CN107686471A - A kind of Fei Luokao former times and its synthetic method of intermediate - Google Patents
A kind of Fei Luokao former times and its synthetic method of intermediate Download PDFInfo
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- CN107686471A CN107686471A CN201710902982.7A CN201710902982A CN107686471A CN 107686471 A CN107686471 A CN 107686471A CN 201710902982 A CN201710902982 A CN 201710902982A CN 107686471 A CN107686471 A CN 107686471A
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- former times
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- fei luokao
- synthetic method
- luokao former
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 39
- 239000000543 intermediate Substances 0.000 claims abstract description 147
- 238000006243 chemical reaction Methods 0.000 claims abstract description 79
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 28
- 230000001035 methylating effect Effects 0.000 claims abstract description 22
- 239000000463 material Substances 0.000 claims abstract description 19
- 230000000977 initiatory effect Effects 0.000 claims abstract description 16
- 238000007069 methylation reaction Methods 0.000 claims abstract description 13
- 238000006277 sulfonation reaction Methods 0.000 claims abstract description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 82
- 239000002904 solvent Substances 0.000 claims description 47
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- -1 methyl sulphonyl Chemical group 0.000 claims description 22
- 238000002425 crystallisation Methods 0.000 claims description 21
- 230000008025 crystallization Effects 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- 238000010792 warming Methods 0.000 claims description 16
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 15
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 15
- RHDUOFVTCTUTFX-UHFFFAOYSA-N methanesulfinic acid;sodium Chemical compound [Na].CS(O)=O RHDUOFVTCTUTFX-UHFFFAOYSA-N 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 230000000640 hydroxylating effect Effects 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 8
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 claims description 8
- 150000004820 halides Chemical class 0.000 claims description 7
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- WIPWTSYHKQQKJC-UHFFFAOYSA-N 3-hydroxy-5,5-dimethyl-4-(4-methylsulfonylphenyl)furan-2-one Chemical class CC1(C)OC(=O)C(O)=C1C1=CC=C(S(C)(=O)=O)C=C1 WIPWTSYHKQQKJC-UHFFFAOYSA-N 0.000 claims description 4
- KLKVIJCBPREUPJ-UHFFFAOYSA-N 4-(4-methylsulfonylphenyl)-2h-furan-5-one Chemical class C1=CC(S(=O)(=O)C)=CC=C1C1=CCOC1=O KLKVIJCBPREUPJ-UHFFFAOYSA-N 0.000 claims description 4
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical group I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 6
- 238000007254 oxidation reaction Methods 0.000 abstract description 5
- 150000003568 thioethers Chemical class 0.000 abstract description 5
- 238000006467 substitution reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000004073 vulcanization Methods 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 238000000034 method Methods 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 16
- 239000007787 solid Substances 0.000 description 12
- 238000003809 water extraction Methods 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229940126062 Compound A Drugs 0.000 description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 5
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 5
- 230000036632 reaction speed Effects 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 3
- 238000007039 two-step reaction Methods 0.000 description 3
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)(*)C(c(cc1)ccc1S(C)(=O)=O)=O Chemical compound CC(C)(*)C(c(cc1)ccc1S(C)(=O)=O)=O 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 125000004799 bromophenyl group Chemical group 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical class CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- FULAPETWGIGNMT-UHFFFAOYSA-N CC(C)(C(c(cc1)ccc1S(C)(=O)=O)=C1OCC2CC2)OC1=O Chemical compound CC(C)(C(c(cc1)ccc1S(C)(=O)=O)=C1OCC2CC2)OC1=O FULAPETWGIGNMT-UHFFFAOYSA-N 0.000 description 1
- KZFCUYQEGLVKTM-UHFFFAOYSA-N CCC(OCC(Cl)=O)=O Chemical compound CCC(OCC(Cl)=O)=O KZFCUYQEGLVKTM-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical class BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- VIHAEDVKXSOUAT-UHFFFAOYSA-N but-2-en-4-olide Chemical class O=C1OCC=C1 VIHAEDVKXSOUAT-UHFFFAOYSA-N 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910001947 lithium oxide Inorganic materials 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006351 sulfination reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- 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
- C07C45/46—Friedel-Crafts reactions
-
- 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
- C07C45/67—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 isomerisation; by change of size of the carbon skeleton
- C07C45/68—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 isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to pharmaceutical synthesis field, there is provided the synthetic method of a kind of Fei Luokao former times and its intermediate.The synthetic method of the Fei Luokao former times intermediates, as initiation material, to avoid the disagreeableness thioether of use environment to carry out methylation reaction as initiation material to brom-acetophenone and methylating reagent and obtain the first intermediate to brom-acetophenone；First intermediate directly obtains the second intermediate through inferior sulfonation reaction, and vulcanization reaction and oxidation reaction are shorten into a step substitution reaction, reactions steps is greatly simplified, shortens the reaction time, improve reaction efficiency.Meanwhile the present invention also uses NBS systems, the reaction of the second intermediate hydroxylization is set to directly obtain Fei Luokao former times intermediates, it is more environment-friendly, it is adapted to large-scale production, improves reaction rate.In addition, the synthetic method of the Fei Luokao former times includes the synthetic method of above-mentioned Fei Luokao former times intermediate, its can by reaction condition milder, it is more environment-friendly in a manner of synthesize Fei Luokao former times.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, in particular to a kind of Fei Luokao former times and its synthetic method of intermediate.
Background technology
Fei Luokao former times, i.e. 3- (cyclo propyl methoxy) -5,5- dimethyl -4- [4- (methyl yellow acyl group) phenyl] -2 (5H) -
Furanone, molecular formula：C17H20O5S。
Fei Luokao former times is a kind of important nonsteroidal anti-inflammatory drug, at present on Fei Luokao former times synthesis report and it is few,
Mainly there are following two methods：
Method one is the Fei Luokao former times of patent document US5981576, US006020343A, WO971645A1 report to synthesize road
Line.Using thioanisole as initiation material, generation compound A is reacted with isobutyryl chloride, compound A hydroxylatings generation compound B, is changed
Compound B oxidized dose such as (MMPP magnesium monoperoxyphthalates) oxidation generation compound C, compound C and acetoxyl group acetyl
Chlorine reaction generation compound D, compound D gives birth to through DBU processing cyclization generation compound E, compound E with Cyclopropylmetyl bromide reaction
Into Fei Luokao former times.Reaction equation such as formula one：
Method two is the Fei Luokao former times synthetic routes of patent document CN104803956A reports.It is former by starting of thioanisole
Material, reacted with isobutyryl chloride and generate compound A, compound A handles to obtain bromination product, the generation of bromination product hydroxylating through bromine
Compound B, compound B oxidized dose such as oxidation generation compound C, compound C and acetoxy acetyl chloride reaction generation chemical combination
Thing D, compound D are through DBU processing cyclization generation compound E, compound E and Cyclopropylmetyl bromide reaction generation Fei Luokao former times.Instead
Ying Shiwei formulas two：
The synthetic method of both the above Fei Luokao former times has the disadvantages that：
Shortcoming 1：Initiation material uses thioanisole, and sulphur ether material generally has niff, meets naked light, height is thermoae
Easy firing explodes, and this material can pollute to environment, has very big environmental protection pressure in America and Europe's production.
Shortcoming 2：The method for above providing two kinds of prepare compound B, method one use sodium hydroxide solution and four chlorinations
Phase transfer catalyst Aliquat336 (tri-n-octyl methyl ammonium chloride) reactions are added in carbon two-phase system to be made.This method needs to make
With carbon tetrachloride, carbon tetrachloride be first kind solvent be it is known can be with carcinogenic and by strong doubt human and environment is harmful to molten
Agent.In the conceived case, should avoid using this kind of solvent.Meanwhile this method in last handling process, it is necessary to cross silica gel column chromatography
Post can just obtain purer compound B, be not suitable for large-scale industrial production；Method two is first carried out using bromine to compound A
Bromo, then carry out hydroxylating in the presence of phase transfer catalyst with sodium hydroxide solution and compound B is made, this method makes
With bromine, there are extremely strong strong toxic and corrosivity, pole is unfavorable for environment and occupational health, through avoiding using as far as possible.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of Fei Luokao former times intermediate, pass through the choosing of different initiation materials
Select, reacted using the condition of milder, avoid to the disagreeableness thioether of environment as starting material, be adapted to extensive raw
Production.
What embodiments of the invention were realized in：
A kind of synthetic method of Fei Luokao former times intermediate, it includes：
, as initiation material, methylation reaction will be carried out to brom-acetophenone and methylating reagent to brom-acetophenone and obtain first
Intermediate；
The first intermediate is carried out into inferior sulfonation reaction with methyl sulfinic acid sodium under cuprous iodide catalysis to obtain among second
Body；
Second intermediate and N-bromosuccinimide are subjected to hydroxylating and obtain Fei Luokao former times intermediates；
The structural formula of first intermediate isThe structural formula of second intermediate isAmong Fei Luokao former times
The structural formula of body is
Further, in a preferred embodiment of the invention, above-mentioned methylating reagent is selected from halide, dimethyl suflfate
Or one kind in methyl tosylate, it is preferable that methylating reagent is halide, it is highly preferred that halide is iodine first
Alkane.
Further, in a preferred embodiment of the invention, above-mentioned methylation reaction includes：Brom-acetophenone will be dissolved in
In first solvent, highly basic and methylating reagent are added, the completely rear extraction liquid separation of reaction, drying, evaporation obtain the first intermediate；
Preferably, the one kind of the first solvent in dimethylformamide, dimethyl sulfoxide (DMSO) or the tert-butyl alcohol, highly basic are selected from hydrogen
One or more in sodium oxide molybdena, lithium hydroxide, potassium hydroxide and potassium tert-butoxide.
Further, in a preferred embodiment of the invention, above-mentioned inferior sulfonation reaction includes：By the first intermediate, methyl
Sulfinic acid sodium, L-PROLINE are added in the second solvent, and cuprous iodide is added when being warming up to 80~120 DEG C, react 40~50h,
Room temperature is cooled to, is extracted, is dried, normal heptane crystallization is added after removing solvent under reduced pressure, obtains the second intermediate；Wherein, second is molten
Agent is dimethyl sulfoxide (DMSO).
Further, in a preferred embodiment of the invention, above-mentioned inferior sulfonation reaction includes：By the first intermediate, methyl
Sulfinic acid sodium, L-PROLINE are added in dimethyl sulfoxide (DMSO), and cuprous iodide is added when being warming up to 100 DEG C, are reacted 48h, are cooled to
Room temperature, extract, dry, add normal heptane crystallization after removing solvent under reduced pressure, obtain the second intermediate.
Further, in a preferred embodiment of the invention, after above-mentioned crystallization, before obtaining the second intermediate, also
Including the product after crystallization is recrystallized with ethyl acetate-normal heptane.
Further, in a preferred embodiment of the invention, above-mentioned hydroxylating includes：Second intermediate is dissolved in
In 3rd solvent, N-bromosuccinimide is added, 80~120 DEG C of 10~14h of reaction is warming up to, is cooled to room temperature, extraction, does
It is dry, remove under reduced pressure methyl tertiary butyl ether(MTBE)-normal heptane crystallization added after solvent, obtain Fei Luokao former times intermediates, wherein, the 3rd solvent
For dimethyl sulfoxide (DMSO).
Further, in a preferred embodiment of the invention, above-mentioned hydroxylating includes：Second intermediate is dissolved in
In dimethyl sulfoxide (DMSO), N-bromosuccinimide is added, 100 DEG C of reaction 12h is warming up to, is cooled to room temperature, extraction, dries, subtract
Pressure adds methyl tertiary butyl ether(MTBE)-normal heptane crystallization after solvent is evaporated off, and obtains Fei Luokao former times intermediates.
Another object of the present invention is to provide a kind of synthetic method of Fei Luokao former times, it was included among above-mentioned Fei Luokao former times
The synthetic method of body, its can by reaction condition milder, it is more environment-friendly in a manner of synthesize Fei Luokao former times.
A kind of synthetic method of Fei Luokao former times, it includes the synthetic method of above-mentioned Fei Luokao former times intermediate.
Further, in a preferred embodiment of the invention, comprise the steps of：
Fei Luokao former times intermediate prepared by the synthetic method of above-mentioned Fei Luokao former times intermediate and acetoxyl group acetyl will be passed through
Chlorine reaction prepares 2- methyl isophthalic acids-[4- (methyl sulphonyl) phenyl] -2- (2- acetoxyl groups acetoxyl group) -1- acetone, and it reacts
Formula is as follows；
By 2- methyl isophthalic acids-[4- (methyl sulphonyl) phenyl] -2- (2- acetoxyl groups acetoxyl group) -1- acetone through DBU at
Cyclization generation 3- hydroxyl -5,5 dimethyl -4- [4- (methyl sulphonyl) phenyl] -2 (5H)-furanones are managed, its reaction equation is as follows；
By the dimethyl -4- of 3- hydroxyls -5,5 [4- (methyl sulphonyl) phenyl] -2 (5H)-furanones and Cyclopropylmetyl bromide
Reaction generation Fei Luokao former times, its reaction equation are as follows；
Fei Luokao former times intermediate and have with intermediate preparation Fei Luokao former times following excellent prepared by the embodiment of the present invention
Point：
(1) synthetic method of Fei Luokao former times intermediate provided in an embodiment of the present invention, using to brom-acetophenone as initiation material,
The disagreeableness thioether of use environment is avoided as initiation material, and methylation reaction is carried out at room temperature, and reaction condition is gentle.
Also, the first intermediate directly obtains the second intermediate through inferior sulfonation reaction, the selection of cuprous iodide and methyl sulfinic acid sodium,
Vulcanization reaction and oxidation reaction are shorten to a step substitution reaction, reactions steps is greatly simplified, shortens the reaction time, carry
High reaction efficiency.
(2) embodiment of the present invention also uses NBS systems, the reaction of the second intermediate hydroxylization is directly obtained in Fei Luokao former times
Mesosome, compared with the method one of prior art, avoid using this harmful reagent of carbon tetrachloride, and be not required to carry out column chromatography,
It is adapted to large-scale production；Compared with the method two of prior art, avoid using bromine, and it is anti-that two-step reaction is reduced into a step
Should, drastically increase reaction speed.In addition, reaction reagent is common agents, can directly it buy, to more environment-friendly side
Formula.
(3) the Fei Luokao former times synthesized using the synthetic method of invention, with reaction condition milder, to more environment-friendly side
Formula synthesizes Fei Luokao former times, is advantageous to be lifted the preparation efficiency and yield of Fei Luokao former times, is more suitable for industrialization large-scale production.
Embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the present invention.It is unreceipted specific in embodiment
Condition person, the condition suggested according to normal condition or manufacturer are carried out.Agents useful for same or the unreceipted production firm person of instrument, it is
The conventional products that can be obtained by commercially available purchase.
The synthetic method of the Fei Luokao former times to the embodiment of the present invention and its intermediate is specifically described below.
Room temperature refers to 10 to 25 DEG C of environment temperature in embodiment.
A kind of synthetic method of the Fei Luokao former times intermediates with structure shown in compound C, its reaction equation is as shown in formula three：
Specifically, the synthetic method of Fei Luokao former times intermediates comprises the following steps：
S1：So that brom-acetophenone as initiation material, will be carried out methylation reaction with methylating reagent to brom-acetophenone and be obtained
First intermediate A 1.
Specifically, brom-acetophenone will be dissolved in the first solvent, and will add highly basic and methylating reagent, added after reacting completely
Enter ethyl acetate and water extraction liquid separation, organic phase anhydrous sodium sulfate drying, remove solvent under reduced pressure and obtain the first intermediate A 1.
The embodiment of the present invention to brom-acetophenone, as initiation material, the first intermediate A 1, the first are generated through methylation reaction
Glycosylation reaction reacts at room temperature, and reaction condition is gentle, avoids the disagreeableness thioether of use environment as initiation material.Adding
When highly basic and methylating reagent, highly basic is first added, is stirred to solid dissolving, then methylating reagent is added dropwise, is stirred overnight at room temperature.
Methylating reagent is slowly added in a manner of being added dropwise, and rate of addition is unsuitable too fast, and slug is caused to prevent from reacting excessively fierceness.
Wherein, the one kind of the first solvent in dimethylformamide, dimethyl sulfoxide (DMSO), the tert-butyl alcohol；Highly basic is selected from hydrogen-oxygen
Change the one or more in sodium, lithium hydroxide, potassium hydroxide and potassium tert-butoxide；Methylating reagent is selected from halide, sulfuric acid
One kind in dimethyl ester or methyl tosylate.Methylating reagent to be substituted the hydrogen of brom-acetophenone by methyl, it is preferable that
Methylating reagent is halide, particularly preferred iodomethane.These reagents are the common agents in chemical reaction, can directly be purchased
, collocation use can obtain the methylate of high yield.
Mol ratio to brom-acetophenone, highly basic, methylating reagent is 1:1~4:1~2, to brom-acetophenone and the first solvent
Amount ratio be 1g/2mL~1g/10mL, the mol ratio and the amount ratio are inventor by creative work and combine itself
Empirical preferred value, carries out methylation reaction in the range of the preferred value, reaction speed faster, yield it is higher, side reaction
Less.It is highly preferred that the mol ratio to brom-acetophenone, highly basic, methylating reagent is 1:1.5~4:1.5~2；To brom-acetophenone
Amount ratio with the first solvent is 1g/4mL~1g/8mL, especially, when being 1g/ to the amount ratio of brom-acetophenone and the first solvent
It is optimal during 4mL.
S2：First intermediate A 1 is subjected to inferior sulfonation reaction with methyl sulfinic acid sodium under cuprous iodide catalysis and obtains second
Intermediate B 1.
Specifically, the first intermediate A 1, methyl sulfinic acid sodium, L-PROLINE are added in the second solvent, it is warming up to 80~
Cuprous iodide is added at 120 DEG C, 40~50h is reacted at 80~120 DEG C, room temperature is cooled to after reaction completely, adds acetic acid
Ethyl ester-water extraction, organic phase anhydrous sodium sulfate drying, adds normal heptane crystallization after removing solvent under reduced pressure, obtains the second intermediate
B1, in the present embodiment, the second solvent is dimethyl sulfoxide (DMSO).
Further, after crystallization, before obtaining the second intermediate B 1, in addition to by the acetic acid second of the product after crystallization
Ester-normal heptane is recrystallized, and the product after crystallization is dissolved in ethyl acetate-normal heptane, again from ethyl acetate-normal heptane
Middle recrystallization, recrystallization can be purified the crude product after crystallization, and then obtain the second pure intermediate B 1.
First intermediate A 1, methyl sulfinic acid sodium, L-PROLINE, the mol ratio of cuprous iodide are 1:1~2:0.2~0.5:
0.2~0.5, it is preferable that mol ratio 1:1.5:0.2:0.2；The amount ratio of first intermediate A 1 and the second solvent is 1g/1mL
~1g/5mL, it is preferable that amount ratio is 1g/1mL~1g/3mL；When amount ratio is that 1g/2mL is optimal.The mol ratio and the dosage
Than being that inventor passes through creative work and with reference to the preferred value that experience obtains, sulfination is carried out in the range of the preferred value
Reaction, reaction speed faster, yield it is higher, side reaction is less.
S3：Second intermediate B 1 is subjected to hydroxylating with N-bromosuccinimide and obtains Fei Luokao former times intermediates C.
Specifically, the second intermediate B 1 is dissolved in the 3rd solvent, adds N-bromosuccinimide (NBS), heating
To 80~120 DEG C of 10~14h of reaction, room temperature is cooled to after reaction completely, adds ethyl acetate and water extraction, the anhydrous sulphur of organic phase
Sour sodium drying, methyl tertiary butyl ether(MTBE)-normal heptane crystallization is added after removing solvent under reduced pressure, obtain Fei Luokao former times intermediate C, this implementation
In example, the 3rd solvent is also dimethyl sulfoxide (DMSO) (DMSO).
The embodiment of the present invention uses NBS/DMSO systems, the hydroxylating of the second intermediate B 1 is directly obtained Fei Luokao former times
Intermediate C, compared with the method one of prior art, avoid and can be endangered using carbon tetrachloride is this to caused by environment and human body
Reagent, and be not required to carry out column chromatography, it is adapted to large-scale production；Compared with the method two of prior art, method two has used pair
The extremely disagreeableness bromine of environment, and be two-step reaction, present invention, avoiding using bromine, and it is single step reaction, greatly
Improve reaction speed and simplify reactions steps.
Second intermediate B 1, the mol ratio of N-bromosuccinimide are 1:0.2~0.5, it is preferable that mol ratio 1:
0.2；The amount ratio of second intermediate B 1 and the 3rd solvent is 1g/2mL~1g/10mL, it is preferable that amount ratio be 1g/3mL~
1g/7mL；More preferably amount ratio 1g/5mL.The mol ratio and the amount ratio are inventor by creative work and combined certainly
The empirical preferred value of body, carries out inferior sulfonation reaction in the range of the preferred value, reaction speed faster, yield it is higher, it is secondary anti-
Should be less.
A kind of synthetic method of Fei Luokao former times, it includes the synthetic method of above-mentioned Fei Luokao former times intermediate.
Further, in a preferred embodiment of the invention, the synthetic method of Fei Luokao former times comprises the steps of：
Fei Luokao former times intermediate prepared by the synthetic method of above-mentioned Fei Luokao former times intermediate and acetoxyl group acetyl will be passed through
Chlorine reaction prepares 2- methyl isophthalic acids-[4- (methyl sulphonyl) phenyl] -2- (2- acetoxyl groups acetoxyl group) -1- acetone, and it reacts
Formula is as follows；
By 2- methyl isophthalic acids-[4- (methyl sulphonyl) phenyl] -2- (2- acetoxyl groups acetoxyl group) -1- acetone through DBU at
Cyclization generation 3- hydroxyl -5,5 dimethyl -4- [4- (methyl sulphonyl) phenyl] -2 (5H)-furanones are managed, its reaction equation is as follows；
By the dimethyl -4- of 3- hydroxyls -5,5 [4- (methyl sulphonyl) phenyl] -2 (5H)-furanones and Cyclopropylmetyl bromide
Reaction generation Fei Luokao former times, its reaction equation are as follows；
The feature and performance of the present invention are described in further detail with reference to embodiments.
Embodiment 1~5 provides the preparation method of the first intermediate A 1.
The preparation of the 1- of embodiment 1 (4- bromophenyls) -2- methyl acetones
The present embodiment provides a kind of preparation method of first intermediate A 1, its using to brom-acetophenone as initiation material, will be right
Brom-acetophenone carries out methylation reaction with methylating reagent and obtains the first intermediate A 1, and its specific preparation process is as follows：
Brom-acetophenone (100g, 1eq) will be dissolved at room temperature in 400mL dimethylformamides, add hydroxide
Sodium (56.3g, 3eq) and iodomethane (133.3g, 2eq), are stirred overnight at room temperature.Reaction completely after add 500mL ethyl acetate and
500mL water, liquid separation is extracted, organic phase anhydrous sodium sulfate drying, solvent is removed under reduced pressure and obtains the first intermediate A 1, i.e.,：1- (4- bromines
Phenyl) -2- methyl acetones, (110g, weak yellow liquid).
The preparation of the 1- of embodiment 2 (4- bromophenyls) -2- methyl acetones
The present embodiment provides a kind of preparation method of first intermediate A 1, its using to brom-acetophenone as initiation material, will be right
Brom-acetophenone carries out methylation reaction with methylating reagent and obtains the first intermediate A 1, and its specific preparation process is as follows：
Brom-acetophenone (5.0g, 1eq) will be dissolved at room temperature in 20mL DMSO, repeated hydrogenation lithia (2.0g,
3.7eq).Iodomethane (5.0g, 1.5eq) is added dropwise after stirring to solid dissolving, is stirred overnight at room temperature.30mL is added after reaction completely
Ethyl acetate and 30mL water, liquid separation is extracted, organic phase anhydrous sodium sulfate drying, solvent is removed under reduced pressure and obtains intermediate A 1, i.e.,：1-
(4- bromophenyls) -2- methyl acetones, (5.8g, weak yellow liquid).
The preparation of the 1- of embodiment 3 (4- bromophenyls) -2- methyl acetones
The present embodiment provides a kind of preparation method of first intermediate A 1, its using to brom-acetophenone as initiation material, will be right
Brom-acetophenone carries out methylation reaction with methylating reagent and obtains the first intermediate A 1, and its specific preparation process is as follows：
Brom-acetophenone (5.0g, 1eq) will be dissolved at room temperature in the 20mL tert-butyl alcohols, then add potassium tert-butoxide (3.9g,
1.5eq), iodomethane (5.0g, 1.5eq) is then added dropwise, is stirred overnight at room temperature.Reaction completely after add 30mL ethyl acetate and
30mL water, liquid separation is extracted, organic phase anhydrous sodium sulfate drying, solvent is removed under reduced pressure and obtains intermediate A 1, i.e.,：1- (4- bromobenzenes
Base) -2- methyl acetones, (5.4g, weak yellow liquid).
The preparation of the 1- of embodiment 4 (4- bromophenyls) -2- methyl acetones
Brom-acetophenone (21.3g, 0.1moL) room temperature will be dissolved in 100mL dimethylformamides, and stir lower addition hydrogen-oxygen
Change potassium (11.2g, 0.2moL), add dimethyl suflfate (25.2g, 0.2moL) room temperature reaction overnight.Added after reaction completely
100mL ethyl acetate, filter off insoluble matter and add water extraction, liquid separation, organic phase anhydrous sodium sulfate drying, remove solvent under reduced pressure
Obtain (4- the bromophenyls) -2- of intermediate A 1 methyl isophthalic acids-acetone) (22g, weak yellow liquid).
The preparation of the 1- of embodiment 5 (4- bromophenyls) -2- methyl acetones
Brom-acetophenone (21.3g, 0.1moL) room temperature will be dissolved in 100mL dimethylformamides, and stir lower addition hydrogen-oxygen
Change potassium (11.2g, 0.2moL), add methyl tosylate (37.2g, 0.2moL) room temperature reaction overnight.After reaction completely
100mL ethyl acetate is added, insoluble matter is filtered off and adds water extraction, liquid separation, organic phase anhydrous sodium sulfate drying, remove under reduced pressure
Solvent obtains (4- the bromophenyls) -2- of intermediate A 1 methyl isophthalic acids-acetone) (22.5g, weak yellow liquid).
Embodiment 6~9 provides the preparation method of the second intermediate B 1.
The preparation of the 2- methyl of embodiment 6-[4- (methyl sulphonyl) phenyl] acetone
A kind of preparation method of second intermediate B 1 is present embodiments provided, it is reaction substrate with the first intermediate A 1,
The second intermediate B 1 is obtained, its specific preparation process is as follows：
By the first intermediate A 1 (110g, 1eq), methyl sulfinic acid sodium (74.1g, 1.5eq) and L-PROLINE (11.1g,
0.2eq) add in 220mL dimethyl sulfoxide (DMSO)s, cuprous iodide (18.5g, 0.2eq) is added when being warming up to 100 DEG C, at 100 DEG C
Lower reaction 48h.Room temperature is cooled to after reaction completely, adds ethyl acetate-water extraction, organic phase is dried, after removing solvent under reduced pressure
Add normal heptane crystallization and obtain crude product, crude product is recrystallized to give the second pure intermediate B 1 with ethyl acetate-normal heptane, i.e.,：2-
Methyl-[4- (methyl sulphonyl) phenyl] acetone, (80g, yield 72.7%, faint yellow solid).
The preparation of the 2- methyl of embodiment 7-[4- (methyl sulphonyl) phenyl] acetone
A kind of preparation method of second intermediate B 1 is present embodiments provided, it is reaction substrate with the first intermediate A 1,
The second intermediate B 1 is obtained, its specific preparation process is as follows：
By the first intermediate A 1 (165g, 1eq), methyl sulfinic acid sodium (111.2g, 1.5eq) and L-PROLINE (16.5g,
0.2eq) add in 330mL dimethyl sulfoxide (DMSO)s, cuprous iodide (27.8g, 0.2eq) is added when being warming up to 100 DEG C, at 100 DEG C
Lower reaction 48h.Room temperature is cooled to after reaction completely, adds ethyl acetate-water extraction, organic phase is dried, after removing solvent under reduced pressure
Add ethyl acetate-normal heptane and obtain the second intermediate B 1, i.e.,：2- methyl-[4- (methyl sulphonyl) phenyl] acetone,
(124.8g, yield 75.6%, faint yellow solid).
The preparation of the 2- methyl of embodiment 8-[4- (methyl sulphonyl) phenyl] acetone
A kind of preparation method of second intermediate B 1 is present embodiments provided, it is reaction substrate with the first intermediate A 1,
The second intermediate B 1 is obtained, its specific preparation process is as follows：
By the first intermediate A 1 (227g, 1eq), methyl sulfinic acid sodium (102.1g, 1eq) and L-PROLINE (34.53g,
0.3eq) add in 681mL dimethyl sulfoxide (DMSO)s, cuprous iodide (57.1g, 0.3eq) is added when being warming up to 80 DEG C, at 80 DEG C
React 50h.Room temperature is cooled to after reacting completely, adds ethyl acetate-water extraction, organic phase is dried, and is added after removing solvent under reduced pressure
Enter normal heptane crystallization and obtain crude product, crude product is recrystallized to give the second pure intermediate B 1 with ethyl acetate-normal heptane, i.e.,：2- first
Base-[4- (methyl sulphonyl) phenyl] acetone, (166g, yield 73.1%, faint yellow solid).
The preparation of the 2- methyl of embodiment 9-[4- (methyl sulphonyl) phenyl] acetone
A kind of preparation method of second intermediate B 1 is present embodiments provided, it is reaction substrate with the first intermediate A 1,
The second intermediate B 1 is obtained, its specific preparation process is as follows：
By the first intermediate A 1 (110g, 1eq), methyl sulfinic acid sodium (99g, 2eq) and L-PROLINE (27.9g, 0.5eq)
Add in 110mL dimethyl sulfoxide (DMSO)s, cuprous iodide (46.1g, 0.5eq) is added when being warming up to 120 DEG C, is reacted at 120 DEG C
40h.Room temperature is cooled to after reaction completely, adds ethyl acetate-water extraction, organic phase is dried, added just after removing solvent under reduced pressure
Heptane crystallization obtains crude product, crude product with ethyl acetate-normal heptane be recrystallized to give it is pure arrive the second pure intermediate B 1, i.e.,：2-
Methyl-[4- (methyl sulphonyl) phenyl] acetone, (78.4g, yield 72.2%, faint yellow solid).
Embodiment 10~12 provides Fei Luokao former times intermediates C preparation method.
The 2- hydroxy-2-methyls of embodiment 10-[4- (methyl sulphonyl) phenyl]-1- acetone
A kind of Fei Luokao former times intermediate C preparation method is present embodiments provided, it is reaction bottom with the second intermediate B 1
Thing, the second intermediate C is obtained, its specific preparation process is as follows：
B1 (80g, 1eq) is dissolved in 400mL DMSO at room temperature, adds NBS (12.6g, 0.2eq).It is warming up to
100 DEG C of reaction 12h.Room temperature is cooled to after reaction completely, adds ethyl acetate and water extraction, organic phase is dried, removed under reduced pressure molten
Crystallized after agent with methyl tertiary butyl ether(MTBE)-normal heptane, obtain pure C, i.e.,：2- hydroxy-2-methyls-(4- methyl sulphonyls) phenyl-
1- acetone, (72.8g, yield 85%, faint yellow solid).
The characterization result for the Fei Luokao former times intermediates C that the present embodiment provides is as follows：
1HNMR (DMSO-d6) δ 1.62 (6H, s), 2.63 (1H, s), 3.09 (3H, s), 8.01-8.21 (4H, M)
The 2- hydroxy-2-methyls of embodiment 11-[4- (methyl sulphonyl) phenyl]-1- acetone
A kind of Fei Luokao former times intermediate C preparation method is present embodiments provided, it is reaction bottom with the second intermediate B 1
Thing, the second intermediate C is obtained, its specific preparation process is as follows：
B1 (80g, 1eq) is dissolved in 560mL DMSO at room temperature, adds NBS (31.1g, 0.5eq).It is warming up to 80
DEG C reaction 14h.Room temperature is cooled to after reaction completely, adds ethyl acetate and water extraction, organic phase is dried, after removing solvent under reduced pressure
Crystallized with methyl tertiary butyl ether(MTBE)-normal heptane, obtain pure C, i.e.,：2- hydroxy-2-methyls-[4- (methyl sulphonyl) phenyl] -1-
Acetone, (75g, yield 86%, faint yellow solid).
The 2- hydroxy-2-methyls of embodiment 12-[4- (methyl sulphonyl) phenyl]-1- acetone
A kind of Fei Luokao former times intermediate C preparation method is present embodiments provided, it is reaction bottom with the second intermediate B 1
Thing, the second intermediate C is obtained, its specific preparation process is as follows：
B1 (80g, 1eq) is dissolved in 240mL DMSO at room temperature, adds NBS (18.9g, 0.3eq).It is warming up to
120 DEG C of reaction 10h.Room temperature is cooled to after reaction completely, adds ethyl acetate and water extraction, organic phase is dried, removed under reduced pressure molten
Crystallized after agent with methyl tertiary butyl ether(MTBE)-normal heptane, obtain pure C, i.e.,：2- hydroxy-2-methyls-[4- (methyl sulphonyl) benzene
Base] -1- acetone, (71.2g, yield 82.8%, faint yellow solid).
The 2- methyl isophthalic acids of embodiment 13-[4- (methyl sulphonyl) phenyl]-2- (2- acetoxyl groups acetoxyl group)-1- acetone
Preparation present embodiments provide intermediate D preparation method：
Intermediate C 5.0g, triethylamine 4.2g, DMAP 0.5g are added in 50mL dichloromethane, stirring.It is cooled to 0 DEG C
4.2g acetoxy acetyl chlorides are added dropwise.After reaction completely plus water extracts, and dries, removes solvent under reduced pressure and obtain intermediate D, i.e.,：2- first
Base -1- [4- (methyl sulphonyl) phenyl] -2- (2- acetoxyl groups acetoxyl group) -1- acetone, (7.0g, yield 99.5%, yellow
Solid).
The preparation of the dimethyl -4- of 14 3- hydroxyls of embodiment -5,5 [4- (methyl sulphonyl) phenyl] -2 (5H)-furanones
Present embodiments provide the preparation method of intermediate E：
Intermediate D 7.0g are dissolved in 50mL acetonitriles, add DBU 6.2g back flow reactions 12h.Cooled down after reaction completely
To room temperature, it is spin-dried for, adds methylene chloride and extracted with water, dries.Remove solvent under reduced pressure, residue adds ethyl acetate stirring, separated out
Solid, intermediate E is obtained with re-crystallizing in ethyl acetate again after filtering, i.e.,：Dimethyl -4- [4- (the sulfonyloxy methyls of 3- hydroxyls -5,5
Base) phenyl] -2 (5H)-furanones.(4.0g, yield 70%, faint yellow solid).
Embodiment 15
Present embodiments provide the preparation method of Fei Luokao former times：
Intermediate E 7.0g is added in 400ml toluene, stirring and dissolving, add the sodium hydroxide water that 2.4g concentration is 50%
Solution, 2.6ml Cyclopropylmetyl bromides and 0.92g TBABs, it is heated to 70 DEG C of reaction 10-18 hours, filtering, by filtrate
Liquid separation is stood, organic phase is separated, anhydrous sodium sulfate drying, is concentrated to dryness, get Fei Luokao former times, yield 54%.
The characterization result for the Fei Luokao former times that the present embodiment provides is as follows：
The characterization result of Fei Luokao former times：1HNMR(CD3COCD3) δ 0.30 (2H, m), 0.55 (2H, m), 1.15 (1H, m),
1.60 (6H, s), 3.32 (3H, s), 4.20 (2H, d), 8.00 (4H, s)
Described, the synthetic method of Fei Luokao former times intermediate provided in an embodiment of the present invention on end, using to brom-acetophenone for
Beginning raw material, the disagreeableness thioether of use environment is avoided as initiation material, and methylation reaction is carried out at room temperature, reacts bar
Part is gentle.Also, the first intermediate directly obtains the second intermediate through inferior sulfonation reaction, dimethyl sulfoxide (DMSO), cuprous iodide and
The selection of methyl sulfinic acid sodium, vulcanization reaction and oxidation reaction are shorten to a step substitution reaction, greatly simplifie reaction step
Suddenly, the reaction time is shortened, improves reaction efficiency.Meanwhile the embodiment of the present invention also uses NBS/DMSO systems, makes in second
Mesosome hydroxylating directly obtains Fei Luokao former times intermediates, compared with the method one of prior art, avoids using four chlorinations
Carbon is this to endanger reagent to caused by environment and human body, and is not required to carry out column chromatography, be adapted to large-scale production；With existing skill
The method two of art is compared, and method two has been used to the extremely disagreeableness bromine of environment, and is two-step reaction, and present invention, avoiding make
With bromine, and it is single step reaction.In addition, reaction reagent is common agents, human body and environment are had no significant hazard, and held
Easily obtain, can be directly from directly buying on the market, collocation use can obtain the Fei Luokao former times intermediates of high yield.
In addition, the synthetic method of Fei Luokao former times provided in an embodiment of the present invention, it includes above-mentioned Fei Luokao former times intermediate
Synthetic method, its can by reaction condition milder, it is more environment-friendly in a manner of synthesize Fei Luokao former times, be advantageous to lifted Fei Luokao former times
Preparation efficiency and yield, be more suitable for industrialization large-scale production.
The preferred embodiments of the present invention are the foregoing is only, are not intended to limit the invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.Within the spirit and principles of the invention, that is made any repaiies
Change, equivalent substitution, improvement etc., should be included in the scope of the protection.
Claims (10)
1. a kind of synthetic method of Fei Luokao former times intermediate, it is characterised in that it includes：
, as initiation material, first is obtained to brom-acetophenone and methylating reagent progress methylation reaction by described to brom-acetophenone
Intermediate；First intermediate is carried out into inferior sulfonation reaction with methyl sulfinic acid sodium under cuprous iodide catalysis to obtain in second
Mesosome；Second intermediate and N-bromosuccinimide are subjected to hydroxylating and obtain the Fei Luokao former times intermediate；
The structural formula of first intermediate isThe structural formula of second intermediate isNon- sieve
The structural formula for examining former times intermediate is
2. the synthetic method of Fei Luokao former times intermediate according to claim 1, it is characterised in that the methylating reagent choosing
One kind from halide, dimethyl suflfate or methyl tosylate, it is preferable that the methylating reagent is halo first
Alkane, it is highly preferred that the halide is iodomethane.
3. the synthetic method of Fei Luokao former times intermediate according to claim 1, it is characterised in that the methylation reaction bag
Include：Brom-acetophenone is dissolved in the first solvent by described, adds highly basic and the methylating reagent, extraction point after reacting completely
Liquid, drying, evaporation obtain first intermediate；
Preferably, the one kind of first solvent in dimethylformamide, dimethyl sulfoxide (DMSO) or the tert-butyl alcohol, the highly basic choosing
One or more from sodium hydroxide, lithium hydroxide, potassium hydroxide and potassium tert-butoxide.
4. the synthetic method of Fei Luokao former times intermediate according to claim 1, it is characterised in that the inferior sulfonation reaction bag
Include：First intermediate, the methyl sulfinic acid sodium, L-PROLINE are added in the second solvent, when being warming up to 80~120 DEG C
The cuprous iodide is added, 40~50h is reacted, is cooled to room temperature, is extracted, dries, normal heptane is added after removing solvent under reduced pressure
Crystallization, obtain second intermediate；Wherein, second solvent is dimethyl sulfoxide (DMSO).
5. the synthetic method of Fei Luokao former times intermediate according to claim 1, it is characterised in that the inferior sulfonation reaction bag
Include：First intermediate, the methyl sulfinic acid sodium, L-PROLINE are added in dimethyl sulfoxide (DMSO), when being warming up to 100 DEG C again
The cuprous iodide is added, 48h is reacted, is cooled to room temperature, is extracted, is dried, normal heptane crystallization is added after removing solvent under reduced pressure, obtains
To second intermediate.
6. the synthetic method of the Fei Luokao former times intermediates according to claim 4 or 5, it is characterised in that after crystallization, obtain
Recrystallized to before second intermediate, in addition to by the product after crystallization with ethyl acetate-normal heptane.
7. the synthetic method of Fei Luokao former times intermediate according to claim 1, it is characterised in that the hydroxylating bag
Include：Second intermediate is dissolved in the 3rd solvent, adds the N-bromosuccinimide, is warming up to 80~120 DEG C
10~14h is reacted, room temperature is cooled to, extraction, dries, removes addition methyl tertiary butyl ether(MTBE)-normal heptane crystallization after solvent under reduced pressure, obtaining
To the Fei Luokao former times intermediate, wherein, the 3rd solvent is dimethyl sulfoxide (DMSO).
8. the synthetic method of Fei Luokao former times intermediate according to claim 1, it is characterised in that the hydroxylating bag
Include：Second intermediate is dissolved in dimethyl sulfoxide (DMSO), adds the N-bromosuccinimide, is warming up to 100 DEG C instead
12h is answered, room temperature is cooled to, extraction, dries, removes addition methyl tertiary butyl ether(MTBE)-normal heptane crystallization after solvent under reduced pressure, obtaining described
Fei Luokao former times intermediates.
9. a kind of synthetic method of Fei Luokao former times, it is characterised in that it includes non-sieve as described in any one of claim 1~8
Examine the synthetic method of former times intermediate.
10. the synthetic method of Fei Luokao former times according to claim 9, it is characterised in that comprise the steps of：
The Fei Luokao former times intermediate prepared by the synthetic method of the Fei Luokao former times intermediate and acetoxyl group acetyl will be passed through
Chlorine reaction prepares 2- methyl isophthalic acids-[4- (methyl sulphonyl) phenyl] -2- (2- acetoxyl groups acetoxyl group) -1- acetone, and it reacts
Formula is as follows；
By the 2- methyl isophthalic acids-[4- (methyl sulphonyl) phenyl] -2- (2- acetoxyl groups acetoxyl group) -1- acetone through DBU at
Cyclization generation 3- hydroxyl -5,5 dimethyl -4- [4- (methyl sulphonyl) phenyl] -2 (5H)-furanones are managed, its reaction equation is as follows；
By the dimethyl -4- of 3- hydroxyls -5,5 [4- (methyl sulphonyl) phenyl] -2 (5H)-furanones and Cyclopropylmetyl bromide
Reaction generation Fei Luokao former times, its reaction equation are as follows；
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108586399A (en) * | 2018-07-03 | 2018-09-28 | 四川青木制药有限公司 | A kind of synthetic method of Fei Luokao former times |
| CN109053505A (en) * | 2018-08-03 | 2018-12-21 | 四川青木制药有限公司 | A kind of synthetic method of Fei Luokao former times important intermediate |
| CN109134318A (en) * | 2018-08-24 | 2019-01-04 | 江苏美迪克化学品有限公司 | A kind of preparation method of 4- mesyl acetophenone and the bromo- 4- mesyl acetophenone of α- |
| WO2019062561A1 (en) * | 2017-09-28 | 2019-04-04 | Sichuan Qingmu Pharmaceutical Co., Ltd. | Synthesis methods of firocoxib and intermediate thereof |
| CN110407742A (en) * | 2019-07-03 | 2019-11-05 | 常州大学 | A kind of method for preparing 3-bromo-4-methanesulfonylpyridine |
| CN112500321A (en) * | 2020-09-25 | 2021-03-16 | 安徽省公众检验研究院有限公司 | Preparation method of feloxicib key intermediate |
| CN112624943A (en) * | 2020-12-28 | 2021-04-09 | 成都伊诺达博医药科技有限公司 | Synthesis method of feloxicib intermediate |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110452198B (en) * | 2019-09-03 | 2021-03-26 | 山东鲁抗舍里乐药业有限公司 | Preparation method of feloxicib |
| CN110452199B (en) * | 2019-09-03 | 2021-03-30 | 山东鲁抗舍里乐药业有限公司 | Preparation method of feloxicib |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1651408A (en) * | 2004-11-26 | 2005-08-10 | 中国科学院上海有机化学研究所 | Amino Acid-Promoted CuI-Catalyzed Coupling Reaction of Aryl Halides and Hydrocarbyl Sulfinates |
| CN104803956A (en) * | 2015-03-06 | 2015-07-29 | 江苏天和制药有限公司 | Synthesis method of firocoxib |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107345140B (en) * | 2016-05-06 | 2021-01-15 | 北京八亿时空液晶科技股份有限公司 | Liquid crystal compound with isobutyl negative dielectric anisotropy and application thereof |
| CN107686471B (en) * | 2017-09-28 | 2020-07-03 | 成都苑东生物制药股份有限公司 | Synthesis method of feloxicib and intermediate thereof |
| CN107778204B (en) * | 2017-10-26 | 2020-04-03 | 扬州天和药业有限公司 | Preparation method of feloxicib intermediate |
-
2017
- 2017-09-28 CN CN201710902982.7A patent/CN107686471B/en active Active
-
2018
- 2018-09-14 CN CN201880054063.1A patent/CN111201212B/en active Active
- 2018-09-14 WO PCT/CN2018/105661 patent/WO2019062561A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1651408A (en) * | 2004-11-26 | 2005-08-10 | 中国科学院上海有机化学研究所 | Amino Acid-Promoted CuI-Catalyzed Coupling Reaction of Aryl Halides and Hydrocarbyl Sulfinates |
| CN104803956A (en) * | 2015-03-06 | 2015-07-29 | 江苏天和制药有限公司 | Synthesis method of firocoxib |
Non-Patent Citations (3)
| Title |
|---|
| JAMES E. GANO 等: "Synthesis of Twist-Twist π-Conjugated Di-sec-alkylstilbenes and Stilbene Polymers", 《J. ORG. CHEM.》 * |
| XU QUAN 等: "C-C Coupling of Ketones with Methanol Catalyzed by a N-Heterocyclic Carbene–Phosphine Iridium Complex", 《CHEM. EUR. J.》 * |
| YU-FENG LIANG 等: "I2- or NBS-Catalyzed Highly Efficient α-Hydroxylation of Ketones with Dimethyl Sulfoxide", 《ORG. LETT.》 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019062561A1 (en) * | 2017-09-28 | 2019-04-04 | Sichuan Qingmu Pharmaceutical Co., Ltd. | Synthesis methods of firocoxib and intermediate thereof |
| CN111201212A (en) * | 2017-09-28 | 2020-05-26 | 四川青木制药有限公司 | Synthesis method of feloxicib and intermediate thereof |
| CN111201212B (en) * | 2017-09-28 | 2022-07-26 | 四川青木制药有限公司 | Synthesis method of feloxicib and intermediate thereof |
| CN108586399A (en) * | 2018-07-03 | 2018-09-28 | 四川青木制药有限公司 | A kind of synthetic method of Fei Luokao former times |
| CN109053505A (en) * | 2018-08-03 | 2018-12-21 | 四川青木制药有限公司 | A kind of synthetic method of Fei Luokao former times important intermediate |
| CN109053505B (en) * | 2018-08-03 | 2020-08-11 | 四川青木制药有限公司 | Synthesis method of important intermediate of feloxicib |
| CN109134318A (en) * | 2018-08-24 | 2019-01-04 | 江苏美迪克化学品有限公司 | A kind of preparation method of 4- mesyl acetophenone and the bromo- 4- mesyl acetophenone of α- |
| CN110407742A (en) * | 2019-07-03 | 2019-11-05 | 常州大学 | A kind of method for preparing 3-bromo-4-methanesulfonylpyridine |
| CN110407742B (en) * | 2019-07-03 | 2022-06-28 | 常州大学 | A kind of method for preparing 3-bromo-4-methanesulfonylpyridine |
| CN112500321A (en) * | 2020-09-25 | 2021-03-16 | 安徽省公众检验研究院有限公司 | Preparation method of feloxicib key intermediate |
| CN112624943A (en) * | 2020-12-28 | 2021-04-09 | 成都伊诺达博医药科技有限公司 | Synthesis method of feloxicib intermediate |
| CN112624943B (en) * | 2020-12-28 | 2022-07-01 | 成都伊诺达博医药科技有限公司 | Synthesis method of feloxicib intermediate |
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