Claims
- 1. Process for the preparation of taxane side chain precursors in which a cis-β-arylglycidate derivative of general formula I in whichAr represents an aryl radical and R represents a hydrocarbon radical, preferably a linear or branched alkyl or a cycloalkyl optionally substituted by one or more alkyl groups, is converted, so as to regio- and stereospecifically introduce the β-Nalkylamide and the (-hydroxyl or their cyclic precursors in a single stage by a Ritter reaction, which consists either:a of the direct synthesis of a linear chain by reacting a cis-β-arylglycidate derivative of general formula I defined above with a nitrile of formula R2—CN in whichR2 represents an aryl radical, in the presence of a protonic acid and of water, in order to obtain a β-arylisoserine derivative of general formula IIa, in which Ar, R and R2 are defined above; orb of the direct synthesis of a cyclic chain by reacting a cis-β-arylglycidate derivative of general formula I defined above with a nitrile of formula R′2—CN in whichR′2 represents R2 defined above or a lower alkyl or lower perhaloalkyl radical, such as trichloromethyl, in the presence of a Lewis acid or of a protonic acid, in anhydrous medium, in order to obtain the oxazoline of general formula IIb in which Ar, R and R′2 are defined above.
- 2. Process according to claim 1, characterized in that R represents an optically pure enantiomer of a highly sterically hindered chiral hydrocarbon radical.
- 3. Process according to claim 2, characterized in that R is one of the enantiomers of the menthyl radical, in particular (+)-menthyl.
- 4. Process according to one of claims 1 to 3, characterized in that the cis-β-phenylglycidate derivative of general formula I is of (2R,3R) configuration and the derivatives of general formulae IIa and IIb obtained are of (2R,3S) configuration.
- 5. Process according to claim 4, characterized in that Ar and R2 represent phenyl.
- 6. Process according to claim 1, characterized in that the protonic acid in stage a is chosen from sulfuric acid, perchloric acid, or tetrafluoroboric acid, the Lewis acid in stage b is chosen from the boron trifluoride acetic acid complex, boron trifluoride etherate, antimony pentachloride, tin tetrachloride, or titanium tetrachloride, and the protonic acid in stage b is tetrafluoroboric acid.
- 7. Process according to claim 1, characterized in that the β-arylisoserine derivative of general formula IIa is converted by protection of the hydroxyl by an appropriate protective group (GP), in order to obtain a derivative of general formula II′a in which Ar, R and R2 are defined in claim 1 and GP represents a protective group for the hydroxyl functional group which is appropriate for the synthesis of taxanes.
- 8. Process according to claim 1, characterized in that the β-arylisoserine derivative of general formula IIa is converted into a novel oxazolidinone cyclic intermediate of general formula IIIa in which Ar and R are defined in claim 1 by reacting a β-arylisoserine derivative of general formula IIa according to claim 1 with a haloalkoxycarbonyl ester, and then cyclized in the presence of a strong organic base, wherein the strong organic base is optionally diazabicycloundecene (DBU), and optionally converted subsequently into the corresponding amide of general formula III′a in which Ar and R are defined above and R″2 represents R′2 defined above, an alkoxy radical or a linear or branched alkyl radical comprising at least one unsaturation.
- 9. Process according to claim 1, characterized in that the oxazoline of general formula IIb is hydrolyzed in acidic medium in order to obtain the β-arylisoserine derivative of general formula IIIb, in which Ar, R and R′2 are defined above, and optionally converted subsequently into a corresponding amide of general formula III′b in which Ar, R, R′2 and R″2 are defined above.
- 10. Process according to claim 1, characterized in that the cis-β-arylglycidate derivative of general formula I in whichAr is as defined in claim 1 and R represents an optically pure enantiomer of a highly sterically hindered chiral hydrocarbon radical, is prepared by reacting the aldehyde of formulaAr—CHOwith the haloacetate of formulaX—CH2—COOR Ar and R being defined above and X representing a halogen.
- 11. Process according to any one of claims 1 to 3 and 6 to 10, characterized in that the derivatives of formulae IIa, II′a, IIb, IIIa, III′a, IIIb and III′b, in which R represents a hydrogen atom, are obtained by controlled saponification.
- 12. Precursor compounds of taxane side chains, characterized in that they are selected from the derivatives of following general formula IIb: in which Ar and R2 are defined in claim 1, and R represents an optically pure enantiomer of a highly sterically hindered chiral hydrocarbon radical.
- 13. Compounds according to claim 12, characterized in that R is one of the enantiomers of the menthyl radical, optionally (+)-menthyl.
- 14. Compounds according to either one of claim 12 or 13, characterized in that the cis-β-phenylglycidate derivative of general formula I is of (2R,3R) configuration, and the derivative of formula IIb is of (2R, 3S) configuration.
- 15. Precursor compounds of taxane side chains, characterized in that they are selected from the derivatives of following general formulae IIIa and III′a: in whichAr, R and R″2 are defined as in claim 1 or 8, or R represents a hydrogen atom.
- 16. Compounds according to claim 15, characterized in that they are of (2R,3S) configuration.
- 17. Process of claim 2, wherein the hydrocarbon radical is a cycloalkyl substituted by one or more alkyl groups.
- 18. Process of claim 17, wherein the cycloalkyl is a cyclohexyl.
- 19. Process of claim 7, wherein the protective group is selected from alkoxy ether, aralkoxy ether, aryloxy ether haloalkoxycarbonyl radicals.
- 20. Process of claim 19, wherein the haloalkoxycarbonyl radicals are selected from methoxymethyl, 1-ethoxyethyl, benzyloxymethyl or (β-trimethyl-silylethoxy) methyl groups, tetrahydropyranyl radicals, β-alkoxycarbonyl radicals, β-halogenated ethers, alkylsilyl ethers, and alkoxyacetyl, aryloxyacetyl, haloacetyl or formyl radicals.
- 21. Process of claim 10, wherein the halogen is chlorine or bromine.
- 22. Process according to claim 4, characterized in that the derivatives of formulae IIa, II′a, IIb, IIIa, III′a, IIIb and III′b, in which R represents a hydrogen atom, are obtained by controlled saponification.
- 23. Process according to claim 5, characterized in that the derivatives of formulae IIa, II′a, IIb, IIIa, III′a, IIIb and III′b, in which R represents a hydrogen atom, are obtained by controlled saponification.
Priority Claims (1)
Number |
Date |
Country |
Kind |
95/12739 |
Oct 1995 |
FR |
|
Parent Case Info
This application is a 371 of PCT/FR96/01679, dated Oct. 25, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/FR96/01676 |
|
WO |
00 |
4/27/1998 |
4/27/1998 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/15562 |
5/1/1997 |
WO |
A |
US Referenced Citations (3)
Number |
Name |
Date |
Kind |
4876399 |
Holton et al. |
Oct 1989 |
|
5463106 |
Correa et al. |
Oct 1995 |
|
5578739 |
Hittinger |
Nov 1996 |
|
Foreign Referenced Citations (2)
Number |
Date |
Country |
WO9113066 |
Sep 1991 |
WO |
WO9310076 |
May 1993 |
WO |