CN101456843B - 5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸的合成方法 - Google Patents
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸的合成方法 Download PDFInfo
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Abstract
本发明涉及医药中间体的制备方法领域,特别涉及一种5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸的制备方法。本发明以对氯苯丙酮和三甲基氯硅烷作用后,与草酰氯反应得到5-(4-氯苯基)-4-甲基-2,3-呋喃二酮(III),5-(4-氯苯基)-4-甲基-2,3-呋喃二酮(III)与2,4-二氯苯肼缩合得粗品,通过重结晶得到的5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸含量达99.5以上,总收率可达60.9%。本发明合成路线短,条件温和,产率较高,反应中间体质量易于控制,适合工业化,并且产品纯度高,质量稳定。
Description
技术领域
本发明属于化学制药领域,具体涉及一种医药中间体5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸的制备方法。
背景技术
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸是一种合成用于治疗肥胖症的新药的重要中间体,用于其合成的新型大麻素受体-1(CBR1)选择性阻断剂盐酸利莫那班(Rimonabant Hydrochloride)已于2006年在多个国家上市。因此,开发该中间体有广阔的市场前景。鉴于其具有明显的社会效益和经济价值,人们研究开发了若干不同的合成方法,但均不具有工业化生产潜力。
文献报道的5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸的合成有五种方法:
方法1(Medicinal Chemistry Research,1995,5(1),54-62):4-氯苯丙酮经α溴代后与乙酰乙酸乙酯在强碱条件下反应,经柱纯化后与2,4-二氯苯胺重氮盐(由2,4-二氯苯胺在酸性条件下与亚硝酸钠反应制得)环合后,再经酯水解得5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸,化学反应式如下。但该方法需要进行色谱纯化,且总产率不足20%,不适合中试放大。
方法2(EP0656354):于超低温(-78℃)条件下,4-氯苯丙酮经六甲基二硅基胺基锂作用后与草酸二乙酯反应,再与2,4-二氯苯肼反应成腙、环合、酯水解得5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸,化学反应式如下。该方法对操作的条件要求较高(无水,无氧,低温),涉及到的原料六甲基二硅基胺基锂价格昂贵,且总产率不足30%,不适合工业化生产。
方法3(EP0656354):4-氯苯丙酮与三甲基氯硅烷生成烯醇硅醚化合物,与草酸单酰氯单乙酯反应后,成腙,环合,酯水解得5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸,化学反应式如下。该法虽然原料价格便宜,但由于第一步反应不完全,原料4-氯苯丙酮难以除去,造成各步中间体均为油状物,不易纯化,给生产过程中的中控带来较大困难,总收率不足40%。
方法4(WO2005115989):以2-氧代-3-甲基丁二酸二乙酯为起始原料,与2,4-二氯苯肼缩合得吡唑酮化合物,再与三氟甲基磺酸酐反应进行烯醇化后,在Pd(PPh3)4存在下与4-氯苯硼酸反应得酯,最后水解得5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸,化学反应式如下。该法采用先环合,再引入侧链的方法合成目标物,但接入4-氯苯基的过程需要使用昂贵的Pd(PPh3)4,大大增加了合成成本,且产率一般(前三步总收率54.1%),不适合工业化生产。
方法5(Tetrahedron Letters,2008,49,2789-2791)将4-[1-(4-氯苯基)丙基-1-烯基]吗啡啉(由4-氯苯丙酮与吗啡啉加成制备得到)和Shiff碱化合物(由2,4-二氯苯胺经重氮化后与氯代乙酰乙酸乙酯反应得到)在碱性条件下环合得酯,最后水解得5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸,化学反应式如下。但该法合成繁琐且产率较低,尤其环合成酯一步的产率仅22%,不适合放大生产。
发明内容
本发明的目的是克服上述现有技术的缺点,提供一条工艺路线合理,步骤较少,操作简单,反应收率较高的5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸的化学合成方法。
本发明是通过以下方案实施的:
(1)将4-氯苯丙酮与三甲基氯硅烷(TMSCl)反应生成烯醇硅醚化合物(II);(2)烯醇硅醚化合物(II)与草酰氯在非极性溶剂中环合反应得呋喃二酮化合物(III);(3)呋喃二酮化合物(III)与2,4-二氯苯肼缩合后,在酸催化条件下环合得5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸(I)。
本发明化学反应式如下:
步骤(2)中所述的非极性溶剂为乙醚、甲苯、异丙醚、甲基叔丁基醚、四氢呋喃、二氯甲烷或氯仿中的一种或几种;优选乙醚或甲苯。
步骤(3)中所述的呋喃二酮化合物(III)与2,4-二氯苯肼缩合反应温度为20-60℃,优选反应温度为20-30℃。
步骤(3)中所述的起催化作用的酸为对甲苯磺酸、苯磺酸、硫酸、高氯酸、甲酸或乙酸中的一种;优选对甲苯磺酸。
本发明优选的实施方案可包括以下步骤:
(1)将4-氯苯丙酮与过量三甲基氯硅烷在无水乙腈中反应,同时加入碘化钠和三乙胺,加热反应生成烯醇硅醚化合物(II)的粗品;
(2)在烯醇硅醚化合物(II)的乙醚或甲苯溶液中,加入草酰氯,(II)与草酰氯摩尔比为1∶1~1∶2,室温反应,直接过滤得纯的呋喃二酮化合物(III);
(3)呋喃二酮化合物(III)与2,4-二氯苯肼(III与2,4-二氯苯肼摩尔比为1∶1)反应后,加入催化量的对甲苯磺酸加热反应,得5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸(I)。
本发明优选步骤化学反应式如下
本发明生产过程中产生的氯化氢等酸气直接通入碱液中,废液通入酸碱池进行中和,再流入废水处理池进行废水处理,乙腈、甲苯等溶剂可通过蒸馏回收再利用。蒸馏完的残留物可通过管道送入焚烧炉焚烧。整个生产过程中的三废处理可基本保持封闭,对环境污染大大减少,而且溶液的回收利用也可大大降低生产成本。
本发明的有益效果:本发明5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸的制备方法,所需原料及试剂价廉易得,成本低;本发明合成路线短,无需经过酯水解反应可直接得到羧酸化合物(I);本发明所设计的路线,能够得到稳定中间体,便于提纯,易于中控;本发明所采用的合成方法操作简单,条件温和;通过重结晶得到的5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸含量达99.5%以上,总收率可达60.9%,适合工业化大生产,且产品质量稳定,完全符合作为药物中间体的要求。
具体实施方式
实施例1:1-(4-氯苯基)-1-三甲基硅氧基丙烯(II)的制备
氮气保护下,将4-氯苯丙酮(168.6g,1.0mol)、三乙胺(202.4g,2.0mol)、碘甲烷(180.0g,1.21mol)和无水乙腈(1.2L)加至5L反应瓶中,搅匀后于室温下慢慢滴加三甲基氯硅烷(217.2g,2.0mol),45℃反应24h,40℃以下减压浓缩,残留物加入甲苯(1.5L),冰水洗涤两次,每次800mL,无水硫酸钠干燥,过滤,浓缩得棕色油状物249.6g,得1-(4-氯苯基)-1-三甲基硅氧基丙烯(II)粗品(GC检测:其中85%II,10%4-氯苯丙酮),无须纯化,可直接投入下一步。
实施例2:5-(4-氯苯基)-4-甲基-2,3-呋喃二酮(III)的制备
实施例1所得1-(4-氯苯基)-1-三甲基硅氧基丙烯(II)粗品溶解于无水乙醚(1.8L),于10-15℃下滴加草酰氯(126.9g,1.0mol),室温搅拌5h,析出大量固体,过滤,冷乙醚洗涤得淡黄绿色固体141.2g,熔点162.9-163.5℃,母液浓缩至800mL并冷却,过滤,洗涤得固体36.5g,熔点162.8-163.5℃,合并上述固体共177.7g,收率79.8%(以4-氯苯丙酮计)。1H-NMR(CDCl3):δ=2.14(s,3H),7.57(d,2H,J=6.9Hz,Ph-H),7.87(d,2H,J=6.9Hz,Ph-H)。
实施例3:5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸(I)的制备
实例2所得5-(4-氯苯基)-4-甲基-2,3-呋喃二酮(III)(111.3g,0.5mol)溶解于甲苯(2L)中,加入2,4-二氯苯肼盐酸盐(106.8g,0.5mol),于室温滴加三乙胺(51g,0.5mol),室温反应8h,过滤,浓缩,残留物加入甲苯(1L)及对甲苯磺酸(8.6g,0.05mol),回流1.5h,冷却,加入5%NaOH溶液(1L),室温剧烈搅拌0.5h,分液,水层用浓盐酸调节PH至2,析出淡黄色固体,过滤,烘干,80%乙酸重结晶得类白色固体145.5g,收率76.3%,总收率60.9%(以4-氯苯丙酮计),熔点215.8-217.0℃。HPLC:99.8%;1H-NMR(DMSO-d6):δ=2.23(s,3H,CH3),7.23(d,2H,J=8.4Hz,Ph-H),7.45(d,2H,J=8.4Hz,Ph-H),7.57(dd,1H,J1=8.5Hz,J2=2.2Hz,Ph-H),7.70(d,1H,J=8.5Hz,Ph-H),7.77(d,1H,J=2.2Hz,Ph-H),12.91(br,1H,COOH)。
实施例4:5-(4-氯苯基)-4-甲基-2,3-呋喃二酮(III)的制备
实施例1所得1-(4-氯苯基)-1-三甲基硅氧基丙烯(II)粗品溶解于甲苯(2.0L),于10-15℃下滴加草酰氯(126.9g,1.0mol),室温搅拌5h,反应液浓缩至500mL并冷却,过滤,冰甲苯洗涤得固体173.5g,收率77.9%(以4-氯苯丙酮计),熔点162.5-163.5℃。
实施例5:5-(4-氯苯基)-4-甲基-2,3-呋喃二酮(III)的制备
实施例1所得1-(4-氯苯基)-1-三甲基硅氧基丙烯(II)粗品溶解于四氢呋喃(2.0L),于10-15℃下滴加草酰氯(126.9g,1.0mol),室温搅拌5h,反应液浓缩至400mL并冷却,过滤,得固体145.0g,收率65.1%(以4-氯苯丙酮计),熔点161.6-163.2℃。
实施例6:5-(4-氯苯基)-4-甲基-2,3-呋喃二酮(III)的制备
实施例1所得1-(4-氯苯基)-1-三甲基硅氧基丙烯(II)粗品溶解于二氯甲烷(2L),于10-15℃下滴加草酰氯(126.9g,1.0mol),室温搅拌5h,浓缩反应液至200mL,搅拌下加入乙醚(1L),于4℃放置12h,析出固体,过滤得淡黄色固体151.2g,熔点161.5-163.2℃,收率67.9%(以4-氯苯丙酮计)
实施例7:5-(4-氯苯基)-4-甲基-2,3-呋喃二酮(III)的制备
实施例1所得1-(4-氯苯基)-1-三甲基硅氧基丙烯(II)粗品溶解于无水乙醚(1.8L),于10-15℃下滴加草酰氯(253.8g,2.0mol),室温搅拌5h,按实施例2所述方法,得固体174.8g,收率78.5%(以4-氯苯丙酮计)。
实施例8:5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸(I)的制备
实例2所得5-(4-氯苯基)-4-甲基-2,3-呋喃二酮(III)(111.3g,0.5mol)溶解于甲苯(2L)中,加入2,4-二氯苯肼盐酸盐(106.8g,0.5mol),于室温滴加三乙胺(51g,0.5mol),于60℃反应5h后按实施例3所述方法,重结晶后得类白色固体110.2g,收率57.8%,总收率46.1%(以4-氯苯丙酮计),含量99.6%。
实施例9:5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸(I)的制备
实例2所得5-(4-氯苯基)-4-甲基-2,3-呋喃二酮(III)(111.3g,0.5mol)溶解于甲苯(2L)中,加入2,4-二氯苯肼盐酸盐(106.8g,0.5mol),于室温滴加三乙胺(51g,0.5mol),室温反应8h,过滤,浓缩,残留物加入甲苯(1L)及对高氯酸(5.0g,0.05mol)后,按实施例3所述方法,重结晶后得类白色固体96.7g,收率50.7%,总收率40.5%(以4-氯苯丙酮计),含量99.7%。
实施例10:5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸(I)的制备
实例2所得5-(4-氯苯基)-4-甲基-2,3-呋喃二酮(III)(111.3g,0.5mol)溶解于甲苯(2L)中,加入2,4-二氯苯肼盐酸盐(106.8g,0.5mol),于室温滴加三乙胺(51g,0.5mol),40℃反应8h,过滤,浓缩,残留物加入甲苯(1L)及硫酸(1mL)后,按实施例3所述方法,重结晶得类白色固体113.8g,收率59.6%,总收率47.6%(以4-氯苯丙酮计),含量99.8%。
实施例11:5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-羧酸(I)的制备
实例2所得5-(4-氯苯基)-4-甲基-2,3-呋喃二酮(III)(111.3g,0.5mol)溶解于甲苯(2L)中,加入2,4-二氯苯肼盐酸盐(106.8g,0.5mol),于室温滴加三乙胺(51g,0.5mol),室温反应8h,过滤,浓缩,残留物加入甲苯(1L)及乙酸(3mL,0.05mol)后,按实施例3所述方法,重结晶得类白色固体122.6g,收率64.3%,总收率51.3%(以4-氯苯丙酮计),含量99.7%。
Claims (9)
2.根据权利要求1所述的方法,其特征在于:步骤(2)中所述的非极性溶剂为乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、甲苯、二氯甲烷或氯仿。
3.根据权利要求2所述的方法,其特征在于:步骤(2)中所述的非极性溶剂为乙醚或甲苯。
4.根据权利要求1所述的方法,其特征在于:步骤(2)中所述的烯醇硅醚化合物(II)与草酰氯的摩尔比为1∶1~1∶2。
5.根据权利要求1所述的方法,其特征在于:步骤(3)中所述的呋喃二酮化合物(III)与2,4-二氯苯肼缩合反应温度为20-60℃。
6.根据权利要求5所述的方法,其特征在于:步骤(3)中所述的呋喃二酮化合物(III)与2,4-二氯苯肼缩合反应温度为20-30℃。
7.根据权利要求1所述的方法,其特征在于:步骤(3)中所述的起催化作用的酸为对甲苯磺酸、苯磺酸、硫酸、高氯酸、甲酸或乙酸。
8.根据权利要求7所述的方法,其特征在于:步骤(3)中所述的起催化作用的酸为对甲苯磺酸。
9.根据权利要求1所述的方法,其特征在于:步骤(3)中所述的呋喃二酮化合物(III)与2,4-二氯苯肼摩尔比为1∶1。
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