CN103408547A - 替诺福韦中间体(r)-1-(6-氨基嘌呤-9-基)-2-丙醇的制备方法 - Google Patents
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Abstract
本发明揭示了一种替诺福韦中间体(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)的制备方法，其制备步骤包括以4，6-二氯-5-硝基嘧啶(II)为原料，与(R)-1-氨基-2-丙醇缩合生成(R)-4-[N-(2-羟基丙基)胺基]-5-硝基-6-氯嘧啶(III)，中间体(III)经还原环化生成(R)-1-(6-氯嘌呤-9-基)-2-丙醇(IV)，中间体(IV)经过氨解生成替诺福韦中间体(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)。该制备方法原料易得，工艺简洁，副反应少，适合工业化生产。
Description
技术领域
本发明属于有机合成路线设计及其原料药和中间体制备技术领域，特别涉及一种替诺福韦中间体的制备方法。
背景技术
替诺福韦酯富马酸盐(Tenofovir disoproxil fumarate，Tenofovir，TDF)是由美国吉尔德(Gilead Sciences)公司研发的用于治疗人类免疫缺陷病毒(HIV)和乙肝病毒(HBV)感染的新药。于2001年获准在美国上市，商品名为韦瑞德(Viread)。全球已有包括中国在内的超过100个国家批准替诺福韦用于艾滋病的治疗。此外，2008年美国食品药品管理局(FDA)批准了替诺福韦酯用于治疗慢性乙型肝炎的新适应症。目前，已经有30多个国家和地区获得了该新型适应症的批准。2011年中国食品药品监督管理局(SFDA)批准替诺福韦酯治疗慢性乙型肝炎的新药临床试验，该药在中国的注册和批准，将给中国的慢性乙肝患者带来新的治疗选择。
替诺福韦酯为单磷酸腺苷的无环核苷磷酸二酯类似物，属于核苷酸类逆转录酶抑制剂。替诺福韦是前药，化学名称为：(R)-9-(2-磷酸甲氧基丙基)腺嘌呤。
吉尔德公司原研的美国专利第US5935946号和第US5922695号报道了以腺嘌呤和S-缩水甘油经催化氢化、成环偶联及酯化水解等反应制得替诺福韦酯。对于手性羟基的引入，中国专利第CN102899367号、第CN102863445号、第CN102295660号、第CN101906119号和第CN101648974号等报道了以手性氯丙醇、(R)-环氧丙烷、(R)-乳酸酯及(R)-1，2-丙二醇为原料，分别与腺嘌呤发生缩合反应生成(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)的方法。中国专利第CN102060876号和第CN101870713号报道了以(R)-碳酸丙烯酯为原料与腺嘌呤缩合生成中间体(I)的方法。除此以外，在缩合、酯化及水解反应的先后顺序和氨基、羟基等官能团的保护方法上也有较多的研究报道。
综上所述，尽管制备替诺福韦及酯的方法多种多样，但其母核原料均为腺嘌呤。因而在发生缩合反应时，或者需要将氨基保护，或者需要通过不同的催化剂来增强其反应的选择性。所以现有工艺普遍步骤较多，且质量难以控制。《Organic Process Research&Development》2010年，第14期，第1194-1201页研究报道了多种已有的工艺制备方法，指出现有以腺嘌呤为起始原料的合成工艺过程中，在生成中间体(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)的同时，还会不同程度地产生工艺杂质(V)和(VI)。
发明内容
为了克服现有技术中的缺陷，本发明的目的在于按照绿色化学的合成理念，提供一种改进的替诺福韦中间体(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)的制备方法，该制备方法具有原料易得、工艺简洁、成本较低和质量可控等特点，故而利于该原料药的工业化生产，促进其经济技术的发展。
为了实现上述目的，本发明所提供的主要技术方案如下：一种替诺福韦中间体(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)的制备方法，
所述制备方法，其制备步骤包括：以4，6-二氯-5-硝基嘧啶(II)为原料，与(R)-1-氨基-2-丙醇发生缩合反应生成(R)-4-[N-(2-羟基丙基)胺基]-5-硝基-6-氯嘧啶(III)，中间体(III)经还原环合反应生成(R)-1-(6-氯嘌呤-9-基)-2-丙醇(IV)，中间体(IV)经过氨解反应生成替诺福韦中间体(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)。
此外，本发明还包括如下附属技术方案：
所述4，6-二氯-5-硝基嘧啶(II)与(R)-1-氨基-2-丙醇发生缩合反应的投料摩尔比为1∶0.85-1.5，优选1∶1-1.3。
所述4，6-二氯-5-硝基嘧啶(II)与(R)-1-氨基-2-丙醇发生缩合反应的促进剂为碱金属或碱上金属的氢氧化物、碱金属或碱上金属的氢化物、碱金属的碳酸盐、碱金属的碳酸氢盐或碱金属的醇盐，优选氢氧化钾、叔丁醇钾或叔丁醇镁。
所述还原环合反应的还原剂为锌粉、铁粉、保险粉、水合肼或催化加氢，优选锌粉或保险粉。
所述还原环合反应的环合剂为甲酸、甲酸甲酯、甲酸乙酯或甲酰胺，优选甲酸。
所述氨解反应的氨化剂为氨水或液氨。
相比于现有技术，本发明所涉及的替诺福韦中间体(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)的制备方法，具有原料易得、工艺简洁、成本较低和质量可控等特点，故而利于该原料药的工业化生产，促进其经济技术的发展。
具体实施方式
以下结合数个较佳实施例对本发明技术方案作进一步非限制性的详细说明。
实施例一：
于反应瓶中加入4，6-二氯-5-硝基嘧啶(II)(1.93g，10mmol)和N，N-二甲基甲酰胺20mL，室温搅拌至溶解。降温至0-5℃，分批加入叔丁醇钾(2.8g，2.5eq)，同时滴加(R)-1-氨基-2-丙醇(0.9g，12mmol)。升至室温，搅拌5～7小时。加入甲苯，降温结晶，过滤。滤饼用乙醇重结晶得到类白色固体(R)-4-[N-(2-羟基丙基)胺基]-5-硝基-6-氯嘧啶(III)2.1g，收率为90.5％。
实施例二：
于反应瓶中加入(R)-4-[N-(2-羟基丙基)胺基]-5-硝基-6-氯嘧啶(III)(2.32g，10mmol)、保险粉(4.35g，2.5eq)、甲醇25mL和蒸馏水25mL，升温至50-60℃，搅拌反应6小时。减压浓缩至体积一半，用二氯甲烷萃取3次。合并有机相，水洗，浓缩至干，加入甲酸25mL，升温至150-170℃，保温反应3小时。加入活性炭脱色。浓缩，用固体析出，用水和甲醇打浆漂洗，过滤，得到淡黄色固体(R)-1-(6-氯嘌呤-9-基)-2-丙醇(IV)1.7g，收率为80.2％。
实施例三：
于反应瓶中加入(R)-1-(6-氯嘌呤-9-基)-2-丙醇(IV)(1.1g，5mmol)和氨气的甲醇饱和溶液50mL，密封搅拌反应16小时。减压浓缩至干。用蒸馏水脱色重结晶，乘热过滤，冷却结晶5小时，得类白色固体(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)0.8g，收率为83.1％。
需要指出的是，上述实施例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
Claims (6)
1.一种替诺福韦中间体(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)的制备方法，
其特征在于所述制备方法，其制备步骤包括：以4，6-二氯-5-硝基嘧啶(II)为原料，与(R)-1-氨基-2-丙醇进行缩合反应生成(R)-4-[N-(2-羟基丙基)胺基]-5-硝基-6-氯嘧啶(III)，所述(R)-4-[N-(2-羟基丙基)胺基]-5-硝基-6-氯嘧啶(III)经还原环合反应生成(R)-1-(6-氯嘌呤-9-基)-2-丙醇(IV)，所述(R)-1-(6-氯嘌呤-9-基)-2-丙醇(IV)经过氨解反应生成替诺福韦中间体(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)。
2.如权利要求1所述(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)的制备方法，其特征在于：所述4，6-二氯-5-硝基嘧啶(II)与(R)-1-氨基-2-丙醇进行缩合反应的投料摩尔比为1∶0.85-1.5。
3.如权利要求1所述(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)的制备方法，其特征在于：所述4，6-二氯-5-硝基嘧啶(II)与(R)-1-氨基-2-丙醇进行缩合反应的促进剂为碱金属或碱土金属的氢氧化物、碱金属或碱土金属的氢化物、碱金属的碳酸盐、碱金属的碳酸氢盐或碱金属的醇盐。
4.如权利要求1所述(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)的制备方法，其特征在于：所述还原环合反应的还原剂为锌粉、铁粉、保险粉、水合肼或催化加氢。
5.如权利要求1所述(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)的制备方法，其特征在于：所述还原环合反应的环合剂为甲酸、甲酸甲酯、甲酸乙酯或甲酰胺。
6.如权利要求1所述(R)-1-(6-氨基嘌呤-9-基)-2-丙醇(I)的制备方法，其特征在于：所述氨解反应的氨化剂为氨水或液氨。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104710424A (zh) * | 2013-12-11 | 2015-06-17 | 河南师范大学 | (r)-(+)-9-(2-羟丙基)腺嘌呤的制备方法 |
| CN106588932A (zh) * | 2016-12-20 | 2017-04-26 | 青岛辰达生物科技有限公司 | 一种替诺福韦中间体的制备方法 |
| CN108285471A (zh) * | 2018-03-16 | 2018-07-17 | 安徽华昌高科药业有限公司 | 一种替诺福韦的制备方法 |
-
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- 2013-07-12 CN CN201310291885.0A patent/CN103408547B/zh active Active
Non-Patent Citations (1)
| Title |
|---|
| JAY F. LARROW ET AL.: "Kinetic resolution of terminal epoxides via highly regisoselective and enantioselective ring opening with TMSN3. An efficient, catalytic route to 1,2-amino alcohols.", 《J.AM.CHEM.SOC.》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104710424A (zh) * | 2013-12-11 | 2015-06-17 | 河南师范大学 | (r)-(+)-9-(2-羟丙基)腺嘌呤的制备方法 |
| CN104710424B (zh) * | 2013-12-11 | 2017-03-01 | 河南师范大学 | (r)‑(+)‑9‑(2‑羟丙基)腺嘌呤的制备方法 |
| CN106588932A (zh) * | 2016-12-20 | 2017-04-26 | 青岛辰达生物科技有限公司 | 一种替诺福韦中间体的制备方法 |
| CN106588932B (zh) * | 2016-12-20 | 2018-08-17 | 郑州泰丰制药有限公司 | 一种替诺福韦中间体的制备方法 |
| CN108285471A (zh) * | 2018-03-16 | 2018-07-17 | 安徽华昌高科药业有限公司 | 一种替诺福韦的制备方法 |
| WO2019174101A1 (zh) * | 2018-03-16 | 2019-09-19 | 安徽华昌高科药业有限公司 | 一种替诺福韦的制备方法 |
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