CN1037271C - 制备鬼臼乙叉甙磷酸酯的中间体 - Google Patents
制备鬼臼乙叉甙磷酸酯的中间体 Download PDFInfo
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- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 title 1
- 229960000752 etoposide phosphate Drugs 0.000 title 1
- 239000000543 intermediate Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- -1 dichloro-acetyl Chemical group 0.000 claims description 27
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 35
- 229910052736 halogen Inorganic materials 0.000 abstract description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 14
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- 230000007062 hydrolysis Effects 0.000 abstract description 10
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- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 abstract description 8
- 150000001720 carbohydrates Chemical class 0.000 abstract description 7
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- 150000002148 esters Chemical class 0.000 abstract description 4
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 229930182470 glycoside Natural products 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
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- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 238000003797 solvolysis reaction Methods 0.000 description 3
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
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- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000006345 epimerization reaction Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- CBPYOHALYYGNOE-UHFFFAOYSA-M potassium;3,5-dinitrobenzoate Chemical compound [K+].[O-]C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 CBPYOHALYYGNOE-UHFFFAOYSA-M 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- FOVRGQUEGRCWPD-UHFFFAOYSA-N (5aR)-9t-beta-D-Glucopyranosyloxy-5t-(4-hydroxy-3,5-dimethoxy-phenyl)-(5ar,8at)-5,8,8a,9-tetrahydro-5aH-furo[3',4';6,7]naphtho[2,3-d][1,3]dioxol-6-on Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(OC3C(C(O)C(O)C(CO)O3)O)C3C2C(OC3)=O)=C1 FOVRGQUEGRCWPD-UHFFFAOYSA-N 0.000 description 1
- YVCVYCSAAZQOJI-JHQYFNNDSA-N 4'-demethylepipodophyllotoxin Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YVCVYCSAAZQOJI-JHQYFNNDSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- GXPHKNHECGMZNQ-UHFFFAOYSA-N carbonochloridoyl 2-phenylacetate Chemical compound C1(=CC=CC=C1)CC(=O)OC(=O)Cl GXPHKNHECGMZNQ-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 230000008878 coupling Effects 0.000 description 1
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- 238000000354 decomposition reaction Methods 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- SMPAPEKFGLKOIC-UHFFFAOYSA-N oxolane;hydrochloride Chemical compound Cl.C1CCOC1 SMPAPEKFGLKOIC-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及制备鬼臼乙叉甙磷酸酯的中间体,其化学式为式(2)。式中R和R4可以相同或不同,分别表示-COCHmX3-m,其中X为卤原子,m为0-2的整数。
Description
本发明涉及制备鬼臼乙叉甙磷酸酯的中间体。
鬼臼乙叉甙磷酸酯是一种具有抗肿瘤活性有益化合物,同鬼臼乙叉甙比,该酯在水中的溶解度得到了改善。日本公开专利(No.192793/1988)和US4904768对其制备方法已作了披露。
US4904768中披露的此法包括直接将鬼臼乙叉甙同磷酰氯或烷基或芳基氯磷酸酯进行反应,通过这类磷化合物与糖化物部分的羟基进行反应,除得到目的化合物外,也有大量的副产物生成,这里磷化合物同鬼臼乙叉甙的4’位相连。因此,为了除去副产物,必须对此法得到的反应混合物进行如柱色谱法一类特殊的处理。此外,日本公开专利(No.192793/1988)中报导的此法用的是其中的糖化物部分的羟基经保护了的鬼臼乙叉甙,因此没产生多少副产物。然而,此法在对糖化物部分进行去保护时,要涉及到使用乙酸和锌,且需用冷冻干燥来对所需的鬼臼乙叉甙磷酸酯进行分离,在进行工业规模生产时,这无疑是一个问题。
本发明涉及制备式(1)表示的鬼臼乙叉甙磷酸酯的方法所说方法包括:于胺存在下,从化合物(2)中去掉R和R1基团,所说化合物(2)的结构式为:在(2)中:R和R1可以相同不同,各表示基团-COCHmX(3-m)(X表示卤原子,m为0-2的整数),本发明还涉及制备通式(2)的化合物和通式(3)的化合物的方法,所说化合物(3)的结构式为:(3)中的R和R1的定义同上。
本发明方法的特征在于:用卤乙酰基团作糖化物部分的保护基团,在胺(特别是叔胺)存在下消去此保护基团,从而使制备鬼臼乙叉甙磷酸酯的产率比公知技术的高,且适宜于工业规模的生产。
在通式(2)和(3)中,R和R1各选自一卤乙酰基、二卤乙酰基和三卤乙乙酰基(本说明书中简称为:“卤乙酰基”)。R和R1基团中的X所定义的卤原子为氟、氯、溴和碘原子。
下面,将对本发明的制备方法作更详细的描述。
在适宜的胺或胺盐存在下,于诸如从醇(甲醇和乙醇)、卤代烃(如二氯甲烷和氯仿)、醚类(四氢呋喃和二噁烷)或由其二种或多种上述溶剂组成的混合溶剂选出的溶剂中,通过溶剂分解从化合物(2)中去掉保护糖化合物部分羟基的卤乙酰基团。所说胺可以是从如一甲基胺和一乙基胺等伯胺,如二甲胺、二乙胺和乙甲胺等仲胺,如三甲胺和三乙胺等叔胺中选出的任何C1-5烷基胺和从苯胺、二乙苯胺等选出的任何芳族胺。根据缓慢差向异构表异构化,优选使用C1-5烷基叔胺(如三乙胺)。所说胺盐可以是伯、仲、叔或芳族胺同乙酸等有机酸形成的盐。所说溶剂分解包括水解、醇解、氨解或氨基分解。用于溶剂分解的试剂有水、上述醇类、氨和上述伯、仲胺类。如使用叔胺或胺盐,优选的溶剂是甲醇或乙醇等醇或醇同其他溶剂的混合物。如使用胺时,在0-70℃(优选0-30℃下)即可容易地消去卤乙酰基团。根据通式(2)化合物计算,所用的胺的量为0.2-15当量,优选1-3个当量,如使用胺盐,于20-70℃(优选30-50℃)下即可容易地消去卤乙酰基团,根据化合物(2)计算,所用的胺盐的量为1-15(优选3-10)个当量。此消除反应在约1-6小时内即可完成。
消除反应完成后,反应混合物用盐酸/四氢呋喃进行中和,浓缩后用四氢呋喃进行溶剂置换。对所得的反应混合物进行过滤以除去形成的胺的盐酸化物。浓缩滤液后加入正己烷。冷却所得反应混合物即得鬼臼乙叉甙磷酸酯。
在本发明中用作起始物料的通式(2)化合物可按如下方法制备。
用容易为钯催化剂等催化还原消去的基团,如取代的或未取代的苄氧基羰基等保护4’-去甲表鬼臼毒素的4’位。取代的苄氧基羰基的实例包括对甲氧基苄氧基羰基、对硝基苄氧基羰基和对氯苄氧基羰基,用惯常方法,于三氟化硼-醚配合物存在下,使经此种方法保护的4’-去甲基表鬼臼毒素同β-D-2,3-二-氧-卤乙酰基-4,6-氧-亚乙基吡喃葡萄糖进行偶合。
上述偶合反应中所用的β-D-2,3-二-氧-卤乙酰基-4,6-氧-亚乙基吡喃葡萄糖可用US4757138或4564675中公开的方法进行制备。
偶合反应完成后,于钯催化剂存在下,对所得产品进行氢化以除去4’的保护基,经此氢化即可获得4’-去甲表鬼臼毒素同β-D-2,3-二-氧卤乙酰基-4,6-氧-亚乙基苷。再于适宜碱存在下,在如四氢呋喃、二噁烷、丙酮、乙腈、氯仿、二氯甲烷或1,2-二氯乙烯等非质子传递溶剂中,使该化合物进一步同磷酰氯反应即形成上述通式(3)表示的4’-氧-二氯磷酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-卤乙酰基-4,6-氧-亚乙基苷。用于此步骤的碱是叔胺、吡啶等不与该产物反应的碱类。
于适宜碱存在下,在中性或酸性条件下,在水中,对反应混合物或所分离的通式(3)化合物进行二氯磷酰基水解,经此水解即得式(2)化合物4’-氧-膦酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-卤乙酰基-4,6-氧-亚乙基苷。用于此水解的碱是不与化合物(3)反应的叔胺或吡啶等芳族胺。保护糖化物部分的羟基的卤乙酰基在水解二氯磷酰基的条件下是稳定的基团。水解过程完成后,将此反应混合物的PH调到1.0-2.5以使通式(2)化合物从水相萃取入有机相,浓缩有机相后,加入正己烷以分离通式(2)化合物。
实施例1
(1)合成4’-氧-二氯磷酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷
把22.03g(27.18mmol)4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷溶于190ml四氢呋喃中。把此溶液冷却到-15℃。在所得溶液中滴加8.34g(54.4mmol)磷酰氯后加入8.25g(81.5mmol)三乙胺。
所得混合物在-10℃至-15℃下反应后,过滤除去形成的三乙胺盐酸化物。把滤液浓缩至60g后加入500ml异丙醚。冷却此混合物以沉淀出晶体。过滤回收晶体得4’-氧-二氯磷酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷。
无水产品重:24.45g(产率:97%)
200MHZ 1H NMR(DMSOd-6)δ1.21(d,3H),2.85-3.10(m,2H),3.59(s,6H),3.41-3.84(m,3H),4.19(m,2H),4.32(m,1H),4.53(d,1H),4.79(q,1H),4.98(m,2H),5.30(d,1H),5.54(t,1H),6.01(s,1H),6.05(s,1H),6.19(s,2H),6.54(s,1H),6.66(s,1H),6.99(s,1H),7.01(s,1H)MS(FAB),m/e,927(M+H)
(2)合成4’-氧-膦酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷
把24.4g(26.37mmol)4’-氧-二氯磷酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷加到400ml水中。0-5℃下向此混合物中滴加入12.28g吡啶以进行水解。水解完成后,向此反应混合物中加入180ml氯仿,用6N的盐酸把此混合物PH调到2以用氯仿萃取产品。
氯仿相用120ml饱和普通盐水溶液洗涤、浓缩后加入360ml正己烷即得4’-氧-膦酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷。
无水产品重:22.99g(产率:97.9%)
200MHZ 1H NMR(DMSOd-6)δ1.21(d,3H),2.83-3.10(m,2H),3.57(s,6H),3.48-3.85(m,3H),4.18(m,2H),4.33(m,1H),4.51(d,1H),4.78(q,1H),4.98(m,2H),5.27(d,1H),5.54(t,1H),6.00(s,1H),6.04(s,1H),6.16(s,2H),6.54(s,1H),6.63(s,1H),6.94(s,1H),7.01(s,1H)MS(FAB),m/e,891(M+H)
(3)合成鬼臼乙叉甙磷酸酯(式(1)化合物)
把22.99g(25.82mmol)4’-氧-膦酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷溶解在150ml甲醇中,将所得溶液冷至5-10℃,接着滴加5.22g(51.64mmol)三乙胺。
将所得混合物在10℃下进行反应。反应完成后,中和反应混合物并用盐酸/四氢呋喃把PH调到2.5-3.0。将所得溶液浓缩至干,残余物中加入四氢呋喃以进行溶解置换。用盐酸四氢呋喃把溶液的PH调到1.0以沉淀出三乙胺盐酸化物。滤出三乙胺盐酸化物、浓缩滤液后加入200ml正己烷、搅拌所得混合物、除去上清液、加入200ml正己烷。此步骤重复几次后得到用过滤即可回收的固体鬼臼乙叉苷磷酸酯。
无水产品重:11.22g(产率:65%)
(按步骤(1)中所用原料计,产率:61.7%)
200MHZ 1H NMR(DMSOd-6)δ1.25(d,3H),2.80-3.00(m,1H),3.61(s,6H),3.02-3.66(m,6H),4.04(dd,1H),4.24(d,2H),4.55-4.59(m,2H),4.72(q,1H),4.95(d,1H),5.23(br,2H),6.03(s,2H),6.23(s,2H),6.53(s,1H),7.01(s,1H)MS(FAB),m/e,669(M+H)
实施例2
(1)合成4’-氧-二氯磷酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷
把9.5g(11.72mmol)4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷溶解在80ml四氢呋喃中。冷却到-50℃后加入3.6g(35.6mmol)三乙胺,接着滴加3.6g(23.5mmol)磷酰氯,所得混合物在-5℃至-15℃下反应。
(2)合成4’-氧-膦酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷
把含4’-氧-二氯磷酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷的上述反应混合物加入225ml水中。25℃下于此混合物中滴加5.8g吡啶以进行水解。水解完成后,加入85ml二氯甲烷,用6N盐酸把PH调至1以用二氯甲烷萃取反应产物。把二氯甲烷相浓缩至30ml。
(3)合成鬼臼乙叉苷磷酸酯(式(1)化合物)
含上述4’-氧-膦酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷的浓缩物中加入65ml甲醇,接着于室温下滴加2.37g(23.4mmol)三乙胺。
室温下所得混合物反应4小时。反应完成后,用盐酸/四氢呋喃中和并调节PH至3。所得溶液浓缩至干后,向残余物中加入四氢呋喃以进行溶解置换。用盐酸/四氢呋喃把所得四氢呋喃溶液的PH调节至0.5以沉淀出形成的三乙胺盐酸化物。滤出三乙胺盐酸化物后的滤液经浓缩后加入200ml正己烷、搅拌所得混合物、除去上清液、加入200ml正己烷。重复此步骤几次得到用过滤即能回收的固体鬼臼乙叉苷酸酯。
无水产品重:5.36g(按步骤(1)中所用原料计,产率:68.4%)
反应混合物中苦异构体含量:0.6%
实施例3
(1)合成4’-氧-二氯磷酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷
把9.5g(11.72mmol)4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷溶于80ml四氢呋喃中。将此溶液冷却到-5℃,于其中加入3.6g(35.6mmol)三乙胺,接着滴加3.6g(23.5mmol)磷酰氯,所得混合物在-5℃至-15℃下反应。
(2)合成4’-氧-膦酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷
把上述获得的含有4’-氧-二氯磷酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷的上述反应混合物加到225ml水中。25℃下向此反应混合物中滴加5.3g吡啶以进行水解。水解完成后,加入85ml二氯甲烷,用6N盐酸把PH调至1,用二氯甲烷萃取反应产物。把二氯甲烷相浓缩至35ml。
(3)合成鬼臼乙叉苷磷酸酯(式(1)化合物)
把65ml甲醇加到4’-氧-膦酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷的所得浓缩物中,接着,室温下滴加1.71g(23.4mmol)二乙胺。
将所得混合物在室温下反应4小时。反应毕,用盐酸/四氢呋喃中和并将PH调至3。把所得溶液浓缩至干,在残余物中加入四氢呋喃以进行溶剂置换。用盐酸/四氢呋喃把所得四氢呋喃溶液的PH调节至1以沉淀出形成的二乙胺盐酸化物。滤出二乙胺盐酸化物后,浓缩滤液,接着加入200ml正己烷、将所得混合物搅拌、滤出上清液,加入200ml正己烷。重复此步骤几次,得到用过滤即可回收的固体鬼臼乙叉苷酸酯。
无水产品重:4.98g(按步骤(1)中所用原料计,产率:63.5%)
反应混合物中苦异构体含量:3.3%
实施例4
(1)合成4’-氧-二氯磷酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷
把9.5g(11.72mmol)4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷溶解在80ml四氢呋喃中。将所得溶液冷到-5℃,加入3.6g(35.6mmol)三乙胺,接着滴加3.6g(23.5mmol)磷酰氯,所得混合物在-5℃至-15℃下反应。
(2)合成4’-氧-膦酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷
将上述所得的含有4’-氧-二氯磷酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷加入到225ml水中。25℃下滴加5.8g吡啶以进行水解。水解毕,加入85ml二氯甲烷,然后用6N盐酸把PH调至1,用二氯甲烷萃取反应产物。把二氯甲烷相浓缩至25ml。
(3)合成鬼臼乙叉苷磷酸酯(式(1)化合物)
在所得的含4’-氧-膦酰基-4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷的浓缩物中加入65ml甲醇,接着,室温下滴加1.39g(23.5mmol)异丙胺。
所得反应混合物在室温下反应4小时。反应毕,用盐酸/四氢呋喃使反应混合物进行中和并把PH调至3。把所得溶液浓缩至干后于残留物中加入四氢呋喃以进行溶剂置换。用盐酸/四氢呋喃把溶液的PH调节至0.6以沉淀出形成的异丙胺盐酸化物。滤出异丙胺盐酸化物,浓缩滤液,接着加入200ml正己烷、搅拌所得混合物、除去上清液,加入200ml正己烷。重复此步骤几次,用过滤进行回收,得到固体鬼臼乙叉苷磷酸酯。
无水产品重:4.33g(按步骤1用原料计,产率:55.3%)
反应混合物中苦异构体含量:2.5%
参考实施例
合成4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷
(1)合成4’-氧-苄氧基羰基-4’-去甲表鬼臼毒素
把22g(55mmol)4’-去甲表鬼臼毒素加到220ml二氯甲烷中。所得混合物冷却至0℃后加入7.35g(72.6mmol)三乙胺和11.25g(66mmol)苄氧基羰酰氯。所得混合物于0-5℃下反应2小时,反应毕,二氯甲烷相用水洗涤后浓缩。向浓缩物中加入40ml丙酮形成一种溶液。于此溶液中加入350ml甲醇以沉淀4’-氧-苄氧基羰基-4’-去甲表鬼臼毒素,过滤、干燥。
无水产品重:22.05g(产率:75.1%)
(2)合成4’-去甲表鬼臼毒素β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基苷
把17.0g(31.8mmol)4’-氧-苄氧基羰基-4’-去甲表鬼臼毒素和17.65g(41.2mmol)β-D-2,3-二-氧-二氯乙酰基-4,6-氧-亚乙基吡喃葡萄糖溶解在240ml二氯甲烷中。将所得溶液冷却到-20℃,加入6.77g(47.7mmol)醚合三氟化硼进行偶合反应。反应毕,向反应混合物中加入58.5g(57.2mmol)吡啶,尔后相继用稀盐酸、碳酸氢钠水溶液和水洗涤所得溶液,浓缩二氯甲烷相。向浓缩物中加入100ml丙酮形成溶液,接着加入1.6g钯黑。向混合物中导入氢气以进行脱苄氧羰基反应。反应毕,从反应混合物中滤出催化剂,浓缩滤液。向浓缩物中加入130ml异丙醚以沉淀出晶形4’-去甲表鬼臼毒素β-D-2,3-二-氧-氯乙酰基-4,6-氧-亚乙基苷,滤出产物晶体并予以干燥。
干品重:22.03g。
产率:85.5%。
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US4904768A (en) * | 1987-08-04 | 1990-02-27 | Bristol-Myers Company | Epipodophyllotoxin glucoside 4'-phosphate derivatives |
US5081234A (en) * | 1990-04-30 | 1992-01-14 | Bristol-Myers Squibb Co. | 4'-demethylepipodophyllotoxin glycosides |
CN1025918C (zh) * | 1990-06-07 | 1994-09-14 | 国家医药管理局上海医药工业研究院 | 抗肿瘤药表鬼臼毒吡喃糖甙的合成新工艺 |
TW260671B (zh) * | 1991-04-29 | 1995-10-21 | Bristol Myers Squibb Co |
-
1992
- 1992-04-24 JP JP4129764A patent/JP3061476B2/ja not_active Expired - Lifetime
-
1993
- 1993-04-14 CA CA002094009A patent/CA2094009C/en not_active Expired - Lifetime
- 1993-04-21 EP EP93106446A patent/EP0567089B1/en not_active Expired - Lifetime
- 1993-04-21 DE DE69300691T patent/DE69300691T2/de not_active Expired - Lifetime
- 1993-04-23 CN CN93106360A patent/CN1033589C/zh not_active Expired - Lifetime
-
1995
- 1995-03-27 US US08/410,811 patent/US5606039A/en not_active Expired - Lifetime
- 1995-06-07 US US08/479,811 patent/US5637680A/en not_active Expired - Lifetime
- 1995-06-30 CN CN95108365A patent/CN1037271C/zh not_active Expired - Lifetime
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1997
- 1997-06-10 CN CN97112747A patent/CN1052235C/zh not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1024197C (zh) * | 1989-06-07 | 1994-04-13 | 布里斯托尔-迈克斯斯奎布公司 | 表鬼臼毒吡喃葡糖甙的酰化衍生物的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
EP0567089B1 (en) | 1995-10-25 |
DE69300691T2 (de) | 1996-03-21 |
JPH05306293A (ja) | 1993-11-19 |
CN1052235C (zh) | 2000-05-10 |
CN1083067A (zh) | 1994-03-02 |
DE69300691D1 (de) | 1995-11-30 |
CN1033589C (zh) | 1996-12-18 |
EP0567089A1 (en) | 1993-10-27 |
CA2094009A1 (en) | 1993-10-25 |
US5606039A (en) | 1997-02-25 |
US5637680A (en) | 1997-06-10 |
CA2094009C (en) | 1999-11-09 |
CN1126214A (zh) | 1996-07-10 |
JP3061476B2 (ja) | 2000-07-10 |
CN1178796A (zh) | 1998-04-15 |
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