CN1502614A - 用于制备紫杉烷衍生物的中间体 - Google Patents
用于制备紫杉烷衍生物的中间体 Download PDFInfo
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- CN1502614A CN1502614A CNA2003101149087A CN200310114908A CN1502614A CN 1502614 A CN1502614 A CN 1502614A CN A2003101149087 A CNA2003101149087 A CN A2003101149087A CN 200310114908 A CN200310114908 A CN 200310114908A CN 1502614 A CN1502614 A CN 1502614A
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- baccatin iii
- taxol
- phenyl
- deacetylation baccatin
- iii
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- 229940123237 Taxane Drugs 0.000 title description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 14
- 238000002360 preparation method Methods 0.000 abstract description 7
- 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 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 125000006239 protecting group Chemical group 0.000 abstract description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 abstract description 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
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 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 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- 229930014667 baccatin III Natural products 0.000 description 15
- 238000003381 deacetylation reaction Methods 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 229960001592 paclitaxel Drugs 0.000 description 13
- 229930012538 Paclitaxel Natural products 0.000 description 12
- 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 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- -1 triethylsilyl Chemical group 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 229960003668 docetaxel Drugs 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)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 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 4
- 230000003595 spectral effect Effects 0.000 description 4
- MEFKFJOEVLUFAY-UHFFFAOYSA-N (2,2,2-trichloroacetyl) 2,2,2-trichloroacetate Chemical compound ClC(Cl)(Cl)C(=O)OC(=O)C(Cl)(Cl)Cl MEFKFJOEVLUFAY-UHFFFAOYSA-N 0.000 description 3
- 241001092054 Cercocarpus Species 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- PLRPKVNZGONHKD-UHFFFAOYSA-N 1,3-oxazolidine-5-carboxylic acid Chemical compound OC(=O)C1CNCO1 PLRPKVNZGONHKD-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 235000009006 Cercocarpus ledifolius Nutrition 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 235000014493 Crataegus Nutrition 0.000 description 2
- 241001092040 Crataegus Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 241001116500 Taxus Species 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- KNWCDYSKJSREAQ-UHFFFAOYSA-N 1,3-oxazolidine-2-carboxylic acid Chemical compound OC(=O)C1NCCO1 KNWCDYSKJSREAQ-UHFFFAOYSA-N 0.000 description 1
- HNNQYHFROJDYHQ-UHFFFAOYSA-N 3-(4-ethylcyclohexyl)propanoic acid 3-(3-ethylcyclopentyl)propanoic acid Chemical compound CCC1CCC(CCC(O)=O)C1.CCC1CCC(CCC(O)=O)CC1 HNNQYHFROJDYHQ-UHFFFAOYSA-N 0.000 description 1
- HOJZAHQWDXAPDJ-UHFFFAOYSA-N 3-anilino-2-hydroxypropanoic acid Chemical class OC(=O)C(O)CNC1=CC=CC=C1 HOJZAHQWDXAPDJ-UHFFFAOYSA-N 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N DL-isoserine Natural products NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 241001116498 Taxus baccata Species 0.000 description 1
- 241000202349 Taxus brevifolia Species 0.000 description 1
- 150000001225 Ytterbium Chemical class 0.000 description 1
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000002521 alkyl halide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 150000004200 baccatin III derivatives Chemical class 0.000 description 1
- 238000006480 benzoylation reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003325 scandium Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
一种用于制备紫杉烷衍生物的式IV的中间体；其中R是叔丁氧羰基、苯甲酰基或者直链或支链脂族酸的残基，R1是苯基或者直链或支链烷基或烯基。
Description
本申请是申请日为2000年2月23日、申请号为00804423.6、发明创造名称为“从10-脱乙酰浆果赤霉素III制备紫杉烷的方法”的申请的分案申请。
技术领域
本发明涉及一种从10-脱乙酰浆果赤霉素III制备紫杉烷(taxanes)的方法，以及一种用于制备紫杉烷衍生物的中间体。
背景技术
紫杉酚(Paclitaxel)是一种已知的具有紫杉烷结构的抗肿瘤药，它的工业制备特别复杂。
紫杉酚首先是通过从短叶紫杉(Taxus brevifolia)的树干树皮提取而分离的，而现在它是从10-脱乙酰浆果赤霉素III[它是存在于不同紫杉属(Taxus)的种、特别是浆果紫杉(Taxus baccata L.)的叶中的中间体]开始合成的，于是克服了与短叶紫杉树皮的可利用性相关的环境问题。
文献中报导了一些合成方法：US Re.34,277(US 4,924,011的重新颁发)公开了从被保护的10-脱乙酰浆果赤霉素III[即，C-7位的羟基被三烷基甲硅烷基(特别是三乙基甲硅烷基)保护，并且在C-10位被乙酰基保护]开始半合成紫杉酚。在WO 98/08832中，C-7位羟基的保护是应用三氯乙酰基进行的。将这样保护的浆果赤霉素III衍生物与乙酰溴反应，随后与合适的苯基异丝氨酸衍生物反应而获得紫杉酚，接着是7位和2′位上的羟基的去保护并进行胺的苯甲酰化。
在WO 93/06094中，紫杉酚是通过β-内酰胺型化合物与7-三乙基甲硅烷基浆果赤霉素III的反应制备的。在酸性介质中去保护而获得所需的产品。
在US 5 476 954中，从10-脱乙酰浆果赤霉素III开始进行紫杉酚的合成，用2，2，2-三氯乙氧羰基(Troc)保护C-7羟基，用Troc或用乙酰基保护C-10羟基。
所以显然，合成紫杉酚的关键步骤是C-7处用可容易地和选择性地除去的基选择性酯化。迄今，7-三乙基甲硅烷基脱乙酰浆果赤霉素III被认为是关键的中间体。应用5～20摩尔甲硅烷基化试剂，关于10-脱乙酰浆果赤霉素III至7-三乙基甲硅烷基-10-脱乙酰浆果赤霉素III的衍生化报导的产率是约85％。随后乙酰化得到7-三乙基甲硅烷基浆果赤霉素III的产率也约为85％。
US 5 621 121和US 5 637 723公开了紫杉烷(包括紫杉酚)的合成，通过将适当保护的浆果赤霉素III或10-脱乙酰浆果赤霉素III与在2-位携带被烷氧基取代(US 5 621 121)或者被三卤烷基、特别是三氯甲基取代(US 5 637 723)的苯基的噁唑烷-5-羧酸反应，接着通过打开噁唑烷环而去保护。
认为特别适合的保护基包括：甲硅烷基、2，2，2-三氯乙氧羰基或2-(2(三氯甲基)丙氧基)羰基。
还可应用基本相同的方法制备Docetaxel(另-种已知的广泛用于临床的紫杉烷衍生物)。
发明内容
现已发现了一种制备紫杉烷(特别是紫杉酚和Docetaxel)的方法，该方法比已知方法获得更高的产率。
示于如下方案的本发明的方法包括：
a)用三氯乙酰基同时保护10-脱乙酰浆果赤霉素III的7-位和10-位上的羟基；
b)接着通过与式(VII)化合物的反应使13-位的羟基酯化：
其中，R是叔丁氧羰基、苯甲酰基或者直链或支链脂族酸的残基，R1是苯基或者直链或支链烷基或烯基；
c)除去三氯乙酸保护基；
d)对于其中R2是乙酰基的那些化合物来说，任选选择性乙酰化10-位上的羟基；
e)将噁唑烷环酸解。
方案
本发明的方法与现有技术的那些方法不同之处在于，应用的反应顺序提供了比上文引述的已知方法更简单的途径和对获得的产率的显著改善。
步骤a)通常是在碱(例如吡啶、三乙胺等)的存在下用三氯乙酸酐在合适的溶剂中进行的。
用噁唑烷-5-羧酸衍生物的酯化是在下列条件下进行的，即，在缩合剂(例如二环己基碳二亚胺)或其它已知试剂存在下，在室温到溶剂的沸腾温度范围内，在无水有机溶剂(优选是脂族烃、芳烃或氯化烃)中进行。
然后，通过用NH4OH/NH4Cl在脂族醇(优选是甲醇)中处理除去7-和10-三氯乙酰基而将生成的噁唑烷酯去保护。
10-位上羟基的选择性乙酰化是用乙酸酐在下列条件下进行的：在铈III盐、钪盐或镱盐存在下，在溶剂(例如四氢呋喃、二氯甲烷、乙酸乙酯)中，在5～40℃范围内的温度下。
在约-2～+2℃范围内的温度下，在溶剂(例如甲醇、乙醇、四氢呋喃)中用有机酸或无机酸处理，生成所需的紫杉烷衍生物。在0℃的温度下、在四氢呋喃中甲酸的应用是特别优选的。
噁唑烷中间体是已知的或者可用已知方法通过异丝氨酸酯与4-甲氧基苯甲醛的反应制备。
证明茴香醛的选择对于噁唑烷的形成特别重要，因为与US 5 621121、5 637 723(Rhne-Poulenc Rorer)和5 821 363(UpJohn)中描述的方法相反，噁唑烷酸可被轻易结晶和调节到95∶5异构体比，这特别适用和有利于后续的步骤。此外，可用茴香醛获得的噁唑烷羧酸在三氯乙酸酯的去保护和随后的乙酰化步骤中特别稳定。在这些条件下，US 5 821 363中应用的2，4-二甲氧基苯甲醛或者US 5 621 121和5 637723(Rhne-Poulenc Rorer)中描述的氯醛或对-三氯甲基苯甲醛不够稳定。
本发明的方法，除了紫杉酚(R＝苯甲酰基，R1＝苯基)和Docetaxel(R＝叔丁氧羰基，R1＝苯基)之外，还有效地、方便地提供其它紫杉烷衍生物。
式IV的化合物以前从未被描述过，所以是本发明的又一目的，作为适用于合成紫杉烷衍生物的中间体。
具体实施方式
如下实施例更详细地阐述了本发明。
实施例1-7，10-双-三氯乙酰基-10-脱乙酰浆果赤霉素III的制备。
将4.77ml三氯乙酸酐(42.32mmol)滴加到10g 10-脱乙酰浆果赤霉素III(18.4mmol)于125ml无水二氯甲烷和42ml吡啶的溶液中。将反应混合物搅拌3小时或无论如何直至反应完全，通过TLC在硅胶上(应用5∶5正己烷/乙酸乙酯混合物作为洗脱剂)检查。反应完毕，添加5ml甲醇破坏过剩的三氯乙酸酐，然后水。用HCl(0.1M水溶液)充分洗涤有机相而除去吡啶，在MgSO4上干燥残余的有机相，真空浓缩至干。获得浅黄色固体(17g)，将它从氯仿中结晶时显示下列化学特性和光谱特性：
IR(KBr)3517，1771，1728，1240，981，819，787，675cm-1；
1H-NMR(200MHz)；δ8.11(Bz AA′)，7.58(Bz C)，7.46(Bz，BB′)，6.50(s，H-10)，5.72(m，H-H-2)，5.02(d，J＝8Hz，H-5)，4.95(m，H-13)，4.37(d，J＝8Hz，H-20a)，4.18(d，J＝8Hz，H-20b)，4.02(d，J＝6Hz，H-3)，2.32(s，4-Ac)，2.22(s，H-18)，1.91(s，H-19)，1.25和1.11(s，H-16，H-17)，m.p.＝172-175℃，[α]D-36°(MeOH；C＝0.6)。
实施例2-13-(2-(4-甲氧苯基)-N-苯甲酰-4-苯基-噁唑烷基-)-10-脱乙酰浆果赤霉素III的制备。
将17g的7，10-双三氯乙酰基-10-脱乙酰浆果赤霉素III溶于250ml无水甲苯，在搅拌下添加12.6g 2-(4-甲氧苯基)-N-苯甲酰-4-苯基-噁唑烷-5-羧酸和6g DCC。在40℃下搅拌一夜后，将反应混合物过滤，浓缩至干。将残余物溶于300ml甲醇/四氢呋喃，添加24ml 2M NH3水溶液。室温下1.5小时后，在真空下浓缩反应混合物至少量体积，然后用水稀释，用乙酸乙酯萃取整个体系。将萃取液浓缩至干，在硅胶柱上纯化残余物，用1∶1乙酸乙酯/石油醚混合物洗脱产品而获得16.8g m.p.135℃和[α]D＝-58°(MeOH，C＝0.5)的标题产品。
实施例3-13-(2-(4-甲氧苯基)-N-苯甲酰-4-苯基-噁唑烷基)浆果赤霉素III的制备。
往13.7g实施例II的产品于200ml四氢呋喃的溶液中添加56ml10％CeCl3·7H2O的四氢呋喃悬浮液，接着添加5.5ml乙酸酐。在室温下搅拌一夜后，将反应混合物过滤，用甲醇处理滤液，浓缩至少量体积；用H2O稀释混合物，用乙酸乙酯萃取产物，获得12g(84％)具有下列物理特性和光谱特性的13-(2-(4-甲氧基亚苄基)-N-苯甲酰-4-苯基-噁唑烷基-)-浆果赤霉素III：
1H-NMR：8.07(d，Bz)，7.60-7.19(m，芳族)，7.48-6.90(AA′，BB′，p-OMePh)，6.33(s，H-10)，5.67(d，J＝5Hz，H-2)，5.56(br s，H-3′)，4.93(d，J＝8Hz，H-5)，4.90(brs，H-2′)，4.45(m，H-7)，4.28(d，J＝8Hz，H-20a)，4.16(d，J＝8Hz，H-20b)，3.82(s，OMe)，2.27(s，Ac)，2.08(s，OAc)，1.66(s，H-19)，1.29-1.16(s，H-16，H-17)，m.p.146℃，[α]D＝-62°(MeOH，C＝0.8).
实施例4-紫杉酚的制备
将12g 13-(2-(4-甲氧苯基)-N-苯甲酰-4-苯基-噁唑烷基)浆果赤霉素III溶于50ml四氢呋喃，在0℃下添加5ml甲酸；在0℃下将反应混合物搅拌3小时，然后用水稀释；用KHCO3中和甲酸，用乙酸乙酯反复萃取悬浮液。用水洗涤乙醚-乙酸(ether-acetic)萃取液，浓缩至少量体积。从相同溶剂中结晶后获得10.5g具有与文献中描述的相同化学-物理特性和光谱特性的紫杉酚。
实施例5-Docetaxel的制备
将17g 7，10-双三氯乙酰基-10-脱乙酰浆果赤霉素III溶于250ml无水甲苯，在搅拌下添加11.6g 2-(4-甲氧苯基)-N-叔丁氧羰基-4-苯基-噁唑烷-5-羧酸和6g DCC。在40℃下搅拌一夜后，将反应混合物过滤，浓缩至干。将残余物溶于300ml甲醇/四氢呋喃，添加24ml2M NH3水溶液。室温下1.5小时后，在真空下浓缩反应混合物至少量体积，然后用水稀释，用乙酸乙酯萃取整个体系。将萃取液浓缩至干，将10g该残余物溶于THF，在0℃下添加5ml甲酸。在0℃下将反应混合物搅拌3小时，然后用水稀释；用KHCO3中和甲酸，用乙酸乙酯反复萃取悬浮液。用水洗涤有机萃取液，浓缩至少量体积。从相同溶剂中结晶后获得9.2g具有与文献中描述的相同化学、物理和光谱特性的Docetaxel。
Claims (1)
1.式IV的中间体
其中，R是叔丁氧羰基、苯甲酰基或者直链或支链脂族酸的残基，R1是苯基或者直链或支链烷基或烯基。
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| US6900342B2 (en) * | 2002-05-10 | 2005-05-31 | Dabur India Limited | Anticancer taxanes such as paclitaxel, docetaxel and their structural analogs, and a method for the preparation thereof |
| CN1303077C (zh) * | 2004-01-16 | 2007-03-07 | 桂林晖昂生化药业有限责任公司 | 合成紫杉烷的制备工艺 |
| US7446126B2 (en) * | 2004-10-08 | 2008-11-04 | Indena S.P.A. | Semisynthesis process for the preparation of 10-deacetyl-N-debenzoyl-paclitaxel |
| EP1712552A1 (en) * | 2005-04-11 | 2006-10-18 | INDENA S.p.A. | Semisynthesis process for the preparation of 10-deacetyl-n-debenzoyl-paclitaxel |
| EP1647552A1 (en) * | 2004-10-08 | 2006-04-19 | INDENA S.p.A. | Semisynthesis process for the preparation of 10-deacetyl-n-debenzoyl-paclitaxel |
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| KR101009467B1 (ko) | 2006-03-13 | 2011-01-19 | 주식회사 셀트리온화학연구소 | 도세탁셀의 합성에 유용한 탁산 유도체 및 그 제조방법 |
| KR100847331B1 (ko) * | 2006-12-14 | 2008-07-21 | 한미약품 주식회사 | 도세탁셀의 제조방법 및 이에 사용되는 중간체 |
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| JP4833126B2 (ja) * | 2007-03-26 | 2011-12-07 | Ｎｔｎ株式会社 | 潤滑剤劣化検出装置および検出装置付き軸受 |
| WO2011134067A1 (en) * | 2010-04-29 | 2011-11-03 | 6570763 Canada Inc. | Novel amino acid molecule and uses thereof |
| WO2016098015A1 (en) * | 2014-12-16 | 2016-06-23 | Khashayar Karimian | New efficient methods for the synthesis of taxane derivatives such as docetaxel and their structural analogous, and a method for the preparation thereof |
| CN115232092A (zh) * | 2022-05-19 | 2022-10-25 | 无锡紫杉药业有限公司 | 一种10-乙酰多西他赛的制备方法 |
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| US5990325A (en) | 1993-03-05 | 1999-11-23 | Florida State University | Process for the preparation of 9-desoxotaxol, 9-desoxobaccatin III and analogs thereof |
| FR2696459B1 (fr) | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Procédé de préparation de dérivés du taxane. |
| FR2696460B1 (fr) | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Procédé de préparation de dérivés du taxane. |
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| CN107056767B (zh) * | 2015-12-04 | 2022-07-15 | 江苏恩华络康药物研发有限公司 | 用于制备水溶性紫杉烷类衍生物的方法及中间体 |
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