CN113666881A - 一种四氮唑沙坦类原料药中致突变性叠氮杂质的合成方法 - Google Patents
一种四氮唑沙坦类原料药中致突变性叠氮杂质的合成方法 Download PDFInfo
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Abstract
一种四氮唑沙坦类原料药中致突变性叠氮杂质的合成方法,沙坦类中间体N‑(三苯基甲基)‑5‑(4'‑溴甲基联苯‑2‑基)四氮唑(BBTT)为起始物料,在与叠氮化钠反应,加水猝灭后,经溶剂提取,蒸除溶剂得三苯基叠氮杂质5‑(4'‑(叠氮甲基)‑[1,1'‑联苯]‑2‑基)‑2‑三苯甲基‑2H‑四唑(Tr‑AZIDO);三苯基叠氮杂质在酸性条件下脱三苯基保护,经碱水洗涤,碱水层加入溶剂调酸使目标产物提取至溶剂层中,浓缩干溶剂得叠氮杂质5‑(4'‑(叠氮甲基)‑[1,1'‑联苯]‑2‑基)‑2H‑四唑(AZIDO)。利用本发明的方法以BBTT为起始物料,可以以较高收率得到较高纯度的叠氮致变性杂质Tr‑AZIDO和AZIDO,更有利于去研究四氮唑沙坦类原料药中叠氮杂质的来源与限度考察。
Description
技术领域
本发明涉及一种四氮唑沙坦类原料药中致突变性叠氮杂质的合成方法,属于医药技术领域。
背景技术
沙坦类降压药都是长效降压药,且较普利类药物有明显的优势,不会引起干咳,不良反应较少。沙坦类药物对心、脑和肾脏也都有良好的器官保护作用。
但是随着人们对沙坦类降压药的不断探索研究,2018年FDA更新调查公告缬沙坦中含有NDEA、NDMA基因毒性杂质(亚硝胺类杂质),国内外各个药企不仅在缬沙坦中,且在其他沙坦类药物中也进行了调查研究。2019年FDA更新调查公告,氯沙坦钾中含有NMBA基因毒性杂质,NMBA是ARB药物中检测到的第三种亚硝基杂质。2021年EDQM发布公告,调查发现在四氮唑沙坦类药物中有叠氮类致突变性杂质Tr-AZIDO和AZIDO。虽然只有少数厂家的药物中有,但也引起了一场风波,很多厂家开始注意此杂质,且开始研究此杂质的限度要求。
发明内容
本发明的目的是提供一种四氮唑沙坦类原料药中致突变性叠氮杂质的合成方法,以沙坦类中间体N-(三苯基甲基)-5-(4'-溴甲基联苯-2-基)四氮唑(BBTT)为起始物料,再与叠氮化钠反应,加水猝灭后,经溶剂提取,蒸除溶剂得三苯基叠氮杂质Tr-AZIDO;三苯基叠氮杂质在酸性条件下脱三苯基保护,经碱水洗涤,碱水层加入溶剂调酸使目标产物提取至溶剂层中,浓缩干溶剂得叠氮杂质AZIDO。最终得到的产品Tr-AZIDO纯度高于95%,收率高于85%,外观为白色结晶性粉末;得到的产品AZIDO纯度高于98%,收率高于80%,外观为白色结晶性粉末。
实现本发明目的所采取的技术方案如下:以沙坦类中间体N-(三苯基甲基)-5-(4'-溴甲基联苯-2-基)四氮唑(BBTT)为起始物料,与叠氮化钠反应,加水猝灭后,经溶剂提取,蒸除溶剂得三苯基叠氮杂质5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2-三苯甲基-2H-四唑(Tr-AZIDO);三苯基叠氮杂质在酸性条件下脱三苯基保护,经碱水洗涤,碱水层加入溶剂调酸使目标产物提取至溶剂层中,浓缩干溶剂得叠氮杂质5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2H-四唑(AZIDO),原料BBTT的纯度为95%-99%;
(1)合成5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2-三苯甲基-2H-四唑(Tr-AZIDO):
所述反应溶剂为二甲基甲酰胺,提取用的溶剂为二氯甲烷,反应温度为20-100℃;反应溶剂DMF与N-(三苯基甲基)-5-(4'-溴甲基联苯-2-基)四氮唑的质量比为1-10,所述叠氮化钠与N-(三苯基甲基)-5-(4'-溴甲基联苯-2-基)四氮唑的质量比为0.12-0.35;
(2)合成5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2H-四唑(AZIDO):
所述酸性条件为盐酸,反应温度为20-80℃;所述碱为氢氧化钠,所述提取溶剂为二氯甲烷,调酸后的pH为2-5;所述反应溶剂与三苯基叠氮杂质5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2-三苯甲基-2H-四唑的质量比为1-10;所述酸量与三苯基叠氮杂质5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2-三苯甲基-2H-四唑的质量比为0.15-1。
合成5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2-三苯甲基-2H-四唑所用反应溶剂为1,4-二氧六环或甲苯或四氢呋喃或乙腈,提取用的溶剂为三氯甲烷或乙酸乙酯或甲苯或二甲苯;合成5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2H-四唑的酸性条件为氯化氢甲醇或氯化氢乙醇或冰醋酸或三氟乙酸,所用碱为碳酸钠或氨水或氢氧化钾或碳酸钾,提取溶剂为三氯甲烷或乙酸乙酯或甲苯或二甲苯。
HPLC的检测方法为:色谱柱: ODS-C18 (250* 4.6 mm, 5 μm),乙腈:水(磷酸调pH=3.2)=3:1,波长220nm,流速1.0mL/min。
本发明的积极效果是:工艺方法简单易操作,利用本发明的方法可以以较高收率得到较高纯度的叠氮致变性杂质Tr-AZIDO和AZIDO,更有利于去研究四氮唑沙坦类原料药中叠氮杂质的来源与限度考察。
附图说明
附图1为合成三苯基叠氮杂质和叠氮杂质的反应式;附图2为Tr-AZIDO的1H NMR图谱;附图3为Tr-AZIDO的HMS图谱;附图4为AZIDO的1H NMR图谱;附图5为AZIDO的HMS图谱。
具体实施方式
下面结合实施例对本发明做进一步说明,但并不限制本发明的实施。
(一)、5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2-三苯甲基-2H-四唑(Tr-AZIDO)的合成
实施例1
2000ml四口烧瓶中加入BBTT(纯度96%)100g、DMF500g、叠氮化钠12g,升温至50℃反应8小时;降温至30℃以下,加入二氯甲烷500g、水500g,搅拌30min,静置30min,分出下层溶剂层,蒸干得Tr-AZIDO, 80.3g,纯度97.5%。
实施例2
2000ml四口烧瓶中加入BBTT(纯度99%)100g、DMF500g、叠氮化钠20g,升温至70℃反应8小时;降温至30℃以下,加入乙酸乙酯500g、水500g,搅拌30min,静置30min,分出下层溶剂层,蒸干得Tr-AZIDO, 84.2g,纯度98.7%。
实施例3
2000ml四口烧瓶中加入BBTT(纯度96%)100g、四氢呋喃500g、叠氮化钠15g、四丁基溴化铵5g,升温至50℃反应8小时;降温至30℃以下,抽滤,滤去不溶物,蒸干得Tr-AZIDO,81.1g,纯度95.9%。
(二)、5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2H-四唑(AZIDO)的合成
实施例1
250ml四口烧瓶中加入Tr-AZIDO 20g、丙酮100g、盐酸(31%)5g,升温至50℃反应4小时,减压蒸干丙酮,加入乙酸乙酯 50g,用液碱(32%)调pH=12,搅拌30min,静置30min,分出上层溶剂层,下层水层加入乙酸乙酯 50g,搅拌下滴加31%盐酸调pH=2。继续搅拌30min,静置30min,分出上层EA层蒸干,加入正己烷20g,降温至0-5℃,搅拌析晶2小时,抽滤得9.5g,HPLC检测纯度为99.0%。
实施例2
250ml四口烧瓶中加入Tr-AZIDO 20g、甲苯80g、盐酸(31%)5g,升温至50℃反应4小时,用液碱(32%)调pH=12,搅拌30min,静置30min,分出上层溶剂层,下层水层加入二氯甲烷50g,搅拌下滴加31%盐酸调pH=3。继续搅拌30min,静置30min,分出下层二氯甲烷,蒸干,加入正己烷20g,降温至0-5℃,搅拌析晶2小时,抽滤得9.0g,HPLC检测纯度为98.8%。
实施例3
250ml四口烧瓶中加入Tr-AZIDO 20g、甲苯80g、冰乙酸8g,升温至60℃反应4小时,用碳酸钾水溶液(20%)调pH=12,搅拌30min,静置30min,分出上层溶剂层,下层水层加入二氯甲烷 50g,搅拌下滴加31%盐酸调pH=3。继续搅拌30min,静置30min,分出下层二氯甲烷层蒸干,加入正己烷20.0g,降温至0-5℃,搅拌析晶2小时,抽滤得8.6g,HPLC检测纯度为98.6%。
HPLC的检测方法为:色谱柱: ODS-C18 (250* 4.6 mm, 5 μm),乙腈:水(磷酸调pH=3.2)=3:1,波长220nm,流速1.0mL/min。
Claims (2)
1.一种四氮唑沙坦类原料药中致突变性叠氮杂质的合成方法,其特征在于:以沙坦类中间体N-(三苯基甲基)-5-(4'-溴甲基联苯-2-基)四氮唑(BBTT)为起始物料,与叠氮化钠反应,加水猝灭后,经溶剂提取,蒸除溶剂得三苯基叠氮杂质5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2-三苯甲基-2H-四唑;三苯基叠氮杂质在酸性条件下脱三苯基保护,经碱水洗涤,碱水层加入溶剂调酸使目标产物提取至溶剂层中,浓缩干溶剂得叠氮杂质5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2H-四唑,原料BBTT的纯度为95%-99%;
(1)合成5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2-三苯甲基-2H-四唑:
所述反应溶剂为DMF,提取用的溶剂为二氯甲烷,反应温度为20-100℃;反应溶剂DMF与N-(三苯基甲基)-5-(4'-溴甲基联苯-2-基)四氮唑的质量比为1-10,所述叠氮化钠与N-(三苯基甲基)-5-(4'-溴甲基联苯-2-基)四氮唑的质量比为0.12-0.35;
(2)合成5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2H-四唑:
所述酸性条件为盐酸,反应温度为20-80℃;所述碱为氢氧化钠,所述提取溶剂为二氯甲烷,调酸后的pH为2-5;所述反应溶剂DMF与三苯基叠氮杂质5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2-三苯甲基-2H-四唑的质量比为1-10;所述酸量与三苯基叠氮杂质5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2-三苯甲基-2H-四唑的质量比为0.15-1。
2.根据权利要求1所述的四氮唑沙坦类原料药中致突变性叠氮杂质的合成方法,其特征在于:合成5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2-三苯甲基-2H-四唑所用反应溶剂为1,4-二氧六环或甲苯或四氢呋喃或乙腈,提取用的溶剂为三氯甲烷或乙酸乙酯或甲苯或二甲苯;合成5-(4'-(叠氮甲基)-[1,1'-联苯]-2-基)-2H-四唑的酸性条件为氯化氢甲醇或氯化氢乙醇或冰醋酸或三氟乙酸,所用碱为碳酸钠或氨水或氢氧化钾或碳酸钾,提取溶剂为三氯甲烷或乙酸乙酯或甲苯或二甲苯。
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