CN115772110A - 一种制备钾离子竞争性阻滞剂非苏拉赞中间体的方法 - Google Patents
一种制备钾离子竞争性阻滞剂非苏拉赞中间体的方法 Download PDFInfo
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- CN115772110A CN115772110A CN202211639672.8A CN202211639672A CN115772110A CN 115772110 A CN115772110 A CN 115772110A CN 202211639672 A CN202211639672 A CN 202211639672A CN 115772110 A CN115772110 A CN 115772110A
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- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000002860 competitive effect Effects 0.000 title abstract description 6
- 229910001414 potassium ion Inorganic materials 0.000 title abstract description 6
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 229940125898 compound 5 Drugs 0.000 claims abstract description 17
- 229940126214 compound 3 Drugs 0.000 claims abstract description 16
- 239000003513 alkali Substances 0.000 claims abstract description 15
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229940125782 compound 2 Drugs 0.000 claims abstract description 12
- KFZUDNZQQCWGKF-UHFFFAOYSA-M sodium;4-methylbenzenesulfinate Chemical compound [Na+].CC1=CC=C(S([O-])=O)C=C1 KFZUDNZQQCWGKF-UHFFFAOYSA-M 0.000 claims abstract description 10
- WCGPCBACLBHDCI-UHFFFAOYSA-N 2,4-difluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C(F)=C1 WCGPCBACLBHDCI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 3
- 238000004537 pulping Methods 0.000 claims description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000000967 suction filtration Methods 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000012445 acidic reagent Substances 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- -1 p-toluenesulfonyl (2, 4-difluorophenyl) isonitrile Chemical compound 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- YNCPXBIZAPNQIJ-UHFFFAOYSA-N 1h-imidazole;sodium Chemical compound [Na].C1=CNC=N1 YNCPXBIZAPNQIJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 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 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
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- 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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种制备钾离子竞争性阻滞剂非苏拉赞中间体的方法。所述方法以对甲苯亚磺酸钠和2,4‑二氟苯甲醛为起始原料,在碱性溶剂及酸催化的条件下反应得到化合物2,再经三氯氧磷脱水得到异腈类化合物3,最后化合物3在强碱作用下与化合物4反应得到化合物5,化合物5最终转化为目标产物中间体1。总收率可达65%以上,具有方法新颖、成本低廉、反应条件温和、纯化方法简单等特点。
Description
技术领域
本发明属于医药中间体有机化学合成领域,具体涉及一种钾离子竞争性阻滞剂非苏拉赞的关键中间体的制备方法。
背景技术
酸相关胃肠疾病(Acid-related diseases,ARDs),是胃肠疾病中最常见的一类疾病,例如胃食管反流病、消化性溃疡病、非糜烂性反流病、幽门螺杆菌感染以及预防低剂量阿司匹林或非甾体抗炎药诱导的消化性溃疡等。近四十年来,控制胃酸的分泌,已经成为全球治疗消化道疾病行之有效的重要治疗手段。抑酸药可以通过抑制胃酸分泌,解除胃酸及胃蛋白酶对胃肠道黏膜和溃疡面的侵蚀、消化作用,减轻疼痛,促进溃疡愈合,而发挥显著的治疗效果。抑制胃酸分泌药物包括了几大种类:胃酸中和剂、胃泌素受体拮抗剂、胆碱能受体拮抗剂、组胺H2受体拮抗剂、质子泵抑制剂(Proton pump inhibitors,PPIs)等。
胃酸分泌的最后一步是通过壁细胞中表达的质子泵(H+/K+-ATP酶)实现的,该酶是一种P型ATP酶(一类可以被ATP驱动使其发生磷酸化的阳离子泵)。H+/K+-ATP酶位于壁细胞的基底外侧膜上。组胺、胃泌素、乙酰胆碱等物质作用于相对应的受体,通过第二信使环磷酸腺苷激活各种蛋白激酶,然后作用于H+/K+-ATP酶,该酶调节细胞质H+与细胞外K+的交换,将细胞内H+泵出,因此,H+/K+-ATP酶是治疗胃酸相关疾病的重要靶点,抑制该酶活性,可以完全阻断由任何刺激引起的胃酸分泌,为胃酸相关胃肠疾病的治疗提供了有价值的方法。
PPIs可分为两类:不可逆型质子泵抑制剂和可逆型质子泵抑制剂(Reversibleproton pump inhibitors,RPPIs);不可逆型质子泵抑制剂通过与H+/K+-ATP酶的α-亚基共价结合来达到抑制作用,现有的药物包括奥美拉唑、兰索拉唑、泮托拉唑、雷贝拉唑、埃索美拉唑、左旋泮托拉唑、艾普拉唑和右旋兰索拉唑等。可逆型质子泵抑制剂主要是钾离子竞争性抑制剂(Potassium-competitive acid blockers,P-CABs),通过与钾离子竞争来抑制胃H+/K+-ATP酶活性,现已上市的有沃诺拉赞、瑞伐拉赞和特戈拉赞,其中以吡咯为母核的沃诺拉赞的抑酸作用最强。
胃酸相关疾病大都是一种慢性病,如果停用PPIs,大多数患者会出现症状复发,因此许多患者需要持续给药治疗。不可逆型质子泵抑制剂在全球范围内已经得到广泛应用,然而仍存在一些医疗上无法解决的问题。RPPIs在酸性环境中化学结构稳定,血浆半衰期长,首次给药就可达到最大效应,停药后泌酸功能迅速恢复。韩国Daewoong制药公司在2020年消化疾病周(DDW)上首次公布新型胃食管反流病药物非苏拉赞(fexuprazan)的III期临床数据,该药物是一种新型的钾离子竞争性阻滞剂,证实fexuprazan具有显著抑制胃酸分泌的疗效,且在缓解烧心以及其他非特异性症状上,甚至比埃索美拉唑更优。
由于非苏拉赞非常有望成为下一个抗酸分泌剂市场中的全球畅销药物,因而其中间体的合成也会成为重要的研究课题之一。
其中,5-(2,4-二氟苯基)-4-甲氧基-1H-吡咯-3-羧酸甲酯(1)(结构如下所示)为非苏拉赞的关键中间体,该结构通过还原、氧化、磺酰胺化、还原胺化即可得到非苏拉赞原料药。
专利WO2016175555首先公开关键中间体化合物1的制备方法,具体路线如下所示:
该路线起始原料不易得,价格昂贵,且收率低,无法进行规模化生产。
专利WO2018236153公开了关键中间体化合物1的制备方法,具体路线如下所示:
该路线反应步骤较长,反应总收率偏低(比专利WO2016175555中的收率高),同时含有剧毒原料,不宜进行工业化生产。
专利CN109867617公开了关键中间体化合物1的制备方法,具体路线如下所示:
该路线合成步骤较短,但原料价格贵,各步反应较条件温和,但纯化条件复杂,成本太高,且产率较低,不适用于大量制备。
专利CN112094219公开了关键中间体化合物1的制备方法,具体路线如下所示:
该路线合成步骤较长,原料价格低廉,但选用了致癌物质硫酸二甲酯与价格较贵的钯碳试剂,不适用于工业化生产。
发明内容
鉴于现有技术的不足,本发明所要解决的技术问题是提供一种合成步骤较短,其原料易得且价格低廉,各步反应条件温和,易于纯化,操作简单,收率较高的非苏拉赞关键中间体5-(2,4-二氟苯基)-4-甲氧基-1H-吡咯-3-羧酸甲酯(1)的制备方法。
为了实现本发明的目的,本发明人通过大量试验研究,最终获得了本发明的下述方案。
在一个方面,本发明提供了一种制备中间体1的方法,所述方法包括:
(1)化合物3:对甲苯磺酰基(2,4-二氟苯基)异腈在强碱作用下与化合物4:甲氧基亚甲基马来酸二甲酯反应,得到化合物5:
(2)化合物5在极性溶剂与碱试剂1作用下反应得到中间体1:5-(2,4-二氟苯基)-4-甲氧基-1H-吡咯-3-羧酸甲酯:
在本发明的一个实施方案中,所述方法还包括:
(b)化合物2:N-[α-对甲苯磺酰基(2,4-二氟苯基)]甲酰胺在碱试剂2条件下与三氯氧磷发生反应得到化合物3:
在本发明的一个实施方案中,所述方法还包括:
(a)2,4-二氟苯甲醛与对甲苯亚磺酸钠在碱性溶剂及酸试剂的条件下反应得到化合物2:
在一个实施方案中,步骤(1)包括:将化合物3和化合物4溶于反应溶剂1中,分批加入强碱进行反应;反应完毕后加入打浆溶剂1打浆,抽滤得到粗产品,再用打浆溶剂2打浆,抽滤得到化合物5。
优选的,步骤(1)中:
反应温度为-10至40℃,优选为10-30℃,更优选为室温。
反应时间为0.5-48h,优选为3-12h。
反应的反应溶剂(反应溶剂1)选自二甲基甲酰胺、乙酸乙酯、二甲基亚砜、四氢呋喃、二氯甲烷、乙二醇二甲醚、乙腈中的一种或多种。
所述强碱选自咪唑钠、叔丁醇钾、甲醇钠、氢化钠、氢化钾、氢氧化钠、氢氧化钾中的一种或多种。在使用氢氧化钠或氢氧化钾的情况下,可选的,加入相转移剂;所述相转移剂选自季铵盐,所述季铵盐具有通式为R1R2R3R4NY的结构,其中R1-R4独立地选自C1-C12直链或支链烷基、C5-C6的环烷基、C6-C10的芳烷基或C6-C10的烷芳基;Y选自氯、溴、碘负离子或硫酸氢根。强碱的摩尔量为化合物3的1.0-6.0倍,优选为1.2-4.0倍,更优选为1.5-2.5倍。
化合物4的摩尔量为化合物3的1.0-6.0倍,优选为1.0-3.0倍。
所述打浆溶剂1和打浆溶剂2独立地选自正庚烷、正己烷、石油醚、乙醚、乙酸乙酯、二氯甲烷、乙腈、丙酮、二氧六环、水、甲醇、乙醇、异丙醇中一种或多种。打浆时温度为0-80℃,优选为10-30℃;打浆时间为1-10h,优选为1-5h。
在一个实施方案中,步骤(2)包括:将化合物5、碱试剂1于极性溶剂中反应,反应完毕后加入打浆溶剂3打浆,抽滤得到粗产品,再用打浆溶剂4打浆,抽滤得到中间体1。
优选的,步骤(2)中:
反应温度为10-100℃,优选为50-90℃。
反应时间为1-36h,优选为6-18h。
所述极性溶剂选自甲醇、乙醇、异丙醇、乙腈、丙酮、二甲基甲酰胺、丙二醇中的一种或多种。
所述碱试剂1选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、甲醇钠、叔丁醇钾中的一种或多种。碱试剂1的摩尔量为化合物5的1.0-8.0倍,优选为1.2-5.0倍,更优选为1.5-3.0倍。
所述打浆溶剂3和打浆溶剂4独立地选自水、甲醇、乙醇、正丙醇、二氯甲烷、乙酸乙酯、甲苯、丙酮、正庚烷、正己烷、石油醚、甲基叔丁基醚中一种或多种。打浆时温度为-10至60℃,优选为10-30℃;打浆时间为1-10h,优选为1-6h。
在一个实施方案中,步骤(b)包括:将化合物2与三氯氧磷加入到反应溶剂2中,搅拌后于冰浴条件下加入碱试剂2进行反应;反应结束后加入水淬灭,用萃取剂萃取,有机层洗涤、干燥、蒸干后重结晶得到化合物3。
优选的,步骤(b)中:
反应温度为10-50℃,优选为20-30℃。
反应时间为1-24h,优选1-6h。
反应的反应溶剂(反应溶剂2)选自甲醇、乙醇、乙腈、丙酮、四氢呋喃、甲苯中的一种或多种。所述碱试剂2选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、碳酸氢钠、三乙胺、吡啶中的一种或多种。碱试剂2的摩尔量为化合物2的2.0-8.0倍,优选为3.0-7.0倍,更优选为4.0-6.0倍。
三氯氧磷的摩尔量为化合物5的1.5-5.0倍,优选为2.0-4.0倍,更优选为2.5-3.5倍。
所述萃取剂选自乙酸乙酯、二氯甲烷、氯仿、甲苯中的一种或多种。
所述重结晶的溶剂选自甲醇、乙醇、正丙醇、四氢呋喃、乙腈、甲苯中的一种或多种。
在一个实施方案中,步骤(a)包括:将对甲苯亚磺酸钠用水溶解,加入2,4-二氟苯甲醛、酸试剂和碱性溶剂进行反应;反应结束后加入打浆溶剂5打浆,抽滤得到粗产品,再用打浆溶剂6打浆,抽滤得到化合物2。
优选的,步骤(a)中:
反应温度为10-100℃,优选为30-70℃。
反应时间为2-36h,优选为4-16h。
所述碱性溶剂选自三乙胺、乙二胺、乙酰胺、甲酰胺中的一种或多种。
所述酸试剂选自盐酸、甲酸、乙酸、丙酸、硫酸、对甲苯磺酸、硝酸、磷酸、氢氟酸、氢溴酸的一种或多种。酸试剂的摩尔量为对甲苯亚磺酸钠的1.0-8.0倍,优选为2.0-5.0倍。
2,4-二氟苯甲醛的摩尔量为对甲苯亚磺酸钠的1.0-4.0倍,优选为1.2-3.0倍,更优选为1.4-2.0倍。
所述打浆溶剂5和6独立地选自水、甲醇、乙醇、异丙醇、正庚烷、正己烷、石油醚、乙醚中一种或多种;打浆时温度为0-80℃,优选为10-30℃;打浆时间为1-24h,优选为1-6h。
在第二个方面,本发明提供了用于合成中间体1的中间体化合物5,其结构如下。
本发明中,Ts为本领域熟知的基团,其表示对甲苯磺酰基。
本发明的有益效果:
本发明提供了钾离子竞争性阻滞剂非苏拉赞的关键中间体1:5-(2,4-二氟苯基)-4-甲氧基-1H-吡咯-3-羧酸甲酯的制备方法。本发明的制备方法步骤较短,其原料易得且价格低廉,各步反应条件温和、易于纯化,操作简单;同时,各步骤收率较高,反应总收率可达65%以上;特别是化合物3至中间体1的收率可达85%以上,产物纯度高。因此,本发明的方法是一种经济有效的制备方法,具有较好的应用前景。
具体实施方式
以下将对发明的优选实例进行详细描述。所举实例是为了更好地对发明内容进行,并不是发明内容仅限于实例。根据发明内容对实施方案的非本质的改进和调整,仍属于发明范畴。
下面实施例中的实验方法,如无特殊说明,均为常规方法。实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。
实施例1:
1.化合物2的合成:在反应瓶中加入60g对甲苯亚磺酸钠,加入20mL水溶解,再加入72g的2,4-二氟苯甲醛、1.2mol的盐酸和150g甲酰胺,在氮气保护下于油浴中搅拌升温至40℃,反应8h。冷却至室温后,加入400mL水,搅拌1h后过滤。滤饼用300mL水淋洗3次得到粗产物。将粗产物用无水乙醚打浆,在20-30℃条件下搅拌3h,最后抽滤并真空干燥。烘干后得到93.8g白色粉末,收率为85.6%,纯度为95.05%。
1H NMR(600MHz,DMSO-d6)δ9.93(dd,J=10.5,1.5Hz,1H),8.02(d,J=1.3Hz,1H),7.73(td,J=8.5,6.3Hz,1H),7.67(d,J=8.3Hz,2H),7.46(d,J=8.1Hz,2H),7.35(ddd,J=10.3,9.2,2.6Hz,1H),7.28(td,J=8.5,2.7Hz,1H),6.51(d,J=10.4Hz,1H),2.41(s,3H).ESI-MS:m/z=348[M+Na]+
2.化合物3的合成:在反应瓶中加入80g化合物2,再加入560mL的无水四氢呋喃和94g的POCl3,先在25℃下搅拌5min。在冰浴条件下缓慢滴加124g的三乙胺,大概用30-45min滴加完成后,最后在20-30℃下反应2h。TLC检测,原料消失后处理:滴加500mL水淬灭,用乙酸乙酯萃取,有机层用饱和碳酸氢钠溶液和食盐水洗涤3次,无水硫酸钠干燥,过滤减压旋蒸除去溶剂得黄色半固体。再用无水正丙醇重结晶,抽滤后得到黄色固体,烘干后得到67.7g的淡黄色粉末,收率为89.6%,纯度为98.08%。
1H NMR(600MHz,DMSO-d6)δ7.73–7.69(m,2H),7.56–7.52(m,2H),7.45–7.40(m,2H),7.26(td,J=8.3,2.2Hz,1H),7.10(s,1H),2.46(s,3H).ESI-MS:m/z=330[M+Na]+
3.化合物5的合成:在反应瓶中加入30g化合物3和17g甲氧基亚甲基马来酸二甲酯,用适量无水乙腈溶解,分批加入17g咪唑钠,在室温下反应6h。反应完毕后加入水打浆4h,抽滤得到粗产品,再用甲醇打浆,抽滤得到白色固体,真空干燥后得到44.2g白色粉末,收率94.0%,纯度为97.62%。
1H NMR(600MHz,DMSO)δ7.72(td,J=8.6,8.5,6.5Hz,1H),7.70–7.66(m,2H),7.49–7.43(m,1H),7.42(d,J=8.2Hz,2H),7.20(td,J=8.4,8.4,2.5Hz,1H),6.11(d,J=1.2Hz,1H),5.79–5.64(m,1H),3.80(s,3H),3.70(s,3H),3.43(s,3H),2.40(s,3H).ESI-MS:m/z=482[M+H]+
4.化合物1的合成:在反应瓶中加入40g化合物5、230g乙醇、23g碳酸钾,在80℃下回流反应10h。反应完毕后加入水打浆6h,抽滤得到粗产品,再用二氯甲烷打浆,抽滤得到白色固体,真空干燥后得到20.8g白色粉末,收率为93.7%,纯度为99.85%。
1H NMR(600MHz,DMSO-d6)δ11.47(s,1H),7.64(td,J=8.7,6.6Hz,1H),7.37–7.34(m,1H),7.33(d,J=3.8Hz,1H),7.17(td,J=8.7,3.0Hz,1H),3.72(s,3H),3.71(s,3H).13CNMR(151MHz,DMSO)δ163.18,161.12(dd,J=246.8,12.1Hz),158.44(dd,J=249.0,12.2Hz),144.17,130.84(dd,J=9.6,5.0Hz),122.99,115.36(dd,J=14.3,3.8Hz),114.01,111.81(dd,J=21.2,3.5Hz),106.94,104.41,61.62,50.62.ESI-MS:m/z=268[M+H]+
最后说明的是,以上优选实施例仅用于说明本发明的技术方案而非限制,尽管通过上述优选实施例已经对本发明进行了详细的描述,但本领域技术人员应当理解,可以在形式上和细节上对其作出各种各样的改变,而不偏离本发明权利要求书所限定的范围。
Claims (8)
4.根据权利要求1所述的方法,其特征在于,步骤(1)包括:将化合物3和化合物4溶于反应溶剂1中,分批加入强碱1进行反应;反应完毕后加入打浆溶剂1打浆,抽滤得到粗产品,再用打浆溶剂2打浆,抽滤得到化合物5;
优选的,所述强碱选自咪唑钠、叔丁醇钾、甲醇钠、氢化钠、氢化钾、氢氧化钠、氢氧化钾中的一种或多种;强碱的摩尔量为化合物3的1.0-6.0倍,优选为1.2-4.0倍,更优选为1.5-2.5倍;
化合物4的摩尔量为化合物3的1.0-6.0倍,优选为1.0-3.0倍。
5.根据权利要求1所述的方法,其特征在于,步骤(2)包括:将化合物5、碱试剂1于极性溶剂中反应,反应完毕后加入打浆溶剂3打浆,抽滤得到粗产品,再用打浆溶剂4打浆,抽滤得到中间体1;
优选的,所述极性溶剂选自甲醇、乙醇、异丙醇、乙腈、丙酮、二甲基甲酰胺、丙二醇中的一种或多种;
所述碱试剂1选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、甲醇钠、叔丁醇钾中的一种或多种;碱试剂1的摩尔量为化合物5的1.0-8.0倍,优选为1.2-5.0倍,更优选为1.5-3.0倍。
6.根据权利要求2所述的方法,其特征在于,步骤(b)包括:将化合物2与三氯氧磷加入到反应溶剂2中,搅拌后于冰浴条件下加入碱试剂2进行反应;反应结束后加入水淬灭,用萃取剂萃取,有机层洗涤、干燥、蒸干后重结晶得到化合物3;
优选的,所述碱试剂2选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、碳酸氢钠、三乙胺、吡啶中的一种或多种;碱试剂2的摩尔量为化合物2的2.0-8.0倍,优选为3.0-7.0倍,更优选为4.0-6.0倍;
三氯氧磷的摩尔量为化合物5的1.5-5.0倍,优选为2.0-4.0倍,更优选为2.5-3.5倍。
7.根据权利要求2所述的方法,其特征在于,步骤(a)包括:将对甲苯亚磺酸钠用水溶解,加入2,4-二氟苯甲醛、酸试剂和碱性溶剂进行反应;反应结束后加入打浆溶剂5打浆,抽滤得到粗产品,再用打浆溶剂6打浆,抽滤得到化合物2;
优选的,所述碱性溶剂选自三乙胺、乙二胺、乙酰胺、甲酰胺中的一种或多种;
所述酸试剂选自盐酸、甲酸、乙酸、丙酸、硫酸、对甲苯磺酸、硝酸、磷酸、氢氟酸、氢溴酸的一种或多种;酸试剂的摩尔量为对甲苯亚磺酸钠的1.0-8.0倍,优选为2.0-5.0倍;
2,4-二氟苯甲醛的摩尔量为对甲苯亚磺酸钠的1.0-4.0倍,优选为1.2-3.0倍,更优选为1.4-2.0倍。
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