is present in said
mixture in a diastereomeric excess of at least 98% relative to
B.
48. The mixture according to claim 45 wherein x and y are R.
49. The mixture according to claim 45 wherein x and y are S.
50. The mixture according to claim 45 wherein x is S and y is
R.
51. A pharmaceutical formulation comprising a mixture according to
claim 45 and a pharmaceutically acceptable carrier.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a U.S. National Phase Application of
PCT/US2007/065659 filed Mar. 30, 2007 and claims priority under 35
U.S.C. .sctn.119(e) to U.S. Provisional Patent Application No.
60/787,837 filed Mar. 31, 2006, which applications are incorporated
herein by reference in their entirety for all purposes.
FIELD OF THE INVENTION
[0002] This invention relates to processes suitable for the
large-scale preparation of enantiomerically- or
diastereomerically-enriched chiral amides and amines prepared by
these processes.
BACKGROUND OF THE INVENTION
[0003] Enantiomerically-enriched chiral primary amines are commonly
used as resolving agents for racemic acids, as chiral auxiliaries
for asymmetric syntheses and as ligands for transition metal
catalysts used in asymmetric catalysis. In addition, many
pharmaceuticals, such as sertraline, contain chiral amine moieties.
Effective methods for the preparation of such compounds are of
great interest to the pharmaceutical industry. Particularly
valuable are processes that allow for the preparation of each
enantiomer or diastereomer, in enantiomeric or diastereomeric
excess, as appropriate, from prochiral or chiral starting
materials.
[0004] Methods are available for the preparation of
enantiomerically enriched amines. For example, the addition of
organometallic reagents to imines or their derivatives is reported
by Watanabe et al., Tetrahedron Asymm. (1995) 6:1531; Denmark et
al., J. Am. Chem. Soc. (1987) 109:2224; Takahashi et al., Chem.
Pharm. Bull. (1982) 30:3160; and the addition of organometallic
reagents to chiral oxazolidines is disclosed by Mokhallalatiet et
al., Tetrahedron Lett. (1994) 35:4267. Although some of these
methods are widely employed, few are amenable to large-scale
production of amines.
[0005] Other approaches involve optical resolution of a single
enantiomer or diastereomer from a mixture. Resolution may be
conducted through stereoselective biotransformation or by the
formation of diastereomeric salts that are separated by
crystallization. The utility and applicability of resolution
methods relying on selective recrystallization are often limited by
the lack of availability of appropriate chiral auxiliaries. In
addition, resolution processes upon racemic mixtures afford a
maximum yield of 50% for either stereoisomer. Therefore, the
resolution of racemic mixtures is generally viewed as an
inefficient process.
[0006] The preparation of an enantiomerically-enriched amine via
conversion of a precursor oxime to the corresponding enamide, which
is subsequently converted to the amine through asymmetric
hydrogenation and deprotection, has been described (WO 99/18065 to
Johnson et al.). The processes are, however, not of general
applicability to a wide range of substrates. Moreover, many of the
recognized processes require a large excess of metallic reagent to
effect the conversion. The result is the generation of significant
amounts of solid metal waste, a trait that is undesirable for
large-scale production processes.
[0007] Therefore, a cost-efficient, scalable method for the
conversion of oximes to corresponding enamides, which does not rely
on a metallic reagent, is needed. The facile, high yield conversion
of readily accessible oximes to the corresponding enamides without
the use of metallic reagents would be a valuable step towards the
large-scale synthesis of chiral amides and amines. The current
invention addresses this and other needs.
SUMMARY OF THE INVENTION
[0008] The present invention provides an efficient and convenient
method for the conversion of an oxime to the corresponding enamide.
The method of the invention accomplishes the desired conversion
without the use of a metallic reagent. The method is appropriate
for large-scale synthesis of enamides, amides, amines, and their
derivatives.
[0009] Thus, in a first aspect, the current invention provides a
method for converting an oxime into an enamide. The method includes
contacting the oxime with a phosphine and an acyl donor, under
conditions appropriate to convert the oxime into the enamide. The
method produces enamides in high yields and is generally applicable
across a wide range of oxime structures. The enamides are readily
converted to the corresponding amines. In an exemplary route,
described in greater detail herein, the enamide is reduced to the
corresponding amide, which is subsequently deacetylated to provide
the amine.
[0010] The method is particularly useful for the large-scale
synthesis of bioactive species, such as those having the
1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine substructure. Examples of
bioactive compounds with this substructure include sertraline and
sertraline analogs, and the trans isomers of sertraline,
norsertraline and analogs thereof. Sertraline, (1S,4S)-cis
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine,
is approved for the treatment of depression by the United States
Food and Drug Administration, and is available under the trade name
ZOLOFT.RTM. (Pfizer Inc., NY, N.Y., USA). In human subjects,
sertraline has been shown to be metabolized to (1S,4S)-cis
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine, also
known as desmethylsertraline or norsertraline.
[0011] Enamides provide a convenient precursor to compounds that
include the 1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine substructure. Accordingly, in
a second aspect, the present invention provides a method of
converting an oxime having the formula:
##STR00001##
into an enamide having the formula:
##STR00002##
[0012] In the formulae above, the symbol R.sup.4 represents
substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl. The symbol R.sup.5 represents H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl or substituted or unsubstituted heterocycloalkyl. The
method includes contacting said oxime with a phosphine and an acyl
donor under conditions appropriate to convert said oxime to said
enamide.
[0013] In a third aspect, the invention provides a mixture
comprising:
##STR00003##
[0014] In the formulae above, Q.sup.- is an anion. The indices c
and f are independently selected numbers from 0 to 1. The indices x
and y independently represent (R) or (S). In an exemplary
embodiment, when x is (R), y is (R) and when x is (S), y is (S). In
another exemplary embodiment, when x is (S), y is (R).
[0015] The present invention provides a general and efficient
method for converting oximes to enamides. Moreover, the invention
provides a method for the stereo-selective synthesis of sertraline
and sertraline analogs, and the trans isomers of sertraline,
norsertraline and analogs thereof. Additional objects, advantages
and embodiments of the present invention are set forth in the
detailed description that follows.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations
[0016] As used herein, "COD" means 1,5-cyclooctadiene.
DEFINITIONS
[0017] Where substituent groups are specified by their conventional
chemical formulae, written from left to right, they equally
encompass the chemically identical substituents, which would result
from writing the structure from right to left, e.g., --CH.sub.2O--
is preferably intended to also recite --OCH.sub.2--.
[0018] The term "alkyl," by itself or as part of another
substituent, means, unless otherwise stated, a straight- or
branched-chain, or cyclic hydrocarbon radical, or combination
thereof, which may be fully saturated, mono- or polyunsaturated and
can include mono-, di- and multivalent radicals, having the number
of carbon atoms designated (i.e. C.sub.1-C.sub.10 means one to ten
carbons). Examples of saturated hydrocarbon radicals include, but
are not limited to, groups such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,
(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for
example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An
unsaturated alkyl group is one having one or more double bonds or
triple bonds. Examples of unsaturated alkyl groups include, but are
not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,
2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-
and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The
term "alkyl," unless otherwise noted, also preferably include those
derivatives of alkyl defined in more detail below, such as
"heteroalkyl." Alkyl groups that are limited to hydrocarbon groups
are termed "homoalkyl". The term "alkyl", as used herein refers to
alkyl, alkenyl and alkynyl moieties, each of which can be mono-,
di- or polyvalent species. Alkyl groups are preferably substituted,
e.g., with one or more groups referred to hereinbelow as an "alkyl
group substituent."
[0019] The term "alkylene" by itself or as part of another
substituent means a divalent radical derived from an alkane, as
exemplified, but not limited, by
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and further includes those
groups described below as "heteroalkylene." Typically, an alkyl (or
alkylene) group will have from 1 to 24 carbon atoms, with those
groups having 10 or fewer carbon atoms being preferred in the
present invention. A "lower alkyl" or "lower alkylene" is a shorter
chain alkyl or alkylene group, generally having eight or fewer
carbon atoms.
[0020] The terms "alkoxy," "alkylamino" and "alkylthio" (or
thioalkoxy) are used in their conventional sense, and refer to
those alkyl groups attached to the remainder of the molecule via an
oxygen atom, an amino group, or a sulfur atom, respectively.
[0021] The term "heteroalkyl," by itself or in combination with
another term, means, unless otherwise stated, a stable straight- or
branched-chain, or cyclic alkyl radical consisting of the stated
number of carbon atoms and at least one heteroatom selected from
the group consisting of B, O, N, Si and S, wherein the heteroatom
may optionally be oxidized and the nitrogen atom may optionally be
quaternized. The heteroatom(s) may be placed at any internal
position of the heteroalkyl group or at a terminus of the chain,
e.g., the position through which the alkyl group is attached to the
remainder of the molecule. Examples of "heteroalkyl" groups
include, but are not limited to, --CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3,
--CH.sub.2--CH.dbd.N--OCH.sub.3, and
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3. Two or more heteroatoms may be
consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3 and
--CH.sub.2--O--Si(CH.sub.3).sub.3. Similarly, the term
"heteroalkylene" by itself or as part of another substituent refers
to a substituted or unsubstituted divalent heteroalkyl radical, as
exemplified, but not limited by,
--CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--. For
heteroalkylene groups, heteroatoms can also occupy either or both
of the chain termini (e.g., alkyleneoxy, alkylenedioxy,
alkyleneamino, alkylenediamino, and the like). Still further, for
alkylene and heteroalkylene linking groups, no orientation of the
linking group is implied by the direction in which the formula of
the linking group is written. For example, the formula
--C(O).sub.2R'-- represents --C(O).sub.2R'-- and, preferably,
--R'C(O).sub.2--.
[0022] The terms "cycloalkyl" and "heterocycloalkyl", by themselves
or in combination with other terms, represent, unless otherwise
stated, cyclic versions of "alkyl" and "heteroalkyl", respectively.
Additionally, for heterocycloalkyl, a heteroatom can occupy the
position at which the heterocycle is attached to the remainder of
the molecule. Examples of cycloalkyl include, but are not limited
to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl,
cycloheptyl, and the like. Examples of heterocycloalkyl include,
but are not limited to, 1-(1,2,5,6-tetrahydropyridyl),
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,
3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,
tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,
2-piperazinyl, and the like.
[0023] The terms "halo" or "halogen," by themselves or as part of
another substituent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. Additionally, terms such as
"haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl.
For example, the term "halo(C.sub.1-C.sub.4)alkyl" is meant to
include, but not be limited to, trifluoromethyl,
2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the
like.
[0024] The term "aryl" means, unless otherwise stated, a
polyunsaturated, aromatic, substituent that can be a single ring or
multiple rings (preferably from 1 to 3 rings, one or more of which
is optionally a cycloalkyl or heterocycloalkyl), which are fused
together or linked covalently. The term "heteroaryl" refers to aryl
groups (or rings) that contain from one to four heteroatoms
selected from N, O, and S, wherein the nitrogen and sulfur atoms
are optionally oxidized, and the nitrogen atom(s) are optionally
quaternized. A heteroaryl group can be attached to the remainder of
the molecule through a heteroatom. Non-limiting examples of aryl
and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,
4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,
2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,
2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,
5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl,
3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl,
2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,
2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.
Substituents for each of the above noted aryl and heteroaryl ring
systems are selected from the group of "aryl group substituents"
described below.
[0025] For brevity, the term "aryl" when used in combination with
other terms (e.g., aryloxy, arylthioxy, arylalkyl) preferably
includes both homoaryl and heteroaryl rings as defined above. Thus,
the term "arylalkyl" optionally includes those radicals in which an
aryl group is attached to an alkyl group (e.g., benzyl, phenethyl,
pyridylmethyl and the like) including those alkyl groups in which a
carbon atom (e.g., a methylene group) has been replaced by, for
example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl,
3-(1-naphthyloxy)propyl, and the like).
[0026] Substituents for the alkyl and heteroalkyl radicals
(including those groups often referred to as alkylene, alkenyl,
heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are
generically referred to as "alkyl group substituents," and they can
be one or more of a variety of groups selected from, but not
limited to: --OR', .dbd.O, .dbd.NR', --NR'R'', --SR', -halogen,
--SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --CONR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''',
--NR''C(O).sub.2R', --NR--C(NR'R''R''').dbd.NR'',
--NR--C(NR'R'')=NR''', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NRSO.sub.2R', --CN and --NO.sub.2 in a number
ranging from zero to (2 m'+1), where m' is the total number of
carbon atoms in such radical. R', R'', R''' and R'''' each
preferably independently refer to hydrogen, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g.,
aryl substituted with 1-3 halogens, substituted or unsubstituted
alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a
compound of the invention includes more than one R group, for
example, each of the R groups is independently selected as are each
R', R'', R''' and R'''' groups when more than one of these groups
is present. When R' and R'' are attached to the same nitrogen atom,
they can be combined with the nitrogen atom to form a 5-, 6-, or
7-membered ring. For example, --NR'R'' is meant to include, but not
be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above
discussion of substituents, one of skill in the art will understand
that the term "alkyl" includes groups with carbon atoms bound to
groups other than hydrogen, such as haloalkyl (e.g., --CF.sub.3 and
--CH.sub.2CF.sub.3) and acyl (e.g., --C(O)CH.sub.3, --C(O)CF.sub.3,
--C(O)CH.sub.2OCH.sub.3, and the like).
[0027] Similar to the substituents described for the alkyl radical,
substituents for the aryl and heteroaryl groups are generically
referred to as "aryl group substituents." The substituents are
selected from, for example: halogen, --OR', .dbd.O, .dbd.NR',
.dbd.N--OR', --NR'R'', --SR', --SiR'R''R''', --OC(O)R', --C(O)R',
--CO.sub.2R', --CONR'R'', --OC(O)NR'R'', --NR''C(O)R',
--NR'--C(O)NR''R''', --NR''C(O).sub.2R',
--NR--C(NR'R''R''').dbd.NR'''', --NR--C(NR'R'').dbd.NR''',
--S(O)R', --S(O).sub.2R', --S(O).sub.2NR'R'', --NRSO.sub.2R', --CN
and --NO.sub.2, --R', --N.sub.3, --CH(Ph).sub.2,
fluoro(C.sub.1-C.sub.4)alkoxy, and fluoro(C.sub.1-C.sub.4)alkyl, in
a number ranging from zero to the total number of open valences on
the aromatic ring system; and where R', R'', R''' and R'''' are
preferably independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heteroaryl. When a compound of the invention includes more than one
R group, for example, each of the R groups is independently
selected as are each R', R'', R''' and R'''' groups when more than
one of these groups is present.
[0028] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally be replaced with a substituent of
the formula -T-C(O)--(CRR').sub.q--U--, wherein T and U are
independently --NR--, --O--, --CRR'-- or a single bond, and q is an
integer from 0 to 3. Alternatively, two of the substituents on
adjacent atoms of the aryl or heteroaryl ring may optionally be
replaced with a substituent of the formula
-A-(CH.sub.2).sub.r--B--, wherein A and B are independently
--CRR'--, --O--, --NR--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2NR'-- or a single bond, and r is an integer of from 1
to 4. One of the single bonds of the new ring so formed may
optionally be replaced with a double bond. Alternatively, two of
the substituents on adjacent atoms of the aryl or heteroaryl ring
may optionally be replaced with a substituent of the formula
--(CRR').sub.s--X--(CR''R''').sub.d--, where s and d are
independently integers of from 0 to 3, and X is --O--, --NR'--,
--S--, --S(O)--, --S(O).sub.2--, or --S(O).sub.2NR'--. The
substituents R, R', R'' and R''' are preferably independently
selected from hydrogen or substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl.
[0029] As used herein, the term "heteroatom" includes oxygen (O),
nitrogen (N), sulfur (S) and silicon (Si).
[0030] The symbol "R" is a general abbreviation that represents a
substituent group that is selected from substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, and substituted or unsubstituted heterocyclyl
groups.
[0031] The term "salt(s)" includes salts of the compounds which are
prepared with relatively nontoxic acids or bases, depending on the
particular substituents found on the compounds described herein.
When compounds of the present invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of base addition salts include sodium, potassium, calcium,
ammonium, organic amino, or magnesium salt, or a similar salt. When
compounds of the present invention contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Examples
of acid addition salts include those derived from inorganic acids
like hydrochloric, hydrobromic, nitric, carbonic,
monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or
phosphorous acids, and the like, as well as the salts derived from
relatively nontoxic organic acids like acetic, propionic,
isobutyric, butyric, maleic, malic, malonic, benzoic, succinic,
suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,
p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
Also included are salts of amino acids such as arginate, and the
like, and salts of organic acids like glucuronic or galactunoric
acids and the like (see, for example, Berge et al., Journal of
Pharmaceutical Science, 66: 1-19 (1977)). Certain specific
compounds of the present invention contain both basic and acidic
functionalities that allow the compounds to be converted into
either base or acid addition salts. Hydrates of the salts are also
included.
[0032] When the compound prepared by a method of the invention is a
pharmacological agent, the salt is preferably a pharmaceutically
acceptable salt. Examples of pharmaceutically acceptable salts are
presented hereinabove, and are generally known in the art. See, for
example, Wermuth, C., PHARMACEUTICAL SALTS: PROPERTIES, SELECTION
AND USE--A HANDBOOK, Verlag Helvetica Chimica Acta (2002)
[0033] The neutral forms of the compounds are preferably
regenerated by contacting the salt with a base or acid and
isolating the parent compound in the conventional manner. The
parent form of the compound differs from the various salt forms in
certain physical properties, such as solubility in polar solvents,
but otherwise the salts are equivalent to the parent form of the
compound for the purposes of the present invention.
[0034] In addition to salt forms, the present invention provides
compounds that are in a prodrug form. Prodrugs of the compounds
described herein are those compounds that readily undergo chemical
changes under physiological conditions to provide the compounds of
the present invention. Additionally, prodrugs can be converted to
the compounds of the present invention by chemical or biochemical
methods in an ex vivo environment. For example, prodrugs can be
slowly converted to the compounds of the present invention when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
[0035] As used herein, and unless otherwise indicated, the term
"prodrug" means a derivative of a compound that can hydrolyze,
oxidize, or otherwise react under biological conditions (in vitro
or in vivo) to provide the compound. Examples of prodrugs include,
but are not limited to, compounds that comprise biohydrolyzable
moieties such as biohydrolyzable amides, biohydrolyzable esters,
biohydrolyzable carbamates, biohydrolyzable carbonates,
biohydrolyzable ureides, and biohydrolyzable phosphate analogs.
Other examples of prodrugs include compounds that comprise NO,
NO.sub.2, --ONO, or --ONO.sub.2 moieties. The term "prodrug" is
accorded a meaning herein such that prodrugs do not encompass the
parent compound of the prodrug. When used to describe a compound of
the invention, the term "prodrug" may also interpreted to exclude
other compounds of the invention.
[0036] As used herein, and unless otherwise indicated, the terms
"biohydrolyzable carbamate," "biohydrolyzable carbonate,"
"biohydrolyzable ureide" and "biohydrolyzable phosphate" mean a
carbamate, carbonate, ureide and phosphate, respectively, of a
compound that either: 1) does not interfere with the biological
activity of the compound but can confer upon that compound
advantageous properties in vivo, such as uptake, duration of
action, or onset of action; or 2) is biologically inactive but is
converted in vivo to the biologically active compound. Examples of
biohydrolyzable carbamates include, but are not limited to, lower
alkylamines, substituted ethylenediamines, aminoacids,
hydroxyalkylamines, heterocyclic and heteroaromatic amines, and
polyether amines.
[0037] As used herein, and unless otherwise indicated, the term
"biohydrolyzable ester" means an ester of a compound that either:
1) does not interfere with the biological activity of the compound
but can confer upon that compound advantageous properties in vivo,
such as uptake, duration of action, or onset of action; or 2) is
biologically inactive but is converted in vivo to the biologically
active compound. Examples of biohydrolyzable esters include, but
are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl
acylamino alkyl esters, and choline esters.
[0038] As used herein, and unless otherwise indicated, the term
"biohydrolyzable amide" means an amide of a compound that either:
1) does not interfere with the biological activity of the compound
but can confer upon that compound advantageous properties in vivo,
such as uptake, duration of action, or onset of action; or 2) is
biologically inactive but is converted in vivo to the biologically
active compound. Examples of biohydrolyzable amides include, but
are not limited to, lower alkyl amides, .alpha.-amino acid amides,
alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
[0039] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms are equivalent to unsolvated
forms and are encompassed within the scope of the present
invention. Certain compounds of the present invention may exist in
multiple crystalline or amorphous forms. In general, all physical
forms are equivalent for the uses contemplated by the present
invention and are intended to be within the scope of the present
invention.
[0040] Certain compounds of the present invention possess
asymmetric carbon atoms (optical centers) or double bonds; the
racemates, diastereomers, geometric isomers and individual isomers
are encompassed within the scope of the present invention.
[0041] As used herein, and unless otherwise indicated, a
composition that is "substantially free" of a compound means that
the composition contains less than about 20% by weight, more
preferably less than about 10% by weight, even more preferably less
than about 5% by weight, and most preferably less than about 3% by
weight of the compound.
[0042] As used herein, the term "substantially free of its cis
stereoisomer" means that a mixture of a compound is made up of a
significantly greater proportion of its trans stereoisomer than of
its optical antipode. In a preferred embodiment of the invention,
the term "substantially free of its cis stereoisomer" means that
the compound is made up of at least about 90% by weight of its
trans stereoisomer and about 10% by weight or less of its cis
stereoisomer. In a more preferred embodiment of the invention, the
term "substantially free of its cis stereoisomer" means that the
compound is made up of at least about 95% by weight of its trans
stereoisomer and about 5% by weight or less of its cis
stereoisomer. In an even more preferred embodiment, the term
"substantially free of its cis stereoisomer" means that the
compound is made up of at least about 99% by weight of its trans
stereoisomer and about 1% or less of its cis stereoisomer.
[0043] The graphic representations of racemic, ambiscalemic and
scalemic or enantiomerically pure compounds used herein are taken
from Maehr, J. Chem. Ed., 62: 114-120 (1985): solid and broken
wedges are used to denote the absolute configuration of a chiral
element; wavy lines indicate disavowal of any stereochemical
implication which the bond it represents could generate; solid and
broken bold lines are geometric descriptors indicating the relative
configuration shown but not implying any absolute stereochemistry;
and wedge outlines and dotted or broken lines denote
enantiomerically pure compounds of indeterminate absolute
configuration.
[0044] The terms "enantiomeric excess" and "diastereomeric excess"
are used interchangeably herein. Compounds with a single
stereocenter are referred to as being present in "enantiomeric
excess." Those with at least two stereocenters are referred to as
being present in "diastereomeric excess."
[0045] The compounds of the present invention may also contain
unnatural proportions of atomic isotopes at one or more of the
atoms that constitute such compounds. For example, the compounds
may be radiolabeled with radioactive isotopes, e.g., tritium
(.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All
isotopic variations of the compounds of the present invention,
whether radioactive or not, are intended to be encompassed within
the scope of the present invention.
INTRODUCTION
[0046] The present invention provides a non-metal mediated method
for the conversion of oximes to the corresponding enamides. The
enamides are formed in high yields and purities, making them
suitable substrates for homogeneous asymmetric hydrogenation, a
process that affords enantiomerically-enriched amides. The amides
can be deprotected to furnish enantiomerically-enriched amines.
Either enantiomer of the amine may be obtained by this method.
Ketones and aldehydes can thus be transformed into
enantiomerically-enriched chiral amines. The process is amenable to
large-scale production.
Methods
A. Oxime to Enamide
[0047] In a first aspect, the present invention provides a method
for converting an oxime into an enamide. The method includes
contacting the oxime with a phosphine and an acyl donor, under
conditions appropriate to convert the oxime into the enamide.
Exemplary conditions are set forth herein.
[0048] In one embodiment, the oxime of use in the method of the
invention has the formula:
##STR00004##
The symbols R.sup.1, R.sup.2 and R.sup.3 represent radicals that
are independently selected from H, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocycloalkyl. At least two of
R.sup.1, R.sup.2 and R.sup.3 are optionally joined to form a ring
system selected from substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl.
[0049] In another exemplary embodiment, the oxime has the
formula:
##STR00005##
The symbol Ar represents substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl. R.sup.4 is H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl or substituted or unsubstituted heterocycloalkyl. The
index a is an integer from 1 to 4.
[0050] In an exemplary embodiment according to this aspect, R.sup.4
is substituted or unsubstituted aryl (e.g., phenyl). In a further
exemplary embodiment, R.sup.4 is phenyl substituted with at least
one halogen atom.
[0051] In yet another exemplary embodiment, R.sup.4 has the
formula:
##STR00006##
in which the symbols X.sup.1 and X.sup.2 represent independently
selected halo moieties. In a preferred embodiment, X.sup.1 and
X.sup.2 are each chloro.
[0052] In another exemplary embodiment, the oxime has the
formula:
##STR00007##
wherein R.sup.4 is selected from substituted or unsubstituted aryl
and substituted or unsubstituted heteroaryl.
[0053] In a further exemplary embodiment, the oxime has the
formula:
##STR00008##
[0054] The preparation of oximes is well known in the art and a
wide range of methods is known and readily practiced by those of
skill in the art. Typically, oximes are prepared by reaction of
ketones or aldehydes with hydroxylamine (or alkyloxyamine) under
one of a variety of conditions. See, e.g., Sandler and Karo,
"ORGANIC FUNCTIONAL GROUP PREPARATIONS," Vol. 3, pp 372-381,
Academic Press, New York, 1972.
[0055] In an exemplary embodiment, optically pure tetralone is
converted into the corresponding oxime according to Scheme 1.
##STR00009##
[0056] In Scheme 1, optically pure tetralone 1 is treated with
hydroxylamine hydrochloride, and sodium acetate in methanol to
afford the oxime 2. Compound 2 can either be isolated or carried
forward as a solution in a suitable solvent to the next step. In
another method, a ketone is converted to the corresponding oxime in
an aromatic hydrocarbon solvent, e.g., toluene.
[0057] According to the process of the invention, the oxime is
converted into an enamide. In an exemplary embodiment, the enamide
has the formula:
##STR00010##
in which R.sup.1-R.sup.3 are as discussed above and R.sup.5 is
selected from H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocycloalkyl.
[0058] In another exemplary embodiment, the enamide has the
formula:
##STR00011##
in which R.sup.4 is selected from substituted or unsubstituted aryl
and substituted or unsubstituted heteroaryl. R.sup.5 is selected
from H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocycloalkyl.
[0059] An exemplary enamide has the formula:
##STR00012##
[0060] In an exemplary embodiment according to this aspect, C-4 of
the ketone, oxime and enamide is of (S)-configuration.
[0061] In a preferred embodiment, the enamide has the formula:
##STR00013##
[0062] C-4 has a configuration selected from (R) and (S) and, in a
preferred embodiment, C-4 is of (S)-configuration. In another
embodiment, the method provides an enamide mixture including both
(S)- and (R)-enantiomers.
Acyl Donor
[0063] Acyl donors of essentially any structure are of use in the
present invention. An exemplary acyl donor has the formula:
Z--C(O)--R.sup.5
in which Z is a leaving group. R.sup.5 is a member selected from H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl.
[0064] In an exemplary embodiment, the acyl donor is an acid
anhydride, in which Z has the formula:
R.sup.6--C(O)--O--
in which R.sup.6 is a member selected from substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl.
[0065] In another exemplary embodiment, R.sup.5 and R.sup.6 are
independently selected substituted or unsubstituted C.sub.1-C.sub.4
moieties.
[0066] In another embodiment, the acyl donor is an anhydride,
preferably acetic anhydride (Ac.sub.2O).
[0067] In another exemplary embodiment, the acyl donor is a member
selected from an acid chloride (Z.dbd.Cl) and an activated ester,
e.g., an N-hydroxy succinimidyl ester.
[0068] The acyl donor can be present in any useful amount and
selection of this amount is within the abilities of those of skill
in the art. In an exemplary embodiment, the acyl donor is used in
an amount from about 1 to about 3 equivalents, preferably from
about 1 to about 2 equivalents and, more preferably, from about 1
to about 1.5 equivalents relative to the oxime substrate.
Phosphine
[0069] Phosphorus reagents, such as phosphines, of any structure
are of use in practicing the present invention. For example, in
general, phosphines have the formula:
P(Q).sub.3
in which each Q is independently selected from H, substituted or
unsubstituted alkyl and substituted or unsubstituted aryl.
[0070] In an exemplary embodiment, each Q is a member independently
selected from substituted or unsubstituted C.sub.1-C.sub.6 alkyl
and substituted or unsubstituted phenyl. Presently preferred
phosphorus reagents include, but are not limited to,
diphenylphosphine (Ph.sub.2PH), triphenylphosphine (Ph.sub.3P),
tri-n-butylphosphine (n-Bu.sub.3P), triethylphosphine (Et.sub.3P),
tri-n-propylphosphine (n-Pr.sub.3P), 1,2-bisdiphenylphosphinoethane
(Ph.sub.2PCH.sub.2CH.sub.2PPh.sub.2), diethyl phosphite
(Et.sub.2OP(O)H), triphenyl phosphite ((PhO).sub.3P),
P-chlorodiphenylphosphine (Ph.sub.2PCl), methyltriphenylphosphonium
bromide (MePh.sub.3PBr), and benzyltriphenylphosphonium chloride
(BnPh.sub.3PCl).
[0071] The phosphorus reagent, such as phosphine, is incorporated
into the reaction mixture in substantially any useful amount.
Exemplary reactions of the invention utilize from about 0.5
equivalents to about 5 equivalents, preferably from about 1
equivalent to about 3 equivalents and, more preferably, from about
1.1 equivalents to about 2 equivalents of the phosphorus reagent
with respect to the carbonyl-containing substrate.
Solvent
[0072] In an exemplary embodiment, the oxime is contacted with the
phosphorus reagents (e.g., phosphine) and the acyl donor in the
presence of an organic solvent. The solvent can be a protic or an
aprotic solvent. In a preferred embodiment, the solvent is an
aprotic solvent. In a further preferred embodiment, the aprotic
solvent is an aromatic solvent (e.g., toluene, xylene and
combinations thereof).
[0073] In an exemplary embodiment, in which the oxime is compound
3, the solvent is preferably toluene.
B. Enamide to Amide
[0074] In another aspect, the current invention provides a method
for converting an enamide to an amide. The method includes,
contacting the enamide with a hydrogenation catalyst and hydrogen
or a hydrogen transfer reagent under conditions appropriate to
hydrogenate a carbon-carbon double bond of the enamide, thereby
converting the enamide to an amide.
[0075] The methods of the present invention are not limited to
practice on enamides characterized by any particular structural
element or membership within any single structural class. The
methods disclosed herein are of broad applicability across a wide
range of enamide structures. Exemplary reagents and reaction
conditions for the conversion of the enamide to the amide are set
forth below.
Catalyst
[0076] The carbon-carbon double bonds of the enamides are reduced
by processes such as hydrogen transfer, in which a hydrogen-donor
such as a secondary alcohol, and in particular isopropanol is used;
and hydrogenation, in which molecular hydrogen is used. Both
hydrogen transfer and hydrogenation processes require a catalyst or
catalytic system to activate the reducing agent, namely an alcohol
or molecular hydrogen, respectively.
[0077] In selected embodiments of the present invention, the
enamide substrate is chiral or prochiral and the reduction,
hydrogen transfer or hydrogenation is performed in a
stereoselective manner. In this embodiment, it is generally
preferred that the catalyst is a chiral catalyst. Also preferred is
that the chiral catalyst is a transition metal catalyst.
[0078] Numerous reports have been published on chiral transition
metal complex catalysts usable in catalytic asymmetric
hydrogenation reactions. Among these, transition metal complexes of
ruthenium, iridium, rhodium, palladium, nickel or the like, which
contain optically active phosphines as ligands, have been reported
to exhibit excellent performance as catalysts for asymmetric
synthetic reactions, and some of them are already used in
industrial application. See, e.g., ASYMMETRIC CATALYSIS IN ORGANIC
SYNTHESIS, Ed., R. Noyori, Wiley & Sons (1994); and G. Franci ,
et al., Angewandte Chemie. Int. Ed., 39: 1428-1430 (2000).
[0079] In a preferred embodiment, the metal in the catalyst is
rhodium (Rh), ruthenium (Ru) or iridium (Ir).
[0080] In an exemplary embodiment, the hydrogenation catalyst used
in the present methods is a chiral complex of a transition metal
with a chiral phosphine ligand, including monodentate and bidentate
ligands. For example, preferred bidentate ligands include
1,2-bis(2,5-dimethylphospholano)ethane (MeBPE),
P,P-1,2-phenylenebis{(2,5-endo-dimethyl)-7-phosphabicyclo[2.2.1]heptane}
(MePennPhos), 5,6-bis(diphenylphosphino) bicyclo[2.2.1]hept-2-ene
(NorPhos) and 3,4-bis(diphenylphosphino)N-benzyl pyrrolidine
(commercially available as catASium.RTM. D).
##STR00014##
[0081] In a preferred embodiment for making the amide derived from
tetralones, the chiral catalyst is
(R,S,R,S)-MePennPhos(COD)RhBF.sub.4, (R,R)-MeBPE(COD)RhBF.sub.4,
(R,R)--NorPhos(COD)RhBF.sub.4 (Brunner et al., Angewandte Chemie
91(8): 655-6 (1979)), or (R,R)-catASium.RTM. D(COD)RhBF.sub.4
(Nagel et al., Chemische Berichte 119(11): 3326-43 (1986)).
[0082] The catalyst is present in the reaction mixture in any
useful amount. Determining an appropriate catalyst structure and an
effective amount of this catalyst is well within the abilities of
those skilled in the art. In an exemplary embodiment, the catalyst
is present in an amount of from about 0.005 mol % to about 1 mol %
Generally, it is preferred that the catalyst be present in an
amount of from about 0.01 mol % to about 0.5 mol % and, even more
preferably, from about 0.02 mol % to about 0.2 mol %.
[0083] In an exemplary embodiment, the enamide is hydrogenated to
the corresponding amide in the presence of from about 0.02 to about
0.3 mol %, preferably, from about 0.03 to about 0.2 mol %, and even
more preferably, from about 0.03 to about 0.1 mol % Rh-MeBPE
catalyst.
[0084] In another exemplary embodiment, the enamide is hydrogenated
to give the amide in the presence of about 0.1 to about 1.0 mol %,
preferably about 0.1 to about 0.5 mol % and, more preferably about
0.3 mol % of a Rh-PennPhos catalyst.
[0085] In another exemplary embodiment, the enamide is hydrogenated
to give the amide in the presence of about 0.005 to about 1.0 mol
%, preferably about 0.01 to about 0.5 mol % and, more preferably
about 0.02 to about 0.1 mol % of (R,R)-NorPhos(COD)RhBF.sub.4
catalyst.
[0086] A presently preferred catalyst of use in the invention
provides the amide in a high yield of at least 85%, preferably at
least 90% and more preferably at least 95% yield from the enamide.
A generally preferred catalyst is one that provides high yields of
amides when the synthesis is on a large scale of at least 300
grams, preferably at least 500 grams, more preferably at least 750
grams and even still more preferably at least 1,000 g. Preferred
catalysts provide the amides in the high yield set forth above when
the reaction is carried out on the large scale, also set forth
above. An exemplary catalyst having these desirable properties is
(R,R)-NorPhos(COD)RhBF.sub.4.
Hydrogen Pressure
[0087] When the conversion of the C--C double bond of the enamide
to the corresponding C--C single bond is effected by hydrogenation,
the pressure of the hydrogen in the reaction vessel can be adjusted
to optimize the reaction yield and stereoselectivity. The methods
of the invention are practiced with any useful hydrogen pressure,
and those with skill in the art will understand how to adjust the
hydrogen pressure to optimize the desired result.
[0088] In an exemplary embodiment, the enamide is hydrogenated, to
afford the amide, at a hydrogen pressure of about 2 to about 10
bar, preferably about 4 to about 8 bar and, more preferably, about
5 to about 6 bar.
Solvent
[0089] The methods of the invention are not limited to practice
with any one solvent or any class of solvents, e.g. protic,
aprotic, aromatic, or aliphatic. Choice of an appropriate solvent
for a particular reaction is well within the abilities of those of
skill in the art.
[0090] In an exemplary embodiment, the enamide is converted to the
amide in the presence of a solvent, which is a protic solvent, an
aprotic solvent, or a mixture thereof. In a preferred embodiment
the solvent is a protic solvent, which is an alcohol, more
preferably, a C.sub.1 to C.sub.4-alcohol. In other preferred
embodiments, the alcohol is methanol, ethanol, n-propanol,
iso-propanol, n-butanol, 2-butanol, or 2,2,2-trifluoroethanol
(CF.sub.3CH.sub.2OH). In a presently preferred embodiment, the
alcohol is iso-propanol.
[0091] In another exemplary embodiment, the aprotic solvent is an
aromatic solvent, a non-aromatic solvent or a mixture thereof.
Exemplary aromatic solvents of use in the present invention include
toluene, benzene, and xylene, and preferably less toxic aromatic
solvents such as toluene and xylene. Exemplary non-aromatic
solvents of use in the methods of the invention include
tetrahydrofuran (THF), dichloromethane (CH.sub.2Cl.sub.2), ethyl
acetate (EtOAc), and acetonitrile (CH.sub.3CN).
[0092] The solvent and substrate are present in essentially any
useful ratio. In an exemplary embodiment, the solvent and substrate
are present in amounts that provide a substrate solution of from
about 0.05 M to about 0.5 M, preferably, from about 0.1 M to about
0.3 M and, more preferably, from about 0.12 M to about 0.34 M.
Amide
[0093] The amides formed by the methods of the invention have
diverse structures and can include alkyl, heteroalkyl, aryl and
heteroaryl substructures. In an exemplary embodiment, the amide has
the formula:
##STR00015##
in which R.sup.1-R.sup.3 and R.sup.5 are as discussed above.
[0094] As discussed previously, the methods of the invention are
useful for preparing amides that include within their structure the
1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine substructure. Thus, in an
exemplary embodiment, the amide has the formula:
##STR00016##
in which R.sup.4 and R.sup.5 are as described above.
[0095] An exemplary amide is a trans amide, having the formula:
##STR00017##
[0096] A further exemplary amide has the formula:
##STR00018##
[0097] In a preferred embodiment, the amide has the formula:
##STR00019##
[0098] In each of the amide formulae above, C-1 and C-4 have a
configuration independently selected from (R) and (S), and in a
preferred embodiment, C-1 is of (R)-configuration, and C-4 is of
(S)-configuration.
Enantiomeric or Diastereomeric Excess
[0099] In a preferred embodiment, the enantiomeric excess (ee) of a
desired enantiomer or the diastereomeric excess (de) of a desired
diastereomer produced by the present method is from about 60% ee/de
to about 99% ee/de, preferably from about 70% ee/de to about 99%
ee/de, more preferably, from about 80% ee/de to about 99% ee/de,
still more preferably, from about 90% cc/de to about 99% ee/de.
[0100] In another preferred embodiment, the invention provides an
amide having an enantiomeric or diastereomeric excess of at least
about 99%, preferably, at least about 99.4% and, more preferably,
at least about 99.8%. Amides that are essentially free of their
optical antipodes are accessible through the methods of the
invention.
[0101] When using rhodium catalyst systems based on chiral
bidentate ligands, such as those derived from
1,2-bis(phospholano)ethane (BPE) ligands,
P,P-1,2-phenylenebis(7-phosphabicyclo[2.2.1]heptane) (PennPhos)
ligands, 5,6-bis(phosphino)bicyclo[2.2.1]hept-2-ene (NorPhos)
ligands, or 3,4-bis(phosphino) pyrrolidine (commercially available
as catASium.RTM. D) ligands, the diastereomeric purity of the trans
amide derived from the corresponding enamide is surprisingly
high.
[0102] In a preferred embodiment, when the amide includes the
1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine subunit, the method provides
(1R,4S)-trans amide, which is substantially free of its cis
isomer.
[0103] In one exemplary embodiment, the enamide is hydrogenated at
about 4 to about 6 bar hydrogen pressure using about 0.03 to about
0.05 mol % of a Rh-Me-BPE catalyst in isopropanol, to give the
trans N-acetyl amide in about 80 to about 99% de, preferably at
least 95% de, and more preferably at least 99% de.
[0104] In another exemplary embodiment, the enamide is hydrogenated
at about 4 to about 5 bar hydrogen pressure, using about 0.2 to
about 0.5 mol % of a Rh-PennPhos catalyst in isopropanol, to give
the trans N-acetyl amide in about 80 to about 99% de, preferably at
least 95% de, and more preferably at least 99% de.
[0105] In yet another exemplary embodiment the enamide is
hydrogenated at about 5 to about 8 bar hydrogen pressure, using
about 0.01 to about 0.05 mol % of (R,R)NorPhos(COD)RhBF.sub.4
catalyst in isopropanol to give the trans N-acetyl amide in about
80-99% de, preferably at least 95% de, and more preferably at least
99% de.
[0106] In a preferred embodiment, the hydrogenation is carried out
at an enamide concentration of about 0.1 M to about 0.3 M.
[0107] In a further exemplary embodiment, the stereoisomerically
enriched amide is purified, or further enriched, by selective
crystallization. In another exemplary embodiment, the amide is
purified, or enriched, to an enantiomeric or diastereomeric purity
of about 90 to about 99% ee/de. In another exemplary embodiment,
the amide is purified, or enriched, to an enantiomeric or
diastereomeric purity of about 95 to about 99% ee/de.
[0108] The product of the hydrogenation or hydrogen transfer can be
enantiomerically or diastereomerically enriched by methods known in
the art, e.g., chiral chromatography, selective crystallization and
the like. It is generally preferred that the enrichment afford a
product at least about 95% of which is a single stereoisomer. More
preferably, at least about 97%, still more preferably at least
about 99% is a single stereoisomer.
[0109] In a presently preferred embodiment, the enriched trans
amide is purified, or enriched, by selective crystallization,
affording the desired trans isomer in about 99% de.
C. Amide to Amine
[0110] In another aspect, the current invention provides methods
for converting an amide formed from the corresponding enamide to an
amine. In an exemplary embodiment, the method includes contacting
the amide with a deacylating reagent under conditions appropriate
to deacylate the amide, thereby forming an amine.
[0111] In an exemplary embodiment, the amine has the formula:
##STR00020##
or a salt thereof. The radicals have the identities set forth
above.
[0112] The amine can be of any desired structure, however, it is
preferably a chiral amine. When the amine is chiral, the
enantiomeric excess (ee) of a desired enantiomer or the
diastereomeric excess (de) of a desired diastereomer produced by
the present method is from about 60% ee/de to about 99% ee/de,
preferably from about 70% ee/de to about 99% ee/de, more
preferably, from about 80% ee/de to about 99% cc/de, still more
preferably, from about 90% cc/de to about 99% cc/de.
[0113] In another preferred embodiment, the invention provides an
amine having an enantiomeric or diastereomeric excess of at least
about 99%, preferably, at least about 99.4% and, more preferably,
at least about 99.8%. Amines that are essentially free of their
optical antipodes are accessible through the methods of the
invention.
[0114] In an exemplary embodiment, the amine includes the
1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine substructure, and has the
formula:
##STR00021##
or a salt thereof.
[0115] In a preferred embodiment, the amine is a trans amine,
having the formula:
##STR00022##
or a salt thereof.
[0116] An exemplary amine has the formula:
##STR00023##
in which Q.sup.- is an anion. The index e is a number from 0 to 1.
The index may take a fractional value, indicating that the amine
salt is a hemi-salt.
[0117] In a preferred embodiment, the amine has the formula:
##STR00024##
wherein Q.sup.- and e are as described above.
[0118] C-1 and C-4 have a configuration independently selected from
(R) and (S). Preferably C-1 is of (R)-configuration, and C-4 is of
(S)-configuration.
[0119] In another preferred embodiment, the amine is in the trans
configuration and is substantially free of the cis isomer.
[0120] The amide is deacylated by any suitable process. Many
methods of deacylating amides to the corresponding amines are known
in the art. In an exemplary embodiment, the deacylating reagent is
an enzyme. Exemplary enzymes of use in this process include those
of the class EC 3.5.1 (e.g., amidase, aminoacylase), and EC
3.4.19.
[0121] In another embodiment, the deacylating reagent is an acid or
a base. The acid or base can be either inorganic or organic.
Mixtures of acids or mixtures of bases are useful as well. When the
deacylating reagent is an acid, it is generally preferred that the
acid is selected so that the acid hydrolysis produces a product
that is a form of the amine. In an exemplary embodiment, the acid
is hydrochloric acid (HCl).
[0122] Other deacylating conditions of use in the present invention
include, but are not limited to, methanesulfonic acid/HBr in
alcoholic solvents, triphenylphosphite/halogen (e.g., bromine,
chlorine) complex and a di-t-butyl dicarbonate/lithium hydroxide
sequence.
[0123] In a preferred embodiment, the amide is deacylated by
treatment with an activating agent, e.g., trifluoromethanesulfonic
anhydride, phosgene, and preferably, oxalyl chloride/pyridine. The
reaction is quenched with an alcohol, preferably a glycol, e.g.,
propylene glycol.
[0124] When the amide includes the
1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or
1,2,3,4-tetrahydro-1-naphthalenamine substructure, the deacylation
conditions preferably are selected such that formation of any
dihydronaphthalene side products are minimized.
[0125] The amine can be isolated or enriched. A currently preferred
method of isolating or enriching the amine includes at least one
step of selective crystallization.
[0126] The amine is optionally N-alkylated or N-acylated to prepare
the corresponding N-alkyl or N-acyl derivative.
[0127] In an exemplary embodiment, the invention provides a method
suitable for the large scale preparation of trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine 5 and
salt forms thereof. In an exemplary embodiment, the process
involves the synthesis of an enamide, e.g. enamide 3, starting from
optically pure (4S)-tetralone 1 via the oxime 2, and subjecting
enamide 3 to catalytic asymmetric hydrogenation to afford amide 4,
which upon N-deacylation affords trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine 5, or a
salt thereof (Scheme 2).
##STR00025## ##STR00026##
[0128] In a preferred embodiment, the compound prepared by the
route of Scheme 2 is (1R,4S)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine. Even
more preferred is the preparation of the compound substantially
free of its cis isomer.
[0129] Compounds according to formula 5 include stereoisomers of
desmethylsertraline. The N-methyl analog of 5 is a stereoisomer of
sertraline.
[0130] The primary clinical use of sertraline is in the treatment
of depression. In addition, U.S. Pat. No. 4,981,870 discloses and
claims the use of sertraline and related compounds for the
treatment of psychoses, psoriasis, rheumatoid arthritis and
inflammation.
[0131] (1R,4S)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine and
(1S,4R)-trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine are
useful in the treatment of CNS-related disorders that are modulated
by monoamine activity (U.S. Patent Application No. 2004/0092605 to
Jerussi et al.; cited references). Those CNS-related disorders
include mood disorders (e.g. depression), anxiety disorders (e.g.,
OCD), behavioral disorders (e.g. ADD and ADHD), eating disorders,
substance abuse disorders and sexual function disorders.
Potentially, these molecules produce diminished side effects as
compared to the current standards of treatment. The compounds are
also useful for the prophylaxis of migraine.
IV. Compositions
[0132] In another aspect, the invention provides a mixture
comprising:
##STR00027##
in which R.sup.4 is a member selected from substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl.
Q.sup.- is an anion. The indices c and f independently represent a
number from 0 to 1. Thus, the structures above encompass
hemi-salts.
[0133] The indices x and y are independently selected from (S) and
(R). In one embodiment, when x is (S), y is (S) and when x is (R),
y is (R). In another embodiment, when x is (S), y is (R).
[0134] In an exemplary embodiment, R.sup.4 is substituted or
unsubstituted aryl. A preferred aryl moiety is a substituted or
unsubstituted phenyl moiety.
[0135] In another exemplary embodiment, the mixture comprises
compounds with the following formulae:
##STR00028##
in which e, f, x and y are as described above.
[0136] The mixtures set forth above are of use in pharmaceutical
formulations. It is generally recognized that stereoisomers of
bioactive compounds may have different properties. For example, the
S-enantiomer of the beta-adrenergic blocking agent, propranolol, is
known to be 100 times more potent than the R-enantiomer. However,
potency is not the only concern in the field of pharmaceuticals.
Optical purity is important since certain isomers may actually be
deleterious rather than simply inert. Mixtures of diastereomers
effectively combine and modulate the properties of each of the pure
diastereomers. Thus, in selected embodiments, the invention
provides mixtures of diastereomeric compounds A and B.
[0137] According to the present invention, a therapeutically
effective amount of A or B, which may be a pure isomer or a mixture
of any A and B, may also be administered to a person in need of
therapy.
[0138] Disorders treatable with compounds prepared by the methods
of the present invention include, but are not limited to,
depression, major depressive disorder, bipolar disorder, chronic
fatigue disorder, seasonal affective disorder, agoraphobia,
generalized anxiety disorder, phobic anxiety, obsessive compulsive
disorder (OCD), panic disorder, acute stress disorder, social
phobia, fibromyalgia, neuropathic pain, posttraumatic stress
disorder, premenstrual syndrome, menopause, perimenopause and male
menopause.
[0139] In addition to their beneficial therapeutic effects,
compounds prepared by methods of the present invention may provide
the additional benefit of avoiding or reducing one or more of the
adverse effects associated with conventional mood disorder
treatments. Such side effects include, for example, insomnia,
breast pain, weight gain, extrapyramidal symptoms, elevated serum
prolactin levels and sexual dysfunction (including decreased
libido, ejaculatory dysfunction and anorgasmia).
[0140] The compounds (and their mixtures) prepared by the methods
of the present invention are also effective for treating disruptive
behavior disorders, such as attention deficit disorder (ADD) and
attention deficit/hyperactivity disorder (ADHD), which is in
accordance with its accepted meaning in the art, as provided in the
DSM-IV-TR.TM.. These disorders are defined as affecting one's
behavior resulting in inappropriate actions in learning and social
situations. Although most commonly occurring during childhood,
disruptive behavior disorders may also occur in adulthood.
[0141] The term "treating" when used in connection with the
foregoing disorders means amelioration, prevention or relief from
the symptoms and/or effects associated with these disorders and
includes the prophylactic administration of a compound of formula A
or B, a mixture thereof, or a pharmaceutically acceptable salt of
either, to substantially diminish the likelihood or seriousness of
the condition.
[0142] Pure compounds and mixtures prepared by the methods of the
present invention are also effective for treating eating disorders.
Eating disorders are defined as a disorder of one's appetite or
eating habits or of inappropriate somatotype visualization. Eating
disorders include, but are not limited to, anorexia nervosa;
bulimia nervosa, obesity and cachexia.
[0143] Mood disorders, such as depressive disorders, e.g.,
dysthymic disorder or major depressive disorder; bipolar disorders,
e.g., bipolar I disorder, bipolar II disorder, and cyclothymic
disorder; mood disorder due to a general medical condition with
depressive, and/or manic features; and substance-induced mood
disorder can be treated using compounds and mixtures of the
invention.
[0144] Anxiety disorders, such as acute stress disorder,
agoraphobia without history of panic disorder, anxiety disorder due
to general medical condition, generalized anxiety disorder,
obsessive-compulsive disorder, panic disorder with agoraphobia,
panic disorder without agoraphobia, posttraumatic stress disorder,
specific phobia, social phobia, and substance-induced anxiety
disorder are treatable with compounds and mixtures of the
invention.
[0145] Compounds and mixtures prepared by methods of the invention
are also effective for treating cerebral function disorders. The
term cerebral function disorder, as used herein, includes cerebral
function disorders involving intellectual deficits, and may be
exemplified by senile dementia, Alzheimer's type dementia, memory
loss, amnesia/amnestic syndrome, epilepsy, disturbances of
consciousness, coma, lowering of attention, speech disorders,
Parkinson's disease and autism.
[0146] The compounds and mixtures are also of use to treat
schizophrenia and other psychotic disorders, such as catatonic,
disorganized, paranoid, residual or differentiated schizophrenia;
schizophreniform disorder; schizoaffective disorder; delusional
disorder; brief psychotic disorder; shared psychotic disorder;
psychotic disorder due to a general medical condition with
delusions and/or hallucinations.
[0147] The compounds of formulae A and B are also effective for
treating sexual dysfunction in both males and females. Disorders of
this type include, for example, erectile dysfunction and orgasmic
dysfunction related to clitoral disturbances.
[0148] Compounds and mixtures prepared by the methods of the
present invention are also useful in the treatment of substance
abuse, including, for example addiction to cocaine, heroin,
nicotine, alcohol, anxiolytic and hypnotic drugs, cannabis
(marijuana), amphetamines, hallucinogens, phenylcyclidine, volatile
solvents, and volatile nitrites. Nicotine addiction includes
nicotine addiction of all known forms, such as, for example,
nicotine addiction resulting from cigarette, cigar and/or pipe
smoking, as well as addiction resulting from tobacco chewing. In
this respect, due to their activity as norepinephrine and dopamine
uptake inhibitors, the compounds of the present invention can
function to reduce the craving for the nicotine stimulus. Bupropion
(ZYBAN.RTM., GlaxoSmithKline, Research Triangle Park, N.C., USA) is
a compound that has activity at both norepinephrine and dopamine
receptors, and is currently available in the United States as an
aid to smoking cessation treatment. As a benefit beyond the
therapeutic activity of buproprion, however, the compounds of the
present invention provide an additional serotonergic component.
[0149] Pure compounds and mixtures prepared by the methods of the
present invention are also effective in the prophylaxis of
migraine.
[0150] Compounds and mixtures prepared by the methods of the
present invention are also useful in the treatment of pain
disorders, including for example fibromyalgia, chronic pain, and
neuropathic pain. The term "fibromyalgia" describes several
disorders, all characterized by achy pain and stiffness in soft
tissues, including muscles, tendons, and ligaments. Various
alternative terms for fibromyalgia disorders have been used in the
past, including generalized fibromyalgia, primary fibromyalgia
syndrome, secondary fibromyalgia syndrome, localized fibromyalgia,
and myofascial pain syndrome. Previously, these disorders were
collectively called fibrositis or fibromyositis syndromes.
Neuropathic pain disorders are thought to be caused by
abnormalities in the nerves, spinal cord, or brain, and include,
but are not limited to: burning and tingling sensations,
hypersensitivity to touch and cold, phantom limb pain, postherpetic
neuralgia, and chronic pain syndrome (including, e.g., reflex
sympathetic dystrophy and causalgia).
[0151] The magnitude of a prophylactic or therapeutic dose of a
compound of formulae A, B or mixtures thereof will vary with the
nature and severity of the condition to be treated and the route of
administration. The dose, and perhaps the dose frequency, will also
vary according to the age, body weight and response of the
individual patient. In general, the total daily dose ranges of
compounds of the present invention will be from about 1 mg per day
to about 500 mg per day, preferably about 1 mg per day to about 200
mg per day, in single or divided doses. Dosages of less than 1 mg
per day of compounds of the invention are also within the scope of
the instant invention.
[0152] Any suitable route of administration may be employed. For
example, oral, rectal, intranasal, and parenteral (including
subcutaneous, intramuscular, and intravenous) routes may be
employed. Dosage forms can include tablets, troches, dispersions,
suspensions, solutions, capsules and patches.
[0153] Pharmaceutical compositions of the present invention include
as active ingredient, a single compound, or a mixture of compounds,
of formula A or B, or a pharmaceutically acceptable salt of A or B,
together with a pharmaceutically acceptable carrier and,
optionally, with other therapeutic ingredients.
[0154] The pharmaceutically acceptable carrier may take a wide
variety of forms, depending on the route desired for
administration, for example, oral or parenteral (including
intravenous). In preparing the composition for oral dosage form,
any of the usual pharmaceutical media may be employed, such as,
water, glycols, oils, alcohols, flavoring agents, preservatives,
and coloring agents in the case of oral liquid preparation,
including suspension, elixirs and solutions. Carriers such as
starches, sugars, microcrystalline cellulose, diluents, granulating
agents, lubricants, binders and disintegrating agents may be used
in the case of oral solid preparations such as powders, capsules
and caplets, with the solid oral preparation being preferred over
the liquid preparations. Preferred solid oral preparations are
tablets or capsules, because of their ease of administration. If
desired, tablets may be coated by standard aqueous or nonaqueous
techniques. Oral and parenteral sustained release dosage forms may
also be used.
[0155] Exemplary formulations, are well known to those skilled in
the art, and general methods for preparing them are found in any
standard pharmacy school textbook, for example, Remington, THE
SCIENCE AND PRACTICE OF PHARMACY, 21st Ed., Lippincott.
[0156] Thus, as set forth herein, the invention is exemplified by
the following aspects and embodiments.
[0157] A method for converting an oxime into an enamide. The method
includes, (a) contacting the oxime with a phosphine and an acyl
donor, under conditions appropriate to convert the oxime into the
enamide.
[0158] The method according to the preceding paragraph in which the
oxime has the formula:
##STR00029##
wherein R.sup.1, R.sup.2 and R.sup.3 are members independently
selected from H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocycloalkyl. At least two of R.sup.1, R.sup.2
and R.sup.3 are optionally joined to form a ring system selected
from substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl
and substituted or unsubstituted heteroaryl.
[0159] The method of any of the preceding paragraphs in which the
oxime has the formula:
##STR00030##
wherein Ar is a member selected from substituted or unsubstituted
aryl and substituted or unsubstituted heteroaryl. R.sup.4 is a
member selected from H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocycloalkyl; and, the index a is
selected from the integers from 1 to 4.
[0160] The method of any of the preceding paragraphs in which
R.sup.4 is substituted or unsubstituted aryl.
[0161] The method of any of the preceding paragraphs in which
R.sup.4 is substituted or unsubstituted phenyl.
[0162] The method of any of the preceding paragraphs in which
R.sup.4 is phenyl substituted with at least one halogen.
[0163] The method of any of the preceding paragraphs in which
R.sup.4 has the formula:
##STR00031##
wherein X.sup.1 and X.sup.2 are independently selected halo
moieties.
[0164] The method of any of the preceding paragraphs in which
X.sup.1 and X.sup.2 are each chloro.
[0165] The method of any of the preceding paragraphs in which Ar is
substituted or unsubstituted phenyl.
[0166] The method of any of the preceding paragraphs in which the
oxime has the formula:
##STR00032##
[0167] The method of any of the preceding paragraphs in which acyl
donor has the formula: Z--C(O)--R.sup.5, wherein Z is a leaving
group. R.sup.5 is a member selected from H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl.
[0168] The method according any of the preceding paragraphs in
which Z has the formula:
R.sup.6--C(O)--O--
wherein R.sup.6 is a member selected from substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl.
[0169] The method according to any of the preceding paragraphs in
which both R.sup.5 and R.sup.6 are independently selected
substituted or unsubstituted C.sub.1-C.sub.4 moieties.
[0170] The method according to any of the preceding paragraphs in
which the phosphine has the formula:
P(Q).sub.3
wherein each Q is a member independently selected from H,
substituted or unsubstituted alkyl and substituted or unsubstituted
aryl.
[0171] The method according to any of the preceding paragraphs in
which each Q is a member independently selected from substituted or
unsubstituted C.sub.1-C.sub.6 alkyl.
[0172] The method according to any of the preceding paragraphs in
which the contacting is in solution with an aprotic solvent.
[0173] The method according to any of the preceding paragraphs in
which the aprotic solvent is an aromatic solvent.
[0174] The method according to any of the preceding paragraphs in
which the aprotic aromatic solvent is selected from toluene, xylene
and combinations thereof.
[0175] The method according to any of the preceding paragraphs in
which enamide has the formula:
##STR00033##
[0176] The method according to any of the preceding paragraphs in
which C-4 has a configuration selected from R, S and mixtures
thereof.
[0177] The method according to any of the preceding paragraphs in
which C-4 is of S configuration.
[0178] The method according to any of the preceding paragraphs
further including: (b) contacting the enamide formed in step (a)
with a hydrogenation catalyst and hydrogen or hydrogen transfer
reagent under conditions appropriate to hydrogenate a carbon-carbon
double bond of the enamide, thereby converting the enamide to an
amide.
[0179] The method according to any of the preceding paragraphs in
which the catalyst is a chiral catalyst.
[0180] The method according to any of the preceding paragraphs in
which the chiral catalyst is a complex of a transition metal with a
chiral phosphine ligand.
[0181] The method according to any of the preceding paragraphs in
which the amide is a racemic or chiral amide.
[0182] The method according to any of the preceding paragraphs in
which amide has the formula:
##STR00034##
[0183] The method according to any of the preceding paragraphs in
which C-1 and C-4 have a configuration independently selected from
R and S.
[0184] The method according to any of the preceding paragraphs in
which C-1 is of R configuration; and C-4 is of S configuration.
[0185] The method according to any of the preceding paragraphs
further including: (c) contacting the amide with a deacylating
reagent under conditions appropriate to deacylate --HNC(O)R.sup.5
of the amide, thereby forming an amine.
[0186] The method according to any of the preceding paragraphs
including: (d) isolating said amine.
[0187] The method according to any of the preceding paragraphs in
which isolating comprises selective crystallization.
[0188] The method according to any of the preceding paragraphs in
which the amine has the formula:
##STR00035##
wherein Q.sup.- is an anion; and e is 0 to 1.
[0189] The method according to any of the preceding claims in which
C-1 and C-4 have a configuration independently selected from R and
S.
[0190] The method according to any preceding claims in which C-1 is
of R configuration; and C-4 is of S configuration.
[0191] A method of converting an oxime having the formula
##STR00036##
into an enamide having the formula:
##STR00037##
wherein R.sup.4 is selected from substituted or unsubstituted aryl
and substituted or unsubstituted heteroaryl. R.sup.5 is selected
from H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocycloalkyl. The method includes: (a) contacting
the oxime with a phosphine and an acyl donor under conditions
appropriate to convert the oxime to the enamide.
[0192] The method according to the preceding paragraph in which C-4
is of S configuration.
[0193] The method according to the preceding paragraphs in which
the phosphine is a trialkylphosphine.
[0194] The method according to the preceding paragraphs in which
the oxime, the acyl donor and the phosphine are dissolved in an
aromatic solvent.
[0195] The method according to the preceding paragraphs in which
the acyl donor is an alkyl anhydride.
[0196] The method according to the preceding paragraphs including:
(b) contacting the enamide formed in step (a) with a chiral
hydrogenation catalyst and hydrogen under conditions appropriate to
hydrogenate a carbon-carbon double bond conjugated to C(O) of the
enamide, thereby converting the enamide to an amide having the
formula:
##STR00038##
wherein C-1 has a configuration selected from R and S.
[0197] The method according to the preceding paragraphs in which
the chiral catalyst includes rhodium complexed to a chiral
phosphine ligand.
[0198] The method according to the preceding paragraphs further
including: (c) contacting the amide with a deacylating reagent
under conditions appropriate to deacylate --HNC(O)R.sup.5 of the
amide, thereby forming an amine having the formula:
##STR00039##
wherein Q.sup.- is an anion. The index e is 0 or 1.
[0199] The method according to the preceding paragraphs in which
the deacylating reagent is an enzyme.
[0200] The method according to the preceding paragraphs in which
the deacylating reagent is an acid.
[0201] A mixture comprising:
##STR00040##
wherein R.sup.4 is a member selected from substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl.
Q.sup.- is an anion. The indices e and f are independently selected
numbers from 0 to 1; and x and y are selected from R and S, such
that when x is R, y is R, and when x is S, y is S.
[0202] The mixture according to the preceding paragraph in which A
is present in the mixture in a diastereomeric excess of at least
90% relative to B.
[0203] The mixture according to the preceding paragraphs in which A
is present in said mixture in a diastereomeric excess of at least
98% relative to B.
[0204] The mixture according to the preceding paragraphs in which x
and y are R.
[0205] The mixture according to the preceding paragraphs in which x
and y are S.
[0206] The mixture according to the preceding paragraphs in which
R.sup.4 is substituted or unsubstituted phenyl.
[0207] A pharmaceutical formulation including a mixture according
to the preceding paragraphs.
[0208] The following examples are provided to illustrate selected
embodiments of the invention and are not to be construed as
limiting its scope.
EXAMPLES
Example 1
Synthesis of
N--((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1-yl)acetamide
(3)
1.1. Synthesis of Oxime 2
[0209] A suspension formed from a mixture of (S)-tetralone 1 (56.0
g, 0.192 mol), hydroxylamine hydrochloride (14.7 g, 0.212 mol), and
sodium acetate (17.4 g, 0.212 mol) in methanol (168 mL) was heated
to reflux for 1 to 5 hours under a N.sub.2 atmosphere. The progress
of the reaction was monitored by HPLC. After the reaction was
complete, the reaction mixture was concentrated in vacuo. The
residue was diluted with toluene (400 mL) and 200 ml water. The
organic layer was separated and washed with an additional 200 mL
water. The organic layer was concentrated and dried to give crude
solid oxime 2 (58.9 g, 100%), m. p. 117-120.degree. C.
[0210] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm) 9.17 (br,
1H, OH), 7.98 (m, 1H), 7.36 (d, 1H, J=8.0 Hz), 7.29 (m, 2H), 7.20
(d, 1H, J==2.4 Hz), 6.91 (m, 2H), 4.11 (dd, 1H, J=7.2 Hz, 4.4 Hz),
2.82 (m, 2H), 2.21 (m, 1H), 2.08 (m, 1H). .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 154.94, 144.41, 140.40, 132.83, 130.92, 130.82,
130.68, 130.64, 129.98, 129.38, 128.12, 127.64, 124.48, 44.52,
29.51, 21.27.
1.2. Synthesis of Enamide 3
[0211] The solution of the crude oxime 2 (59 g, 0.193 mol) in
toluene (500 mL) was purged with N.sub.2 for 30 min. Et.sub.3P (25
g, 0.212 mol) was charged. After stirring for 10 min, acetic
anhydride (21.6 g, 20 mL, 0.212 mol) was added. The reaction
mixture was refluxed for 8 to 13 h. Progress of the reaction was
monitored by HPLC. The reaction mixture was cooled to room
temperature. 6N NaOH (aq) (86 mL, 0.516 mol) and 1.0 M
(n-Bu).sub.4NOH in methanol (1.0 mL) were added. The hydrolysis was
complete in about 2 to 4 h. The organic layer was separated and
diluted with EtOAc (300 mL) and 2-BuOH (30 mL). The diluted organic
solution was washed with 1% HOAc (aq) solution (300 mL) and DI
water (3.times.300 mL) and concentrated to about 350 mL of a slurry
in vacuo. The slurry was diluted with heptane (100 mL) and 2-BuOH
(4 mL) and heated to reflux to form a clear solution. Heptane (50
to 200 mL) was slowly added until a cloudy solution formed. The
suspension was slowly cooled to rt. The product was filtered out,
washed with 30% toluene and 70% heptane (3.times.100 mL) solution
and dried in a vacuum oven to give 56.9 g white solid (enamide 3,
89% yield), m. p. 167-168.degree. C.
[0212] (S)-Tetralone 1 (50.0 g, 0.172 mol) was slurried in methanol
(150 mL) with hydroxylamine hydrochloride (13.1 g, 0.189 mol) and
sodium acetate (15.5 g, 0.189 mol). The resulting suspension was
heated to reflux for 2 to 6 h under an inert atmosphere with
progress monitored by HPLC. On completion, the mixture was cooled
to 25.degree. C., diluted with toluene (300 mL) and quenched with
1.7 N NaOH (100 mL). The mixture was concentrated in vacuo under
reduced pressure, the aqueous layer removed and the organic layer
washed further with DI water (100 mL). Further toluene (300 mL) was
charged to the vessel and water removed by azeotropic distillation.
Once at ambient temperature, n-Bu.sub.3P (47.1 mL, 0.183 mol) was
charged to the reactor, followed by acetic anhydride (32.5 mL,
0.344 mol). The reaction was heated to reflux and monitored by
HPLC. After 20-24 h, the reaction was cooled to ambient temperature
and quenched with 6 N NaOH (120 mL). This mixture was allowed to
react for 2 to 6 h before the aqueous layer was removed. The
organic phase was washed with DI water (100 mL). Concentration of
the mixture in vacuo, cooling to room temperature and diluting with
isopropanol (50 mL) was done prior to addition of heptane to assist
with crystallization. An initial charge of heptane (50 mL) was
followed by an additional 650 mL. Aging of the slurry followed by
filtration, washing (4.times.100 mL heptane) and drying yielded a
light yellow solid (enamide 3, 44.1 g, 77%).
[0213] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm) 7.35 (d, 1H,
J=8.4 Hz), 7.26 (m, 3H), 7.17 (m, 1H), 7.05 (dd, 1H, J=8.0, 1.6
Hz), 7.00 (br, 1H), 6.87 (m, 0.82H, 82% NH rotamer), 6.80 (br,
0.18H, 18% NH rotamer), 6.31 (t, 0.82H, 14.8 Hz, 82% H rotamer),
5.91 (br, 0.18H, 18% H rotamer), 4.12 (br, 0.18H, 18% H rotamer),
4.03 (t, 0.82H, J=8.0 Hz, 82% H rotamer), 2.72 (m, 1H), 2.61 (ddd,
1H, J=16.8, 8.0, 4.8 Hz), 2.17 (s, 2.46H, 82% CH.sub.3 rotamer),
1.95 (s, 0.54H, 18% CH.sub.3 rotamer). 100 MHz .sup.13C NMR
(CDCl.sub.3) .delta. 169.3, 143.8, 137.7, 132.3, 131.8, 131.4,
130.5, 130.3, 130.2, 128.8, 128.1, 127.8, 127.2, 123.8, 122.5,
121.2, 117.5, 42.6, 30.3, 24.1.
Example 2
Synthesis of
N-((1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)aceta-
mide (4)
[0214] The enamide 3 (24 g, 72 mmol) was slurried in degassed
isopropanol (200 mL). The resulting slurry was transferred to the
appropriate reactor. Prior to the addition of the catalyst
solution, the content of the reactor was purged with nitrogen. A
solution of (R,R)-MeBPE(COD)RhBF.sub.4 catalyst (20.1 mg, 0.036
mmol, 0.05 mol %) in isopropanol (IPA) (100 mL) was added to the
reactor. The content was cooled to 0.degree. C. and purged with
nitrogen three times. The reactor was then purged with hydrogen and
pressurized to 90 prig. The reaction was aged with agitation at
0.degree. C. for 7.5 h and conversion was monitored by the hydrogen
uptake. The content was then warmed to RT and hydrogen was vented.
After purging with nitrogen, the contents were drained. The
reaction mixture was heated to 50.degree. C. and filtered through a
pad of Celite. The clear orange solution was concentrated to
.about.50% volume (150 mL) and diluted with toluene (5.9 g, 5 wt
%). The suspension was heated to 65.degree. C. and water (14.7 mL)
was added dropwise to form a cloudy solution. The slurry was slowly
cooled to -10.degree. C. and aged for 30 minutes. The solid was
filtered and washed with cold IPA (2.times.45 mL). The cake was
dried under vacuum at 45.degree. C. overnight to afford 20.0 g (83%
yield) of trans acetamide 4 (>99% de).
[0215] .sup.1H NMR (CDCl.sub.3) 400 MHz .delta. 7.34 (dd, 2H,
J=7.9, 2.4 Hz), 7.23 (t, 1H, J=7.5 Hz), 7.15 (m, 2H), 6.85 (dd, 1H,
J=8.2, 2.0 Hz), 6.82 (d, 1H, J=7.7 Hz), 5.72 (d, 1H, J=8.4 Hz),
5.31 (dd, 1H, J=13.2, 8.1 Hz), 4.10 (dd, 1H, J=7.0, 5.9 Hz), 2.17
(m, 2H), 2.06 (s, 3H), 1.87 (m, 1H). 1.72 (m, 1H); .sup.13C NMR
(CDCl.sub.3) 100 MHz .delta. 169.7, 146.9, 138.8, 137.7, 132.6,
130.8, 130.6, 130.5, 130.3, 128.4, 128.3, 127.9, 127.4, 47.9, 44.9,
30.5, 28.4, 23.8.
Example 3
Synthesis of
(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine
hydrochloride (5)
[0216] A solution of trans-acetamide 4 (9.0 g, 26.9 mmol),
n-propanol (45 mL) and 5M hydrochloric acid (45 mL) was refluxed
for approximately 48 h (90-93.degree. C.). During this time, the
reaction temperature was maintained at .gtoreq.90.degree. C. by
periodically collecting the distillate until the reaction
temperature was >92.degree. C. Additional n-propanol was added
periodically to maintain the solution at its original volume. After
the hydrolysis was complete, the solution was slowly cooled to
0.degree. C., resulting in a slurry, which was aged for one hour at
0.degree. C. The reaction mixture was filtered, and the cake was
washed with 1:1 methanol/water (20 mL), followed by t-butyl methyl
ether (20 mL). The wet-cake was dried under vacuum at 45 to
50.degree. C. to afford 7.0 g of the amine hydrochloride 5 (80%
yield).
[0217] .sup.1H NMR (DMSO-d.sub.6) .delta. 1.81-1.93 (m, 2H),
2.12-2.21 (m, 1H), 2.28-2.36 (m, 1H), 4.28 (t, 1H, J=6.8), 4.59
(br.s, 1H), 6.84 (d, 1H, J=7.6), 7.05 (dd, 1H, J=8.4, 1.6), 7.25
(t, 1H, J=7.6), 7.32 (t, 1H, J=7.6), 7.37 (d, 1H, J=1.6), 7.56 (d,
1H, J=8.4), 7.76 (d, 1H, J=7.2), 8.80 (br.s, 3H); .sup.13C NMR
(DMSO-d.sub.6) 147.4, 138.9, 133.6, 131.0, 130.5, 130.4, 130.1,
129.0, 128.9, 128.4, 128.2, 126.8, 47.9, 43.1, 27.8, 25.2.
Example 4
In Situ Formation/Acylation of Oxime
[0218] Oxime 2 was acylated in situ to afford the intermediate 2A,
which undergoes reductive acylation to provide a mixture of the
acylated enamide 3 and the diacylated analog 3A. The reaction was
carried out in either toluene or o-xylene at reflux. The mixture of
3 and 3A was then treated with an aqueous solution of base such as
sodium hydroxide or sodium carbonate, with or without a phase
transfer catalyst (e.g. tetrabutylammonium hydrogen
sulfate/hydroxide), to convert the intermediate 3A to the desired
enamide 3. Exemplary reaction conditions for the conversion of
oxime 2 to enamide 3 are shown in Schemes 3a and 3 b.
##STR00041##
##STR00042##
Example 5
Catalytic Asymmetric Hydrogenation of the Enamide 3 Using
(R,S,R,S)-MePenn Phos(COD)RhBF.sub.4 as the Catalyst
[0219] As shown in Scheme 4, the enamide 3 was subjected to
homogeneous catalytic asymmetric hydrogenation in the presence of a
chiral catalyst, H.sub.2, and a solvent. In this example the
catalyst was derived from the complex of the transition metal
rhodium with the chiral phosphine ligand,
(1R,2S,4R,5S)--P,P-1,2-phenylenebis{(2,5-endo-dimethyl)-7-phosphabicyclo[-
2.2.1]heptane}(R,S,R,S-MePennPhos). The hydrogenations were carried
out at a substrate concentration of about 0.12 M to about 0.24 M of
compound 3.
##STR00043##
Example 6
Catalytic Asymmetric Hydrogenation of the Enamide 3 Using
(R,R)-MeBPE Rh(COD)BF.sub.4 as the Catalyst
[0220] As shown in Scheme 5, the enamide 3 was subjected to
homogeneous catalytic asymmetric hydrogenation in the presence of a
chiral catalyst, H.sub.2, and a solvent. In this example the
catalyst was derived from the complex of the transition metal
rhodium with the chiral phosphine ligand,
(R,R)-1,2-bis(2,5-dimethylphospholano)ethane (R,R-MeBPE). The
hydrogenations were carried out in the concentration range of about
0.12 M to about 0.24 M relative to the substrate 3.
##STR00044##
Example 7
Asymmetric Hydrogenation Catalyzed by
(R,R)-Norphos(COD)RH--BF.sub.4
[0221] A slurry of the (S)-enacetamide,
N--((S)-4-(3,4-dichloropheyl)-3,4-dihydronaththalen-1-yl)acetamide
(60.4 g, 0.18 mol), in isopropanol (595.0 g) was purged of oxygen
with vacuum/nitrogen cycles. The homogeneous catalyst precursor
(referred to as a "catalyst"), (R,R)-Norphos(COD)RH--BF4 was added
as a solution in methanol (34.6 mg, 0.025 mol %, 0.53 mL). After
purging the system with hydrogen several times, the vessel was
filled with hydrogen at the desired reaction pressure (approx 7
bar). The mixture was stirred at 25.degree. C. and reaction
progress was monitored by hydrogen uptake. Once the reaction was
judged to be complete (hydrogen uptake and HPLC), the pressure was
released and the system was purged repeatedly with nitrogen. The
light yellow slurry was diluted with isopropanol (194.7 g), heated
to dissolution (65.degree. C.) and polish filtered. The mixture was
heated to reflux to dissolve all solids. The solution was slowly
cooled to 60-65.degree. C. at which time the product crystallized.
The antisolvent, water (262 g), was added at about 60-65.degree.
C., then the mixture was cooled to 0.degree. C. over two hours and
held at that temperature for aging. Filtration of the lightly
colored solid was followed by washing with cold isopropanol
(2.times.61 g). Drying of the off white solid under reduced
pressure at 50-55.degree. C. provided the (1R,4S)-acetamide in 99%
de (56.6 g, 93% yield).
Example 8
Oxime and Enamide Formation
[0222] Chiral (4S)-tetralone (100.0 g, 0.34 mol) was reacted with
hydroxylamine hydrochloride (28.7 g, 0.41 mol) and sodium acetate
(33.8 g, 0.41 mol) in toluene (1.37 L) for approximately 2 h at
103.degree. C. Water was removed from the reaction mixture by
azeotropic distillation. The reaction was quencher at 25.degree. C.
with 2 N sodium hydroxide (167.0 g). The aqueous phase was
separated and the organic phase was washed once with water (400.0
g). Toluene (700.0 g) was added was added and the resulting organic
solution, containing the oxime, was dried by azeotropic
distillation under reduced pressure to the desired reaction
concentration. Triethylphosphine (89.0 g, 0.38 mol, 50 wt % in
toluene) is added, followed by addition of acetic anhydride (38.5
g, 0.38 mol), which afforded the oxime acetate intermediate. The
reaction mixture was allowed to react at reflux (112-113.degree.
C.) until the remaining oxime acetate is <2% of the product, as
determined by HPLC. The reaction mixture was cooled to
20-25.degree. C. and the minor enimide by-product was hydrolyzed
(to enacetamide) using 6 N sodium hydroxide (210 g) in conjunction
with the phase transfer reagent, tertbutylammonium hydroxide (5.0
g). The biphasic mixture was allowed to phase separate and the
aqueous phase was discarded. The organic phase was washed with 0.5%
acetic acid aqueous solution (67.degree. C., 600.0 g). The aqueous
phase was removed and the organic phase was washed once with water
(67.degree. C., 600.0 g) to remove inorganic salts. The organic
phase was concentrated and the warm solution was polish filtered to
remove additional inorganic salts. Heptanes (150 g) and 2-butanol
(7.0 g) were added and the slurry was heated to 100.degree. C. in
order to achieve dissolution. The solution was cooled to
approximately 85.degree. C. to initiate crystallization. Additional
heptanes (190 g) were added to the slurry at 85.degree. C., and the
mixture was then cooled to 0.degree. C. The slurry was aged at
0.degree. C. for 15 min., then filtered and washed three times with
a solution consisting of a mixture of heptanes and toluene (125 g).
The product was vacuum dried at 35-45.degree. C. 17.8 g (89% yield)
of a white crystalline solid, (S)-enacetamide was recovered.
[0223] The method according to this example was applied to a number
of substrates, the results of which are set forth in Table 1.
TABLE-US-00001 TABLE 1 Oximes and Enamides Produced Enamide En-
reaction try Oxime, yield time Enamide, yield 1 ##STR00045## 16.5 h
##STR00046## 2 ##STR00047## 22 h ##STR00048## 3 ##STR00049## 23 h
##STR00050## 4 ##STR00051## 19 h ##STR00052## 5 ##STR00053## 24 h
##STR00054## 6 ##STR00055## 21.5 h ##STR00056## 7 ##STR00057## 21.5
h ##STR00058## 8 ##STR00059## 5.3 h ##STR00060## 9 ##STR00061## 10
h ##STR00062## 10 ##STR00063## 10 h ##STR00064## 11 ##STR00065##
22.5 h ##STR00066## 12 ##STR00067## 28 h ##STR00068## 13
##STR00069## <22 h ##STR00070##
Example 9
Amide Deprotection
[0224] A solution of (1R,4S)-acetamide in dry THF (212.7 g, 239.3
mL) was treated with dry pyridine (8.7 g, 8.9 mL, 110 mmol). The
resulting clear, colorless solution was cooled to approximately
0.degree. C. Oxalyl chloride (12.9 g, 8.9 mL, 101.6 mmol) was added
dropwise to the stirred solution, with care to control the exotherm
and effervescence of CO and CO.sub.2. The addition of the
activating reagent was accompanied by the formation of a slurry.
The slurry was allowed to stir cold for a short period (approx. 15
min) prior to sampling for conversion assessment. Once the reaction
was complete, dry propylene glycol was added to the reaction,
resulting in a minor exotherm. The reaction was warmed to
25.degree. C., during which time the slurry changed in color and
consistency. HPLC analysis of a second sample showed completion
before the addition of 1-propanol (96.9 g, 120.5 mL). 6N HCl (128.0
g, 120.0 mL) was added. The mixture was heated to effect
dissolution and the resulting mixture was polish filtered. THF was
removed by atmospheric distillation. After concentration of the
mixture, it was slowly cooled to 3.degree. C. The resulting lightly
colored slurry was filtered to yield and off-white cake. The cake
was first washed with 17 wt % n-PrOH in deionized water (72.6 g, 75
mL total) and then with cold mtBE (55.5 g, 75 mL). The off-white
wet cake was dried under vacuum at 45-50.degree. C. The product was
recovered as an off-white to white solid (24.8 g, 84.1% yield) with
excellent purity (>99% purity by HPLC).
[0225] All publications and patent documents cited in this
application are incorporated by reference in their entirety for all
purposes to the same extent as if each individual publication or
patent document were so individually denoted. By their citation of
various references in this document, Applicants do not admit any
particular reference is "prior art" to their invention.
* * * * *