WO1996040667B1 - Paclitaxel synthesis from precursor compounds and methods of producing the same - Google Patents
Paclitaxel synthesis from precursor compounds and methods of producing the sameInfo
- Publication number
- WO1996040667B1 WO1996040667B1 PCT/US1996/010228 US9610228W WO9640667B1 WO 1996040667 B1 WO1996040667 B1 WO 1996040667B1 US 9610228 W US9610228 W US 9610228W WO 9640667 B1 WO9640667 B1 WO 9640667B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- deprotecting
- side chain
- acylating
- protecting group
- replace
- Prior art date
Links
- 229930012538 Paclitaxel Natural products 0.000 title claims abstract 3
- 229960001592 paclitaxel Drugs 0.000 title claims abstract 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 title claims abstract 3
- 238000000034 method Methods 0.000 title claims 8
- 150000001875 compounds Chemical class 0.000 title claims 4
- 238000003786 synthesis reaction Methods 0.000 title abstract 2
- 230000015572 biosynthetic process Effects 0.000 title 1
- 239000002243 precursor Substances 0.000 title 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 7
- 229910052757 nitrogen Inorganic materials 0.000 claims 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 150000003512 tertiary amines Chemical class 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract 1
- 125000003834 baccatin III group Chemical group 0.000 abstract 1
Abstract
A semi-synthesis of taxol using a protected baccatin III backbone which is esterified with a suitably protected side chain acid.
Claims
1. A process of producing paclitaxel from an intermediate compound having the general formula:
Formula (a)
2. The process of claim 1 wherein the step of deprotecting at C-7 occurs before the removal of the hydrogenatable C-2' benzyl protecting group.
3. The process of claim 2 wherein the step of deprotecting and acylating the side chain nitrogen occurs before the step of deprotecting at C-7.
4. The process of claim 2 wherein the step of deprotecting at C-7 occurs before the step of deprotecting and acylating the side chain nitrogen.
5. The process of claim 1 wherein the step of deprotecting and acylating the side chain nitrogen is accomplished by dissolving the compound of Formula (a) in isopropanol and thereafter adding Pearlman's catalyst under a hydrogen atmosphere for a first interval of time to form a first mixture and thereafter reducing said first mixture to residue and taking up said residue in a solvent, adding a tertiary amine base and thereafter adding benzoyl chloride.
6. The process of claim 5 wherein said solvent is selected from a group consisting of ethyl acetate and toluene.
7. The process of claim 5 wherein the tertiary amine base is triethylamine.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9502252A JPH11513978A (en) | 1995-06-07 | 1996-06-07 | Synthesis of paclitaxel from its precursor compound and method for its production |
| EA199800031A EA000436B1 (en) | 1995-06-07 | 1996-06-07 | A process of producing paclitaxel |
| AT96918485T ATE209640T1 (en) | 1995-06-07 | 1996-06-07 | PACLITAXEL SYNTHESIS FROM PRECURSOR COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| EP96918485A EP0832080B9 (en) | 1995-06-07 | 1996-06-07 | Paclitaxel synthesis from precursor compounds and methods of producing the same |
| DE69617425T DE69617425T2 (en) | 1995-06-07 | 1996-06-07 | PACLITAXEL SYNTHESIS FROM PRECURSOR CONNECTIONS AND METHOD FOR THE PRODUCTION THEREOF |
| AU61131/96A AU706406B2 (en) | 1995-06-07 | 1996-06-07 | Paclitaxel synthesis from precursor compounds and methods of producing the same |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/483,084 US5675025A (en) | 1995-06-07 | 1995-06-07 | Paclitaxel synthesis from precursor compounds and methods of producing the same |
| US08/483,084 | 1995-06-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1996040667A1 WO1996040667A1 (en) | 1996-12-19 |
| WO1996040667B1 true WO1996040667B1 (en) | 1997-01-30 |
Family
ID=23918590
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1996/010228 WO1996040667A1 (en) | 1995-06-07 | 1996-06-07 | Paclitaxel synthesis from precursor compounds and methods of producing the same |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US5675025A (en) |
| EP (1) | EP0832080B9 (en) |
| JP (1) | JPH11513978A (en) |
| AT (1) | ATE209640T1 (en) |
| AU (1) | AU706406B2 (en) |
| CA (1) | CA2222989A1 (en) |
| DE (1) | DE69617425T2 (en) |
| EA (1) | EA000436B1 (en) |
| GE (1) | GEP19991748B (en) |
| WO (1) | WO1996040667A1 (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100225535B1 (en) * | 1996-08-27 | 1999-10-15 | 정지석 | Manufacturing method of paclitaxel |
| PT1019347E (en) * | 1997-08-21 | 2003-08-29 | Univ Florida State | METHOD FOR TAXAN SYNTHESIS |
| US6150537A (en) | 1997-12-12 | 2000-11-21 | Emory University | Methods for the esterification of alcohols and compounds useful therefor as potential anticancer agents |
| ES2230849T3 (en) | 1998-05-01 | 2005-05-01 | Tapestry Pharmaceuticals, Inc. | USEFUL PROCEDURES AND INTERMEDIARIES FOR THE SYNTHESIS OF PACLITAXEL FROM C-7, C-10 DI-CBZ BACATINA III. |
| US6066749A (en) * | 1998-05-01 | 2000-05-23 | Napro Biotherapeutics, Inc. | Method for conversion of C-2'-O-protected-10-hydroxy taxol to c-2'-O-protected taxol:useful intermediates in paclitaxel synthesis |
| US6048990A (en) * | 1998-05-01 | 2000-04-11 | Napro Biotherapeutics, Inc. | Method for selective acylation of C-2'-O-protected-10-hydroxy-taxol at the C-10 position |
| US6002025A (en) * | 1999-02-24 | 1999-12-14 | Bcm Developement Inc. | Method for the purification of taxanes |
| US6136999A (en) * | 1999-06-21 | 2000-10-24 | Napro Biotherapeutics, Inc. | C-2 hydroxyl protected-n-acyl (2R,3S)-3-phenylisoserine substituted phenyl activated esters and method for production thereof |
| US6143902A (en) * | 1999-06-21 | 2000-11-07 | Napro Biotherapeutics, Inc. | C-2 hydroxyl protected-N-acyl (2R,3S)-3-phenylisoserine N-imido activated esters and method for production thereof |
| US6452024B1 (en) | 2000-02-22 | 2002-09-17 | Chaichem Pharmaceuticals International | Process for extraction and purification of paclitaxel from natural sources |
| US6358996B1 (en) | 2000-06-09 | 2002-03-19 | Napro Biotherapeutics, Inc. | Stable isotope labeling of paclitaxel |
| AU2002254400B2 (en) * | 2001-03-23 | 2007-08-09 | Napro Biotherapeutics, Inc. | Molecular conjugates for use in treatment of cancer |
| US6452025B1 (en) * | 2001-04-25 | 2002-09-17 | Napro Biotherapeutics, Inc. | Three-step conversion of protected taxane ester to paclitaxel |
| US6653501B2 (en) | 2001-06-27 | 2003-11-25 | Napro Biotherapeutics, Inc. | Chiral resolution method for producing compounds useful in the synthesis of taxanes |
| US7981928B2 (en) | 2002-09-05 | 2011-07-19 | Nanodynamics, Inc. | Chemotherapy method using x-rays |
| EP1599457A4 (en) * | 2003-02-04 | 2008-05-07 | Natural Pharmaceuticals Inc | Method and composition for preparing a compound using a benzolating agent essentially free of ring chlorination |
| US6759539B1 (en) | 2003-02-27 | 2004-07-06 | Chaichem Pharmaceuticals International | Process for isolation and purification of paclitaxel from natural sources |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2601676B1 (en) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF TAXOL AND DESACETYL-10 TAXOL |
| FR2629818B1 (en) * | 1988-04-06 | 1990-11-16 | Centre Nat Rech Scient | PROCESS FOR THE PREPARATION OF TAXOL |
| FR2629819B1 (en) * | 1988-04-06 | 1990-11-16 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF BACCATIN III AND DESACETYL-10 BACCATIN III DERIVATIVES |
| US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
| US5015744A (en) * | 1989-11-14 | 1991-05-14 | Florida State University | Method for preparation of taxol using an oxazinone |
| US5136060A (en) * | 1989-11-14 | 1992-08-04 | Florida State University | Method for preparation of taxol using an oxazinone |
| FR2658513B1 (en) * | 1990-02-21 | 1994-02-04 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF CIS-BETA-PHENYLGLYCIDIC- (2R, 3R) ACID. |
| FR2680506B1 (en) * | 1991-08-19 | 1994-09-02 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF BETA-PHENYLISOSERIN DERIVATIVES AND THEIR USE. |
| FR2687150B1 (en) * | 1992-02-07 | 1995-04-28 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF TAXANE DERIVATIVES. |
-
1995
- 1995-06-07 US US08/483,084 patent/US5675025A/en not_active Expired - Fee Related
-
1996
- 1996-06-07 GE GEAP19964063A patent/GEP19991748B/en unknown
- 1996-06-07 EA EA199800031A patent/EA000436B1/en not_active IP Right Cessation
- 1996-06-07 DE DE69617425T patent/DE69617425T2/en not_active Expired - Fee Related
- 1996-06-07 CA CA002222989A patent/CA2222989A1/en not_active Abandoned
- 1996-06-07 EP EP96918485A patent/EP0832080B9/en not_active Expired - Lifetime
- 1996-06-07 AT AT96918485T patent/ATE209640T1/en not_active IP Right Cessation
- 1996-06-07 JP JP9502252A patent/JPH11513978A/en not_active Ceased
- 1996-06-07 WO PCT/US1996/010228 patent/WO1996040667A1/en active IP Right Grant
- 1996-06-07 AU AU61131/96A patent/AU706406B2/en not_active Ceased
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