TWI522335B - 用於藉由氫化1,1-二氟-2-硝基乙烷製備2,2-二氟乙基胺之方法 - Google Patents
用於藉由氫化1,1-二氟-2-硝基乙烷製備2,2-二氟乙基胺之方法 Download PDFInfo
- Publication number
- TWI522335B TWI522335B TW099133783A TW99133783A TWI522335B TW I522335 B TWI522335 B TW I522335B TW 099133783 A TW099133783 A TW 099133783A TW 99133783 A TW99133783 A TW 99133783A TW I522335 B TWI522335 B TW I522335B
- Authority
- TW
- Taiwan
- Prior art keywords
- difluoroethylamine
- nitroethane
- catalyst
- difluoro
- acid
- Prior art date
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- OVRWUZYZECPJOB-UHFFFAOYSA-N 2,2-difluoroethanamine Chemical compound NCC(F)F OVRWUZYZECPJOB-UHFFFAOYSA-N 0.000 title claims description 29
- QEIZZZUXHGSLPS-UHFFFAOYSA-N 1,1-difluoro-2-nitroethane Chemical compound [O-][N+](=O)CC(F)F QEIZZZUXHGSLPS-UHFFFAOYSA-N 0.000 title claims description 17
- 238000004519 manufacturing process Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims description 26
- 239000003054 catalyst Substances 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000007868 Raney catalyst Substances 0.000 claims description 7
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 229910052697 platinum Inorganic materials 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000002253 acid Substances 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 238000005984 hydrogenation reaction Methods 0.000 description 17
- 239000002904 solvent Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 12
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
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- 229960000583 acetic acid Drugs 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- GKIRPKYJQBWNGO-QPLCGJKRSA-N zuclomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(/Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-QPLCGJKRSA-N 0.000 description 4
- JIKDQMLRRHUBKY-UHFFFAOYSA-N 1,1,1-trifluoro-2-nitroethane Chemical compound [O-][N+](=O)CC(F)(F)F JIKDQMLRRHUBKY-UHFFFAOYSA-N 0.000 description 3
- DLDVBXDBFUGBCT-UHFFFAOYSA-N 1,1-difluoro-1-nitroethane Chemical compound CC(F)(F)[N+]([O-])=O DLDVBXDBFUGBCT-UHFFFAOYSA-N 0.000 description 3
- -1 Aliphatic Fluoro Nitro Compounds Chemical class 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910045601 alloy Inorganic materials 0.000 description 3
- 239000000956 alloy Substances 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052759 nickel Inorganic materials 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 description 2
- NPPWGLOLKPCGMA-UHFFFAOYSA-N 3-ethoxy-1,1,1-trifluoropropan-2-amine Chemical compound CCOCC(N)C(F)(F)F NPPWGLOLKPCGMA-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 229940117389 dichlorobenzene Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 229910000856 hastalloy Inorganic materials 0.000 description 2
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- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000000737 periodic effect Effects 0.000 description 2
- 238000010966 qNMR Methods 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SEQRDAAUNCRFIT-UHFFFAOYSA-N 1,1-dichlorobutane Chemical compound CCCC(Cl)Cl SEQRDAAUNCRFIT-UHFFFAOYSA-N 0.000 description 1
- RELMFMZEBKVZJC-UHFFFAOYSA-N 1,2,3-trichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1Cl RELMFMZEBKVZJC-UHFFFAOYSA-N 0.000 description 1
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- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
- NVJUHMXYKCUMQA-UHFFFAOYSA-N 1-ethoxypropane Chemical compound CCCOCC NVJUHMXYKCUMQA-UHFFFAOYSA-N 0.000 description 1
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 description 1
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- YSVKPVHTHFECBE-UHFFFAOYSA-N 2,2-difluoroethanamine;hydrochloride Chemical compound Cl.NCC(F)F YSVKPVHTHFECBE-UHFFFAOYSA-N 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- ATEBGNALLCMSGS-UHFFFAOYSA-N 2-chloro-1,1-difluoroethane Chemical compound FC(F)CCl ATEBGNALLCMSGS-UHFFFAOYSA-N 0.000 description 1
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- B01J35/391—Physical properties of the active metal ingredient
- B01J35/392—Metal surface area
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- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
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- B01J37/0201—Impregnation
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- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B2203/00—Integrated processes for the production of hydrogen or synthesis gas
- C01B2203/10—Catalysts for performing the hydrogen forming reactions
- C01B2203/1041—Composition of the catalyst
- C01B2203/1047—Group VIII metal catalysts
- C01B2203/1052—Nickel or cobalt catalysts
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Description
本發明係關於製備2,2-二氟乙基胺及/或其酸加成鹽之方法,其包括1,1-二氟-2-硝基乙烷之催化性氫化作用。
2,2-二氟乙基胺為活性成份製備中重要的中間物。已知有各種製備2,2-二氟乙基胺之方法。
Donetti等人(J. Med. Chem. 1989,32,957-961)描述了由2,2-二氟乙醯胺進行2,2-二氟乙基胺鹽酸鹽之合成。此處係以二硼烷於四氫呋喃(THF)中之溶液來製備所欲的胺。產率為48%。
Kluger等人(JACS 1982,104,10,2891-2897)描述由醯胺與硼酸鈉和三氟化硼乙醚錯合物進行2,2-二氟乙基胺之合成。產率為60%。
Kollonitsch(US 4,030,994)亦描述2,2-二氟乙基胺之合成,亦即乙基胺與氟氧基三氟甲烷於氟化氫中在UV的照射下之反應。
2,2-二氟乙基胺之製備亦描述於Dickey等人(Ind. Eng. Chem. 1956,209-213)中。文中2,2-二氟-1-氯乙烷係於高壓鍋中與28%氫氧化銨(亦即28%的氨水溶液)反應。由此得到65%產率之胺。
這些方法無法在經濟上可行的工業規模來進行。產率低及使用昂貴和危險的化學品,例如硼酸鈉/BF3或二硼烷阻礙了Donetti等人及Kluger等人之方法供工業規模製備2,2-二氟乙基胺之適用性。Kollonitsch等人之方法使用危險的化學品,且得到不純的2,2-二氟乙基胺。因為就相當低的產率卻需要非常長的反應時間,所以Dickey等人之方法同樣地不適合工業用途或不經濟。再者,反應混合物具高度腐蝕性且就此理由其經濟可行性亦令人質疑。
由已知的製備2,2-二氟乙基胺之方法,本發明之目的係發現替代的方法,藉由此法可簡單地及廉價地製備2,2-二氟乙基胺。廉價的方法,請了解係指在無任何龐大投資下可施行的方法,因為原料(例如)為無危險及/或得到夠高的產率和純度之所欲的2,2-二氟乙基胺。得到對應的2,2-二氟乙基胺酸加成鹽同樣為有利的,因為其可直接轉變為2,2-二氟乙基胺。
1,1-二氟-2-硝基乙烷為方便可得的原料,因為其可以DE-A1-3305201中所述的方法製備得到高產率及良好純度。因此,希望發現能將1,1-二氟-2-硝基乙烷還原成所欲的胺之方法。
Knunyants等人("Aliphatic Fluoro Nitro Compounds Communication 3",Russian Chemical Bulletin(1964),Seiten 1538-1541)描述了烷氧基氟硝基丙烷於雷尼鎳(Raney-nickel)上之催化性氫化作用(雷尼鎳為一由鋁鎳合金之微粒所組成的固體催化劑),在氫氣的存在下得到1-(烷氧基甲基)-2,2,2-三氟乙基胺。特言之,係描述1-(乙氧基甲基)-2,2,2-三氟乙基胺與氫氣於雷尼鎳上在高壓鍋中60 atm的氫氣壓下(大約60巴)之氫化作用。經後續處理後,分離出77%產率之1-(乙氧基甲基)-2,2,2-三氟乙基胺為鹽酸鹽。
Knunyants等人(in Izvestiya Akademii Nauk SSSR(1966),(2),第250-253頁俄文版,及於Russian Chemical Bulletin(1966)中,"Aliphatic Fluoro Nitro Compounds Communication 4",第226-228頁英文版)描述了使用金屬鈀或鐵於鹽酸中將氟化硝基烴(特別是1,1,1-三氟-2-硝基乙烷)氫化之方法,得到對應的胺。在1,1,1-三氟-2-硝基乙烷還原作用中使用金屬鈀僅產生N-(2,2,2-三氟乙基)羥基胺,當於鹽酸中使用鐵則可得到77%產率之所欲的2,2,2-三氟乙基胺鹽酸鹽。此反應包括將1,1,1-三氟-2-硝基乙烷與鹽酸和鐵屑共同於90至95℃加熱,然後以氫氧化鈉鹼化並以蒸氣將三氟乙基胺蒸餾出。分離產物為鹽酸鹽。
然而,Knunyants等人(1966)描述了1,1-二氟-2-硝基乙烷之催化性氫化作用。已發現,Knunyants等人所述的還原及氫化方法不能直接用於還原1,1-二氟-2-硝基乙烷。因此,以鐵於鹽酸中在Knunyants所述的條件下進行1,1-二氟-2-硝基乙烷之還原氫化作用無法產生2,2-二氟乙基胺。
已發現一種1,1-二氟-2-硝基乙烷之催化性氫化作用之方法,藉由此法可製備良好產率及高純度的2,2-二氟乙基胺或對應的酸加成鹽,一般而言其不需要後續複雜的純化,且同時為簡單及廉價之方法。
本發明因此係提供製備2,2-二氟乙基胺及/或其酸加成鹽之方法,其包括1,1-二氟-2-硝基乙烷之催化性氫化作用。
本發明之方法係藉由下列流程圖中之實例來說明:
本發明之催化性氫化作用係在催化劑的存在下,以導入反應容器中或於反應容器中原位產生之氫氣來進行。
適合用於本發明之催化性氫化作用的催化劑包括一或多種的週期表8-10族的金屬,特別是一或多種選自鐵、釕、鋨、鈷、銠、銥、鎳、鈀及鉑之金屬。除了其催化活性外,適合的催化劑在所選的反應條件下為惰性。金屬可以任何的化合物形式存在,例如元素、膠體、鹽或氧化物形式與錯合劑錯合之螯合物或為合金,就此,合金亦可包括其他金屬,例如鋁以及上列之金屬。金屬可以撐體形式存在,亦即載負任何撐體,較佳地無機撐體。適合的撐體實例有碳(木炭或活性碳)、氧化鋁、二氧化矽、二氧化鋯或二氧化鈦。根據本發明較佳的催化劑係於無機撐體上含有一或多種週期表的第8-10族金屬。根據本發明特佳的係給予包括鉑及/或鈀,並視需要披覆於無機撐體上。此等催化劑有例如活性碳上PtO2、Pd(OH)2[皮爾曼型催化劑(Pearlman-type catalyst)]及林德拉催化劑(Lindlar catalyst)。使用雷尼鎳並不佳,因為其在酸性條件下不穩定。鎳從合金中移出,並與酸的陰離子共同形成對應的鎳鹽。因此,本發明排除雷尼鎳為適合的催化劑。
在本發明之方法中,以所用的1,1-二氟-2-硝基乙烷為基準,係使用約0.01至約30重量%濃度之催化劑。催化劑較佳地係使用約0.1至約25重量%之濃度。
在本發明之方法中,在第一步驟(i)通常係先載入1,1-二氟-2-硝基乙烷和催化劑,及於第二步驟(ii)導入或產生氫。步驟(i)和(ii)可顛倒。亦可連續或分批氫化。
催化性氫化作用可於高壓鍋中在升高的壓力下(亦即至高約200巴),或在標準的氫氣壓下進行。特別是在高反應溫度,升高的壓力有助於其進行。可藉由供應惰性氣體,例如氮或氬來提高額外的壓力。本發明之氫化作用較佳地係在範圍從約1至約30巴之壓力下進行,更佳地在約5至約25巴範圍內之壓力。
在本發明一實施例中,係在氫化後及視需要移除催化劑後加入足量的無機或有機酸或其混合物。適合的酸有,例如鹽酸、硫酸、甲酸或乙酸。此舉能得到2,2-二氟乙基胺之對應的酸加成鹽,然後將其如文中所述分離及/或轉變為游離的2,2-二氟乙基胺。
在本發明另一實施例中,催化性氫化作用係在足量的無機或有機酸或其混合物之存在下進行。適合的酸有,例如鹽酸、硫酸、甲酸或乙酸。在此實施例中,催化劑必須不能為酸敏感性。因此較佳的氫化催化劑(特別是)為包含鉑及/或鈀之催化劑。酸可以濃縮的形式或與水來添加。較佳的,係在氫化前將酸加到反應混合物中,如此溶劑-酸係以理想的情況存在。酸的存在導致經由氫化形成的產物立即轉變為2,2-二氟乙基胺之對應的酸加成鹽,其結果為有較低量的副產物形成,因而提高產率。低於20小時的反應時間亦已產生良好的產率。然後將形成的酸加成鹽如文中所述分離及/或轉變為游離的2,2-二氟乙基胺。
根據本發明,足量的無機或有機酸或其混合物請了解係指,以此量2,2-二氟乙基胺產物能完全以質子化形式存在。就單價酸的情況(例如HCl),以所用的1,1-二氟-2-硝基乙烷基準,至少需要一當量的酸,就二價酸的情況(例如H2SO4),至少需要0.5當量的酸。
一般而言在溶劑的存在下進行本發明之方法為有利的。然而,催化性氫化作用亦可在無溶劑下進行。溶劑有利地係以反應混合物在整個製程中仍能有效地攪拌之量來使用。有利地,以所用的1,1-二氟-2-硝基乙烷為基準,係使用1至50倍的溶劑量,較佳地2至40倍的溶劑量及更佳地2至30倍的溶劑量。
施行本發明方法之有用的溶劑包括所有在反應條件下為惰性的有機溶劑,所用的溶劑類型依照反應製程的類型而定,更特而言之依照所用的催化劑類型及/或氫來源(導入氫氣或原為產生氫氣)而定。根據本發明亦請了解溶劑係指純溶劑之混合物。
適合本發明之溶劑(特別是)有鹵烴,例如氯烴類如四氯乙烯、四氯乙烷、二氯丙烷、二氯甲烷、二氯丁烷、氯仿、四氯化碳、三氯乙烷、三氯乙烯、五氯乙烷、二氟苯、1,2-二氯乙烷、氯苯、溴苯、二氯苯、氯甲苯、三氯苯;醇類例如甲醇、乙醇、異丙醇、丁醇;醚類例如乙基丙基醚、甲基第三丁基醚、正丁醚、苯甲醚、苯基乙基醚、環己基甲基醚、甲醚、乙醚、二甲基甘醇、苯基醚、丙醚、異丙醚、正丁醚、異丁醚、異戊基醚、乙二醇二甲醚、異丙基乙基醚、甲基第三丁醇醚、四氫呋喃、二烷、二氯乙醚及環氧乙烷及/或環氧丙烷之聚醚;脂系、環脂系或芳香系烴類例如戊烷、己烷、庚烷、辛烷、壬烷及可經氟和氯原子取代之工業級烴類,例如二氯甲烷、三氯甲烷、四氯化碳、氟苯、氯苯或二氯苯;例如具有沸點範圍在例如40℃至250℃組份之石油溶劑油、異丙基甲苯、沸點範圍在70℃至190℃間之石油餾份、環己烷、甲基環己烷、石油醚、輕汽油、辛烷、苯、甲苯、氯苯、溴苯、二甲苯;酯類例如乙酸甲酯、乙酸乙酯、乙酸丁酯、乙酸異丁酯及碳酸二甲酯、及碳酸二丁酯或碳酸乙烯酯。另一本發明之溶劑為水。
在本發明方法中,所用的溶劑較佳地為氯烴類或醇類。
本發明之方法可在廣泛的溫度範圍內進行(例如約-20℃至約100℃的範圍)。較佳地係在從約0℃至約40℃的溫度範圍內進行催化性氫化作用。
本發明氫化作用之反應時間一般係在30分鐘及24小時之間。更長的反應時間為可能的且不會有任何有害的效應,但就經濟的觀點而言為不利的。
當催化性氫化作用後2,2-二氟乙基胺以游離的形式存在時,若需要,係以蒸餾純化。當催化性氫化作用後2,2-二氟乙基胺以酸加成鹽存在時,若需要,較佳地係以結晶純化。
2,2-二氟乙基胺之水溶性的酸加成鹽一般係由水溶液中萃取來純化。藉由將對應的酸加成鹽與有機或無機鹼(例如NaHCO3、Na2CO3或NaOH)反應,釋放出游離的2,2-二氟乙基胺。隨後,將二氟乙基胺直接由水溶液蒸餾出或萃取至有機溶劑中。
本發明係參照下列實例詳細說明,然而該等實例不應視為限制本發明之方式。
將5毫莫耳的1,1-二氟-2-硝基乙烷先載入甲醇中並與20%重量比的PtO2於氮氣下混合。將反應混合物於室溫(約20℃)及20巴的氫氣壓下攪拌16小時。待氫化混合物冷卻至0℃後,釋放壓力,亦即減壓,並將催化劑過濾出。然後加入7.5毫莫耳溶於甲醇之的HCl。於減壓下移除溶劑(本處為甲醇)後,得到固體形式之560毫克80%的2,2-二氟乙基胺鹽酸鹽。其相當80%之理論上產率。
NMR(MeOD): 6.19至6.0 ppm(m,1H) 3.2-3.13(m,2H);
M+: 81
將5毫莫耳的1,1-二氟-2-硝基乙烷先載入帶有1.5當量鹽酸之甲醇中並與20%重量比的PtO2於氮氣下混合。將反應混合物於室溫(約20℃)及20巴的氫氣壓下攪拌7小時。待氫化混合物冷卻至0℃後,釋放壓力,亦即減壓,並將催化劑過濾出。然後加入7.5毫莫耳溶於甲醇之的HCl。於減壓下移除溶劑(本處為甲醇)後,得到固體形式之560毫克95%的2,2-二氟乙基胺鹽酸鹽。其相當95%之理論上產率。
NMR(MeOD): 6.19至6.0 ppm(m,1H) 3.2-3.13(m,2H);
M+: 81
於25毫升的氫化高壓鍋中(材質:Hastelloy,機械式螺旋槳攪拌器)先載入1.0克(0.007莫耳,1.0當量)的二氟硝基乙烷(約80%之二氯甲烷溶液)於9毫升乙醇及0.880克(0.009莫耳,1.3當量)濃硫酸中,以及0.100克的20%活性碳Pd(0H)2(皮爾曼型催化劑)。充入氫氣後,於室溫及20巴的氫氣下進行氫化約3小時(攪拌器速度約600 rpm)。過濾及清洗催化劑後,得到16.6克淡黃色的反應混合物。以定量NMR分析後,得到90%之產率。
於25毫升的氫化高壓鍋中(材質:Hastelloy,機械式螺旋槳攪拌器)先載入2.0克(0.010莫耳,1.0當量)的二氟硝基乙烷(約60%之二氯甲烷溶液)於9毫升水及1.270克(0.013莫耳,1.3當量)濃硫酸中,以及0.100克的20%活性碳Pd(OH)2(皮爾曼型催化劑)。充入氫氣後,於室溫及20巴的氫氣下進行氫化約3小時(攪拌器速度約600 rpm)。過濾及清洗催化劑後,得到17.8克淡黃色的反應混合物。以定量NMR分析後,得到88%之產率。
將5毫莫耳的1,1-二氟-2-硝基乙烷先載入甲醇和濃乙酸(=冰乙酸)之比例4:1的混合物中,並與20%重量比之雷尼鎳於氮氣下混合。將反應混合物於室溫(約)及20巴的氫氣壓下攪拌7小時。待氫化混合物冷卻至0℃後,釋放壓力,亦即減壓,並將催化劑過濾出。然後於減壓下移除溶劑(本處為甲醇),得到固體形式之560毫克95%的2,2-二氟乙基胺鹽酸鹽。其相當80%之理論上產率。2,2-二氟乙基胺在本處係以單乙醯基-2,2-二氟乙基胺及其乙酸鹽之混合物存在。雷尼鎳催化劑無法完全回收,因為鎳與乙酸反應並產生乙酸鎳。
13C-NMR(MeOD)單乙醯基-2,2-二氟乙基胺:-CHF2(115.3 ppm);-CH2(42.7 ppm),CO2-(173.9 ppm);-CH3(22.3 ppm)
13C-NMR(MeOD)2,2-二氟乙基胺呈乙酸鹽:-CHF2(115.4 ppm);-CH2(43 ppm),CO2-(176.5 ppm);-CH3(21.7 ppm)
將11.1克(0.1莫耳的二氟硝基乙烷,0.1克的氯化鐵,23克的鐵屑於50毫升的濃鹽酸和80毫升水之混合物中在回流下加熱2 h。隨後將反應混合物與32克的NaOH於100毫升水中混合。蒸氣蒸餾後,將蒸餾液以鹽酸酸化並於減壓下濃縮。其無法分離任何二氟乙基胺鹽酸鹽。
Claims (4)
- 一種製備2,2-二氟乙基胺之方法,其特徵為將1,1-二氟-2-硝基乙烷進行催化性氫化作用,其中用於催化性氫化作用之催化劑包含一或多種選自鈀及鉑之金屬,其限制條件為雷尼鎳除外。
- 如申請專利範圍第1項之方法,其中該催化性氫化作用係在無機或有機酸之存在下進行。
- 如申請專利範圍第1或2項之方法,其中該催化劑為活性碳上之PtO2、Pd(OH)2及林德拉催化劑。
- 如申請專利範圍第1至2項中任一項之方法,其中該催化性氫化作用係包括將氫氣導入反應容器中或於原位產生氫。
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