CN106432071A - 5‑氰基‑4‑甲氧基‑2‑吡啶甲酸的盐酸盐的制备及其应用 - Google Patents
5‑氰基‑4‑甲氧基‑2‑吡啶甲酸的盐酸盐的制备及其应用 Download PDFInfo
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- CN106432071A CN106432071A CN201610801679.3A CN201610801679A CN106432071A CN 106432071 A CN106432071 A CN 106432071A CN 201610801679 A CN201610801679 A CN 201610801679A CN 106432071 A CN106432071 A CN 106432071A
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- China
- Prior art keywords
- carboxylic acid
- methoxyl group
- pyridine carboxylic
- cyano group
- bromo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- HMZJFXOTGXHJGQ-UHFFFAOYSA-N 5-cyano-4-methoxypyridine-2-carboxylic acid Chemical compound C(#N)C=1C(=CC(=NC=1)C(=O)O)OC HMZJFXOTGXHJGQ-UHFFFAOYSA-N 0.000 title abstract 7
- 150000003840 hydrochlorides Chemical class 0.000 title abstract 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
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- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 2
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
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- 230000008025 crystallization Effects 0.000 description 4
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
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- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- VXKWYPOMXBVZSJ-UHFFFAOYSA-N tetramethyltin Chemical compound C[Sn](C)(C)C VXKWYPOMXBVZSJ-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
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Abstract
本发明提出一种5‑氰基‑4‑甲氧基‑2‑吡啶甲酸的盐酸盐的制备方法,所述制备方法是以5‑溴‑4‑甲氧基‑2‑甲基吡啶为原料通过氧化,再酯化形成5‑溴‑4‑甲氧基‑2‑吡啶甲酸甲酯,在四(三苯基膦)钯催化下,与亲核试剂反应,得到5‑氰基‑4‑甲氧基‑2‑吡啶甲酸甲酯,水解得到5‑氰基‑4‑甲氧基‑2‑吡啶甲酸;与酸作用形成盐。本发明提出了新的合成路线,制得的中间体5‑氰基‑4‑甲氧基‑2‑吡啶甲酸(H4),可以在常规的条件下与盐酸反应得到5‑氰基‑4‑甲氧基‑2‑吡啶甲酸盐酸盐。可提供制备利尿剂、促尿钠排泄药、心血管病和由过量的盐和水滞留造成的疾病的有价值的药物活性化合物的中间体。
Description
技术领域
本发明属于有机合成领域,具体涉及一种杂环化合物医药中间体及其制备方法。
背景技术
5-氰基-4-甲氧基-2-吡啶甲酸盐酸盐化合物是合成化学药物:肾外髓钾通道抑制剂的一种重要的可选择使用的中间体,含有这种吡啶结构的肾外髓钾通道抑制剂,可用作利尿剂和促尿钠排泄药,也可用于治疗和预防由过量的盐和水滞留造成的失调症,包括心血管病,如高血压及慢性和急性心力衰竭。
这种可供筛选合成一种肾外髓钾通道抑制剂的中间体化学结构如下:
目前这种结构的化合物合成工艺路线未见报道。
发明内容
针对现有技术存在的不足之处,本发明的目的是提出以有取代基的吡啶甲酸作为合成5-氰基-4-甲氧基-2-吡啶甲酸盐酸盐的起始原料或其中间体,所述的有取代基的吡啶甲酸的盐酸盐的制备方法。
本发明的第二个目的是提出所述有取代基的吡啶甲酸的盐酸盐的应用。
实现本发明上述目的的技术方案为:
一种5-氰基-4-甲氧基-2-吡啶甲酸的盐酸盐的制备方法,所述5-氰基-4-甲氧基-2-吡啶甲酸的结构式为:
本发明涉及具有结构式H4的化合物及其可药用盐,即式H4的化合物与无机或有机的酸加成的盐,例如但不限于,与氯化氢、溴化氢、磷酸、硫酸、硝酸、苯磺酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、三氟乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、特戊酸、二乙基乙酸、丙二酸、丁二酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡糖酸、抗坏血酸、柠檬酸、己二酸等形成的盐。
具体地,本发明提出一种5-氰基-4-甲氧基-2-吡啶甲酸的盐酸盐的制备方法,以5-溴-4-甲氧基-2-甲基吡啶为原料通过氧化,得到5-溴-4-甲氧基-2-吡啶甲酸,再通过5-溴-4-甲氧基-2-吡啶甲酸酯化形成5-溴-4-甲氧基-2-吡啶甲酸甲酯,在四(三苯基膦)钯(Pd(PPh3)4)催化下,与亲核试剂反应,得到5-氰基-4-甲氧基-2-吡啶甲酸甲酯,在弱碱性条件下水解,得到5-氰基-4-甲氧基-2-吡啶甲酸(H4);在有机溶剂中与酸作用,形成5-氰基-4-甲氧基-2-吡啶甲酸的盐。
进一步地,所述的制备方法,包括步骤:
S1以5-溴-4-甲氧基-2-甲基吡啶(CAS号886372-61-8)(H0)为原料,以高锰酸钾或高锰酸钠为氧化剂,进行氧化反应,达到反应终点后,将反应产物溶解于碱性溶液中,用有机溶剂萃取除杂,分离水相酸化后用有机溶剂萃取有机相得到5-溴-4-甲氧基-2-吡啶甲酸(H1);
S2:5-溴-4-甲氧基-2-吡啶甲酸在酸性条件下与醇类化合物发生酯化反应,形成5-溴-4-甲氧基-2-吡啶甲酸甲酯(H2),所述醇类化合物为甲醇、乙醇、丙醇、丁醇中的一种;
S3:在气体保护和四(三苯基膦)钯(Pd(PPh3)4)催化条件下,5-溴-4-甲氧基-2-吡啶甲酸甲酯(H2)与亲核试剂反应,得到5-氰基-4-甲氧基-2-吡啶甲酸甲酯(H3),所述亲核试剂为氰化亚铜(CuCN)、Zn(CN)2和NaCN中的一种,反应的温度为80~100℃;
S4:5-氰基-4-甲氧基-2-吡啶甲酸甲酯(H3)在气体保护和弱碱性条件下水解,得到5-氰基-4-甲氧基-2-吡啶甲酸(H4);所述弱碱性条件是将5-氰基-4-甲氧基-2-吡啶甲酸甲酯(H3)溶于ROH水溶液中而形成,所述弱碱是指氢氧化锂或氢氧化铵,所述ROH为甲醇、乙醇、丙醇、丁醇、异丁醇、叔丁醇中的一种或多种;所述ROH水溶液中的弱碱浓度为1~5mol/L。
S5:5-氰基-4-甲氧基-2-吡啶甲酸在无水异丙醇中与盐酸作用,形成5-氰基-4-甲氧基-2-吡啶甲酸盐酸盐。
本发明还对制备反应中的条件进行了优化,以下为本发明优选技术方案,但实现本发明目的手段不限于此:
所述S1的氧化反应在有机溶剂中进行,所述有机溶剂为丙酮、丁酮、戊酮中的一种或多种;所述氧化剂加入的温度为-2℃~5℃,加入氧化剂后在-2℃~5℃保持1~3小时,再升温至15~35℃反应。
其中,所述S2中,5-溴-4-甲氧基-2-吡啶甲酸以0.1~0.5mol/L浓度溶于ROH中,按与ROH的体积比0.01~0.1:1加入硫酸,在60~70℃下反应10~20小时,然后加入酯类化合物。所述硫酸为市购浓硫酸,质量分数在96~99%范围内。所述ROH为甲醇、乙醇、丙醇、丁醇、异丁醇、叔丁醇中的一种或多种。
本制备方法中的气体保护,指非氧化性气体保护,具体可以是氮气、氩气、氦气、氖气、无氧空气中的一种或多种,或其他有机合成中可采用的气体保护。
优选地,所述S3中,5-溴-4-甲氧基-2-吡啶甲酸甲酯(H2)溶于N,N-二甲基甲酰胺(DMF)和乙腈(MeCN)体积比1:1~3的混合溶剂中,在氩气或氮气保护下反应。
其中,所述S3中,每摩尔的5-溴-4-甲氧基-2-吡啶甲酸甲酯(H2)加入5~15mol的亲核试剂、0.1~2%mol四(三苯基膦)钯(Pd(PPh3)4,以5-溴-4-甲氧基-2-吡啶甲酸甲酯计量)和1~2molPPh3,反应的温度为80~100℃。
其中,所述S4中,5-氰基-4-甲氧基-2-吡啶甲酸甲酯(H3)与ROH水溶液的摩尔体积比可以为0.1~0.5mol/L;水解反应后酸化后用酯类化合物萃取分离。ROH的含义同前,ROH在水溶液中的质量分数可以为10~30%。
步骤S5中,反应温度控制-20~0℃,反应后用丙酮和石油醚混合溶剂淋洗,得到产物。S5中盐酸的用量按照化学计量关系加入,也可稍过量;丙酮和石油醚混合溶剂中二者的体积比为1:1~5。
本发明所述制备方法制备得到的5-氰基-4-甲氧基-2-吡啶甲酸的盐酸盐。
所述的5-氰基-4-甲氧基-2-吡啶甲酸的盐酸盐在肾外髓钾通道抑制剂的制备中的应用。
上述反应的反应路线如下:
本发明的有益效果为:
本发明提出一种新型的以有取代基的吡啶甲酸合成5-氰基-4-甲氧基-2-吡啶甲酸盐酸盐的新的合成路线,制得的中间体5-氰基-4-甲氧基-2-吡啶甲酸(H4),可以在常规的条件下与盐酸反应得到5-氰基-4-甲氧基-2-吡啶甲酸盐酸盐。提供了制备利尿剂、促尿钠排泄药、心血管病和由过量的盐和水滞留造成的疾病的有价值的药物活性化合物。
本发明合成路线简单,以较简单的方式引入氰基;反应条件温和,降低了危险性。
具体实施方式
下面结合具体实施例,对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明,但不应用来限制本发明的范围。
实施例中所用药剂,如无特别说明,均为市购。
实施例中,如无特别说明,所采用的手段均为本领域常规的技术手段。实施例1.由5-溴-4-甲氧基-2-甲基吡啶(H0)合成5-溴-4-甲氧基-2-吡啶甲酸(H1)
其合成方法如下:
在三口瓶中,安装机械搅拌器和温度计,将10克(0.05mol)5-溴-4-甲氧基-2-甲基吡啶溶于100ml丙酮溶液,降温到0℃,慢慢加入5%KMnO4水溶液100ml,在0℃保持2小时,在升温到室温继续反应16小时,用薄层色谱板TLC检测反应终点,直到5-溴-4-甲氧基-2-甲基吡啶消失,加入20ml乙二醇终止反应,继续搅拌30min,过滤除去MnO2固体,将反应液浓缩至干,加入100ml 5%NaHCO3使其完全溶解,转移到分液器,加入50ml乙酸乙酯分别萃取3次,分出水相,用1NHCl调节水相pH值到1,分3次每次加入100ml乙醚萃取,合并有机相,用无水硫酸钠干燥,过滤,浓缩回收乙醚,用乙酸乙酯和正己烷混合物溶剂结晶,真空室温下干燥恒重,得到类白色固体,收率75%,用核磁共振谱表征化合物结构。
1HNMR(CDCl3):σ9.23ppm(1H),σ8.30ppm(1H),σ3.83ppm(3H);
13CNMR(CDCl3):σ170.1ppm(1C),σ167ppm(1C),σ154.2ppm(1C),σ148.3ppm(1C),σ110.2-110.4ppm(2C),σ55.2ppm(1C)。
实施例2.由5-溴-4-甲氧基-2-吡啶甲酸(H1)合成5-溴-4-甲氧基-2-吡啶甲酸甲酯(H2)
其合成方法如下:
在三口瓶中,安装机械搅拌器和温度计,将20克(0.05mol)5-溴-4-甲氧基-2-吡啶甲酸(H1)溶于200mL甲醇,加入10ml硫酸(质量分数98%的浓硫酸),升温至60~70℃,保温继续反应16小时,用薄层色谱板TLC检测,直到原料消失,停止反应,浓缩至干,加入100ml乙酸乙酯,加入50ml5%NaHCO3中和,用水洗到中性,用无水硫酸钠干燥,过滤,浓缩,用甲苯和乙酸乙酯混合物溶剂结晶,得到类白色固体,收率95%,用核磁共振谱表征化合物结构。
1HNMR(CDCl3):σ9.23ppm(1H),σ8.48ppm(1H),σ3.93ppm(3H),σ3.83ppm(3H).
13CNMR(CDCl3):σ170.1ppm(1C),σ167ppm(1C),σ154.2ppm(1C),σ148.3ppm(1C),σ110.2-110.4ppm(2C),σ55.2ppm(1C),σ51.6ppm(1C).
实施例3.由5-溴-4-甲氧基-2-吡啶甲酸甲酯(H2)合成5-氰基-4-甲氧基-2-吡啶甲酸甲酯(H3)
其合成反应如下:
在三口瓶中,安装机械搅拌器和温度计,将12.5克(0.05mol)5-溴-4-甲氧基-2-吡啶甲酸甲酯(H2)溶于200ml体积比(1:2)DMF/MeCN溶剂中,通入氩气置换保护,加入44克(0.5mol)CuCN、1克Pd(PPh3)4以及20克PPh3,保温90℃,用TLC检测直到原料消失,停止反应,浓缩至干,加入50ml5%NaHCO3和50ml 5%NaCl溶液,每次用100ml乙酸乙酯萃取,共萃取3次,合并有机相,用水洗到中性,用无水硫酸镁干燥,过滤浓缩,用乙酸乙酯和石油醚(体积比1:1)溶剂结晶,得到灰白色固体,收率60%。
用核磁共振谱表征化合物结构:
1HNMR(CDCl3):σ9.21ppm(1H),σ8.47ppm(1H),σ3.91ppm(3H),σ3.81ppm(3H);
13CNMR(CDCl3):σ171ppm(1C),σ166ppm(1C),σ154ppm(1C),σ152.5ppm(1C),σ117ppm(1C),σ110ppm(1C),σ99.8ppm(1C),σ55.3ppm(1C),σ52ppm(1C)。
实施例4.由5-氰基-4-甲氧基-2-吡啶甲酸甲酯(H3)合成5-氰基-4-甲氧基-2-吡啶甲酸(H4)其合成方法如下:
在三口瓶中,安装机械搅拌器和温度计,将12.5克(0.05mol)5-氰基-4-甲氧基-2-吡啶甲酸甲酯(H2)溶于200ml、含2mol/L LiOH的20%MeOH水溶液中,通入氩气保护,在室温搅拌,用TLC检测直到原料消失,停止反应,加入1mol/L的HCl和水中和到pH=7-8,浓缩抽干过量的甲醇,加入100ml蒸馏水,同50ml 5%NaHCO3和50ml 5%NaCl使浆状物完全溶解,每次用50ml乙酸乙酯萃取3次,收集水相,用1mol/L HCl调节pH=1-2,用50ml乙酸乙酯萃取3次,用无水硫酸镁干燥,过滤浓缩,用乙酸乙酯石油醚(体积比1:1)溶剂结晶,得到白色固体,收率90%。
用核磁共振谱表征化合物结构。
1HNMR(CDCl3):σ9.25ppm(1H),σ8.50ppm(1H),σ3.94ppm(3H);
13CNMR(CDCl3):σ171ppm(1C),σ167ppm(1C),σ154ppm(1C),σ152.5ppm(1C),σ117ppm(1C),σ110ppm(1C),σ99.8ppm(1C),σ55.3ppm(1C).
实施例5.由5-氰基-4-甲氧基-2-吡啶甲酸(H4)合成5-氰基-4-甲氧基-2-吡啶甲酸盐酸盐(H5)
其合成反应如下:
在三口瓶中,安装机械搅拌器和温度计,将12.5克(0.05mol)5-氰基-4-甲氧基-2-吡啶甲酸溶于200ml异丙醇中,通入氩气保护,在室温搅拌,加入计量的浓盐酸,降低温度到-10℃,继续搅拌3小时,过滤,用丙酮和石油醚(体积比1:2)混合溶剂淋洗,得到白色固体,收率90%。
虽然,上文中已经用一般性说明、具体实施方案及物性测试对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (10)
1.一种5-氰基-4-甲氧基-2-吡啶甲酸的盐酸盐的制备方法,其特征在于,其中5-氰基-4-甲氧基-2-吡啶甲酸的结构式为:
所述盐为式H4的化合物与盐酸加成的盐;
所述的制备方法,是以5-溴-4-甲氧基-2-甲基吡啶为原料,通过氧化得到5-溴-4-甲氧基-2-吡啶甲酸,再通过5-溴-4-甲氧基-2-吡啶甲酸酯化形成5-溴-4-甲氧基-2-吡啶甲酸甲酯,在四(三苯基膦)钯催化下,与亲核试剂反应,得到5-氰基-4-甲氧基-2-吡啶甲酸甲酯,在弱碱性条件下水解,得到5-氰基-4-甲氧基-2-吡啶甲酸;在有机溶剂中与酸作用,形成5-氰基-4-甲氧基-2-吡啶甲酸的盐。
2.根据权利要求1所述的5-氰基-4-甲氧基-2-吡啶甲酸的盐酸盐的制备方法,其特征在于,包括步骤:
S1以5-溴-4-甲氧基-2-甲基吡啶为原料,以高锰酸钾或高锰酸钠为氧化剂,进行氧化反应,达到反应终点后,将反应产物溶解于弱碱性溶液中,用有机溶剂萃取除杂,分离出水相经过酸化处理,再用有机相萃取得到5-溴-4-甲氧基-2-吡啶甲酸;
S2:5-溴-4-甲氧基-2-吡啶甲酸,在酸性条件下与醇类化合物发生酯化反应,形成5-溴-4-甲氧基-2-吡啶甲酸甲酯,所述醇类化合物为甲醇、乙醇、丙醇或丁醇中的一种;
S3:在气体保护和四(三苯基膦)钯催化条件下,5-溴-4-甲氧基-2-吡啶甲酸甲酯与亲核试剂反应,得到5-氰基-4-甲氧基-2-吡啶甲酸甲酯,所述亲核试剂为氰化亚铜、Zn(CN)2和NaCN中的一种,反应的温度为80~100℃;
S4:5-氰基-4-甲氧基-2-吡啶甲酸甲酯在气体保护和弱碱性条件下水解,得到5-氰基-4-甲氧基-2-吡啶甲酸;所述弱碱性条件是将5-氰基-4-甲氧基-2-吡啶甲酸甲酯溶于ROH水溶液中而形成,所述弱碱为氢氧化锂,氢氧化铵中一种或两种,所述ROH为甲醇、乙醇、丙醇、丁醇、异丁醇、叔丁醇中的一种或多种;所述ROH水溶液中的弱碱浓度为1~5mol/L;
S5:5-氰基-4-甲氧基-2-吡啶甲酸在无水异丙醇中与盐酸作用,形成5-氰基-4-甲氧基-2-吡啶甲酸盐酸盐。
3.根据权利要求2所述的5-氰基-4-甲氧基-2-吡啶甲酸的盐酸盐的制备方法,其特征在于,所述S1的氧化反应在有机溶剂中进行,所述有机溶剂为丙酮、乙醇、乙二醇中的一种或多种;所述氧化剂加入的温度为-2℃~5℃,加入氧化剂后在-2℃~5℃保持1~3小时,再升温至15~35℃反应。
4.根据权利要求2所述的5-氰基-4-甲氧基-2-吡啶甲酸的盐酸盐的制备方法,其特征在于,所述S2中,5-溴-4-甲氧基-2-吡啶甲酸以0.1~0.5mol/L浓度溶于ROH中,按与ROH的体积比0.01~0.1:1加入硫酸,在60~70℃下反应10~20小时,然后加入酯类化合物。
5.根据权利要求2所述的5-氰基-4-甲氧基-2-吡啶甲酸的盐酸盐的制备方法,其特征在于,所述S3中,5-溴-4-甲氧基-2-吡啶甲酸甲酯溶于N,N-二甲基甲酰胺和乙腈体积比1:1~3的混合溶剂中,在氩气或氮气保护下反应。
6.根据权利要求2所述的5-氰基-4-甲氧基-2-吡啶甲酸的盐酸盐的制备方法,其特征在于,所述S3中,每摩尔的5-溴-4-甲氧基-2-吡啶甲酸甲酯加入5~15mol的亲核试剂、0.1~2%四(三苯基膦)钯和1~2mol PPh3,反应的温度为80~100℃。
7.根据权利要求2所述的5-氰基-4-甲氧基-2-吡啶甲酸的盐酸盐的制备方法,其特征在于,所述S4中,5-氰基-4-甲氧基-2-吡啶甲酸甲酯溶于ROH水溶液中的摩尔浓度为0.1~0.5mol/L;水解反应后用酯类化合物萃取分离。
8.根据权利要求2~7任一项所述5-氰基-4-甲氧基-2-吡啶甲酸的盐酸盐的制备方法,其特征在于,所述S5中,反应温度控制-20~0℃,反应后用丙酮和石油醚混合溶剂淋洗,得到产物。
9.权利要求1~8任一所述制备方法制备得到的5-氰基-4-甲氧基-2-吡啶甲酸盐酸盐。
10.权利要求9所述的5-氰基-4-甲氧基-2-吡啶甲酸盐酸盐在肾外髓钾通道抑制剂的制备中的应用。
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