CN107043341A - Diaryl sulfide analog derivative and preparation method thereof - Google Patents
Diaryl sulfide analog derivative and preparation method thereof Download PDFInfo
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- CN107043341A CN107043341A CN201710221864.XA CN201710221864A CN107043341A CN 107043341 A CN107043341 A CN 107043341A CN 201710221864 A CN201710221864 A CN 201710221864A CN 107043341 A CN107043341 A CN 107043341A
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- diaryl sulfide
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- analog derivative
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- diaryl
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- -1 Diaryl sulfide analog Chemical class 0.000 title claims abstract description 116
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 15
- 150000003624 transition metals Chemical class 0.000 claims abstract description 15
- 150000007530 organic bases Chemical class 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 238000004440 column chromatography Methods 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000008367 deionised water Substances 0.000 claims description 2
- 229910021641 deionized water Inorganic materials 0.000 claims description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims 2
- 239000000463 material Substances 0.000 claims 2
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 229930013930 alkaloid Natural products 0.000 claims 1
- 150000003797 alkaloid derivatives Chemical class 0.000 claims 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 239000000758 substrate Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 150000003568 thioethers Chemical class 0.000 abstract description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 abstract description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 13
- 239000003480 eluent Substances 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 10
- 239000012043 crude product Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 239000012265 solid product Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000012824 chemical production Methods 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000005244 neohexyl group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000011895 specific detection Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 0 *CCc(c(*)c1)c(*)c(*)c1Sc1c(*)[n]c2c1cc(*)cc2 Chemical compound *CCc(c(*)c1)c(*)c(*)c1Sc1c(*)[n]c2c1cc(*)cc2 0.000 description 2
- TZOVOULUMXXLOJ-UHFFFAOYSA-N 1-methyl-4-[(4-methylphenyl)disulfanyl]benzene Chemical compound C1=CC(C)=CC=C1SSC1=CC=C(C)C=C1 TZOVOULUMXXLOJ-UHFFFAOYSA-N 0.000 description 2
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 150000002898 organic sulfur compounds Chemical class 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- AIPBFVQVQASOGX-UHFFFAOYSA-N 1-bromohept-1-yne Chemical compound CCCCCC#CBr AIPBFVQVQASOGX-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- NNPRNGRENISUMK-UHFFFAOYSA-N 4-methyl-n,n-bis(prop-2-ynyl)benzenesulfonamide Chemical compound CC1=CC=C(S(=O)(=O)N(CC#C)CC#C)C=C1 NNPRNGRENISUMK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- AZQCFLDDJHERFZ-UHFFFAOYSA-N Br.C#Cc1ccccc1 Chemical compound Br.C#Cc1ccccc1 AZQCFLDDJHERFZ-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- BLJGMOALIMJPLT-UHFFFAOYSA-N C#CC(C=C1)=CC=C1Cl.Br Chemical compound C#CC(C=C1)=CC=C1Cl.Br BLJGMOALIMJPLT-UHFFFAOYSA-N 0.000 description 1
- HTGGAYLWTDOFDK-PKNBQFBNSA-N CC(C)c(cccc1)c1Sc1ccc(/C=C/C(N(CC2)CCN2C(C)=O)=O)cc1[N+]([O-])=O Chemical compound CC(C)c(cccc1)c1Sc1ccc(/C=C/C(N(CC2)CCN2C(C)=O)=O)cc1[N+]([O-])=O HTGGAYLWTDOFDK-PKNBQFBNSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102100022339 Integrin alpha-L Human genes 0.000 description 1
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- RMVRSNDYEFQCLF-UHFFFAOYSA-N Sc1ccccc1 Chemical compound Sc1ccccc1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000003426 co-catalyst Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- PXSXRABJBXYMFT-UHFFFAOYSA-N n-hexylhexan-1-amine Chemical compound CCCCCCNCCCCCC PXSXRABJBXYMFT-UHFFFAOYSA-N 0.000 description 1
- JACMPVXHEARCBO-UHFFFAOYSA-N n-pentylpentan-1-amine Chemical compound CCCCCNCCCCC JACMPVXHEARCBO-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940100684 pentylamine Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000003744 tubulin modulator Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
- C07C321/24—Thiols, sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
- C07C321/28—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
- C07C321/30—Sulfides having the sulfur atom of at least one thio group bound to two carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及有机合成领域,且特别涉及一种二芳基硫醚类衍生物及其制备方法。本发明提供一系列新的二芳基硫醚类衍生物相对于普通硫醚衍生物起有多环的存在,其结构更加复杂多样,应用前景更广阔。该制备方法包括以下步骤:在无水无氧体系中,将二炔类化合物、烃基炔溴、无水乙腈、过渡金属催化剂和有机碱混合并反应得到中间体。在90‑115℃条件下,将中间体、芳基二硫醚和甲苯混合反应。该制备方法不但底物合成简单、试剂比较便宜,并且具有高原子经济性、绿色环保的得到目标分子,给二芳基硫醚类衍生物的工业化生产提供了一条很有价值的途径。
The invention relates to the field of organic synthesis, and in particular to a diaryl sulfide derivative and a preparation method thereof. The invention provides a series of new diaryl sulfide derivatives which have multiple rings compared with common thioether derivatives, the structures are more complex and diverse, and the application prospects are broader. The preparation method comprises the following steps: in an anhydrous and oxygen-free system, mixing and reacting a diacetylenic compound, a hydrocarbyl alkyne bromide, anhydrous acetonitrile, a transition metal catalyst and an organic base to obtain an intermediate. Under the condition of 90-115°C, the intermediate, aryl disulfide and toluene were mixed and reacted. The preparation method not only has simple substrate synthesis and relatively cheap reagents, but also has high atom economy and environmental protection to obtain target molecules, which provides a valuable way for the industrial production of diaryl sulfide derivatives.
Description
技术领域technical field
本发明涉及有机合成领域,且特别涉及一种二芳基硫醚类衍生物及其制备方法。The invention relates to the field of organic synthesis, and in particular to a diaryl sulfide derivative and a preparation method thereof.
背景技术Background technique
二芳基硫醚类衍生物广泛应用于医药、农业、染料、轻化用品、高聚材料等领域。一些具有生物活性的二芳基硫醚化合物在医药分子研究中展示了其独特的药理作用,例如二芳基硫醚化合物I被用作白细胞对抗药(LFA-1),化合物II是作为一种微管蛋白抑制剂能够显著抑制人类MCF-7乳房癌细胞的生长。Diaryl sulfide derivatives are widely used in medicine, agriculture, dyes, light chemical products, high polymer materials and other fields. Some biologically active diaryl sulfide compounds have demonstrated their unique pharmacological effects in the study of medical molecules. For example, diaryl sulfide compound I is used as a leukocyte antidote (LFA-1), and compound II is used as a Tubulin inhibitors can significantly inhibit the growth of human MCF-7 breast cancer cells.
随着有机硫化合物在合成中的广泛应用,近年来有机硫化合物在有机合成中的应用得到普遍重视。二芳基硫醚类化合物的合成路径引起了无数有机合成工作者的积极思考,并且得出了一些很有效的方法。通过芳环碳与硫原子的C―S偶联是二芳基硫醚类化合物合成的主要途径,过渡金属催化被广泛应用于二芳基硫醚类化合物的C―S偶联反应。With the wide application of organosulfur compounds in synthesis, the application of organosulfur compounds in organic synthesis has received widespread attention in recent years. The synthetic route of diaryl sulfide compounds has aroused the active thinking of countless organic synthesis workers, and some very effective methods have been obtained. The C—S coupling reaction of aromatic ring carbon and sulfur atom is the main way to synthesize diaryl sulfides, and transition metal catalysis is widely used in the C—S coupling reaction of diaryl sulfides.
过渡金属催化合成二芳基硫醚的三种主要方法中,钯类催化剂较高的毒性、不菲的价格、及对含磷配体的依赖制约了其在工业化生产中应用。铜、镍类催化剂也需在加入配体及其它添加剂的情况下才能发挥催化作用,而额外试剂的加入必然也对反应条件及原料分子结构中基团的兼容性起了一定的限制作用。因此,高效性、产率高、具有原子经济性的绿色合成方法在C―S偶联反应制备二芳基硫醚类化合物的研究中成为了一个新的导向。Among the three main methods for the synthesis of diaryl sulfides catalyzed by transition metals, the high toxicity, high price, and dependence on phosphorus-containing ligands of palladium catalysts restrict their application in industrial production. Copper and nickel catalysts also need to add ligands and other additives to play a catalytic role, and the addition of additional reagents must also limit the reaction conditions and the compatibility of the groups in the molecular structure of the raw materials. Therefore, the green synthesis method with high efficiency, high yield and atom economy has become a new direction in the research on the preparation of diaryl sulfide compounds by C—S coupling reaction.
发明内容Contents of the invention
本发明的目的在于提供一种二芳基硫醚类衍生物,该多环芳硫醚衍生物有多环的存在,其结构更加复杂多样,在化工生产、临床医药中也将表现出更加广阔的用途前景。The object of the present invention is to provide a kind of diaryl sulfide derivatives, the polycyclic aromatic sulfide derivatives have multiple rings, and its structure is more complex and diverse, and it will also show a wider range of applications in chemical production and clinical medicine. prospects for use.
本发明的另一目的在于提供一种二芳基硫醚类衍生物的制备方法,该方法克服了以往反应中路线过长,底物和反应条件要求苛刻,取代官能团扩展有限的等缺点。Another object of the present invention is to provide a method for preparing diaryl sulfide derivatives, which overcomes the shortcomings of the previous reactions, such as long routes, harsh substrate and reaction conditions, and limited expansion of substituted functional groups.
本发明解决其技术问题是采用以下技术方案来实现的:The present invention solves its technical problem and adopts the following technical solutions to realize:
本发明提供一种二芳基硫醚类衍生物,其结构式为:The present invention provides a kind of diaryl sulfide derivatives, its structural formula is:
其中,Y=C(CO2R)2或者TsN,R选自直链烷基或支链烷基,Ts为对甲基苯磺酰基;R1选自直链烷基、支链烷基或者芳香烃基团中任意一种基团;R2选自氢基、卤素基团、直链烷基、支链烷基或者烷氧基及其衍生物中的任意一种基团;R2可处于苯环的任意位置。Wherein, Y=C(CO 2 R) 2 or TsN, R is selected from straight chain alkyl or branched chain alkyl, Ts is p-toluenesulfonyl; R 1 is selected from straight chain alkyl, branched chain alkyl or Any group in the aromatic hydrocarbon group; R2 is selected from any group in hydrogen group, halogen group, straight chain alkyl, branched chain alkyl or alkoxy group and its derivatives ; R2 can be in Any position of the benzene ring.
本发明还提供一种二芳基硫醚类衍生物的制备方法,包括以下步骤:在无水无氧体系中,将二炔类化合物、烃基炔溴、无水乙腈、过渡金属催化剂和有机碱混合并反应得到中间体。在90-115℃条件下,将中间体、芳基二硫醚和甲苯混合并反应。The present invention also provides a preparation method of diaryl sulfide derivatives, comprising the following steps: in an anhydrous and oxygen-free system, diacetylenic compound, hydrocarbyl alkyne bromide, anhydrous acetonitrile, transition metal catalyst and organic base Mix and react to give the intermediate. Under the condition of 90-115°C, the intermediate, aryl disulfide and toluene are mixed and reacted.
本发明二芳基硫醚类衍生物及其制备方法的有益效果是:本发明提供的一系列新的二芳基硫醚类衍生物相对于普通硫醚衍生物有多环的存在,其结构更加复杂多样,在化工生产、临床医药中也将表现出更加广阔的用途前景。本发明的制备方法以不同的多重炔烃底物通过串联反应构筑二芳基硫醚类化合物,该反应克服了以往反应中路线过长,底物和反应条件要求苛刻,取代官能团扩展有限的等缺点,该反应不但底物合成简单、试剂比较便宜,并且具有高原子经济性、绿色环保的得到目标分子,给二芳基硫醚类衍生物的工业化生产提供了一条很有价值的途径。The beneficial effects of the diaryl sulfide derivatives and the preparation method thereof of the present invention are: a series of new diaryl sulfide derivatives provided by the present invention have polycyclic existence relative to common thioether derivatives, and their structure It is more complex and diverse, and it will also show a broader application prospect in chemical production and clinical medicine. The preparation method of the present invention uses different multiple alkyne substrates to construct diaryl sulfide compounds through series reactions. This reaction overcomes the problems of long routes, harsh substrate and reaction conditions, and limited expansion of substituted functional groups in previous reactions. Disadvantages, this reaction is not only simple to synthesize the substrate, and the reagents are relatively cheap, but also has high atom economy and environmental protection to obtain the target molecule, which provides a valuable way for the industrial production of diaryl sulfide derivatives.
附图说明Description of drawings
为了更清楚地说明本发明实施例或现有技术中的技术方案,以下将对实施例中所需要使用的附图作简单地介绍。In order to illustrate the embodiments of the present invention or the technical solutions in the prior art more clearly, the following will briefly introduce the drawings required in the embodiments.
图1为本发明实施例1制备得到的二芳基硫醚类衍生物的核磁共振氢谱;Fig. 1 is the proton nuclear magnetic resonance spectrum of the diaryl sulfide derivatives prepared in Example 1 of the present invention;
图2为本发明实施例1制备得到的二芳基硫醚类衍生物的核磁共振碳谱;Fig. 2 is the carbon nuclear magnetic resonance spectrum of the diaryl sulfide derivatives prepared in Example 1 of the present invention;
图3为本发明实施例2制备得到的二芳基硫醚类衍生物的核磁共振氢谱;Fig. 3 is the proton nuclear magnetic resonance spectrum of the diaryl sulfide derivatives prepared in Example 2 of the present invention;
图4为本发明实施例2制备得到的二芳基硫醚类衍生物的核磁共振碳谱;Fig. 4 is the carbon nuclear magnetic resonance spectrum of the diaryl sulfide derivatives prepared in Example 2 of the present invention;
图5为本发明实施例3制备得到的二芳基硫醚类衍生物的核磁共振氢谱;Figure 5 is the H NMR spectrum of the diaryl sulfide derivatives prepared in Example 3 of the present invention;
图6为本发明实施例3制备得到的二芳基硫醚类衍生物的核磁共振碳谱;Fig. 6 is the carbon nuclear magnetic resonance spectrum of the diaryl sulfide derivatives prepared in Example 3 of the present invention;
图7为本发明实施例4制备得到的二芳基硫醚类衍生物的核磁共振氢谱;Figure 7 is the H NMR spectrum of the diaryl sulfide derivatives prepared in Example 4 of the present invention;
图8为本发明实施例4制备得到的二芳基硫醚类衍生物的核磁共振碳谱。Fig. 8 is the carbon nuclear magnetic resonance spectrum of the diaryl sulfide derivatives prepared in Example 4 of the present invention.
具体实施方式detailed description
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.
在本发明的描述中,需要说明的是,术语“第一”、“第二”等仅用于区分描述,而不能理解为指示或暗示相对重要性。In the description of the present invention, it should be noted that the terms "first", "second" and so on are only used for distinguishing descriptions, and should not be understood as indicating or implying relative importance.
下面对本发明实施例的二芳基硫醚类衍生物及其制备方法进行具体说明。The diaryl sulfide derivatives of the embodiments of the present invention and their preparation methods are described in detail below.
本发明实施例提供的一种二芳基硫醚类衍生物,其结构式为:A diaryl sulfide derivative provided in the embodiment of the present invention has a structural formula:
其中,Y=C(CO2R)2或者TsN,R选自直链烷基或支链烷基,Ts为对甲基苯磺酰基;R1选自直链烷基、支链烷基或者芳香烃基团中任意一种基团;R2选自氢基、卤素基团、直链烷基、支链烷基或者烷氧基及其衍生物中的任意一种基团;R2可处于苯环的任意位置。Wherein, Y=C(CO 2 R) 2 or TsN, R is selected from straight chain alkyl or branched chain alkyl, Ts is p-toluenesulfonyl; R 1 is selected from straight chain alkyl, branched chain alkyl or Any group in the aromatic hydrocarbon group; R2 is selected from any group in hydrogen group, halogen group, straight chain alkyl, branched chain alkyl or alkoxy group and its derivatives ; R2 can be in Any position of the benzene ring.
本发明实施例中R中的直链烷基选自甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、正壬基、正癸基或者其他无支链的烷基中的任意一种基团。优选地R中的直链烷基为乙基。R中的支链烷基选自异丙基、异丁基、叔丁基、异戊基、叔戊基、新戊基、异己基、叔己基、新己基等具有支链的烷基中的任意一种基团。The linear alkyl group in R in the embodiment of the present invention is selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl Or any one of other unbranched alkyl groups. Preferably the linear alkyl group in R is ethyl. The branched chain alkyl in R is selected from isopropyl, isobutyl, tert-butyl, isopentyl, tert-amyl, neopentyl, isohexyl, tert-hexyl, neohexyl and other alkyl groups with branching any group.
在本发明实施例中R1中的直链烷基选自甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、正壬基、正癸基或者其他无支链的烷基中的任意一种基团。优选地R1中的直链烷基为正戊基。R1中的支链烷基选自异丙基、异丁基、叔丁基、异戊基、叔戊基、新戊基、异己基、叔己基、新己基等具有支链的烷基中的任意一种基团。R1中的芳香烃基团选自对氯苯基、间氟苯基、邻溴苯基或苄基等含有苯环的基团中任意一种基团。进一步优选地,R1中的芳香烃基团为对氯苯基。In the embodiment of the present invention, the linear alkyl group in R1 is selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n- Any one of decyl or other unbranched alkyl groups. Preferably the linear alkyl group in R1 is n -pentyl. The branched chain alkyl group in R1 is selected from branched alkyl groups such as isopropyl, isobutyl, tert-butyl, isopentyl, tert-pentyl, neopentyl, isohexyl, tert-hexyl, neohexyl, etc. of any group. The aromatic hydrocarbon group in R1 is selected from any one of groups containing benzene rings such as p-chlorophenyl, m-fluorophenyl, o-bromophenyl or benzyl. Further preferably, the aromatic hydrocarbon group in R is p - chlorophenyl.
在本发明实施例中R2中的卤素基团选自氟基、氯基、溴基或者碘基中任意一种基团。R2中的烷氧基可以是甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、异戊氧基、叔戊氧基、新戊氧基或者其他的烷氧基团。R2中的直链烷基选自甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、正壬基、正癸基或者其他无支链的烷基中的任意一种基团。优选地R2中的直链烷基为甲基。R2中的支链烷基选自异丙基、异丁基、叔丁基、异戊基、叔戊基、新戊基、异己基、叔己基、新己基等具有支链的烷基中的任意一种基团。In the embodiment of the present invention, the halogen group in R 2 is selected from any one of fluorine, chlorine, bromine or iodine. The alkoxy in R2 can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy radical, tert-pentyloxy, neopentyloxy or other alkoxy groups. The linear alkyl group in R2 is selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl or other unbranched Any one of the chain alkyl groups. Preferably the linear alkyl group in R2 is methyl. The branched chain alkyl group in R2 is selected from branched alkyl groups such as isopropyl, isobutyl, tert-butyl, isopentyl, tert-pentyl, neopentyl, isohexyl, tert-hexyl, neohexyl, etc. of any group.
本发明实施例还提供一种二芳基硫醚类衍生物的制备方法:The embodiment of the present invention also provides a preparation method of diaryl sulfide derivatives:
具体的反应式为:The specific reaction formula is:
具体的合成包括以下步骤:Concrete synthesis comprises the following steps:
S1、制备中间体;S1, preparation of intermediates;
在无水无氧体系中,将二炔类化合物和烃基炔溴加入到无水乙腈中,而后加入过渡金属催化剂和有机碱混合并在室温下搅拌12-20小时反应得到中间体。In an anhydrous and oxygen-free system, add a diacetylenic compound and an alkyne bromide into anhydrous acetonitrile, then add a transition metal catalyst and an organic base, mix and stir at room temperature for 12-20 hours to obtain an intermediate.
采用无水无氧体系是为了保证过渡金属催化剂的活性,若反应体系中存在水或者氧气将会使得过渡金属催化剂失去活性,进而不能合成得到中间体,影响二芳基硫醚类衍生物的生成。而采用过渡金属作为催化剂降低了反应所需的能量,使得反应能够顺利进行。优选地,所用的二炔类化合物为碳原子桥连的二炔类化合物或者是氮原子桥连的二炔类化合物。The anhydrous and oxygen-free system is used to ensure the activity of the transition metal catalyst. If water or oxygen exists in the reaction system, the transition metal catalyst will lose its activity, and then the intermediate cannot be synthesized, which will affect the formation of diaryl sulfide derivatives. . The use of transition metals as catalysts reduces the energy required for the reaction, allowing the reaction to proceed smoothly. Preferably, the diynes used are carbon-atom-bridged diynes or nitrogen-atom-bridged diynes.
优选地,过渡金属催化剂为Pd(PPh3)2Cl2和CuI,Pd(PPh3)2Cl2和CuI的物质的量之比为2.8-3.2:1。采用Pd(PPh3)2Cl2和CuI混合作为催化剂时,Pd(PPh3)2Cl2作为催化剂,而CuI作为助催化剂,提升催化剂的效能,加快反应速率,提高产率。二者使用的比例保证了催化效果,进一步地加快反应速率,减少副产物。Preferably, the transition metal catalyst is Pd(PPh 3 ) 2 Cl 2 and CuI, and the ratio of the amounts of Pd(PPh 3 ) 2 Cl 2 to CuI is 2.8-3.2:1. When Pd(PPh 3 ) 2 Cl 2 and CuI are used as the catalyst, Pd(PPh 3 ) 2 Cl 2 is used as the catalyst, and CuI is used as the co-catalyst to improve the efficiency of the catalyst, accelerate the reaction rate and increase the yield. The ratio of the two ensures the catalytic effect, further accelerates the reaction rate and reduces by-products.
优选地,有机碱为胺类化合物,例如甲胺、乙胺、丙胺、丁胺、戊胺、二乙胺、二丙胺、二丁胺、二戊胺、二己胺、三乙胺等。进一步优选地有机碱为三乙胺。三乙胺可以反应生成的溴化氢反应,进而促进整个反应平衡向生成物方向进行。Preferably, the organic base is an amine compound, such as methylamine, ethylamine, propylamine, butylamine, pentylamine, diethylamine, dipropylamine, dibutylamine, dipentylamine, dihexylamine, triethylamine and the like. It is further preferred that the organic base is triethylamine. Triethylamine can react with the generated hydrogen bromide, and then promote the entire reaction equilibrium to the direction of the product.
进一步优选地,二炔类化合物、烃基炔溴、过渡金属催化剂和有机碱物质的量之比为1:2-3:0.03-0.05:2-5,二炔类化合物在无水乙腈中的浓度为0.5-0.8mol/L。在该优选值范围内进行的反应速率快,产率高,副反应少。Further preferably, the ratio of the amount of diacetylenic compound, hydrocarbyl alkyne bromide, transition metal catalyst and organic base substance is 1:2-3:0.03-0.05:2-5, the concentration of diacetylenic compound in anhydrous acetonitrile It is 0.5-0.8mol/L. The reaction rate carried out within this preferred value range is fast, the yield is high, and side reactions are few.
S2、纯化中间体;S2, purification of intermediates;
纯化中间体,是去除中间体内可能含有的杂质,减少杂质对后续反应的影响,同时减少二芳基硫醚类衍生物内可能含有的杂质。甚至中间体内含有的杂质可能导致后续不能反应生成得到二芳基硫醚类衍生物。Purifying the intermediate is to remove the impurities that may be contained in the intermediate, reduce the impact of the impurities on the subsequent reaction, and reduce the impurities that may be contained in the diaryl sulfide derivatives. Even the impurities contained in the intermediate may lead to the inability to generate diaryl sulfide derivatives in the subsequent reaction.
纯化是将二炔类化合物、烃基炔溴、无水乙腈、过渡金属催化剂和有机碱混合并反应得到的第一反应液首先采用质量百分比为15%的盐酸溶液洗涤去除有机碱,而后再用质量百分比为10%的碳酸氢钠溶液洗涤去除盐酸溶液中的盐酸,再用饱和食盐水洗涤以去除碳酸氢钠。接着采用乙酸乙酯萃取洗涤后第一反应液,除去水相。然后使用无水硫酸镁干燥萃取后得到的有机相。干燥后使用旋转蒸发仪旋蒸以去除有机相中的有机溶剂。最后再用柱层析纯化旋蒸后得到物质,得到纯度高的中间体。其中,柱层析采用的淋洗剂为乙酸乙酯与石油醚的混合液,混合液中乙酸乙酯与石油醚的体积比为1:40-60。采用上述的淋洗液能够良好的分离中间体和杂质。Purification is to mix and react the first reaction solution obtained by diacetylenic compound, alkyne bromide, anhydrous acetonitrile, transition metal catalyst and organic base, first use 15% by mass percentage of hydrochloric acid solution to remove the organic base, and then use mass percent Wash with 10% sodium bicarbonate solution to remove hydrochloric acid in hydrochloric acid solution, and then wash with saturated brine to remove sodium bicarbonate. Then, ethyl acetate was used to extract and wash the first reaction liquid, and the water phase was removed. The organic phase obtained after extraction was then dried using anhydrous magnesium sulfate. After drying, use a rotary evaporator to remove the organic solvent in the organic phase. Finally, column chromatography is used to purify the substance obtained after rotary evaporation to obtain an intermediate with high purity. Wherein, the eluent used in column chromatography is a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate and petroleum ether in the mixture is 1:40-60. The above-mentioned eluent can be used to separate intermediates and impurities well.
S3、合成得到二芳基硫醚类衍生物粗品;S3, synthesize and obtain the crude product of diaryl sulfide derivatives;
在90-115℃条件下,将中间体和芳基二硫醚在甲苯溶剂中搅拌混合反应16-24小时,得到二芳基硫醚类衍生物粗品。温度为影响该反应的重要因素,若温度高于或低于该温度范围则生成物质的结构将发生变化,得不到本发明所需的二芳基硫醚类衍生物。Under the condition of 90-115° C., the intermediate and aryl disulfide are mixed and reacted in toluene solvent for 16-24 hours to obtain the crude product of diaryl sulfide derivatives. Temperature is an important factor affecting the reaction. If the temperature is higher or lower than the temperature range, the structure of the resulting substance will change, and the desired diaryl sulfide derivatives of the present invention cannot be obtained.
优选地,中间体与芳基二硫醚的物质的量之比为1:0.6-1.2。甲苯作为溶剂时,中间体在甲苯中的浓度是0.1-0.3mol/L。在该优选值范围内进行的反应速率快,产率高、副产物少。Preferably, the substance amount ratio of the intermediate to the aryl disulfide is 1:0.6-1.2. When toluene is used as a solvent, the concentration of the intermediate in toluene is 0.1-0.3mol/L. The reaction rate carried out within this preferred value range is fast, the yield is high, and by-products are few.
S4、纯化二芳基硫醚类衍生物粗品;S4, purifying the crude product of diaryl sulfide derivatives;
反应得到的二芳基硫醚类衍生物粗品内含有杂质,这些杂质会影响对二芳基硫醚类衍生物结构的鉴定或者影响后续的使用。因此,需要对其进行进一步地纯化。The crude product of diaryl sulfide derivatives obtained from the reaction contains impurities, which will affect the identification of the structure of the diaryl sulfide derivatives or affect the subsequent use. Therefore, it needs to be further purified.
将制备得到的二芳基硫醚类衍生物粗品即第二反应液经过去离子水洗涤后,用乙酸乙酯萃取,用无水硫酸镁干燥萃取液。过滤后,用旋转蒸发仪蒸干萃取液中溶剂。二芳基硫醚类衍生物粗品用柱层析的方法分体提纯,柱层析的淋洗剂为乙酸乙酯与石油醚的混合液,混合液中乙酸乙酯与石油醚的体积比为1:30-60,柱层析产率约为80%。The prepared crude diaryl sulfide derivatives, that is, the second reaction solution, was washed with deionized water, extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. After filtration, the solvent in the extract was evaporated to dryness with a rotary evaporator. The crude product of diaryl sulfide derivatives is separated and purified by column chromatography. The eluent of column chromatography is a mixed solution of ethyl acetate and sherwood oil, and the volume ratio of ethyl acetate and sherwood oil in the mixed solution is 1:30-60, the column chromatography yield is about 80%.
本发明实施例制备得到的二芳基硫醚类衍生物的结构通过1H NMR和13C NMR来测定。The structures of the diaryl sulfide derivatives prepared in the examples of the present invention were determined by 1 H NMR and 13 C NMR.
本发明实施例提供的一系列新的二芳基硫醚类衍生物相对于普通硫醚衍生物有多环的存在,其结构更加复杂多样。并且,本发明实施例提供的制备方法简便、高效、绿色环保,在化工生产,给二芳基硫醚类衍生物的工业化生产提供了一条很有价值的途径。The series of new diaryl sulfide derivatives provided by the examples of the present invention are more complex and diverse in structure than common thioether derivatives which have multiple rings. Moreover, the preparation method provided by the embodiment of the present invention is simple, efficient, and environmentally friendly, and provides a valuable way for the industrial production of diaryl sulfide derivatives in chemical production.
以下结合实施例对本发明的特征和性能作进一步的详细描述。The characteristics and performance of the present invention will be described in further detail below in conjunction with the examples.
实施例1Example 1
本实施例提供的一种二芳基硫醚类衍生物,其结构式如(I)式所示。A diaryl sulfide derivative provided in this embodiment has a structural formula as shown in formula (I).
本实施例还提供一种制备上述二芳基硫醚类衍生物的方法:This embodiment also provides a method for preparing the above-mentioned diaryl sulfide derivatives:
将丙二酸二乙酯桥连的二炔化合物(20mmol)与对氯苯乙炔溴(48mmol)加入到反应瓶中,混合在Pd(PPh3)2Cl2和CuI作为催化剂的无水无氧催化体系中,其中催化剂的量为0.8mmol,Pd(PPh3)2Cl2:CuI=3:1。以三乙胺(50mmol)作碱,以无水乙腈(40mL)为溶剂,室温下搅拌反应12小时,将反应产物先后用15%的盐酸溶液、10%的碳酸氢钠溶液、饱和食盐水分别洗涤;然后用乙酸乙酯萃取,减压旋干,柱层析(淋洗剂中乙酸乙酯与石油醚的体积比为1:40)得到浅棕色固体产物。Diethyl malonate bridged diyne compound (20mmol) and p-chlorophenylacetylene bromide (48mmol) were added to the reaction flask, mixed in anhydrous and oxygen-free solution with Pd(PPh 3 ) 2 Cl 2 and CuI as catalyst In the catalytic system, the amount of the catalyst is 0.8 mmol, and Pd(PPh 3 ) 2 Cl 2 :CuI=3:1. With triethylamine (50mmol) as the base and anhydrous acetonitrile (40mL) as the solvent, the reaction was stirred at room temperature for 12 hours, and the reaction product was successively washed with 15% hydrochloric acid solution, 10% sodium bicarbonate solution, and saturated saline, respectively. Washing; then extracted with ethyl acetate, spin-dried under reduced pressure, column chromatography (the volume ratio of ethyl acetate and petroleum ether in the eluent was 1:40) to obtain a light brown solid product.
在95℃的条件下,将中间体(1mmol)与二对氯苯基二硫醚(0.8mmol)加入到5毫升甲苯溶剂中,反应18小时,得到二芳基硫醚类衍生物粗品。Under the condition of 95° C., the intermediate (1 mmol) and di-p-chlorophenyl disulfide (0.8 mmol) were added into 5 ml of toluene solvent, and reacted for 18 hours to obtain crude diaryl sulfide derivatives.
将二芳基硫醚类衍生物粗品加水洗涤后,用乙酸乙酯萃取,减压旋干,柱层析(淋洗剂中乙酸乙酯与石油醚的体积比为1:40)分离可得到纯化的目标产物,即二芳基硫醚类衍生物,柱层析产率约为82%。Wash the crude diaryl sulfide derivatives with water, extract with ethyl acetate, spin dry under reduced pressure, and separate by column chromatography (the volume ratio of ethyl acetate and petroleum ether in the eluent is 1:40) to obtain The purified target product, ie diaryl sulfide derivatives, has a column chromatography yield of about 82%.
二芳基硫醚类衍生物的结构通过1H NMR和13C NMR来测定,具体图谱见图1和图2。The structures of the diaryl sulfide derivatives were determined by 1 H NMR and 13 C NMR, and the specific spectra are shown in Fig. 1 and Fig. 2 .
白色固体产物:White solid product:
1H NMR(300MHz,CDCl3):δ7.24―7.21(m,4H),7.10―7.02(m,8H),6.90―6.87(d,2H,J=8.1Hz),6.70―6.68(d,2H,J=8.4Hz),4.21―4.14(q,4H,J=7.2Hz),3.76(s,2H),3.46(s,2H),2.28(s,3H),2.23(s,3H),1.24―1.19(t,6H,J=7.2Hz); 1 H NMR (300MHz, CDCl 3 ): δ7.24-7.21(m, 4H), 7.10-7.02(m, 8H), 6.90-6.87(d, 2H, J=8.1Hz), 6.70-6.68(d, 2H, J=8.4Hz), 4.21―4.14(q, 4H, J=7.2Hz), 3.76(s, 2H), 3.46(s, 2H), 2.28(s, 3H), 2.23(s, 3H), 1.24-1.19 (t, 6H, J = 7.2Hz);
13C NMR(75.5MHz,CDCl3):δ171.3,148.1,145.2,144.3,138.5,137.2,136.6,136.0,135.4,134.6,134.6,133.1,132.7,132.6,131.2,129.9,129.4,128.7,128.7,128.1,127.5,121.2,120.8,97.3,87.2,62.0,58.7,42.0,41.2,21.1,21.0,14.0。 13 C NMR (75.5MHz, CDCl 3 ): δ171.3, 148.1, 145.2, 144.3, 138.5, 137.2, 136.6, 136.0, 135.4, 134.6, 134.6, 133.1, 132.7, 132.6, 131.2, 129.9, 129.4, 128.8 , 127.5, 121.2, 120.8, 97.3, 87.2, 62.0, 58.7, 42.0, 41.2, 21.1, 21.0, 14.0.
实施例2Example 2
本实施例提供的一种二芳基硫醚类衍生物,其结构式如(II)式所示。A diaryl sulfide derivative provided in this example has a structural formula as shown in formula (II).
本实施例还提供一种制备上述二芳基硫醚类衍生物的方法:This embodiment also provides a method for preparing the above-mentioned diaryl sulfide derivatives:
将N,N-二炔丙基对甲基苯磺酰胺(20mmol)与1-溴庚炔(60mmol)加入到反应瓶中,混合在Pd(PPh3)2Cl2和CuI作为催化剂的无水无氧催化体系中,其中催化剂的量为0.6mmol,Pd(PPh3)2Cl2:CuI=3.2:1。以三乙胺(60mmol)作碱,以无水乙腈(25mL)为溶剂,室温下搅拌反应20小时,将反应产物先后用15%的盐酸溶液、10%的碳酸氢钠溶液、饱和食盐水分别洗涤;然后用乙酸乙酯萃取,减压旋干,柱层析(淋洗剂中乙酸乙酯与石油醚的体积比为1:50)得到浅棕色固体产物。Add N,N-dipropargyl-p-toluenesulfonamide (20mmol) and 1-bromoheptyne (60mmol) into the reaction flask, mix in Pd(PPh 3 ) 2 Cl 2 and CuI as a catalyst in anhydrous In an oxygen-free catalytic system, the amount of the catalyst is 0.6 mmol, and Pd(PPh 3 ) 2 Cl 2 :CuI=3.2:1. With triethylamine (60mmol) as the base and anhydrous acetonitrile (25mL) as the solvent, the reaction was stirred at room temperature for 20 hours, and the reaction product was successively washed with 15% hydrochloric acid solution, 10% sodium bicarbonate solution, and saturated saline, respectively. Washing; then extracted with ethyl acetate, spin-dried under reduced pressure, column chromatography (the volume ratio of ethyl acetate and petroleum ether in the eluent was 1:50) to obtain a light brown solid product.
在90℃的条件下,将中间体(1mmol)与二苯基二硫醚(1.2mmol)加入到7毫升甲苯溶剂中,反应24小时,得到二芳基硫醚类衍生物粗品。Under the condition of 90° C., the intermediate (1 mmol) and diphenyl disulfide (1.2 mmol) were added into 7 ml of toluene solvent, and reacted for 24 hours to obtain crude diaryl sulfide derivatives.
将二芳基硫醚类衍生物粗品加水洗涤后,用乙酸乙酯萃取,减压旋干,柱层析(淋洗剂中乙酸乙酯与石油醚的体积比为1:30)分离可得到纯化的目标产物,即二芳基硫醚类衍生物,柱层析产率约为78%。Wash the crude diaryl sulfide derivatives with water, extract with ethyl acetate, spin dry under reduced pressure, and separate by column chromatography (the volume ratio of ethyl acetate and petroleum ether in the eluent is 1:30) to obtain The purified target product, ie diaryl sulfide derivatives, has a column chromatography yield of about 78%.
二芳基硫醚类衍生物的结构通过1H NMR和13C NMR来测定,具体检测图谱见图3和图4。The structures of the diaryl sulfide derivatives are determined by 1 H NMR and 13 C NMR, and the specific detection spectra are shown in Fig. 3 and Fig. 4 .
白色固体产物:White solid product:
1H NMR(300MHz,CDCl3):δ7.57―7.54(d,2H,J=8.4Hz),7.27―7.24(d,2H,J=8.1Hz),7.18―7.14(m,5H),7.08―7.06(d,1H,J=7.2Hz),6.98―6.90(m,4H),4.60(s,2H),4.17(s,2H),3.05―3.00(t,2H,J=7.5Hz),2.49―2.45(t,2H,J=6.9Hz),2.41(s,3H),1.64―1.57(m,2H),1.47―1.27(m,10H),0.96―0.91(t,3H,J=6.9Hz),0.86―0.82(t,3H,J=7.5Hz); 1 H NMR (300MHz, CDCl 3 ): δ7.57-7.54(d, 2H, J=8.4Hz), 7.27-7.24(d, 2H, J=8.1Hz), 7.18-7.14(m, 5H), 7.08 ―7.06(d,1H,J=7.2Hz),6.98―6.90(m,4H),4.60(s,2H),4.17(s,2H),3.05―3.00(t,2H,J=7.5Hz), 2.49-2.45(t, 2H, J=6.9Hz), 2.41(s, 3H), 1.64-1.57(m, 2H), 1.47-1.27(m, 10H), 0.96-0.91(t, 3H, J=6.9 Hz), 0.86-0.82 (t, 3H, J=7.5Hz);
13C NMR(125.5MHz,CDCl3):δ151.1,143.5,141.3,138.8,138.4,135.8,135.5,134.9,133.4,129.8,129.1,129.1,128.9,127.6,126.5,126.5,125.3,120.1,100.7,76.1,55.9,54.7,34.6,32.1,31.1,30.3,28.4,22.5,22.2,21.5,19.7,14.0,14.0。 13 C NMR (125.5MHz, CDCl 3 ): δ151.1, 143.5, 141.3, 138.8, 138.4, 135.8, 135.5, 134.9, 133.4, 129.8, 129.1, 129.1, 128.9, 127.6, 126.5, 126.5, 125.3, 16 , 55.9, 54.7, 34.6, 32.1, 31.1, 30.3, 28.4, 22.5, 22.2, 21.5, 19.7, 14.0, 14.0.
实施例3Example 3
本实施例提供的一种二芳基硫醚类衍生物,其结构式如(III)式所示。A diaryl sulfide derivative provided in this example has a structural formula as shown in formula (III).
本实施例还提供一种制备上述二芳基硫醚类衍生物的方法:This embodiment also provides a method for preparing the above-mentioned diaryl sulfide derivatives:
将丙二酸二异丙酯桥连的二炔化合物(20mmol)与对甲氧基苯乙炔溴(40mmol)加入到反应瓶中,混合在Pd(PPh3)2Cl2和CuI作为催化剂的无水无氧催化体系中,其中催化剂的量为1.0mmol,Pd(PPh3)2Cl2:CuI=3:1。以三乙胺(100mmol)作碱,以无水乙腈(29mL)为溶剂,室温下搅拌反应16小时,将反应产物先后用15%的盐酸溶液、10%的碳酸氢钠溶液、饱和食盐水分别洗涤;然后用乙酸乙酯萃取,减压旋干,柱层析(淋洗剂中乙酸乙酯与石油醚的体积比为1:60)得到浅棕色固体产物。Diisopropylmalonate-bridged diyne compound (20mmol) and p-methoxyphenylacetylene bromide (40mmol) were added to the reaction flask, and mixed in Pd(PPh 3 ) 2 Cl 2 and CuI as the catalyst without In the water anaerobic catalytic system, where the amount of the catalyst is 1.0 mmol, Pd(PPh 3 ) 2 Cl 2 :CuI=3:1. With triethylamine (100mmol) as the base and anhydrous acetonitrile (29mL) as the solvent, the reaction was stirred at room temperature for 16 hours, and the reaction product was successively washed with 15% hydrochloric acid solution, 10% sodium bicarbonate solution and saturated saline respectively Washing; then extracted with ethyl acetate, spin-dried under reduced pressure, column chromatography (the volume ratio of ethyl acetate and petroleum ether in the eluent was 1:60) to obtain a light brown solid product.
在115℃的条件下,将中间体(1mmol)与二对甲苯基二硫醚(1.1mmol)加入到3.4毫升甲苯溶剂中,反应16小时,得到二芳基硫醚衍生物粗产品。Under the condition of 115° C., the intermediate (1 mmol) and di-p-tolyl disulfide (1.1 mmol) were added into 3.4 ml of toluene solvent, and reacted for 16 hours to obtain a crude product of diaryl sulfide derivative.
将二芳基硫醚衍生物粗产品加水洗涤后,用乙酸乙酯萃取,减压旋干,柱层析(淋洗剂中乙酸乙酯与石油醚的体积比为1:50)分离可得到纯化的目标产物,即二芳基硫醚衍生物,柱层析产率约为81%。After the diaryl sulfide derivative crude product is washed with water, it is extracted with ethyl acetate, spin-dried under reduced pressure, and separated by column chromatography (the volume ratio of ethyl acetate and petroleum ether in the eluent is 1:50) to obtain The purified target product, ie diaryl sulfide derivative, has a column chromatography yield of about 81%.
二芳基硫醚衍生物的结构通过1H NMR和13C NMR来测定,具体检测图谱见图5和图6。The structures of the diaryl sulfide derivatives were determined by 1 H NMR and 13 C NMR, and the specific detection spectra are shown in Fig. 5 and Fig. 6 .
白色固体产物:White solid product:
1H NMR(300MHz,CDCl3):δ7.16―7.08(m,4H),6.99(s,4H),6.90―6.73(m,8H),5.05―4.97(m,2H),3.82(s,3H),3.78(s,3H),3.74(s,2H),3.40(s,2H),2.25(s,3H),2.22(s,3H),1.23―1.15(m,12H,J=6.3Hz); 1 H NMR (300MHz, CDCl 3 ): δ7.16-7.08(m,4H),6.99(s,4H),6.90-6.73(m,8H),5.05-4.97(m,2H),3.82(s, 3H), 3.78(s, 3H), 3.74(s, 2H), 3.40(s, 2H), 2.25(s, 3H), 2.22(s, 3H), 1.23-1.15(m, 12H, J=6.3Hz );
13C NMR(75.5MHz,CDCl3):δ171.0,159.7,158.7,148.9,144.7,144.1,136.3,136.2,135.8,135.3,134.9,133.1,133.0,132.9,131.0,129.7,129.4,128.6,127.7,121.7,115.2,113.9,112.7,98.3,85.7,69.3,58.6,55.3,55.3,42.1,41.2,21.5,21.5,21.0。 13 C NMR (75.5MHz, CDCl 3 ): δ171.0, 159.7, 158.7, 148.9, 144.7, 144.1, 136.3, 136.2, 135.8, 135.3, 134.9, 133.1, 133.0, 132.9, 131.0, 129.7, 129.4, 127. , 115.2, 113.9, 112.7, 98.3, 85.7, 69.3, 58.6, 55.3, 55.3, 42.1, 41.2, 21.5, 21.5, 21.0.
实施例4Example 4
本实施例提供的一种二芳基硫醚类衍生物,其结构式如(IV)式所示。A diaryl sulfide derivative provided in this example has a structural formula as shown in formula (IV).
本实施例还提供一种制备上述二芳基硫醚类衍生物的方法:This embodiment also provides a method for preparing the above-mentioned diaryl sulfide derivatives:
将丙二酸二甲酯桥连的二炔化合物(20mmol)与苯乙炔溴(52mmol)加入到反应瓶中,混合在Pd(PPh3)2Cl2和CuI作为催化剂的无水无氧催化体系中,其中催化剂的量为0.8mmol,Pd(PPh3)2Cl2:CuI=3:1。以三乙胺(80mmol)作碱,以无水乙腈(33mL)为溶剂,室温下搅拌反应14小时,将反应产物先后用15%的盐酸溶液、10%的碳酸氢钠溶液、饱和食盐水分别洗涤;然后用乙酸乙酯萃取,减压旋干,柱层析(淋洗剂中乙酸乙酯与石油醚的体积比为1:50)得到浅棕色固体产物。Add dimethyl malonate-bridged diyne compound (20mmol) and phenylacetylene bromide (52mmol) into the reaction flask, mix in anhydrous and oxygen-free catalytic system with Pd(PPh 3 ) 2 Cl 2 and CuI as catalyst , wherein the amount of the catalyst is 0.8 mmol, Pd(PPh 3 ) 2 Cl 2 :CuI=3:1. With triethylamine (80mmol) as the base and anhydrous acetonitrile (33mL) as the solvent, the reaction was stirred at room temperature for 14 hours, and the reaction product was successively washed with 15% hydrochloric acid solution, 10% sodium bicarbonate solution, and saturated saline, respectively. Washing; then extracted with ethyl acetate, spin-dried under reduced pressure, column chromatography (the volume ratio of ethyl acetate and petroleum ether in the eluent was 1:50) to obtain a light brown solid product.
在100℃的条件下,将中间体(1mmol)与二对甲苯基二硫醚(1.0mmol)加入到10毫升甲苯溶剂中,反应22小时,得到二芳基硫醚衍生物粗产品。Under the condition of 100° C., the intermediate (1 mmol) and di-p-tolyl disulfide (1.0 mmol) were added into 10 ml of toluene solvent, and reacted for 22 hours to obtain a crude product of diaryl sulfide derivative.
将二芳基硫醚衍生物粗产品加水洗涤后,用乙酸乙酯萃取,减压旋干,柱层析(淋洗剂中乙酸乙酯与石油醚的体积比为1:60)分离可得到纯化的目标产物,即二芳基硫醚衍生物,柱层析产率约为78%。After the diaryl sulfide derivative crude product is washed with water, it is extracted with ethyl acetate, spin-dried under reduced pressure, and separated by column chromatography (the volume ratio of ethyl acetate and petroleum ether in the eluent is 1:60) to obtain The purified target product, ie diaryl sulfide derivative, has a column chromatography yield of about 78%.
二芳基硫醚衍生物的结构通过1H NMR和13C NMR来测定,具体检测图谱见图7和图8。The structures of the diaryl sulfide derivatives were determined by 1 H NMR and 13 C NMR, and the specific detection spectra are shown in Fig. 7 and Fig. 8 .
白色固体产物:White solid product:
1H NMR(300MHz,CDCl3):δ7.31―7.28(m,3H),7.24―7.19(m,5H),7.11―7.00(m,6H),6.89―6.87(d,2H,J=8.1Hz),6.75―6.72(d,2H,J=8.1Hz),3.80(s,2H),3.72(s,6H),3.47(s,2H),2.29(s,3H),2.22(s,3H); 1 H NMR (300MHz, CDCl 3 ): δ7.31-7.28(m, 3H), 7.24-7.19(m, 5H), 7.11-7.00(m, 6H), 6.89-6.87(d, 2H, J=8.1 Hz), 6.75-6.72(d, 2H, J=8.1Hz), 3.80(s, 2H), 3.72(s, 6H), 3.47(s, 2H), 2.29(s, 3H), 2.22(s, 3H );
13C NMR(75.5MHz,CDCl3):δ171.8,149.7,144.7,144.0,140.2,136.8,136.5,135.9,135.1,135.0,132.9,131.5,129.8,129.7,129.4,128.6,128.5,128.2,128.0,127.4,127.2,122.9,121.2,98.3,86.6,58.7,53.1,42.1,41.4,21.1,21.0。 13 C NMR (75.5MHz, CDCl 3 ): δ171.8, 149.7, 144.7, 144.0, 140.2, 136.8, 136.5, 135.9, 135.1, 135.0, 132.9, 131.5, 129.8, 129.7, 129.4, 128.6, 128.5, 1278. , 127.2, 122.9, 121.2, 98.3, 86.6, 58.7, 53.1, 42.1, 41.4, 21.1, 21.0.
综上所述,本发明实施例1-4提供的一系列新的二芳基硫醚类衍生物相对于普通硫醚衍生物,本发明制备的二芳基硫醚类衍生物有多环的存在,其结构更加复杂多样,在化工生产、临床医药中也将表现出更加广阔的用途前景。本发明的制备方法克服了以往反应中路线过长,底物和反应条件要求苛刻,取代官能团扩展有限的等缺点,该制备方法不但底物合成简单、试剂比较便宜,并且具有高原子经济性、绿色环保的得到目标分子,给二芳基硫醚类衍生物的工业化生产提供了一条很有价值的途径。In summary, a series of new diaryl sulfide derivatives provided by Examples 1-4 of the present invention are compared with common sulfide derivatives, and the diaryl sulfide derivatives prepared by the present invention are polycyclic Its structure is more complex and diverse, and it will also show a broader application prospect in chemical production and clinical medicine. The preparation method of the present invention overcomes the shortcomings of the previous reaction, such as the route being too long, the substrate and reaction conditions being harsh, and the extension of the substituted functional group limited. Obtaining the target molecule in an environment-friendly way provides a valuable way for the industrial production of diaryl sulfide derivatives.
以上所描述的实施例是本发明一部分实施例,而不是全部的实施例。本发明的实施例的详细描述并非旨在限制要求保护的本发明的范围,而是仅仅表示本发明的选定实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。The embodiments described above are some, not all, embodiments of the present invention. The detailed description of the embodiments of the invention is not intended to limit the scope of the claimed invention but to represent only selected embodiments of the invention. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without creative efforts fall within the protection scope of the present invention.
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