CN108059607B - 亚砜基乙酸或砜基乙酸类衍生物、其药物组合物、制备方法和用途 - Google Patents
亚砜基乙酸或砜基乙酸类衍生物、其药物组合物、制备方法和用途 Download PDFInfo
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- CN108059607B CN108059607B CN201610986779.8A CN201610986779A CN108059607B CN 108059607 B CN108059607 B CN 108059607B CN 201610986779 A CN201610986779 A CN 201610986779A CN 108059607 B CN108059607 B CN 108059607B
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- Prior art keywords
- phenyl
- acetic acid
- sulfoxide
- compound
- acid
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- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- VYNUATGQEAAPAQ-UHFFFAOYSA-N 2-sulfonylacetic acid Chemical compound OC(=O)C=S(=O)=O VYNUATGQEAAPAQ-UHFFFAOYSA-N 0.000 title description 5
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 18
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 17
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 8
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 8
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 99
- -1 sulfoxide acetic acid derivative Chemical class 0.000 claims description 66
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000003472 antidiabetic agent Substances 0.000 claims description 3
- 230000000879 anti-atherosclerotic effect Effects 0.000 claims description 2
- 229940127218 antiplatelet drug Drugs 0.000 claims description 2
- 229940044601 receptor agonist Drugs 0.000 claims description 2
- 239000000018 receptor agonist Substances 0.000 claims description 2
- 239000000883 anti-obesity agent Substances 0.000 claims 1
- 229940125708 antidiabetic agent Drugs 0.000 claims 1
- 229940125710 antiobesity agent Drugs 0.000 claims 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 14
- KHEDIYCQDPMFKF-UHFFFAOYSA-N 2-(sulfooxy)acetic acid Chemical compound OC(=O)COS(O)(=O)=O KHEDIYCQDPMFKF-UHFFFAOYSA-N 0.000 abstract description 10
- 230000001270 agonistic effect Effects 0.000 abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 152
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 117
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- 238000005481 NMR spectroscopy Methods 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- 230000015572 biosynthetic process Effects 0.000 description 46
- 238000003786 synthesis reaction Methods 0.000 description 45
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 238000000034 method Methods 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 26
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 25
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 25
- 239000003208 petroleum Substances 0.000 description 25
- 229910001868 water Inorganic materials 0.000 description 25
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 24
- 101710142060 Free fatty acid receptor 1 Proteins 0.000 description 23
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 23
- 239000008103 glucose Substances 0.000 description 23
- 150000003462 sulfoxides Chemical group 0.000 description 22
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 21
- 239000003153 chemical reaction reagent Substances 0.000 description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 19
- 239000008280 blood Substances 0.000 description 19
- 210000004369 blood Anatomy 0.000 description 19
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 19
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 150000007529 inorganic bases Chemical class 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 229940086542 triethylamine Drugs 0.000 description 10
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- BZCALJIHZVNMGJ-HSZRJFAPSA-N Fasiglifam Chemical compound CC1=CC(OCCCS(C)(=O)=O)=CC(C)=C1C1=CC=CC(COC=2C=C3OC[C@@H](CC(O)=O)C3=CC=2)=C1 BZCALJIHZVNMGJ-HSZRJFAPSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 239000011575 calcium Substances 0.000 description 9
- 229910052791 calcium Inorganic materials 0.000 description 9
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 9
- 150000007530 organic bases Chemical group 0.000 description 9
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- 150000002367 halogens Chemical class 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- 239000007800 oxidant agent Substances 0.000 description 8
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 7
- 239000000556 agonist Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 125000004452 carbocyclyl group Chemical group 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 6
- 230000002218 hypoglycaemic effect Effects 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000011550 stock solution Substances 0.000 description 6
- ZXDTWWZIHJEZOG-UHFFFAOYSA-N (2,6-dimethylphenyl)boronic acid Chemical compound CC1=CC=CC(C)=C1B(O)O ZXDTWWZIHJEZOG-UHFFFAOYSA-N 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- KBDHNNLJAIZVBC-UHFFFAOYSA-N CC1=C(C(=CC=C1)C)C2=CC=CC(=C2)COC3=CC=C(C=C3)SCC(=O)O Chemical compound CC1=C(C(=CC=C1)C)C2=CC=CC(=C2)COC3=CC=C(C=C3)SCC(=O)O KBDHNNLJAIZVBC-UHFFFAOYSA-N 0.000 description 5
- 239000012981 Hank's balanced salt solution Substances 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 150000001242 acetic acid derivatives Chemical class 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- IDHGYOQGMVANDO-UHFFFAOYSA-N 4-chloro-2,3-dihydro-1h-inden-1-ol Chemical compound C1=CC=C(Cl)C2=C1C(O)CC2 IDHGYOQGMVANDO-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- 150000001982 diacylglycerols Chemical class 0.000 description 4
- 229940043279 diisopropylamine Drugs 0.000 description 4
- ONYPOOPLTKMOLC-UHFFFAOYSA-N ethyl 2-(4-hydroxyphenyl)sulfanylacetate Chemical compound CCOC(=O)CSC1=CC=C(O)C=C1 ONYPOOPLTKMOLC-UHFFFAOYSA-N 0.000 description 4
- 230000003914 insulin secretion Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- BIEBZGCKLFWMCR-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-indene Chemical group C1C=CC=C2CCCC21 BIEBZGCKLFWMCR-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 238000007410 oral glucose tolerance test Methods 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- CNWINRVXAYPOMW-FCNJXWMTSA-N 1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-1D-myo-inositol 4,5-biphosphate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)O[C@H](COC(=O)CCCCCCCCCCCCCCCCC)COP(O)(=O)O[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H]1O CNWINRVXAYPOMW-FCNJXWMTSA-N 0.000 description 2
- TZXFWWLEMDTIOR-UHFFFAOYSA-N 2-[3-(bromomethyl)phenyl]-1,3-dimethylbenzene Chemical group BrCC=1C=C(C=CC=1)C1=C(C=CC=C1C)C TZXFWWLEMDTIOR-UHFFFAOYSA-N 0.000 description 2
- MBGUKJYEJSSXPY-UHFFFAOYSA-N 2-[[3-(2,6-dimethylphenyl)phenyl]methoxy]thiophene Chemical compound CC1=C(C(=CC=C1)C)C1=CC(=CC=C1)COC=1SC=CC=1 MBGUKJYEJSSXPY-UHFFFAOYSA-N 0.000 description 2
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical compound Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 description 2
- NPAXPTHCUCUHPT-UHFFFAOYSA-N 3,4,7,8-tetramethyl-1,10-phenanthroline Chemical compound CC1=CN=C2C3=NC=C(C)C(C)=C3C=CC2=C1C NPAXPTHCUCUHPT-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- VQFOHZWOKJQOGO-UHFFFAOYSA-N 4-fluorobenzenecarbothioamide Chemical compound NC(=S)C1=CC=C(F)C=C1 VQFOHZWOKJQOGO-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- 229960003329 sulfinpyrazone Drugs 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及下面通式(I)所示结构的亚砜基乙酸或砜基乙酸类衍生物、及其药学上可接受的盐或含有该类衍生物的药物组合物以及其制备方法。所述的亚砜基乙酸或砜基乙酸类衍生物对GPR40受体显示出较高的激动活性，可用作制备治疗糖尿病和/或代谢综合症的药物。
Description
技术领域
本发明涉及一种亚砜基乙酸或砜基乙酸类衍生物、及其药学上可接受的盐或含有该类衍生物的药物组合物以及其制备方法。本发明还涉及所述的亚砜基乙酸或砜基乙酸类衍生物、及其药学上可接受的盐或含有该类衍生物的药物组合物在制备G蛋白偶联受体40(GPR40)激动剂，和在制备治疗糖尿病和代谢综合症等疾病的药物中的用途。
背景技术
糖尿病是当人体不能产生足够的胰岛素或是不能有效的利用胰岛素引起的慢性代谢性疾病。糖尿病患者长期存在的高血糖将导致各种组织，特别是眼、肾、心脏、血管、神经的慢性损害等功能障碍。根据国际糖尿病联盟(International Diabetes Federation)的公布的最新统计数据，2015年，全球已有4.15亿成年糖尿病患者(20-79岁)，预计2040年将增加至6.42亿。其中，中国已有糖尿病患者1.09亿，居全球之首，预计2040年将增加至1.50亿。糖尿病在中国和其他发展中国家的快速增长，已给这些国家的社会和经济发展带来非常沉重的负担。全球用于治疗糖尿病和预防并发症的费用估计达到7950亿到1404亿。因此，国内外防止和治疗糖尿病的形势都非常严峻。
目前抗II型糖尿病的药物主要有胰岛素增敏剂，如二甲双胍、噻唑烷二酮类。减少肾葡萄糖重吸收，如葡萄糖协同转运蛋白2(SGLT2)抑制剂。胰岛素分泌促进剂，如磺酰脲类、格列奈类、胰高血糖素样肽-1(GLP-1)类。但是多数药物在降血糖的同时会伴有导致低血糖的风险，而且，一些药物还会引起体重增加、胃肠道不适、水肿、骨折风险增高等副作用。
GPR40，又称游离脂肪酸1(FFA1)受体，属于G-蛋白偶联受体(GPCR)家族，具有经典的七次跨膜结构，其主要分布在胰岛β细胞肠内分泌细胞。GPR40的内源性激动剂为中、长链脂肪酸，如癸酸、油酸、二十二碳六烯酸。内源性激动剂与GPR40结合后，活化的GPR40与异源三聚G蛋白Gq/11结合，促进磷脂酶C(PLC)水解4,5-二磷酸磷脂酰肌醇(PIP2)生成三磷酸肌醇(IP3)和二脂酰甘油(DAG)。IP3作用于IP3R引起内质网钙库中钙离子的释放，促进胰岛素分泌8；同时，DAG也可以直接激活蛋白激酶C或通过激动DAG-敏感的蛋白激酶D1(PrKD1)使纤维状肌动蛋白(F-Actin)聚合，活化胰岛素颗粒的胞吐作用而分泌胰岛素。GPR40受体也是血糖依赖型促胰岛素分泌靶点。即仅在血糖浓度过高时，药物才会促进胰岛素分泌；在血糖浓度正常时，即使给药胰岛素分泌量也不会增加。这样就大大降低了产生低血糖的风险。基于以上特点，GPR40激动剂可以用来治疗II型糖尿病以及相关适应症。因此，发现和改造GPR40激动剂，对于科学研究和临床应用都有非常重要的价值。
目前公开了一系列的GPR40激动剂的专利申请，其中包括WO2011069958、US2011053974、WO2016019863、WO2010085525、US2012004166、US20150148347、WO2015020184、WO2014073904和WO2015088868等。
尽管目前已经公布了一系列的GPR40激动剂的专利申请，但仍需开发新的具有更好药效的化合物。本发明设计具有通式(I)所示结构的亚砜基乙酸或砜基乙酸类衍生物能够激动GPR40受体以及降血糖活性。
发明内容
本发明的一个目的是提供一类通式(I)所示的亚砜基乙酸或砜基乙酸类衍生物、其外消旋体、对映异构体或非对映异构体、或它们的药学上可接受的盐。所述化合物对GPR40受体显示出较高的激动活性，可用作治疗糖尿病和/或代谢综合症的药物。
本发明的再一目的为提供制备上述通式(I)所示的亚砜基乙酸或砜基乙酸类衍生物的方法。
本发明的再一目的为提供包含治疗有效量的选自根据本发明通式(I)所示的亚砜基乙酸或砜基乙酸类衍生物和其药学上可接受的盐中的一种或多种作为活性成分的药物组合物。所述药物组合物任选可以进一步包含药学上可接受的载体、佐剂或辅料。
本发明的再一目的为提供上述通式(I)所示的亚砜基乙酸或砜基乙酸类衍生物、其外消旋体、对映异构体或非对映异构体、或它们的药学上可接受的盐、或者包含上述通式(I)所示的亚砜基乙酸或砜基乙酸类衍生物、其外消旋体、对映异构体或非对映异构体、或它们的药学上可接受的盐的药物组合物在制备用于治疗糖尿病和/或代谢综合症的药物中的用途。
本发明的再一目的为提供一种药物组合物，其包含治疗有效量的选自根据本发明的通式(I)所示的亚砜基乙酸或砜基乙酸类衍生物、其外消旋体、对映异构体、非对映异构体、和它们的药学上可接受的盐中的一种或多种作为活性成分以及其他药学上可接受的治疗剂，特别是其他治疗糖尿病的药物。所述药物组合物任选可以进一步包含药学上可接受的载体、佐剂或辅料。
本发明的再一目的为提供一种治疗糖尿病和/或代谢综合症的方法，所述方法包括给需要该治疗的患者给药治疗有效量的选自根据本发明通式(I)所示的亚砜基乙酸或砜基乙酸类衍生物、其外消旋体、对映异构体或非对映异构体、或它们的药学上可接受的盐中的一种或多种，或根据本发明的包含治疗有效量的选自根据本发明的化合物和其药学上可接受的盐中的一种或多种作为活性成分的药物组合物。
本发明的第一方面，提供了一种通式(I)所述的亚砜基乙酸或砜基乙酸类衍生物、其外消旋体、对映异构体或非对映异构体或它们的药学上可接受的盐：
其中：R3为
所述R4为羟基，氨基，-NHOH或
n为1或2；
Y为-O-，-O-CH2-，-NH-CH2-，-CH2-O-，-CH2-NH-或-C≡C-；
环C为苯环，噻吩环或吡啶环；
环A为苯环，噻吩环，噻唑环，吡啶环，茚环或四氢茚环；
R2为氢、卤素、氰基、羟基、硝基、氨基、C1-C6烷基、C1-C6烷氧基、C3-C10碳环基或C3-C10碳氧环基，所述C1-C6烷基、C1-C6烷氧基、C3-C10碳环基、C3-C10碳氧环基任选进一步被一个或多个选自卤素、氰基、羟基的取代基所取代；
环B为苯环，吡啶环，吡唑环，嘧啶环，异恶唑环或不存在；
R1和R5为环B上的取代基，且各自独立地选自氢、卤素、氰基、羟基、硝基、氨基、C1-C6烷基、C1-C6烷氧基、C3-C10碳环基或C3-C10碳氧环基，所述C1-C6烷基、C1-C6烷氧基、C3-C10碳环基或C3-C10碳氧环基任选进一步被一个或多个选自卤素、氰基或羟基的取代基所取代；
优选地，
R3为
其中R4为羟基，-NHOH或
n为1或2；
Y为-O-，-O-CH2-，-CH2-O-或-C≡C-；
环C为苯环或噻吩环；
环A为苯环，噻唑环或四氢茚环；
R2为氢、卤素或C1-C6烷基，所述C1-C6烷基进一步被一个或多个选自卤素、氰基或羟基的取代基所取代；
环B独立选自苯环、吡啶环、吡唑环、异恶唑环或不存在；
R1和R5为环B上的取代基，且各自独立地选自氢、卤素、氰基、C1-C6烷基或C1-C6烷氧基，所述C1-C6烷基进一步被一个或多个选自卤素、氰基或羟基的取代基所取代；
进一步优选地，
R3为
其中R4为羟基，-NHOH或
n为1或2；
Y为-O-、-O-CH2-、-CH2-O-或-C≡C-；
环C为苯环或噻吩环；
环A为苯环，噻唑环或四氢茚环；
R2为氢、氟、氯、溴、甲基或三氟甲基；
环B为苯环、吡啶环、吡唑环、异恶唑环或不存在；
R1和R5为环B上的取代基，且各自独立地选自氢、氟、氯、溴、甲基或甲氧基。
在本发明一个优选的实施方案中，所述通式(I)的化合物为由以下通式之一表示的化合物：
其中，环A，环B，环C，R1，R2和R5与通式(I)中的限定相同。
在本发明的一个优选的实施方案中，所述通式(I)的化合物为发明的化合物优选选自下列化合物中：
或其外消旋体、对映异构体、非对映异构体、及其药学上可接受的盐。
本发明的化合物可含有一个或多个不对称中心，因而可作为外消旋体和单一对映异构体、非对映异构体混合物和单一非对映异构体出现。本发明的化合物在亚砜官能团处可有一个不对称中心，根据分子中各取代基的性质，可出现其他不对称中心。这类不对称中心会各自独立的产生两个光学异构体，本发明范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。
在本发明的第二方面，还提供了一种制备本发明的通式(I)的化合物的方法，所述方法为以下方案之一。
方案一：
其中环A、环B、环C、R1、R2和R5的定义如通式(I)中所述,所述PG可以是乙基或叔丁基。
方案一包括如下步骤：
(a)醇类化合物(IV)可以通过硼酸类化合物(II)和溴代化合物(III)溶于溶剂中，在碱的存在和钯催化剂的催化下，70-100℃下反应得到。其中所述的钯催化剂选自四(三苯基膦)钯、氯化钯、乙酸钯、三氟乙酸钯、三(二亚苄基丙酮)二钯、双(乙腈)氯化钯等，优选为四(三苯基膦)钯；所述的碱选自碳酸钠、碳酸钾、碳酸铯、磷酸钾、磷酸一氢钾等，优选为碳酸钠；所述的溶剂选自四氢呋喃，1,4-二氧六环，异丙醇和水的中一种或几种，优选为1,4-二氧六环和水体积比为1:3～1:4的混合溶剂；
(b)将得到的醇类化合物(IV)在四溴化碳或四氯化碳(优选四溴化碳)和三苯基膦的作用下，反应得到溴代化合物(V)；
(d)然后溴代化合物(V)与硫醚化合物(VIII)在碱性作用下，经SN2亲和反应得到化合物(IX)，其中碱选自有机碱和无机碱，有机碱选自三乙胺、二异丙基胺等，无机碱选自氢氧化钾、氢氧化钠、碳酸钠、碳酸钾、碳酸铯、磷酸钾、磷酸一氢钾等；优选为碳酸钾；
(c)化合物(VIII)可以通过化合物(VI)和(VII)在碱性条件下反应制备，所述碱选自有机碱和无机碱，有机碱选自三乙胺、二异丙基胺等；
(e)化合物(IX)可被氧化剂在室温下氧化成化合物(X)，所述的氧化剂选自过氧化氢、间氯过氧苯甲酸、过氧乙酸等，最优为间氯过氧苯甲酸；
(f)化合物(IX)可被氧化剂在-20℃下氧化成化合物(XI)，所述的氧化剂选自过氧化氢、间氯过氧苯甲酸、过氧乙酸等，最优为间氯过氧苯甲酸；
(g)化合物(X)或化合物(XI)在碱性条件下水解，分别得到化合物(XIII)和(XII)，所述碱选自有机碱和无机碱，无机碱选自氢氧化钾、氢氧化钠、氢氧化锂、一水氢氧化锂等，优选为一水氢氧化锂。
方案二：
化合物(XIV)在丁基锂下存在下形成负离子，其与硫粉和化合物(VII)反应也可以得到化合物(IX)。
其中环A、环B、环C、R1、R2和R5的定义如通式(I)中所述，PG可以是乙基或叔丁基。
方案二包括如下步骤：
(h)化合物(XIV)在锂试剂存在下形成负离子，然后进一步与硫粉和化合物(VII)反应得到化合物(IX)；所述锂试剂选自正丁基锂和叔丁基锂，优选正丁基锂；
(e)化合物(IX)可被氧化剂在-20℃下氧化成化合物(XI)，所述的氧化剂选自过氧化氢、间氯过氧苯甲酸、过氧乙酸等，最优为间氯过氧苯甲酸；
(f)化合物(IX)可被氧化剂在室温下氧化成化合物(X)，所述的氧化剂选自过氧化氢、间氯过氧苯甲酸、过氧乙酸等，最优为间氯过氧苯甲酸；
(g)化合物(X)或化合物(XI)在碱性条件下水解，分别得到化合物(XIII)或(XII)，所述碱选自有机碱和无机碱，无机碱选自氢氧化钾、氢氧化钠、氢氧化锂、一水氢氧化锂等，优选为一水氢氧化锂。
方案三:
亚砜基类化合物手性拆分路线：
其中环A、环B、环C、R1、R2和R5的定义如通式(I)中所述，PG可以是乙基或叔丁基。
方案三包括如下步骤：
(i)化合物(IX)在碱性条件下水解，得到化合物(XV)，所述碱选自有机碱和无机碱，无机碱选自氢氧化钾、氢氧化钠、氢氧化锂、一水氢氧化锂等，优选为一水氢氧化锂；
(j)化合物(XV)与手性辅助试剂(如(L)-薄荷醇)在缩合剂和碱的作用下，缩合得到化合物(XVI)，其中所述的缩合剂选自1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)、二环己基碳二亚胺(DCC)等，优选为EDCI；所述的碱选自三乙胺、二异丙基胺、N,N-二甲基-4-吡啶胺等，优选为N,N-二甲基-4-吡啶胺；
(k)化合物(XVI)在氧化物下氧化得到(XVII)；所述的氧化剂选自过氧化氢、间氯过氧苯甲酸、过氧乙酸等，最优为间氯过氧苯甲酸；
(l)非对映异构体(XVII)用手性柱拆分得到光学纯的化合物(XVIII)和化合物(XIX)；
(m)然后化合物(XVIII)或化合物(XIV)分别在碱性条件下水解，得到化合物(XX)或化合物(XXI)，所述碱选自有机碱和无机碱，无机碱选自氢氧化钾、氢氧化钠、氢氧化锂、一水氢氧化锂等，优选为一水氢氧化锂。
方案四：
其中环A、环B、环C、R1、R2和R5的定义如通式(I)中所述，PG可以是乙基或叔丁基。
方案四包括如下步骤：
(n)方案一中合成的化合物(XI)同盐酸羟胺在碱性条件下反应，得到化合物(XXII)，所述碱选自氢氧化钾、氢氧化钠、氢氧化锂、一水氢氧化锂等，优选为氢氧化钾；
(o)方案一中合成的化合物(XII)和甘氨酸乙酯盐酸盐，在碱和缩合剂作用下，缩合得到化合物(XXIII)，其中所述的缩合剂选自1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)、二环己基碳二亚胺(DCC)等，优选EDCI；所述的碱选自三乙胺、二异丙基胺，N,N-二甲基-4-吡啶胺等，优选为N,N-二甲基-4-吡啶胺；
(p)化合物(XXIII)在碱性条件下水解，得到化合物(XXIV)，所述碱选自有机碱和无机碱，无机碱选自氢氧化钾、氢氧化钠、氢氧化锂、一水氢氧化锂等，优选为一水氢氧化锂。
对本发明的化合物，在亚砜官能团处可有一个不对称中心，导致对映异构体的外消旋混合物。在实施例中提供了制备手性化合物的方法，对映异构体混合物可通过各种方法如与手性碱形成盐和结晶，手性色谱等方式分离成各个异构体。
本发明的术语“保护基团”或“PG”是指一个取代基与其它官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括氰基乙基、2-(三甲基硅烷基)乙基、2-(三甲基硅烷基)乙基甲基、2-(对甲苯磺酰基)乙基、2-(对硝基苯磺酰基)乙基、2-(二苯基膦基)乙基、硝基乙基等。
本发明的另一方面涉及通式(I)所述的化合物或其药学上可接受的盐在制备GPR40受体激动剂的药物中的用途。
本发明的另一方面涉及通式(I)所述的化合物或其药学上可接受的盐在制备用于治疗糖尿病和/或代谢综合征的药物中的用途。
本发明的另一方面涉及一种药物组合物，其含有治疗有效剂量的通式(I)所述的化合物或其其药学上可接受的盐及其可药用的载体(例如，稀释剂、赋形剂等)。
在一些实施方案中，所述药物组合物更进一步地包含抗糖尿病药物、抗高血糖药物、抗肥胖症药物、抗血小板药物、抗动脉粥样硬化药物或其组合。
本发明的另一方面涉及通式(I)所述的化合物或其药学上可接受的盐，或药物组合物治疗糖尿病和/或代谢综合征的用途。
附图说明
图1本发明化合物S2在C57/BL6小鼠OGTT模型上的降血糖作用；
图2本发明化合物S2在C57/BL6小鼠OGTT模型上的降血糖作用(以TAK-875为对照)。
具体实施方式
下面结合制备实施例对本发明作进一步描述，但不限制本发明。
化合物的1HNMR数据测试使用Varian Mercury-300Hz或Varian Mercury-400Hz核磁共振，用氘代氯仿(CDCl3)为溶剂，以四甲基硅烷(TMS)为内标，化学位移单位为ppm。比旋光由P-1030(A012360639)自动旋光仪测定。所有反应溶剂均按常规方法进行纯化。柱层析用硅胶(200-300目)为青岛海洋化工分厂生产；TLC硅胶板为烟台化工厂生产的HSGF-254型薄层层析硅胶板，薄层层析使用的层析板厚度为0.2±0.03mm。采用紫外、碘、高锰酸钾等方法显色。减压蒸除有机溶剂在旋转蒸发仪中进行。(2,6-二甲基苯基)硼酸,四三苯基膦钯等原料通常是从市售来源可获得的，比如Aldrich Chemicals Co.和Acros Organics，有机溶剂石油醚(沸程60-90℃)，二氯甲烷，乙酸乙酯，甲醇均为分析纯，由上海泰坦科技股份有限公司或者国药集团化学试剂有限公司提供，所用试剂和溶剂除特别说明外，均未经特别处理。
制备实施例1
2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)
反应试剂和条件：i)(2,6-二甲基苯基)硼酸,四三苯基膦钯,碳酸钠，水，1,4-二氧六环；ii)三苯基膦，四溴化碳，二氯甲烷；iii)2-溴乙酸乙酯，三乙胺，二氯甲烷；iv)碳酸钾，丙酮；v)间氯过氧苯甲酸，二氯甲烷，-20℃至室温；vi)一水合氢氧化锂，四氢呋喃，甲醇，水。
合成步骤
步骤1(2',6'-二甲基-[1,1'-二苯基]-3-基)甲醇
密封的回流冷凝管烧瓶装置中加入磁子、(2,6-二甲基苯基)硼酸(780mg，5mmol)、(3-溴苯基)甲醇(500μL，4.17mmol)、四三苯基膦钯(241mg，0.21mmol)和碳酸钠(884mg，8.34mmol)。抽换气三次，注入37.5mL 1,4-二氧六环和12.5mL水，反应过夜。二氯甲烷萃取，无水硫酸钠干燥，用乙酸乙酯/石油醚过硅胶柱，得无色油状物447mg。
1H NMR(300MHz,CDCl3)δ7.46–7.29(m,2H),7.10(t,J＝11.1Hz,5H),4.73(d,J＝5.7Hz,2H),2.01(s,6H)。
步骤2 3'-(溴甲基)-2,6-二甲基-1,1'-联苯
将(2',6'-二甲基-[1,1'-二苯基]-3-基)甲醇(447mg，2.1mmol)溶于20mL二氯甲烷。在冰浴下，加入三苯基膦(829mg，3.16mmol)和四溴化碳(1.047g，3.16mmol)。反应1h后，浓缩，用乙酸乙酯/石油醚过硅胶柱，得到无色油状物500mg。
1H NMR(300MHz,CDCl3)δ7.43–7.32(m,2H),7.20–7.04(m,5H),4.52(s,2H),2.02(s,6H)。
步骤3 2-((4-羟基苯基)巯基)乙酸乙酯
称取4-羟基苯硫酚(300mg，2.378mmol)溶于10mL的二氯甲烷中。加入三乙胺(1.6mL，11.89mmol)和2-溴乙酸乙酯(248μL，2.615mmol)，反应两个小时。萃取，旋干。
1H NMR(300MHz,CDCl3)δ7.33(d,J＝8.3Hz,2H),6.73(d,J＝8.3Hz,2H),4.12(q,J＝7.1Hz,2H),3.47(s,2H),1.20(t,J＝7.4Hz,3H)。
步骤4 2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)巯基)乙酸乙酯
称取步骤3中制备的2-((4-羟基苯基)巯基)乙酸乙酯(800mg，3.769mmol)溶于10mL丙酮中，加入碳酸钾(1.42g，10.228mmol)。搅拌30min后，加入3'-(溴甲基)-2,6-二甲基-1,1'-联苯(943mg，3.426mmol)，反应过夜。二氯甲烷萃取，无水硫酸钠干燥，用乙酸乙酯/石油醚过硅胶柱，得无色油状物285mg。
1H NMR(400MHz,CDCl3)δ7.50–7.34(m,4H),7.22–7.07(m,5H),6.92(d,J＝8.7Hz,2H),5.10(s,2H),4.23–4.11(m,2H),3.51(s,2H),2.01(s,6H),1.21(t,J＝7.1Hz,3H)。
步骤5 2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸乙酯
称取2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)巯基)乙酸乙酯(285mg，0.701mmol)溶于5mL的二氯甲烷。冷却至-20℃，将间氯过氧苯甲酸86.38％(140mg，0.701mmol)溶于3mL二氯甲烷，缓慢注入上体系。1h后，升至室温。二氯甲烷萃取，无水硫酸钠干燥，用乙酸乙酯/石油醚过硅胶柱，得白色固体166mg。
1H NMR(300MHz,CDCl3)δ7.63(d,J＝8.8Hz,2H),7.52–7.35(m,2H),7.24–7.03(m,7H),5.17(s,2H),4.13(t,J＝6.5Hz,2H),3.87(d,J＝13.5Hz,1H),3.62(d,J＝13.5Hz,1H),2.01(s,6H),1.21(t,J＝7.2Hz,3H)。
步骤6 2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)
称取2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸乙酯(166mg，0.393mmol)溶于2mL的四氢呋喃，再加入2mL的甲醇和1mL的水。加入一水合氢氧化锂(50mg,1.179mmol)，反应30min后，用稀盐酸调至酸性。二氯甲烷萃取，无水硫酸钠干燥，浓缩，石油醚重结晶，得到白色固体130mg。
1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.8Hz,2H),7.49(t,J＝7.6Hz,1H),7.42(d,J＝7.6Hz,1H),7.25–7.08(m,7H),5.19(s,2H),3.87(d,J＝14.6Hz,1H),3.69(d,J＝14.5Hz,1H),2.03(s,6H)。
制备实施例2
(S)-2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S2)
反应试剂和条件：(i)一水合氢氧化锂，四氢呋喃，甲醇，水；(ii)(L)-薄荷醇，4-二甲氨基吡啶，二氯甲烷；(iii)间氯过氧苯甲酸，二氯甲烷，-20℃；(iv)一水合氢氧化锂，四氢呋喃，甲醇，水。
合成步骤
步骤1 2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)巯基)乙酸
合成2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)巯基)乙酸的步骤与合成2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸的步骤相同
步骤2 2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)巯基)乙酸L-薄荷醇酯
称取2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)巯基)乙酸(366mg,0.967mmol)、L-薄荷醇(454mg，2.901mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(556mg，2.901mmol)和4-二甲氨基吡啶(DMAP)(59mg，0.484mmol)溶于10mL的无水二氯甲烷，室温反应过夜。二氯甲烷萃取，无水硫酸钠干燥，用乙酸乙酯/石油醚过硅胶柱，得无色油状物438mg。
1H NMR(400MHz,CDCl3)δ7.51–7.39(m,4H),7.22(t,J＝2.4Hz,1H),7.20–7.16(m,1H),7.16–7.09(m,3H),6.97–6.90(m,2H),5.11(s,2H),4.69(td,J＝10.9,4.4Hz,1H),3.54(s,2H),2.04(s,6H),1.98–1.90(m,1H),1.77(dtd,J＝14.1,7.0,2.7Hz,1H),1.67(ddt,J＝16.3,6.4,3.2Hz,2H),1.55–1.41(m,1H),1.41–1.31(m,1H),1.10–1.01(m,1H),1.00–0.94(m,1H),0.91(d,J＝6.6Hz,4H),0.86(d,J＝7.0Hz,4H),0.71(d,J＝6.9Hz,3H)。
步骤3 2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸L-薄荷醇酯
称取2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)巯基)乙酸L-薄荷醇酯(438mg，0.848mmol)溶于10mL的二氯甲烷。降温至-20℃，将间氯过氧苯甲酸(70％)(209mg，0.848mmol)溶于5mL的二氯甲烷缓慢的注入上液。反应1h。萃取，旋干，过柱。然后于室温下使用大赛璐公司IC 10mmx250mm手性柱进行手性拆分，该柱用乙醇:己烷(25:75)，以4mL/min的流速洗脱。在出峰时间t1＝11分钟，t2＝13分钟时，分别得到两种无色油状物，即组分一(230mg)和组分二(230mg)。
1H NMR(300MHz,CDCl3)δ7.64(d,J＝8.7Hz,2H),7.51–7.33(m,2H),7.23–7.03(m,7H),5.15(s,2H),4.67(td,J＝11.0,4.5Hz,1H),3.89(d,J＝13.4Hz,1H),3.64(d,J＝13.2Hz,1H),2.01(s,6H),1.79(dd,J＝8.3,5.4Hz,2H),1.66(d,J＝11.5Hz,2H),1.28(dt,J＝8.6,5.9Hz,3H),1.13–0.91(m,1H),0.87(dd,J＝6.6,2.8Hz,8H),0.72(d,J＝7.0Hz,3H)。
步骤4(S)-2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S2)
称取步骤3中制备的组分一(220mg，0.520mmol)溶于4mL的四氢呋喃，再加入4mL的甲醇和2mL的水。加入一水合氢氧化锂(65mg，1.56mmol)，反应30min后，分别用稀盐酸调至酸性。二氯甲烷萃取，无水硫酸钠干燥，浓缩，石油醚重结晶，得到白色固体100mg。
1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.8Hz,2H),7.49(t,J＝7.6Hz,1H),7.42(d,J＝7.6Hz,1H),7.25–7.08(m,7H),5.19(s,2H),3.87(d,J＝14.6Hz,1H),3.69(d,J＝14.5Hz,1H),2.03(s,6H)。[α]20 D＝-104.554(c＝0.5,CH3OH)。
制备实施例3
(R)-2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S3)
称取实施2中2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸L-薄荷醇酯制得的组份二(220mg，0.520mmol)溶于4mL的四氢呋喃，再加入4mL的甲醇和2mL的水。加入一水合氢氧化锂(65mg，1.56mmol)，反应30min后，分别用稀盐酸调至酸性。二氯甲烷萃取，无水硫酸钠干燥，浓缩，石油醚重结晶，得到白色固体110mg。
1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.8Hz,2H),7.49(t,J＝7.6Hz,1H),7.42(d,J＝7.6Hz,1H),7.25–7.08(m,7H),5.19(s,2H),3.87(d,J＝14.6Hz,1H),3.69(d,J＝14.5Hz,1H),2.03(s,6H)。[α]20 D＝101.787(c＝0.5,CH3OH)。
通过结晶和单晶衍射实验，确定该化合物的绝对构型为R型。
制备实施例4
2-((3-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S4)
合成步骤同实施例1
1H NMR(400MHz,CDCl3)δ7.50–7.36(m,3H),7.26–7.06(m,7H),5.14(s,2H),3.75(br,2H),2.05(d,J＝23.8Hz,6H)。
制备实施例5
2-((4-((4-氯-2,3-二氢-1H-茚-1-基)氧)苯基)亚砜基)乙酸(S5)
反应试剂和条件：i)硼氢化钠，甲醇；ii)2-((4-羟基苯基)巯基)乙酸乙酯，偶氮二甲酸二乙酯，三苯基膦，四氢呋喃，0℃-室温；iii)间氯过氧苯甲酸，二氯甲烷，-20℃；iv)一水合氢氧化锂，四氢呋喃，甲醇，水.
合成步骤1 4-氯-2,3-二氢-1H-茚-1-醇
称取4-氯-2,3-二氢-1H-茚-1-酮(200mg，1.2mmol)溶于10mL甲醇中，加入硼氢化钠(46mg，1.2mmol)，室温下反应1h。萃取，无水硫酸钠干燥，浓缩，得4-氯-2,3-二氢-1H-茚-1-醇(100mg)。
1H NMR(400MHz,CDCl3)δ7.33(d,J＝7.8Hz,1H),7.28(d,J＝7.4Hz,1H),7.22(t,J＝7.9Hz,1H),5.35–5.25(m,1H),3.13(ddd,J＝16.7,8.7,4.6Hz,1H),2.94–2.78(m,1H),2.61–2.49(m,1H),2.05–1.94(m,1H)。
步骤2 2-((4-((4-氯-2,3-二氢-1H-茚-1-基)氧基)苯基)巯基)乙酸乙酯
称取步骤1中制得的4-氯-2,3-二氢-1H-茚-1-醇(100mg，0.593mmol)、2-((4-羟基苯基)巯基)乙酸乙酯(84mg，0.395mmol)和三苯基膦(166mg，0.632mmol)溶于6mL的四氢呋喃，冰浴下，注入偶氮二甲酸二乙酯(100μL，0.632mmol)，升至室温反应3h。二氯甲烷萃取，无水硫酸钠干燥，浓缩，石油醚/乙酸乙酯过硅胶柱，得到无色油状物70mg。
1H NMR(300MHz,CDCl3)δ7.44(d,J＝8.7Hz,2H),7.30(dd,J＝7.5,2.4Hz,2H),7.24–7.15(m,1H),6.93(d,J＝8.7Hz,2H),5.76(dd,J＝6.6,4.4Hz,1H),4.16(q,J＝7.1Hz,2H),3.53(s,2H),3.17(ddd,J＝16.3,8.9,5.4Hz,1H),3.08–2.81(m,1H),2.74–2.47(m,1H),2.21(dq,J＝7.4,4.9Hz,1H),1.23(t,J＝7.1Hz,3H)。
步骤3 2-((4-((4-氯-2,3-二氢-1H-茚-1-基)氧基)苯基)亚砜基)乙酸乙酯
合成步骤同2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸乙酯
1H NMR(300MHz,CDCl3)δ7.66(d,J＝8.7Hz,2H),7.32(t,J＝6.8Hz,2H),7.21(t,J＝7.9Hz,1H),7.12(d,J＝8.6Hz,2H),5.85(dd,J＝6.2,4.4Hz,1H),4.16(q,J＝7.1Hz,2H),3.89(d,J＝13.5Hz,1H),3.65(d,J＝13.5Hz,1H),3.28–3.12(m,1H),3.08–2.92(m,1H),2.72–2.55(m,1H),2.29–2.15(m,1H),1.23(t,J＝7.1Hz,3H)。
步骤4 2-((4-((4-氯-2,3-二氢-1H-茚-1-基)氧)苯基)亚砜基)乙酸(S5)
合成步骤同2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)
1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.7Hz,2H),7.35(t,J＝8.7Hz,2H),7.24(t,J＝7.7Hz,1H),7.17(d,J＝8.6Hz,2H),5.87(dd,J＝6.4,4.0Hz,1H),3.90(d,J＝15.9Hz,1H),3.81(d,J＝14.3Hz,1H),3.21(ddd,J＝16.4,8.6,5.5Hz,1H),3.02(ddd,J＝16.8,8.7,5.3Hz,1H),2.71–2.58(m,1H),2.31–2.18(m,1H)。
制备实施例6
2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)砜基)乙酸(S6)
反应试剂和条件i)间氯过氧苯甲酸，二氯甲烷，室温；ii)一水合氢氧化锂，四氢呋喃，甲醇，水；
合成步骤
步骤1 2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)砜基)乙酸乙酯
称取2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)巯基)乙酸乙酯(135mg，0.332mmol)溶于3mL的二氯甲烷中，加入间氯过氧苯甲酸(246mg，0.996mmol)反应过夜，萃取，干燥，V乙酸乙酯/(V乙酸乙酯+V石油醚)＝15/100过硅胶柱，得到产物白色固体132mg。
1H NMR(300MHz,CDCl3)δ7.87(d,J＝8.8Hz,2H),7.47(t,J＝7.7Hz,1H),7.39(d,J＝7.7Hz,1H),7.23–7.03(m,7H),5.20(s,2H),4.15(q,J＝7.0Hz,2H),4.08(s,2H),2.01(s,6H),1.21(t,J＝7.2Hz,3H)。
步骤2 2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)砜基)乙酸(S6)
合成步骤同2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)
1H NMR(300MHz,CDCl3)δ7.88(d,J＝8.8Hz,2H),7.47(t,J＝7.6Hz,1H),7.39(d,J＝7.9Hz,1H),7.20(s,1H),7.19–7.05(m,6H),5.20(s,2H),4.12(s,2H),2.00(s,6H)。
制备实施例7
2-((3-((2',6'-二甲基-[1,1'-联苯基]-4-基)甲氧基)苯基)亚砜基)乙酸(S7)
合成步骤同实施例1
1H NMR(300MHz,CDCl3)δ7.48(dd,J＝7.5,4.3Hz,3H),7.37(d,J＝1.1Hz,1H),7.17(dt,J＝14.6,8.0Hz,7H),5.16(s,2H),3.89(d,J＝15.2Hz,1H),3.68(d,J＝14.2Hz,1H),2.03(s,6H)。
制备实施例8
2-((4-((2-甲基苯基)氧基)苯基)亚砜基)乙酸(S8)
合成步骤同实施例1
1H NMR(300MHz,CDCl3)δ7.65(d,J＝8.6Hz,2H),7.38(d,J＝7.2Hz,1H),7.33–7.19(m,4H),7.14(d,J＝8.5Hz,2H),5.09(s,2H),3.85(d,J＝15.0Hz,1H),3.71(d,J＝14.5Hz,1H),2.37(s,3H)。
制备实施例9
2-((4-((2-甲基苯基)氧基)苯基)砜基)乙酸(S9)
合成步骤同实施例6
1H NMR(400MHz,CDCl3)δ7.96(d,J＝8.6Hz,2H),7.73(d,J＝8.6Hz,2H),7.53(d,J＝7.5Hz,1H),7.30(ddd,J＝12.9,9.6,3.7Hz,2H),7.22(dd,J＝7.4,1.4Hz,1H),7.19(d,J＝1.2Hz,0H),4.21(s,2H),2.54(s,3H)。
制备实施例10
2-((4-(邻甲基苯乙炔基)苯基)亚砜基)乙酸异构体1(S10)
反应试剂和条件：i)2-溴乙酸乙酯，碳酸钾，N,N-二甲基甲酰胺；ii)1-乙炔基-2-甲苯，碘化亚铜，一氯二三苯基膦钯，三乙胺，N,N-二甲基甲酰胺；iii)一水氢氧化锂，四氢呋喃，甲醇，水；iv)L-薄荷醇，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，N,N-二甲氨基吡啶，二氯甲烷；v)间氯过氧苯甲酸，二氯甲烷，-20℃；vi)大赛璐公司IC 10mmx 250mm，V乙醇/(V乙醇+V正己烷)＝10/100，t1＝14.960分钟，t2＝17.224分钟。
合成步骤
步骤1 2-((4-溴苯基)巯基)乙酸乙酯
称取4-溴苯硫酚(644mg，3.406mmol)溶于10mL的N,N-二甲基甲酰胺中，加入碳酸钾(1.4g，10.218mmol)，加入2-溴乙酸乙酯(567μL，5.109mmol)室温搅拌过夜。反应完毕后，乙酸乙酯萃取，干燥，石油醚过硅胶柱。
1H NMR(400MHz,CDCl3)δ7.42(d,J＝8.6Hz,2H),7.28(d,J＝8.6Hz,2H),4.17(q,J＝7.1Hz,2H),3.61(s,2H),1.23(t,J＝7.1Hz,3H)。
步骤2 2-((4-(邻甲基苯乙炔基)苯基)巯基)乙酸乙酯
称取2-((4-溴苯基)巯基)乙酸乙酯(694mg，2.522mmol)、1-乙炔基-2-甲苯(477μL，3.783mmol)、一氯二三苯基膦钯(89mg，0.126mmol)和碘化亚铜(48mg，0.252mmol)于100mL的烧瓶中。加入20mL的N,N-二甲基甲酰胺和1.7mL的三乙胺中，升至90℃，反应过夜。萃取，干燥，用乙酸乙酯-石油醚混合溶液(V/V＝5/95)过硅胶柱，得到无色油状物669mg。
1H NMR(300MHz,CDCl3)δ7.51–7.42(m,3H),7.36(d,J＝8.3Hz,2H),7.23(d,J＝4.1Hz,2H),7.20–7.11(m,1H),4.19(q,J＝7.2Hz,2H),3.67(s,2H),2.50(s,3H),1.25(t,J＝7.1Hz,3H)。
步骤3 2-((4-(邻甲基苯乙炔基)苯基)巯基)乙酸
合成步骤同2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)
1H NMR(300MHz,CDCl3)δ7.52–7.44(m,3H),7.37(d,J＝8.0Hz,2H),7.23(d,J＝2.9Hz,2H),7.20–7.12(m,1H),3.72(s,2H),2.50(s,3H)。
步骤4 2-((4-(邻甲基苯乙炔基)苯基)巯基)乙酸(L)-薄荷醇酯
合成步骤同2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)巯基)乙酸L-薄荷醇酯
1H NMR(400MHz,CDCl3)δ7.49(dd,J＝14.5,7.8Hz,3H),7.38(d,J＝8.4Hz,2H),7.28–7.24(m,2H),7.23–7.15(m,1H),4.72(td,J＝10.9,4.3Hz,1H),3.69(s,2H),2.53(s,3H),1.96(d,J＝12.3Hz,1H),1.81–1.74(m,1H),1.73–1.63(m,2H),1.48(ddd,J＝11.9,8.1,3.6Hz,1H),1.42–1.33(m,1H),1.13–0.94(m,2H),0.92(d,J＝6.5Hz,3H),0.87(d,J＝7.1Hz,3H),0.71(d,J＝6.9Hz,3H)。
步骤5 2-((4-(邻甲基苯乙炔基)苯基)亚砜基)乙酸(L)-薄荷醇酯
合成步骤同2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸乙酯
HPLC手性拆分条件：大赛璐公司IC 10mmx250mm手性柱，该柱用乙醇和己烷的混合溶液V乙醇/(V乙醇+V正己烷)＝10/100，以4mL/min的流速洗脱，在出峰时间t1＝14.960分钟，t2＝17.224分钟时，分别得到两种无色油状物，即组分一(60mg)和组分二(80mg)
组分一：
1H NMR(400MHz,CDCl3)δ7.77–7.64(m,4H),7.53(d,J＝7.5Hz,1H),7.28(d,J＝13.8Hz,2H),7.25–7.18(m,1H),4.73(td,J＝10.9,4.4Hz,1H),3.91(d,J＝13.5Hz,1H),3.72(d,J＝13.5Hz,1H),2.54(s,3H),1.85(dd,J＝12.5,10.2Hz,2H),1.69(d,J＝13.2Hz,2H),1.53–1.44(m,1H),1.42–1.34(m,1H),1.05(dt,J＝17.3,10.6Hz,1H),0.91(d,J＝6.9Hz,6H),0.86(dd,J＝12.4,4.7Hz,1H),0.77(d,J＝6.9Hz,3H)。
组分二：
1H NMR(400MHz,CDCl3)δ7.77–7.64(m,4H),7.53(d,J＝7.5Hz,1H),7.28(d,J＝13.8Hz,2H),7.25–7.18(m,1H),4.73(td,J＝10.9,4.4Hz,1H),3.91(d,J＝13.5Hz,1H),3.72(d,J＝13.5Hz,1H),2.54(s,3H),1.85(dd,J＝12.5,10.2Hz,2H),1.69(d,J＝13.2Hz,2H),1.53–1.44(m,1H),1.42–1.34(m,1H),1.05(dt,J＝17.3,10.6Hz,1H),0.91(d,J＝6.9Hz,6H),0.86(dd,J＝12.4,4.7Hz,1H),0.77(d,J＝6.9Hz,3H)。
步骤6 2-((4-(邻甲基苯乙炔基)苯基)亚砜基)乙酸异构体1(S10)
合成步骤同2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)，对组分一进行水解，得40mg 2-((4-(邻甲基苯乙炔基)苯基)亚砜基)乙酸异构体1(S10)。
1H NMR(400MHz,CDCl3)δ7.71(s,4H),7.52(d,J＝7.4Hz,1H),7.32–7.24(m,2H),7.20(td,J＝7.1,1.7Hz,1H),3.94–3.80(m,2H),2.53(s,3H)。
制备实施例11
2-((4-(邻甲基苯乙炔基)苯基)亚砜基)乙酸异构体2(S11)
合成步骤同2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)，对实施例10中组分二进行水解，得60mg 2-((4-(邻甲基苯乙炔基)苯基)亚砜基)乙酸异构体2(S11)。
1H NMR(400MHz,CDCl3)δ7.71(s,4H),7.52(d,J＝7.4Hz,1H),7.32–7.24(m,2H),7.20(td,J＝7.1,1.7Hz,1H),3.94–3.80(m,2H),2.53(s,3H)。
制备实施例12
2-((4-(邻甲基苯乙炔基)苯基)砜基)乙酸(S12)
反应试剂和条件：i)间氯过氧苯甲酸，二氯甲烷，室温；ii)一水合氢氧化锂，四氢呋喃，甲醇，水，0℃。
步骤1 2-((4-(邻甲基苯乙炔基)苯基)砜基)乙酸(L)-薄荷醇酯
以实施例10第4步的产物作为起始原料，合成步骤同2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)砜基)乙酸乙酯。
1H NMR(300MHz,CDCl3)δ7.88(d,J＝8.8Hz,2H),7.37(d,J＝7.3Hz,1H),7.33–7.19(m,3H),7.11(d,J＝8.9Hz,2H),5.11(s,2H),4.67(td,J＝10.9,3.9Hz,1H),4.08(s,2H),2.37(s,3H),1.91(d,J＝12.6Hz,1H),1.82–1.72(m,1H),1.66(d,J＝9.6Hz,2H),1.41(s,1H),1.37–1.14(m,1H),1.10–0.94(m,2H),0.87(dd,J＝11.3,6.8Hz,6H),0.70(d,J＝6.9Hz,3H)。
步骤2 2-((4-(邻甲基苯乙炔基)苯基)砜基)乙酸(S12)
合成步骤同2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)砜基)乙酸(S6)
1H NMR(400MHz,CDCl3)δ7.97(d,J＝8.6Hz,2H),7.74(d,J＝8.6Hz,2H),7.54(d,J＝7.7Hz,1H),7.36–7.26(m,2H),7.22(t,J＝7.4Hz,1H),4.20(s,2H),2.55(s,3H)。
制备实施例13
2-((4-(((R)-4-(三氟甲基)-2,3-二氢-1H-茚-1-基)氧基)苯基)亚砜基)乙酸(S13)
反应试剂和条件：i)三乙胺，甲酸，钌催化剂(RuCl[(S,S)-Tsdpen](mesitylene))；ii)2-((4-羟基苯基)巯基)乙酸乙酯，三苯基膦，偶氮二甲酸二乙酯，四氢呋喃；iii)间氯过氧苯甲酸，二氯甲烷，-20℃；iv)一水合氢氧化锂，四氢呋喃，甲醇，水。
合成步骤
步骤1(S)-4-三氟甲基-2,3-二氢-1H-茚-1-醇
在冰浴下，往三乙胺中(1.05mL，7.494mmol)缓慢滴加甲酸(330μL，8.743mmol)。然后，室温下加入4-(三氟甲基)-2,3-二氢-1H-茚-1-酮(500mg，2.498mmol)。完全溶解后，室温加入钌试剂(RuCl[(S,S)-Tsdpen](mesitylene))(78mg，0.125mmol)。氮气保护下，室温搅拌反应3h。乙酸乙酯萃取，有机层用饱和氯化钠溶液洗，无水硫酸钠干燥，过滤，旋干，乙酸乙酯-石油醚混合溶剂(V/V＝10/90)过硅胶柱，得到深红色油状物，产率85％。
1H NMR(300MHz,CDCl3)δ7.91(d,J＝8.0Hz,1H),7.63–7.41(m,1H),7.32(t,J＝7.8Hz,1H),5.25(t,J＝6.4Hz,1H),3.55(ddd,J＝16.9,8.4,4.5Hz,1H),3.30–3.12(m,1H),2.56(dt,J＝12.3,7.5Hz,1H),2.03–1.92(m,1H)。
步骤2(R)-2-((4-((4-三氟甲基-2,3-二氢-1H-茚-1-基)氧基)苯基)巯基)乙酸乙酯
合成步骤同2-((4-((4-氯-2,3-二氢-1H-茚-1-基)氧基)苯基)巯基)乙酸乙酯
1H NMR(300MHz,CDCl3)δ7.97(d,J＝7.9Hz,1H),7.51(d,J＝7.5Hz,1H),7.46(d,J＝8.8Hz,2H),7.33(t,J＝7.7Hz,1H),6.95(d,J＝8.8Hz,2H),5.81–5.67(m,1H),4.16(q,J＝7.1Hz,2H),3.74–3.55(m,1H),3.46–3.24(m,1H),2.62(td,J＝13.7,7.6Hz,1H),2.31–2.18(m,1H),1.24(t,J＝7.1Hz,3H)。
步骤3(R)-2-((4-((4-三氟甲基-2,3-二氢-1H-茚-1-基)氧基)苯基)亚砜基基)乙酸乙酯
合成步骤同2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸乙酯
1H NMR(300MHz,CDCl3)δ7.99(d,J＝7.8Hz,1H),7.67(d,J＝8.3Hz,2H),7.52(d,J＝7.6Hz,1H),7.35(t,J＝7.6Hz,1H),7.14(d,J＝8.3Hz,2H),5.82(t,J＝5.6Hz,1H),4.17(q,J＝7.3Hz,2H),3.90(d,J＝14.0Hz,1H),3.65(d,J＝13.4Hz,1H),3.63–3.51(m,1H),3.48–3.28(m,1H),2.78–2.54(m,1H),2.36–2.12(m,1H),1.24(t,J＝7.0Hz,4H)。
步骤4 2-((4-(((R)-4-(三氟甲基)-2,3-二氢-1H-茚-1-基)氧基)苯基)亚砜基)乙酸(S13)
合成步骤同2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)
1H NMR(300MHz,CDCl3)δ8.01(dd,J＝13.2,8.3Hz,1H),7.68(d,J＝8.2Hz,3H),7.57(dd,J＝27.0,6.8Hz,1H),7.35(t,J＝7.9Hz,1H),7.21–7.10(m,2H),5.82(t,J＝5.3Hz,1H),3.87(d,J＝14.5Hz,1H),3.76(d,J＝14.0Hz,1H),3.69–3.52(m,1H),3.41(dt,J＝19.7,9.2Hz,1H),2.66(dt,J＝12.9,6.8Hz,1H),2.32–2.14(m,1H)。
制备实施例14
2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)-N-羟乙酰胺(S14)
反应试剂和条件：i)盐酸羟胺，氢氧化钾，甲醇。
将盐酸羟胺(66mg，0.947mmol)溶于1mL的甲醇。冷却至0℃，将氢氧化钾(80mg，1.422mmol)溶于1mL的甲醇加入上液。
称取实施例1步骤5中制备的2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸乙酯(100mg，0.237mmol)溶于1mL甲醇。将上液缓慢加入此体系中。反应1h，调pH至约2，二氯甲烷萃取三次，低温旋干后，石油醚重结晶，得到白色固体，产率80％。
1H NMR(400MHz,DMSO-d6)δ10.71(d,J＝10.4Hz,1H),9.16(s,1H),7.64(dd,J＝17.4,8.8Hz,2H),7.53–7.41(m,2H),7.23(d,J＝8.7Hz,3H),7.13(t,J＝7.8Hz,4H),5.25(s,2H),3.65(d,J＝13.2Hz,1H),3.49(d,J＝13.2Hz,1H),1.94(s,6H)。
制备实施15
2-(2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酰氨基)乙酸(S15)
反应试剂和条件：i)甘氨酸盐酸盐，偶氮二甲酸二乙酯，N,N-二甲氨基吡啶，二氯甲烷；ii)一水合氢氧化锂，四氢呋喃，甲醇，水。
步骤1 2-(2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酰氨基)乙酸乙酯
将案例11步骤6中制备的2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(50mg，0.127mmol)同甘氨酸盐酸盐(53mg，0.380mmol)、偶氮二甲酸二乙酯(73mg，0.380mmol)和N,N-二甲氨基吡啶(16mg，0.127mmol)溶于2mL的二氯甲烷，室温搅拌反应5h。
反应完毕后，加入10mL二氯甲烷，饱和氯化钠溶液洗三次。无水硫酸钠干燥，浓缩过硅胶柱用乙酸乙酯-石油醚的混合溶液洗脱(V乙酸乙酯/V石油醚＝30:70)。得到无色油状产物56mg。
1H NMR(300MHz,CDCl3)δ7.59(d,J＝8.7Hz,2H),7.51–7.35(m,3H),7.23–7.06(m,7H),5.15(s,2H),4.22(q,J＝7.1Hz,2H),4.02(d,J＝5.3Hz,2H),3.70(d,J＝14.1Hz,1H),3.53(d,J＝14.2Hz,1H),2.01(s,6H),1.28(t,J＝7.2Hz,3H)。
步骤2 2-(2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酰氨基)乙酸(S15)
反应操作步骤同2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)
1H NMR(400MHz,DMSO-d6)δ8.47(t,J＝5.3Hz,1H),7.63(d,J＝8.8Hz,2H),7.55–7.41(m,2H),7.27–7.06(m,7H),5.25(s,2H),3.78(d,J＝5.2Hz,4H),1.95(s,6H)。
制备实施例16
2-((4-((2',6'-二甲基-[1,1'-联苯基]-4-基)甲氧基)苯基)亚砜基)乙酸(S16)
合成步骤同实施例1
1H NMR(300MHz,DMSO-d6)δ7.68(d,J＝8.7Hz,2H),7.53(d,J＝7.8Hz,2H),7.24(d,J＝8.7Hz,2H),7.20–7.06(m,5H),5.21(s,2H),3.92(d,J＝14.2Hz,1H),3.79(d,J＝14.3Hz,1H),1.95(s,6H)。
制备实施例17
2-((4-((3-(3-氯吡啶-4-基)苯基)氧基)苯基)亚砜基)乙酸(S17)
反应试剂和条件：i)三苯基膦，偶氮二甲酸二乙酯，四氢呋喃；ii)3-氯-4-吡啶联硼酸酯,(2,6-二甲基苯基)硼酸，四三苯基膦钯，碳酸钠，水，1,4-二氧六环；iii)间氯过氧苯甲酸，二氯甲烷，-20℃至室温；iv)一水合氢氧化锂，四氢呋喃，甲醇，水。
步骤1 2-((4-((3-溴苯基)氧基)苯基)巯基)乙酸乙酯
合成步骤同2-((4-((4-氯-2,3-二氢-1H-茚-1-基)氧基)苯基)巯基)乙酸乙酯
1H NMR(300MHz,CDCl3)δ7.58(s,1H),7.44(t,J＝9.3Hz,3H),7.33(d,J＝7.5Hz,1H),7.26(d,J＝7.6Hz,1H),6.90(d,J＝8.2Hz,2H),5.01(s,2H),4.14(q,J＝7.2Hz,2H),3.52(s,2H),1.21(t,J＝7.1Hz,3H)。
步骤2 2-((4-((3-(3-氯吡啶基-4-基)苯基)氧基)苯基)巯基)乙酸乙酯
合成步骤同(2',6'-二甲基-[1,1'-二苯基]-3-基)甲醇
1H NMR(300MHz,CDCl3)δ8.68(s,1H),8.53(d,J＝5.0Hz,1H),7.57–7.39(m,6H),7.29(d,J＝4.8Hz,1H),6.93(d,J＝8.8Hz,2H),5.12(s,2H),4.19–4.10(m,2H),3.52(s,2H),1.21(t,J＝7.1Hz,3H)。
步骤3 2-((4-((3-(3-氯吡啶基-4-基)苯基)氧基)苯基)亚砜基)乙酸乙酯
合成步骤同2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸乙酯
1H NMR(300MHz,CDCl3)δ8.68(s,1H),8.53(d,J＝5.0Hz,1H),7.64(d,J＝8.7Hz,2H),7.58–7.41(m,4H),7.29(d,J＝4.9Hz,1H),7.12(d,J＝8.7Hz,2H),5.18(s,2H),4.14(q,J＝7.1Hz,2H),3.87(d,J＝13.5Hz,1H),3.63(d,J＝13.5Hz,1H),1.20(t,J＝7.1Hz,3H)。
步骤4 2-((4-((3-(3-氯吡啶基-4-基)苯基)氧基)苯基)亚砜基)乙酸(S17)
合成步骤同2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)
1H NMR(300MHz,CDCl3)δ8.67(s,1H),8.52(d,J＝5.6Hz,1H),7.66(d,J＝8.3Hz,2H),7.49(dd,J＝17.1,4.1Hz,4H),7.32(d,J＝5.1Hz,1H),7.12(d,J＝8.4Hz,2H),5.18(s,2H),3.79(dd,J＝16.6,12.5Hz,2H)。
制备实施例18
2-((4-((3-(3,5-二甲基异恶唑-4-基)苯基)氧基)苯基)亚砜基)乙酸(S18)
反应试剂和条件：i)间氯过氧苯甲酸，二氯甲烷，-20℃；ii)(2,6-二甲基苯基)硼酸，四三苯基膦钯，碳酸钠，水，1,4-二氧六环；iii)三苯基膦，偶氮二甲酸二乙酯，四氢呋喃；iv)一水合氢氧化锂，四氢呋喃，甲醇，水。
步骤1 2-((4-羟基苯基)亚砜基)乙酸乙酯
合成步骤同2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸乙酯
1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.5Hz,2H),6.99(d,J＝8.5Hz,2H),4.16(q,J＝7.1Hz,2H),3.97(d,J＝13.7Hz,1H),3.70(d,J＝13.7Hz,1H),1.22(t,J＝7.1Hz,3H)。
步骤2(3-(3,5-二甲基异恶唑-4-基)苯基)甲醇
合成步骤同(2',6'-二甲基-[1,1'-二苯基]-3-基)甲醇
1H NMR(300MHz,CDCl3)δ7.43(t,J＝7.5Hz,1H),7.36(d,J＝7.7Hz,1H),7.26(s,1H),7.18(d,J＝7.4Hz,1H),4.75(d,J＝5.5Hz,2H),2.40(s,3H),2.27(s,3H)。
步骤3 2-((4-((3-(3,5-二甲基异恶唑-4-基)苯基)氧基)苯基)亚砜基)乙酸乙酯
合成步骤同2-((4-((4-氯-2,3-二氢-1H-茚-1-基)氧基)苯基)巯基)乙酸乙酯
1H NMR(300MHz,CDCl3)δ7.65(d,J＝8.8Hz,2H),7.44(dd,J＝15.9,7.4Hz,2H),7.31(s,1H),7.23(s,1H),7.12(d,J＝8.6Hz,2H),5.16(s,2H),4.14(q,J＝7.3Hz,2H),3.88(d,J＝13.5Hz,1H),3.63(d,J＝13.6Hz,1H),2.40(s,3H),2.26(s,3H),1.22(t,J＝7.2Hz,3H)。
步骤4 2-((4-((3-(3,5-二甲基异恶唑-4-基)苯基)氧基)苯基)亚砜基)乙酸(S18)
合成步骤同2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)
1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.7Hz,2H),7.51(t,J＝7.7Hz,1H),7.44(d,J＝7.9Hz,1H),7.33(s,1H),7.27(d,J＝7.9Hz,1H),7.16(d,J＝8.6Hz,2H),5.19(s,2H),3.87(d,J＝14.6Hz,1H),3.72(d,J＝14.4Hz,1H),2.42(s,3H),2.28(s,3H)。
制备实施例19
2-((4-((3-(1-甲基-1H-吡唑-4-基)苄基)氧基)苯基)亚砜基)乙酸(S19)
合成步骤同实施例1
1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.88(s,1H),7.68(d,J＝8.1Hz,3H),7.54(d,J＝7.6Hz,1H),7.39(t,J＝7.8Hz,1H),7.29(d,J＝7.4Hz,1H),7.24(d,J＝8.5Hz,2H),5.18(s,2H),3.93(d,J＝14.2Hz,1H),3.87(s,3H),3.80(d,J＝14.2Hz,1H)。
制备实施例20
2-((4-((2-(4-氟苯基)-4-甲基噻唑-5-基)甲氧基)苯基)亚砜基)乙酸(S20)
反应试剂和条件：i)劳森试剂，四氢呋喃，回流；ii)2-氯乙酰乙酸乙酯，乙醇，回流；iii)四氢铝锂，乙醚；iv)2-((4-羟基苯基)巯基)乙酸乙酯，三苯基膦，偶氮二甲酸二乙酯，四氢呋喃；v)间氯过氧苯甲酸，二氯甲烷，-20℃；vi)一水合氢氧化锂，四氢呋喃，甲醇，水。
合成步骤
步骤1 4-氟硫代苯甲酰胺
将4-氟苯甲酰胺(2g，14.375mmol)和劳森试剂(6.395g，15.813mmol)溶于45mL的四氢呋喃中，加热回流反应4h。石油醚和二氯甲烷重结晶得到黄色固体2g。
1H NMR(400MHz,CDCl3)δ7.93(dd,J＝8.7,5.2Hz,2H),7.11(t,J＝8.6Hz,2H)。
步骤2 2-(4-氟苯基)-4-甲基噻唑-5-甲酸乙酯
将4-氟硫代苯甲酰胺(500mg,3.222mmol)和2-氯乙酰乙酸乙酯(1.337mL,9.666mmol)溶于15mL的乙醇中，加热回流2h。浓缩，用石油醚-乙酸乙酯混合溶液(V/V＝10/90)洗脱液过硅胶色谱柱，得到无色油状物800mg。
1H NMR(300MHz,CDCl3)δ7.95(dd,J＝8.7,5.2Hz,2H),7.13(t,J＝8.6Hz,2H),4.35(dd,J＝15.4,8.3Hz,2H),2.77(s,3H),1.38(t,J＝7.2Hz,3H)。
步骤3(2-(4-氟苯基)-4-甲基噻唑-5-基)甲醇
将2-(4-氟苯基)-4-甲基噻唑-5-甲酸乙酯(1g,3.769mmol)溶于30mL的乙醚中，0℃加入四氢铝锂(430mg,11.308mmol)。升至室温，搅拌反应3h。用石油醚-乙酸乙酯混合溶液(V/V＝50/50)过硅胶色谱柱。得到600mg白色固体。
1H NMR(300MHz,DMSO-d6)δ7.90(dd,J＝8.9,5.4Hz,2H),7.29(t,J＝8.9Hz,2H),5.53(t,J＝5.5Hz,1H),4.61(d,J＝5.5Hz,2H),2.32(s,3H)。
步骤4 2-((4-((2-(4-氟苯基)-4-甲基噻唑-5-基)甲氧基)苯基)巯基)乙酸乙酯
合成步骤同2-((4-((4-氯-2,3-二氢-1H-茚-1-基)氧基)苯基)巯基)乙酸乙酯
1H NMR(300MHz,CDCl3)δ7.89(dd,J＝8.6,5.4Hz,2H),7.44(d,J＝8.8Hz,2H),7.11(t,J＝8.6Hz,2H),6.92(d,J＝8.8Hz,2H),5.16(s,2H),4.14(q,J＝7.1Hz,2H),3.53(s,2H),2.48(s,3H),1.21(t,J＝7.1Hz,3H)。
步骤5 2-((4-((2-(4-氟苯基)-4-甲基噻唑-5-基)甲氧基)苯基)亚砜基)乙酸乙酯
合成步骤同2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸乙酯
1H NMR(400MHz,CDCl3)δ7.92(dd,J＝8.1,5.6Hz,2H),7.69(d,J＝8.6Hz,2H),7.20–7.07(m,4H),5.26(s,2H),4.17(q,J＝7.1Hz,2H),3.90(d,J＝13.5Hz,1H),3.66(d,J＝13.6Hz,1H),2.53(s,3H),1.24(t,J＝7.1Hz,3H)。
步骤6 2-((4-((2-(4-氟苯基)-4-甲基噻唑-5-基)甲氧基)苯基)亚砜基)乙酸(S20)
合成步骤同2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)
1H NMR(300MHz,DMSO-d6)δ7.94(dd,J＝8.3,5.6Hz,2H),7.67(d,J＝8.6Hz,2H),7.31(t,J＝8.8Hz,2H),7.22(d,J＝8.5Hz,2H),5.38(s,2H),3.92(d,J＝14.3Hz,1H),3.78(d,J＝14.3Hz,1H),2.43(s,3H)。
制备实施例21
2-((5-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)噻吩-2-基)亚砜基)乙酸(S21)
反应试剂和条件：i)3-溴卞醇，碘化亚铜，3,4,7,8-四甲基-1,10-菲罗啉，碳酸铯，80℃；ii)2,6-二甲基苯硼酸，四三苯基磷钯，碳酸钠，二氧六环-水混合溶液(V/V＝3:1)，100℃；iii)正丁基锂，硫粉，2-溴乙酸叔丁酯，四氢呋喃，-78℃至室温；iv)间氯过氧苯甲酸，二氯甲烷，-20℃；v)一水合氢氧化锂，四氢呋喃，甲醇，水。
步骤1 2-((3-溴苄基)氧基)噻吩
碘化亚铜(38mg，0.2mmol)，3,4,7,8-四甲基-1,10-菲啰啉(94mg，0.4mmol)和碳酸铯(987mg，3mmol)置于反应瓶中，氮气保护。加入2-碘噻吩(221μL，2mmol)和3-溴卞醇(1mL，8.34mmol)，加热至80℃，反应24h。冷却至室温，滤过一层薄硅胶，乙酸乙酯冲洗，旋干，用二氯甲烷-石油醚混合溶液(V二氯甲烷/V石油醚＝10/90)过硅胶色谱柱，得无色油状物320mg。
1H NMR(300MHz,CDCl3)δ7.58(s,1H),7.47(d,J＝7.4Hz,1H),7.34(d,J＝7.5Hz,1H),7.25(d,J＝15.4Hz,1H),6.71(dd,J＝5.4,3.9Hz,1H),6.58(d,J＝5.8Hz,1H),6.27(d,J＝3.7Hz,1H),5.04(s,2H)。
步骤2 2-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)噻吩
合成步骤同(2',6'-二甲基-[1,1'-二苯基]-3-基)甲醇
1H NMR(300MHz,CDCl3)δ7.50–7.37(m,2H),7.15(dt,J＝20.6,7.3Hz,5H),6.76–6.65(m,1H),6.56(d,J＝5.8Hz,1H),6.27(d,J＝3.7Hz,1H),5.12(s,2H),2.02(s,6H)。
步骤3 2-((5-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)噻吩-2-基)巯基)乙酸叔丁酯
称取2-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)噻吩(200mg，0.679mmol)溶于6mL的无水四氢呋喃中。冷却至-78℃后，加入n-BnLi(2.5M)(272μL，0.679mmol)搅拌反应30min。将硫粉(22mg，0.679mmol)加入反应液。待反应液呈黄色透明后，加入2-溴乙酸叔丁酯(100μL，0.679mmol)加入反应液，升至室温，搅拌反应30min。饱和氯化铵溶液淬灭。加入20mL乙酸乙酯后，饱和氯化钠溶液洗多次，无水硫酸钠干燥，浓缩，用乙酸乙酯-石油醚混合溶液(V/V＝5/95)过硅胶色谱柱，得到100mg无色油状物。
1H NMR(300MHz,CDCl3)δ7.45(t,J＝7.5Hz,1H),7.38(d,J＝7.6Hz,1H),7.21–7.07(m,5H),6.89(d,J＝3.9Hz,1H),6.13(d,J＝4.0Hz,1H),5.10(s,2H),3.32(s,2H),2.01(s,6H),1.44(s,9H)。
步骤4 2-((5-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)噻吩-2-基)亚砜基)乙酸叔丁酯
合成步骤同2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸乙酯
1H NMR(400MHz,CDCl3)δ7.47(t,J＝7.5Hz,1H),7.39(d,J＝7.7Hz,1H),7.23(d,J＝4.1Hz,1H),7.20(s,1H),7.16(d,J＝7.6Hz,2H),7.11(d,J＝7.4Hz,2H),6.25(d,J＝4.1Hz,1H),5.18(s,2H),4.05(d,J＝13.6Hz,1H),3.74(d,J＝13.6Hz,1H),2.02(s,6H),1.39(s,9H)。
步骤5 2-((5-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)噻吩-2-基)亚砜基)乙酸(S21)
合成步骤同2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)
1H NMR(400MHz,CDCl3)δ7.47(t,J＝7.5Hz,1H),7.38(d,J＝7.5Hz,1H),7.31(d,J＝4.1Hz,1H),7.21–7.14(m,3H),7.11(d,J＝7.3Hz,2H),6.28(d,J＝4.1Hz,1H),5.19(s,2H),3.91(q,J＝14.4Hz,2H),2.01(s,6H)。
制备实施例22
2-((4-((3-(4,6-二甲基嘧啶-5-基)苯基)氧基)苯基)亚砜基)乙酸(S22)
反应试剂和条件：i)四三苯基磷钯，碳酸钠，1,4-二氧六环，水，80℃；ii)硼氢化钠，甲醇；iii)2-((4-羟基苯基)巯基)乙酸乙酯，偶氮二甲酸二乙酯，三苯基膦，四氢呋喃，0℃-室温；iv)间氯过氧苯甲酸，二氯甲烷，-20℃；v)一水合氢氧化锂，四氢呋喃，甲醇，水。
步骤1 3-(4,6-二甲基哌啶-5-基)苯甲醛
称取5-溴-4,6-二甲基嘧啶(500mg，2.687mmol)、(3-甲酰苯基)硼酸(605mg，4.031mmol)、四三苯基膦钯(311mg，0.269mmol)和碳酸钠(855mg，8.061mmol)于100mL的烧瓶中。加入21mL的二氧六环和7mL的水,80℃下反应5h。反应完毕后，加入40mL的乙酸乙酯，饱和氯化钠溶液洗3次，无水硫酸钠干燥有机相，过滤，浓缩，用乙酸乙酯-石油醚混合溶液(V乙酸乙酯/V石油醚＝20/80)洗脱液过硅胶色谱柱，得到白色固体600mg。
1H NMR(300MHz,CDCl3)δ10.08(s,1H),8.97(s,1H),7.95(d,J＝7.7Hz,1H),7.67(dd,J＝17.9,9.8Hz,1H),7.50(dd,J＝19.0,8.1Hz,1H),2.26(s,6H)。
步骤2 3-(4,6-二甲基哌啶-5-基)苯甲醇
合成步骤同4-氯-2,3-二氢-1H-茚-1-醇
1H NMR(300MHz,CDCl3)δ8.92(s,1H),7.74–7.36(m,1H),7.19(s,1H),7.09(d,J＝7.5Hz,1H),4.78(s,2H),2.26(s,6H)。
步骤3 2-((4-((3-(4,6-二甲基哌啶-5-基)苯基)氧基)苯基)巯基)乙酸乙酯
合成步骤同2-((4-((4-氯-2,3-二氢-1H-茚-1-基)氧基)苯基)巯基)乙酸乙酯
1H NMR(400MHz,CDCl3)δ8.97(s,1H),7.63–7.37(m,3H),7.25(s,1H),7.16(d,J＝7.2Hz,1H),6.94(d,J＝8.7Hz,2H),5.14(s,2H),4.16(q,J＝7.1Hz,2H),3.54(s,2H),2.28(s,6H),1.24(t,J＝7.1Hz,3H)。
步骤4 2-((4-((3-(4,6-二甲基哌啶-5-基)苯基)氧基)苯基)亚砜基)乙酸乙酯
合成步骤同2-((4-((2',6'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸乙酯
1H NMR(400MHz,CDCl3)δ8.98(s,1H),7.67(d,J＝8.7Hz,2H),7.60–7.48(m,2H),7.25(s,1H),7.19(d,J＝7.4Hz,1H),7.14(d,J＝8.7Hz,2H),5.20(s,2H),4.17(q,J＝7.6Hz,2H),3.90(d,J＝13.5Hz,1H),3.65(d,J＝13.5Hz,1H),2.29(s,6H),1.24(t,J＝7.1Hz,3H)。
步骤5 2-((4-((3-(4,6-二甲基哌啶-5-基)苯基)氧基)苯基)亚砜基)乙酸(S22)
合成步骤同2-((4-((2',6'-二甲基-[1,1'-二苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S1)
1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),7.67(d,J＝8.7Hz,2H),7.55(d,J＝5.4Hz,2H),7.39(s,1H),7.29(d,J＝5.3Hz,1H),7.23(d,J＝8.8Hz,2H),5.26(s,2H),3.92(d,J＝14.2Hz,1H),3.79(d,J＝14.2Hz,1H),2.18(s,6H)。
制备实施例23
2-((4-((2'-氟-5'-甲氧基-[1,1'-联苯基]-3-基)甲氧基)苯基)亚砜基)乙酸(S23)
反应操作步骤同实施例1
1H NMR(300MHz,DMSO-d6)δ7.65(d,J＝8.5Hz,3H),7.50(s,3H),7.23(t,J＝8.2Hz,3H),6.99(ddd,J＝12.3,7.6,4.2Hz,2H),5.23(s,2H),3.91(d,J＝14.0Hz,1H),3.84–3.69(m,4H)。
制备实施例24
2-((4-((3-(吡啶-4-基)苄基)氧基)苯基)亚砜基)乙酸(S24)
反应操作步骤同实施例18
1H NMR(300MHz,DMSO-d6)δ8.63(d,J＝4.9Hz,2H),7.90(s,1H),7.83–7.62(m,5H),7.56(s,2H),7.23(d,J＝8.4Hz,2H),5.25(s,2H),3.91(d,J＝14.3Hz,1H),3.78(d,J＝14.3Hz,1H),2.48(s,2H)。
实验实施例1
本发明的化合物体外对GPR40的激动作用体外GPR40激动活性评价
本发明的化合物对HEK293/hGPR40细胞(稳定表达GPR40/Gα16的HEK293细胞)的激动活性。人胚胎肾细胞HEK293购自美国标准菌种收藏所(ATCC)。
本发明使用以下方法测试本发明化合物的GPR40的激动活性：
供试品：本发明全部化合物，分别按照本发明实施例中的方法制备；
对照品：TAK-875，其结构式为
制备汉克斯平衡盐溶液HBSS(钙流实验专用)：按照Glucagon receptor mediatescalcium signaling by coupling to G alpha q/11 and G alpha i/o in HEK293cells.J Recept Signal Transduct Res.2009,29(6),318-25文献中报道的配制方法进行配制汉克斯平衡盐溶液，配方为0.3mmol/L Na2HPO4·12H2O，5.4mmol/L KCl，0.4mmol/LKH2PO4，4.2mmol/L NaHCO3，0.6mmol/L MgSO4，0.5mmol/L MgCl2·6H2O，137mmol/L NaCl，1.3mmol/L CaCl2，用去离子水配置并调节pH至7.4。
制备钙缓冲液(用HBSS配制，现配现用)：配方为5.6mmol/L D-葡萄糖，250μM/L苯磺唑酮(Sigma，S9509)，以制备的HBSS作为溶剂配置。
制备Fluo-4AM荧光染料溶液(用钙缓配制)：配方为0.03％(体积/体积)聚氧乙烯蓖麻油(Biochemika，27963)和2μM/L Fluo-4，AM(Invitrogen，F14202)，以制备的钙缓冲液作为溶液配置。
按照Discovery of DS-1558:A Potent and Orally Bioavailable GPR40Agonist.Acs Med.Chem.Lett.,2015,6(3),pp 266–270和Discovery and Optimizationof Potent GPR40 Full Agonists Containing Tricyclic Spirocycles.AcsMed.Chem.Lett.,2013,4(6),pp 551–555文献中报道的配制方法配制化合物储存液，并进行细胞实验。
配化合物储存液的流程：
配制方法：首先将化合物溶解于二甲亚砜中配制成10mM储存液，取1μL储存液加入9μL二甲亚砜中，得到浓度是1mM的溶液，然后再从1mM的溶液中取1μL加入9μL的二甲亚砜中，得到浓度是100μM，以此类推，配制得到工作浓度为100μM、10μM、1μM、100nM、10nM、1nM、0.1nM的化合物储存液。
化合物梯度稀释之后每个浓度下取3μL加入97μL钙缓冲液中混匀。空白对照样的配制方法为以3μL DMSO加入97μL钙缓冲液中混匀。
细胞实验：
1、细胞铺板：将稳定表达GPR40/Gα16的HEK293细胞种于96孔板，置于37℃、5％CO2的细胞培养箱过夜培养。
2、染料孵育：吸去培养液，加入新鲜配制的染料40μL/孔，37℃培养箱内恒温孵育45分钟。将染料吸尽弃去，用新鲜配制的40μL钙缓冲液洗一遍后，换上50μL钙缓冲液。
3、检测信号值：加入25μL预先配制的化合物储存液，用Flextation仪在525nm处检测荧光值。
4、将梯度浓度与对应的钙流信号值的结果用Graphpad Prism 5.0进行曲线拟合，计算出各化合物的EC50见表1。
表1：实施例对GPR40受体的激动活性。
| 化合物编号 | EC<sub>50</sub>(nM) | 化合物编号 | EC<sub>50</sub>(nM) | 化合物编号 | EC<sub>50</sub>(nM) |
| TAK-875 | 35.80 | S1 | A | S2 | A |
| S3 | C | S4 | D | S5 | D |
| S6 | B | S7 | D | S8 | D |
| S9 | C | S10 | C | S11 | D |
| S12 | C | S13 | D | S14 | C |
| S15 | D | S16 | B | S17 | B |
| S18 | C | S19 | D | S20 | C |
| S21 | B | S22 | C | S23 | B |
| S24 | B |
10nM<A<100nM；100nM<B<1μM；1μM<C<10μM；10μM<D。
结论：由表1可以看出，设计合成的化合物对GPR40受体的都具有不同程度的激动活性,其中多个化合物对GPR40受体有较高的活性。
实验实施例2
化合物S2在ICR小鼠口服葡萄糖耐量实验(OGTT)模型上的降血糖作用
C57/BL6雄性小鼠，SPF级，8-10周龄，体重大约在25g左右，购买于上海斯莱克实验动物有限公司。将小鼠随机分组，分为空白对照组和给药组，给药组分为两个剂量(10mg/kg和30mg/kg)，每组7只。实验前，小鼠饥饿时间为16小时(即下午5点至第二天早上9点)，给药前(-30min)，用血糖试纸测量空腹血糖，并记录实验结果。然后口服给药，实验分三组，以0.5％羧甲基纤维素钠(CMC-Na)作为阴性对照，化合物S2(10mg/kg和30mg/kg)作为实验组。30min后(0min时间点)，测血糖并记录结果。测完血糖后立即口服1.5g/kg葡萄糖。然后分别在15、30、60、90和120min时测试血糖水平并记录结果。实验结果显示，10mg/kg化合物S2具有很好地改善糖耐量效果，同时重复了一次，得到同样类似的实验效果，结果如下：
根据上述结果，以0.5％CMC-Na作为阴性对照，20mg/kg化合物TAK-875作为阳性对照，10mg/kg化合物S2作为实验组，重复上述实验。实验前，小鼠饥饿时间为16小时，给药前(-60min)，用血糖试纸测量空腹血糖，并记录实验结果。然后口服20mg/kg化合物TAK-875，30min后，分别口服0.5％CMC-Na阴性对照组和10mg/kg化合物S2实验组。30min后(0min时间点)，测量血糖并记录结果。测完血糖后立即口服1.5g/kg葡萄糖，然后分别在15、30、60、90和120min时测试血糖水平并记录结果。实验结果初步显示，与阳性化合物TAK-875相比，10mg/kg化合物S2具有更好地改善糖耐量效果，实验结果如图1。
根据图1所示的结果，以0.5％CMC-Na作为阴性对照，20mg/kg化合物TAK-875作为阳性对照，10mg/kg化合物S2作为实验组，重复上述实验。实验前，小鼠饥饿时间为16小时，给药前(-60min)，用血糖试纸测量空腹血糖，并记录实验结果。然后口服20mg/kg化合物TAK-875，30min后，分别口服0.5％CMC-Na阴性对照组和10mg/kg化合物S2实验组。30min后(0min时间点)，测量血糖并记录结果。测完血糖后立即口服1.5g/kg葡萄糖，然后分别在15、30、60、90和120min时测试血糖水平并记录结果。实验结果初步显示，与阳性化合物TAK-875相比，10mg/kg化合物S2具有更好地改善糖耐量效果，实验结果如图2。
Claims (5)
1.亚砜基乙酸类衍生物及其药学上可接受的盐，其中，所述亚砜基乙酸类衍生物选自以下化合物：
2.一种药物组合物，其含有治疗有效剂量的选自权利要求1所述的亚砜基乙酸类衍生物及其药学上可接受的盐，以及可药用的载体。
3.根据权利要求2所述的药物组合物，更进一步地包含其他抗糖尿病药物、其他抗高血糖药物、抗肥胖症药物、抗血小板药物、抗动脉粥样硬化的药物或其组合。
4.根据权利要求1所述的亚砜基乙酸类衍生物及其药学上可接受的盐或根据权利要求2或3所述的药物组合物在制备用作GPR40受体激动剂的药物中的用途。
5.根据权利要求1所述的亚砜基乙酸类衍生物及其药学上可接受的盐或根据权利要求2或3所述的药物组合物在制备用于治疗糖尿病和/或代谢综合征的药物中的用途。
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