CN103183713B - 5-脱氧-d-呋喃核糖氧苷类化合物的制备方法 - Google Patents
5-脱氧-d-呋喃核糖氧苷类化合物的制备方法 Download PDFInfo
- Publication number
- CN103183713B CN103183713B CN201110455649.9A CN201110455649A CN103183713B CN 103183713 B CN103183713 B CN 103183713B CN 201110455649 A CN201110455649 A CN 201110455649A CN 103183713 B CN103183713 B CN 103183713B
- Authority
- CN
- China
- Prior art keywords
- capecitabine
- compound
- ribose
- preparation
- under
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- -1 5-deoxy-D-ribofuranose oxygen glycosides compound Chemical class 0.000 title claims description 20
- 229930182470 glycoside Natural products 0.000 title claims description 13
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229960004117 capecitabine Drugs 0.000 claims abstract description 36
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims abstract description 27
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- 238000006206 glycosylation reaction Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- RMVRSNDYEFQCLF-UHFFFAOYSA-N phenyl mercaptan Natural products SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000005864 Sulphur Substances 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 239000002808 molecular sieve Substances 0.000 claims description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical group [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 claims description 2
- 238000007070 tosylation reaction Methods 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical class OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- LJSQFQKUNVCTIA-UHFFFAOYSA-N diethyl sulfide Chemical compound CCSCC LJSQFQKUNVCTIA-UHFFFAOYSA-N 0.000 claims 1
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical compound C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 125000003107 substituted aryl group Chemical group 0.000 claims 1
- 125000000101 thioether group Chemical group 0.000 claims 1
- 150000003568 thioethers Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 229940017687 beta-d-ribose Drugs 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 238000005858 glycosidation reaction Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 6
- 150000002016 disaccharides Chemical class 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 230000013595 glycosylation Effects 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract description 2
- WDRISBUVHBMJEF-MROZADKFSA-N 5-deoxy-D-ribose Chemical compound C[C@@H](O)[C@@H](O)[C@@H](O)C=O WDRISBUVHBMJEF-MROZADKFSA-N 0.000 abstract 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 abstract 1
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 239000013558 reference substance Substances 0.000 abstract 1
- 229910000077 silane Inorganic materials 0.000 abstract 1
- 239000000047 product Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 0 CCCCCOC(NC(C(F)=CN1C(*C2C)C(*)C2O)=NC1=*)=O Chemical compound CCCCCOC(NC(C(F)=CN1C(*C2C)C(*)C2O)=NC1=*)=O 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- HMFHBZSHGGEWLO-AIHAYLRMSA-N alpha-D-ribose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-AIHAYLRMSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 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 1
- 229940053867 xeloda Drugs 0.000 description 1
Classifications
-
- 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
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及了一种抗肿瘤用药卡培他滨的有关物质3'-O-(5''-脱氧-β-D-核糖)卡培他滨和3'-O-(5''-脱氧-α-D-核糖)卡培他滨的制备方法，解决此二个在卡培他滨生产过程中产生的杂质只能从反应液中分离得到的问题。该方法首先制备5-脱氧-D-核糖给体，经与硅烷保护的卡培他滨发生糖基化反应后，脱除保护基制得目标产物。本发明可以通过化学方法制备卡培他滨生产过程中产生的双糖苷化有关物质，为卡培他滨的质量控制提供了合格的对照品。
Description
技术领域
本发明涉及化工和药物化学领域，涉及5-脱氧-D-呋喃核糖氧苷类化合物的制备方法，可以应用于抗肿瘤药卡培他滨生产过程中产生的两种双糖苷化有关物质的合成。
背景技术
卡培他滨，商品名希罗达，由瑞士罗氏公司开发，临床用于紫杉醇和包括有蒽环类抗生素化疗方案治疗无效的晚期原发性或转移性乳腺癌的进一步治疗。该药在生产过程中会产生多个双糖苷化杂质，目前只能通过分离反应液得到杂质化合物，实施较困难，质量控制不稳定，且未见公开资料报道过卡培他滨双糖苷化有关物质的合成方法。
发明内容
本发明的目的是提供5-脱氧-D-呋喃核糖氧苷类化合物的制备方法。
本发明还涉及卡培他滨生产过程中产生的3'-O-(5''-脱氧-β-D-核糖)卡培他滨，3'-O-(5''-脱氧α-D-核糖)卡培他滨的制备方法。
本发明的目的是这样实现的：
本发明的合成方法是以四乙酰核糖为原料制备适当的硫苷糖给体，用保护基保护卡培他滨核糖的C2-羟基，与硫苷糖给体在适当的催化剂下进行糖苷化反应，脱去保护基团，得到目标化合物。
本发明中所述的硫苷糖给体的制备特征是以四乙酰核糖为原料，在路易斯酸催化下与烷基硫醇或芳基硫酚在二氯甲烷中发生成硫苷反应，碱性条件下脱去乙酰基，用异丙亚甲基保护C2,C3-羟基，C5-羟基对甲苯磺酰化，还原，酸性条件下脱去异丙亚甲基，引入保护基，得到结构式为（I）的化合物。
（I）
其中，Lg为苯硫酚基或取代芳基硫酚基，乙硫基或脂肪硫基。
Pg为1-10个碳的酰基，苯甲酰基或取代苯甲酰基，苄基或取代苄基，烷基硅基。
本发明中适当保护的卡培他滨特征是以保护基保护卡培他滨的C2-羟基，得到结构式为（II）的化合物。
（II）
其中Pg为1-10个碳的酰基，苯甲酰基或取代苯甲酰基，苄基或取代苄基，烷基硅基。
本发明中所述的一种合成抗肿瘤药卡培他滨生产过程中产生的糖苷化杂质的方法，其特征是在有机溶剂中和惰性气体保护下，上述的结构为（I）的化合物与上述的结构为（II）的部分保护的卡培他滨在适当催化剂和脱水剂存在下，于-78℃至室温下，反应0.5～2小时，加入适当的淬灭剂，得到结构式为（III）的化合物，脱除保护基，得到最终产品。
（III）
其中，Pg为1-10个碳的酰基，苯甲酰基或取代苯甲酰基，苄基或取代苄基，烷基硅基。
所述的有机溶剂为二氯甲烷，二氯乙烷，甲苯，四氢呋喃，烷基醚，乙腈或他们的混合溶剂。
所述的惰性气体为氮气，氩气。
所述的催化剂为N-碘代丁二酰亚胺/三氟甲磺酸金属盐，N-碘代丁二酰亚胺/路易斯酸，碘单质。
所述的脱水剂为分子筛。
所述的淬灭剂是三乙胺，硫代硫酸钠。
所述的适当的脱除保护基条件是氢氧化钠，甲醇钠，催化氢化，四丁基氟化铵。
本发明的技术效果是：建立了5-脱氧-D-呋喃核糖-O-苷类化合物的通用制备方法，并以此方法成功合成了抗肿瘤药卡培他滨生产过程中产生的两种双糖苷化有关物质。
附图说明
图1为抗肿瘤药卡培他滨生产过程中产生的两个双糖苷化杂质的结构。
图2为实施例1的合成路线。
图3为实施例2的合成路线。
图4为实施例3的合成路线。
图5为实施例4的合成路线。
具体实施方式：
实施例1 2,3-二-O-叔丁基二甲基硅基-5-脱氧-β-D-呋喃核糖苯硫苷糖给体的合成
取16g四乙酰核糖与6g苯硫酚溶解于100mL二氯甲烷中，冰浴条件下滴加BF3-Et2O 2mL，加毕，撤去冰浴反应4小时，反应液用饱和碳酸氢钠洗至中性，分出有机层，浓缩，得微黄色油状物。将该油状物分散在250mL甲醇中，通氨气至饱和，反应12小时，减压蒸除溶剂，得微黄色油状物。将该油状物分散在200mL丙酮中，缓慢滴加1mL浓硫酸，加毕，室温反应12小时，加入10g碳酸氢钠，搅拌至反应液呈弱碱性，减压浓缩，所得残留物溶解于200mL二氯甲烷，水洗，有机层以无水硫酸钠干燥。过滤，滤液加入100mL三乙胺，分批加入10g对甲苯磺酰氯，室温反应5小时，反应液用水洗，有机层浓缩，所得固体用无水乙醇重结晶，得白色针状结晶15.4g，收率70.3%。
取上述产品11g，分散于200mL甲醇中，缓慢滴加5mL浓硫酸，油浴50℃反应24小时，二氯甲烷提取，无水硫酸钠干燥。过滤，滤液中加入咪唑4g，叔丁基二甲基氯硅烷15g，加热回流反应24小时，向反应液中加水搅拌2小时，分液，有机层分别用1mol/L盐酸和饱和食盐水洗，无水硫酸钠干燥。过滤，滤液浓缩至干，得无色油状物，溶解于50mL DMSO中，加入硼氢化钠1.3g，80℃反应3小时，反应完毕缓缓向反应液中加入1mol/L盐酸至不再产生气泡，产品用二氯甲烷提取，柱层析，得无色油状物产品6.3g，收率55.1%。
实施例2 2'-O-叔丁基二甲基硅基卡培他滨的合成
取卡培他滨3.6g，溶解于100mL无水二氯甲烷中，加入1g咪唑，2g叔丁基二甲基氯硅烷，搅拌反应1小时，加水终止反应，分出有机层，柱层析得2'-O-叔丁基二甲基硅基卡培他滨2.5g，收率52.7%。
实施例3 3'-(5''-脱氧-2'',3''-二-O-叔丁基二甲基硅基-β-D-核糖)-2'-O-叔丁基二甲基硅基卡培他滨和3'-(5''-脱氧-2,3-二- O-叔丁基二甲基硅基-α-D-核糖)-3'-O-叔丁基二甲基硅基卡培他滨的合成
取2'-O-叔丁基二甲基硅基卡培他滨473mg，2,3-二-O-叔丁基二甲基硅基-5-脱氧-β-D-呋喃核糖苯硫苷糖给体680mg，N-碘代丁二酰亚胺520mg用无水二氯甲烷溶解，加入分子筛，氩气保护下搅拌2小时，加入三氟甲磺酸银100mg，继续搅拌2小时，加入饱和硫代硫酸钠溶液，搅拌10分钟，分液，柱层析，得3'-(5''-脱氧-2'',3''-二-O-叔丁基二甲基硅基-β-D-核糖)-2'-O-叔丁基二甲基硅基卡培他滨460mg，收率56.3%；得3'-(5''-脱氧-2,3-二- O-叔丁基二甲基硅基-α-D-核糖)-3'-O-叔丁基二甲基硅基卡培他滨220mg，收率26.9%。
实施例4 3'-O-(5''-脱氧-β-D-核糖)卡培他滨和3'-O-(5''-脱氧-α-D-核糖)卡培他滨的制备
将上述所得产品3'-(5''-脱氧-2'',3''-二-O-叔丁基二甲基硅基-β-D-核糖)-2'-O-叔丁基二甲基硅基卡培他滨460mg溶解于10mL无水四氢呋喃中，加入200mg四丁基氟化铵，室温反应3小时，二氯甲烷提取产品，水洗，分出有机层，柱层析，得产品3'-O-(5''-脱氧-β-D-核糖)卡培他滨204mg，收率76.4%。
ESI-MS(m/z): 498.2 [M+Na]+
1H NMR (δ, CDCl3, 600MHz): 0.90 (s, 2H, H-11), 1.32-1.35 (m, 7H, H-9, H-10, 5’-CH3), 1.42 (d, 3H, 5-CH3), 1.67-1.68 (m, 2H, H-8), 3.79 (t, 1H, H-3), 4.00-4.01 (m, 1H, H-3’), 4.03-4.05 (m, 1H, H-4’), 4.13 (s, 1H, H-2’), 4.16-4.18 (m, 2H, H-7), 4.20-4.21 (m, 1H, H-4), 4.23 (s, 1H, H-2), 5.02 (s, 1H, H-1’), 5.71 (s, 1H, H-1).
13C NMR (δ, CDCl3, 600MHz): 14.09 (C-11), 18.78 (C-5), 19.71 (C-5’), 22.45 (C-10), 28.04 (C-9), 28.40 (C-8), 67.01 (C-7), 74.62 (C-2), 75.58 (C-2’), 75.77 (C-3’), 78.22 (C-4), 79.83 (C-4’), 81.89 (C-3), 91.70 (C-1), 107.96 (C-1’).
将上述所得产品3'-(5''-脱氧-2,3-二- O-叔丁基二甲基硅基-α-D-核糖)-3'-O-叔丁基二甲基硅基卡培他滨220mg溶解于10mL无水四氢呋喃中，加入100mg四丁基氟化铵，室温反应3小时，二氯甲烷提取产品，水洗，分出有机层，柱层析，得产品3'-O-(5''-脱氧-α-D-核糖)卡培他滨100mg，收率78.7%。
ESI-MS(m/z): 498.2 [M+Na]+
1H NMR (δ, CDCl3, 600MHz): 0.91 (t, 3H, H-11), 1.36-1.27 (d, 3H, 5’-CH3), 1.35-1.36 (m, 4H, H-9, H-10), 1.44-1.45 (d, 3H, 5-CH3), 1.69 (m, 2H, H-8), 3.75-3.76 (d, 1H, H-3’), 3.81-3.83 (t, 1H, H-3), 4.16 (m, 4H, H-2’, H-4’, H-7), 4.30 (s, 1H, H-2), 4.35-4.36 (m, 1H, H-4), 5.11-5.12 (d, 1H, H=1’), 5.82 (d, 1H, H-1), 7.64 (br s, 1H, N-H).
13C NMR (δ, CDCl3, 600MHz): 14.15 (C-11), 18.92 (C-5), 19.68 (C-5’), 22.50 (C-10), 28.07 (C-9), 28.44 (C-8), 66.97 (C-7), 71.89 (C-2’), 74.37 (C-2), 74.55 (C-3’), 79.64 (C-4), 81.29 (C-3),81.59(C-4’),90.54(C-1),103.43(C-1’) 。
Claims (4)
1.5-脱氧-D-呋喃核糖氧苷类化合物的制备方法，其特征在于，包括如下步骤：
（1）以四乙酰核糖为原料制备适当的硫苷糖给体（I）；
以四乙酰核糖为原料，在路易斯酸催化下与烷基硫醇或芳基硫酚在二氯甲烷中发生成硫苷反应，碱性条件下脱去乙酰基，用异丙亚甲基保护C2,C3-羟基，C5-羟基对甲苯磺酰化，还原，酸性条件下脱去异丙亚甲基，引入适当保护基，得到结构式为（ ）的化合物
（2）用保护基保护卡培他滨核糖的C2-羟基，得（II）；
以保护基保护卡培他滨的C2-羟基，得到结构式为（）的化合物：
（3）在催化剂下进行糖苷化反应，脱去保护基，得到目标化合物；
在有机溶剂和惰性气体保护下，化合物（）与化合物（）在催化剂和脱水剂存在下，于-78℃至室温下，反应0.5～2小时，加入淬灭剂得到结构式为（）的化合物，再经过分离，脱除保护基，得到目标化合物：所述的催化剂为N-碘代丁二酰亚胺/三氟甲磺酸金属盐，N-碘代丁二酰亚胺/路易斯酸，碘单质；所述的脱水剂为分子筛；所述的淬灭剂为三乙胺，硫代硫酸钠；
（） （） （）
其中，Lg为苯硫醚基或取代芳基硫醚基，乙硫醚基或脂肪硫醚基；
Pg为1-10个碳的酰基，苯甲酰基或取代苯甲酰基，苄基或取代苄基，烷基硅基。
2.如权利要求1所述的制备方法，其特征在于，所述的有机溶剂为二氯甲烷，二氯乙烷，甲苯，四氢呋喃，烷基醚，乙腈或他们的混合溶剂。
3.如权利要求1所述的制备方法，其特征在于，所述的惰性气体为氮气，氩气。
4.如权利要求1所述的制备方法，其特征在于，所述的脱除保护基条件为氢氧化钠，甲醇钠，催化氢化，四丁基氟化铵。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110455649.9A CN103183713B (zh) | 2011-12-31 | 2011-12-31 | 5-脱氧-d-呋喃核糖氧苷类化合物的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110455649.9A CN103183713B (zh) | 2011-12-31 | 2011-12-31 | 5-脱氧-d-呋喃核糖氧苷类化合物的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103183713A CN103183713A (zh) | 2013-07-03 |
| CN103183713B true CN103183713B (zh) | 2015-08-05 |
Family
ID=48675188
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110455649.9A Expired - Fee Related CN103183713B (zh) | 2011-12-31 | 2011-12-31 | 5-脱氧-d-呋喃核糖氧苷类化合物的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103183713B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910773B (zh) * | 2014-04-08 | 2015-11-25 | 宁波美诺华药业股份有限公司 | 卡培他滨杂质的合成方法 |
| CN109651466A (zh) * | 2018-12-20 | 2019-04-19 | 深圳市祥根生物科技有限公司 | 卡培他滨杂质g的制备方法 |
| CN115073540B (zh) * | 2022-07-28 | 2023-08-25 | 四川大学 | 一种菊粉型蔗果低聚糖单体的合成方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1583753A (zh) * | 2004-05-26 | 2005-02-23 | 中国药科大学 | 具有释放NO功能的噁二唑并[3,4－d]嘧啶苷类化合物及其药学上的用途 |
| WO2011010967A1 (en) * | 2009-07-23 | 2011-01-27 | Scinopharm Taiwan Ltd. | Process for producing flurocytidine derivatives |
-
2011
- 2011-12-31 CN CN201110455649.9A patent/CN103183713B/zh not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1583753A (zh) * | 2004-05-26 | 2005-02-23 | 中国药科大学 | 具有释放NO功能的噁二唑并[3,4－d]嘧啶苷类化合物及其药学上的用途 |
| WO2011010967A1 (en) * | 2009-07-23 | 2011-01-27 | Scinopharm Taiwan Ltd. | Process for producing flurocytidine derivatives |
Non-Patent Citations (1)
| Title |
|---|
| 余建鑫,等.抗肿瘤药物卡培他滨的合成工艺改进.《中国药物化学杂志》.2005,第15卷(第03期),173-175,187. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103183713A (zh) | 2013-07-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3150616B1 (en) | Mixture of rp/sp gemcitabine-[phenyl-(benzyloxy-l-alaninyl)]-phosphate | |
| ES2533710T3 (es) | Proceso para la preparación de derivados de morfolinil antraciclina | |
| CA2966138C (en) | Thionucleoside derivative or salt thereof, and pharmaceutical composition | |
| CN110753697B (zh) | 磷酸酯衍生物的合成 | |
| US20160311851A1 (en) | Methods for the synthesis of ceragenins | |
| MX2007011666A (es) | Derivados de fosforamidato de compuestos nucleosidicos para el uso en el tratamiento del cancer. | |
| CN103183713B (zh) | 5-脱氧-d-呋喃核糖氧苷类化合物的制备方法 | |
| KR20180053320A (ko) | 뉴클레오시드 포스포아미데이트 프로드러그의 제조방법 및 이의 중간체 | |
| NZ585129A (en) | Methods for preparing capecitabine and beta-anomer-rich trialkyl carbonate compound used therein | |
| EP0107486A1 (en) | Aminonaphthacene derivatives and their production | |
| Minato et al. | Synthesis and antitumor activity of des-AB analogue of steroidal saponin OSW-1 | |
| CN109836465B (zh) | 一种制备盐酸表柔比星的方法 | |
| CN109836404B (zh) | 盐酸表柔比星中间体化合物 | |
| WO2016110761A1 (en) | PROCESS FOR PRODUCING 1-β-D-ARABINOFURANOSYLCYTOSINE AND 2,2'-O-CYCLOCYTIDINE | |
| EP2716293B1 (en) | Anti-tumor agent | |
| Vega-Pérez et al. | Stereoselective synthesis of epoxyalkyl glycoside precursors of glycosyl glycerol analogues from alkenyl glycosides of N-acetyl-d-glucosamine derivatives | |
| KR101259648B1 (ko) | 2′,2′-디플루오로뉴클레오시드 및 중간체의 새로운 제조방법 | |
| CN1247610C (zh) | 虎眼万年青皂甙osw－1类型皂甙的23位杂原子取代的类似物及其合成方法和用途 | |
| CN104098594B (zh) | 生物素-鬼臼毒素酯化衍生物及其药物组合物和其制备方法与应用 | |
| Chéry et al. | Reductive opening of carbohydrate phenylsulfonylethylidene (PSE) acetals | |
| CN103265608B (zh) | 茄次碱烷型糖苷生物碱及其汇聚式合成方法 | |
| CN104098627B (zh) | 一类n‑三氟乙酰表柔红霉素的硒代衍生物，其制备方法及应用 | |
| CA2029748A1 (en) | Alkoxymethylidene epipodophyllotoxin glucosides | |
| Sun et al. | Synthesis of an isomeric nucleoside enantiomers of 1, 3-bis (1'-deoxy-β-ribofuranose-2'-yl)-thymine | |
| Bertounesque et al. | Synthesis of a highly functionalized γ-lactone as a precursor of 9-pentyl anthracyclines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150805 |