Process for the stereoselective preparation of phenylisoserine derivatives used in making taxols

• US 5,290,957 A
• Filed: 11/20/1992
• Issued: 03/01/1994
• Est. Priority Date: 05/22/1990
• Status: Expired due to Fees

• Current Assignee: Rhone-Poulenc Rorer S.A.
• Original Assignee: Rhone-Poulenc SA (Sanofi )
• Inventors: Correa, Arlene, Denis, Jean-Noel, Greene, Andrew-Elliot
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US07/949,548
• Time in Patent Office: 466 Days
• Field of Search: 549/510, 560/29, 562/418, 562/444
• US Class Current: 549/510
• CPC Class Codes: C07C 231/18 by stereospecific synthesis
• CPC Class Codes: C07C 269/06 by reactions not involving the formation of carbamate groups
• CPC Class Codes: C07D 305/14 condensed with carbocyclic rings or ring systems
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A stereoselective process for preparing phenylisoserine derivatives is disclosed. Benzylamine is reacted with an agent for introducing a phenyl or a t-butoxycarbonyl group. The product undergoes double anionization and then is reacted with acrolein to provide a mixture of alcohol syn and anti diasteroisomers. The syn isomer is isolated by chromatography. Whereupon, the hydroxyl is protected and the product is oxidized to provide the phenylisoserine derivative.

Claims

1. Process for the stereoselective preparation of phenylisoserine derivatives of formula ##STR7## in which R is a phenyl or tert-butoxy radical and R₁ is a protecting group for the hydroxyl group, comprising treating benzylamine with an agent for introducing a benzoyl or t-butoxycarbonyl group to give the product of formula ##STR8## which, after double anionization, is reacted with acrolein to give the alcohol of formula ##STR9## in the form of a syn and anti mixture, from which the syn form:

##STR10## is separated, the hydroxyl group of said syn form is protected and the alcohol protected in this way is then oxidized to give the phenylisoserine derivative of formula (I) in the syn form, which is optionally separated into enantiomers.

2. Process according to claim 1, wherein the agent for introducing the benzoyl or t-butoxycarbonyl group is benzoyl chloride or di-t-butyl dicarbonate, which is reacted with benzylamine in an inert organic solvent, in the presence of an inorganic base, or an organic base.

3. Process according to claim 1, wherein acrolein is reacted with N-benzylbenzamide or t-butyl benzylcarbamate, previously anionized by reaction with 2 equivalents of an organolithium derivative, in an inert organic solvent, at a temperature of about -100°

C.

4. Process according to claim 1, wherein the hydroxyl group of the alcohol is protected in accordance with known methods and the protected alcohol is then oxidized by means of an oxidizing agent selected from sodium periodate in the presence of a catalytic amount of a ruthenium derivative, or potassium permanganate.

6. Process according to claim 2, wherein the inorganic base is sodium hydroxide or sodium bicarbonate or carbonate.

7. Process according to claim 2 wherein the organic base is triethylamine or 4-dimethylaminopyridine.

8. Process according to claim 3, wherein the organolithium derivative is s-butyllithium.

9. Process according to claim 3, wherein the inert organic solvent is tetrahydrofuran.

10. Process according to claim 2, wherein the organic solvent is methylene chloride.

5. Process for the preparation of baccatin III and 10-deacetylbaccatin III derivatives of formula ##STR11## in which R is a phenyl radical or a tert-butoxy radical and R₂ is a hydrogen atom or an acetyl radical, comprising treating benzylamine with an agent for introducing a benzoyl or t-butoxycarbonyl group, to obtain the product of formula ##STR12## which, after double anionization, is reacted with acrolein to give the alcohol of the formula ##STR13## in the form of a syn and anti mixture, from which the syn form:

##STR14## is separated, the hydroxyl group of said syn form is protected and the alcohol protected in this way is then oxidized to give the phenylisoserine derivative of formula;

##STR15## in which R₁ is a protecting group for the hydroxyl group, in the syn form, the enantiomers of which are optionally separated, and which is reacted with a taxane derivative of formula ##STR16## in which R₃ is an acetyl radical or a protecting group for the hydroxyl group and R₄ is a protecting group for the hydroxyl group, and then the product of formula (II) is isolated after replacing the protecting groups R₁ and R₄ with hydrogen atoms and optionally replacing R₃ with a hydrogen atom.