US5614645A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Methods for making 2-debenzoyl and -2-acyl taxol derivatives
Assignee: Virginia Tech Intellectual Properties Inc
•
Filing: 1995-06-07
•
Granted: 1997-03-25
•
Expires: 2015-06-07
Abstract
Abstract The present invention relates a method of making to 2-debenzoyl-2-acyl taxol derivatives, and analogues thereof.
Inventors
- 👤 David G. I. Kingston
- 👤 Ashok G. Chaudhary
- 👤 Milind M. Gharpure
- 👤 John M. Rimoldi
- 👤 A. A. Leslie Gunatilaka
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 12:38
CPC Classifications
C; C07; C07D; C07D405/00; C07D405/02; C07D405/12; A; A61; A61P; A61P35/00; C07D305/00; C07D305/14; C07D409/00; C07D409/02; C07D409/12; C07F; C07F7/00; C07F7/02; C07F7/08; C07F7/18; C07F7/1804; Y; Y02; Y02P; Y02P20/00; Y02P20/50; Y02P20/55
Claims Analysis
Total Claims: 42
Claim 1
Independent Claim
187 words
A method for making a taxol analogue having a hydroxy substituent at the C-2 position from a taxol analogue having a benzoyloxy substituent at the C-2 position, comprising: a step of base catalyzed hydrolysis under phase transfer conditions of a compound having the formula ##STR25## wherein said benzoyloxy substiunt at the C-2 position is replaced by a hydroxyl to make a compound having the formula: ##STR26## wherein R 5 is H , R 2 is selected from the group consisting of H, OH, oxy protecting group and acyloxy, and R 3 is selected from the group consisting of H, OH, and acyloxy, and wherein R 6 is selected from the group consisting of H, OH, oxy protecting group and acyloxy, wherein said acyloxy can be the same or different, and R 4 is H or OH; and R 1 and R 7 are the same or different nd have the general formula: ##STR27## wherein Ar is phenyl or substituted phenyl; Z is selected from the group consisting of alkoxy, phenyl, and substituted phenyl; and Y is selected from the ground consisting of H, acyl, and protecting group.
Claim 2
Independent Claim
187 words
A method for making a taxol analogue having a hydroxy substituent at the C-2 position from a taxol analogue having a benzoyloxy substituent at the C-2 position, comprising: a step of base catalyzed hydrolysis under phase transfer conditions of a compound having the formula ##STR25## wherein said benzoyloxy substiunt at the C-2 position is replaced by a hydroxyl to make a compound having the formula: ##STR26## wherein R 5 is H , R 2 is selected from the group consisting of H, OH, oxy protecting group and acyloxy, and R 3 is selected from the group consisting of H, OH, and acyloxy, and wherein R 6 is selected from the group consisting of H, OH, oxy protecting group and acyloxy, wherein said acyloxy can be the same or different, and R 4 is H or OH; and R 1 and R 7 are the same or different nd have the general formula: ##STR27## wherein Ar is phenyl or substituted phenyl; Z is selected from the group consisting of alkoxy, phenyl, and substituted phenyl; and Y is selected from the ground consisting of H, acyl, and protecting group.
Claim 3
Dependent Claim
26 words
The method of claim 1, wherein R 4 is OH and R 2 is elected from the group consisting of OH, oxy protecting group and acyloxy.
Claim 4
Independent Claim
211 words
A method for making a taxol analogue having a hydroxy substituent at the C-2 position from a taxol analogue having a benzoyloxy substituent at the C-2 position, comprising: a step of base catalyzed hydrolysis under phase transfer conditions of a compound having the formula: ##STR28## wherein said benzoyloxy substituent at the C-2 position is replaced by a hydroxyl and further comprising a reaction with an acylating agent comprising an acid halide, B-lactam, anhydride, or carboxylic acid occurring subsequently to the replacement of said benzoyl moiety by H, to make a compound having the formula: ##STR29## wherein R 5 is acyl, R 2 is selected from the group consisting of H, OH, oxy protecting group and acyloxy, and R 3 is selected from the group consisting of H, OH, and acyloxy, and wherein R 6 is selected from the group consisting of H, OH, oxy protecting group and acyloxy, and wherein said acyloxy can be the same or different, and R 4 is H or OH; and R 1 and R 7 are the same or different and have the general formula: ##STR30## wherein Ar is phenyl or substituted phenyl; Z is selected from the group consisting of alkoxy, phenyl, and substituted phenyl; and Y is H, acyl, or a protecting, group.
Claim 5
Independent Claim
211 words
A method for making a taxol analogue having a hydroxy substituent at the C-2 position from a taxol analogue having a benzoyloxy substituent at the C-2 position, comprising: a step of base catalyzed hydrolysis under phase transfer conditions of a compound having the formula: ##STR28## wherein said benzoyloxy substituent at the C-2 position is replaced by a hydroxyl and further comprising a reaction with an acylating agent comprising an acid halide, B-lactam, anhydride, or carboxylic acid occurring subsequently to the replacement of said benzoyl moiety by H, to make a compound having the formula: ##STR29## wherein R 5 is acyl, R 2 is selected from the group consisting of H, OH, oxy protecting group and acyloxy, and R 3 is selected from the group consisting of H, OH, and acyloxy, and wherein R 6 is selected from the group consisting of H, OH, oxy protecting group and acyloxy, and wherein said acyloxy can be the same or different, and R 4 is H or OH; and R 1 and R 7 are the same or different and have the general formula: ##STR30## wherein Ar is phenyl or substituted phenyl; Z is selected from the group consisting of alkoxy, phenyl, and substituted phenyl; and Y is H, acyl, or a protecting, group.
Claim 6
Dependent Claim
79 words
The method of claim 3, wherein R 1 and R 7 are the same, Y is H, R 3 is OC(O)CH 3 , R 4 is OH and R 6 is OH, and further comprising a step of protecting the hydroxyl groups at the C-2' and C-7 positions prior to said step of base catalyzed hydrolysis; and further comprising a step of deprotecting said C-2' and C-7 positions by acid catalyzed hydrolysis following said reaction with an acylating agent.
Claim 7
Dependent Claim
77 words
The method of claim 4, wherein Ar is C 6 H 5 , Z is selected from the group consisting of C 6 H 5 and OC(CH 3 ) 3 , and further wherein said step of protecting the hydroxyl groups comprises reacting with a trialkylsilylhalide, and wherein said base catalyzed hydrolysis consists of reacting a 2',7-trialkylsilyl-protected derivative of said second compound in a mixture comprising aqueous sodium hydroxide, an organic solvent and a phase transfer catalyst.
Claim 8
Dependent Claim
30 words
The method of claim 5, wherein said reaction with an acylating agent comprises reaction with a carboxylic acid conducted in the presence of dicyclohexylcarbodiimide and a catalytic amount of 4-pyrrolidinopyridine.
Claim 9
Dependent Claim
14 words
The method of claim 6, wherein R 5 is QC(O) and Q is thiophene.
Claim 10
Dependent Claim
27 words
The method of claim 2, wherein said base catalyzed hydrolysis comprises reaction in a mixture comprising aqueous sodium hydroxide, an organic solvent and a phase transfer catalyst.
Claim 11
Dependent Claim
33 words
The method of claim 3, wherein R 5 has the formula: ##STR31## wherein T, U, W, V, and X are independently selected from the group consisting of hydrogen, halogen, cyano, alkoxy, and azido.
Claim 12
Dependent Claim
49 words
The method of claim 9, wherein R 3 is C(O)CH 3 , Ar is C 6 H 5 , Z is selected from the group consisting of C 6 H 5 and OC(CH 3 ) 3 , and Y is selected from the group consisting of H and triethylsilyl.
Claim 13
Dependent Claim
50 words
The method of claim 10, wherein Y is triethylsilyl and R 6 is triethylsilyloxy and further wherein said second compound is debenzoylated via reaction in a mixture comprising aqueous sodium hydroxide, a phase transfer catalyst, and an organic solvent, to yield a compound having a hydroxyl at the C-2 position.
Claim 14
Dependent Claim
36 words
The method of claim 11, wherein T, U, W and V are H, and further comprising a step wherein said compound having a hydroxyl at the C-2 position is reacted with meta-C 6 H 4 X--COOH.
Claim 15
Dependent Claim
11 words
The method of claim 12 where X is N 3 .
Claim 16
Independent Claim
69 words
A method for debenzoylating and reacylating the C-2 position of a taxol analogue comprising: mixing, in the presence of a phase transfer catalyst, a taxol analogue having a benzoyloxy substituent at the C-2 position in organic solvent and aqueous sodium hydroxide to produce a C-2 debenzoylated taxol analogue dissolved in said organic phase; and reacting said C-2 debenzoylated taxol analogue with a carboxylic acid to reacylate the C-2 position.
Claim 17
Independent Claim
69 words
A method for debenzoylating and reacylating the C-2 position of a taxol analogue comprising: mixing, in the presence of a phase transfer catalyst, a taxol analogue having a benzoyloxy substituent at the C-2 position in organic solvent and aqueous sodium hydroxide to produce a C-2 debenzoylated taxol analogue dissolved in said organic phase; and reacting said C-2 debenzoylated taxol analogue with a carboxylic acid to reacylate the C-2 position.
Claim 18
Dependent Claim
24 words
The method of claim 14 herein said reaction with a carboxylic acid is conducted in the presence of dicyclohexylcarbodiimide and a catalytic amount 4-pyrrolidinopyridine.
Claim 19
Dependent Claim
15 words
The method of claim 15 wherein said phase transfer catalyst is a quaternary ammonium salt.
Claim 20
Dependent Claim
13 words
The method of claim 15 wherein said phase catalyst is tetrabutylammonium hydrogen sulfate.
Claim 21
Dependent Claim
20 words
The method of claim 14 wherein said taxol analogue having a benzoyloxy substituent at the C-2 position is a 2',7-trialkylsilyltaxol.
Claim 22
Dependent Claim
21 words
The method of claim 18 further comprising a process of making said 2',7-trialkylsilyltaxol is prepared by reacting taxol with triethylsilyl chloride.
Claim 23
Dependent Claim
15 words
The method of claim 18 wherein said phase transfer catalyst is a quaternary ammonium salt.
Claim 24
Dependent Claim
25 words
The method of claim 20 wherein said reaction with a carboxylic acid is conducted in the presence of dicyclohexylcarbodiimide and a catalytic amount of 4-pyrrolidinopyridine.
Claim 25
Dependent Claim
14 words
The method of claim 21 wherein said quaternary ammonium salt is tetrabutylammonium hydrogen sulfate.
Claim 26
Dependent Claim
14 words
The method of claim 22 wherein said carboxylic acid is a substituted benzoic acid.
Claim 27
Dependent Claim
11 words
The method of claim 23 wherein said organic solvent comprises benzene.
Claim 28
Dependent Claim
28 words
The method of claim 23 further comprising, subsequent to reacylating the C-2 position, reaction with formic acid to remove the trialkylsilyl groups from said C-2' and C-7 positions.
Claim 29
Independent Claim
67 words
A method for debenzoylating and reacylating the C-2' position of a taxol analogue comprising: reacting lithium hydroxide with a taxol analogue having a benzoyloxy substituent at the C-2 position having t-butoxycarbonyloxy or trialkylsilyloxy groups at the C-2' and C-7 positions, to produce a C-2 debenzoylated taxol analogue; and reacting said C-2 debenzoylated taxol analogue with a carboxylic acid or an acid halide to reacylate said C-2 position.
Claim 30
Independent Claim
67 words
A method for debenzoylating and reacylating the C-2' position of a taxol analogue comprising: reacting lithium hydroxide with a taxol analogue having a benzoyloxy substituent at the C-2 position having t-butoxycarbonyloxy or trialkylsilyloxy groups at the C-2' and C-7 positions, to produce a C-2 debenzoylated taxol analogue; and reacting said C-2 debenzoylated taxol analogue with a carboxylic acid or an acid halide to reacylate said C-2 position.
Claim 31
Dependent Claim
17 words
The method of claim 26 wherein the step of reacting with lithium hydroxide is conducted in tetrahydrofuran.
Claim 32
Dependent Claim
28 words
The method of claim 22 wherein the C-2 position is reacylated by reaction with a carboxylic acid in the presence of dicyclohexylcarbodiimide and a catalytic amount of 4-pyrrolidinopyridine.
Claim 33
Dependent Claim
29 words
The method of claim 26 wherein said taxol analogue having a benzoyloxy substituent at the C-2 position has an amido at the C-3' position having a t-butoxycarbonyloxy substituent thereon.
Claim 34
Dependent Claim
34 words
The method of claim 26 further comprising a process of making said taxol analogue having a benzoyloxy substituent at the C-2 position comprising: reacting taxol with di-t-butyldicarbonate and 4-dimethylaminopyridine to produce 2',7,N-tri(t-butoxycarbonyl) taxol (7).
Claim 35
Dependent Claim
53 words
The method of claim 26 further comprising a process of making said taxol analogue having a benzoyloxy substituent at the C-2 position comprising: reacting taxol with di-t-butyldicarbonate to produce 2'-(t-butyloxycarbonyloxy)taxol (14) followed by addition of triethylsilyl chloride to produce 2'-(t-butyloxycarbonyloxy)-7-(triethylsilyl)taxol, and followed by addition of di-t-butyldicarbonate and 4-dimethylaminopyridine to produce 2',N-(t-butyloxycarbonyloxy)-7-(triethylsilyl)taxol (16) .
Claim 36
Dependent Claim
28 words
The method of claim 30 further comprising, subsequent to reacylating the C-2 position, reaction with formic acid to remove the trialkylsilyl groups from said C-2' and C-7 positions.
Claim 37
Dependent Claim
17 words
The method of claim 30 wherein the step of reacting with lithium hydroxide is conducted in tetrahydrofuran.
Claim 38
Dependent Claim
28 words
The method of claim 33 wherein the C-2 position is reacylated by reaction with a carboxylic acid in the presence of dicyclohexylcarbodiimide and a catalytic amount of 4-pyrrolidinopyridine.
Claim 39
Dependent Claim
52 words
The method of claim 2, wherein R 1 and R 7 are the same, Y is H, R 3 is OC(O)CH 3 , and R 6 is OH, and further comprising a step of protecting the hydroxyl groups at the C-2' and C-7 positions prior to said step of base catalyzed hydrolysis.
Claim 40
Dependent Claim
77 words
The method of claim 35, wherein Ar is C 6 H 5 , Z is selected from the group consisting of C 6 H 5 and OC(CH 3 ) 3 , and further wherein said step of protecting the hydroxyl groups comprises reacting with a trialkylsilylhalide, and wherein said base catalyzed hydrolysis consists of reacting a 2',7-trialkylsilyl-protected derivative of said second compound in a mixture comprising aqueous sodium hydroxide, an organic solvent and a phase transfer catalyst.
Claim 41
Dependent Claim
15 words
The method of claim 36 wherein said phase transfer catalyst is a quaternary ammonium salt.
Claim 42
Dependent Claim
15 words
The method of claim 8 wherein said phase transfer catalyst is a quaternary ammonium salt.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2000-03-24 | 2000-09-23 | 2001-03-25 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2004-03-24 | 2004-09-23 | 2005-03-25 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2008-03-24 | 2008-09-23 | 2009-03-25 | $7700.00 | Window Closed / Lapsed |