EP0552041A2
Expired / Lapsed
EP
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Enzymatic processes for resolution of enantiomeric mixtures of compounds useful as intermediates in the preparation of taxanes
Assignee: ER Squibb and Sons LLC
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Filing: 1993-01-15
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Granted: —
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Expires: 2013-01-15
Abstract
Abstract Methods for the enzymatic resolution of mixtures of enantiomers, such as beta -lactam compounds, which may be employed as intermediates in the preparation of taxanes such as taxol, the latter useful in the pharmaceutical field.
Inventors
- 👤 Ramesh N. Patel
- 👤 Laszlo J. Szarka
- 👤 Richard A. Partyka
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-29 21:43
CPC Classifications
C; C12; C12P; C12P13/00; C12P13/001; C07; C07D; C07D205/00; C07D205/02; C07D205/06; C07D205/08; C07D305/00; C07D305/14; C12P13/02; C12P17/00; C12P17/10; C12P41/00; C12P41/003; C12P41/004; C12P41/005; C07B; C07B2200/00; C07B2200/07
Claims Analysis
Total Claims: 20
Claim 1
Independent Claim
141 words
A method for the resolution of a mixture I comprising the enantiomers Ia and Ib, where R¹ is in the cis position relative to R² in both Ia and Ib, or where R¹ is in the trans position relative to R² in both Ia and Ib: where R¹ is hydroxyl; halo; or -O-C(O)-R⁴ where R⁴ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl or heterocyclo; R² is aryl; alkyl; alkenyl; or alkynyl; R³ is hydrogen; R⁴; -C(O)-OR⁴; or -C(O)-R⁴ where R⁴ is independently selected from those groups recited for R⁴ above; comprising the step of contacting said mixture I with an enzyme or microorganism capable of catalyzing the stereoselective conversion of one of said compounds Ia or Ib to a non-enantiomeric form, and effecting said conversion, and wherein, optionally, protection and deprotection of the compounds of said mixture I may be employed.
Claim 2
Dependent Claim
19 words
The method of claim 1, wherein said stereoselective conversion is selected from stereoselective hydrolysis, stereoselective esterification and stereoselective dehalogenation.
Claim 3
Dependent Claim
17 words
The method of claim 2, wherein said stereoselective conversion is selected from stereoselective hydrolysis and stereoselective esterification.
Claim 4
Dependent Claim
269 words
The method of claim 1, wherein a mixture I comprising the enantiomers Ia(1) and Ib(1) is resolved: to form a mixture II comprising the compounds IIa(1) and IIb(1): comprising one of the following steps (i), (ii), or (iii): (i) where R¹ is -O-C(O)-R⁴, and R⁴ is independently selected from those groups recited for R⁴ above; and one of R 1a or R 1b is the same as R¹ and the other of R 1a or R 1b is hydroxyl; the step of contacting said mixture I, in the presence of water and/or an organic alcohol, with an enzyme or microorganism capable of catalyzing the stereoselective hydrolysis of mixture I to provide said mixture II; or (ii) where R¹ is hydroxyl; and one of R 1a or R 1b is hydroxyl and the other of R 1a or R 1b is R⁴-C(O)-O-, and R⁴ is independently selected from those groups recited for R⁴ above; the step of contacting said mixture I, in the presence of a compound III: R⁴-C(O)-L (III) where R⁴ is as defined above for R 1a or R 1b and L is a leaving group, with an enzyme or microorganism capable of catalyzing the stereoselective esterification of mixture I to provide said mixture II; or (iii) where R¹ is a halogen atom; and one of R 1a or R 1b is halogen and the other of R 1a or R 1b is hydroxyl; the step of contacting said mixture I, in the presence of a hydroxide ion donor, with an enzyme or microorganism capable of catalyzing the stereoselective dehalogenation of mixture I to provide said mixture II.
Claim 5
Dependent Claim
37 words
The method of claim 3, wherein a mixture I is employed which comprises Ia(1) and Ib(1) : where R¹ is alkanoyloxy or hydroxy; R² is phenyl or substituted phenyl; and R³ is hydrogen, phenyl or substituted phenyl.
Claim 6
Dependent Claim
13 words
The method of claim 5, wherein an esterase, lipase or protease is employed.
Claim 7
Independent Claim
353 words
A method for the resolution of a mixture IV comprising the enantiomers IVa and IVb: R²-T a -C(O)-OR⁶ (IVa) and R²-T b -C(O)-OR⁶ (IVb) where T a is and T b is T a is and T b is where R¹ is in the erythro position relative to the group W in both IVa and IVb, or R¹ is in the threo position relative to the group W in both IVa and IVb; W is -NHR³ or -N₃ ; R¹ is hydroxyl; halo; or -O-C(O)-R⁴ where R⁴ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl or heterocyclo; R² is aryl; alkyl; alkenyl; or alkynyl; R³ is hydrogen; R⁴; -C(O)-OR⁴; or -C(O)-R⁴ where R⁴ is independently selected from those groups recited for R⁴ above; R⁶ is hydrogen; or R⁴ where R⁴ is independently selected from those groups recited for R⁴ above; comprising the step of contacting said mixture IV with an enzyme or microorganism capable of catalyzing the stereoselective conversion of one of said compounds IVa or IVb to a non-enantiomeric form, and effecting said conversion and wherein, optionally, protection and deprotection of the compounds of said mixture IV may be employed; with the provisos that: (i) when T a is T b is and R² is phenyl: stereoselective esterification with lipase and vinyl acetate is not conducted when R¹ is hydroxyl, W is butanoylamino and R⁶ is ethyl, and stereoselective hydrolysis with lipase is not conducted when R¹ is butanoyloxy, W is butanoylamino and R⁶ is ethyl or when R¹ is butanoyloxy, W is -N₃ and R⁶ is methyl or ethyl; (ii) when T a is T b is and R² is phenyl: stereoselective esterification with lipase from Pseudomonas fluorescens and acetic anhydride is not conducted when R¹ is hydroxyl, W is -N₃ and R⁶ is methyl, and stereoselective hydrolysis with lipase is not conducted when W is -N₃, R⁶ is methyl and R¹ is R⁴-C(O)-O- where R⁴ is methyl, chloromethyl, butyl, isobutyl, octyl or cyclohexyl or when W is -N₃, R⁶ is ethyl and R¹ is butanoyloxy; and (iii) N-acetyl- or N-haloacetyl-β-phenylserine is not stereoselectively hydrolyzed to β-phenylserine with acylase I or carboxypeptidase.
Claim 8
Dependent Claim
270 words
The method of claim 7, wherein a mixture IV comprising the enantiamers IVa(1) and IVb(1) is resolved: to form a mixture V comprising compounds Va(1) and Vb(1) : comprising one of the following steps (i), (ii), or (iii) : (i) where R¹ is -O-C(O)-R⁴, and R⁴ is independently selected from those groups recited for R⁴ above; and one of R 1a or R 1b is the same as R¹ and the other of R 1a or R 1b is hydroxyl; the step of contacting said mixture IV, in the presence of water and/or an organic alcohol, with an enzyme or microorganism capable of catalyzing the stereoselective hydrolysis of mixture IV to provide said mixture V; or (ii) where R¹ is hydroxyl; and one of R 1a or R 1b is hydroxyl and the other of R 1a or R 1b is R⁴-C(O)-O-, and R⁴ is independently selected from those groups recited for R⁴ above; the step of contacting said mixture IV, in the presence of a compound III: R⁴-C(O)-L (III) where R⁴ is as defined above for R 1a or R 1b and L is a leaving group, with an enzyme or microorganism capable of catalyzing the stereoselective esterification of mixture IV to provide said mixture V; or (iii) where R¹ is a halogen atom; and one of R 1a or R 1b is halogen and the other of R 1a or R 1b is hydroxyl; the step of contacting said mixture IV, in the presence of a hydroxide ion donor, with an enzyme or microorganism capable of catalyzing the stereoselective dehalogenation of mixture IV to provide said mixture V.
Claim 9
Dependent Claim
308 words
The method of claim 7, wherein a mixture IV comprising the enantiomers IVa(1) and IVb(1) is resolved: to form a mixture VI comprising compounds VIa(1) and VIb(1) : comprising one of the following steps (i), (ii), or (iii): (i) where R⁶ is hydrogen; and one of R 6a or R 6b is hydrogen and the other of R 6a or R 6b is R⁴ where R⁴ is independently selected from those groups recited for R⁴ above; the step of contacting said mixture IV, in the presence of an organic alcohol of the formula VII: R⁴-OH (VII) where R⁴ is as defined above for R 6a or R 6b , with an enzyme or microorganism capable of catalyzing the stereoselective esterification of mixture IV to provide said mixture VI; or (ii) where R⁶ is R⁴ and R⁴ is independently selected from those groups recited for R⁴ above; and one of R 6a or R 6b is the same as R⁶ and the other of R 6a or R 6b is hydrogen; the step of contacting said mixture IV, in the presence of water, with an enzyme or microorganism capable of catalyzing the stereoselective hydrolysis of mixture IV to provide said mixture VI; or (iii) where R⁶ is R⁴ and R⁴ is independently selected from those groups recited for R⁴ above; and one of R 6a or R 6b is the same as R⁶ and the other of R 6a or R 6b is R⁷, where R⁷ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl or heterocyclo, except that R⁷ is not the same as R⁶; the step of contacting said mixture IV, in the presence of an organic alcohol of the formula VIII: R⁷-OH (VIII) where R⁷ is as defined above, with an enzyme or microorganism capable of catalyzing the stereoselective transesterification of mixture IV to provide said mixture VI.
Claim 10
Dependent Claim
32 words
The method of claim 4, wherein R¹ is acetyloxy; R² is phenyl; R³ is hydrogen; R 1a is acetyloxy; and R 1b is hydroxyl; and wherein stereoselective hydrolysis employing lipase is conducted.
Claim 11
Dependent Claim
56 words
The method of claim 10, wherein said lipase is selected from lipase PS-30 from Pseudomonas sp., lipase P-30 from Pseudomonas sp., lipase GC-20 from Geotrichum candidum , lipase N from Rhizopus niveus , lipase APF from Aspergillus niger , lipase AY-30 from Candida sp., lipase AK from Pseudomonas sp., Pseudomonas fluorescens lipase and porcine pancreatic lipase.
Claim 12
Dependent Claim
32 words
The method of claim 4, wherein R¹ is acetyloxy; R² is phenyl; R³ is methoxyphenyl; R 1a is acetyloxy; and R 1b is hydroxyl; and wherein stereoselective hydrolysis employing lipase is conducted.
Claim 13
Dependent Claim
14 words
The method of claim 12, wherein said lipase is lipase PS-30 from Pseudomonas sp.
Claim 14
Dependent Claim
32 words
The method of claim 4, wherein R¹ is hydroxyl; R² is phenyl; R³ is hydrogen; R 1a is acetyloxy; and R 1b is hydroxyl; and wherein stereoselective esterification with lipase is employed.
Claim 15
Dependent Claim
15 words
The method of claim 14, wherein a compound III which is isopropenyl acetate is employed.
Claim 16
Dependent Claim
33 words
The method of claim 14, wherein said lipase is selected from lipase P-30 from Pseudomonas sp., lipase GC-20 from Geotrichum candidum, lipase AY-30 from Candida sp., and lipase N from Rhizopus niveus .
Claim 17
Independent Claim
18 words
The method of any preceding claim, wherein, further, the non-enantiomeric compounds obtained are separated by a separation step.
Claim 18
Dependent Claim
18 words
The method of claim 17, wherein said separation step is an extraction, distillation, crystallization, or column chromatography step.
Claim 19
Independent Claim
21 words
The method of any preceding claim, wherein a compound obtained by said method is employed in the preparation of a taxane.
Claim 20
Dependent Claim
10 words
The method of claim 19, wherein said taxane is taxol.
References Cited (Backward Citations)
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