U.S. patent application number 10/227402 was filed with the patent office on 2003-01-30 for methods for the preparation of intermediates in the synthesis of hiv-protease inhibitors.
Invention is credited to Borer, Bennett C., Busse, Juliette K., Zook, Scott E..
Application Number | 20030023092 10/227402 |
Document ID | / |
Family ID | 22578030 |
Filed Date | 2003-01-30 |
United States Patent
Application |
20030023092 |
Kind Code |
A1 |
Borer, Bennett C. ; et
al. |
January 30, 2003 |
Methods for the preparation of intermediates in the synthesis of
HIV-protease inhibitors
Abstract
Methods for the preparation of chemical intermediates in the
synthesis of HIV-protease inhibitors related to and including
nelfinavir mesylate are disclosed. The method of this invention
comprises converting tetrohydran derivatives into oxazolines to
provide key reaction intermediates for the preparation of
nelfinavir. Also disclosed is a method for the preparation of a
chiral amino alcohol from an epoxy-tetrahydrofuran.
Inventors: |
Borer, Bennett C.; (La
Jolla, CA) ; Zook, Scott E.; (San Diego, CA) ;
Busse, Juliette K.; (San Diego, CA) |
Correspondence
Address: |
FITZPATRICK CELLA HARPER & SCINTO
30 ROCKEFELLER PLAZA
NEW YORK
NY
10112
US
|
Family ID: |
22578030 |
Appl. No.: |
10/227402 |
Filed: |
August 26, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10227402 |
Aug 26, 2002 |
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09986146 |
Nov 7, 2001 |
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6472534 |
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09986146 |
Nov 7, 2001 |
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09690093 |
Oct 17, 2000 |
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6403799 |
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60160695 |
Oct 21, 1999 |
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Current U.S.
Class: |
546/271.4 ;
548/237 |
Current CPC
Class: |
C07D 307/22 20130101;
Y02P 20/55 20151101; C07D 413/06 20130101; A61P 43/00 20180101;
C07D 263/14 20130101; A61P 31/18 20180101 |
Class at
Publication: |
546/271.4 ;
548/237 |
International
Class: |
C07D 413/04; C07D
263/08 |
Claims
We claim:
1. A method for the preparation of an oxazoline, 72comprising
treating the tetrahydrofuran, wherein R.sub.a is --COR(1) and
R.sub.b is hydrogen, --COR(3), --SO.sub.2R(2) or a suitable
hydroxyl protecting group with an oxophilic electrophilic reagent
in a manner that is effective to provide the oxazoline, wherein
R.sub.b is hydrogen, --COR(3), --SO.sub.2R(2) or a suitable
hydroxyl protecting group and R.sub.c is hydrogen, --COR(3) or
--SO.sub.2R(2); wherein R(1), R(2) and R(3) independently represent
a substituted or unsubstituted alkyl, aryl, cycloalkyl,
heterocycloalkyl or heteroaryl group.
2. The method according to claim 1, comprising treating the
tetrahydrofuran with about 1 to about 20 molar equivalents of the
oxophilic electrophilic reagent.
3. The method according to claim 1, wherein said oxophilic
electrophilic reagent comprises a combination of about 1 to about
20 molar equivalents of a suitable acid and about 1 to about 20
molar equivalents of a suitable acid anhydride, wherein the
anhydride and the acid are used in a relative molar ratio of from
about 1:5 to about 5:1, respectively.
4. The method according to claim 1, wherein said oxophilic
electrophilic reagent comprises a combination of about 2 to about
20 molar equivalents of a suitable acid and about 2 to about 20
molar equivalents of a suitable acid anhydride, wherein the
anhydride and the acid are used in a relative molar ratio of from
about 1:1 to about 5:1, respectively.
5. The method according to claim 1, wherein said oxophilic
electrophilic reagent comprises about 7.5 molar equivalents of a
suitable acid and 15 molar equivalents of a suitable acid
anhydride.
6. The method according to claim 1 wherein said tetrahydrofuran is
treated with an anhydride under acidic conditions to form said
oxazoline.
7. A method for the preparation of an oxazoline having the formula:
73wherein R(1), R(2) and R(3) independently represent substituted
or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or
heteroaryl, said method comprising the steps of: (1) treating an
amino-tetrahydrofuran, or a salt thereof, having the formula: 74 in
a manner that is effective to convert said amino-tetrahydrofuran,
or a salt thereof, to a tetrahydrofuran-amide, having the formula:
75(2) treating the tetrahydrofuran-amide with a substituted or
unsubstituted alkyl or aryl sulfonylating reagent to convert said
tetrahydrofuran-amide to an tetrahydrofuran amide-sulfonate having
the formula: 76 comprising the step-wise treatment of the
tetrahydrofuran-amide with at least one molar equivalent amount of
the sulfonylating reagent, followed by treatment with a base,
wherein the molar equivalent amount of base used in the treatment
is less than the molar equivalent amount of the sulfonylating
reagent, and (3) treating the tetrahydrofuran amide-sulfonate with
an oxophilic electrophilic reagent in a manner that is effective to
convert said tetrahydrofuran amide-sulfonate to said oxazoline.
8. A method for the preparation of an oxazoline diol having the
formula: 77said method comprising the steps of: (1) treating an
amino-tetrahydrofuran, or a salt thereof, having the formula: 78 in
a manner that is effective to convert the amino-tetrahydrofuran, or
a salt thereof, to a tetrahydrofuran-amide having the formula:
79(2) treating the tetrahydrofuran-amide with an oxophilic
electrophilic reagent in a manner that is effective to convert said
tetrahydrofuran-amide to an oxazoline diester having the formula:
80(3) hydrolyzing the oxazoline diester to said oxazoline diol;
wherein R(1) and R(3) independently represent substituted or
unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or
heteroaryl.
9. A method for the preparation of an oxazoline diol having the
formula: 81comprising the steps of: (1) treating an
amino-tetrahydrofuran or a salt thereof, having the formula: 82 in
a manner that is effective to convert the amino-tetrahydrofuran or
a salt thereof, to a tetrahydrofuran-amide having the formula:
83(2) treating the tetrahydrofuran-amide with a substituted or
unsubstituted alkyl or aryl sulfonylating reagent, in a manner
effective to convert said tetrahydrofuran-amide to a fused
tetrahydrofuranyloxazoline having the formula: 84(3) hydrolyzing
the fused tetrahydrofuranyloxazoline to a tetrahydrofuran-amide
having the formula: 85(4) treating the tetrahydrofuran-amide with
an oxophilic electrophilic reagent in a manner that is effective to
convert said tetrahydrofuran-amide to an oxazoline diester having
the formula: 86(5) hydrolyzing the oxazoline diester to said
oxazoline diol; wherein R(1) and R(3) independently represent
substituted or unsubstituted alkyl, aryl, cycloalkyl,
heterocycloalkyl or heteroaryl.
10. A method for the preparation of an oxazoline having the
formula: 87wherein R(1) is substituted or unsubstituted alkyl,
aryl, cycloalkyl, heterocycloalkyl or heteroaryl, R(10) is a
suitable hydroxyl protecting group and R(11) is H or substituted
alkyl sulfonyl, comprising the steps of (1) treating an
amino-tetrahydrofuran or a salt thereof, having the formula: 88 in
a manner that is effective to convert the amino-tetrahydrofuran or
a salt thereof, to a tetrahydrofuran-hydroxy-ami- de having the
formula: 89(2) treating the tetrahydrofuran-hydroxy-amide in a
manner effective to protect the hydroxyl moiety of the
hydroxy-amide to form a protected tetrahydrofuran-amide, having the
formula: 90(3) treating the protected tetrahydrofuran-amide with an
oxophilic electrophilic reagent in a manner that is effective to
convert said tetrahydrofuran-amide to said protected oxazoline;
wherein said oxophilic electrophilic reagent is selected from an
oxophilic Lewis acid, an oxophilic protic acid, or triflic
anhydride.
11. A method for the preparation of nelfinavir comprising the steps
of: (1) treating an amino-tetrahydrofuran, or a salt thereof,
having the formula: 91 in a manner that is effective to convert the
amino-tetrahydrofuran, or a salt thereof, to a
tetrahydrofuran-amide having the formula: 92(2) treating the
tetrahydrofuran-amide to convert said tetrahydrofuran-amide to a
tetrahydrofuran amide-sulfonate having the formula: 93 comprising
the step-wise treatment of the tetrahydrofuran-amide with at least
one molar equivalent amount of the sulfonylating reagent, followed
by treatment with a base, wherein the molar equivalent amount of
base used in the treatment is less than the molar equivalent amount
of the sulfonylating reagent, and (3) treating the
tetrahydrofuran-amide sulfonate with an oxophilic electrophilic
reagent in a manner that is effective to convert said
tetrahydrofuran amide-sulfonate to an oxazoline having the formula:
94(4) treating the oxazoline in a manner that is effective to
convert said oxazoline to a compound having the formula: 95(5)
converting said compound to nelfinavir; wherein R(2) and R(3) are
independently selected from substituted or unsubstituted alkyl,
aryl, cycloalkyl, heterocycloalkyl or heteroaryl, and R(5) is a
substituted or unsubstituted NH-alkyl, NH-aryl, O-alkyl, or O-aryl
group, wherein each alkyl or aryl moiety may be substituted or
unsubstituted.
12. A method for the preparation of nelfinavir comprising the steps
of: (1) treating an amino-tetrahydrofuran or a salt thereof, having
the formula: 96 in a manner that is effective to convert the
amino-tetrahydrofuran or a salt thereof, to a tetrahydrofuran-amide
having the formula: 97(2) treating the tetrahydrofuran-amide with
an oxophilic electrophilic reagent in a manner that is effective to
convert said tetrahydrofuran-amide to an oxazoline triester having
the formula: 98(3) hydrolyzing the oxazoline triester to an
oxazoline triol having the formula: 99(4) protecting the oxazoline
triol with a suitable hydroxyl protecting group, in a manner that
is effective to convert said oxazoline triol to a di-protected
oxazoline having the formula: 100(5) treating the di-protected
oxazoline with a substituted or unsubstituted alkyl or aryl
sulfonylating reagent, in a manner effective to convert said
oxazoline to a sulfonylated-di-protected oxazoline having the
formula: 101(6) treating the sulfonylated-di-protected oxazoline
with 3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a
manner that is effective to convert said oxazoline to a compound
having the formula: 102(7) converting said compound to nelfinavir;
wherein R(2) and R(3) are independently selected from substituted
or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or
heteroaryl, R(5) is a substituted or unsubstituted HN-alkyl,
NH-aryl, O-alkyl, or O-aryl group, wherein each alkyl or aryl
moiety may be substituted or unsubstituted , and R(7) is any
suitable hydroxyl protecting group.
13. A method for the preparation of nelfinavir comprising the steps
of: (1) treating an amino-tetrahydrofuran, or a salt thereof,
having the formula: 103 in a manner that is effective to convert
the amino-tetrahydrofuran or a salt thereof, to a
tetrahydrofuran-amide having the formula: 104(2) treating the
tetrahydrofuran-amide with a substituted or unsubstituted alkyl or
aryl sulfonylating reagent, in a manner effective to convert said
tetrahydrofuran-amide to a fused tetrahydrofuranyloxazoline having
the formula: 105(3) hydrolyzing the fused
tetrahydrofuranyloxazoline to a tetrahydrofuran-amide having the
formula: 106(4) treating the tetrahydrofuran-amide with an
oxophilic electrophilic reagent in a manner that is effective to
convert said tetrahydrofuran-amide to an oxazoline triester having
the formula: 107(5) hydrolyzing the oxazoline triester to an
oxazoline triol having the formula: 108(6) treating the oxazoline
triol with a substituted or unsubstituted alkyl or aryl
sulfonylating reagent, in a manner effective to convert said
oxazoline to a protected oxazoline having the formula: 109(7)
treating the protected oxazoline with 3S,4aR,8aR-3-N-t-butylcarbox-
amidodecahydroisoquinoline in a manner that is effective to convert
said oxazoline to a compound having the formula: 110(8) converting
said compound to nelfinavir; wherein R(3) is selected from
substituted or unsubstituted alkyl, aryl, cycloalkyl,
heterocycloalkyl or heteroaryl, R(5) is a substituted or
unsubstituted HN-alkyl, NH-aryl, O-alkyl, or O-aryl group, wherein
each alkyl or aryl moiety may be substituted or unsubstituted, R(8)
is a substituted or unsubstituted alkyl or aryl sulfonyl and R(9)
is hydrogen or R(8).
14. A method for the preparation of nelfinavir comprising the steps
of: (1) treating an amino-tetrahydrofuran, or a salt thereof,
having the formula: 111 in a manner that is effective to convert
the amino-tetrahydrofuran or a salt thereof, to a
tetrahydrofuran-amide having the formula: 112(2) treating the
tetrahydrofuran-amide in a manner that is effective to convert the
tetrahydrofuran-amide to a protected tetrahydrofuran-amide, having
the formula: 113(3) treating the protected tetrahydrofuran-amide
with an oxophilic electrophilic reagent selected from an oxophilic
Lewis acid, an oxophilic protic acid, or triflic anhydride in a
manner that is effective to convert the tetrahydrofuran-amide to a
protected oxazoline having the formula: 114(4) treating the
protected oxazoline with 3S,4aR,8aR-3-N-t-butylcarbox-
amidodecahydroisoquinoline in a manner that is effective to convert
said oxazoline to a compound having the formula: 115(5) converting
said compound to nelfinavir; wherein R(1) is substituted or
unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or
heteroaryl, R(5) is a substituted or unsubstituted NH-alkyl,
NH-aryl, O-alkyl, or O-aryl group, wherein each alkyl or aryl
moiety may be substituted or unsubstituted, R(10) is a suitable
hydroxyl protecting group and R(11) is H or substituted alkyl
sulfonyl.
15. The method according to any one of claims 1 to 10 wherein R(1)
is CF.sub.3, a substituted or unsubstituted phenyl, or a
C.sub.1-C.sub.6 alkyl.
16. The method according to any one of claims 1 to 10 wherein R(1)
is 116
17. The method according to any one of claims 7 to 9 or 11 to 13,
comprising treating the tetrahydrofuran with about 1 to about 20
molar equivalents of the oxophilic electrophilic reagent.
18. The method according to any one of claims 7 to 9 or 11 to 13,
wherein said oxophilic electrophilic reagent comprises a
combination of about 1 to about 20 molar equivalents of a suitable
acid and about 1 to about 20 molar equivalents of a suitable acid
anhydride, wherein the anhydride and the acid are used in a
relative molar ratio of from about 1:5 to about 5:1,
respectively.
19. The method according to any one of claims 7 to 9 or 11 to 13,
wherein said oxophilic electrophilic reagent comprises a
combination of about 2 to about 20 molar equivalents of a suitable
acid and about 2 to about 20 molar equivalents of a suitable acid
anhydride, wherein the anhydride and the acid are used in a
relative molar ratio of from about 1:1 to about 5:1,
respectively.
20. The method according to any one of claims 7 to 9 or 11 to 13,
wherein said oxophilic electrophilic reagent comprises about 7.5
molar equivalents of a suitable acid and 15 molar equivalents of a
suitable acid anhydride.
21. The method according to any one of claims 7 to 9 or 11 to 13,
wherein R(3) is methyl or phenyl.
22. The method according to any one of claims 7 to 9 or 11 to 13,
wherein said tetrahydrofuran-amide is treated with acetic anhydride
and sulfuric acidic to form said oxazoline.
23. The method according to claim 15 wherein R(3) is methyl.
24. The method according to any one of claims 7 to 10, wherein the
amino-tetrahydrofuran is treated with an compound having the
formula R(1)COX, wherein X is chloro or bromo, to form the
tetrahydrofuran-amide and R(1) is 117
25. The method according to claims 11 to 14 wherein R(5) is
HN-t-Bu.
26. The method according to claim 12, wherein R(7) is
trialkylsilyl, dialkyl-monoarylsilyl, diaryl-monoalkylsilyl,
substituted or unsubstituted aroyl or alkanoyl.
27. The method according to claim 12, wherein R(7) is
trimethylsilyl, tert-butyl-di-methylsilyl, benzoyl, or
para-nitrobenzoyl.
28. The method according to claim 12, wherein R(7) is a
para-nitrobenzoyl.
29. The method according to claim 13, wherein R(8) is a substituted
or unsubstituted alkyl or aryl sulfonyl.
30. The method according to claim 13, wherein R(8) is
p-toluenesulfonyl.
31. A method of the preparation of a chiral amino-tetrahydrofuran,
1, or a salt thereof: 118said method comprising the steps of: (1)
treating an epoxy-tetrahydrofuran having the formula: 119 with an
aminating reagent to form a stereoisomeric mixture of
amino-tetrahydrofurans having the formulae: 120(2) treating the
amino-tetrahydrofuran mixture in a manner effective to separate the
amino-tetrahydrofuran stereoisomers, and (3) isolating the
amino-tetrahydrofuran, 1, or a salt thereof; wherein R(6) is
hydrogen or a suitable nitrogen protecting group.
32. The method according to claim 31, wherein the
amino-tetrahydrofuran, 1, is substantially enantiomerically
pure.
33. The method according to claim 31, wherein R(6) is a substituted
or unsubstituted alkanoyl, aroyl, arylalkylcarbonyl, arylalkyl,
heteroarylalkyl, wherein the alkyl, aryl or heteroaryl is
substituted or unsubstituted.
34. The method according to claim 31, wherein the aminating reagent
is a chiral aminating reagent.
35. The method according to claim 34, wherein R(6) is 121
36. The method according to claim 34, comprising separating the
amino-tetrahydrofuran stereoisomers by crystallization or
chromatography.
37. The method according to claim 36, further comprising removing
the R(6) substituent from the separated amino-tetrahydrofuran
stereoisomers.
38. The method according to claim 31, wherein the aminating reagent
is an achiral aminating reagent.
39. The method according to claim 38 further comprising treating
the amino-tetrahydrofuran mixture with a chiral auxiliary reagent
to produce diastereomeric amino-tetrahydrofurans.
40. The method according to claim 39, comprising separating the
amino-tetrahydrofuran diastereomers by crystallization or
chromatography.
41. The method according to claim 40, further comprising removing
the chiral auxiliary reagent from the separated
amino-tetrahydrofuran stereoisomers.
Description
[0001] This application claims benefit of the filing date of U.S.
Provisional Patent Application No. 60/160,695, the disclosure of
which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to chemical methods of preparing
intermediates in the synthesis of the protease inhibitor nelfinavir
mesylate and its free base, which is useful for treatment of HIV
infected individuals.
[0004] 2. Related Background Art
[0005] Treatment of HIV-infected individuals with HIV-protease
inhibitors has emerged as an important method for preventing or
inhibiting the rapid proliferation of the virus in human tissue.
HIV-protease inhibitors block a key enzymatic pathway in the virus
resulting in substantially decreased viral loads, which slows the
steady decay of the immune system and its resulting deleterious
effects on human health. The HIV-protease inhibitor nelfinavir
mesylate has shown to be an effective treatment for HIV-infected
individuals. Nelfinavir mesylate, and a method for its preparation
are disclosed in U.S. Pat. No. 5,484,926, which is incorporated
herein by reference. 1
[0006] Other procedures for the preparation of nelfinavir mesylate
and its free base have been reported. For example, PCT/JP96/02756
(WO97/11937) discloses the preparation of nelfinavir mesylate and
its free base using oxazoline intermediates, which may be obtained
from a 1,3-dioxepan-5-ol, or a derivative thereof. PCT/JP96/02757
(WO97/11938) discloses a related method, wherein the
1,3-dioxepan-5-ol is converted to nelfinavir mesylate and its free
base via N-benzyloxycarbonyl-amino-butane diol intermediates. Each
of these methods reportedly provide some improvement in the
efficiency of the preparation of nelfinavir. However, further
improvement would be desirable.
SUMMARY OF THE INVENTION
[0007] This invention relates to efficient and cost-effective
methods for the preparation of nelfinavir mesylate and its free
base. Specifically, the methods of this invention comprise the
preparation of an oxazoline, 2
[0008] comprising treating the tetrahydrofuran, wherein R.sub.a is
--COR(1) and R.sub.b is hydrogen, --COR(3), --SO.sub.2R(2) or a
suitable hydroxyl protecting group, with an oxophilic electrophilic
reagent in a manner that is effective to provide the oxazoline,
wherein R.sub.b is hydrogen, --COR(3), --SO.sub.2R(2) or a suitable
hydroxyl protecting group and R.sub.c is H, --COR(3) or
--SO.sub.2R(2); wherein R(1), R(2) and R(3) independently represent
a substituted or unsubstituted alkyl, aryl, cycloalkyl,
heterocycloalkyl or heteroaryl group. Advantageously, the methods
of this invention provide nelfinavir mesylate and its free base in
relatively high yield and employ fewer synthetic steps than the
prior art methods.
[0009] This invention also relates to methods for making
intermediate compounds that are useful in the method of preparation
of nelfinavir mesylate and its free base. In addition, this
invention relates to methods for the preparation of chiral starting
materials that are useful in the methods for the preparation of
nelfinavir mesylate and its free base according to this
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0010] This invention provides novel and useful methods for the
conversion of amino-tetrahydrofuran derivatives to oxazoline
intermediates that are useful in the preparation of nelfinavir
mesylate and nelfinavir free base. All compounds of the inventive
methods of this invention that contain at least one chiral center
may exist as single stereoisomers, racemates and/or mixtures of
enantiomers and/or diastereomers unless otherwise indicated. All
such single stereoisomers, racemates and mixtures thereof are
intended to be within the scope of this invention. Moreover, the
scope of this invention is not intended to be limited to reactions
of selected isomers. Although the reaction schemes described herein
may be illustrated using compounds depicted as a single enantiomer
or diastereomer, the methods of this invention are intended to
encompass reactions of any isomer or racemic mixture of these
compounds.
[0011] When used to describe a particular compound, the term
"chiral" is used herein to indicate that the compound is
substantially enantiomerically and/or diastereomerically pure, for
example, as in the term "chiral amino-tetrahydrofuran." Compounds
that are substantially enatiomerically pure contain at least 90% of
a single isomer and preferably contain at least 95% of a single
isomer. More preferably, the chiral compounds in this invention
contain at least 97.5% of a single isomer and most preferably
contain at least 99% of a single isomer. Compounds identified
herein as single stereoisomers are meant to describe compounds that
are present in a form that contains at least 90% of a single
isomer. The term "racemic" or "racemic mixture" refers to a mixture
of equal amounts of enantiomeric compounds, which encompasses
mixtures of enantiomers and/or mixtures of enantiomeric
diastereomers.
[0012] The method of this invention provides for the conversion of
an amino-tetrahydrofuran, I, to an oxazoline, II, as illustrated
below: 3
[0013] wherein R.sub.a is hydrogen or --COR(1)
[0014] R.sub.b is hydrogen, --COR(3), --SO.sub.2R(2) or a suitable
hydroxyl protecting group;
[0015] R.sub.c is hydrogen, --COR(3) or --SO.sub.2R(2);
[0016] wherein R(1), R(2) and R(3) independently represent a
substituted or unsubstituted alkyl, aryl, cycloalkyl,
heterocycloalkyl or heteroaryl group.
[0017] As used herein, the term "alkyl" represents a straight or
branched chain alkyl group, preferably having one to eight, more
preferably having one to six, and most preferably having from one
to four carbon atoms. The term "C.sub.1-C.sub.6 alkyl" represents a
straight or branched alkyl chain having from one to six carbon
atoms. Exemplary C.sub.1-C.sub.6 alkyl groups include methyl,
ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,
pentyl, neo-pentyl, hexyl, isohexyl, and the like. The term
"C.sub.1-C.sub.6 alkyl" includes within its definition the term
"C.sub.1-C4 alkyl."
[0018] The term "cycloalkyl" represents a group comprising a
saturated or partially unsaturated, mono- or poly-carbocyclic ring,
preferably having 5-14 ring carbon atoms. Exemplary cycloalkyls
include monocyclic rings having from 3-7, preferably 3-6, carbon
atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cyclohexenyl, cycloheptyl and the like. An exemplary
cycloalkyl is a C.sub.5-C.sub.7 cycloalkyl, which is a hydrocarbon
ring structure containing from five to seven carbon atoms.
[0019] The term "aryl" represents a group comprising an aromatic,
monovalent monocyclic, bicyclic, or tricyclic radical containing 6,
10, 14, or 18 carbon ring atoms, to which may be fused one or more
cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups
which may be unsubstituted or substituted by one or more of the
substituents described below Illustrative examples of aryl groups
include, but are not limited to, phenyl, napthyl, anthryl,
phenanthryl, fluoren-2-yl, indan-5-yl, and the like.
[0020] The term "heterocycloalkyl" represents a group comprising a
non-aromatic, monovalent monocyclic, bicyclic, or tricyclic
radical, which is saturated or unsaturated, containing 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms and which
includes 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen,
oxygen and sulfur, and to which may be fused one or more cycloalkyl
groups, aryl groups, or heteroaryl groups which may be
unsubstituted or substituted by one ore more of the substituents
described below. Illustrative examples of heterocycloalkyl groups
include, but are not limited to azetidinyl, pyrrolidyl, piperidyl,
piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazi- nyl,
tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl,
1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl,
1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl,
azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl,
oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.
[0021] The term "heteroaryl" represents a group comprising an
aromatic monovalent monocyclic, bicyclic, or tricyclic radical,
containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18
ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from
nitrogen, oxygen and sulfur, to which may be fused one or more
cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which
may be unsubstituted or substituted by one or more of the
substituents described below. Illustrative examples of heteroaryl
groups include, but are not limited to, thienyl, pyrrolyl,
imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl,
thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,
benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl,
chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl,
indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,
naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl,
benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl,
carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl,
perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl,
phenothiazinyl, and phenoxazinyl.
[0022] In this invention, each of the above alkyl, aryl,
cycloalkyl, heterocycloalkyl, or heteroaryl groups may be
substituted by one or more substituents. If the substituents
themselves are not compatible with the methods of this invention,
the substituent may be protected with a suitable protecting group
that is stable to the reaction conditions used in these methods.
The protecting group may be removed at a suitable point in the
reaction sequence of the method to provide a desired intermediate
or target compound. Suitable protecting groups and the methods for
protecting and de-protecting different substituents using such
suitable protecting groups are well known to those skilled in the
art; examples of which may be found in T. Green & P. Wuts,
Protective Groups in Organic Synthesis (2nd Ed. 1991), which is
incorporated herein by reference in its entirety. In some
instances, a substituent may be specifically selected to be
reactive under the reaction conditions used in the methods of this
invention. Under these circumstances, the reaction conditions
convert the selected substituent into another substituent that is
either useful in an intermediate compound in the methods of this
invention or is a desired substituent in a target compound.
[0023] Exemplary substituents that may be present on an alkyl group
include aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro
(NO.sub.2), amino, alkylamino, dialkylamino, carbamoyl,
alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,
dialkylamino, alkoxy, aryloxy, halogen, hydroxyl, alkanoyl,
acyloxy, aroyl, aroyloxy, carboxyl, alkoxycarbonyl,
aryloxycarbonyl, alkylcarbonylamino, arylcarbonylamino, mercapto,
alkylthio, arylthio, wherein any of the aryl, cycloalkyl,
heterocycloalkyl, heteroaryl moieties present in the above
substituents may be further substituted by one or more of alkyl,
aryl, nitro (NO.sub.2), amino, halogen, hydroxyl, alkoxy, aryloxy,
mercapto, alkylthio or arylthio. Exemplary substituents that may be
present on the above aryl, cycloalkyl, heterocycloalkyl or
heteroaryl groups include alkyl, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, nitro (NO.sub.2), amino, alkylamino,
dialkylamino, carbamoyl, alkylaminocarbonyl, dialkylaminocarbonyl,
arylaminocarbonyl, dialkylamino, alkoxy, aryloxy, halogen,
hydroxyl, alkanoyl, acyloxy, aroyl, aroyloxy, carboxyl,
alkoxycarbonyl, aryloxycarbonyl, alkylcarbonylamino,
arylcarbonylamino, mercapto, alkylthio, arylthio, wherein any of
the alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties
present in the above substituents may be further substituted by one
or more of alkyl, aryl, nitro (NO.sub.2), amino, halogen, hydroxyl,
alkoxy, aryloxy, mercapto, alkylthio or arylthio.
[0024] The terms "halogen" and "halo" represent chloro, fluoro,
bromo or iodo substituents.
[0025] Exemplary substituted alkyls include
halo(C.sub.1-C.sub.4)alkyl, which represents a straight or branched
alkyl chain having from one to four carbon atoms with 1-3 halogen
atoms attached to it. Exemplary halo(C.sub.1-C.sub.4)alkyl groups
include chloromethyl, 2-bromoethyl, 1-chloroisopropyl,
3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl,
trifluoromethyl, and the like. Another exemplary substituted alkyl
is hydroxy(C.sub.1-C.sub.4)alkyl, which represents a straight or
branched alkyl chain having from one to four carbon atoms with a
hydroxy group attached to it. Exemplary hydroxy(C.sub.1-C.sub.4)al-
kyl groups include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2-hydroxyisopropyl, 4-hydroxybutyl, and the like. Yet another
exemplary substituted alkyl is C.sub.1-C.sub.4
alkylthio(C.sub.1-C.sub.4)alkyl, which is a straight or branched
C.sub.1-C.sub.4 alkyl group with a C.sub.1-C.sub.4 alkylthio group
attached to it. Exemplary C.sub.1-C.sub.4
alkylthio(C.sub.1-C.sub.4)alkyl groups include methylthiomethyl,
ethylthiomethyl, propylthiopropyl, sec-butylthiomethyl, and the
like. Another exemplary substituted alkyl is
heterocycloalkyl(C.sub.1-C.sub.4)a- lkyl or
heteroaryl(C.sub.1-C.sub.4)alkyl, which is a straight or branched
alkyl chain having from one to four carbon atoms to which is
attached a heterocycloalkyl or heteroaryl group. Exemplary
heterocycloalkyl(C.sub.1-- C.sub.4)alkyl and
heteroaryl(C.sub.1-C.sub.4)alkyl groups include pyrrolylmethyl,
quinolinylmethyl, 1-indolylethyl, 2-furylethyl, 3-thien-2-ylpropyl,
1-imidazolyisopropyl, 4-thiazolylbutyl and the like. Yet another
exemplary substituted alkyl is aryl(C.sub.1-C.sub.4)alkyl, which is
a straight or branched alkyl chain having from one to four carbon
atoms with an aryl group attached to it. Exemplary
aryl(C.sub.1-C.sub.4)alkyl groups include phenylmethyl (benzyl),
2-phenylethyl, 3-naphthyl-propyl, 1-naphthylisopropyl,
4-phenylbutyl and the like.
[0026] Exemplary substituted aryls include a phenyl or naphthyl
ring substituted with one or more substituents, preferably one to
three substituents, independently selected from halogen, hydroxyl,
morpholino(C.sub.1-C.sub.4)alkoxycarbonyl, pyridyl
(C.sub.1-C.sub.4)alkoxycarbonyl, halo(C.sub.1-C.sub.4)alkyl,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, carboxy,
C.sub.1-C.sub.4 alkoxycarbonyl, carbamoyl,
N--(C.sub.1-C.sub.4)alkylaminocarbonyl, amino,
C.sub.1-C.sub.4alkylamino, di(C.sub.1-C.sub.4)alkylamino or a group
of the formula --(CH.sub.2).sub.a--R.sub.7 where a is 1, 2, 3 or 4
and R.sub.7 is hydroxy, C.sub.1-C.sub.4 alkoxy, carboxy,
C.sub.1-C.sub.4 alkoxycarbonyl, amino, carbamoyl, C.sub.1-C.sub.4
alkylamino or di(C.sub.1-C.sub.4)alkylamino.
[0027] Exemplary substituted heterocycloalkyls and heteroaryls may
be substituted with 1,2 or 3 substituents independently selected
from halogen, halo(C.sub.1-C.sub.4)alkyl, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, carboxy, C.sub.1-C.sub.4 alkoxycarbonyl,
carbamoyl, N--(C.sub.1-C.sub.4)alkylcarbamoyl
N--(C.sub.1-C.sub.4)alkylam- inocarbonyl, amino,
C.sub.1-C.sub.4alkylamino, di(C.sub.1-C.sub.4)alkylami- no or a
group having the structure --(CH.sub.2).sub.a--R.sup.7 where a is
1, 2, 3 or 4 and R.sup.7 is hydroxy, C.sub.1-C.sub.4 alkoxy,
carboxy, C.sub.1-C.sub.4 alkoxycarbonyl, amino, carbamoyl,
C.sub.1-C.sub.4alkylami- no or di(C.sub.1-C.sub.4)alkylamino.
[0028] Examples of substituted heterocycloalkyls include, but are
not limited to, 3-N-t-butyl carboxamide decahydroisoquinolinyl and
6-N-t-butyl carboxamide octahydro-thieno[3,2-c]pyridinyl. Examples
of substituted heteroaryls include, but are not limited to,
3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl,
4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl,
3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl,
4-methylisoquinolinyl, 6,8-dibromoquinolinyl, 4,8-dimethylnaphthyl,
2-methyl-1,2,3,4-tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl,
2-t-butoxycarbonyl-1,2,3,4-isoquinolin-7-yl and the like.
[0029] In general terms, the conversion of a tetrahydrofuran, I, to
an oxazoline, II, may be conducted by treatment of the
tetrahydrofuran, wherein R.sub.a is --COR(1) and R.sub.b is
hydrogen, --COR(3), --SO.sub.2R(2) or a suitable hydroxyl
protecting group, with an oxophilic electrophilic reagent that
facilitates tetrahydrofuran ring-opening to provide the oxazoline,
wherein R.sub.b is hydrogen, --COR(3), --SO.sub.2R(2) or a suitable
hydroxyl protecting group and R.sub.c is hydrogen, --COR(3) or
--SO.sub.2R(2). Accordingly, the hydroxyl protecting groups that
may be suitable for use in the method of this invention (as
R.sub.b) include those hydroxyl protecting groups that are stable
to the oxophilic electrophilic reagents or reagent combinations
described herein. Suitable protecting groups and the methods for
protecting and de-protecting hydroxyl substituents using such
suitable protecting groups are well known to those skilled in the
art; examples of which may be found in T. Green & P. Wuts,
supra.
[0030] Typically, the first step in the method of this invention
comprises the formation of the chiral tetrahydrofuran amide, B,
from the known amino-tetrahydrofuran, A, using any suitable,
conventional procedure. Examples of such conventional procedures
may be found in T. Green & P. Wuts, supra, and include
treatment with a suitable acid halide, R(1)COX, in the presence of
a base, where X is a halogen, treatment with a suitable acid,
R(1)COOH, in the presence of a suitable coupling reagent, e.g.
dicyclohexylcarbodiimide, and the like. Preferably, this reaction
is conducted using an acid chloride in the presence of
triethylamine base. 4
[0031] In one embodiment of this invention, the hydroxyl moiety of
the chiral tetrahydrofuran amide, B, may be substituted by R.sub.b,
where R.sub.b is --SO.sub.2R(2) or a suitable protecting group, as
defined above. Preferably, the hydroxyl moiety is converted to an
alkyl or arylsulfonate (--SO.sub.2R(2)), more preferably, a
mesylate or tosylate. The methods for forming such --OSO.sub.2R(2)
groups are well know in the art and may be accomplished using any
suitable conventional procedure. Examples of such conventional
procedures may also be found in T. Green & P. Wuts, supra.
Preferably, this reaction is conducted using methanesulfonyl
chloride or p-toluenesulfonyl chloride in the presence of
triethylamine base. 5
[0032] This hydroxy-substituted, chiral tetrahydrofuran amide, C,
may then be converted to a chiral oxazoline, D. This conversion may
be conducted using an oxophilic electrophilic reagent that
facilitates tetrahydrofuran ring-opening and oxazoline
ring-formation. As used herein the term "oxophilic electrophilic
reagent" refers to a single reagent, or a set of reagents which
when combined generate an oxophilic electrophilic intermediate,
which facilitates tetrahydrofuran ring-opening and oxazoline
ring-formation. Examples of oxophilic electrophilic reagents
include, but are not limited to, suitable oxophilic Lewis acids
(for example, metal halide Lewis acids, such as titanium
tetrachloride, or strong oxophilic protic acids, such as
trifluoromethanesulfonic acid (triflic acid)), a suitable acid
anhydride, a combination of a suitable acid anhydride or a suitable
acid halide with a suitable Lewis acid. Suitable anhydrides and
acid halides include the anhydrides and acid halides (e.g., acid
chlorides) of any conventional alkyl or aryl carboxylic or sulfonic
acid as well as anhydrides of strong acids, for example, triflic
anhydride. Suitable Lewis acids include well-known metal halide
Lewis acids, such as titanium tetrachloride, aluminum trichloride
and the like, and strong protic acids, such as sulfuric acid,
nitric acid, phosphoric acid, trifluoroacetic acid,
trifluoromethanesulfonic acid and the like. Generally, the reaction
of the tetrahydrofuran-amide with an oxophilic electrophilic
reagent to form the oxazoline may be conducted at a temperature of
between -40.degree. C. and 70.degree. C. in aprotic solvents,
including, but not limited to ethyl acetate, isopropyl acetate,
dichloromethane, benzene and toluene, using about 1 to about 20
molar equivalents of the oxophilic electrophilic reagent (relative
to the tetrahydrofuran-amide).
[0033] In the course of this reaction, the primary hydroxyl moiety
formed on opening of the tetrahydrofuran may become substituted
with the "cationic" moiety of the acid used in the reaction. When
employing a Lewis acid or a strong protic acid as the oxophilic
electrophilic reagent, the resulting oxazoline contains an
unsubstituted primary hydroxyl moiety (where R.sub.c is H) either
because the "cationic moiety" of the acid is H.sup.+ or because the
rapid hydrolysis of any intermediate formed using such reagents
generates this product. The resulting hydroxyl moiety may be
converted to into any art-recognized derivative using conventional
techniques (e.g., an ether via alkylation, an ester via acylation,
a carbonate by treatment with an alkyl- or aryl-oxycarbonyl
chloride, or equivalent thereof, a carbamate by treatment with an
isocyante, etc.).
[0034] For the preparation of nelfinavir and nelfinavir mesylate,
the tetrahydrofuran amide is preferably converted to an
oxazoline-ester derivative by treatment with an oxophilic
electrophilic reagent comprising a suitable anhydride, for example,
triflic anhydride, or with a combination of an anhydride or acid
halide with a Lewis acid. Such reagents are capable of generating
acylium ion intermediates and are well known in the art. For
example, a suitable acylium intermediate may be prepared in situ by
treatment of a suitable acid anhydride, optionally with a suitable
protic acid, or by treatment of a suitable acid halide with a
suitable Lewis acid. Suitable acid anhydrides, acid halides and
Lewis acids are as described hereinabove. In the course of the
reaction employing these reagents, the primary hydroxyl moiety
formed on opening of the tetrahydrofuran becomes substituted with
the alkyl or aryl carboxyl moiety of the anhydride or acid halide
(illustrated as R.sub.c above, where R.sub.c is --COR(3), as
defined above) used in the reaction. As exemplified herein, a
useful oxophilic electrophilic reagent combination is comprised of
acetic anhydride and sulfuric acid. Accordingly, in this embodiment
of the method of this invention, the resulting oxazoline contains
an acetylated primary hydroxyl moiety.
[0035] Generally, conversion of the tetrahydrofuran-amide to the
oxazoline may be accomplished using an excess molar equivalent
amount of each reagent of an oxophilic electrophilic reagent
combination. This reaction may be conducted at a temperature of
between -40.degree. C. and 70.degree. C. in aprotic solvents,
including, but not limited to ethyl acetate, isopropyl acetate,
dichloromethane, benzene and toluene, using about 1 to about 20
molar equivalents of a suitable acid and about 1 to about 20 molar
equivalents of a suitable anhydride (relative to the
tetrahydrofuran-amide) and using the acid anhydride and acid in a
relative molar ratio of from about 1:5 to about 5:1
(anhydride:acid). Preferably, the conversion may be accomplished
using an excess molar equivalent amount of the oxophilic
electrophilic reagent, i.e., at least 2 to about 20 molar
equivalents of the oxophilic electrophilic reagent. More
preferably, the reaction may be conducted using about 2 to about 20
molar equivalents of acid and about 2 to about 20 molar equivalents
of a suitable anhydride, wherein the ratio of anhydride to acid is
from about 1:1 to about 5:1. For example, as exemplified herein,
the conversion may be accomplished using 7.5 equivalents of a
strong acid and 15 equivalents of an acid anhydride (i.e., wherein
the ratio of anhydride to acid is 2:1 (in the range of from about
1.5:1 to about 3:1).
[0036] As described in PCT/JP96/02756 (WO97/11937), the disclosure
of which is incorporated by reference herein, the resulting
oxazoline, D, may be used for the preparation of intermediates,
useful in the preparation of nelfinavir, especially Compounds 20
and 19, 6
[0037] where R(4) is a substituted or unsubstituted alkyl, aryl,
cycloalkyl, heterocycloalkyl, or heteroaryl group and R(5) is a
substituted or unsubstituted NH-alkyl, NH-aryl, O-alkyl, or O-aryl
group, wherein each alkyl or aryl moiety may be unsubstituted or
substituted with the substituents described above. 7
[0038] In another embodiment of the method of this invention, the
tetrahydrofuran-amide, B, may be directly converted to oxazoline,
E. The amide may be treated in a manner similar to that described
above. For example, the tetrahydrofuran-amide, B, may be treated
directly with a suitable acid anhydride in the presence of a
suitable acid, such as, for example, acetic anhydride and sulfuric
acid, to form an oxazoline diester, E. Each hydroxyl moiety of the
resulting oxazoline becomes substituted with the alkyl or aryl
carboxyl moiety (illustrated as --COR(3), where R(3) is as defined
above) of the anhydride used in the reaction. Accordingly, if
acetic anhydride is used in this method, both hydroxyl moieties of
the resulting oxazoline will be acetylated. 8
[0039] Each of the alkyl or aryl carboxyl moieties of oxazoline
diester, E, may be removed (hydrolyzed to the corresponding
hydroxyl moieties) using conventional procedures, for example, by
treatment with a suitable base in a suitable solvent, to form the
oxazoline diol, F. Bases that are suitable for effecting this
hydrolysis are well known in the art and include potassium
carbonate, sodium hydroxide, potassium hydroxide, and the like.
Solvents that are suitable for this hydrolysis are similarly well
known in the art and include, but are not limited to, lower
alkanols (methanol, ethanol, isopropanol, etc.). Examples of other
conventional procedures for the hydrolysis of esters may be found
in T. Green & P. Wuts, supra. 9
[0040] Conversion of the oxazoline diol, F, to nelfinavir via
compound 19 may be conducted in a manner similar to that described
in PCT/JP96/02757 (WO97/11938) for the conversion of 2(R),
3-dihydroxy-1(R)-phenylsulfanylm- ethyl-propyl)-carbamic acid
benzyl ester to nelfinavir mesylate and its free base. The
disclosure of PCT/JP96/02757 (WO97/11938) is incorporated by
reference herein. For example, selective functionalization of the
primary and secondary hydroxyl moieties of oxazoline diol, F, may
be accomplished by first selectively protecting the primary
hydroxyl moiety using a suitable hydroxyl protecting group.
Suitable hydroxyl protecting groups and the methods for protecting
and de-protecting hydroxyl substituents using such suitable
protecting groups are well known to those skilled in the art;
examples of which may be found in T. Green & P. Wuts, supra.
Preferably, the primary hydroxyl moiety is protected as a
para-nitrobenzoate ester. The secondary hydroxyl moiety may
thereafter be functionalized by conversion to a leaving group. The
term "leaving group" as used herein refers to any group that
departs from a molecule in a substitution reaction by breakage of a
bond. Examples of leaving groups include, but are not limited to,
substituted or unsubstituted arylsulfonates and alkylsulfonates,
prepared using a substituted or unsubstituted aryl or alkylsulfonyl
halide. Preferably, the hydroxyl moiety is converted to a mesylate.
This sulfonylated-protected oxazoline may then be converted to
Compound 20 by addition of
3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline (PHIQ), as
described in PCT/JP96/02757.
[0041] In a preferred embodiment of the method of this invention,
R(1) is 10
[0042] where the R.sub.p is a suitable phenolic hydroxyl protecting
group, examples of which may be found in T. Green and P. Wuts,
supra. In a more preferred embodiment of this invention, R(1) is
11
[0043] wherein the acetyl moiety used to protect the phenolic
hydroxyl moiety is reactive to the hydrolysis conditions used to
convert E to F. Accordingly, in this embodiment of the invention,
oxazoline F is a triol, wherein R(1) is 12
[0044] Selective functionalization of the phenolic, primary and
secondary hydroxyl moieties of the oxazoline triol, may be
accomplished by first selectively protecting the phenolic hydroxyl
moiety using a suitable hydroxyl protecting group. Preferably, the
phenolic hydroxyl moiety is protected as a para-nitrobenzoate
ester. The primary hydroxyl moiety may then be protected using the
same or different protecting group. If the same protecting groups
is used, the phenolic and primary hydroxyl moieties may be
protected in a single step. The secondary hydroxyl moiety may
thereafter be functionalized by conversion to a mesylate. This
sulfonylated-di-protected oxazoline may then be converted to
Compound 20 by addition of
3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline (PHIQ), in a
manner similar to that described in PCT/JP96/02757.
[0045] This invention also provides a method for the preparation of
a chiral tetrahydrofuran amide, wherein the 4-hydroxyl moiety
possesses stereochemistry opposite to that of the chiral
tetrahydrofuran amide, B, described hereinabove. This method
comprises conversion of the tetrahydrofuran amide, B, to a fused
tetrahydrofuranyloxazoline, G, by treatment with a substituted or
unsubstituted sulfonylating reagent using two equivalents of a
base. This reaction may be conducted at a temperature of between
-78.degree. C. and 100.degree. C. in suitable solvents, including,
but not limited to ethyl acetate, isopropyl acetate, toluene,
benzene, dichloromethane, tetrahydrofuran, and the like. 13
[0046] This fused heterocycle, G, may then be converted to chiral
tetrahydrofuran amide, H, by treatment with aqueous acids,
including, but not limited to, aqueous hydrochloric acid sulfuric
acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric
acid, and the like. This reaction may be conducted at a temperature
of between -40.degree. C. and 100.degree. C. in suitable solvents,
including, but not limited to water, alcoholic solvents, or
mixtures thereof, where suitable alcoholic solvents include, but
are not limited to lower alkanols, such as methanol, isopropanol,
ethanol, and the like. 14
[0047] The tetrahydrofuran-amide, H, may be converted to the
oxazoline diester, J, by treatment with an acid anhydride and an
acid, according the methods described above. Hydrolysis of the
alkyl or aryl carboxyl moieties of the oxazoline diester, J, to
form diol, K, may also be accomplished according to the methods
described above. 15
[0048] The primary hydroxyl moiety of the resulting oxazoline diol,
K, may be functionalized by conversion to a leaving group, by
treatment with a substituted or unsubstituted aryl or alkylsulfonyl
halide, as described above. Preferably, the primary hydroxyl is
converted to a tosylate or mesylate. Treatment of this
functionalized oxazoline with a nucleophile,
3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline (PHIQ) in
the presence of a base, under conventional conditions, provides
Compound 19. Conversion of Compound 19 into nelfinavir may be
accomplished in a manner similar to that described in
PCT/JP96/02757.
[0049] In another embodiment of this invention, the
tetrahydrofuran-amide, H, 16
[0050] may be converted to a protected tetrahydrofuran-amide, L,
where R(10) may be any suitable hydroxyl protecting group. 17
[0051] The protected tetrahydrofuran-amide, L, may then be
converted directly to a protected oxazoline, M, by treatment with
an oxophilic Lewis acid, an oxophilic protic acid, or triflic
anhydride, wherein R(10) is any suitable protecting group for a
hydroxyl moiety and R(11) is H or substituted alkyl sulfonyl.
18
[0052] Conversion of the protected oxazoline, M, to nelfinavir may
be conducted in a manner similar to that described hereinabove.
[0053] This invention further provides a method for the preparation
of the chiral amino-tetrahydrofuran, A, or a salt thereof, 19
[0054] comprising treating the achiral fused epoxy-tetrahydrofuran,
N, 20
[0055] with an amine reagent to form Compounds O or P, or a mixture
thereof. This reaction may be conducted at a temperature of between
-50.degree. C. and 100.degree. C. in suitable solvents, including,
but not limited to alcoholic solvents, such as methanol,
isopropanol, ethanol, and the like or aprotic solvents, such as
isopropyl acetate, ethyl acetate, tetrahydrofuran, and the like.
21
[0056] The amine reagent used in this method may be a chiral or an
achiral aminating reagent. If the aminating reagent is chiral
(i.e., R(6) is a chiral moiety), the mixture of
amino-tetrahydrofurans formed is a diastereomeric mixture that may
be treated using conventional techniques to provide separated
amino-tetrahydrofuran diastereoisomers. After the isomers are
separated, the chiral moiety of the chiral aminating reagent may be
removed to provide each of the resolved amino-tetrahydrofuran
enantiomers, or salts thereof. For the purposes of this separation,
substituent R(6) is a suitable nitrogen protecting group that
possesses a chiral center that is substantially enantiomerically
pure. Preferably, R(6) is composed of at least 97.5% of a single
isomer and more preferably, is composed of at least 99% of a single
isomer. Moreover, the R(6) nitrogen protecting group must be
removable under conditions that do not racemize the chiral
amino-tetrahydrofuran, 1. Preferably, R(6) is a substantially
enantiomerically pure substituted or unsubstituted alkanoyl, aroyl,
arylalkylcarbonyl, arylalkyl or heteroarylalkyl, wherein the alkyl,
aryl or heteroaryl moieties may be substituted with any of the
alkyl, aryl or heteroaryl moieties described above. Most
preferably, R(6) is 22
[0057] If the aminating reagent is achiral, for example, ammonia,
the mixture of amino-tetrahydrofurans formed is an enantiomeric
mixture that may be treated with a chiral reagent in a manner
effective to provide a diastereomeric mixture of
amino-tetrahydrofurans, wherein the chiral reagent contains a
chiral auxiliary substituent. This diastereomeric mixture may be
treated using conventional techniques to provide separated
amino-tetrahydrofuran diastereoisomers. After the isomers are
separated, the chiral auxiliary substituent may be separated from
each of the separated amino-tetrahydrofurans to provide the
resolved amino-tetrahydrofuran enantiomers, or salts thereof.
[0058] Exemplary techniques useful for the separation of
stereoisomers are described in Enantiomers, Racemates and
Resolutions, J. Jacques, A. Collet, S. Wilen, Krieger Pub. Co.,
(1991) Malabar, Fla., the disclosure of which is incorporated
herein by reference. Examples of such separation techniques include
crystallization, chromatography, and the like. Advantageously, the
chiral amino-tetrahydrofuran prepared by this method is
substantially enantiomerically pure, containing at least 90% of a
single isomer and preferably containing at least 95% of a single
isomer. More preferably, the chiral amino-tetrahydrofuran prepared
by this method contains at least 97.5% of a single isomer and most
preferably contains at least 99% of a single isomer.
[0059] Specifically, this invention provides a method for the
preparation of: 23
[0060] wherein R(1) is substituted or unsubstituted alkyl, aryl,
cycloalkyl, heterocycloalkyl or heteroaryl, as defined above.
Preferably, R(1) is a substituted or unsubstituted phenyl, or a
substituted or unsubstituted C.sub.1-C.sub.6 alkyl. More
preferably, R(1) is a substituted phenyl or CF.sub.3. 24
[0061] R(2) is a substituted or unsubstituted alkyl, aryl,
cycloalkyl, heterocycloalkyl or heteroaryl. Preferably, R(2) is a
substituted or unsubstituted alkyl or aryl. More preferably, R(2)
is methyl, phenyl or tolyl. Most preferably, R(2) is methyl. R(3)
is a substituted or unsubstituted alkyl, aryl, cycloalkyl,
heterocycloalkyl or heteroaryl. Preferably, R(3) is a substituted
or unsubstituted alkyl or aryl. More preferably, R(3) is methyl or
phenyl. Most preferably, R(3) is methyl.
[0062] A preferred embodiment of this method comprises the steps
of:
[0063] (1) treating amino-tetrahydrofuran, 1, or a salt thereof,
25
[0064] in a manner that is effective to convert the
amino-tetrahydrofuran, 1, or a salt thereof, to
tetrahydrofuran-amide, 2, 26
[0065] (2) treating tetrahydrofuran-amide, 2, in a manner that is
effective to convert the tetrahydrofuran-amide, 2, to
tetrahydrofuran amide-sulfonate, 3, 27
[0066] comprising the step-wise treatment of tetrahydrofuran-amide,
2, with at least one molar equivalent amount of a sulfonylating
reagent, followed by treatment with a base, wherein the molar
equivalent amount of base used in the treatment is less than the
molar equivalent amount of the sulfonylating reagent, and
[0067] (3) treating tetrahydrofuran amide-sulfonate, 3, in a manner
that is effective to convert the tetrahydrofuran amide-sulfonate,
3, to the oxazoline, 18.
[0068] Preferably, tetrahydrofuran-amide, 2, may be treated first
with a substituted or unsubstituted alkyl or aryl sulfonyl
chloride, followed by treatment with less than a molar equivalent
amount (with respect to the amount of sulfonyl chloride) of a base,
in a manner effective to convert the tetrahydrofuran-amide, 2, to
tetrahydrofuran amide-sulfonate, 3, and tetrahydrofuran
amide-sulfonate, 3, may be treated with an oxophilic electrophilic
reagent in a manner that is effective to convert the
tetrahydrofuran amide-sulfonate, 3, to the oxazoline, 18.
[0069] This invention also provides a method for the preparation of
Compound 19: 28
[0070] wherein R(4) is a substituted or unsubstituted alkyl, aryl,
cycloalkyl, heterocycloalkyl, or heteroaryl group and R(5) is a
substituted or unsubstituted NH-alkyl, NH-aryl, O-alkyl, or O-aryl
group, wherein each alkyl or aryl moiety may be substituted or
unsubstituted with the substituents described above. Most
preferably, R(4) is 29
[0071] and R(5) is N-t-butyl. This method is comprised of the
following steps:
[0072] (1) treating amino-tetrahydrofuran, 1, or a salt thereof,
30
[0073] in a manner that is effective to convert the
amino-tetrahydrofuran, 1, or a salt thereof, to
tetrahydrofuran-amide, 2, 31
[0074] (2) treating tetrahydrofuran-amide, 2, in a manner that is
effective to convert the tetrahydrofuran-amide, 2 to
tetrahydrofuran amide-sulfonate, 3, 32
[0075] comprising the step-wise treatment of tetrahydrofuran-amide,
2, with at least one molar equivalent amount of a sulfonylating
reagent, followed by treatment with a base, wherein the molar
equivalent amount of base used in the treatment is less than the
molar equivalent amount of the sulfonylating reagent, and
[0076] (3) treating tetrahydrofuran amide-sulfonate, 3, in a manner
that is effective to convert the tetrahydrofuran amide-sulfonate,
3, to the oxazoline, 18, 33
[0077] (4) treating oxazoline, 18, in a manner that is effective to
convert the oxazoline, 18, to Compound 20, 34
[0078] and
[0079] (5) treating Compound 20 in a manner that is effective to
convert Compound 20 to Compound 19.
[0080] Preferably, tetrahydrofuran-amide, 2, may be treated first
with a substituted or unsubstituted alkyl or aryl sulfonyl
chloride, followed by treatment with less than a molar equivalent
amount (with respect to the amount of sulfonyl chloride) of a base,
in a manner effective to convert the tetrahydrofuran-amide, 2, to
tetrahydrofuran amide-sulfonate, 3, and tetrahydrofuran
amide-sulfonate, 3, may be treated with an oxophilic electrophilic
reagent in a manner that is effective to convert the
tetrahydrofuran amide-sulfonate, 3, to the oxazoline, 18; oxazoline
18 may be treated with
3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinolin- e in a
manner that is effective to convert oxazoline 18 to Compound 20,
which maybe converted to Compound 19, according to the procedures
described in PCT/JP96/02756 (WO97/11937).
[0081] Another method of this invention comprises the method for
the preparation of Compound 20: 35
[0082] comprising the steps of:
[0083] (1) treating amino-tetrahydrofuran, 1, or a salt thereof,
36
[0084] in a manner that is effective to convert the
amino-tetrahydrofuran, 1, or a salt thereof, to
tetrahydrofuran-amide, 2, 37
[0085] (2) treating tetrahydrofuran-amide, 2, in a manner that is
effective to convert the tetrahydrofuran-amide, 2, to oxazoline
triester, 4, 38
[0086] (3) treating oxazoline triester, 4, in a manner that is
effective to convert the oxazoline triester, 4, to oxazoline triol,
5, 39
[0087] (4) treating oxazoline, 5, in a manner that is effective to
convert the oxazoline triol, 5, to Compound 6 or Compound 7, 40
[0088] (5) treating Compound 7 in a manner that is effective to
convert Compound 7 to Compound 8, 41
[0089] (6) treating Compound 8 in a manner that is effective to
convert Compound 8 to Compound 20;
[0090] wherein R(7) is any suitable protecting group for a hydroxyl
moiety. Suitable hydroxyl protecting groups and the methods for
protecting and de-protecting hydroxyl substituents using such
suitable protecting groups are well known to those skilled in the
art; examples of which may be found in T. Green & P. Wuts,
supra. Preferably, R(7) is trialkylsilyl, dialkyl-monoarylsilyl,
diaryl-monoalkylsilyl, substituted or unsubstituted aroyl or
alkanoyl. Preferably, R(7) is trimethylsilyl,
tert-butyldimethylsilyl, benzoyl, para-nitrobenzoyl,
triisopropylsilyl, and the like. Most preferably, R(7) is a
para-nitrobenzoyl (PNB) moiety.
[0091] Preferably, tetrahydrofuran-amide, 2, may be treated with an
oxophilic electrophilic reagent in a manner that is effective to
convert the tetrahydrofuran-amide, 2, to oxazoline triester, 4.
Oxazoline triester, 4, may be hydrolyzed to oxazoline triol, 5. The
phenolic hydroxyl moiety of oxazoline triol, 5, may be protected
with a suitable hydroxyl protecting group, in a manner that is
effective to convert the oxazoline triol, 5, to protected
oxazoline, 6. Alternatively, both the phenolic and primary hydroxyl
moieties of oxazoline triol, 5, may be protected with a suitable
hydroxyl protecting group, in a manner that is effective to convert
the oxazoline triol, 5, to di-protected oxazoline, 7. Di-protected
oxazoline, 7, may be treated with a substituted or unsubstituted
alkyl or aryl sulfonylating reagent, in a manner that is effective
to convert the oxazoline, 7, to a sulfonylated-di-protected
oxazoline, 8. The sulfonylated-di-protected oxazoline, 8, may be
treated with 3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline
in a manner that is effective to convert the oxazoline, 8, to
Compound 20.
[0092] Yet another method according to this invention comprises a
method for the preparation of Compound 19: 42
[0093] This method comprises the steps of:
[0094] (1) converting amino-tetrahydrofuran, 1, 43
[0095] or a salt thereof to tetrahydrofuran-amide, 2, 44
[0096] (2) converting tetrahydrofuran-amide, 2, to oxazoline
triester, 4, 45
[0097] (3) converting oxazoline triester, 4 to oxazoline triol 5,
46
[0098] (4) converting oxazoline triol, 5 to di-protected oxazoline,
7; 47
[0099] wherein the di-protected oxazoline, 7, may be converted to
nelfinavir via Compound 19 using the method described in
PCT/JP96/02757.
[0100] For example, the di-protected oxazoline, 7, may be converted
to Compound 19 by the method comprising the steps of:
[0101] (1) converting di-protected oxazoline, 7, to
sulfonylated-di-protected oxazoline, 8, 48
[0102] (2) converting the sulfonylated-di-protected oxazoline, 8,
to Compound 20, 49
[0103] and
[0104] (3) converting Compound 20 to Compound 19.
[0105] Preferably, tetrahydrofuran-amide, 2, may be treated with an
oxophilic electrophilic reagent in a manner that is effective to
convert the tetrahydrofuran-amide, 2, to oxazoline triester, 4.
Oxazoline triester, 4, may be hydrolyzed to oxazoline triol, 5. The
phenolic and primary hydroxyl moieties of oxazoline triol, 5, may
be protected with a suitable hydroxyl protecting group, in a manner
that is effective to convert the oxazoline triol, 5, to
di-protected oxazoline, 7. The di-protected oxazoline, 7, may be
treated with a substituted or unsubstituted alkyl or aryl
sulfonylating reagent, in a manner that is effective to convert the
oxazoline, 7, to a sulfonylated-di-protected oxazoline, 8. The
sulfonylated-di-protected oxazoline, 8, may be treated with
3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner
that is effective to convert the oxazoline, 8, to Compound 20.
[0106] Still another method according to this invention relates to
a method for the preparation of Compound 19: 50
[0107] wherein the method comprises the steps of:
[0108] (1) converting amino-tetrahydrofuran, 1, or a salt thereof
to tetrahydrofuran-amide, 2,
[0109] (2) converting tetrahydrofuran-amide, 2, to fused
tetrahydrofuranyloxazoline, 9, 51
[0110] (3) converting the fused tetrahydrofuranyloxazoline, 9, to
tetrahydrofuran-amide, 10, 52
[0111] (4) converting the tetrahydrofuran-amide, 10, to an
oxazoline triester, 11, 53
[0112] (5) converting the oxazoline triester, 11, to oxazoline
triol, 12, 54
[0113] (6) converting the oxazoline triol, 12, to a functionalized
oxazoline, 13, 55
[0114] wherein R(8) together with the oxygen to which it is
attached forms a suitable leaving group and R(9) is H or R(8),
[0115] (7) converting the functionalized oxazoline, 13, to Compound
20, 56
[0116] (8) converting Compound 20 to Compound 19, 57
[0117] Preferably, tetrahydrofuran-amide, 2, may be treated with a
substituted or unsubstituted alkyl or aryl sulfonylating reagent,
in a manner effective to convert the tetrahydrofuran-amide, 2, to
fused tetrahydrofuranyloxazoline, 9. The fused
tetrahydrofuranyloxazoline, 9, may be hydrolyzed to
tetrahydrofuran-amide, 10. Tetrahydrofuran-amide, 10, may be
treated with an oxophilic electrophilic reagent in a manner that is
effective to convert the tetrahydrofuran-amide, 10, to oxazoline
triester, 11. Oxazoline triester, 11, may be hydrolyzed to
oxazoline triol, 12. Oxazoline triol, 12, may be functionalized by
treatment with a substituted or unsubstituted alkyl or aryl
sulfonylating reagent in a manner effective to convert oxazoline,
12, to a functionalized sulfonylated oxazoline, 13. Oxazoline, 13,
may be treated with
3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline in a manner
that is effective to convert the oxazoline to Compound 20.
[0118] Another method of this invention comprises the method for
the preparation of Compound 20: 58
[0119] comprising the steps of:
[0120] (1) treating amino-tetrahydrofuran, 1, or a salt thereof,
59
[0121] in a manner that is effective to convert the
amino-tetrahydrofuran, 1, or a salt thereof, to
tetrahydrofuran-hydroxy-a- mide, 10, 60
[0122] (2) treating tetrahydrofuran-hydroxy-amide, 10, in a manner
that is effective to protect the hydroxyl moiety of the
tetrahydrofuran-amide, 10, to form a protected
tetrahydrofuran-amide, 21, 61
[0123] (3) treating the protected tetrahydrofuran-amide, 21, in a
manner that is effective to convert the tetrahydrofuran-amide, 21,
to a protected oxazoline, 22, 62
[0124] (4) treating protected oxazoline, 22, in a manner that is
effective to convert the oxazoline, 22, to Compound 20;
[0125] wherein R(10) is any suitable protecting group for a
hydroxyl moiety and R(11) is H or substituted alkyl sulfonyl.
[0126] Suitable R(10) hydroxyl protecting groups and the methods
for protecting and de-protecting hydroxyl substituents using such
suitable protecting groups are well known to those skilled in the
art; examples of which may be found in T. Green & P. Wuts,
supra.
[0127] Preferably, the hydroxyl moiety of tetrahydrofuran-amide,
10, may be protected with a suitable hydroxyl protecting group, in
a manner that is effective to convert the tetrahydrofuran-amide,
10, to a protected tetrahydrofuran-amide, 21, where R(10) is any
suitable protecting group. The protected tetrahydrofuran-amide, 21,
may be treated with an oxophilic electrophilic reagent in a manner
that is effective to convert the protected tetrahydrofuran-amide,
21, to a protected oxazoline, 22. Preferably, the
tetrahydrofuran-amide, 21, is treated with an oxophilic Lewis acid,
an oxophilic protic acid, or triflic anhydride.
[0128] Another method of the invention relates to a method for
preparing a chiral amino-tetrahydrofuran, 1, or a salt thereof in
substantially diastereomerically pure form.
[0129] The method comprises the steps of: (1) converting fused
epoxy-tetrahydrofuran, 14, 63
[0130] to a stereoisomeric mixture of amino-tetrahydrofurans,
[0131] (2) treating the stereoisomeric mixture of
amino-tetrahydrofurans in a manner effective to resolve the
amino-tetrahydrofuran stereoisomers, and
[0132] (3) isolating the resolved stereoisomers of
amino-tetrahydrofuran, 1 and 1', or a salt thereof 64
[0133] The epoxy-tetrahydrofuran, 14, may be treated with an
aminating reagent to form the stereoisomeric mixture of
amino-tetrahydrofurans, 1 and 1'.
[0134] As described herein, the compounds of this invention may be
used as salts. The salts may be pharmaceutically acceptable salts.
The term "pharmaceutically acceptable salt" refers to those salts
that retain the biological effectiveness and properties of the free
acids and bases and/or that are not biologically or otherwise
undesirable.
[0135] Examples of pharmaceutically acceptable salts include, but
are not limited to, sulfates, pyrosulfates, bisulfates, sulfites,
bisulfites, phosphates, monohydrogenphosphates,
dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,
bromides, iodides, acetates, propionates, decanoates, caprylates,
acrylates, formates, isobutyrates, caproates, heptanoates,
propiolates, oxalates, malonates, succinates, suberates, sebacates,
fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,
benzoates, chlorobenzoates, methylbenzoates, nitrobenzoates,
dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,
sulfonates, phenylsulfonates, toluenesulfonates, methanesulfonates,
propanesulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, phenylacetates, phenylpropionates,
phenylbutyrates, citrates, lactates, hydroxybutyrates, glycolates,
tartrates and mandelates. Although any pharmaceutically acceptable
salt of the compounds described hereinabove may be prepared,
preferred salts are p-toluenesulfonate salts.
[0136] If a compound of an inventive method of this invention is a
base, the desired salt may be prepared by any suitable method known
to the art, including treatment of the free base with an acid. Such
treatment provides the salt as a protonated base, together with a
counterion, which may include, but is not limited to, inorganic
ions, such as halogens, pseudohalogens, sulfates, hydrogen
sulfates, nitrates, hydroxides, phosphates, hydrogen phosphates,
dihydrogen phosphates, perchlorates, and related complex inorganic
anions, and organic ions, such as carboxylates, sulfonates,
bicarbonates and carbonates. Exemplary acids useful in the method
of this invention include inorganic acids, such as hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid
and the like, and organic acids, such as acetic acid, maleic acid,
succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic
acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids
such as glucuronic acid and galacturonic acid, alpha-hydroxy acids
such as citric acid and tartaric acid, amino acids such as aspartic
acid and glutamic acid, aromatic acids such as benzoic acid and
cinnamic acid, sulfonic acids such as p-toluenesulfonic acid,
phenylsulfonic acid or methanesulfonic acid, or the like.
[0137] If a compound of an inventive method of this invention is an
acid, the desired salt may be prepared by any suitable method known
to the art, including treatment of the free acid with an inorganic
or organic base, such as an amine (primary, secondary or tertiary),
or an alkali metal or alkaline earth metal hydroxide or the like.
Illustrative examples of suitable salts include organic salts
derived from amino acids such as glycine and arginine, ammonia,
primary, secondary and tertiary amines, cyclic amines such as
piperidine, morpholine and piperazine, and inorganic salts derived
from sodium, calcium, potassium, magnesium, manganese, iron,
copper, zinc, aluminum, and lithium.
[0138] This invention also provides novel and useful methods for
producing intermediates that are especially useful in the
preparation of nelfinavir mesylate and nelfinavir free base.
Particularly useful intermediates are Compounds 19' and 20'. As
illustrated below, these compounds may be prepared from chiral
tetrahydrofuran Compounds 1' or 2'.
[0139] Compound 18' may be prepared by the reaction sequence
illustrated in Scheme I, below. In this embodiment of the method of
this invention, chiral amino-tetrahydrofuran, 1', is treated with
3-acetoxy-2-methylbenzo- yl chloride (AMBC) under conditions
effective to form an amide, (12-acetoxy-3-methyl benzamide, 2') or
a salt thereof. The resulting amide, tetrahydrofuran-amide, 2', may
be treated with methanesulfonyl chloride in the presence of a base,
such as, for example, triethylamine, under conditions effective to
derivatize the secondary alcohol of tetrahydrofuran-amide, 2',
providing an intermediate mesylate tetrahydrofuran amide-sulfonate,
3', which need not be isolated. For example, this reaction may be
conducted by first treating tetrahydrofuran 2' with at least one
molar equivalent of methanesulfonyl chloride, followed by addition
of less than a molar equivalent amount (with respect to the amount
of methanesulfonyl chloride) of triethylamine. Tetrahydrofuran
amide-sulfonate, 3', may then be treated with an anhydride, such
as, for example, acetic anhydride, and a strong acid, such as, for
example, sulfuric acid, under conditions effective to produce
Compound 18'. For example, tetrahydrofuran amide-sulfonate, 3', may
be treated with 15 molar equivalents of acetic anhydride and 7.5
molar equivalents of a strong acid, such as, for example, sulfuric
acid, to produce Compound 18'. Other strong acids useful in this
treatment step include trifluoromethanesulfonic acid, nitric acid,
phosphoric acid, and the like. 65
[0140] It is considered within the ordinary skill of one in the art
through routine experimentation to determine the reaction
conditions (solvent, reaction time, temperature, etc.) that are
effective to produce all of the compounds, described herein. For
example, the above-described reactions for the conversion of
amino-tetrahydrofuran, 1', to Compound 19', using the
moisture-sensitive acid chloride, AMBC, and sulfonyl chloride,
mesylchloride, would preferably be conducted in an aprotic solvent
(i.e., one that is not water or an alcohol). Preferably, the
aprotic solvent is an aprotic solvent, e.g. ethyl acetate,
isopropyl acetate, toluene, benzene and the like.
[0141] The preparation of Compound 20', as illustrated in the
reaction sequence of Scheme II, below, may also be prepared from
the amino-tetrahydrofuran, 1', or a pharmaceutically acceptable
salt thereof. As in the above-described reaction sequence, the
first step of this sequence involves the formation of the amide
intermediate, tetrahydrofuran-amide, 2'. This amide intermediate
may be treated directly with an anhydride, such as, for example,
acetic anhydride, and a strong acid, such as, for example, sulfuric
acid, to form oxazoline triester, 4'. Each of the acetoxy moieties
of oxazoline triester, 4', may be removed (hydrolyzed to the
corresponding hydroxyl moieties), by treatment with a suitable base
in a suitable solvent, to form the oxazoline triol, 5'. Bases that
are suitable for effecting this hydrolysis are known in the art and
include potassium carbonate, sodium hydroxide, potassium hydroxide,
and the like. Solvents that are suitable for effecting this
hydrolysis are similarly known in the art and include lower
alkanols (methanol, ethanol, isopropanol, etc.).
[0142] Advantageously, the phenolic, primary and secondary hydroxyl
moieties of oxazoline triol, 5' may be selectively protected, as
illustrated below. For example, the phenolic hydroxyl moiety may be
protected as the p-nitrobenzoate, Compound 6', using p-nitrobenzoyl
chloride. The primary hydroxyl moiety of Compound 6' may then be
selectively protected using the same or a different protecting
group. Alternatively, both the phenolic and primary hydroxyl
moieties of oxazoline triol, 5', may be protected using
p-nitrobenzoyl chloride to form the di-p-nitrobenzoate, Compound
7'. This process may be conducted in a single step, using two
equivalents of p-nitrobenzoyl chloride, or in a stepwise process,
as described above. 66
[0143] As illustrated in Scheme III, treating Compound 7' with
methanesulfonyl chloride (although another substituted or
unsubstituted alkyl or aryl sulfonyl chloride may be used) in the
presence of a base, such as, for example, triethylamine, provided
Compound 8', which may be converted into Compound 20' by addition
of 3S,4aR,8aR-3-N-t-butylcarboxam- idodecahydroisoquinoline (PHIQ)
in the presence of potassium carbonate and methanol. Further
treatment with thiophenol provided nelfinavir. Treatment of
Compound 7' with the sulfonyl chloride and base may be conducted
using conventional conditions. 67
[0144] An alternative reaction sequence for preparing Compound 19'
beginning with the formation of tetrahydrofuran-amide, 2', from
amino-tetrahydrofuran, 1', comprises the formation of the fused
tetrahydrofuranyloxazoline, 9', as illustrated in Scheme IV, below.
Treatment of the tetrahydrofuran-amide, 2', with methanesulfonyl
chloride (although another substituted or unsubstituted alkyl or
aryl sulfonyl chloride may be used) in the presence of a base, such
as, for example, triethylamine, provides the novel fused
tetrahydrofuranyloxazoline, 9'. Acid treatment of this oxazoline
provides the tetrahydrofuran-amide, 10', wherein the
stereochemistry of the 4-hydroxyl moiety is opposite that of the
starting tetrahydrofuran, 2'. Treatment of the
tetrahydrofuran-amide, 10', with acetic anhydride in the presence
of a strong acid, such as sulfuric or nitric acid, affords Compound
11', a triacetate. Hydrolysis of this triacetate provides triol,
12'. 68
[0145] As illustrated in Scheme V, treatment of triol 12' with
p-toluenesulfonyl chloride or another substituted or unsubstituted
alkyl or aryl sulfonyl chloride in the presence of a base, such as,
for example, triethylamine, provides the primary tosylate, Compound
13'. Treatment with this tosylate with a nucleophile,
3S,4aR,8aR-3-N-t-butylca- rboxamidodecahydroisoquinoline (PHIQ) in
the presence of a base, under conventional conditions, provides
Compound 19'. Conversion of Compound 19' into nelfinavir can be
accomplished, under conventional conditions, for example, by
treatment with thiophenol. 69
[0146] Another embodiment of this invention, illustrated in Scheme
VI, provides for the preparation of amino alcohol, 1, from fused
epoxy-tetrahydrofuran, 14. Treatment of 1 with
(S)-.alpha.-methylbenzylam- ine, or another chiral amine,
containing at least 97.5% of a single enantiomer, results in the
opening of the epoxide to provide a mixture of diastereomeric
Compounds 15' and 16'. This reaction may be conducted using an
appropriate solvent such as a mixture of isopropyl amine and water.
Crystallization of the diastereomers selectively provides Compound
15'. De-protection of the benzyl moiety of Compound 15' may be
conducted using conventional procedures, e.g. hydrogenolysis
(hydrogen in the presence of 5% palladium on carbon). The
amino-alcohol, 1, is hygroscopic and is preferably isolated as a
salt, for example, as the p-toluenesulfonic acid salt, 17. 70
[0147] Alternatively, the chiral amino-tetrahydrofuran, 1, may be
prepared from the fused epoxy-tetrahydrofuran, 14, using aqueous
ammonia, an achiral reagent, to provide a mixture of racemic 1 and
1', which may be resolved using conventional resolution techniques,
as illustrated in Scheme VII. For example, the racemic
amino-compound may be treated with a chiral acid to form a mixture
of diastereomeric salts, which may then be separated by
crystallization or chromatography. Neutralization and extractive
work-up provides diastereomerically pure amino-tetrahydrofuran, 1,
and recovery of the chiral acid. 71
[0148] Chiral acids that may be used in the resolution of racemic
amino-tetrahydrofuran, 1, include L-tartaric acid,
(1R)-(-)-10-camphorsulfonic acid, L-2-pyrrolidone-5-carboxylic
acid, (-)-di-O,O'-benzoyl-L-tartaric acid, (-)-mono-(1R)-methyl
phthalate, S (+) mandelic acid, L-asparatic acid,
(-)-di-O,O'-benzoyl-L-tartaric acid mono(dimethylamide),
(-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid, L(-)-malic
acid, and D(-)-quinic acid.
[0149] It is understood that the compounds described herein may
exist in different forms, such as stable and metastable crystalline
forms and isotropic and amorphous forms, all of which are included
within the scope of this invention
[0150] As used herein, the term "PHIQ" refers to the reagent
3S,4aR,8aR-3-N-t-butylcarboxamidodecahydroisoquinoline, "AMBC"
refers to the reagent 3-acetoxy-2-methylbenzoyl chloride, "MTBE"
refers to the solvent methyl t-butyl ether, "MIBK" refers to the
solvent methylisobutyl ketone and "PNB" refers to a p-nitrobenzoyl
moiety.
EXAMPLE 1
Synthesis of (3R, 4S) 4-Amino-tetrahydro-furan-3-ol
toluene-4-sulfonic acid salt, 17
[0151] (S)-.alpha.-Methylbenzyl amine (304 g, 2.51 mol) and
3,4-epoxytetrahydrofuran 14 (200 g, 2.32 mol) were dissolved in
2-propanol (1 L) and water (1 L). The solution was heated to
reflux, with stirring, for 18 hours. The 2-propanol (ca. 1 L) was
removed under reduced pressure and water (1 L) was added. The
resulting slurry was stirred at room temperature for 16 hours and
filtered. The white solids were washed with water (500 mL), then
dried in a vacuum oven at room temperature to constant weight to
afford crude Compound 15' (170.1 g). The crude material was
recrystallized by dissolving the solids in 2-propanol (354 mL) and
heptane (1 L) at 60.degree. C. The solution was seeded at
55.degree. C. with pure Compound 15' and allowed to cool to room
temperature over 18 hours. The solids were filtered, washed with
heptane (200 mL) and dried in a vacuum oven at room temperature to
constant weight to give pure Compound 15' (123.2 g, 26%).
[0152] A 2 L Parr flask was charged with the pure Compound 15'
(120.7 g), 2-propanol (840 mL) and 5% palladium on carbon (12 g).
The flask was shaken at 26 psi of hydrogen gas for 44 hours.
Additional 5% palladium on carbon (6 g) was added and the mixture
was shaken at 26 psi of hydrogen gas for 20 hours. The mixture was
filtered through Celite, which was washed with 2-propanol (200 mL).
Filtration through Celite and washing was repeated.
para-Toluenesulfonic acid (110.8 g) was added to the solution and
the solution was concentrated under reduced pressure to 1 L.
Methyl-t-butyl ether (MTBE, 1.5 L) was added and the resulting
solids were filtered, washed with MTBE (250 mL) and dried in a
vacuum oven at 40.degree. C. to constant weight to afford pure
Compound 17 (138 g, 86%).
EXAMPLE 2
Synthesis of Acetic acid
3-(4R-hydroxy-tetrahydro-furan-3S-ylcarbamoyl)-2-- methyl-phenyl
ester, 2'
[0153] The amine salt, 17 (25.0 g, 90.9 mmol) and AMBC
(3-acetoxy-2-methylbenzoyl chloride, 20.4 g, 95.9 mmol) were
slurried in ethyl acetate (188 mL) at room temperature. With water
bath cooling, triethylamine (25.9 mL, 186.1 mmol) was added at a
rate sufficient to maintain the temperature below 25.degree. C. The
slurry was stirred at room temperature for 1 hour 45 minutes to
give 90.8 mmol of a suspension of tetrahydrofuran-amide, 2'.
EXAMPLE 3
Synthesis of
(2R)-1-acetoxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5dihydr-
ooxazol-4-yl)-2-methanesulfonyloxyethane, 18'
[0154] The reaction product mixture of Example 2 (containing 90.8
mmol of tetrahydrofuran-amide 2') was cooled in an ice/acetone bath
and methanesulfonyl chloride (17.6 mL, 227 mmol) was added in one
portion. Triethylamine (19 mL, 136.2 mmol) was added dropwise at a
rate sufficient to keep the internal temperature below 10.degree.
C. Acetic anhydride (129 mL, 1362 mmol) was added in one portion
and the cooling bath was removed. Sulfuric acid (98%, 38 mL, 681
mmol) was added in three portions at 15 minute intervals. The
mixture was stirred at room temperature for 17 hours. A suspension
of sodium bicarbonate (305 g, 3632 mmol, 40 equiv.) in 1 liter of
water was prepared. This was overlaid with ethyl acetate (250 mL).
The reaction mixture from above was added to the sodium bicarbonate
slurry dropwise over 2 hours. The layers were separated and the
aqueous layer was washed with ethyl acetate (200 mL). The combined
organic layers were washed with saturated sodium bicarbonate (200
mL) and brine (200 mL). The organic layer was dried (MgSO.sub.4),
filtered and evaporated to give 90.8 mmol of an oil of 18'.
EXAMPLE 4
Synthesis of (3S, 4aS,
8aS)-2-{(2R)-2-[(4S)-2-(3-Hydroxy-2-methylphenyl)-4-
,5-dihydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylic
acid t-butylamide, 20'
[0155] The crude product of Example 3,
(2R)-1-acetoxy-2-((4S)-2-(3-acetoxy-
-2-methylphenyl)-4,5-dihydrooxazol-4-yl)-2methanesulfonyloxyethane,
18' (1.98 kg, 3.30 mol) was suspended in a mixed solvent of
methanol (6.50 L) and water (6.50 L), and (3S, 4aS,
8aS)-decahydroisoquinoline-3-carboxylic acid t-butylamide, 642 g,
2.62 mol) and potassium carbonate (1.36 kg, 9.81 mol) were
successively added, which was followed by stirring at 50.degree. C.
for 5.5 hours. Water (6.50 L) was added to cool the reaction
mixture to room temperature and the resulting crystals were
collected by filtration. These crude crystals were again suspended
in water (6.50 L), stirred, washed and collected by filtration. The
obtained crystals were re-suspended in methyl isobutyl ketone (10.0
L) and the suspension was subjected to azeotropic dehydration. The
resulting slurry was cooled to room temperature and crystals were
collected by filtration to give 902 g (1.07 mol) of the title
compound, as colorless crystals.
[0156] Other bases that are suitable for use in this reaction
include, sodium carbonate, sodium hydroxide, potassium hydroxide
and the like. This reaction may be conducted at a temperature of
between -78.degree. C. and 100.degree. C. in a suitable solvent or
suitable solvent mixtures including, but not limited to alcoholic
solvents (for example, methanol, ethanol, propanol, isopropanol,
and the like), water, ethyl acetate, isopropyl acetate, and the
like. Preferably, the reaction is conducted as described above.
EXAMPLE 5
Synthesis of (3S, 4aS,
8aS)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl-amino)--
4-phenylthiobutyl]decahydroisoquinoline-3-carboxylic acid
t-butylamide, 19'
[0157] (3S, 4aS,
8aS)-2-{(2R)-2-[(4S)-2-(3-Hydroxy-2-methylphenyl)-4,5-dih-
ydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylic
acid t-butylamide (701 g, 1.53 mol), obtained as in Example 4, was
suspended in methyl isobutyl ketone (7.00 L), and thiophenol (314
mL, 3.06 mol) and potassium hydrogencarbonate (76.6 g, 0.765 mol)
were added. The mixture was heated to reflux for 12 hours under a
nitrogen atmosphere. After the completion of the reaction, toluene
(7.00 L) was added, and the precipitated crystals were collected by
filtration and washed with toluene. These crude crystals were
washed in a mixed solvent of acetone and water (1:1), with heating,
to give 695 g (1.22 mol) of the title compound (80% yield) as
colorless crystals.
[0158] While the invention has been described in terms of various
preferred embodiments using specific examples, those skilled in the
art will recognize through routine experimentation that various
changes and modifications can be made without departing from the
spirit and scope of the invention, as defined in the appended
claims.
* * * * *