U.S. patent application number 15/265549 was filed with the patent office on 2017-03-09 for asymmetric syntheses for spiro-oxindole compounds useful as therapeutic agents.
The applicant listed for this patent is Xenon Pharmaceuticals Inc.. Invention is credited to Sultan Chowdhury, Jianmin Fu, Michael Edward Grimwood, Ivan William Hemeon, Tarek Suhayl Mansour, Shaoyi Sun.
Application Number | 20170066777 15/265549 |
Document ID | / |
Family ID | 47902379 |
Filed Date | 2017-03-09 |
United States Patent
Application |
20170066777 |
Kind Code |
A1 |
Sun; Shaoyi ; et
al. |
March 9, 2017 |
ASYMMETRIC SYNTHESES FOR SPIRO-OXINDOLE COMPOUNDS USEFUL AS
THERAPEUTIC AGENTS
Abstract
This invention is directed to asymmetric syntheses of certain
spiro-oxindole derivatives, which are useful for the treatment
and/or prevention of sodium channel-mediated diseases or
conditions, such as pain.
Inventors: |
Sun; Shaoyi; (Coquitlam,
CA) ; Fu; Jianmin; (Coquitlam, CA) ;
Chowdhury; Sultan; (Surrey, CA) ; Hemeon; Ivan
William; (Surrey, CA) ; Grimwood; Michael Edward;
(North Vancouver, CA) ; Mansour; Tarek Suhayl;
(New City, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Xenon Pharmaceuticals Inc. |
Burnaby |
|
CA |
|
|
Family ID: |
47902379 |
Appl. No.: |
15/265549 |
Filed: |
September 14, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13794147 |
Mar 11, 2013 |
9487535 |
|
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15265549 |
|
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61623336 |
Apr 12, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 405/06 20130101;
A61P 25/00 20180101; C07D 491/107 20130101; C07D 405/04 20130101;
C07D 491/20 20130101; C07D 405/14 20130101; C07D 209/34 20130101;
C07D 405/10 20130101 |
International
Class: |
C07D 491/20 20060101
C07D491/20; C07D 405/14 20060101 C07D405/14; C07D 405/04 20060101
C07D405/04; C07D 405/06 20060101 C07D405/06 |
Claims
1.-30. (canceled)
31. A compound of formula (11): ##STR00169## wherein: p and r are
each independently 1, 2, 3 or 4; Pg.sup.1 and Pg.sup.2 are each
independently an oxygen protecting group; R.sup.1 is hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl,
cycloalkylalkyl, heteroaryl, heterocyclyl, --R.sup.8--C(O)R.sup.5,
--R.sup.8--C(O)OR.sup.5, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--S(O).sub.2--R.sup.5, --R.sup.9--S(O).sub.m--R.sup.5 (where m is
0, 1 or 2), --R.sup.8--OR.sup.5, --R.sup.8--CN,
--R.sup.9--P(O)(OR).sub.2, or --R.sup.9--O--R.sup.9--OR.sup.5; or
R.sup.1 is aralkyl substituted by --C(O)N(R.sup.6)R.sup.7 where:
R.sup.6 is hydrogen, alkyl, aryl or aralkyl; and R.sup.7 is
hydrogen, alkyl, haloalkyl, --R.sup.9--CN, --R.sup.9--OR.sup.5,
--R.sup.9--N(R.sup.4)R.sup.5, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or
heteroarylalkyl; or R.sup.6 and R.sup.7, together with the nitrogen
to which they are attached, form a N-heterocyclyl or a
N-heteroaryl; and wherein each aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl groups for R.sup.6 and R.sup.7 may be optionally
substituted by one or more substituents selected from the group
consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl,
--R.sup.8--CN, --R.sup.8--OR.sup.5, heterocyclyl and heteroaryl; or
R.sup.1 is independently aralkyl optionally substituted by one or
more substituents selected from the group consisting of
--R.sup.8--OR.sup.5, --C(O)OR.sup.5, halo, haloalkyl, alkyl, nitro,
cyano, aryl, aralkyl, heterocyclyl and heteroaryl; or R.sup.1 is
independently --R.sup.9--N(R.sup.1)R.sup.11,
--R.sup.9--N(R.sup.12)C(O)R.sup.11 or
--R.sup.9--N(R.sup.10)C(O)N(R.sup.10)R.sup.11 where: each R.sup.10
is hydrogen, alkyl, aryl, aralkyl or heteroaryl; each R.sup.11 is
hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,
aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
heteroarylalkyl, --R.sup.9--OC(O)R.sup.5, --R.sup.9--C(O)OR.sup.5,
--R.sup.9--C(O)N(R.sup.4)R.sup.5, --R.sup.9--C(O)R.sup.5,
--R.sup.9--N(R.sup.4)R.sup.5, --R.sup.9--OR.sup.5, or
--R.sup.9--CN; and R.sup.12 is hydrogen, alkyl, aryl, aralkyl or
--C(O)R.sup.5; and wherein each aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl for R.sup.10 and R.sup.11 may be optionally
substituted by one or more substituents selected from the group
consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl,
nitro, --R.sup.8--CN, --R.sup.8--OR.sup.5, --R.sup.8--C(O)R.sup.5,
heterocyclyl and heteroaryl; or R.sup.1 is independently
heterocyclylalkyl or heteroarylalkyl where the heterocyclylalkyl or
the heteroarylalkyl group is optionally substituted by one or more
substituents selected from the group consisting of oxo, alkyl,
halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R.sup.8--OR.sup.5, --R.sup.8--C(O)OR.sup.5,
--R.sup.8--N(R.sup.4)R.sup.5, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--R.sup.8--N(R.sup.5)C(O)R.sup.4, --R.sup.8--S(O).sub.mR.sup.4
(where m is 0, 1 or 2), --R.sup.8--CN, or --R.sup.8--NO.sub.2; each
R.sup.2 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl,
haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl,
aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
heteroarylalkyl, --R.sup.8--CN, --R.sup.8--NO.sub.2,
--R.sup.8--OR.sup.5, --R.sup.8--N(R.sup.4)R.sup.5,
--N.dbd.C(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--OS(O).sub.2CF.sub.3, --R.sup.8--C(O)R.sup.4, --C(S)R.sup.4,
--C(R.sup.4).sub.2C(O)R.sup.5, --R.sup.8--C(O)OR.sup.4,
--C(S)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)C(O)R.sup.4,
--N(R.sup.5)C(S)R.sup.4, --N(R.sup.5)C(O)OR.sup.4,
--N(R.sup.5)C(S)OR.sup.4, --N(R.sup.5)C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)S(O).sub.nR.sup.4,
--N(R.sup.5)S(O).sub.nN(R.sup.4)R.sup.5,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5,
--N(R.sup.5)C(.dbd.NR.sup.5)N(R.sup.4)R.sup.5, and
--N(R.sup.5)C(.dbd.N--CN)N(R.sup.4)R.sup.5, wherein each m is
independently 0, 1, or 2 and each n is independently 1 or 2; and
wherein each of the cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl groups for R.sup.2 may be optionally substituted by
one or more substituents selected from the group consisting of
alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R.sup.8--CN, --R.sup.8--NO.sub.2, --R.sup.8--OR.sup.5,
--R.sup.8--N(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5, --R.sup.8--C(O)R.sup.4,
--R.sup.8--C(O)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(O)R.sup.4, and --N(R.sup.5)S(O).sub.nR.sup.4, wherein
each m is independently 0, 1, or 2 and each n is independently 1 or
2; or any two adjacent R.sup.2's, together with the adjacent carbon
ring atoms to which they are directly attached, may form a fused
ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl,
and the other R.sup.2's, if present, are as defined above; each
R.sup.3 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl,
haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl,
aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
heteroarylalkyl, --R.sup.8--CN, --R.sup.8--NO.sub.2,
--R.sup.8--OR.sup.5, --R.sup.8--N(R.sup.4)R.sup.5,
--N.dbd.C(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--OS(O).sub.2CF.sub.3, --R.sup.8--C(O)R.sup.4, --C(S)R.sup.4,
--C(R.sup.4).sub.2C(O)R.sup.5, --R.sup.8--C(O)OR.sup.4,
--C(S)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)C(O)R.sup.4,
--N(R.sup.5)C(S)R.sup.4, --N(R.sup.5)C(O)OR.sup.4,
--N(R.sup.5)C(S)OR.sup.4, --N(R.sup.5)C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)S(O).sub.nR.sup.4,
--N(R.sup.5)S(O).sub.nN(R.sup.4)R.sup.5,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5,
--N(R.sup.5)C(.dbd.NR.sup.5)N(R.sup.4)R.sup.5, and
--N(R.sup.5)C(N.dbd.C(R.sup.4)R.sup.5)N(R.sup.4)R.sup.5, wherein
each m is independently 0, 1, or 2 and each n is independently 1 or
2; or any two adjacent R.sup.3's, together with the adjacent carbon
ring atoms to which they are directly attached, may form a fused
ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl,
and the other R.sup.3's, if present, are as defined above; each
R.sup.4 and R.sup.5 is independently selected from group consisting
of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, and heteroarylalkyl; or when R.sup.4
and R.sup.5 are each attached to the same nitrogen atom, then
R.sup.4 and R.sup.5, together with the nitrogen atom to which they
are attached, may form a N-heterocyclyl or a N-heteroaryl; each
R.sup.8 is a direct bond or a straight or branched alkylene chain,
a straight or branched alkenylene chain or a straight or branched
alkynylene chain; and each R.sup.9 is a straight or branched
alkylene chain, a straight or branched alkenylene chain or a
straight or branched alkynylene chain; as a racemic mixture of
enantiomers or as a non-racemic mixture of enantiomers, or a
pharmaceutically acceptable salt thereof.
32.-33. (canceled)
34. A compound of formula (12) or a compound of formula (13):
##STR00170## wherein: each p and r are independently 1, 2, 3 or 4;
each Pg.sup.1 and Pg.sup.2 is independently an oxygen protecting
group; each R.sup.1 is independently hydrogen, alkyl, alkenyl,
alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl,
heterocyclyl, --R.sup.8--C(O)R.sup.5, --R.sup.8--C(O)OR.sup.5,
--R.sup.8--C(O)N(R.sup.4)R.sup.5, --S(O).sub.2--R.sup.5,
--R.sup.9--S(O).sub.m--R.sup.5 (where m is 0, 1 or 2),
--R.sup.8--OR.sup.5, --R.sup.8--CN, --R.sup.9--P(O)(OR).sub.2, or
--R.sup.9--O--R.sup.9--OR.sup.5; or each R.sup.1 is independently
aralkyl substituted by --C(O)N(R.sup.6)R.sup.7 where: R.sup.6 is
hydrogen, alkyl, aryl or aralkyl; and R.sup.7 is hydrogen, alkyl,
haloalkyl, --R.sup.9--CN, --R.sup.9--OR.sup.5,
--R.sup.9--N(R.sup.4)R.sup.5, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or
heteroarylalkyl; or R.sup.6 and R.sup.7, together with the nitrogen
to which they are attached, form a N-heterocyclyl or a
N-heteroaryl; and wherein each aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl groups for R.sup.6 and R.sup.7 may be optionally
substituted by one or more substituents selected from the group
consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl,
--R.sup.8--CN, --R.sup.8--OR.sup.5, heterocyclyl and heteroaryl; or
each R.sup.1 is independently aralkyl optionally substituted by one
or more substituents selected from the group consisting of
--R.sup.8--OR.sup.5, --C(O)OR.sup.5, halo, haloalkyl, alkyl, nitro,
cyano, aryl, aralkyl, heterocyclyl and heteroaryl; or each R.sup.1
is independently --R.sup.9--N(R.sup.10)R.sup.11,
--R.sup.9--N(R.sup.12)C(O)R.sup.11 or
--R.sup.9--N(R.sup.10)C(O)N(R.sup.10)R.sup.11 where: each R.sup.10
is hydrogen, alkyl, aryl, aralkyl or heteroaryl; each R.sup.11 is
hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,
aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
heteroarylalkyl, --R.sup.9--OC(O)R.sup.5, --R.sup.9--C(O)OR.sup.5,
--R.sup.9--C(O)N(R.sup.4)R.sup.5, --R.sup.9--C(O)R.sup.5,
--R.sup.9--N(R.sup.4)R.sup.5, --R.sup.9--OR.sup.5, or
--R.sup.9--CN; and R.sup.12 is hydrogen, alkyl, aryl, aralkyl or
--C(O)R.sup.5; and wherein each aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl for R.sup.10 and R.sup.11 may be optionally
substituted by one or more substituents selected from the group
consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl,
nitro, --R.sup.8--CN, --R.sup.8--OR.sup.5, --R.sup.8--C(O)R.sup.5,
heterocyclyl and heteroaryl; or each R.sup.1 is independently
heterocyclylalkyl or heteroarylalkyl where the heterocyclylalkyl or
the heteroarylalkyl group is optionally substituted by one or more
substituents selected from the group consisting of oxo, alkyl,
halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R--OR.sup.5, --R.sup.8--C(O)OR.sup.5,
--R.sup.8--N(R.sup.4)R.sup.5, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--R.sup.8--N(R.sup.5)C(O)R.sup.4, --R.sup.8--S(O).sub.mR.sup.4
(where m is 0, 1 or 2), --R.sup.8--CN, or --R.sup.8--NO.sub.2; each
R.sup.2 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl,
haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl,
aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
heteroarylalkyl, --R.sup.8--CN, --R.sup.8--NO.sub.2,
--R.sup.8--OR.sup.5, --R.sup.8--N(R.sup.4)R.sup.5,
--N.dbd.C(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--OS(O).sub.2CF.sub.3, --R.sup.8--C(O)R.sup.4, --C(S)R.sup.4,
--C(R.sup.4).sub.2C(O)R.sup.5, --R.sup.8--C(O)OR.sup.4,
--C(S)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)C(O)R.sup.4,
--N(R.sup.5)C(S)R.sup.4, --N(R.sup.5)C(O)OR.sup.4,
--N(R.sup.5)C(S)OR.sup.4, --N(R.sup.5)C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)S(O).sub.nR.sup.4,
--N(R.sup.5)S(O).sub.nN(R.sup.4)R.sup.5,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5,
--N(R.sup.5)C(.dbd.NR.sup.5)N(R.sup.4)R.sup.5, and
--N(R.sup.5)C(.dbd.N--CN)N(R.sup.4)R.sup.5, wherein each m is
independently 0, 1, or 2 and each n is independently 1 or 2; and
wherein each of the cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl groups for R.sup.2 may be optionally substituted by
one or more substituents selected from the group consisting of
alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R.sup.8--CN, --R.sup.8--NO.sub.2, --R.sup.8--OR.sup.5,
--R.sup.8--N(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5, --R.sup.8--C(O)R.sup.4,
--R.sup.8--C(O)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(O)R.sup.4, and --N(R.sup.5)S(O).sub.nR.sup.4, wherein
each m is independently 0, 1, or 2 and each n is independently 1 or
2; or any two adjacent R.sup.2's, together with the adjacent carbon
ring atoms to which they are directly attached, may form a fused
ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl,
and the other R.sup.2's, if present, are as defined above; each
R.sup.3 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl,
haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl,
aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
heteroarylalkyl, --R.sup.8--CN, --R.sup.8--NO.sub.2,
--R.sup.8--OR.sup.5, --R.sup.8--N(R.sup.4)R.sup.5,
--N.dbd.C(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--OS(O).sub.2CF.sub.3, --R.sup.8--C(O)R.sup.4, --C(S)R.sup.4,
--C(R.sup.4).sub.2C(O)R.sup.5, --R.sup.8--C(O)OR.sup.4,
--C(S)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)C(O)R.sup.4,
--N(R.sup.5)C(S)R.sup.4, --N(R.sup.5)C(O)OR.sup.4,
--N(R.sup.5)C(S)OR.sup.4, --N(R.sup.5)C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)S(O).sub.nR.sup.4,
--N(R.sup.5)S(O).sub.nN(R.sup.4)R.sup.5,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5,
--N(R.sup.5)C(.dbd.NR.sup.5)N(R.sup.4)R.sup.5, and
--N(R.sup.5)C(N.dbd.C(R.sup.4)R.sup.5)N(R.sup.4)R.sup.5, wherein
each m is independently 0, 1, or 2 and each n is independently 1 or
2; or any two adjacent R.sup.3's, together with the adjacent carbon
ring atoms to which they are directly attached, may form a fused
ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl,
and the other R.sup.3's, if present, are as defined above; each
R.sup.4 and R.sup.5 is independently selected from group consisting
of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, and heteroarylalkyl; or when R.sup.4
and R.sup.5 are each attached to the same nitrogen atom, then
R.sup.4 and R.sup.5, together with the nitrogen atom to which they
are attached, may form a N-heterocyclyl or a N-heteroaryl; each
R.sup.8 is a direct bond or a straight or branched alkylene chain,
a straight or branched alkenylene chain or a straight or branched
alkynylene chain; and each R.sup.9 is a straight or branched
alkylene chain, a straight or branched alkenylene chain or a
straight or branched alkynylene chain; as an isolated
(S)-enantiomer or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%, or a
pharmaceutically acceptable salt thereof.
35.-38. (canceled)
39. A method of preparing a compound of formula (I): ##STR00171##
as an isolated (S)-enantiomer, or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, or a pharmaceutically acceptable salt thereof;
wherein: p and r are each independently 1, 2, 3 or 4; R.sup.1 is
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl,
cycloalkylalkyl, heteroaryl, heterocyclyl, --R.sup.8--C(O)R.sup.5,
--R.sup.8--C(O)OR.sup.5, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--S(O).sub.2--R.sup.5, --R.sup.9--S(O).sub.m--R.sup.5 (where m is
0, 1 or 2), --R.sup.8--OR.sup.5, --R.sup.8--CN,
--R.sup.9--P(O)(OR).sub.2, or --R.sup.9--O--R.sup.9--OR.sup.5; or
R.sup.1 is aralkyl substituted by --C(O)N(R.sup.6)R.sup.7 where:
R.sup.6 is hydrogen, alkyl, aryl or aralkyl; and R.sup.7 is
hydrogen, alkyl, haloalkyl, --R.sup.9--CN, --R.sup.9--OR.sup.5,
--R.sup.9--N(R.sup.4)R.sup.5, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or
heteroarylalkyl; or R.sup.6 and R.sup.7, together with the nitrogen
to which they are attached, form a N-heterocyclyl or a
N-heteroaryl; and wherein each aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl groups for R.sup.6 and R.sup.7 may be optionally
substituted by one or more substituents selected from the group
consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl,
--R.sup.8--CN, --R.sup.8--OR.sup.5, heterocyclyl and heteroaryl; or
R.sup.1 is aralkyl optionally substituted by one or more
substituents selected from the group consisting of
--R.sup.8--OR.sup.5, --C(O)OR.sup.5, halo, haloalkyl, alkyl, nitro,
cyano, aryl, aralkyl, heterocyclyl and heteroaryl; or R.sup.1 is
--R.sup.9--N(R.sup.10)R.sup.11, --R.sup.9--N(R.sup.12)C(O)R.sup.11
or --R.sup.9--N(R.sup.10)C(O)N(R.sup.10)R.sup.11 where: each
R.sup.10 is hydrogen, alkyl, aryl, aralkyl or heteroaryl; each
R.sup.11 is hydrogen, alkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, heteroarylalkyl, --R.sup.9--OC(O)R.sup.5,
--R.sup.9--C(O)OR.sup.5, --R.sup.9--C(O)N(R.sup.4)R.sup.5,
--R.sup.9--C(O)R.sup.5, --R.sup.9--N(R.sup.4)R.sup.5,
--R.sup.9--OR.sup.5, or --R.sup.9--CN; and R.sup.12 is hydrogen,
alkyl, aryl, aralkyl or --C(O)R.sup.5; and wherein each aryl,
aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl and heteroarylalkyl for R.sup.10 and
R.sup.11 may be optionally substituted by one or more substituents
selected from the group consisting of alkyl, cycloalkyl, aryl,
aralkyl, halo, haloalkyl, nitro, --R.sup.8--CN,
--R.sup.8--OR.sup.5, --R.sup.8--C(O)R.sup.5, heterocyclyl and
heteroaryl; or R.sup.1 is heterocyclylalkyl or heteroarylalkyl
where the heterocyclylalkyl or the heteroarylalkyl group is
optionally substituted by one or more substituents selected from
the group consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, heteroarylalkyl, --R.sup.8--OR.sup.5,
--R.sup.8--C(O)OR.sup.5, --R.sup.8--N(R.sup.4)R.sup.5,
--R.sup.8--C(O)N(R.sup.4)R.sup.5, --R.sup.8--N(R.sup.5)C(O)R.sup.4,
--R.sup.8--S(O).sub.mR.sup.4 (where m is 0, 1 or 2), --R.sup.8--CN,
or --R.sup.8--NO.sub.2; each R.sup.2 is independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy,
halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, heteroarylalkyl, --R.sup.8--CN,
--R.sup.8--NO.sub.2, --R.sup.8--OR.sup.5,
--R.sup.8--N(R.sup.4)R.sup.5, --N.dbd.C(R.sup.4)R.sup.5,
--S(O).sub.mR.sup.4, --OS(O).sub.2CF.sub.3, --R.sup.8--C(O)R.sup.4,
--C(S)R.sup.4, --C(R.sup.4).sub.2C(O)R.sup.5,
--R.sup.8--C(O)OR.sup.4, --C(S)OR.sup.4,
--R.sup.8--C(O)N(R.sup.4)R.sup.5, --C(S)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(O)R.sup.4, --N(R.sup.5)C(S)R.sup.4,
--N(R.sup.5)C(O)OR.sup.4, --N(R.sup.5)C(S)OR.sup.4,
--N(R.sup.5)C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)S(O).sub.nR.sup.4,
--N(R.sup.5)S(O).sub.nN(R.sup.4)R.sup.5,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5,
--N(R.sup.5)C(.dbd.NR.sup.5)N(R.sup.4)R.sup.5, and
--N(R.sup.5)C(.dbd.N--CN)N(R.sup.4)R.sup.5, wherein each m is
independently 0, 1, or 2 and each n is independently 1 or 2; and
wherein each of the cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl groups for R.sup.2 may be optionally substituted by
one or more substituents selected from the group consisting of
alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R.sup.8--CN, --R.sup.8--NO.sub.2, --R.sup.8--OR.sup.5,
--R.sup.8--N(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5, --R.sup.8--C(O)R.sup.4,
--R.sup.8--C(O)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(O)R.sup.4, and --N(R.sup.5)S(O).sub.nR.sup.4, wherein
each m is independently 0, 1, or 2 and each n is independently 1 or
2; or any two adjacent R.sup.2's, together with the adjacent carbon
ring atoms to which they are directly attached, may form a fused
ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl,
and the other R.sup.2's, if present, are as defined above; each
R.sup.3 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl,
haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl,
aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
heteroarylalkyl, --R.sup.8--CN, --R.sup.8--NO.sub.2,
--R.sup.8--OR.sup.5, --R.sup.8--N(R.sup.4)R.sup.5,
--N.dbd.C(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--OS(O).sub.2CF.sub.3, --R.sup.8--C(O)R.sup.4, --C(S)R.sup.4,
--C(R.sup.4).sub.2C(O)R.sup.5, --R.sup.8--C(O)OR.sup.4,
--C(S)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)C(O)R.sup.4,
--N(R.sup.5)C(S)R.sup.4, --N(R.sup.5)C(O)OR.sup.4,
--N(R.sup.5)C(S)OR.sup.4, --N(R.sup.5)C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)S(O).sub.nR.sup.4,
--N(R.sup.5)S(O).sub.nN(R.sup.4)R.sup.5,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5,
--N(R.sup.5)C(.dbd.NR.sup.5)N(R.sup.4)R.sup.5, and
--N(R.sup.5)C(N.dbd.C(R.sup.4)R.sup.5)N(R.sup.4)R.sup.5, wherein
each m is independently 0, 1, or 2 and each n is independently 1 or
2; or any two adjacent R.sup.3's, together with the adjacent carbon
ring atoms to which they are directly attached, may form a fused
ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl,
and the other R.sup.3's, if present, are as defined above; each
R.sup.4 and R.sup.5 is independently selected from group consisting
of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, and heteroarylalkyl; or when R.sup.4
and R.sup.5 are each attached to the same nitrogen atom, then
R.sup.4 and R.sup.5, together with the nitrogen atom to which they
are attached, may form a N-heterocyclyl or a N-heteroaryl; each
R.sup.8 is a direct bond or a straight or branched alkylene chain,
a straight or branched alkenylene chain or a straight or branched
alkynylene chain; and each R.sup.9 is a straight or branched
alkylene chain, a straight or branched alkenylene chain or a
straight or branched alkynylene chain; wherein the method comprises
treating a compound of formula (22): ##STR00172## where p, r,
R.sup.2 and R.sup.3 are each as described above for the compound of
formula (I), as an isolated (S)-enantiomer, or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, or a pharmaceutically
acceptable salt thereof, with a compound of formula (2): X--R.sup.1
(2); where X is halo and R.sup.1 is as described above for the
compound of formula (I), or a pharmaceutically acceptable salt
thereof, under suitable N-alkylation conditions to provide a
compound of formula (I), as described above.
40.-79. (canceled)
80. A method of preparing a compound of formula (I): ##STR00173##
as an isolated (S)-enantiomer, or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, or a pharmaceutically acceptable salt thereof;
wherein: p and r are each independently 1, 2, 3 or 4; R.sup.1 is
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl,
cycloalkylalkyl, heteroaryl, heterocyclyl, --R.sup.8--C(O)R.sup.5,
--R.sup.8--C(O)OR.sup.5, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--S(O).sub.2--R.sup.5, --R.sup.9--S(O).sub.m--R.sup.5 (where m is
0, 1 or 2), --R.sup.8--OR.sup.5, --R.sup.8--CN,
--R.sup.9--P(O)(OR).sub.2, or --R.sup.9--O--R.sup.9--OR.sup.5; or
R.sup.1 is aralkyl substituted by --C(O)N(R.sup.6)R.sup.7 where:
R.sup.6 is hydrogen, alkyl, aryl or aralkyl; and R.sup.7 is
hydrogen, alkyl, haloalkyl, --R.sup.9--CN, --R.sup.9--OR.sup.5,
--R.sup.9--N(R.sup.4)R.sup.5, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or
heteroarylalkyl; or R.sup.6 and R.sup.7, together with the nitrogen
to which they are attached, form a N-heterocyclyl or a
N-heteroaryl; and wherein each aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl groups for R.sup.6 and R.sup.7 may be optionally
substituted by one or more substituents selected from the group
consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl,
--R.sup.8--CN, --R.sup.8--OR.sup.5, heterocyclyl and heteroaryl; or
R.sup.1 is aralkyl optionally substituted by one or more
substituents selected from the group consisting of
--R.sup.8--OR.sup.5, --C(O)OR.sup.5, halo, haloalkyl, alkyl, nitro,
cyano, aryl, aralkyl, heterocyclyl and heteroaryl; or R.sup.1 is
--R.sup.9--N(R.sup.1)R.sup.11, --R.sup.9--N(R.sup.12)C(O)R.sup.11
or --R.sup.9--N(R.sup.10)C(O)N(R.sup.10)R.sup.11 where: each
R.sup.10 is hydrogen, alkyl, aryl, aralkyl or heteroaryl; each
R.sup.11 is hydrogen, alkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, heteroarylalkyl, --R.sup.9--OC(O)R.sup.5,
--R.sup.9--C(O)OR.sup.5, --R.sup.9--C(O)N(R.sup.4)R.sup.5,
--R.sup.9--C(O)R.sup.5, --R.sup.9--N(R.sup.4)R.sup.5,
--R.sup.9--OR.sup.5, or --R.sup.9--CN; and R.sup.12 is hydrogen,
alkyl, aryl, aralkyl or --C(O)R.sup.5; and wherein each aryl,
aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl and heteroarylalkyl for R.sup.10 and
R.sup.11 may be optionally substituted by one or more substituents
selected from the group consisting of alkyl, cycloalkyl, aryl,
aralkyl, halo, haloalkyl, nitro, --R.sup.8--CN,
--R.sup.8--OR.sup.5, --R.sup.8--C(O)R.sup.5, heterocyclyl and
heteroaryl; or R.sup.1 is heterocyclylalkyl or heteroarylalkyl
where the heterocyclylalkyl or the heteroarylalkyl group is
optionally substituted by one or more substituents selected from
the group consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, heteroarylalkyl, --R.sup.8--OR.sup.5,
--R.sup.8--C(O)OR.sup.5, --R.sup.8--N(R.sup.4)R.sup.5,
--R.sup.8--C(O)N(R.sup.4)R.sup.5, --R.sup.8--N(R.sup.5)C(O)R.sup.4,
--R.sup.8--S(O).sub.mR.sup.4 (where m is 0, 1 or 2), --R.sup.8--CN,
or --R.sup.8--NO.sub.2; each R.sup.2 is independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy,
halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, heteroarylalkyl, --R.sup.8--CN,
--R.sup.8--NO.sub.2, --R.sup.8--OR.sup.5,
--R.sup.8--N(R.sup.4)R.sup.5, --N.dbd.C(R.sup.4)R.sup.5,
--S(O).sub.mR.sup.4, --OS(O).sub.2CF.sub.3, --R.sup.8--C(O)R.sup.4,
--C(S)R.sup.4, --C(R.sup.4).sub.2C(O)R.sup.5,
--R.sup.8--C(O)OR.sup.4, --C(S)OR.sup.4,
--R.sup.8--C(O)N(R.sup.4)R.sup.5, --C(S)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(O)R.sup.4, --N(R.sup.5)C(S)R.sup.4,
--N(R.sup.5)C(O)OR.sup.4, --N(R.sup.5)C(S)OR.sup.4,
--N(R.sup.5)C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)S(O).sub.nR.sup.4,
--N(R.sup.5)S(O).sub.nN(R.sup.4)R.sup.5,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5,
--N(R.sup.5)C(.dbd.NR.sup.5)N(R.sup.4)R.sup.5, and
--N(R.sup.5)C(.dbd.N--CN)N(R.sup.4)R.sup.5, wherein each m is
independently 0, 1, or 2 and each n is independently 1 or 2; and
wherein each of the cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl groups for R.sup.2 may be optionally substituted by
one or more substituents selected from the group consisting of
alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R.sup.8--CN, --R.sup.8--NO.sub.2, --R.sup.8--OR.sup.5,
--R.sup.8--N(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5, --R.sup.8--C(O)R.sup.4,
--R.sup.8--C(O)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(O)R.sup.4, and --N(R.sup.5)S(O).sub.nR.sup.4, wherein
each m is independently 0, 1, or 2 and each n is independently 1 or
2; or any two adjacent R.sup.2's, together with the adjacent carbon
ring atoms to which they are directly attached, may form a fused
ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl,
and the other R.sup.2's, if present, are as defined above; each
R.sup.3 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl,
haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl,
aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
heteroarylalkyl, --R.sup.8--CN, --R.sup.8--NO.sub.2,
--R.sup.8--OR.sup.5, --R.sup.8--N(R.sup.4)R.sup.5,
--N.dbd.C(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--OS(O).sub.2CF.sub.3, --R.sup.8--C(O)R.sup.4, --C(S)R.sup.4,
--C(R.sup.4).sub.2C(O)R.sup.5, --R.sup.8--C(O)OR.sup.4,
--C(S)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)C(O)R.sup.4,
--N(R.sup.5)C(S)R.sup.4, --N(R.sup.5)C(O)OR.sup.4,
--N(R.sup.5)C(S)OR.sup.4, --N(R.sup.5)C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)S(O).sub.nR.sup.4,
--N(R.sup.5)S(O).sub.nN(R.sup.4)R.sup.5,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5,
--N(R.sup.5)C(.dbd.NR.sup.5)N(R.sup.4)R.sup.5, and
--N(R.sup.5)C(N.dbd.C(R.sup.4)R.sup.5)N(R.sup.4)R.sup.5, wherein
each m is independently 0, 1, or 2 and each n is independently 1 or
2; or any two adjacent R.sup.3's, together with the adjacent carbon
ring atoms to which they are directly attached, may form a fused
ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl,
and the other R.sup.3's, if present, are as defined above; each
R.sup.4 and R.sup.5 is independently selected from group consisting
of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, and heteroarylalkyl; or when R.sup.4
and R.sup.5 are each attached to the same nitrogen atom, then
R.sup.4 and R.sup.5, together with the nitrogen atom to which they
are attached, may form a N-heterocyclyl or a N-heteroaryl; each
R.sup.8 is a direct bond or a straight or branched alkylene chain,
a straight or branched alkenylene chain or a straight or branched
alkynylene chain; and each R.sup.9 is a straight or branched
alkylene chain, a straight or branched alkenylene chain or a
straight or branched alkynylene chain; wherein the method comprises
the following steps: (a) treating a compound of formula (1):
##STR00174## where p and R.sup.2 are each as defined above for the
compound of formula (I), or a pharmaceutically acceptable salt
thereof, with a compound of formula (14): X-Pg.sup.3 (14); where X
is halo and Pg.sup.3 is a nitrogen protecting group, under suitable
nitrogen protecting conditions to provide a compound of formula
(15): ##STR00175## where p and R.sup.2 are each as described above
for the compound of formula (I), and Pg.sup.3 is a nitrogen
protecting group, or a pharmaceutically acceptable salt thereof;
(b) treating a compound of formula (15) under suitable Grignard
reaction conditions with an intermediate Grignard addition product
formed from the treatment of a compound of formula (4):
##STR00176## where r and R.sup.3 are each as defined above for the
compound of formula (I), with a Grignard reagent of formula (5):
RMgX (5); where R is alkyl and X is iodo, bromo or chloro, under
suitable conditions to provide a compound of formula (16):
##STR00177## where p, r, R.sup.2 and R.sup.3 are each as described
above for the compound of formula (I) and Pg.sup.3 is a nitrogen
protecting group, as a racemic mixture of enantiomers or as a
non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof; (c) treating a compound of formula (16)
with a compound of formula (7): Pg.sup.1X (7) where X is halo and
Pg.sup.1 is an oxygen protecting group under suitable protecting
conditions to provide a compound of formula (17): ##STR00178##
where p, r, R.sup.2 and R.sup.3 are each as described above for the
compound of formula (I), Pg.sup.1 is an oxygen protecting group and
Pg.sup.3 is a nitrogen protecting group, as a racemic mixture of
enantiomers or as a non-racemic mixture of enantiomers, or a
pharmaceutically acceptable salt thereof; (d) treating a compound
of formula (17) under suitable dehydroxylation conditions to
provide a compound of formula (18): ##STR00179## where p, r,
R.sup.2 and R.sup.3 are each as described above for the compound of
formula (I), Pg.sup.1 is an oxygen protecting group and Pg.sup.3 is
a nitrogen protecting group, as a racemic mixture of enantiomers or
as a non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof; (e) treating a compound of formula (18)
with a compound of formula (10): Pg.sup.2OCH.sub.2X (10); where
Pg.sup.2 is an oxygen protecting group and X is halo, under
suitable C-alkylation conditions comprising the presence of a phase
transfer catalyst to provide a compound of formula (19):
##STR00180## where p, r, R.sup.2 and R.sup.3 are each as described
above for the compound of formula (I), Pg.sup.1 and Pg.sup.2 are
each independently an oxygen protecting group and Pg.sup.3 is a
nitrogen protecting group, as an isolated (S)-enantiomer, or a
non-racemic mixture of enantiomers having an enantiomeric excess of
the (S)-enantiomer of greater than 80%, or a pharmaceutically
acceptable salt thereof; (f) treating a compound of formula (19)
under suitable deprotection conditions to provide a compound of
formula (20): ##STR00181## where p, r, R.sup.2 and R.sup.3 are each
as described above for the compound of formula (I), and Pg.sup.3 is
a nitrogen protecting group, as an isolated (S)-enantiomer, or a
non-racemic mixture of enantiomers having an enantiomeric excess of
the (S)-enantiomer of greater than 80%, or a pharmaceutically
acceptable salt thereof; (g) treating a compound of formula (20)
under suitable Mitsunobu reaction conditions to provide the
compound of formula (21): ##STR00182## where p, r, R.sup.2 and
R.sup.3 are each as described above for the compound of formula
(I), and Pg.sup.3 is a nitrogen protecting group, as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%, or a
pharmaceutically acceptable salt thereof; (h) treating a compound
of formula (21) under suitable nitrogen deprotecting conditions to
provide a compound of formula (22): ##STR00183## where p, r,
R.sup.2 and R.sup.3 are each as described above for the compound of
formula (I), as an isolated (S)-enantiomer, or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, or a pharmaceutically
acceptable salt thereof; and (i) treating a compound of formula
(22) with a compound of formula (2): X--R.sup.1 (2); where X is
halo and R.sup.1 is as described above for the compound of formula
(I), or a pharmaceutically acceptable salt thereof, under suitable
N-alkylation conditions to provide a compound of formula (I), as an
isolated (S)-enantiomer, or a non-racemic mixture of enantiomers
having an enantiomeric excess of the (S)-enantiomer of greater than
80%, or a pharmaceutically acceptable salt thereof.
81. A compound of formula (19), a compound of formula (20), a
compound of formula (21) or a compound of formula (22):
##STR00184## wherein: each p and r is independently 1, 2, 3 or 4;
each Pg.sup.1 and Pg.sup.2 is independently an oxygen protecting
group; each Pg.sup.3 is a nitrogen protecting group; each R.sup.2
is independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R.sup.8--CN, --R.sup.8--NO.sub.2, --R.sup.8--OR.sup.5,
--R.sup.8--N(R.sup.4)R.sup.5, --N.dbd.C(R.sup.4)R.sup.5,
--S(O).sub.mR.sup.4, --OS(O).sub.2CF.sub.3, --R.sup.8--C(O)R.sup.4,
--C(S)R.sup.4, --C(R.sup.4).sub.2C(O)R.sup.5,
--R.sup.8--C(O)OR.sup.4, --C(S)OR.sup.4,
--R.sup.8--C(O)N(R.sup.4)R.sup.5, --C(S)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(O)R.sup.4, --N(R.sup.5)C(S)R.sup.4,
--N(R.sup.5)C(O)OR.sup.4, --N(R.sup.5)C(S)OR.sup.4,
--N(R.sup.5)C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)S(O).sub.nR.sup.4,
--N(R.sup.5)S(O).sub.nN(R.sup.4)R.sup.5,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5,
--N(R.sup.5)C(.dbd.NR.sup.5)N(R.sup.4)R.sup.5, and
--N(R.sup.5)C(.dbd.N--CN)N(R.sup.4)R.sup.5, wherein each m is
independently 0, 1, or 2 and each n is independently 1 or 2; and
wherein each of the cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl groups for R.sup.2 may be optionally substituted by
one or more substituents selected from the group consisting of
alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R.sup.8--CN, --R.sup.8--NO.sub.2, --R.sup.8--OR.sup.5,
--R.sup.8--N(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5, --R.sup.8--C(O)R.sup.4,
--R.sup.8--C(O)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(O)R.sup.4, and --N(R.sup.5)S(O).sub.nR.sup.4, wherein
each m is independently 0, 1, or 2 and each n is independently 1 or
2; or any two adjacent R.sup.2's, together with the adjacent carbon
ring atoms to which they are directly attached, may form a fused
ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl,
and the other R.sup.2's, if present, are as defined above; each
R.sup.3 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl,
haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl,
aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
heteroarylalkyl, --R.sup.8--CN, --R.sup.8--NO.sub.2,
--R.sup.8--OR.sup.5, --R.sup.8--N(R.sup.4)R.sup.5,
--N.dbd.C(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--OS(O).sub.2CF.sub.3, --R.sup.8--C(O)R.sup.4, --C(S)R.sup.4,
--C(R.sup.4).sub.2C(O)R.sup.5, --R.sup.8--C(O)OR.sup.4,
--C(S)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)C(O)R.sup.4,
--N(R.sup.5)C(S)R.sup.4, --N(R.sup.5)C(O)OR.sup.4,
--N(R.sup.5)C(S)OR.sup.4, --N(R.sup.5)C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)S(O).sub.nR.sup.4,
--N(R.sup.5)S(O).sub.nN(R.sup.4)R.sup.5,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5,
--N(R.sup.5)C(.dbd.NR.sup.5)N(R.sup.4)R.sup.5, and
--N(R.sup.5)C(N.dbd.C(R.sup.4)R.sup.5)N(R.sup.4)R.sup.5, wherein
each m is independently 0, 1, or 2 and each n is independently 1 or
2; or any two adjacent R.sup.3's, together with the adjacent carbon
ring atoms to which they are directly attached, may form a fused
ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl,
and the other R.sup.3's, if present, are as defined above; each
R.sup.4 and R.sup.5 is independently selected from group consisting
of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, and heteroarylalkyl; or when R.sup.4
and R.sup.5 are each attached to the same nitrogen atom, then
R.sup.4 and R.sup.5, together with the nitrogen atom to which they
are attached, may form a N-heterocyclyl or a N-heteroaryl; and each
R.sup.8 is a direct bond or a straight or branched alkylene chain,
a straight or branched alkenylene chain or a straight or branched
alkynylene chain; as an isolated (S)-enantiomer or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, or a pharmaceutically
acceptable salt thereof.
82.-86. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of U.S. Provisional Patent Application No. 61/623,336,
filed Apr. 12, 2012. This application is incorporated herein by
reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to improved methods of
preparing certain spiro-oxindole compounds as well as various
intermediates involved therein. In particular, this invention is
directed to asymmetric syntheses of certain spiro-oxindole
compounds, and their pharmaceutically acceptable salts, which are
useful in treating sodium channel-mediated diseases or conditions,
such as pain, as well as other diseases and conditions associated
with the mediation of sodium channels.
BACKGROUND OF THE INVENTION
[0003] Sodium channels play a diverse set of roles in maintaining
normal and pathological states, including the long recognized role
that voltage gated sodium channels play in the generation of
abnormal neuronal activity and neuropathic or pathological pain.
Damage to peripheral nerves following trauma or disease can result
in changes to sodium channel activity and the development of
abnormal afferent activity including ectopic discharges from
axotomised afferents and spontaneous activity of sensitized intact
nociceptors. These changes can produce long-lasting abnormal
hypersensitivity to normally innocuous stimuli, or allodynia.
Examples of neuropathic pain include, but are not limited to,
post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy,
chronic lower back pain, phantom limb pain, and pain resulting from
cancer and chemotherapy, chronic pelvic pain, complex regional pain
syndrome and related neuralgias.
[0004] There have been some advances in treating neuropathic pain
symptoms by using medications, such as gabapentin, and more
recently pregabalin, as short-term, first-line treatments. However,
pharmacotherapy for neuropathic pain has generally had limited
success with little response to commonly used pain reducing drugs,
such as NSAIDS and opiates. Consequently, there is still a
considerable need to explore novel treatment modalities.
[0005] There remain a limited number of potent effective sodium
channel blockers with a minimum of adverse events in the clinic.
There is also an unmet medical need to treat neuropathic pain and
other sodium channel associated pathological states effectively and
without adverse side effects.
[0006] PCT Published Patent Application No. WO 2006/110917, PCT
Published Patent Application No. WO 2010/045251, PCT Published
Patent Application No. WO 2010/045197, PCT Published Patent
Application No. WO 2011/047174 and PCT Published Patent Application
No. WO 2011/002708 discloses certain spiro-oxindole compounds.
These compounds are disclosed therein as being useful for the
treatment of sodium channel-mediated diseases, preferably diseases
related to pain, central nervous conditions such as epilepsy,
anxiety, depression and bipolar disease; cardiovascular conditions
such as arrhythmias, atrial fibrillation and ventricular
fibrillation; neuromuscular conditions such as restless leg
syndrome; neuroprotection against stroke, neural trauma and
multiple sclerosis; and channelopathies such as erythromelalgia and
familial rectal pain syndrome.
[0007] Methods of preparing these compounds and pharmaceutical
compositions containing them are also disclosed in PCT Published
Patent Application No. WO 2006/110917, PCT Published Patent
Application No. WO 2010/045251, PCT Published Patent Application
No. WO 2010/045197, PCT Published Patent Application No. WO
2011/047174 and PCT Published Patent Application No. WO
2011/002708.
[0008] There exists, therefore, a need for additional methods of
preparing certain spiro-oxindole compounds.
SUMMARY OF THE INVENTION
[0009] The present invention is directed to asymmetric syntheses of
certain spiro-oxindole compounds as enantiomers, or as
pharmaceutically acceptable salts thereof.
[0010] These compounds, which are disclosed in PCT Published Patent
Application No. WO 2006/110917, PCT Published Patent Application
No. WO 2010/045251, PCT Published Patent Application No. WO
2011/047174, PCT Published Patent Application No. WO 2011/002708,
PCT Published Patent Application No. WO 2011/047173, and/or PCT
Published Patent Application No. WO 2011/106729, are useful in
treating sodium channel-mediated diseases and conditions, such as
pain.
[0011] Accordingly, in one aspect, this invention is directed to
methods of preparing a compound of formula (I):
##STR00001##
as an isolated (S)-enantiomer, or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof; [0012] wherein: [0013] p
and r are each independently 1, 2, 3 or 4; [0014] R.sup.1 is
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl,
cycloalkylalkyl, heteroaryl, heterocyclyl, --R.sup.8--C(O)R.sup.5,
--R.sup.8--C(O)OR.sup.5, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--S(O).sub.2--R.sup.5, --R.sup.9--S(O).sub.m--R.sup.5 (where m is
0, 1 or 2), --R.sup.8--OR.sup.5, --R.sup.8--CN,
--R.sup.9--P(O)(OR).sub.2, or --R.sup.9--O--R.sup.9--OR.sup.5;
[0015] or R.sup.1 is aralkyl substituted by --C(O)N(R.sup.6)R.sup.7
where: [0016] R.sup.6 is hydrogen, alkyl, aryl or aralkyl; and
[0017] R.sup.7 is hydrogen, alkyl, haloalkyl, --R.sup.9--CN,
--R.sup.9--OR.sup.5, --R.sup.9--N(R.sup.4)R.sup.5, aryl, aralkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl; [0018] or R.sup.6 and R.sup.7,
together with the nitrogen to which they are attached, form a
N-heterocyclyl or a N-heteroaryl; [0019] and wherein each aryl,
aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for
R.sup.6 and R.sup.7 may be optionally substituted by one or more
substituents selected from the group consisting of alkyl,
cycloalkyl, aryl, aralkyl, halo, haloalkyl, --R.sup.8--CN,
--R.sup.8--OR.sup.5, heterocyclyl and heteroaryl; [0020] or R.sup.1
is aralkyl optionally substituted by one or more substituents
selected from the group consisting of --R.sup.8--OR.sup.5,
--C(O)OR.sup.5, halo, haloalkyl, alkyl, nitro, cyano, aryl,
aralkyl, heterocyclyl and heteroaryl; [0021] or R.sup.1 is
--R.sup.9--N(R.sup.10)R.sup.11, --R.sup.9--N(R.sup.12)C(O)R.sup.11
or --R.sup.9--N(R.sup.10)C(O)N(R.sup.10)R.sup.11 where: [0022] each
R.sup.10 is hydrogen, alkyl, aryl, aralkyl or heteroaryl; [0023]
each R.sup.11 is hydrogen, alkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, heteroarylalkyl, --R.sup.9--OC(O)R.sup.5,
--R.sup.9--C(O)OR.sup.5, --R.sup.9--C(O)N(R.sup.4)R.sup.5,
--R.sup.9--C(O)R.sup.5, --R.sup.9--N(R.sup.4)R.sup.5,
--R.sup.9--OR.sup.5, or --R.sup.9--CN; and [0024] R.sup.12 is
hydrogen, alkyl, aryl, aralkyl or --C(O)R.sup.5; [0025] and wherein
each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl and heteroarylalkyl for R.sup.10 and
R.sup.11 may be optionally substituted by one or more substituents
selected from the group consisting of alkyl, cycloalkyl, aryl,
aralkyl, halo, haloalkyl, nitro, --R.sup.8--CN,
--R.sup.8--OR.sup.5, --R.sup.8--C(O)R.sup.5, heterocyclyl and
heteroaryl; [0026] or R.sup.1 is heterocyclylalkyl or
heteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl
group is optionally substituted by one or more substituents
selected from the group consisting of oxo, alkyl, halo, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R.sup.8--OR.sup.5, --R.sup.8--C(O)OR.sup.5,
--R.sup.8--N(R.sup.4)R.sup.5, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--R.sup.8--N(R.sup.5)C(O)R.sup.4, --R.sup.8--S(O).sub.mR.sup.4
(where m is 0, 1 or 2), --R.sup.8--CN, or --R.sup.8--NO.sub.2; each
R.sup.2 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl,
haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl,
aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
heteroarylalkyl, --R.sup.8--CN, --R.sup.8--NO.sub.2,
--R.sup.8--OR.sup.5, --R.sup.8--N(R.sup.4)R.sup.5,
--N.dbd.C(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--OS(O).sub.2CF.sub.3, --R.sup.8--C(O)R.sup.4, --C(S)R.sup.4,
--C(R.sup.4).sub.2C(O)R.sup.5, --R.sup.8--C(O)OR.sup.4,
--C(S)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)C(O)R.sup.4,
--N(R.sup.8)C(S)R.sup.4, --N(R.sup.5)C(O)OR.sup.4,
--N(R.sup.5)C(S)OR.sup.4, --N(R.sup.5)C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)S(O).sub.nR.sup.4,
--N(R.sup.5)S(O).sub.nN(R.sup.4)R.sup.5,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5,
--N(R.sup.5)C(.dbd.NR.sup.5)N(R.sup.4)R.sup.5, and
--N(R.sup.5)C(.dbd.N--CN)N(R.sup.4)R.sup.5, wherein each m is
independently 0, 1, or 2 and each n is independently 1 or 2; [0027]
and wherein each of the cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and
heteroarylalkyl groups for R.sup.2 may be optionally substituted by
one or more substituents selected from the group consisting of
alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl,
haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R.sup.8--CN, --R.sup.8--NO.sub.2, --R.sup.8--OR.sup.5,
--R--N(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5, --R.sup.8--C(O)R.sup.4,
--R.sup.8--C(O)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(O)R.sup.4, and --N(R.sup.5)S(O).sub.nR.sup.4, wherein
each m is independently 0, 1, or 2 and each n is independently 1 or
2; [0028] or any two adjacent R.sup.2's, together with the adjacent
carbon ring atoms to which they are directly attached, may form a
fused ring selected from cycloalkyl, aryl, heterocyclyl and
heteroaryl, and the other R.sup.2's, if present, are as defined
above; [0029] each R.sup.3 is independently selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo,
haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl,
aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, heteroarylalkyl, --R.sup.8--CN, --R.sup.8--NO.sub.2,
--R--OR.sup.5, --R.sup.8--N(R.sup.4)R.sup.5,
--N.dbd.C(R.sup.4)R.sup.5, --S(O).sub.mR.sup.4,
--OS(O).sub.2CF.sub.3, --R.sup.8--C(O)R.sup.4, --C(S)R.sup.4,
--C(R.sup.4).sub.2C(O)R.sup.5, --R.sup.8--C(O)OR.sup.4,
--C(S)OR.sup.4, --R.sup.8--C(O)N(R.sup.4)R.sup.5,
--C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)C(O)R.sup.4,
--N(R.sup.5)C(S)R.sup.4, --N(R.sup.5)C(O)OR.sup.4,
--N(R.sup.5)C(S)OR.sup.4, --N(R.sup.5)C(O)N(R.sup.4)R.sup.5,
--N(R.sup.5)C(S)N(R.sup.4)R.sup.5, --N(R.sup.5)S(O).sub.nR.sup.4,
--N(R.sup.5)S(O).sub.nN(R.sup.4)R.sup.5,
--R.sup.8--S(O).sub.nN(R.sup.4)R.sup.5,
--N(R.sup.5)C(.dbd.NR.sup.5)N(R.sup.4)R.sup.5, and
--N(R.sup.5)C(N.dbd.C(R.sup.4)R.sup.5)N(R.sup.4)R.sup.5, wherein
each m is independently 0, 1, or 2 and each n is independently 1 or
2; [0030] or any two adjacent R.sup.3's, together with the adjacent
carbon ring atoms to which they are directly attached, may form a
fused ring selected from cycloalkyl, heterocyclyl, aryl or
heteroaryl, and the other R.sup.3's, if present, are as defined
above; [0031] each R.sup.4 and R.sup.5 is independently selected
from group consisting of hydrogen, alkyl, alkenyl, alkynyl,
haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
[0032] or when R.sup.4 and R.sup.5 are each attached to the same
nitrogen atom, then R.sup.4 and R.sup.5, together with the nitrogen
atom to which they are attached, may form a N-heterocyclyl or a
N-heteroaryl; [0033] each R.sup.8 is a direct bond or a straight or
branched alkylene chain, a straight or branched alkenylene chain or
a straight or branched alkynylene chain; and [0034] each R.sup.9 is
a straight or branched alkylene chain, a straight or branched
alkenylene chain or a straight or branched alkynylene chain; [0035]
or a pharmaceutically acceptable salt thereof.
[0036] One method of preparing the compound of formula (I), as
described above, as an isolated (S)-enantiomer, or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, preferably greater than 90%,
more preferably greater than 95%, most preferably greater than 99%,
or a pharmaceutically acceptable salt thereof; comprises treating a
compound of formula (13):
##STR00002##
where p, r, R.sup.1, R.sup.2 and R.sup.3 are as defined above for
the compound of formula (I), as an isolated (S)-enantiomer, or as a
non-racemic mixture of enantiomers having an enantiomeric excess of
the (S)-enantiomer of greater than 80%, preferably greater than
90%, more preferably greater than 95%, most preferably greater than
99%, or a pharmaceutically acceptable salt thereof, under suitable
Mitsunobu reaction conditions to provide the compound of formula
(I), as described above.
[0037] Another method of preparing the compound of formula (I), as
described above, as an isolated (S)-enantiomer, or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, preferably greater than 90%,
more preferably greater than 95%, most preferably greater than 99%,
or a pharmaceutically acceptable salt thereof; comprises treating a
compound of formula (22):
##STR00003##
where p, r, R.sup.2 and R.sup.3 are as described above for the
compound of formula (I), as an isolated (S)-enantiomer, or a
non-racemic mixture of enantiomers having an enantiomeric excess of
the (S)-enantiomer of greater than 80%, preferably greater than
90%, more preferably greater than 95%, most preferably greater than
99%, or a pharmaceutically acceptable salt thereof, with a compound
of formula (2):
X--R.sup.1 (2);
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro, and R.sup.1 is as described above for the compound of
formula (I), or a pharmaceutically acceptable salt thereof, under
suitable N-alkylation conditions to provide a compound of formula
(I), as described above.
[0038] Another method of preparing the compound of formula (I), as
described above, as an isolated (S)-enantiomer, or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, preferably greater than 90%,
more preferably greater than 95%, most preferably greater than 99%,
or a pharmaceutically acceptable salt thereof; comprises the
following steps: [0039] (a) treating a compound of formula (1):
[0039] ##STR00004## [0040] where p and R.sup.2 are as described
above for the compound of formula (I), or a pharmaceutically
acceptable salt thereof, with a compound of formula (2):
[0040] X--R.sup.1 (2); [0041] where R.sup.1 is a defined above for
the compound of formula (I) and X is halo, typically iodo, bromo or
chloro, preferably bromo or chloro, under suitable N-alkylation
conditions to provide a compound of formula (3):
[0041] ##STR00005## [0042] where p, R.sup.1 and R.sup.2 are as
described above for the compound of formula (I), or a
pharmaceutically acceptable salt thereof; [0043] (b) treating a
compound of formula (3) under suitable Grignard reaction conditions
with an intermediate product formed from the treatment of a
compound of formula (4):
##STR00006##
[0043] where r and R.sup.3 are as defined above for the compound of
formula (I), with a Grignard reagent of formula (5):
RMgX (5); [0044] where R is alkyl and X is iodo, bromo or chloro,
under suitable conditions to form a compound of formula (6):
[0044] ##STR00007## [0045] where p, r, R.sup.1, R.sup.2 and R.sup.3
are as defined above for the compound of formula (I), as a racemic
mixture of enantiomers or as a non-racemic mixture of enantiomers,
or a pharmaceutically acceptable salt thereof; [0046] (c) treating
a compound of formula (6) with a compound of formula (7):
[0046] Pg.sup.1X (7); [0047] where X is halo, typically iodo, bromo
or chloro, preferably bromo or chloro, and Pg.sup.1 is an oxygen
protecting group under suitable protecting conditions to provide a
compound of formula (8):
[0047] ##STR00008## [0048] where p, r, R.sup.1, R.sup.2 and R.sup.3
are as defined above for the compound of formula (I) and Pg.sup.1
is an oxygen protecting group, as a racemic mixture of enantiomers
or as a non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof; [0049] (d) treating a compound of formula
(8) under suitable dehydroxylation conditions to provide a compound
of formula (9):
[0049] ##STR00009## [0050] where p, r, R.sup.1, R.sup.2 and R.sup.3
are as defined above for the compound of formula (I) and Pg.sup.1
is an oxygen protecting group, as a racemic mixture of enantiomers
or as a non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof; [0051] (e) treating a compound of formula
(9) with a compound of formula (10):
[0051] Pg.sup.2OCH.sub.2X (10); [0052] where Pg.sup.2 is an oxygen
protecting group and X is halo, typically iodo, bromo or chloro,
preferably bromo or chloro, under suitable C-alkylation conditions
comprising the presence of a phase transfer catalyst to provide a
compound of formula (11):
[0052] ##STR00010## [0053] where p, r, R.sup.1, R.sup.2 and R.sup.3
are each as defined above for the compound of formula (I) and
Pg.sup.1 and Pg.sup.2 are each independently an oxygen protecting
group, as a racemic mixture of enantiomers or as a non-racemic
mixture of enantiomers, or a pharmaceutically acceptable salt
thereof; [0054] (f) treating a compound of formula (11) under
suitable recrystallization conditions to provide a compound of
formula (12):
[0054] ##STR00011## [0055] where p, r, R.sup.1, R.sup.2 and R.sup.3
are as defined above for the compounds of formula (I) and Pg.sup.1
and Pg.sup.2 are each independently an oxygen protecting group, as
an isolated (S)-enantiomer or a non-racemic mixture of enantiomers
having an enantiomeric excess of the (S)-enantiomer of greater than
80%, preferably greater than 90%, more preferably greater than 95%,
most preferably greater than 99%, or a pharmaceutically acceptable
salt thereof; [0056] (g) treating a compound of formula (12) under
suitable deprotecting conditions to provide a compound of formula
(13):
[0056] ##STR00012## [0057] where p, r, R.sup.1, R.sup.2 and R.sup.3
are as defined above for the compounds of formula (I), as an
isolated (S)-enantiomer or a non-racemic mixture of enantiomers
having an enantiomeric excess of the (S)-enantiomer of greater than
80%, preferably greater than 90%, more preferably greater than 95%,
most preferably greater than 99%, or a pharmaceutically acceptable
salt thereof; [0058] (h) treating a compound of formula (13) under
suitable Mitsunobu reaction conditions to provide the compound of
formula (I), as described above, as an isolated (S)-enantiomer or a
non-racemic mixture of enantiomers having an enantiomeric excess of
the (S)-enantiomer of greater than 80%, preferably greater than
90%, more preferably greater than 95%, most preferably greater than
99%, or a pharmaceutically acceptable salt thereof.
[0059] Another method of preparing the compound of formula (I), as
described above, as an isolated (S)-enantiomer, or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, preferably greater than 90%,
more preferably greater than 95%, most preferably greater than 99%,
or a pharmaceutically acceptable salt thereof; comprises the
following steps: [0060] (a) treating a compound of formula (1):
[0060] ##STR00013## [0061] where p and R.sup.2 are each as defined
above for the compound of formula (I), or a pharmaceutically
acceptable salt thereof, with a compound of formula (14):
[0061] X-Pg.sup.3 (14); [0062] where halo, typically iodo, bromo or
chloro, preferably bromo or chloro, and Pg.sup.3 is a nitrogen
protecting group, under suitable nitrogen protecting conditions to
provide a compound of formula (15):
[0062] ##STR00014## [0063] where p and R.sup.2 are each as
described above for the compound of formula (I), and Pg.sup.3 is a
nitrogen protecting group, or a pharmaceutically acceptable salt
thereof; [0064] (b) treating a compound of formula (15) under
suitable Grignard reaction conditions with an intermediate product
formed from the treatment of a compound of formula (4):
[0064] ##STR00015## [0065] where r and R.sup.3 are each as defined
above for the compound of formula (I), with a Grignard reagent of
formula (5):
[0065] RMgX (5); [0066] where R is alkyl and X is iodo, bromo or
chloro, preferably bromo or chloro, under suitable conditions to
provide a compound of formula (16):
[0066] ##STR00016## [0067] where p, r, R.sup.2 and R.sup.3 are each
as described above for the compound of formula (I) and Pg.sup.3 is
a nitrogen protecting group, as a racemic mixture of enantiomers or
as a non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof; [0068] (c) treating a compound of formula
(16) with a compound of formula (7):
[0068] Pg.sup.1X (7); [0069] where X is halo, typically iodo, bromo
or chloro, preferably bromo or chloro, and Pg.sup.1 is an oxygen
protecting group under suitable protecting conditions to provide a
compound of formula (17):
[0069] ##STR00017## [0070] where p, r, R.sup.2 and R.sup.3 are each
as described above for the compound of formula (I), Pg.sup.1 is an
oxygen protecting group and Pg.sup.3 is a nitrogen protecting
group, as a racemic mixture of enantiomers or as a non-racemic
mixture of enantiomers, or a pharmaceutically acceptable salt
thereof; [0071] (d) treating a compound of formula (17) under
suitable dehydroxylation conditions to provide a compound of
formula (18):
[0071] ##STR00018## [0072] where p, r, R.sup.2 and R.sup.3 are each
as described above for the compound of formula (I), Pg.sup.1 is an
oxygen protecting group and Pg.sup.3 is a nitrogen protecting
group, as a racemic mixture of enantiomers or as a non-racemic
mixture of enantiomers, or a pharmaceutically acceptable salt
thereof; [0073] (e) treating a compound of formula (18) with a
compound of formula (10):
[0073] Pg.sup.2OCH.sub.2X (10); [0074] where Pg.sup.2 is an oxygen
protecting group and X is halo, typically iodo, bromo or chloro,
preferably bromo or chloro, under suitable C-alkylation conditions
comprising the presence of a phase transfer catalyst to provide a
compound of formula (19):
[0074] ##STR00019## [0075] where p, r, R.sup.2 and R.sup.3 are each
as described above for the compound of formula (I), Pg.sup.1 and
Pg.sup.2 are each independently an oxygen protecting group and
Pg.sup.3 is a nitrogen protecting group, as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof; [0076] (f) treating a compound of formula (19) under
suitable deprotection conditions to provide a compound of formula
(20):
[0076] ##STR00020## [0077] where p, r, R.sup.2 and R.sup.3 are each
as described above for the compound of formula (I), and Pg.sup.3 is
a nitrogen protecting group, as an isolated (S)-enantiomer, or a
non-racemic mixture of enantiomers having an enantiomeric excess of
the (S)-enantiomer of greater than 80%, preferably greater than
90%, more preferably greater than 95%, most preferably greater than
99%, or a pharmaceutically acceptable salt thereof; [0078] (g)
treating a compound of formula (20) under suitable Mitsunobu
reaction conditions to provide the compound of formula (21):
[0078] ##STR00021## [0079] where p, r, R.sup.2 and R.sup.3 are each
as described above for the compound of formula (I), and Pg.sup.3 is
a nitrogen protecting group, as an isolated (S)-enantiomer, or a
non-racemic mixture of enantiomers having an enantiomeric excess of
the (S)-enantiomer of greater than 80%, preferably greater than
90%, more preferably greater than 95%, most preferably greater than
99%, or a pharmaceutically acceptable salt thereof; [0080] (h)
treating a compound of formula (21) under suitable nitrogen
deprotecting conditions to provide a compound of formula (22):
[0080] ##STR00022## [0081] where p, r, R.sup.2 and R.sup.3 are each
as described above for the compound of formula (I), as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof; and [0082] (i) treating a compound of formula (22) with a
compound of formula (2):
[0082] X--R.sup.1 (2); [0083] where X is halo, typically iodo,
bromo or chloro, preferably bromo or chloro, and R.sup.1 is as
described above for the compound of formula (I), or a
pharmaceutically acceptable salt thereof, under suitable
N-alkylation conditions to provide a compound of formula (I), as
described above, as an isolated (S)-enantiomer, or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, preferably greater than 90%,
more preferably greater than 95%, most preferably greater than 99%,
or a pharmaceutically acceptable salt thereof.
[0084] Another aspect of this invention is a compound of formula
(11):
##STR00023##
wherein p, r, R.sup.1, R.sup.2 and R.sup.3 are each as described
above for the compounds of formula (I) and Pg.sup.1 and Pg.sup.2
are each independently an oxygen protecting group; as a racemic
mixture of enantiomers or as a non-racemic mixture of enantiomers,
or a pharmaceutically acceptable salt thereof.
[0085] Another aspect of this invention is a compound of formula
(12) or a compound of formula (13):
##STR00024##
wherein each p, r, R.sup.1, R.sup.2 and R.sup.3 is as described
above for the compounds of formula (I) and Pg.sup.1 and Pg.sup.2
are each independently an oxygen protecting group; as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof.
[0086] Another aspect of this invention is a compound of formula
(19), a compound of formula (20), a compound of formula (21) or a
compound of formula (22):
##STR00025##
wherein each p, r, R.sup.1, R.sup.2 and R.sup.3 is as described
above for the compounds of formula (I), each Pg.sup.1 and each
Pg.sup.2 is independently an oxygen protecting group, and each
Pg.sup.3 is a nitrogen protecting group; as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof.
[0087] These aspects of the invention and others are described in
more detail below.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0088] As used in the specification and appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0089] "Alkyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
no unsaturation, having from one to twelve carbon atoms, preferably
one to eight carbon atoms, more preferably one to six carbon atoms,
and which is attached to the rest of the molecule by a single bond,
e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl,
n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,
2-methylhexyl, and the like. When specifically stated in the
specification, an alkyl group may be optionally substituted by one
of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano,
nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo,
trimethylsilanyl, --OR.sup.20, --OC(O)--R.sup.20,
--N(R.sup.20).sub.2, --C(O)R.sup.20, --C(O)OR.sup.20,
--C(O)N(R.sup.20).sub.2, --N(R.sup.20)C(O)OR.sup.22,
--N(R.sup.20)C(O)R.sup.22, --N(R.sup.20)S(O).sub.tR.sup.22 (where t
is 1 to 2), --S(O).sub.tOR.sup.22 (where t is 1 to 2),
--S(O)R.sup.22 (where p is 0 to 2), and
--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 to 2) where each
R.sup.20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl; and each R.sup.22 is alkyl,
haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0090] "Alkenyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one double bond, having from two to twelve
carbon atoms, preferably two to eight carbon atoms and which is
attached to the rest of the molecule by a single bond, e.g.,
ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl,
and the like. When specifically stated in the specification, an
alkenyl group may be optionally substituted by one of the following
groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl,
cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl,
--OR.sup.20, --OC(O)--R.sup.20, --N(R.sup.20).sub.2,
--C(O)R.sup.20, --C(O)OR.sup.20, --C(O)N(R.sup.20).sub.2,
--N(R.sup.20)C(O)OR.sup.22, --N(R.sup.20)C(O)R.sup.22,
--N(R.sup.20)S(O).sub.tR.sup.22 (where t is 1 to 2),
--S(O).sub.tOR.sup.22 (where t is 1 to 2), --S(O)R.sup.22 (where p
is 0 to 2), and --S(O).sub.tN(R.sup.20).sub.2 (where t is 1 to 2)
where each R.sup.20 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R.sup.22
is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0091] "Alkynyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one triple bond, having from two to twelve
carbon atoms, preferably one to eight carbon atoms and which is
attached to the rest of the molecule by a single bond, e.g.,
ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. When
specifically stated in the specification, an alkynyl group is
optionally substituted by one or more of the following groups:
alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl,
heterocyclyl, heteroaryl, oxo, trimethylsilanyl, --OR.sup.20,
--OC(O)--R.sup.20, --N(R.sup.20).sub.2, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)N(R.sup.20).sub.2,
--N(R.sup.20)C(O)OR.sup.22, --N(R.sup.20)C(O)R.sup.22,
--N(R.sup.20)S(O).sub.tR.sup.22 (where t is 1 to 2),
--S(O).sub.tOR.sup.22 (where t is 1 to 2), --S(O)R.sup.22 (where p
is 0 to 2), or --S(O).sub.tN(R.sup.20).sub.2 (where t is 1 to 2),
where each R.sup.20 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R.sup.22
is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0092] "Alkylene" or "alkylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing no unsaturation and having from one to twelve
carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and
the like. The alkylene chain is attached to the rest of the
molecule through a single bond and to the radical group through a
single bond. The points of attachment of the alkylene chain to the
rest of the molecule and to the radical group can be through one
carbon or any two carbons within the chain. When specifically
stated in the specification, an alkylene chain may be optionally
substituted by one of the following groups: alkyl, alkenyl, halo,
haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl,
heteroaryl, oxo, trimethylsilanyl, --OR.sup.20, --OC(O)--R.sup.20,
--N(R.sup.20).sub.2, --C(O)R.sup.20, --C(O)OR.sup.20,
--C(O)N(R.sup.20).sub.2, --N(R.sup.20)C(O)OR.sup.22,
--N(R.sup.20)C(O)R.sup.22, --N(R.sup.20)S(O).sub.tR.sup.22 (where t
is 1 to 2), --S(O).sub.tOR.sup.22 (where t is 1 to 2),
--S(O)R.sup.22 (where p is 0 to 2), and
--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 to 2) where each
R.sup.20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl; and each R.sup.22 is alkyl,
haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0093] "Alkenylene" or "alkenylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing at least one double bond and having from two
to twelve carbon atoms, e.g., ethenylene, propenylene,
n-butenylene, and the like. The alkenylene chain is attached to the
rest of the molecule through a single bond and to the radical group
through a double bond or a single bond. The points of attachment of
the alkenylene chain to the rest of the molecule and to the radical
group can be through one carbon or any two carbons within the
chain. When specifically stated in the specification, an alkenylene
chain may be optionally substituted by one of the following groups:
alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl,
heterocyclyl, heteroaryl, oxo, trimethylsilanyl, --OR.sup.20,
--OC(O)--R.sup.20, --N(R.sup.20).sub.2, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)N(R.sup.20).sub.2,
--N(R.sup.20)C(O)OR.sup.22, --N(R.sup.20)C(O)R.sup.22,
--N(R.sup.20)S(O).sub.tR.sup.22 (where t is 1 to 2),
--S(O).sub.tOR.sup.22 (where t is 1 to 2), --S(O)R.sup.22 (where p
is 0 to 2), and --S(O).sub.tN(R.sup.20).sub.2 (where t is 1 to 2)
where each R.sup.20 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R.sup.22
is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0094] "Alkynylene" or "alkynylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing at least one triple bond and having from two
to twelve carbon atoms, e.g., propynylene, n-butynylene, and the
like. The alkynylene chain is attached to the rest of the molecule
through a single bond and to the radical group through a double
bond or a single bond. The points of attachment of the alkynylene
chain to the rest of the molecule and to the radical group can be
through one carbon or any two carbons within the chain. When
specifically stated in the specification, an alkynylene chain may
be optionally substituted by one of the following groups: alkyl,
alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl,
heterocyclyl, heteroaryl, oxo, trimethylsilanyl, --OR.sup.20,
--OC(O)--R.sup.20, --N(R.sup.20).sub.2, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)N(R.sup.20).sub.2,
--N(R.sup.20)C(O)OR.sup.22, --N(R.sup.20)C(O)R.sup.22,
--N(R.sup.20)S(O).sub.tR.sup.22 (where t is 1 to 2),
--S(O).sub.tOR.sup.22 (where t is 1 to 2), --S(O)R.sup.22 (where p
is 0 to 2), and --S(O).sub.tN(R.sup.20).sub.2 (where t is 1 to 2)
where each R.sup.20 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R.sup.22
is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0095] "Aryl" refers to a hydrocarbon ring system radical
comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic
ring. For purposes of this invention, the aryl radical may be a
monocyclic, bicyclic, tricyclic or tetracyclic ring system, which
may included fused or bridged ring systems. Aryl radicals include,
but are not limited to, aryl radicals derived from aceanthrylene,
acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,
chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,
indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene,
and triphenylene. When specifically stated in the specification, an
aryl group may be optionally substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl,
aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R.sup.21--OR.sup.20, --R.sup.21--OC(O)--R.sup.20,
--R.sup.21--N(R.sup.20).sub.2, --R.sup.21--C(O)R.sup.20,
--R.sup.21--C(O)OR.sup.20, --R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.22,
--R.sup.21--N(R.sup.20)C(O)R.sup.22,
--R.sup.21--N(R.sup.20)S(O).sub.tR.sup.22 (where t is 1 to 2),
--R.sup.21--N.dbd.C(OR.sup.20)R.sup.20,
--R.sup.21--S(O).sub.tOR.sup.22 (where t is 1 to 2),
--R.sup.21--S(O).sub.PR.sup.22 (where p is 0 to 2), and
--R.sup.21--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 to 2) where
each R.sup.20 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R.sup.21 is
independently a direct bond or a straight or branched alkylene or
alkenylene chain; and each R.sup.22 is alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0096] "Aralkyl" refers to a radical of the formula
--R.sub.b--R.sub.c where R.sub.b is an alkylene chain as defined
above and R.sub.c is one or more aryl radicals as defined above,
for example, benzyl, diphenylmethyl and the like. When specifically
stated in the specification, the alkylene chain part of the aralkyl
radical may be optionally substituted as described above for an
optionally substituted alkylene chain. When specifically stated in
the specification, the aryl part of the aralkyl radical may be
optionally substituted as described above for an optionally
substituted aryl group.
[0097] "Cycloalkyl" refers to a stable non-aromatic monocyclic or
polycyclic hydrocarbon radical consisting solely of carbon and
hydrogen atoms, which may include fused or bridged ring systems,
having from three to fifteen carbon atoms, preferably having from
three to ten carbon atoms, and which is saturated or unsaturated
and attached to the rest of the molecule by a single bond.
Monocyclic radicals include, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptly, and cyclooctyl. Polycyclic
radicals include, for example, adamantyl, norbornyl, decalinyl, and
the like. When specifically stated in the specification, a
cycloalkyl group may be optionally substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo,
aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R.sup.21--OR.sup.20, --R.sup.21--OC(O)--R.sup.20,
--R.sup.21--N(R.sup.20).sub.2, --R.sup.21--C(O)R.sup.20,
--R.sup.21--C(O)OR.sup.20, --R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.22,
--R.sup.21--N(R.sup.20)C(O)R.sup.22,
--R.sup.21--N(R.sup.20)S(O).sub.tR.sup.22 (where t is 1 to 2),
--R.sup.21--N.dbd.C(OR.sup.20)R.sup.20,
--R.sup.21--S(O).sub.tOR.sup.22 (where t is 1 to 2),
--R.sup.21--S(O).sub.PR.sup.22 (where p is 0 to 2), and
--R.sup.21--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 to 2) where
each R.sup.20 is independently hydrogen, alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R.sup.21 is
independently a direct bond or a straight or branched alkylene or
alkenylene chain; and each R.sup.22 is alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0098] "Cycloalkylalkyl" refers to a radical of the formula
--R.sub.bR.sub.g where R.sub.b is an alkylene chain as defined
above and R.sub.g is a cycloalkyl radical as defined above. When
specifically stated in the specification, the alkylene chain and/or
the cycloalkyl radical may be optionally substituted as defined
above for optionally substituted alkylene chain and optionally
substituted cycloalkyl.
[0099] "Halo" refers to bromo, chloro, fluoro or iodo.
[0100] "Haloalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more halo radicals, as defined above,
e.g., trifluoromethyl, difluoromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl,
3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
The alkyl part of the haloalkyl radical may be optionally
substituted as defined above for an alkyl group.
[0101] "Heterocyclyl" refers to a stable 3- to 18-membered
non-aromatic ring radical which consists of two to twelve carbon
atoms and from one to six heteroatoms selected from the group
consisting of nitrogen, oxygen and sulfur. Unless stated otherwise
specifically in the specification, the heterocyclyl radical may be
a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which
may include fused or bridged ring systems; and the nitrogen, carbon
or sulfur atoms in the heterocyclyl radical may be optionally
oxidized; the nitrogen atom may be optionally quaternized; and the
heterocyclyl radical may be partially or fully saturated. Examples
of such heterocyclyl radicals include, but are not limited to,
dioxolanyl, dioxinyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,
imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,
morpholinyl, octahydroindolyl, octahydroisoindolyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,
oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl,
pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl,
tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl,
tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,
1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. When
specifically stated in the specification, a heterocyclyl group may
be optionally substituted by one or more substituents selected from
the group consisting of alkyl, alkenyl, halo, haloalkyl,
haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
heteroarylalkyl, --R.sup.21--OR.sup.20,
--R.sup.21--OC(O)--R.sup.20, --R.sup.21--N(R.sup.20).sub.2,
--R.sup.21--C(O)R.sup.20, --R.sup.21--C(O)OR.sup.20,
--R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.22,
--R.sup.21--N(R.sup.20)C(O)R.sup.22,
--R.sup.21--N(R.sup.20)S(O).sub.tR.sup.22 (where t is 1 to 2),
--R.sup.21--N.dbd.C(OR.sup.20)R.sup.20,
--R.sup.21--S(O).sub.tOR.sup.22 (where t is 1 to 2),
--R.sup.21--S(O).sub.PR.sup.22 (where p is 0 to 2), and
--R.sup.21--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 to 2) where
each R.sup.20 is independently hydrogen, alkyl, alkenyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R.sup.21 is
independently a direct bond or a straight or branched alkylene or
alkenylene chain; and each R.sup.22 is alkyl, alkenyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0102] "N-heterocyclyl" refers to a heterocyclyl radical as defined
above containing at least one nitrogen and where the point of
attachment of the heterocyclyl radical to the rest of the molecule
is through a nitrogen atom in the heterocyclyl radical. When
specifically stated in the specification, an N-heterocyclyl radical
may be optionally substituted as described above for an optionally
substituted heterocyclyl radicals.
[0103] "Heterocyclylalkyl" refers to a radical of the formula
--R.sub.bR.sub.h where R.sub.b is an alkylene chain as defined
above and R.sub.h is a heterocyclyl radical as defined above, and
if the heterocyclyl is a nitrogen-containing heterocyclyl, the
heterocyclyl may be attached to the alkyl radical at the nitrogen
atom. When specifically stated in the specification, the alkylene
chain of the heterocyclylalkyl radical may be optionally
substituted as defined above for an optionally substituted alkyene
chain. When specifically stated in the specification, the
heterocyclyl part of the heterocyclylalkyl radical may be
optionally substituted as defined above for an optionally
substituted heterocyclyl group.
[0104] "Heteroaryl" refers to a 5- to 14-membered ring system
radical comprising hydrogen atoms, one to thirteen carbon atoms,
one to six heteroatoms selected from the group consisting of
nitrogen, oxygen and sulfur, and at least one aromatic ring. For
purposes of this invention, the heteroaryl radical may be a
monocyclic, bicyclic, tricyclic or tetracyclic ring system, which
may include fused or bridged ring systems; and the nitrogen, carbon
or sulfur atoms in the heteroaryl radical may be optionally
oxidized; the nitrogen atom may be optionally quaternized. Examples
include, but are not limited to, azepinyl, acridinyl,
benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl,
benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,
benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,
benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,
benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl
(benzothiophenyl), benzotriazolyl,
benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl,
benzimidazolthionyl, carbazolyl, cinnolinyl, dibenzofuranyl,
dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl,
indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,
isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl,
2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl,
1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl,
1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl,
pyrazolyl, pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl,
pryrimidinonyl, pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl,
quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl,
quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl,
thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl,
thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl,
and thiophenyl (i.e. thienyl). When specifically stated in the
specification, a heteroaryl group may be optionally substituted by
one or more substituents selected from the group consisting of
alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo,
nitro, thioxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
--R.sup.21--OR.sup.20, --R.sup.21--OC(O)--R.sup.20,
--R.sup.21--N(R.sup.20).sub.2, --R.sup.21--C(O)R.sup.20,
--R.sup.21--C(O)OR.sup.20, --R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.22,
--R.sup.21--N(R.sup.20)C(O)R.sup.22,
--R.sup.21--N(R.sup.20)S(O).sub.tR.sup.22 (where t is 1 to 2),
--R.sup.21--N.dbd.C(OR.sup.20)R.sup.20,
--R.sup.21--S(O).sub.tOR.sup.22 (where t is 1 to 2),
--R.sup.21--S(O).sub.PR.sup.22 (where p is 0 to 2), and
--R.sup.21--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 to 2) where
each R.sup.20 is independently hydrogen, alkyl, alkenyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R.sup.21 is
independently a direct bond or a straight or branched alkylene or
alkenylene chain; and each R.sup.22 is alkyl, alkenyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0105] "N-heteroaryl" refers to a heteroaryl radical as defined
above containing at least one nitrogen and where the point of
attachment of the heteroaryl radical to the rest of the molecule is
through a nitrogen atom in the heteroaryl radical. When
specifically stated in the specification, an N-heteroaryl radical
may be optionally substituted as described above for an optionally
substituted heteroaryl radicals.
[0106] "Heteroarylalkyl" refers to a radical of the formula
--R.sub.bR.sub.i where R.sub.b is an alkylene chain as defined
above and R.sub.i is a heteroaryl radical as defined above. When
specifically stated in the specification, the heteroaryl part of
the heteroarylalkyl radical may be optionally substituted as
defined above for an optionally substituted heteroaryl group. When
specifically stated in the specification, the alkylene chain part
of the heteroarylalkyl radical may be optionally substituted as
defined above for an optionally substituted alkylene chain.
[0107] "Pharmaceutically acceptable salt" includes both acid and
base addition salts.
[0108] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as, but are not limited to, hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid and the like, and
organic acids such as, but not limited to, acetic acid,
2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid,
aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,
capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic
acid, citric acid, cyclamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic
acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric
acid, lactic acid, lactobionic acid, lauric acid, maleic acid,
malic acid, malonic acid, mandelic acid, methanesulfonic acid,
mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic
acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid,
orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic
acid, pyroglutamic acid, pyruvic acid, salicylic acid,
4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,
tartaric acid, thiocyanic acid, p-toluenesulfonic acid,
trifluoroacetic acid, undecylenic acid, and the like.
[0109] "Pharmaceutically acceptable base addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free acids, which are not biologically or
otherwise undesirable. These salts are prepared from addition of an
inorganic base or an organic base to the free acid. Salts derived
from inorganic bases include, but are not limited to, the sodium,
potassium, lithium, ammonium, calcium, magnesium, iron, zinc,
copper, manganese, aluminum salts and the like. Preferred inorganic
salts are the ammonium, sodium, potassium, calcium, and magnesium
salts. Salts derived from organic bases include, but are not
limited to, salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins, such as
ammonia, isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, diethanolamine, ethanolamine,
deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, benethamine, benzathine,
ethylenediamine, glucosamine, methylglucamine, theobromine,
triethanolamine, tromethamine, purines, piperazine, piperidine,
N-ethylpiperidine, polyamine resins and the like. Particularly
preferred organic bases are isopropylamine, diethylamine,
ethanolamine, trimethylamine, dicyclohexylamine, choline and
caffeine.
[0110] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0111] The compounds prepared herein may contain one or more
asymmetric centres and may thus give rise to enantiomers that may
be defined, in terms of absolute stereochemistry, as (R)- or (S)-
or, as (D)- or (L)- for amino acids. The present invention is meant
to include all such possible enantiomers, as well as their racemic
and optically pure forms. Optically active (+) and (-), (R)- and
(S)-, or (D)- and (L)-isomers may be prepared using chiral synthons
or chiral reagents, or resolved using conventional techniques, for
example, chromatography and fractional crystallisation, or by the
techniques disclosed herein. Conventional techniques for the
preparation/isolation of individual enantiomers include chiral
synthesis from a suitable optically pure precursor or resolution of
the racemate (or the racemate of a salt or derivative) using, for
example, chiral high pressure liquid chromatography (HPLC).
[0112] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present invention contemplates various stereoisomers and mixtures
thereof and includes "enantiomers", which refers to two
stereoisomers whose molecules are nonsuperimposeable mirror images
of one another.
[0113] The designations "R" and "S" are used to denote the
three-dimensional arrangement of atoms (or the configuration) of
the stereogenic center of an enantiomer. The designations may
appear as a prefix or as a suffix herein; they may or may not be
separated from the enantiomer name by a hyphen; they may or may not
be hyphenated; and they may or may not be surrounded by
parentheses. The designations or prefixes "(+) and (-)" may be
employed herein to designate the sign of rotation of
plane-polarized light by the compound, with (-) meaning that the
compound is levorotatory (rotates to the left). A compound prefixed
with (+) is dextrorotatory (rotates to the right).
[0114] "Resolution" or "resolving" when used in reference to a
racemic compound or mixture refers to the separation of a racemate
into its two enantiomeric forms (i.e., (+) and (-); (R) and (S)
forms).
[0115] "Enantiomeric excess" or "ee" refers to a product wherein
one enantiomer is present in excess of the other, and is defined as
the absolute difference in the mole fraction of each enantiomer.
Enantiomeric excess is typically expressed as a percentage of an
enantiomer present in a mixture relative to the other enantiomer.
For purposes of this invention, a compound prepared by the methods
disclosed herein may exist as an isolated (S)-enantiomer or a
non-racemic mixture where the (S)-enantiomer is present in
enantiomeric excess of greater than 80%, preferably greater than
90%, more preferably greater than 95% and most preferably greater
than 99% of the (R)-enantiomer.
[0116] The chemical naming protocol and structure diagrams used
herein are a modified form of the I.U.P.A.C. nomenclature system,
using the ACD/Name Version 9.07 software program. For complex
chemical names employed herein, a substituent group is named before
the group to which it attaches. For example, cyclopropylethyl
comprises an ethyl backbone with cyclopropyl substituent. In the
chemical structure diagrams herein all bonds are identified, except
for some carbon atoms, which are assumed to be bonded to sufficient
hydrogen atoms to complete the valency. Stereochemistry is
designated herein through the use of the conventional solid wedge
bonds and dashed wedge bonds, i.e., a solid wedge bond indicates
that the bond is above the plane of the paper and a dashed wedge
bond indicates that the bond is below the plane of the paper. Wavy
bonds are intended to indicate that the bonds are either above the
plane of the paper or below the plane of the paper. Straight bonds
are intended to include all possible stereochemical
configurations.
[0117] Thus, for example, a compound of formula (I) herein, i.e.,
the compound of formula (Ia1):
##STR00026##
is named herein as
(S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzo-
dioxole-7,3'-indol]-2'(1'H)-one.
EMBODIMENTS OF THE INVENTION
[0118] Of the various aspects of the invention disclosed above in
the Summary of the Invention, certain embodiments are
preferred.
[0119] One aspect of the invention described herein is a method of
preparing a compound of formula (I), as described above in the
Summary of the Invention; as an isolated (S)-enantiomer, or a
non-racemic mixture of enantiomers having an enantiomeric excess of
the (S)-enantiomer of greater than 80%, preferably greater than
90%, more preferably greater than 95%, most preferably greater than
99%, or a pharmaceutically acceptable salt thereof, wherein the
method comprises treating a compound of formula (13):
##STR00027##
where p, r, R.sup.1, R.sup.2 and R.sup.3 are as described above in
the Summary of the Invention for the compound of formula (I), as an
isolated (S)-enantiomer or a non-racemic mixture of enantiomers
having an enantiomeric excess of the (S)-enantiomer of greater than
80%, preferably greater than 90%, more preferably greater than 95%,
most preferably greater than 99%, or a pharmaceutically acceptable
salt thereof, under suitable Mitsunobu reaction conditions to
provide the compound of formula (I), as described above in the
Summary of the Invention. The compound of formula (I) is preferably
a compound of formula (Ia):
##STR00028##
where q is 1 or 2 and p, R.sup.1 and R.sup.2 are each as described
above in the Summary of the Invention for the compound of formula
(I), as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof. More preferably the
compound of formula (I) is a compound of formula (Ia1):
##STR00029##
as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof.
[0120] The compound of formula (13) is preferably a compound of
formula (13a):
##STR00030##
where q is 1 or 2 and p, R.sup.1 and R.sup.2 are each as described
above in the Summary of the Invention for the compounds of formula
(I), as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof. More preferably, the
compound of formula (13a) is a compound of formula (13a1):
##STR00031##
as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof.
[0121] The method described above for treating the compound of
formula (13) under standard Mitsunobu reaction conditions to form
the compound of formula (I) may further comprise a deprotection
step prior to treating the compound of formula (13), wherein the
deprotection step comprises treating a compound of formula
(12):
##STR00032##
wherein p, r, R.sup.1, R.sup.2 and R.sup.3 are each as described
above in the Summary of the Invention for the compounds of formula
(I) and Pg.sup.1 and Pg.sup.2 are each independently an oxygen
protecting group, as an isolated (S)-enantiomer or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, preferably greater than 90%,
more preferably greater than 95%, most preferably greater than 99%,
or a pharmaceutically acceptable salt thereof, under suitable
deprotecting conditions to provide a compound of formula (13), as
described above. Preferably, the compound of formula (12) is a
compound of formula (12a):
##STR00033##
where q is 1 or 2, Pg.sup.1 and Pg.sup.2 are each independently an
oxygen protecting group and p, R.sup.1 and R.sup.2 are each as
described above in the Summary of the Invention for the compounds
of formula (I), as an isolated (S)-enantiomer or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, preferably greater than 90%,
more preferably greater than 95%, most preferably greater than 99%,
or a pharmaceutically acceptable salt thereof. More preferably, the
compound of formula (12a) is a compound of formula (12a1):
##STR00034##
where Pg.sup.1 and Pg.sup.2 are each independently an oxygen
protecting group, as an isolated (S)-enantiomer or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, preferably greater than 90%,
more preferably greater than 95%, most preferably greater than 99%,
or a pharmaceutically acceptable salt thereof.
[0122] The method described above for treating a compound of
formula (12) under suitable deprotecting conditions to provide a
compound of formula (13) may further comprise a recrystallization
step prior to treating the compound of formula (12), wherein the
recrystallization step comprises treating a compound of formula
(11):
##STR00035##
wherein p, r, R.sup.1, R.sup.2 and R.sup.3 are each as described
above in the Summary of the Invention for the compounds of formula
(I) and Pg.sup.1 and Pg.sup.2 are each independently an oxygen
protecting group, as a racemic mixture of enantiomers or as a
non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof, under suitable recrystallization
conditions to provide a compound of formula (12), as described
above. Preferably, the compound of formula (11) is a compound of
formula (11a):
##STR00036##
where q is 1 or 2, p, R.sup.1 and R.sup.2 are each as described
above in the Summary of the Invention for the compounds of formula
(I) and Pg.sup.1 and Pg.sup.2 are each independently an oxygen
protecting group, as a racemic mixture of enantiomers or as a
non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof. More preferably, the compound of formula
(11a) is a compound of formula (11a1):
##STR00037##
where Pg.sup.1 and Pg.sup.2 are each independently an oxygen
protecting group, as a racemic mixture of enantiomers or as a
non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof.
[0123] The method described above for treating a compound of
formula (11) under suitable recrystallization conditions to provide
a compound of formula (12) may further comprise a C-alkylation step
prior to treating the compound of formula (11), wherein the
C-alkylation step comprises treating a compound of formula (9):
##STR00038##
where p, r, R.sup.1, R.sup.2 and R.sup.3 are each as described
above in the Summary of the Invention for the compounds of formula
(I) and Pg.sup.1 is an oxygen protecting group, as a racemic
mixture of enantiomers or as a non-racemic mixture of enantiomers,
or a pharmaceutically acceptable salt thereof, with a compound of
formula (10):
Pg.sup.2OCH.sub.2X (10);
under suitable C-alkylation conditions comprising the presence of a
phase transfer catalyst to provide a compound of formula (11), as
described above. Preferably, the compound of formula (9) is a
compound of formula (9a):
##STR00039##
where q is 1 or 2, p, R.sup.1 and R.sup.2 are each as described
above in the Summary of the Invention for the compounds of formula
(I) and Pg.sup.1 is an oxygen protecting group, as a racemic
mixture of enantiomers or as a non-racemic mixture of enantiomers,
or a pharmaceutically acceptable salt thereof. More preferably, the
compound of formula (9a) is a compound of formula (9a1):
##STR00040##
where Pg.sup.1 is an oxygen protecting group, as a racemic mixture
of enantiomers or as a non-racemic mixture of enantiomers, or a
pharmaceutically acceptable salt thereof.
[0124] Preferably the phase transfer catalyst used in the
C-alkylation step described above is is a quaternary ammonium salt
of quinidine or a quaternary ammonium salt of cinchonine.
[0125] The method described above for treating a compound of
formula (9) with a compound of formula (10) under suitable
C-alkylation conditions to provide a compound of formula (11) may
further comprise a dehydroxylation step prior to treating the
compound of formula (9), wherein the dehydroxylation step comprises
treating a compound of formula (8):
##STR00041##
where p, r, R.sup.1, R.sup.2 and R.sup.3 are each as described
above in the Summary of the Invention for the compounds of formula
(I) and Pg.sup.1 is an oxygen protecting group, as a racemic
mixture of enantiomers or as a non-racemic mixture of enantiomers,
or a pharmaceutically acceptable salt thereof, under suitable
dehydroxylation conditions to provide a compound of formula (9), as
described above. Preferably, the compound of formula (8) is a
compound of formula (8a):
##STR00042##
where q is 1 or 2, p, R.sup.1 and R.sup.2 are each as described
above in the Summary of the Invention for the compounds of formula
(I) and Pg.sup.1 is an oxygen protecting group, as a racemic
mixture of enantiomers or as a non-racemic mixture of enantiomers,
or a pharmaceutically acceptable salt thereof. More preferably, the
compound of formula (8a) is a compound of formula (8a1):
##STR00043## [0126] where Pg.sup.1 is an oxygen protecting group,
as a racemic mixture of enantiomers or as a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof.
[0127] The method described above for treating a compound of
formula (8) under suitable dehydroxylation conditions to provide a
compound of formula (9) may further comprise a protecting step
prior to treating the compound of formula (8), wherein the
protecting step comprises treating a compound of formula (6):
##STR00044##
where p, r, R.sup.1, R.sup.2 and R.sup.3 are each as described
above in the Summary of the Invention for the compounds of formula
(I), as a racemic mixture of enantiomers or as a non-racemic
mixture of enantiomers, or a pharmaceutically acceptable salt
thereof, with a compound of formula (7):
Pg.sup.1X (7);
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro, and Pg.sup.1 is an oxygen protecting group under
suitable protecting conditions to provide a compound of formula
(8), as described above. Preferably the compound of formula (6) is
a compound of formula (6a):
##STR00045##
where q is 1 or 2 and p, R.sup.1 and R.sup.2 are each as described
above in the Summary of the Invention for the compounds of formula
(I), as a racemic mixture of enantiomers or as a non-racemic
mixture of enantiomers, or a pharmaceutically acceptable salt
thereof.
[0128] More preferably, the compound of formula (6a) is a compound
of formula (6a1):
##STR00046##
as a racemic mixture of enantiomers or as a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof.
[0129] The method described above for treating a compound of
formula (6) with a compound of formula (7) under suitable
protecting conditions to provide a compound of formula (8) may
further comprise a Grignard addition step, wherein the Grignard
addition step comprises first treating a compound of formula
(4):
##STR00047##
where r and R.sup.3 are as described above for the compound of
formula (I), with a Grignard reagent of formula (5):
RMgX (5);
where X is iodo, bromo or chloro, preferably bromo or chloro, and R
is alkyl, under suitable conditions to form an intermediate
Grignard addition product; and then treating a compound of formula
(3):
##STR00048##
where p, R.sup.1 and R.sup.2 are each as described above in the
Summary of the Invention for the compounds of formula (I), or a
pharmaceutically acceptable salt thereof, with the intermediate
Grignard addition product formed above under suitable Grignard
reaction conditions to provide a compound of formula (6), as
described above. Preferably the compound of formula (3) is a
compound of formula (3a):
##STR00049##
where p, R.sup.1 and R.sup.2 are each as described above in the
Summary of the Invention for the compounds of formula (I), or a
pharmaceutically acceptable salt thereof. More preferably the
compound of formula (3a) is a compound of formula (3a1):
##STR00050##
or a pharmaceutically acceptable salt thereof. Preferably the
compound of formula (4) is a compound of formula (4a):
##STR00051##
where q is 1 or 2. More preferably, the compound of formula (4a) is
a compound of formula (4a1):
##STR00052##
[0130] The method described above for first treating a compound of
formula (4) with a Grignard reagent of formula (5) to form an
intermediate Grignard addition product and then treating a compound
of formula (3) with the intermediate Grignard addition product to
provide a compound of formula (6), as described above, may further
comprise a N-alkylation step prior to treating the compound of
formula (3) or the compound of formula (4), wherein the
N-alkylation step comprises treating a compound of formula (1):
##STR00053##
where p and R.sup.2 are each as described above in the Summary of
the Invention for the compounds of formula (I), or a
pharmaceutically acceptable salt thereof, with a compound of
formula (2):
X--R.sup.1 (2);
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro, and R.sup.1 is as described above in the Summary of the
Invention for the compounds of formula (I), under suitable
N-alkylation conditions to provide a compound of formula (3), as
described above. Preferably, the compound of formula (1) is a
compound of formula (1a):
##STR00054##
or a pharmaceutically acceptable salt thereof. Preferably, the
compound of formula (2) is a compound of formula (2a):
##STR00055##
where X is halo, typically iodo, bromo or chloro, preferably bromd
or chloro.
[0131] Another aspect of the invention described herein is a method
of preparing a compound of formula (I), as described above in the
Summary of the Invention; wherein the method comprises the
following steps:
[0132] (a) treating a compound of formula (1):
##STR00056##
where p and R.sup.2 are each as described above in the Summary of
the Invention for the compound of formula (I), or a
pharmaceutically acceptable salt thereof, with a compound of
formula (2):
X--R.sup.1 (2);
where R.sup.1 is as described above in the Summary of the Invention
for the compound of formula (I) and X is halo, typically iodo,
bromo or chloro, preferably bromo or chloro, under suitable
N-alkylation conditions to provide a compound of formula (3):
##STR00057##
where p, R.sup.1 and R.sup.2 are each as described above in the
Summary of the Invention for the compound of formula (I), or a
pharmaceutically acceptable salt thereof;
[0133] (b) treating a compound of formula (3) under suitable
Grignard reaction conditions with an intermediate Grignard addition
product formed from the treatment of a compound of formula (4):
##STR00058##
where r and R.sup.3 are each as described above in the Summary of
the Invention for the compound of formula (I), with a Grignard
reagent of formula (5):
RMgX (5);
where R is alkyl and X is iodo, bromo or chloro, preferably bromo
or chloro, under suitable conditions to form a compound of formula
(6):
##STR00059##
where p, r, R.sup.1, R.sup.2 and R.sup.3 are each as described
above in the Summary of the Invention for the compound of formula
(I), as a racemic mixture of enantiomers or as a non-racemic
mixture of enantiomers, or a pharmaceutically acceptable salt
thereof; (c) treating a compound of formula (6) with a compound of
formula (7):
Pg.sup.1X (7);
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro, and Pg.sup.1 is an oxygen protecting group under
suitable protecting conditions to provide a compound of formula
(8):
##STR00060##
where p, r, R.sup.1, R.sup.2 and R.sup.3 are each as described
above in the Summary of the Invention for the compound of formula
(I) and Pg.sup.1 is an oxygen protecting group, as a racemic
mixture of enantiomers or as a non-racemic mixture of enantiomers,
or a pharmaceutically acceptable salt thereof;
[0134] (d) treating a compound of formula (8) under suitable
dehydroxylation conditions to provide a compound of formula
(9):
##STR00061##
where p, r, R.sup.1, R.sup.2 and R.sup.3 are each as described
above in the Summary of the Invention for the compound of formula
(I) and Pg.sup.1 is an oxygen protecting group, as a racemic
mixture of enantiomers or as a non-racemic mixture of enantiomers,
or a pharmaceutically acceptable salt thereof;
[0135] (e) treating a compound of formula (9) with a compound of
formula (10):
Pg.sup.2OCH.sub.2X (10);
where Pg.sup.2 is an oxygen protecting group and X is halo,
typically iodo, bromo or chloro, preferably bromo or chloro, under
suitable C-alkylation conditions comprising the presence of a phase
transfer catalyst to provide a compound of formula (11):
##STR00062##
where p, r, R.sup.1, R.sup.2 and R.sup.3 are each as described
above in the Summary of the Invention for the compound of formula
(I) and Pg.sup.1 and Pg.sup.2 are each independently an oxygen
protecting group, as a racemic mixture of enantiomers or as a
non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof;
[0136] (f) treating a compound of formula (11) under suitable
recrystallization conditions to provide a compound of formula
(12):
##STR00063##
where p, r, R.sup.1, R.sup.2 and R.sup.3 are each as described
above in the Summary of the Invention for the compound of formula
(I) and Pg.sup.1 and Pg.sup.2 are each independently an oxygen
protecting group, as an isolated (S)-enantiomer or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, preferably greater than 90%,
more preferably greater than 95%, most preferably greater than 99%,
or a pharmaceutically acceptable salt thereof;
[0137] (g) treating a compound of formula (12) under suitable
deprotecting conditions to provide a compound of formula (13):
##STR00064##
where p, r, R.sup.1, R.sup.2 and R.sup.3 are each as described
above in the Summary of the Invention for the compound of formula
(I), as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof;
[0138] (h) treating a compound of formula (13) under suitable
Mitsunobu reaction conditions to provide the compound of formula
(I), as defined above, as an isolated (S)-enantiomer or a
non-racemic mixture of enantiomers having an enantiomeric excess of
the (S)-enantiomer of greater than 80%, preferably greater than
90%, more preferably greater than 95%, most preferably greater than
99%, or a pharmaceutically acceptable salt thereof.
[0139] A preferred method of preparing a compound of formula (I),
as described above in the Summary of the Invention, is the method
wherein the method comprises treating a compound of formula
(22):
##STR00065##
where p, r, R.sup.2 and R.sup.3 are each as described above in the
Summary of the Invention for the compound of formula (I), as an
isolated (S)-enantiomer, or a non-racemic mixture of enantiomers
having an enantiomeric excess of the (S)-enantiomer of greater than
80%, preferably greater than 90%, more preferably greater than 95%,
most preferably greater than 99%, or a pharmaceutically acceptable
salt thereof, with a compound of formula (2):
X--R.sup.1 (2);
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro, and R.sup.1 is as described above in the Summary of the
Invention for the compound of formula (I), or a pharmaceutically
acceptable salt thereof, under suitable N-alkylation conditions to
provide a compound of formula (I), as described above. Preferably,
the compound of formula (I) is a compound of formula (Ia):
##STR00066##
where q is 1 or 2 and p, R.sup.1 and R.sup.2 are each as described
above in the Summary of the Invention for the compound of formula
(I), as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof. More preferably, the
compound of formula (Ia) is a compound of formula (Ia1):
##STR00067##
as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof; or the compound of
formula (Ia) is a compound of formula (Ia2):
##STR00068##
as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof. Preferably, the compound
of formula (2) is a compound of formula (2a):
##STR00069##
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro, or the compound of formula (2) is a compound of formula
(2b):
##STR00070##
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro.
[0140] Preferably, the compound of formula (22) is a compound of
formula (22a):
##STR00071##
where q is 1 or 2 and p and R.sup.2 are are each as described above
in the Summary of the Invention for the compound of formula (I), as
an isolated (S)-enantiomer or a non-racemic mixture of enantiomers
having an enantiomeric excess of the (S)-enantiomer of greater than
80%, preferably greater than 90%, more preferably greater than 95%,
most preferably greater than 99%, or a pharmaceutically acceptable
salt thereof. More preferably, the compound of formula (22a) is a
compound of formula (22a1):
##STR00072##
as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof, or a compound of formula
(22a2):
##STR00073##
as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof.
[0141] The method described above for treating a compound of
formula (22) with a compound of formula (2) under suitable
N-alkylation conditions to provide a compound of formula (I), as
described above, may further comprise a deprotection step prior to
treating the compound of formula (22), wherein the deprotection
step comprises treating a compound of formula (21):
##STR00074##
where p, r, R.sup.2 and R.sup.3 are each as described above in the
Summary of the Invention for the compound of formula (I), and
Pg.sup.3 is a nitrogen protecting group, as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof, under suitable nitrogen deprotection conditions to provide
a compound of formula (22), as described above. Preferably, the
compound of formula (21) is a compound of formula (21a):
##STR00075##
where q is 1 or 2, p and R.sup.2 are each as described above in the
Summary of the Invention for the compound of formula (I) and
Pg.sup.3 is a nitrogen protecting group, as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof. More preferably, the compound of formula (21a) is a
compound of formula (21a1):
##STR00076##
where Pg.sup.3 is an nitrogen protecting group, as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof, or the compound of formula (21a) is a compound of formula
(21a2):
##STR00077##
where Pg.sup.3 is an nitrogen protecting group, as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof.
[0142] The method described above for treating a compound of
formula (21) under suitable nitrogen deprotection conditions to
provide a compound of formula (22), may further comprise an
intramolecular cyclization step prior to treating the compound of
formula (21), as described above, where the intramolecular
cyclization step comprises treating a compound of formula (20):
##STR00078##
where p, r, R.sup.2 and R.sup.3 are each as described above in the
Summary of the Invention for the compound of formula (I), and
Pg.sup.3 is a nitrogen protecting group, as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof, under suitable Mitsunobu reaction conditions, to provide
the compound of formula (21), as described above. Preferably, the
compound of formula (20) is a compound of formula (20a):
##STR00079##
where q is 1 or 2, p and R.sup.2 are each as described above in the
Summary of the Invention for the compound of formula (I) and
Pg.sup.3 is a nitrogen protecting group, as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof. More preferably, the compound of formula (20a) is a
compound of formula (20a1):
##STR00080##
where Pg.sup.3 is a nitrogen protecting group, as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof, or the compound of formula (20a) is a compound of formula
(20a2):
##STR00081##
where Pg.sup.3 is a nitrogen protecting group, as an isolated
(S-enantiomer or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof.
[0143] The method described above for treating a compound of
formula (20) under standard Mitsunobu reaction conditions to
provide a compound of formula (21), as described above, may further
comprise a deprotection step prior to treating the compound of
formula (20), as described above, wherein the deprotection step
comprises treating a compound of formula (19):
##STR00082##
where p, r, R.sup.2 and R.sup.3 are each as described above in the
Summary of the Invention for the compound of formula (I), Pg.sup.1
and Pg.sup.2 are each independently an oxygen protecting group and
Pg.sup.3 is a nitrogen protecting group, as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof, under suitable deprotection conditions to provide a
compound of formula (20), as described above. Preferably, the
compound of formula (19) is a compound of formula (19a):
##STR00083##
where q is 1 or 2, p and R.sup.2 are each as described above in the
Summary of the Invention for the compound of formula (I), Pg.sup.1
and Pg.sup.2 are each independently an oxygen protecting group and
Pg.sup.3 is a nitrogen protecting group, as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof. More preferably, the compound of formula (19a) is a
compound of formula (19a1):
##STR00084##
where Pg.sup.1 and Pg.sup.2 are each independently an oxygen
protecting group and Pg.sup.3 is a nitrogen protecting group, as an
isolated (S)-enantiomer, or a non-racemic mixture of enantiomers
having an enantiomeric excess of the (S)-enantiomer of greater than
80%, preferably greater than 90%, more preferably greater than 95%,
most preferably greater than 99%, or a pharmaceutically acceptable
salt thereof, or the compound of formula (19a) is a compound of
formula (19a2):
##STR00085##
where Pg.sup.1 and Pg.sup.2 are each independently an oxygen
protecting group and Pg.sup.3 is a nitrogen protecting group, as an
isolated (S)-enantiomer, or a non-racemic mixture of enantiomers
having an enantiomeric excess of the (S)-enantiomer of greater than
80%, preferably greater than 90%, more preferably greater than 95%,
most preferably greater than 99%, or a pharmaceutically acceptable
salt thereof.
[0144] The method described above for treating a compound of
formula (19) under suitable deprotection conditions to provide a
compound of formula (20), as described above, may further comprise
a C-alkylation step prior to treating the compound of formula (19),
wherein the C-alkylation step comprises treating a compound of
formula (18):
##STR00086##
where p, r, R.sup.2 and R.sup.3 are each as described above in the
Summary of the Invention for the compound of formula (I), Pg.sup.1
is an oxygen protecting group and Pg.sup.3 is a nitrogen protecting
group, as a racemic mixture of enantiomers or as a non-racemic
mixture of enantiomers, or a pharmaceutically acceptable salt
thereof, with a compound of formula (10):
Pg.sup.2OCH.sub.2X (10);
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro, and Pg.sup.2 is an oxygen protecting group, under
suitable C-alkylation conditions comprising the presence of a phase
transfer catalyst to provide a compound of formula (19), as
described above. Preferably, the compound of formula (18) is a
compound of formula (18a):
##STR00087##
where q is 1 or 2, p and R.sup.2 are each as described above in the
Summary of the Invention for the compound of formula (I), Pg.sup.1
is an oxygen protecting group and Pg.sup.3 is a nitrogen protecting
group, as a racemic mixture of enantiomers or as a non-racemic
mixture of enantiomers, or a pharmaceutically acceptable salt
thereof. More preferably, the compound of formula (18a) is a
compound of formula (18a1):
##STR00088##
where Pg.sup.1 is an oxygen protecting group and Pg.sup.3 is a
nitrogen protecting group, as a racemic mixture of enantiomers or
as a non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof, or the compound of formula (18a) is a
compound of formula (18a2):
##STR00089##
where Pg.sup.1 is an oxygen protecting group and Pg.sup.3 is a
nitrogen protecting group, as a racemic mixture of enantiomers or
as a non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof. Preferably, the phase transfer catalyst
utilized in this step is a quaternary ammonium salt of quinidine or
a quaternary ammonium salt of cinchonine.
[0145] The method described above for treating a compound of
formula (18) with a compound of formula (10) under suitable
C-alkylatioin conditions to provide a compound of formula (19), as
described above, may further comprise a dehydroxylation step prior
to treating the compound of formula (18), as described above,
wherein the dehydroxylation step comprises treating a compound of
formula (17):
##STR00090##
where p, r, R.sup.2 and R.sup.3 are each as described above in the
Summary of the Invention for the compound of formula (I), Pg.sup.1
is an oxygen protecting group and Pg.sup.3 is a nitrogen protecting
group, as a racemic mixture of enantiomers or as a non-racemic
mixture of enantiomers, or a pharmaceutically acceptable salt
thereof, under suitable dehydroxylation conditions to provide a
compound of formula (18), as described above. Preferably, the
compound of formula (17) is a compound of formula (17a):
##STR00091##
where q is 1 or 2, p and R.sup.2 are each as described above in the
Summary of the Invention for the compound of formula (I), Pg.sup.1
is an oxygen protecting group and Pg.sup.3 is a nitrogen protecting
group, as a racemic mixture of enantiomers or as a non-racemic
mixture of enantiomers, or a pharmaceutically acceptable salt
thereof. More preferably, the compound of formula (17a) is a
compound of formula (17a1):
##STR00092##
where Pg.sup.1 is an oxygen protecting group and Pg.sup.3 is a
nitrogen protecting group, as a racemic mixture of enantiomers or
as a non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof, or the compound of formula (17a) is a
compound of formula (17a2):
##STR00093##
where Pg.sup.1 is an oxygen protecting group and Pg.sup.3 is a
nitrogen protecting group, as a racemic mixture of enantiomers or
as a non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof.
[0146] The method described above for treating a compound of
formula (17) under suitable dehydroxylation conditions to provide a
compound of formula (18), as described above, may further comprise
a protecting step prior to treating the compound of formula (17),
as described above, wherein the protecting step comprises treating
a compound of formula (16):
##STR00094##
where p, r, R.sup.2 and R.sup.3 are each as described above in the
Summary of the Invention for the compound of formula (I) and
Pg.sup.3 is a nitrogen protecting group, as a racemic mixture of
enantiomers or as a non-racemic mixture of enantiomers, or a
pharmaceutically acceptable salt thereof, with a compound of
formula (7):
Pg.sup.1X (7);
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro, and Pg.sup.1 is an oxygen protecting group under
suitable protecting conditions to provide a compound of formula
(17), as described above. Preferably, the compound of formula (16)
is a compound of formula (16a):
##STR00095##
where q is 1 or 2, p and R.sup.2 are each as described above in the
Summary of the Invention for the compound of formula (I) and
Pg.sup.3 is a nitrogen protecting group, as a racemic mixture of
enantiomers or as a non-racemic mixture of enantiomers, or a
pharmaceutically acceptable salt thereof. More preferably, the
compound of formula (16a) is a compound of formula (16a1):
##STR00096##
where Pg.sup.3 is a nitrogen protecting group, as a racemic mixture
of enantiomers or as a non-racemic mixture of enantiomers, or a
pharmaceutically acceptable salt thereof, or the compound of
formula (16a) is a compound of formula (16a2):
##STR00097##
where Pg.sup.3 is a nitrogen protecting group, as a racemic mixture
of enantiomers or as a non-racemic mixture of enantiomers, or a
pharmaceutically acceptable salt thereof.
[0147] The method described above for treating a compound of
formula (16) with a compound of formula (7) under suitable
protecting conditions to provide a compound of formula (17), as
described above, may further comprise a Grignard addition step
prior to treating a compound of formula (16), as described above,
wherein the Grignard addition step comprises first treating a
compound of formula (4):
##STR00098##
where r and R.sup.3 are each as described above in the Summary of
the Invention for the compound of formula (I), with a Grignard
reagent of formula (5):
RMgX (5)
where X is iodo, bromo or chloro, preferably bromo or chloro, and R
is alkyl, under suitable conditions to form an intermediate
Grignard addition product; and then treating a compound of formula
(15):
##STR00099##
where p and R.sup.2 are each as described above in the Summary of
the Invention for the compound of formula (I), and Pg.sup.3 is a
nitrogen protecting group, or a pharmaceutically acceptable salt
thereof, with the intermediate Grignard addition product formed in
substep a) above under suitable Grignard reaction conditions to
provide a compound of formula (16), as described above. Preferably,
the compound of formula (15) is a compound of formula (15a):
##STR00100##
where p and R.sup.2 are each as described above in the Summary of
the Invention for the compound of formula (I) and Pg.sup.3 is a
nitrogen protecting group, or a pharmaceutically acceptable salt
thereof. Preferably, the compound of formula (4) is a compound of
formula (4a):
##STR00101##
where q is 1 or 2. More preferably, the compound of formula (4a) is
a compound of formula (4a1):
##STR00102##
or the compound of formula (4a) is a compound of formula (4a2):
##STR00103##
[0148] The method described above for first treating a compound of
formula (4) with a Grignard reagent of formula (5) to form an
intermediate Grignard addition product and then treating a compound
of formula (15) with the intermediate Grignard addition product to
provide a compound of formula (16), as described above, may further
comprise a protecting step prior to treating the compound of
formula (4) or the compound of formula (15), as described above,
wherein the protecting step comprises treating a compound of
formula (1):
##STR00104##
where p and R.sup.2 are each as described above in the Summary of
the Invention for the compound of formula (I), or a
pharmaceutically acceptable salt thereof, with a compound of
formula (14):
X-Pg.sup.3 (14);
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro, and Pg.sup.3 is a nitrogen protecting group, under
suitable nitrogen protecting conditions to provide a compound of
formula (15), as described above. Preferably, the compound of
formula (1) is a compound of formula (1a):
##STR00105##
where p and R.sup.2 are each as described above in the Summary of
the Invention for the compound of formula (I), or a
pharmaceutically acceptable salt thereof.
[0149] Another preferred method of preparing a compound of formula
(I), as described above in the Summary of the Invention, comprises
the following steps:
[0150] (a) treating a compound of formula (1):
##STR00106##
where p and R.sup.2 are each as defined above for the compound of
formula (I), or a pharmaceutically acceptable salt thereof, with a
compound of formula (14):
X-Pg.sup.3 (14);
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro, and Pg.sup.3 is a nitrogen protecting group, under
suitable nitrogen protecting conditions to provide a compound of
formula (15):
##STR00107##
where p and R.sup.2 are each as described above for the compound of
formula (I), and Pg.sup.3 is a nitrogen protecting group, or a
pharmaceutically acceptable salt thereof;
[0151] (b) treating a compound of formula (15) under suitable
Grignard reaction conditions with an intermediate Grignard addition
product formed from the treatment of a compound of formula (4):
##STR00108##
where r and R.sup.3 are each as defined above for the compound of
formula (I), with a Grignard reagent of formula (5):
RMgX (5);
where R is alkyl and X is iodo, bromo or chloro, preferably bromo
or chloro, under suitable conditions to provide a compound of
formula (16):
##STR00109##
where p, r, R.sup.2 and R.sup.3 are each as described above for the
compound of formula (I) and Pg.sup.3 is a nitrogen protecting
group, as a racemic mixture of enantiomers or as a non-racemic
mixture of enantiomers, or a pharmaceutically acceptable salt
thereof; (c) treating a compound of formula (16) with a compound of
formula (7):
Pg.sup.1X (7);
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro, and Pg.sup.1 is an oxygen protecting group under
suitable protecting conditions to provide a compound of formula
(17):
##STR00110##
where p, r, R.sup.2 and R.sup.3 are each as described above for the
compound of formula (I), Pg.sup.1 is an oxygen protecting group and
Pg.sup.3 is a nitrogen protecting group, as a racemic mixture of
enantiomers or as a non-racemic mixture of enantiomers, or a
pharmaceutically acceptable salt thereof;
[0152] (d) treating a compound of formula (17) under suitable
dehydroxylation conditions to provide a compound of formula
(18):
##STR00111##
where p, r, R.sup.2 and R.sup.3 are each as described above for the
compound of formula (I), Pg.sup.1 is an oxygen protecting group and
Pg.sup.3 is a nitrogen protecting group, as a racemic mixture of
enantiomers or as a non-racemic mixture of enantiomers, or a
pharmaceutically acceptable salt thereof;
[0153] (e) treating a compound of formula (18) with a compound of
formula (10):
Pg.sup.2OCH.sub.2X (10);
where Pg.sup.2 is an oxygen protecting group and X is halo,
typically iodo, bromo or chloro, preferably bromo or chloro, under
suitable C-alkylation conditions comprising the presence of a phase
transfer catalyst to provide a compound of formula (19):
##STR00112##
where p, r, R.sup.2 and R.sup.3 are each as described above for the
compound of formula (I), Pg.sup.1 and Pg.sup.2 are each
independently an oxygen protecting group and Pg.sup.3 is a nitrogen
protecting group, as an isolated (S)-enantiomer, or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, preferably greater than 90%,
more preferably greater than 95%, most preferably greater than 99%,
or a pharmaceutically acceptable salt thereof;
[0154] (f) treating a compound of formula (19) under suitable
deprotection conditions to provide a compound of formula (20):
##STR00113##
where p, r, R.sup.2 and R.sup.3 are each as described above for the
compound of formula (I), and Pg.sup.3 is a nitrogen protecting
group, as an isolated (S)-enantiomer, or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof;
[0155] (g) treating a compound of formula (20) under suitable
Mitsunobu reaction conditions to provide the compound of formula
(21):
##STR00114##
where p, r, R.sup.2 and R.sup.3 are each as described above for the
compound of formula (I), and Pg.sup.3 is a nitrogen protecting
group, as an isolated (S)-enantiomer, or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof;
[0156] (h) treating a compound of formula (21) under suitable
nitrogen deprotecting conditions to provide a compound of formula
(22):
##STR00115##
where p, r, R.sup.2 and R.sup.3 are each as described above for the
compound of formula (I), as an isolated (S)-enantiomer, or a
non-racemic mixture of enantiomers having an enantiomeric excess of
the (S)-enantiomer of greater than 80%, preferably greater than
90%, more preferably greater than 95%, most preferably greater than
99%, or a pharmaceutically acceptable salt thereof; and
[0157] (i) treating a compound of formula (22) with a compound of
formula (2):
X--R.sup.1 (2);
where X is halo, typically iodo, bromo or chloro, preferably bromo
or chloro, and R.sup.1 is as described above for the compound of
formula (I), or a pharmaceutically accceptable salt thereof, under
suitable N-alkylation conditions to provide a compound of formula
(I), as an isolated (S)-enantiomer, or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof.
[0158] Another aspect of the invention, as described above in the
Summary of the Invention, provides intermediates useful in the
methods described herein.
[0159] One intermediate is a compound of formula (11):
##STR00116##
wherein Pg.sup.1 and Pg.sup.2 are each independently an oxygen
protecting group and p, r, R.sup.1, R.sup.2 and R.sup.3 are each as
described above in the Summary of the Invention for the compounds
of formula (I). Preferably, the compound of formula (11) is a
compound of formula (11a):
##STR00117##
where q is 1 or 2, p, R.sup.1 and R.sup.2 are each as defined above
for the compounds of formula (11) and Pg.sup.1 and Pg.sup.2 are
each independently an oxygen protecting group, as a racemic mixture
of enantiomers or as a non-racemic mixture of enantiomers, or a
pharmaceutically acceptable salt thereof. Preferably, the compound
of formula (11a) is a compound of formula (11a1):
##STR00118##
where Pg.sup.1 and Pg.sup.2 are each independently an oxygen
protecting group, as a racemic mixture of enantiomers or as a
non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof.
[0160] Other intermediates are a compound of formula (12) or a
compound of formula (13):
##STR00119##
wherein each Pg.sup.1 and Pg.sup.2 is independently an oxygen
protecting group, and each p, r, R.sup.1, R.sup.2 and R.sup.3 are
as defined above in the Summary of the Invention for compounds of
formula (I), as an isolated (S)-enantiomer or a non-racemic mixture
of enantiomers having an enantiomeric excess of the (S)-enantiomer
of greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof. Preferably, the compound
of formula (12) is a compound of formula (12a):
##STR00120##
where q is 1 or 2, Pg.sup.1 and Pg.sup.2 are each independently an
oxygen protecting group and p, R.sup.1 and R.sup.2 are each as
defined above for compounds of formula (12), as an isolated
(S)-enantiomer or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof. More preferably, the compound of formula (12a) is a
compound of formula (12a1):
##STR00121##
where Pg.sup.1 and Pg.sup.2 are each independently an oxygen
protecting group, as an isolated (S)-enantiomer or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, preferably greater than 90%,
more preferably greater than 95%, most preferably greater than 99%,
or a pharmaceutically acceptable salt thereof. Preferably, the
compound of formula (13) is a compound of formula (13a):
##STR00122##
where q is 1 or 2 and p, R.sup.1 and R.sup.2 are each as defined
above for compounds of formula (13), as an isolated (S)-enantiomer
or a non-racemic mixture of enantiomers having an enantiomeric
excess of the (S)-enantiomer of greater than 80%, preferably
greater than 90%, more preferably greater than 95%, most preferably
greater than 99%, or a pharmaceutically acceptable salt thereof.
More preferably, the compound of formula (13a) is a compound of
formula (13a1):
##STR00123##
as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof.
[0161] Other intermediates useful in the method of the invention
are a compound of formula (19), a compound of formula (20), a
compound of formula (21) or a compound of formula (22):
##STR00124##
wherein each Pg.sup.1 and Pg.sup.2 is independently an oxygen
protecting group, each Pg.sup.3 is a nitrogen protecting group, and
each p, r, R.sup.2 and R.sup.3 is as described above in the Summary
of the Invention for compounds of formula (I), as an isolated
(S)-enantiomer or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof. Preferably, the compound of formula (19), the compound of
formula (20), the compound of formula (21) and the compound of
formula (22) are compounds of formula (19a), formula (20a), formula
(21a) and formula (22a), respectively:
##STR00125##
where each q is independently 1 or 2, each Pg.sup.1 and each
Pg.sup.2 is independently an oxygen protecting group, each Pg.sup.3
is a nitrogen protecting group, and each p, each R.sup.2 and each
R.sup.3 is as defined above in Claim 80, as an isolated
(S)-enantiomer or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%, or a pharmaceutically acceptable salt
thereof.
[0162] Preferably, the compound of formula (19a) is a compound of
formula (19a1) or of formula (19a2):
##STR00126##
wherein each Pg.sup.1 and each Pg.sup.2 is independently an oxygen
protecting group and each Pg.sup.3 is a nitrogen protecting group,
as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof.
[0163] Preferably, the compound of formula (20a) is a compound of
formula (20a1) or formula (20a2):
##STR00127##
wherein each Pg.sup.3 is independently a nitrogen protecting group,
as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof.
[0164] Preferably, the compound of formula (21a) is a compound of
formula (21a1) or of formula (21a2):
##STR00128##
wherein each Pg.sup.3 is independently a nitrogen protecting group,
as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof.
[0165] Preferably, the compound of formula (22a) is a compound of
formula (22a1) or of formula (22a2):
##STR00129##
as an isolated (S)-enantiomer or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%, or a
pharmaceutically acceptable salt thereof.
[0166] Specific embodiments of the methods of the invention,
including the suitable conditions for each of the above described
steps, are described in more detail below in the Methods of the
Invention.
Methods of the Invention
[0167] The methods of the invention are directed to asymmetric
syntheses of a compound of formula (I), as set forth above in the
Summary of the Invention, as an isolated (S)-enantiomer, or a
non-racemic mixture of the (S)-enantiomer and the (R)-enantiomer
having an enantiomeric excess of the (S)-enantiomer greater than
80%, preferably greater than 90%, more preferably greater than 95%
and most preferably greater than 99%.
[0168] It is understood that one skilled in the art would be able
to make in a similar manner as described below other compounds of
the invention not specifically illustrated below by using the
appropriate starting components and modifying the parameters of the
synthesis as needed. In general, starting components may be
obtained from sources such as Sigma Aldrich, Lancaster Synthesis,
Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc.
or synthesized according to sources known to those skilled in the
art (see, e.g., Smith, M. B. and J. March, Advanced Organic
Chemistry: Reactions, Mechanisms, and Structure, 5th edition
(Wiley, December 2000)) or prepared as described herein or in PCT
Published Patent Application No. WO 2006/110917, PCT Published
Patent Application No. WO 2010/45251, PCT Published Patent
Application No. WO 2010/045197, PCT Published Patent Application
No. WO 2011/047174 and PCT Published Patent Application No. WO
2011/002708.
[0169] It is also understood that in the following description,
combinations of substituents and/or variables of the depicted
formulae are permissible only if such contributions result in
stable compounds.
[0170] "Suitable Mitsunobu reaction conditions" as used herein
generally refers to reaction conditions which allow for the
formation of a C--O bond by the condensation of an acidic component
with an alcohol (either primary secondary or benzyl alcohol) in the
presence of triphenylphosphine or another suitable phosphine and an
azodicarboxylic acid derivative, such as, but not limited to,
diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate
(DIAD) or dibenzyl azodicarboxylate (DBAD). "Suitable Mitsunobu
reaction conditions" are further described herein in the
description of Reaction Scheme 1 and Reaction Scheme 2 and are
further described in Hughes, D. L., Org. Prep. (1996), 28, 127-164
and Kumara Swamy, K. C., et al., "Mitsunobu and Related Reactions:
Advances and Applications", Chem. Rev. (2009), 109, 2551-2651.
[0171] "Suitable deprotection conditions" as used herein generally
refers to reaction conditions which allow for the simple cleavage
of protecting groups. For example, the cleavage of a benzyl
protecting group is normally performed by catalytic hydrogenation
and can be performed with good selectivity under mild conditions
using a heterogeneous palladium on carbon (Pd/C) catalyst in the
presence of hydrogen gas or a hydrogen transfer agent (e.g.,
ammonium formate or isopropanol). Efficient removal of protecting
groups depends on selection of the most active and selective
catalyst and an optimized set of reaction conditions. "Suitable
deprotection conditions" are further described herein in the
description of Reaction Scheme 1 and Reaction Scheme 2 and are
further described in detail in Greene, T. W. and Wuts, P. G. M.
Greene's Protective Groups in Organic Synthesis (2006), 4.sup.th
Ed. Wiley.
[0172] "Suitable recrystallization conditions" as used herein
generally refers to reaction conditions which allow for the
crystallization process of forming a solid (i.e., a crystal) from a
solution. "Suitable recrystallization conditions" also refers to
reaction conditions which allow for the separation of a chemical
solid-liquid whereby a mass transfer of a solute from the liquid
solution to a pure solid crystalline phase occurs. Suitable
crystals are obtained through a variation of the solubility
conditions of the solute in the solvent, including, but not
limited, to ethanol, ethyl acetate, tetrahydrofuran or diethyl
ether. Mixtures of solvents can also be used in which the solute is
dissolved in a solvent in which there is high solubility followed
by the addition of an anti-solvent in which the solute is less
soluble but impurities are soluble, leading to the formation of a
pure crystalline solid phase. Crystallization may also be induced
by the addition of seed crystals of previously crystallized
material to a solution containing the same solute. These seed
crystals serve as nucleation sites upon which further
crystallization takes place, speeding up the process of forming a
pure solid crystalline phase. "Suitable recrystallization
conditions" are further described herein in the description of
Reaction Scheme 1 and Reaction Scheme 2 and are described in
further detail in Mersmann, A., Crystallization Technology Handbook
(2001), CRC; 2nd ed.
[0173] "Suitable C-alkylation conditions" as used herein generally
refers to reaction conditions which allow for the transfer of an
optionally substituted alkyl from one molecule to another to form a
carbon-carbon bond. For example, an intermediate in the Reaction
Schemes illustrated below may be treated with an alkylating agent,
such as, but not limited to, benzyl halide, in the presence of a
base, such as, but not limited to, sodium methoxide, to yield a
product wherein a carbon-carbon bond is formed. C-alkylation
reactions can be carried out under phase-transfer conditions in
which one or more substrates are dissolved in a solvent in which
the base is not soluble, typically an organic solvent such as, but
not limited to, toluene, ethyl acetate, dioxane, or diethyl ether
is used with an inorganic base such as, but not limited to, lithium
hydroxide, sodium hydroxide, potassium hydroxide, potassium
phosphate, sodium bicarbonate, cesium carbonate, or potassium
carbonate. The base can be used as a solid or be dissolved in water
to form an insoluble aqueous solution. A phase-transfer catalyst is
used to transfer the base from the insoluble phase to the soluble
organic phase where it can react with the substrate and effect a
C-alkylation. Phase-transfer catalysts are often large organic
cations that have partial solubility in organic and aqueous
solvents such as, but not limited to, tetraalkylammonium halides
and tetraalkylphosphonium halides. "Suitable C-alkylation
conditions" are further described herein in the description of
Reaction Scheme 1 and Reaction Scheme 2 and are described in
further detail in Smith, M. B. and J. March, Advanced Organic
Chemistry: Reactions, Mechanisms, and Structure, 5th edition
(Wiley, December 2000).
[0174] "Suitable dehydroxylation conditions" as used herein
generally refers to reaction conditions which allow for the
dehydration of an alcohol in the presence of a strong acid, such
as, but not limited to, trifluoroacetic acid or sulphuric acid.
"Suitable dehydroxylation conditions" are further described herein
in the description of Reaction Scheme 1 and Reaction Scheme 2 and
are described in further detail in Smith, M. B. and J. March,
Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,
5th edition (Wiley, December 2000).
[0175] "Suitable N-alkylation conditions" as used herein generally
refers to reaction conditions which allow for the alkylation of the
relevant nitrogen and is usually reductive amination in the
presence of a reducing agent, such as, but not limited to, sodium
borohydride, and an aldehyde or alkylation using a base, such as,
but not limited to, potassium carbonate, and an alkylating agent,
such as, but not limited to, a benzyl halide. "Suitable
N-alkylation conditions" are further described herein in the
description of Reaction Scheme 1 and Reaction Scheme 2 and are
described in further detail in Greene, T. W. and P. G. M. Wuts,
Greene's Protective Groups in Organic Synthesis (2006), 4.sup.th
Ed., Wiley.
[0176] "Suitable Grignard addition conditions" as used herein
generally refers to reaction conditions which allow for the
addition of an organomagnesium halide (i.e., Grignard reagent) to a
ketone or aldehyde to form a tertiary or secondary alcohol,
respectively. "Suitable Grignard addition conditions" are further
described herein in the description of Reaction Scheme 1 and
Reaction Scheme 2 and are described in detail in Smith, M. B. and
J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure, 5th edition (Wiley, December 2000); Garst, J. F. and
Ungvary, F., "Mechanism of Grignard reagent formation"; and
Grignard Reagents; Richey, R. S., Ed.; John Wiley & Sons: New
York, 2000; pp 185-275.
[0177] It will be appreciated by those skilled in the art that in
the process described below the functional groups of intermediate
compounds may need to be protected by suitable protecting groups.
Such functional groups include hydroxy, amino, mercapto and
carboxylic acid. Suitable protecting groups for an oxygen atom
("oxygen protecting groups") include, but are not limited to,
trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl,
t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl,
and the like. Suitable protecting groups for a nitrogen atom
("nitrogen protecting groups") include, but are not limited to,
benzhydryl (diphenylmethyl), t-butoxycarbonyl, benzyloxycarbonyl,
and the like. Suitable protecting groups for a sulfur atom ("sulfur
protecting groups") include --C(O)--R (where R is alkyl, aryl or
aralkyl), p-methoxybenzyl, trityl and the like. Suitable protecting
groups for carboxylic acid include alkyl, aryl or arylalkyl
esters.
[0178] Protecting groups may be added or removed in accordance with
standard techniques, which are known to one skilled in the art and
as described herein.
[0179] "Oxygen protecting groups", "nitrogen protecting groups",
"suitable protecting conditions" and "suitable deprotection
conditions" as used herein are further described herein in the
description of Reaction Scheme 1 and Reaction Scheme 2 and are
described in further detail in Greene, T. W. and P. G. M. Wuts,
Greene's Protective Groups in Organic Synthesis (2006), 4.sup.th
Ed., Wiley.
[0180] The advantages of the asymmetric syntheses of the compounds
of formula (I) as described herein over the syntheses disclosed in
PCT Published Patent Application No. WO 2006/110917, PCT Published
Patent Application No. WO 2010/045251, PCT Published Patent
Application No. WO 2010/045197, PCT Published Patent Application
No. WO 2011/047174 and PCT Published Patent Application No. WO
2011/002708 are as follows: [0181] 1. The asymmetric syntheses
disclosed herein do not require simulated moving bed (SMB)
chromatography technology for resolving the enantiomers of a
racemic mixture of a compound of formula (I), thereby eliminating a
costly step. [0182] 2. Chirality is introduced in the compound at
an earlier step, thereby eliminating undesirable intermediates and
final products. [0183] 3. Overall yield of the compound of formula
(I) is higher for the asymmetric syntheses than for the published
processes. [0184] 4. Overall cost for the synthesis of the compound
of formula (I) is lower than for the published processes due to the
reduction of the amount of solvents required.
A. Asymmetric Synthesis of Compounds of Formula (I), Formula (Ia),
and Formula (Ia1) by Method A
[0185] Compounds of formula (I), as described above in the Summary
of the Invention, can be prepared by "Method A", as described below
in Reaction Scheme 1 where p, r, R.sup.1, each R.sup.2 and each
R.sup.3 are as described above in the Summary of the Invention for
compounds of formula (I), R is alkyl, each X is independently halo,
typically iodo, bromo or chloro, preferably bromo or chloro, except
for the Grignard reagent of formula (5) wherein X is iodo, bromo or
chloro, preferably bromo or chloro, and Pg.sup.1 and Pg.sup.2 are
each independently an oxygen protecting group, such as benzyl,
alkyl, tert-butyldiphenylsilyl or triphenylsilyl:
##STR00130## ##STR00131##
[0186] Compounds of formula (1), (2), (4), (5), (7) and (10) are
commercially available, or can be prepared according to methods
known to one skilled in the art or by the methods disclosed in PCT
Published Patent Application No. WO 2006/110917, PCT Published
Patent Application No. WO 2010/45251, PCT Published Patent
Application No. WO 2010/045197, PCT Published Patent Application
No. WO 2011/047174 and PCT Published Patent Application No. WO
2011/002708.
[0187] In general, compounds of formula (I) are prepared according
to Method A, as described above in Reaction Scheme 1, by first
treating a compound of formula (1), or a pharmaceutically
acceptable salt thereof, with an excess molar amount of a compound
of formula (2) under suitable N-alkylation conditions, for example,
in a polar aprotic solvent, such as acetonitrile,
dimethylformamide, tetrahydrofuran, dioxane or dimethoxyethane, in
the presence of a base, such as cesium carbonate, anhydrous
potassium carbonate, sodium hydride, or calcium hydride, at a
temperature of between about 15.degree. C. and about 30.degree. C.
and with stirring for a period of time of between about 1 hour and
about 16 hours. The resulting compound of formula (3) is isolated
from the reaction mixture by standard isolation techniques, such as
filtration.
[0188] The compound of formula (3) so formed is then treated with a
slightly excess molar amount of an intermediate Grignard addition
product prepared by treating a compound of formula (4) in an polar
aprotic solvent, such as tetrahydrofuran, dioxane, dimethoxyethane,
diethyl ether, tert-butyl methyl ether, or dichloromethane, with a
slightly excess molar amount of a Grignard reagent of formula (5)
in a polar aprotic solvent, such as tetrahydrofuran, diethyl ether,
or dioxane under suitable Grignard reaction conditions, such as at
a temperature of between about 0.degree. C. and about 25.degree.
C., to provide a compound of formula (6), which is isolated from
the reaction mixture by standard isolation techniques, such as
extraction, filtrate and concentration.
[0189] The compound of formula (6) in an polar aprotic solvent,
such as dimethylformamide, acetonitrile, or tetrahydrofuran in the
presence of a base, such as cesium carbonate or potassium
carbonate, is then treated with a slightly excess molar amount of a
compound of formula (7) where Pg.sup.1 is an oxygen protecting
group, preferably benzyl, under suitable oxygen protecting
conditions (i.e., the protecting step), such as at a temperature of
between about 0.degree. C. and about 5.degree. C. for a period of
time of between about 15 minutes and about 1 hour, followed by
warming to ambient temperature and stirring for a period of time of
between about 1 hour to about 24 hours. The resulting compound of
formula (8) is isolated from the reaction mixture by standard
techniques, such as precipitation and filtration.
[0190] The removal of the hydroxyl group at the C3 position of the
oxindole ring (i.e., the dehydroxylation step) in the compound of
formula (8) is achieved by treating the compound of formula (8) in
a polar aprotic solvent, such as dichloromethane, or without any
solvent under suitable conditions, such as treatment with a silane
reagent, such as triethylsilane or triphenylsilane in the presence
of an acid, such as, but not limited to, trifluoroacetic acid, to
yield the compound of formula (9), which is isolated from the
reaction mixture by standard isolation techniques, such as
concentration and extraction.
[0191] The compound of formula (11) is prepared by asymmetric phase
transfer-catalyzed C-alkylation wherein a mixture of less than
equimolar amount, preferably less than 20%, of a phase transfer
catalyst, such as a quaternary ammonium salt of quinidine or
cinchonine, preferably a quaternary ammonium salt of cinchonine,
and excess base, such as potassium hydroxide, sodium hydroxide,
lithium hydroxide or cesium hydroxide, preferably potassium
hydroxide, in a non-polar solvent, such as toluene, is cooled to a
temperature of between about -20.degree. C. and about 25.degree. C.
To this mixture is added a solution of a compound of formula (9)
and an excess molar amount of a compound of formula (10) where
Pg.sup.2 is an oxygen protecting group, preferably benzyl, over a
period of time of between about 5 minutes to about 2 hours with
stirring. The compound of formula (11) is isolated from the
reaction mixture by standard isolation conditions, such as
extraction, followed by acid wash, concentration, and filtration as
an isolated (S)-enantiomer, or a non-racemic mixture of enantiomers
having an enantiomeric excess of the (S)-enantiomer of greater than
80%, preferably greater than 90%, more preferably greater than 95%,
most preferably greater than 99%.
[0192] A quaternary ammonium salt of cinchonine can be prepared by
refluxing a suspension of cinchonine and a suitable alkyl halide,
such as, but not limited to, 9-chloromethylanthracene or
1-bromomethylnaphthalene, in a suitable solvent, such as, but not
limited to, anhydrous toluene, tetrahydrofuran. The product is
isolated by means of crystallization using suitable solvent, such
as, but not limited to, diethyl ether or methanol (E. J. Corey and
M. C. Noe, Org. Synth. 2003; 80:38-45).
[0193] The compound of formula (11) is then dissolved in a protic
solvent, such as ethanol, at reflux temperatures, and allowed to
cool to ambient temperature. A seed crystal of the racemic compound
of formula (11) is then added to the cooled solution.
Crystallization of the solution afforded the compound of formula
(12) as an isolated (S)-enantiomer, or a non-racemic mixture of
enantiomers having an enantiomeric excess of the (S)-enantiomer of
greater than 80%, preferably greater than 90%, more preferably
greater than 95%, most preferably greater than 99%.
[0194] The compound of formula (12) is then deprotected under
suitable deprotection (reduction) conditions, such as treating a
mixture of the compound of formula (12), 10% palladium on carbon
and a weak acid, such as acetic acid, formic acid or
trifluoroacetic acid in a protic/polar aprotic solvent mixture,
such as a mixture of a lower alkanol in tetrahydrofuran, ethyl
acetate, or dioxane, preferably a 1:1 mixture of ethanol and
tetrahydrofuran, in the presence of a silane reagent, such as
triethylsilane, in an aprotic polar solvent, such as
tetrahydrofuran or ethanol, at ambient temperature. The resulting
compound of formula (13) as an isolated (S)-enantiomer, or a
non-racemic mixture of enantiomers having an enantiomeric excess of
the (S)-enantiomer of greater than 80%, preferably greater than
90%, more preferably greater than 95%, most preferably greater than
99%, is isolated from the reaction mixture by standard isolation
techniques, such as filtration and concentration.
[0195] Intramolecular cyclization of a compound of formula (13) to
provide a compound of formula (I) is achieved by treating a
compound of formula (13) to suitable Mitsunobu reaction conditions,
such as the employment of a phosphine reagent, preferably, but not
limited to, triphenylphosphine, tributylphosphine,
2-(diphenylphosphino)pyridine, 4-(diphenylphosphino)dimethylaniline
and 4-(N,N-dimethylamino)phenyldiphenylphosphine, and an
azodicarboxylate ester, such as, but not limited to,
diethylazodicarboxylate, diisopropylazodicarboxylate,
di-tert-butylazodicarboxylate or tetramethyldiazenedicarboxamide,
in a polar aprotic solvent, preferably, but not limited to,
tetrahydrofuran, dichloromethane or ethyl acetate. The resulting
compound of formula (I) is isolated from the reaction mixture by
standard isolation techniques, such as extraction, filtration and
concentration, as an isolated (S)-enantiomer, or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80% preferably greater than 90%,
more preferably greater than 95%, most preferably greater than
99%.
[0196] The above described Method A is particularly efficient with
respect to yield and enantiomeric excess of the desired product
when the R.sup.1 group does not participate in competing side
reactions, such as reduction when the compound of formula (12) is
deprotected to form the compound of formula (13).
[0197] A specific method of preparing the compounds of formula (I)
as set forth above in Reaction Scheme 1 is illustrated below in
Reaction Scheme 1A for the preparation of compounds of formula
(Ia), where p, R.sup.1 and R.sup.2 are as defined above in the
Summary of the Invention for the compounds of formula (I), q is 1
or 2, each X is independently halo, typically iodo, bromo or
chloro, preferably bromo or chloro, except for the Grignard reagent
of formula (5) wherein X is iodo, bromo or chloro, preferably bromo
or chloro, and Pg.sup.1 and Pg.sup.2 are each independently an
oxygen protecting group, such as hydrogen, benzyl, alkyl,
methoxymethyl (MOM), benzyloxymethyl (BOM),
tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl or
triphenylsilyl.
##STR00132## ##STR00133##
[0198] Compounds of formulae (1a) and (4a) are commercially
available, or can be prepared according to methods known to one
skilled in the art or by the methods disclosed in PCT Published
Patent Application No. WO 2006/110917, PCT Published Patent
Application No. WO 2010/45251, PCT Published Patent Application No.
WO 2010/045197, PCT Published Patent Application No. WO 2011/047174
and PCT Published Patent Application No. WO 2011/002708.
[0199] A more specific method of preparing the compounds of formula
(I) as set forth above in Reaction Scheme 1A is illustrated below
in Reaction Scheme 1A1 for the preparation of compounds of formula
(Ia1), where each X is independently halo, typically iodo, bromo or
chloro, preferably bromo or chloro, except for the Grignard reagent
of formula (5) wherein X is iodo, bromo or chloro, preferably bromo
or chloro, R is alkyl, and Pg.sup.1 and Pg.sup.2 are each
independently an oxygen protecting group, preferably benzyl:
##STR00134## ##STR00135##
[0200] The compounds of formulae (2a) and (4a1) are commercially
available, or can be prepared according to methods known to one
skilled in the art or by the methods disclosed in PCT Published
Patent Application No. WO 2006/110917, PCT Published Patent
Application No. WO 2010/45251, PCT Published Patent Application No.
WO 2010/045197, PCT Published Patent Application No. WO 2011/047174
and PCT Published Patent Application No. WO 2011/002708. The
cinchonium phase transfer catalyst can be prepared according to
methods known to one skilled in the art or by the methods disclosed
herein.
[0201] The specific experimental conditions and parameters for the
above Reaction Scheme 1A1 are described in more detail below in the
Examples.
B. Asymmetric Synthesis of Compounds of Formula (I), Formula (Ia),
and Formula (Ia2) by Method B
[0202] Compounds of formula (I), as described above in the Summary
of the Invention, can be prepared by Method B as described below in
Reaction Scheme 1 where p, r, R.sup.1, each R.sup.2 and each
R.sup.3 are as described above in the Summary of the Invention for
compounds of formula (I), R is alkyl, each X is independently halo,
typically iodo, bromo or chloro, preferably bromo or chloro, except
for the Grignard reagent of formula (5) wherein X is iodo, bromo or
chloro, preferably bromo or chloro, and Pg.sup.1 and Pg.sup.2 are
each independently an oxygen protecting group, such as hydrogen,
benzyl, alkyl, MOM, BOM, tert-butyldimethylsilyl,
tert-butyldiphenylsilyl, trimethylsilyl or triphenylsilyl, and
Pg.sup.3 is a nitrogen protecting group, such as benzhydryl
(diphenylmethyl) or benzyl, tert-butoxycarbonyl,
para-methoxybenzyl, 2,4-dimethoxybenzyl:
##STR00136## ##STR00137##
[0203] Compound of formulae (1), (14), (4), (5), (7), (10) and (2)
are commercially available, or can be prepared according to methods
known to one skilled in the art or by the methods disclosed in PCT
Published Patent Application No. WO 2006/110917, PCT Published
Patent Application No. WO 2010/45251, PCT Published Patent
Application No. WO 2010/045197, PCT Published Patent Application
No. WO 2011/047174 and PCT Published Patent Application No. WO
2011/002708.
[0204] In general, compounds of formula (I) are prepared according
to Method B, as described above in Reaction Scheme 2, by first
treating a compound of formula (1), or a pharmaceutically
acceptable salt thereof, in a polar aprotic solvent, such as,
dimethylformamide, in the presence of a base, such as sodium
hydroxide, at a temperature of between about 0.degree. C. and about
50.degree. C., preferably at between about 0.degree. C. and about
5.degree. C. or preferably at between about 15.degree. C. and
35.degree. C., with an excess molar amount of a compound of formula
(14) in a polar aprotic solvent, such as dimethyl formamide, at
ambient temperature. The reaction mixture is heated to a
temperature of between about ambient temperature and about
60.degree. C. for a period of time of between about 2 hours and 16
hours. The reaction mixture is then cooled to a temperature of
between about 0.degree. C. and 5.degree. C. and quenched with the
addition of water. Alternatively, the cooled reaction mixture is
used in the next step without quenching the reaction with water.
The resulting compound of formula (15) is then isolated from the
reaction mixture by standard isolation techniques, such as
precipitation, filtration, water wash and evaporation of
solvent.
[0205] The compound of formula (15) so formed is then treated with
a slightly excess molar amount of an intermediate Grignard addition
product prepared by treating a compound of formula (4) in an polar
aprotic solvent, such as tetrahydrofuran or dioxane and
dimethoxyethane, with a Grignard reagent of formula (5), such as
isopropylmagnesium chloride, in a polar aprotic solvent, such as
tetrahydrofuran, dioxane, or ether, under suitable Grignard
reaction conditions, such as at a temperature of between about
0.degree. C. and about 25.degree. C., to provide a compound of
formula (16), which is isolated from the reaction mixture by
standard isolation techniques, such as extraction, filtrate and
concentration.
[0206] The compound of formula (16) in an polar aprotic solvent,
such as dimethylformamide or acetonitrile, in the presence of a
base, such as cesium carbonate or potassium carbonate, is then
treated with a slightly excess molar amount of a compound of
formula (7) where Pg.sup.1 is an oxygen protecting group,
preferably benzyl, under suitable oxygen protecting conditions
(i.e., the protecting step), such as ambient temperature for a
period of time of between about 2 hours and about 16 hours or for a
period of time of about 90 hours. The resulting compound of formula
(17) is isolated from the reaction mixture by standard techniques,
such as precipitation and filtration.
[0207] The removal of the hydroxyl group at the C3 position of the
oxindole ring (i.e., the dehydroxylation step) in the compound of
formula (17) is achieved by treating the compound of formula (17)
in a polar aprotic solvent, such as dichloromethane, dichloroethane
or without any solvent under suitable conditions, such as treatment
with a silane reagent, such as triethylsilane or triphenylsilane,
in the presence of an acid, such as, but not limited to,
trifluoroacetic acid or acetic acid, to yield the compound of
formula (18), which is isolated from the reaction mixture by
standard isolation techniques, such as concentration and
extraction.
[0208] The compound of formula (19) is prepared by asymmetric phase
transfer-catalyzed C-alkylation wherein a mixture of a phase
transfer catalyst in less than equimolar amount, preferably less
than 20%, such as a quaternary ammonium salt of quinidine or
cinchonine, preferably a quaternary ammonium salt of cinchonine,
and excess of an aqueous solution of a base, such as potassium
hydroxide, sodium hydroxide, lithium hydroxide or cesium hydroxide,
preferably potassium hydroxide and a non-polar solvent, such as
toluene, is cooled to a temperature of between about -25.degree. C.
and about 25.degree. C. To this mixture is added a solution of a
compound of formula (18) and an excess molar amount of a compound
of formula (10), preferably where Pg.sup.2 is an oxygen protecting
group, preferably benzyl, in an non-polar/polar aprotic solvent
mixture, preferably 1:1, such as toluene/tetrahydrofuran, over a
period of time of between about 5 minutes to about 2 hours with
stirring. The compound of formula (19) is isolated from the
reaction mixture by standard isolation conditions, such as
extraction with organic solvent, such as ethyl acetate, followed by
acid wash, concentration, and filtration as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%.
[0209] A quaternary ammonium salt of cinchonine can be prepared by
refluxing a suspension of cinchonine and a suitable alkyl halide
such as but not limited to, 9-chloromethylanthracene or
1-bromomethylnaphthalene, in a suitable solvent, such as but not
limited to, anhydrous toluene or tetrahydrofuran. The product is
isolated by filtration or by means of crystallization using a
suitable solvent such as but not limited to diethyl ether or
methanol (E. J. Corey and M. C. Noe, Org. Synth. 2003;
80:38-45).
[0210] The compound of formula (19) is then deprotected under
suitable deprotection (reduction) conditions, such as treating a
mixture of the compound of formula (19), a suitable metal catalyst
such as, but not limited to, 10% palladium on carbon or palladium
(II) hydroxide and a weak acid, such as acetic acid, formic acid,
or trifluoroacetic acid, in a protic/polar aprotic solvent mixture,
such as a mixture of a lower alkanol, such as ethanol or methanol,
in tetrahydrofuran or ethyl acetate, preferably a 1:1 mixture of
ethanol and tetrahydrofuran, with a silane reagent, such as
triethylsilane or triphenylsilane, in a protic/polar aprotic
solvent, such as tetrahydrofuran, ethyl acetate, ethanol, methanol,
at ambient temperature, or with hydrogen gas at atmospheric
pressure or at 15 psi. The resulting compound of formula (20) is
isolated from the reaction mixture by standard isolation
techniques, such as filtration and concentration as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%.
[0211] Intramolecular cyclization of a compound of formula (20) to
provide a compound of formula (21) is achieved by treating a
compound of formula (20) to suitable Mitsunobu reaction conditions,
such as the employment of a phosphine reagent, preferably, but not
limited to, triphenylphosphine, tributylphosphine,
2-(diphenylphosphino)pyridine, 4-(diphenylphosphino)dimethylaniline
and 4-(N,N-dimethylamino)phenyldiphenylphosphine, and an
azodicarboxylate ester, such as, but not limited to,
diethylazodicarboxylate, diisopropylazodicarboxylate,
di-tert-butylazodicarboxylate, di-n-butylazodicarboxylate or
tetramethyldiazenedicarboxamide, in a polar aprotic solvent,
preferably, but not limited to, tetrahydrofuran, dichloromethane or
ethyl acetate. The resulting compound of formula (21) is isolated
from the reaction mixture by standard isolation techniques, such as
extraction, acid wash, filtration and concentration as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%.
[0212] The compound of formula (21) is the deprotected under
suitable deprotection conditions, such as treating the compound of
formula (21) with a silane reagent, such as triethylsilane, in the
presence of an acid, such as trifluoroacetic acid, and heating the
reaction mixture at reflux for a period of time of between about 30
minutes and 3 hours. The reaction mixture is then cooled to ambient
temperature and concentrated.
[0213] The compound of formula (22) is then isolated from the
concentrate by standard isolation techniques, such as extraction
and concentration as an isolated (S)-enantiomer, or a non-racemic
mixture of enantiomers having an enantiomeric excess of the
(S)-enantiomer of greater than 80%, preferably greater than 90%,
more preferably greater than 95%, most preferably greater than
99%.
[0214] The compound of formula (22) in a polar aprotic solvent,
such as dimethylformamide, in the presence of a base, such as
cesium carbonate, is treated with an excess molar amount of a
compound of formula (2), or a pharmaceutically acceptable salt
thereof. The resulting reaction mixture is heated to a temperature
of between about 50.degree. C. and 100.degree. C., preferably to
about 80.degree. C., for a period of time of between about 30
minutes and about 3 hours. The reaction mixture is then cooled to
ambient temperature and the compound of formula (I) is then
isolated from the reaction mixture by standard isolation
techniques, such as filtration, extraction, concentration and
purification by column chromatography as an isolated
(S)-enantiomer, or a non-racemic mixture of enantiomers having an
enantiomeric excess of the (S)-enantiomer of greater than 80%,
preferably greater than 90%, more preferably greater than 95%, most
preferably greater than 99%.
[0215] A specific method of preparing the compounds of formula (I)
as set forth above in Reaction Scheme 2 is illustrated below in
Reaction Scheme 2A for the preparation of compounds of formula
(Ia), where p, R.sup.1 and R.sup.2 are as defined above for the
compounds of formula (I), as described in the Summary of the
Invention, q is 1 or 2, each X is independently halo, typically
iodo, bromo or chloro, preferably bromo or chloro, except for the
Grignard reagent of formula (5) wherein X is iodo, bromo or chloro,
preferably bromo or chloro, R is alkyl, and Pg.sup.1 and Pg.sup.2
are each independently an oxygen protecting group, such as
hydrogen, benzyl, alkyl, tert-butyldiphenylsilyl or triphenylsilyl,
and Pg.sup.3 is a nitrogen protecting group, such as benzhydryl
(diphenylmethyl):
##STR00138## ##STR00139##
[0216] Compounds of formulae (1a) and (4a) are commercially
available, or can be prepared according to methods known to one
skilled in the art or by the methods disclosed in PCT Published
Patent Application No. WO 2006/110917, PCT Published Patent
Application No. WO 2010/45251, PCT Published Patent Application No.
WO 2010/045197, PCT Published Patent Application No. WO 2011/047174
and PCT Published Patent Application No. WO 2011/002708.
[0217] A more specific method of preparing the compounds of formula
(I) as set forth above in Reaction Scheme 2A is illustrated below
in Reaction Scheme 2A1 for the preparation of compounds of formula
(Ia1), where each X is independently halo, typically iodo, bromo or
chloro, preferably bromo or chloro, except for the Grignard reagent
of formula (5) wherein X is iodo, bromo or chloro, preferably bromo
or chloro, R is alkyl, and Pg.sup.1 and Pg.sup.2 are each
independently an oxygen protecting group, preferably benzyl and
Pg.sup.3 is a nitrogen protecting group, preferably benzhydryl
(diphenylmethyl):
##STR00140## ##STR00141##
[0218] The compounds of formulae (2a) and (4a1) are commercially
available, or can be prepared according to methods known to one
skilled in the art or by the methods disclosed in PCT Published
Patent Application No. WO 2006/110917, PCT Published Patent
Application No. WO 2010/45251, PCT Published Patent Application No.
WO 2010/045197, PCT Published Patent Application No. WO 2011/047174
and PCT Published Patent Application No. WO 2011/002708. The
cinchonium phase transfer catalyst can be prepared according to
methods known to one skilled in the art or by methods disclosed
herein.
[0219] Another more specific method of preparing the compounds of
formula (I) as set forth above in Reaction Scheme 2A is illustrated
below in Reaction Scheme 2A2 for the preparation of compounds of
formula (Ia2), where each X is independently halo, typically iodo,
bromo or chloro, preferably bromo or chloro, except for the
Grignard reagent of formula (5) wherein X is iodo, bromo or chloro,
preferably bromo or chloro, R is alkyl, and Pg.sup.1 and Pg.sup.2
are each independently an oxygen protecting group, preferably
benzyl and Pg.sup.3 is a nitrogen protecting group, preferably
benzhydryl (diphenylmethyl):
##STR00142## ##STR00143##
[0220] The compounds of formulae (2b) and (4a2) are commercially
available, or can be prepared according to methods known to one
skilled in the art or by the methods disclosed in PCT Published
Patent Application No. WO 2006/110917, PCT Published Patent
Application No. WO 2010/45251, PCT Published Patent Application No.
WO 2010/045197, PCT Published Patent Application No. WO 2011/047174
and PCT Published Patent Application No. WO 2011/002708.
[0221] Several of the steps disclosed in the above Reaction Schemes
may be combined. For example, the steps from compound of formula
(15a) to the formation of compound of formula (18a) and/or the
steps from compound of formula (16a) to the formation of the
compound of formula (19a) can be combined. Furthermore, the steps
from compound of formula (18a) to the formation of the compound of
formula (Ia1) can be combined; however, such combination requires
flash column chromatography for purification of the product.
[0222] All of the compounds described above and below as being
prepared which may exist in free base or acid form may be converted
to their pharmaceutically acceptable salts by treatment with the
appropriate inorganic or organic base or acid by methods known to
one skilled in the art. Salts of the compounds prepared below may
be converted to their free base or acid form by standard
techniques. It is understood that all salts of the compounds of the
invention are intended to be within the scope of the invention.
Furthermore, all compounds of the invention which contain an acid
or an ester group can be converted to the corresponding ester or
acid, respectively, by methods known to one skilled in the art or
by methods described herein.
[0223] The following Examples, which are directed to the
preparation of the intermediates, starting materials and/or
compounds of the invention are provided as a guide to assist in the
practice of the invention, and are not intended as a limitation on
the scope of the invention.
Example 1
Synthesis of
1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione
Compound of formula (3a1)
##STR00144##
[0225] A. A nitrogen-flushed 10 L reactor was charged with cesium
carbonate (1330 g, 4080 mmol) and acetonitrile (4500 mL). To this
stirred mixture was added isatin (500 g, 3400 mmol) followed by
2-(bromomethyl)-5-(trifluoromethyl)furan (983 mL, 4080 mmol). The
stirred mixture was heated to 28.degree. C. for 16 h and was then
filtered and concentrated in vacuo. The resulting material was
dissolved in N,N-dimethylformamide to which water was added. The
suspension was filtered to afford
1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione (953
g) as an orange solid in quantitative yield.
[0226] B. Alternatively, to a solution of isatin (5.0 g, 34 mmol)
in N,N-dimethylformamide (100 mL) was added
2-(bromomethyl)-5-(trifluoromethyl)furan (5.2 mL, 38 mmol) and
anhydrous potassium carbonate (11.7 g, 85 mmol) while stirring
under a nitrogen atmosphere at ambient temperature. After 1.5 h,
the reaction mixture was filtered and the filtrate was poured into
water (1350 mL) with vigorous stirring. The solid was filtered and
washed with water to obtain
1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione (10.0
g) as an orange solid in quantitative yield: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.66-7.59 (m, 2H), 7.19-7.14 (m, 1H), 7.05 (d,
J=7.9 Hz, 1H), 6.76-6.75 (m, 1H), 6.46 (d, J=3.4 Hz, 1H), 4.94 (s,
2H); MS (ES+) m/z 295.9 (M+1).
Example 2
Synthesis of
3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)furan-
-2-yl]methyl}-1,3-dihydro-2H-indol-2-one Compound of formula
(6a1)
##STR00145##
[0228] To a cooled (0.degree. C.) solution of sesamol (87.7 g, 635
mmol) in tetrahydrofuran (750 mL) was added dropwise a 2.0 M
solution of isopropylmagnesium chloride in tetrahydrofuran (265 mL,
530 mmol). The mixture was stirred for 30 minutes at 0.degree. C.
and a solution of
1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione (125
g, 423 mmol) in tetrahydrofuran (450 mL) was added via dropping
funnel. The mixture was stirred at 0.degree. C. for 40 minutes,
allowed to warm to ambient temperature, stirred for 16 h and
diluted with ethyl acetate (300 mL). The mixture was washed with
saturated aqueous ammonium chloride (3.times.300 mL) and brine
(3.times.300 mL), dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated in vacuo to dryness and the residue
triturated in diethyl ether to afford
3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)furan-
-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (162 g) as a colorless
solid in 88% yield: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.91
(s, 1H), 7.49 (d, 1H), 7.43-7.38 (m, 1H), 7.24-7.19 (m, 1H), 7.01
(d, J=7.8 Hz, 1H), 6.71-6.70 (m, 1H), 6.57 (s, 1H), 6.33-6.32 (m,
1H), 6.26 (s, 1H), 5.88-5.86 (m, 2H), 4.90 (q, J=16.3 Hz, 2H), 4.43
(s, 1H); MS (ES-) m/z 431.8 (M-1).
Example 3
Synthesis of
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-hydroxy-1-{[5-(trifluoromethyl)f-
uran-2-yl]methyl}-1,3-dihydro-2H-indol-2-one Compound of formula
(8a1)
##STR00146##
[0230] To a cooled (0.degree. C.) mixture of
3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)furan-
-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (105 g, 242 mmol) and
potassium carbonate (67.4 g, 488 mmol) in anhydrous
N,N-dimethylformamide (500 mL) was added benzyl bromide (35 mL, 290
mmol) dropwise over 30 minutes. The mixture was allowed to warm to
ambient temperature, stirred for 22 h and poured into ice-cold
water (2500 mL) with vigorous stirring. The resulting suspension
was filtered and the colorless solid washed with water (3000 mL)
and hexanes (1000 mL), re-suspended in water (2000 mL) and stirred
for 3 days. The suspension was filtered and washed with water (1500
mL) to afford
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-hydroxy-1-{[5-(trifluoromethyl)f-
uran-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (125 g) as a colorless
solid in 99% yield: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.40
(s, 1H), 7.32-7.23 (m, 4H), 7.08-6.93 (m, 4H), 6.65 (d, J=7.8 Hz,
1H), 6.57-6.56 (m, 1H), 6.44 (s, 1H), 6.18-6.16 (m, 1H), 5.93 (s,
2H), 4.64-4.53 (m, 3H), 3.65-3.60 (m, 2H); MS (ES+) m/z 505.8
(M-18).
Example 4
Synthesis of
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-{[5-(trifluoromethyl)furan-2-yl]-
methyl}-1,3-dihydro-2H-indol-2-one Compound of formula (9a1)
##STR00147##
[0232] To a cooled (0.degree. C.) solution of
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-hydroxy-1-{[5-(trifluoromethyl)f-
uran-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (58.0 g, 111 mmol) in
dichloromethane (350 mL) was added triethylsilane (150 mL) and
trifluoroacetic acid (300 mL). The solution was allowed to warm to
ambient temperature, stirred for 17 h and concentrated in vacuo.
The residue was triturated in diethyl ether (100 mL) to afford
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-{[5-(trifluoromethyl)furan-2-yl]-
methyl}-1,3-dihydro-2H-indol-2-one (33.4 g) as a colorless solid in
59% yield: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.29-7.20 (m,
4H), 7.04-6.97 (m, 4H), 6.75 (d, J=7.8 Hz, 1H), 6.66 (s, 1H),
6.62-6.61 (m, 1H), 6.55 (s, 1H), 6.21-6.20 (m, 1H), 5.91-5.90 (m,
2H), 4.84-4.65 (m, 4H), 4.21-4.13 (m, 1H); MS (ES+) m/z 507.8
(M+1).
Example 5
Synthesis of (9S)-1-(anthracen-9-ylmethyl)cinchonan-1-ium-9-ol
chloride (Phase-transfer catalyst)
##STR00148##
[0234] A. A suspension of cinchonine (31.3 g, 106 mmol) and
9-chloromethylanthracene (25.3 g, 112 mmol) in anhydrous toluene
(320 mL) in a foil-wrapped flask was heated at reflux for 3.5 h.
The reaction was allowed to cool to ambient temperature and diethyl
ether (400 mL) was added. The suspension was cooled to 10.degree.
C. and the resulting precipitate was filtered and washed with
diethyl ether/toluene (1:1 v/v, 200 mL), followed by diethyl ether
(200 mL). The solid was heated at reflux in ethanol (400 mL) along
with decolorizing charcoal (46 g) for 1 h. The warm solution was
filtered through a pad of diatomaceous earth and the pad was rinsed
with ethanol (150 mL). A solid crystallized upon cooling to ambient
temperature. The solid was collected by filtration to afford
(9S)-1-(anthracen-9-ylmethyl)cinchonan-1-ium-9-ol chloride (27.2 g)
as a pale yellow solid in 49% yield. The filtrate was concentrated
to a volume of 70 mL, inducing the formation of a further crop of
crystals that were filtered to afford a further crop of
(9S)-1-(anthracen-9-ylmethyl)cinchonan-1-ium-9-ol chloride (5.6 g)
in 10% yield: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.29 (d,
J=8.8 Hz, 1H), 8.93 (d, J=8.4 Hz, 1H), 8.87-8.86 (m, 1H), 8.42 (d,
J=9.0 Hz, 1H), 8.27 (s, 1H), 8.06 (d, J=4.4 Hz, 1H), 7.86 (s, 1H),
7.60-7.54 (m, 2H), 7.46 (d, J=8.3 Hz, 1H), 7.33-6.91 (m, 7H), 6.49
(d, J=13.3 Hz, 1H), 5.64-5.53 (m, 1H), 5.03 (d, J=10.5 Hz, 1H),
4.87 (d, J=17.2 Hz, 1H), 4.76-4.68 (m, 1H), 4.46-4.40 (m, 1H),
4.28-4.20 (m, 1H), 2.51-2.44 (m, 1H), 2.37-2.27 (m, 1H), 1.99-1.65
(m, 4H), 1.52 (br s, 1H), 1.41-1.33 (m, 1H), 0.67-0.60 (m, 1H); MS
(ES+) m/z 484.9 (M-35).
[0235] B. Alternatively, a mixture of cinchonine (130 g, 442 mmol),
9-chloromethylanthracene (157 g, 663 mmol) and anhydrous toluene
(1.4 L) was heated at reflux under nitrogen atmosphere for 18 h and
was allowed to cool to ambient temperature. Methyl tert-butyl ether
(1.9 L) was added and the mixture was stirred at 15-25.degree. C.
for 0.5 h, during which time a solid was deposited. The solid was
collected by filtration, washed with toluene (100 mL) and dried in
vacuo below 60.degree. C. for 12 h to afford
(9S)-1-(anthracen-9-ylmethyl)cinchonan-1-ium-9-ol chloride (156 g)
as a colorless solid in 67% yield: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.29 (d, 1H), 8.93 (d, 1H), 8.86 (d, 1H), 8.42
(d, 1H), 8.27 (s, 1H), 8.06 (d, 1H), 7.86 (s, 1H), 7.57 (t, 2H),
7.46 (d, 1H), 7.33-6.91 (m, 7H), 6.49 (d, 1H), 5.58 (ddd, 1H), 5.03
(d, 1H), 4.87 (d, 1H), 4.76-4.68 (m, 1H), 4.43 (t, 1H), 4.24 (t,
1H), 2.48 (t, 1H), 2.37-2.27 (m, 1H), 1.99-1.65 (m, 4H), 1.52 (br
s, 1H), 1.41-1.33 (m, 1H), 0.67-0.60 (m, 1H); MS (ES+) m/z 484.9 (M
-35).
Example 6
Synthesis of
(3S)-3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-{[5-(-
trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one
Compound of formula (12a1)
##STR00149##
[0237] A. A mixture of 50% w/w aqueous potassium hydroxide (73 mL,
650 mmol), toluene (250 mL) and
(9S)-1-(anthracen-9-ylmethyl)cinchonan-1-ium-9-ol chloride (1.04 g,
2.00 mmol) was degassed with nitrogen and cooled in an ice/salt
bath to an internal temperature of -10.degree. C. To this mixture
was added a solution of
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-{[5-(trifluoromethyl)furan-2-yl]-
methyl}-1,3-dihydro-2H-indol-2-one (10.1 g, 19.9 mmol) and benzyl
chloromethyl ether (3.6 mL, 26 mmol) in degassed toluene (110 mL)
dropwise via syringe pump over 1.5 h. The mixture was stirred for a
further 0.5 h, diluted with ethyl acetate (100 mL) and the phases
were separated. The organic phase was washed with 1 N hydrochloric
acid (3.times.150 mL) and brine (2.times.150 mL), dried over sodium
sulfate and filtered. The filtrate was concentrated in vacuo to
afford gummy material which was then filtered through a pad of
silica gel. The pad was washed with hexanes/ethyl acetate (1:1 v/v,
300 mL). The filtrate was concentrated in vacuo and the residue was
triturated in a mixture of diethyl ether and hexanes to afford
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-{[5-(trifl-
uoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one as a
colorless solid. A second crop of
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-{[5-(trifl-
uoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one was
obtained from the filtrate by concentrating in vacuo to dryness and
triturating the residue in a mixture of diethyl ether and hexanes
to afford
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-{[5-(trifl-
uoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one as a
colorless solid. The combined solids were dissolved in ethanol (120
mL), heated at reflux and the resultant solution was allowed to
cool to ambient temperature. To this solution was added a seed
crystal of racemic
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-{[5-(trifl-
uoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one and the
mixture was allowed to stand at ambient temperature for 24 h. The
crystals were removed by filtration and the filtrate was
concentrated in vacuo to afford
(3S)-3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]--
1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one
(9.50 g, >99.5% ee) as a colorless solid in 66% yield. The solid
was recrystallized a second time via the above procedure to afford
a further crop of
(3S)-3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-
-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one
(1.70 g, >99.5% ee) as a colorless solid in 14% yield.
[0238] B. Alternatively, a mixture of 50% w/w aqueous potassium
hydroxide (146 mL, 1300 mmol), toluene (500 mL), and
(9S)-1-(anthracen-9-ylmethyl)cinchonan-1-ium-9-ol chloride (0.51 g,
0.98 mmol) was degassed with nitrogen and cooled in an ice/salt
bath to an internal temperature of -18.degree. C. To this mixture
was added a solution of
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-{[5-(trifluoromethyl)furan-2-yl]-
methyl}-1,3-dihydro-2H-indol-2-one (20.0 g, 39.4 mmol) and benzyl
chloromethyl ether (6.0 mL, 43 mmol) in degassed toluene (220 mL)
dropwise via syringe pump over 2 h. The mixture was stirred for a
further 15 minutes, diluted with ethyl acetate (250 mL) and the
phases were separated. The organic phase was washed with 1 N
hydrochloric acid (3.times.200 mL) and brine (3.times.250 mL),
dried over sodium sulfate and filtered. The filtrate was
concentrated in vacuo. The residue was dissolved in ethanol (285
mL), decolorizing charcoal (21 g) was added and the mixture was
heated at reflux for 1 h. The mixture was filtered while hot
through a pad of diatomaceous earth. The filtrate was concentrated
in vacuo and the residue was dissolved in ethanol (300 mL). The
mixture was heated at reflux and was allowed to cool to ambient
temperature. To this solution was added a seed crystal of racemic
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-{[5-(trifl-
uoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one and the
mixture was allowed to stand at ambient temperature for 24 h. The
crystals were removed by filtration and the filtrate was
concentrated in vacuo to dryness. The residue was triturated in
diethyl ether to afford
(3S)-3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-{[5-(-
trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (17.0
g) as a colorless solid in 69% yield: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.36-7.26 (m, 4H), 7.21-7.15 (m, 4H), 7.01-6.97
(m, 4H), 6.89-6.86 (m, 2H), 6.46-6.43 (m, 2H), 6.35-6.34 (m, 1H),
5.93-5.88 (m, 3H), 4.77 (d, J=16.9 Hz, 1H), 4.57 (d, J=10.6 Hz,
1H), 4.44 (d, J=10.5 Hz, 1H), 4.38 (q, J=12.1 Hz, 2H), 4.06 (dd,
J=8.4, 19.7 Hz, 2H), 3.34 (d, J=16.9 Hz, 1H); MS (ES+) m/z 627.8
(M+1); ee (enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5%
acetonitrile in methyl tert-butyl ether).
Example 7
Synthesis of
(3S)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluor-
omethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one Compound of
formula (13a1)
##STR00150##
[0240] To a mixture of
(3S)-3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-{[5-(-
trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (10.3
g, 16.4 mmol), 10% w/w palladium on carbon, 50% wetted powder (4.0
g, 1.9 mmol) and acetic acid (4.7 mL, 82 mmol) in a 1:1 v/v
degassed mixture of ethanol/tetrahydrofuran (170 mL) was added a
solution of triethylsilane (5.9 mL, 37 mmol) in degassed
tetrahydrofuran (50 mL) at ambient temperature dropwise via syringe
pump over 75 minutes. After stirring at ambient temperature for a
further 2.5 h, further triethylsilane (0.26 mL, 1.6 mmol) in
tetrahydrofuran (5 mL) was added over 15 minutes. The mixture was
stirred for a further 3.5 h at ambient temperature and the mixture
filtered through a pad of diatomaceous earth and the pad was rinsed
with ethyl acetate (100 mL) and the filtrate was concentrated in
vacuo to afford
(3S)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluor-
omethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one as a
colorless solid that was carried forward without further
purification: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.79 (s,
1H), 7.44-7.37 (m, 2H), 7.30-7.24 (m, 1H), 7.02 (d, J=7.8 Hz, 1H),
6.69-6.68 (m, 1H), 6.57 (s, 1H), 6.54 (s, 1H), 6.30-6.29 (m, 1H),
5.88-5.84 (m, 2H), 4.96 (q, J=16.5 Hz, 2H), 4.76 (dd, J=8.8, 10.8
Hz, 1H), 4.15-4.08 (m, 1H), 1.83-1.79 (m, 1H); MS (ES+) m/z 447.8
(M+1).
Example 8
Synthesis of
(7S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benz-
odioxole-7,3'-indol]-2'(1'H)-one Compound of formula (Ia1)
##STR00151##
[0242] To a cooled (0.degree. C.) solution of
(3S)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluor-
omethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one prepared
according to the procedure described in Example 7 (16.4 mmol) and
2-(diphenylphosphino)pyridine (5.2 g, 20 mmol) in anhydrous
tetrahydrofuran (170 mL) was added di-tert-butylazodicarboxylate
(4.5 g, 20 mmol). The mixture was stirred for 2 h at 0.degree. C.,
then the reaction was diluted with ethyl acetate (170 mL), washed
with 3 N hydrochloric acid (7.times.50 mL) and brine (2.times.100
mL), dried over anhydrous sodium sulfate, filtered and concentrated
in vacuo. The residue was dissolved in ethanol (80 mL),
decolorizing charcoal (15 g) was added and the mixture was heated
at reflux for 1 h. The mixture was filtered while hot through a pad
of diatomaceous earth. The filtrate was concentrated in vacuo and
the residue triturated in a mixture of diethyl ether/hexanes to
afford
(7S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro-[furo[2,3-f][1,3]ben-
zodioxole-7,3'-indol]-2'(1'H)-one (1.30 g) as a colorless solid in
18% yield. The mother liquor from the trituration was concentrated
in vacuo, trifluoroacetic acid (20 mL) was added and the mixture
stirred for 3 h at ambient temperature. The mixture was diluted
with ethyl acetate (100 mL), washed with saturated aqueous ammonium
chloride (100 mL), 3 N hydrochloric acid (4.times.60 mL) and brine
(2.times.100 mL), dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by column
chromatography, eluting with a gradient of ethyl acetate in hexanes
to afford further
(7S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro-[furo[2,3-f][1,3]ben-
zodioxole-7,3'-indol]-2'(1'H)-one (2.6 g) as a colorless solid (37%
yield, overall yield 55% over 2 steps): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.29-6.96 (m, 4H), 6.73 (s, 1H), 6.50 (s, 1H),
6.38 (s, 1H), 6.09 (s, 1H), 5.85 (br s, 2H), 5.06 (d, J=16.0 Hz,
1H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1H); MS (ES+) m/z 429.8
(M+1); ee (enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5%
acetonitrile in methyl tert-butyl ether).
Example 9
Synthesis of 1-(diphenylmethyl)-1H-indole-2,3-dione Compound of
formula (15a)
##STR00152##
[0244] A. To a suspension of hexanes-washed sodium hydride (34.0 g,
849 mmol) in anhydrous N,N-dimethylformamide (400 mL) at 0.degree.
C. was added a solution of isatin (99.8 g, 678 mmol) in anhydrous
N,N-dimethylformamide (400 mL) dropwise over 30 minutes. The
reaction mixture was stirred for 1 h at 0.degree. C. and a solution
of benzhydryl bromide (185 g, 745 mmol) in anhydrous
N,N-dimethylformamide (100 mL) was added dropwise over 15 minutes.
The reaction mixture was allowed to warm to ambient temperature,
stirred for 16 h and heated at 60.degree. C. for 2 h. The mixture
was cooled to 0.degree. C. and water (500 mL) was added. The
mixture was poured into water (2 L), causing a precipitate to be
deposited. The solid was collected by suction filtration and washed
with water (2000 mL) to afford
1-(diphenylmethyl)-1H-indole-2,3-dione (164 g) as an orange solid
in 77% yield.
[0245] B. Alternatively, to a mixture of isatin (40.0 g, 272 mmol),
cesium carbonate (177 g, 543 mmol) and N,N-dimethylformamide (270
mL) at 80.degree. C. was added dropwise a solution of benzhydryl
bromide (149 g, 544 mmol) in N,N-dimethylformamide (200 mL) over 30
minutes. The reaction mixture was heated at 80.degree. C. for 3 h,
allowed to cool to ambient temperature and filtered through a pad
of diatomaceous earth. The pad was rinsed with ethyl acetate (1000
mL). The filtrate was washed with saturated aqueous ammonium
chloride (4.times.200 mL), 1 N hydrochloric acid (200 mL) and brine
(4.times.200 mL), dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The residue was triturated with diethyl
ether to afford 1-(diphenylmethyl)-1H-indole-2,3-dione (59.1 g) as
an orange solid in 69% yield. The mother liquor from the
trituration was concentrated in vacuo and the residue triturated in
diethyl ether to afford a further portion of
1-(diphenylmethyl)-1H-indole-2,3-dione (8.2 g) in 10% yield:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.60 (d, J=7.4 Hz, 1H),
7.34-7.24 (m, 11H), 7.05-6.97 (m, 2H), 6.48 (d, J=8.0 Hz, 1H); MS
(ES+) m/z 313.9 (M+1).
[0246] C. Alternatively, a mixture of isatin (500 g, 3.4 mol) and
anhydrous N,N-dimethylformamide (3.5 L) was stirred at
15-35.degree. C. for 0.5 h. Cesium carbonate (2.2 kg, 6.8 mol) was
added and the mixture stirred at 55-60.degree. C. for 1 h. A
solution of benzhydryl bromide (1.26 kg, 5.1 mol) in anhydrous
N,N-dimethylformamide (1.5 L) was added and the resultant mixture
stirred at 80-85.degree. C. for 1 h, allowed to cool to ambient
temperature and filtered. The filter cake was washed with ethyl
acetate (12.5 L). To the combined filtrate and washes was added 1 N
hydrochloric acid (5 L). The phases were separated and the aqueous
phase was extracted with ethyl acetate (2.5 L). The combined
organic extracts were washed with 1 N hydrochloric acid
(2.times.2.5 L) and brine (3.times.2.5 L) and concentrated in vacuo
to a volume of approximately 750 mL. Methyl tert-butyl ether (2 L)
was added and the mixture was cooled to 5-15.degree. C., causing a
solid to be deposited. The solid was collected by filtration,
washed with methyl tert-butyl ether (250 mL) and dried in vacuo at
50-55.degree. C. for 16 h to afford
1-(diphenylmethyl)-1H-indole-2,3-dione (715 g) as an orange solid
in 67% yield: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.60 (d,
J=7.4 Hz, 1H), 7.34-7.24 (m, 11H), 7.05-6.97 (m, 2H), 6.48 (d,
J=8.0 Hz, 1H); MS (ES+) m/z 313.9 (M+1).
Example 10
Synthesis of
1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihyd-
ro-2H-indol-2-one Compound of formula (16a1)
##STR00153##
[0248] A. To a solution of sesamol (33.1 g, 239 mmol) in anhydrous
tetrahydrofuran (500 mL) at 0.degree. C. was added dropwise a 2 M
solution of isopropylmagnesium chloride in tetrahydrofuran (104 mL,
208 mmol), followed by 1-(diphenylmethyl)-1H-indole-2,3-dione (50.0
g, 160 mmol) and tetrahydrofuran (100 mL). The reaction mixture was
stirred at ambient temperature for 5 h, diluted with ethyl acetate
(1500 mL), washed with saturated aqueous ammonium chloride (400 mL)
and brine (2.times.400 mL), dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. The residue was triturated with
a mixture of diethyl ether and hexanes to afford
1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihyd-
ro-2H-indol-2-one (70.7 g) as a colorless solid in 98% yield:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.12 (br s, 1H),
7.45-7.43 (m, 1H), 7.30-7.22 (m, 10H), 7.09-7.07 (m, 2H), 6.89 (s,
1H), 6.56-6.55 (m, 1H), 6.47-6.46 (m, 1H), 6.29-6.28 (m, 1H), 5.86
(s, 2H), 4.52 (br s, 1H); MS (ES+) m/z 433.7 (M-17).
[0249] B. Alternatively, a mixture of sesamol (0.99 kg, 7.2 mol)
and anhydrous tetrahydrofuran (18 L) was stirred at 15-35.degree.
C. for 0.5 h and cooled to -5-0.degree. C. Isopropyl magnesium
chloride (2.0 M solution in tetrahydrofuran, 3.1 L, 6.2 mol) was
added, followed by 1-(diphenylmethyl)-1H-indole-2,3-dione (1.50 kg,
4.8 mol) and further anhydrous tetrahydrofuran (3 L). The mixture
was stirred at 15-25.degree. C. for 5 h. Ethyl acetate (45 L) and
saturated aqueous ammonium chloride (15 L) were added. The mixture
was stirred at 15-25.degree. C. for 0.5 h and was allowed to settle
for 0.5 h. The phases were separated and the organic phase was
washed with brine (2.3 L) and concentrated in vacuo to a volume of
approximately 4 L. Methyl tert-butyl ether (9 L) was added and the
mixture concentrated in vacuo to a volume of approximately 4 L.
Heptane (6 L) was added and the mixture was stirred at
15-25.degree. C. for 2 h, causing a solid to be deposited. The
solid was collected by filtration, washed with methyl tert-butyl
ether (0.3 L) and dried in vacuo at 50-55.degree. C. for 7 h to
afford
1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihyd-
ro-2H-indol-2-one (2.12 kg) as an off-white solid in 98% yield:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.12 (br s, 1H),
7.45-7.43 (m, 1H), 7.30-7.22 (m, 10H), 7.09-7.07 (m, 2H), 6.89 (s,
1H), 6.56-6.55 (m, 1H), 6.47-6.46 (m, 1H), 6.29-6.28 (m, 1H), 5.86
(s, 2H), 4.52 (br s, 1H); MS (ES+) m/z 433.7 (M-17).
Example 11
Synthesis of
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1,3-d-
ihydro-2H-indol-2-one Compound of formula (17a1)
##STR00154##
[0251] A. A mixture of
1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihyd-
ro-2H-indol-2-one (30.0 g, 66.5 mmol), benzyl bromide (8.3 mL, 70
mmol), and potassium carbonate (18.4 g, 133 mmol) in anhydrous
N,N-dimethylformamide (100 mL) was stirred at ambient temperature
for 16 h. The reaction mixture was filtered and the solid was
washed with N,N-dimethylformamide (100 mL). The filtrate was poured
into water (1000 mL) and the resulting precipitate was collected by
suction filtration and washed with water to afford
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1,3-d-
ihydro-2H-indol-2-one (32.0 g) as a beige solid in 83% yield:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.42-7.28 (m, 9H),
7.22-7.14 (m, 6H), 7.10-6.93 (m, 3H), 6.89-6.87 (m, 2H), 6.53 (d,
J=7.6 Hz, 1H), 6.29 (br s, 1H), 5.88 (s, 1H), 5.85 (s, 1H), 4.66
(d, J=14.2 Hz, 1H), 4.51 (d, J=14.1 Hz, 1H), 3.95 (s, 1H); MS (ES+)
m/z 542.0 (M+1), 523.9 (M-17).
[0252] B. Alternatively, to a solution of
1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihyd-
ro-2H-indol-2-one (2.1 kg, 4.6 mol) in anhydrous
N,N-dimethylformamide (8.4 L) at 20-30.degree. C. was added
potassium carbonate (1.3 kg, 9.2 mol), followed by benzyl bromide
(0.58 L, 4.8 mol). The mixture was stirred at 20-30.degree. C. for
80 h and filtered. The filter cake was washed with
N,N-dimethylformamide (0.4 L) and the filtrate was poured into
water (75 L), causing a solid to be deposited. The mixture was
stirred at 15-25.degree. C. for 7 h. The solid was collected by
filtration, washed with water (2 L) and dried in vacuo at
50-60.degree. C. for 48 h to afford
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1,3-d-
ihydro-2H-indol-2-one (2.11 kg) as an off-white solid in 84% yield:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.42-7.28 (m, 9H),
7.22-7.14 (m, 6H), 7.10-6.93 (m, 3H), 6.89-6.87 (m, 2H), 6.53 (d,
J=7.6 Hz, 1H), 6.29 (br s, 1H), 5.88 (s, 1H), 5.85 (s, 1H), 4.66
(d, J=14.2 Hz, 1H), 4.51 (d, J=14.1 Hz, 1H), 3.95 (s, 1H); MS (ES+)
m/z 542.0 (M+1).
Example 12
Synthesis of
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-(diphenylmethyl)-1,3-dihydro-2H--
indol-2-one Compound of formula (18a1)
##STR00155##
[0254] A. To a solution of
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1,3-d-
ihydro-2H-indol-2-one (32.0 g, 57.7 mmol) in dichloromethane (100
mL) was added trifluoroacetic acid (50 mL) followed by
triethylsilane (50 mL). The reaction mixture was stirred at ambient
temperature for 2 h and concentrated in vacuo. The residue was
dissolved in ethyl acetate (250 mL), washed with saturated aqueous
ammonium chloride (3.times.100 mL) and brine (3.times.100 mL),
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo. The residue was triturated with diethyl ether to afford
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-(diphenylmethyl)-1,3-dihy-
dro-2H-indol-2-one (19.0 g) as a colorless solid in 61% yield:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.31-7.23 (m, 15H),
7.10-6.88 (m, 4H), 6.50-6.45 (m, 3H), 5.86 (s, 2H), 4.97-4.86 (m,
3H); MS (ES+) m/z 525.9 (M+1).
[0255] B. Alternatively, to a solution of
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1,3-d-
ihydro-2H-indol-2-one (2.0 kg, 3.7 mol) in dichloromethane (7 L) at
20-30.degree. C. was added trifluoracetic acid (2.5 L), followed by
triethylsilane (3.1 L). The mixture was stirred at 15-35.degree. C.
for 4 h and concentrated in vacuo to dryness. To the residue was
added ethyl acetate (16 L) and the mixture was stirred at
15-35.degree. C. for 0.5 h, washed with saturated aqueous ammonium
chloride (3.times.7 L) and brine (3.times.7 L) and concentrated in
vacuo to a volume of approximately 7 L. Methyl tert-butyl ether (9
L) was added and the mixture concentrated in vacuo to a volume of
approximately 9 L and stirred at 10-20.degree. C. for 2.5 h, during
which time a solid was deposited. The solid was collected by
filtration, washed with methyl tert-butyl ether (0.4 L) and dried
in vacuo at 50-55.degree. C. for 7 h to afford
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-(diphenylmethyl)-1,3-dihydro-2H--
indol-2-one (1.26 kg) as an off-white solid in 65% yield: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.31-7.23 (m, 15H), 7.10-6.88 (m,
4H), 6.50-6.45 (m, 3H), 5.86 (s, 2H), 4.97-4.86 (m, 3H); MS (ES+)
m/z 525.9 (M+1).
Example 13
Synthesis of
(3S)-3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-(diph-
enylmethyl)-1,3-dihydro-2H-indol-2-one Compound of formula
(19a1)
##STR00156##
[0257] A. To a nitrogen-degassed mixture of 50% w/w aqueous
potassium hydroxide (69.6 mL, 619 mmol), toluene (100 mL), and
(9S)-1-(anthracen-9-ylmethyl)cinchonan-1-ium-9-ol chloride (0.50 g,
0.95 mmol) cooled in an ice/salt bath to an internal temperature of
-18.degree. C. was added a nitrogen-degassed solution of
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-(diphenylmethyl)-1,3-dihydro-2H--
indol-2-one (10.0 g, 19.0 mmol) and benzyl chloromethyl ether (2.9
mL, 21 mmol) in toluene/tetrahydrofuran (1:1 v/v, 80 mL) dropwise
over 1 h. The reaction mixture was stirred for 3.5 h and diluted
with ethyl acetate (80 mL). The organic phase was washed with 1 N
hydrochloric acid (3.times.150 mL) and brine (2.times.100 mL),
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo to afford
(3S)-3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-(diph-
enylmethyl)-1,3-dihydro-2H-indol-2-one (12.6 g) as a colorless
solid in quantitative yield: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.42 (d, 2H), 7.24-6.91 (m, 21H), 6.69-6.67 (m, 2H), 6.46
(d, J=7.7 Hz, 1H), 6.15 (s, 1H), 5.83-5.81 (m, 2H), 4.53-4.31 (m,
3H), 4.17-4.09 (m, 3H); MS (ES+) m/z 646.0 (M+1); ee (enantiomeric
excess) 90% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl
tert-butyl ether).
[0258] B. Alternatively, a mixture of 50% w/v aqueous potassium
hydroxide (4.2 kg), toluene (12 L) and
(9S)-1-(anthracen-9-ylmethyl)cinchonan-1-ium-9-ol chloride (0.06
kg, 0.1 mol) was degassed with dry nitrogen and cooled to -18 to
-22.degree. C. To this mixture was added a cold (-18 to -22.degree.
C.), nitrogen-degassed solution of
3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-1-(diphenylmethyl)-1,3-dihydro-2H--
indol-2-one (1.2 kg, 2.3 mol) and benzyl chloromethyl ether (0.43
kg, 2.8 mol) in toluene (10 L) and tetrahydrofuran (10 L) at -18 to
22.degree. C. over 3 h. The mixture was stirred at -18 to
-22.degree. C. for 5 h, allowed to warm to ambient temperature and
diluted with ethyl acetate (10 L). The phases were separated and
the organic layer was washed with 1 N hydrochloric acid (3.times.18
L) and brine (2.times.12 L) and concentrated in vacuo to dryness to
afford
(3S)-3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-(diph-
enylmethyl)-1,3-dihydro-2H-indol-2-one (1.5 kg) as a colorless
solid in quantitative yield: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.42 (d, 2H), 7.24-6.91 (m, 21H), 6.69-6.67 (m, 2H), 6.46
(d, J=7.7 Hz, 1H), 6.15 (s, 1H), 5.83-5.81 (m, 2H), 4.53-4.31 (m,
3H), 4.17-4.09 (m, 3H); MS (ES+) m/z 646.0 (M+1); ee (enantiomeric
excess) 90% (HPLC, ChiralPak IA).
Example 14
Synthesis of
(3S)-1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymeth-
yl)-1,3-dihydro-2H-indol-2-one Compound of formula (20a1)
##STR00157##
[0260] A. A mixture of
(3S)-3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-(diph-
enylmethyl)-1,3-dihydro-2H-indol-2-one (8.8 g, 14 mmol), 10% w/w
palladium on carbon (50% wetted powder, 3.5 g, 1.6 mmol), and
acetic acid (3.9 mL, 68 mmol) in a nitrogen-degassed mixture of
ethanol/tetrahydrofuran (1:1 v/v, 140 mL) was stirred under
hydrogen gas (1 atm) at ambient temperature for 4 h. The reaction
mixture was filtered through a pad of diatomaceous earth and the
pad was rinsed with ethyl acetate (100 mL). The filtrate was
concentrated in vacuo to afford
(3S)-1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymeth-
yl)-1,3-dihydro-2H-indol-2-one as a colorless solid that was
carried forward without further purification: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.81 (br s, 1H), 7.35-7.24 (m, 11H), 7.15-7.01
(m, 3H), 6.62 (s, 1H), 6.54-6.47 (m, 2H), 5.86-5.84 (m, 2H), 4.76
(d, J=11.0 Hz, 1H), 4.13-4.04 (m, 1H), 2.02 (s, 1H); MS (ES+) m/z
465.9 (M+1); ee (enantiomeric excess) 93% (HPLC, Chiralpak IA, 2.5%
acetonitrile in methyl tert-butyl ether).
[0261] B. Alternatively, a glass-lined hydrogenation reactor was
charged with
(3S)-3-[6-(benzyloxy)-1,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1--
(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (0.1 kg, 0.15 mol),
tetrahydrofuran (0.8 L), ethanol (0.4 L), acetic acid (0.02 L) and
20% w/w palladium (11) hydroxide on carbon (0.04 kg). The reactor
was purged three times with nitrogen. The reactor was then purged
three times with hydrogen and was then pressurized to 50-55
lb/in.sup.2 with hydrogen. The mixture was stirred at 20-30.degree.
C. for 5 h under a 50-55 lb/in.sup.2 atmosphere of hydrogen. The
reactor was purged and the mixture was filtered. The filtrate was
concentrated in vacuo to a volume of approximately 0.2 L and methyl
tert-butyl ether (0.4 L) was added. The mixture was concentrated in
vacuo to a volume of approximately 0.2 L and methyl tert-butyl
ether (0.2 L) was added, followed by heptane (0.25 L). The mixture
was stirred at ambient temperature for 2 h, during which time a
solid was deposited. The solid was collected by filtration, washed
with heptane (0.05 L) and dried in vacuo at a temperature below
50.degree. C. for 8 h to afford
(3S)-1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymeth-
yl)-1,3-dihydro-2H-indol-2-one (0.09 kg) as a colorless solid in
95% yield: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.81 (br s,
1H), 7.35-7.24 (m, 11H), 7.15-7.01 (m, 3H), 6.62 (s, 1H), 6.54-6.47
(m, 2H), 5.86-5.84 (m, 2H), 4.76 (d, J=11.0 Hz, 1H), 4.13-4.04 (m,
1H), 2.02 (s, 1H); MS (ES+) m/z 465.9 (M+1); ee (enantiomeric
excess) 91% (HPLC, ChiralPak IA).
Example 15
Synthesis of
(7S)-1'-(diphenylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'-
(1'H)-one Compound of formula (21a1)
##STR00158##
[0263] A. To a cooled (0.degree. C.) solution of
(3S)-1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymeth-
yl)-1,3-dihydro-2H-indol-2-one prepared according to the procedure
described in Example 14 (13.6 mmol) and
2-(diphenylphosphino)pyridine (4.3 g, 16 mmol) in anhydrous
tetrahydrofuran (140 mL) was added di-tert-butylazodicarboxylate
(3.8 g, 17 mmol). The reaction mixture was stirred at 0.degree. C.
for 3 h, diluted with ethyl acetate (140 mL), washed with 3 N
hydrochloric acid (6.times.50 mL) and brine (2.times.100 mL), dried
over anhydrous sodium sulfate, filtered and concentrated in vacuo.
The residue was triturated with a mixture of diethyl ether and
hexanes to afford
(7S)-1'-(diphenylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'-
(1'H)-one (4.55 g) as a colorless solid in a 75% yield over 2
steps: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.34-7.24 (m,
10H), 7.15-7.13 (m, 1H), 7.04 (s, 1H), 6.99-6.95 (m, 2H), 6.50-6.48
(m, 2H), 6.06 (s, 1H), 5.85-5.83 (m, 2H), 4.96 (d, J=8.9 Hz, 1H),
4.69 (d, J=8.9 Hz, 1H); MS (ES+) m/z 447.9 (M+1); ee (enantiomeric
excess) 93% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl
tert-butyl ether).
[0264] B. Alternatively, to a cooled (0-5.degree. C.) solution of
(3S)-1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymeth-
yl)-1,3-dihydro-2H-indol-2-one (1.0 kg, 2.1 mol) and
2-(diphenylphosphino)pyridine (0.66 kg, 2.5 mol) in anhydrous
tetrahydrofuran (20 L) was added over 2 h a solution of
di-tert-butylazodicarboxylate (0.62 kg, 2.7 mmol) in anhydrous
tetrahydrofuran (5 L). The mixture was stirred for 4 h at
0-5.degree. C. and was allowed to warm to ambient temperature. The
mixture was diluted with ethyl acetate (20 L), washed with 3 N
hydrochloric acid (6.times.8 L) and brine (2.times.12 L) and
concentrated in vacuo to a volume of approximately 1.5 L. Methyl
tert-butyl ether (4 L) was added and the mixture concentrated in
vacuo to a volume of approximately 1.5 L. Methyl tert-butyl ether
(2 L) and heptane (2 L) were added and the mixture was stirred at
ambient temperature for 2 h, during which time a solid was
deposited. The solid was collected by filtration, washed with
heptane (0.5 L) and dried in vacuo below 50.degree. C. for 8 h to
afford
(7S)-1'-(diphenylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'-
(1'H)-one (0.76 kg) as a colorless solid in 79% yield: .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.34-7.24 (m, 10H), 7.15-7.13 (m,
1H), 7.04 (s, 1H), 6.99-6.95 (m, 2H), 6.50-6.48 (m, 2H), 6.06 (s,
1H), 5.85-5.83 (m, 2H), 4.96 (d, J=8.9 Hz, 1H), 4.69 (d, J=8.9 Hz,
1H); MS (ES+) m/z 447.9 (M+1); ee (enantiomeric excess) 92% (HPLC,
ChiralPak IA).
Example 16
Synthesis of
(7S)-spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-one
Compound of formula (22a1)
##STR00159##
[0266] A. To a solution of
(7S)-1'-(diphenylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'-
(1'H)-one (4.55 g, 10.2 mmol) in trifluoroacetic acid (80 mL) was
added triethylsilane (7 mL). The reaction mixture was heated at
reflux for 2.5 h, allowed to cool to ambient temperature and
concentrated in vacuo. The residue was triturated with a mixture of
diethyl ether and hexanes to afford
(7S)-spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-one
(2.30 g) as a colorless solid in 80% yield: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.27 (br s, 1H), 7.31-7.26 (m, 1H), 7.17-7.15
(m, 1H), 7.07-7.02 (m, 1H), 6.96-6.94 (m, 1H), 6.53-6.52 (m, 1H),
6.24-6.23 (m, 1H), 5.88-5.87 (m, 2H), 4.95 (d, J=8.6 Hz, 1H), 4.68
(d, J=8.9 Hz, 1H); MS (ES+) m/z 281.9 (M+1); ee (enantiomeric
excess) 99% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl
tert-butyl ether).
[0267] B. Alternatively, a mixture of
(7S)-1'-(diphenylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'-
(1'H)-one (0.70 kg, 1.6 mol), trifluoroacetic acid (12 L) and
triethylsilane (1.1 L) was heated at reflux under nitrogen
atmosphere for 3 h, allowed to cool to ambient temperature and
concentrated in vacuo to dryness. To the residue was added ethyl
acetate (0.3 L), methyl tert-butyl ether (1 L) and heptane (3.5 L),
causing a solid to be deposited. The solid was collected by
filtration, taken up in dichloromethane (3 L), stirred at ambient
temperature for 1 h and filtered. The filtrate was concentrated in
vacuo to dryness. The residue was taken up in ethyl acetate (0.3
L), methyl tert-butyl ether (1 L) and heptane (3.5 L), causing a
solid to be deposited. The solid was collected by filtration and
dried in vacuo below 50.degree. C. for 8 h to afford
(7S)-spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-one
(0.40 kg) as a colorless solid in 91% yield: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.27 (br s, 1H), 7.31-7.26 (m, 1H), 7.17-7.15
(m, 1H), 7.07-7.02 (m, 1H), 6.96-6.94 (m, 1H), 6.53-6.52 (m, 1H),
6.24-6.23 (m, 1H), 5.88-5.87 (m, 2H), 4.95 (d, J=8.6 Hz, 1H), 4.68
(d, J=8.9 Hz, 1H); MS (ES+) m/z 281.9 (M+1); ee (enantiomeric
excess) 98.6% (HPLC, ChiralPak IA).
Example 17
Synthesis of
(7S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benz-
odioxole-7,3'-indol]-2'(1'H)-one Compound of formula (Ia1)
##STR00160##
[0269] A. To a mixture of
(7S)-6H-spiro[[1,3]dioxolo[4,5-f]benzofuran-7,3'-indolin]-2'-one
(1.80 g, 6.41 mmol) and 2-(bromomethyl)-5-(trifluoromethyl)furan
(1.47 g, 6.41 mmol) in acetone (200 mL) was added cesium carbonate
(3.13 g, 9.61 mmol). The reaction mixture was heated at reflux for
2 h and filtered while hot through a pad of diatomaceous earth. The
filtrate was concentrated in vacuo to afford
(7S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-][1,3]benzo-
dioxole-7,3'-indol]-2'(1'H)-one (2.71 g) as a colorless solid in
quantitative yield (97% purity by HPLC). The product was
crystallized from a mixture of methanol and hexanes to afford
(7S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-][1,3]benzo-
dioxole-7,3'-indol]-2'(1'H)-one (1.46 g) as colorless needles in
53% yield. The mother liquor was concentrated in vacuo and
subjected to a second crystallization in methanol and hexanes to
afford further
(7S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benz-
odioxole-7,3'-indol]-2'(1'H)-one (0.469 g) as a colorless solid in
17% yield (total yield 70%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.29-6.96 (m, 4H), 6.73 (s, 1H), 6.50 (s, 1H), 6.38 (s,
1H), 6.09 (s, 1H), 5.85 (br s, 2H), 5.06 (d, J=16.0 Hz, 1H),
4.93-4.84 (m, 2H), 4.68-4.65 (m, 1H); MS (ES+) m/z 429.8 (M+1); ee
(enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5%
acetonitrile in methyl tert-butyl ether).
[0270] B. Alternatively, to a solution of
(7S)-spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-one
(0.40 kg, 1.4 mol) in anhydrous N,N-dimethylformamide (5 L) was
added cesium carbonate (1.2 kg, 3.4 mol), followed by
2-(bromomethyl)-5-(trifluromethyl)furan (0.24 L, 1.7 mol). The
mixture was heated at 80-85.degree. C. for 3 h, allowed to cool to
ambient temperature and filtered through a pad of diatomaceous
earth. The pad was washed with ethyl acetate (8 L). The combined
filtrate and washes were washed with water (4 L), saturated aqueous
ammonium chloride (2.times.4 L) and brine (2.times.4 L) and
concentrated in vacuo to dryness. The residue was purified by
recrystallization from tert-butyl methyl ether (0.4 L) and heptane
(0.8 L), followed by drying of the resultant solid in vacuo at
40-50.degree. C. for 8 h to afford
(7S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-][1,3]benzo-
dioxole-7,3'-indol]-2'(1'H)-one (0.37 kg) as a colorless solid in
61% yield: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.29-6.96 (m,
4H), 6.73 (s, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 6.09 (s, 1H), 5.85
(br s, 2H), 5.06 (d, J=16.0 Hz, 1H), 4.93-4.84 (m, 2H), 4.68-4.65
(m, 1H); MS (ES+) m/z 429.8 (M+1); ee (enantiomeric excess) >99%
(HPLC, Chiralpak IA).
Example 18
Synthesis of
1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-y-
l)-1,3-dihydro-2H-indol-2-one Compound of formula (16a2)
##STR00161##
[0272] To a cooled (0.degree. C.) solution of
2,3-dihydro-1,4-benzodioxin-6-ol (54.0 g, 355 mmol) in
tetrahydrofuran (600 mL) was added dropwise a 2 M solution of
isopropylmagnesium chloride in tetrahydrofuran (178 mL, 356 mmol).
The reaction mixture was stirred for at 0.degree. C. for 45 min.
and 1-(diphenylmethyl)-1H-indole-2,3-dione (85.8 g, 274 mmol) was
added. The reaction mixture was stirred at 0.degree. C. for 3 h,
allowed to warm to ambient temperature and stirred for a further 16
h. The mixture was cooled to 0.degree. C. and a mixture of
2,3-dihydro-1,4-benzodioxin-6-ol (54.0 g, 355 mmol),
isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 178
mL, 356 mmol) and tetrahydrofuran (600 mL) was added. The reaction
was stirred at 0.degree. C. for 2.5 h, allowed to warm to ambient
temperature and stirred for a further 20 h. Water (250 mL) was
added and the mixture was diluted with ethyl acetate (1000 mL),
washed with saturated aqueous ammonium chloride (3.times.500 mL)
and brine (3.times.500 mL), dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. The residue was triturated with
diethyl ether to afford
1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodio-
xin-6-yl)-1,3-dihydro-2H-indol-2-one (117 g) as a colorless solid
in 92% yield: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.94 (br s,
1H), 7.47-7.44 (m, 1H), 7.31-7.19 (m, 10H), 7.10-7.07 (m, 2H), 6.89
(s, 1H), 6.60-6.59 (m, 1H), 6.47-6.44 (m, 1H), 6.38-6.37 (m, 1H),
4.35 (s, 1H), 4.20-4.19 (m, 2H), 4.14-4.13 (m, 2H); MS (ES+) m/z
447.8 (M-17).
Example 19
Synthesis of
3-[7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-(diphenylmethyl)-3-h-
ydroxy-1,3-dihydro-2H-indol-2-one Compound of formula (17a2)
##STR00162##
[0274] To a mixture of
1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-y-
l)-1,3-dihydro-2H-indol-2-one (70 g, 150 mmol) and potassium
carbonate (41.6 g, 301 mmol) in anhydrous N,N-dimethylformamide
(420 mL) was added benzyl chloride (26 mL, 230 mmol). The reaction
mixture was heated at 50.degree. C. for 4.5 h, allowed to cool to
ambient temperature and poured into ice-water (2.5 L), causing a
precipitate to be deposited. The solid was collected by suction
filtration, washed with water (2 L) and triturated with a mixture
of diethyl ether and hexanes to afford
3-[7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-(diphenylmethyl)-3-h-
ydroxy-1,3-dihydro-2H-indol-2-one (73.2 g) as a colorless solid in
87% yield: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.35-7.13 (m,
16H), 7.06-6.88 (m, 4H), 6.46 (d, 1H), 6.23 (s, 1H), 4.69 (d,
J=13.9 Hz, 1H), 4.55 (d, J=14.4 Hz, 1H), 4.16 (s, 4H), 3.58 (s,
1H); MS (ES+) m/z 537.8 (M-17).
Example 20
Synthesis of
3-[7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-(diphenylmethyl)-1,3-
-dihydro-2H-indol-2-one Compound of formula (18a2)
##STR00163##
[0276] To a cooled (0.degree. C.) solution of
3-[7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-(diphenylmethyl)-3-h-
ydroxy-1,3-dihydro-2H-indol-2-one (72.8 g, 130 mmol) in
dichloromethane (100 mL) was added trifluoroacetic acid (100 mL)
and triethylsilane (104 mL). The reaction mixture was allowed to
warm to ambient temperature, stirred for 16 h and concentrated in
vacuo. The residue was taken up in a biphasic mixture of ethyl
acetate (500 mL) and saturated aqueous ammonium chloride (200 mL),
causing a precipitate to be deposited. The solid was collected by
suction filtration and washed with ethyl acetate (100 mL) and water
(100 mL) to afford
3-[7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-(diphenylmethyl)-1,3-
-dihydro-2H-indol-2-one (38.4 g) as a colorless solid in 55% yield.
The filtrates were combined and the phases were separated. The
organic phase was washed with saturated aqueous ammonium chloride
(200 mL) and brine (2.times.200 mL), dried over anhydrous sodium
sulfate, filtered and concentrated in vacuo. The residue was
triturated with diethyl ether to afford a further amount of
3-[7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-(diphenylmethyl)-1,3-
-dihydro-2H-indol-2-one (14.7 g) as a colorless solid in 21% yield:
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.34-7.19 (m, 15H),
7.09-7.03 (m, 1H), 6.94-6.90 (m, 4H), 6.52-6.49 (m, 2H), 4.97-4.79
(m, 3H), 4.17 (s, 4H); MS (ES+) m/z 539.9 (M+1).
Example 21
Synthesis of
(3S)-3-[7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-6-yl]-3-[(benzyloxy)met-
hyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one Compound of
formula (19a2)
##STR00164##
[0278] To a nitrogen-degassed mixture of 50% w/w aqueous potassium
hydroxide (68.4 mL, 609 mmol), toluene (650 mL), and
(9S)-1-(anthracen-9-ylmethyl)cinchonan-1-ium-9-ol chloride (0.48 g,
0.92 mmol) cooled in an ice/salt bath to an internal temperature of
-16.degree. C. was added dropwise over 45 minutes a mixture of
3-[7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-(diphenylmethyl)-1,3-
-dihydro-2H-indol-2-one (10.1 g, 18.7 mmol), benzyl chloromethyl
ether (2.5 mL, 18 mmol) and ethyl acetate (750 mL). The mixture was
stirred for 1 h at -16.degree. C. and a further portion of benzyl
chloromethyl ether (0.7 mL, 5 mmol) was added. The mixture was
stirred at -16.degree. C. for a further 3 h and 1 N hydrochloric
acid (250 mL) was added. The organic phase was washed with 1 N
hydrochloric acid (3.times.300 mL) and brine (3.times.300 mL),
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo. The residue was triturated with diethyl ether to afford
(3S)-3-[7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-6-yl]-3-[(benzyl-
oxy)methyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (9.74 g)
as a beige solid in 79% yield: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.44 (d, J=7.2 Hz, 2H), 7.24-6.91 (m, 21H), 6.66 (br s,
2H), 6.46 (d, J=7.6 Hz, 1H), 6.09 (s, 1H), 4.51 (d, J=12.3 Hz, 1H),
4.42-4.37 (m, 2H), 4.21-4.12 (m, 7H); MS (ES+) m/z 659.8 (M+1); ee
(enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5%
acetonitrile in methyl tert-butyl ether).
Example 22
Synthesis of
(3S)-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-3--
(hydroxymethyl)-1,3-dihydro-2H-indol-2-one Compound of formula
(20a2)
##STR00165##
[0280] To a solution of
(3S)-3-[7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-6-yl]-3-[(benzyloxy)met-
hyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (9.74 g, 14.8
mmol) in nitrogen-degassed tetrahydrofuran (100 mL) was added 10%
w/w palladium on carbon (60% wetted powder, 4.50 g, 2.54 mmol). The
reaction mixture was shaken in a Parr apparatus under a hydrogen
atmosphere (10 lb/in.sup.2 gauge) for 16 h and filtered through a
pad of diatomaceous earth. The pad was rinsed with ethyl acetate
(200 mL) and the filtrate was concentrated in vacuo. The residue
was triturated with diethyl ether (100 mL) to afford
(3S)-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-
-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (6.70 g) as a
colorless solid in 95% yield: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 9.00 (br s, 1H), 7.34 (br s, 9H), 6.98-6.81 (m, 5H),
6.24-6.22 (m, 2H), 5.13 (br s, 1H), 4.18 (s, 5H), 3.94-3.91 (m,
1H), 2.51 (s, 1H); MS (ES+) m/z 479.9 (M+1); ee (enantiomeric
excess) >99.5% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl
tert-butyl ether).
Example 23
Synthesis of
(8S)-1'-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,-
3'-indol]-2'(1'H)-one Compound of formula (21a2)
##STR00166##
[0282] To a cooled (0.degree. C.) solution of
(3S)-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-3--
(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (6.3 g, 14 mmol) in
tetrahydrofuran (100 mL) was added 2-(diphenylphosphino)pyridine
(3.98 g, 15.1 mmol) followed after 5 minutes by
diisopropylazodicarboxylate (3.05 g, 15.1 mmol). The reaction
mixture was stirred for 0.5 h at 0.degree. C. and was concentrated
in vacuo. The residue was taken up in ethyl acetate (200 mL),
washed with 3 N hydrochloric acid (3.times.100 mL) and brine
(3.times.100 mL), dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The residue was stirred in a mixture of
tetrahydrofuran (100 mL) and 3 N aqueous sodium hydroxide (100 mL)
at ambient temperature for 1 h and was then diluted with ethyl
acetate (100 mL). The organic phase was separated, washed with
brine (3.times.100 mL), dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. The residue was triturated in
diethyl ether to afford
(8S)-1'-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,-
3'-indol]-2'(1'H)-one (5.13 g) as a colorless solid in 85% yield:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.45-7.26 (m, 10H), 7.20
(d, J=7.2 Hz, 1H), 7.13-7.08 (m, 1H), 7.02-6.97 (m, 1H), 6.90 (s,
1H), 6.59-6.53 (m, 2H), 6.03 (s, 1H), 4.86 (d, J=9.3 Hz, 1H), 4.73
(d, J=9.4 Hz, 1H), 4.18-4.11 (m, 4H); MS (ES+) m/z 461.9 (M+1).
Example 24
Synthesis of
(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3'-indol]-2'(1'H)-on-
e Compound of formula (22a2)
##STR00167##
[0284] To a solution of
(8S)-1'-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,-
3'-indol]-2'(1'H)-one (5.13 g, 11.1 mmol) in trifluoroacetic acid
(17 mL) was added triethylsilane (8.9 mL). The reaction mixture was
heated at reflux for 5 h, allowed to cool to ambient temperature
and concentrated in vacuo. The residue was triturated with diethyl
ether to afford
(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3'-indol]-2'(1'H)-on-
e (2.7 g) as a beige solid in 82% yield: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.78 (s, 1H), 7.27-7.22 (m, 1H), 7.15 (d, J=7.1
Hz, 1H), 7.06-7.01 (m, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.51 (br s,
1H), 6.32 (br s, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.65 (d, J=9.0 Hz,
1H), 4.20-4.12 (m, 4H); MS (ES+) m/z 295.9 (M+1); ee (enantiomeric
excess) >99.5% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl
tert-butyl ether).
Example 25
Synthesis of
(8S)-1'-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2-
,3-g][1,4]benzodioxine-8,3'-indol]-2'(1'H)-one Compound of formula
(Ia2)
##STR00168##
[0286] To a solution of
(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3'-indol]-2'(1'H)-on-
e (2.58 g, 8.7 mmol) in 1,4-dioxane (100 mL) was added cesium
carbonate (7.12 g, 21.9 mmol) and
2-(bromomethyl)-3-(trifluoromethyl)pyridine (3.08 g, 9.60 mmol).
The mixture was heated at reflux for 3 h, allowed to cool to
ambient temperature and stirred for a further 16 h. The mixture was
filtered through a pad of diatomaceous earth and the pad was rinsed
with ethyl acetate (200 mL). The filtrate was concentrated in vacuo
and the residue was triturated with a mixture of hexanes and
diethyl ether to afford
(8S)-1'-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro-
[furo[2,3-g][1,4]benzodioxine-8,3'-indol]-2'(1'H)-one (3.08 g) as a
beige solid in 77% yield: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.64-8.62 (m, 1H), 7.96 (d, J=7.7 Hz, 1H), 7.32-7.12 (m, 3H),
7.02-6.97 (m, 1H), 6.61-6.58 (m, 2H), 6.48-6.47 (m, 1H), 5.40 (d,
J=17.4 Hz, 1H), 5.12 (d, J=17.4 Hz, 1H), 5.00-4.96 (m, 1H),
4.73-4.70 (m, 1H), 4.18-4.11 (m, 4H); MS (ES+) m/z 454.9 (M+1); ee
(enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5%
acetonitrile in methyl tert-butyl ether).
[0287] All of the U.S. patents, U.S. patent application
publications, U.S. patent applications, PCT published patent
applications, foreign patents, foreign patent applications and
non-patent publications referred to in this specification are
incorporated herein by reference in their entirety.
[0288] Although the foregoing invention has been described in some
detail to facilitate understanding, it will be apparent that
certain changes and modifications may be practiced within the scope
of the appended claims. Accordingly, the described embodiments are
to be considered as illustrative and not restrictive, and the
invention is not to be limited to the details given herein, but may
be modified within the scope and equivalents of the appended
claims.
* * * * *