U.S. patent application number 10/502440 was filed with the patent office on 2005-04-21 for process for producing dioxolane nucleoside analogues.
This patent application is currently assigned to SHIRE BIOCHEM INC. Invention is credited to Bydlinski, Gregory, Cimpoia, Alex, Yu, Qing.
Application Number | 20050085638 10/502440 |
Document ID | / |
Family ID | 27613448 |
Filed Date | 2005-04-21 |
United States Patent
Application |
20050085638 |
Kind Code |
A1 |
Bydlinski, Gregory ; et
al. |
April 21, 2005 |
Process for producing dioxolane nucleoside analogues
Abstract
The present invention relates to a process conducted in a single
reaction vessel for producing a dioxolane nucleoside analogue of
formula I or a pharmaceutically acceptable salt thereof; the
process comprising the steps of adding a Lewis acid, a silylating
agent and a non-silylated purine or pyrimidine base or an analogue
thereof to a dioxolane of formula II. The invention also provides a
process for producing a dioxolane compound of formula III; by
reacting a dioxolane compound of formula IV in a suitable solvent
in the presence of DIB and I.sub.2, using a suitable source of
energy.
Inventors: |
Bydlinski, Gregory;
(Montreal, CA) ; Yu, Qing; (Laval, CA) ;
Cimpoia, Alex; (Verdun, CA) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Assignee: |
SHIRE BIOCHEM INC
Quebec
CA
|
Family ID: |
27613448 |
Appl. No.: |
10/502440 |
Filed: |
July 23, 2004 |
PCT Filed: |
January 23, 2003 |
PCT NO: |
PCT/CA03/00085 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60350968 |
Jan 25, 2002 |
|
|
|
Current U.S.
Class: |
544/276 ;
544/277; 544/310 |
Current CPC
Class: |
C07D 405/04 20130101;
C07D 473/16 20130101; C07D 473/32 20130101; C07D 473/00 20130101;
C07D 317/34 20130101 |
Class at
Publication: |
544/276 ;
544/277; 544/310 |
International
Class: |
C07D 473/12; C07D
473/14; C07D 047/02 |
Claims
1. A process conducted in a single reaction vessel for producing a
dioxolane nucleoside analogue of formula I or a pharmaceutically
acceptable salt thereof; 29the process comprising the steps of
adding: a Lewis acid; a silylating agent; and a non-silylated
purine or pyrimidine base or an analogue thereof; to a dioxolane of
formula II in a suitable solvent; 30wherein; R.sub.1 is a hydroxyl
protecting group; R.sub.2 is a purine or pyrimidine base or an
analogue thereof; L is a leaving group; and wherein said process is
conducted at a suitable temperature.
2. The process according to claim 1, wherein the Lewis acid is
TMSI.
3. The process according to claim 1, wherein L is acetoxy,
benzoyloxy or iodide.
4. The process according to claim 1, wherein L is acetoxy.
5. The process according to claim 1, wherein R.sub.1 is C.sub.1-6
alkyl, C.sub.6-12 aryl, C.sub.6-12 arylalkyl, CO--C.sub.1-6 alkyl,
CO--C.sub.1-6 alkoxy, CO--C.sub.6-12 aryloxy, or CO--C.sub.6-12
arylalkyl.
6. The process according to claim 1, wherein R.sub.1 is acetyl,
pivaloyl, benzoyl or benzyl.
7. The process according to claim 1, wherein R.sub.1 is
benzoyl.
8. The process according to claim 1, wherein the suitable
temperature is about -78.degree. C. or warmer.
9. The process according to claim 8, wherein the suitable
temperature is about -15.degree. C. or warmer.
10. The process according to claim 8, wherein the suitable
temperature is about room temperature.
11. The process according to claim 1, wherein the Lewis acid is
TMSI, and wherein said Lewis acid is used in a molar ratio of about
1.0 equivalent to about 2.0 equivalents with respect to the
dioxolane of formula II.
12. The process according to claim 11, wherein TMSI is used in a
molar ratio of about 1.0 equivalent to about 1.5 equivalents with
respect to the dioxolane of formula II.
13. The process according to claim 11, wherein TMSI is used in a
molar ratio of about 1.0 equivalent to about 1.2 equivalents with
respect to the dioxolane of formula II.
14. The process according to claim 2, wherein said process
comprises the steps of: a) first adding TMSI to a solution of the
dioxolane of formula II and allowing the resulting mixture to react
for a suitable period of time; and b) adding the silylating agent
and the purine or pyrimidine base R.sub.2 to the mixture resulting
from step a).
15. The process according to claim 1, wherein the silylating agent
is chosen from HMDS, bis(trimethylsilyl)acetamide, TMSI,
trimethylsilyl chloride, tButyl-dimethylsilyl
trifluoromethanesulfonate or trimethylsilyl
trifluoromethanesulfonate.
16. The process according to claim 1, wherein the silylating agent
is HMDS.
17. The process according to claim 1, wherein the silylating agent
is used in a molar ratio of about 1.0 equivalent to about 5.0
equivalents with respect to the purine or pyrimidine base
R.sub.2.
18. The process according to claim 1, wherein the silylating agent
is used in a molar ratio of about 1.0 equivalent to about 2.5
equivalents with respect to the purine or pyrimidine base
R.sub.2.
19. The process according to claim 1, wherein the silylating agent
is used in a molar ratio of about 1.0 equivalent to about 1.5
equivalents with respect to the purine or pyrimidine base
R.sub.2.
20. The process according to claim 1, wherein R.sub.2 is chosen
from: 31wherein; R.sub.3 is H, C.sub.1-6 alkyl, C.sub.1-6 acyl or
CO--R.sub.9; R.sub.4 and R.sub.5 are each, independently, H,
C.sub.1-6 alkyl, bromide, chloride, fluoride, iodide or CF.sub.3;
R.sub.6, R.sub.7 and R.sub.8 are each, independently, H, bromide,
chloride, fluoride, iodide, amino, hydroxyl or C.sub.3-6
cycloalkylamino, and R.sub.9 is H or C.sub.1-6 alkyl.
21. The process according to claim 20, wherein R.sub.2 is: 32
22. The process according to claim 1, wherein R.sub.2 is: 33
23. The process according to claim 1, wherein R.sub.2 is: 34
24. The process according to claim 1, wherein R.sub.2 is: 35
25. A process for producing a dioxolane compound of formula III:
36the process comprising the step of reacting a dioxolane compound
of formula IV in a suitable solvent; 37in the presence of DIB and
I.sub.2, wherein said process is conducted using a suitable source
of energy; and wherein R.sub.10 is an hydroxyl protecting
group.
26. The process according to claim 25, wherein the dioxolane
compound of formula IV is added to a mixture of DIB and I.sub.2
over a suitable period of time.
27. The process according to claim 25, wherein the dioxolane
compound of formula IV is added to a mixture of DIB, I.sub.2 and
acetic acid over a suitable period of time.
28. The process according to claim 25, wherein R.sub.10 is
C.sub.1-6 alkyl, C.sub.6-12 aryl, C.sub.6-12 arylalkyl,
CO--C.sub.1-6 alkyl, alkoxy, CO--C.sub.6-12 aryloxy, or
CO--C.sub.6-12 arylalkyl.
29. The process according to claim 28, wherein R.sub.10 is acetyl,
pivaloyl, benzoyl or benzyl.
30. The process according to claim 28, wherein R.sub.10 is
benzoyl.
31. The process according to claim 25, wherein the suitable solvent
is toluene or dichloromethane.
32. The process according to claim 31, wherein the suitable solvent
is dichloromethane.
33. The process according to claim 25, wherein DIB is used in a
molar ratio of about 1.0 equivalent to about 2.5 equivalents with
respect to the dioxolane compound of formula III.
34. The process according to claim 33, wherein DIB is used in a
molar ratio of about 1.1 equivalent to about 1.5 equivalents with
respect to the dioxolane compound of formula III.
35. The process according to claim 25, wherein I.sub.2 is used in a
molar ratio of about 0.1 equivalent to about 1.0 equivalent with
respect to the dioxolane compound of formula III.
36. The process according to claim 35, wherein I.sub.2 is used in a
molar ratio of about 0.3 equivalent to about 0.5 equivalent with
respect to the dioxolane compound of formula III.
37. The process according to claim 25, wherein the suitable source
of energy is light.
38. The process according to claim 37, wherein the suitable source
of energy is tungsten lamp light.
39. The process according to claim 37, wherein the suitable source
of energy is daylight.
40. The process according to claim 1, wherein the suitable source
of energy is heat.
41. The process according to claim 1, further comprising the step
of removing the protecting group R.sub.1 to produce a compound of
formula Ia or a pharmaceutically acceptable salt thereof. 38
42. A process according to claim 1, comprising: a) first adding
said Lewis acid to a solution of the dioxolane of formula II in
said solvent, and allowing the resulting mixture to react for a
suitable period of time; and b) thereafter adding said silylating
agent and the purine or pyrimidine base R.sub.2 to said mixture
resulting.
43. A process according to claim 2, wherein L is acetoxy,
benzoyloxy or iodide.
44. A process according to claim 2, wherein L is acetoxy.
45. A process according to claim 2, wherein R.sub.1 is acetyl,
pivaloyl, benzoyl or benzyl.
46. A process according to claim 2, wherein R.sub.1 is benzoyl.
47. A process according to claim 2, wherein the silylating agent
HMDS, bis(trimethylsilyl)acetamide, TMSI, trimethylsilyl chloride,
tButyl-dimethylsilyl trifluoromethanesulfonate or trimethylsilyl
trifluoromethanesulfonate.
48. A process according to claim 2, wherein the silylating agent is
HMDS.
49. A process according to claim 2, wherein R.sub.2 is: 39wherein;
R.sub.3 is H, C.sub.1-6 alkyl, C.sub.1-6 acyl and CO--R.sub.9;
R.sub.4 and R.sub.5 are each, independently, H, C.sub.1-6 alkyl,
bromide, chloride, fluoride, iodide or CF.sub.3; R.sub.6, R.sub.7
and R.sub.8 are each, independently, H, bromide, chloride,
fluoride, iodide, amino, hydroxyl or C.sub.3-6 cycloalkylamino; and
R.sub.9 is H or C.sub.1-6 alkyl.
50. A process according to claim 2, wherein R.sub.2 is: 40
51. A process according to claim 2, wherein R.sub.2 is: 41
52. A process according to claim 2, wherein R.sub.2 is: 42
53. A process according to claim 2, wherein R.sub.2 is: 43
54. A process conducted in a single reaction vessel for producing a
dioxolane nucleoside analogue of formula I or a pharmaceutically
acceptable salt thereof; 44the process comprising adding: a Lewis
acid, wherein said Lewis acid is TMSI; a silylating agent selected
from HMDS, bis(trimethylsilyl)acetamide, TMSI, trimethylsilyl
chloride, tButyl-dimethylsilyl trifluoromethanesulfonate and
trimethylsilyl trifluoromethanesulfonate; and a non-silylated
purine or pyrimidine base or an analogue thereof; to a dioxolane of
formula II in a suitable solvent; 45wherein; R.sub.1 is a hydroxyl
protecting group selected from acetyl, pivaloyl, benzoyl and
benzyl; R.sub.2 is a purine or pyrimidine base or an analogue
thereof; L is a leaving group selected from acetoxy, benzoyloxy and
iodide; wherein said process is conducted at a suitable
temperature.
55. A process according to claim 54, wherein R.sub.2 is chosen
from: 46wherein; R.sub.3 is H, C.sub.1-6 alkyl, C.sub.1-6 acyl or
CO--R.sub.9; R.sub.4 and R.sub.5 are each, independently, H,
C.sub.1-6 alkyl, bromide, chloride, fluoride, iodide or CF.sub.3;
R.sub.6, R.sub.7 and R.sub.8 are each independently H, bromide,
chloride, fluoride, iodide, amino, hydroxyl or C.sub.3-6
cycloalkylamino; and R.sub.9 is H or C.sub.1-6 alkyl.
56. A process according to claim 54, wherein R.sub.2 is: 47
57. A process according to claim 54, wherein R.sub.2 is: 48
58. A process according to claim 54, wherein R.sub.2 is: 49
59. A process according to claim 54, wherein R.sub.2 is: 50
60. A process according to claim 54, wherein L is acetoxy.
61. A process according to claim 54, wherein R.sub.1 is
benzoyl.
62. A process according to claim 54, wherein the silylating agent
is HMDS.
63. A process according to claim 54, wherein said process
comprises: first adding TMSI to a solution of the dioxolane of
formula II and allowing the resulting mixture to react for a
suitable period of time; and adding the silylating agent and the
purine or pyrimidine base R.sub.2 to the mixture resulting from
step a).
64. A process for producing a dioxolane compound of formula III:
51the process comprising reacting a dioxolane compound of formula
IV in a suitable solvent; 52in the presence of DIB and I.sub.2,
wherein the dioxolane compound of formula IV is added to a mixture
of DIB and I.sub.2; R.sub.10 is an hydroxyl protecting group chosen
from acetyl, pivaloyl, benzoyl or benzyl; said process is conducted
using a suitable source of energy.
65. A process according to claim 64, wherein DIB is used in a molar
ratio of about 1.0 equivalent to about 2.5 equivalents with respect
to the dioxolane compound of formula III.
66. A process according to claim 64, wherein DIB is used in a molar
ratio of about 1.1 equivalent to about 1.5 equivalents with respect
to the dioxolane compound of formula III.
67. A process according to claim 64, wherein I.sub.2 is used in a
molar ratio of about 0.1 equivalent to about 1.0 equivalent with
respect to the dioxolane compound of formula III.
68. A process according to claim 64, wherein I.sub.2 is used in a
molar ratio of about 0.3 equivalent to about 0.5 equivalent with
respect to the dioxolane compound of formula III.
69. A process for producing a dioxolane compound of formula III:
the process comprising reacting a dioxolane compound of formula IV
in a suitable solvent; 53in the presence of DIB and I.sub.2,
wherein the dioxolane compound of formula IV is added to a mixture
of DIB, I.sub.2 and acetic acid; R.sub.10 is an hydroxyl protecting
group chosen from acetyl, pivaloyl, benzoyl or benzyl; said process
is conducted using a suitable source of energy.
70. A process according to claim 69, wherein DIB is used in a molar
ratio of about 1.0 equivalent to about 2.5 equivalents with respect
to the dioxolane compound of formula III.
71. A process according to claim 69, wherein DIB is used in a molar
ratio of about 1.1 equivalent to about 1.5 equivalents with respect
to the dioxolane compound of formula III.
72. A process according to claim 69, wherein I.sub.2 is used in a
molar ratio of about 0.1 equivalent to about 1.0 equivalent with
respect to the dioxolane compound of formula III.
73. A process according to claim 69, wherein I.sub.2 is used in a
molar ratio of about 0.3 equivalent to about 0.5 equivalent with
respect to the dioxolane compound of formula III.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a process for, producing
dioxolane nucleoside analogues and their precursors.
BACKGROUND OF THE INVENTION
[0002] Nucleoside analogues are an important class of therapeutic
agents. More particularly, dioxolane nucleoside analogues in which
a substituted 1,3-dioxolane is replacing the carbohydrate found in
natural nucleoside have shown to have biological activity.
[0003] Diokolane analogues were first reported by Belleau et al. in
EP 0337713 published Oct. 19, 1989, in U.S. Pat. No. 5,041,449
issued Aug. 20, 1991 and U.S. Pat. No. 5,270,315 issued Dec. 14,
1993.
[0004]
9-(.beta.-D-2-hydroxymethyl-1,3-dioxolane-4-yl)-2,6-diaminopurine
(.beta.-D-DAPD) and 9-(.beta.-D-hydroxymethyl
1,3-dioxolane-4-yl)-9-guani- ne (.beta.-D-DXG) have been reported
by Gu et al. (Antimicrob. Agents Chemother. (1999), 43(10), pp
2376-2382 and Nucleosides Nucleotides (1999), 18(4&5), pp
891-892) to have useful efficacy against HIV-1 in various cell
system.
[0005] Additionally, it was also reported (Weitman et al Clinical
Cancer Research (2000), 6(4), pp 1574-1578 and Giles et al Journal
of Clinical Oncology (2001), 19(3), pp 762-771 and also Gourdeau et
al Cancer Chemother. Pharmacol. (2001), 47(3), pp 236-240) that
1-(.beta.-L-2-hydroxymethyl-1,3-dioxolane-4-yl)-cytosine
(.beta.-L-OddC, troxacitabine) have shown efficacy for the
treatment of various forms of cancers (e.g. solid tumours, adult
leukemia and lymphomas).
[0006] DAPD and troxacitabine are currently in clinical
development.
[0007] The production of drug compound has to deal with issues such
as cost and efficacy, as well as, environmental concerns and
management of waste. Although several methods exist for the
production of dioxolane nucleoside analogues, there is always a
need for further development of new chemical processes for
producing such compounds.
SUMMARY OF THE INVENTION
[0008] In one aspect, the present invention relates to a process
conducted in a single reaction vessel for producing a dioxolane
nucleoside analogue of formula I or a pharmaceutically acceptable
salt thereof; 1
[0009] the process comprising the steps of adding:
[0010] a) a Lewis acid;
[0011] b) a silylating agent; and
[0012] c) a non-silylated purine or pyrimidine base or an analogue
thereof;
[0013] to a dioxolane of formula II in a suitable solvent; 2
[0014] wherein;
[0015] R.sub.1 is a hydroxyl protecting group;
[0016] R.sub.2 is a purine or pyrimidine base or an analogue
thereof;
[0017] L is a leaving group; and wherein said process is conducted
at a suitable temperature.
[0018] In another aspect, there is provided a process for producing
a dioxolane compound of formula III: 3
[0019] the process comprising the step of reacting a dioxolane
compound of formula IV in a suitable solvent; 4
[0020] in the presence of DIB and I.sub.2, wherein said process is
conducted using a suitable source of energy; wherein R.sub.10 is an
hydroxyl protecting group.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The present invention relates to a process conducted in a
single reaction vessel for producing a dioxolane nucleoside
analogue of formula I or a pharmaceutically acceptable salt
thereof; 5
[0022] the process comprising the steps of adding:
[0023] a) a Lewis acid;
[0024] b) a silylating agent; and
[0025] c) a non-silylated purine or pyrimidine base or an analogue
thereof;
[0026] to a dioxolane of formula II in a suitable solvent; 6
[0027] wherein;
[0028] R.sub.1 is a hydroxyl protecting group;
[0029] R.sub.2 is a purine or pyrimidine base or an analogue
thereof;
[0030] L is a leaving group; and wherein said process is conducted
at a suitable temperature.
[0031] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. All
publications, patent applications, patents, and other references
mentioned herein are incorporated by reference in their entirety.
In case of conflict, the present specification, including
definitions, will control. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting.
[0032] As used in this application, the term "alkyl" represents an
unsubstituted or substituted (e.g. by a halogen, nitro, CONH.sub.2,
COOH, O--C.sub.1-6 alkyl, O--C.sub.2-6 alkenyl, O--C.sub.2-6
alkynyl, hydroxyl, amino, or COOQ, wherein Q is C.sub.1-6 alkyl;
C.sub.2-6 alkenyl; C.sub.2-6 alkynyl) straight chain, branched
chain or cyclic hydrocarbon moiety (e.g. isopropyl, ethyl,
fluorohexyl or cyclopropyl). The term alkyl is also meant to
include alkyls in which one or more hydrogen atoms is replaced by
an halogen, more preferably, the halogen is fluoro (e.g. CF.sub.3--
or CF.sub.3CH.sub.2--).
[0033] The terms "alkenyl" and "alkynyl", represent an alkyl
containing at least one unsaturated group (e.g. allyl).
[0034] The term "alkoxy" represents an alkyl which is covalently
bonded to the adjacent atom through an oxygen atom.
[0035] The term "aryl" represents an unsaturated carbocyclic
moiety, optionally mono- or di-substituted with OH, SH, amino,
halogen or C.sub.1-6 alkyl.
[0036] The term "arylalkyl", represents an aryl group attached to
the adjacent atom by a C.sub.1-6 alkyl (e.g., benzyl).
[0037] The term "aryloxy" represents an aryl which is covalently
bonded to the adjacent atom through an oxygen atom.
[0038] The term "Acyl" is defined as a radical derived from a
carboxylic acid, obtained by replacement of the --OH group. Like
the acid to which it is related, an acyl radical may be straight
chain, branched chain or cyclic aliphatic or aromatic, substituted
(e.g. by a halogen, nitro, CONH.sub.2, COOH, O--C.sub.1-6 alkyl,
O--C.sub.2-6 alkenyl, O--C.sub.2-6 alkynyl, hydroxyl, amino, or
COOQ, wherein Q is C.sub.1-6 alkyl; C.sub.2-6 alkenyl; C.sub.2-6
alkynyl) or unsubstituted, Useful examples of acyl includes acetyl,
propionyl, pivaloyl, hexanoyl, trifluoroacetyl, cyclohexanoyl and
benzoyl.
[0039] "Acyloxy" is defined as an acyl group attached to the
adjacent group by an oxygen atom (e.g. acetoxy, benzoyloxy).
[0040] As used in this application, the term "cycloalkyl"
represents an "alkyl" as defined above which forms a ring (e.g.
Cyclopropyl, cyclopentyl or cyclohexyl).
[0041] The term "cycloalkylamino" represents a cycloalkyl which is
covalently bonded to the adjacent atom through a nitrogen atom.
[0042] The term "hydroxyl protecting group" is well known in the
field of organic chemistry. Such protecting groups may be found in
T. Greene, Protective Groups In Organic Synthesis, (John Wiley
& Sons, 1981). Example of hydroxy protecting groups include but
are not limited to benzyl, acetyl, benzoyl, pivaloyl and
isopropyloxycarbonyl.
[0043] A "dioxolane ring" is any substituted or unsubstituted five
member monocyclic ring that has an oxygen in the 1 and 3 positions
of the ring as illustrated below: 7
[0044] Halogens are chosen from F. Cl, I, and Br.
[0045] As used in this application, the term "purine or pyrimidine
or an analogue" is meant to be a purine or pyrimidine base found in
a nucleotide-or an analogue thereof which mimics such bases in that
their structures (the kinds of atoms and their arrangement) are
similar to the normal bases but may possess additional or lack
certain of the functional properties of the normal bases. Such
analogues include those derived by replacement of a CH moiety by a
nitrogen atom (for example, 5-azapyrimidines such as 5-azacytosine)
or vice versa (for example 7-deazapurines, such as 7-deazaadenosine
or 7-deazaguanosine) or both (e.g. 7-deaza, 8-azapurines).
Analogues of such bases also include those compounds wherein ring
substituents are either incorporated, removed or modified by
conventional substituents known in the art e.g. halogen, hydroxyl,
amino, C.sub.1-6 alkyl. Such purine or pyrimidine bases, analogues
and derivatives will be well known to those skilled in the art.
[0046] The term "TMSI" means trimethylsilyl iodide.
[0047] The term "HMDS" means hexamethyldisilazane.
[0048] The term "DIB" means diacetoxy iodobenzene.
[0049] The term "leaving group" means a functional group that is
cleaved from the parent molecule under the reaction conditions.
[0050] The term "single reaction vessel" means the chemical
reactions involved in the process are conducted in one vessel
typically used for chemical synthesis.
[0051] The term "Lewis acid"is well known in the field of
nucleoside and nucleotide chemistry. Such Lewis acid may be found
in Chemistry of NUCLEOSIDES AND NUCLEOTIDES Vol 1 and Vol 2.,
(Edited by LEROY B. TOWNSEND, 1988). Examples of a Lewis acid
includes but are not limited to trimethylsilyl triflate and
TMSI.
[0052] The term "suitable solvent" means an inert organic solvent
that will allow the process to occur under the reaction conditions
(e.g. dichloromethane).
[0053] The term "suitable temperature" means a temperature that
will allow the process to occur under the reaction conditions, and
provide the desired product without adversely affecting the
reaction.
[0054] It will be appreciated by a person of skill in the art that
the term "suitable period of time" means the time necessary for
obtaining a sufficient chemical transformation of the starting
material, obtaining the desired purity or the desired yield of the
reaction product or a combination of those. The reaction can
typically be monitored, if desired, by thin layer chromatography or
high performance liquid chromatography (HPLC).
[0055] It will also be appreciated that TMSI can be obtained from a
commercial source or be prepared readily from a number of precursor
reagents (e.g. trimethylsilyl chloride and sodium iodide).
[0056] The term "suitable source of energy" means a source of
energy useful to carry out the desired chemical process without
adversely affecting the reaction. Examples of energy include but
are not limited to light (e.g. daylight or tungsten lamp light) or
heat.
[0057] It will be appreciated by those skilled in the art that
compound I, compound Ia, compound II, compound III and compound IV
contain at least two chiral centers (at C-2 and C-4 of the
dioxolane ring). The compounds can thus exist in the form of
different optical isomers (R and S) and geometric isomers (cis and
trans). All such optical isomers, geometric isomers and mixtures
thereof, including racemic mixtures are included within the scope
of the invention.
[0058] In one embodiment, the process of the present invention
comprises those wherein the following embodiments are present,
either independently or in combination.
[0059] In one embodiment of the invention, the Lewis acid is chosen
from SnCl.sub.4, AlCl.sub.3, trimethylsilyl triflate,
trimethylsilyl nonaflate, trimethylsilyl perchlorate, TMSI, TMSCl,
TMSBr or TiCl.sub.4.
[0060] In one embodiment, the Lewis acids have the formula V: 8
[0061] wherein R.sub.9, R.sub.10 and R.sub.11, are independently
selected from the group consisting of hydrogen; C.sub.1-20 alkyl
(e.g. methyl, ethyl, ethyl, t-butyl), optionally substituted by
halogens (F, Cl, Br, I), C.sub.6-20 alkoxy (e.g., methoxy) or
C.sub.6-20 aryloxy (e.g., phenoxy); C.sub.7-20 aralkyl (e.g.,
benzyl), optionally substituted by halogen, C.sub.1-20 alkyl or
C.sub.1-20 alkoxy (e.g., p-methoxybenzyl); C.sub.6-20 aryl (e.g.,
phenyl), optionally substituted by halogens, C.sub.1-20 alkyl or
C.sub.1-20 alkoxy; trialkylsilyl; fluoro; bromo; chloro and iodo;
and
[0062] R.sub.12 is selected from the group consisting of halogen
(F, Cl, Br, I) preferably I (iodo);
[0063] In another embodiment, the Lewis acid is TMSI.
[0064] In one embodiment, L is chosen from acetoxy, benzoyloxy or
iodide.
[0065] In one embodiment, L is acyloxy.
[0066] In one embodiment, L is acetoxy.
[0067] In one embodiment, L is benzoyloxy.
[0068] In one embodiment L is a halogen.
[0069] In one embodiment, L is iodide.
[0070] In one embodiment of the invention, R.sub.1 is chosen from
C.sub.1-6 alkyl, C.sub.6-12 aryl, C.sub.6-12 arylalkyl,
CO---.sub.1-6 alkyl, CO--C.sub.1-6 alkoxy, CO--C.sub.6-12 aryloxy,
or CO--C.sub.6-12 arylalkyl.
[0071] In one embodiment of the invention, R.sub.1 is chosen from
acetyl, pivaloyl, benzoyl or benzyl.
[0072] In one embodiment of the invention, R.sub.1 is benzoyl.
[0073] In one embodiment, the suitable temperature is about
-78.degree. C. or warmer.
[0074] In another embodiment, the suitable temperature is about
-15.degree. C. or warmer.
[0075] In still another embodiment, the suitable temperature is
about room temperature.
[0076] In one embodiment, the Lewis acid is TMSI, and said Lewis
acid is used in a molar ratio of about 1.0 equivalent to about 2.0
equivalents with respect to the dioxolane of formula II.
[0077] In a further embodiment, TMSI is used in a molar ratio of
about 1.0 equivalent to about 1.5 equivalents with respect to the
dioxolane of formula II.
[0078] In still a further embodiment, TMSI is used in a molar ratio
of about 1.0 equivalent to about 1.2 equivalents with respect to
the dioxolane of formula II.
[0079] In one embodiment of the invention, the process for
producing a dioxolane nucleoside of formula I comprises the steps
of:
[0080] a) first adding TMSI to a solution of the dioxolane of
formula II and allowing the resulting mixture to react for a
suitable period of time; and
[0081] b) adding the silylating agent and the purine or pyrimidine
base R.sub.2 to the mixture resulting from step a).
[0082] In one embodiment, the silylating agent is chosen from HMDS,
bis(trimethylsilyl)acetamide, TMSI, trimethylsilyl chloride,
tButyl-dimethylsilyl trifluoromethanesulfonate or trimethylsilyl
trifluoromethanesulfonate.
[0083] In a further embodiment, the silylating agent is HMDS.
[0084] In one embodiment, the silylating agent is used in a molar
ratio of about 1.0 equivalent to about 5.0 equivalents with respect
to the purine and pyrimidine base R.sub.2.
[0085] In one embodiment, the silylating agent is used in a molar
ratio of about 1.0 equivalent to about 2.5 equivalents with respect
to the purine and pyrimidine base R.sub.2.
[0086] In one embodiment, the silylating agent is used in a molar
ratio of about 1.0 equivalent to about 1.5 equivalents with respect
to the purine and pyrimidine base R.sub.2.
[0087] In one embodiment, R.sub.2 is chosen from: 9
[0088] wherein;
[0089] R.sub.3 is chosen from H, C.sub.1-6 alkyl, C.sub.1-6 acyl
and CO--R.sub.9;
[0090] wherein R.sub.9 is H or C.sub.1-6 alkyl;
[0091] R.sub.4 and R.sub.5 are each independently chosen from H,
C.sub.1-6 alkyl, bromide, chloride, fluoride, iodide or CF.sub.3;
and R.sub.6, R.sub.7 and R.sub.8 are each independently chosen from
H, bromide, chloride, fluoride, iodide, amino, hydroxyl or
C.sub.3-6 cycloalkylamino.
[0092] In another embodiment, R.sub.2 is chosen from: 10
[0093] In one embodiment, R.sub.2 is: 11
[0094] In a further embodiment, R.sub.2 is: 12
[0095] In one embodiment of the invention, the process for
producing a dioxolane nucleoside of formula I further comprises the
step of removing the protecting group R.sub.1 to produce a compound
of formula Ia or a 13
[0096] pharmaceutically acceptable salt thereof;
[0097] According to another aspect of the invention, there is
provided a process for producing a dioxolane compound 14
[0098] of formula III:
[0099] the process comprising the step of reacting a dioxolane
compound of formula IV in a suitable solvent; 15
[0100] in the presence of DIB and I.sub.2, wherein said process is
conducted using a suitable source of energy; and wherein R.sub.10
is an hydroxyl protecting group.
[0101] In one embodiment of the invention, the dioxolane compound
of formula IV is added to a mixture of DIB and I.sub.2 over a
suitable period of time.
[0102] In a further embodiment of the invention, the dioxolane
compound of formula IV is added to a mixture of DIB, I.sub.2 and
acetic acid over a suitable period of time.
[0103] In one embodiment, R.sub.10 is chosen from C.sub.1-6 alkyl,
C.sub.6-12 aryl, C.sub.6-12 arylalkyl, CO--C.sub.1-16 alkyl,
CO--C.sub.1-6 alkoxy, C--C.sub.6-12 aryloxy, or CO--C.sub.6-12
arylalkyl.
[0104] In one embodiment, R.sub.10 is chosen from acetyl, pivaloyl,
benzoyl or benzyl.
[0105] In one embodiment, R.sub.10 is benzoyl.
[0106] In one embodiment, the suitable solvent for the process for
producing a dioxolane compound of formula III is toluene or
dichloromethane.
[0107] In a further embodiment, the suitable solvent is
dichloromethane.
[0108] In a further embodiment of the invention, DIB is used in a
molar ratio of about 1.0 equivalent to about 2.5 equivalents with
respect to the dioxolane compound of formula III.
[0109] In still a further embodiment, DIB is used in a molar ratio
of about 1.1 equivalent to about 1.5 equivalents with respect to
the dioxolane compound of formula III.
[0110] In one embodiment, I.sub.2 is used in a molar ratio of about
0.1 equivalent to about 1.0 equivalent with respect to the
dioxolane compound of formula III.
[0111] In one embodiment, I.sub.2 is used in a molar ratio of about
0.3 equivalent to about 0.5 equivalent with respect to the
dioxolane compound of formula III.
[0112] In one embodiment, the suitable source of energy is
light.
[0113] In a further embodiment, the suitable source of energy is
tungsten lamp light.
[0114] In still a further embodiment, the suitable source of energy
is daylight.
[0115] In one embodiment, the suitable source of energy is
heat.
[0116] There is also provided pharmaceutically acceptable salts of
the compounds of formula I and formula Ia of the present invention.
The term pharmaceutically acceptable salts of the compounds of
formula I and formula Ia is meant to include those compounds
derived from pharmaceutically acceptable inorganic and organic
acids and bases. Examples of suitable acids include hydrochloric,
hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic,
phosphoric, glycolic, lactic, salicylic, succinic,
toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic,
formic, benzoic, malonic, naphthalene-2-sulphonic and
benzenesulphonic acids.
[0117] Salts derived from appropriate bases include alkali metal
(e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and
NR.sub.4+ (where R is C.sub.1-4 alkyl) salts.
[0118] The following examples are provided to illustrate various
embodiments of the present invention and shall not be considered as
limiting in scope. Useful intermediates in those synthesis are
prepared according to known procedures described in:
[0119] 1) PCT publication number WO 00/39143 by NGUYEN-BA, Nghe et
al. 6 Jul. 2000
[0120] 2) PCT publication number WO 00/47759 by CIMPOIA, Alex et
al. 17 Aug. 2000
[0121] 3) U.S. Pat. No. 6,022,876 by CHUNG, K. Chu et al Feb. 8,
2000
[0122] 4) U.S. Pat. No. 5,817,667 by CHUNG, K. Chu et al Oct. 6,
1998
EXAMPLES
Example 1
Preparation of Benzoic Acid
4(R,S)-acetoxy-[1,3]dioxolan-2(R)-ylmethyl Ester (Compound 2)
[0123] 16
[0124] Intermediate 1 can be prepared according to known procedures
described in PCT publication number WO 00/39143 by NGUYEN-BA, Nghe
et al. 6 Jul. 2000 and PCT publication number WO 00/47759 by
CIMPOIA, Alex et al. 17 Aug. 2000.
[0125] To a solution of DIB (6.36 g, 19.8 mmol) and iodine (1.368
g, 5.4 mmol) in dichloromethane (24 mL) at room temperature was
added a solution of
2(R)-Benzoyloxymethyl-[1,3]dioxolane-4(R)-carboxylic acid (5.04 g,
18 mmol) in dichloromethane (27 mL) over 2.5 hours. The solution
was then stirred for an additional 4 hours at room temp. The
reaction was quenched with a solution of sodium thiosulfate
pentahydrate (4.92 g, 18 mmol) in water (50 mL) and stirred for 15
minutes. The layers where allowed to separate and the organic phase
was collected. The aqueous phase was extracted with dichloromethane
(25 mL) and the organic phases were combined and dried over sodium
sulfate. The sodium sulfate was removed and the solvent was
evaporated to dryness. The crude product was placed under
high-vacuum overnight. The crude oil was column purified with
(EtOAc/Hex:1/3) to give 4.24 g. (88.5% yield) (HPLC 99%).
[0126] (Trans) Benzoic acid 4(S)-acetoxy-[1,3]dioxolan-2
(R)-ylmethyl ester, .delta. (CDCl.sub.3); 8.08 (d, 2H), 7.58 (m,
1H), 7.47 (m, 2H), 6.40 (d, 1H), 5.48 (t, 1H), 4.49 (m, 2H), 4.20
(d, 1H), 4.06 (d of d, 1H), 2.02 (s, 3H): (Cis) Benzoic acid
4(R)-acetoxy-[1,3]dioxolan-2 (R)-ylmethyl ester, .delta.
(CDCl.sub.3); 8.05 (d, 2H), 7.55 (m, 1H), 7.45 (m, 2H), 6.47 (d,
1H), 5.57 (t, 1H), 4.47 (d, 2H), 4.24 (d of d, 1H), 4.00 (d of d,
1H), 2.11 (s, 3H).
Example 2
Preparation of Benzoic Acid
4(R,S)-(2-amino-6-chloro-purin-9-yl)-[1,3]diox-
olan-2(R)-ylmethyl
[0127] 17
[0128] TMSI (28.2 mL, 198.12 mol eq.) was added dropwise to a
dichloromethane (750 mL) solution of benzoic acid
4-acetoxy-[1,3]dioxolan- -2(R)-ylmethyl ester (52.75 g, 198.12
mmol, 1 eq) at -15.degree. C. After 2.5 h at -15.degree. C.,
bissilylated 2-amino-6-chloropurine (62 g, 198 mmol, 1 eq) was
added to the reaction mixture as a solid and the stirring was
continued at the same temperature for another 2.5 h. The reaction
mixture was then allowed to warm up slowly to RT with continued
stirring for 40 h. The reaction mixture was quenched into a
saturated aqueous NaHCO.sub.3 solution (1 L). The mixture was
treated with Na.sub.2S.sub.2O.sub.3 (1 g) and stirred for 20 min.
The mixture was filtered through a small pad of celite. The organic
phase was separated and the aqueous phase was back-extracted with
dichloromethane (1.times.200 mL). The combined organic phase was
concentrated to give 87 g of the crude product. Column purification
(DCM/MeOH:96/4) of the crude yielded 67.7 g (81% assuming that it
is a 1:1 chloro/Iodo mixture at C-6) of the coupled product with
cis/trans ratio 2.3:1.
[0129] Cis 6-chloropurine dioxolane .delta. (CDCl.sub.3); 8.05 (s,
1H), 8.00 (d, 2H), 7.58 (m, 1H), 7.44 (m, 2H), 6.38 (d, 1H), 5.43
(t, 1H), 5.18 (bs, 2H), 4.68 (m, 3H), 4.31 (d of d, 1H): Cis
6-iodoropurine dioxolane .delta. (DMSO); 8.13 (s, 1H), 7.82 (d,
2H), 7.68 (t, 1H), 7.52 (m, 2H), 6.92 (bs, 2H), 6.28 (d, 1H), 5.38
(t, 1H), 4.75 (d, 1H), 4.46 (m, 2H), 4.28 (m, 1H): Trans
6-chloropurine dioxolane .delta. (CDCl.sub.3); 8.08 (d, 2H), 7.95
(s, 1H), 7.60 (m, 1H), 7.47 (m, 2H), 6.43 (t, 1H), 5.85 (t, 1H),
5.21 (bs, 2H), 4.50 (m, 4H): Trans, 6-iodopurine dioxolane .delta.
(DMSO); 8.22 (s, 1H), 8.00 (d, 2H), 7.68 (t, 1H), 7.52 (m, 2H),
6.92 (bs, 2H), 6.37 (m, 1H), 5.84 (m, 1H), 4.50 (m, 4H).
Example 3
Preparation of Benzoic Acid
4(R)-(2-amino-6-chloro-purin-9-yl)-[1,3]dioxol- an-2(R)-ylmethyl
Ester
[0130] 18
[0131] Hexamethyldisilazane (HMDS, 190 g, 1.18 moles) is charged to
a solution of 2-(R)-Benzoyloxymethyl-4-(R,S)-acetoxy-1,3-dioxolane
(311 g, 1.17 moles) in dichloromethane (6.75 kg), followed by
2-amino-6-chloropurine (199 g, 1.17 moles) and trimethylsilyl
iodide (TMSI, 280 g, 1.40 moles). The reaction mixture is agitated
at 19-25.degree. C. for 19-24 hr. The reaction is checked by
in-process TLC (2:1/hexane:ethyl acetate) for complete reaction.
The reaction mixture is heated at reflux for 1 hr. Aqueous 2%
sodium thiosulfate solution (3.6 kg) is then added to the reaction
mixture at 10-15.degree. C. and agitated for 30-60 minutes. The
reaction mixture is checked by in-process TLC (7:3 v/v ethyl
acetate/hexane) for complete deprotection. Aqueous 10% sodium
hydroxide solution (737 g) is added to the mixture to adjust the pH
to 8-10. The organic layer is separated. The aqueous layer is
extracted with dichlordmethane (750 g). The organic layers are
combined, dried over magnesium sulfate (95 g) and filtered. The
filter cake is washed with dichloromethane (750 g). The combined
organic filtrate is distilled until distillation stops at
45-50.degree. C. An in-process TDS is performed and the amount of
dissolved solid (Q) calculated from the TDS value. Ethyl acetate
(534 g) is added to the pot residue and distilled under partial
vacuum at a maximum pot temperature of 50.degree. C. The ethyl
acetate distillation is repeated until a total of 1.3.times.Q of
ethyl acetate distillate is obtained. Toluene (700 g) is added to
the pot residue. The mixture is agitated at 19-25.degree. C. for
16-24 hours and at 0-5.degree. C. for 2-3 hours. The precipitate is
filtered and the filter cake washed with 10% ethyl acetate/hexane
(300 g). The solid product is dried under vacuum at 40-45.degree.
C. to yield 284 g (64.0% total yield) of a 2/1 cis (3A) to trans
(3B) mixture (yield 3A cis:42%). The isomers were separated by
column chromatography on silica gel, using a gradient of methanol
from 1% to 5% in dichloromethane.
Example 4
Preparation of Benzoic Acid
[4(R,S)-(2-amino-6-iodo-purin-9-yl)-[1,3]dioxo- lan-2(R)-ylmethyl
Ester (Compound I-3A)
[0132] 19
[0133] 2-(R)-Benzoyloxymethyl-4-(R,S)-acetoxy-1,3-dioxolane (12.98
g, 40 mmol) in methylene chloride (200 mL) was cooled to
-15.degree. C. under argon atmosphere and TMSI (6.85 mL, 48 mmol,
1.2 eq) was added with stirring. The light yellow solution was
stirred at -15.degree. C. until all the starting material had
disappeared (2 hours) by TLC (DCM/MeOH:9/1). HMDS (12.6 mL, 60
mmol, 1.5 eq) was added followed by the addition of
2-amino-6-iodopurine (11.5 g, 44 mmol, 1.1 eq). The light yellow
suspension obtained was stirred at -15.degree. C. (2 hours) and at
23.degree. C. (20 hours) at which time TLC indicated that the
reaction was completed. The mixture was diluted with methylene
chloride (150 mL) and poured into water (200 mL). The mixture was
vigorously stirred (3 hours) and the phases were separated. The
organic phase was washed with aqueous 10% K.sub.2SO.sub.4 (20 mL)
and water (50 mL). The organic phase was evaporated to a brown
residue. The residue was dissolved in methanol (200 ml). After
stirring at 23.degree. C. for 2 hours TLC showed that complete
desilylation had occurred. The methanol was evaporated under
reduced pressure to give a residue which contains Benzoic acid
4(R,S)-(2-amino-6-iodo-purin-9-yl)-[1,3]dioxolan-2(R)-ylmethyl
ester (20.1 g, cis/trans:2.8/1).
[0134] Cis iodopurine dioxolane .delta. (DMSO); 8.13 (s, 1H), 7.82
(d, 2H), 7.68 (t, 1H), 7.52 (m, 2H), 6.92 (bs, 2H), 6.28 (d, 1H),
5.38 (t, 1H), 4.75 (d, 1H), 4.46 (m, 2H), 4.28 (m, 1H): Trans
iodopurine dioxolane .delta. (DMSO); 8.22 (s, 1H), 8.00 (d, 2H),
7.68 (t, 1H), 7.52 (m, 2H), 6.92 (bs, 2H), 6.37 (m, 1H), 5.84 (m,
1H), 4.50 (m, 4H).
Example 5
Preparation of Benzoic Acid
4(R,S)-(2-amino-6-cyclopropylamino-purin-9-yl)-
-[1,3]dioxolan-2(R)-ylmethyl Ester (Compound 6A and 6B)
[0135] 20
[0136] To a solution of of benzoic acid
4-acetoxy-[1,3]dioxolan-2(R)-ylmet- hyl ester (6.02 g, 18.8 mm) in
dichloroethane (56 mL) was charged TMSI (3.2 mL) at -15.degree. C.
After the addition the reaction was stirred for 2 hours at
-15.degree. C. HMDS (5.9 mL, 28.2 mm) was added followed by
2-amino-6-cyclopropylaminopurine (3.57 g, 18.8 mm). The reaction
was allowed to warm up to room temperature and was stirred for 48
hours followed by 3 hours of reflux. The reaction was cooled to
room temperature and poured into saturated sodium bicarbonate
solution. The mixture was filtered through a pad of Celite and the
organic layer was separated. The aqueous layer was back-extracted
with dichloromethane (2.times.20 mL). The combined organic phases
were dried over sodium sulfate and concentrated to a residue. The
crude product was purified by flash chromatography
(40/60:EtOAc/Hexane followed by DCM/MeOH:25/1) to produce benzoic
acid 4(R,S)-(2-amino-6-cyclopropylamino-purin-9-yl)-[1,3]-
dioxolan-2(R)-ylmethyl ester benzoate-cyclopropylaminopurine (2.25
g, 27% yield, cis/trans:1/1.25).
[0137] (Cis) Benzoic acid
4(R)-(2-amino-6-cyclopropylamino-purin-9-yl)-[1,-
3]dioxolan-2(R)-ylmethyl ester, .delta. (CDCl.sub.3); 8.03 (d, 2H),
7.74 (s, 1H), 7.58 (t, 1H), 7.43 (m, 2H), 6.38 (d, 1H), 5.80 (bs,
1H), 5.43 (t, 1H), 4.90 (bs, 2H), 4.62 (s, 2H), 4.57 (m, 1H), 4.30
(d of d, 1H), 3.05 (bs, 1H), 0.88 (m, 2H), 0.65 (m, 2H).
[0138] Trans Benzoic acid
4(S)-(2-amino-6-cyclopropylamino-purin-9-yl)-[1,-
3]dioxolan-2(R)-ylmethyl ester, .quadrature. (CDCl.sub.3); 8.07 (d,
2H), 7.65 (s, 1H), 7.57 (t, 1H), 7.47 (m, 2H), 6.41 (d, 1H), 5.83
(t, 1H), 5.74 (bs, 1H), 4.85 (bs, 2H), 4.56 (s, 2H), 4.47 (m, 2H),
2.98. (bs, 1H), 0.88 (m, 2H), 0.65 (m, 2H).
Example 6
Preparation of [4 (R)--
(2-Amino-6-chloro-purin-9-yl)-[1,3]dioxolan-2(R)-y- l]-methanol
(Compound 4)
[0139] 21
[0140] Benzoic acid
4(R)-(2-amino-6-chloro-purin-9-yl)-[1,3]dioxolan-2(R)-- ylmethyl
ester (2.4 kg, 6.3 moles) and methanol (6.24 L) were combined under
inert atmosphere. 25% MeONa/MeOH (33.6 g) was added at room
temperature and the reaction mixture was stirred for 16-24 hours.
The reaction was monitored by HPLC for complete deprotection of the
benzoate ester. The reaction mixture was cooled to 2.degree. C. for
2 hours. The solids were collected by filtration and dried in vacuo
to give the desired compound (1.2 kg, 71% yield). .delta. (DMSO);
8.25 (s, 1H), 7.00 (s, 2H), 6.25 (d, 1H), 5.13 (t, 1H), 5.04 (s,
1H), 4.54 (d, 1H), 4.18 (d of d, 1H), 3.58 (m, 2H).
Example 7
Preparation Benzoic Acid
4(R)-(2-amino-6-cyclopropylamino-purin-9-yl)-[1,3-
]dioxolan-2(R)-ylmethyl Ester (Compound 6A)
[0141] 22
[0142] Benzoic acid
4(R)-(2-amino-6-chloro-purin-9-yl)-[1,3]dioxolan-2(R)-- ylmethyl
ester (1266 g, cis/trans:1.9/1), ethanol (20 L), and
cyclopropylamine (643 g) were refluxed for 16 hours. The reaction
mixture was cooled and concentrated to a residue. The residue was
dissolved in dichloromethane (3.6 L) and agitated with an aqueous
solution of sodium bicarbonate for 30 minutes. After settling the
organic layer was separated and the aqueous was back-extracted with
dichloromethane (2.times.750 mL). The combined organic layers were
concentrated to give a yellow-brown foam (1304 g) of material (9)
which is suitable for reaction in the subsequent deprotection step
in NH.sub.3/MeOH.
Example 8
Preparation of
[4(R)-(2-Amino-6-cyclopropylamino-purin-9-yl)-[1,3]dioxolan-
-2(R)-yl]-
[0143] 23
[0144]
[4(R)-(2-Amino-6-chloro-purin-9-yl)-[1,3]dioxolan-2(R)-yl]-methanol
(1.2 kg, 4.5 moles), ethanol (15.2 L) and cyclopropylamine (756 g)
were refluxed under nitrogen for 16 hours. The reaction was
monitored for completion by HPLC. Once completed the reaction
mixture was hot-filtered and allowed to cool to 0.degree. C.
slowly. The solids were filtered and subsequently recrystallized
from ethanol to give [4(R)-(2-Amino-6-cyclopr-
opylamino-purin-9-yl)-[1,3]dioxolan-2(R)-yl]-methanol (1.0 kg,
77%).
[0145] .delta. (DMSO); 7.84 (s, 1H), 7.37 (bs, 1H), 6.20 (d, 1H),
5.91 (bs, 2H), 5.15 (t, 1H), 5.02 (t, 1H), 4.42 (d, 1H), 4.18 (m,
1H), 3.58 (m, 2H), 3.02 (bs, 1H), 0.64 (m, 2H), 0.57 (m, 2H).
Example 9
Preparation
[4(R)-(2-Amino-6-cyclopropylamino-purin-9-yl)-[1,3]dioxolan-2(-
R)-yl]-methanol (Compound 5)
[0146] 24
[0147] Benzoic acid
4(R)-(2-amino-6-cyclopropylamino-purin-9-yl)-[1,3]diox-
olan-2(R)-ylmethyl ester crude (1304 g) was stirred with
NH.sub.3/MeOH (20 L, 2M) for 20 hours at room temperature. Excess
ammonia was removed by sparging nitrogen gas through the reaction
mixture. The volatiles were removed in vacuo to give a black syrup
which was further purified by column chromatography (MeOH/DCM:25/1)
to give crude final product (910 g). The crude product was
crystallized from ethyl acetate/ethanol to give
[4(R)-(2-Amino-6-cyclopropylamino-purin-9-yl)-[1,3]dioxolan-2(R)-yl]-meth-
anol (455 g, 41% yield from acetoxy-sugar)
Example 10
Preparation of Benzoic Acid
4(R,S)acetoxy-[1,3]dioxolan-2(S)-ylmethyl Ester (8)
[0148] 25
[0149] Intermediate 7 can be prepared according to known procedures
described in U.S. Pat. No. 6,022,876 by CHUNG, K. Chu et al Feb. 8,
2000 and U.S. Pat. No. 5,817,667 by CHUNG, K. Chu et al Oct. 6,
1998.
[0150] To a solution of DIB (882.3 g, 2.74 moles, 1.3 eq) and
iodine (159.9 g, 0.63 mole, 0.3 eq) in dichloromethane (3.5 L) at
room temperature (20-25.degree. C.) was added a solution of acid
(532.0 g, 2.10 mole, 1.0 eq) in dichloromethane (3.2 L) over 2
hours (during the addition the batch temperature reached 40.degree.
C.). The solution was then stirred for an additional 2 hours at
room temperature in the presence of visible light. TLC showed the
absence of starting material. The reaction was quenched slowly
(keep batch temperature<25.degree. C.) with a solution of sodium
thiosulfate pentahydrate (568 g, 2.29 mole, 1.09 eq) in water (4.0
L) and was stirred for 15 minutes. The layers were allowed to
separate and the bottom organic phase was collected. The aqueous
phase was back-extracted with dichloromethane (2.times.630 mL) and
the organic phases were combined and dried over sodium sulfate. The
sodium sulfate was filtered and the solvent was evaporated to give
a brown oil (955 g) which was sparged (25-50 torr, bath temperature
80.degree. C., batch temperature 40-65.degree. C., 10 hours) with
nitrogen to yield crude product(500 g) which was suitable for use
in the subsequent sugar-base coupling. HPLC qualitative analysis
showed that the crude contained (295 g, 59.1% area) of
diastereomeric acetoxy-sugar, (135 g, 27.2% area) of diastereomeric
homo-coupled acyloxy-sugar and (11.3 g, 2.3% area) iodobenzene. The
yield of usable material was estimated as follows: Purity=HPLC % of
acetoxy sugar+1/2(HPLC % of homo-coupled
acyloxy-sugar)=59.1%+1/2(27.2%)=72.7% Corrected yield of usable
material=72.7%.times.500 g=363.5 g (1.37 moles, 65% yield). (cis)
Benzoic acid 4(R)-acetoxy-(1,3]dioxolan-2(R)-ylmethyl ester.
.delta. (CDCl.sub.3); 8.08 (d, 2H), 7.58 (m, 1H), 7.47 (m, 2H),
6.40 (d, 1H), 5.48 (t, 1H), 4.49 (m, 2H), 4.20 (d, 1H), 4.06 (d of
d, 1H), 2.02 (s, 3H) (trans) Benzoic acid
4(R)-acetoxy-[1,3]dioxolan-2(S) ylmethyl ester .delta.
(CDCl.sub.3); 8.05 (d, 2H), 7.55 (m, 1H), 7.45 (m, 2H), 6.47 (d,
1H), 5.57 (t, 1H), 4.47 (d, 2H), 4.24 (d of d, 1H), 4.00 (d of d,
1H), 2.11 (s, 3H).
Example 11
Preparation of Benzoic Acid
4(R,S)-acetoxy-[1,3]dioxolan-2(S)-ylmethyl Ester (8)
[0151] 26
[0152] A solution of cis-acid (2.39 kg) in dichloromethane (4.2 kg)
was added in 5 portions (each portion was added over 2 hours
keeping the batch temperature less than 30.degree. C.) to a
solution of DIB (4.03 kg), iodine (1.06 kg) and acetic acid (1.50
kg) in dichloromethane (12.6 kg) in the presence of a 100 watt
tungsten lamp. The reaction mixture was stirred until TLC showed
the absence of starting material. The reaction was cooled to
15.degree. C. and a solution of sodium thiosulfate (1.89 kg) in
water (10.5 kg) was slowly added keeping the batch temperature
below 25.degree. C. The contents were stirred for 30 minutes. The
layers were allowed to separate for 30 minutes and the bottom
organic phase was collected. Water (10.5 kg) was charged to the
organic phase. The contents were stirred for 30 minutes. The layers
were allowed to separate for 30 minutes and the bottom organic
phase was collected. A solution of sodium carbonate (0.2 kg) in
water (10.5 kg) was charged to the organic phase. The contents were
stirred for 30 minutes. The layers were allowed to separate for 30
minutes and the bottom organic phase was collected. The organic
phase was reduced in volume in vacuo until the distillation stops
(maximum bath temperature 45.degree. C.). The crude product was
column chromatographed to give a cis-trans mixture of acetoxy sugar
(15) (2.1 kg, 96.6% pure, 93.9% yield).
Example 12
Preparation of Benzoic Acid
4(R,S)-(4-acetylamino-2-oxo-2H-pyrimidin-1-yl)-
-[1,3]dioxolan-2(S)-ylmethyl (9A and 9B)
[0153] 27
[0154] A solution of Benzoic acid
4(R,S)-acetoxy-[1,3]dioxolan-2(S)-ylmeth- yl ester (20 g) in
methylene chloride (400 mL) was cooled to 0-5.degree. C. and TMSI
(19.54 g, 1.3 eq) was added with stirring at 0-5.degree. C. until
the formation (ca. 2 hours) of the iodosugar was completed by TLC.
To the iodosugar solution was added HMDS (36.36 g, 3.0 eq),
followed by N-acetylcytosine (10.35 g, 0.9 eq). The reaction
mixture was stirred at 0-5.degree. C. and was monitored by TLC.
After the reaction (3 hours) was completed 10% sodium thiosulfate
solution was charged to the reaction mixture and the resulting
mixture was stirred for 15 minutes. The organic layer was separated
and was treated with 5% sodium bicarbonate solution (100 mL) and
was filtered. The organic layer was separated and was concentrated
under vacuum at 50.degree. C. (bath temperature) until distillation
stops. The solid residue (28.21 g, 120% yield) was treated with
acetone (129 mL) and isopropyl acetate (294 mL). The mixture was
heated at reflux for 15-30 minutes and was cooled to ambient
temperature over 1 hour. The solid precipitate was filtered and was
dried to afford a cis/trans mixture of protected cytosine-dioxolane
(16.9 g, 72% yield, 4/1:cis/trans). The 2 isomers were separated by
crystalization. (Cis) Benzoic acid
4(S)-(4-acetylamino-2-oxo-2H-pyrimidin-1-yl)-[1,3]dioxolan-2-
(S)-ylmethyl: (CDCl.sub.3); 9.13 (s, 1H), 8.15 (d, 1H), 8.05 (d,
2H), 7.65 (t, 1H), 7.50 (t, 2H), 7.25 (d, 1H), 6.26 (m, 1H), 5.37
(t, 1H), 4.82 (d of d, 1H), 4.61 (d of d, 1H), 4.31 (m, 2H), 2.24
(s, 3H): (Trans) Benzoic acid
4(R)-(4-acetylamino-2-oxo-2H-pyrimidin-1-yl)-[1,3]dioxolan-2(S)-ylme-
thyl (CDCl.sub.3); 8.70 (bs, 1H), 8.06 (d, 2H), 7.85 (d, 1H), 7.61
(t, 1H), 7.48 (m, 3H), 6.22 (m, 1H), 5.78 (t, 1H), 4.64 (q, 1H),
4.50 (m, 2H), 4.15 (d of d, 1H), 2.24 (s, 3H).
Example 13
Preparation of 4-Amino-1-{2(S)-hydroxymethyl-[1,3]dioxolan-4
(S)-yl}-1H-pyrimidin-2-one(10)
[0155] 28
[0156] Protected cis cytosine-dioxolane (139.0 g, 0.387 moles, 1.0
eq) was slurried in MeOH/EtOH:1/1 (560 mL, 4 vol) at room
temperature (20.degree. C.). Solid MeONa (1.4 g, 95%, 1.33 g
(corrected), 24.6 mm, 6.36 m %) was charged to the reaction
mixture. Thee reaction was monitored by TLC (MeCl.sub.2/MeOH:9/1)
for the disappearance of starting material (RF 0.47) and the
appearance of product (RF 0.06). The reaction mixture appearance
changes from a slurry to a solution as the reaction progresses.
After 3 hours of stirring at room temperature the reaction was
completed. The reaction mixture was concentrated in vacuo to 1/2
the original volume (to 300 mL). Toluene (400 mL) was charged to
the reaction mixture. The reaction mixture was further concentrated
in vacuo to a final volume of 500 mL. The resulting slurry was
cooled in an ice bath for 1 hour. The solids were filtered and were
washed with ethyl acetate (2.times.75 mL). The solids were dried at
room temperature under high vacuum until constant weight to yield
cytosine-dioxolane (82.2 g, >99% yield, purity 99.64%). (DMSO);
7.79 (d, 1H), 7.20 (bs, 1H), 7.12 (bs, 1H), 6.17 (t, 1H), 5.70 (d,
1H), 5.16 (t, 1H), 4.90 (t, 1H), 4.05 (m, 2H), 3.63 (m, 2H).
* * * * *