CN114920655A - 一种2-氟-3-三氟甲基苯胺的制备方法 - Google Patents
一种2-氟-3-三氟甲基苯胺的制备方法 Download PDFInfo
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- YKPDYPPZLUZONK-UHFFFAOYSA-N 2-fluoro-3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1F YKPDYPPZLUZONK-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 15
- HOXARLOFJWVUQH-UHFFFAOYSA-N 2,5-dichloro-1-nitro-3-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1Cl HOXARLOFJWVUQH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 10
- DYBYUWVMLBBEMA-UHFFFAOYSA-N 1,4-dichloro-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(Cl)=CC=C1Cl DYBYUWVMLBBEMA-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 6
- 230000000802 nitrating effect Effects 0.000 claims abstract description 6
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 8
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 8
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 6
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000011698 potassium fluoride Substances 0.000 claims description 4
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- 239000004323 potassium nitrate Substances 0.000 claims description 4
- 235000010333 potassium nitrate Nutrition 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 238000006396 nitration reaction Methods 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 229910021583 Cobalt(III) fluoride Inorganic materials 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- WZJQNLGQTOCWDS-UHFFFAOYSA-K cobalt(iii) fluoride Chemical compound F[Co](F)F WZJQNLGQTOCWDS-UHFFFAOYSA-K 0.000 claims description 2
- 239000012025 fluorinating agent Substances 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- JCZMXVGQBBATMY-UHFFFAOYSA-N nitro acetate Chemical compound CC(=O)O[N+]([O-])=O JCZMXVGQBBATMY-UHFFFAOYSA-N 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000011775 sodium fluoride Substances 0.000 claims description 2
- 235000013024 sodium fluoride Nutrition 0.000 claims description 2
- 239000004317 sodium nitrate Substances 0.000 claims description 2
- 235000010344 sodium nitrate Nutrition 0.000 claims description 2
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 claims description 2
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
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- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
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- 239000005457 ice water Substances 0.000 description 3
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- 239000000203 mixture Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000007167 Hofmann rearrangement reaction Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 102000001307 androgen receptors Human genes 0.000 description 2
- 108010080146 androgen receptors Proteins 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
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- 239000000575 pesticide Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- BGVGHYOIWIALFF-UHFFFAOYSA-N 1-fluoro-2-(trifluoromethyl)benzene Chemical compound FC1=CC=CC=C1C(F)(F)F BGVGHYOIWIALFF-UHFFFAOYSA-N 0.000 description 1
- XVEAMDNSCPPPCP-UHFFFAOYSA-N 2-fluoro-3-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(F)(F)F)=C1F XVEAMDNSCPPPCP-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
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- 239000006227 byproduct Substances 0.000 description 1
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- 239000012847 fine chemical Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000004812 organic fluorine compounds Chemical class 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
Classifications
-
- 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
- C07C209/36—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 by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
- C07C209/365—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 by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst by reduction with preservation of halogen-atoms in compounds containing nitro groups and halogen atoms bound to the same carbon skeleton
-
- 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
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- 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
- 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
-
- 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
- Y02P20/582—Recycling of unreacted starting or intermediate materials
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种2‑氟‑3‑三氟甲基苯胺的制备方法,包括:a)将2,5‑二氯三氟甲苯溶解于第一溶剂中,加入硝化试剂,反应得到3‑硝基‑2,5‑二氯三氟甲苯;将3‑硝基‑2,5‑二氯三氟甲苯溶解于第二溶剂中,加入氟化试剂,反应得到2‑氟‑3‑硝基‑5‑氯三氟甲苯;将2‑氟‑3‑硝基‑5‑氯三氟甲苯溶解于第三溶剂中,加入催化剂、还原剂,反应得到2‑氟‑3‑三氟甲基苯胺。本发明制备得到的2‑氟‑3‑三氟甲基苯胺总收率达到68%以上,纯度则在95%以上,反应原料低廉易得、反应操作简单、反应步骤少、三废少。
Description
技术领域
本发明涉及有机化学合成技术领域,具体涉及一种2-氟-3-三氟甲基苯胺的制备方法。
背景技术
由于氟原子具有半径小、电负性强的特点,分子中含氟的化合物具有一些特殊的物理化学性质。它们被用于药物化学、材料科学等多个领域中。含三氟甲基结构的化合物在有机氟化合物中占据相当大的比例,其品种系列化、性能优异化,因而成为有机中间体研发的热点之一。
2-氟-3-三氟甲基苯胺作为一种重要的精细化工中间体,应用于糖尿病高血脂症治疗药物、酪氨酸激酶抑制剂、肝炎病毒抑制剂、预防及治疗癌症等疾病的医药产品及杀虫剂和除草剂等农药产品的研究开发中。其中,雄激素受体(AR)拮抗剂普克鲁胺在用于新冠肺炎防治的三期临床阶段取得突破,引起人们的关注。
文献报道2-氟-3-三氟甲基苯胺的制备方法主要有以下几种:
一、专利DE3737986和专利EP318704公开了以2-氟-5-氯三氟甲苯为起始原料,经过硝化、还原反应制备2-氟-3-三氟甲基苯胺的方法,反应路线如下:
该路线所用的原料价格昂贵,成本高,不适合工业化生产。
二、专利CN112624911公开了以2-氟三氟甲苯为起始原料,经低温反应制备成2-氟-3-三氟甲基苯甲酸,再经氨化、霍夫曼重排制得的方法,反应路线如下:
该路线步骤多,需要使用无水无氧低温反应,原料成本高,反应条件苛刻;酰氯制备的副产物对环境不友好;霍夫曼重排反应易受条件影响。工艺繁琐,三废多,具有一定安全隐患。
发明内容
因此,本发明要解决的技术问题在于现有的反应过程中使用价格昂贵的原料、苛刻的反应条件、危害性大的有毒试剂,操作繁琐以及收率不高的问题,从而提供一种工艺路线简单、成本低廉、产率高、纯度高、适合工业化生产的2-氟-3-三氟甲基苯胺的制备方法。
为此,本发明提供了一种2-氟-3-三氟甲基苯胺的制备方法,包括如下步骤:
a)将2,5-二氯三氟甲苯溶解于第一溶剂中,加入硝化试剂,反应得到3-硝基-2,5-二氯三氟甲苯;
b)将3-硝基-2,5-二氯三氟甲苯溶解于第二溶剂中,加入氟化试剂,反应得到2-氟-3-硝基-5-氯三氟甲苯;
c)将2-氟-3-硝基-5-氯三氟甲苯溶解于第三溶剂中,加入催化剂、还原剂,反应得到2-氟-3-三氟甲基苯胺;
反应过程为:
优选地,所述第一溶剂为浓硫酸、发烟硫酸、乙酸、乙酸酐、丙酸、丙酸酐、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,3-二甲基咪唑啉酮、N-甲基吡咯烷酮、苯氰或环丁砜中的至少一种;
所述硝化试剂为浓硝酸、发烟硝酸、硝酸钾、硝酸钠或乙酰基硝酸酯中的至少一种。
优选地,步骤a)中所述反应温度为0~45℃,反应时间为1~16h;
所述2,5-二氯三氟甲苯与硝化试剂的摩尔比为1:1~1:1.2。
优选地,所述第二溶剂为甲醇、乙醇、异丙醇、正丁醇、异丁醇、叔丁醇、乙腈、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,3-二甲基咪唑啉酮、N-甲基吡咯烷酮、苯氰或环丁砜中的至少一种;
所述氟化试剂为氟化钾、氟化钠、氟化铯、四氟乙烯、三氟化钴等中的至少一种。
优选地,步骤b)中所述反应温度为60~120℃,反应时间为2~60h;
所述3-硝基-2,5-二氯三氟甲苯与氟化试剂的摩尔比为1:1~1:1.2。
优选地,所述第三溶剂为水、二氯甲烷、二氯乙烷、四氢呋喃、2-甲基四氢呋喃、甲醇、乙醇、异丙醇、正丁醇、异丁醇、叔丁醇、乙酸、丙酸、乙腈、乙酸乙酯、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,3-二甲基咪唑啉酮、N-甲基吡咯烷酮、苯氰或环丁砜中的的至少一种;
所述催化剂为钯碳催化剂、氢氧化钯碳催化剂、铂碳催化剂、醋酸钯、氯化钯、兰尼镍催化剂、氢氧化钠或氢氧化钾中的的至少一种;
所述还原剂为锌粉、铁粉、氢气、水合联氨或甲酸铵中的的至少一种。
优选地,步骤b)中所述反应温度为10~40℃,反应压力为1.5~5atm。
优选地,所述2-氟-3-硝基-5-氯三氟甲苯与催化剂的质量比为20:1~6:1。
本发明技术方案,具有如下优点:
1.本发明的一种2-氟-3-三氟甲基苯胺的制备方法,以2,5-二氯三氟甲苯为原料,依次经过硝化、氟化和还原三步反应合成一种医药中间体2-氟-3-三氟甲基苯胺,制备得到的2-氟-3-三氟甲基苯胺总收率达到68%以上,纯度则在95%以上;
2.本发明的一种2-氟-3-三氟甲基苯胺的制备方法,反应原料低廉易得、反应操作简单、反应步骤少、三废少,各反应步骤中未使用现有合成方法中常用的易燃易爆、剧毒或不易保存的的试剂,反应条件温和,避免对环境以及操作人员的危害,具有良好的工业化前景,提供了适合工业化大生产的新思路。
具体实施方式
提供下述实施例是为了更好地进一步理解本发明,并不局限于所述最佳实施方式,不对本发明的内容和保护范围构成限制,任何人在本发明的启示下或是将本发明与其他现有技术的特征进行组合而得出的任何与本发明相同或相近似的产品,均落在本发明的保护范围之内。
实施例中未注明具体实验步骤或条件者,按照本领域内的文献所描述的常规实验步骤的操作或条件即可进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规试剂产品。
实施例1
一种2-氟-3-三氟甲基苯胺的制备方法,包括如下步骤:
a)3-硝基-2,5-二氯三氟甲苯的制备
25g 2,5-二氯三氟甲苯加入65g浓硫酸中,室温搅拌下慢慢滴加10mL发烟硝酸,滴加完毕后室温继续搅拌16h。将反应液慢慢倾倒在150g冰水中,析出淡黄色固体。抽滤,滤饼水洗,干燥,得到26.5g类白色固体。收率87.6%,HPLC纯度>98.5%。
b)2-氟-3-硝基-5-氯三氟甲苯的制备
26g 3-硝基-2,5-二氯三氟甲苯溶解在50mL二甲基亚砜中,升温至100℃,分批加入5.9g氟化钾,反应结束后降至室温,加入200mL水稀释,析出类白色固体。抽滤,滤饼水洗,干燥,粗品用70%乙醇重结晶得到20g白色固体。收率82.1%,HPLC纯度>97%。
c)2-氟-3-氨基三氟甲苯的制备
20g 2-氟-3-硝基-5-氯三氟甲苯溶解在100mL四氢呋喃中,加入1g 5%钯碳催化剂,氮气置换后通入氢气,于室温3.5atm下搅拌反应16h。抽滤,滤液浓缩,得到14g淡黄色液体,收率95.3%,GC纯度>95%。
反应总收率为68.5%。
实施例2
一种2-氟-3-三氟甲基苯胺的制备方法,包括如下步骤:
a)3-硝基-2,5-二氯三氟甲苯的制备
25g 2,5-二氯三氟甲苯加入65g浓硫酸中,升温至45℃,搅拌下慢慢滴加10mL浓硝酸,滴加完毕后保温反应1h。将反应液慢慢倾倒在150g冰水中,析出淡黄色固体。抽滤,滤饼水洗,干燥,得到26g类白色固体。收率86%,HPLC纯度>98%。
b)2-氟-3-硝基-5-氯三氟甲苯的制备
26g 3-硝基-2,5-二氯三氟甲苯溶解在150mL乙腈中,加入6.1g氟化钾,搅拌回流反应60h,反应结束后降至室温。反应混合物浓缩,加入100mL水稀释,析出类白色固体。抽滤,滤饼水洗,干燥,粗品用70%乙醇重结晶得到19.5g白色固体。收率80%,HPLC纯度>96%。
c)2-氟-3-氨基三氟甲苯的制备
19.5g 2-氟-3-硝基-5-氯三氟甲苯溶解在100mL2-甲基四氢呋喃中,加入1g 10%氢氧化钯碳催化剂,氮气置换后通入氢气,于室温1.5atm下搅拌反应16h。抽滤,滤液浓缩,得到14.2g淡黄色液体,收率99%,GC纯度>95%。
反应总收率为68.1%。
实施例3
一种2-氟-3-三氟甲基苯胺的制备方法,包括如下步骤:
a)3-硝基-2,5-二氯三氟甲苯的制备
25g 2,5-二氯三氟甲苯加入65g浓硫酸中,降温至5℃,搅拌下慢慢加入11g硝酸钾,加完后升至室温反应16h。将反应液慢慢倾倒在150g冰水中,析出淡黄色固体。抽滤,滤饼水洗,干燥,得到27g类白色固体。收率89%,HPLC纯度>98%。
b)2-氟-3-硝基-5-氯三氟甲苯的制备
26g 3-硝基-2,5-二氯三氟甲苯溶解在50mLN,N-二甲基甲酰胺中,加入15.2g氟化铯,升温至100℃搅拌反应2h,反应结束后降至室温,加入200mL水稀释,析出类白色固体。抽滤,滤饼水洗,干燥,粗品用70%乙醇重结晶得到20.5g白色固体。收率84.2%,HPLC纯度>96%。
c)2-氟-3-氨基三氟甲苯的制备
20.5g2-氟-3-硝基-5-氯三氟甲苯溶解在100mL四氢呋喃中,加入4g新制的兰尼镍,氮气置换后通入氢气,于40℃、5atm下搅拌反应16h。抽滤,滤液浓缩,得到15g淡黄色液体,收率100%,GC纯度>95%。
反应总收率为74.9%。
显然,上述实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (8)
2.根据权利要求1所述的2-氟-3-三氟甲基苯胺的制备方法,其特征在于,所述第一溶剂为浓硫酸、发烟硫酸、乙酸、乙酸酐、丙酸、丙酸酐、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,3-二甲基咪唑啉酮、N-甲基吡咯烷酮、苯氰或环丁砜中的至少一种;
所述硝化试剂为浓硝酸、发烟硝酸、硝酸钾、硝酸钠或乙酰基硝酸酯中的至少一种。
3.根据权利要求1或2所述的2-氟-3-三氟甲基苯胺的制备方法,其特征在于,步骤a)中所述反应温度为0~45℃,反应时间为1~16h;
所述2,5-二氯三氟甲苯与硝化试剂的摩尔比为1:1~1:1.2。
4.根据权利要求1所述的2-氟-3-三氟甲基苯胺的制备方法,其特征在于,所述第二溶剂为甲醇、乙醇、异丙醇、正丁醇、异丁醇、叔丁醇、乙腈、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,3-二甲基咪唑啉酮、N-甲基吡咯烷酮、苯氰或环丁砜中的至少一种;
所述氟化试剂为氟化钾、氟化钠、氟化铯、四氟乙烯、三氟化钴等中的至少一种。
5.根据权利要求1或4所述的2-氟-3-三氟甲基苯胺的制备方法,其特征在于,步骤b)中所述反应温度为60~120℃,反应时间为2~60h;
所述3-硝基-2,5-二氯三氟甲苯与氟化试剂的摩尔比为1:1~1:1.2。
6.根据权利要求1所述的2-氟-3-三氟甲基苯胺的制备方法,其特征在于,所述第三溶剂为水、二氯甲烷、二氯乙烷、四氢呋喃、2-甲基四氢呋喃、甲醇、乙醇、异丙醇、正丁醇、异丁醇、叔丁醇、乙酸、丙酸、乙腈、乙酸乙酯、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,3-二甲基咪唑啉酮、N-甲基吡咯烷酮、苯氰或环丁砜中的的至少一种;
所述催化剂为钯碳催化剂、氢氧化钯碳催化剂、铂碳催化剂、醋酸钯、氯化钯、兰尼镍催化剂、氢氧化钠或氢氧化钾中的的至少一种;
所述还原剂为锌粉、铁粉、氢气、水合联氨或甲酸铵中的的至少一种。
7.根据权利要求1或6所述的2-氟-3-三氟甲基苯胺的制备方法,其特征在于,步骤b)中所述反应温度为10~40℃,反应压力为1.5~5atm。
8.根据权利要求7所述的2-氟-3-三氟甲基苯胺的制备方法,其特征在于,所述2-氟-3-硝基-5-氯三氟甲苯与催化剂的质量比为20:1~6:1。
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