CN104513147B - The preparation method of fluorenes ethanone derivatives - Google Patents
The preparation method of fluorenes ethanone derivatives Download PDFInfo
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- CN104513147B CN104513147B CN201410668438.7A CN201410668438A CN104513147B CN 104513147 B CN104513147 B CN 104513147B CN 201410668438 A CN201410668438 A CN 201410668438A CN 104513147 B CN104513147 B CN 104513147B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- -1 fluorenes ethanone derivatives Chemical class 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- 238000006243 chemical reaction Methods 0.000 claims abstract description 75
- 238000000034 method Methods 0.000 claims abstract description 51
- 229910052794 bromium Inorganic materials 0.000 claims description 40
- 239000000460 chlorine Substances 0.000 claims description 33
- 229910052801 chlorine Inorganic materials 0.000 claims description 32
- 229910052740 iodine Inorganic materials 0.000 claims description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 27
- 239000003513 alkali Substances 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 26
- 239000011777 magnesium Substances 0.000 claims description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims description 21
- 229910052749 magnesium Inorganic materials 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 230000021736 acetylation Effects 0.000 claims description 16
- 238000006640 acetylation reaction Methods 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 229910052744 lithium Inorganic materials 0.000 claims description 11
- 229910052684 Cerium Inorganic materials 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 230000002140 halogenating effect Effects 0.000 claims description 10
- 229910052725 zinc Inorganic materials 0.000 claims description 9
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 239000002841 Lewis acid Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 150000007517 lewis acids Chemical class 0.000 claims description 7
- 229910052802 copper Inorganic materials 0.000 claims description 6
- 230000026030 halogenation Effects 0.000 claims description 6
- 238000005658 halogenation reaction Methods 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
- 229910052742 iron Inorganic materials 0.000 claims description 6
- 229910006024 SO2Cl2 Inorganic materials 0.000 claims description 5
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 229910017699 MgY2 Inorganic materials 0.000 claims description 3
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 230000035484 reaction time Effects 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000000376 reactant Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000011701 zinc Substances 0.000 description 8
- 101100118680 Caenorhabditis elegans sec-61.G gene Proteins 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 0 *C1(*)c(cc(*)cc2)c2-c2c1cc(*)cc2 Chemical compound *C1(*)c(cc(*)cc2)c2-c2c1cc(*)cc2 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000010009 beating Methods 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- VRTWBAAJJOHBQU-KMWAZVGDSA-N ledipasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N([C@@H](C1)C=2NC(=CN=2)C=2C=C3C(F)(F)C4=CC(=CC=C4C3=CC=2)C=2C=C3NC(=NC3=CC=2)[C@H]2N([C@@H]3CC[C@H]2C3)C(=O)[C@@H](NC(=O)OC)C(C)C)CC21CC2 VRTWBAAJJOHBQU-KMWAZVGDSA-N 0.000 description 4
- 229960002461 ledipasvir Drugs 0.000 description 4
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- DKSYLEFLMUQPDJ-UHFFFAOYSA-N FC(c1c2)(c(cc(cc3)I)c3-c1ccc2Br)F Chemical compound FC(c1c2)(c(cc(cc3)I)c3-c1ccc2Br)F DKSYLEFLMUQPDJ-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 2
- 229960002063 sofosbuvir Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 1
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- NNSCELKFMDAANJ-UHFFFAOYSA-N C=C(CC(C(c1c2ccc([Br]=C)c1)(F)F)C2=C)I Chemical compound C=C(CC(C(c1c2ccc([Br]=C)c1)(F)F)C2=C)I NNSCELKFMDAANJ-UHFFFAOYSA-N 0.000 description 1
- FHDSGPFSJVYLAL-UHFFFAOYSA-N CC(c1ccc(C2C=CC(Br)=CC2C2(F)F)c2c1)=O Chemical compound CC(c1ccc(C2C=CC(Br)=CC2C2(F)F)c2c1)=O FHDSGPFSJVYLAL-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- QUXHCILOWRXCEO-UHFFFAOYSA-M magnesium;butane;chloride Chemical compound [Mg+2].[Cl-].CCC[CH2-] QUXHCILOWRXCEO-UHFFFAOYSA-M 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
- C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
-
- 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
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Landscapes
- 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 kind of preparation method of fluorenes ethanone derivatives, particularly, the invention provides a kind of preparation method of formula 1 compound, wherein, the definition of each group is described in description. Described compound can be used as intermediate prepared by Lei Dipawei, for the preparation of the synthetic key intermediate of Lei Dipawei, and then preparation Lei Dipawei. The inventive method is with low cost, and reaction condition gentleness is applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical intermediate preparation field, particularly, the invention provides a kind of Lei Dipawei and closeBecome the preparation method of intermediate.
Background technology
Lei Dipawei (Ledipasvir, LDV) is the third liver medicine of Gilead exploitation, and FDA authorizesThe breakthrough therapy identification of LDV/SOF (Sofosbuvir) fixed dosage composition of medicine, this combination treatment is expected toBe as short as in time of 8 weeks and cure genotype 1HCV patient, simultaneously without injection of interferon or associating Li BaweiWoods (Ribavirin).
At present, in Lei Dipawei preparation method known in the art, mostly need process as shown in the formula the pass shown in 7Key intermediate(wherein X, X1Be halogen). Therefore, for industrializationProduce Lei Dipawei, this area needs a kind of method of 7 compounds of synthesis type expeditiously.
US20100310512 has reported a kind of formula 7 compounds process for production thereof as follows:
With the method preparation formula 7 compounds, in fluorination reaction process, BAST is heated and easily decomposes, and has larger peaceFull hidden danger; In acetyl group introducing process, lack selectively, use expensive Pd reagent, and the method also needsUse hypertoxic organotin to react, therefore limited largely the use of this method.
US2013324740 has reported the method for being prepared as follows:
It is safer that said method carries out fluorination reaction, and acetylizad better selective, but Weinreb acylAmine (being the chloro-N-methoxyl group-N-of 2-methyl-acetamide) is more expensive, is not suitable for suitability for industrialized production.
In sum, this area is in the urgent need to developing the method for new preparation formula 7 compounds.
Summary of the invention
The invention provides a kind of method of new preparation formula 7 compounds.
A first aspect of the present invention, provides a kind of preparation method of formula 1 compound,
Wherein X1For Cl, Br or I;
Each X2Be selected from respectively as F or H;
The method comprises:
(a) by step (a1), (a2), (a3) or (a4), formula 2 compounds are made to formula 3, formula as raw material4, formula 5 or formula 6 compounds,
(a1), by formula 2 compounds and alkali reaction, make formula 3 compounds;
Wherein X1、X2The same, X3For Br, I or H, M is Li, the lithium alkylide that alkali is C1-C4;
(a2), by formula 2 compounds and alkali reaction, make formula 4 compounds;
Wherein X1、X2The same; X4For Br or I;
M' is Mg;
Alkali is alkyl RMgBr, acetenyl halogenation magnesium, propinyl magnesium halide, the butynyl halogenation of C1-C4Magnesium, or its combination;
(a3), by formula 2 compounds and alkali reaction, make formula 3 compounds; Then by formula 3 compounds and LouisThis acid reaction, makes formula 5 compounds:
Wherein X1、X2、X3And M as above defines, the lithium alkylide that alkali is C1-C4, lewis acid is MgY2、ZnY2、CuY、CuY2、FeY2、FeY3、CeY3Or its any combination, Y is Cl, Br or iodine, M "Be selected from lower group: Mg, Zn, Cu, Fe, Ce or its combination, m is 1 or 2;
(a4), by formula 2 compounds and alkali reaction, make formula 4 compounds; Then by formula 4 compounds and LouisThis acid reaction, makes formula 6 compounds:
Wherein X1、X2、X4, M' and m as above define, alkali is selected from lower group: C1-C4 RMgBr, secondAlkynyl magnesium halide, propinyl magnesium halide, butynyl magnesium halide, or its combination; Lewis acid is selected from lower group:ZnY2、CuY、CuY2、FeY2、FeY3、CeY3, or its combination, Y is Cl, Br or iodine, M " 'Be selected from lower group: Zn, Cu, Fe, Ce, or its combination;
(b) by any one or the multiple compounds and the acetylation examination that are selected from formula 3, formula 4, formula 5, formula 6Agent reaction, makes formula 1 compound.
In another preference, each X2Identical.
In another preference, each X2All F.
In another preference, in step (a1), reaction temperature is generally-80 DEG C to-30 DEG C.
In another preference, in step (a1), common 5 minutes～24 hours of reaction time, be preferably0.5-6 hour.
In another preference, in step (a2), reaction temperature is-40 DEG C to 40 DEG C.
In another preference, in step (a2), common 5 minutes～24 hours of reaction time, be preferably0.5-6 hour.
In another preference, in the second step reaction of step (a3), reaction temperature is-80 to 40 DEG C.
In another preference, in the reaction of the second step of step (a3), the reaction time is common 5 minutes～24 littleTime, be preferably 0.5-6 hour.
In another preference, in the second step reaction of step (a4), reaction temperature is-40 to 40 DEG C.
In another preference, in the reaction of the second step of step (a4), the reaction time is common 5 minutes～24 littleTime, be preferably 0.5-6 hour.
In another preference, m is 1.
In another preference, M " being Mg, Zn, Ce or its combination, M " ' is Zn, Ce or its combination.
In another preference, M ", M " ' is the Fe of divalence.
In another preference, described reaction (a1), (a2), (a3), (a4), (b) carry out in atent solvent.
In another preference, the atent solvent in described reaction (a1), (a2), (a3), (a4), (b) is phaseSame or essentially identical.
In another preference, described atent solvent is selected from lower group: THF, methyltetrahydrofuran, methylTertbutyl ether, ether, diethoxymethane, or its combination.
In another preference, described acetylation reagent is selected from lower group:
H3CCOOCOR1, wherein R1For the alkyl of H or C1-C4;
H3CCOOR2, wherein R2For COOR3，R3For the alkyl of C1-C4;
H3CCOY, wherein Y is Cl, Br or I;
H3CCOOR3, wherein R3Definition as above;
H3CCONMe(OMe)，H3CCONR1R3，R1And R3The same;
Wherein n is 0,1 or 2;
Or any combination of above-mentioned acetylation reagent.
In another preference, described acetylation reagent is selected from lower group: H3CCOOCOR1、H3CCOY、H3CCONMe(OMe)、H3CCONR1R3, or its combination; Wherein, the definition of each group as above.
In another preference, described RMgBr is C3 RMgBr.
In another preference, described acetylation reagent is selected from lower group: aceticanhydride, chloroacetic chloride,H3CCONMe (OMe), or its combination.
A second aspect of the present invention, provides a kind of as shown in the formula the compound shown in 1a:
In formula, X1For halogen (Cl, Br, I).
In another preference, X1For Br.
A third aspect of the present invention, provides a kind of preparation method as shown in the formula 7 compounds, described method bagDraw together step:
(1), in atent solvent, formula 1a compound is reacted with halogenating agent, thereby make formula 7 compounds
In formula, X1For halogen (Cl, Br, I); X is halogen (Cl, Br or I).
In another preference, in step (1), reaction temperature is generally-50 DEG C to 50 DEG C.
In another preference, in step (1), common 5 minutes～24 hours of reaction time, be preferably0.5-6 hour.
In another preference, described atent solvent is selected from lower group: carrene, chloroform, 1,2-dichloroEthane, chlorobenzene, or its combination.
In another preference, described halogenating agent is selected from lower group: bromine, chlorine, SO2Cl2Or I2。
A fourth aspect of the present invention, provides the preparation method of a kind of Lei Dipawei, and described method comprises step:
(1) formula 1a compound is reacted with halogenating agent, thereby makes formula 7 compounds:
In formula, X1For halogen (Cl, Br, I); X is halogen (Cl, Br or I).
In another preference, in step (1), reaction temperature is generally-50 DEG C to 50 DEG C.
In another preference, in step (1), common 5 minutes～24 hours of reaction time, be preferably0.5-6 hour.
In another preference, described atent solvent is selected from lower group: carrene, chloroform, 1,2-dichloroEthane, chlorobenzene or its any combination.
Halogenating agent is: bromine, chlorine, SO2Cl2Or I2。
(2) using formula 7 compounds as intermediate, thereby make Lei Dipawei (Ledipasvir, LDV).
In another preference, described method also comprises step: use the method as described in first aspect present inventionPreparation formula 1a compound.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and at below (as embodiment)In can combine mutually between specifically described each technical characterictic, thereby form new or preferred technical sideCase. As space is limited, tire out and state no longer one by one at this.
Detailed description of the invention
The inventor, through long-term and deep research, is surprised to find that, adopts compound as shown in Equation 2React with alkali, then carry out acetylizad method, can prepare suc as formula 1 simple and convenient, at low costShown Lei Dipawei intermediate, and then the synthetic key intermediate of the Lei Dipawei shown in preparation formula 7. DescribedMethod Atom economy good, and easily realize, reaction condition gentleness, has good industrial value.Based on above-mentioned discovery, inventor has completed the present invention.
Term
As used herein, term " C1-C4 alkyl " refers to have the alkyl of 1-4 carbon atom, as methyl, secondBase, propyl group, normal-butyl, the tert-butyl group, or similar group.
Term " C1-C4 lithium alkylide " refers to have the alkyl lithium reagents of 1-4 carbon atom, as lithium methide, tertiary fourthBase lithium, or similar reagents.
Term " C1-C4 RMgBr " refers to have the RMgBr of 1-4 carbon atom, as propyl group magnesium chloride,Butylmagnesium chloride, or similar reagents.
Term " halogen " refers to fluorine, chlorine, bromine, iodine. Especially, in this article, unless otherwise noted, carryAnd " halogen " part is all preferably chlorine, bromine or iodine.
Formula 1 compound and preparation thereof
The present invention relates to compound and preparation method thereof shown in formula 1,
Wherein X1For halogen (Cl, Br, I), X2For F or H.
This formula 1 compound is the intermediate of compound shown in formula 7, and formula 7 is synthetic Lei Dipawei (Ledipasvir)Key intermediate, can be by formula 1 through the convenient preparation of the reaction such as chloro, bromo, iodo.
Particularly, the preparation method of formula 1 compound provided by the invention comprises the following steps (a) and step (b):
(a) by (a1), (a2), (a3) or (a4), make formula 2 compounds as raw material formula 3, formula 4,Formula 5 or formula 6 compounds, in this step, by selecting different alkali, can be made into different metal reagents.For carrying out next step coupling reaction. Wherein the actual conditions of each step is as follows:
(a1), by formula 2 compounds and alkali reaction, make formula 3 compounds;
Wherein X1、X2The same, X3For Br, I or H, M is Li, in step (a1), can selectAlkali comprises the lithium alkylide of (but being not limited to): C1-C4;
The reaction condition of described step (a1), as temperature, in the reaction time, solvent etc. have no particular limits,Those skilled in the art can be according to actual needs, selects suitable temperature, by the conventional method in this areaDefinite reaction ends such as (as TLC), solvent can be selected arbitrarily not the atent solvent with reactant reaction. ?In another preference, in step (a1), reaction temperature is generally-80 DEG C to-30 DEG C; Common 5 points of reaction timeClock～24 hour are preferably 0.5-6 hour.
(a2), by formula 2 compounds and alkali reaction, make formula 4 compounds;
Wherein X1、X2The same; X4For Br or I; M' is Mg; In step (a2), the alkali that can selectComprise (but being not limited to): C1-C4 alkyl RMgBr, acetenyl halogenation magnesium, propinyl magnesium halide,Butynyl magnesium halide, or its combination;
The reaction condition of described step (a2), as temperature, in the reaction time, solvent etc. have no particular limits,Those skilled in the art can select according to actual needs. In another preference, in step (a2), reactionTemperature is-40 DEG C to 40 DEG C; Common 5 minutes～24 hours of reaction time was preferably 0.5-6 hour.
(a3), by formula 2 compounds and alkali reaction, make formula 3 compounds; Then by formula 3 compounds and LouisThis acid reaction, makes formula 5 compounds:
Wherein X1、X2、X3And M as above defines, in step (a3), the alkali that can select comprises (but alsoBe not limited to): the lithium alkylide of C1-C4.
In step (a3), the lewis acid that can select comprises (but being not limited to): MgY2、ZnY2、CuY、CuY2、FeY2、FeY3、CeY3, or its combination; Wherein, Y is Cl, Br or iodine, M " be selected from lower group:Mg, Zn, Cu, Fe, Ce or its combination, m is 1 or 2; Preferably, described lewis acid and instituteThe M stating " is corresponding.
The reaction condition of described step (a3), as temperature, in the reaction time, solvent etc. have no particular limits,Those skilled in the art can select according to actual needs. In another preference, the first step of step (a3)The actual conditions of reaction can be with reference to step (a1); In the second step reaction of step (a3), reaction temperature is-80To 20 DEG C; Common 5 minutes～24 hours of reaction time was preferably 0.5-6 hour.
(a4), by formula 2 compounds and alkali reaction, make formula 4 compounds; Then by formula 4 compounds and LouisThis acid reaction, makes formula 6 compounds:
Wherein X1、X2、X4, M' and m as above define, in step (a4), the alkali that can select comprise (butBe not limited to): C1-C4 RMgBr, acetenyl halogenation magnesium, propinyl magnesium halide, butynyl magnesium halide,Or its combination.
In step (a4), the lewis acid that can select comprises (but being not limited to): ZnY2、CuY、CuY2、FeY2、FeY3、CeY3, or its combination, Y is Cl, Br or iodine, M " ' be selected from lower group: Zn, Cu, Fe,Ce, or its combination.
The reaction condition of described step (a4), as temperature, in the reaction time, solvent etc. have no particular limits,Those skilled in the art can select according to actual needs. In another preference, the first step of step (a4)The actual conditions of reaction can be with reference to step (a2); In the second step reaction of step (a4), reaction temperature is-40To 40 DEG C; Common 5 minutes～24 hours of reaction time was preferably 0.5-6 hour.
(b) by any one or the multiple compounds and the acetylation examination that are selected from formula 3, formula 4, formula 5, formula 6Agent reaction, makes formula 1 compound.
In another preference, above-mentioned various in, each X2Identical; Preferably, each X2All F.
In another preference, above-mentioned various in, m is 1.
In another preference, above-mentioned various in, M " being Mg, Zn, Ce or its combination, M " ' be Zn,Ce or its combination; In another preference, M ", M " ' is the Fe of divalence.
In another preference, described reaction (a1), (a2), (a3), (a4), (b) carry out in atent solvent.
In another preference, the atent solvent in described reaction (a1), (a2), (a3), (a4), (b) is phaseSame or essentially identical; Be preferably the atent solvent that is selected from lower group: THF, methyltetrahydrofuran, methyl-tertButyl ether, ether, diethoxymethane, or its combination.
In described step (b), can select suitable acetylation reagent known in the art, a class is preferredDescribed acetylation reagent be selected from lower group:
H3CCOOCOR1, wherein R1For the alkyl of H or C1-C4;
H3CCOOR2, wherein R2For COOR3，R3For the alkyl of C1-C4;
H3CCOY, wherein Y is Cl, Br or I;
H3CCOOR3, wherein R3Definition as above;
H3CCONMe(OMe)，H3CCONR1R3，R1And R3The same;
Wherein n is 0,1 or 2;
Or any combination of above-mentioned acetylation reagent.
In another preference, described acetylation reagent is selected from lower group: H3CCOOCOR1、H3CCOY、H3CCONMe(OMe)、H3CCONR1R3, or its combination; Wherein, the definition of each group as above. MorePreferably, described acetylation reagent is selected from lower group: aceticanhydride, chloroacetic chloride, H3CCONMe (OMe), orIts combination.
Preferably, above-mentioned step (a) is used RMgBr as alkali, and preferred described RMgBr isC3 RMgBr.
In the present invention, also provide formula 1 compound that a class is new, the structure of described noval chemical compound as shown in the formulaShown in 1a:
In formula, X1For halogen (Cl, Br, I).
In another preference, X1For Br.
The preparation of formula 7 compounds
In the present invention, also provide the preparation method of a class as shown in the formula 7 compounds, described method comprises step:
(i), in atent solvent, formula 1a compound is reacted with halogenating agent, thereby makes formula 7 compounds:
In formula, X1For halogen (Cl, Br, I); X is halogen (Cl, Br or I).
The reaction condition of described step (i), as temperature, in the reaction time, solvent etc. have no particular limits,Those skilled in the art can be according to actual needs, selects suitable temperature, by the conventional method in this areaDefinite reaction ends such as (as TLC), solvent can be selected arbitrarily not the atent solvent with reactant reaction. ?In another preference, in step (i), reaction temperature is generally-50 DEG C to 50 DEG C; Common 5 points of reaction timeClock～24 hour are preferably 0.5-6 hour.
In another preference, described atent solvent is selected from lower group: carrene, chloroform, 1,2-dichloroEthane, chlorobenzene, or its combination.
In described step (i), preferred described halogenating agent is selected from lower group: bromine, chlorine, SO2Cl2Or I2。
The preparation of Lei Dipawei
The present invention also provides the preparation method of a kind of Lei Dipawei, and described method comprises step:
(i), in atent solvent, formula 1a compound is reacted with halogenating agent, thereby makes formula 7 compounds:
In formula, X1For halogen (Cl, Br, I); X is halogen (Cl, Br or I).
The reaction condition of described step (i), as temperature, in the reaction time, solvent etc. have no particular limits,Those skilled in the art can be according to actual needs, selects suitable temperature, by the conventional method in this areaDefinite reaction ends such as (as TLC), solvent can be selected arbitrarily not the atent solvent with reactant reaction. ?In another preference, in step (i), reaction temperature is generally-50 DEG C to 50 DEG C; Common 5 points of reaction timeClock～24 hour are preferably 0.5-6 hour.
In another preference, described atent solvent is selected from lower group: carrene, chloroform, 1,2-dichloroEthane, chlorobenzene or its any combination.
In described step (i), preferred described halogenating agent is selected from lower group: bromine, chlorine, SO2Cl2Or I2。
(ii) using formula 7 compounds as intermediate, thereby make Lei Dipawei (Ledipasvir, LDV). Wherein,Described preparation method has no particular limits, the method preparation that can adopt this area to report, or byThose skilled in the art are in conjunction with technology designed, designed known in the art, and such version should be considered toWithin falling within protection scope of the present invention.
In another preference, described method also comprises step: use the method as described in first aspect present inventionPreparation formula 1a compound.
Compared with prior art, major advantage of the present invention comprises:
(1), in preparation method of the present invention, raw material formula 2 compounds can adopt US2013324740 similar approachPreparation, technique is simple, and security is good;
(2) in preparation method of the present invention, can be with comparatively inexpensive alkali (as alkyl lithium reagents, RMgBrDeng) carry out acylation reaction, without using expensive Metal Palladium reagent; Meanwhile, the inventive method is with cheapnessThe acylating reagent being easy to get substitutes Weinreb acid amides, has significantly reduced the cost of raw material;
(3) the inventive method Atom economy is good, has reduced three waste discharge; The larger examination of inapplicable toxicity simultaneouslyAgent, reaction condition gentleness, course of reaction safety, synthesis technique is very easily realized, and has good industrialization valencyValue;
(4) the inventive method also provides the noval chemical compound shown in formula 1, and this compound can be used as Lei DipaweiSynthetic intermediate, prepare expeditiously Lei Dipawei key intermediate formula 7 compounds.
Below in conjunction with specific embodiment, further set forth the present invention. Should be understood that these embodiment are only for explanationThe present invention and being not used in limits the scope of the invention. The experiment side of unreceipted actual conditions in the following exampleMethod, conventionally according to normal condition, or the condition of advising according to manufacturer. Unless otherwise indicated, otherwisePercentage and umber are calculated by weight.
Embodiment 1
(1) in reaction bulb, add 2.5g compound 2A, the anhydrous THF of 25mL, stirring and dissolving. ObtainSolution is bathed and is cooled to-5 DEG C with cryosel, and (concentration is 2 slowly to drip 3.93mLi-PrMgCl tetrahydrofuran solutionMol/L), time for adding is 10 minutes, and dropping process keeps temperature to be no more than 0 DEG C, drips rear systemAt-5～0 DEG C, react 1 hour, obtain reactant mixture.
(2) in another one there-necked flask, add 2.59g acetic anhydride, nitrogen replacement 3 times, cryosel is bathed and is cooled to-5 DEG C, the grignard reagent preparing above (being the reactant mixture of preparation in step (1)) is added drop-wise in aceticanhydride,Time for adding 20 minutes, dropping process keeps temperature to be no more than 0 DEG C, drips rear system at-5～0 DEG CReact 1 hour.
(3) 20mL saturated ammonium chloride solution is added drop-wise to cancellation reaction in system, separatory; Water ethyl acetateExtraction once, merges organic phase, and saturated sodium bicarbonate solution washs once, and system pH is 8, saturated common saltOnce, anhydrous sodium sulfate drying 30 minutes, concentrates in water washing.
(4) the concentrated thick product 30mL n-hexane obtaining refluxes and pulls an oar 1 hour, is slowly as cold as room temperature, mistakeFilter, filter cake washs once with n-hexane, obtains the yellow product of 1.4g, yield 72.44% after being dried.
Product C-0011HNMR (400MHz, CDCl3)δ8.199(1H,s)，8.115(1H,d,J＝8)；7.816(1H,s)，7.640(2H,t,J＝8)，7.506(1H,d,J＝8)，2.664(3H,s)
Embodiment 2
(1) thermometer will be housed, addition funnel, the there-necked flask nitrogen replacement of nitrogen protection device three times, reactionIn bottle, add 4.07g compound 2A, the anhydrous THF of 50mL, stirring and dissolving. The solution dry ice obtainingAcetone bath is cooled to-70 DEG C, and (concentration is 2.5 slowly to drip 4mL n-BuLi/tetrahydrofuran solutionMol/L), time for adding is 10 minutes, and dropping process keeps temperature to be no more than-65 DEG C, drips rear systemAt-65 DEG C, react 1 hour, obtain reactant mixture.
(2) 3.06g aceticanhydride is slowly added drop-wise in above-mentioned reactant mixture, time for adding 10 minutes, dropping processKeep temperature to be no more than-65 DEG C, drip rear system and at-55 DEG C, react 1 hour.
(3) 20mL saturated ammonium chloride solution is added drop-wise to cancellation reaction in system, and cancellation process temperature is no more than25 DEG C, stir separatory 20 minutes; Water is extracted with ethyl acetate once, merges organic phase, saturated foodOnce, anhydrous sodium sulfate drying 30 minutes, concentrates in salt water washing.
(4) the concentrated thick product 30mL n-hexane obtaining refluxes and pulls an oar 1 hour, is slowly as cold as room temperature, mistakeFilter, filter cake washs once with n-hexane, and products obtained therefrom is again with 20mL methanol eddy making beating 1 hour, coolingTo room temperature, to filter, solid air blast is dried material and within 2 hours, is obtained the yellow product of 0.5g, yield 15%.
Product C-0011HNMR (400MHz, CDCl3)δ8.199(1H,s)，8.115(1H,d,J＝8)；7.816(1H,s)，7.640(2H,t,J＝8)，7.506(1H,d,J＝8)，2.664(3H,s)
Embodiment 3
Thermometer will be housed, addition funnel, the there-necked flask nitrogen replacement of nitrogen protection device three times, reaction bulbIn add 2.5g compound 2A, the anhydrous THF of 25mL, stirring and dissolving. The solution obtaining is bathed cold with cryoselBut arrive-5 DEG C, slowly drip 3.93mLi-PrMgCl tetrahydrofuran solution (concentration is 2mol/L), when droppingBetween be 10 minutes, dropping process keep temperature be no more than 0 DEG C, drip rear system and react at-5～0 DEG C0.5 hour. System temperature drops to-20 DEG C, adds 0.25g anhydrous cerium chloride, stirs 30 minutes at this temperature.In another one there-necked flask, add 2.59g acetic anhydride, nitrogen replacement 3 times, cryosel is bathed and is cooled to-5 DEG C, onThe grignard reagent that face prepares is added drop-wise in aceticanhydride, time for adding 20 minutes, and dropping process keeps temperature not superCross 0 DEG C, drip rear system and at-5～0 DEG C, react 1 hour.
20mL saturated ammonium chloride solution is added drop-wise to cancellation reaction in system, and cancellation process temperature is no more than 25 DEG C,Stir separatory 20 minutes; Water is extracted with ethyl acetate once, merges organic phase, and saturated sodium bicarbonate is moltenLiquid washs once, and system pH is 8, saturated common salt water washing once, anhydrous sodium sulfate drying 30 minutes, denseContracting.
The concentrated thick product 30mL n-hexane obtaining refluxes and pulls an oar 1 hour, is slowly as cold as room temperature, filter,Filter cake washs once with n-hexane, and products obtained therefrom air blast is dried material and within 2 hours, obtained the yellow product of 1.2g, yield62.09％。
Embodiment 4
Thermometer will be housed, addition funnel, the there-necked flask nitrogen replacement of nitrogen protection device three times, reaction bulbIn add 4.07g compound 2A, the anhydrous THF of 50mL, stirring and dissolving. The solution dry ice acetone obtainingBath is cooled to-70 DEG C, slowly drips 4mL n-BuLi/tetrahydrofuran solution (concentration is 2.5mol/L), dripsAdding the time is 10 minutes, and dropping process keeps temperature to be no more than-65 DEG C, drips rear system at-65 DEG CReact 0.5 hour, then at this temperature, add 0.2g anhydrous zinc chloride, react 0.5 hour. 3.06g aceticanhydrideSlowly be added drop-wise in above-mentioned reaction, time for adding 10 minutes, dropping process keeps temperature to be no more than-65 DEG C, dripsAdd rear system reacts 1 hour at-55 DEG C.
20mL saturated ammonium chloride solution is added drop-wise to cancellation reaction in system, and cancellation process temperature is no more than 25 DEG C,Stir separatory 20 minutes; Water is extracted with ethyl acetate once, merges organic phase, saturated common salt water washingOnce, anhydrous sodium sulfate drying 30 minutes, concentrated.
The concentrated thick product 30mL n-hexane obtaining refluxes and pulls an oar 1 hour, is slowly as cold as room temperature, filter,Filter cake washs once with n-hexane, and products obtained therefrom is pulled an oar 1 hour with 20mL methanol eddy again, cool to room temperature,Filter, solid air blast is dried material and within 2 hours, is obtained the yellow product of 1.5g, yield 45%.
Embodiment 5
(1) thermometer will be housed, addition funnel, the there-necked flask nitrogen replacement of nitrogen protection device three times, reactionIn bottle, add 3.6g compound 2B, the anhydrous THF of 40mL, stirring and dissolving. The solution dry ice obtainingAcetone bath is cooled to-70 DEG C, and (concentration is 2.5 slowly to drip 4.4mL n-BuLi/tetrahydrofuran solutionMol/L), time for adding is 10 minutes, and dropping process keeps temperature to be no more than-65 DEG C, drips rear systemAt-65 DEG C, react 1 hour, obtain reactant mixture.
(2) 4.08g aceticanhydride is slowly added drop-wise in above-mentioned reactant mixture, time for adding 10 minutes, dropping processKeep temperature to be no more than-65 DEG C, drip rear system and at-55 DEG C, react 1 hour.
(3) 20mL saturated ammonium chloride solution is added drop-wise to cancellation reaction in system, and cancellation process temperature is no more than25 DEG C, stir separatory 20 minutes; Water is extracted with ethyl acetate once, merges organic phase, saturated common saltOnce, anhydrous sodium sulfate drying 30 minutes, concentrates in water washing.
(4) the concentrated thick product 30mL n-hexane obtaining refluxes and pulls an oar 1 hour, is slowly as cold as room temperature, mistakeFilter, filter cake washs once with n-hexane, and products obtained therefrom is again with 20mL methanol eddy making beating 1 hour, coolingTo room temperature, to filter, solid air blast is dried material and within 2 hours, is obtained the yellow product of 0.678g, yield 21%.
Embodiment 6
(1) thermometer will be housed, addition funnel, the there-necked flask nitrogen replacement of nitrogen protection device three times, reactionIn bottle, add 3.6g compound 2B, the anhydrous THF of 40mL, stirring and dissolving. The solution dry ice obtainingAcetone bath is cooled to-70 DEG C, and (concentration is 2.5 slowly to drip 4.4mL n-BuLi/tetrahydrofuran solutionMol/L), time for adding is 10 minutes, and dropping process keeps temperature to be no more than-65 DEG C, drips rear systemAt-65 DEG C, react 1 hour, obtain reactant mixture.
(2) 2.75g chloroacetic chloride is slowly added drop-wise in above-mentioned reactant mixture, and time for adding 10 minutes, drippedJourney keeps temperature to be no more than-65 DEG C, drips rear system and at-55 DEG C, reacts 1 hour.
(3) 20mL saturated ammonium chloride solution is added drop-wise to cancellation reaction in system, and cancellation process temperature is no more than25 DEG C, stir separatory 20 minutes; Water is extracted with ethyl acetate once, merges organic phase, saturated common saltOnce, anhydrous sodium sulfate drying 30 minutes, concentrates in water washing.
(4) the concentrated thick product 30mL n-hexane obtaining refluxes and pulls an oar 1 hour, is slowly as cold as room temperature, mistakeFilter, filter cake washs once with n-hexane, and products obtained therefrom is again with 15mL methanol eddy making beating 1 hour, coolingTo room temperature, to filter, solid air blast is dried material and within 2 hours, is obtained the yellow product of 0.45g, yield 13.9%.
Embodiment 7
In the there-necked flask of 500ml, add 6.9g (21.4mmol, 1.0eq) compound 1a, 200ml acetic acid is differentPropyl ester and 20ml isopropyl alcohol, reactant mixture cools to 0-10 DEG C, adds 0.57g (10mol%) phosphorus tribromide,Then drip the isopropyl acetate solution of 3.3g (20.6mmol, 0.96eq) bromine, within approximately 30 minutes, drip.
Reactant liquor adds in the saturated solution of sodium bisulfite of 50ml and excessive bromine, separates organic phase, waterExtract once with 20ml ethyl acetate mutually, merge organic phase, anhydrous sodium sulfate drying. Concentrate to obtain crude product 8.5g(containing raw material, a bromo-derivative and two bromo-derivatives). 42.5ml for crude product (5vol) isopropyl alcohol making beating purifying, obtains6.0g target compound (yield: 70%).
1HNMR(400MHz,CDCl3)δ8.21(d,J＝1.0Hz,1H),8.14(d,J＝8.0Hz,1H),7.81(d,J＝1.4Hz,1H),7.65(t,J＝10.3Hz,2H),7.51(d,J＝8.1Hz,1H),4.52–4.39(m,2H),1.59(s,1H).
Embodiment 8
In the there-necked flask of 500ml, 6.9g (21.4mmol, 1.0eq) compound 1a, 69ml acetonitrile, 1mlAcetic acid, is warmed up to 30-35 DEG C, drips 3.1g (1.1eq) sulfonic acid chloride (being dissolved in advance in 10ml acetonitrile), dripsAfter having added, keep 3 hours at 30-35 DEG C, TLC tracks to raw material and disappears. 100ml is also poured in reaction intoWater in, filter out faint yellow solid.
42.5ml for crude product (5vol) isopropyl alcohol making beating purifying, obtain 7.0g target compound (yield:81.7％)。
All documents of mentioning in the present invention are all quoted as a reference in this application, just as each section of documentQuoted separately as a reference. In addition should be understood that after having read above-mentioned instruction content of the present invention,Those skilled in the art can make various changes or modifications the present invention, and these equivalent form of values fall within this Shen equallyPlease appended claims limited range.
Claims (10)
1. the preparation method of formula 1 compound,
Wherein X1For Cl, Br or I;
Each X2Be selected from respectively as F or H;
It is characterized in that, the method comprises:
(a) by step (a1), (a2), (a3) or (a4), formula 2 compounds are made to formula 3, formula as raw material4, formula 5 or formula 6 compounds,
(a1), by formula 2 compounds and alkali reaction, make formula 3 compounds;
Wherein X1、X2The same, X3For Br, I or H, M is Li, the lithium alkylide that alkali is C1-C4;
(a2), by formula 2 compounds and alkali reaction, make formula 4 compounds;
Wherein X1、X2The same; X4For Br or I;
M' is Mg;
Alkali is alkyl RMgBr, acetenyl halogenation magnesium, propinyl magnesium halide, the butynyl halogenation of C1-C4Magnesium, or its combination;
(a3), by formula 2 compounds and alkali reaction, make formula 3 compounds; Then by formula 3 compounds and LouisThis acid reaction, makes formula 5 compounds:
Wherein X1、X2、X3And M as above defines, the lithium alkylide that alkali is C1-C4, lewis acid is MgY2、ZnY2、CuY、CuY2、FeY2、FeY3、CeY3Or its any combination, Y is Cl, Br or iodine, M "Be selected from lower group: Mg, Zn, Cu, Fe, Ce or its combination, m is 1 or 2;
(a4), by formula 2 compounds and alkali reaction, make formula 4 compounds; Then by formula 4 compounds and LouisThis acid reaction, makes formula 6 compounds:
Wherein X1、X2、X4, M' and m as above define, alkali is selected from lower group: C1-C4 RMgBr, secondAlkynyl magnesium halide, propinyl magnesium halide, butynyl magnesium halide, or its combination; Lewis acid is selected from lower group:ZnY2、CuY、CuY2、FeY2、FeY3、CeY3, or its combination, Y is Cl, Br or iodine, M " 'Be selected from lower group: Zn, Cu, Fe, Ce, or its combination;
(b) by any one or the multiple compounds and the acetylation examination that are selected from formula 3, formula 4, formula 5, formula 6Agent reaction, makes formula 1 compound.
2. the method for claim 1, is characterized in that, described acetylation reagent is selected from lower group:
H3CCOOCOR1, wherein R1For the alkyl of H or C1-C4;
H3CCOOR2, wherein R2For COOR3，R3For the alkyl of C1-C4;
H3CCOY, wherein Y is Cl, Br or I;
H3CCOOR3, wherein R3Definition as above;
H3CCONMe(OMe)，H3CCONR1R3，R1And R3The same;
Wherein n is 0,1 or 2;
Or any combination of above-mentioned acetylation reagent.
3. the method for claim 1, is characterized in that, described acetylation reagent is selected from lower group:H3CCOOCOR1、H3CCOY、H3CCONMe(OMe)、H3CCONR1R3, or its combination; ItsIn, R1For the alkyl of H or C1-C4, R3For the alkyl of C1-C4, Y is Cl, Br or I.
4. the method for claim 1, is characterized in that: described RMgBr is C3 Ge Shi examinationAgent.
5. method as claimed in claim 2, is characterized in that, described acetylation reagent is selected from lower group:Aceticanhydride, chloroacetic chloride, H3CCONMe (OMe), or its combination.
6. one kind as shown in the formula the compound shown in 1a
In formula, X1For halogen.
7. compound as claimed in claim 6, is characterized in that, X1For Cl, Br or I.
8. as shown in the formula a preparation method for 7 compounds, it is characterized in that, described method comprises step:
(1), in atent solvent, formula 1a compound is reacted with halogenating agent, thereby make formula 7 compounds
In formula, X1For halogen; X is halogen.
9. method as claimed in claim 8, is characterized in that, X1For Cl, Br or I, X be Cl,Br or I.
10. method as claimed in claim 8, is characterized in that, described halogenating agent is selected from lower group: bromineElement, chlorine, SO2Cl2Or I2。
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Inventor after: Huang Chengjun Inventor after: Wei Zhewen Inventor after: Fu Shaojun Inventor after: Li Wei Inventor after: Ren Yi Inventor before: Huang Chengjun Inventor before: Wei Zhewen Inventor before: Fu Shaojun Inventor before: Li Wei Inventor before: Zhang Xixuan |
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Denomination of invention: Preparation method of fluorenone derivatives Granted publication date: 20160511 Pledgee: China Minsheng Banking Corp Shanghai branch Pledgor: SHANGHAI FOREFRONT PHARMCEUTICAL Co.,Ltd. Registration number: Y2024310000803 |