CN1265087A - 环丙基乙炔的制备方法 - Google Patents
环丙基乙炔的制备方法 Download PDFInfo
- Publication number
- CN1265087A CN1265087A CN98807551A CN98807551A CN1265087A CN 1265087 A CN1265087 A CN 1265087A CN 98807551 A CN98807551 A CN 98807551A CN 98807551 A CN98807551 A CN 98807551A CN 1265087 A CN1265087 A CN 1265087A
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- CN
- China
- Prior art keywords
- cyclopropyl
- halo
- ethene
- reaction
- lithium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 37
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 37
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 18
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 54
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 42
- 239000003054 catalyst Substances 0.000 claims description 37
- 239000003795 chemical substances by application Substances 0.000 claims description 34
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 24
- 230000002140 halogenating effect Effects 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- -1 sodium alkoxide Chemical class 0.000 claims description 20
- 229910052751 metal Inorganic materials 0.000 claims description 19
- 239000002184 metal Substances 0.000 claims description 19
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 16
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 15
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 14
- 150000003053 piperidines Chemical class 0.000 claims description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 13
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 12
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical class CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 11
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical group [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical group ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 9
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 8
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 8
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 claims description 8
- 239000011654 magnesium acetate Substances 0.000 claims description 8
- 235000011285 magnesium acetate Nutrition 0.000 claims description 8
- 229940069446 magnesium acetate Drugs 0.000 claims description 8
- 239000004246 zinc acetate Substances 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 6
- 239000001639 calcium acetate Substances 0.000 claims description 6
- 229960005147 calcium acetate Drugs 0.000 claims description 6
- 235000011092 calcium acetate Nutrition 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 229940071257 lithium acetate Drugs 0.000 claims description 6
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 claims description 6
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 6
- 229960000314 zinc acetate Drugs 0.000 claims description 6
- 235000013904 zinc acetate Nutrition 0.000 claims description 6
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 5
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 5
- 150000004703 alkoxides Chemical class 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 5
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 5
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 5
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 4
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 3
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims description 3
- 150000001336 alkenes Chemical class 0.000 claims 3
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims 3
- HFNUUHLSQPLBQI-UHFFFAOYSA-N acetic acid;calcium Chemical compound [Ca].CC(O)=O HFNUUHLSQPLBQI-UHFFFAOYSA-N 0.000 claims 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical class CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 11
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 238000011914 asymmetric synthesis Methods 0.000 abstract description 3
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 abstract description 3
- OTZXZTJDUFZCNC-ONEGZZNKSA-N (e)-3-cyclopropylprop-2-enoic acid Chemical compound OC(=O)\C=C\C1CC1 OTZXZTJDUFZCNC-ONEGZZNKSA-N 0.000 abstract 2
- 241000725303 Human immunodeficiency virus Species 0.000 abstract 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 abstract 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 239000003125 aqueous solvent Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 239000003999 initiator Substances 0.000 description 6
- 229960002317 succinimide Drugs 0.000 description 6
- 238000010189 synthetic method Methods 0.000 description 6
- MSIDGEINKGACAX-UHFFFAOYSA-N 2-bromoethenylcyclopropane Chemical group BrC=CC1CC1 MSIDGEINKGACAX-UHFFFAOYSA-N 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 230000026030 halogenation Effects 0.000 description 5
- 238000005658 halogenation reaction Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- IBXNCJKFFQIKKY-UHFFFAOYSA-N 1-pentyne Chemical compound CCCC#C IBXNCJKFFQIKKY-UHFFFAOYSA-N 0.000 description 4
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical compound C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001311 chemical methods and process Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 230000036039 immunity Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 125000003835 nucleoside group Chemical group 0.000 description 3
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 241001430294 unidentified retrovirus Species 0.000 description 3
- 230000029812 viral genome replication Effects 0.000 description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-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
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-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
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 125000005210 alkyl ammonium group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 239000003849 aromatic solvent Substances 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 150000003983 crown ethers Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229940117389 dichlorobenzene Drugs 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 2
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 2
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
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- 239000012044 organic layer Substances 0.000 description 2
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Abstract
本发明涉及环丙基乙炔合成的新方法,该化合物是有用的人免疫缺乏病毒(HIV)反转录酶抑制剂(S)-6-氯-4-环丙基乙炔基-4-三氟甲基-1,4-二氢-2H-3,1-苯并噁嗪-2-酮不对称合成中的必需试剂。在此方法中,环丙烷甲醛与丙二酸缩合形成3-环丙基丙烯酸;3-环丙基丙烯酸卤化形成(E,Z)-1-卤-2-环丙基乙烯;和(E,Z)-1-卤-2-环丙基乙烯脱卤化氢形成环丙基乙炔。该改进方法提供了从廉价、容易获得的起始物以高转化率得到环丙基乙炔,高的总产率和可以工业规模生产。
Description
发明领域
本发明涉及环丙基乙炔合成的新方法,环丙基乙炔是有用的人免疫缺乏病毒(HIV)反转录酶抑制剂(S)-6-氯-4-环丙基乙炔基-4-三氟甲基-1,4-二氢-2H-3,1-苯并噁嗪-2-酮的不对称合成的必需试剂。
发明背景
反转录是反录病毒复制的一般特征。病毒复制需要病毒编码反转录酶通过病毒RNA染色体的反转录产生病毒序列的DNA副本。因此,反转录酶是临床上反录病毒感染的化学疗法的相关靶子,因为抑制病毒编码反转录酶可以中断病毒复制。
许多化合物对于人免疫缺乏病毒(HIV)的治疗是有效的,而HIV是引起人免疫***逐渐被破坏并导致AIDS发作的反录病毒。通过HIV反转录酶抑制有效的治疗,对于核苷基抑制剂例如叠氮胸腺嘧啶核苷和非核苷基抑制剂都是已知的。发现苯并噁嗪酮是有用的HIV反转录酶的非核苷基抑制剂。通式(VI)的(S)-6-氯-4-环丙基乙炔基-4-三氟甲基-1,4-二氢-2H-3,1-苯并噁嗪-2-酮:不仅是潜在的反转录酶抑制剂,而且也可以有效的抗HIV反转录酶抗性。由于(S)-6-氯-4-环丙基乙炔基-4-三氟甲基-1,4-二氢-2H-3,1-苯并噁嗪-2-酮是重要的反转录酶抑制剂,所以需要开发经济和有效的合成方法来制备此类化合物。
环丙基乙炔是化合物(VI)合成的重要试剂。Thompson等在Tetrahedron Letters 1995,36,937-940中,描述苯并噁嗪酮对映体的不对称合成通过高的对映体选择性乙炔化物加成,接着与缩合剂环化形成下式的苯并噁嗪酮。作为试剂的环丙基乙炔,通过在0-80℃下,在环己烷中5-氯戊炔和正丁基锂环化,接着用氯化铵骤停反应,以65%的产率合成。此方法以低产率产生环丙基乙炔,由于它是难以操作的试剂,所以作为大规模的商业生产方法导不可行的。
Thompson等,在PCT国际专利申请号WO 9622955 A1中描述,(S)-6-氯-4-环丙基乙炔基-4-三氟甲基-1,4-二氢-2H-3,1-苯并噁嗪-2-酮合成中有用的环丙基乙炔的改进合成法。申请WO 9622955 A1公开的方法,在公斤规模上的总合成不能连续生产,而本发明作了重要的改进。
上述环丙基乙炔的合成方法使用了有毒、难以操作的试剂、相对昂贵的原料、不完全转化和低产率,这些都使全合成方法不可行和得到纯度低的环丙基乙炔。因此,需要发现一种新的大规模的环丙基乙炔的合成路线,其可以改进以上这些局限并以高产率得到所需的环丙基乙炔。
本发明公开了新化合物和新的大规模的制备环丙基乙炔的方法。上述公开的环丙基乙炔的制备方法主要在以下方面有所改进,使用价格经济和易得的起始物;使用方便的和高产率的化学方法;和可以形成结晶并在保存中不易破坏第一中间产物,3-环丙基丙烯酸。本发明提供了从环丙烷甲醛制备环丙基乙炔的新的化学方法。此方法提供了高产率(>90%),将环丙烷甲醛与丙二酸方便的反应制得3-环丙基丙烯酸。接下来以方便的反应条件高产率地将3-环丙基丙烯酸转变成环丙基乙烯基卤化物。最后以高产率和适宜的纯度通过脱卤化氢从环丙基乙烯基卤化物制备环丙基乙炔,以便使制得的环丙基乙炔可以保存或以在惰性溶剂中的溶液使用。
上面列举的参考文献都没有描述本发明的环丙基乙炔的合成方法。
发明概述
本发明涉及一种适合大规模生产环丙基乙炔的改进方法。在此方法中,环丙烷甲醛与丙二酸缩合形成3-环丙基丙烯酸;3-环丙基丙烯酸卤化形成(E,Z)-1-卤代-2-环丙基乙烯;和(E,Z)-1-卤代-2-环丙基乙烯脱去卤化氢形成环丙基乙炔。此改进的方法提供了从廉价的、容易获得的起始物以高的总产率高转化率获得环丙基乙炔,并可以工业规模生产。发明详述
在第一个实施方案中,本发明提供环丙基乙炔的制备方法包括:(1)在碱催化剂的存在下,将环丙烷甲醛与丙二酸或丙二酸代替物反
应形成3-环丙基丙烯酸,(2)3-环丙基丙烯酸与金属催化剂和卤化剂反应形成(E,Z)-1-卤代-2-
环丙基乙烯;和(3)(E,Z)-1-卤代-2-环丙基乙烯与强碱反应形成环丙基乙炔。
在优选的实施方案中,本发明提供了环丙基乙炔的制备方法,其中的丙二酸代替物选自2,3-二甲基-1,3-二噁烷-4,6-二酮、丙二酸二甲酯、丙二酸二乙酯和丙二酸单甲酯。
在另一优选实施方案中,本发明提供了环丙基乙炔的制备方法,其中碱催化剂选自吡啶、吡咯烷、哌啶、吗啉、N-甲基吗啉、1,4-二氮杂双环[2.2.2]辛烷、N,N-二甲基氨基吡啶、N,N-二乙基苯胺、喹啉、N,N-二异丙基乙胺、氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铯、碳酸钠、碳酸钾、碳酸锂、碳酸铯、醇钠、醇锂和醇钾,其中醇盐选自甲醇盐、乙醇盐、丁醇盐、叔丁醇盐和叔戊醇盐。
在另一优选实施方案中,本发明提供了环丙基乙炔的制备方法,其中金属催化剂选自醋酸锂、醋酸镁、醋酸锌、醋酸钙、碘化铜和溴化铜。
在另一优选实施方案中,本发明提供了环丙基乙炔的制备方法,其中卤化剂选自N-氯代琥珀酰亚胺、N-溴代琥珀酰亚胺和N-碘代琥珀酰亚胺。
在进一步优选实施方案中,本发明提供的环丙基乙炔的制备方法,包括:(1)在选自吡啶、吡咯烷、哌啶、吗啉、N-甲基吗啉、1,4-二氮杂双
环[2.2.2]辛烷、N,N-二甲基氨基吡啶、N,N-二乙基苯胺、喹啉、
N,N-二异丙基乙胺、氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铯、
碳酸钠、碳酸钾、碳酸锂、碳酸铯、醇钠、醇锂和醇钾,其中醇
盐选自甲醇盐、乙醇盐、丁醇盐、叔丁醇盐和叔戊醇盐的碱催化
剂存在下,将环丙烷甲醛与丙二酸反应形成3-环丙基丙烯酸,(2)3-环丙基丙烯酸与选自醋酸锂、醋酸镁、醋酸锌、醋酸钙、碘化
铜和溴化铜的金属催化剂和卤化剂反应形成(E,Z)-1-卤代-2-环丙
基乙烯;和(3)(E,Z)-1-卤代-2-环丙基乙烯与甲基锂、叔丁醇钾、氢氧化钾或氨基
化钠反应形成环丙基乙炔。
在更优选的实施方案中,本发明提供环丙基乙炔的制备方法,包括:(1)在选自吡啶、吡咯烷、哌啶、吗啉或其结合的碱催化剂存在下,
将环丙烷甲醛与丙二酸反应形成3-环丙基丙烯酸,(2)3-环丙基丙烯酸与选自醋酸锂、醋酸镁、醋酸锌、醋酸钙、碘化
铜和溴化铜的金属催化剂和卤化剂反应形成(E,Z)-1-卤代-2-环丙
基乙烯;和(3)(E,Z)-1-卤代-2-环丙基乙烯与叔丁醇钾、氢氧化钾或氨基化钠反应
形成环丙基乙炔。
在更进一步优选的实施方案中,本发明提供环丙基乙炔的制备方法,包括:(1)在选自吡啶、吡咯烷、哌啶、吗啉或其结合的碱催化剂存在下,
将环丙烷甲醛与丙二酸反应形成3-环丙基丙烯酸;(2)3-环丙基丙烯酸与醋酸锂和卤化剂反应形成(E,Z)-1-卤代-2-环丙
基乙烯;和(3)(E,Z)-1-卤代-2-环丙基乙烯与甲基锂、叔丁醇钾、氢氧化钾或氨基
化钠反应形成环丙基乙炔。
在最优选的实施方案中卤化剂是N-溴代琥珀酰亚胺。
在第二个实施方案中,本发明提供了环丙基乙炔的制备方法,此方法包括步骤(2)3-环丙基丙烯酸与金属催化剂和卤化剂在相转移剂的存在下反应形成(E,Z)-1-卤代-2-环丙基乙烯。
在第三个实施方案中,本发明提供了环丙基乙炔的方法,此方法包括步骤(3)在相转移剂的存在下,(E,Z)-1-卤代-2-环丙基乙烯与强碱反应形成环丙基乙炔。
在第四个实施方案中,本发明提供了C3H5CH=CHBr化合物。
在第五个实施方案中,本发明提供了C3H5CH=CHCl化合物。
本发明的方法对环丙基乙炔的制备有用,它是(S)-6-氯-4-环丙基乙炔基-4-三氟甲基-1,4-二氢-2H-3,1-苯并噁嗪-2-酮合成中必需的中间体,后者作为人免疫缺乏病毒(HIV)反转录酶抑制剂是有用的,也提供了(S)-6-氯-4-环丙基乙炔基-4-三氟甲基-1,4-二氢-2H-3,1-苯并噁嗪-2-酮合成中有用的中间体化合物。此HIV反转录酶抑制剂对HIV抑制和HIV感染的治疗是有用的。此HIV反转录酶抑制剂对含HIV的体外样品或预期暴露于HIV的样品的抑制有用。此HIV反转录酶抑制剂可用于抑制体液样品(例如体液或***)中存在的HIV,该样品含有或可能含有或暴露于HIV。此HIV反转录酶抑制剂作为标准品或参照化合物也是有用的,可以用于试验或测定抑制病毒复制和/或抑制HIV反转录酶的能力,例如在药物研制过程中。因此,此HIV反转录酶抑制剂可以用作此测定的对照或参照化合物和可以作为质控标准品。
本文要求保护的合成方法的各个反应在适合的溶剂中进行,这些溶剂可以容易的被有机合成领域的技术人员选择,所说的适合的溶剂一般是基本上与起始物(反应剂)、中间体或产物在反应进行的温度下(可以是从溶剂的凝固点至溶剂的沸点)不反应的任何溶剂,除非此溶剂使用的目的是骤冷反应。给定的反应可以在一种溶剂或多于一种溶剂的混合物中进行。根据特定的反应步骤,特定反应步骤适合的溶剂可以独立于其它反应步骤选择。
适合的卤化溶剂包括氯苯、二氯甲烷、氯仿、四氯化碳、二氯苯、二氯乙烷和三氯乙烷。
适合的醚溶剂包括:四氢呋喃、***、乙二醇二甲醚、乙二醇二***、二甘醇二甲醚、二甘醇二***、三甘醇二甲醚、苯甲醚或叔丁基甲基醚。
适合的烃或芳香族溶剂包括:苯、环己烷、戊烷、己烷、甲苯、环庚烷、甲基环己烷、庚烷、乙基苯、间二甲苯、邻二甲苯、对二甲苯、辛烷、1,2-二氢化茚、壬烷、萘和。
本文使用的术语“碱催化剂”是指可以使丙二酸和环丙基甲醛的羰基碳缩合,使形成环丙基丙烯酸的任何试剂。碱催化剂的例子包括,但不限于烷基胺和芳香胺例如:吡啶、吡咯烷、哌啶、吗啉、N-甲基吗啉、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、N,N-二甲基氨基吡啶、N,N-二乙基苯胺、喹啉和N,N-二异丙基乙基胺;以及氢氧化钠、氢氧化钾、氢氧化锂或氢氧化铯;碳酸钠、碳酸钾、碳酸锂或碳酸铯;和醇盐碱例如钠、锂或钾的甲醇盐、乙醇盐、丁醇盐、叔丁醇盐和叔戊醇盐。
本文使用的术语“金属催化剂”是指在步骤(2)中可以催化脱羧作用并接着通过卤化剂使环丙基丙烯酸卤化成(E,Z)1-卤代-2-环丙基乙烯的混合物的任何试剂。金属催化剂的实施例包括,但不限于氨基甲酸钠、氨基甲酸钾、氨基甲酸锂、溴化铜和醋酸金属盐,包括但不限于醋酸锂、醋酸镁、醋酸锌和醋酸钙。
本文使用的术语“卤化剂”是指在步骤(2)的条件下在碱催化剂存在下,使环丙基丙烯酸卤化成(E,Z)1-卤代-2-环丙基乙烯的任何试剂。卤化剂的例子包括,但不限于N-溴代琥珀酰亚胺、N-氯代琥珀酰亚胺、N-碘代琥珀酰亚胺、Br2、Cl2、三苯膦二溴化物和三苯膦二氯化物。
本文使用的术语“强碱”是指那些因其存在而促进从1-卤代-2-环丙基乙烯合成环丙基乙炔的任意的碱。适合的碱可以由有机合成领域的技术人员选择。适合的碱包括,但不限于无机碱例如碱金属、碱土金属和铵氢氧化物和醇盐。适合的碱也包括,但不限于金属酰胺和烷基锂。适合的强碱的例子是二异丙基氨基锂、氨基化钠、甲醇钠、叔丁醇钾、丁醇钠、叔戊醇钾和叔戊醇钠、氢氧化钾、氢氧化钠、甲基锂、丁基锂、己基锂、苯基锂和叔烷基铵氢氧化物。
本发明预期可以至少在多克规模、公斤规模、多公斤规模或工业规模上实践。本文使用的多克规模,优选至少一种起始物为10克或更多,更优选至少50克或更多,特别优选至少100克或更多。本文使用的多公斤规模是指所使用的至少一种起始物超过一公斤。本文使用的工业规模是指除实验室规模以外足以的提供用于临床试验或配给消费者的产品。合成
本发明的主题是提供环丙基乙炔合成的改进方法,该化合物在作为HIV反转录酶抑制剂有用的苯并噁嗪酮合成中是有用的。本发明的方法,通过举例说明但不作为限制,可以参考流程1进一步了解。流程1详细描述了以环丙烷甲醛和丙二酸为起始物的环丙基乙炔的一般合成方法。另外,有机合成领域的技术人员也可以用如下步骤(1)中的丙二酸替代物反应,类似地,也可以用其它的卤化剂代替下述的卤代琥珀酰亚胺进行反应。流程1
步骤1.缩合:环丙基丙烯酸的制备
此步骤通过在适合的非水溶剂中和在适合的温度下,在适合的碱催化剂的存在下,环丙烷甲醛与丙二酸反应形成环丙基丙烯酸。一般情况下,环丙烷甲醛与约1-2摩尔当量的丙二酸反应,如果需要可以搅拌和加热使反应物溶解,另外与约0.1-5.0摩尔当量的适合的碱催化剂反应并加热至足以形成环丙基丙烯酸的温度。在环丙基丙烯酸形成的过程中,生成水并可以通过标准方法除去。可以通过有机合成领域的技术人员已知的后处理的标准方法从反应物中分离出环丙基丙烯酸,为稳定的固体。标准后处理方法的例子显示于实施例1和2中。
适合的非水溶剂是环丙烷甲醛易溶的任何烃类、醚、卤代烃或芳族溶剂,和可以与碱联合使用,并对丙二酸有一定的溶解性。这些溶剂可以包括但不限于戊烷、己烷、庚烷、甲苯、二甲苯、苯、、叔丁基甲基醚、二烷基醚(乙基、丁基)、二苯基醚、氯苯、二氯甲烷、氯仿、四氯化碳、乙腈、二氯苯、二氯乙烷和三氯乙烷。优选的非水溶剂是庚烷、甲苯和吡啶。
缩合反应适合的温度是室温至非水溶剂的回流温度,有机合成领域的技术人员容易决定反应温度。优选在回流温度下进行反应。
优选的碱催化剂是烷基胺和芳香胺,特别是吡啶、吡咯烷、哌啶和吗啉或它们的结合。最优选哌啶或吗啉与吡啶联合使用。
另外可以使用“丙二酸替换物”。此处使用的丙二酸替换物的例子,如2,2-二甲基-1,3-二噁烷-4,6-二酮或适合的丙二酸单或双酯,如丙二酸二甲酯或丙二酸二乙酯或丙二酸单甲酯也可以使用。在使用2,2-二甲基-1,3-二噁烷-4,6-二酮时,也可以使用弱碱如醋酸钠进行缩合反应。另外的丙二酸替换物如氰乙酸、丙二酸单(C1-C6)烷基酯或丙二酸双(C1-C6)烷基酯也可以用来进行缩合反应。此处所说的“烷基”是指有特定碳原子数的包括支链和直链的饱和脂族烃;例如“C1-C6烷基”是指有1-6个碳原子的烷基,即甲基、乙基、丙基、丁基、戊基、己基和它们的支链异构体。而且,有机合成领域的技术人员知道在步骤(1)中使用丙二酸替换物可以形成被保护的环丙基丙烯酸,如环丙基丙烯酸酯。已知该产物容易通过酸或碱水解,通过本领域技术人员已知的方法转变成所需的产物,环丙基丙烯酸。
本领域的技术人员可以根据反应温度、碱催化剂和非水溶剂来决定优选的步骤1的反应时间。反应时间一般约为1-48小时。优选反应时间为约1-12小时。步骤2.卤化:(E,Z)-1-卤代-2-环丙基乙烯的制备
本步骤包括在金属催化剂的存在下,通过卤化剂进行环丙基丙烯酸的卤化。一般情况下,环丙基丙烯酸和约0.01-0.5摩尔当量,优选0.05-0.2摩尔当量,更优选0.05-0.15摩尔当量,最优选约0.1摩尔当量的溶解在适合的溶剂中的金属催化剂混合,然后加入约1.0-1.3摩尔当量的卤化剂。根据催化剂将反应物搅拌足够的时间,优选约2分钟至约48小时,更优选约30分钟至约3小时,形成1卤代-2-环丙基乙烯的E,Z混合物。(E,Z)-1-卤代-2-环丙基乙烯可以通过蒸馏从反应物中作为稳定的液体分离或通过用水骤冷反应,然后通过标准的后处理方法处理。标准后处理的例子见实施例3。
优选的步骤(2)的金属催化剂是醋酸锂、醋酸镁、醋酸锌、醋酸钙、碘化铜和溴化铜。最优选醋酸锂。
步骤(2)优选的卤化剂是N-氯琥珀酰亚胺、N-溴琥珀酰亚胺和N-碘琥珀酰亚胺;更优选N-氯琥珀酰亚胺和N-溴琥珀酰亚胺;最优选N-溴琥珀酰亚胺。
步骤(2)优选的溶剂是乙腈水溶液和丙酮水溶液;最优选乙腈水溶液,97∶3乙腈∶水。在含水溶剂***中所需的水量是使金属催化剂溶解和成为均相***的足量水。
此外,步骤(2)的反应可以在任意的相转移剂的存在下进行。适合的相转移剂包括季铵氯化物336、冠醚和四烷基卤化铵。四辛基氯化铵和四丁基溴化铵是适合的四烷基氯化铵的例子。
另外,步骤(2)可以在有机溶剂,例如饱和烃、芳香烃和醚,在相转移剂的存在下进行。优选的有机溶剂是苯甲醚、二甲苯和乙腈。步骤3:消除反应:环丙基乙炔的制备
本步骤包括从1-卤代-2-环丙基乙烯中消除卤化氢得到环丙基乙炔。一般情况下,在装备有监测和控制反应温度设备的反应容器中装有适合的非水溶剂和根据碱不同而约1-3当量的强碱。优选使用2当量的强碱。边搅拌边加入1-卤代-2-环丙基乙烯,加入的速率为使内温不超过环丙基乙炔的沸点;优选约35℃。加入时,搅拌反应约10分钟至约24小时,优选约10分钟至约4小时,最优选约1小时,在室温形成环丙基乙炔。按反应条件和试剂,本领域的技术人员可以决定适合的搅拌时间。用水或弱酸如醋酸骤冷反应。然后可以通过蒸馏(减压蒸馏或常压蒸馏)分离环丙基乙炔。如果溶剂沸点高,例如二甲基亚砜,优选减压蒸馏。如果溶剂沸点低,可以使用常压蒸馏。
步骤(3)的非水溶剂是液氨、四氢呋喃、二甲基亚砜、N-甲基吡咯烷酮、二甲基甲酰胺、二噁烷、***、二苯醚、二丁醚、苯甲醚、氯苯、甲苯、二甲苯、、十二烷和各种混合的长链烷。优选溶剂是二甲基亚砜。已知步骤(3)适合的溶剂不与步骤(3)中加入的强碱反应。
优选的1-卤代-2-环丙基乙烯是1-溴-2-环丙基乙烯和1-氯-2-环丙基乙烯。
步骤(3)的强碱是氨基化钠、甲醇钠、叔丁醇钾、二异丙基氨基锂、丁醇钠、叔戊醇钾和钠、氢氧化钾、氢氧化钠、甲基锂、丁基锂、己基锂、苯基锂和叔烷基铵氢氧化物。优选的碱为氨基化钠、氢氧化钾和叔丁醇钾;更优选氨基化钠和叔丁醇钾;和最优选叔丁醇钾。
此外,步骤(3)的反应可以在任意的相转移剂的存在下进行。适合的相转移剂包括季铵氯化物336、冠醚和四丁基溴化铵。
以下实施例为了进一步解释本发明。这些实施例只是为了解释本发明,而不是为了限制本发明的范围。实施例13-环丙基丙烯酸(1)的制备
将环丙烷甲醛(100g,1.43mol,1当量)、丙二酸(297g,2.85mol,2当量)和吡啶(565g,7.15mol,5当量)在装备有回流冷凝器和搅拌的适合的容器中一起搅拌。剧烈搅拌此悬浮液并温热至约50℃,这期间丙二酸逐渐溶解。然后加入哌啶(15ml,15mmol,1mol%)并将反应混合物加热至80-85℃(内温)。在保持此温度约1.5小时后,将此反应混合物加热以便保持回流(约115℃)3小时。然后将反应混合物冷却至0℃,并加500ml冷水,然后边剧烈搅拌边缓慢地加入680ml浓盐酸水溶液。逐渐形成淡黄色结晶,过滤分离并用冷水洗涤几次。第一批产物干燥至恒重后产量为68g(43%)3-环丙基丙烯酸。用乙酸乙酯(3×400ml)萃取母液并将合并的有机层真空浓缩,得到第二批产物28g(17%)。将残余的母液然后进一步浓缩和再次过滤,得到21g(13%)产物。总产量为112g(70%)。所需产物的熔点63-65℃(未校正)和得到满意的1H NMR和质谱。实施例23-环丙基丙烯酸(1)的制备:
用11.5g(110mmol)丙二酸处理环丙烷甲醛(7.0g,100mmol)的50ml甲苯溶液。用0.87g(10mmol,10mol%)吗啉,然后用3.95g(50mmol,50mol%)哌啶处理搅拌着的悬浮液。然后将此混合物加热回流除去残余的水。从反应混合物中分离水约1小时,在此期间中分离出的水比理论水量稍多(2ml)。反应混合物为澄清、淡黄色的溶液。然后将反应物冷却至室温,用50ml 10%的盐酸水溶液洗涤,并用50ml水洗涤两次。将甲苯溶液浓缩至约四分之一体积,用40ml正庚烷稀释并搅拌冷却至约5℃。从溶液中沉淀出产物,为细小的淡黄色针晶。过滤收集产物并干燥至恒重。产量约8.5g(76%)。通过减压蒸发母液至干可以得到第二批产物(1.7g),然后用冷(0℃)正庚烷研制所得的残余物,总产量10.2g(91%)。实施例3(E,Z)-1-溴-2-环丙基乙烯(2b)的制备
将步骤1得到的环丙基丙烯酸(30g,268mmol,1当量,实施例1制得)和醋酸锂二水合物(2.73g,26.8mmol,0.1当量)溶解在300ml乙腈和水(9ml)中。将此溶液在室温搅拌约5分钟,然后用N-溴琥珀酰亚胺(57.2g,321mmol,1.2当量)处理。在室温下搅拌此反应混合物45分钟;然后用100ml水骤冷并用己烷(3×300ml)萃取。用硫酸镁干燥合并的有机层,过滤和减压浓缩。获得的所需产物通过1H NMR和GC分析测定为立体化学异构体的混合物(无色液体,32g,82%产率;沸点45℃/~20mmHg)。实施例4环丙基乙炔的制备:
向装备有搅拌器和监测温度装置的合适的反应瓶中加入DMSO(20ml)和叔丁醇钾(2.24g,20mmol),得到淡黄色溶液。以保持内温不超过35℃的速率加入环丙基溴代乙烯2b(1.47g,10mmol)。在加入完成后,再在室温搅拌30分钟使反应完全。然后用水(约20mmol,约0.4ml)处理此反应混合物。从反应混合物中直接真空蒸馏得到纯净的环丙基乙炔,产率约80%。实施例53-环丙基丙烯酸(1)的制备:
在一装备有机械搅拌器、内热电偶和迪安-斯达克装置和与氮气导入管相连的回流冷凝器和油扩散器的3L,四颈圆底烧瓶中加入环丙基甲醛(92%,300g(326g),4.28mol,1当量)的庚烷溶液(1.07L)。向此搅拌着的溶液中一次加入丙二酸(534.1g,5.14mol,1.2当量),接着加入吡啶(173ml,2.14mol,0.5当量)。然后在30℃(可以温热至35℃以帮助丙二酸溶解)剧烈搅拌15分钟(避免结块)并小心加入催化量的哌啶(42.33ml,0.1当量,0.428mols)。加入完成后,将此混合物加热至75℃至开始回流。回流2小时后,内温升至95℃并再稳定回流2小时。从迪安-斯达克分水器收集水73ml。通过1H NMR监测反应显示在此段时间后没有剩醛。
然后将此反应混合物冷却至0℃,并缓慢加入HCl水溶液(670ml,0.8当量),并保持内温小于10℃。缓慢形成淡黄色细小沉淀。在0℃搅拌此不均匀的混合物2小时,然后通过3000ml多孔玻璃布氏漏斗过滤。用稀HCl水溶液(1×0.5N,500ml)和水(2×500ml)洗涤固体滤饼。此类白色固体在空气流和室温下干燥过夜得到453g(94%)的环丙基丙烯酸。
Claims (14)
1.环丙基乙炔的制备方法,此方法包括:(1)在碱催化剂的存在下,将环丙烷甲醛与丙二酸或丙二酸的替换物
反应形成3-环丙基丙烯酸,(2)3-环丙基丙烯酸与金属催化剂和卤化剂反应形成(E,Z)-1-卤代-2-
环丙基乙烯;和(3)(E,Z)-1-卤代-2-环丙基乙烯与强碱反应形成环丙基乙炔。
2.权利要求1的方法,其中丙二酸替换物选自2,2-二甲基-1,3-二噁烷-4,6-二酮、丙二酸二甲酯、丙二酸二乙酯和丙二酸单甲酯。
3.权利要求1的方法,其中碱催化剂选自吡啶、吡咯烷、哌啶、吗啉、N-甲基吗啉、1,4-二氮杂双环[2.2.2]辛烷、N,N-二甲基氨基吡啶、N,N-二乙基苯胺、喹啉、N,N-二异丙基乙胺、氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铯、碳酸钠、碳酸钾、碳酸锂、碳酸铯、醇钠、醇锂和醇钾,其中醇盐选自甲醇盐、乙醇盐、丁醇盐、叔丁醇盐和叔戊醇盐。
4.权利要求1的方法,其中金属催化剂选自醋酸锂、醋酸镁、醋酸锌、醋酸钙、碘化铜和溴化铜。
5.权利要求1的方法,其中卤化剂选自N-氯代琥珀酰亚胺、N-溴代琥珀酰亚胺和N-碘代琥珀酰亚胺。
6.权利要求1的方法包括:(1)在碱催化剂的存在下,环丙烷甲醛与丙二酸反应形成3-环丙基丙
烯酸,碱催化剂选自:吡啶、吡咯烷、哌啶、吗啉、N-甲基吗啉、
1,4-二氮杂双环[2.2.2]辛烷、N,N-二甲基氨基吡啶、N,N-二乙基
苯胺、喹啉、N,N-二异丙基乙胺、氢氧化钠、氢氧化钾、氢氧化
锂、氢氧化铯、碳酸钠、碳酸钾、碳酸锂、碳酸铯、醇钠、醇锂
和醇钾,其中醇盐选自甲醇盐、乙醇盐、丁醇盐、叔丁醇盐和叔
戊醇盐;(2)3-环丙基丙烯酸与金属催化剂和卤化剂反应形成(E,Z)-1-卤代-2-
环丙基乙烯,金属催化剂选自:醋酸锂、醋酸镁、醋酸锌、醋酸
钙、碘化铜和溴化铜;和(3)(E,Z)-1-卤代-2-环丙基乙烯与甲基锂、叔丁醇钾、氢氧化钾或氨基
化钠反应形成环丙基乙炔。
7.权利要求6的方法,包括: (1)在碱催化剂的存在下,环丙烷甲醛与丙二酸反应形成3-环丙基丙
烯酸,碱催化剂选自:吡啶、吡咯烷、哌啶、吗啉或其结合;(2)3-环丙基丙烯酸与金属催化剂和卤化剂反应形成(E,Z)-1-卤代-2-
环丙基乙烯,金属催化剂选自:醋酸锂、醋酸镁、醋酸锌、醋酸
钙、碘化铜和溴化铜;和(3)(E,Z)-1-卤代-2-环丙基乙烯与叔丁醇钾、氢氧化钾或氨基化钠反应
形成环丙基乙炔。
8.权利要求6的方法,包括:(1)在碱催化剂的存在下,环丙烷甲醛与丙二酸反应形成3-环丙基丙
烯酸,碱催化剂选自:吡啶、吡咯烷、哌啶、吗啉或其结合;(2)3-环丙基丙烯酸与醋酸锂和卤化剂反应形成(E,Z)-1-卤代-2-环丙
基乙烯;和(3)(E,Z)-1-卤代-2-环丙基乙烯与甲基锂、叔丁醇钾、氢氧化钾或氨基
化钠反应形成环丙基乙炔。
9.权利要求1的方法,进一步包括步骤(2)在相转移剂的存在下,3-环丙基丙烯酸与金属催化剂和卤化剂反应形成(E,Z)-1-卤代-2-环丙基乙烯。
10.权利要求1的方法,进一步包括步骤(3)在相转移剂的存在下,(E,Z)-1-卤代-2-环丙基乙烯与强碱反应形成环丙基乙炔。
11.权利要求6的方法,其中卤化剂是N-溴代琥珀酰亚胺。
12.权利要求7的方法,其中卤化剂是N-溴代琥珀酰亚胺。
13.权利要求8的方法,其中卤化剂是N-溴代琥珀酰亚胺。
14.式C3H5CH=CHBr的化合物。
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US6359164B1 (en) * | 1998-10-01 | 2002-03-19 | Zhe Wang | Process for the preparation of cyclopropylacetylene |
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