Title: Process for the preparation of 2'-halo-.beta.-L-arabinofuranosyl nucleosides
Abstract: The present invention is directed to the process for the preparation of 2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleosides, and in particular, 2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymine (L-FMAU), from L-arabinose, which is commercially available and less expensive than L-ribose or L-xylose, in ten steps. All of the reagents and starting materials are inexpensive and no special equipment is required to carry out the reactions.
Patent Number: 6,870,048 Issued on 03/22/2005 to Sznaidman
| Inventors:
|
Sznaidman; Marcos (Durham, NC)
|
| Assignee:
|
Triangle Pharmaceuticals (Durham, NC)
|
| Appl. No.:
|
112403 |
| Filed:
|
March 29, 2002 |
| Current U.S. Class: |
536/27.4; 536/28.5; 536/28.51; 536/28.52; 536/28.53; 536/28.54; 536/28.1; 536/25.3; 536/25.31 |
| Intern'l Class: |
C07H 019//19; C07H 019//06 |
| Field of Search: |
536/27.4,28.5,28.51,28.52,28.53,28.54,28.1,25.3,25.31
|
References Cited [Referenced By]
U.S. Patent Documents
| 5565438 | Oct., 1996 | Chu et al.
| |
| 5567688 | Oct., 1996 | Chu et al.
| |
| 5587362 | Dec., 1996 | Chu et al.
| |
| 5808040 | Sep., 1998 | Chu et al.
| |
| Foreign Patent Documents |
| WO 95/20595 | Mar., 1995 | WO.
| |
Other References
Sznaidman, M. L., Nucleosides, Nucleotides & Nucleic Acids, 2002, 21(2),
155-163.
Albert, M., et al. "A Novel Direct Route to 2-Deoxy-2-fluoro-aldoses and
their Corresponding Derivatives." Tetrahedron. 54:4839-4848, 1998.
Balog, A., et al. "A Practical Asymmetric Synthesis of a Pseudomonic Acid
Precursor from D-Arabinose or D-Xylose." Synthetic Comm. 26(5):935-944,
1996.
Bols, M., et al. "Preparation of 2,3-Epoxyaldonolactones and their
Conversion into 2-Fluoro-2-deoxy-aldonolactones and -sugars." Acta Chem.
Scand. 44(3):252-256, 1990.
Chu, C.K., et al. "Use of 2'-Fluoro-5-Methyl-B-L-Arabinofuranosyluracil as
a Novel Antiviral Agents for Hepatitis B Virus and Epstein-Barr Virus."
Antimicrobial Agents Chemother. 39(4):979-981, Apr. 1995.
Du, J., et al. "A Practical Synthesis of L-FMAU From L-Arabinose."
Nucleosides & Nucleosides. 18(2):187-195, 1999.
Fristad, W.E., et al. "Conversion of Alkenes to 1,2-Diazides and
1,2-Diamines." J. Org. Chem. 50:3647-3649, 1985.
Ma, T., et al. "Structure-Activity Relationships of
1-(2-Deoxy-2-fluoro-.beta.-L-aradinofuranosyl)pyrimidine Nucleosides as
Anti-Hepatitis B Virus Agents." J. Med. Chem. 39(14):2835-2843, 1996.
Ryan, K.J., et al. "[55] 9-B-L-Ribofuranosyladenine (`L-Adenosine`):
Configurational Inversion within a Furanoid Ring." Synthetic Procedures in
Nucleic Acid Chemistry VI. 163-167.
Smiatacz, Z., et al. "Configuration and Conformation of the Products of
Reaction of 3,4-Di-O-Acetyl-2-Deoxy-2-Nitroso-B-D-Arabinopyranosyl
Chloride with Pyrazole." Carbohydr. Res. 172:171-182, 1988.
Wright, J.A., et al. "Nucleosides. LX.sup.1A Fluorocarbohydrates. XXII.
.sup.1b Synthesis of 2-Deoxy-2-fluoro-D-arabinose and
9-(2-Deoxy-2-fluoro-.alpha.-and -.beta.-D-arabinofuranosyl)adenines.sup.2
" J. Org. Chem. 34(9):2632-2636, Sep. 1969.
|
Primary Examiner: Wilson; James O
Assistant Examiner: Owens, Jr.; Howard V.
Attorney, Agent or Firm: Knowles, Esq.; Sherry M.
King & Spalding, LLP
Parent Case Text
This application claims priority to U.S. Provisional Application No.
60/280,307, filed on Mar. 30, 2001.
Claims
What is claimed is:
1. A process for the preparation of a
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside of the formula (I):
##STR54##
wherein X is a halogen and B is a pyrimidine, purine, heterocyclic or
heteroaromatic base which includes the steps of:
(a) halogenating an optionally protected L-arabinal of the formula (III):
##STR55##
wherein each of R.sup.3 is independently hydrogen, alkyl, acyl or silyl
and deprotecting, if necessary, to form the
2-deoxy-2-halo-L-arabinopyranose of the formula (II):
##STR56##
wherein each of R.sup.1 and R.sup.2 is independently hydrogen, alkyl, acyl
or silyl;
(b) converting the 2-deoxy-2-halo-L-arabinopyranose to the
2-deoxy-2-halo-L-arabinofuranose; and
(c) coupling the arabinofuranose to a pyrimidine, purine, heterocyclic or
heteroaromatic base to form a 2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl
nucleoside of the formula (I).
2. A process for the preparation of a
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside of the formula (I):
##STR57##
wherein X is a halogen and B is a pyrimidine, purine, heterocyclic or
heteroaromatic base by a process comprising:
(a) halogenating an optionally protected L-arabinose of the formula (IV):
##STR58##
wherein each of R.sup.3 and R.sup.4 is independently hydrogen, alkyl, acyl
or silyl by substituting OR.sup.1 with a halogen to obtain a compound of
the formula (V):
##STR59##
wherein X.sup.1 is a halogen;
(b) reducing the compound of formula (V) to form a compound of formula
(III):
##STR60##
(c) halogenating the compound of formula (III) and deprotecting if
necessary to form a 2-deoxy-2-halo-L-arabinopyranose of the formula (II):
##STR61##
wherein each of R.sup.1 and R.sup.2 is independently hydrogen, alkyl, acyl
or silyl;
(d) converting the 2-deoxy-2-halo-L-arabinopyranose to the
2-deoxy-2-halo-L-arabinofuranose; and
(e) coupling the arabinofuranose to a pyrimidine, purine, heterocyclic or
heteroaromatic base to form a 2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl
nucleoside of the formula (I).
3. A process for the preparation of a
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside of the formula (I):
##STR62##
wherein X is a halogen and B is a pyrimidine, purine, heterocyclic or
heteroaromatic base comprising the steps of:
(a) halogenating an optionally protected L-arabinose of the formula (IV):
##STR63##
wherein each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is independently
hydrogen, alkyl, acyl or silyl by substituting OR.sup.1 with a halogen to
obtain a compound of the formula (V):
##STR64##
wherein X.sup.1 is a halogen;
(b) reducing the compound of formula (V) to form a compound of formula
(III):
##STR65##
(c) halogenating the compound of formula (III) and deprotecting if
necessary to form the 2-deoxy-2-halo-L-arabinopyranose of the formula
(II):
##STR66##
wherein X is a halogen;
(d) converting the 2-deoxy-2-halo-L-arabinopyranose to a
2-deoxy-2-halo-L-arabinofuranose;
(e) optionally substituting OR.sup.1 with O-Acyl or a halogen;
(f) coupling the arabinofuranose to an optionally protected pyrimidine,
purine, heterocyclic or heteroaromatic base; and
(g) deprotecting, if necessary, to obtain the
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside.
4. A process for the preparation of a
2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymine (L-FMAU) by preparing
a 2-deoxy-2-halo-L-arabinofuranose comprising the steps of:
(a) fluorinating an optionally protected L-arabinal of the formula (III):
##STR67##
wherein each R.sup.3 is independently hydrogen, alkyl, acyl, or silyl and
deprotecting, if necessary, to form the 2-deoxy-2-fluoro-L-arabinopyranose
of the formula (II-a):
##STR68##
wherein each of R.sup.1 and R.sup.2 is independently hydrogen, alkyl,
acyl, or silyl;
(b) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a
2-deoxy-2-fluoro-L-arabinofuranose; and
(c) coupling the arabinofuranose to an optionally protected thymine base to
form 2'-deoxy-2'-fluoro-.beta.-L-arabinofuranose thymine.
5. A process for the preparation of
2'-deoxy-2'-fluoro-.beta.-L-arabinofuranose thymine (L-FMAU) by preparing
a 2-deoxy-2-halo-L-arabinofuranose comprising the steps of:
(a) halogenating an optionally protected L-arabinose of the formula (IV):
##STR69##
wherein each of R.sup.3 and R.sup.4 is independently hydrogen, alkyl,
acyl, or silyl by substituting OR.sup.1 with a halogen, to obtain a
compound of the formula (V):
##STR70##
wherein X.sup.1 is a halogen;
(b) reducing the compound of formula (V) to form a compound of formula
(III):
##STR71##
(c) fluorinating the compound of formula (III) and deprotecting if
necessary to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula
(II-a):
##STR72##
wherein each of R.sup.1 and R.sup.2 is independently hydrogen, alkyl,
acyl, or silyl;
(d) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a
2-deoxy-2-fluoro-L-arabinofuranose; and
(e) coupling the arabinofuranose to an optionally protected thymine base to
form 2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymine.
6. A process for the preparation of
2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymine (L-FMAU) comprising:
(a) halogenating an optionally protected L-arabinose of the formula (IV):
##STR73##
wherein each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is independently
hydrogen, alkyl, acyl or silyl by substituting OR.sup.1 with a halogen, to
obtain a compound of the formula (V):
##STR74##
wherein X.sup.1 is a halogen;
(b) reducing the compound of formula (V) to form a compound of formula
(III):
##STR75##
(c) fluorinating the compound of formula (III) and deprotecting if
necessary to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula
(II-a):
##STR76##
(d) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a
2-deoxy-2-fluoro-L-arabinofuranose;
(e) optionally substituting OR.sup.1 with O-Acyl or a halogen;
(f) coupling the arabinofuranose to an optionally protected thymine; and
(g) deprotecting, if necessary, to obtain the
2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymidine.
7. The process of any one of claims 1-3 or 4-6, wherein the halogenation of
the compound of formula (III) is accomplished in nitromethane:water.
8. The process of any one of claims 1-3 or 4-6, wherein the halogenation of
the compound of formula (III) is accomplished in acetone:water.
9. The process of any one of claims 1-3 or 4-6, wherein the conversion of
the L-arabinopyranose to the L-arabinofuranose is accomplished using one
equivalent of sulfuric acid.
10. The process of any one of claims 1-3 or 4-6, wherein the conversion of
the L-arabinopyranose to the L-arabinofuranose is accomplished in dry
methanol.
11. The process of any one of claims 4-6, wherein the fluorination of the
compound of formula (III) is accomplished using (F-TEDA-BF.sub.4).
Description
FIELD OF THE INVENTION
This invention is in the area of the synthesis of
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleosides, and is
specifically directed to an efficient method of synthesis and
manufacturing of 1-(2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl)-thymine
(L-FMAU).
BACKGROUND OF THE INVENTION
Infection by hepatitis B virus is a problem of enormous dimensions.
Hepatitis B virus has reached epidemic levels worldwide. It is estimated
that as many as 350 million people worldwide are persistently infected
with HBV, many of whom develop associated pathologies such as chronic
hepatic insufficiency, cirrhosis, and hepatocellular carcinoma. After a
two to three month incubation period in which the host is unaware of the
infection, HBV infection can lead to acute hepatitis and liver damage,
that causes abdominal pain, jaundice, and elevated blood levels of certain
enzymes. About 1-2% of these develop fulminant hepatitis, a rapidly
progressive, often fatal form of the disease in which massive sections of
the liver are destroyed, with a mortality rate of 60-70%.
The Epstein-Barr virus is a member of the genus Lymphocryptovirus, which
belongs to the subfamily gammaherpesvirine. It is notably lymphotropic.
EBV has the classic structure of herpes viruses, viz., its double-stranded
DNA genome is contained within an icosapentahedral nucleocapsid, which, in
turn, is surrounded by a lipid envelope studded with viral glycoproteins.
EBV is now recognized as a cause of B-cell lymphoproliferative diseases,
and has been linked to a variety of other severe and chronic illnesses,
including a rare progressive mononucleosis-like syndrome and oral hairy
leukoplakia in AIDS patients. The suggestion that EBV is a major cause of
chronic fatigue has not withstood scrutiny. EBV is primarily transmitted
through saliva, although some infections are transmitted by blood
transfusion. More than 85% of patients in the acute phase of infectious
mononucleosis secrete EBV.
It has been discovered that certain L-nucleosides, mirror images of the
natural DNA constituents may inhibit DNA synthesis at the triphosphate
level probably by tight binding to the viral polymerase in the first stage
of viral DNA synthesis.
2'-Deoxy-2'-fluoro-.beta.-L-arabinofuranosyl nucleosides have the general
formula:
##STR1##
wherein B is a pyrimidine, purine, heterocyclic or heteroaromatic base.
Reported Syntheses of L-FMAU
Yung Chi Cheng, Chung K. Chu and others first reported that
1-(2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl)-thymine (L-FMAU) exhibits
superior activity against hepatitis B virus and Epstein Barr virus in
1994. See U.S. Pat. Nos. 5,587,362; 5,567,688; 5,565,438 and 5,808,040 and
International Patent Application published as WO 95/20595.
##STR2##
The Cheng patents describe a synthesis of L-FMAU from the sugar L-xylose
(formula A) as well as the sugar L-ribose (formula B).
##STR3##
These patents describe the synthesis of L-FMAU from L-xylose via conversion
to the key intermediate
1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-L-ribofuranose (see for example the
'688 patent, starting at column 4, line 62). The key intermediate was
synthesized from L-xylose in a total yield of 20% (see also L. Vargha,
Chem. Ber., 1954, 87, 1351; Holy, A., et al., Synthetic Procedures in
Nucleic Acid Chemistry, V1, 163-67). This synthesis was also reported in
Ma, T.; Pai, S. B.; Zhu, Y. L; Lin, T. S.; Shanmunganathan, K.; Du, J. F.;
Wang, C. G.; Kim, H.; Newton, G. M.; Cheng, Y. C.; Chu, C. K. J. Med.
Chem. 1996, 39, 2835. The inversion of the hydroxy group of L-xylose was
achieved via the formation of the
5-O-benzoyl-1,2-O-isopropylidene-.alpha.-L-ribofuranoside, followed by a
stereoselective hydride transfer during the reduction of the cycloketone
furanoside with NaBH.sub.4. The resulting ribofuranoside was then
converted to 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-L-ribofuranose, the key
intermediate in the synthesis of L-FMAU (See Scheme A).
##STR4##
1-O-Acetyl-2,3,5-tri-O-benzoyl-.beta.-L-ribofuranose can also be
synthesized directly from the more expensive starting material L-ribose
(see for example the '688 patent, starting at column 6, line 30; and Holy,
A., et al., Synthetic Procedures in Nucleic Acid Chemistry, V1, 163-67).
This alternative synthesis of
1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-L-ribofuranose (yield of 53%) was
also reported by Chu, C. K. et al. Antimicrobial Agents Chemother. 1995,
39, 979. This synthetic route to L-FMAU is set out below in Scheme B.
##STR5##
The key intermediate was subsequently fluorinated in a nucleophilic
displacement reaction at C.sub.2 to obtain
1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-L-arbinofuranose, which was condensed
with a desired base, such as thymine (5-methyluracil) through the
bromosugar to provide the 2'-deoxy-2'-fluoro-arabinofuranosyl nucleosides
in various yields.
Chu et al. later developed a synthesis for the production of L-FMAU from
L-arabinose in 14 steps and an overall yield of 8% (Du, J.; Choi, Y.; Lee,
K.; Chun, B. K.; Hong, J. H.; Chu, C. K. Nucleosides and Nucleosides 1999,
18, 187). L-Arabinose was converted to L-ribose in 5 steps (Scheme C).
L-Ribose was then used in the synthesis
1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-L-ribofuranose, which as described
above led to the formation of L-FMAU.
##STR6##
The processes mentioned above either start from an expensive sugar
(L-ribose or L-xylose) and/or are very long, with low yields. In addition,
they involve the use of a nucleophilic form of fluoride such as KHF.sub.2
or Et.sub.3 N-3HF, which is difficult to handle and requires the
displacement of an activated hydroxyl group. The instability of DAST
prevents its use on large scale. The conversion of
1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-L-ribofuranose (TBAR) to
1,3,5-tri-O-benzoyl-.beta.-L-ribofuranose generates
2,3,5-tri-O-benzoyl-.beta.-L-ribofuranose as a side-product, though it can
be reconverted to TBAR.
Reported Syntheses of 1-O-methyl-2-deoxy-2-fluoro-arabinofuranoside
The synthesis of 1-O-methyl-2-deoxy-2-fluoro-.alpha.-D-arabinofuranoside,
has been reported by Wright et al. (Wright, J. A.; Taylor, N. F.; Fox, J.
J. J. Org. Chem 1969, 34, 2632, and references therein). In this report,
D-xylose is used as the starting material, which after a conversion to the
corresponding furanose and a series of protection reactions, gave an epoxy
furanoside as an intermediate. This compound was further converted to
5-O-benzyl-1-O-methyl-2-deoxy-2-fluoro-.alpha.-D-arabinofuranoside, which
after removal of the benzyl group afforded
1-O-methyl-2-deoxy-2-fluoro-.alpha.-D-arabinofuranoside (Scheme D).
##STR7##
The synthesis of the 1-O-methyl-2-deoxy-2-fluoro-.beta.-D-arabinofuranoside
(the anomer of the above compound) was reported by Marquez et al.
(Wysocki, R. J.; Siddiqui, M. A.; Barchi, J. J.; Driscoll, J. S.; Marquez,
V. E. Synthesis 1991, 1005). D-ribose was converted in several steps to
1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-.beta.-D-arabinofuranose, the
corresponding bromo sugar derivative was produced under HBr/AcOH condition
and the reaction of potassium carbonate in methanol gave the desired
compound (Scheme E).
##STR8##
Reported Synthesis of 2-deoxy-2-fluoro-D-arabinospyranose
2-deoxy-2-fluoro-D-arabinopyranose was previously made from D-arabinose via
D-arabinal as it is shown in Scheme F (Albano, E. L et al. Carbohyd. Res.
1971, 19, 63).
##STR9##
The same material was made from D-Ribose as shown below in Scheme G (Bols,
M.; Lundt, I.; Acta Chem. Scand. 1990, 44, 252).
##STR10##
Reported Synthesis of 2-deoxy-2-fluoro-3,4-di-O-acetyl-D-arahinospyranose
The title compound was previously made as a result of an electrophilic
addition of SELECTFLUOR.TM. on D-arabinal (Albert, M. et al, Tefrahedron
1998, 54, 4839; Scheme H).
##STR11##
In light of the commercial importance of L-FMAU, and its use in the
treatment of patients afflicted with hepatitis B and Epstein Barr virus,
it is an object of the invention to provide an improved synthesis of
L-FMAU and related nucleosides.
It is another object of the invention to provide a synthesis of
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleosides from inexpensive
starting materials in relatively high yield.
SUMMARY OF THE INVENTION
The present invention is a process for the preparation of
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleosides, and in particular,
2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymine (L-FMAU), from
L-arabinose, which is commercially available and less expensive than
L-ribose or L-xylose. The process involves the initial synthesis of a
2-deoxy-2-halo-3,4-di-O-protected-L-arabinospyranose, via an electrophilic
halogenating agent, and in particular a fluorinating reagent. Deprotection
and isomerization affords a 2-deoxy-2-halo-L-arabinofuranoside, a key
intermediate in this synthesis. The 3- and 5-hydroxyl groups can then be
protected, preferably by benzoylation, and the 1-position can be
activated, preferably halogenated, and even more preferably brominated.
This compound can then be condensed with a protected pyrimidine, purine,
heterocyclic or heteroaromatic base to form the desired
2'-deoxy-2'-fluoro-L-arabinofuranosyl-nucleoside.
This process for the preparation of
2'-deoxy-2'-fluoro-L-arabinofuranosyl-nucleoside, and in particular,
L-FMAU, is the first synthesis of this class of nucleosides from
L-arabinose in ten steps. All of the reagents and starting materials are
inexpensive and no special equipment is required to carry out the
reactions. A key step for the synthesis is the conversion of a pyranoside,
2-deoxy-2-halo-L-arabinopyranose, into a furanoside,
2-deoxy-2-halo-L-arabinofuranoside.
In particular, in one embodiment of the present invention, a process for
the preparation of a 2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside
of the formula (I):
##STR12##
wherein X is a halogen (F, Cl, Br or I), though preferably fluorine; and B
is a pyrimidine, purine, heterocyclic or heteroaromatic base; is provided,
comprising
(a) obtaining a 2-deoxy-2-halo-L-arabinopyranose of the formula (II):
##STR13##
wherein each of R.sup.1 and R.sup.2 is independently hydrogen or a
suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) converting the 2-deoxy-2-halo-L-arabinopyranose to a
2-deoxy-2-halo-L-arabinofuranose;
(c) optionally substituting OR.sup.1 with a suitable leaving group, such as
O-Acyl (including OAc) or a halogen (F, Br, Cl or I), though preferably a
halogen, and even more preferably Br;
(d) coupling the arabinofuranose to an optionally protected pyrimidine,
purine, heterocyclic or heteroaromatic base; and
(e) deprotecting, if necessary, to obtain the
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside.
In another embodiment of the invention, a process for the preparation of a
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside of the formula (I):
##STR14##
wherein X is a halogen (F, Cl, Br or I), though preferably fluorine; and B
is a pyrimidine, purine, heterocyclic or heteroaromatic base; is provided,
comprising
(a) obtaining an optionally protected L-arabinose of the formula (IV):
##STR15##
wherein each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is independently
hydrogen or a suitable oxygen protecting group such as alkyl, acyl or
silyl;
(b) substituting OR.sup.1 with a halogen (F, Br, Cl or I), preferably Br,
to obtain a compound of the formula (V);
##STR16##
wherein X.sup.1 is a halogen (F, Br, Cl or I), preferably Br;
(c) reducing the compound of formula (V) to form a compound of formula
(III)
##STR17##
d) halogenating the compound of formula (III) and deprotecting if necessary
to form the 2-deoxy-2-halo-L-arabinopyranose of the formula (II):
##STR18##
wherein X is a halogen (F, Br, Cl or I), preferably F;
(e) converting the 2-deoxy-2-halo-L-arabinopyranose to a
2-deoxy-2-halo-L-arabinofuranose;
(f) optionally substituting OR.sup.1 with a suitable leaving group, such as
O-Acyl (including OAc) or a halogen (F, Br, Cl or I), though preferably a
halogen, and even more preferably Br;
(g) coupling the arabinofuranose to an optionally protected pyrimidine,
purine, heterocyclic or heteroaromatic base; and
(h) deprotecting, if necessary, to obtain the
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside.
In one particular embodiment of the present invention, the conversion of
the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose
is accomplished using one equivalent of sulfuric acid. In a further
embodiment of the present invention, the conversion of the
2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose is
accomplished in dry methanol. In a preferred embodiment, the conversion of
the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose
is accomplished using one equivalent of sulfuric acid in dry methanol.
In another embodiment of the present invention, a process for the
preparation of 2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymine
(L-FMAU) comprising
(a) obtaining a 2-deoxy-2-fluoro-L-arabinopyranose of the formula (II-a):
##STR19##
wherein each of R.sup.1 and R.sup.2 is independently hydrogen or a
suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a
2-deoxy-2-fluoro-L-arabinofuranose;
(c) optionally substituting OR.sup.1 with a suitable leaving group, such as
O-Acyl (including OAc) or a halogen (F, Br, Cl or I), though preferably a
halogen, and even more preferably Br;
(d) coupling the arabinofuranose to an optionally protected thymidine; and
(e) deprotecting, if necessary, to obtain the
2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymidine.
In yet another embodiment of the invention, a process for the preparation
of 2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymine (L-FMAU)
comprising
(a) obtaining an optionally protected L-arabinose of the formula (IV):
##STR20##
wherein each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is independently
hydrogen or a suitable oxygen protecting group such as alkyl, acyl or
silyl;
(b) substituting OR.sup.1 with a halogen (F, Br, Cl or I), preferably Br,
to obtain a compound of the formula (V);
##STR21##
wherein X.sup.1 is a halogen (F, Br, Cl or I), preferably Br;
(c) reducing the compound of formula (V) to form a compound of formula
(III)
##STR22##
(d) fluorinating the compound of formula (III) and deprotecting if
necessary to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula
(II-a);
##STR23##
(f) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a
2-deoxy-2-fluoro-L-arabinofuranose;
(g) optionally substituting OR.sup.1 with a suitable leaving group, such as
O-Acyl (including OAc) or a halogen (F, Br, Cl or I), though preferably a
halogen, and even more preferably Br;
(h) coupling the arabinofuranose to an optionally protected thymine; and
(i) deprotecting, if necessary, to obtain the
2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymidine.
In a particular embodiment of the present invention, the halogenation, and
in particular, the fluorination, of the compound of formula (III) is
accomplished in nitromethane: water. In an alternate embodiment, the
halogenation, and in particular, the fluorination, of the compound of
formula (III) is accomplished in acetone: water.
In one particular embodiment of the present invention, the conversion of
the 2-deoxy-2-fluoro-L-arabinopyranose to a
2-deoxy-2-fluoro-L-arabinofuranose is accomplished using one equivalent of
sulfuric acid. In a further embodiment of the present invention, the
conversion of the 2-deoxy-2-fluoro-L-arabinopyranose to a
2-deoxy-2-fluoro-L-arabino-furanose is accomplished in dry methanol. In a
preferred embodiment, the conversion of the
2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabinofuranose
is accomplished using one equivalent of sulfuric acid in dry methanol.
In one embodiment of the invention the
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside, and in particular
the 2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymine, can be further
functionalized, such as phosphorylated or acylated to form
pharmaceutically acceptable salts or prodrugs.
BRIEF DESCRIPTION OF THE FIGURE
FIG. 1 is a non-limiting example of a process for the preparation of
2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymine, according to the
present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is a process for the preparation of
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleosides, and in particular,
2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymine (L-FMAU), from
L-arabinose, which is commercially available and less expensive than
L-ribose or L-xylose. The process involves the initial synthesis of a
2-deoxy-2-halo-3,4-di-O-protected-L-arabinospyranose, and in particular
2-deoxy-2-fluoro-3,4-di-O-acetyl-L-arabinospyranose, via an electrophilic
halogenating agent, and in particular a fluorinating reagent. Deprotection
and isomerization affords a 2-deoxy-2-halo-L-arabinofuranoside, and in
particular, 1-O-methyl-2-deoxy-2-fluoro-L-arabinofuranoside, a key
intermediate in this synthesis. The 3- and 5-hydroxyl groups can then be
protected, preferably by benzoylation, and the 1-position can be
activated, preferably halogenated, and even more preferably brominated to
form, for example,
1-bromo-3,5-di-O-benzoyl-2-deoxy-2-fluoro-L-arbinofuranose. This compound
can then be condensed with a protected pyrimidine, purine, heterocyclic or
heteroaromatic base to form the desired
2'-deoxy-2'-fluoro-L-arabinofuranosyl-nucleoside.
This process for the preparation of
2'-deoxy-2'-fluoro-L-arabinofuranosyl-nucleoside, and in particular,
L-FMAU, is the first synthesis of this class of nucleosides from
L-arabinose in ten steps. All of the reagents and starting materials are
inexpensive and no special equipment is required to carry out the
reactions. A key step for the synthesis is the conversion of a pyranoside,
2-deoxy-2-halo-L-arabinopyranose, into a furanoside,
2-deoxy-2-halo-L-arabinofuranoside.
The term "L-FMAU analog" or "related nucleoside" as used herein refers to a
nucleoside that is formed from a pyrimidine or purine base that is coupled
to a 2-fluoro-arabinofuranosyl moiety.
In particular, in one embodiment of the present invention, a process for
the preparation of a 2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside
of the formula (I):
##STR24##
wherein X is a halogen (F, Cl, Br or I), though preferably fluorine; and B
is a pyrimidine, purine, heterocyclic or heteroaromatic base; is provided,
comprising
(a) obtaining a 2-deoxy-2-halo-L-arabinopyranose of the formula (II):
##STR25##
wherein each of R.sup.1 and R.sup.2 is independently hydrogen or a
suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) converting the 2-deoxy-2-halo-L-arabinopyranose to a
2-deoxy-2-halo-L-arabinofuranose;
(c) optionally substituting OR.sup.1 with a suitable leaving group, such as
O-Acyl (including OAc) or a halogen (F, Br, Cl or I), though preferably a
halogen, and even more preferably Br;
(d) coupling the arabinofuranose to an optionally protected pyrimidine,
purine, heterocyclic or heteroaromatic base; and
(e) deprotecting, if necessary, to obtain the
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside.
In a particular embodiment of the invention, the
2-deoxy-2-halo-L-arabinopyranose of the formula (II):
##STR26##
wherein R.sup.1 and R.sup.2 is as defined above, is provided by a process,
comprising
(a) obtaining an optionally protected L-arabinal of the formula (III)
##STR27##
wherein each of R.sup.3 is independently hydrogen or a suitable oxygen
protecting group such as alkyl, acyl or silyl;
(b) halogenating the compound of formula (III) and deprotecting, if
necessary, to form the 2-deoxy-2-halo-L-arabinopyranose of the formula
(II).
In an even more particular embodiment of the invention, the
2-deoxy-2-halo-L-arabinopyranose of the formula (II):
##STR28##
wherein R.sup.1 and R.sup.2 is as defined above, is provided by a process,
comprising
(a) obtaining an optionally protected L-arabinose of the formula (IV):
##STR29##
wherein each of R.sup.3 and R.sup.4 is independently hydrogen or a
suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) substituting OR.sup.1 with a halogen (F, Br, Cl or I), preferably Br,
to obtain a compound of the formula (V);
##STR30##
wherein X.sup.1 is a halogen (F, Br, Cl or I), preferably Br;
(c) reducing the compound of formula (V) to form a compound of formula
(III)
##STR31##
(d) halogenating the compound of formula (III) and deprotecting if
necessary to form the 2-deoxy-2halo-L-arabinopyranose of the formula (II).
In one embodiment of the invention, a process for the preparation of a
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside of the formula (I):
##STR32##
wherein X is a halogen (F, Cl, Br or I), though preferably fluorine; and B
is a pyrimidine, purine, heterocyclic or heteroaromatic base; is provided,
comprising
(a) obtaining an optionally protected L-arabinose of the formula (IV):
##STR33##
wherein each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is independently
hydrogen or a suitable oxygen protecting group such as alkyl, acyl or
silyl;
(b) substituting OR.sup.1 with a halogen (F, Br, Cl or I), preferably Br,
to obtain a compound of the formula (V);
##STR34##
wherein X.sup.1 is a halogen (F, Br, Cl or I), preferably Br;
(c) reducing the compound of formula (V) to form a compound of formula
(III)
##STR35##
(d) halogenating the compound of formula (III) and deprotecting if
necessary to form the 2-deoxy-2-halo-L-arabinopyranose of the formula
(II):
##STR36##
wherein X is a halogen (F, Br, Cl or I), preferably F;
(e) converting the 2-deoxy-2-halo-L-arabinopyranose to a
2-deoxy-2-halo-L-arabinofuranose;
(f) optionally substituting OR.sup.1 with a suitable leaving group, such as
O-Acyl (including OAc) or a halogen (F, Br, Cl or I), though preferably a
halogen, and even more preferably Br;
(g) coupling the arabinofuranose to an optionally protected pyrimidine,
purine, heterocyclic or heteroaromatic base; and
(h) deprotecting, if necessary, to obtain the
2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside.
In one particular embodiment of the present invention, the conversion of
the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose
is accomplished using one equivalent of sulfuric acid. In a further
embodiment of the present invention, the conversion of the
2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabino-furanose is
accomplished in dry methanol. In a preferred embodiment, the conversion of
the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose
is accomplished using one equivalent of sulfuric acid in dry methanol.
In another embodiment of the present invention, a process for the
preparation of 2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymine
(L-FMAU) comprising
(a) obtaining a 2-deoxy-2-fluoro-L-arabinopyranose of the formula (II-a):
##STR37##
wherein each of R.sup.1 and R.sup.2 is independently hydrogen or a
suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a
2-deoxy-2-fluoro-L-arabinofuranose;
(c) optionally substituting OR.sup.1 with a suitable leaving group, such as
O-Acyl (including OAc) or a halogen (F, Br, Cl or I), though preferably a
halogen, and even more preferably Br;
(d) coupling the arabinofuranose to an optionally protected thymidine; and
(e) deprotecting, if necessary, to obtain the
2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymidine.
In a particular embodiment of the invention, the
2-deoxy-2-fluoro-L-arabinopyranose of the formula (II-a):
##STR38##
wherein R.sup.1 and R.sup.2 is as defined above, is provided by a process,
comprising
(a) obtaining an optionally protected L-arabinal of the formula (III)
##STR39##
wherein each of R.sup.3 is independently hydrogen or a suitable oxygen
protecting group such as alkyl, acyl or silyl;
(b) fluorinating the compound of formula (III) and deprotecting, if
necessary, to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula
(II-a).
In an even more particular embodiment of the invention, the
2-deoxy-2-halo-L-arabinopyranose of the formula (II-a):
##STR40##
wherein R.sup.1 and R.sup.2 is as defined above, is provided by a process,
comprising
(a) obtaining an optionally protected L-arabinose of the formula (IV):
##STR41##
wherein each of R.sup.3 and R.sup.4 is independently hydrogen or a
suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) substituting OR.sup.1 with a halogen (F, Br, Cl or I), preferably Br,
to obtain a compound of the formula (V);
##STR42##
wherein X.sup.1 is a halogen (F, Br, Cl or I), preferably Br;
(c) reducing the compound of formula (V) to form a compound of formula
(III)
##STR43##
(d) fluorinating the compound of formula (III) and deprotecting if
necessary to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula
(II-a).
In one embodiment of the invention, a process for the preparation of
2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymine (L-FMAU) comprising
(a) obtaining an optionally protected L-arabinose of the formula (IV):
##STR44##
wherein each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is independently
hydrogen or a suitable oxygen protecting group such as alkyl, acyl or
silyl;
(b) substituting OR.sup.1 with a halogen (F, Br, Cl or I), preferably Br,
to obtain a compound of the formula (V);
##STR45##
wherein X.sup.1 is a halogen (F, Br, Cl or I), preferably Br;
(c) reducing the compound of formula (V) to form a compound of formula
(III)
##STR46##
(d) fluorinating the compound of formula (III) and deprotecting if
necessary to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula
(II-a);
##STR47##
(f) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a
2-deoxy-2-fluoro-L-arabinofuranose;
(g) optionally substituting OR.sup.1 with a suitable leaving group, such as
O-Acyl (including OAc) or a halogen (F, Br, Cl or I), though preferably a
halogen, and even more preferably Br;
(h) coupling the arabinofuranose to an optionally protected thymine; and
(i) deprotecting, if necessary, to obtain the
2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl thymidine.
In a particular embodiment of the present invention, the halogenation, and
in particular, the fluorination, of the compound of formula (III) is
accomplished in nitromethane: water. In an alternate embodiment, the
halogenation, and in particular, the fluorination, of the compound of
formula (III) is accomplished in acetone: water.
In one particular embodiment of the present invention, the conversion of
the 2-deoxy-2-fluoro-L-arabinopyranose to a
2-deoxy-2-fluoro-L-arabinofuranose is accomplished using one equivalent of
sulfuric acid. In a further embodiment of the present invention, the
conversion of the 2-deoxy-2-fluoro-L-arabinopyranose to a
2-deoxy-2-fluoro-L-arabinofuranose is accomplished in dry methanol. In a
preferred embodiment, the conversion of the
2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabinofuranose
is accomplished using one equivalent of sulfuric acid in dry methanol.
Non limiting examples of fluorinating agents that can be used in the
electrophilic addition of fluorine to L-arabinal include: trifluoromethyl
hypofluorite (CF.sub.3 OF), acetyl hypoflurite (CH.sub.3 COOF), xenon
difluoride (XeF.sub.2), elemental fluorine (F.sub.2). In a preferred
embodiment the fluorinating agent is SELECTFLUOR.TM. (F-TEDA-BF.sub.4).
I. Nucleosides which can be Synthesized According to the Present Invention
The invention as disclosed herein can be used to produce compounds of
formula (C).
##STR48##
wherein each R and R' is independently hydrogen, alkyl, acyl, aryl,
monophosphate, diphosphate, triphosphate, amino acid, or an oxygen
protecting group;
X is a halogen (F, Cl, Br or I), and preferably fluorine; and
B is a pyrimidine, purine, heterocyclic or heteroaromatic base.
These compounds either possess antiviral (i.e., anti-hepatitis B virus or
anti-Epstein-Barr virus) activity, are metabolized to a compound that
exhibits such activity, or can be used in a manufacturing process to
prepare compounds having such activity.
II. Definitions
As used herein, the term "substantially free of" or "substantially in the
absence of" refers to a nucleoside composition that includes at least 95%
to 98%, or more preferably, 99% to 100%, of the designated enantiomer of
that nucleoside. In a preferred embodiment, the compound is prepared
substantially free of its corresponding .beta.-D isomer.
The term "enantiomerically enriched" is used throughout the specification
to describe a nucleoside which includes at least about 95%, preferably at
least 96%, more preferably at least 97%, even more preferably, at least
98%, and even more preferably at least about 99% or more of a single
enantiomer of that nucleoside. When a nucleoside of a particular
configuration (D or L) is referred to in this specification, it is
presumed that the nucleoside is an enantiomerically enriched nucleoside,
unless otherwise stated.
The term alkyl, as used herein, unless otherwise specified, refers to a
saturated straight, branched, or cyclic, primary, secondary, or tertiary
hydrocarbon, typically of C.sub.1 to C.sub.18, includes lower alkyl, and
specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl,
cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and
2,3-dimethyl-butyl. The alkyl group can be optionally substituted with
functional groups as desired, as known to those skilled in the art, for
example, as taught in Greene, et al., Protective Groups in Organic
Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated
by reference. The term lower alkyl, as used herein, and unless otherwise
specified, refers to a C.sub.1 to C.sub.4 saturated straight, branched, or
if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including
both substituted and unsubstituted forms.
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 or organic synthesis. Suitable protecting groups are described, for
example, in Greene, et al. "Protective Groups in Organic Synthesis," John
Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
The term aryl, as used herein, and unless otherwise specified, refers to
phenyl, biphenyl, or naphthyl, and preferably phenyl. The aryl group can
be optionally substituted as known to those skilled in the art, for
example, as taught in Greene, et al., "Protective Groups in Organic
Synthesis," John Wiley and Sons, Second Edition, 1991.
The term acyl refers to moiety of the formula --C(O)R', wherein R' is
alkyl; aryl, alkaryl, aralkyl, heteroaromatic, heterocyclic, alkoxyalkyl
including methoxymethyl; arylalkyl including benzyl; aryloxyalkyl, such as
phenoxymethyl; aryl including phenyl optionally substituted with halo
groups C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.4 alkoxy or the
residue of an amino acid.
The term silyl refers to moiety of the formula --SiR'.sub.3, wherein each
R' is independently alkyl or aryl group as defined herein. The alkyl or
aryl group can be optionally substituted as known to those skilled in the
art, for example, as taught in Greene, et al., "Protective Groups in
Organic Synthesis," John Wiley and Sons, Second Edition, 1991.
The term "halogen," as used herein, includes fluorine, chlorine, bromine
and iodine.
The term purine or pyrimidine base includes, but is not limited to,
adenine, 6-alkylpurines, 6-acylpurines (wherein acyl is C(O)(alkyl, aryl,
alkylaryl, or arylalkyl), 6-benzylpurine, 6-halopurine, N.sup.6 -acyl
purine, 6-hydroxyalkyl purine, 6-thioalkyl purine, N.sup.2 -alkylpurines,
N.sup.2 -alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine,
5-methyl-cytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or
4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil,
C.sup.5 -alkylpyrimidines, C.sup.5 -benzyl-pyrimidines, C.sup.5
-halopyrimidines, C.sup.5 -vinylpyrimidine, C.sup.5 -acetylenic
pyrimidine, C.sup.5 -acyl pyrimidine, C.sup.5 -hydroxyalkyl pyrimidine,
C.sup.5 -amidopyrimidine, C.sup.5 -cyanopyrimidine, C.sup.5
-nitro-pyrimidine, C.sup.5 -aminopyrimidine, 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-chloro-purine.
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, acyl
groups such as acetyl and propionyl, methanesulfonyl, and
p-toluenesulfonyl. The heteroaromatic group can be optionally substituted
as described above for aryl.
The term heteroaryl or heteroaromatic, as used herein, refers to an
aromatic that includes at least one sulfur, oxygen, nitrogen or phosphorus
in the aromatic ring. The term heterocyclic refers to a nonaromatic cyclic
group wherein there is at least one heteroatom, such as oxygen, sulfur,
nitrogen or phosphorus in the ring. Nonlimiting examples of heteroaryl and
heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl,
isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl,
benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl,
pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl,
oxazolyl, thiazolyl, iso-thiazolyl, 1,2,4-thiadiazolyl, isooxazolyl,
pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl,
hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole,
1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole,
pyrimidine or pyridazine, and pteridinyl, aziridines, thiazole,
isothiazole, 1,2,3-oxadiazole, thiazine, pyridine, pyrazine, piperazine,
pyrrolidine, oxaziranes, phenazine, phenothiazine, morpholinyl, pyrazolyl,
pyridazinyl, pyrazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl,
pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl,
imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolo-pyrimidinyl, adenine,
N.sup.6 -alkylpurines, N.sup.6 -benzylpurine, N.sup.6 -halopurine, N.sup.6
-vinypurine, N.sup.6 -acetylenic purine, N.sup.6 -acyl purine,N.sup.6
-hydroxyalkyl purine, N.sup.6 -thioalkyl purine, thymine, cytosine,
6-azapyrimidine, 2-mercaptopyrmidine, uracil, N.sup.5 -alkylpyrimidines,
N.sup.5 -benzylpyrimidines, N.sup.5 -halopyrimidines, N.sup.5
-vinylpyrimidine, N.sup.5 -acetylenic pyrimidine, N.sup.5 -acyl
pyrimidine, N.sup.5 -hydroxyalkyl purine, and N.sup.6 -thioalkyl purine,
and isoxazolyl. The heteroaromatic group can be optionally substituted as
described above for aryl. The heterocyclic or heteroaromatic group can be
optionally substituted with one or more substituent selected from halogen,
haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido, amino,
alkylamino, dialkylamino. The heteroaromatic can be partially or totally
hydrogenated as desired. As a nonlimiting example, dihydropyridine can be
used in place of pyridine. Functional oxygen and nitrogen groups on the
heterocyclic or heteroaryl group 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-butyl-diphenylsilyl, trityl or substituted trityl, alkyl groups, acyl
groups such as acetyl and propionyl, methanesulfonyl, and
p-toluenylsulfonyl.
These purine or pyrimidine bases, heteroaromatics and heterocycles can be
substituted with alkyl groups or aromatic rings, bonded through single or
double bonds or fused to the heterocycle ring system. The purine base,
pyrimidine base, heteroaromatic or heterocycle may be bound to the sugar
moiety through any available atom, including the ring nitrogen and ring
carbon (producing a C-nucleoside).
III. Detailed Description of the Process Steps
Preparation of Starting Material--2-deoxy-2-halo-L-arabinopyranose (II)
The key starting material for this process is an appropriately substituted
2-deoxy-2-halo-L-arabinopyranose (II). The
2-deoxy-2-halo-L-arabinopyranose (II) can be purchased or can be prepared
by any known means including standard reduction and electrophilic addition
techniques. In one embodiment, the 2-deoxy-2-halo-L-arabinopyranose (II)
is prepared from L-arabinal followed by halogenation. The L-arabinal can
be purchased or can be prepared by any known means including standard
reduction techniques. For example, the L-arabinal can be prepared from an
appropriately protected L-arabinose, preferably protected with an acyl
group such as with an acetyl group, according to the following protocol.
##STR49##
L-Arabinose (1) can be protected by methods well known to those skilled in
the art, as taught in Greene, et al., Protective Groups in Organic
Synthesis, John Wiley and Sons, Second Edition, 1991, to form an
appropriately protected L-arabinose (2), wherein each P is independently
hydrogen or an appropriate oxygen protecting group such as an alkyl, acyl
or silyl group, though preferably an acyl group such as an acetyl group.
The protection can be carried out in any appropriate solvent that
facilitates the desired result. In one embodiment the reaction is carried
out in a mild base, such as pyridine. This reaction can be accomplished at
any temperature that allows the reaction to proceed at an acceptable rate
without promoting decomposition or excessive side products. The preferred
temperature is from 0.degree. C. to room temperature.
The appropriately substituted L-arabinose (2) can then be halogenated,
preferably brominated, using an appropriate halide under any suitable
conditions, though preferably acidic conditions, to obtain a
1-.alpha.-halo-2,3,4-tri-O-protected-L-arabinopyranose (3), such as
1-.alpha.-bromo-2,3,4-tri-O-acetyl-L-arabinopyranose. The halogenation can
be carried out in any appropriate solvent that facilitates the desired
result. In one non-limiting example, compound (2) can be halogenated with
H--X, wherein X is F, Cl, Br or I, though preferably Br, optionally with a
suitable acid, preferably an acyl acid such as acetic acid, optionally
with an acyl anhydride such as acetic anhydride. This reaction can be
accomplished at any temperature that allows the reaction to proceed at an
acceptable rate without promoting decomposition or excessive side
products. The preferred temperature is from room temperature to refluxing
conditions.
The 1-.alpha.-halo-2,3,4-tri-O-protected-L-arabinopyranose (3) can then be
reduced using any suitable reducing agent to obtain the L-arabinal (4).
Possible reducing agents are reagents that promote reduction, including
but not limited to, zinc dust in the presence of CuSO.sub.4.pentahydrate
and sodium acetate in AcOH/H.sub.2 O. This reaction can be accomplished at
any temperature that allows the reaction to proceed at an acceptable rate
without promoting decomposition or excessive side products. The preferred
temperature is from below -5.degree. C. to room temperature. The
L-arabinal can be prepared in any solvent that is suitable for the
temperature and the solubility of the reagents. Solvents can consist of
any protic solvent including, but not limiting to, alcohol, such as
methanol, ethanol, isopropanol, butanol, pentanol or hexanol, acyl acid
such as acetic acid, water or any combination thereof, though preferably
the solvent is acetic acid and water.
##STR50##
The L-arabinal (4) can then be halogenated, preferably fluorinated, using
an appropriate electrophilic halogenating reagent to afford compound (5).
Possible electrophilic halogenating agents are reagents that promote
regiospecific halogenation. In one particular embodiment, an electrophilic
fluorinating agent is used. Non-limiting examples of fluorinating agents
that can be used in the electrophilic addition of fluorine to L-arabinal
include, but not limited to, trifluoromethyl hypofluorite (CF.sub.3 OF),
acetyl hypoflurite (CH.sub.3 COOF), xenon difluoride (XeF.sub.2),
elemental fluorine (F.sub.2). In an alternate embodiment the fluorinating
agent is SELECTFLUOR.TM.. This reaction can be accomplished at any
temperature that allows the reaction to proceed at an acceptable rate
without promoting decomposition or excessive side products. The preferred
temperature is from room temperature to refluxing conditions. The
halogenation can be prepared in any solvent that is suitable for the
temperature and the solubility of the reagents. Solvents can consist of
any polar protic or aprotic solvent including, but not limiting to,
alcohol, such as methanol, ethanol, isopropanol, butanol, pentanol or
hexanol, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile,
nitromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO),
dimethyl-acetamide, water, or any combination thereof, though preferably
the solvent is water/nitromethane and water/acetone: (1/2).
The optionally protected 2-deoxy-2-halo-L-arabinopyranose (5) can then be
deprotected, if necessary, by methods well known to those skilled in the
art, as taught in Greene, et al., Protective Groups in Organic Synthesis,
John Wiley and Sons, Second Edition, 1991, to obtain the
2-deoxy-2-halo-L-arabinopyranose (II). The deprotection can be carried out
in any appropriate solvent that facilitates the desired result. This
reaction can be accomplished at any temperature that allows the reaction
to proceed at an acceptable rate without promoting decomposition or
excessive side products. For example, acyl protecting groups, and in
particular an acetyl group, can be deprotected with sodium methoxide in
methanol at room temperature.
In one preferred embodiment of the invention, this procedure, can be
tailored to produce the critical intermediate compounds for the synthesis
of L-FMAU or L-FMAU analogs.
Preparation of 2-deoxy-2-halo-L-arabinofuranose
##STR51##
The 2-deoxy-2-halo-L-arabinopyranose (II) is reacted with any suitable acid
(in gas or liquid form), such as, but not limited to sulfuric or
hydrochloric acid in either catalytic amounts or in excess to form a
2-deoxy-2-halo-L-arabinofuranose (7). In a one embodiment of the present
invention, 1 molar equivalent of sulfuric acid is used for this reaction.
This reaction can be accomplished at any temperature that allows the
reaction to proceed at an acceptable rate without promoting decomposition
or excessive side products. The preferred temperature is from room
temperature to refluxing conditions. This reaction can be carried out in
any solvent that is suitable for the temperature and the solubility of the
reagents. Solvents can consist of any polar protic or aprotic solvent
including, but not limiting to, an alcohol, such as methanol, ethanol,
isopropanol, butanol, pentanol or hexanol, acetone, ethyl acetate,
dithianes, THF, dioxane, acetonitrile, nitromethane, dimethylformamide
(DMF), dimethylsulfoxide (DMSO), dimethyl-acetamide, water, or any
combination thereof, though preferably the solvent is methanol.
The 2-deoxy-2-halo-L-arabinofuranose (7) can be optionally protected by
methods well known to those skilled in the art, as taught in Greene, et
al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second
Edition, 1991, to form an appropriately protected
2-deoxy-2-halo-L-arabinofuranose (8), wherein each P is independently
hydrogen or an appropriate oxygen protecting group such as an alkyl, acyl
or silyl group, though preferably an acyl group such as a benzoyl group.
The protection can be carried out in any appropriate solvent that
facilitates the desired result. In one embodiment the reaction is carried
out in a mild base, such as pyridine. This reaction can be accomplished at
any temperature that allows the reaction to proceed at an acceptable rate
without promoting decomposition or excessive side products. The preferred
temperature is from 0.degree. C. to room temperature.
Preparation of 2'-deoxy-2'-halo-.beta.-L-arabinofuranosyl nucleoside
##STR52##
The appropriately protected 2-deoxy-2-halo-L-arabinofuranose (8) is
optionally activated to form an activated 2-deoxy-2-halo-L-arabinofuranose
(9), wherein LG is a suitable leaving group, such as O-Acyl (including
OAc) or a halogen (F, Br, Cl or I), though preferably a halogen, and even
more preferably Br. In one non-limiting example, compound (8) is
halogenated with halogenated with H--X, wherein X is F, Cl, Br or I,
though preferably Br, optionally with a suitable acid, preferably an acyl
acid such as acetic acid, to afford compound (9). This reaction can be
accomplished at any temperature that allows the reaction to proceed at an
acceptable rate without promoting decomposition or excessive side
products. The preferred temperature is room temperature. This reaction can
be carried out in any solvent that is suitable for the temperature and the
solubility of the reagents. Solvents can consist of any polar protic or
aprotic solvent including, but not limiting to, an alcohol, such as
methanol, ethanol, isopropanol, butanol, pentanol or hexanol, acetone,
ethyl acetate, dithianes, THF, dioxane, acetonitrile, nitromethane,
dichloromethane, dichloroethane, diethyl ether, dimethylformamide (DMF),
dimethylsulfoxide (DMSO), dimethyl-acetamide, water, or any combination
thereof, though preferably the solvent is dichloromethane.
##STR53##
The activated 2-deoxy-2-halo-L-arabinofuranose (9) can then be coupled with
an optionally protected pyrimidine, purine, heterocyclic or heteroaromatic
base to afford the optionally protected
2'-deoxy-2'-halo-L-arabinonucleoside (11). Solubilizing substituents can
be added to the purine base, pyrimidine base, heteroaromatic or
heterocycle to promote solubility in the desired solvent system. It should
also be understood that certain functional groups of the purine base,
pyrimidine base, heteroaromatic or heterocycle might need to be protected
to prevent unnecessary side reactions. The reactive moieties can be
protected using conventional means and appropriate protecting groups well
known to those skilled in the art, as taught in
