Method for preparing taxane derivatives
Provided is a method for preparing a taxane derivative, comprising: carrying out condensation of a phenylisoserine derivatives having a protective group introduced thereto or a mixture of isomers thereof, as a side chain, with a baccatin III derivative or 10-deacetyl-baccatin III derivative to obtain a mixture of isomers; separating the isomers via chromatography; and carrying out a reversion of the stereochemical structure of a selectively separated isomer, which is suitable for producing a taxane derivative in a large scale with high yield.
1. A method for preparing a taxane derivative represented by the following Chemical Formula (I), comprising the steps of:
1) carrying out condensation of a side chain with baccatin III represented by the following Chemical Formula III or 10-deacetyl-baccatin III derivative, having protective group(s) introduced to 7-hydroxyl group and/or 10-hydroxyl group, to obtain a mixture of a compound represented by the following Chemical Formula IVa with a compound represented by the following Chemical Formula IVb, wherein the side chain is selected from a (2R,3S)-phenylisoserine derivative, represented by the following Chemical Formula IIa and having protected groups introduced to 2-hydroxyl group and 3-amino group, and a mixture of the derivative with an isomer thereof, a (2S,3S)-phenylisoserine derivative, represented by the following Chemical Formula IIb;
2) deprotecting the side chain of the mixture (IVa, IVb) obtained from step 1) at C-2 position thereof to obtain a mixture of a compound represented by the following Chemical Formula Va with a compound represented by the following Chemical Formula Vb;
3) separating the mixture (Va, Vb) obtained from step 2) via chromatography to obtain each isomer compound;
4) carrying out a stereochemical reversion of one isomer compound (Vb) in the compounds obtained from step 3) into the other isomer compound (Va); and
5) deprotecting the isomer compound (Va) obtained from steps 3) and 4) at C-7 and/or C-10 position thereof to obtain a taxane derivative represented by the following Chemical Formula I:
wherein R 1 and R 2 are independently acetyl (Ac), tert-butyldimethylsilyl (TBS), triethylsilyl (TES), ethoxyethyl (EE), or 2,2,2-trichloroethoxycarbonyl (Troc);
R 3 is benzoyl (Bz) or tert-butoxycarbonyl (Boc);
R 4 is Ac, TBS, TES, EE, or Troc;
R 1 ′ is Ac or H; and
Ph is phenyl.
2. A method for preparing a taxane derivative represented by the following Chemical Formula (I), comprising the steps of:
1) carrying out condensation of a side chain with baccatin III represented by Chemical Formula III or 10-deacetyl-baccatin III derivative, having protective group(s) introduced to 7-hydroxyl group and/or 10-hydroxyl group, to obtain a mixture of a compound represented by Chemical Formula IVa with a compound represented by Chemical Formula IVb, wherein the side chain is selected from a (2R,3S)-phenylisoserine derivative, represented by Chemical Formula IIa and having protected groups introduced to 2-hydroxyl group and 3-amino group, and a mixture of the derivative with an isomer thereof, a (2S,3S)-phenylisoserine derivative, represented by Chemical Formula IIb;
2) separating the mixture (IVa, IVb) obtained from step 1) via chromatography to obtain each isomer compound;
3) deprotecting the side chain of each isomer compound obtained from step 2) at C-2 position thereof to obtain a compound represented by Chemical Formula Va and a compound represented by Chemical Formula Vb;
4) carrying out a stereochemical reversion of one isomer compound (Vb) in the compounds obtained from step 3) into the other isomer compound (Va); and
5) deprotecting the isomer compound (Va) obtained from steps 3) and 4) at C-7 and/or C-10 position thereof to obtain a taxane derivative represented by Chemical Formula I:
wherein R 1 , R 2 , R 3 , R 4 , R 1 ′ and Ph are the same as defined in claim 1 .
3. A method for preparing a taxane derivative represented by the following Chemical Formula (I), comprising the steps of:
1) carrying out condensation of a side chain with baccatin III represented by Chemical Formula III or 10-deacetyl-baccatin III derivative, having protective group(s) introduced to 7-hydroxyl group and/or 10-hydroxyl group, to obtain a mixture of a compound represented by Chemical Formula IVa with a compound represented by Chemical Formula IVb, wherein the side chain is selected from a (2R,3S)-phenylisoserine derivative, represented by Chemical Formula IIa and having protected groups introduced to 2-hydroxyl group and 3-amino group, and a mixture of the derivative with an isomer thereof, a (2S,3S)-phenylisoserine derivative, represented by Chemical Formula IIb;
2) deprotecting the mixture (IVa, IVb) obtained from step 1) at C-7 and/or C-10 position thereof to obtain a mixture of a compound represented by the following Chemical Formula VIa with a compound represented by the following Chemical Formula VIb;
3) separating the mixture (VIa, VIb) obtained from step 2) via chromatography to obtain each isomer compound;
4) deprotecting the side chain of each isomer compound obtained from step 3) at C-2 position thereof; and
5) carrying out a stereochemical reversion of one isomer compound having a (2S,3S)-side chain in the compounds obtained from step 4) into the other isomer compound having a (2R,3S)-side chain to obtain a taxane derivative represented by Chemical Formula I:
wherein R 1 , R 2 , R 3 , R 4 , R 1 ′ and Ph are the same as defined in claim 1 .
4. The method for preparing a taxane derivative according to claim 1 , wherein the side chain in step 1) is a racemic mixture of (2R,3S)-phenylisoserine derivative (IIa) with (2S,3S)-phenylisoserine derivative (IIb).
5. The method for preparing a taxane derivative according to claim 1 , wherein the chromatography is carried out in a normal phase chromatography mode using a column packed with silica gel having a particle diameter of 5-120 micrometers (μm).
6. The method for preparing a taxane derivative according to claim 1 , wherein the stereochemical reversion is carried out by reacting the mixture of isomers with triphenylphosphine and diethylazodicarboxylate or di-tert-butylazodicarboxylate in the presence of an organic solvent.
7. The method for preparing a taxane derivative according to claim 1 , wherein the taxane derivative is docetaxel or paclitaxel.
8. The method for preparing a taxane derivative according to claim 2 , wherein the side chain in step 1) is a racemic mixture of (2R,3S)-phenylisoserine derivative (IIa) with (2 S,3S)-phenylisoserine derivative (IIb).
9. The method for preparing a taxane derivative according to claim 2 , wherein the chromatography is carried out in a normal phase chromatography mode using a column packed with silica gel having a particle diameter of 5-120 micrometers (μm).
10. The method for preparing a taxane derivative according to claim 2 , wherein the stereochemical reversion is carried out by reacting the mixture of isomers with triphenylphosphine and diethylazodicarboxylate or di-tert-butylazodicarboxylate in the presence of an organic solvent.
11. The method for preparing a taxane derivative according to claim 2 , wherein the taxane derivative is docetaxel or paclitaxel.
12. The method for preparing a taxane derivative according to claim 3 , wherein the side chain in step 1) is a racemic mixture of (2R,3S)-phenylisoserine derivative (IIa) with (2S,3S)-phenylisoserine derivative (IIb).
13. The method for preparing a taxane derivative according to claim 3 , wherein the chromatography is carried out in a normal phase chromatography mode using a column packed with silica gel having a particle diameter of 5-120 micrometers (μm).
14. The method for preparing a taxane derivative according to claim 3 , wherein the stereochemical reversion is carried out by reacting the mixture of isomers with triphenylphosphine and diethylazodicarboxylate or di-tert-butylazodicarboxylate in the presence of an organic solvent.
15. The method for preparing a taxane derivative according to claim 3 , wherein the taxane derivative is docetaxel or paclitaxel.