US5319112A
Expired / Lapsed
US
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Method for the conversion of cephalomannine to taxol and for the preparation of N-acyl analogs of taxol
Assignee: Virginia Tech Intellectual Properties Inc
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Filing: 1992-08-18
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Granted: 1994-06-07
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Expires: 2012-08-18
Abstract
Abstract The natural product cephalomannine can be converted to the important anticancer natural product taxol by a simple process involving the steps of hydrogenation, benzoylation at the C-2'-position, protection of the C-7 position, and reaction with oxalyl chloride, followed by reaction with diphenylcarbodiimide and deprotection. The same process can be applied to mixtures of taxol and cephalomannine, thus obviating the need for the separation of these closely related compounds. In addition, the selection of an acylating reagent other than the benzoyl group allows the preparation of taxol analogs with other N-acyl substituents.
Inventors
- 👤 David G. I. Kingston
- 👤 Anthony A. Molinero
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-01 17:37
CPC Classifications
C; C07; C07D; C07D305/00; C07D305/14
Claims Analysis
Total Claims: 16
Claim 1
Independent Claim
71 words
A method for synthesizing taxol from cephalomannine comprising the step of substituting the 2-methyl-2-butenoyl moiety on the C-13 side-chain of cephalomannine with a benzoyl group; wherein said step of substituting comprises conversion of the butenyl moiety at the C-3' position of cephalomannine to a butyl moiety via hydrogenation, and subsequent replacement of said butyl moiety with an oxalyl-containing moiety, followed by the conversion of said oxalyl-containing moiety to a benzoyl moiety.
Claim 2
Independent Claim
71 words
A method for synthesizing taxol from cephalomannine comprising the step of substituting the 2-methyl-2-butenoyl moiety on the C-13 side-chain of cephalomannine with a benzoyl group; wherein said step of substituting comprises conversion of the butenyl moiety at the C-3' position of cephalomannine to a butyl moiety via hydrogenation, and subsequent replacement of said butyl moiety with an oxalyl-containing moiety, followed by the conversion of said oxalyl-containing moiety to a benzoyl moiety.
Claim 3
Independent Claim
45 words
A method for synthesizing taxol from cephalomannine comprising the step of attaching a benzoyl group to the C-2' position of the cephalomannine side chain, and transfer of said benzoyl group from the C-2' position onto the nitrogen at the C-3' position of the C-13 side-chain.
Claim 4
Independent Claim
45 words
A method for synthesizing taxol from cephalomannine comprising the step of attaching a benzoyl group to the C-2' position of the cephalomannine side chain, and transfer of said benzoyl group from the C-2' position onto the nitrogen at the C-3' position of the C-13 side-chain.
Claim 5
Dependent Claim
15 words
The method of claim 1, wherein said cephalomannine is present in a mixture with taxol.
Claim 6
Dependent Claim
78 words
The method of claim 1 further comprising conversion of the hydroxyl group at the C-2' position to a benzoyl group; and protection of the C-7 position with a protecting group; wherein said conversion of the hydroxyl group at the C-2' position occurs after said hydrogenation and before said replacement of said butyl moiety with an oxalyl-containing moiety, and further wherein said conversion of the hydroxyl group at the C-2' position is followed by protection of the C-7 position.
Claim 7
Dependent Claim
19 words
The method of claim 4, wherein said protecting group is selected from the group comprised of 2,2,2-trichloroethyloxycarbonyl, and trialkylsiloxy.
Claim 8
Dependent Claim
22 words
The method of claim 4, wherein said replacement of said butyl moiety with an oxalyl-containing moiety comprises formation of an iminio compound.
Claim 9
Dependent Claim
28 words
The method of claim 6, further comprising reaction of said iminio compound with water to form an oxamic acid substituent at the C-3' position of the side chain.
Claim 10
Dependent Claim
30 words
The method of claim 7, further comprising cleavage of the C-3' amido bond of said oxamic acid derivative to enable acyl transfer from the 2' position onto said N-3' position.
Claim 11
Dependent Claim
15 words
The method of claim 8, further comprising deprotection of the C-7 position to form taxol.
Claim 12
Independent Claim
153 words
A method for converting cephalomannine to taxol comprising the following steps: A) hydrogenation of a first mixture comprising cephalomannine to form a second mixture comprising dihydrocephalomannine; B) reaction of said second mixture with benzoic acid in the presence of an activating agent to form a third mixture; C) reaction of said third mixture with a protecting group to form a fourth mixture comprising a derivative of said dihydrocephalomannine having a protecting group at the C-7 position; D) reaction of said fourth mixture with a compound capable of reacting with the side chain amino group of said dihydrocephalomannine as modified by said steps B and C to form an iminio compound; E) reaction of said iminio compound with water; F) reaction of the product of Step E with diphenylcarbodiimide to form taxol with a protecting group at the C-7 position; and G) removal of said protecting group at the C-7 position to form taxol.
Claim 13
Independent Claim
153 words
A method for converting cephalomannine to taxol comprising the following steps: A) hydrogenation of a first mixture comprising cephalomannine to form a second mixture comprising dihydrocephalomannine; B) reaction of said second mixture with benzoic acid in the presence of an activating agent to form a third mixture; C) reaction of said third mixture with a protecting group to form a fourth mixture comprising a derivative of said dihydrocephalomannine having a protecting group at the C-7 position; D) reaction of said fourth mixture with a compound capable of reacting with the side chain amino group of said dihydrocephalomannine as modified by said steps B and C to form an iminio compound; E) reaction of said iminio compound with water; F) reaction of the product of Step E with diphenylcarbodiimide to form taxol with a protecting group at the C-7 position; and G) removal of said protecting group at the C-7 position to form taxol.
Claim 14
Dependent Claim
28 words
The method of claim 10, wherein said iminio compound formed in Step D is formed by reaction of oxalylchloride with said dihydrocephalomannine having a protecting group at C-7.
Claim 15
Independent Claim
97 words
A method for converting the cephalomannine in a cephalomannine-taxol mixture to taxol, comprising the steps of: 1) hydrogenation of said cephalomannine-taxol mixture reducing the butenoyl moiety in said cephalomannine, 2) benzoylation of the reduced cephalomannine at the C-2' position, 3) protection of the C-7 hydroxyl group of the modified cephalomannine with a protecting group, 4) reaction of a mixture comprising material resulting from step 3 with oxalyl chloride followed by addition of water, 5) reaction of a solution comprising material resulting from step 4 with diphenylcarbodiimide, and 6) removal of said protecting group from the C-7 position.
Claim 16
Independent Claim
97 words
A method for converting the cephalomannine in a cephalomannine-taxol mixture to taxol, comprising the steps of: 1) hydrogenation of said cephalomannine-taxol mixture reducing the butenoyl moiety in said cephalomannine, 2) benzoylation of the reduced cephalomannine at the C-2' position, 3) protection of the C-7 hydroxyl group of the modified cephalomannine with a protecting group, 4) reaction of a mixture comprising material resulting from step 3 with oxalyl chloride followed by addition of water, 5) reaction of a solution comprising material resulting from step 4 with diphenylcarbodiimide, and 6) removal of said protecting group from the C-7 position.
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| 3.5 Years (Year 4) | 1997-06-06 | 1997-12-06 | 1998-06-07 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2001-06-06 | 2001-12-06 | 2002-06-07 | $3760.00 | Window Closed / Lapsed |
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