CN110963922B - 一种2，4，6-三氟苯甲胺的制备方法 - Google Patents
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/40—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of hydroxylamino or oxyimino groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- 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
- Y02P20/584—Recycling of catalysts
Abstract
一种2，4，6‑三氟苯甲胺的制备方法，以均三氟苯为原料，用四氢呋喃为溶剂，在低温下，通过正丁基锂进行锂化，N,N‑二甲基甲酰胺进行醛基化得到2，4，6‑三氟苯甲醛，简单浓缩后，未经分离的2，4，6‑三氟苯甲醛粗品和羟胺反应生成高纯度的肟。肟再在镍催化剂的作用下与氢气反应得到粗品，粗品经过蒸馏后得到目标产物2，4，6‑三氟苯甲胺。
Description
技术领域
本发明属于医药化工领域。
背景技术
艾滋病是一种危害性极大的传染病，由感染艾滋病病毒（HIV病毒）引起。Bicteravir（化学式1）是Gilead 公司开发的治疗HIV的药物，由Bicteravir（50mg）、Emtricitabine（200mg）、与Tenofovir alafenamide（25mg）三种成分组成的药物Biktarvy，于2018年2月8日经FDA批准在美国上市。
化学式1. Bictegravir的结构.
2，4，6-三氟苄胺是合成Bictegravir的重要中间体，就其合成方法而言，文献报道的方法主要有以下几种：专利CN104610068A报道了以1，3，5-三氟苯为原料，通过低温下锂化、醛基化、还原、卤代、氨解制备1，3，5-三氟苄胺的方法，产品纯度99%左右（式1）。
专利CN107778183A、CN106349083A均报道了以2，4，6-三氟苯甲腈为原料，通过氢化反应来制备2，4，6-三氟苄胺的方法。其中，CN10778183A还对原料2，4，6-三氟苯甲腈的制备方法进行了报道（式2）。
上述文献报道的两种方法中，第一种方法产品的收率高，纯度也能达到99%左右，但是其合成线路较长，使用了价格较贵的硼氢化物，产品的成本较高；在氯代反应中使用了氯化亚砜和吡啶，对环境不友好，有较大的环保压力。而第二种方法中，虽然使用了价廉易得的原料，但在后续反应过程需要使用价格昂贵的钯催化剂才能得到高的收率，而用价廉的镍催化剂时，反应收率很低，这样导致产品的成本高；此外，此线路在第一步反应中使用环丁砜为溶剂，该溶剂沸点高、水溶性好，回收困难，环保压力大；虽然文献中未提及产品中杂质的情况，但从反应线路看，此线路还可能存在反应选择性不好的问题，产物中杂质的数量和含量较高，给分离和纯化带来困难。
发明内容
针对现有技术的缺陷，申请人旨在找到更为理想的合成线路和工艺，避开现有方法的不足。本发明反应线路短；原材料价格便宜、易得，收率较高，产品的原料成本低；后处理过程简单，中间体易于分享和纯化，易于生产和生产控制；工艺稳定，产品质量好；使用可回收、对环境影响小的醚类、烃类、醇类有机溶剂，对环境更为友好。
具体的反应过程如下式所示：
以均三氟苯为原料，用四氢呋喃为溶剂，在低温下，通过正丁基锂进行锂化，N,N-二甲基甲酰胺进行醛基化得到2，4，6-三氟苯甲醛，简单浓缩后，未经分离的2，4，6-三氟苯甲醛粗品和羟胺反应生成高纯度的肟。肟再在镍催化剂的作用下与氢气反应得到粗品，粗品经过蒸馏后得到目标产物2，4，6-三氟苯甲胺。
具体实施例
，4，6-三氟苯甲醛肟的合成
实施例1：向1L反应瓶中加入66g均三氟苯，500mL 四氢呋喃，搅拌均匀，氮气保护下降温到-80℃。缓缓滴加225mL 的2.5M正丁基锂正己烷溶液，加毕，再加入36.5g无水N,N-二甲基甲酰胺，保温反应至反应完全。将反应液加入到250mL的4M稀盐酸中淬灭，分出有机相，水相用甲基叔丁基醚萃取，合并有机相，减压脱溶后得粗品，气相色谱检测纯度92.1%。
向上述粗品中加入300mL甲醇，搅拌溶解完全，得到2，4，6-三氟苯甲醛的甲醇溶液；在另一反应瓶中加入37.5g盐酸羟胺和150g水，分批次加入46.5g碳酸氢钠中和，得到羟胺水溶液。将制备好的羟胺水溶液滴加到2，4，6-三氟苯甲醛的甲醇溶液中，反应液渐渐变浑浊，有固体析出，滴加完毕后，继续搅拌至反应完全。过滤，滤饼用甲醇-水混合溶液洗涤，收集滤饼，烘干后得黄色固体71.7g, 收率81.9%，气相色谱检测其纯度为96.2%。
实施例2：向2L反应瓶中加入132g均三氟苯，1200mL 四氢呋喃，搅拌均匀，氮气保护下降温到-60℃。缓缓滴加500mL 的2.5M正丁基锂正己烷溶液，加毕，再加入76.6g无水N,N-二甲基甲酰胺，保温反应至反应完全。将反应液加入到600mL的4M稀盐酸中淬灭，分出有机相，水相用甲基叔丁基醚萃取，合并有机相，减压脱溶后得粗品，粗品直接用于下一步反应。
向上述粗品中加入800mL95%乙醇，搅拌溶解完全，得到2，4，6-三氟苯甲醛的乙醇溶液；在另一反应瓶中加入75g盐酸羟胺和400g水，分批次加入95g碳酸氢钠中和，得到羟胺水溶液。将制备好的羟胺水溶液滴加到2，4，6-三氟苯甲醛的乙醇溶液中，反应液渐渐变浑浊，有固体析出，滴加完毕后，继续搅拌至反应完全。过滤，滤饼用乙醇-水混合溶液洗涤，收集滤饼，烘干后得黄色固体134.7g, 收率76.9%，气相色谱检测其纯度为98.4%。
实施例3：向2L反应瓶中加入132g均三氟苯，2000mL 2-甲基四氢呋喃，搅拌均匀，氮气保护下降温到-70℃。缓缓滴加500mL 的2.5M正丁基锂正己烷溶液，加毕，再加入76.6g无水N,N-二甲基甲酰胺，保温反应至反应完全。将反应液加入到600mL的4M稀盐酸中淬灭，分出有机相，水相用2-甲基四氢呋喃萃取，合并有机相，得到2，4，6-三氟苯甲醛的2-甲基四氢呋喃溶液。在另一反应瓶中加入75g盐酸羟胺和1000g水，分批次加入79.2g醋酸钠中和，得到羟胺水溶液。将制备好的羟胺水溶液滴加到2，4，6-三氟苯甲醛的2-甲基四氢呋喃溶液中，反应液渐渐变浑浊，有固体析出，滴加完毕后，继续搅拌至反应完全。过滤，滤饼用水混合溶液洗涤，收集滤饼，烘干后得黄色固体75.6g。将过滤得到的母液蒸馏，收集约1200mL馏出液后，将蒸馏液冷却至室温，过滤、烘干后又得到28.3g产品，共103.9g产品，收率59.3%，气相色谱检测其纯度为98.5%。
2，4，6-三氟苯甲胺的合成
实施例4: 向1升不锈钢反应釜中加入28.2g 2，4，6-三氟苯甲醛肟，400g无水甲醇，搅拌至完全溶解；再加入8g兰尼镍，关闭釜盖。用氮气置换釜内空气，再用氢气置换釜内氮气，再充氢气到0.2MPa, 加热到40℃反应。反应完全后，放出釜内余气，用氮气置换后，打开釜盖，取出反应液，过滤，滤液浓缩，再进行减压蒸馏得无色液体8.61g，收率33.2%，气相色谱检测其纯度为99.3%。
实施例5: 向10升不锈钢反应釜中加入320g 2，4，6-三氟苯甲醛肟，5200g无水甲醇，搅拌至完全溶解；再加入100g兰尼镍，关闭釜盖。用氮气置换釜内空气，再用氢气置换釜内氮气，再充氢气到1.0MPa, 20℃反应。反应完全后，放出釜内余气，用氮气置换后，打开釜盖，取出反应液，过滤，滤液浓缩，再进行减压蒸馏得无色液体215.5g，收率73.2%，气相色谱检测其纯度为99.2%。
实施例6: 向1升不锈钢反应釜中加入51.5g 2，4，6-三氟苯甲醛肟，650g无水乙醇，搅拌至完全溶解；再加入20g兰尼镍，关闭釜盖。用氮气置换釜内空气，再用氢气置换釜内氮气，再充氢气到0.6MPa, 保温30℃反应。反应完全后，放出釜内余气，用氮气置换后，打开釜盖，取出反应液，过滤，滤液浓缩，再进行减压蒸馏得无色液体30.1g，收率63.5%，气相色谱检测其纯度为99.5%。
Claims (3)
1.一种2，4，6-三氟苯甲胺的制备方法，其特征在于，包括以下步骤：
a)以均三氟苯为原料，通过正丁基锂进行锂化，N,N-二甲基甲酰胺进行醛基化得到2，4，6-三氟苯甲醛；
b)2，4，6-三氟苯甲醛和羟胺反应制备得到肟；
c)肟在镍催化剂的作用下与氢气反应制备得到2，4，6-三氟苯甲胺；
步骤a)中制备得到的2，4，6-三氟苯甲醛，简单浓缩后，未经分离，直接用于下一步反应。
2.如权利要求1所述的方法，步骤b)中所用的羟胺是盐酸羟胺通过和碳酸氢钠反应制备得到。
3.如权利要求1所示的方法，步骤c)中所用的镍催化剂为兰尼镍。
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