CN102757365B - 一种制备帕拉米韦关键中间体的方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 24
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 title claims abstract description 12
- 229960001084 peramivir Drugs 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 230000002829 reductive effect Effects 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 230000021736 acetylation Effects 0.000 claims description 7
- 238000006640 acetylation reaction Methods 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 229910001510 metal chloride Inorganic materials 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- FQRMVGKAQSXDPC-FNORWQNLSA-N (ne)-n-(2-ethylbutylidene)hydroxylamine Chemical compound CCC(CC)\C=N\O FQRMVGKAQSXDPC-FNORWQNLSA-N 0.000 abstract description 2
- 239000012345 acetylating agent Substances 0.000 abstract 2
- 238000012805 post-processing Methods 0.000 abstract 2
- 230000000397 acetylating effect Effects 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 238000010791 quenching Methods 0.000 abstract 1
- 230000000171 quenching effect Effects 0.000 abstract 1
- 238000007142 ring opening reaction Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- -1 amino imino Chemical group 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
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- 229910052728 basic metal Inorganic materials 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 150000001940 cyclopentanes Chemical class 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
- 229910021381 transition metal chloride Inorganic materials 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种制备帕拉米韦关键中间体的方法，该方法以中间体（II）为原料，经还原开环后，反应体系无需后处理，一锅法加入乙酰化试剂得到帕拉米韦中间体（I）(1S,2S,3S,4R,1’S)-3-(1-乙酰氨基-2-乙基丁基)-4-(Boc)-氨基-2-羟基环戊烷-1-羧酸酯。该方法省却了中间复杂的后处理过程，直接用乙酰化试剂淬灭和乙酰化，操作简单，其收率大于80%。
Description
技术领域
本发明涉及一种制备帕拉米韦关键中间体(1S,2S,3S,4R,1’S)-3-(1-乙酰氨基-2-乙基丁基)-4-(Boc)-氨基-2-羟基环戊烷-1-羧酸酯的方法，属于药物合成领域。
背景技术
帕拉米韦，英文名称Peramivir，化学名为(1S,2S,3S,4R,1’S)-(-)-3-[(1’-乙酰氨基-2’-乙基)丁基]-4{[(氨基亚氨基)甲基]氨基}-2-羟基环戊烷-1-羧酸，结构式如I所示。该药物是由美国生物晶体药品股份有限公司开发的一种环戊烷衍生物类神经胺酸酶抑制剂，能够有效抑制各类流感病毒的复制，具有耐受性好，毒副性小，能够注射等优点，是一种前景广阔的抗流感病毒药物。
现有技术中与帕拉米韦的合成方法有关的专利文献包括，CN1227466，CN1367776,CN1282316,CN和WO01/00577A1等公开了多个合成方案。以2-氮杂双环[2.2.1]庚-5-烯-3-酮为原料，经开环，氨基保护，Diels-Alder加成，还原开环，乙酰化，上甲脒，水解甲酯的合成路线。其中的还原开环，再乙酰化得到的即为重要中间体(1S,2S,3S,4R,1’S)-3-(1-乙酰氨基-2-乙基丁基)-4-(Boc)-氨基-2-羟基环戊烷-1-羧酸酯。该方法中还原开环、乙酰化分两步完成，中间需要比较繁琐的后处理过程，分离纯化出还原开环后的产物才进行乙酰化，工艺复杂，且收率低，不易于产量化生产。
发明内容
本发明提供一种制备帕拉米韦关键中间体(1S,2S,3S,4R,1’S)-3-(1-乙酰氨基-2-乙基丁基)-4-(Boc)-氨基-2-羟基环戊烷-1-羧酸酯的新方法，以中间体(Ⅱ)为原料(本发明采用的中间体II，可以采用上述的专利公开方法制备)，经还原开环后不需要后处理，直接进行乙酰化反应，得到帕拉米韦中间体(Ⅰ)，两步收率大于80%。
一种制备帕拉米韦关键中间体(1S,2S,3S,4R,1’S)-3-(1-乙酰氨基-2-乙基丁基)-4-(Boc)-氨基-2-羟基环戊烷-1-羧酸酯的新方法，包括化合物II经还原开环，再乙酰化得到化合物I的反应步骤，在无水溶液中还原开环后直接将反应液以乙酰化试剂淬灭后再乙酰化，其中R为烷基或环烷基。
所述还原开环以金属硼氢化物和金属氯化物为组合还原剂，无水溶液为中性。所述还原开环和淬灭的条件为：中性溶液，反应温度为-50℃至室温之间。
所述组合还原剂为NaBH4/NiCl2.6H2O。
化合物II可经多种还原方式开环，本发明采用金属硼氢化物和金属氯化物的组合还原、PtO2/H2体系还原以及Pd/C/H2还原等，其中金属硼氢化物包括NaBH4、KBH4、LiBH4、NaBH3CN、NaBH(OAc)3等碱金属与硼氢化物的配对，金属氯化物包括NiCl2.6H2O,CoCl2等过渡金属氯化物。
当还原剂为金属硼氢化物和金属氯化物的组合时，反应一般在质子溶剂中进行，反应温度在-50℃至室温之间，优选-15-10℃，特别优选0℃。
反应完全后将反应液直接以各种以乙酰化试剂如乙酸酐、乙酰氯或乙酰混酐淬灭，优选淬灭和乙酰化反应所用的乙酰化试剂相同，优选乙酸酐；乙酰化试剂用量一般为化合物II的1当量至50当量之间，优选2-20当量，特别优选10当量；淬灭反应温度为-50℃至室温之间；优选-15-10℃，特别优选0℃。
反应结束后化合物I可以通过常规方法如萃取，洗涤，结晶，重结晶等方法纯化得到，优选的纯化方法为柱层析或重结晶。
本专利中，除非另作说明：
“烷基”包括1-8个碳原子的直链和支链，以1–3个碳原子为佳。烷基可包括例如甲基，乙基，丙基，异丙基，丁基，异丁基，仲丁基，叔丁基，戊基等。
“环烷基”表示3-8个碳原子的饱和单环结构，例如环丙基，环丁基，环戊基，环己基等。
本发明涉及如方案1所示提供一种制备帕拉米韦关键中间体(1S,2S,3S,4R,1’S)-3-(1-乙酰氨基-2-乙基丁基)-4-(Boc)-氨基-2-羟基环戊烷-1-羧酸甲酯的新方法。本发明采用一锅法制备化合物I，中间没有复杂的后处理过程，工艺也是常规的工艺步骤，操作简单，其两步收率高于80%。
方案1
具体实施方式
下面结合实施例对本发明作进一步的详细说明。
实施例1
(1S,2S,3S,4R,1’S)-3-(1-乙酰氨基-2-乙基丁基)-4-(Boc)-氨基-2-羟基环戊烷-1-羧酸甲酯（Ⅰ）的制备:
将化合物Ⅱ(1g,2.82mmol),NiCl2·6H2O（0.7g,2.94mmol）溶于10mL甲醇和5mL四氢呋喃的混合溶剂中，冷却至-15℃，将NaBH4（0.3g，7.9mmol）缓慢加到上述体系中，加完后搅拌反应（维持体系温度-5–-10℃），TLC监控（PE:EtOAC=5：1，碘缸显色）。待原料消失后，向反应体系中滴加醋酐（3g,26mol），0℃下继续搅拌2小时(TLC:DCM:MeOH=10：1,溶液由黑色变成绿色)。以25%的氨水（2.6g,0.038mol）调pH值至9.6，低温旋去甲醇，再加入20mL水和30mL乙酸乙酯搅拌分层，水层以乙酸乙酯（30mL×2）反萃，合并有机相，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩得粗产品。粗品经快速柱层析（二氯甲烷：甲醇100：0--100：2）得白色固体产物Ⅰ。
产量：0.95g，收率：85%。
MS（M+1）：400。1H NMR(400MHz,CDCl3)δ7.57(d,J=10.1Hz,1H),4.75(d,J=9.4Hz,1H),4.27–4.23(m,1H),4.17(d,J=1.7Hz,1H),4.14(d,J=7.2Hz,1H),4.03(t,J=9.5Hz,1H),3.75(s,1H),3.72(d,J=2.0Hz,3H),2.87–2.81(m,1H),2.51(dt,J=13.5,8.9Hz,1H),2.10(s,3H),2.08–2.05(m,2H),2.02–1.96(m,1H),1.69(t,J=6.9Hz,2H),1.46(s,9H),1.28(s,1H),0.86(d,J=7.4Hz,3H),0.80(t,J=7.3Hz,3H).
Claims (4)
1.一种制备帕拉米韦关键中间体(1S,2S,3S,4R,1’S)-3-(1-乙酰氨基-2-乙基丁基)-4-(Boc)-氨基-2-羟基环戊烷-1-羧酸酯的方法，包括化合物II经还原开环，再乙酰化得到化合物I的反应步骤，其特征在于：在无水溶液中还原开环后直接将反应液以乙酰化试剂淬灭再乙酰化，其中R为烷基或环烷基；
其中，还原开环以金属硼氢化物和金属氯化物为组合还原剂，无水溶液为中性；
所述乙酰化和淬灭所使用的试剂为乙酸酐、乙酰氯或乙酰混酐，用量为化合物II的1-50当量；所述淬灭和乙酰化采用同种乙酰化试剂；
所述还原开环和淬灭的条件为：中性溶液，反应温度为-50℃至室温之间。
2.根据权利要求1所述的方法，所述组合还原剂为NaBH4/NiCl2.6H2O。
3.根据权利要求1或2所述的方法，乙酰化试剂的用量为化合物II的2-20当量。
4.根据权利要求3所述的方法，所述反应温度为-15℃至10℃。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1282316A (zh) * | 1997-12-17 | 2001-01-31 | 生物晶体药品股份有限公司 | 用作神经氨酸酶抑制剂的取代环戊烷和环戊烯化合物 |
| CN1367776A (zh) * | 1999-06-28 | 2002-09-04 | 生物晶体药品股份有限公司 | 制备取代环戊烷衍生物的方法及其新的晶体结构 |
| WO2009021404A1 (fr) * | 2007-08-14 | 2009-02-19 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. | Hydrates d'acide (1s, 2s, 3s, 4r)-3-[(1s)-1-acétylamino-2-éthylbutyl]-4-guanidino-2-hydroxylcyclopentyl-1-carboxylique et leurs utilisations pharmaceutiques |
| CN101538228A (zh) * | 2008-03-21 | 2009-09-23 | 北京普世康医药技术有限公司 | 抗流感和禽流感病毒药物化合物帕拉米韦的合成方法 |
-
2011
- 2011-04-29 CN CN 201110110078 patent/CN102757365B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1282316A (zh) * | 1997-12-17 | 2001-01-31 | 生物晶体药品股份有限公司 | 用作神经氨酸酶抑制剂的取代环戊烷和环戊烯化合物 |
| CN1367776A (zh) * | 1999-06-28 | 2002-09-04 | 生物晶体药品股份有限公司 | 制备取代环戊烷衍生物的方法及其新的晶体结构 |
| WO2009021404A1 (fr) * | 2007-08-14 | 2009-02-19 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. | Hydrates d'acide (1s, 2s, 3s, 4r)-3-[(1s)-1-acétylamino-2-éthylbutyl]-4-guanidino-2-hydroxylcyclopentyl-1-carboxylique et leurs utilisations pharmaceutiques |
| CN101538228A (zh) * | 2008-03-21 | 2009-09-23 | 北京普世康医药技术有限公司 | 抗流感和禽流感病毒药物化合物帕拉米韦的合成方法 |
Non-Patent Citations (4)
| Title |
|---|
| "BCX-1812 (RWJ-270201): Discovery of a;Y. Sudhakar Babu等;《J. Med. Chem.》;20000831;第43卷(第19期);第3482-3486页 * |
| "Stereoselective Total Synthesis of Racemic BCX-1812 (RWJ-270201);Tomoko Mineno等;《J. Org. Chem.》;20030731;第68卷(第17期);第6591-6596页 * |
| Tomoko Mineno等."Stereoselective Total Synthesis of Racemic BCX-1812 (RWJ-270201).《J. Org. Chem.》.2003,第68卷(第17期),第6591-6596页. |
| Y. Sudhakar Babu等."BCX-1812 (RWJ-270201): Discovery of a.《J. Med. Chem.》.2000,第43卷(第19期),第3482-3486页. |
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