CN113943247A - 一种比沙可啶的制备方法 - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- KHOITXIGCFIULA-UHFFFAOYSA-N Alophen Chemical compound C1=CC(OC(=O)C)=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OC(C)=O)C=C1 KHOITXIGCFIULA-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 229960000503 bisacodyl Drugs 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
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- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
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- 238000012544 monitoring process Methods 0.000 description 6
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000007605 air drying Methods 0.000 description 4
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- 239000007810 chemical reaction solvent Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
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- 239000000126 substance Substances 0.000 description 2
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- 239000008346 aqueous phase Substances 0.000 description 1
- RFVHVYKVRGKLNK-UHFFFAOYSA-N bis(4-methoxyphenyl)methanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC=C(OC)C=C1 RFVHVYKVRGKLNK-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000002650 habitual effect Effects 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供式Ⅰ所示的制备方法，比沙可啶的制备方法。
Description
技术领域
本发明属于药物化学领域，主要涉及式Ⅰ所示的比沙可啶的制备方法。
背景技术
比沙可啶（Ⅰ）（Bisacodyl）勃林格殷格翰公司原研，用于急、慢便秘和习惯性便秘。
发明内容
本发明提供式Ⅰ所示的比沙可啶制备方法。
本发明制备方法，包含以下步骤：
（1）在有机溶剂中4,4'-二甲氧基二苯甲酮（II）经还原得到式（III）化合物
（2）化合物（III）经卤代得（IV）化合物；
（3）化合物（IV）与化合物（V）经傅克烷基化得化合物（VI）；
（4）化合物（VI）醚键水解得到化合物（I）
其中步骤1优选以下条件：
反应溶剂建议为甲醇，乙醇，异丙醇。优选甲醇；
反应温度建议为25~75oC，优选65~75 oC。
步骤2优选以下条件：
反应使用溶剂建议为二氯甲烷，氯仿，甲苯。优选氯仿；
反应温度建议为50~80oC，优选70~80 oC。
步骤3优选以下条件：
反应溶剂建议为氯仿，四氢呋喃，甲基叔丁基醚。优选四氢呋喃；
反应温度建议为25~65oC，优选55~65oC；
步骤4优选以下条件
反应溶剂建议为丙酮，四氢呋喃，甲醇。优选甲醇；
反应温度建议为25~65oC，优选55~65oC；
本发明为氯雷他定中间体的制备提供了新的方法。
具体实施方式
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例1：
（1）先三口瓶中加入化合物II 30.0 g，加入150 ml甲醇，常温搅拌使体系溶清，溶清后分批加入硼氢化钠9.4 g，升温至70 oC反应3 h，TLC监控反应完成，冰浴将体系温度降至0~5 oC，用10 ml纯化水淬灭反应，淬灭完毕后旋干所有溶剂得 33.0 g白色固体即为化合物III粗品。
（2）取33.0 g化合物III粗品，加入氯仿150 ml，开启搅拌，缓慢滴加氯化亚砜36.0g，加毕后升温至体系回流，TLC监控反应完全后，体系冰浴降温至5~10 oC加水60ml淬灭反应，淬灭完毕后分液，收集下层有机相，水相用30ml氯仿洗，洗毕后分液收集有机相，无水硫酸钠干燥2h，有机相旋干后得黄色油状物即为化合物IV 26.1g。
（3）取25.0 g化合物IV，置于三口瓶中，加入125 ml四氢呋喃，加入无水三氯化铝25.2g，搅拌下滴加吡啶8.3 g，滴加完毕后升温至60 oC反应，TLC监控反应完全后降至0~5oC，向体系中加水125 ml，充分搅拌后分液，留存上层有机相。有机相再用2×125 ml水洗后用125 ml饱和氯化钠水溶液洗，洗毕后收集所有有机相，旋干黄色固体，粗品用甲基叔丁基醚100ml打浆，打浆完毕2h过滤，收集滤饼置于50oC鼓风干燥箱干燥，得23.0 g类白色固体即为化合物VI。
（4）将20.0 g化合物VI置于三口瓶中，加四氢呋喃100 ml，浓盐酸11 ml，开启加热，升温至60 oC反应8 h，TLC检测原料点消失，降温至0~5 oC，用6 mol/L氢氧化钠调PH值至7-8，调毕后旋干体系中的四氢呋喃，旋干后加乙酸乙酯60ml萃取水相，分液后再用2×20ml乙酸乙酯洗水相，分液收集所有有机相。有机相再用60 ml饱和食盐水洗，收集有机相，旋干溶剂得黄色固体，固体用乙醇/异丙醚（体积比=1/2）60ml重结晶，抽滤，收集固体置于50 oC鼓风干燥箱干燥，得白色固体即得为化合物I 18.3g。
实施例2：
（1）先三口瓶中加入化合物II 30.0 g，加入150 ml异丙醇，常温搅拌使体系溶清，溶清后分批加入硼氢化钠9.4 g，升温至70 oC反应5 h，TLC监控反应完成，冰浴将体系温度降至0~5 oC，用10 ml纯化水淬灭反应，淬灭完毕后旋干所有溶剂得 31.0 g白色固体即为化合物III粗品。
（2）取31.0 g化合物III粗品，加入甲苯150 ml，开启搅拌，缓慢滴加氯化亚砜35.0g，加毕后升温至体系回流，TLC监控反应完全后，体系冰浴降温至5~10 oC加水60ml淬灭反应，淬灭完毕后分液，收集下层有机相，水相用30 ml氯仿洗，洗毕后分液收集有机相，无水硫酸钠干燥2h，有机相旋干后得黄色油状物即为化合物IV 25.0g。
（3）取25.0 g化合物IV，置于三口瓶中，加入125 ml氯仿，加入无水三氯化铝25.2g，搅拌下滴加吡啶8.3 g，滴加完毕后升温至60 oC反应，TLC监控反应完全后降至0~5oC，向体系中加水125 ml，充分搅拌后分液，留存上层有机相。有机相再用2×125 ml水洗后用125 ml饱和氯化钠水溶液洗，洗毕后收集所有有机相，旋干黄色固体，粗品用甲基叔丁基醚100ml打浆，打浆完毕2h过滤，收集滤饼置于50oC鼓风干燥箱干燥，得20.0 g类白色固体即为化合物VI。
（4）将20.0 g化合物VI置于三口瓶中，加甲醇100 ml，浓盐酸11 ml，开启加热，升温至60 oC反应8 h，TLC检测原料点消失，降温至0~5 oC，用6 mol/L氢氧化钠调PH值至7-8，调毕后旋干体系中的四氢呋喃，旋干后加乙酸乙酯60ml萃取水相，分液后再用2×20ml乙酸乙酯洗水相，分液收集所有有机相。有机相再用60 ml饱和食盐水洗，收集有机相，旋干溶剂得黄色固体，固体用甲醇/异丙醚（体积比=1/2）60ml重结晶，抽滤，收集固体置于50 oC鼓风干燥箱干燥，得白色固体即得为化合物I 15.1g。
Claims (9)
1.比沙可啶的制备方法，其特征在于，包括以下步骤：
1）将式II的化合物溶于有机溶剂中，加入硼氢化钠回流反应，得到式III的化合物；
2）式III溶解于有机溶剂中，经氯化亚砜卤代得化合物IV；
3）式IV溶解于有机溶剂中，与化合物V经傅克烷基化得化合物VI；
4）式VI溶解于有机溶剂中，酸性条件下水解得化合物I；
2.根据权利要求1的方法，其步骤1采用的有机溶剂优选甲醇。
3.根据权利要求1的方法，其步骤1反应温度优选65~75 oC。
4.根据权利要求1的方法，其步骤2采用的有机溶剂优选氯仿。
5.根据权利要求1的方法，其步骤2反应温度优选70~80 oC。
6.根据权利要求1的方法，其步骤3采用的有机溶剂优选四氢呋喃。
7.根据权利要求1的方法，其步骤3反应温度优选55~65 oC。
8.根据权利要求1的方法，其步骤4采用的有机溶剂优选甲醇。
9.根据权利要求1的方法，其步骤4反应温度优选55~65 oC。
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