US4621140A
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Process for preparing 2,6-substituted-9-(1,3-dihydroxy-2-propoxymethyl)-purines and certain derivatives
Assignee: Hoffmann La Roche Inc
•
Filing: 1984-02-23
•
Granted: 1986-11-04
•
Expires: 2004-02-23
Abstract
Abstract Process and novel intermediates for preparing 9-(1,3-dihydroxy-2-propoxymethyl)guanine and 2,6-diamino-9-(1,3-dihydroxy-2-propoxymethyl)purine and certain esters thereof. The present process and intermediates reduce the number of reaction steps to prepare these compounds as compared to prior processes. The products are useful as antiviral agents.
Inventors
- 👤 Julien P. H. Verheyden
- 👤 John C. Martin
- 👤 Daniel P. C. McGee
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-29 02:46
CPC Classifications
C; C07; C07D; C07D473/00; C07C; C07C317/00; C07C323/00; C07C43/00; C07C43/02; C07C43/03; C07C43/14; C07C43/178; C07C43/1785
Claims Analysis
Total Claims: 95
Claim 1
Independent Claim
56 words
A process for preparing a compound of the formula ##STR8## wherein each R 1 is a removable group and W is a protected guanine, 2-amino-6-chloropurine or 2,6-dichloropurine which comprises reacting a compound of the formula ##STR9## wherein R 1 is as defined above and n is 0 or 1 with a protected guanine, 2-amino-6-chloropurine or 2,6-dichloropurine.
Claim 2
Dependent Claim
56 words
A process for preparing a compound of the formula ##STR8## wherein each R 1 is a removable group and W is a protected guanine, 2-amino-6-chloropurine or 2,6-dichloropurine which comprises reacting a compound of the formula ##STR9## wherein R 1 is as defined above and n is 0 or 1 with a protected guanine, 2-amino-6-chloropurine or 2,6-dichloropurine.
Claim 3
Dependent Claim
13 words
The process of claim 1 wherein R 1 is a sterically hindered group.
Claim 4
Dependent Claim
21 words
The process of claim 1 wherein R 1 is R 5 C(O) wherein R 5 is alkyl or optionally substituted phenyl.
Claim 5
Dependent Claim
14 words
The process of claim 1 wherein R 1 is an optionally substituted benzyl group.
Claim 6
Dependent Claim
35 words
The process of claim 1 wherein the two R 1 's together is ZZ 1 C< wherein Z is optionally substituted phenyl and Z 1 is hydrogen or Z and Z 1 are both methyl.
Claim 7
Dependent Claim
16 words
The process of claim 1 wherein the protected purine is in admixture with a disubstituted sulfoxide.
Claim 8
Dependent Claim
11 words
The process of claim 6 wherein the disubstituted sulfoxide is dimethylsulfoxide.
Claim 9
Dependent Claim
12 words
The process of claim 7 wherein the protected purine is protected guanine.
Claim 10
Dependent Claim
12 words
The process of claim 7 wherein the protected purine is protected 2-amino-6-chloropurine.
Claim 11
Dependent Claim
12 words
The process of claim 7 wherein the protected purine is protected 2,6-dichloropurine.
Claim 12
Dependent Claim
239 words
A process for preparing a compound of the formula ##STR10## wherein Y is hydroxy or amino and R 2 is hydrogen or a sterically hindered acyl group which comprises (a) reacting glycerol or epichlorohydrin with a removable group precursor to form a compound of the formula ##STR11## wherein each R 1 is a removable group; (b) reacting the compound prepared in (a) with a disubstituted sulfoxide to form a compound of the formula ##STR12## wherein R 1 is as defined above and n is O; (c) optionally hydrolyzing the compound prepared in (b) wherein the two R 1 's together is ZZ 1 C< wherein Z is optionally substituted phenyl and Z 1 is hydrogen or Z and Z 1 are both methyl and then reacting with an acyl chloride of the formula R 5 C(O)Cl wherein R 5 is alkyl or optionally substituted phenyl; (d) optionally oxidizing the sulfur atom of the compound prepared in (b) or (c) to form a compound wherein n is 1; (e) reacting the compound prepared in (b), (c) or (d) with a protected purine selected from the group consisting of protected guanine, 2-amino-6-chloropurine and 2,6-dichloropurine to form a compound of the formula ##STR13## wherein R 1 is a removable group and W is a protected purine; and (f) contacting the compound formed in (e) with a base or an acid or with a hydrogen donor to form a compound of formula (I).
Claim 13
Dependent Claim
239 words
A process for preparing a compound of the formula ##STR10## wherein Y is hydroxy or amino and R 2 is hydrogen or a sterically hindered acyl group which comprises (a) reacting glycerol or epichlorohydrin with a removable group precursor to form a compound of the formula ##STR11## wherein each R 1 is a removable group; (b) reacting the compound prepared in (a) with a disubstituted sulfoxide to form a compound of the formula ##STR12## wherein R 1 is as defined above and n is O; (c) optionally hydrolyzing the compound prepared in (b) wherein the two R 1 's together is ZZ 1 C< wherein Z is optionally substituted phenyl and Z 1 is hydrogen or Z and Z 1 are both methyl and then reacting with an acyl chloride of the formula R 5 C(O)Cl wherein R 5 is alkyl or optionally substituted phenyl; (d) optionally oxidizing the sulfur atom of the compound prepared in (b) or (c) to form a compound wherein n is 1; (e) reacting the compound prepared in (b), (c) or (d) with a protected purine selected from the group consisting of protected guanine, 2-amino-6-chloropurine and 2,6-dichloropurine to form a compound of the formula ##STR13## wherein R 1 is a removable group and W is a protected purine; and (f) contacting the compound formed in (e) with a base or an acid or with a hydrogen donor to form a compound of formula (I).
Claim 14
Dependent Claim
13 words
The process of claim 11 wherein R 1 is a sterically hindered group.
Claim 15
Dependent Claim
21 words
The process of claim 11 wherein R 1 is R 5 C(O) wherein R 5 is alkyl or optionally substituted phenyl.
Claim 16
Dependent Claim
14 words
The process of claim 11 wherein R 1 is an optionally substituted benzyl group.
Claim 17
Dependent Claim
35 words
The process of claim 11 wherein the two R 1 's together is ZZ 1 C< wherein Z is optionally substituted phenyl and Z 1 is hydrogen or Z and Z 1 are both methyl.
Claim 18
Dependent Claim
9 words
A process of claim 11 wherein Y is hydroxy.
Claim 19
Dependent Claim
9 words
A process of claim 11 wherein Y is amino.
Claim 20
Dependent Claim
15 words
The process of claim 11 which comprises contacting compound of formula (VI) with a base.
Claim 21
Dependent Claim
17 words
The process of claim 17 wherein the base is ammonium hydroxide, ammonia, sodium hydroxide or sodium methoxide.
Claim 22
Dependent Claim
28 words
The process of claim 19 wherein each R 1 is a sterically hindered acyl group or R 5 C(O) wherein R 5 is alkyl or optionally substituted phenyl.
Claim 23
Dependent Claim
44 words
The process of claim 20 which comprises contacting the compound of the formula (VI) wherein W is acyl protected guanine with a methanolic solution of ammonium hydroxide or a methanolic solution of ammonia to form the compound of formula (I) wherein Y is hydroxy.
Claim 24
Dependent Claim
10 words
The process of claim 21 wherein R 2 is hydrogen.
Claim 25
Dependent Claim
14 words
The process of claim 21 wherein R 2 is a sterically hindered acyl group.
Claim 26
Dependent Claim
43 words
The process of claim 20 which comprises contacting the compound of formula (VI) wherein W is acyl protected 2-amino-6-chloropurine with a methanolic solution of ammonium hydroxide or a methanolic solution of ammonia to form the compound of formula (I) wherein Y is amino.
Claim 27
Dependent Claim
10 words
The process of claim 24 wherein R 2 is hydrogen.
Claim 28
Dependent Claim
14 words
The process of claim 24 wherein R 2 is a sterically hindered acyl group.
Claim 29
Dependent Claim
70 words
The process of claim 20 which comprises contacting the compound of formula (VI) wherein W is acyl protected 2,6-dichloropurine with a methanolic solution of ammonium hydroxide or a methanolic solution of ammonia and further contacting the compound so formed with methanolic solution of ammonium hydroxide or a methanolic solution of ammonia under increased temperature to form the compound of formula (I) wherein Y is amino and R 2 is hydrogen.
Claim 30
Dependent Claim
11 words
The process of claim 11 wherein the base is sodium hydroxide.
Claim 31
Dependent Claim
42 words
The process of claim 28 which comprises contacting the compound of formula (VI) wherein W is acyl protected 2-amino-6-chloropurine with an aqueous solution of sodium hydroxide to form the compound of formula (I) wherein Y is hydroxy and R 2 is hydrogen.
Claim 32
Dependent Claim
15 words
The process of claim 11 which comprises contacting compound of formula (VI) with an acid.
Claim 33
Dependent Claim
50 words
The process of claim 30 wherein each R 1 is a sterically hindered silyl group, diphenylmethyl or a triphenylmethyl group, or the two R 1 's together is ZZ 1 C< wherein Z is optionally substituted phenyl and Z 1 is hydrogen or Z and Z 1 are both methyl.
Claim 34
Dependent Claim
11 words
The process of claim 31 wherein the acid is acetic acid.
Claim 35
Dependent Claim
57 words
The process of claim 32 which comprises contacting a compound of formula (VI) wherein W is defined in claim 11 with an aqueous solution of acetic acid and optionally with a methanolic solution of ammonium hydroxide or a methanolic solution of ammonia to form a compound of formula (I) wherein Y is as defined in claim 11.
Claim 36
Dependent Claim
27 words
The process of claim 33 wherein the compound of formula (VI) is first contacted with a methanolic solution of ammonium hydroxide or a methanolic solution of ammonia.
Claim 37
Dependent Claim
21 words
The process of claim 34 wherein the compound of formula (VI) is first contacted with an aqueous solution of acetic acid.
Claim 38
Dependent Claim
16 words
The process of claim 11 wherein the protected purine is in admixture with a disubstituted sulfoxide.
Claim 39
Dependent Claim
11 words
The process of claim 36 wherein the disubstituted sulfoxide is dimethylsulfoxide.
Claim 40
Dependent Claim
12 words
The process of claim 37 wherein the protected purine is protected guanine.
Claim 41
Dependent Claim
12 words
The process of claim 37 wherein the protected purine is protected 2-amino-6-chloropurine.
Claim 42
Dependent Claim
12 words
The process of claim 37 wherein the protected purine is protected 2,6-dichloropurine.
Claim 43
Dependent Claim
28 words
The process of claim 11 wherein compound of formula (VI) is contacted with a hydrogen donor to form a compound of formula (I) wherein R 2 is hydrogen.
Claim 44
Dependent Claim
15 words
The process of claim 41 wherein each R 1 is an optionally substituted benzyl group.
Claim 45
Dependent Claim
21 words
The process of claim 42 wherein compound of formula (VI) is contacted with hydrogen in the presence of a hydrogenation catalyst.
Claim 46
Dependent Claim
11 words
The process of claim 43 wherein the hydrogenation catalyst is palladium-on-carbon.
Claim 47
Dependent Claim
21 words
The process of claim 43 which further comprises contacting the compound formed in claim 43 with a base or an acid.
Claim 48
Dependent Claim
15 words
The process of claim 45 which comprises contacting compound of formula (VI) with a base.
Claim 49
Dependent Claim
17 words
The process of claim 46 wherein the base is ammonium hydroxide, ammonia, sodium hydroxide or sodium methoxide.
Claim 50
Dependent Claim
15 words
The process of claim 45 which comprises contacting compound of formula (VI) with an acid.
Claim 51
Dependent Claim
11 words
The process of claim 48 wherein the acid is acetic acid.
Claim 52
Dependent Claim
13 words
The process of claim 41 wherein the hydrogen donor is cyclohexene or 1,4-cyclohexadiene.
Claim 53
Dependent Claim
11 words
The process of claim 50 wherein the hydrogen donor is cyclohexene.
Claim 54
Dependent Claim
112 words
A process for preparing a compound of the formula ##STR14## wherein Y is hydroxy or amino and R 2 is hydrogen or a sterically hindered acyl group which comprises (a) reacting a compound of the formula ##STR15## wherein R 1 is a removable group and n is 0 or 1 with a protected purine selected from the groups consisting of protected guanine, 2-amino-6-chloropurine and 2,6-dichloropurine to form a compound of the formula ##STR16## wherein R 1 is as defined above and W is a protected purine; and (b) contacting the compound formed in (a) with a base or an acid or with a hydrogen donor to form a compound of formula (I).
Claim 55
Dependent Claim
112 words
A process for preparing a compound of the formula ##STR14## wherein Y is hydroxy or amino and R 2 is hydrogen or a sterically hindered acyl group which comprises (a) reacting a compound of the formula ##STR15## wherein R 1 is a removable group and n is 0 or 1 with a protected purine selected from the groups consisting of protected guanine, 2-amino-6-chloropurine and 2,6-dichloropurine to form a compound of the formula ##STR16## wherein R 1 is as defined above and W is a protected purine; and (b) contacting the compound formed in (a) with a base or an acid or with a hydrogen donor to form a compound of formula (I).
Claim 56
Dependent Claim
13 words
The process of claim 52 wherein R 1 is a sterically hindered group.
Claim 57
Dependent Claim
21 words
The process of claim 52 wherein R 1 is R 5 C(O) wherein R 5 is alkyl or optionally substituted phenyl.
Claim 58
Dependent Claim
14 words
The process of claim 52 wherein R 1 is an optionally substituted benzyl group.
Claim 59
Dependent Claim
35 words
The process of claim 52 wherein the two R 1 's together is ZZ 1 C< wherein Z is optionally substituted phenyl and Z 1 is hydrogen or Z and Z 1 are both methyl.
Claim 60
Dependent Claim
9 words
A process of claim 52 wherein Y is hydroxy.
Claim 61
Dependent Claim
9 words
A process of claim 52 wherein Y is amino.
Claim 62
Dependent Claim
15 words
The process of claim 52 which comprises contacting compound of formula (VI) with a base.
Claim 63
Dependent Claim
17 words
The process of claim 59 wherein the base is ammonium hydroxide, ammonia, sodium hydroxide or sodium methoxide.
Claim 64
Dependent Claim
28 words
The process of claim 60 wherein each R 1 is a sterically hindered acyl group or R 5 C(O) wherein R 5 is alkyl or optionally substituted phenyl.
Claim 65
Dependent Claim
44 words
The process of claim 61 which comprises contacting the compound of the formula (VI) wherein W is acyl protected guanine with a methanolic solution of ammonium hydroxide or a methanolic solution of ammonia to form the compound of formula (I) wherein Y is hydroxy.
Claim 66
Dependent Claim
10 words
The process of claim 62 wherein R 2 is hydrogen.
Claim 67
Dependent Claim
14 words
The process of claim 62 wherein R 2 is a sterically hindered acyl group.
Claim 68
Dependent Claim
43 words
The process of claim 61 which comprises contacting the compound of formula (VI) wherein W is acyl protected 2-amino-6-chloropurine with a methanolic solution of ammonium hydroxide or a methanolic solution of ammonia to form the compound of formula (I) wherein Y is amino.
Claim 69
Dependent Claim
10 words
The process of claim 65 wherein R 2 is hydrogen.
Claim 70
Dependent Claim
14 words
The process of claim 65 wherein R 2 is a sterically hindered acyl group.
Claim 71
Dependent Claim
70 words
The process of claim 61 which comprises contacting the compound of formula (VI) wherein W is acyl protected 2,6-dichloropurine with a methanolic solution of ammonium hydroxide or a methanolic solution of ammonia and further contacting the compound so formed with methanolic solution of ammonium hydroxide or a methanolic solution of ammonia under increased temperature to form the compound of formula (I) wherein Y is amino and R 2 is hydrogen.
Claim 72
Dependent Claim
11 words
The process of claim 60 wherein the base is sodium hydroxide.
Claim 73
Dependent Claim
48 words
The process of claim 69 which comprises contacting the compound of formula (VI) wherein W is acyl protected 2-amino-6-chloropurine with an aqueous solution of sodium hydroxide or a methanolic solution of ammonia to form the compound of formula (I) wherein Y is hydroxy and R 2 is hydrogen.
Claim 74
Dependent Claim
15 words
The process of claim 52 which comprises contacting compound of formula (VI) with an acid.
Claim 75
Dependent Claim
47 words
The process of claim 71 wherein each R 1 is a sterically hindered silyl, diphenylmethyl or triphenylmethyl or the two R 1 's together are ZZ 1 C< wherein Z is optionally substituted phenyl and Z 1 is hydrogen or Z and Z 1 are both methyl.
Claim 76
Dependent Claim
11 words
The process of claim 72 wherein the acid is acetic acid.
Claim 77
Dependent Claim
57 words
The process of claim 73 which comprises contacting a compound of formula (VI) wherein W is defined in claim 52 with an aqueous solution of acetic acid and optionally with a methanolic solution of ammonium hydroxide or a methanolic solution of ammonia to form a compound of formula (I) wherein Y is as defined in claim 52.
Claim 78
Dependent Claim
27 words
The process of claim 74 wherein the compound of formula (VI) is first contacted with a methanolic solution of ammonium hydroxide or a methanolic solution of ammonia.
Claim 79
Dependent Claim
21 words
The process of claim 74 wherein the compound of formula (VI) is first contacted with an aqueous solution of acetic acid.
Claim 80
Dependent Claim
28 words
The process of claim 52 wherein compound of formula (VI) is contacted with a hydrogen donor to form a compound of formula (I) wherein R 2 is hydrogen.
Claim 81
Dependent Claim
15 words
The process of claim 77 wherein each R 1 is an optionally substituted benzyl group.
Claim 82
Dependent Claim
21 words
The process of claim 78 wherein compound of formula (VI) is contacted with hydrogen in the presence of a hydrogenation catalyst.
Claim 83
Dependent Claim
11 words
The process of claim 79 wherein the hydrogenation catalyst is palladium-on-carbon.
Claim 84
Dependent Claim
21 words
The process of claim 79 which further comprises contacting the compound formed in claim 79 with a base or an acid.
Claim 85
Dependent Claim
17 words
The process of claim 81 which comprises contacting the compound formed in claim 79 with a base.
Claim 86
Dependent Claim
17 words
The process of claim 82 wherein the base is ammonium hydroxide, ammonia, sodium hydroxide or sodium methoxide.
Claim 87
Dependent Claim
17 words
The process of claim 79 which comprises contacting the compound formed in claim 79 with an acid.
Claim 88
Dependent Claim
11 words
The process of claim 84 wherein the acid is acetic acid.
Claim 89
Dependent Claim
13 words
The process of claim 77 wherein the hydrogen donor is cyclohexene or 1,4-cyclohexadiene.
Claim 90
Dependent Claim
11 words
The process of claim 86 wherein the hydrogen donor is cyclohexene.
Claim 91
Dependent Claim
16 words
The process of claim 52 wherein the protected purine is in admixture with a disubstituted sulfoxide.
Claim 92
Dependent Claim
11 words
The process of claim 88 wherein the disubstituted sulfoxide is dimethylsulfoxide.
Claim 93
Dependent Claim
12 words
The process of claim 89 wherein the protected purine is protected guanine.
Claim 94
Dependent Claim
12 words
The process of claim 89 wherein the protected purine is protected 2-amino-6-chloropurine.
Claim 95
Dependent Claim
12 words
The process of claim 89 wherein the protected purine is protected 2,6-dichloropurine.
References Cited (Backward Citations)
US4423050A
Cited
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1989-11-03 | 1990-05-05 | 1990-11-04 | $2000.00 | Window Closed / Lapsed |
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