CN107686471B - Synthesis method of feloxicib and intermediate thereof - Google Patents
Synthesis method of feloxicib and intermediate thereof Download PDFInfo
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- CN107686471B CN107686471B CN201710902982.7A CN201710902982A CN107686471B CN 107686471 B CN107686471 B CN 107686471B CN 201710902982 A CN201710902982 A CN 201710902982A CN 107686471 B CN107686471 B CN 107686471B
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- bromophenylketone
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- 238000001308 synthesis method Methods 0.000 title abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- 238000000034 method Methods 0.000 claims abstract description 59
- LFABNOYDEODDFX-UHFFFAOYSA-N bis(4-bromophenyl)methanone Chemical compound C1=CC(Br)=CC=C1C(=O)C1=CC=C(Br)C=C1 LFABNOYDEODDFX-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000007069 methylation reaction Methods 0.000 claims abstract description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 19
- 238000005805 hydroxylation reaction Methods 0.000 claims abstract description 12
- 230000011987 methylation Effects 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000006351 sulfination reaction Methods 0.000 claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims description 53
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 45
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 31
- 238000001035 drying Methods 0.000 claims description 26
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
- 238000001704 evaporation Methods 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 18
- -1 methyl tert-butyl Chemical group 0.000 claims description 18
- 230000002194 synthesizing effect Effects 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 16
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 16
- LYPGDCWPTHTUDO-UHFFFAOYSA-M sodium;methanesulfinate Chemical compound [Na+].CS([O-])=O LYPGDCWPTHTUDO-UHFFFAOYSA-M 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000012022 methylating agents Substances 0.000 claims description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 11
- 229930182821 L-proline Natural products 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 229960002429 proline Drugs 0.000 claims description 11
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 claims description 9
- WIPWTSYHKQQKJC-UHFFFAOYSA-N 3-hydroxy-5,5-dimethyl-4-(4-methylsulfonylphenyl)furan-2-one Chemical compound CC1(C)OC(=O)C(O)=C1C1=CC=C(S(C)(=O)=O)C=C1 WIPWTSYHKQQKJC-UHFFFAOYSA-N 0.000 claims description 8
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 claims description 6
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000008020 evaporation Effects 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
- 230000008569 process Effects 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- WKSVNJXBAJROBQ-UHFFFAOYSA-N CC(=O)OCC(=O)OCC(=O)OCC(=O)OCC(=O)OC(C)(C)C(=O)C1=CC=C(C=C1)S(=O)(=O)C Chemical compound CC(=O)OCC(=O)OCC(=O)OCC(=O)OCC(=O)OC(C)(C)C(=O)C1=CC=C(C=C1)S(=O)(=O)C WKSVNJXBAJROBQ-UHFFFAOYSA-N 0.000 claims description 2
- 230000001035 methylating effect Effects 0.000 claims description 2
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 claims 2
- 229960003580 felodipine Drugs 0.000 claims 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 7
- 150000003568 thioethers Chemical class 0.000 abstract description 6
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- JCVYQVHAGOZGIX-UHFFFAOYSA-N bis(2-bromophenyl)methanone Chemical compound BrC1=CC=CC=C1C(=O)C1=CC=CC=C1Br JCVYQVHAGOZGIX-UHFFFAOYSA-N 0.000 abstract 1
- 238000005987 sulfurization reaction Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 116
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 238000002360 preparation method Methods 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 16
- 238000000605 extraction Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 229940126062 Compound A Drugs 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 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 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 5
- 230000001590 oxidative effect Effects 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
- HDXKXAAGIHTZJJ-UHFFFAOYSA-N 3-(4-methylsulfonylphenyl)butan-2-one Chemical compound CC(=O)C(C)C1=CC=C(S(C)(=O)=O)C=C1 HDXKXAAGIHTZJJ-UHFFFAOYSA-N 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
- 230000036632 reaction speed Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- YEMWINDXAKRPBK-UHFFFAOYSA-N heptane;2-methoxy-2-methylpropane Chemical compound COC(C)(C)C.CCCCCCC YEMWINDXAKRPBK-UHFFFAOYSA-N 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 238000007039 two-step reaction Methods 0.000 description 3
- PMFLKZHWZXWOEH-UHFFFAOYSA-N 1-(4-bromophenyl)-2-methylpropan-1-one Chemical compound CC(C)C(=O)C1=CC=C(Br)C=C1 PMFLKZHWZXWOEH-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- UXGJQQXURDIXEB-UHFFFAOYSA-N 2-hydroxy-2-methyl-1-(4-methylsulfonylphenyl)propan-1-one Chemical compound CC(C)(O)C(=O)C1=CC=C(S(C)(=O)=O)C=C1 UXGJQQXURDIXEB-UHFFFAOYSA-N 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
- 238000001914 filtration Methods 0.000 description 2
- 230000000640 hydroxylating effect Effects 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- USSBDBZGEDUBHE-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate Chemical compound [Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O USSBDBZGEDUBHE-UHFFFAOYSA-L 0.000 description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000004073 vulcanization Methods 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- VDIBNQONSVFIBN-UHFFFAOYSA-N CC(=O)OCC(=O)OCC(=O)OCC(=O)OC(C)(C)C(=O)C1=CC=C(C=C1)S(=O)(=O)C Chemical compound CC(=O)OCC(=O)OCC(=O)OCC(=O)OC(C)(C)C(=O)C1=CC=C(C=C1)S(=O)(=O)C VDIBNQONSVFIBN-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 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
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of drug synthesis, and provides a synthesis method of feloxicib and an intermediate thereof. The synthesis method of the felicoxib intermediate takes the p-bromophenylketone as an initial raw material, avoids using thioether which is not environment-friendly as the initial raw material, and performs methylation reaction on the bromophenylketone and a methylation reagent to obtain a first intermediate; the first intermediate is directly subjected to sulfination reaction to obtain a second intermediate, and the sulfuration reaction and the oxidation reaction are shortened to one-step substitution reaction, so that the reaction steps are greatly simplified, the reaction time is shortened, and the reaction efficiency is improved. Meanwhile, the invention also adopts an NBS system, so that the second intermediate is subjected to hydroxylation reaction to directly obtain the feloxicib intermediate, the environment is more friendly, the method is suitable for large-scale production, and the reaction rate is improved. In addition, the synthesis method of the felicoxib comprises the synthesis method of the felicoxib intermediate, and the felicoxib can be synthesized in a milder and more environment-friendly mode under reaction conditions.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a synthesis method of felicoxib and an intermediate thereof.
Background
Fenocoxib, i.e. 3- (cyclopropylmethoxy) -5, 5-dimethyl-4- [4- (methylxanthoyl) phenyl]-2(5H) -furanone of formula: c17H20O5S。
The floricoxib is an important nonsteroidal anti-inflammatory drug, and currently, few reports about the synthesis of the floricoxib exist, and the two methods are mainly as follows:
the first method is a synthetic route of the felicoxib reported in patent documents US5981576, US006020343A and WO971645A 1. The method comprises the following steps of taking the thiobenzol as a starting material, reacting with isobutyryl chloride to generate a compound A, hydroxylating the compound A to generate a compound B, oxidizing the compound B by an oxidant such as (MMPP monoperoxyphthalate magnesium) to generate a compound C, reacting the compound C with acetoxyacetyl chloride to generate a compound D, treating the compound D with DBU to close a ring to generate a compound E, and reacting the compound E with cyclopropylmethyl bromide to generate the felocoxib. The reaction formula is as follows:
the second method is a synthetic route of feloxicib reported in patent document CN 104803956A. The method comprises the following steps of taking the thiobenzol as an initial raw material, reacting with isobutyryl chloride to generate a compound A, treating the compound A with liquid bromine to obtain a brominated product, hydroxylating the brominated product to generate a compound B, oxidizing the compound B with an oxidant such as an oxidant to generate a compound C, reacting the compound C with acetoxyacetyl chloride to generate a compound D, treating the compound D with DBU to close a ring to generate a compound E, and reacting the compound E with cyclopropylmethyl bromide to generate the felocoxib. The reaction formula is shown as formula II:
the above two methods for synthesizing feloxicib have the following disadvantages:
disadvantage 1: the starting material adopts the thiobenzol sulfide, and the thioethers generally have unpleasant odor and are easy to burn and explode when meeting open fire and high heat, so that the substances can cause pollution to the environment, and have great environmental protection pressure in European and American production.
And (2) disadvantage: the two methods for preparing the compound B are provided, and the compound B is prepared by adding a phase transfer catalyst Aliquat336 (trioctylmethylammonium chloride) into a sodium hydroxide solution and carbon tetrachloride two-phase system for reaction. This process requires the use of carbon tetrachloride, a first class of solvents known to be carcinogenic and strongly suspected of being harmful to humans and the environment. Where possible, the use of such solvents should be avoided. Meanwhile, in the post-treatment process, the method needs a silica gel chromatographic column to obtain a relatively pure compound B, and is not suitable for large-scale industrial production; in the second method, liquid bromine is adopted to bromize the compound A, and then hydroxylation reaction is carried out on the compound A by using a sodium hydroxide solution under the action of a phase transfer catalyst to prepare a compound B.
Disclosure of Invention
The invention aims to provide a synthesis method of a felicoxib intermediate, which selects different starting materials and adopts milder conditions for reaction, thereby avoiding taking thioether which is not friendly to the environment as the starting material and being suitable for large-scale production.
The embodiment of the invention is realized by the following steps:
a method of synthesizing a feloxib intermediate comprising:
taking p-bromophenylketone as an initial raw material, and carrying out methylation reaction on the p-bromophenylketone and a methylation reagent to obtain a first intermediate;
carrying out sulfinylation reaction on the first intermediate and sodium methanesulfinate under the catalysis of cuprous iodide to obtain a second intermediate;
carrying out hydroxylation reaction on the second intermediate and N-bromosuccinimide to obtain a feloxicib intermediate;
the first intermediate has a structural formula of
The second intermediate has the structural formula
The structural formula of the feloxicib intermediate is shown as
Further, in a preferred embodiment of the present invention, the methylating agent is selected from one of methyl halide, dimethyl sulfate or methyl p-toluenesulfonate, preferably, the methylating agent is methyl halide, and more preferably, the methyl halide is methyl iodide.
Further, in a preferred embodiment of the present invention, the methylation reaction comprises: dissolving p-bromophenylketone in a first solvent, adding a strong base and a methylating reagent, and after complete reaction, extracting, separating, drying and evaporating to obtain a first intermediate;
preferably, the first solvent is selected from one of dimethylformamide, dimethyl sulfoxide or tert-butyl alcohol, and the strong base is selected from one or more of sodium hydroxide, lithium hydroxide, potassium hydroxide and potassium tert-butoxide.
Further, in a preferred embodiment of the present invention, the sulfination reaction comprises: adding the first intermediate, sodium methanesulfinate and L-proline into a second solvent, heating to 80-120 ℃, adding cuprous iodide, reacting for 40-50 h, cooling to room temperature, extracting, drying, removing the solvent by reduced pressure evaporation, and adding n-heptane for crystallization to obtain a second intermediate; wherein the second solvent is dimethyl sulfoxide.
Further, in a preferred embodiment of the present invention, the sulfination reaction comprises: adding the first intermediate, sodium methanesulfinate and L-proline into dimethyl sulfoxide, heating to 100 ℃, adding cuprous iodide, reacting for 48 hours, cooling to room temperature, extracting, drying, evaporating under reduced pressure to remove the solvent, and adding n-heptane for crystallization to obtain a second intermediate.
Further, in a preferred embodiment of the present invention, after the above crystallization and before the second intermediate is obtained, the crystallization is further performed by recrystallizing the crystallized product with ethyl acetate-n-heptane.
Further, in a preferred embodiment of the present invention, the hydroxylation reaction includes: and dissolving the second intermediate in a third solvent, adding N-bromosuccinimide, heating to 80-120 ℃, reacting for 10-14 h, cooling to room temperature, extracting, drying, evaporating under reduced pressure to remove the solvent, and adding methyl tert-butyl ether-N-heptane for crystallization to obtain the felicoxib intermediate, wherein the third solvent is dimethyl sulfoxide.
Further, in a preferred embodiment of the present invention, the hydroxylation reaction includes: and dissolving the second intermediate in dimethyl sulfoxide, adding N-bromosuccinimide, heating to 100 ℃ for reaction for 12 hours, cooling to room temperature, extracting, drying, evaporating under reduced pressure to remove the solvent, and adding methyl tert-butyl ether-N-heptane for crystallization to obtain the feloxicib intermediate.
Another object of the present invention is to provide a method for synthesizing felicoxib, which comprises the above method for synthesizing felicoxib intermediate, and which can synthesize felicoxib in a milder and more environmentally friendly manner.
A method for synthesizing feloxicib, which comprises a method for synthesizing the feloxicib intermediate.
Further, in a preferred embodiment of the present invention, the following steps are included:
reacting the feloxicib intermediate prepared by the synthesis method of the feloxicib intermediate with acetoxyacetyl chloride to prepare 2-methyl-1- [4- (methylsulfonyl) phenyl ] -2- (2-acetoxy) -1-propanone, wherein the reaction formula is as follows;
treating 2-methyl-1- [4- (methylsulfonyl) phenyl ] -2- (2-acetoxy) -1-acetone with DBU to form 3-hydroxy-5, 5 dimethyl-4- [4- (methylsulfonyl) phenyl ] -2(5H) -furanone with the reaction formula;
reacting 3-hydroxy-5, 5 dimethyl-4- [4- (methylsulfonyl) phenyl ] -2(5H) -furanone with cyclopropylmethyl bromide to yield feloxicib, which has the formula;
the intermediate of the felicoxib prepared by the embodiment of the invention and the preparation of the felicoxib by using the intermediate have the following advantages:
(1) the synthesis method of the felicoxib intermediate provided by the embodiment of the invention takes the p-bromophenyl ketone as the starting material, avoids using thioether which is not friendly to the environment as the starting material, and has the advantages of room temperature methylation and mild reaction conditions. And the first intermediate directly obtains a second intermediate through sulfination reaction, and the selection of cuprous iodide and sodium methanesulfinate shortens the vulcanization reaction and the oxidation reaction into one-step substitution reaction, greatly simplifies the reaction steps, shortens the reaction time and improves the reaction efficiency.
(2) The embodiment of the invention also adopts an NBS system, so that the hydroxylation reaction of the second intermediate directly obtains the felicoxib intermediate, compared with the method I in the prior art, the method avoids using carbon tetrachloride which is a harmful reagent, does not need column chromatography, and is suitable for large-scale production; compared with the second method in the prior art, the method avoids using liquid bromine, reduces the two-step reaction into one-step reaction, and greatly improves the reaction speed. In addition, the reaction reagents are common reagents, can be directly purchased, and are more environment-friendly.
(3) The felicoxib synthesized by the synthesis method is synthesized in a mode of milder reaction conditions and more environment-friendly, so that the preparation efficiency and yield of the felicoxib are improved, and the method is more suitable for industrial large-scale production.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The following describes a method for synthesizing feloxib and intermediates thereof according to embodiments of the present invention.
In the examples room temperature means ambient temperatures of 10 to 25 ℃.
A synthetic method of a feloxicib intermediate with a structure shown as a compound C is disclosed, and the reaction formula is shown as a formula III:
specifically, the synthesis method of the feloxib intermediate comprises the following steps:
s1: p-bromophenylketone is taken as an initial raw material, and methylation reaction is carried out on the p-bromophenylketone and a methylation reagent to obtain a first intermediate A1.
Specifically, p-bromophenylketone is dissolved in a first solvent, strong base and a methylating agent are added, ethyl acetate and water are added for extraction and liquid separation after complete reaction, organic phase anhydrous sodium sulfate is dried, and the solvent is evaporated under reduced pressure to obtain a first intermediate A1.
The p-bromophenylketone is used as an initial raw material, the first intermediate A1 is generated through methylation, the methylation is carried out at room temperature, the reaction condition is mild, and the use of thioether which is not friendly to the environment is avoided as the initial raw material. When adding the strong base and the methylating agent, firstly adding the strong base, stirring until the solid is dissolved, then dropwise adding the methylating agent, and stirring at room temperature overnight. The methylating agent is slowly added in a dropwise manner, and the dropwise adding speed is not too fast so as to prevent the reaction from being too violent and causing the material flushing.
Wherein, the first solvent is one of dimethylformamide, dimethyl sulfoxide and tertiary butanol; the strong base is selected from one or more of sodium hydroxide, lithium hydroxide, potassium hydroxide and potassium tert-butoxide; the methylating agent is selected from one of methyl halide, dimethyl sulfate or methyl p-toluenesulfonate. The methylating agent is such that the hydrogen of the p-bromophenylketone is replaced by a methyl group, preferably the methylating agent is a methyl halide, particularly preferably methyl iodide. These reagents are common reagents in chemical reactions, are directly purchased and can be matched to obtain methylated products with high yield.
The molar ratio of the p-bromophenylketone to the strong base to the methylating agent is 1: 1-4: 1-2, the dosage ratio of the p-bromophenylketone to the first solvent is 1g/2 mL-1 g/10mL, the molar ratio and the dosage ratio are optimal values obtained by creative work of an inventor in combination with self experience, methylation reaction is carried out within the optimal value range, the reaction speed is higher, the yield is higher, and side reactions are less. More preferably, the molar ratio of the p-bromophenylketone to the strong base to the methylating agent is 1: 1.5-4: 1.5-2; the dosage ratio of the p-bromophenylketone to the first solvent is 1g/4 mL-1 g/8mL, and particularly, the dosage ratio of the p-bromophenylketone to the first solvent is 1g/4 mL.
S2: and (3) carrying out sulfinylation reaction on the first intermediate A1 and sodium methanesulfinate under the catalysis of cuprous iodide to obtain a second intermediate B1.
Specifically, adding the first intermediate A1, sodium methanesulfinate and L-proline into a second solvent, heating to 80-120 ℃, adding cuprous iodide, reacting at 80-120 ℃ for 40-50 h, cooling to room temperature after the reaction is completed, adding ethyl acetate-water for extraction, drying organic phase anhydrous sodium sulfate, evaporating under reduced pressure to remove the solvent, and adding n-heptane for crystallization to obtain a second intermediate B1, wherein the second solvent is dimethyl sulfoxide in the embodiment.
Further, after crystallization and before obtaining the second intermediate B1, the method further comprises recrystallizing the crystallized product with ethyl acetate-n-heptane, dissolving the crystallized product in ethyl acetate-n-heptane, and recrystallizing from ethyl acetate-n-heptane again, wherein recrystallization can purify the crystallized crude product, thereby obtaining the pure second intermediate B1.
The molar ratio of the first intermediate A1 to the sodium methanesulfinate to the L-proline to the cuprous iodide is 1: 1-2: 0.2-0.5, preferably 1:1.5:0.2: 0.2; the dosage ratio of the first intermediate A1 to the second solvent is 1g/1 mL-1 g/5mL, preferably, the dosage ratio is 1g/1 mL-1 g/3 mL; the optimal dosage ratio is 1g/2 mL. The molar ratio and the dosage ratio are the optimal values obtained by the inventor through creative work and combined with own experience, and the sulfination reaction is carried out within the optimal value range, so that the reaction speed is higher, the yield is higher, and the side reaction is less.
S3: and carrying out hydroxylation reaction on the second intermediate B1 and N-bromosuccinimide to obtain a filocoxib intermediate C.
Specifically, dissolving the second intermediate B1 in a third solvent, adding N-bromosuccinimide (NBS), heating to 80-120 ℃ for reaction for 10-14 h, cooling to room temperature after the reaction is completed, adding ethyl acetate and water for extraction, drying with organic phase anhydrous sodium sulfate, evaporating under reduced pressure to remove the solvent, and adding methyl tert-butyl ether-N-heptane for crystallization to obtain the felicoxib intermediate C, wherein the third solvent is also dimethyl sulfoxide (DMSO).
The embodiment of the invention adopts an NBS/DMSO system, so that the hydroxylation reaction of the second intermediate B1 directly obtains the felicoxib intermediate C, compared with the method I in the prior art, the method avoids using a reagent which is carbon tetrachloride and can cause harm to the environment and human bodies, does not need column chromatography, and is suitable for large-scale production; compared with the second method in the prior art, the second method uses liquid bromine which is not friendly to the environment, and the two-step reaction is adopted.
The molar ratio of the second intermediate B1 to the N-bromosuccinimide is 1: 0.2-0.5, preferably 1: 0.2; the dosage ratio of the second intermediate B1 to the third solvent is 1g/2 mL-1 g/10mL, preferably, the dosage ratio is 1g/3 mL-1 g/7 mL; more preferably in an amount of 1g/5 mL. The molar ratio and the dosage ratio are the optimal values obtained by the inventor through creative work and combined with own experience, and the sulfination reaction is carried out within the optimal value range, so that the reaction speed is higher, the yield is higher, and the side reaction is less.
A method for synthesizing feloxicib, which comprises a method for synthesizing the feloxicib intermediate.
Further, in a preferred embodiment of the present invention, the method for synthesizing feloxib comprises the following steps:
reacting the feloxicib intermediate prepared by the synthesis method of the feloxicib intermediate with acetoxyacetyl chloride to prepare 2-methyl-1- [4- (methylsulfonyl) phenyl ] -2- (2-acetoxy) -1-propanone, wherein the reaction formula is as follows;
treating 2-methyl-1- [4- (methylsulfonyl) phenyl ] -2- (2-acetoxy) -1-acetone with DBU to form 3-hydroxy-5, 5 dimethyl-4- [4- (methylsulfonyl) phenyl ] -2(5H) -furanone with the reaction formula;
reacting 3-hydroxy-5, 5 dimethyl-4- [4- (methylsulfonyl) phenyl ] -2(5H) -furanone with cyclopropylmethyl bromide to yield feloxicib, which has the formula;
the features and properties of the present invention are described in further detail below with reference to examples.
Examples 1-5 provide methods for preparing first intermediate a 1.
EXAMPLE 11 preparation of- (4-bromophenyl) -2-methylpropanone
The embodiment provides a preparation method of a first intermediate a1, which uses p-bromophenylketone as a starting material, and performs a methylation reaction on the p-bromophenylketone and a methylation reagent to obtain a first intermediate a1, and the preparation method specifically comprises the following steps:
p-bromophenylketone (100g, 1eq) was dissolved in 400mL of dimethylformamide at room temperature, and sodium hydroxide (56.3g, 3eq) and iodomethane (133.3g, 2eq) were added thereto, followed by stirring at room temperature overnight. After the reaction is completed, adding 500mL of ethyl acetate and 500mL of water, extracting and separating liquid, drying the organic phase by anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain a first intermediate A1, namely: 1- (4-bromophenyl) -2-methylpropanone, (110g, light yellow liquid).
Example 21 preparation of- (4-bromophenyl) -2-methylpropanone
The embodiment provides a preparation method of a first intermediate a1, which uses p-bromophenylketone as a starting material, and performs a methylation reaction on the p-bromophenylketone and a methylation reagent to obtain a first intermediate a1, and the preparation method specifically comprises the following steps:
p-bromophenylketone (5.0g, 1eq) was dissolved in 20mL of DMSO at room temperature, and lithium hydroxide (2.0g, 3.7eq) was added. After stirring until the solid dissolved, methyl iodide (5.0g, 1.5eq) was added dropwise and stirred at room temperature overnight. After the reaction is completed, adding 30mL of ethyl acetate and 30mL of water, extracting and separating liquid, drying the organic phase by anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain an intermediate A1, namely: 1- (4-bromophenyl) -2-methylpropanone, (5.8g, light yellow liquid).
Example 31 preparation of (4-bromophenyl) -2-methylpropanone
The embodiment provides a preparation method of a first intermediate a1, which uses p-bromophenylketone as a starting material, and performs a methylation reaction on the p-bromophenylketone and a methylation reagent to obtain a first intermediate a1, and the preparation method specifically comprises the following steps:
p-bromophenylketone (5.0g, 1eq) was dissolved in 20mL of t-butanol at room temperature, potassium t-butoxide (3.9g, 1.5eq) was added, methyl iodide (5.0g, 1.5eq) was added dropwise, and the mixture was stirred at room temperature overnight. After the reaction is completed, adding 30mL of ethyl acetate and 30mL of water, extracting and separating liquid, drying the organic phase by anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain an intermediate A1, namely: 1- (4-bromophenyl) -2-methylpropanone, (5.4g, light yellow liquid).
EXAMPLE 41 preparation of (4-bromophenyl) -2-methylpropanone
P-bromophenylketone (21.3g, 0.1moL) was dissolved in 100mL of dimethylformamide at room temperature, and potassium hydroxide (11.2g, 0.2moL) was added with stirring, and dimethyl sulfate (25.2g, 0.2moL) was added thereto and reacted at room temperature overnight. After completion of the reaction, 100mL of ethyl acetate was added, insoluble materials were filtered off, water was added for extraction, liquid separation was performed, the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give intermediate A1 (4-bromophenyl) -2-methyl-1-propanone) (22g, pale yellow liquid).
EXAMPLE 51 preparation of (4-bromophenyl) -2-methylpropanone
P-bromophenylketone (21.3g, 0.1moL) was dissolved in 100mL of dimethylformamide at room temperature, and potassium hydroxide (11.2g, 0.2moL) was added with stirring, followed by methyl p-toluenesulfonate (37.2g, 0.2moL) and reacted at room temperature overnight. After completion of the reaction, 100mL of ethyl acetate was added, insoluble materials were filtered off, water was added for extraction, liquid separation was performed, the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give intermediate A1 (4-bromophenyl) -2-methyl-1-propanone) (22.5g, pale yellow liquid).
Examples 6-9 provide methods for preparing second intermediate B1.
EXAMPLE 62 preparation of methyl- [4- (methylsulfonyl) phenyl ] propanone
This example provides a method for preparing a second intermediate B1, which uses a first intermediate a1 as a reaction substrate to obtain a second intermediate B1, and the method comprises the following steps:
the first intermediate A1(110g, 1eq), sodium methanesulfinate (74.1g, 1.5eq) and L-proline (11.1g, 0.2eq) were added to 220mL of dimethyl sulfoxide, and cuprous iodide (18.5g, 0.2eq) was added at 100 ℃ to react for 48h at 100 ℃. Cooling to room temperature after complete reaction, adding ethyl acetate-water for extraction, drying an organic phase, evaporating under reduced pressure to remove the solvent, adding n-heptane for crystallization to obtain a crude product, and recrystallizing the crude product with ethyl acetate-n-heptane to obtain a pure second intermediate B1, namely: 2-methyl- [4- (methylsulfonyl) phenyl ] propanone, (80g, yield 72.7%, light yellow solid).
EXAMPLE 72 preparation of methyl- [4- (methylsulfonyl) phenyl ] propanone
This example provides a method for preparing a second intermediate B1, which uses a first intermediate a1 as a reaction substrate to obtain a second intermediate B1, and the method comprises the following steps:
the first intermediate A1(165g, 1eq), sodium methanesulfinate (111.2g, 1.5eq) and L-proline (16.5g, 0.2eq) were added to 330mL of dimethyl sulfoxide, and cuprous iodide (27.8g, 0.2eq) was added at 100 ℃ to react for 48 h. After the reaction is completed, cooling to room temperature, adding ethyl acetate-water for extraction, drying an organic phase, evaporating under reduced pressure to remove the solvent, and adding ethyl acetate-n-heptane to obtain a second intermediate B1, namely: 2-methyl- [4- (methylsulfonyl) phenyl ] propanone, (124.8g, 75.6% yield, light yellow solid).
EXAMPLE 82 preparation of methyl- [4- (methylsulfonyl) phenyl ] propanone
This example provides a method for preparing a second intermediate B1, which uses a first intermediate a1 as a reaction substrate to obtain a second intermediate B1, and the method comprises the following steps:
the first intermediate A1(227g, 1eq), sodium methanesulfinate (102.1g, 1eq) and L-proline (34.53g, 0.3eq) were added to 681mL of dimethyl sulfoxide, and cuprous iodide (57.1g, 0.3eq) was added thereto at a temperature of 80 ℃ to react for 50 hours at 80 ℃. Cooling to room temperature after complete reaction, adding ethyl acetate-water for extraction, drying an organic phase, evaporating under reduced pressure to remove the solvent, adding n-heptane for crystallization to obtain a crude product, and recrystallizing the crude product with ethyl acetate-n-heptane to obtain a pure second intermediate B1, namely: 2-methyl- [4- (methylsulfonyl) phenyl ] propanone, (166g, 73.1% yield, light yellow solid).
EXAMPLE 92 preparation of methyl- [4- (methylsulfonyl) phenyl ] propanone
This example provides a method for preparing a second intermediate B1, which uses a first intermediate a1 as a reaction substrate to obtain a second intermediate B1, and the method comprises the following steps:
the first intermediate A1(110g, 1eq), sodium methanesulfinate (99g, 2eq) and L-proline (27.9g, 0.5eq) were added to 110mL of dimethyl sulfoxide, and cuprous iodide (46.1g, 0.5eq) was added at 120 ℃ to react for 40h at 120 ℃. Cooling to room temperature after complete reaction, adding ethyl acetate-water for extraction, drying an organic phase, evaporating under reduced pressure to remove the solvent, adding n-heptane for crystallization to obtain a crude product, and recrystallizing the crude product with ethyl acetate-n-heptane to obtain a pure to pure second intermediate B1, namely: 2-methyl- [4- (methylsulfonyl) phenyl ] propanone, (78.4g, 72.2% yield as a pale yellow solid).
Examples 10-12 provide methods for the preparation of felicoxib intermediate C.
Example 102-hydroxy-2-methyl- [4- (methylsulfonyl) phenyl ] -1-propanone
This example provides a preparation method of felicoxib intermediate C, in which second intermediate B1 is used as a reaction substrate to obtain second intermediate C, and the specific preparation steps are as follows:
b1(80g, 1eq) was dissolved in 400mL DMSO at room temperature, followed by addition of NBS (12.6g, 0.2 eq). The temperature is increased to 100 ℃ for reaction for 12 h. Cooling to room temperature after complete reaction, adding ethyl acetate and water for extraction, drying an organic phase, evaporating under reduced pressure to remove a solvent, and crystallizing by using methyl tert-butyl ether-n-heptane to obtain pure C, namely: 2-hydroxy-2-methyl- (4-methylsulfonyl) phenyl-1-propanone, (72.8g, 85% yield, light yellow solid).
The characterization results for felicoxib intermediate C provided in this example are as follows:
1HNMR(DMSO-d6)δ1.62(6H，s)，2.63(1H，s)，3.09(3H，s)，8.01-8.21(4H，M)
example 112-hydroxy-2-methyl- [4- (methylsulfonyl) phenyl ] -1-propanone
This example provides a preparation method of felicoxib intermediate C, in which second intermediate B1 is used as a reaction substrate to obtain second intermediate C, and the specific preparation steps are as follows:
b1(80g, 1eq) was dissolved in 560mL DMSO at room temperature, and NBS (31.1g, 0.5eq) was added. The temperature is increased to 80 ℃ for reaction for 14 h. Cooling to room temperature after complete reaction, adding ethyl acetate and water for extraction, drying an organic phase, evaporating under reduced pressure to remove a solvent, and crystallizing by using methyl tert-butyl ether-n-heptane to obtain pure C, namely: 2-hydroxy-2-methyl- [4- (methylsulfonyl) phenyl ] -1-propanone, (75g, yield 86%, light yellow solid).
Example 122-hydroxy-2-methyl- [4- (methylsulfonyl) phenyl ] -1-propanone
This example provides a preparation method of felicoxib intermediate C, in which second intermediate B1 is used as a reaction substrate to obtain second intermediate C, and the specific preparation steps are as follows:
b1(80g, 1eq) was dissolved in 240mL DMSO at room temperature, followed by addition of NBS (18.9g, 0.3 eq). The temperature is increased to 120 ℃ for reaction for 10 h. Cooling to room temperature after complete reaction, adding ethyl acetate and water for extraction, drying an organic phase, evaporating under reduced pressure to remove a solvent, and crystallizing by using methyl tert-butyl ether-n-heptane to obtain pure C, namely: 2-hydroxy-2-methyl- [4- (methylsulfonyl) phenyl ] -1-propanone, (71.2g, yield 82.8%, light yellow solid).
Example 132 preparation of methyl-1- [4- (methylsulfonyl) phenyl ] -2- (2-acetoxyacetoxyacetoxy-acetoxy) -1-propanone this example provides a preparation of intermediate D:
5.0g of intermediate C, 4.2g of triethylamine and 0.5g of DMAP were added to 50mL of dichloromethane and stirred. The temperature is reduced to 0 ℃ and 4.2g of acetoxyacetyl chloride are added dropwise. After the reaction is completed, water is added for extraction, drying is carried out, and the solvent is removed by reduced pressure evaporation to obtain an intermediate D, namely: 2-methyl-1- [4- (methylsulfonyl) phenyl ] -2- (2-acetoxyacetoxyacetoxyacetoxy-acetoxy) -1-propanone, (7.0g, 99.5% yield, yellow solid).
EXAMPLE 143 preparation of hydroxy-5, 5 dimethyl-4- [4- (methylsulfonyl) phenyl ] -2(5H) -furanone
This example provides a method for the preparation of intermediate E:
intermediate D7.0 g was dissolved in 50mL acetonitrile and DBU 6.2g was added for 12h reflux. After the reaction is completed, cooling to room temperature, spin-drying, adding dichloromethane and water for extraction, and drying. The solvent is evaporated under reduced pressure, the residue is added with ethyl acetate and stirred to precipitate a solid, and after filtration, the solid is recrystallized by ethyl acetate to obtain an intermediate E, namely: 3-hydroxy-5, 5 dimethyl-4- [4- (methylsulfonyl) phenyl ] -2(5H) -furanone. (4.0g, yield 70%, light yellow solid).
Example 15
This example provides a method for the preparation of feloxicib:
adding 7.0g of the intermediate E7 to 400ml of toluene, stirring for dissolving, adding 2.4g of 50% sodium hydroxide aqueous solution, 2.6ml of cyclopropylmethyl bromide and 0.92g of tetrabutylammonium bromide, heating to 70 ℃, reacting for 10-18 hours, filtering, standing and separating filtrate, separating an organic phase, drying with anhydrous sodium sulfate, and concentrating to dryness to obtain the felocoxib with the yield of 54%.
The characterization results of filocoxib provided in this example are as follows:
characterization results for felovioxib:1HNMR(CD3COCD3)δ0.30(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)
finally, the synthesis method of the felicoxib intermediate provided by the embodiment of the invention takes the p-bromophenyl ketone as the starting material, avoids using thioether which is not environment-friendly as the starting material, and has the advantages of room temperature methylation and mild reaction conditions. And the second intermediate is directly obtained from the first intermediate through sulfination reaction, and dimethyl sulfoxide, cuprous iodide and sodium methanesulfinate are selected, so that the vulcanization reaction and the oxidation reaction are shortened to one-step substitution reaction, the reaction steps are greatly simplified, the reaction time is shortened, and the reaction efficiency is improved. Meanwhile, the embodiment of the invention also adopts an NBS/DMSO system, so that the hydroxylation reaction of the second intermediate directly obtains the feloxicib intermediate, compared with the method I in the prior art, the method avoids using a reagent which is carbon tetrachloride and can cause harm to the environment and human bodies, does not need column chromatography, and is suitable for large-scale production; compared with the second method in the prior art, the second method uses liquid bromine which is extremely unfriendly to the environment and is a two-step reaction, and the invention avoids using the liquid bromine and is a one-step reaction. In addition, the reaction reagents are common reagents, have no obvious harm to human bodies and the environment, are easy to obtain, can be directly purchased from the market, and can be matched for use to obtain the felicoxib intermediate with high yield.
In addition, the synthesis method of the felicoxib provided by the embodiment of the invention comprises the synthesis method of the felicoxib intermediate, and the felicoxib can be synthesized in a milder reaction condition and more environment-friendly manner, so that the preparation efficiency and yield of the felicoxib are improved, and the method is more suitable for industrial large-scale production.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A method for synthesizing a feloxib intermediate, comprising:
taking p-bromophenylketone as an initial raw material, and carrying out methylation reaction on the p-bromophenylketone and a methylation reagent to obtain a first intermediate; carrying out sulfinylation reaction on the first intermediate and sodium methanesulfinate under the catalysis of cuprous iodide to obtain a second intermediate; carrying out hydroxylation reaction on the second intermediate and N-bromosuccinimide to obtain the feloxicib intermediate;
the structural formula of the first intermediate is
The structural formula of the second intermediate is
The structural formula of the feloxicib intermediate is shown as
Wherein the methylation reaction comprises: dissolving the p-bromophenylketone in a first solvent, adding a strong base and the methylating reagent, and after complete reaction, extracting, separating, drying and evaporating to obtain a first intermediate; wherein the molar ratio of the p-bromophenylketone, the strong base and the methylating agent is 1: 1-4: 1-2, and the dosage ratio of the p-bromophenylketone to the first solvent is 1g/2 mL-1 g/10 mL;
the sulfination reaction comprises: adding the first intermediate, the sodium methanesulfinate and the L-proline into a second solvent, heating to 80-120 ℃, adding the cuprous iodide, reacting for 40-50 h, cooling to room temperature, extracting, drying, removing the solvent by reduced pressure evaporation, and adding n-heptane for crystallization to obtain a second intermediate; wherein the second solvent is dimethyl sulfoxide; the molar ratio of the first intermediate to the sodium methanesulfinate to the L-proline to the cuprous iodide is 1: 1-2: 0.2-0.5, and the dosage ratio of the first intermediate to the second solvent is 1g/1 mL-1 g/5 mL;
the hydroxylation reaction comprises the following steps: dissolving the second intermediate in a third solvent, adding the N-bromosuccinimide, heating to 80-120 ℃, reacting for 10-14 h, cooling to room temperature, extracting, drying, evaporating the solvent under reduced pressure, and adding methyl tert-butyl ether-N-heptane for crystallization to obtain the felicoxib intermediate, wherein the third solvent is dimethyl sulfoxide; the molar ratio of the second intermediate to the N-bromosuccinimide is 1: 0.2-0.5, and the dosage ratio of the second intermediate to the third solvent is 1g/2 mL-1 g/10 mL.
2. The method for synthesizing the feloxib intermediate according to claim 1, wherein the methylating agent is selected from one of methyl halide, dimethyl sulfate or methyl p-toluenesulfonate.
3. The method for synthesizing a feloxib intermediate according to claim 1, wherein the methylating agent is a methyl halide.
4. A process for the synthesis of a feloxib intermediate according to claim 3, wherein the methyl halide is methyl iodide.
5. The method for synthesizing the feloxicib intermediate according to claim 1, wherein the first solvent is selected from one of dimethylformamide, dimethyl sulfoxide and tert-butyl alcohol, and the strong base is selected from one or more of sodium hydroxide, lithium hydroxide, potassium hydroxide and potassium tert-butoxide.
6. The method of synthesizing a feloxib intermediate according to claim 1, wherein the sulfinylation reaction comprises: and adding the first intermediate, the sodium methanesulfinate and the L-proline into dimethyl sulfoxide, heating to 100 ℃, adding the cuprous iodide, reacting for 48 hours, cooling to room temperature, extracting, drying, removing the solvent by reduced pressure evaporation, and adding n-heptane for crystallization to obtain the second intermediate.
7. The method for synthesizing the feloxib intermediate according to claim 6, further comprising recrystallizing the crystallized product with ethyl acetate-n-heptane after crystallization and before obtaining the second intermediate.
8. A process for the synthesis of a feloxib intermediate according to claim 1, wherein the hydroxylation reaction comprises: and dissolving the second intermediate in dimethyl sulfoxide, adding the N-bromosuccinimide, heating to 100 ℃, reacting for 12h, cooling to room temperature, extracting, drying, evaporating under reduced pressure to remove the solvent, and adding methyl tert-butyl ether-N-heptane for crystallization to obtain the felicoxib intermediate.
9. A method for synthesizing feloxicib, comprising:
preparing the felodipine intermediate according to the method for synthesizing the felodipine intermediate as defined in any one of claims 1 to 8;
reacting the feloxicib intermediate with acetoxyacetyl chloride to produce 2-methyl-1- [4- (methylsulfonyl) phenyl ] -2- (2-acetoxyacetoxyacetoxyacetoxyacetoxy) -1-propanone according to the formula;
treating the 2-methyl-1- [4- (methylsulfonyl) phenyl ] -2- (2-acetoxy) -1-acetone with DBU to form 3-hydroxy-5, 5 dimethyl-4- [4- (methylsulfonyl) phenyl ] -2(5H) -furanone, wherein the reaction formula is shown as follows;
reacting said 3-hydroxy-5, 5 dimethyl-4- [4- (methylsulfonyl) phenyl ] -2(5H) -furanone with cyclopropylmethyl bromide to form felocoxib, which is represented by the formula;
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| CN108586399B (en) * | 2018-07-03 | 2020-02-18 | 四川青木制药有限公司 | Synthesis method of feloxicib |
| 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 |
| CN109134318B (en) * | 2018-08-24 | 2020-04-17 | 江苏美迪克化学品有限公司 | Preparation method of 4-methylsulfonyl acetophenone and α -bromo-4-methylsulfonyl acetophenone |
| CN110407742B (en) * | 2019-07-03 | 2022-06-28 | 常州大学 | Method for preparing 3-bromo-4-methylsulfonylpyridine |
| 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 |
| 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 |
| 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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|---|---|---|---|---|
| CN1651408A (en) * | 2004-11-26 | 2005-08-10 | 中国科学院上海有机化学研究所 | Amino acid accelerated CuI catalyzed aryl halide and coupling reaction of alkyl sulfonate |
| CN104803956A (en) * | 2015-03-06 | 2015-07-29 | 江苏天和制药有限公司 | Synthesis method of firocoxib |
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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 accelerated CuI catalyzed aryl halide and coupling reaction of alkyl sulfonate |
| 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 |
|---|
| C-C Coupling of Ketones with Methanol Catalyzed by a N-Heterocyclic Carbene–Phosphine Iridium Complex;Xu Quan 等;《Chem. Eur. J.》;20150114;第21卷;3576-3579 * |
| I2- or NBS-Catalyzed Highly Efficient α-Hydroxylation of Ketones with Dimethyl Sulfoxide;Yu-Feng Liang 等;《Org. Lett.》;20150204;第17卷;876-879 * |
| Synthesis of Twist-Twist π-Conjugated Di-sec-alkylstilbenes and Stilbene Polymers;James E. Gano 等;《J. Org. Chem.》;20030405;第68卷;3710-3713 * |
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