Claims
- 1. A method of preparing (2R,3S)-3-benzoyl-2-hydroxy-3-phenylpropionate of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-7β-methylthiomethyloxy-9-oxo-tax-11-ene, formula (XXXIV),
- 2. The method according to claim 1, wherein said baccatin III is reacted in a Pummerer reaction to obtain said methylthiomethyl-baccatin III derivative.
- 3. The method according to claim 1, wherein said baccatin III is reacted with dimethyl sulfide and benzoyl peroxide to obtain said methylthiomethyl-baccatin III derivative.
- 4. The method according to claim 2, wherein the alkali metal or alkaline earth metal base is at least one compound selected from sodium hexamethyl-disilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), lithium hexamethyldisilazide (LiHMDS), potassium diisopropylamide (KDA), lithium diisopropylamide (LDA), sodium hydride (NaH), potassium hydride (KH), lithium hydride (LiH), calcium hydride (CaH2) I magnesium hydride (MgH2), and n-butylLi.
- 5. The method according to claim 4, wherein said at least one compound is a hexamethyl disilazide.
- 6. The method according to claim 5, wherein said hexamethyl disilazide is sodium hexamethyl disilazide, and R is Na.
- 7. The method according to claim 6, wherein G1 is selected from methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), trialkylsilyl, triphenylmethyl (trityl), TIPSO, tert-butoxycarbonyl (t-BOC), ethoxyethyl (EE), f-MOC, and TROC.
- 8. The method according to claim 7, wherein G1 is ethoxyethyl.
- 9. The method according to claim 5, wherein said hexamethyl disilazide is lithium hexamethyl disilazide, and R is Li.
- 10. The method according to claim 9, wherein G1 is selected from methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), trialkylsilyl, triphenylmethyl (trityl), tert-butoxycarbonyl (t-BOC), ethoxyethyl (EE), f-MOC, and TROC.
- 11. The method according to claim 10, wherein G1 is ethoxyethyl.
- 12. The method according to claim 3, wherein the alkali metal or alkaline earth metal base is at least one compound selected from sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), lithium hexamethyldisilazide (LiHMDS), potassium diisopropylamide (KDA), lithium diisopropylamide (LDA), sodium hydride (NaH), potassium hydride (KH), lithium hydride (LiH), calcium hydride (CaH2) I magnesium hydride (MgH2), and n-butylLi.
- 13. The method according to claim 12, wherein said at least one compound is a hexamethyl disilazide.
- 14. The method according to claim 13, wherein said hexamethyl disilazide is sodium hexamethyl disilazide, and R is Na.
- 15. The method according to claim 14, wherein G1 is selected from methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), trialkylsilyl, triphenylmethyl (trityl), tert-butoxycarbonyl (t-BOC), ethoxyethyl (EE), f-MOC, and TROC.
- 16. The method according to claim 15, wherein G1 is ethoxyethyl.
- 17. The method according to claim 13, wherein said hexamethyl disilazide is lithium hexamethyl disilazide, and R is Li.
- 18. The method according to claim 17, wherein G1 is selected from methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), trialkylsilyl, triphenylmethyl (trityl), tert-butoxycarbonyl (t-BOC), ethoxyethyl (EE), f-MOC, and TROC.
- 19. The method according to claim 18, wherein G1 is ethoxyethyl.
- 20. A method of preparing (2R,3S)-3-benzoyl-2-hydroxy-3-phenylpropionate of 4,10β-diacetoxy-2a-benzoyloxy-5β,20-epoxy-1,13a-dihydroxy-7β-methylthiomethyloxy-9-oxo-tax-11-ene, formula (XXXIV)
- 21. The method according to claim 20, wherein said protected taxoid is reacted in a Pummerer reaction to obtain said methylthiomethyloxy-paclitaxel derivative.
- 22. The method according to claim 20, wherein said protected taxoid is reacted with dimethyl sulfide and benzoyl peroxide to obtain said methylthiomethyloxy-paclitaxel derivative.
- 23. The method according to claim 20, wherein the alkali metal or alkaline earth metal base is at least one compound selected from sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), lithium hexamethyldisilazide (LiHMDS), potassium diisopropylamide (KDA), lithium diisopropylamide (LDA), sodium hydride (NaH), potassium hydride (KH), lithium hydride (LiH), calcium hydride (CaH2), magnesium hydride (MgH2), and n-butylLi.
- 24. The method according to claim 15, wherein said at least one compound is a hexamethyl disilazide.
- 25. The method according to claim 16, wherein said hexamethyl disilazide is sodium hexamethyl disilazide, and R is Na.
- 26. The method according to claim 17, wherein G1 is selected from methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), trialkylsilyl, triphenylmethyl (trityl), tert-butoxycarbonyl (t-BOC), ethoxyethyl (EE), f-MOC, and TROC.
- 27. The method according to claim 26, wherein G1 is ethoxyethyl.
- 28. The method according to claim 16, wherein said hexamethyl disilazide is lithium hexamethyl disilazide, and R is Li.
- 29. The method according to claim 28, wherein G1 is selected from methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), trialkylsilyl, triphenylmethyl (trityl), tert-butoxycarbonyl (t-BOC), ethoxyethyl (EE), f-MOC, and TROC.
- 30. The method according to claim 29, wherein G1 is ethoxyethyl.
- 31. The method according to claim 21, wherein the alkali metal or alkaline earth metal base is at least one compound selected from sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), lithium hexamethyldisilazide (LiHMDS), potassium diisopropylamide (KDA), lithium diisopropylamide (LDA), sodium hydride (NaH), potassium hydride (KH), lithium hydride (LiH), calcium hydride (CaH2), magnesium hydride (MgH2), and n-butylLi.
- 32. The method according to claim 31, wherein said at least one compound is a hexamethyl disilazide.
- 33. The method according to claim 32, wherein said hexamethyl disilazide is sodium hexamethyldisilazide, and R is Na.
- 34. The method according to claim 33, wherein G1 is selected from methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), trialkylsilyl, triphenylmethyl (trityl), tert-butoxycarbonyl (t-BOC), ethoxyethyl (EE), f-MOC, and TROC.
- 35. The method according to claim 34, wherein G1 is ethoxyethyl.
- 36. The method according to claim 32, wherein said hexamethyldisilazide is lithium hexamethyldisilazide, and R is Li.
- 37. The method according to claim 36, wherein G1 is selected from methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), trialkylsilyl, triphenylmethyl (trityl), tert-butoxycarbonyl (t-BOC), ethoxyethyl (EE), f-MOC, and TROC.
- 38. The method according to claim 37, wherein G1 is ethoxyethyl.
- 39. A method of preparing a methylthiomethyl-paclitaxel derivative, comprising:
metalizing a methylthiomethyloxy-baccatin III derivative with an alkali metal or alkaline earth metal base, to produce a metalized methylthiomethyl-baccatin III derivative of formula (A), wherein R is an alkali metal or alkaline earth metal; coupling a 7-methylthiomethyl-baccatin III derivative with with a β-lactam, wherein said β-lactam comprises a lactam of formula 46wherein Y is oxygen; G1 is an hydroxyl protecting group; R2″ is phenyl; and R3″ is phenyl; producing a 2′-protected methylthiomethyl-paclitaxel derivative; and optionally deprotecting said 2′-protected methylthiomethyl-paclitaxel derivative.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part of U.S. patent application Ser. No. 09/528,448, filed Mar. 17, 2000; which is a continuation-in-part of U.S. patent application Ser. No. 09/271,300, filed Mar. 17, 1999, now U.S. Pat. No. 6,040,466; which is a continuation-in-part of U.S. patent application Ser. No. 08/913,972, filed Sep. 26, 1997, now U.S. Pat. No. 5,889,043; and a continuation of PCT/FR96/00441, filed Mar. 25, 1996.
[0002] U.S. patent application Ser. No. 09/528,448, filed Mar. 17, 2000, in turn is also a continuation-in-part of U.S. patent application Ser. No. 09/516,019, filed Feb. 29, 2000, now U.S. Pat. No. 6,218,553; which is a divisional of Ser. No. 08/481,205, filed Jun. 7, 1995; now U.S. Pat. No. 6,187,916; which is a continuation of Ser. No. 08/383,610, filed Feb. 2, 1995, now abandoned; which is a continuation of Ser. No. 08/011,922, filed Feb. 1, 1993, now abandoned. All of these patents and applications are hereby specifically incorporated herein by reference in their entirety.
Divisions (1)
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08481205 |
Jun 1995 |
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09516019 |
Feb 2000 |
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Continuations (2)
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Continuation in Parts (5)
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08913972 |
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PCT/FR96/00441 |
Mar 1996 |
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09271300 |
Mar 1999 |
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