U.S. patent application number 14/808147 was filed with the patent office on 2016-01-28 for preparation of 2'-fluoro-2'-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives.
The applicant listed for this patent is Gilead Pharmasset LLC. Invention is credited to Byoung-Kwon Chun, Jinfa Du, Suguna Rachakonda, Peiyuan Wang.
Application Number | 20160024061 14/808147 |
Document ID | / |
Family ID | 36060603 |
Filed Date | 2016-01-28 |
United States Patent
Application |
20160024061 |
Kind Code |
A1 |
Chun; Byoung-Kwon ; et
al. |
January 28, 2016 |
PREPARATION OF 2'-FLUORO-2'-ALKYL-SUBSTITUTED OR OTHER OPTIONALLY
SUBSTITUTED RIBOFURANOSYL PYRIMIDINES AND PURINES AND THEIR
DERIVATIVES
Abstract
The present invention provides (i) processes for preparing a
2'-deoxy-2'-fluoro-2'-methyl-D-ribonolactone derivatives, (ii)
conversion of intermediate lactones to nucleosides with potent
anti-HCV activity, and their analogues, and (iii) methods to
prepare the anti-HCV nucleosides containing the
2'-deoxy-2'-fluoro-2'-C-methyl-B-D-ribofuranosyl nucleosides from a
preformed, preferably naturally-occurring, nucleoside.
Inventors: |
Chun; Byoung-Kwon;
(Pleasanton, CA) ; Wang; Peiyuan; (San Mateo,
CA) ; Du; Jinfa; (Redwood City, CA) ;
Rachakonda; Suguna; (Copley, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Pharmasset LLC |
Foster City |
CA |
US |
|
|
Family ID: |
36060603 |
Appl. No.: |
14/808147 |
Filed: |
July 24, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13917173 |
Jun 13, 2013 |
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14808147 |
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11225425 |
Sep 13, 2005 |
8492539 |
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13917173 |
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60666230 |
Mar 29, 2005 |
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60610035 |
Sep 15, 2004 |
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60609783 |
Sep 14, 2004 |
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Current U.S.
Class: |
549/34 ;
549/296 |
Current CPC
Class: |
A61P 31/14 20180101;
C07H 19/06 20130101; C07D 307/20 20130101; C07D 307/33 20130101;
C07D 407/04 20130101; C07H 15/203 20130101; C07D 317/30 20130101;
C07D 411/04 20130101; C07D 317/00 20130101; C07D 405/04 20130101;
A61K 31/7072 20130101 |
International
Class: |
C07D 411/04 20060101
C07D411/04; C07D 407/04 20060101 C07D407/04 |
Claims
1-9. (canceled)
10. A compound of formulae IIIa, IIIb or IIIc ##STR00022## wherein
each R.sup.1 i.s independently lower alkyl (C.sub.1-C.sub.6),
optionally substituted phenyl, or optionally substituted benzyl;
R.sup.2 and R.sup.3 are independently hydrogen, lower alkyl
(C.sub.1-C.sub.6), hydroxymethyl, methoxymethyl, halomethyl,
optionally substituted ethenvi, optionally substituted ethynyl, or
optionally substituted allyl; and R.sup.4 is independently
hydrogen, aryl, arylalkyl, and lower alkyl (C.sub.1-C.sub.10).
11. A compound of claim 10, wherein each R.sup.1 is lower alkyl
(C.sub.1-C.sub.6); R.sup.2 and R.sup.3 are independently hydrogen,
or lower alkyl (C.sub.1-C.sub.6); and R.sup.4 is lower alkyl
(C.sub.1-C.sub.10).
12. The compound of claim 10, having the formula ##STR00023##
Description
CLAIM TO PRIORITY
[0001] This application a continuation of U.S. patent application
Ser. No. 11/225,425, filed Sep. 13, 2005, which claims the benefit
of Provisional Patent Application Ser. No. 60/609,783, filed Sep.
14, 2004, Provisional Patent Application Ser. No. 60/610,035, filed
Sep. 15, 2004, and Provisional Patent Application Ser. No.
60/666,230, filed Mar. 29, 2005. The entire contents of all of the
above-mentioned applications are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention provides (i) processes for preparing a
2-deoxy-2-fluoro-2-methyl-D-ribonolactone derivatives, (ii)
conversion of intermediate lactones to nucleosides with potent
anti-HCV activity, and their analogues, and (iii) methods to
prepare the anti-HCV nucleosides containing the
2'-deoxy-2'-fluoro-2'-C-methyl-.beta.-D-ribofuranosyl nucleosides
from a preformed, preferably naturally-occurring, nucleoside.
BACKGROUND OF THE INVENTION
[0003] HCV infection has reached epidemic levels worldwide, and has
tragic effects on the infected patients. Presently there is no
effective treatment for this infection and the only drugs available
for treatment of chronic hepatitis C are various forms of alpha
interferon (IFN-.alpha.), either alone or in combination with
ribavirin. However, the therapeutic value of these treatments has
been compromised largely due to adverse effects, which highlights
the need for development of additional options for treatment.
[0004] HCV is a small, enveloped virus in the Flaviviridae family,
with a positive single-stranded RNA genome of .about.9.6 kb within
the nucleocapsid. The genome contains a single open reading frame
(ORF) encoding a polyprotein of just over 3,000 amino acids, which
is cleaved to generate the mature structural and nonstructural
viral proteins. ORF is flanked by 5' and 3' non-translated regions
(NTRs) of a few hundred nucleotides in length, which are important
for RNA translation and replication. The translated polyprotein
contains the structural core (C) and envelope proteins (E1, E2, p7)
at the N-terminus, followed by the nonstructural proteins (NS2,
NS3, NS4A, NS4B, NS5A, NS5B). The mature structural proteins are
generated via cleavage by the host signal peptidase. The junction
between NS2 and NS3 is autocatalytically cleaved by the NS2/NS3
protease, while the remaining four junctions are cleaved by the
N-terminal serine protease domain of NS3 complexed with NS4A. The
NS3 protein also contains the NTP-dependent helicase activity which
unwinds duplex RNA during replication. The NS5B protein possesses
RNA-dependent RNA polymerase (RDRP) activity, which is essential
for viral replication. Unlike HBV or HIV, no DNA is involved in the
replication of HCV.
[0005] U.S. Patent Publication (US 2005/0009737 A1) discloses that
1-(2-deoxy-2-fluoro-2-C-methyl-.beta.-D-ribofuranosyl)cytosine (14)
is a potent and selective anti-HCV agent. Previously known
synthetic procedures (Schemes 1-3) for this compound are quite
inefficient, with very low overall yields and are not amendable to
large-scale.
##STR00001##
##STR00002##
##STR00003##
[0006] Previously known methods for the preparation of
(2'R)-2'-deoxy-2'-fluoro-2'-C-methyl nucleosides, and its
analogues, from D-xylose, cytidine, or uridine employed DAST or
Deoxofluor.RTM. for the key fluorination reaction. However, DAST
and Deoxofluor.RTM. are expensive, hazardous for industrial
synthesis, and provide often unreliable results. Therefore, these
alkylaminosulfur trifluorides are not suitable for industrial
production.
[0007] As a part of an effort to find better fluorination
conditions, it has been discovered that opening of a cyclic sulfate
with non-alkylaminosulfur trifluoride fluorinating agents is an
excellent way to synthesize the anti-HCV nucleoside,
(2'R)-2'-deoxy-2'-fluoro-2'-C-methylcytidine. In addition, it was
discovered that this novel synthetic route can be adopted to other
nucleosides including the anti-HCV nucleoside,
D-2-deoxy-2-fluoro-cytidine (Devos, et al, U.S. Pat. No.
6,660,721), anti-HBV nucleosides, D and
L-2',3'-didehydro-2',3'-dideoxy-2'-fluoro-nucleosides (Schinazi, et
al, U.S. Pat. No. 6,348,587) (I and II, FIG. 3) as well as other
2'-substituted nucleosides such as D- and L-FMAU (Su, et al., J
Med. Chem, 1986, 29, 151-154; Chu, et al., U.S. Pat. No.
6,512,107).
[0008] What is needed is a novel and cost effective process for the
synthesis of 2'-C-alkyl-2'-deoxy-2'-substituted-D-ribopyranosyl
nucleosides that have activity against HCV.
SUMMARY OF INVENTION
[0009] The present invention as disclosed herein relates to various
intermediates and synthetic methods for the preparation of
compounds of general formulas [I] and [II],
##STR00004##
wherein [0010] X is halogen (F, Cl, Br), [0011] Y is N or CH,
[0012] Z is halogen, OH, OR'SH, SR', NH.sub.2, NHR', or R' [0013]
R.sup.2 is alkyl of C.sub.1-C.sub.3, vinyl, or ethynyl; [0014]
R.sup.3 ' and R.sup.5' can be same or different H, alkyl, aralkyl,
acyl, cyclic acetal such as 2',3'-O-isopropylidene or
2',3-O-benzylidene, or 2',3'-cyclic carbonate. [0015] R.sup.2,
R.sup.4, and R.sup.5 are independently H, halogen including F, Cl,
Br, I, OH, OR', SH, SR', N.sub.3, NH.sub.2, NHR', NR'.sub.2,
NHC(O)OR', lower alkyl of C.sub.1-C.sub.6, halogenated (F, Cl, Br,
I) lower alkyl of C.sub.1-C.sub.6 such as CF.sub.3 and
CH.sub.2CH.sub.2F, lower alkenyl of C.sub.2-C.sub.6 such as
CH.dbd.CH.sub.2, halogenated (F, Cl, Br, I) lower alkenyl of
C.sub.2-C.sub.6 such as CH.dbd.CHCl, CH.dbd.CHBr and CH.dbd.CHI,
lower alkynyl of C.sub.2-C.sub.6 such as C.dbd.CH, halogenated (F,
Cl, Br, I) lower alkynyl of C.sub.2-C.sub.6, lower alkoxy of
C.sub.1-C.sub.6 such as CH.sub.2OH and CH.sub.2CH.sub.2OH,
halogenated (F, Cl, Br, I) lower alkoxy of C.sub.1C.sub.6,
CO.sub.2H, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, CH.dbd.CHCO.sub.2R'; and, [0016] R' is an
optionally substituted alkyl or acyl of C.sub.1-C.sub.12
(particularly when the alkyl is an amino acid residue), cycloalkyl,
optionally substituted alkynyl of C.sub.2-C.sub.6, optionally
substituted lower alkenyl of C.sub.2-C.sub.6, or optionally
substituted acyl.
DETAILED DESCRIPTION
[0017] Presently no preventive means against Flaviviridae,
including hepatitis C virus (HCV), Dengue virus (DENV), West Nile
virus (WNV) or Yellow Fever virus (YFV), infection is available.
The only approved therapies are for treatment of HCV infection with
alpha interferon alone or in combination with the nucleoside
ribavirin, but the therapeutic value of these treatments has been
compromised largely due to adverse effects. It was recently
discovered that a group of nucleosides, including
2'-deoxy-2'-fluoro-2'-C-methylcytidine, exhibit potent and
selective activity against replication of HCV in a replicon system.
However, the difficulty of chemical synthesis of this and analogous
nucleosides impedes further biophysical, biochemical,
pharmacological evaluations mandatory for development of clinical
drugs for treatment of Flaviviridae infection.
[0018] The present invention provides an efficient preparation of
nucleosides and intermediates containing the
2-deoxy-2-fluoro-2-C-methyl-D-ribofuranosyl moiety.
Definitions
[0019] The term "independently" is used herein to indicate that the
variable, which is independently applied, varies independently from
application to application. Thus, in a compound such as
R.sup.aXYR.sup.a, wherein R.sup.a is "independently carbon or
nitrogen", both R.sup.a can be carbon, both R.sup.a can be
nitrogen, or one R.sup.a can be carbon and the other R.sup.a
nitrogen.
[0020] As used herein, the terms "enantiomerically pure" or
"enantiomerically enriched" refers to a nucleoside composition that
comprises at least approximately 95%, and preferably approximately
97%, 98%, 99% or 100% of a single enantiomer of that
nucleoside.
[0021] As used herein, the term "substantially free of" or
"substantially in the absence of" refers to a nucleoside
composition that includes at least 85 or 90% by weight, preferably
95% to 98% by weight, and even more preferably 99% to 100% by
weight, of the designated enantiomer of that nucleoside. In a
preferred embodiment, in the methods and compounds of this
invention, the compounds are substantially free of enantiomers
[0022] The term "alkyl," as used herein, unless otherwise
specified, refers to a saturated straight or branched hydrocarbon
chain of typically C.sub.1 to C.sub.10, and specifically includes
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,
isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl,
cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and
2,3-dimethylbutyl, and the like. The term includes both substituted
and unsubstituted alkyl groups. Alkyl groups can be optionally
substituted with one or more moieties selected from the group
consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy,
aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,
phosphate, or phosphonate. One or more of the hydrogen atoms
attached to carbon atom on alkyl may be replaced by one or more
halogen atoms, e.g. fluorine or chlorine or both, such as
trifluoromethyl, difluoromethyl, fluorochloromethyl, and the like.
The hydrocarbon chain may also be interrupted by a heteroatom, such
as N, O or S.
[0023] The term "lower alkyl," as used herein, and unless otherwise
specified, refers to a C.sub.1 to C.sub.4 saturated straight or
branched alkyl group, including both substituted and unsubstituted
forms as defined above. Unless otherwise specifically stated in
this application, when alkyl is a suitable moiety, lower alkyl is
preferred. Similarly, when alkyl or lower alkyl is a suitable
moiety, unsubstituted alkyl or lower alkyl is preferred.
[0024] The term "cycloalkyl", as used herein, unless otherwise
specified, refers to a saturated hydrocarbon ring having 3-8 carbon
atoms, preferably, 3-6 carbon atoms, such as cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group may
also be substituted on the ring by an alkyl group, such as
cyclopropylmethyl and the like.
[0025] The terms "alkylamino" or "arylamino" refer to an amino
group that has one or two alkyl or aryl substituents,
respectively.
[0026] The term "protected," as used herein and unless otherwise
defined, refers to a group that is added to an oxygen, nitrogen, or
phosphorus atom to prevent its further reaction or for other
purposes. A wide variety of oxygen and nitrogen protecting groups
are known to those skilled in the art of organic synthesis.
Non-limiting examples include: C(O)-alkyl, C(O)Ph, C(O)aryl,
CH.sub.3, CH.sub.2-alkyl, CH.sub.2-alkenyl, CH.sub.2Ph,
CH.sub.2-aryl, CH.sub.2O-alkyl, CH.sub.2O-aryl, SO.sub.2-alkyl,
SO.sub.2-aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,
and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).
[0027] The term "aryl," as used herein, and unless otherwise
specified, refers to phenyl, biphenyl, or naphthyl, and preferably
phenyl. The term includes both substituted and unsubstituted
moieties. The aryl group can be substituted with one or more
substituents, including, but not limited to hydroxyl, halo, amino,
alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic
acid, sulfate, phosphonic acid, phosphate, or phosphonate, either
unprotected, or protected as necessary, as known to those skilled
in the art, for example, as taught in T. W. Greene and P. G. M.
Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley
& Sons, 1999.
[0028] The terms "alkaryl" or "alkylaryl" refer to an alkyl group
with an aryl substituent. The terms "aralkyl" or "arylalkyl" refer
to an aryl group with an alkyl substituent, as for example,
benzyl.
[0029] The term "halo," as used herein, includes chloro, bromo,
iodo and fluoro.
[0030] The term "acyl ester" or "O-linked ester" refers to a
carboxylic acid ester of the formula C(O)R' in which the
non-carbonyl moiety of the ester group, R', is a straight or
branched alkyl, or cycloalkyl or lower alkyl, alkoxyalkyl including
methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as
phenoxymethyl, aryl including phenyl optionally substituted with
halogen (F, Cl, Br, I), C.sub.1 to C.sub.4 alkyl or C.sub.1 to
C.sub.4 alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl
including methanesulfonyl, the mono, di or triphosphate ester,
trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl
(e.g. dimethyl-t-butyl silyl) or diphenylmethylsilyl. Aryl groups
in the esters optimally include a phenyl group.
[0031] The term "acyl" refers to a group of the formula R''C(O)--,
wherein R'' is a straight or branched alkyl, or cycloalkyl, amino
acid, aryl including phenyl, alkylaryl, aralkyl including benzyl,
alkoxyalkyl including methoxymethyl, aryloxyalkyl such as
phenoxymethyl; or substituted alkyl (including lower alkyl), aryl
including phenyl optionally substituted with chloro, bromo, fluoro,
iodo, C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.4 alkoxy,
sulfonate esters such as alkyl or aralkyl sulphonyl including
methanesulfonyl, the mono, di or triphosphate ester, trityl or
monomethoxy-trityl, substituted benzyl, alkaryl, aralkyl including
benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as
phenoxymethyl. Aryl groups in the esters optimally comprise a
phenyl group. In particular, acyl groups include acetyl,
trifluoroacetyl, methylacetyl, cyclopropylacetyl, cyclopropyl
carboxy, propionyl, butyryl, isobutyryl, hexanoyl, heptanoyl,
octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl,
diphenylacetyl,
.alpha.-methoxy-.alpha.-trifluoromethyl-phenylacetyl, bromoacetyl,
2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl,
2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl,
trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl,
fluoroacetyl, bromodifluoroacetyl, methoxyacetyl,
2-thiopheneacetyl, chlorosulfonylacetyl, 3-methoxyphenylacetyl,
phenoxyacetyl, tert-butylacetyl, trichloroacetyl,
monochloro-acetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl,
perfluoro-heptanoyl, 7H-dodeca-fluoroheptanoyl,
7-chlorododecafluoro-heptanoyl, 7-chloro-dodecafluoro-heptanoyl,
7H-dodecafluoroheptanoyl, 7H-dodeca-fluoroheptanoyl,
nona-fluoro-3,6-dioxa-heptanoyl, nonafluoro-3,6-dioxaheptanoyl,
perfluoroheptanoyl, methoxybenzoyl, methyl
3-amino-5-phenylthiophene-2-carboxyl,
3,6-dichloro-2-methoxy-benzoyl,
4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl, 2-bromo-propionyl,
omega-aminocapryl, decanoyl, n-pentadecanoyl, stearyl,
3-cyclopentyl-propionyl, 1-benzene-carboxyl, O-acetylmandelyl,
pivaloyl acetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl,
2,6-pyridinedicarboxyl, cyclopropane-carboxyl,
cyclobutane-carboxyl, perfluorocyclohexyl carboxyl,
4-methylbenzoyl, chloromethyl isoxazolyl carbonyl,
perfluorocyclohexyl carboxyl, crotonyl,
1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl,
1-pyrrolidinecarbonyl, 4-phenylbenzoyl. When the term acyl is used,
it is meant to be a specific and independent disclosure of acetyl,
trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl,
butyryl, isobutyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl,
phenylacetyl, diphenylacetyl, ct-trifluoromethyl-phenylacetyl,
bromoacetyl, 4-chloro-benzeneacetyl, 2-chloro-2,2-diphenylacetyl,
2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl,
perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl,
2-thiopheneacetyl, tert-butylacetyl, trichloroacetyl,
monochloro-acetyl, dichloroacetyl, methoxybenzoyl,
2-bromo-propionyl, decanoyl, n-pentadecanoyl, stearyl,
3-cyclopentyl-propionyl, 1-benzene-carboxyl, pivaloyl acetyl,
1-adamantane-carboxyl, cyclohexane-carboxyl,
2,6-pyridinedicarboxyl, cyclopropane-carboxyl,
cyclobutane-carboxyl, 4-methylbenzoyl, crotonyl,
1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl,
4-phenylbenzoyl.
[0032] The term "lower acyl" refers to an acyl group in which R'',
above defined, is lower alkyl.
[0033] The term "natural nucleic base" and "modified nucleic base"
refer to "purine" or "pyrimidine" bases as defined below.
[0034] The term "purine" or "pyrimidine" base includes, but is not
limited to, adenine, N.sup.6-alkylpurines, N.sup.6-acylpurines
(wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl),
N.sup.6-benzylpurine, N.sup.6-halopurine, N.sup.6-vinylpurine,
N.sup.6-acetylenic purine, N.sup.6-acyl purine,
N.sup.6-hydroxyalkyl purine, N.sup.6-allylaminopurine,
N.sup.6-thioallyl purine, N.sup.6-alkylpurines,
N.sup.2-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine,
5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2-
and/or 4-mercaptopyrimidine, uracil, 5-halouracil, including
5-fluorouracil, C.sup.5-alkylpyrimidines,
C.sup.5-benzylpyrimidines, C.sup.5-halopyrimidines,
C.sup.5-vinylpyrimidine, C.sup.5-acetylenic pyrimidine,
C.sup.5-acyl pyrimidine, N.sup.4-acetylcytosine,
N.sup.4-benzoylcytosine, N.sup.4-alkyl pyrimidine,
C.sup.5-hydroxyalkyl purine, C.sup.5-amidopyrimidine,
C.sup.5-cyanopyrimidine, C.sup.5-iodopyrimidine,
C.sup.6-iodo-pyrimidine, C.sup.5-Br-vinyl pyrimidine,
C.sup.6-Br-vinyl pyrimidine, C.sup.5-nitropyrimidine,
C.sup.5-amino-pyrimidine, N.sup.2-alkylpurines,
N.sup.2-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl,
triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and
pyrazolopyrimidinyl. Purine bases include, but are not limited to,
guanine, adenine, hypoxanthine, 2,6-diaminopurine, and
6-chloropurine. Functional oxygen and nitrogen groups on the base
can be protected as necessary or desired. Suitable protecting
groups are well known to those skilled in the art, and include
trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and
t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as
acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
[0035] The term "amino acid" includes naturally occurring and
synthetic .alpha., .beta. .gamma. or .delta. amino acids, and
includes but is not limited to, amino acids found in proteins, i.e.
glycine, alanine, valine, leucine, isoleucine, methionine,
phenylalanine, tryptophan, proline, serine, threonine, cysteine,
tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,
arginine and histidine. In a preferred embodiment, the amino acid
is in the L-configuration. Alternatively, the amino acid can be a
derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl,
phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl,
threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl,
aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl,
.beta.-alanyl, .beta.-valinyl, .beta.-leucinyl, .beta.-isoleucinyl,
.beta.-prolinyl, .beta.-phenylalaninyl, .beta.-tryptophanyl,
.beta.-methioninyl, .beta.-glycinyl, .beta.-serinyl,
.beta.-threoninyl, .beta.-cysteinyl, .beta.-tyrosinyl,
.beta.-asparaginyl, .beta.-glutaminyl, .beta.-aspartoyl,
.beta.-glutaroyl, .beta.-lysinyl, .beta.-argininyl or
.beta.-histidinyl. When the term amino acid is used, it is
considered to be a specific and independent disclosure of each of
the esters of .alpha., .beta. .gamma. or .delta. glycine, alanine,
valine, leucine, isoleucine, methionine, phenylalanine, tryptophan,
proline, serine, threonine, cysteine, tyrosine, asparagine,
glutamine, aspartate, glutamate, lysine, arginine and histidine in
the D and L-configurations.
[0036] The term "pharmaceutically acceptable salt or prodrug" is
used throughput the specification to describe any pharmaceutically
acceptable form (such as an ester, phosphate ester, salt of an
ester or a related group) of a compound which, upon administration
to a patient, provides the active compound. Pharmaceutically
acceptable salts include those derived from pharmaceutically
acceptable inorganic or organic bases and acids. Suitable salts
include those derived from alkali metals such as potassium and
sodium, alkaline earth metals such as calcium and magnesium, among
numerous other acids well known in the pharmaceutical art.
Pharmaceutically acceptable salts may also be acid addition salts
when formed with a nitrogen atom. Such salts are derived from
pharmaceutically acceptable inorganic or organic acids, such as
hydrochloric, sulfuric, phosphoric, acetic, citric, tartaric, and
the like. Pharmaceutically acceptable prodrugs refer to a compound
that is metabolized, for example hydrolyzed or oxidized, in the
host to form the compound of the present invention. Typical
examples of prodrugs include compounds that have biologically
labile protecting groups on a functional moiety of the active
compound. Prodrugs include compounds that can be oxidized, reduced,
aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed,
dehydrolyzed, alkylated, dealkylated, acylated, deacylated,
phosphorylated, dephosphorylated to produce the active
compound.
[0037] Applicants have developed a novel, practical and efficient
process for the synthesis of
2-C-alkyl-2-deoxy-2-substituted-D-ribofuranose derivatives, the key
intermediates to 14 (Scheme 1) and derivatives and analogues
thereof using or without using chiral catalysts. The key step in
the synthesis of 14 is asymmetric conversion of 41 to 42 using
chiral catalysts (Scheme 4). The previous disclosed synthesis of 42
required Sharpless AD catalysts, such as dihydroquinidine (DHQD)
and derivatives. The present invention as disclosed herein relates
to the stereoselective preparation of 41 to 42 using osmium, osmate
or permanganate without chiral catalysts. The applicants in this
present invention also develop a practical and efficient process
for the synthesis of 49 from 42 by using the nucleophilic opening
of the cyclic sulfate 50 (Scheme 6) in highly stereospecific and
regioselective manner. The procedure depicted in Schemes 4, 5 and 6
are the current method of choice for preparative synthesis of 14
and related derivatives.
##STR00005##
##STR00006##
##STR00007##
I. Preparation of the Compounds
(i) Synthesis of the Cyclic Sulfite (IIIa) and Cyclic Sulfate
(IIIb)
[0038] This invention relates to the process for the preparation of
the 2'-F-nucleosides and other 2'-substituted nucleosides of the
general formula IB and IB-L- by using the nucleophilic opening of
the cyclic sulfite, IIIa (X.dbd.SO), sulfate, IIIb
(X.dbd.SO.sub.2), of the formula, III in highly stereospecific and
regioselective manner, via the lactones of the formula, IV.
##STR00008##
Wherein the formula IB, IB-L, III, IV has following specifications:
[0039] R.sup.1 is independently a lower alkyl (C.sub.1-C.sub.6)
including, but not limited to methyl, ethyl, optionally substituted
phenyl, optionally substituted benzyl; alternatively R.sup.1 is a
part of cyclic alkylene including ethylene (--CH.sub.2CH.sub.2--),
or trimethylene (--CH.sub.2CH.sub.2CH.sub.2--) forming cyclic
pentyl or cyclic hexanyl group; [0040] R.sup.2, R.sup.3 are
independently hydrogen, a lower alkyl (C.sub.1-C.sub.6) including,
but not limited to methyl, hydroxymethyl, methoxymethyl, halomethyl
including, but not limited to fluoromethyl, ethyl, propyl,
optionally substituted ethenyl including, but not limited to vinyl,
halovinyl (F--CH.dbd.C), optionally substituted ethynyl including,
but not limited to haloethynyl (F--C.ident.C), optionally
substituted allyl including, but not limited to haloallyl
(FHC.dbd.CH--CH.sub.2--); [0041] R.sup.4 is independently hydrogen,
aryl including, but not limited to phenyl, aryl alkyl including,
but not limited to benzyl, lower alkyl including, but not limited
to, methyl, ethyl, propyl. Nu is halogen (F, Cl, Br), N.sub.3, CN,
NO.sub.3, CF.sub.3, OR or NR where R is acyl including, but not
limited to acetyl, benzoyl, arylalkyl including but not limited to
benzyl, lower alkyl including, but not limited to, methyl, ethyl,
propyl, CH.sub.2R where R is hydrogen, lower alkyl including, but
not limited to, methyl, ethyl, propyl; [0042] X is SO.sub.2, SO, or
CO; and [0043] B is a natural or modified nucleic base. In one
embodiment, formula, IB is:
##STR00009##
[0043] wherein, [0044] R.sup.2, R.sup.3 are independently hydrogen,
a lower alkyl (C.sub.1-C.sub.6) including, but not limited to
methyl, hydroxymethyl, methoxymethyl, halomethyl including, but not
limited to fluoromethyl, ethyl, propyl, optionally substituted
ethenyl including, but not limited to vinyl, halovinyl
(F--CH.dbd.C), optionally substituted ethnyl including, but not
limited to haloethnyl (F--C.dbd.C), optionally substituted allyl
including, but not limited to haloallyl (FHC.dbd.CH--CH.sub.2--);
[0045] B is a natural or modified nucleic base.
[0046] The present invention as disclosed herein relates to
processes for the synthesis of a compound,
2-alkyl-4,5-di-O-protected-2,3-dihydroxy-pentanoic-acid ester of
the following general formula 42B, which is the important
intermediate in the synthesis of anti-HCV nucleosides of general
formulas [I] and [II] (below).
##STR00010##
wherein R', R''=isopropylidene, benzylidene or cyclohexylidene or a
like, or a part of cyclic group including ethylene
(--CH.sub.2CH.sub.2--), or trimethylene
(--CH.sub.2CH.sub.2CH.sub.2--) forming cyclopentyl or cyclohexanyl
group, respectively; R' and R'' can be independently lower alkyl of
C.sub.1-C.sub.6, or aryl of C.sub.6-C.sub.20),benzyl and other
optionally substituted benzyl, trialkylsilyl, t-butyl-dialkylsyl,
t-butyldiphenylsilyl, TIPDS, THP, MOM, MEM and other optionally
ether protecting groups; or H, acetyl, benzoyl and other optionally
substituted acyl (R' and R'' are --C(O)--R, wherein R can be lower
alkyl of C.sub.1-C.sub.6, or aryl of C.sub.6-C.sub.20, benzyl or
other optionally substituted benzyl);
[0047] R.sub.1, R.sub.2 are independently hydrogen, aryl
(C.sub.6-C.sub.20) and a lower alkyl (C.sub.1-C.sub.6) including
methyl, hydroxymethyl, methoxymethyl, halomethyl including
fluoromethyl, ethyl, propyl, optionally substituted ethenyl
including vinyl, halovinyl (F--CH.dbd.C), optionally substituted
ethynyl including haloethynyl (F--C.ident.C), optionally
substituted allyl including haloallyl (FHC.dbd.CH--CH.sub.2--);
and
[0048] R.sub.3 is independently hydrogen, aryl including phenyl,
aryl alkyl including, but not limited to benzyl, lower alkyl
(C.sub.1-6) including methyl, ethyl, or propyl.
[0049] The invention as disclosed herein also relates to processes
for making compounds of the following general formula 49B, which
are prepared from
2-alkyl-4,5-di-O-protected-2,3-dihydroxy-pentanoic-acid ester
derivatives of general formula [42B].
##STR00011##
wherein R.sup.3 and R.sup.5 can be independently H, CH.sub.3, Ac,
Bz, pivaloyl, or 4-nitrobenzoyl, 3-nitrobenzoyl, 2-nitrobenzoyl,
4-chlorobenzoyl, 3-chlorobenzoyl, 2-chlorobenzoyl, 4-methylbenzoyl,
3-methylbenzoyl, 2-methylbenzoyl, para-phenylbenzoyl, and other
optionally substituted acyl (R.sup.3 and R.sup.5 are --C(O)--R, R
can be independently lower alkyl of C.sub.1-C.sub.6,, or aryl of
C.sub.6-C.sub.20), benzyl, 4-methoxybenzyl and other optionally
substituted benzyl (R.sup.3 and R.sup.5 can be independently aryl
of C.sub.6-C.sub.20), trityl, trialkylsilyl, t-butyl-dialkylsyl,
t-butyldiphenylsilyl, TIPDS, THP, MOM, MEM and other optionally
ether protecting groups (R.sup.3 and R.sup.5 can be independently
alkyl of C.sub.1-C.sub.10), or R.sup.3 and R.sup.5 are linked
through --SiR.sub.2--O--SiR.sub.2-- or --SiR.sub.2--, wherein R is
a lower alkyl group such as Me, Et, n-Pr or i-Pr.
##STR00012##
wherein [0050] X is halogen (F, Cl, Br), [0051] Y is N or CH,
[0052] Z is, halogen, OH, OR', SH, SR', NH.sub.2, NHR', or R'
[0053] R.sup.2' is alkyl of C.sub.1-C.sub.3, vinyl, or ethynyl
[0054] R.sup.3' and R.sup.5' can be same or different H, alkyl,
aralkyl, acyl, cyclic acetal such as 2',3'-O-isopropylidene or
2',3-O-benzylidene, or 2',3'-cyclic carbonate. [0055] R.sup.2,
R.sup.4, R.sup.5 and R.sup.6 are independently H, halogen including
F, Cl, Br, I, OH, OR', SH, SR', N.sub.3, NH.sub.2, NHR', NR'',
NHC(O)OR', lower alkyl of C.sub.1-C.sub.6, halogenated (F, Cl, Br,
I) lower alkyl of C.sub.1-C.sub.6 such as CF.sub.3 and
CH.sub.2CH.sub.2F, lower alkenyl of C.sub.2-C.sub.6 such as
CH.dbd.CH.sub.2, halogenated (F, Cl, Br, I) lower alkenyl of
C.sub.2-C.sub.6 such as CH.dbd.CHCl, CH.dbd.CHBr and CH.dbd.CHI,
lower alkynyl of C.sub.2-C.sub.6 such as C.dbd.CH, halogenated (F,
Cl, Br, I) lower alkynyl of C.sub.2-C.sub.6, lower alkoxy of
C.sub.1-C.sub.6 such as CH.sub.2OH and CH.sub.2CH.sub.2OH,
halogenated (F, Cl, Br, I) lower alkoxy of C.sub.1-C.sub.6,
CO.sub.2H, CO.sub.2R', CONH.sub.2, CONHR', CONR'.sub.2,
CH.dbd.CHCO.sub.2H, CH.dbd.CHCO.sub.2R'; and, [0056] R' and R'' are
the same or different and are optionally substituted alkyl of
C.sub.1-C.sub.12 (particularly when the alkyl is an amino acid
residue), cycloalkyl, optionally substituted alkynyl of
C.sub.2-C.sub.6, optionally substituted lower alkenyl of
C.sub.2-C.sub.6, or optionally substituted acyl.
[0057] The reaction of the cyclic sulfate ester, 50 (Scheme 6) with
tetraethylammonium fluoride or tetramethylammonium fluoride 51
(Scheme 6) quantitatively generated the fluorinated sulfate, in
highly stereospecific and regioselective manner. Following acid
catalyzed cyclization afforded the
2-fluoro-2-C-methyl-.gamma.-ribonolactone, 53 in high yield. The
present invention is based on this discovery and provides a process
for the preparation of the 2'-deoxy-2'-substituted nucleosides, I
and II, using the reactions described herein.
[0058]
(2S,3R,4R)-4,5-O-alkylidene-2-dimethyl-2,3,4,5-tetrahydroxy-2-methy-
-1-pentanoic acid ethyl ester (42B), can be prepared by asymmetric
dihydroxylation (AD) or stereoselective dihydroxylation of the
Wittig product 41 with or without chiral catalysts. Wittig product
41, in turn, can be prepared readily from the protected (R)
glyceraldehyde (Schemes 7, 8), where R.sup.1 is independently a
lower alkyl (C.sub.1-C.sub.6) including, but not limited to methyl,
ethyl, optionally substituted phenyl, optionally substituted
benzyl. Or R.sup.1 is a part of cyclic group including ethylene
(--CH.sub.2CH.sub.2--), or trimethylene
(--CH.sub.2CH.sub.2CH.sub.2--) forming cyclopentyl or cyclohexanyl
group, respectively. R.sup.2, R.sup.3 are independently hydrogen, a
lower alkyl (C.sub.1-C.sub.6) including, but not limited to methyl,
hydroxymethyl, methoxymethyl, halomethyl including, but not limited
to fluoromethyl, ethyl, propyl, optionally substituted ethenyl
including, but not limited to vinyl, halovinyl (F--CH.dbd.C),
optionally substituted ethynyl including, but not limited to
haloethynyl (F--C.ident.C), optionally substituted allyl including,
but not limited to haloallyl (FHC.dbd.CH--CH.sub.2--); and R.sup.4
is acyl including, but not limited to acetyl, benzoyl, arylalkyl
including but not limited to benzyl, lower alkyl (C.sub.1-10)
including, but not limited to, methyl, ethyl, propyl, CH.sub.2R
where R is hydrogen, lower alkyl (C.sub.1-10) including, but not
limited to, methyl, ethyl, propyl.
##STR00013##
[0059] The diol (42B) can be converted to the cyclic sulfite (IIIa)
by treatment with thionyl chloride (SOCl.sub.2) in presence of an
alkylamine such as triethylamine, diisopropyl ethylamine, or
pyridine, which can then be oxidized using the oxidants selected
from a first group consisting of RuCl.sub.3, KMnO.sub.4, and TEMPO
or a combination of the first group and one of the second group
consisting of NaIO.sub.4, KIO.sub.4, HIO.sub.4, mCPBA, NaOCl, and
oxone. The solvent of this step is selected from one or more of the
group consisting of chloroform, methylene chloride,
1,2-dichloroethane, diethyl ether, tetrahydrofuran, benzene, and
toluene, alone or in combination with water. (Gao Y et al J. Am.
Chem. Soc. 1988, 110, 7538-7539, Berridge et al J. Org. Chem. 1990,
55, 1211-1217). It is also possible that the diol is directly
converted to the cyclic sulfate (IIIb) by treatment with
sulfurylchloride, or sulfuryl diimidazole. On the other hand, the
diol 42B can be converted to the cyclic carbonate (IIIc) by
treatment with carbonyl diimidazole or carbonyl dimethoxide (Scheme
8) (Chang, et al Tetrahedron Lett. 1996, 37, 3219-3222).
##STR00014##
(ii) Synthesis of the substituted 2-deoxy-D-ribono-.gamma.-lactone,
53B
[0060] The cyclic sulfate (IIIb, Scheme 8) can be converted to the
fluorinated sulfate ester of the formula, 51B (Scheme 9), in high
yield and with high regioselectivity and stereospecificity, by
treatment with tetraalkylammonium fluoride including, but not
limited to tetramethylammonium fluoride (TMAF), tetraethylammonium
fluoride (TEAF), or tetrabutylammomnium fluoride (TBAF), or
tris(dimehtylamino)sulfur (trimethylsilyl)difluoride (TAS-F)
(Fuentes J, et al Tetrahedron lett. 1998, 39, 7149-7152) in an
aprotic polar solvent such as acetone, tetrahydrofuran,
N,N-dimethylformamide, or acetonitrile (Scheme 9). Metal fluorides
such as silver fluoride (AgF), potassium fluoride (KF), cesium
fluoride (CsF), or rubidium fluoride (RbF), can be used alone or
with catalytic amount of tetraalkylammonium fluoride, crown-ether,
diglyme, or polyethylene glycol, or other phase transfer
catalyst.
[0061] The cyclic sulfate (IIIb) can be converted to other
2-substituted sulfates of the formula 51B by treatment with
NaBH.sub.4, tetraalkylammonium chloride, tetraalkylammonium
bromide, NaN.sub.3 or LiN.sub.3, NH.sub.4OR, NH.sub.4SCN,
CF.sub.3I-tetrakis(dimethylamino)-ethylene (TDAE), and
tetraalkylammonium nitrate (Gao et al J. Am. Chem. Soc. 1988, 110,
7538-7539), KCN, LiCu(R).sub.2 where R is methyl, ethyl, ethylenyl,
or ethnyl. Similarly, the cyclicsulfite (IIIa) can be converted to
the substituted ester 52B (Chang et al. Tetrahedron Lett. 1996, 37,
3219-3222). Then compounds of the formula MB and 52B can be
converted to the substituted lactones of the formula 53B by
treatment with an acid in H.sub.2O-containing organic solvent such
as methanol, ethanol, or acetonitrile.
[0062] In Formula 53B, R.sup.2, R.sup.3 is independently hydrogen,
a lower alkyl (C.sub.1-C.sub.6) including, but not limited to
methyl, hydroxymethyl, methoxymethyl, halomethyl including, but not
limited to fluoromethyl, ethyl, propyl, optionally substituted
ethenyl including, but not limited to vinyl, halovinyl
(F--CH.dbd.C), optionally substituted ethynyl including, but not
limited to haloethynyl (F--C.ident.C), optionally substituted allyl
including, but not limited to haloallyl (FHC.dbd.CH--CH.sub.2--).
Nu is halogen (F, Cl, Br), N.sub.3, CN, NO.sub.3, CF.sub.3, SCN, OR
or NR.sub.2 where R is acyl including, but not limited to acetyl,
benzoyl, arylalkyl including but not limited to benzyl, lower alkyl
(C.sub.1-10) including, but not limited to methyl, ethyl, propyl,
CH.sub.2R where R is hydrogen, lower alkyl (C.sub.1-10) including,
but not limited to methyl, ethyl, propyl.
##STR00015##
(iii) The Protection of the D-ribono-.gamma.-lactone, 53B
[0063] 53B can be selectively protected with appropriate protection
agents to the 5-protected lactones of the formula 53C with an
appropriate base in an appropriate solvent. The protecting group
includes, but is not limited to the following: trityl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyloxymethyl,
benzoyl, toluoyl, 4-phenyl benzoyl, 2-, 3-, or 4-nitrobenzoyl, 2-,
3-, or 4-chlorobenzoyl, other substituted benzoyl. The base
includes, but is not limited to the following: imidazole, pyridine,
4-(dimethylamino)pyridine, triethytlamine, diisopropylethylamine,
1,4-diazabicyclo[2,2,2]-octane. The solvent includes, but is not
limited to the following: pyridine, dichloromethane, chloroform,
1,2-dichloroethane, tetrahydrofuran.
##STR00016##
[0064] Alternatively, the lactone 53B can be fully protected with
appropriate protection agents with an appropriate base in an
appropriate solvent. The protecting group (R.sup.5, R.sup.6)
includes, but is not limited to the following: methoxymethyl,
methoxyethyl, benzyloxymethyl, ethoxymethyl, trityl, triethylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, acyl including acetyl,
pivaloyl, benzoyl, toluoyl, 4-phenyl benzoyl, 2-, 3-, or
4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, other substituted
benzoyl. The base includes, but is not limited to the following
list: imidazole, pyridine, 4-(dimethylamino)pyridine,
triethytlamine, diisopropylethylamine,
1,4-diazabicyclo[2,2,2]octane. The solvent includes, but is not
limited to pyridine, dichloromethane, chloroform,
1,2-dichloroethane, tetrahydrofuran (Scheme 10).
(ii) Complexation Directed .beta.-glycosylation
##STR00017##
[0066] Coupling of 2-deoxy-2-fluoro-2-C-methyl-ribofuranoside (54:
Nu=F, R.sup.3=Me, R.sup.5=R.sup.6=pivaloyl) with silylated
N.sup.4-benzoylcytosine in the presence of trimethylsilyl
trifluoromethanesulfonate (TMSOTf) in CHCl.sub.3 gave a mixture of
.alpha./.beta.-anomers with a ratio of 2/1 in favor of
.alpha.-isomer. However, .beta.-anomer was obtained as major
product (.alpha./.beta.=1/4.9) in the same reaction catalyzed by
SnCl.sub.4 under similar conditions. Possible mechanisms are
proposed in Scheme 10A (R.sup.5 and R.sup.6 are O-protecting groups
that can be acyl or silyl or alkyl or aralkyl with C.sub.1-20).
Treatment of 54 with silylated N.sup.4-benzoylcytosine in the
presence of TMSOTf in CHCl.sub.3 formed an oxonium intermediate
54-i. Silylated base could attack 54-1 from up-side to give
.beta.-anomer 55B or from bottom to provide .alpha.-anomer
55B-alpha. Because of stereohinderance at up-side caused by
2-methyl group, silylated base attacked intermediate 54-i mainly
from bottom (less stereohindered side) to afford a mixture of
.alpha./.beta.-anomers with a ratio of 2/1 in favor of
.alpha.-anomer. While treatment of 54 with silylated
N.sup.4-benzoylcytosine in the presence of SnCl.sub.4 , a complex
54-ii was formed instead of oxonium 54-i. Silyated
N.sup.4-benzoylcytosine attacked 54-ii from less stereohindered
up-side to give a mixture of .alpha./.beta.-anomers with a ratio of
1/5 in favor of .beta.-anomer.
[0067] Compound 54 can be made from the protected lactone of the
formula, 49B, which can be reduced with DIBAL-H or lithium
tri-tert-butoxyaluminum hydride and other hydride reducing agent to
the lactol, which can then converted either to the acylate by
acylation with acyl halide, or acyl anhydride, in presence of an
appropriate base in an appropriate solvent. Acyl halide or acyl
anhydride includes, but is not limited to the following list:
acetic chloride, optionally substituted benzoyl chloride, acetic
anhydride, optionally substituted benzoyl anhydride. The base
includes, but is not limited to the following: imidazole, pyridine,
4-(dimethylamino)pyridine, triethytlamine, diisopropylethylamine,
1,4-diazabicyclo[2,2,2]octane. The solvent includes, but is not
limited to the following list: pyridine, dichloromethane,
chloroform, 1,2-dichloroethane, tetrahydrofuran.
(iii) Synthesis of the L-nucleosides, IB-L
[0068] The processes for the D-series of the formula I and II can
be used for preparation of the L-nucleosides of the formula, IB-L
from the (S)-glyceraldehydes (Scheme 11).
##STR00018##
(iv) Synthesis of
2-alkyl-4,5-di-O-protected-2,3-dihydroxy-pentanoic acid
[0069] Currently, the most preferable procedure for the synthesis
of nucleosides of general structures I and II is the preparation of
a derivative of the 2-deoxy-2-fluoro-2-C-methyl-D-ribofuranosyl
moiety of I and II as shown in Scheme 4, Scheme 5 and Scheme 6,
above through (i) synthesis of the intermediate, derivatives of
2-alkyl-4,5-di-O-protected-2,3-dihydroxy-pentanoic-acid ester of
general structure I, (ii) conversion of 42B into the 3,5-protected
2-deoxy-2-fluoro-2-C-methyl-D-ribono-y-latone of general structure
49B, and (iii) conversion of 49B into purine and pyrimidine
nucleosides of general structures of I and II. The key step in
Scheme 4 is the stereoselective osmium catalyzed dihydroxylation of
olefinic intermediate 41 into 42 in the presence of the expensive
Sharpless AD catalyst. Instead of the Sharpless catalyst, if other
chiral compounds such as L-quinidine are used, the reaction also
goes smoothly giving the desired 42. Kishi et al. have proposed
that in OsO.sub.4 dihydroxylation of allylic alcohol derivatives
(esters, ethers, acetals or ketals), the major course of reaction
would occur on the face of the olefinic bond opposite to that of
the preexisting hydroxyl or alkoxyl group, (Tetrahedron Lett, 1983,
24, 3943). Some examples are shown in Scheme 12 (Tetrahedron Lett,
1983, 24, 3947). In every case, the major product arose from
addition of OSO.sub.4 from the anti side of the oxygen on the
neighboring secondary carbon. However, stereoselectivity is not
high enough for preparative synthesis.
##STR00019## ##STR00020##
[0070] Encouraged by Kishi's rule, which presents that the
stereochemistry is formulated as arising from the preferential
approach of osmium tetroxide to occur on the face of the olefinic
bond opposite to that of the preexisting hydroxyl or alkoxyl group,
dihydroxylations of 41 under the original conditions but without
any chiral catalysts, including Sharpless AD catalyst, were
conducted. Dihydroxylation of 41 using
Ke.sub.3Fe(CN).sub.6/K.sub.2OsO.sub.2(OH).sub.4/K.sub.2CO.sub.3
system without chiral catalysts gives the product in 77% yield,
which product is a 5:1 mixture of isomers with the predominant
isomer being the desired 42. The reaction of olefin 41 with
OsO.sub.4 using N-methylmorpholine N-oxide (NMO) as the oxidant
without chiral catalysts gave a 5:1 mixture of 42 and its isomer in
79% yield. Most surprisingly, when t-butylhydroperoxide (TBHP) is
used as oxidant in the presence of catalytic amount of OSO.sub.4 in
acetone and ammonium acetate as buffer (the reagent combination was
used in the synthesis of alditols by Masamune and Sharpless (J.
Org. Chem, 1982, 47, 1373)), the crystalline product isolated is
the virtually pure desired 42. This procedure is therefore far
superior to the OSO.sub.4/NMO and Fe(CN).sub.6.sup.3- methods. At
10 mmolar scale, the desired diol 42 is formed exclusively, and is
isolated in 87% yield. No contamination by the other isomer was
detected in this product by vigorous .sup.1H NMR analyses.
[0071] It is well known that in OSO.sub.4 oxidation the
intermediate is cyclic osmate V (below) (Criegee, Liebigs Ann.
Chem., 1936, 522, 75). cis-Dihydroxylation of olefins with
potassium permanganate in alkaline media has been known for quite
some time (Robinson and Robinson, J. Chem. Soc., 1925, 127, 1628),
and this reaction appears to proceed through a cyclic ester VI.
Thus attempts at permanganate dihydroxylation have been
performed.
##STR00021##
[0072] Previous reports have indicated that permanganate
dihydroxylation of olefins in acid or neutral conditions causes
over-oxidation of the initial diol products with concomitant
production of ketones and carboxylates. Only in alkaline conditions
further oxidation of the diol products can be decelerated. As 41 is
a carboxylic ester the reaction cannot be done in aqueous alkali.
Hazra et al. (J. Chem. Soc. Perkin Trans. I, 1994, 1667) describes
successful dihydroxylation of highly substituted olefins to the
corresponding diols using tetradecyltrimethylammonium permanganate
(TDTAP) in a mixture of t-BuOH, dichloromethane and water in the
presence of 0.1 equivalent of KOH. Application of this method to
dihydroxylation of 41 results in rapid formation (within 10 minutes
at room temperature) of a mixture of 42 and its diastereomer in an
8:1 ratio, which is isolated in 71% yield. Oxidation occurs much
faster in similar reactions without KOH, but the yield of 42 is not
improved.
[0073] Mukaiyama et al. (Chem. Lett., 1983, 173) disclosed
dihydroxylation of olefins with KMnO.sub.4 and 18-crown-6 ether in
dichloromethane at -40.degree. C. Attempts at dihydroxylation of 41
under Mukaiyama's conditions but at different temperatures offer a
6:1 mixture of 42 and its diastereomer in 50% yield at -40.degree.
C. and the same mixture in 94% yield at -10.degree. C.
[0074] Surprisingly, in contrast to the teaching of the prior of
art which discloses that oxidation of a double bond with KMnO.sub.4
proceeds via diol wherein the resultant diol is rapidly oxidized
further without the presence of base, diol 42 was found to be
isolable when the corresponding 41 is treated with KMnO.sub.4
without added alkali and crown ether. In pure t-butanol, oxidation
does not proceed even at room temperature conditions for two days.
Addition of water to the mixture promotes the reaction. It is found
that the more water in the reaction media the faster the reaction
proceeds with poor selectivity of 42 production; the less water the
slower the reaction but improved selectivity. In any case, the
yield is rather poor due to further oxidation.
[0075] Most surprisingly, and in contradiction to the prior art,
treatment of 41 with KMnO.sub.4 in acetone is found to give a 10:1
mixture in quantitative yield, the desired 42 being the major
component. The stereoselectivity is found to be improved by
performing the reaction in a mixture of acetone and pyridine.
[0076] The following Examples are set forth to aid in an
understanding of the invention. This section is not intended to,
and should not be interpreted to, limit in any way the invention
set forth in the claims which follow thereafter.
EXAMPLES
Example 1
(2S,3R,4R)-4,5-O-isopropylidene-2,3-O-sulfuryl-2,3,4,5-tetrahydroxy-2-meth-
yl-pentanoic acid ethyl ester (IIIb, R.sup.1.dbd.CH.sub.3,
R.sup.2.dbd.H, R.sup.3.dbd.CH.sub.3)
[0077] To a solution of
(2S,3R,4R)-4,5-O-isopropylidene-2,3,4,5-tetrahydroxy-2-methyl-pentanoic
acid ethyl ester (R.sup.1.dbd.CH.sub.3, R.sup.2.dbd.H,
R.sup.3.dbd.CH.sub.3) (2.0 g, 8.06 mmol) in anhydrous methylene
chloride (40 mL) containing triethyl amine (3.4 mL) was added at
0.degree. C. thionyl chloride (0.88 mL, 12.08 mmol) dropwise over
10 min. The resulting reaction mixture was stirred at 0.degree. C.
for 10 min, diluted with cold ether (100 mL), washed with water (50
mL.times.2) and brine (50 mL.times.2), dried with sodium sulfate,
and concentrated to give a residue (IIIa, R.sup.1.dbd.CH.sub.3,
R.sup.2.dbd.H, R.sup.3.dbd.CH.sub.3) which was dissolved in
acetonitrile-tetrachloromethane (10:10 mL). To the obtained
solution was added at room temperature sodium periodate (2.58 g,
12.06 mmol), ruthenium trichloride (16 mg, 0.077 mmol), and water
(14 mL) subsequently. The resulting reaction mixture was stirred at
room temperature for 10 min, diluted ether (100 mL), washed with
water (50 mL.times.2), saturated sodium bicarbonate solution (50
mL.times.2), and brine (50 mL.times.2), dried with sodium sulfate,
concentrated, and co-evaporated with toluene (30 mL.times.3) to a
syrupy residue, the sulfate IIIb (2.23 g, 89%) which was used for
the next reaction without further purification. .sup.1H NMR
(CDCl.sub.3) .delta. (ppm) 5.04 (d, 1H, J=9.6 Hz, H-3), 4.37 (m,
1H, H-4), 4.29 (q, 2H, J=7.6 Hz, CH.sub.2CH.sub.3), 4.17 (dd, 1H,
J=5.6, 9.6 Hz, H-5), 4.05 (dd, 1H, J=3.2, 9.6 Hz, H-5'), 1.8 (s,
3H,CH.sub.3-2), 1.38 (s, 3H, (CH.sub.3).sub.2C), 1.32 (t, 3H,
J=6.8Hz, CH.sub.2CH.sub.3), 1.31 (s, 3H, (CH.sub.3).sub.2C).
Example 2
Tetrabutylammonium salt of
(2R,3S,4R)-2-fluoro-4,5-O-isopropylidene-2-methyl-3-sulfooxy-3,4,5-trihyd-
roxypentanoic acid ethyl ester (51B, R.sup.1.dbd.CH.sub.3,
R.sup.2.dbd.H, R.sup.3.dbd.CH.sub.3, Nu=F,
M.sup.+=tetrabutylammonium)
[0078] Method 1: To a solution of the sulfate IIIb from Example 1
(628 mg, 2.02 mmol) in anhydrous tetrahydrofuran was added at
0.degree. C. tetrabutylammonium fluoride (1M in tetrahydrofuran,
dried with 4 .ANG. molecular sieves) dropwise over 5 min. The
resulting reaction mixture was stirred at 0.degree. C. for 20 min,
another 2 mL of tetrabutylammonium fluoride (1M in tetrahydrofuran,
dried with 4 .ANG. molecular sieves, 3 mL) was added, and then the
reaction mixture was stirred at 0.degree. C. for 2 hours, then
concentrated, and purified by silica gel column chromatography
(EtOAc) to give to the fluorinated sulfate, as a syrup (350 mg,
38%). .sup.1H NMR (CDCl.sub.3) .delta. (ppm) 4.66 (dd, 1H, J=9.6,
25.6 Hz, H-3), 4.48 (dd, 1H, J=5.2, 8.8 Hz, H-4), 4.20, 4.07 (2m,
4H, H-5, OCH.sub.2CH.sub.3), 3.21 (m, 8H,
N(CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.4), 1.69 (d, 3H, J=22.4 Hz,
CH.sub.3-2), 1.59 (m, 8H,
N(CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.4), 1.39 (m, 8H,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.4), 1.27-1.25(m, 9H,
OCH.sub.2CH.sub.3, (CH.sub.3).sub.2C), 0.96 (t, 12H, J=6.8 Hz,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.4.
[0079] Method 2: To a solution of the cyclic sulfate IIIb (480 mg,
1.55 mmol) in anhydrous tetrahydrofuran was added at 0.degree. C.
tetrabutylammonium fluoride (1M in tetrahydrofuran, neutralized
with HF-pyridine, 3.1 mL) dropwise over 5 min. The resulting
reaction mixture was stirred for 39 hours, concentrated, and
purified by silica gel column chromatography
(CH.sub.2Cl.sub.2:MeOH=10:1) to the fluorinated sulfate as a syrup
(280 mg, 39%).
Example 3
2-Deoxy-2-fluoro-2-C-methyl-D-ribono-y-lactone (53B, R.sup.2.dbd.H,
R.sup.3.alpha.CH.sub.3, Nu=F)
[0080] A mixture of the product of Example 2(170 mg, 0.370 mmol),
trifluoroacetic acid (0.8 mL), and water (2 mL) in acetonitrile (10
mL) was heated at 80.degree. C. for 1.5 hours, diluted with ethyl
acetate (15 mL), washed with water (10 mL) and saturated sodium
bicarbonate solution (10 mL). The aqueous layer was saturated with
NaCl and extracted with ethyl acetate (10 mL). The combined organic
layer was dried with sodium sulfate, filtered, and concentrated to
give a residue, which was purified by silica gel column
chromatography (hexanes:ethyl acetate=1:1 to
CH.sub.2Cl.sub.2:MeOH=20:1) to give the desired compound as a white
solid (60 mg, 100%). .sup.1H NMR (CDCl.sub.3) .delta. (ppm) 6.06
(d, 1H, J=6.8 Hz, HO-3), 5.16 (t, 1H, J=4.8 Hz, HO-5), 4.26 (m, 1H,
H-4), 3.98 (ddd, 1H, J=7.2, 8.0, 23.2 Hz, H-3), 3.78 (ddd, 1H,
J=2.0, 5.2, 12.8 Hz, H-5), 3.55 (ddd, 1H, J=4.4, 5.6, 12.4 Hz,
H-5'), 1.48 (d, 3H, J=24 Hz, CH.sub.3-2); .sup.13C NMR (CDCl.sub.3)
.delta. (ppm) 171.2 (d, J=21.2 Hz, C-1), 92.5 (d, J=177.5 Hz, C-2),
83.37 (C-4), 70.2 (d, J=15.9 Hz, C-3), 59.0 (C-5), 17.1 (d, J=25.0
Hz, CH.sub.3-C-2).
Example 4
3,5-Di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribono-.gamma.-lactone
(49B, R.sup.2.dbd.H, R.sup.3.dbd.CH.sub.3, R.sup.5=Bz, R.sup.6=Bz,
Nu=F)
[0081] The compound of Example 3 (60 mg, 0.16 mmol) was dissolved
in anhydrous pyridine (1 mL) and benzoyl chloride (0.3 mL) was
added. The resulting reaction mixture was stirred at room
temperature for 20 min, water added (1 mL), stirred for 20 min,
diluted with ethyl acetate (5 mL), washed with water (2 mL) and 1M
HCl (2 mL.times.3), and dried with sodium sulfate. Upon filtration
and concentration, the residue was purified by silica gel column
chromatography (hexanes:ethyl acetate=10:1) to give
3,5-di-O-benzoyl-2-deoxy-2-fluoro-D-ribono-.gamma.-lactone as a
white solid (118 mg, 87%). .sup.1H NMR (CDCl.sub.3) .delta. (ppm)
8.08 (m, 2H, aromatic), 7.99 (m, 2H, aromatic), 7.63 (m, 1H,
aromatic), 7.58 (m, 1H, aromatic), 7.49 (m, 2H, aromatic), 7.43 (m,
2H, aromatic), 5.51 (dd, 1H, J=7.2, 17.6 Hz, H-3), 5.00 (m, 1H,
H-4), 4.78 (dd, 1H, J=3.6, 12.8 Hz, H-5), 4.59 (dd, 1H, J=5.2, 12.8
Hz, H-5''), 1.75 (d, 3H, J=23.6 Hz, CH.sub.3-2)
Example 5
Tetraethylammonium salt of (2R, 3S,
4R)-4,5-dihydroxy-2-fluoro-4,5-O-isopropylidene-2-methyl-3-sulfooxy-penta-
noic acid ethyl ester (51B, R.sup.1.dbd.CH.sub.3, R.sup.2.dbd.H,
R.sup.3.dbd.CH.sub.3, Nu=F, M.sup.+=tetraethylammonium)
[0082] Method 1. To a solution of the sulfate IIIb (Scheme 9) (1.96
g, 6.32 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added
at 0.degree. C. tetraethylammonium fluoride hydrate (1.39 g, 9.13
mmol) in one portion. The resulting reaction mixture was stirred
for 30 min, concentrated, and co-evaporated with toluene to give a
semi-solid (51b) (3.35 g, crude, proton NMR showed virtually one
product). .sup.1H NMR (CDCl.sub.3) .delta. (ppm) 4.61 (dd, 1H,
J=9.2, 25.6 Hz, H-3), 4.51 (dd, 1H, J=5.2, 9.2 Hz, H-4), 4.23-4.05
(m, 4H, H-5, OCH.sub.2CH.sub.3), 3.32 (q, 8H, J=7.2 Hz,
N(CH.sub.2CH.sub.3).sub.4), 1.69 (d, 3H, J=23. 2 Hz, CH.sub.3-2),
1.31-1.24 (m, 21H, OCH.sub.2CH.sub.3, (CH.sub.3).sub.2C,
N(CH.sub.2CH.sub.3).sub.4.
[0083] Method 2: To a solution of the sulfate IIIb (148 mg, 0.477
mmol) in anhydrous acetonitrile (2 mL) was added at 0.degree. C.
tetraethylammonium fluoride hydrate (107 mg, 0.717 mmol) in one
portion. The resulting reaction mixture was stirred for 24 hours,
concentrated, and co-evaporated with toluene to give a semi-solid
(257 mg, crude, proton NMR showed virtually one product).
Example 6
Preparation of 1-(2-deoxy-2-fluoro-2-methyl-3,5-O-3,5
dipivaloyl-ribofuranosyly-N.sup.4-benzoylcytosine (11b, R.sup.5
.dbd.R.sup.6 pivaloyl, R.sup.2.dbd.H, R.sup.3=Me)
[0084] To a solution of 49B, (Scheme 6) (Nu=F, R.sup.2--H,
R.sup.3=Me, R.sup.5.dbd.R.sup.6=pivaloyl, 3.44g, 10.36 mmol) in THF
(70 mL) was added LiAl (t-BuO).sub.3H (13.47 mmol, 1M in THF, 13.47
mL) at -20.degree. C. to -10.degree. C. and the resulting solution
was stirred at -10.degree. C. to -15.degree. C. for 2 h. To the
solution was added an additional LiAl (t-BuO).sub.3H (1.35 mL, 1.35
mmol) and the solution was stirred at -10.degree. C. for 1 h. Ice
water (50 mL) was added. The mixture was extracted with EtOAc (200
mL), and the organic layer was washed with water, brine and dried
(Na.sub.2SO.sub.4). Solvent was removed to give crude lactol which
was dissolved in CH.sub.2Cl.sub.2 (50 mL). To the solution were
added Et.sub.3N (31.08 mmol, 4.24 mL), 4-dimethylaminopyridine (1
mmol, 122mg) and trimethylacetyl chloride (20.7 mmol, 2.55 mL), and
the mixture was stirred at room temperature for 16 h. Water (20 mL)
was added, and the resulting mixture was stirred at room
temperature for 10 min. EtOAc (200 mL) was added, and organic
solution was washed with water, brine, and dried
(Na.sub.2SO.sub.4). Solvent was removed and the residue was
co-evaporated with toluene (2.times.20 mL) to give a crude
intermediate (5, 6.74 g) for the next coupling reaction without
purification.
[0085] A suspension of N.sup.4-benzoylcytosine (6.06 mmol, 1.30 g)
and (NH.sub.4).sub.2SO.sub.4 (30 mmg) in HMDS (16.7 mL) was
refluxed for 5 h, and the clear solution was concentrated to
dryness under reduced pressure. The residue was dissolved in
1,2-dichloroethane (50 mL). To the solution were added crude 54
(1.96 g, Scheme 6) and SnCl.sub.4 (1.42 mL, 12.12 mmol) at room
temperature. The solution was refluxed for 24 h. and cooled to
0.degree. C. To the solution were added NaHCO.sub.3 (6.11 g, 72.72
mmol) and EtOAc (50 mL). To the mixture was added H.sub.2O (2 mL)
slowly, and the resulting mixture was stirred at room temperature
for 20 min. Solid was removed by filtration. The organic solution
was washed with water, brine and dried (Na.sub.2SO.sub.4). Solvent
was removed to give syrup as crude mixture of
.beta./.alpha.-anomers with a ratio of 4/1 in favor to
.beta.-isomer. The crude product was dissolved in MeOH (1 mL) at
50.degree. C. To the solution was added hexanes (10 mL). The
mixture was allowed to stay at room temperature for 1 h, then
0.degree. C. for 2 h.
[0086] Crystals were collected by filtration, washed with hexanes
to give product 55, Scheme 6 (323 mg, 20.3% from 49). Mother liquor
was concentrated to dryness and purified by column chromatography
(20-50% EtOAc in hexanes) to give second crop of 55. H-NMR
(CDCl.sub.3): .delta. 8.82 (br s, 1H, NH), 8.10, 7.89, 7.62, 7.52
(m, 7H, H-5, H-6, 5Ph-H), 6.41 (d, J=18.4 Hz, 1H, H-1'), 5.10 (m,
1H, H-3'), 4.45 (d, J=9.6 Hz, 1H, H-4'), 4.36 (t, J=2.8 Hz, 2H,
H-5'), 1.35 (d, J=22.0 Hz, 3H, Me), 1.29, 1.23 [ss, 18H,
C(Me).sub.3].
Example 7
(2S, 3R)-3-[(4R)-2,2-Dimethyl-[1,
3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-propionic acid ethyl ester
(42)
4-Methylmorpholine N-oxide as oxidant with Osmium catalyst
[0087] To a stirred solution of compound 41 (214 mg, 0.1 mmol) in
t-BuOH under argon was added a solution of 4-methylmorpholine
N-oxide (0.47 mL, 50 wt % solution in H.sub.2O) and water (0.2 mL).
A 2.5 wt % solution of osmium tetraoxide in tert-butyl alcohol
(0.51 mL) is added, and the mixture is stirred for 5 h at room
temperature in a water bath. The mixture is evaporated in vacuo to
a syrup, which is azeotroped with H.sub.2O (3.times.10 mL) to
remove 4-methylmorpholine. The residue is dried by addition and
evaporation of EtOH (2.times.10 mL) to give a residue, which was
purified by silica gel column chromatography with 20% EtOAc in
hexanes to provide the desired product and its isomer (196 mg, 79%)
as a solid. Proton NMR indicates that the ratio of the desired
product to its isomer is around 5:1. Recrystallization of the
mixture from hexanes/ethyl acetate gives pure product (91 mg, 37.4%
from starting material) as a crystalline solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.18 (t, J=7.2 Hz, 3H, --OCH.sub.2CH.sub.3),
1.24 (s, 3H, CH.sub.3), 1.25 (s, 3H, CH.sub.3), 1.28 (s, 3H,
2-CH.sub.3), 3.67 (t, J=7.2 Hz, 1H), 3.85, 4.06 and 4.12 (m, 4H),
4.97 (s, 1H, 2-OH, D.sub.2O exchangeable), 5.14 (d, J=7.6 Hz, 2-OH,
D.sub.2O exchangeable).
Example 8
(2S, 3R)-3-[(4R)-2,2-Dimethyl-[1,
3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-propionic acid ethyl ester
(42)
Potassium Ferricyanide as Oxidant with Osmium Catalyst
[0088] A 100 mL round-bottomed flask, equipped with a magnetic
stirrer, is charged with 5 mL of tert-butyl alcohol, 5 mL of water,
and a mixture of K.sub.3Fe(CN).sub.6 (0.98 g), K.sub.2CO.sub.3
(0.41 g), and K.sub.2OsO.sub.2(OH).sub.4 (3.2 mg). Stirring at room
temperature produced two clear phases; the lower aqueous phase
appears bright yellow. Methanesulfonamide (95 mg) is added at this
point. The mixture is cooled to 0.degree. C. whereupon some of
salts precipitate out, 214 mg (1 mmol) of the compound 41 is added
at once, and the heterogeneous slurry is stirred vigorously at
0.degree. C. for 24 h. To the mixture is added solid sodium sulfite
(1.5 g) while stirring at 0.degree. C., and then the mixture is
allowed to warm to room temperature and stirred for 30-60 min.
Ethyl acetate (10 mL) is added, and after separation of the layers,
the aqueous phase is further extracted with EtOAc. The organic
layer is dried over Na.sub.2SO.sub.4 and concentrated to dryness.
The residue is purified by silica gel column chromatography with
20% EtOAc in hexanes to provide the product (190 mg, 77%) as a
solid, proton NMR indicates that the ratio of the desired product
to its isomer is around 5:1. Recrystallization of the mixture with
hexanes/ethyl acetate gave pure diol product (102 mg, 41% from
starting material) as a crystalline solid. The .sup.1H NMR spectrum
of this product is identical to that of an authentic specimen.
Example 9
(2S,
3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-p-
ropionic acid ethyl ester (42)
t-Butylhydroperoxide as Oxidant at Room Temperature with Osmium
Catalyst
[0089] A 50 mL of flask, equipped with magnetic stirrer, is charged
with 2 mL of acetone, 214 mg (1 mmol) of compound 41, 65 mg of
Et.sub.4NOAc.4H.sub.2O, and 0.3 mL of tert-butyl hydroperoxide
(5.about.6 M in decane). After stirring at room temperature until
the Et.sub.4NOAc a clear solution is obtained, the resulting
solution is cooled in an ice bath and 5 mL of OSO.sub.4 (2.5 wt %
in t-BuOH) is added in one portion. The solution immediately
becomes brownish purple. After 1 h the ice bath is removed and the
reaction mixture is allowed to warm to room temperature and stirred
for 14 h. The rest of the procedure is done exactly the same way as
described above. After flash column chromatography, 178 mg (72%) of
product is obtained as a solid. In an expanded .sup.1H NMR, a tiny
bump is observed at .delta. 1.26 indicating the presence of an
isomer in less than 4% in the product.
Example 10
(2S,
3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-p-
ropionic acid ethyl ester (42)
t-Butyhydroperoxide as Oxidant at 0.degree. C. with Osmium
Catalyst
[0090] A 250 mL of flask, equipped with magnetic stirrer, is
charged with 20 mL of acetone, 2.14 g (10 mmol) of compound 41, 650
mg of Et.sub.4NOAc..sub.4H.sub.2O, and 3 mL of tert-butyl
hydroperoxide (5.about.6 M in decane). After stirring at room
temperature until the Et.sub.4NOAc has dissolved, the resulting
solution is cooled in an ice bath and 5 mL of OsO.sub.4 (2.5 wt %
in t-BuOH) is added in one portion. The solution immediately
becomes brownish purple. The reaction mixture is then stirred at
0.degree. C. for 6.5 h (monitored by TLC, hexanes: ethyl
acetate=4:1, Rf=0.18). Ether (40 mL) is added at 0.degree. C. and
the resulting mixture is treated with 5 mL of freshly prepared 10%
NaHSO.sub.3 solution in one portion. The ice bath is removed and
stirring is continued for 1 h. EtOAc (100 mL) and H.sub.2O (50 mL)
are added to the mixture. After separation of the layers, the
aqueous phase is further extracted with EtOAc. The organic layer is
washed with brine, dried (MgSO.sub.4) and concentrated. The residue
is purified by a flash silica gel column chromatography with 20%
EtOAc in hexanes to provide the product (2.16 g, 87%) as a solid.
No contamination of an isomer is detected in this product by
vigorous .sup.1H NMR analyses.
Example 11
(2S,
3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-p-
ropionic acid ethyl ester (42)
Tetradecyltimethylammonium Permanganate (TDTAP) as Oxidant
[0091] To a stirred solution of compound 41 (214 mg, 1 mmol), in
t-BuOH (10 mL) and CH.sub.2Cl.sub.2 (2 mL) at room temperature is
added a solution of KOH (6 mg, 0.1 mmol) in water followed by TDTAP
(0.420 g, 1.12 mmol) in small portions over a period of five
minutes. TLC after 5 minutes showed that the reaction is complete.
The solution is quenched by using 10 mL of saturated sodium
bisulfite. The reaction mixture is concentrated in vacuo and the
residue extracted with ethyl acetate (3.times.15 mL), dried
(Na.sub.2SO.sub.4), evaporated to give a white solid, which is
further dissolved in 5 mL of CH.sub.2Cl.sub.2, passed it through a
plug of silica gel topped with Celite, washed with ethyl acetate
(50 ml). The filtrate is dried in vacuo to give viscous oil (174 mg
71% yield) as an 8:1 mixture of which the predominant isomer is the
titled compound.
Example 12
(2S,
3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-p-
ropionic acid ethyl ester (42)
Potassium Permanganate as Oxidant with 18-Crown-6 ether--A (at
-40.degree. C.)
[0092] To a solution of compound 41 (214 mg, 1 mmol) in
CH.sub.2Cl.sub.2 (10 mL) and 18-crown-6-ether (37.5 mg, 0.1 mmol)
is added KMnO.sub.4 (158 mg, 1 mmol) in portions at -40.degree. C.,
and the mixture stirred for 2 h at the same temperature. During
this time the reaction mixture turns to dark brown. After the
reaction was complete, mixture is quenched with saturated solution
of sodium bisulfite (10 mL). The resulting colorless mixture is
filtered through a frit, and extracted the filtrate with ethyl
acetate (2.times.25 ml), dried (Na.sub.2SO.sub.4) and concentrated
to give a viscous oil consisting of 10-20% of unreacted olefin
starting material along with the desired diols and its isomer in a
ratio of 6:1 (.sup.1H NMR). Olefin starting material can be removed
by passing through a small pad of silica gel using 5% ethyl
acetate: hexane. A 6:1 mixture of the desired diols is eluted from
the column with 20% ethyl acetate/hexane, and obtained as a white
solid (200 mg .about.80%) upon evaporation of the solvent.
Example 13
(2S,
3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-p-
ropionic acid ethyl ester (42)
Potassium Permanganate as Oxidant with 18-Crown-6 ether--B (at
-10.degree. C.)
[0093] To a solution of compound 41 (214 mg, 1 mmol) in
CH.sub.2Cl.sub.2 (10 ml) is added 37.5 mg (0.1 mmol) of
18-crown-6-ether, and mixture is cooled to -10.degree. C.
KMnO.sub.4 (237 mg, 1.5 mmol) is added in portions, and the mixture
stirred at -10.degree. C. for 2 h. During this time the reaction
mixture turns to dark brown, which is treated with saturated
solution of sodium bisulfite (10 mL). The resulting mixture is
filtered through a frit, and the filtrate is extracted with ethyl
acetate (2.times.25 ml), dried (Na.sub.2SO.sub.4) and evaporated to
give a white solid (240 mg, 94.4%) consisting of the desired
product and its isomer in a ratio of 6:1.
Example 14
(2S,
3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-p-
ropionic acid ethyl ester (42)
Potassium Permanganate as Oxidant in 1:9 H.sub.2O/t-BuOH
[0094] To a solution of compound 41 (214 mg, 1 mmol) in t-BuOH (9
mL) and H.sub.2O (1 mL) at 0.degree. C. is added KMnO.sub.4 (237
mg, 1.5 mmol) in portions and the mixture stirred at the same
temperature for 2 h. An additional amount (79 mg, 0.5 mmol) of
KMnO.sub.4 is charged and the mixture is stirred for another 30
minutes. After work up as above, 128 mg (50%) of a mixture of
isomers in a ratio of 8:1 is obtained as a white solid in which the
major component is the desired product.
Example 15
(2S,
3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-p-
ropionic acid ethyl ester (42)
Potassium Permanganate as Oxidant in 9:1 H.sub.2O/t-BuOH
[0095] To a solution of compound 41 (214 mg, 1 mmol) in H.sub.2O (9
mL) and t-BuOH (1 mL) at 0.degree. C. is added KMnO.sub.4 (237 mg,
1.5 mmol) in portions and stirred at the same temperature for 30
minutes. During this time the mixture turns to dark brown.
Saturated solution of sodium bisulfite (10 mL) is added to the
mixture, which is filtered, and the filtrate is extracted with
ethyl acetate (3.times.25 ml), dried (Na.sub.2SO.sub.4), and
concentrated to give a 4:1 mixture of diol isomers as a white solid
(128 mg, 50%), in which the titled compound is the major
component.
Example 16
(2S,
3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-p-
ropionic acid ethyl ester (42)
Potassium Permanganate as Oxidant in H.sub.2O at 0.degree. C.
[0096] A solution of KMnO.sub.4 (158 mg, 1.0 mmol) in H.sub.2O (10
mL) is added to compound 41 (214 mg, 1 mmol), and the mixture is
stirred at 0.degree. C. for 1 hour. The reaction mixture is
quenched with saturated solution of sodium bisulfite (10 mL), and
the mixture is worked up as above. A white solid (80 mg, 32%) that
is obtained is a 4:1 mixture of diol isomers in which the titled
compound is the predominant component.
Example 17
(2S,
3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-p-
ropionic acid ethyl ester (42)
Potassium Permanganate as Oxidant in Acetone
[0097] To a solution of compound 41 (214 mg, 1 mmol) in acetone (10
mL) is added 37.5 mg, 0.1 mmol) and cooled the reaction mixture to
0.degree. C. To this cold solution is added KMnO.sub.4 (237 mg, 1.5
mmol) in portions, and the reaction mixture is stirred for 2 h at
the same temperature. During this time the reaction mixture turns
to dark brown. The reaction mixture is quenched with saturated
solution of sodium bisulfite (10 ml) where the solution becomes
colorless. The reaction mixture is extracted with ethyl acetate
(3.times.25 ml), dried and evaporated the mixture to give a white
solid (245 mg, 96.4%) in the ratio of 10:1.
Example 18
(2S,
3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-p-
ropionic acid ethyl ester (42)
Potassium Permanganate as Oxidant in a Mixture of Acetone and
Pyridine
[0098] To a solution of compound 41 (214 mg, 1 mmol) in a mixture
of acetone (9 mL) and pyridine (1 mL) at 0.degree. C. is added
KMnO.sub.4 (158 mg, 1.0 mmol) and stirred at same temperature for 1
hr. After work up of the reaction mixture as above, 164 mg (67%) of
white solid which is practically pure product. Vigorous .sup.1H NMR
analyses reveal the crude white solid contains about 6% of the
diastere-omer of the titled compound.
Example 19
(2S,
3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-p-
ropionic acid ethyl ester (42) in the
RuCl.sub.3/CeCl.sub.3/NaIO.sub.4 system
[0099] In a 50 mL round-bottomed flask equipped with magnetic
stirring bar, a mixture of NaIO.sub.4(321 mg, 1.5 mmol) and
CeCl.sub.3.7H.sub.2O (37 mg, 0.1 mmol) in 0.45 mL of water is
stirred and gently heated until a bright yellow suspension is
formed. After cooling to 0.degree. C., EtOAc (1.25 mL) and
acetonitrile (1.5 mL) are added and the suspension is stirred for 2
minutes. A 0.1 M aqueous solution of RuCl.sub.3 (25 .mu.L) is added
and the mixture is stirred for 2 minutes. A solution of the
compound 41, (214 mg, 1 mmol) in EtOAc (0.25 mL) is added in one
portion and the resulting slurry is stirred at 0.degree. C. for 1
hour. Solid Na.sub.2SO.sub.4 (0.5 g) is added followed by EtOAc (3
mL). The solid is filtered off, and the filter cake is washed
several times with EtOAc. Then the filtrate is washed with
saturated Na.sub.2SO.sub.3 solution and the organic layer is dried
(Na.sub.2SO.sub.4) and concentrated to dryness. The residue is
purified by silica gel column chromatography with 20% EtOAc in
hexanes to provide a syrup (150 mg, 60%). .sup.1H NMR indicates
that the ratio of the desired product to its isomer is
approximately 1.6:1.
Example 20
Reduction and Acylation of Compound 49
[0100] To a solution of
3,5-dibenzoyl-2-fluoro-2-deoxy-2-methyl-D-ribono-lactone (49, 23 g,
61.77 mmol, scheme 6) in anhydrous THF (400 ml) was added LiAl
(.sup.1-OBu).sub.3H (75 mL 1M in THF, 75.0 mmol) over a period of
15 min at -20 to -10.degree. C. and the resulting solution was
stirred at the same temperature until all the starting material was
consumed. After 5 hours, -10-20% starting material was left,
therefore additional 10 mL of LiAl (t-OBu.sub.3H (10 mmol) was
added at the same temperature and stirred for an hour when TLC
indicated all starting material was consumed. To this reaction
mixture were added DMAP (7.5 g) and Ac.sub.2O (58.2 g, 616 mmol)
and the solution was stirred at -10.degree. C. for .about.2-3 h.
Upon completion of reaction (as indicated by TLC) the reaction
mixture was diluted with ethyl acetate (400 ml) and 200 ml of
water. The organic layer was separated and the aqueous layer was
washed with ethyl acetate (2.times.100 ml). The combined organic
layer was washed with water (3.times.150 ml), brine and dried over
anhy. Na.sub.2SO.sub.4. The solvent was removed under reduced
pressure and coevaporated with toluene (2.times.100 mL) to give
crude acetate as a clear brown oil. This oil was passed through a
plug of silica gel (50 g) and washed with 20% ethyl acetate/hexanes
until all the acetate was recovered. The solvent was evaporated
under reduced pressure to give the desired acetate (54, 32 g) as a
colorless oil.
Example 21
1-(2-deoxy-2-fluoro-2-methyl-3-5-O-dibenzoyl-.beta.-D-ribofuranosyl)-N4-be-
nzoylcytosine (55)
[0101] To a suspension of N.sup.4-benzoylcytosine (20.39 g, 94.74
mmol) in 400 ml of HMDS was added (NH.sub.4)2SO.sub.4 (250 mg) and
heated under reflux for 4 h. Excess HMDS was removed under reduced
pressure. The oily residue was dissolved in chlorobenzene (1 L). To
this solution were added a solution of the acetate (25 g) in
chlorobenzene (250 mL) and SnCl.sub.4 (190.4 mmol, 49 g) and the
mixture was stirred at room temperature for 2 h followed by heating
at .about.65.degree. C. for 16 h. The reaction mixture was cooled
to 0.degree. C. to which NaHCO.sub.3 (96 g, 1.14 mol) and ethyl
acetate (500 ml) were added followed by careful addition of water
(20 ml). This mixture was allowed to stir at room temperature for
30 min. The mixture was filtered under vacuum, the residue washed
with ethyl acetate. The organic layer was washed with water, brine
(2.times.250 mL) and dried over anhydrous Na.sub.2SO.sub.4. Solvent
was removed under reduced pressure to give a pale yellowish-brown
solid. This was dissolved in MeOH (250 mL) heated under reflux for
30 minutes, cooled to room temperature and filtered, to give the
desired product (55, 8.0 g) as a off-white solid.
Example 22
1-(2-deoxy-2-fluoro-2-C-methyl-.beta.-D-ribofuranosyl)cytosine
(14)
[0102] A suspension of 55 from Example 21 (16.7 g, 30.8 mmol,
scheme 6) was treated with methanolic ammonia (750 mL, 7M in MeOH)
and stirred at room temperature for 12 h and concentrated to
dryness under reduced pressure to give pale yellow solid. THF (400
mL) was added to the solid and heated under reflux for 30 minutes
and cooled to room temperature. The solid formed was collected by
filtration and washed with THF to give 14 (6.7 g, 88%) as an
off-white powder.
* * * * *