CN105985227A - Preparation method and application of 4,4'-dihalide acetodiphenyl - Google Patents
Preparation method and application of 4,4'-dihalide acetodiphenyl Download PDFInfo
- Publication number
- CN105985227A CN105985227A CN201510063671.7A CN201510063671A CN105985227A CN 105985227 A CN105985227 A CN 105985227A CN 201510063671 A CN201510063671 A CN 201510063671A CN 105985227 A CN105985227 A CN 105985227A
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- China
- Prior art keywords
- sodium
- potassium
- compound
- chloride
- carbonate
- Prior art date
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- Pending
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 16
- 230000021736 acetylation Effects 0.000 claims abstract description 8
- 238000006640 acetylation reaction Methods 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 66
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 20
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 16
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 16
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 12
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- -1 heteropolyacids Chemical compound 0.000 claims description 10
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 8
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 8
- 235000011056 potassium acetate Nutrition 0.000 claims description 8
- 239000011736 potassium bicarbonate Substances 0.000 claims description 8
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 8
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 235000011181 potassium carbonates Nutrition 0.000 claims description 8
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 8
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 239000001632 sodium acetate Substances 0.000 claims description 8
- 235000017281 sodium acetate Nutrition 0.000 claims description 8
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 235000017550 sodium carbonate Nutrition 0.000 claims description 8
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012312 sodium hydride Substances 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 8
- 239000008096 xylene Substances 0.000 claims description 8
- 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 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Chemical group 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 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 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
- 239000005695 Ammonium acetate Substances 0.000 claims description 5
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 5
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical group ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 5
- 235000019257 ammonium acetate Nutrition 0.000 claims description 5
- 229940043376 ammonium acetate Drugs 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 claims description 4
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 claims description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000001099 ammonium carbonate Substances 0.000 claims description 4
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 4
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 4
- 235000011009 potassium phosphates Nutrition 0.000 claims description 4
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 238000005580 one pot reaction Methods 0.000 claims description 3
- FUKOTTQGWQVMQB-UHFFFAOYSA-N (2-bromoacetyl) 2-bromoacetate Chemical compound BrCC(=O)OC(=O)CBr FUKOTTQGWQVMQB-UHFFFAOYSA-N 0.000 claims description 2
- PNVPNXKRAUBJGW-UHFFFAOYSA-N (2-chloroacetyl) 2-chloroacetate Chemical compound ClCC(=O)OC(=O)CCl PNVPNXKRAUBJGW-UHFFFAOYSA-N 0.000 claims description 2
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 claims description 2
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 claims description 2
- LKRZCUQFUCYWLZ-UHFFFAOYSA-N 2-chloroacetyl bromide Chemical compound ClCC(Br)=O LKRZCUQFUCYWLZ-UHFFFAOYSA-N 0.000 claims description 2
- RBWNDBNSJFCLBZ-UHFFFAOYSA-N 7-methyl-5,6,7,8-tetrahydro-3h-[1]benzothiolo[2,3-d]pyrimidine-4-thione Chemical compound N1=CNC(=S)C2=C1SC1=C2CCC(C)C1 RBWNDBNSJFCLBZ-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 239000004254 Ammonium phosphate Substances 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 2
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims description 2
- 235000019289 ammonium phosphates Nutrition 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 claims description 2
- DAMJCWMGELCIMI-UHFFFAOYSA-N benzyl n-(2-oxopyrrolidin-3-yl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1CCNC1=O DAMJCWMGELCIMI-UHFFFAOYSA-N 0.000 claims description 2
- NYENCOMLZDQKNH-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)bismuthanyl trifluoromethanesulfonate Chemical compound [Bi+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F NYENCOMLZDQKNH-UHFFFAOYSA-K 0.000 claims description 2
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims description 2
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 2
- UPWPDUACHOATKO-UHFFFAOYSA-K gallium trichloride Chemical compound Cl[Ga](Cl)Cl UPWPDUACHOATKO-UHFFFAOYSA-K 0.000 claims description 2
- BQYMOILRPDTPPJ-UHFFFAOYSA-J hafnium(4+);trifluoromethanesulfonate Chemical compound [Hf+4].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F BQYMOILRPDTPPJ-UHFFFAOYSA-J 0.000 claims description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 2
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 claims description 2
- 229910001486 lithium perchlorate Inorganic materials 0.000 claims description 2
- 239000011565 manganese chloride Substances 0.000 claims description 2
- 235000002867 manganese chloride Nutrition 0.000 claims description 2
- 229940099607 manganese chloride Drugs 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 claims description 2
- 229910052720 vanadium Inorganic materials 0.000 claims description 2
- 239000010457 zeolite Substances 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- FKRSSPOQAMALKA-CUPIEXAXSA-N daclatasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C=2C=CC(=CC=2)C=2N=C(NC=2)[C@H]2N(CCC2)C(=O)[C@@H](NC(=O)OC)C(C)C)=CN1 FKRSSPOQAMALKA-CUPIEXAXSA-N 0.000 abstract description 14
- 229960005449 daclatasvir Drugs 0.000 abstract description 13
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 5
- 235000010290 biphenyl Nutrition 0.000 abstract description 4
- 239000004305 biphenyl Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- VJOJRNLHYWDBDL-UHFFFAOYSA-N 1-[5-chloro-2-(4-chlorophenyl)phenyl]ethanone Chemical group CC(=O)C1=CC(Cl)=CC=C1C1=CC=C(Cl)C=C1 VJOJRNLHYWDBDL-UHFFFAOYSA-N 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 1
- XZWYAMYRMMMHKM-UHFFFAOYSA-N 1-(2-phenylphenyl)ethanone Chemical group CC(=O)C1=CC=CC=C1C1=CC=CC=C1 XZWYAMYRMMMHKM-UHFFFAOYSA-N 0.000 description 1
- YSTSBXDVNKYPTR-UHFFFAOYSA-N 1-[4-(4-acetylphenyl)phenyl]ethanone Chemical group C1=CC(C(=O)C)=CC=C1C1=CC=C(C(C)=O)C=C1 YSTSBXDVNKYPTR-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 101800001014 Non-structural protein 5A Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- ZGBNXRPXEYFLLJ-YDPTYEFTSA-N [(2S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(carboxyamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamic acid Chemical compound CC(C)[C@H](NC(O)=O)C(=O)N1CCC[C@H]1c1ncc([nH]1)-c1ccc(cc1)-c1ccc(cc1)-c1cnc([nH]1)[C@@H]1CCCN1C(=O)[C@@H](NC(O)=O)C(C)C ZGBNXRPXEYFLLJ-YDPTYEFTSA-N 0.000 description 1
- 229960002118 asunaprevir Drugs 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of 4,4'-dihalide acetodiphenyl and an application of 4,4'-dihalide acetodiphenyl in synthesis of a Daclatasvir intermediate. The raw materials of biphenyl and a halogen acetylation reagent have the advantages of low cost and easy acquisition; the Daclatasvir intermediate is synthesized by 4,4'-dihalide acetodiphenyl through a one kettle way, the processes are simplified, and the reaction yield is greatly increased.
Description
Technical Field
The invention relates to a preparation method of 4,4' -dihalo acetyl biphenyl and application thereof in synthesizing a Daclatasvir intermediate.
Background
Daclatasvir (Daclatasvir, CAS number 1009119-64-5) is an NS5A inhibitor developed by behcet masonpoint, inc, in combination with asunaprevir (CAS number 630420-16-5), and has been approved by the FDA drug for the treatment of patients with hepatitis c of genotype 1b in 2014. The chemical name of Daclatasvir is: n, N '- [ [1,1' -biphenyl ] -4,4 '-diylbis [ 1H-imidazole-5, 2-diyl- (2S) -2, 1-pyrrolidinediyl [ (1S) -1- (1-methylethyl) -2-oxo-2, 1-ethanediyl ] ] ] biscarbamic acid C, C' -dimethyl ester having the following structure:
the preparation method of Daclatasvir has been reported in research, and the following three synthetic routes are reported in patents US20080050336a1, US20090043107a1 and WO2012048421a 1:
route one:
and a second route:
and a third route:
in the first and third routes, a boron reagent and a Pd reagent are used, the price is high, and heavy metal Pd needs to be removed in the post-treatment; the second route adopts 4,4' -diacetyl biphenyl as a raw material, the price is high, and the post-treatment of the bromination reaction is complicated. Therefore, a synthetic route for preparing the Daclatasvir intermediate, which has the advantages of cheap and easily available raw materials, simple and convenient operation and suitability for industrial production, is urgently needed to be provided.
Disclosure of Invention
The invention aims to provide a preparation method of 4,4' -dihalo-acetylbiphenyl, which comprises the steps of carrying out Friedel-crafts acylation reaction on a compound II and a halogen acetylation reagent to generate a compound I in one step, wherein the reaction is shown as a reaction formula 2;
wherein,
x is chlorine or bromine;
the halogen acetylation reagent is chloroacetyl chloride, bromoacetyl bromide, bromoacetyl chloride, chloroacetyl bromide, chloroacetic anhydride or bromoacetic anhydride, preferably chloroacetyl chloride or bromoacetyl bromide; the molar ratio of the haloacetylation reagent to the feeding amount of the compound II is 1: 2-1: 10, preferably 1: 2-1: 4;
the friedel-crafts acylation reaction may be carried out in the presence of a catalyst selected from one or more of aluminum chloride, zinc chloride, ferric chloride, titanium tetrachloride, tin tetrachloride, indium chloride, zirconium chloride, antimony trichloride, manganese chloride, cobalt chloride, copper chloride, gallium chloride, antimony pentachloride, lithium perchlorate, silver perchlorate, scandium triflate, ytterbium triflate, bismuth triflate, hafnium triflate, boron trifluoride, polyphosphoric acid, zeolites, heteropolyacids, hydrogen fluoride, hydrogen chloride, trifluoromethanesulfonic acid, sulfuric acid, and the catalyst may be immobilized on silica gel, activated carbon, or diatomaceous earth.
The friedel-crafts acylation reaction can be carried out in a suitable solvent selected from one or more of carbon tetrachloride, dichloromethane, carbon disulfide, acetonitrile, chloroform, 1, 2-dichloroethane; preferably: one or more of dichloromethane, carbon disulfide and carbon tetrachloride;
the temperature of the Friedel-crafts acylation reaction is-20 ℃ to 100 ℃, and the reaction time is 0.5 to 36 hours; the preferable reaction temperature is 20-80 ℃, and the reaction time is 3-14 hours.
The invention also provides application of the compound I generated by the Friedel-crafts acylation reaction in preparing a Daclatasvir intermediate, namely the invention also provides a method for preparing a Daclatasvir intermediate IV (compound IV), which comprises the following steps: (1) carrying out Friedel-crafts acylation reaction on the compound II and a halogen acetylation reagent to generate a compound I; (2) reacting compound I with compound III in the presence of a base to form compound IV, as shown in scheme 3:
wherein,
r is Boc, CBz, Ac, Bz or Bn, preferably Boc, CBz or Bn;
x is chlorine or bromine;
the base in the step (2) is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium amide, potassium amide, diisopropylethylamine, potassium phosphate, sodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, pyridine, triethylamine, ethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 4-dimethylaminopyridine and sodium bis (trimethylsilyl) amide; the base is preferably one or more of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, diisopropylethylamine, pyridine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, and sodium bis (trimethylsilyl) amide.
The molar ratio of the compound I to the alkali charge is 1: 1-1: 5, preferably 1:1 to 1: 3; the molar ratio of the compound I to the compound III is 1: 2-1: 15, preferably 1: 2-1: 10, most preferably 1:2 to 1: 5;
the reaction temperature of the step (2) is 20-150 ℃, and preferably 30-120 ℃; the reaction time of the step (2) is 0.5-36 hours, preferably 0.5-10 hours;
the reaction of step (2) may be carried out in a suitable solvent selected from the group consisting of one or more solvents selected from benzene, toluene, chlorobenzene, xylene, acetonitrile, 2-butanone, acetone, 1, 3-dimethyl-2-imidazolidinone, dichloromethane, 1, 2-dichloroethane, chloroform, dimethylsulfoxide, dimethylsulfone, sulfolane, hexamethylphosphoramide, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, isopropanol, N-butanol, t-butanol, polyethylene glycol, dioxane, tetraethylene glycol dimethyl ether, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, water, N-hexane, cyclohexane, dichloromethane, dichloroethane, chloroform and quinoline; preferably one or more selected from the group consisting of benzene, toluene, chlorobenzene, xylene, acetonitrile, 1, 3-dimethyl-2-imidazolidinone, dichloromethane, chloroform, dimethylsulfoxide, dimethylsulfone, sulfolane, hexamethylphosphoramide, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, isopropanol, dioxane, tetrahydrofuran and water;
optionally, compound IV may be isolated or used without isolation for the preparation of Daclatasvir.
The present invention also provides a process for the preparation of Daclatasvir intermediate V (compound V) by a "one-pot" process comprising the steps of: (1) reacting the compound I with a compound III in the presence of a base to generate a compound IV; (2) directly adding an ammoniation reagent into the reaction solution to obtain a compound V, as shown in a reaction formula 4:
wherein,
r is Boc, CBz, Ac, Bz or Bn, preferably Boc, CBz or Bn;
x is chlorine or bromine, preferably chlorine;
the base in the step (1) is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium amide, potassium amide, diisopropylethylamine, potassium phosphate, sodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, pyridine, triethylamine, ethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 4-dimethylaminopyridine and sodium bis (trimethylsilyl) amide; the base is preferably one or more of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, diisopropylethylamine, pyridine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, and sodium bis (trimethylsilyl) amide.
The molar ratio of the compound I to the alkali charge is 1: 1-1: 5, preferably 1:1 to 1: 3; the molar ratio of the compound I to the compound III is 1: 2-1: 15, preferably 1: 2-1: 10, most preferably 1:2 to 1: 5;
the ammoniation reagent is ammonia gas, ammonia water, ammonium carbonate, ammonium acetate, ammonium sulfate, ammonium nitrate or ammonium phosphate; the ammoniating agent is preferably ammonia gas, ammonium carbonate or ammonium acetate.
The molar ratio of compound I to ammoniating agent is 1: 2-1: 10, preferably 1: 2-1: 4.
the reaction of the steps (1) and (2) may be carried out in the presence of a solvent selected from one or more of benzene, toluene, chlorobenzene, xylene, acetonitrile, 2-butanone, acetone, 1, 3-dimethyl-2-imidazolidinone, dichloromethane, 1, 2-dichloroethane, chloroform, dimethylsulfoxide, dimethylsulfone, sulfolane, hexamethylphosphoramide, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, isopropanol, N-butanol, t-butanol, polyethylene glycol, dioxane, tetraethylene glycol dimethyl ether, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, water, N-hexane, cyclohexane, dichloromethane, dichloroethane, chloroform, and quinoline; preferably one or more selected from the group consisting of benzene, toluene, chlorobenzene, xylene, acetonitrile, 1, 3-dimethyl-2-imidazolidinone, dichloromethane, chloroform, dimethylsulfoxide, dimethylsulfone, sulfolane, hexamethylphosphoramide, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, isopropanol, dioxane, tetrahydrofuran and water;
the reaction temperature in the step (1) is 20-150 ℃, and preferably 30-120 ℃; the reaction time is 0.5-36 hours, preferably 0.5-10 hours; the reaction temperature of the step (2) is 20-150 ℃, and preferably 30-120 ℃; the reaction time is 0.5 to 36 hours, preferably 3 to 20 hours.
Advantageous effects
(1) The raw materials of the method of the invention, such as biphenyl and halogen acetylation reagent, are equally cheap and easy to obtain;
(2) the Daclatasvir key intermediate V can be obtained by three-step reaction of cheap and easily-obtained raw materials such as biphenyl, a halogen acetylation reagent and the like, wherein proline substitution reaction and ammoniation ring closure can be realized by a one-pot method, so that the process is greatly simplified, and the reaction yield is improved.
In a word, the method has the advantages of simple and easy operation, stable process, easy control, convenient and safe treatment after reaction, no harm to human health and environment, low production cost, high product yield, good purity, avoidance of heavy metal and the like, and can be economically and conveniently used for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are intended to be purely exemplary of the invention. These examples are not meant to impose any limitation on the invention. It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention within the scope and spirit of the invention. It is to be understood that the invention is intended to cover such alternatives and modifications as may be included within the scope of the appended claims.
EXAMPLE 14 preparation of 4,4' -Dichloroacetylbiphenyl
Dispersing 108.1g of anhydrous aluminum trichloride (2.5eq) in 200mL of dichloromethane, cooling to 0-10 ℃, dropwise adding 91.5g of chloroacetyl chloride (2.5eq) at 0-10 ℃, causing slight heat release, stirring for 1-2h at 20-35 ℃ after dropwise adding, controlling the reaction liquid at 10-20 ℃ after the solid is basically dissolved (the reaction liquid is colorless to light yellow), dropwise adding 50g of biphenyl (1eq, dissolved in 50mL of dichloromethane), changing the color of the reaction liquid into black in the dropwise adding process, discharging HCl gas, stirring for 30min at 10-20 ℃ after dropwise adding, and heating and refluxing for 16-20 h. The reaction was cooled to 10-20 ℃ and stirred for 2h, filtered and the filter cake was washed with 100mL of dichloromethane. After the filtrate is dripped to be dry, slowly adding the solid into (600mL of water +83mL of concentrated hydrochloric acid, stirring and controlling the temperature at 20-30 ℃, wherein the solid is very fine and is not easy to filter due to low temperature), stirring for 1-2h at 20-30 ℃ after the solid is added, filtering, and washing a filter cake with water until the filtrate is basically neutral. The solid was dried by air blowing at 100 ℃ for 16-20h to give 74g of 4,4' -dichloroacetylbiphenyl as a grey solid, HPLC 98.6%. The molar yield was 74.4%.
EXAMPLE 2 preparation of Compound V
20g of 4,4' -dichloroacetylbiphenyl (1eq), 28.03g of Boc-L-proline (2eq), 0.54g of potassium iodide (0.05eq) and 14.5g of triethylamine (2.2eq) are sequentially added into 100mL of acetonitrile, and the mixture is heated to 50-60 ℃ for reaction for 16-20h under the protection of nitrogen. Concentrating the reaction solution to dryness, adding 300mL of toluene to dissolve, adding 100.4g of ammonium acetate (20eq), protecting with nitrogen, heating to 80-90 ℃ and reacting for 16-20 h. And (3) post-treatment: concentrating the reaction solution to a small volume, dissolving the reaction solution with 300mL of dichloromethane, washing the reaction solution with 200mL of 2 water, drying a dichloromethane layer with anhydrous sodium sulfate, filtering, washing a filter cake with dichloromethane, concentrating the solution to a small volume, slowly adding 50mL of methanol to disperse the solution to separate out a solid, concentrating the solid, heating the solid to 50-60 ℃ with 150mL of methanol, stirring the solid for 1h, cooling the solid to 20-30 ℃ and stirring the solid for 1h, filtering, washing the solid with methanol, and drying the solid to obtain 27.8g of yellow solid. Molar yield: 68.5 percent.
Claims (11)
1. A preparation method of 4,4' -dihalo-acetylbiphenyl is characterized in that a compound II and a halogen acetylation reagent are subjected to Friedel-crafts acylation reaction to generate a compound I in one step, as shown in a reaction formula 2;
wherein,
x is chlorine or bromine.
2. The process according to claim 1, wherein the haloacetylation agent is chloroacetyl chloride, bromoacetyl bromide, bromoacetyl chloride, chloroacetyl bromide, chloroacetic anhydride or bromoacetic anhydride, preferably chloroacetyl chloride or bromoacetyl bromide.
3. The method of claim 1, wherein the friedel-crafts acylation reaction is carried out in the presence of a catalyst selected from one or more of aluminum chloride, zinc chloride, ferric chloride, titanium tetrachloride, tin tetrachloride, indium chloride, zirconium chloride, antimony trichloride, manganese chloride, cobalt chloride, copper chloride, gallium chloride, antimony pentachloride, lithium perchlorate, silver perchlorate, scandium triflate, ytterbium triflate, bismuth triflate, hafnium triflate, boron trifluoride, polyphosphoric acid, zeolites, heteropolyacids, hydrogen fluoride, hydrogen chloride, trifluoromethanesulfonic acid, sulfuric acid.
4. The method of claim 1, wherein: the Friedel-crafts acylation reaction is carried out in a solvent, and the solvent is one or more selected from carbon tetrachloride, dichloromethane, carbon disulfide, acetonitrile, chloroform and 1, 2-dichloroethane; preferably one or more selected from dichloromethane, carbon disulphide and carbon tetrachloride.
5. The method of claim 1, wherein: the reaction temperature of the Friedel-crafts acylation reaction is-20 ℃ to 100 ℃, and preferably 20 ℃ to 80 ℃.
6. A process for the preparation of compound IV, comprising the steps of: (1) carrying out Friedel-crafts acylation reaction on the compound II and a halogen acetylation reagent to generate a compound I; (2) reacting compound I with compound III in the presence of a base to form compound IV, as shown in scheme 3:
wherein,
r is Boc, CBz, Ac, Bz or Bn, preferably Boc, CBz or Bn;
x is chlorine or bromine.
7. The method of claim 6, wherein: the base is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium amide, potassium amide, diisopropylethylamine, potassium phosphate, sodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, pyridine, triethylamine, ethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 4-dimethylaminopyridine and sodium bis (trimethylsilyl) amide; the base is preferably one or more of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, diisopropylethylamine, pyridine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, and sodium bis (trimethylsilyl) amide.
8. The method of claim 6, wherein: the reaction of step (2) is carried out in a solvent selected from one or more of benzene, toluene, chlorobenzene, xylene, acetonitrile, 2-butanone, acetone, 1, 3-dimethyl-2-imidazolidinone, dichloromethane, 1, 2-dichloroethane, chloroform, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethylphosphoramide, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, isopropanol, N-butanol, t-butanol, polyethylene glycol, dioxane, tetraethylene glycol dimethyl ether, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, water, N-hexane, cyclohexane, dichloromethane, dichloroethane, chloroform, and quinoline; preferably one or more selected from the group consisting of benzene, toluene, chlorobenzene, xylene, acetonitrile, 1, 3-dimethyl-2-imidazolidinone, dichloromethane, chloroform, dimethylsulfoxide, dimethylsulfone, sulfolane, hexamethylphosphoramide, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, isopropanol, dioxane, tetrahydrofuran and water.
9. The method of claim 6, wherein: the reaction temperature in the step (2) is 20 to 150 ℃, preferably 30 to 120 ℃.
10. A one-pot process for preparing compound V, comprising the steps of: (1) reacting the compound I with a compound III in the presence of a base to generate a compound IV; (2) directly adding an ammoniation reagent into the reaction solution to obtain a compound V, as shown in a reaction formula 4:
wherein,
r is Boc, CBz, Ac, Bz and Bn, preferably Boc, CBz or Bn;
x is chlorine or bromine, preferably chlorine;
the base is independently selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium amide, potassium amide, diisopropylethylamine, potassium phosphate, sodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, pyridine, triethylamine, ethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 4-dimethylaminopyridine and sodium bis (trimethylsilyl) amide; the base is preferably one or more of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, diisopropylethylamine, pyridine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, and sodium bis (trimethylsilyl) amide;
the ammoniation reagent is ammonia gas, ammonia water, ammonium carbonate, ammonium acetate, ammonium sulfate, ammonium nitrate or ammonium phosphate; the ammoniating agent is preferably ammonia, ammonium carbonate and ammonium acetate.
11. The method of claim 10, wherein: step (1) is carried out in a solvent selected from one or more of benzene, toluene, chlorobenzene, xylene, acetonitrile, 2-butanone, acetone, 1, 3-dimethyl-2-imidazolidinone, dichloromethane, 1, 2-dichloroethane, chloroform, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethylphosphoramide, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, isopropanol, N-butanol, t-butanol, polyethylene glycol, dioxane, tetraethylene glycol dimethyl ether, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, water, N-hexane, cyclohexane, dichloromethane, dichloroethane, chloroform, and quinoline; preferably one or more selected from the group consisting of benzene, toluene, chlorobenzene, xylene, acetonitrile, 1, 3-dimethyl-2-imidazolidinone, dichloromethane, chloroform, dimethylsulfoxide, dimethylsulfone, sulfolane, hexamethylphosphoramide, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, isopropanol, dioxane, tetrahydrofuran and water;
the reaction temperature of the compound I and the compound III is 20-150 ℃, and preferably 30-120 ℃;
the reaction temperature of the compound IV and the ammoniation reagent is 20-150 ℃, and preferably 30-120 ℃.
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| CN105153128A (en) * | 2015-10-15 | 2015-12-16 | 上海众强药业有限公司 | Novel method for synthesizing daclatasvir intermediate |
| CN108727171A (en) * | 2017-04-21 | 2018-11-02 | 上海迪赛诺化学制药有限公司 | 4,4 '-two（2- acetyl bromides）The preparation method of biphenyl |
| CN110860307A (en) * | 2019-11-27 | 2020-03-06 | 吉林大学 | Beta molecular sieve catalyst, preparation method and application thereof in preparation of aromatic ketone by acylation method |
| CN111995507A (en) * | 2020-09-23 | 2020-11-27 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
| CN116037186A (en) * | 2022-12-31 | 2023-05-02 | 江苏新瀚新材料股份有限公司 | Carbon-coated iron-cobalt bimetallic nanoparticle catalyst for Friedel-crafts acylation reaction and preparation method thereof |
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| CN111995507B (en) * | 2020-09-23 | 2022-07-22 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
| CN116037186A (en) * | 2022-12-31 | 2023-05-02 | 江苏新瀚新材料股份有限公司 | Carbon-coated iron-cobalt bimetallic nanoparticle catalyst for Friedel-crafts acylation reaction and preparation method thereof |
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