U.S. patent application number 14/873417 was filed with the patent office on 2016-01-28 for indole and benzofuran fused isoquinuclidene derivatives and processes for preparing them.
The applicant listed for this patent is DemeRx,Inc.. Invention is credited to Robert M. Moriarty.
Application Number | 20160024075 14/873417 |
Document ID | / |
Family ID | 48946142 |
Filed Date | 2016-01-28 |
United States Patent
Application |
20160024075 |
Kind Code |
A1 |
Moriarty; Robert M. |
January 28, 2016 |
INDOLE AND BENZOFURAN FUSED ISOQUINUCLIDENE DERIVATIVES AND
PROCESSES FOR PREPARING THEM
Abstract
Provided herein are indole and benzofuran fused isoquinuclidene
derivatives. Also provided herein are processes, preferably
enantioselective processes, for preparing such derivatives
including processes for preparing (-) and (+) noribogaine or a salt
thereof, in substantially enantiomerically pure forms.
Inventors: |
Moriarty; Robert M.;
(Michiana Shores, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DemeRx,Inc. |
Miami |
FL |
US |
|
|
Family ID: |
48946142 |
Appl. No.: |
14/873417 |
Filed: |
October 2, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13749593 |
Jan 24, 2013 |
9150584 |
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14873417 |
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61590740 |
Jan 25, 2012 |
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61591258 |
Jan 26, 2012 |
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Current U.S.
Class: |
540/579 |
Current CPC
Class: |
C07D 491/22 20130101;
C07D 471/22 20130101; C07D 453/00 20130101 |
International
Class: |
C07D 453/00 20060101
C07D453/00 |
Claims
1-10. (canceled)
11. A compound of Formula (I)-j or (VI)-j: ##STR00097## or a salt
or enantiomer thereof wherein k is 1, 2, or 3; each R.sup.1 is
independently selected from the group consisting of hydrogen, halo,
amino, hydroxy, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cyano, nitro,
-N.sub.3, and -CO.sub.2H or an ester thereof, wherein the alkyl,
alkoxy, alkenyl, or the alkylnyl group is optionally substituted
with 1-3 substituents selected from the group consisting of keto,
halo, amino, hydroxy, cyano, nitro, --N.sub.3, phenyl optionally
substituted with 1-3 substituents selected from the group
consisting of C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy, and
--CO.sub.2H or an ester thereof; R.sup.2 is hydrogen or
C(R.sup.2).sub.2 is a keto group; R.sup.3 is selected from the
group consisting of hydrogen, halo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, wherein the
alkyl, alkenyl, or the alkylnyl group is optionally substituted
with 1-3 substituents selected from the group consisting of keto,
halo, amino, hydroxy, cyano, nitro, --N.sub.3, and --CO.sub.2H or
an ester thereof; each R.sup.4 independently is selected from the
group consisting of hydrogen, hydroxy, --SR.sup.41, --OR.sup.42,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl, wherein the alkyl, alkenyl, or the alkynyl group is
optionally substituted with 1-3 substituents selected from the
group consisting of keto, halo, C.sub.1-C.sub.6 alkoxy, amino,
hydroxy, cyano, nitro, --NHCOCH.sub.3, --N.sub.3, and --CO.sub.2H
or an ester thereof, or the 2 R.sup.4 groups together with the
carbon atom to which they are bonded to form a keto (C.dbd.O)
group, a Schiff base (=NR.sup.43), a vinylidene moiety of formula
=CR.sup.48R.sup.49, or form a cyclic ketal or thioketal, which
cyclic ketal or thioketal is of formula: ##STR00098## each R.sup.41
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl optionally substituted with 1-3 substituents
selected from the group consisting of C.sub.6-C.sub.10 aryl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.10 heteroaryl,
C.sub.3-C.sub.8 heterocyclyl, halo, amino, --N.sub.3, hydroxy,
C.sub.1-C.sub.6 alkoxy, silyl, nitro, cyano, and CO.sub.2H or an
ester thereof, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.6-C.sub.10 aryl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8
cycloalkyl, and C.sub.3-C.sub.8 heterocyclyl; each R.sup.42 is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl optionally substituted with 1-3 substituents selected from
the group consisting of C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8
heterocyclyl, halo, amino, -N.sub.3, hydroxy, C.sub.1-C.sub.6
alkoxy, silyl, nitro, cyano, and CO.sub.2H or an ester thereof,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl; where X in
both occurrences is either oxygen or sulfur; m is 1, 2, 3, or 4; n
is 1 or 2; R.sup.43 is selected from the group consisting of
C.sub.6-C.sub.10 aryl and C.sub.2-C.sub.10 heteroaryl; R.sup.44 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl and
C.sub.6-C.sub.10 aryl; R.sup.48 is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl, wherein the
alkyl, alkenyl, or the alkynyl group is optionally substituted with
1-3 substituents selected from the group consisting of keto,
C.sub.1-C.sub.6 alkoxy, amino, hydroxy, cyano, nitro,
-NHCOCH.sub.3, and -CO.sub.2H or an ester thereof; R.sup.49 is
hydrogen or C.sub.1-C.sub.6 alkyl; and R.sup.51 is selected from
the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl
optionally substituted with 1-3 substituents selected from the
group consisting of keto, halo, amino, hydroxy, cyano, nitro,
--N.sub.3, and --CO.sub.2H or an ester thereof; wherein the
C.sup.14 content of a compound of Formula (I), that is ibogaine,
ibogamine, noribogaine, or methoxy ibogaine is less than 0.9
ppt.
12. The compound of claim 11, of Formula (IA): ##STR00099## wherein
k and R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.51 are defined
as in claim 11.
13. The compound of claim 11, of Formula (IIA): ##STR00100##
wherein k and R.sup.1, R.sup.2, R.sup.4, and R.sup.51 are defined
as in claim 11.
14. The compound of claim 11, of Formula (IIIA): ##STR00101##
wherein k and R.sup.1, R.sup.3, R.sup.4, and R.sup.51 are defined
as in claim 11.
15. The compound of claim 11, of Formula (IVA): ##STR00102##
wherein R.sup.11 is selected from the group consisting of hydrogen
and C.sub.1-C.sub.6 alkyl optionally substituted with 1-3
substituents selected from the group consisting of halo, amino,
hydroxy, cyano, nitro, --N.sub.3, and --CO.sub.2H or an ester
thereof, and phenyl optionally substituted with 1-3 substituents
selected from the group consisting of C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy; k is 1 or 2; and R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and R.sup.51 are defined as in claim 11.
16. The compound of claim 11, of Formula (IVC) or (VIA):
##STR00103## wherein R.sup.11 is selected from the group consisting
of hydrogen and C.sub.1-C.sub.6 alkyl optionally substituted with
1-3 substituents selected from the group consisting of halo, amino,
hydroxy, cyano, nitro, --N.sub.3, and --CO.sub.2H or an ester
thereof, and phenyl optionally substituted with 1-3 substituents
selected from the group consisting of C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy; k is 1 or 2; and R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and R.sup.51 are defined as in claim 11.
17. An isolated enantiomer of a compound of any one of claims 11-16
in substantial enantiomeric excess.
18. The compound of claim 11 of Formula (VA): ##STR00104## wherein
the substituents are as tabulated below: TABLE-US-00003 R.sup.1
R.sup.11 C(R.sup.2).sub.2 R.sup.45 R.sup.46 R.sup.47 H, 4-Me, 6-Me,
7- Bn C.dbd.O CR.sup.45CR.sup.46 is -- -- Me, 4-OH, 6-OH, 7-
C.dbd.O OH, 4-OMe, 6- OMe, or 7-OMe H, 4-Me, 6-Me, 7- Bn C.dbd.O
CR.sup.45CR.sup.46 is -- -- Me, 4-OH, 6-OH, 7- C.dbd.CR.sup.48H,
R.sup.48 OH, 4-OMe, 6- is Me, Et, Pr, OMe, or 7-OMe Bu H, 4-Me,
6-Me, 7- Bn CH.sub.2 CR.sup.45CR.sup.46 is -- -- Me, 4-OH, 6-OH, 7-
C.dbd.CR.sup.48H, R.sup.48 OH, 4-OMe, 6- is Me, Et, Pr, OMe, or
7-OMe Bu H, 4-Me, 6-Me, 7- Bn C.dbd.O CH.dbd.CHR.sup.47 OH H, or
C.sub.1-C.sub.4 alkyl optionally Me, 4-OH, 6-OH, 7- substituted
with an OMe group, OH OH, 4-OMe, 6- group, an amide, or with an
amino OMe, or 7-OMe group H, 4-Me, 6-Me, 7- Bn C.dbd.O
C.ident.CR.sup.47 OH H or C.sub.1-C.sub.4 alkyl optionally
substituted Me, 4-OH, 6-OH, 7- with an OMe group, OH group, an OH,
4-OMe, 6- amide, or with an amino group OMe, or 7-OMe H, 4-Me,
6-Me, 7- Bn C.dbd.O CH.sub.2CH.sub.2R.sup.47 H C.sub.1-C.sub.4
alkyl optionally substituted with Me, 4-OH, 6-OH, 7- an OMe group,
OH group, an amide, OH, 4-OMe, 6- or with an amino group OMe, or
7-OMe H, 4-Me, 6-Me, 7- Bn C.dbd.O CH.sub.2CH.sub.2R.sup.47 OH
C.sub.1-C.sub.4 alkyl optionally substituted with Me, 4-OH, 6-OH,
7- an OMe group, OH group, an amide, OH, 4-OMe, 6- or with an amino
group OMe, or 7-OMe H, 4-Me, 6-Me, 7- Bn CH.sub.2 CH.dbd.CHR.sup.47
OH H or C.sub.1-C.sub.4 alkyl optionally substituted Me, 4-OH,
6-OH, 7- with an OMe group, OH group, an OH, 4-OMe, 6- amide, or
with an amino group OMe, or 7-OMe H, 4-Me, 6-Me, 7- Bn CH.sub.2
C.ident.CR.sup.47 OH H or C.sub.1-C.sub.4 alkyl optionally
substituted Me, 4-OH, 6-OH, 7- with an OMe group, OH group, an OH,
4-OMe, 6- amide, or with an amino group OMe, or 7-OMe H, 4-Me,
6-Me, 7- Bn CH.sub.2 CH.sub.2CH.sub.2R.sup.47 H C.sub.1-C.sub.4
alkyl optionally substituted with Me, 4-OH, 6-OH, 7- an OMe group,
OH group, an amide, OH, 4-OMe, 6- or with an amino group OMe, or
7-OMe H, 4-Me, 6-Me, 7- Bn CH.sub.2 CH.sub.2CH.sub.2R.sup.47 OH
C.sub.1-C.sub.4 alkyl optionally substituted with Me, 4-OH, 6-OH,
7- an OMe group, OH group, an amide, OH, 4-OMe, 6- or with an amino
group OMe, or 7-OMe H, 4-Me, 6-Me, 7- H C.dbd.O CH.dbd.CHR.sup.47
OH H or C.sub.1-C.sub.4 alkyl optionally substituted Me, 4-OH,
6-OH, 7- with an OMe group, OH group, an OH, 4-OMe, 6- amide, or
with an amino group OMe, or 7-OMe H, 4-Me, 6-Me, 7- H C.dbd.O
C.ident.CR.sup.47 OH H or C.sub.1-C.sub.4 alkyl optionally
substituted Me, 4-OH, 6-OH, 7- with an OMe group, OH group, an OH,
4-OMe, 6- amide, or with an amino group OMe, or 7-OMe H, 4-Me,
6-Me, 7- H C.dbd.O CH.sub.2CH.sub.2R.sup.47 H C.sub.1-C.sub.4 alkyl
optionally substituted with Me, 4-OH, 6-OH, 7- an OMe group, OH
group, an amide, OH, 4-OMe, 6- or with an amino group OMe, or 7-OMe
H, 4-Me, 6-Me, 7- H C.dbd.O CH.sub.2CH.sub.2R.sup.47 OH
C.sub.1-C.sub.4 alkyl optionally substituted with Me, 4-OH, 6-OH,
7- an OMe group, OH group, an amide, OH, 4-OMe, 6- or with an amino
group OMe, or 7-OMe H, 4-Me, 6-Me, 7- H CH.sub.2 CH.dbd.CHR.sup.47
OH H or C.sub.1-C.sub.4 alkyl optionally substituted Me, 4-OH,
6-OH, 7- with an OMe group, OH group, an OH, 4-OMe, 6- amide, or
with an amino group OMe, or 7-OMe H, 4-Me, 6-Me, 7- H CH.sub.2
C.ident.CR.sup.47 OH H or C.sub.1-C.sub.4 alkyl optionally
substituted Me, 4-OH, 6-OH, 7- with an OMe group, OH group, an OH,
4-OMe, 6- amide, or with an amino group OMe, or 7-OMe H, 4-Me,
6-Me, 7- H CH.sub.2 CH.sub.2CH.sub.2R.sup.47 H C.sub.1-C.sub.4
alkyl optionally substituted with Me, 4-OH, 6-OH, 7- an OMe group,
OH group, an amide, OH, 4-OMe, 6- or with an amino group OMe, or
7-OMe H, 4-Me, 6-Me, 7- H CH.sub.2 CH.sub.2CH.sub.2R.sup.47 OH
C.sub.1-C.sub.4 alkyl optionally substituted with Me, 4-OH, 6-OH,
7- an OMe group, OH group, an amide, OH, 4-OMe, 6- or with an amino
group OMe, or 7-OMe
19. The compound of claim 11 of Formula (VIC): ##STR00105## wherein
the substituents are as tabulated below: TABLE-US-00004 R.sup.1
R.sup.11 C(R.sup.2).sub.2 R.sup.45 R.sup.47 H, 4-Me, 6-Me, 7- Bn
C.dbd.O CH.dbd.CHR.sup.47 H or C.sub.1-C.sub.4 alkyl optionally
substituted Me, 4-OH, 6-OH, 7- with an OMe group, OH group, an OH,
4-OMe, 6- amide, or with an amino group OMe, or 7-OMe H, 4-Me,
6-Me, 7- Bn C.dbd.O C.ident.CR.sup.47 H or C.sub.1-C.sub.4 alkyl
optionally substituted Me, 4-OH, 6-OH, 7- with an OMe group, OH
group, an OH, 4-OMe, 6- amide, or with an amino group OMe, or 7-OMe
H, 4-Me, 6-Me, 7- Bn C.dbd.O CH.sub.2CH.sub.2R.sup.47
C.sub.1-C.sub.4 alkyl optionally substituted with Me, 4-OH, 6-OH,
7- an OMe group, OH group, an amide, or OH, 4-OMe, 6- with an amino
group OMe, or 7-OMe H, 4-Me, 6-Me, 7- Bn CH.sub.2 CH.dbd.CHR.sup.47
H or C.sub.1-C.sub.4 alkyl optionally substituted Me, 4-OH, 6-OH,
7- with an OMe group, OH group, an OH, 4-OMe, 6- amide, or with an
amino group OMe, or 7-OMe H, 4-Me, 6-Me, 7- Bn CH.sub.2
C.ident.CR.sup.47 H or C.sub.1-C.sub.4 alkyl optionally substituted
Me, 4-OH, 6-OH, 7- with an OMe group, OH group, an OH, 4-OMe, 6-
amide, or with an amino group OMe, or 7-OMe H, 4-Me, 6-Me, 7- Bn
CH.sub.2 CH.sub.2CH.sub.2R.sup.47 C.sub.1-C.sub.4 alkyl optionally
substituted with Me, 4-OH, 6-OH, 7- an OMe group, OH group, an
amide, or OH, 4-OMe, 6- with an amino group OMe, or 7-OMe
20. The compound of claim 11, wherein R.sup.51 is C.sub.1-C.sub.6
alkyl optionally substituted with 1-3 substituents selected from
the group consisting of keto, halo, amino, hydroxy, cyano, nitro,
--N.sub.3, and --CO.sub.2H or an ester thereof.
21. The compound of claim 11, wherein R.sup.1 is a non-hydrogen
substituent, and k is 2.
22. The compound of claim 11, wherein R.sup.1 is a non-hydrogen
substituent, and k is 3.
23. The compound of claim 18, wherein R.sup.47 is CH.sub.2OMe,
(CH.sub.2).sub.2OMe, (CH.sub.2).sub.3OMe, (CH.sub.2).sub.4OMe),
CH.sub.2OH, (CH.sub.2).sub.20H, (CH.sub.2).sub.3OH,
(CH.sub.2).sub.4OH), (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, (CH.sub.2).sub.4NHCCOMe), ##STR00106##
24. The compound of claim 18, wherein R.sup.47 is methyl, ethyl,
propyl, or butyl each optionally substituted with an OMe group, OH
group, an amide, or with an amino group.
25. The compound of claim 19, wherein R.sup.47 is CH.sub.2OMe,
(CH.sub.2).sub.2OMe, (CH.sub.2).sub.3OMe, (CH.sub.2).sub.4OMe),
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH,
(CH.sub.2).sub.4OH), (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, (CH.sub.2).sub.4NHCCOMe), ##STR00107##
26. The compound of claim 18, wherein R.sup.47 is methyl, ethyl,
propyl, or butyl each optionally substituted with an OMe group, OH
group, an amide, or with an amino group.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C. 119(e)
of U.S. Provisional Application Ser. Nos. 61/590,740 filed
1-25-2012 and 61/591,258 filed 1-26-2012 and each of which is
hereby incorporated by reference into this application in its
entirety.
FIELD OF THE INVENTION
[0002] Provided herein are indole and benzofuran fused
isoquinuclidene derivatives, and processes, preferably
enantioselective processes, for preparing such derivatives
including processes for preparing (-) and (+) noribogaine, in
substantially enantiomerically pure forms. In certain aspects, the
processes provided herein employ the novel isoquinuclidene, R,R
7-oxo-2-azabicyclo[2.2.2]oct-5-ene, or a protected derivative
thereof (see, U.S. application no. 61/741,798, which is
incorporated herein in its entirety by reference). In other
aspects, this invention provides (-) or (+) noribogaine or a salt,
preferably a pharmaceutically acceptable salt, of each thereof,
preferably in a substantially enantiomerically pure form, prepared
according to the processes provided herein, and also provides
pharmaceutical compositions comprising (-) noribogaine or a salt
thereof thus prepared.
STATE OF THE ART
[0003] Noribogaine is a well known compound whose structure
combines the features, for example, of tyrptamine, and
isoquinuclidene. The naturally occurring enantiomer of noribogaine
can be depicted by the following formula:
##STR00001##
[0004] This enantiomer of noribogaine and its pharmaceutically
acceptable salts have recently received significant attention as a
non-addictive alkaloid useful in treating drug dependency (U.S.
Pat. No. 6,348,456) and as a potent analgesic (U.S. Pat. No.
7,220,737). Both of these patents are incorporated herein by
reference in their entirety.
[0005] Synthesizing compounds to include the isoquinuclidene
moiety, especially in a substantially enantiomerically pure form is
a challenging task. Heretofore, Iboga alkaloids, such as
ibogaine:
##STR00002##
were conventionally prepared from one of its naturally occurring
precursors such as voacangine:
##STR00003##
or isolated from plant sources. The naturally occurring enantiomer
of noribogaine is prepared by O-demethylation of naturally
occurring ibogaine or prepared by decarboxylation and
O-demethylation of naturally occurring voacangine. Voacangine and
Ibogaine are obtained from plants where both the supply is limited
and the quality of the supply is unpredictable.
SUMMARY OF THE INVENTION
[0006] Provided herein are indole and benzofuran fused
isoquinuclidene derivatives, and processes, preferably
enantioselective processes, for preparing such derivatives
including processes for preparing (-) or (+) noribogaine or a salt
thereof, in substantially enantiomerically pure forms.
[0007] In certain aspects, the processes provided herein employ the
novel 1R,4R 7-oxo-2-azabicyclo[2.2.2]oct-5-ene or a protected
derivative thereof
[0008] In another aspect, this invention provides (-) noribogaine
or a salt, preferably a pharmaceutically acceptable salt, thereof,
preferably in a substantially enantiomerically pure form, prepared
according to the processes provided herein. In another aspect, this
invention provides a composition comprising the (-) noribogaine or
a pharmaceutically acceptable salt thereof and at least one
pharmaceutically acceptable excipient.
[0009] This invention also provides processes for preparing (+)
noribogaine.
[0010] As used herein, "pharmaceutically acceptable" refers to a
safe and non-toxic composition, which is suitable for in vivo,
preferably for human administration. Pharmaceutically acceptable
salts or excipients are well known to the skilled artisan.
BRIEF DESCRIPTION OF THE FIGURE
[0011] FIG. 1 illustrates a .sup.1H-NMR spectrum in CDCl.sub.3 of
compound 3:
##STR00004##
[0012] FIG. 2 illustrates a .sup.1H-NMR spectrum in CDC1.sub.3 of
compound 1:
##STR00005##
[0013] FIG. 3 illustrates a .sup.1H-NMR spectrum in CDCl.sub.3 of
compound 2:
##STR00006##
DETAILED DESCRIPTION OF THE INVENTION
[0014] Provided herein are indole and benzofuran fused
isoquinuclidene derivatives, and processes, preferably
enantioselective processes, for preparing such derivatives
including processes for preparing (-) and (+) noribogaine or a salt
of each thereof, in substantially enantiomerically pure forms.
Before this invention is described in greater detail, the following
terms will be defined.
[0015] As used herein and in the appended claims, the singular
forms "a", "an", and "the" include plural referents unless the
context clearly dictates otherwise. Thus, for example, reference to
"a salt" includes a plurality of such salts.
Definitions
[0016] As used herein, "alkenyl" refers to hydrocarbyl groups
having from 2 to 10 carbon atoms and at least one and up to 3
carbon carbon double bonds. Examples of alkenyl include vinyl,
allyl, dimethyl allyl, and the like.
[0017] As used herein, "alkoxy" refers to --O-alkyl.
[0018] As used herein, "alkyl" refers to hydrocarbyl groups having
from 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and
still more preferably 1-4 carbon atoms. The alkyl group may contain
linear or branched carbon chains. This term is exemplified by
groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl,
t-butyl, n-pentyl, n-decyl and the like.
[0019] As used herein, "alkynyl" refers to hydrocarbyl groups
having from 2 to 10 carbon atoms and at least one and up to 2
carbon carbon triple bonds. Examples of alkynyl include ethynyl,
propargyl, dimethylpropargyl, and the like.
[0020] As used herein, "amino" refers to --NR.sup.xR.sup.y wherein
each R.sup.x and R.sup.y independently is hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.10
heteroaryl, or C.sub.3-C.sub.8 heterocyclyl, or R.sup.x and R.sup.y
together with the nitrogen atom they are bonded to form a 5-10
membered heterocyclyl ring containing 1-2 nitrogen and/or oxygen
atoms, which heterocyclyl ring is optionally substituted with 1-3,
preferably, 1-2, or more preferably, a single, C.sub.1-C.sub.3
alkyl group.
[0021] As used herein, "aryl" refers to an aromatic carbocyclic
group of from 6 to 14 carbon atoms having a single ring (e.g.,
phenyl) or multiple condensed rings (e.g., naphthyl or anthryl)
which condensed rings may or may not be aromatic (e.g.,
2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like)
provided that the point of attachment is at an aromatic carbon
atom.
[0022] As used herein, "base" refers to a compound that can accept
a proton or donate a lone electron pair. Examples of bases include,
alkali (OH), carbonate, bicarbonate, alkoxides (alkyl-O(.sup.-)),
hydrides (alkali metal hydrides and CaH.sub.2), amides
(NH.sub.2(.sup.-) R.sup.bNH(.sup.-), or (R.sup.b).sub.2N(.sup.-) ,
wherein R.sup.b is alkyl or 2 R.sup.bs together with the nitrogen
form a 5-6 membered ring), and neutral nitrogen containing bases
such as (R.sup.b).sub.3N, pyridine, 4-N,N-dialkylpyridine, and the
like. As used herein nucleophilic bases refer to preferably neutral
nitrogen containing bases that can catalyze the addition of an acyl
halide or a sulfonyl halide(such as R.sup.bCOX or R.sup.bSO.sub.2X)
to an --OH, --NH.sub.2, or an --NHR.sup.b group. Preferred examples
include, 4-N,N-dialkylpyridines.
[0023] As used herein, a "Bronsted acid" refers to a compound that
can donate a proton.
[0024] As used herein, the term "chlorinated solvent" refers to
chlorinated methane and ethane, which are preferably
trichlorinated, and more preferably dichlorinated. Yet more
preferably, the chlorinated solvent is dihloromethane.
[0025] As used herein, the term "comprising" or "comprises" is
intended to mean that the compositions and methods include the
recited elements, but not excluding others. "Consisting essentially
of" when used to define compositions and methods, shall mean
excluding other elements of any essential significance to the
combination for the stated purpose. Thus, a composition consisting
essentially of the elements as defined herein would not exclude
other materials or steps that do not materially affect the basic
and novel characteristic(s) of the claimed invention. "Consisting
of" shall mean excluding more than trace elements of other
ingredients and substantial method steps. Embodiments defined by
each of these transition terms are within the scope of this
invention.
[0026] As used herein, "cycloalkyl" refers to cyclic hydrocarbyl
groups of from 3 to 10 carbon atoms having single or multiple
condensed rings, which condensed rings may be aromatic or contain a
heteroatom, provided that the point of attachment is at a
cycloalkyl carbon atom. Cycloalkyl includes, by way of example,
adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the
like. Cycloalkyl rings are preferably saturated, though, cycloalkyl
rings including 1-2 carbon carbon double bonds are also
contemplated provided that the ring is not aromatic.
[0027] As used herein, "C.sub.x" refers to a group having x carbon
atoms, wherein x is an integer, for example, C.sub.4 alkyl refers
to an alkyl group having 4 carbon atoms.
[0028] As used herein, "ee" refers to enantiomeric excess and is
expressed as (e.sup.1-e.sup.2)% where e.sup.1 and e.sup.2 are the
two enantiomers. For example, if the % of e.sup.1 is 95 and the %
of e.sup.2 is 5, then the e.sup.1 enantiomer is present in an ee of
90%. The ee of an enantiomer in a mixture of enantiomers is
determined following various methods well known to the skilled
artisan, such as using chiral lanthanide based nuclear magnetic
resonance shift reagents, forming derivatives with chiral compounds
such as chiral hydroxyacids, amino acids, and the like. Various
physical measurements such as circular dichroism, optical rotation,
etc. are also useful in determining the ee of a mixture of
enantiomers.
[0029] As used herein, "deprotection condition" refers to reaction
conditions that transform a phenolic ether to the corresponding
phenol and includes reacting with various Lewis acids such as
BBr.sub.3, and when the alkyl group in the ether is a methyl group
containing at least one phenyl or substituted phenyl group,
reacting under hydrogenation conditions.
[0030] As used herein, --CO.sub.2H "ester" refers to
--CO.sub.2R.sup.E wherein R.sup.E is selected from the group
consisting of C.sub.6-C.sub.10 aryl and C.sub.1-C.sub.6 alkyl
optionally substituted with 1-3 C.sub.6-C.sub.10 aryl groups.
[0031] As used herein "Fischer indole synthesis condition" refers
to reaction conditions for reacting phenylhydrazine with a ketone
containing at least one a-methylene group and an acid to provide an
indole derivative. Bronsted acids such as HCl, H.sub.2SO.sub.4,
polyphosphoric acid and p-toluenesulfonic acid are useful, as are
Lewis acids such as boron trifluoride, zinc chloride, iron
chloride, and aluminum chloride.
[0032] As used herein, "fluoroalkyl" refers to an alkyl group
substituted with up to 5, or preferably up to 3 fluoro groups.
[0033] As used herein, "halo" refers to F, Cl, Br, or I.
[0034] As used herein, "heteroaryl" refers to an aromatic group of
from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the
group consisting of oxygen, nitrogen, sulfur within the ring,
wherein the nitrogen and/or sulfur atom(s) of the heteroaryl are
optionally oxidized (e.g., N-oxide, --S(O)- or --S(O).sub.2-),
provided that the ring has at least 5 ring atoms and up to 14, or
preferably from 5-10, ring atoms. Such heteroaryl groups can have a
single ring (e.g., pyridyl or furyl) or multiple condensed rings
(e.g., indolizinyl or benzothienyl) wherein the condensed rings may
or may not be aromatic and/or contain a heteroatom provided that
the point of attachment is through an atom of the aromatic
heteroaryl group. Examples of heteroaryls include pyridyl,
pyrrolyl, indolyl, thiophenyl, furyl, and the like.
[0035] As used herein, "heterocyclyl" or heterocycle refers to a
cycloalkyl group of from 1 to 10 carbon atoms and 1 to 4
heteroatoms selected from the group consisting of oxygen, nitrogen,
sulfur within the ring, wherein the nitrogen and/or sulfur atom(s)
of the heteroaryl are optionally oxidized (e.g., N-oxide, --S(O)-
or --S(O).sub.2-), provided that the ring has at least 3 and up to
14, or preferably from 5-10 ring atoms. Such heterocyclyl groups
can have a single ring or multiple condensed rings wherein the
condensed rings may not contain a heteroatom and/or may contain an
aryl or a heteroaryl moiety, provided that the point of attachment
is through an atom of the non-aromatic heterocyclyl group. Examples
of heterocyclyl include pyrrolidinyl, piperadinyl, piperazinyl, and
the like. Heterocyclyl rings are preferably saturated, though,
heterocyclyl rings including 1-2 carbon carbon double bonds are
also contemplated provided that the ring is not aromatic.
[0036] As used herein, "hydrogenation conditions" refer to
conditions including hydrogen gas at atmospheric or higher pressure
and catalysts that catalyze the reaction of the hydrogen with a
hydrogen reactive group, such as a benzyl group or a carbon carbon
double/triple bond. Catalysts useful for hydrogenation include
palladium, platinum, and rhodium metals and their oxides or
hydroxides, preferably supported on a material such as carbon or
alumina
[0037] As used herein, "protecting group" or "Pg" refers to well
known functional groups which, when bound to a functional group,
render the resulting protected functional group inert to the
reaction to be conducted on other portions of the compound and the
corresponding reaction condition, and which can be reacted to
regenerate the original functionality under deprotection
conditions. The protecting group is selected to be compatible with
the remainder of the molecule. In one embodiment, the protecting
group is an "amine protecting group" which protects an --NH-- or an
--NH.sub.2-- moiety, for example during the syntheses described
here. Examples of amine protecting groups include, for instance,
benzyl, acetyl, oxyacetyl, carbonyloxybenzyl (Cbz), Fmoc, and the
like. In another embodiment, the protecting group is a "hydroxy
protecting group" which protects a hydroxyl functionality during
the synthesis described here. Examples of hydroxyl protecting
groups include, for instance, benzyl, p-methoxybenzyl,
p-nitrobenzyl, allyl, trityl, dialkylsilylethers, such as
dimethylsilyl ether, and trialkylsilyl ethers such as
trimethylsilyl ether, triethylsilyl ether, and t-butyldimethylsilyl
ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-,
di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl,
trichloroacetyl, trifluoroacetyl; and carbonates such as methyl,
ethyl, 2,2,2-trichloroethyl, allyl, and benzyl. As the skilled
artisan would appreciate, one or more of these protecting groups
are also useful as amine protecting groups. Additional examples of
amine, hydroxy, and keto protecting groups are found in standard
reference works such as Greene and Wuts, Protective Groups in
Organic Synthesis., 2d Ed., 1991, John Wiley & Sons, and McOmie
Protective Groups in Organic Chemistry, 1975, Plenum Press. Methods
for protecting and deprotecting hydroxyl, --NH--, --NH.sub.2--, and
keto groups disclosed herein can be found in the art, and
specifically in Greene and Wuts, supra, and the references cited
therein.
[0038] As used herein, a "Lewis acid" refers to a compound that can
donate a lone electron pair.
[0039] As used herein, a "non nucleophilic base" refers to a base
that is capable of abstracting an acidic hydrogen, e.g., from an
--OH or --NH-moiety, but does not readily take part in a
nucleophilic substitution reaction. Preferably such bases are metal
hydrides such as alkali metal hydridies or CaH.sub.2.
[0040] As used herein, "oxidizing agent" refers to a compound that
can accept electrons, and e.g., convert a CH(OH) group to a keto
group. Examples of oxidizing agents are well known, and non
limiting examples include hexavalent chromium reagents such as
pyridinium chlorochromate, pyridinium dichromate, hypervalent
iodine, and hypochlorite.
[0041] As used herein, "reducing agent" refers to a compounds that
can donate electrons or a hydride in a reaction. Preferred examples
include borohydrides such as NaBH.sub.4/CeCl.sub.3, and alanes such
as diisobutyl aluminum hydride.
[0042] As used herein, a salt refers to preferably a salt of a
mineral acid, or an organic acid such as a carboxylic acid or a
sulfonic acid, and/or to alkali, alkaline earth, and various
ammonium (including tetraalkyl ammonium, pyridinum, imidazolium and
the like) salts. Non limiting examples of acid salts include salts
of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric
acid, methane sulfonic acid, phosphorous acid, nitric acid,
perchloric acid, acetic acid, tartaric acid, lactic acid, succinic
acid, and citric acid.
[0043] As used herein, the term "((S)-binol)" refers to the
(S)-enantiomer of 1,1'-bi-2-naphthol, and "((R)-binol)" refers to
the (R)-enantiomer of 1,1'-bi-2-naphthol.
[0044] As used herein, "silyl" refers to Si(Rz).sub.3 wherein each
R.sup.z independently is C.sub.1-C.sub.6 alkyl or C.sub.6-C.sub.10
aryl.
[0045] As used herein, "substantially enantiomerically enriched,"
"substantially enantiomerically pure" or "substantial enantiomeric
excess" or grammatical equivalents thereof refers to an enantiomer
in an enantiomeric mixture with at least 95% ee, preferably 98% ee,
or more preferably 99% ee.
Compounds of the Invention
[0046] In one aspect, this invention provides compounds of Formulas
(I) and (VI):
##STR00007##
or a salt or enantiomer thereof wherein [0047] k is 1, 2, or 3;
[0048] each R.sup.1 is independently selected from the group
consisting of hydrogen, halo, amino, hydroxy, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, cyano, nitro, --N.sub.3, and --CO.sub.2H
or an ester thereof, wherein the alkyl, alkoxy, alkenyl, or the
alkylnyl group is optionally substituted with 1-3 substituents
selected from the group consisting of keto, halo, amino, hydroxy,
cyano, nitro, --N.sub.3, phenyl optionally substituted with 1-3
substituents selected from the group consisting of C.sub.1-C.sub.6
alkyl and C.sub.1-C.sub.6 alkoxy, and --CO.sub.2H or an ester
thereof; [0049] R.sup.2 is hydrogen or C(R.sup.2).sub.2 is a keto
group; [0050] R.sup.3 is selected from the group consisting of
hydrogen, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, wherein the alkyl, alkenyl, or the
alkylnyl group is optionally substituted with 1-3 substituents
selected from the group consisting of keto, halo, amino, hydroxy,
cyano, nitro, --N.sub.3, and --CO.sub.2H or an ester thereof;
[0051] each R.sup.4 independently is selected from the group
consisting of hydrogen, hydroxy, --SR.sup.41, --OR.sup.42,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl, wherein the alkyl, alkenyl, or the alkynyl group is
optionally substituted with 1-3 substituents selected from the
group consisting of keto, halo, C.sub.1-C.sub.6 alkoxy, amino,
hydroxy, cyano, nitro, --NHCOCH.sub.3, --N.sub.3, and --CO.sub.2H
or an ester thereof, or the 2 R.sup.4 groups together with the
carbon atom to which they are bonded to form a keto (C.dbd.O)
group, a Schiff base (.dbd.NR.sup.43), a vinylidene moiety of
formula .dbd.CR.sup.48R.sup.49, or form a cyclic ketal or
thioketal, which cyclic ketal or thioketal is of formula:
[0051] ##STR00008## [0052] each R.sup.41 is independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl optionally
substituted with 1-3 substituents selected from the group
consisting of C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8 heterocyclyl, halo,
amino, --N.sub.3, hydroxy, C.sub.1-C.sub.6 alkoxy, silyl, nitro,
cyano, and CO.sub.2H or an ester thereof, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 aryl, C.sub.2-C.sub.10
heteroaryl, C.sub.3-C.sub.8 cycloalkyl, and C.sub.3-C.sub.8
heterocyclyl; [0053] each R.sup.42 is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl optionally
substituted with 1-3 substituents selected from the group
consisting of C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.2-C.sub.10 heteroaryl, C.sub.3-C.sub.8 heterocyclyl, halo,
amino, --N.sub.3, hydroxy, C.sub.1-C.sub.6 alkoxy, silyl, nitro,
cyano, and CO.sub.2H or an ester thereof, C.sub.2-C.sub.6 alkenyl,
and C.sub.2-C.sub.6 alkynyl; [0054] where X in both occurrences is
either oxygen or sulfur; [0055] m is 1, 2, 3, or 4; [0056] n is 1
or 2; [0057] R.sup.43 is selected from the group consisting of
C.sub.6-C.sub.10 aryl and C.sub.2-C.sub.10 heteroaryl; [0058]
R.sup.44 is selected from the group consisting of C.sub.1-C.sub.6
alkyl and C.sub.6-C.sub.10 aryl; [0059] R.sup.48 is hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl, wherein the alkyl, alkenyl, or the alkynyl group is
optionally substituted with 1-3 substituents selected from the
group consisting of keto, C.sub.1-C.sub.6 alkoxy, amino, hydroxy,
cyano, nitro, --NHCOCH.sub.3, and --CO.sub.2H or an ester thereof;
[0060] R.sup.49 is hydrogen or C.sub.1-C.sub.6 alkyl; [0061]
R.sup.5 is selected from the group consisting of --O-- and
N--R.sup.51; and [0062] R.sup.51 is selected from the group
consisting of hydrogen and C.sub.1-C.sub.6 alkyl optionally
substituted with 1-3 substituents selected from the group
consisting of keto, halo, amino, hydroxy, cyano, nitro, --N.sub.3,
and --CO.sub.2H or an ester thereof; [0063] wherein the C.sup.14
content of a compound of Formula (I), that is tabernanthine,
ibogamine, ibogaline, ibogamine, and noribogaine is less than 0.9
ppt, preferably less than 0.8 ppt, or more preferably less than 0.8
ppt.
[0064] A keto substituent, as used herein, substitutes a
--CH.sub.2-- group to a --C(.dbd.O)-group. In one embodiment, the
compound of Formula (I) excludes a compound selected from Iboga
alkaloids. As used herein, Iboga alkaloids are alkaloids, isolated
from the plant Tabernanthe Iboga that contain a tryptamine and an
isoquinuclidene moiety as present in ibogaine or noribogaine. In
one embodiment, the excluded iboga alkaloid is tabernanthine,
ibogamine, ibogaline, ibogamine, or noribogaine.
[0065] In one embodiment, the compound of Formula (I) is of Formula
(IA) or (IB):
##STR00009##
wherein k and R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are
defined as in Formula (I) above.
[0066] In another embodiment, the compound of Formula (I) is of
Formula (IIA) or (IIB):
##STR00010##
wherein k and R.sup.1, R.sup.2, R.sup.4, and R.sup.5 are defined as
in Formula (I) above.
[0067] In another embodiment, the compound of Formula (I) is of
Formula (IIIA) or (IIIB):
##STR00011##
wherein k and R.sup.1, R.sup.3, R.sup.4, and R.sup.5 are defined as
in Formula (I) above.
[0068] In another embodiment, the compound of Formula (I) is of
Formula (WA) or (WB):
##STR00012## [0069] wherein R.sup.11 is selected from the group
consisting of hydrogen and C.sub.1-C.sub.6 alkyl optionally
substituted with 1-3 substituents selected from the group
consisting of halo, amino, hydroxy, cyano, nitro, --N.sub.3,
--CO.sub.2H or an ester thereof, and phenyl optionally substituted
with 1-3 substituents selected from the group consisting of
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy; [0070] k is 1 or
2; [0071] and R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are
defined as in Formula (I) above.
[0072] In another embodiment, the compound of Formula (I) is of
Formula (WC), (IVD), (VIA), or (VIB):
##STR00013## [0073] wherein R.sup.11 is selected from the group
consisting of hydrogen and C.sub.1-C.sub.6 alkyl optionally
substituted with 1-3 substituents selected from the group
consisting of halo, amino, hydroxy, cyano, nitro, --N.sub.3, and
--O.sub.2H or an ester thereof, and phenyl optionally substituted
with 1-3 substituents selected from the group consisting of
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy; [0074] k is 1 or
2; [0075] and R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are
defined as in Formula (I) above.
[0076] In another embodiment, the present invention provides
compounds of formula (VA):
##STR00014##
[0077] as tabulated below:
TABLE-US-00001 R.sup.1 R.sup.11 C(R.sup.2).sub.2 R.sup.45 R.sup.46
R.sup.47 H, 4-Me, 6-Me, 7- Bn C.dbd.O CR.sup.45CR.sup.46 is -- --
Me, 4-OH, 6-OH, 7- C.dbd.O OH, 4-OMe, 6- OMe, or 7-OMe H, 4-Me,
6-Me, 7- Bn C.dbd.O CR.sup.45CR.sup.46 is -- -- Me, 4-OH, 6-OH, 7-
C.dbd.CR.sup.48H, OH, 4-OMe, 6- R.sup.48 is Me, OMe, or 7-OMe Et,
Pr, Bu H, 4-Me, 6-Me, 7- Bn CH.sub.2 CR.sup.45CR.sup.46 is -- --
Me, 4-OH, 6-OH, 7- C.dbd.CR.sup.48H, OH, 4-OMe, 6- R.sup.48 is Me,
OMe, or 7-OMe Et, Pr, Bu H, 4-Me, 6-Me, 7- Bn C.dbd.O
CH.dbd.CHR.sup.47 OH H or C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr,
Bu) Me, 4-OH, 6-OH, 7- optionally substituted with an OMe OH,
4-OMe, 6- group (e.g., CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or
7-OMe (CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group
(e.g., CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., ##STR00015## H, 4-Me, 6-Me, 7- Bn C.dbd.O
C.ident.CR.sup.47 OH H or C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr,
Bu) Me, 4-OH, 6-OH, 7- optionally substituted with an OMe OH,
4-OMe, 6- group (e.g., CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or
7-OMe (CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group
(e.g., CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., ##STR00016## H, 4-Me, 6-Me, 7- Bn C.dbd.O
CH.sub.2CH.sub.2R.sup.47 H C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr,
Bu) Me, 4-OH, 6-OH, 7- optionally substituted with an OMe OH,
4-OMe, 6- group (e.g., CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or
7-OMe (CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group
(e.g., CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., ##STR00017## H, 4-Me, 6-Me, 7- Bn C.dbd.O
CH.sub.2CH.sub.2R.sup.47 OH C.sub.1-C.sub.4 alkyl (e.g., Me, Et,
Pr, Bu) Me, 4-OH, 6-OH, 7- optionally substituted with an OMe OH,
4-OMe, 6- group (e.g., CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or
7-OMe (CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group
(e.g., CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., ##STR00018## H, 4-Me, 6-Me, 7- Bn CH.sub.2
CH.dbd.CHR.sup.47 OH H or C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr,
Bu) Me, 4-OH, 6-OH, 7- optionally substituted with an OMe OH,
4-OMe, 6- group (e.g., CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or
7-OMe (CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group
(e.g., CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., ##STR00019## H, 4-Me, 6-Me, 7- Bn CH.sub.2
C.ident.CR.sup.47 OH H or C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr,
Bu) Me, 4-OH, 6-OH, 7- optionally substituted with an OMe OH,
4-OMe, 6- group (e.g., CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or
7-OMe (CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group
(e.g., CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00020##
H, 4-Me, 6-Me, 7- Bn CH.sub.2 CH.sub.2CH.sub.2R.sup.47 H
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally substituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00021##
H, 4-Me, 6-Me, 7- Bn CH.sub.2 CH.sub.2CH.sub.2R.sup.47 OH
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally substituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00022##
H, 4-Me, 6-Me, 7- H C.dbd.O CH.dbd.CHR.sup.47 OH H or
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally substituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00023##
H, 4-Me, 6-Me, 7- H C.dbd.O C.ident.CR.sup.47 OH H or
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally substituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00024##
H, 4-Me, 6-Me, 7- H C.dbd.O CH.sub.2CH.sub.2R.sup.47 H
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally substituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00025##
H, 4-Me, 6-Me, 7- H C.dbd.O CH.sub.2CH.sub.2R.sup.47 OH
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally substituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00026##
H, 4-Me, 6-Me, 7- H CH.sub.2 CH.dbd.CHR.sup.47 OH H or
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optioanlly substituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00027##
H, 4-Me, 6-Me, 7- H CH.sub.2 C.ident.CR.sup.47 OH H or
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally substituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00028##
H, 4-Me, 6-Me, 7- H CH.sub.2 CH.sub.2CH.sub.2R.sup.47 H
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally substituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00029##
H, 4-Me, 6-Me, 7- H CH.sub.2 CH.sub.2CH.sub.2R.sup.47 OH
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally subsituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2,
##STR00030##
[0078] In another embodiment, this invention provides a compound of
Formula (VIC):
as tabulated below:
##STR00031##
TABLE-US-00002 R.sup.1 R.sup.11 C(R.sup.2).sub.2 R.sup.45 R.sup.47
H, 4-Me, 6-Me, 7- Bn C.dbd.O CH.dbd.CHR.sup.47 H or C.sub.1-C.sub.4
alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7- optionally
substituted with an OMe OH, 4-OMe, 6- group (e.g., CH.sub.2OMe,
(CH.sub.2).sub.2OMe, OMe, or 7-OMe (CH.sub.2).sub.3OMe, and
(CH.sub.2).sub.4OMe), OH group (e.g., CH.sub.2OH,
(CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and (CH.sub.2).sub.4OH), an
amide (e.g., (CH.sub.2).sub.2NHCOMe, (CH.sub.2).sub.3NHCOMe, and
(CH.sub.2).sub.4NHCCOMe) or with an amino group (e.g.,
CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00032## H, 4-Me, 6-Me, 7-
Bn C.dbd.O C.ident.CR.sup.47 H or C.sub.1-C.sub.4 alkyl (e.g., Me,
Et, Pr, Bu) Me, 4-OH, 6-OH, 7- optionally substituted with an OMe
OH, 4-OMe, 6- group (e.g., CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe,
or 7-OMe (CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group
(e.g., CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00033##
H, 4-Me, 6-Me, 7- Bn C.dbd.O CH.sub.2CH.sub.2R.sup.47
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally substituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00034##
H, 4-Me, 6-Me, 7- Bn CH.sub.2 CH.dbd.CHR.sup.47 H or
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally subsituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00035##
H, 4-Me, 6-Me, 7- Bn CH.sub.2 C.ident.CR.sup.47 H or
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally substituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2, ##STR00036##
H, 4-Me, 6-Me, 7- Bn CH.sub.2 CH.sub.2CH.sub.2R.sup.47
C.sub.1-C.sub.4 alkyl (e.g., Me, Et, Pr, Bu) Me, 4-OH, 6-OH, 7-
optionally substituted with an OMe OH, 4-OMe, 6- group (e.g.,
CH.sub.2OMe, (CH.sub.2).sub.2OMe, OMe, or 7-OMe
(CH.sub.2).sub.3OMe, and (CH.sub.2).sub.4OMe), OH group (e.g.,
CH.sub.2OH, (CH.sub.2).sub.2OH, (CH.sub.2).sub.3OH, and
(CH.sub.2).sub.4OH), an amide (e.g., (CH.sub.2).sub.2NHCOMe,
(CH.sub.2).sub.3NHCOMe, and (CH.sub.2).sub.4NHCCOMe) or with an
amino group (e.g., CO.sub.2(CH.sub.2).sub.2NMe.sub.2,
##STR00037##
As used herein, Me, Et, Pr, Bu and Bn, refer to methyl, ethyl,
propyl, butyl, and benzyl, respectively.
[0079] In another embodiment, this invention provides an isolated
enantiomer of a compound of any one of Formulas (I), (IA), (IB),
(IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (IVC), (IVD), (VA),
(VI), (VIA), (VIB), or (VIC) in substantial enantiomeric
excess.
[0080] In one embodiment, this invention provides a compound of
formula:
##STR00038##
[0081] in a substantially enantiomerically enriched form, or a salt
of each thereof, wherein R.sup.1 is C.sub.1-C.sub.4 alkyl
optionally substituted with a phenyl or a substituted phenyl group,
wherein the substituted phenyl is substituted with 1-3
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy groups and R.sub.2
is hydrogen or C(R.sup.2).sub.2 is C.dbd.O.
[0082] In another embodiment, R.sub.2 is hydrogen. In another
embodiment, C(R.sup.2).sub.2 is C=0. In another embodiment, R.sup.1
is methyl or benzyl. In another embodiment, the compound is
provided as an isolated enantiomer in substantial enantiomeric
excess.
[0083] In another embodiment, this invention provides (+)
noribogaine. In another embodiment, the (+) noribogaine has a
.sup.14C content of less than 1 ppt, preferably less than 0.9 ppt,
and more preferably less than 0.8 ppt.
[0084] .sup.14C has a half-life of about 5,730 years and is
generated in the upper atmosphere as .sup.14CO.sub.2.
[0085] The amount of .sup.14CO.sub.2 present is approximately 1 ppt
(parts per trillion) and, through photosynthesis, accumulates in
plants resulting in a .sup.14C content of plant material of
approximately 1 ppt. Accordingly, plant derived compounds are
expected to have approximately 1 ppt .sup.14C. Conversely, the
synthetic compounds disclosed herein are derived from fossil fuels,
which, due to .sup.14C decay, would have a .sup.14C content of less
than 1 ppt .sup.14C. Accordingly, provided herein are synthetic
indole and benzofuran fused isoquinuclidene derivative having a
.sup.14C content of less than 1 ppt, preferably, less than 0.90
ppt, or more preferably less than 0.8 ppt.
Processes of the Invention
[0086] Compounds of this invention are prepared as schematically
illustrated below:
##STR00039## ##STR00040##
[0087] In the scheme above, k, R.sup.1, R.sup.2, R.sup.3, and
R.sup.5 are defined as in any aspect or embodiment herein. Compound
i is obtained, following the procedure described in U.S.
application Ser. No. 13/358,446, which is incorporated herein in
its entirety by reference. Compound ii is available commercially or
prepared easily from commercially available material following
steps well known in the art.
[0088] In one embodiment, this invention provides a process for
preparing compound iii comprising contacting compound i with
compound ii under conditions to provide compound iii. Accordingly,
in step 1, compound i is coupled with compound ii, preferably in an
inert solvent, in the presence of an amide or an ester coupling
reagent. Various such coupling agents such as carbodiimides or
(O-Benzotriazole-N,N,N',N'-tetramethyl uroniumhexafluorophosphate)
HBTU or (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium
hexafluorophosphate) HATU, and their immobilized derivatives are
well known in the art and available commercially, for example, from
Sigma-Aldrich Co. The reaction is carried out under suitable
conditions to effect reaction completion. Typically, the reaction
is carried out at 0-50.degree. C. for a period of time sufficient
to provide a substantial amount of the product, which can be
ascertained by using routine methods such as thin layer
chromatography, .sup.1H-nuclear magnetic resonance (NMR)
spectroscopy, and the likes. The product can be isolated and
optionally purified using standard purification techniques, such as
liquid chromatography, crystallization, and precipitation, or the
products may be used for a subsequent reaction without further
purification.
[0089] In another embodiment, this invention provides a process for
preparing compound iv comprising subjecting compound iii under
conditions to provide compound iv. Accordingly, in step 2, compound
iii is made to undergo an intramolecular Heck type cylization,
preferably in an inert solvent, in the presence of 100-130 mole %,
with respect to compound iii, of a Pd(II) salt, and an oxidant such
as a silver (I). A reducing agent, such as a borohydride is used to
reductively workup the reaction mixture to provide compound iv. The
reaction is carried out at 30-90.degree. C. for a period of time
sufficient to provide a substantial amount of the product, which
can be ascertained by using routine methods such as thin layer
chromatography, NMR spectroscopy, and the likes. The product can be
isolated and optionally purified using standard purification
techniques, such as liquid chromatography, crystallization, and
precipitation, or the products may be used for a subsequent
reaction without further purification.
[0090] In another embodiment, this invention provides a process for
preparing compound vi comprising contacting compound v with
R.sup.4-M, wherein R.sup.4 is C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, or C.sub.3-C.sub.6 alkynyl, optionally
substituted with a protected form of amino or hydroxy, and M is
lithium or magnesium halide, under conditions to provide compound
vi. Accordingly, in step 3, compound v, which is compound iv
wherein C(R.sup.4).sub.2 is a keto group, and which is readily
obtained from compound iv, where C(R.sup.4).sub.2 is a cyclic ketal
or thioketal by deprotection, is reacted with an R.sup.4 anion
equivalent, R.sup.4-M, wherein M is lithium, a magnesium halide,
and the like. The reaction is carried out, preferably with about a
10 fold excess of the R.sup.4-M in an inert solvent such as ether
or tetrahydrofuran at a temperature of -5.degree. C. to 15.degree.
C. for a period of time sufficient to provide a substantial amount
of the product, which can be ascertained by using routine methods
such as thin layer chromatography, .sup.1H-nuclear magnetic
resonance (NMR) spectroscopy, and the likes. After aqueous work-up
using, for example, water, aqueous NH.sub.4Cl or aqueous tartrate,
the product can be isolated and optionally purified using standard
purification techniques, such as liquid chromatography,
crystallization, and precipitation, or the products may be used for
a subsequent reaction without further purification.
[0091] In another embodiment, this invention provides a process for
preparing compound vii comprising subjecting compound vi under
conditions to provide compound vii. Accordingly, in step 4,
compound vi is dehydrated, preferably using an acid such as a
sulfonic acid to provide compound vii. The dehydration is carried
out in an inert solvent, preferably at a temperature where the
solvent refluxes, for a period of time sufficient to provide a
substantial amount of the product, which can be ascertained by
using routine methods such as thin layer chromatography, NMR
spectroscopy, and the likes. Various solvents useful for this
purpose is well known in the art and will be apparent to the
skilled artisan upon reading this disclosure. The product can be
isolated and optionally purified using standard purification
techniques, such as liquid chromatography, crystallization, and
precipitation, or the products may be used for a subsequent
reaction without further purification.
[0092] In another embodiment, this invention provides a process for
preparing compound viii comprising subjecting compound vii under
conditions to provide compound viii. Accordingly, in step 5, the
amide carbonyl of compound vii is reduced to a --CH.sub.2- moiety
by reacting with a borohydride, optionally activated with a Lewis
acid, such as BF.sub.3 etherate, or with an aluminum hydride. The
reaction is performed in an inert solvent, preferably, an ether or
tetrahydrofuran at a temperature of 0-50.degree. C. or in a
refluxing solvent. The reaction is carried out for a period of time
sufficient to provide a substantial amount of the product, which
can be ascertained by using routine methods such as thin layer
chromatography, NMR spectroscopy, and the likes. The product can be
isolated and optionally purified using standard purification
techniques, such as liquid chromatography, crystallization, and
precipitation, or the products may be used for a subsequent
reaction without further purification.
[0093] In another embodiment, this invention provides a process for
preparing compound ix comprising subjecting compound viii under
conditions to provide compound ix. Accordingly, in step 6, compound
viii is hydrogenated to provide compound viii. The hydrogenation is
carried out using Pd or Pt or their oxides or hydroxides adsorbed
on a solid support such as carbon, alumina, and the like,
preferably in an amount less than 100 mole % with respect to
compound viii, and hydrogen. The hydrogenation is carried out in an
inert solvent, such as an alcohol, ethyl acetate, or an ether, at
15-30.degree. C. for a period of time sufficient to provide a
substantial amount of the product, which can be ascertained by
using routine methods such as thin layer chromatography, NMR
spectroscopy, and the likes. The product can be isolated and
optionally purified using standard purification techniques, such as
liquid chromatography, crystallization, and precipitation.
[0094] In certain process embodiments, C(R.sup.4).sub.2 is a keto
(C.dbd.O) group. In other process embodiments, for compounds i and
iii, C(R.sup.4).sub.2 is is cyclic ketal or thioketal. In other
process embodiments, R.sup.5 is NH. In certain other process
embodiments, R.sup.5 is 0. In certain other process embodiments,
for compounds, vi-ix, R.sup.4 is C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl, optionally
substituted with 1-3 substituents, as provided herein, or their
protected forms that will be apparent to the skilled artisan.
[0095] It will be apparent to the skilled artisan upon reading this
disclosure that the sequence of steps shown in Scheme 1, are
preferred illustrative sequences, and can be altered in manners
apparent to the skilled artisan to obtain the compounds provided
herein.
[0096] Compounds of this invention where C(R.sup.4).sub.2 is
C.dbd.CR.sup.48R.sup.49 are conveniently prepared from the
corresponding keto compound (C(R.sup.4).sub.2 is keto) following
Wittig and other related olefination procedures, as is well known
to the skilled artisan.
[0097] In certain other of its process embodiments, this invention
provides processes, preferably, enantioselective processes, for
preparing (-) noribogaine, in a substantially enantiomerically pure
form, as schematically illustrated below, where the reagents
indicated are merely illustrative and are not limiting, as
discussed in further detail below.
##STR00041## ##STR00042##
[0098] In one embodiment, this invention provides a process for
preparing compound 2 comprising contacting compound 1 with
5-benzyloxyindoleacetic acid under conditions to provide compound
2. Thus, in step 1, Compound 1 is coupled with the benzyloxy
substituted indole acetic acid to provide compound 2. The coupling
is performed preferably in an inert solvent, such as a chlorinated
solvent such as dichloromethane, or in tetrahydrofuran, or
acetonitrile, in the presence of a amide or ester coupling reagent.
Various such coupling agents such as carbodiimides or HBTU or HATU,
and their immobilized derivatives are well known in the art and
available commercially, for example, from Sigma-Aldrich Co. In a
preferred embodiment, the coupling is performed in the presence of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and a hindered
base, such as diisopropylethyl amine (DIPEA). In one embodiment,
The reaction is carried out at 0-50.degree. C. for a period of time
sufficient to provide a substantial amount of the product, which
can be ascertained by using routine methods such as thin layer
chromatography, NMR spectroscopy, and the likes. FIG. 3
demonstrates the .sup.1H-NMR spectrum of compound 2. The product
can be isolated and optionally purified using standard purification
techniques, such as liquid chromatography, crystallization, and
precipitation, or the product may be used for a subsequent reaction
without further purification.
[0099] In another embodiment, this invention provides a process for
preparing compound 3 comprising subjecting compound 2 under
conditions to provide compound 3. Thus, in step 2, compound 2 is
deprotected by reacting with an aqueous acid. Various mineral acids
such as sulfuric acid or hydrochloric acid, and sulfonic acids,
such as toluene sulfonic acid are useful as the acid. Following the
deprotection, the deprotected compound is subjected to an
intramolecular Heck type cylization. Various art known palladium
reagents, such as palladium chloride and complexes thereof (such as
the bis acetonitrile complex) are useful as the cyclization
reagent, used in 100-130 mole % with respect to compound 2, further
in presence of an oxidant, such as a Ag(I) salt. Reductive workup,
employing a borohydride was demonstrated to provide compound 3
(see, FIG. 1). The reaction is carried out in an inert solvent,
such as acetonitrile, alcohols, acetic acid, and mixtures thereof,
at 30-90.degree. C., preferably at 60-80.degree. C. for a period of
time sufficient to provide a substantial amount of the product,
which can be ascertained by using routine methods such as thin
layer chromatography, NMR spectroscopy, and the likes. The product
can be isolated and optionally purified using standard purification
techniques, such as liquid chromatography, crystallization, and
precipitation, or the product may be used for a subsequent reaction
without further purification.
[0100] In another embodiment, this invention provides a process for
preparing compound 4 comprising contacting compound 3 with an ethyl
anion equivalent under conditions to provide compound 4. As used
herein, an ethyl anion equivalent is an anion that after this
reaction is easily converted to an ethyl group. Thus, in step 3,
compound 3 is reacted with an ethyl anion equivalent, such as,
vinyl magnesium bromide (in a 10 fold mole/mole excess with respect
to compound 3), in ether, tetrahydrofuran or a mixture thereof to
provide after aqueous work up, compound 4. The reaction is carried
out for a period of time sufficient to provide a substantial amount
of the product, which can be ascertained by using routine methods
such as thin layer chromatography, NMR spectroscopy, and the likes.
The product can be isolated and optionally purified using standard
purification techniques, such as liquid chromatography,
crystallization, and precipitation, or the product may be used for
a subsequent reaction without further purification.
[0101] In another embodiment, this invention provides a process for
preparing compound 5 comprising subjecting compound 4 under
conditions to provide compound 5. Thus, in step 4, compound 4 is
dehydrated to provide compound 5. The dehydration is performed
preferably using an acid such as a sulfonic acid such as toluene
sulfonic acid to provide compound vii. The dehydration is carried
out in an inert solvent, preferably at a temperature where the
solvent refluxes, for a period of time sufficient to provide a
substantial amount of the product, which can be ascertained by
using routine methods such as thin layer chromatography, NMR
spectroscopy, and the likes. Various solvents useful for this
purpose is well known in the art and will be apparent to the
skilled artisan upon reading this disclosure. The product can be
isolated and optionally purified using standard purification
techniques, such as liquid chromatography, crystallization, and
precipitation, or the product may be used for a subsequent reaction
without further purification.
[0102] In another embodiment, this invention provides a process for
preparing compound 6 comprising subjecting compound 5 under
conditions to provide compound 6. Thus, in step 5, the amide
carbonyl of compound 5 is reduced to provide compound 6, by
reacting with a borohydride, optionally activated with a Lewis
acid, such as BF.sub.3 etherate, or with an aluminum hydride. A
preferred reagent is lithium aluminum hydride. The reaction is
performed in an inert solvent, preferably, an ether or
tetrahydrofuran at a temperature of 0-50.degree. C. or in a
refluxing solvent. The reaction is carried out for a period of time
sufficient to provide a substantial amount of the product, which
can be ascertained by using routine methods such as thin layer
chromatography, NMR spectroscopy, and the likes. The product can be
isolated and optionally purified using standard purification
techniques, such as liquid chromatography, crystallization, and
precipitation, or the product may be used for a subsequent reaction
without further purification.
[0103] In another embodiment, this invention provides a process for
preparing (-) noribogaine or a salt thereof comprising subjecting
compound 6 under conditions to provide (-) noribogaine or a salt
thereof In step 6, compound 6 is hydrogenated to provide (-)
noribogaine or a salt thereof The hydrogenation is carried out
using Pd, Pt, Rh or their oxides or hydroxides adsorbed on a solid
support such as carbon, alumina, and the like, preferably in an
amount less than 100 mole % with respect to compound 6, and
hydrogen. A preferred reagent is PtO.sub.2. The hydrogenation is
carried out in an inert solvent, such as an alcohol, ethyl acetate,
or an ether. The hydrogenation is carried out at 15-30.degree. C.
for a period of time sufficient to provide a substantial amount of
the product, which can be ascertained by using routine methods such
as thin layer chromatography, NMR spectroscopy, and the likes. The
product can be isolated and optionally purified using standard
purification techniques, such as liquid chromatography,
crystallization, and precipitation. The compound obtained from
compound 6 following the process described above showed the
following .sup.1H-NMR chemical shifts (7.27 (d), 7.05 (d) , 6.8
(d), 3.85-3.72 (m), 3.67-3.58 (m), 3.54 (m), 3.44 (m), 3.32 (t) ,
2.42-2.28 (m), 2.27-2.14 (m) , 2.00-1.77 (m) , 1.63-1.54 (m) , 1.23
(t)), which are the same as those observed for (-) noribogaine,
thereby demonstrating the preparation of (-) noribogaine according
to this invention.
[0104] It will be apparent to the skilled artisan upon reading this
disclosure that certain sequence of steps shown in Scheme 2, are
preferred illustrative sequences, and can be altered in manners
apparent to the skilled artisan to obtain the compounds provided
herein.
[0105] Compound 1, utilized in the processes above is prepared as
illustrated schematically below:
##STR00043##
[0106] Conjugate addition of vinyl magnesium bromide, oxazolidine
ring cleavage, and keto group protection converts compound 7 to
compound 8. Compound 8 is oxidized using NMO and
tetrapropylammonium perruthenate to provides compound 9.
Olefination of 9 yields the 1,5 divinyl substrate piperidine (10).
Grubbs ring closing metathesis cyclization of 10 using the well
known and commercially available Grubbs' or Schrock catalysts
yields optically active (11) which is the carbonyl group and N-
protected derivative compound 6. Deprotection of compound 11 with
methyl lithium was demonstrated to provide compound 1. The
.sup.1H-NMR of compound 1 is provided in FIG. 2. The reactions are
carried out, preferably in an inert solvent that will be apparent
to the skilled artisan upon reading this disclosure, and at
temperatures that will also be apparent to the skilled artisan upon
reading this disclosure. The reactions are performed for a period
of time sufficient to provide a substantial amount of the product,
which can be ascertained by using routine methods such as thin
layer chromatography, .sup.1H-nuclear magnetic resonance (NMR)
spectroscopy, and the likes. The products can be isolated and
optionally purified using standard purification techniques, such as
liquid chromatography, crystallization, precipitation, and
distillation under reduced pressure, or the products may be used
for a subsequent reaction without further purification.
[0107] Other processes of this invention for preparing (-) and (+)
noribogaine are schematically illustrated and described below.
##STR00044## ##STR00045##
##STR00046## ##STR00047##
[0108] Thus, in one embodiment, this invention provides a process
for preparing a compound of formula:
##STR00048##
comprising contacting benzoquinone with a diene compound of
formula:
##STR00049##
and a Ti((S)-binol)Cl.sub.2 catalyst under conditions to provide
the compound of formula:
##STR00050##
It is contemplated that other silicon protecting group such as
TIPS, TBDMS, or triphenyl silyl can be reasonably used in place of
TBS. Benzoquinone is combined with, e.g., at least an equimolar
amount of the diene in an inert chlorinated solvent in presence of
a catalytic amount, preferably 20%-35% molar amount, still more
preferably, 25%-30% molar amount with respect to benzoquinone, of
Ti((S)-binol)Cl.sub.2. The concentration of the reactants and the
catalyst in the reaction solvent are as follows: benzoquinone,
0.05-0.2 molar, preferably 0.09-0.13 molar, still more preferably
0.11 molar: diene, 0.05-0.2 molar, preferably 0.1-0.14 molar, still
more preferably 0.12 molar; and the catalyst, 0.01-0.1 molar,
preferably 0.02-0.06 molar, still more preferably 0.03 molar. The
reaction is performed at room temperature for a period of time
sufficient to effect a substantial completion of the reaction.
[0109] While performing the above reaction under the conditions
described, it was surprisingly observed that the desired enantiomer
was obtained in 96% ee. Such a high ee allows the reaction to be
used for manufacturing highly enantiomerically pure noribogaine
suitable for human administration at reasonable manufacturing
costs. The ee obtained for this reaction surpasses the 87% ee
reported by White et al., Helv. Chim. Acta, Vol. 85 (2002),
4306-4327 (White), and incorporated herein in its entirety by
reference. In White, despite optimization, a higher ee was not
obtained. See, White at page 4314. An 87% ee corresponds to 93.5%
of the major enantiomer. A process with 87% ee is undesirable from
a manufacturing standpoint because it lowers chemical yield of the
desired enantiomer, and adds one or more extra steps to separate
the desired enantiomer from the undesired enantiomer. However, it
is well known that when the ee excess is already around 87% after
substantial optimization, it is challenging to improve it further.
Under the conditions White reported, toluene was used as the
reaction solvent and the following concentrations of the reactants
and the catalyst were used: benzoquinone (0.83 molar), diene (0.97
molar), and catalyst (0.25 molar). Furthermore, according to White,
4 angstrom molecular sieves used during in situ preparation of the
catalyst was removed by centrifugation.
[0110] Therefore it was surprising that in the above reaction, when
dichloromethane was used in place of toluene, the concentrations of
the reactants and the catalyst were reduced by about 7 fold, and
the molecular sieves used for preparing the catalyst were filtered
off instead of being removed by centrifugation, the ee of the diene
obtained increased to 96%. Or in other words, the reaction produced
98% of the desired enantiomer.
[0111] In another embodiment, this invention provides a process for
preparing a compound of formula:
##STR00051##
comprising contacting benzoquinone with a diene compound of
formula:
##STR00052##
and a Ti((R)-binol)Cl.sub.2 catalyst under Diels Alder reaction
conditions to provide the compound of formula:
##STR00053##
It is contemplated that another silicon protecting group be
reasonably used in place of OTBS. Preferred reaction conditions for
this reaction are the same as those described above for the Diels
Alder reaction using a Ti((S)-binol)Cl.sub.2 catalyst.
Ti((R)-binol)Cl.sub.2 or Ti((S)-binol)Cl.sub.2 is preferably
prepared in situ by reacting (R) or (S)-binol with
Ti(--OCHMe.sub.2).sub.2Cl.sub.2.
[0112] In another embodiment, this invention provides a process for
preparing a compound of formula:
##STR00054##
comprising contacting the compound of formula:
##STR00055##
with a reducing agent under conditions to provide the compound of
formula:
##STR00056##
[0113] In a preferred embodiment, the reducing agent is
diisobutylaluminum hydride.
[0114] In another embodiment, this invention provides a process for
preparing a compound of formula:
##STR00057##
comprising the steps of : [0115] (i) contacting the compound of
formula
[0115] ##STR00058## [0116] under hydrogenation conditions to
provide a compound of formula
[0116] ##STR00059## [0117] (ii) contacting the compound of
formula:
##STR00060##
[0117] with an oxidizing agent under conditions to provide a
compound of formula:
##STR00061##
(iii) contacting the compound of formula:
##STR00062##
with methanol and pyridinium para toluene sulfonate to provide a
compound of formula:
##STR00063##
(iv) contacting the compound of formula:
##STR00064##
with triisopropyl silyl chloride and imidazole to provide the
compound of formula:
##STR00065##
(v) contacting the compound of formula:
##STR00066##
with a salt of NH.sub.2OH and a base to provide the compound of
formula:
##STR00067##
(vi) contacting the compound of formula
##STR00068##
with R.sup.sSO.sub.2Cl wherein Rs is alkyl, fluoroalkyl, aryl, or
aryl substiotuted with an alkyl or a halogen group, a base, and
optionally a nucleophilic catalyst such as
4-N,N-dialkylaminopyridine to provide a compound of formula:
##STR00069##
(vii) contacting the compound of formula:
##STR00070##
with fluoride anion to provide the compound of formula:
##STR00071##
(viii) contacting the compound of formula:
##STR00072##
with R.sup.sSO.sub.2Cl wherein R.sup.s is alkyl, fluoroalkyl, aryl,
or aryl substituted with an alkyl or a halogen group, a base, and
optionally a 4-N,N-dialkylaminopyridine to provide a compound of
formula:
##STR00073##
(ix) contacting the compound of formula:
##STR00074##
with a non ncucleophilic base to provide a compound of formula:
##STR00075##
and (x) contacting the compound of formula:
##STR00076##
with an acid to provide the compound of formula:
##STR00077##
[0118] Steps (i) to (x) can be performed substantially according to
the methods described in White, supra. In step (i), the
hydrogenation is performed preferably employing a catalyst such
Rh/Al.sub.2O.sub.3 and hydrogen, which catalyst does not produce
substantial amounts of the hydrogenolyzed product. Upon
hydrogenolysis, the allylic hydroxy group(s) can be replaced by
hydrogen atom(s). A variety of oxidizing agents can be employed for
step (ii) such as for example pyridinum dichromate, pyridinium
chlorochromate, and the like. Those oxidizing agents are preferred
that would not convert the tributylsilyloxy (OTBS) group to an --OH
group. The selective ketalization of the less hindered ketone in
step (iii) is performed using a mild acid catalyst such as
pyridinium para tolune sulfonate (PPTS). In step (v), a salt of
NH.sub.2OH is reacted with the ketone and a base to provide the
oxime. A variety of bases may be employed, including without
limitation, acetates, preferably alkali metal acetates, alkali, and
nitrogen containing bases such as pyridine, triethyl amine and the
like. In step (vi), a variety of sulfonyl chlorides may be used,
including without limitation para toluene sulfonyl chloride. In
step (vi), a variety of bases may be employed, including without
limitation, alkali and nitrogen containing bases such as pyridine,
triethyl amine and the like. Preferred nucleophilic catalysts
include 4-N,N-dimethylaminopyridine and 4-pyrrolidinopyridine. In
step (vii) a variety of fluoride sources may be used including
tertiary alkyl ammonium fluorides, such a tetrabutylammonium
fluoride. In step (viii), a variety of bases may be employed,
including without limitation, alkali and nitrogen containing bases
such as pyridine, triethyl amine and the like. Preferred
nucleophilic catalysts include 4-N,N-dimethylaminopyridine and
4-pyrrolidinopyridine. In step (ix), preferred non-nucleophilic
bases used include, hydrides such as sodium, potassium and calcium
hydrides. In step (x), a variety of acids can be used to convert
the dimethyl ketal to the ketone. These reactions are carried out
in solvents that are inert under the reaction conditions. The
reactions are carried out for a time sufficient to provide
substantial amount of the desired product. The reactions are
monitored by thin layer chromatography. Depending on the amount of
impurity present, a product may be separated by column
chromatography, crystallization, or such other techniques well
known to the skilled artisan, or the reaction product may be used
without further purification in the next step.
[0119] In another embodiment, this invention provides a process for
converting:
##STR00078##
[0120] following the process provided hereinabove for
synthesizing:
##STR00079##
[0121] In another embodiment, this invention provides a process for
preparing a compound of formula:
##STR00080##
comprising contacting a ketoamide compound of formula:
##STR00081##
with a substituted phenyl hydrazine of formula:
##STR00082##
or a salt thereof, wherein R.sup.1 is C.sub.1-C.sub.4 alkyl
optionally substituted with 1-3 phenyl or substituted phenyl
groups, wherein the substituted phenyl is substituted with 1-3
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy groups, under
Fischer indole synthesis conditions to provide the keto ibogaine
derivative of formula:
##STR00083##
[0122] In another embodiment, R.sup.1 is methyl. In another
embodiment, R.sup.1 is a methyl group substituted with 1-3,
preferably 1-2, more preferably 1 phenyl group, which phenyl group
is optionally substituted with 1-3 C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkoxy groups. In another embodiment, R.sup.1 is
benzyl. When R.sup.1 is methyl, it is preferred to not use a boron
based Lewis acid, such as BF.sub.3 etherate, for this
transformation.
[0123] In another embodiment, the ketoamide compound is present at
least 80%, preferably at least 90%, more preferably at least 95%,
or still more preferably at least 98% as the
(5aR,7R,9S,9aS)-9-ethyl-3,4,5a,6,7,8,9,9a-octahydro-1,7-methano-1H-benz[b-
]azepine-2,5-dione enantiomer:
##STR00084##
[0124] In other words, the ketoamide compound contains, at least
60%, preferably at least 80%, more preferably at least 90%, or
still more preferably at least 96% ee of the
(5aR,7R,9S,9aS)-9-ethyl-3,4,5a,6,7,8,9,9a-octahydro-1,7-methano-1H-benz[b-
]azepine-2,5-dione enantiomer. In another embodiment, the keto
ibogaine derivative is present at least 80%, preferably at least
90%, more preferably at least 95%, or still more preferably at
least 98% as the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer.
[0125] It is surprising that a substituted hydrazine containing an
electron donating 4-alkoxy substituent effectively provides the
tricyclic indole under Fischer indole synthesis conditions. The
ketoamide compound is combined with at least an equimolar amount of
the substituted phenylhydrazine or a salt thereof, in the presence
of an acid or a mixture of acids. Suitable acids include carboxylic
Bronsted acids such as acetic acid and Lewis acids such as BF.sub.3
and its solvates such as etherates. The reaction is performed at
40.degree. C.-60.degree. C., and may optionally be warmed up to
70.degree. C.-90.degree. C., for a period of time sufficient to
effect a substantial completion of the reaction. Suitable solvent
include acetic acid, propionic acid and the like. Suitable salts of
the substituted phenylhydrazine include salts of mineral acids,
such as HC1.
[0126] In another embodiment, this invention provides a method of
synthesis comprising contacting a ketoamide compound of
formula:
##STR00085##
with a substituted phenyl hydrazine of formula:
##STR00086##
or a salt thereof, wherein R.sup.1 is C.sub.1-C.sub.4 alkyl
optionally substituted with 1-3 phenyl or substituted phenyl
groups, wherein the substituted phenyl is substituted with 1-3
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy groups, under
Fischer indole synthesis conditions to provide a keto ibogaine
derivative of formula:
##STR00087##
[0127] In another embodiment, the ketoamide compound is present at
least 80%, preferably at least 90%, more preferably at least 95%,
or still more preferably at least 98% as the
(5aS,7S,9R,9aR)-9-ethyl-3,4,5a,6,7,8,9,9a-octahydro-1,7-methano-1H-benz[b-
]azepine-2,5-dione enantiomer:
##STR00088##
[0128] In another embodiment, the keto ibogaine derivative is
present at least 80%, preferably at least 90%, more preferably at
least 95%, or still more preferably at least 98% as the 2(S), 4(R),
5(R), 6(R) and 18(S) enantiomer.
[0129] In another embodiment, the process further comprises
subjecting the keto ibogaine derivative:
##STR00089##
[0130] under amide reduction conditions to provide ibogaine or the
derivative thereof of formula:
##STR00090##
[0131] The keto ibogaine derivative is contacted with at least an
equimolar, preferably 4-6 molar excess of a borohydride, preferably
NaBH.sub.4 and a Lewis acid, preferably, BF.sub.3 etherate, in an
inert solvent such as tetrahydrofuran. The reaction is performed
initially at 0.degree. C. and then at room temperature for a a
period of time sufficient to effect a substantial completion of the
reaction.
[0132] In another embodiment, the process further comprises
subjecting the keto ibogaine derivative:
##STR00091##
[0133] under amide reduction conditions to provide ibogaine or a
derivative thereof of formula:
##STR00092##
[0134] In another embodiment, the process further comprises
deprotecting the compound of formula:
##STR00093##
[0135] under deprotection conditions to provide naturally occurring
(-) noribogaine:
##STR00094##
[0136] In another embodiment, the noribogaine obtained is present
at least 80%, preferably at least 90%, more preferably at least
95%, or still more preferably at least 98% as the (-) or naturally
occurring 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer of
noribogaine. In another embodiment, R.sup.1 is C.sub.1-C.sub.4
alkyl, and the deprotection is performed by using BBr.sub.3 in an
inert solvent under conditions well known to the skilled artisan.
In another embodiment, R.sup.1 is benzyl and the deprotection is
performed by using hydrogenolysis or catalytic hydrogenation
conditions.
[0137] In another embodiment, the process further comprises
deprotecting the compound of formula:
##STR00095##
under deprotection conditions to provide noribogaine:
##STR00096##
or a salt thereof
[0138] In another embodiment, the noribogaine obtained is present
at least 80%, preferably at least 90%, more preferably at least
95%, or still more preferably at least 98% as the (+) or nonnatural
2(S), 4(R), 5(R), 6(R) and 18(S) enantiomer of noribogaine.
[0139] In another aspect, this invention provides (-) noribogaine
and (+)noribogaine, and intermediates thereto, preferably in
substantially enantiomerically pure forms, prepared according to
the processes provided herein.
Utility
[0140] The indole isoquinuclidene derivative (-) noribogaine has
utility in the treatment of drug dependency and as an analgesic.
See U.S. Pat. Nos. 6,348,456 7,220,737, supra. The indole and
benzofuran fused isoquinuclidene derivatives provided and (+)
noribogaine herein have utility to test their interaction with the
opioid receptors to better understand the mechanism of (-)
noribogaine's analgesic action. The novel compounds provided herein
also have utility as intermediates to synthetic noribogaine or as
compounds having activity in drug dependency or as analgesics.
* * * * *