CN115594665A - 拉司米地坦的新制备方法 - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- RUJTWTUYVOEEFW-UHFFFAOYSA-N 1-(6-bromopyridin-2-yl)ethanone Chemical compound CC(=O)C1=CC=CC(Br)=N1 RUJTWTUYVOEEFW-UHFFFAOYSA-N 0.000 claims abstract description 4
- SJZATRRXUILGHH-UHFFFAOYSA-N 2,4,6-trifluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=C(F)C=C1F SJZATRRXUILGHH-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940125782 compound 2 Drugs 0.000 claims abstract description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- MYGXGCCFTPKWIH-UHFFFAOYSA-N 4-chloro-1-methylpiperidine Chemical group CN1CCC(Cl)CC1 MYGXGCCFTPKWIH-UHFFFAOYSA-N 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- RTEVQEDKZPFGNP-UHFFFAOYSA-N 4-bromo-1-methylpiperidine Chemical compound CN1CCC(Br)CC1 RTEVQEDKZPFGNP-UHFFFAOYSA-N 0.000 claims description 2
- 101150003085 Pdcl gene Proteins 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
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- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 claims 1
- 229960000245 rasagiline Drugs 0.000 claims 1
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- XIFPGOFGUAEGAC-UHFFFAOYSA-N (6-bromopyridin-2-yl)-(1-methylpiperidin-4-yl)methanone Chemical compound C1CN(C)CCC1C(=O)C1=CC=CC(Br)=N1 XIFPGOFGUAEGAC-UHFFFAOYSA-N 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
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- 239000011734 sodium Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000007112 amidation reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000006138 lithiation reaction Methods 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
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- 238000001035 drying Methods 0.000 description 2
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- YVUBWJOBCFNMES-UHFFFAOYSA-N formamide;pyridine Chemical compound NC=O.C1=CC=NC=C1 YVUBWJOBCFNMES-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
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- -1 1-methylpiperidine-4-carbonyl Chemical group 0.000 description 1
- NHTZOVLQKKXFJM-UHFFFAOYSA-N 1-methylpiperidine-4-carbonyl chloride;hydrochloride Chemical compound Cl.CN1CCC(C(Cl)=O)CC1 NHTZOVLQKKXFJM-UHFFFAOYSA-N 0.000 description 1
- HCKNAJXCHMACDN-UHFFFAOYSA-N 1-methylpiperidine-4-carboxylic acid Chemical compound CN1CCC(C(O)=O)CC1 HCKNAJXCHMACDN-UHFFFAOYSA-N 0.000 description 1
- SIFIJQFBERMWMU-UHFFFAOYSA-N 2,4,6-trifluorobenzoyl chloride Chemical compound FC1=CC(F)=C(C(Cl)=O)C(F)=C1 SIFIJQFBERMWMU-UHFFFAOYSA-N 0.000 description 1
- FEYDZHNIIMENOB-UHFFFAOYSA-N 2,6-dibromopyridine Chemical compound BrC1=CC=CC(Br)=N1 FEYDZHNIIMENOB-UHFFFAOYSA-N 0.000 description 1
- HBOJNFXMGHTSCI-UHFFFAOYSA-N 2-bromo-6-(1-methylpiperidin-4-yl)pyridine Chemical compound C1CN(C)CCC1C1=CC=CC(Br)=N1 HBOJNFXMGHTSCI-UHFFFAOYSA-N 0.000 description 1
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 1
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 1
- NKQIZBOGYBMJDU-UHFFFAOYSA-N 6-(1-methylpiperidin-4-yl)pyridin-2-amine Chemical compound C1CN(C)CCC1C1=CC=CC(N)=N1 NKQIZBOGYBMJDU-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 206010034960 Photophobia Diseases 0.000 description 1
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- 239000004480 active ingredient Substances 0.000 description 1
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- 230000009435 amidation Effects 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 231100000869 headache Toxicity 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- XEDHVZKDSYZQBF-UHFFFAOYSA-N lasmiditan Chemical compound C1CN(C)CCC1C(=O)C1=CC=CC(NC(=O)C=2C(=CC(F)=CC=2F)F)=N1 XEDHVZKDSYZQBF-UHFFFAOYSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- HPSNOVOYRZPVAW-UHFFFAOYSA-N n-methoxy-n,1-dimethylpiperidine-4-carboxamide Chemical compound CON(C)C(=O)C1CCN(C)CC1 HPSNOVOYRZPVAW-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 208000017376 neurovascular disease Diseases 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Substances ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- ZISSAWUMDACLOM-UHFFFAOYSA-N triptane Chemical class CC(C)C(C)(C)C ZISSAWUMDACLOM-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
本发明提供了一种拉司米地坦的制备方法，其以市购的2‑乙酰基‑6‑溴吡啶与2,4,6‑三氟苯甲酸为原料在有一定条件下，五步合成拉司米地坦。本发明的制备方法重点在合成化合物2（(6‑溴‑2‑吡啶基)(1‑甲基‑4‑哌啶基)甲酮），经过不同的起始物料反应、不同的反应机理制备拉司米地坦，无需采用手性制备色谱柱分离步骤，可以直接得到高纯度的拉司米地坦。该方法收率高、后处理简便、生产成本低、适合工业化生产。
Description
技术领域
本发明涉及一种新的拉司米地坦的制备方法。
背景技术
偏头痛是一种长期常见的、周期性反复发作的神经血管性疾病,发作时伴有中重度搏动样头痛,单侧常见,或双侧交替发作或累及双侧,伴随某些自主神经症状,如惧声、恶心、呕吐、畏光等,具有发病时间长、病情迁延、难于治愈等特点。可发生于任何年龄,首次发病多见于青春期。女性患病率高于男性，偏头痛对生活质量的影响很大,世界卫生组织(WHO)2001年发布的报告,将常见疾病按健康寿命损失年排列,偏头痛位列前20位,并将严重的偏头痛定为最致残的疾病,类同于痴呆、瘫痪和严重精神病。（治疗急性偏头痛新药的有效成分是拉司米地坦(lasmiditan),制剂的稳定成分是半琥珀酸盐,由美国礼来公司(Eli Lilly)于2003年3月最先研制,礼来公司于2018年11月14日向美国食品药品管理局(FDA)提交新药上市申请,2019年10月11日获准上市。半琥珀酸拉司米地坦片的商品名为Reyvow®。拉司米地坦是口服、中枢神经系统渗透性、选择性、5-羟色胺1F亚型(5-HT1F)激动药,其作用机制不同于目前用于治疗偏头痛“地坦”类新型药物,不具有血管收缩效应,对于患有心血管疾病或处于心血管疾病风险的偏头痛患者更为安全,是20年来唯一获准用于成人急性偏头痛治疗药。
拉司米地坦化学名称：2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamidehemisuccinate。
其结构式
拉司米地坦可以通过多种方式制备得到，主要由以下两种方法制备：
路线一：WO2003/84949（US8748459/CN100352817C）原研化合物专利
2-氯吡啶为原料，于正丁基锂和2-二甲基氨基乙醇作用下超低温金属锂化，和N-甲氧基-N-甲基-1-甲基哌啶-4-甲酰胺反应，得到6-氯-2-(1-甲基哌啶-4-)甲酰胺吡啶，然后和二苯甲酮亚胺于Pd2(dba)3/BINAP作用下缩合，浓盐酸脱保护制备2-氨基-6-(1-甲基哌啶-4-)甲酰基吡啶，再与2,4,6-三氟苯甲酰氯经酰胺化反应、琥珀酸成盐得到目标产物。路线如下：
第一步反应用丁基锂在-78°C反应，反应条件苛刻，不利于放大。第二步反应用Pd2(dba)3作催化剂，价格昂贵且不能回收套用。后三步反应产物均用柱层析分离提纯。
路线二：WO2003/84949（US8748459/CN100352817C）原研化合物专利
哌啶-4-甲酸为原料，与甲醛在钯碳催化下加氢进行N-甲基化反应，得N-甲基-4-哌啶甲酸，然后经草酰氯酰氯化反应，得N-甲基-4-哌啶酰氯盐酸盐，在三乙胺作用下，与二甲胺进行酰胺化，生成N,N’-二甲基-N-甲基-4-哌啶酰胺，然后在正丁基锂作用下超低温金属锂化，与2,6-二溴吡啶反应，得到2-溴-6-(1-甲基哌啶-4-基酰基)-吡啶，再在氨气/乙二醇体系中，经氧化亚铜催化，于密封高压釜中进行氨化反应，得2-氨基-6-(1-甲基哌啶-4-基酰基)-吡啶再与2,4,6-三氟苯甲酰氯经酰胺化反应、琥珀酸成盐得到目标产物。路线如下：
第三步反应用丁基锂在-78oC反应，反应条件苛刻，不利于放大。
因此，寻找一种条件温和，收率高，后处理简单，纯度高，适合工业化生产的合成路线是非常必要的。
发明内容
针对现有技术的不足，本发明的技术方案是提供本发明提供了一种拉司米地坦的制备方法，无需采用制备色谱柱制备，可以直接得到高纯度的拉司米地坦。该方法收率高、后处理简便、生产成本低、适合工业化生产。
本发明提供了一种拉司米地坦的制备方法，其以市购的2-乙酰基-6-溴吡啶与2,4,6-三氟苯甲酸为原料在有一定条件下，五步合成拉司米地坦。本发明的制备方法重点在合成化合物2，经过不同的起始物料反应、不同的反应机理制备拉司米地坦，
合成路线:
合成布瓦西坦的步骤主要包括五步，：首先，2-乙酰基-6-溴吡啶（化合物1）与N-甲基4-卤哌啶在一定条件下发生加成反应生成化合物2，之后氨基化，与2,4,6-三氟苯甲酸形成的酰氯缩合形成酰胺进一步成半琥珀酸盐，得到目标产物拉司米地坦（即化合物7）。。
在合成拉司米地坦第一步中，催化剂为PdCl2、FeCl2、CuCl2、CuCl2，优选为其中一种或者是混合催化剂。
在合成拉司米地坦第一步中，卤代试剂为N-甲基4-氯哌啶、N-甲基4-溴哌啶。
在合成拉司米地坦第一步中，添加剂优选为叔丁醇钠、碳酸钠、碳酸钾。
本发明的制备方法一种条件温和，适合工业化生产，无需液相制备柱，后处理简单，纯度高。拉司米地坦的总杂小于0.5%，单杂小于0.1%，达到原料药（API）级别，适合工业化生产。本发明是一种绿色合成工艺。
具体实施方式
下面通过实施例的方式进一步说明本专利，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未标明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1
拉司米地坦的制备方法，包括以下工艺步骤
（1）将化合物1（100.0 g，0.50mol）和800 ml乙腈加入到三口瓶中，开启搅拌。加入氯化铜(5.0g，50 mmol）于体系中，再加入N-甲基4-氯哌啶（93.5 g，0.70mol），分批加入叔丁醇钠（67.3g，0.70mol），室温反应6小时，反应停止。加入500 mL 1M的盐酸溶液搅拌30分钟，转移到2 L分液漏斗中, 萃取分液，收集有机相，加入无水Na2SO4干燥2小时。抽滤，除去无水Na2SO4，滤液于50℃下浓缩。得到浅棕色固体物即目标产物130.2g，收率92.0%。得到产物在接下来氨化，与酰氯对接，成盐得到目标产物拉司米地坦,HPLC为99.82%,单杂小于0.1%，总杂小于0.5%。
实施例2
（1）将化合物1（100.0 g，0.50mol）和800 ml乙腈加入到三口瓶中，开启搅拌。加入氯化铜 (5.0g，50 mmol）于体系中，再加入N-甲基4-氯哌啶（93.5 g，0.70mol），分批加入碳酸钾（96.7g，0.70mol），室温反应8小时，反应停止。加入500 mL 1M的盐酸溶液搅拌30分钟，转移到2 L分液漏斗中, 萃取分液，收集有机相，加入无水Na2SO4干燥2小时。抽滤，除去无水Na2SO4，滤液于50℃下浓缩。得到浅棕色固体物即目标产物126.0g，收率89.0%。得到产物在接下来氨化，与酰氯对接，成盐得到目标产物拉司米地坦，HPLC为99.78%,单杂小于0.1%，总杂小于0.5%。
Claims (4)
1.拉司米地坦的一种制备方法，其特征在于：它是由下述合成路线制备而成：第一步是2-乙酰基-6-溴吡啶（化合物1）与N-甲基4-卤哌啶在一定条件下发生加成反应生成化合物2，之后氨基化，与2,4,6-三氟苯甲酸形成的酰氯缩合形成酰胺进一步成半琥珀酸盐，得到目标产物拉司米地坦（即化合物7）
。
2.根据权利要求1的方法，在合成拉司米地坦第一步中，催化剂为PdCl2、FeCl2、CuCl2、CuCl2，优选为其中一种或者是混合催化剂。
3.根据权利要求1的方法，在合成拉司米地坦第一步中，卤代试剂为N-甲基4-氯哌啶、N-甲基4-溴哌啶。
4.根据权利要求1的方法，在合成拉司米地坦第一步中，添加剂优选为叔丁醇钠、碳酸钠、碳酸钾。
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