US2005085638A1PendingUtilityA1
Process for producing dioxolane nucleoside analogues
Est. expiryJan 25, 2022(expired)· nominal 20-yr term from priority
C07D 473/16C07D 473/00C07D 473/32C07D 405/04C07D 317/34
43
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Claims
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 2 , using a suitable source of energy.
Claims
exact text as granted — not AI-modified1 . 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 in a suitable solvent;
wherein;
R 1 is a hydroxyl protecting group;
R 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 1 is C 1-6 alkyl, C 6-12 aryl, C 6-12 arylalkyl, CO—C 1-6 alkyl, CO—C 1-6 alkoxy, CO—C 6-12 aryloxy, or CO—C 6-12 arylalkyl.
6 . The process according to claim 1 , wherein R 1 is acetyl, pivaloyl, benzoyl or benzyl.
7 . The process according to claim 1 , wherein R 1 is benzoyl.
8 . The process according to claim 1 , wherein the suitable temperature is about −78° C. or warmer.
9 . The process according to claim 8 , wherein the suitable temperature is about −15° 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 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 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 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 2 .
20 . The process according to claim 1 , wherein R 2 is chosen from:
wherein;
R 3 is H, C 1-6 alkyl, C 1-6 acyl or CO—R 9 ;
R 4 and R 5 are each, independently, H, C 1-6 alkyl, bromide, chloride, fluoride, iodide or CF 3 ;
R 6 , R 7 and R 8 are each, independently, H, bromide, chloride, fluoride, iodide, amino, hydroxyl or C 3-6 cycloalkylamino, and
R 9 is H or C 1-6 alkyl.
21 . The process according to claim 20 , wherein R 2 is:
22 . The process according to claim 1 , wherein R 2 is:
23 . The process according to claim 1 , wherein R 2 is:
24 . The process according to claim 1 , wherein R 2 is:
25 . A process for producing a dioxolane compound of formula III:
the process comprising the step of reacting a dioxolane compound of formula IV in a suitable solvent;
in the presence of DIB and I 2 , wherein said process is conducted using a suitable source of energy; and wherein R 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 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 2 and acetic acid over a suitable period of time.
28 . The process according to claim 25 , wherein R 10 is C 1-6 alkyl, C 6-12 aryl, C 6-12 arylalkyl, CO—C 1-6 alkyl, alkoxy, CO—C 6-12 aryloxy, or CO—C 6-12 arylalkyl.
29 . The process according to claim 28 , wherein R 10 is acetyl, pivaloyl, benzoyl or benzyl.
30 . The process according to claim 28 , wherein R 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 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 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 1 to produce a compound of formula Ia or a pharmaceutically acceptable salt thereof.
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 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 1 is acetyl, pivaloyl, benzoyl or benzyl.
46 . A process according to claim 2 , wherein R 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 2 is:
wherein;
R 3 is H, C 1-6 alkyl, C 1-6 acyl and CO—R 9 ;
R 4 and R 5 are each, independently, H, C 1-6 alkyl, bromide, chloride, fluoride, iodide or CF 3 ;
R 6 , R 7 and R 8 are each, independently, H, bromide, chloride, fluoride, iodide, amino, hydroxyl or C 3-6 cycloalkylamino; and
R 9 is H or C 1-6 alkyl.
50 . A process according to claim 2 , wherein R 2 is:
51 . A process according to claim 2 , wherein R 2 is:
52 . A process according to claim 2 , wherein R 2 is:
53 . A process according to claim 2 , wherein R 2 is:
54 . 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 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;
wherein;
R 1 is a hydroxyl protecting group selected from acetyl, pivaloyl, benzoyl and benzyl;
R 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 2 is chosen from:
wherein;
R 3 is H, C 1-6 alkyl, C 1-6 acyl or CO—R 9 ;
R 4 and R 5 are each, independently, H, C 1-6 alkyl, bromide, chloride, fluoride, iodide or CF 3 ;
R 6 , R 7 and R 8 are each independently H, bromide, chloride, fluoride, iodide, amino, hydroxyl or C 3-6 cycloalkylamino; and
R 9 is H or C 1-6 alkyl.
56 . A process according to claim 54 , wherein R 2 is:
57 . A process according to claim 54 , wherein R 2 is:
58 . A process according to claim 54 , wherein R 2 is:
59 . A process according to claim 54 , wherein R 2 is:
60 . A process according to claim 54 , wherein L is acetoxy.
61 . A process according to claim 54 , wherein R 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 2 to the mixture resulting from step a).
64 . A process for producing a dioxolane compound of formula III:
the process comprising reacting a dioxolane compound of formula IV in a suitable solvent;
in the presence of DIB and I 2 , wherein the dioxolane compound of formula IV is added to a mixture of DIB and I 2 ;
R 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 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 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; in the presence of DIB and I 2 , wherein the dioxolane compound of formula IV is added to a mixture of DIB, I 2 and acetic acid; R 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 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 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.Join the waitlist — get patent alerts
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