CN112079729A - 一种3-烷基-5-三氟甲基苯胺的制备方法 - Google Patents
一种3-烷基-5-三氟甲基苯胺的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 20
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 15
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- 238000006243 chemical reaction Methods 0.000 claims description 43
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- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
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- 239000004327 boric acid Substances 0.000 abstract 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 abstract 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07C209/32—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 nitro groups
- C07C209/325—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 nitro groups reduction by other means than indicated in C07C209/34 or C07C209/36
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- C07C2531/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- C07C2531/24—Phosphines
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种3‑烷基‑5‑三氟甲基苯胺的有效合成方法。该方法包含烷基化反应与还原反应。烷基化反应以化合物II 3‑溴‑5‑硝基三氟甲苯和烷基硼酸为底物,在钯催化剂和碳酸钾水溶液的条件下,在氮气环境下于二氧六环中100℃进行反应而得到结构通式III所示的烷基化产物。而后的还原反应,以化合物III为底物,在锌与浓盐酸条件下溶于乙醇中80℃进行反应而得到结构通式I所示的3‑烷基‑5‑三氟甲基苯胺。该方法经济,底物3‑溴‑5‑硝基三氟甲苯与烷基硼酸试剂均非常廉价;烷基化步骤无需用酸,对环境友好;烷基化反应产率高,产物I可进行克级制备。
Description
技术领域
本发明属于精细化工领域,具体涉及3-烷基-5-三氟甲基苯胺的制备方法。
背景技术
3-烷基-5-三氟甲基苯胺是部分抗高血压药,精神病药和除草剂的中间体(JP02045451A),特别指出3-甲基-5-三氟甲基苯胺合成DDR1抑制剂的中间体(WO2020079652A1),有较高的实用价值。目前3-烷基-5-三氟甲基苯胺价格昂贵,其它3-烷基-5-三氟甲基苯胺更是没有商业产品,难以购得;而关于合成3-甲基-5-三氟甲基苯胺的文献极少。
以3-甲基-5-三氟甲基苯胺为例,一般的合成路线是先对3-甲基三氟甲苯进行间位硝化,再还原硝基。其中成本方面原料3-甲基三氟甲苯价格较为昂贵,而其它3-烷基三氟甲苯更是难以购得;实验过程方面硝化反应较危险且对环境不友好;反应性方面硝化选择性差,导致总收率很低,限制了3-烷基-5-三氟甲基苯胺在大规模工业生产中的应用。因此,发展一种更经济、更便捷、更高效的3-烷基-5-三氟甲基苯胺合成方法具有重要的应用前景和经济价值。这其中涉及两个重要的问题:一是如何开发使用常见、易得的原料即可完成的合成路线,二是如何在合成过程中尽可能地减少对环境不友好的副产物产生。
发明内容
本发明的目的是提供一种3-烷基-5-三氟甲基苯胺的合成方法。
本发明提供的制备式I所示化合物3-烷基-5-三氟甲基苯胺的方法,包括烷基化反应、还原反应;
具体步骤如下:
将式II所示化合物3-溴-5-硝基三氟甲苯与烷基化试剂溶解在有机溶剂中,然后加入碱的水溶液,经置换惰性气体保护后再加入催化剂混匀反应,亲核烷基化反应完毕得到所述式III所示化合物3-溴-5-烷基三氟甲苯;将简单纯化后的式III所示化合物溶解在有机溶剂中,加入还原性金属,滴加酸混匀反应,还原反应完毕得到所述式I所示化合物;
所述式I、式III中,R为C1-C6的烷基;
所述C1-C6的烷基为如下基团中的任意一种:甲基、乙基、正丙基、异丙基、正丁基、异丁基、环己基;
上述烷基化反应方法中,所述惰性气体为氮气和氩气的至少一种。
所述烷基化试剂为甲基硼酸、三甲基硼氧六环、乙基硼酸、正丙基硼酸、异丙基硼酸、正丁基硼酸、异丁基硼酸或环己基硼酸的任意一种。
所述碱为磷酸钾、碳酸铯、碳酸钠或碳酸钾,优选碳酸钠。
所述催化剂为双(三苯基膦)二氯化钯或四三苯基膦钯,优选四三苯基膦钯。
所述催化剂的投料摩尔用量为所述式II所示化合物的0.5~2.5%,优选1.0%。
所述碱的水溶液为碱的质量浓度为20%至50%的水溶液,优选35%的水溶液,其投料摩尔用量以其中所含碱的投料摩尔用量计,为所述式II所示化合物的1.0~2.5倍,优选1.5倍。
所述烷基化试剂的投料摩尔用量为所述式II所示化合物的1.0~1.5倍,优选1.1倍。
所述反应在溶剂中进行;所述溶剂为N,N-二甲基甲酰胺、甲苯、乙二醇二甲醚或1,4-二氧六环,优选1,4-二氧六环。
所述反应步骤中,温度为90~120℃,优选100℃;时间为2~6小时,优选4小时。反应是否完毕可通过薄层色谱或者气相色谱进行监测。
在烷基化反应完毕后,可将反应体系按照常规方法进行分离简单提纯,优选的分离方式为:将反应之后的原液转移到圆底烧瓶中,转移时可用一些乙酸乙酯或二氯甲烷冲洗原容器,以减少损失;减压浓缩后用石油醚、正己烷或环己烷萃取多次,收集有机相浓缩旋干得到所述式III所示化合物粗品,称重并计算产率,后可直接用于下一步还原反应。
具体的所述还原反应的反应条件为:将中间产物所述式III所示化合物粗品溶于有机溶剂中,加入还原性金属,然后在滴加酸性试剂,惰性气体保护加热回流反应过夜。
上述还原反应方法中,所述惰性气体为氮气和氩气的至少一种。
所述还原性金属为锌、镓或铁,优选锌。
所述酸性试剂为冰醋酸、甲酸、氯化铵或浓盐酸,优选浓盐酸。
所述酸性试剂的投料摩尔用量为所述式III所示化合物的2.0~4.0倍,优选3.0倍。
所述还原性金属的投料摩尔用量为所述式III所示化合物的2.0~4.0倍,优选3.0倍。
所述反应在溶剂中进行;所述溶剂为乙醇或甲醇,优选乙醇。
所述反应步骤中,温度为25~90℃,优选80℃;时间为6~24小时,优选12小时。反应是否完毕可通过薄层色谱或者气相色谱进行监测。
在还原反应完毕后,可将反应体系按照常规方法进行分离提纯,优选的分离方式为:将反应之后的原液转移到圆底烧瓶中,转移时可用一些二氯甲烷冲洗原容器,以减少损失;减压浓缩后加入二氯甲烷溶解,用碳酸氢钠、碳酸钠或氢氧化钠调PH值到8,再加水稀释,用二氯甲烷萃取多次,收集有机相加入一定量100~200目的硅胶,减压浓缩除去溶剂得到含产物的硅胶;使用100~200目的硅胶和石油醚装柱,使用干法上柱;用石油醚作为洗脱剂进行洗脱,快速过柱得到所述式I所示化合物的溶液,旋蒸掉溶剂后真空干燥,称重并计算产率。
本发明提供的合成3-烷基-5-三氟甲基苯胺的方法,具有以下特点:(1)经济。反应原料3-溴-5-硝基三氟甲苯,是便宜易得的化工原料,所使用的碱和溶剂亦非常的廉价易得,所使用的催化剂虽然不廉价,但所需加入量很少,反应所得的产物为高附加值的3-烷基-5-三氟甲基苯胺。(2)绿色。两步反应的溶剂均为友好溶剂,甲基化步骤的条件不涉及浓酸,该过程所产生的副产物只有中和反应产物水和钠盐,对环境几乎没有污染。(3)高效。甲基化不存在选择性的问题,产率高;还原反应体系成熟,两步总收率高,以合成3-甲基-5-三氟甲基苯胺为例,做克级实验总收率可超过75%。
附图说明
图1为3-甲基-5-三氟甲基苯胺的合成路线图。
图2为实施例1中所得到的3-甲基-5-三氟甲基苯胺的氢谱图。
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。下述实施例中所用的材料、试剂等,如无特别说明均能从公开商业途径而得。
实施例1
称取10.0g 3-溴-5-硝基三氟甲苯(37.0mmol)溶于100.0mL 1,4-二氧六环中,加入2.4g甲基硼酸(40.7mmol),把6.0g碳酸钠(56.6mmol)溶入10.0mL水中入,置换氮气再加入0.4g四三苯基膦钯(0.4mmol),氮气保护100℃反应4个小时。薄层色谱监测反应原料反应完全,将反应液旋干,用10.0mL石油醚萃取三次,收集有机相,旋干得到9.0g粗品,直接用于下一步。将原料粗品溶于50.0mL乙醇中,加入8.6g锌粒(131.5mmol),然后滴加13.5g浓盐酸(36%~38%(w/v),131.5mmol),氮气保护80℃加热回流反应12个小时。薄层色谱监测原料反应完全,将反应液直接旋干,加入30.0mL二氯甲烷溶解,用碳酸氢钠调PH值到8,再加30.0mL水稀释,用30.0mL二氯甲烷萃取三次,收集有机相,旋干得到7.1g粗品,再用石油醚作洗脱剂进行快速柱分离,得到产物5.0g,目标产物3-甲基-5-三氟甲基苯胺的分离产率为77%。由附图的氢谱可知,化合物结构正确。
实施例2
称取10.0g 3-溴-5-硝基三氟甲苯(37.0mmol)溶于100.0mL 1,4-二氧六环中,加入3.0g乙基硼酸(40.7mmol),把6.0g碳酸钠(56.6mmol)溶入10.0mL水中入,置换氮气再加入0.4g四三苯基膦钯(0.4mmol),氮气保护100℃反应4个小时。薄层色谱监测反应原料反应完全,将反应液旋干,用10.0mL石油醚萃取三次,收集有机相,旋干得到8.9g粗品,直接用于下一步。将原料粗品溶于50.0mL乙醇中,加入8.6g锌粒(131.5mmol),然后滴加13.5g浓盐酸(36%~38%(w/v),131.5mmol),氮气保护80℃加热回流反应12个小时。薄层色谱监测原料反应完全,将反应液直接旋干,加入30.0mL二氯甲烷溶解,用碳酸氢钠调PH值到8,再加30.0mL水稀释,用30.0mL二氯甲烷萃取三次,收集有机相,旋干得到7.5g粗品,再用石油醚作洗脱剂进行快速柱分离,得到产物5.2g,目标产物3-乙基-5-三氟甲基苯胺的分离产率为74%。
实施例3
称取10.0g 3-溴-5-硝基三氟甲苯(37.0mmol)溶于100.0mL 1,4-二氧六环中,加入3.6g异丙基硼酸(40.7mmol),把6.0g碳酸钠(56.6mmol)溶入10.0mL水中入,置换氮气再加入0.4g四三苯基膦钯(0.4mmol),氮气保护100℃反应4个小时。薄层色谱监测反应原料反应完全,将反应液旋干,用10.0mL石油醚萃取三次,收集有机相,旋干得到9.1g粗品,直接用于下一步。将原料粗品溶于50.0mL乙醇中,加入8.6g锌粒(131.5mmol),然后滴加13.5g浓盐酸(36%~38%(w/v),131.5mmol),氮气保护80℃加热回流反应12个小时。薄层色谱监测原料反应完全,将反应液直接旋干,加入30.0mL二氯甲烷溶解,用碳酸氢钠调PH值到8,再加30.0mL水稀释,用30.0mL二氯甲烷萃取三次,收集有机相,旋干得到7.6g粗品,再用石油醚作洗脱剂进行快速柱分离,得到产物5.1g,目标产物3-乙基-5-三氟甲基苯胺的分离产率为68%。
实施例3
称取10.0g 3-溴-5-硝基三氟甲苯(37.0mmol)溶于100.0mL 1,4-二氧六环中,加入5.2g环己基硼酸(40.7mmol),把6.0g碳酸钠(56.6mmol)溶入10.0mL水中入,置换氮气再加入0.4g四三苯基膦钯(0.4mmol),氮气保护100℃反应4个小时。薄层色谱监测反应原料反应完全,将反应液旋干,用10.0mL石油醚萃取三次,收集有机相,旋干得到10.2g粗品,直接用于下一步。将原料粗品溶于50.0mL乙醇中,加入8.6g锌粒(131.5mmol),然后滴加13.5g浓盐酸(36%~38%(w/v),131.5mmol),氮气保护80℃加热回流反应12个小时。薄层色谱监测原料反应完全,将反应液直接旋干,加入30.0mL二氯甲烷溶解,用碳酸氢钠调PH值到8,再加30.0mL水稀释,用30.0mL二氯甲烷萃取三次,收集有机相,旋干得到8.7g粗品,再用石油醚作洗脱剂进行快速柱分离,得到产物6.6g,目标产物3-乙基-5-三氟甲基苯胺的分离产率为73%。
Claims (7)
1.一种制备式I所示化合物的方法,其特征在于,包括如下步骤:
烷基化反应:将式II所示化合物3-溴-5-硝基三氟甲苯与烷基化试剂溶解在有机溶剂中,然后加入碱的水溶液,经置换惰性气体保护后再加入催化剂混匀反应,亲核烷基化反应完毕得到式III所示化合物3-溴-5-烷基三氟甲苯;
还原反应:将纯化后的式III所示化合物溶解在有机溶剂中,加入还原性金属,滴加酸性试剂混匀,在惰性气体保护下加热搅拌,还原反应完毕得到所述式I所示化合物;
所述式I、式III中,R为C1-C6的烷基;
所述C1-C6的烷基为如下基团中的任意一种:甲基、乙基、正丙基、异丙基、正丁基、异丁基、环己基;
上述烷基化反应方法中,所述惰性气体为氮气和氩气的至少一种;
所述烷基化试剂选自甲基硼酸、三甲基硼氧六环、乙基硼酸、正丙基硼酸、异丙基硼酸、正丁基硼酸、异丁基硼酸或环己基硼酸的至少一种;
所述碱选自磷酸钾、碳酸铯、碳酸钠或碳酸钾的至少一种;
所述催化剂选自双(三苯基膦)二氯化钯或四三苯基膦钯的至少一种;
所述还原性金属为锌、镓或铁的至少一种;
所述酸性试剂为冰醋酸、甲酸、氯化铵或浓盐酸的至少一种。
2.根据权利要求1所述的方法,其特征在于:所述烷基化试剂的投料摩尔用量为所述式II所示化合物的1.0~1.5倍;具体为1.1倍;
所述碱的水溶液的投料摩尔用量以碱的投料摩尔用量计,为所述式II所示化合物的1.0~2.5倍,具体为1.5倍;
所述催化剂的投料摩尔用量为所述式II所示化合物的0.5~2.5%,具体为1.0%;
所述酸性试剂的投料摩尔用量为所述式III所示化合物的2.0~4.0倍,具体为3.0倍;
所述还原性金属的投料摩尔用量为所述式III所示化合物的2.0~4.0倍,具体为3.0倍。
3.根据权利要求1或2所述的方法,其特征在于:所述碱的水溶液为碱的质量百分浓度为20%~50%的水溶液;具体为碱的质量百分浓度为35%的水溶液。
4.根据权利要求1或2所述的方法,其特征在于:所述烷基化反应和还原反应均在溶剂中进行。
5.根据权利要求4所述的方法,其特征在于:所述烷基化反应步骤中,溶剂选自N,N-二甲基甲酰胺、甲苯、乙二醇二甲醚或1,4-二氧六环中的至少一种;
所述还原反应步骤中,溶剂选自乙醇或甲醇中的至少一种。
6.根据权利要求1或2所述的方法,其特征在于:所述烷基化反应步骤中,温度为90~120℃,具体为100℃;时间为2~6小时,具体为4小时;
所述还原反应步骤中,温度为25~90℃,具体为80℃;时间为6~24小时,具体为12小时。
7.根据权利要求1或2所述的方法,其特征在于:所述反应步骤中,反应装置为密闭的反应装置或附加回流装置的反应容器,具体为大型玻璃回流装置。
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