CN116396212B - 一种高纯度吡仑帕奈中间体的制备方法 - Google Patents
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 16
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 claims abstract description 14
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
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- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
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- 235000015165 citric acid Nutrition 0.000 claims description 2
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- 238000010438 heat treatment Methods 0.000 claims 1
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- UUDAMDVQRQNNHZ-UHFFFAOYSA-N (S)-AMPA Chemical compound CC=1ONC(=O)C=1CC(N)C(O)=O UUDAMDVQRQNNHZ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- DHADXDMPEUWEAS-UHFFFAOYSA-N (6-methoxypyridin-3-yl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=N1 DHADXDMPEUWEAS-UHFFFAOYSA-N 0.000 description 1
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
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- 238000009098 adjuvant therapy Methods 0.000 description 1
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
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- 238000009835 boiling Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
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- 230000001037 epileptic effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
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- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- PRMWGUBFXWROHD-UHFFFAOYSA-N perampanel Chemical compound O=C1C(C=2C(=CC=CC=2)C#N)=CC(C=2N=CC=CC=2)=CN1C1=CC=CC=C1 PRMWGUBFXWROHD-UHFFFAOYSA-N 0.000 description 1
- 229960005198 perampanel Drugs 0.000 description 1
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Classifications
-
- 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种高纯度吡仑帕奈中间体的制备方法,包括以下步骤:将起始化合物III与酸在反应溶剂中反应成盐制得中间体II;将中间体II水解制得吡仑帕奈中间体I,所述吡仑帕奈中间体I为5‑(2‑吡啶基)‑1,2‑二氢吡啶‑2‑酮。本发明方法成功制备得到高纯度的吡仑帕奈中间体I,其中的聚合杂质IV‑a,IV‑b,V‑a均低于0.10%,该高纯度中间体I可用于制备得到高纯度吡仑帕奈。
Description
技术领域
本发明属于医药技术领域,特别涉及一种高纯度吡仑帕奈中间体的制备方法。
背景技术
吡仑帕奈(perampanel)是一种非竞争性α-氨基-3-羟基-5-甲基异恶唑-4-丙酸(AMPA)受体拮抗药,用于对12岁以上、伴有或不伴有继发性全身大发作的部分发作癫痫病患者进行辅助治疗。
5-(2-吡啶基)-1,2-二氢吡啶-2-酮(以下简称为中间体I)是制备吡仑帕奈的重要中间体。制备中间体I的起始化合物III为高沸点油状液体(1.00 mmHg,104oC),难以通过常规精制手段进行纯化。在现有工艺条件下起始化合物III纯度仅有70~80%,并且含有聚合杂质IV和杂质V。杂质IV和V在水解步骤中分别衍生为杂质IV-a、杂质IV-b和杂质V-a。结构式如下:
衍生杂质IV-a、杂质IV-b和杂质V-a与吡仑帕奈中间体I结构相似,难以通过柱层析、重结晶方法等纯化手段除去,该类聚合物可以衍生在成品吡仑帕奈中,并且在后续制备工艺中呈富集增加趋势,降低成品吡仑帕奈质量,易引起不良反应。对于原料药来讲,起始原料的质量往往对合成工艺和终产品质量有较大影响。根据质量源于设计(QbD)的研究理念,有必要在源头控制上述杂质。
发明内容
本发明为解决上述技术问题,提供一种高纯度吡仑帕奈中间体的制备方法。
本发明是采用以下技术方案得以实现的。
一种高纯度吡仑帕奈中间体的制备方法,包括以下步骤:
S1.将起始化合物III与酸在反应溶剂中反应成盐制得中间体II;
S2.将中间体II水解制得吡仑帕奈中间体I,所述吡仑帕奈中间体I为5-(2-吡啶基)-1,2-二氢吡啶-2-酮;反应过程如下:
进一步的,步骤S1中,所述酸选用有机质子酸,有机质子酸的pKa为1~5。
更进一步的,所述有机质子酸选自草酸、富马酸、酒石酸、柠檬酸、苯磺酸、对甲基苯磺酸、甲磺酸中的一种或几种的混合物。
进一步的,步骤S1中,酸与起始化合物III的摩尔比为(0.5~4.0):1。
进一步的,中间体II中,酸的数量n=0.5~2。
进一步的,步骤S1中,所述反应溶剂为酯类溶剂和/或醚类溶剂、低级醇和水的混合物。
更进一步的,所述酯类溶剂选自乙酸乙酯、醋酸异丙酯中的一种或两种的混合物。
更进一步的,所述醚类溶剂选用乙二醇二甲醚。
更进一步的,所述低级醇选自甲醇、乙醇、异丙醇中的一种或几种的混合物。
更进一步的,酯类溶剂和/或醚类溶剂、低级醇和水的体积比为(5~15):(0.5~3):(0.25~1),优选为(5~9):(0.5~2):(0.25~1)。
进一步的,步骤S1中,反应温度为20~80℃,反应时间为1~5小时。
进一步的,步骤S2中,反应结束将反应液pH调至7.0~8.0析晶。
本申请具有以下有益效果。
本发明方法成功制备得到高纯度的吡仑帕奈中间体I,其中的聚合杂质IV-a,IV-b,V-a均低于0.10%,采用本发明制备得到的中间体I可制备得到高纯度的吡仑帕奈。本发明制备过程简单,制备条件温和,具有广阔的应用前景。
附图说明
图1是本发明实施例1制备得到的粗品化合物III的高效液相色谱图;
图2是本发明实施例1制备得到的吡仑帕奈中间体I的高效液相色谱图;
图3是本发明实施例1制备得到的吡仑帕奈中间体I的质谱图谱;
图4是本发明实施例1制备得到的吡仑帕奈中间体I的核磁图谱。
具体实施方式
下面结合实施例对本发明进行进一步的说明。
实施例1
一种高纯度吡仑帕奈中间体的制备方法,包括以下步骤:
将2-甲氧基-5-吡啶硼酸(105 g,0.69 mol)、2-溴吡啶(90g,0.57mol)和醋酸钯(3.21 g,0.014 mol)、三苯基膦(15 g,0.057 mol)、碳酸钾(237g,1.72mol)、乙二醇二甲醚(900 ml)和纯化水(900 ml)在氮气条件下回流5小时。反应结束后,加入乙酸乙酯(1000ml),收集有机层混合物,分别用10%氯化铵水溶液和10%氯化钠水溶液洗涤,减压浓缩有机层混合物得到粗品化合物III,纯度83.42%,杂质IV 2.87%,杂质V 1.31%。
将粗品起始化合物III (30.00 g,0.16 mol)加入到乙酸乙酯(450 ml)、甲醇(15ml)和纯化水(7.5 ml)的混合物中,然后加入草酸(7.25 g,0.08 mol),将混合物升温至75℃并保温搅拌2小时,待固体充分析出后,降温至室温,抽滤、干燥得到中间体II-1(22.00g),纯度98.26%。
将中间体II-1 (10.00 g,0.036 mol)加入到浓盐酸(22 ml)和纯化水(22 ml)中,升温至回流,保温回流至反应完全。使用氢氧化钠水溶液调pH值至7.5,降温至0℃,抽滤、干燥得到吡仑帕奈中间体I (5.93 g),纯度99.77%,最大单杂0.07%。
实施例2
一种高纯度吡仑帕奈中间体的制备方法,包括以下步骤:
将实施例1中制得的起始化合物III (20.00 g,0.11 mol)加入到乙二醇二甲醚(100 ml)、乙醇(60 ml)和纯化水(20 ml)的混合物中,然后加入草酸(29.01 g,0.32 mol),将混合物保温20℃并保温搅拌5小时,待固体充分析出后,降温至室温,抽滤、干燥得到中间体II-2(26.00 g),纯度96.82%。
将中间体II-2(16.00 g,0.044 mol)加入到浓盐酸(26 ml)和纯化水(26 ml)中,升温至回流,保温回流至反应完全。使用氢氧化钠水溶液调pH值至7.0,降温至0℃,抽滤、干燥得到吡仑帕奈中间体I(6.50 g),纯度99.84%,最大单杂0.06%。
实施例3
一种高纯度吡仑帕奈中间体的制备方法,包括以下步骤:
将实施例1中制得的起始化合物III(15.00 g,0.08mol)加入到乙酸乙酯(150ml)、异丙醇(15 ml)和纯化水(7.5ml)的混合物中,然后加入富马酸(11.22 g,0.097mol),将混合物升温至75℃并保温搅拌1小时,待固体成分析出后,降温至室温,抽滤、干燥得到中间体II-3(21.00 g),纯度96.98%。
将中间体II-3(15.00 g, 0.05mol)加入到浓盐酸(30 ml)和纯化水(30 ml)中,升温至回流,保温回流搅拌至反应完全。使用氢氧化钠水溶液调pH值至7.5,降温至0℃,抽滤、干燥得到吡仑帕奈中间体I(7.00 g),纯度99.76%,最大单杂0.09%。
实施例4
一种高纯度吡仑帕奈中间体的制备方法,包括以下步骤:
将实施例1中制得的起始化合物III(15.00 g,0.08mol)加入到醋酸异丙酯(300ml)、甲醇(15 ml)和纯化水(7.5 ml)的混合物中,然后加入酒石酸(14.51 g,0.097mol),将混合物升温至80℃并保温搅拌2小时,待固体充分析出后,降温至室温、抽滤、干燥得到中间体II-4(20.00 g),纯度96.18%。
将中间体II-4(10.00 g,0.03mol)加入到浓盐酸(18 ml)和纯化水(18 ml)中,升温至回流,保温回流搅拌至反应完全。使用氢氧化钠水溶液调pH值至7.0,降温至0℃,抽滤、干燥得到吡仑帕奈中间体I(5.12 g),纯度99.87%,最大单杂0.07%。
实施例5
一种高纯度吡仑帕奈中间体的制备方法,包括以下步骤:
将实施例1中制得的起始化合物III(15.00 g,0.08mol)加入到乙二醇二甲醚(150ml)、乙酸乙酯(150 ml)、甲醇(45 ml)和纯化水(15 ml)的混合物中,然后加入柠檬酸(7.74g,0.051mol),将混合物升温至75℃并保温搅拌2小时,待固体充分析出后,降温至室温、抽滤、干燥得到中间体II-5(19.00 g),纯度96.35%。
将中间体II-5(10.00 g,0.035mol)加入到浓盐酸(16 ml)和纯化水(16 ml)中,升温至回流,保温回流搅拌至反应完全。使用氢氧化钠水溶液调pH值至7.5,降温至0℃,抽滤、干燥得到吡仑帕奈中间体I(4.20 g),纯度99.77%,最大单杂0.08%。
对比例
一种吡仑帕奈中间体的制备方法,包括以下步骤:
将实施例1中制得的起始化合物III (10.00 g,0.05mol)加入4M盐酸(27 ml,0.32mol)中升温至回流。待反应结束后,用甲基叔丁基醚(50 ml)萃取反应液;然后用8M氢氧化钠水溶液调pH至13后,再次用甲基叔丁基醚(50 ml)萃取反应液;接着加入稀盐酸调pH至7.5,使用正丁醇(150 ml)萃取。将正丁醇混合物减压浓缩后得到中间体I,纯度94.46%,杂质IV-a(0.32%),杂质IV-b(0.61%),杂质V-a(1.64%)。
本具体实施方式的实施例均为本发明的较佳实施例,并非依此限制本发明的保护范围,故:凡依本发明的结构、形状、原理所做的等效变化,均应涵盖于本发明的保护范围之内。
Claims (6)
1.一种高纯度吡仑帕奈中间体的制备方法,其特征在于:包括以下步骤:
S1.将起始化合物III与有机质子酸HX在反应溶剂中反应成盐制得中间体II;所述有机质子酸选自草酸、富马酸、酒石酸、柠檬酸中的一种或几种的混合物;所述反应溶剂为酯类溶剂和/或醚类溶剂、低级醇和水的混合物,酯类溶剂和/或醚类溶剂、低级醇和水的体积比为(5~15):(0.5~3):(0.25~1);
S2.将中间体II加入到浓盐酸和纯化水中,升温至回流,保温回流至反应完全;使用氢氧化钠水溶液调pH值,降温至0°C,抽滤、干燥得到吡仑帕奈中间体I,所述吡仑帕奈中间体I为5-(2-吡啶基)-1,2-二氢吡啶-2-酮;反应过程如下:
中间体II中,有机质子酸的数量n=0.5~2。
2.根据权利要求1所述的一种高纯度吡仑帕奈中间体的制备方法,其特征在于:步骤S1中,所述有机质子酸的pKa为1~5。
3.根据权利要求1所述的一种高纯度吡仑帕奈中间体的制备方法,其特征在于:步骤S1中,有机质子酸与起始化合物III的摩尔比为(0.5~4.0):1。
4.根据权利要求1所述的一种高纯度吡仑帕奈中间体的制备方法,其特征在于:所述酯类溶剂选自乙酸乙酯、醋酸异丙酯中的一种或两种的混合物。
5.根据权利要求1所述的一种高纯度吡仑帕奈中间体的制备方法,其特征在于:所述醚类溶剂选用乙二醇二甲醚。
6.根据权利要求1所述的一种高纯度吡仑帕奈中间体的制备方法,其特征在于:所述低级醇选自甲醇、乙醇、异丙醇中的一种或几种的混合物。
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