CN1058497C - 7－三烷基甲硅烷基浆果赤霉素ⅲ的制备方法 - Google Patents
7－三烷基甲硅烷基浆果赤霉素ⅲ的制备方法 Download PDFInfo
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- CN1058497C CN1058497C CN95192429A CN95192429A CN1058497C CN 1058497 C CN1058497 C CN 1058497C CN 95192429 A CN95192429 A CN 95192429A CN 95192429 A CN95192429 A CN 95192429A CN 1058497 C CN1058497 C CN 1058497C
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- baccatin iii
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- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)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)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 title claims abstract description 59
- 229930014667 baccatin III Natural products 0.000 title claims abstract description 28
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 238000003381 deacetylation reaction Methods 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- -1 aliphatic ester Chemical class 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 150000004075 acetic anhydrides Chemical class 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epoxy Compounds (AREA)
- Silicon Compounds (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Saccharide Compounds (AREA)
- Liquid Deposition Of Substances Of Which Semiconductor Devices Are Composed (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Internal Circuitry In Semiconductor Integrated Circuit Devices (AREA)
- Silicon Polymers (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Processes Of Treating Macromolecular Substances (AREA)
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Abstract
由10-脱乙酰基浆果赤霉素III制备7-三烷基甲硅烷基浆果赤霉素III的方法。
Description
本发明涉及一种具有下述通式(I)的7-三烷基甲硅烷基浆果赤霉素III的新的制备方法：
式中符号R可相同或不相同，它代表含有1-4个碳原子的，或许由苯基取代的烷基，所述的7-三烷基甲硅烷基浆果赤霉素III是由具有下述通式的10-脱乙酰基浆果赤霉素III制备的：
在通式(I)中，优选地，这些符号R中的每一个都表示含有1-4个碳原子的直链或支化的烷基。更优选地，这些符号R中的每一个都表示乙基。
具体地由J-N.Denis和A.E.Greene，J.Amer.Chem.Soc.，110，5917-5919(1998)人们知道，以化学式(II)的10-脱乙酰基浆果赤霉素III作为原料，通过首先使塔三烷(taxane)环的7-位选择性甲硅烷基化，得到7-三烷基甲硅烷基-10-脱乙酰基浆果赤霉素III，然后使如此得到的7-三烷基甲硅烷基-10-脱乙酰基浆果赤霉素III在10位选择性乙酰化，制备出通式(I)的产品。
根据已知的方法，用过量的下述通式的三烷基甲硅烷基卤处理10-脱乙酰基浆果赤霉素III进行甲硅烷化基反应：
Hal-Si(R)3 (III)
其中Hal表示卤素原子，R如前面所定义，这个反应是在诸如吡啶之类的碱性有机溶剂中，于温度约20℃的条件下进行操作的。一般地，可达到7-三烷基甲硅烷基-10-脱乙酰基浆果赤霉素III产率为约85％。
根据已知的方法，在诸如吡啶之类的碱性有机溶剂中，于温度约0℃的条件下进行操作，由过量的乙酰氯处理7-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素III进行乙酰基化。一般地，由7-三乙基甲硅烷基浆果赤霉素III开始，化学式(I)的7-三烷基甲硅烷氧基浆果赤霉素III的产率为约85％。
这样，根据已知的方法，7-三烷基甲硅烷基浆果赤霉素III的产率为约72％。
现在发现，这正构成本发明的主题，不用分离中间产物7-三烷基甲硅烷基-10-脱乙酰基浆果赤霉素III而进行甲硅烷基化和乙酰基化，可以较高的产率得到通式(I)的产品。
根据本发明，10-脱乙酰基浆果赤霉素III在选自吡啶和由一个或多个含有1-4个碳原子的烷基取代的吡啶之类有机碱性溶剂的溶液里，在温度0-15℃下用通式(III)的甲硅烷基化试剂处理，然后在温度约20℃下用乙酐处理。
采用本发明的方法需要使用比已知方法少得多的甲硅烷基化试剂。一般地，相对于每摩尔10-脱乙酰基浆果赤霉素III要使用1.5-2.5摩尔甲硅烷基化试剂。
一般地，相对于每摩尔10-脱乙酰基浆果赤霉素III要使用5-7摩尔乙酐。
7-三烷基甲硅烷基浆果赤霉素III由其在诸如乙酸乙酯之类脂族酯中的溶液开始，用异丙醚之类的醚在水中沉淀和结晶，可以分离7-三烷基甲在浆果赤霉素III。一般地，由使用的10-脱乙酰基浆果赤霉素III开始的产率是约80％。
本发明得到的7-三烷基甲硅烷基浆果赤霉素III在分离后或以诸如乙酸乙酯之类脂族酯溶液形式可根据如EP-0 336 840专利或国际申请WO 92/09589中描述的已知方法用于制备(2R，3S)-3-苯甲酰氨基-2-羟基-3-苯基丙酸4，10-二乙酸基-2α-苯甲酰氧基-5β，20-环氧-1，7β-二羟基-9-氧-紫杉-11-烯-13α-酯或其衍生物。
下面实施例说明实施本发明的方法。实施例
在293.9克在2.7升吡啶中的10-脱乙酰基浆果赤霉素III溶液中，在1小时20分钟加入182克三乙基甲硅烷基氯。所得到的溶液在5℃搅拌40小时。这时加入360克乙酐，同时将温度保持在5℃。得到的悬浮液在20℃搅拌48小时，然后倒入40升冰水。采用过滤分离所得到的沉淀，再用2升水洗涤8次，最后将沉淀溶解在3升乙酸乙酯中。在硫酸镁上干燥有机相。在过滤并减压浓缩后，在异丙醚中结晶所得到的产物。这样得到7-三乙基甲硅烷基浆果赤霉素III，其产率是77％，7-三乙基甲硅烷基浆果赤霉素III具有如下特性：-熔点：254℃-质子核磁共振谱：(400MHz；CDCl3，δ，ppm)：0.58(mt，6H：乙基CH2)；0.92(t，J＝7.5Hz，9H：乙基CH3)；1.02(s，3H：CH3)；1.18(s，3H：CH3)；1.68(s，3H：CH3)；1.75(宽的s，1H：在1位的OH)；1.87和2.53(2mt，每个1H：在6位的CH2)；2.18(s，6H：CH3和COCH3)；2.27(mt，2H：在14位的CH2)；2.28(s，3H：COCH3)；2.47(宽的s，1H：在13位的OH)；3.88(d，J＝7Hz，1H：H3)；4.13和4.30(2d，J＝8.5Hz，每个1H：在20位的CH2)；4.50(dd，J＝11和7Hz，1H：在7位的H)；4.81(mt，1H：在13位的H)；4.95(宽的d，J＝10Hz，1H：在5位的H)；5.63(d，J＝7Hz，1H：H2)；6.46(s，1H：在10位的H)；7.46(t，J＝8.5Hz，2H：在间位的-OCOC6H5)；7.60(t，J＝8.5Hz，1H：在-OCOC6H5对位上的H)；8.10(d，J＝8.5Hz，2H：在-OCOC6H5邻位上的H)。
Claims (10)
1.具有下述通式(I)的7-三烷基甲硅烷基浆果赤霉素III的制备方法：式中R相同或不同，表示C1-4直链或支链烷基，其特征在于用下述通式(III)所示甲硅烷基化试剂处理具有下述通式(II)的10-脱乙酰基浆果赤霉素III：Hal-Si(R)3 (III)式中Hal表示卤素原子，R如前面所限定，然后用乙酐处理而不用分离中间产物7-三烷基甲硅烷基-10-脱乙酰基浆果赤霉素III。
2.根据权利要求1的方法，其特征在于在碱性有机溶剂中操作。
3.根据权利要求2的方法，其特征在于碱性有机溶剂选自吡啶和被一个或多个含有1-4个碳原子的烷基取代的吡啶。
4.根据权利要求2的方法，其特征在于碱性有机溶剂是吡啶。
5.根据权利要求1的方法，其特征在于相对于每摩尔10-脱乙酰基浆果赤霉素III使用1.5-2.5摩尔甲硅烷基化试剂。
6.根据权利要求1的方法，其特征在于相对于每摩尔10-脱乙酰基浆果赤霉素III使用5-7摩尔乙酐。
7.根据权利要求1的方法，其特征在于在温度0-15℃下用甲硅烷基化试剂进行处理。
8.根据权利要求1的方法，其特征在于在温度约20℃下用乙酐进行处理。
9.权利要求1-8中任一项的方法制备的通式(I)的7-三烷基甲硅烷基浆果赤霉素III，其中每个R符号表示含有1-3个碳原子的烷基。
10.权利要求1-8中任一项的方法制备的通式(I)的7-三烷基甲硅烷基浆果赤霉素III，其中每个R符号表示乙基。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9403979A FR2718137B1 (fr) | 1994-04-05 | 1994-04-05 | Procédé de préparation de trialcoylsilyl-7 baccatine III. |
| FR94/03979 | 1994-04-05 |
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| Publication Number | Publication Date |
|---|---|
| CN1145073A CN1145073A (zh) | 1997-03-12 |
| CN1058497C true CN1058497C (zh) | 2000-11-15 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN95192429A Expired - Lifetime CN1058497C (zh) | 1994-04-05 | 1995-04-03 | 7－三烷基甲硅烷基浆果赤霉素ⅲ的制备方法 |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | US5670658A (zh) |
| EP (1) | EP0754185B1 (zh) |
| JP (1) | JP3718225B2 (zh) |
| KR (1) | KR100399246B1 (zh) |
| CN (1) | CN1058497C (zh) |
| AT (1) | ATE160351T1 (zh) |
| AU (1) | AU683560B2 (zh) |
| BG (1) | BG62735B1 (zh) |
| BR (1) | BR9507444A (zh) |
| CA (1) | CA2186916C (zh) |
| CZ (1) | CZ288397B6 (zh) |
| DE (1) | DE69501080T2 (zh) |
| DK (1) | DK0754185T3 (zh) |
| EE (1) | EE03240B1 (zh) |
| ES (1) | ES2109103T3 (zh) |
| FI (1) | FI115970B (zh) |
| FR (1) | FR2718137B1 (zh) |
| GE (1) | GEP19991537B (zh) |
| GR (1) | GR3025448T3 (zh) |
| HU (1) | HU214158B (zh) |
| LT (1) | LT4185B (zh) |
| LV (1) | LV11691B (zh) |
| MX (1) | MX9604466A (zh) |
| NO (1) | NO305839B1 (zh) |
| NZ (1) | NZ284490A (zh) |
| PL (1) | PL316588A1 (zh) |
| RO (1) | RO115631B1 (zh) |
| RU (1) | RU2127729C1 (zh) |
| SK (1) | SK280448B6 (zh) |
| TW (1) | TW284765B (zh) |
| UA (1) | UA44730C2 (zh) |
| WO (1) | WO1995026967A1 (zh) |
| ZA (1) | ZA952733B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5973160A (en) * | 1992-12-23 | 1999-10-26 | Poss; Michael A. | Methods for the preparation of novel sidechain-bearing taxanes |
| US7288665B1 (en) | 1997-08-18 | 2007-10-30 | Florida State University | Process for selective derivatization of taxanes |
| ATE234800T1 (de) | 1997-08-21 | 2003-04-15 | Univ Florida State | Verfahren zur synthese von taxanen |
| CZ2003837A3 (cs) | 2000-09-22 | 2004-12-15 | Bristol-Myers Squibb Company | Způsob pro snížení toxicity při kombinovaných chemoterapiích |
| AU2003273671A1 (en) * | 2002-10-09 | 2004-05-04 | Phytogen Life Sciences, Inc. | Novel taxanes and methods related to use and preparation thereof |
| US7202370B2 (en) * | 2003-10-27 | 2007-04-10 | Conor Medsystems, Inc. | Semi-synthesis of taxane intermediates from 9-dihydro-13-acetylbaccatin III |
| MXPA06012606A (es) * | 2004-05-14 | 2007-01-31 | Immunogen Inc | Un metodo facil para sintetizar compuestos de bacatina iii. |
| CZ298333B6 (cs) * | 2005-09-26 | 2007-08-29 | Zentiva, A. S | Zpusob prípravy 7-trialkylsilylbaccatinu III |
| KR101671537B1 (ko) | 2008-08-11 | 2016-11-01 | 넥타르 테라퓨틱스 | 다분지형 중합체 알카노에이트 컨쥬게이트 |
| WO2012088391A1 (en) | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Non-ring hydroxy substituted taxanes and methods for synthesizing the same |
| WO2012088445A1 (en) | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds |
| WO2012088422A1 (en) | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
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| WO1993006094A1 (en) * | 1991-09-23 | 1993-04-01 | Florida State University | Metal alkoxides |
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| US4823167A (en) * | 1986-12-16 | 1989-04-18 | Baxter International Inc. | Catheter calibration device |
| FR2629818B1 (fr) * | 1988-04-06 | 1990-11-16 | Centre Nat Rech Scient | Procede de preparation du taxol |
| MX9102128A (es) | 1990-11-23 | 1992-07-08 | Rhone Poulenc Rorer Sa | Derivados de taxano,procedimiento para su preparacion y composicion farmaceutica que los contiene |
| US5597931A (en) * | 1992-03-30 | 1997-01-28 | Sloan-Kettering Institute For Cancer Research | Total synthesis of taxol and analogues thereof |
| US5475011A (en) * | 1993-03-26 | 1995-12-12 | The Research Foundation Of State University Of New York | Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment |
| US5405972A (en) * | 1993-07-20 | 1995-04-11 | Florida State University | Synthetic process for the preparation of taxol and other tricyclic and tetracyclic taxanes |
| US5449790A (en) * | 1994-04-06 | 1995-09-12 | Hauser Chemical Research, Inc. | Preparation of 10-deacetylbaccatin III and 7-protected-10-deacetylbaccatin III derivatives from 10-deacetyl taxol A, 10-deacetyl taxol B, and 10-deacetyl taxol C |
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1994
- 1994-04-05 FR FR9403979A patent/FR2718137B1/fr not_active Expired - Fee Related
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1995
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1996
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1997
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993006094A1 (en) * | 1991-09-23 | 1993-04-01 | Florida State University | Metal alkoxides |
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