CN110621660B - 盐酸罗匹尼罗的纯化方法 - Google Patents
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- XDXHAEQXIBQUEZ-UHFFFAOYSA-N Ropinirole hydrochloride Chemical compound Cl.CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 XDXHAEQXIBQUEZ-UHFFFAOYSA-N 0.000 title claims abstract description 80
- UHSKFQJFRQCDBE-UHFFFAOYSA-N Ropinirole hydrochloride Natural products CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 title claims abstract description 79
- 229960002349 ropinirole hydrochloride Drugs 0.000 title claims abstract description 79
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000000746 purification Methods 0.000 title claims abstract description 9
- 239000012535 impurity Substances 0.000 claims abstract description 35
- 238000003756 stirring Methods 0.000 claims abstract description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000012044 organic layer Substances 0.000 claims abstract description 22
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000001035 drying Methods 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims abstract description 10
- 239000010410 layer Substances 0.000 claims abstract description 9
- VKDWFHAQOZYATG-UHFFFAOYSA-N N-despropyl ropinirole Chemical compound CCCNCCC1=CC=CC2=C1CC(=O)N2 VKDWFHAQOZYATG-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000008065 acid anhydrides Chemical class 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001266 acyl halides Chemical class 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012346 acetyl chloride Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- 150000001263 acyl chlorides Chemical class 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000005793 Restless legs syndrome Diseases 0.000 description 3
- -1 nitrostyrene compound Chemical class 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- MWDNYZPRNANTLQ-UHFFFAOYSA-N 1-ethyl-3H-indol-2-one hydrochloride Chemical compound Cl.C(C)N1C(CC2=CC=CC=C12)=O MWDNYZPRNANTLQ-UHFFFAOYSA-N 0.000 description 2
- YPQAFWHSMWWPLX-UHFFFAOYSA-N 1975-50-4 Chemical compound CC1=C(C(O)=O)C=CC=C1[N+]([O-])=O YPQAFWHSMWWPLX-UHFFFAOYSA-N 0.000 description 2
- PHDOYZATHWYOJK-UHFFFAOYSA-N 2-(2-bromoethyl)benzaldehyde Chemical compound BrCCC1=CC=CC=C1C=O PHDOYZATHWYOJK-UHFFFAOYSA-N 0.000 description 2
- VDVJKASXRBDEQM-UHFFFAOYSA-N 3-(2-bromoethyl)aniline Chemical compound NC1=CC=CC(CCBr)=C1 VDVJKASXRBDEQM-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- HEBMCVBCEDMUOF-UHFFFAOYSA-N isochromane Chemical compound C1=CC=C2COCCC2=C1 HEBMCVBCEDMUOF-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- LWIOFILTAJJDLA-UHFFFAOYSA-N 2-methyl-3-nitrophenylacetic acid Chemical compound CC1=C(CC(O)=O)C=CC=C1[N+]([O-])=O LWIOFILTAJJDLA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000001913 cyanates Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
提供一种盐酸罗匹尼罗4‑2‑二正丙基胺乙基‑1,3‑二氢‑2H‑吲哚‑2‑酮盐酸盐的纯化方法。该方法包括:将含有杂质A单丙基罗匹尼罗的盐酸罗匹尼罗加入水中,并加入有机溶剂,室温下搅拌溶清加入碱,搅拌后静置分层,除去水层,任选地用无水硫酸镁干燥有机层并过滤,向有机层加入酰氯或酸酐,搅拌后,浓缩有机层至干,向得到的油状物中加入有机溶剂,加入浓盐酸搅拌后得到盐酸罗匹尼罗。所述方法能够有效地除去盐酸罗匹尼罗中的杂质A,能够以较好的收率和纯度获得盐酸罗匹尼罗,从而控制杂质A使产品纯度达到药用标准。
Description
技术领域
本发明涉及盐酸罗匹尼罗的纯化方法,特别地,涉及去除盐酸罗匹尼罗杂质A单丙基罗匹尼罗的纯化方法。杂质A的结构(I)为:
背景技术
盐酸罗匹尼罗由GlaxoSmithKline(GSK)开发,美国食品药品管理局(FDA)批准第一个盐酸罗匹尼罗(Ropinirole hydrochloride)仿制药。
盐酸罗匹尼罗用于治疗中度到重度的多动腿综合征(Restless Legs Syndrome,RLS)。除此之外,FDA还曾批准盐酸罗匹尼罗用于治疗帕金森氏症。因为盐酸罗匹尼罗治疗帕金森氏症的用途受到了专利保护,所以盐酸罗匹尼罗仿制药仅能获准治疗多动腿综合征。一旦原研药厂的盐酸罗匹尼罗治疗帕金森氏症的用途专利期满后,仿制药生产商才可能寻求获准该药治疗帕金森氏症的可能。盐酸罗匹尼罗的结构式为如以下式(II)所示:
目前专利或者非专利文献已报道的制备盐酸罗匹尼罗的方法主要有五种,其分别以2-甲基-3-硝基-苯甲酸为原料(US4452808)、以3-溴乙基苯胺为原料(WO1994/015918)、以异苯并二氢吡喃为原料(EP0300614、US4997954)、以4-吲哚甲醛为原料(US2007032540)、以邻溴乙基苯甲醛为原料(US0156505)合成盐酸罗匹尼罗。
具体而言,专利US4452808以2-甲基-3-硝基-苯甲酸为原料,利用硼烷氢化反应,加氯化亚砜制得酰氯、腈化、水解得到2-甲基-3-硝基-苯乙酸,然后再制得酰胺,加氢还原、缩合、氧化水解,最后加氢还原,成盐得到盐酸罗匹尼罗;专利WO1994/015918以3-溴乙基苯胺为原料,经过成环、氧化、取代、还原得到盐酸罗匹尼罗;而专利EP0300614、US4997954以异苯并二氢吡喃为原料,经过溴化开环,在强碱作用下制得硝基苯乙烯化合物,再经过闭环、还原、取代反应得到盐酸罗匹尼罗;专利US2007032540以4-吲哚甲醛为原料,经过硝基甲烷反应得到硝基苯乙烯化合物,再经过加氢还原、与丙酸加成、还原,最后氧化得到盐酸罗匹尼罗;最后,专利US0156505以邻溴乙基苯甲醛为原料,经取代、与硝基甲烷反应得到硝基苯乙烯化合物,再经过环化、氧化、水解等得到盐酸罗匹尼罗。
但是上述文献都未提及一个重要的生产问题,即在盐酸罗匹尼罗生产的一步中间体中,因氧化过强产生副产物单丙基杂质,在最后一道工序时,该杂质转变为盐酸罗匹尼罗杂质A,即单丙基罗匹尼罗,该杂质在诸多合成路线中都会产生。特别要提出的是,在专利US4452808中,该杂质A是合成盐酸罗匹尼罗的中间体中含有的副产物,经过氢化还原再成盐得到含有杂质A的盐酸罗匹尼罗。由于该杂质A结构与盐酸罗匹尼罗产品相似,很难用常规手段实现分离。常用的溶剂洗涤、打浆、重结晶等方法很难去除杂质A,同时还会影响盐酸罗匹尼罗产品的收率。因此需要一种简便、廉价以及有效的纯化工艺来除去该杂质A。
发明内容
发明人研发了一种盐酸罗匹尼罗4-2-二正丙基胺乙基-1,3-二氢-2H-吲哚-2-酮盐酸盐的纯化方法,能够简便、廉价以及有效地除去杂质A(结构式I)。
具体而言,本发明提供了结构式(II)所示的盐酸罗匹尼罗4-2-二正丙基胺乙基-1,3-二氢-2H-吲哚-2-酮盐酸盐的纯化方法,其包括如下步骤:
(1)将含有结构式(I)所示的杂质A单丙基罗匹尼罗的盐酸罗匹尼罗与水和有机溶剂混合,室温下搅拌溶清加入碱,搅拌后静置分层,除去水层;其中所述有机溶剂为非质子溶剂;所述碱为碱金属或碱土金属的氢氧化物、碳酸盐或碳酸氢盐,或者为由C1-C6烷基单取代或多取代的胺;
(2)将得到的有机层用无水硫酸镁干燥,过滤;或有机层不加无水硫酸镁,直接进行下步操作;
(3)向有机层中加入结构式(IV)的酰卤或酸酐,搅拌并浓缩;
(4)浓缩至干后,向得到的油状物中加入有机溶剂,加入浓盐酸搅拌后,得到盐酸罗匹尼罗;其中所述有机溶剂为醇。
上述步骤(1)中,室温下搅拌溶清加入碱之后,例如可搅拌20分钟以上,然后静置分层。其中有机溶剂的以毫升计的体积用量可为盐酸罗匹尼罗以克计的质量的2~20倍,优选为5~15倍,更优选为8~12倍。水的以毫升计的体积用量可为盐酸罗匹尼罗以克计的质量的5~20倍。步骤(1)中碱的摩尔用量为盐酸罗匹尼罗摩尔用量的1.5~25倍,优选为5~15倍。此外,步骤(1)中的有机溶剂可为二氯甲烷、正己烷、环己烷、乙酸乙酯、乙酸异丙酯、甲苯、二甲苯或甲基叔丁基醚。步骤(1)中的碱可以选自碳酸钠、氢氧化钾、氢氧化钠、碳酸钾、碳酸氢钠、三乙胺或二异丙基胺。
步骤(3)中,向有机层中加入酰卤或酸酐,可搅拌例如10分钟,浓缩。酰卤或酸酐的摩尔用量可为盐酸罗匹尼罗杂质A摩尔量的1~5倍。除杂试剂酰卤或酸酐可选自乙酰氯、丙酰氯、苯甲酰氯、乙酸酐或苯甲酸酐等;优选为乙酰氯、苯甲酰氯或乙酸酐。酰卤或酸酐的摩尔用量为盐酸罗匹尼罗杂质A摩尔量的1~5倍。
步骤(4)中,加入浓盐酸搅拌后,可将料液冷却、甩滤并烘干得到盐酸罗匹尼罗。步骤(4)中,可将有机层浓缩至干后,向得到的油状物中加入一定量的有机溶剂,溶剂以毫升计的体积用量可为盐酸罗匹尼罗以克计的重量的2~20倍。控制反应液温度为15±5℃,缓慢加入一定量的浓盐酸,浓盐酸的用量可为盐酸罗匹尼罗摩尔用量的2~10倍,优选2~5倍。继续搅拌例如30分钟。可将料液冷却至5±5℃并继续搅拌40分钟,甩滤并烘干得到盐酸罗匹尼罗。其中,所使用浓盐酸的质量浓度为37%,其用量以浓盐酸中的HCl的量来计算。其中步骤(4)的有机溶剂可为甲醇、乙醇、异丙醇或正丁醇。
以上各步骤中均需要严格做好氮气保护。
本发明通过上述方法,能够有效除去盐酸罗匹尼罗中的杂质A,能够以较好的收率和纯度获得盐酸罗匹尼罗,从而控制杂质A使产品纯度达到药用标准。
具体实施方式
以下的实施例在于详细说明本发明,而非限制本发明。
所有过程均需做好氮气保护,后面不再反复说明。
实施例1
取4-2-二正丙基胺乙基-1,3-二氢-2H-吲哚-2-酮盐酸盐(盐酸罗匹尼罗,结构式II)(8.9g,0.03摩尔)、二氯甲烷90ml、纯化水135ml于250ml烧瓶中搅拌,同时缓慢加入氢氧化钠(6g,0.15摩尔)。加毕后继续搅拌20分钟,静置分层。去掉水层,用3g无水硫酸镁干燥有机层,搅拌30分钟,过滤并分离有机层。
向有机层中加入盐酸罗匹尼罗杂质A摩尔量2倍的乙酰氯,搅拌10分钟,浓缩至干得到油状物。
向得到的油状物中加入125ml异丙醇,控制反应液温度15±5℃,缓慢加入9.0g浓盐酸(质量浓度为37%),加入完毕后,继续搅拌30分钟。最后将料液冷却至5±5℃继续搅拌1h,甩滤至干。
烘干得到盐酸罗匹尼罗粗品,收率90%。HPLC检测纯度为99.89%,杂质A含量为未检出(N.D)。
盐酸罗匹尼罗有关物质的HPLC分析方法如下:
仪器:高效液相色谱仪配备紫外检测器
色谱柱:Waters XterraTM RP18250×4.6mm,5μm
流动相A:2.84g Na2HPO4溶于1000ml水中,用1摩尔/L的NaOH调pH11.0
流动相B:乙腈
稀释液:流动相A∶流动相B=70∶30(%V/V)
色谱柱温:25℃ 检测波长:250nm
流速:1.0ml/分钟 运行时间:35分钟
进样量:20μL
梯度表:
称取50mg盐酸罗匹尼罗标准品,精密称定于100ml容量瓶中,用稀释液溶解并稀释至刻度,混匀(盐酸罗匹尼罗浓度500μg/ml)。
实施例2
取4-2-二正丙基胺乙基-1,3-二氢-2H-吲哚-2-酮盐酸盐(盐酸罗匹尼罗,结构式II)(8.9g,0.03摩尔)、正己烷90ml、纯化水135ml于250ml烧瓶中搅拌,同时缓慢加入8.4g氢氧化钾。加毕后继续搅拌20分钟,静置分层,去掉水层。
有机层中加入盐酸罗匹尼罗杂质A摩尔量2倍的乙酸酐,搅拌10分钟,浓缩至干得到油状物。
向得到的油状物中加入125ml乙醇,控制反应液温度15±5℃,缓慢加入9.0g浓盐酸,加入完毕后,继续搅拌30分钟。最后将料液冷却至5±5℃继续搅拌1h,甩滤至干。
烘干得到盐酸罗匹尼罗粗品,收率88%。HPLC检测纯度为99.91%,杂质A含量0.02%。
实施例3
取4-2-二正丙基胺乙基-1,3-二氢-2H-吲哚-2-酮盐酸盐(盐酸罗匹尼结构式II)(8.9g,0.03摩尔)、乙酸乙酯90ml、纯化水135ml于250ml烧瓶中搅拌,同时缓慢加入15.9g碳酸钠。加毕后继续搅拌20分钟,静置分层。去掉水层,用3g无水硫酸镁干燥有机层,搅拌30分钟,过滤并分离有机层。
有机层中加入盐酸罗匹尼罗杂质A摩尔量2倍的丙酰氯,搅拌10分钟,浓缩至干得到油状物。
向得到的油状物中加入125ml甲醇,控制反应液温度15±5℃,缓慢加入9.0g浓盐酸,加入完毕后,继续搅拌30分钟。最后将料液冷却至5±5℃继续搅拌1h,甩滤至干。
烘干得到盐酸罗匹尼罗粗品,收率85%。HPLC检测纯度为99.88%,杂质A含量0.01%。
实施例4
取4-2-二正丙基胺乙基-1,3-二氢-2H-吲哚-2-酮盐酸盐(盐酸罗匹尼罗,结构式II)(8.9g,0.03摩尔)、甲苯90ml、纯化水135ml于250ml烧瓶中搅拌,同时缓慢加入20.7g碳酸钾。加毕后继续搅拌20分钟,静置分层。去掉水层,用3g无水硫酸镁干燥有机层,搅拌30分钟,过滤并分离有机层。
有机层中加入盐酸罗匹尼罗杂质A摩尔量2倍的苯甲酰氯,搅拌10分钟,浓缩至干得到油状物。
向得到的油状物中加入125ml异丙醇,控制反应液温度15±5℃,缓慢加入9.0g浓盐酸,加入完毕后,继续搅拌30分钟。最后将料液冷却至5±5℃继续搅拌1h,甩滤至干。
烘干得到盐酸罗匹尼罗粗品,收率90%。HPLC检测纯度为99.94%,杂质A含量为未检出(N.D)。
实施例5
取4-2-二正丙基胺乙基-1,3-二氢-2H-吲哚-2-酮盐酸盐(盐酸罗匹尼罗,结构式II)(8.9g,0.03摩尔)、甲苯90ml、纯化水135ml于250ml烧瓶中搅拌,同时缓慢加入20.7g碳酸钾。加毕后继续搅拌20分钟,静置分层。去掉水层,用3g无水硫酸镁干燥有机层,搅拌30分钟,过滤并分离有机层。
有机层中加入盐酸罗匹尼罗杂质A摩尔量1倍的苯甲酰氯,搅拌10分钟,浓缩至干得到油状物。
向得到的油状物中加入125ml异丙醇,控制反应液温度15±5℃,缓慢加入12.0g浓盐酸,加入完毕后,继续搅拌30分钟。最后将料液冷却至5±5℃继续搅拌1h,甩滤至干。
烘干得到盐酸罗匹尼罗粗品,收率90%。HPLC检测纯度为99.93%,杂质A含量为0.03%。
实施例6
取4-2-二正丙基胺乙基-1,3-二氢-2H-吲哚-2-酮盐酸盐(盐酸罗匹尼罗,结构式II)(8.9g,0.03摩尔)、甲苯90ml、纯化水135ml于250ml烧瓶中搅拌,同时缓慢加入20.7g碳酸钾。加毕后继续搅拌20分钟,静置分层。去掉水层,用3g无水硫酸镁干燥有机层,搅拌30分钟,过滤并分离有机层。
有机层中加入盐酸罗匹尼罗杂质A摩尔量5倍的苯甲酰氯,搅拌10分钟,浓缩至干得到油状物。
向得到的油状物中加入125ml异丙醇,控制反应液温度15±5℃,缓慢加入6.0g浓盐酸,加入完毕后,继续搅拌30分钟。最后将料液冷却至5±5℃继续搅拌1h,甩滤至干。
烘干得到盐酸罗匹尼罗粗品,收率91%。HPLC检测纯度为99.95%,杂质A含量为0.01%。
下表是用不同杂质A(单丙基罗匹尼罗)含量的盐酸罗匹尼罗纯化后的对照表。
Claims (10)
1.一种结构式(II)所示的盐酸罗匹尼罗4-2-二正丙基胺乙基-1,3-二氢-2H-吲哚-2-酮盐酸盐的纯化方法,其特征在于,包括如下步骤:
其中,-R代表C1-C6的烷基或C6-C10的芳香族基团;
(1)将含有结构式(I)所示的杂质A单丙基罗匹尼罗的盐酸罗匹尼罗与水和有机溶剂混合,室温下搅拌溶清加入碱,搅拌后静置分层,除去水层;其中所述有机溶剂为非质子溶剂;所述碱为碱金属或碱土金属的氢氧化物、碳酸盐或碳酸氢盐,或者为由C1-C6烷基单取代或多取代的胺;
(2)将得到的有机层用无水硫酸镁干燥,过滤;或有机层不加无水硫酸镁,直接进行下步操作;
(3)向有机层中加入结构式(IV)的酰卤或酸酐,搅拌并浓缩;
(4)浓缩至干后,向得到的油状物中加入有机溶剂,加入浓盐酸搅拌后,得到盐酸罗匹尼罗;其中所述有机溶剂为醇。
2.根据权利要求1所述的方法,其特征在于,步骤(1)中有机溶剂以毫升计的体积用量为盐酸罗匹尼罗以克计的质量的2~20倍,水的以毫升计的体积用量为盐酸罗匹尼罗以克计的质量的5~20倍。
3.根据权利要求1所述的方法,其特征在于,步骤(1)中碱的摩尔用量为盐酸罗匹尼罗摩尔用量的1.5~25倍。
4.根据权利要求1所述的方法,其特征在于,步骤(1)中的有机溶剂为二氯甲烷、正己烷、环己烷、乙酸乙酯、乙酸异丙酯、甲苯、二甲苯或甲基叔丁基醚。
5.根据权利要求1所述的方法,其特征在于,步骤(1)中所述的碱选自碳酸钠、氢氧化钾、氢氧化钠、碳酸钾、碳酸氢钠、三乙胺或二异丙基胺。
6.根据权利要求1-5任一项所述的方法,其特征在于,步骤(3)中的酰卤或酸酐选自乙酰氯、丙酰氯、苯甲酰氯、乙酸酐或苯甲酸酐,其摩尔用量为杂质A摩尔量的1~5倍。
7.根据权利要求6所述的方法,其中所述酰卤或酸酐选自乙酰氯、苯甲酰氯或乙酸酐。
8.根据权利要求1-5任一项所述的方法,其特征在于,步骤(4)中有机溶剂以毫升计的体积用量为盐酸罗匹尼罗以克计的质量的2~20倍。
9.根据权利要求1-5任一项所述的方法,其特征在于,步骤(4)中浓盐酸的摩尔用量为盐酸罗匹尼罗摩尔量的2~10倍。
10.根据权利要求1-5任一项所述的方法,其特征在于,步骤(4)中的有机溶剂为甲醇、乙醇、异丙醇或正丁醇。
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