CN113402373A - Preparation method of polysubstituted diphenyl ketone - Google Patents
Preparation method of polysubstituted diphenyl ketone Download PDFInfo
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- CN113402373A CN113402373A CN202110632792.4A CN202110632792A CN113402373A CN 113402373 A CN113402373 A CN 113402373A CN 202110632792 A CN202110632792 A CN 202110632792A CN 113402373 A CN113402373 A CN 113402373A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical class C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- 238000005618 Fries rearrangement reaction Methods 0.000 claims abstract description 27
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 230000002140 halogenating effect Effects 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 12
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 12
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 12
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 23
- 238000005660 chlorination reaction Methods 0.000 claims description 22
- 230000008569 process Effects 0.000 claims description 21
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 20
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- 125000002252 acyl group Chemical group 0.000 claims description 17
- 238000006482 condensation reaction Methods 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 14
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 14
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 12
- 239000012320 chlorinating reagent Substances 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 10
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
- 239000008096 xylene Substances 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000001263 acyl chlorides Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 4
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 3
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims description 3
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims 10
- 239000000126 substance Substances 0.000 claims 1
- 239000000047 product Substances 0.000 description 66
- 239000012074 organic phase Substances 0.000 description 34
- 238000004128 high performance liquid chromatography Methods 0.000 description 33
- -1 polysubstituted benzophenone ((5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone) Chemical class 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 238000001228 spectrum Methods 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 150000008366 benzophenones Chemical class 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 239000002274 desiccant Substances 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 238000010183 spectrum analysis Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- SHSGDXCJYVZFTP-UHFFFAOYSA-N 4-ethoxybenzoic acid Chemical compound CCOC1=CC=C(C(O)=O)C=C1 SHSGDXCJYVZFTP-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 3
- JRHHJNMASOIRDS-UHFFFAOYSA-N 4-ethoxybenzaldehyde Chemical compound CCOC1=CC=C(C=O)C=C1 JRHHJNMASOIRDS-UHFFFAOYSA-N 0.000 description 3
- XLWQUESMILVIPR-UHFFFAOYSA-N 4-ethoxybenzoyl chloride Chemical compound CCOC1=CC=C(C(Cl)=O)C=C1 XLWQUESMILVIPR-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical group [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000012965 benzophenone Substances 0.000 description 3
- XZNQFPSOLGYVDO-UHFFFAOYSA-N bis(4-ethoxyphenyl)methanone Chemical compound C1=CC(OCC)=CC=C1C(=O)C1=CC=C(OCC)C=C1 XZNQFPSOLGYVDO-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 229960003834 dapagliflozin Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BHRILQRVZAKUJL-UHFFFAOYSA-N BrC=1C=CC(=C(C=1)C(=O)C1=CC=C(C=C1)F)O Chemical compound BrC=1C=CC(=C(C=1)C(=O)C1=CC=C(C=C1)F)O BHRILQRVZAKUJL-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical class ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000002500 ions Chemical group 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical class CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001256 steam distillation Methods 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- VRJLNIGAFQQBPI-UHFFFAOYSA-N (4-bromophenyl) 4-fluorobenzoate Chemical compound C1=CC(F)=CC=C1C(=O)OC1=CC=C(Br)C=C1 VRJLNIGAFQQBPI-UHFFFAOYSA-N 0.000 description 1
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 description 1
- VSMDINRNYYEDRN-UHFFFAOYSA-N 4-iodophenol Chemical compound OC1=CC=C(I)C=C1 VSMDINRNYYEDRN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229940110266 farxiga Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of polysubstituted diphenyl ketone, which comprises the following steps: (1) taking a compound shown in a formula II and a compound shown in a formula III as raw materials, and synthesizing a compound shown in a formula IV; (2) carrying out Fries rearrangement reaction on the compound shown as the formula IV to generate a compound shown as a formula V; (3) contacting a compound shown as a formula V with a halogenating reagent to carry out halogenation reaction to prepare polysubstituted diphenyl ketone shown as a formula I; wherein X is selected from H, F, Cl, Br and I; r1Selected from H, F, Cl, Br, I and RO, R is selected from alkyl of H, C1-C6; x' is selected from F, Cl, Br and I. The invention can improve the yield and selectivity of the target product.
Description
Technical Field
The invention relates to a preparation method of polysubstituted diphenyl ketone, belonging to the field of pharmaceutical chemistry synthesis.
Background
The polysubstituted diphenyl ketone has wide application, for example, can be used as an intermediate or a raw material for synthesizing medicaments, taking dapagliflozin (Farxigan) as an example, the structural formula of the dapagliflozin is shown as the following formula A, it is a novel antidiabetic drug, is the 1 st SGLT2 inhibitor approved to be marketed for treating type 2 diabetes mellitus, is also a sodium-glucose cotransporter 2 inhibitor (approved by the European drug administration (EMA) to be marketed in 11/12/2012, and is approved by the U.S. Food and Drug Administration (FDA) for treating type 2 diabetes mellitus in 1/8/2014, under the trade name Farxiga), and can be used as an important choice for treating diabetes mellitus drugs, and polysubstituted benzophenone ((5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone) shown in the following formula I-1 is an important intermediate for synthesizing dapagliflozin.
At present, polysubstituted benzophenone compounds such as 5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone and the like are mainly prepared by friedel-crafts acylation reaction of substituted benzoyl chloride and phenetole, for example, patent document WO201022313 a2 discloses a scheme for preparing 5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone according to the following reaction scheme 1, wherein raw materials used in the scheme are expensive and high in cost, and isomers of products which are difficult to separate are easily generated (for example, the ortho-position of phenetole in the above patent document is reacted with substituted benzoyl chloride to generate the ortho-position isomer of 5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone), so that the selectivity and yield of target products are low.
Patent document CN107311847A discloses a scheme for producing a poly-substituted benzophenone according to the route shown in the following reaction formula 2 and patent document 106928040a discloses a scheme for producing a poly-substituted benzophenone according to the route shown in the following reaction formula 3, which also have the disadvantages of low yield of the target product, high cost, and the like.
Therefore, optimizing the preparation process of the polysubstituted diphenyl ketone, reducing the cost and improving the selectivity and yield of the target product are important subjects faced by those skilled in the art.
Disclosure of Invention
The invention provides a preparation method of polysubstituted diphenyl ketone, which has the advantages of low cost, high selectivity and yield of target products and the like and can effectively overcome the defects in the prior art.
The invention provides a preparation method of polysubstituted diphenyl ketone, which comprises the following steps: (1) taking a compound shown in a formula II and a compound shown in a formula III as raw materials, and synthesizing a compound shown in a formula IV; (2) carrying out Fries rearrangement reaction on the compound shown as the formula IV to generate a compound shown as a formula V; (3) contacting a compound shown as a formula V with a halogenating reagent to carry out halogenation reaction to prepare polysubstituted diphenyl ketone shown as a formula I;
wherein X is selected from H, F, Cl, Br and I; r1Selected from H, F, Cl, Br, I and RO, R is selected from alkyl of H, C1-C6; x' is selected from F, Cl, Br and I.
According to an embodiment of the present invention, the step (1) includes: contacting a compound shown as a formula III with a first chlorinating agent for acyl chlorination reaction to obtain an acyl chlorination product; and (3) carrying out condensation reaction on the acyl chloride product and the compound shown in the formula II to synthesize the compound shown in the formula IV.
According to one embodiment of the present invention, the acid chlorination reaction and the condensation reaction are carried out in a first solvent, and the condensation reaction is carried out in the presence of a base, wherein the molar ratio of the compound represented by formula III to the compound represented by formula II to the base is 1: (1.0-5.0): (1.0-5.0).
According to an embodiment of the invention, the base comprises an inorganic base and/or an organic base, the organic base comprises at least one of triethylamine, trimethylamine, diisopropylethylamine, 1, 8-diazabicycloundec-7-ene, pyridine, imidazole, triethylene diamine, N-dimethylaminopyridine, N-methylmorpholine, the inorganic base comprises sodium hydroxide and/or potassium hydroxide; and/or the first solvent comprises at least one of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, ethylbenzene, xylene and chlorobenzene.
According to one embodiment of the present invention, the reaction temperature of the acyl chlorination reaction is-50 ℃ to 100 ℃; and/or the reaction temperature of the condensation reaction is 35-40 ℃.
According to an embodiment of the present invention, the Fries rearrangement reaction is performed under the catalysis of a catalyst, wherein the molar ratio of the compound represented by the formula IV to the catalyst is 1: (1.0-5.0); and/or the catalyst comprises at least one of aluminum trichloride, boron trifluoride, zinc chloride, ferric chloride, titanium tetrachloride, stannic chloride, trifluoromethanesulfonate, hydrogen fluoride and methanesulfonic acid.
According to an embodiment of the present invention, the Fries rearrangement reaction is performed in a second solvent comprising at least one of dichloromethane, 1, 2-dichloroethane, chloroform, carbon disulfide, nitrobenzene, benzonitrile, 1, 2-dichlorobenzene, chlorobenzene; and/or the reaction temperature of the Fries rearrangement reaction is 50-200 ℃.
According to an embodiment of the present invention, the molar ratio of the compound of formula V to the halogenating agent is 1: (1.0-5.0).
According to an embodiment of the invention, the halogenating agent comprises a second chlorinating agent comprising at least one of phosphorus oxychloride, phosphorus trichloride, thionyl chloride, carbon tetrachloride, N-chlorosuccinimide, chlorine gas, phosphorus pentachloride.
According to an embodiment of the present invention, the halogenation reaction is performed in a third solvent comprising at least one of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, ethylbenzene, xylene, chlorobenzene; and/or the reaction temperature of the halogenation reaction is 50-200 ℃.
The preparation method of the polysubstituted diphenyl ketone provided by the invention has the advantages of cheap and easily-obtained raw materials, simple operation, short synthetic route, low cost, high raw material conversion rate and high yield and selectivity of the target product, so that the subsequent purification process of the target product can be simplified, the quality of the target product can be improved, and the preparation method has important significance for practical industrial application.
Drawings
FIG. 1 shows the NMR spectra of poly-substituted benzophenone of formula I prepared in example 1: (1H-NMR) chart;
FIG. 2 shows the preparation of polysubstituted benzophenone of formula I from example 21H-NMR chart;
FIG. 3 shows the preparation of polysubstituted benzophenone of formula I from example 31H-NMR chart.
Detailed Description
The present invention is described in further detail below in order to enable those skilled in the art to better understand the aspects of the present invention.
The preparation method of the polysubstituted diphenyl ketone provided by the invention comprises the following steps: (1) taking a compound shown in a formula II and a compound shown in a formula III as raw materials, and synthesizing a compound shown in a formula IV; (2) carrying out Fries rearrangement reaction on the compound shown as the formula IV to generate a compound shown as a formula V; (3) contacting a compound shown as a formula V with a halogenating reagent to carry out halogenation reaction to prepare polysubstituted diphenyl ketone shown as a formula I;
wherein X is selected from H, F, Cl, Br and I; r1Selected from H, F, Cl, Br, I and RO, R is selected from alkyl of H, C1-C6; x' is selected from F, Cl, Br and I.
In the preparation process, the phenolic compound shown in the formula II and the aromatic carboxylic acid compound shown in the formula III are esterified to generate the phenolic ester of the aromatic carboxylic acid shown in the formula IV, then the phenolic ester of the aromatic carboxylic acid is rearranged into the ortho-position acylphenolic compound shown in the formula V through Fries rearrangement reaction, and then the hydroxyl group of the compound shown in the formula V is halogenated through halogenation reaction under the condition of a halogenating reagent to prepare the target compound shown in the formula 1. In the Fries rearrangement process, the phenolic ester of the aromatic carboxylic acid can be rearranged into an ortho-position or para-position acyl phenol compound, but because the para-position of the compound shown in the formula IV has a substituent (X) and can only be rearranged into the ortho-position acyl phenol compound shown in the formula V, a parent structure (the compound shown in the formula V) can be obtained in a high-selectivity manner under the preparation system, so that the selectivity and the yield of the compound shown in the formula I can be improved, the atom utilization rate is improved, the subsequent purification process of a target product is simplified, the production efficiency of the target multi-substituted diphenyl ketone is obviously improved, the cost is saved, and the actual industrial production is facilitated.
In some embodiments, X may be Br, R1Can be ethoxy (OCH)2CH3[ OEt, i.e. R is ethyl (CH)2CH3and/Et)), X' can be Cl, and the polysubstituted diphenyl ketone is 5-bromo-2-chlorophenyl) (4-ethoxyphenyl) ketone, so that the preparation efficiency of the 5-bromo-2-chlorophenyl) (4-ethoxyphenyl) ketone can be remarkably improved, the conversion rate of raw materials is high, the yield and selectivity of the 5-bromo-2-chlorophenyl) (4-ethoxyphenyl) ketone are high, the molar yield can reach over 75 percent, and the purity can reach over 99 percent.
In general, step (1) may comprise: contacting a compound shown as a formula III with a first chlorinating agent for acyl chlorination reaction to obtain an acyl chlorination product; the acyl chloride product and the compound shown in the formula II are subjected to condensation reaction to synthesize the compound shown in the formula IV, so that the preparation efficiency and the selectivity of the target product are further improved.
Specifically, in some embodiments, the acylchlorination reaction and the condensation reaction are carried out in a first solvent, and the condensation reaction is carried out in the presence of a base, and such that the molar ratio of the compound of formula III to the compound of formula II is 1: (1.0-5.0), wherein the molar ratio of the compound shown in the formula III to the alkali is 1: (1.0-5.0), namely, the molar ratio of the compound shown in the formula III to the compound shown in the formula II to the alkali is 1: (1.0-5.0): (1.0-5.0), wherein the molar ratio of the compound represented by the formula III to the compound represented by the formula II is, for example, 1:1, 1:2, 1:3, 1:4, 1:5 or a range composed of any two of the compounds, and the molar ratio of the compound represented by the formula III to the base is, for example, 1:1, 1:2, 1:3, 1:4, 1:5 or a range composed of any two of the compounds.
Wherein, the base can comprise an inorganic base and/or an organic base, the organic base comprises at least one of triethylamine, trimethylamine, diisopropylethylamine, 1, 8-diazabicycloundecen-7-ene (DBU), pyridine, imidazole, triethylene Diamine (DABCO), N-dimethylaminopyridine and N-methylmorpholine, the inorganic base comprises sodium hydroxide and/or potassium hydroxide, the organic base is generally preferred, the triethylamine is more preferred, and the product yield is further improved. The first solvent may include at least one of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, ethylbenzene, xylene, chlorobenzene, preferably dichloromethane. The first chlorinating agent includes, for example, at least one of oxalyl chloride, thionyl chloride, triphosgene, phosphorus oxychloride, phosphorus pentachloride, and the like.
To further improve the efficiency of the preparation, the above-mentioned acid chlorination reaction may be carried out under the action of a catalyst, which may include N, N-dimethylformamide.
Further, the reaction temperature of the acyl chlorination reaction may be-50 ℃ to 100 ℃, for example, 0 ℃ to 50 ℃, preferably 20 ℃ to 30 ℃ (room temperature). The reaction temperature of the condensation reaction can be 35-40 ℃.
In specific implementation, the compound represented by the formula III may be mixed with a first solvent (if a catalyst is present, the compound represented by the formula III, the catalyst and the first solvent may be mixed) to obtain a first mixed system; adjusting the temperature of the first mixed system to 0-10 ℃ (e.g., 0 ℃,3 ℃, 5 ℃,7 ℃, 10 ℃), adding a first chlorinating agent (e.g., the chlorinating agent can be added dropwise into the first mixed system), adjusting the temperature to the reaction temperature of the acyl chlorination reaction, and carrying out the acyl chlorination reaction under a stirring state to generate an acyl chlorination product, so as to obtain a solution containing the acyl chlorination product; wherein, the acyl chlorination reaction can be tracked by High Performance Liquid Chromatography (HPLC), namely, the compound shown in formula III in the reaction system is detected by HPLC, and the stirring is stopped (namely, the acyl chlorination reaction is finished) after the compound shown in formula III is basically completely reacted, and the acyl chlorination reaction time is generally at least 2 hours.
Then, mixing the compound shown in the formula II, alkali and a first solvent to obtain a second mixed system; adjusting the temperature of the second mixed system to 0-10 ℃, adding the solution containing the acyl chloride product (for example, the solution containing the acyl chloride product can be dropwise added into the second mixed system), and then heating to the reaction temperature of the condensation reaction to carry out the condensation reaction, so as to generate the poly-substituted diphenyl ketone shown in the formula I; wherein, the condensation reaction can be tracked by HPLC, namely, the compound shown in formula II in the reaction system is detected by HPLC, after the compound shown in formula II is basically completely reacted (namely, the condensation reaction is finished), the reaction system is cooled to 0-10 ℃, water is added for quenching reaction, the mixture is stirred uniformly and then is kept stand for layering, the upper layer is an organic phase containing the compound shown in formula IV, the lower layer is an aqueous phase, the organic phase and the aqueous phase are separated, the organic phase is washed by aqueous solutions such as sodium bicarbonate solution and/or salt water, the organic phase is subjected to dewatering and drying by drying agents such as anhydrous sodium sulfate and the like, after the drying agents in the organic phase are removed by filtration and the like, the compound shown in formula IV in the organic phase is separated out by concentration under reduced pressure to obtain the compound shown in formula IV, or the first product crude product obtained after concentration under reduced pressure is dissolved in an organic solvent for recrystallization, to obtain the compound shown in the formula IV.
Through the synthesis process in the step (1), the compound shown in the formula IV with high yield and purity can be obtained, the molar yield can reach more than 92%, and the purity can reach more than 97.8%, so that the subsequent processes of Fries rearrangement reaction, halogenation reaction and the like are facilitated, and the yield and the purity of a target product are improved; in addition, the synthesis process of the step (1) also has the advantages of cheap and easily available raw materials, mild conditions and the like, and is favorable for further reducing energy consumption and cost.
Generally, the Fries Rearrangement (Fries Rearrangement) reaction is carried out under catalysis by a catalyst, which may include Lewis acids (Lewis) and/or protonic acids, and in some embodiments, the catalyst includes at least one of aluminum trichloride, boron trifluoride, zinc chloride, ferric chloride, titanium tetrachloride, tin tetrachloride, triflate, hydrogen fluoride, methanesulfonic acid, and preferably includes Lewis acids such as aluminum trichloride. Taking aluminum trichloride as a catalyst as an example, the process and mechanism of Fries rearrangement reaction are mainly as follows: the carbonyl oxygen of the phenolic ester (compound shown in formula IV) is coordinated with the aluminum atom of aluminum trichloride to form an aluminum base, then the aluminum base is arranged on the oxygen atom of the phenolic group, the C-O bond is broken to generate a phenolic aluminum compound acyl positive ion group, the acyl positive ion group is substituted in the electrophilic direction at the ortho position of the phenolic group on the benzene ring (the para position has a substituent X, so that the para position cannot be substituted in the electrophilic direction), and then the hydroxyl arone product (compound shown in formula V) is obtained by hydrolysis.
In some embodiments, the molar ratio of the compound of formula IV to the catalyst may be 1: (1.0-5.0), for example, in the range of 1:1, 1:2, 1:3, 1:4, 1:5 or any two thereof, is favorable for further improving the reaction efficiency and obtaining the target product with high yield and purity.
For Fries rearrangement reaction, in principle, a para-position product is generally a kinetic control product, and an ortho-position product enables a thermodynamic control product to be obtained mainly at a higher temperature, under the preparation system of the invention, the para-position of the compound shown in the formula IV has a substituent (X), and the Fries rearrangement reaction is slow at a lower temperature, so that the temperature is properly increased, which is more beneficial to complete reaction efficiency and raw material conversion, but the energy consumption required by overhigh temperature is larger, the requirements on equipment are harsh, and the carbonization of a substrate is easy to cause, so that the yield of a target product is influenced, and the factors are comprehensively considered, in some preferred embodiments, the reaction temperature of the Fries rearrangement reaction can be generally controlled to be 50-200 ℃, such as 50 ℃, 80 ℃, 100 ℃, 120 ℃, 150 ℃, 180 ℃, 200 ℃ or the range of any two of the two, preferably 80-90 ℃.
In some embodiments, the Fries rearrangement reaction is performed in the second solvent, the second solvent may include at least one of dichloromethane, 1, 2-dichloroethane, chloroform, carbon disulfide, nitrobenzene, benzonitrile, 1, 2-dichlorobenzene, and chlorobenzene, and relatively speaking, the nitrobenzene is used as the second solvent to facilitate further improvement of the Fries rearrangement reaction efficiency, and after the Fries rearrangement reaction is finished, the nitrobenzene in a product system is conveniently distilled out through steam distillation and the like to be recycled, so that the cost is further saved, the amount of three wastes is reduced, and the Fries rearrangement reaction is more environment-friendly.
In specific implementation, the compound shown in formula IV, the catalyst and the second solvent may be mixed to obtain a third mixed system, the third mixed system is heated to the reaction temperature of the Fries rearrangement reaction, and the Fries rearrangement reaction is performed under stirring to generate the compound shown in formula V; the method comprises the following steps of (1) tracking Fries rearrangement reaction by HPLC, namely detecting a compound shown in formula IV in a reaction system by HPLC, after the compound shown in formula IV basically reacts completely (namely Fries rearrangement reaction is finished), adding ice water to quench the reaction, removing a solvent in the system by means of distillation and the like, then adding an organic solvent and water into the reaction system, uniformly stirring the mixture, standing the mixture for layering, removing an organic phase containing the compound shown in formula IV at the upper layer, removing a water phase at the lower layer, separating the organic phase from the water phase, washing the organic phase by using an aqueous solution such as sodium bicarbonate solution and/or salt solution, drying the organic phase by using a drying agent such as anhydrous sodium sulfate and the like, removing the drying agent in the organic phase by means of filtration and the like, and then precipitating the compound shown in formula IV in the organic phase by means of reduced pressure concentration to obtain a second product crude product; and then, dissolving the second product crude product in an organic solvent, and then recrystallizing to obtain the compound shown in the formula V.
Through the process of the step (2), the compound shown in the formula V with high yield and purity can be obtained, the molar yield can reach more than 68%, the purity can reach more than 98%, the subsequent processes such as halogenation reaction and the like are facilitated, and the yield and the purity of the target product are improved.
By further investigation, in step (3), the molar ratio of the compound of formula V to the halogenating agent may be 1: (1.0-5.0), for example, 1:1, 1:2, 1:3, 1:4, 1:5 or any two thereof.
The halogenating agent may specifically include a chlorinating agent, and accordingly, the halogenating reaction includes a chlorination reaction, and in some embodiments, the halogenating agent includes a second chlorinating agent, and the second chlorinating agent may include at least one of phosphorus oxychloride, phosphorus trichloride, thionyl chloride, carbon tetrachloride, N-chlorosuccinimide (NCS), chlorine gas, and phosphorus pentachloride, which are relatively weak in activity of thionyl chloride, slow in raw material conversion, incomplete in reaction, difficult to separate from a product system during a post-treatment process of phosphorus trichloride and phosphorus oxychloride, and easy to generate more acid water, the chlorinating agents such as chlorine gas and NCS are easy to perform electrophilic substitution reaction, and chlorine atoms are introduced on an aromatic ring, so in the preparation system of the present invention, phosphorus pentachloride is preferably used, and a byproduct generated after the halogenation reaction of phosphorus pentachloride is phosphorus oxychloride, on one hand, the boiling point of phosphorus oxychloride is about 105.8 ℃, the method is beneficial to recovery through distillation and other modes, and on the other hand, the phosphorus oxychloride can be used as a chlorination reagent, so that the economic utilization rate of atoms is improved, the pollution to the environment is reduced, and the industrial production requirement is met.
Generally, the halogenation reaction is carried out in a third solvent comprising at least one of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, ethylbenzene, xylene, chlorobenzene, preferably toluene.
Further, the reaction temperature of the halogenation reaction may be 50 to 200 ℃, for example, 50 ℃, 80 ℃, 100 ℃, 120 ℃, 150 ℃, 180 ℃, 200 ℃ or any two thereof.
In specific implementation, the compound shown in the formula V, the halogenating reagent and the third solvent can be mixed to obtain a fourth mixed system; heating the fourth mixed system to the reaction temperature of halogenation reaction to carry out halogenation reaction to generate the polysubstituted diphenyl ketone shown in the formula I; wherein, the halogenation reaction can be tracked by HPLC, that is, the compound shown in formula V in the reaction system is detected by HPLC, after the compound shown in formula V is basically completely reacted (namely, the halogenation reaction is finished), the system is cooled to room temperature, a third solvent in the system is removed by means of reduced pressure distillation and the like, a byproduct (such as phosphorus oxychloride byproduct and the like converted from phosphorus pentachloride) converted from a halogenating reagent is recovered, then an organic solvent and water are added into the system, the mixture is stirred uniformly and then stands for layering, the upper layer is an organic phase containing the polysubstituted diphenyl ketone shown in formula I, the lower layer is an aqueous phase, the organic phase and the aqueous phase are separated, the organic phase is washed by using an aqueous solution such as sodium bicarbonate solution and/or saline water and the like, then the organic phase is dehydrated and dried by using a drying agent such as anhydrous sodium sulfate and the like, and after the drying agent in the organic phase is removed by means of filtration and the like, then, the compound shown in the formula I in the organic phase is separated out through decompression and concentration to obtain a third product crude product; and then dissolving the third product crude product in an organic solvent and then recrystallizing to obtain the compound shown in the formula V.
Through the process of the step (3), the polysubstituted diphenyl ketone shown in the formula I with high yield and purity can be obtained, the molar yield can reach more than 72%, and the purity can reach more than 98.5%.
In the present invention, the organic solvent used may include at least one of petroleum ether, ethyl acetate, n-hexane, n-heptane, toluene, chlorobenzene, 1, 2-dichloroethane, dichloromethane, acetonitrile, acetone, ethanol, methanol, unless otherwise specified. In the specific implementation process, reagents such as raw materials, auxiliary materials and the like can be in industrial grade.
To make the objects, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to specific embodiments, and it is obvious that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. Unless otherwise specified, the reagents used below are conventional and are either commercially available or prepared according to conventional preparative methods.
Example 1
1. Synthesis of Compound (4-ethoxybenzoic acid p-bromophenyl ester)
Synthesizing a compound shown in a formula IV by taking 4-ethoxybenzoic acid and p-bromophenol as raw materials and oxalyl chloride as a first chlorination reagent, wherein the synthesis process is as follows:
adding 4-ethoxybenzoic acid (50g, 0.30mol, 1.00eq), dichloromethane (500mL) and N, N-dimethylformamide (0.5mL) into a 1000mL four-mouth reaction bottle, after the addition is finished, obtaining a first mixed system, cooling the first mixed system to 5 ℃, dropwise adding oxalyl chloride (38.6g, 0.31mol, 1.02eq), after the dropwise adding is finished, raising the temperature of the system to room temperature, and continuously stirring for 2.0 hours at the room temperature (the system is clear, the HPLC tracking reaction is finished) to obtain a dichloromethane solution of 4-ethoxybenzoyl chloride;
p-bromophenol (51.90g, 0.30mol, 1.0eq), triethylamine (60.71g, 0.6mol, 2.0eq), and dichloromethane (200mL) were added to another 2000mL four-necked reaction flask, and stirred and dissolved to obtain a second mixed system; cooling the second mixed system to 0-10 ℃, dropwise adding a dichloromethane solution of 4-ethoxybenzoyl chloride (55.4 g of the added 4-ethoxybenzoyl chloride is calculated by the theory of 100% purity, 1.0eq), dropwise adding for about 1.0 hour, and then heating the system to 35-40 ℃ for reaction for 3.0 hours (HPLC tracking reaction is finished); cooling the system to 0-10 ℃, adding water (400g) into the system to quench the reaction, uniformly stirring the mixture, standing the mixture for layering, separating an organic phase and a water phase, sequentially washing the organic phase by using a saturated sodium bicarbonate solution (400g) and a salt solution (400g), adding anhydrous sodium sulfate into the organic phase to remove water and dry the organic phase, filtering out solid matters such as a drying agent in the organic phase, and concentrating the organic phase under reduced pressure to obtain a compound product (about 88.64g) shown in the formula IV; the reaction scheme of the synthesis process is as follows:
the structure of the product of the compound shown in the formula IV is shown as (IV) in the specification through hydrogen nuclear magnetic resonance spectroscopy, carbon spectroscopy and mass spectrometry, wherein the structure of the product of the compound shown in the formula IV is shown as the specification1The results of H-NMR analysis were as follows:1H NMR(400MHz,CDCl3)δ:8.11(d,2H),7.52(d,2H),7.09(d,2H),6.96(d,2H),4.12(q,2H),1.46(t,3H)；
the product p-bromophenyl 4-ethoxybenzoate was obtained in 92% molar yield and 97.8% HPLC purity (molar yield and HPLC purity in examples 2 and 3 were calculated as in the present example) according to the following procedure:
(1) the molar yield w is x1/x2, x1 is the actual number of moles calculated by dividing the mass (about 88.64g) of the product of the compound of formula IV obtained by the above preparation process by the molecular weight of the compound of formula IV, and x2 is the theoretical number of moles of the compound of formula IV converted from the amount (moles) of the compound of formula II;
(2) HPLC purity was calculated as follows: HPLC detection is carried out on the compound product shown in the formula IV to obtain the peak area of each component, and the sum of the peak areas of each component is calculated to be AGeneral assemblyWherein the peak area of the compound shown as the formula IV is A1Then, HPLC purity is equal to A1/AGeneral assembly。
2. Preparation of a Compound represented by the formula V ((5-bromo-2-hydroxyphenyl) (4-ethoxyphenyl) methanone)
Adding anhydrous aluminum trichloride (32g, 0.24mol, 1.02eq), a compound represented by the formula IV (75.5g, 0.235mol, 1.00eq) and nitrobenzene (500mL) into a 1000mL four-neck reaction flask, heating the obtained third mixed system to 80-90 ℃ under the protection of nitrogen, stirring for 1.0 hour (HPLC tracking reaction is finished), adding ice water (300g) to quench the reaction, removing nitrobenzene in the system by steam distillation, adding dichloromethane (500mL) and water (300g) into the obtained residue, stirring for dissolving, standing for layering, separating an organic phase and an aqueous phase, washing the organic phase with a saturated sodium bicarbonate solution (300g) and a salt solution (300g), adding anhydrous sodium sulfate into the organic phase for dewatering and drying, filtering out a drying agent and the like in the organic phase, concentrating the organic phase under reduced pressure, obtaining a second product crude product; dissolving the second crude product in ethanol for recrystallization to obtain a compound product shown in the formula V (a light yellow solid, about 64.2 g); the reaction scheme for this process is as follows:
the structure of the product of the compound shown in the formula V is shown as the formula (V) through nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum analysis, wherein the structure of the product of the compound shown in the formula V is shown as the formula (V)1The results of H-NMR analysis were as follows:1H NMR(400MHz,CDCl3)δ:11.87(s,1H),7.75(d,2H),7.64(d,1H),7.46(S,1H),7.04(m,3H),4.17(q,2H),1.50(t,3H)；
the molar yield of the product compound of formula V was 85.0% and HPLC purity 98.3% as determined by the following procedure (molar yield and HPLC purity in examples 2 and 3 were calculated in the same manner as in this example):
(1) the molar yield w is x3/x4, x3 is the actual number of moles calculated by dividing the mass (about 64.2g) of the product of the compound of formula V obtained by the above preparation process by the molecular weight of the compound of formula V, and x4 is the theoretical number of moles of the compound of formula V converted from the amount (moles) of the compound of formula IV;
(2) HPLC purity was calculated as follows: HPLC detection is carried out on the compound product shown in the formula V, the peak area of each component is obtained, and the sum of the peak areas of the components is calculated to be BGeneral assemblyWherein the peak area of the compound represented by the formula V is B1Then, HPLC purity is equal to B1/BGeneral assembly。
3. Preparation of polysubstituted Diphenyl methanone ((5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone) of the formula I
A1000 mL four-necked reaction flask was charged with the compound represented by the formula V (64.2g, 0.20mol, 1.00eq), toluene (300mL), and phosphorus pentachloride (43.75g, 0.21mol, 1.05eq) to obtain a fourth mixed system; heating the fourth mixed system to 110-120 ℃, carrying out reflux reaction for 6.0 hours (after HPLC tracking reaction), cooling the system to room temperature, carrying out reduced pressure evaporation on toluene in the system and recovering phosphorus oxychloride, adding dichloromethane (500mL) and water (300mL) into the obtained residue, stirring the obtained residue, dissolving the obtained residue, standing the obtained mixture for layering, separating an organic phase and a water phase, washing the organic phase by using a saturated sodium bicarbonate solution (300g) and a saline solution (300g) in sequence, adding anhydrous sodium sulfate into the organic phase for dewatering and drying, filtering solid matters such as a drying agent in the organic phase, and carrying out reduced pressure concentration on the organic phase to obtain a crude product (about 72.2g) of a third product; dissolving the crude third product in ethanol (100mL) for recrystallization to obtain a poly-substituted diphenyl ketone product (white solid, about 51.6g) shown as the formula I; the reaction scheme for this process is as follows:
the structure of the compound product shown in the formula I is shown as the formula (I) through nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum analysis, wherein the polysubstituted diphenyl ketone product shown in the formula I1The results of H-NMR analysis were as follows:1H NMR(400MHz,CDCl3)δ:7.70(d,2H),7.53(d,1H),7.51(s,1H),7.30(d,1H)，6.92(d,2H)，4.10(q,2H)，1.43(t,3H)，1H-NMthe R spectrum is shown in figure 1;
the molar yield of the polysubstituted benzophenone product of formula I was 76.1% and the HPLC purity was 99.0% as determined by the following procedure (the molar yield and HPLC purity in examples 2 and 3 were calculated in the same manner as in this example):
(1) the molar yield w is x5/x6, x5 is the actual number of moles calculated by dividing the mass (about 51.6g) of the polysubstituted benzophenone product represented by formula I obtained through the above preparation process by the molecular weight of the polysubstituted benzophenone represented by formula I, and x6 is the theoretical number of moles of the compound represented by formula I converted from the amount (number of moles) of the compound represented by formula V;
(2) HPLC purity was calculated as follows: carrying out HPLC detection on the polysubstituted diphenyl ketone product shown in the formula I to obtain the peak area of each component, and calculating the sum of the peak areas of the components to be CGeneral assemblyWherein the peak area of the polysubstituted diphenyl ketone shown in the formula I is C1Then, HPLC purity is equal to C1/CGeneral assembly。
Example 2
1. Synthesis of a Compound represented by the formula IV (4-p-bromophenyl fluorobenzoate)
The procedure of example 1 was repeated except for using 4-fluorobenzoic acid in place of 4-ethoxybenzoic acid in example 1 in an amount of 2.0g to give the product compound of formula IV (about 3.53g) in a molar yield of 84.0% and an HPLC purity of 97.5%; the structure of the compound shown in the formula IV is shown in the following (IV) through nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum analysis,1the results of H-NMR analysis were as follows:1h NMR (400MHz in CDCl 3). delta.8.20 (m,2H),7.55(d,2H),7.18(t,2H),7.10(d, 2H). The reaction formula of the synthesis process is as follows:
2. preparation of a Compound represented by the formula V ((5-bromo-2-hydroxyphenyl) (4-fluorophenyl) methanone)
The compound (4-fluorobenzoic acid p-bromophenyl ester) shown as the formula IV is adopted, the using amount is 3.0gThe procedure of example 1 was followed to give the product compound of formula V (about 2.31g) in 77.0% molar yield and 98.2% HPLC purity; the structure of the compound product shown in the formula V is shown in the following (V) through nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum analysis,1the results of H-NMR analysis were as follows:1h NMR (400MHz in CDCl 3). delta.11.90 (s,1H),8.18(m,2H),7.53(s,1H), 7.48(d,1H),7.18(t,2H),7.04(d, 1H). The reaction formula of the process is as follows:
3. preparation of polysubstituted Diphenyl methanone ((5-bromo-2-chlorophenyl) (4-fluorophenyl) methanone) of formula I
Using the procedure of example 1 with the compound represented by the above formula V ((5-bromo-2-hydroxyphenyl) (4-fluorophenyl) methanone), in an amount of 2.4g, the product compound represented by the formula I (about 1.99g) was obtained in a molar yield of 78.0% and an HPLC purity of 98.6%; the structure of the compound product shown in the formula I is shown in the following (I) through nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum analysis,1the results of H-NMR analysis were as follows:1H NMR(400MHz,CDCl3)δ:7.82(m,2H),7.57(m,1H),7.49(s,1H),7.33(d,1H)，7.15(t,2H)；1the H-NMR spectrum is shown in FIG. 2. The reaction formula of the process is as follows:
example 3
1. Synthesis of Compound (4-Ethoxybenzoic acid p-iodophenyl ester)
P-iodophenol was used in an amount of 2.0g in place of p-bromophenol in example 1 with reference to the procedure in example 1 to give a product of the compound represented by formula IV (about 2.98g) in a molar yield of 89.0% and an HPLC purity of 98.1%; the structure of the compound shown in the formula IV is shown in the following (IV) through nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum analysis,1the results of H-NMR analysis were as follows:1h NMR (400MHz in CDCl 3). delta.8.13 (d,2H),7.54(d,2H),7.11(d,2H),6.97(d,2H),4.13(q,2H),1.48(t, 3H). The reaction formula of the synthesis process is as follows:
2. preparation of Compound (5-iodo-2-hydroxyphenyl) (4-ethoxyphenyl) methanone) of formula V
Using 3.0g of the compound represented by the above formula IV (p-iodophenyl 4-ethoxybenzoate), the procedure of example 1 was repeated to give a product of the compound represented by the formula V (about 2.04g) in a molar yield of 68.0% and an HPLC purity of 98.0%; the structure of the compound product shown in the formula V is shown in the following (V) through nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum analysis,1the results of H-NMR analysis were as follows:1h NMR (400MHz in CDCl 3). delta.11.93 (S,1H),7.80(d,2H),7.66(d,1H),7.49(S,1H),7.07(m,3H),4.18(q,2H),1.51(t, 3H). The reaction formula of the process is as follows:
3. preparation of polysubstituted Diphenyl methanone ((2-chloro-5-iodophenyl) (4-ethoxyphenyl) methanone) of formula I
Using 2.1g of the compound represented by formula V (5-iodo-2-hydroxyphenyl) (4-ethoxyphenyl) methanone) in the procedure of example 1, the product of the compound represented by formula I (about 1.59g) was obtained in a molar yield of 72.0% and an HPLC purity of 98.5%; the structure of the compound product shown in the formula I is shown in the following (I) through nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum analysis,1the results of H-NMR analysis were as follows:1H NMR(400MHz,CDCl3)δ:7.75(d,2H),7.71(dd,1H),7.65(s,1H),7.18(d,1H)，6.92(d,2H)，4.11(q,2H)，1.44(t,3H)；1the H-NMR spectrum is shown in FIG. 3. The reaction formula of the process is as follows:
the embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of polysubstituted diphenyl ketone is characterized by comprising the following steps:
(1) taking a compound shown in a formula II and a compound shown in a formula III as raw materials, and synthesizing a compound shown in a formula IV;
(2) carrying out Fries rearrangement reaction on the compound shown as the formula IV to generate a compound shown as a formula V;
(3) contacting a compound shown as a formula V with a halogenating reagent to carry out halogenation reaction to prepare polysubstituted diphenyl ketone shown as a formula I;
wherein the content of the first and second substances,
x is selected from H, F, Cl, Br and I;
R1selected from H, F, Cl, Br, I and RO, R is selected from alkyl of H, C1-C6;
x' is selected from F, Cl, Br and I.
2. The method according to claim 1, wherein the step (1) comprises:
contacting a compound shown as a formula III with a first chlorinating agent for acyl chlorination reaction to obtain an acyl chlorination product;
and (3) carrying out condensation reaction on the acyl chloride product and the compound shown in the formula II to synthesize the compound shown in the formula IV.
3. The method according to claim 2, wherein the acid chlorination reaction and the condensation reaction are carried out in a first solvent, and the condensation reaction is carried out in the presence of a base, and the molar ratio of the compound represented by the formula III to the compound represented by the formula II to the base is 1: (1.0-5.0): (1.0-5.0).
4. The production method according to claim 3,
the base comprises an inorganic base and/or an organic base, the organic base comprises at least one of triethylamine, trimethylamine, diisopropylethylamine, 1, 8-diazabicycloundec-7-ene, pyridine, imidazole, triethylene diamine, N-dimethylaminopyridine and N-methylmorpholine, and the inorganic base comprises sodium hydroxide and/or potassium hydroxide; and/or the presence of a gas in the gas,
the first solvent comprises at least one of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, ethylbenzene, xylene and chlorobenzene.
5. The production method according to any one of claims 2 to 4,
the reaction temperature of the acyl chlorination reaction is-50 ℃ to 100 ℃; and/or the presence of a gas in the gas,
the reaction temperature of the condensation reaction is 35-40 ℃.
6. The process according to claim 1, wherein the Fries rearrangement reaction is carried out in the presence of a catalyst, wherein,
the molar ratio of the compound shown in the formula IV to the catalyst is 1: (1.0-5.0); and/or the presence of a gas in the gas,
the catalyst comprises at least one of aluminum trichloride, boron trifluoride, zinc chloride, ferric chloride, titanium tetrachloride, stannic chloride, trifluoromethanesulfonate, hydrogen fluoride and methanesulfonic acid.
7. The production method according to claim 1 or 6,
the Fries rearrangement reaction is carried out in a second solvent, and the second solvent comprises at least one of dichloromethane, 1, 2-dichloroethane, chloroform, carbon disulfide, nitrobenzene, benzonitrile, 1, 2-dichlorobenzene and chlorobenzene; and/or the presence of a gas in the gas,
the reaction temperature of the Fries rearrangement reaction is 50-200 ℃.
8. The method according to claim 1, wherein the molar ratio of the compound of formula V to the halogenating agent is 1: (1.0-5.0).
9. The method of claim 1 or 8, wherein the halogenating agent comprises a second chlorinating agent comprising at least one of phosphorus oxychloride, phosphorus trichloride, thionyl chloride, carbon tetrachloride, N-chlorosuccinimide, chlorine gas, phosphorus pentachloride.
10. The production method according to claim 1 or 8,
the halogenation reaction is carried out in a third solvent, and the third solvent comprises at least one of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, ethylbenzene, xylene and chlorobenzene; and/or the presence of a gas in the gas,
the reaction temperature of the halogenation reaction is 50-200 ℃.
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| CN103408414A (en) * | 2013-07-19 | 2013-11-27 | 北京格林凯默科技有限公司 | Preparation method of 2-hydroxyl-4-substituted arone compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2013034048A1 (en) * | 2011-09-08 | 2013-03-14 | Merck Sharp & Dohme Corp. | Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases |
| CN103408414A (en) * | 2013-07-19 | 2013-11-27 | 北京格林凯默科技有限公司 | Preparation method of 2-hydroxyl-4-substituted arone compound |
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| A. G. PINKUS ETAL: ""SYNTHESIS OF 2-CHLORO- AND 2,5-DICHLOROBENZOPHENONES"", 《ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL》 * |
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