CN107522634A - 联芳基脲类羧酸衍生物或其盐及其制备方法和用途 - Google Patents
联芳基脲类羧酸衍生物或其盐及其制备方法和用途 Download PDFInfo
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- CN107522634A CN107522634A CN201610455177.XA CN201610455177A CN107522634A CN 107522634 A CN107522634 A CN 107522634A CN 201610455177 A CN201610455177 A CN 201610455177A CN 107522634 A CN107522634 A CN 107522634A
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- Prior art keywords
- substitution
- alkyl
- halogen
- methyl
- phenyl
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- -1 Biaryl ureas carboxylic acid Chemical class 0.000 title claims abstract description 117
- 235000013877 carbamide Nutrition 0.000 title claims abstract description 42
- 150000003839 salts Chemical class 0.000 title claims abstract description 28
- 238000004519 manufacturing process Methods 0.000 title description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 88
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 206010061218 Inflammation Diseases 0.000 claims abstract description 8
- 230000004054 inflammatory process Effects 0.000 claims abstract description 8
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 7
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 5
- 208000009386 Experimental Arthritis Diseases 0.000 claims abstract description 4
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 4
- 201000011510 cancer Diseases 0.000 claims abstract description 4
- 208000006673 asthma Diseases 0.000 claims abstract description 3
- 201000002491 encephalomyelitis Diseases 0.000 claims abstract description 3
- 208000002551 irritable bowel syndrome Diseases 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 126
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 123
- 238000006467 substitution reaction Methods 0.000 claims description 118
- 229910052736 halogen Inorganic materials 0.000 claims description 96
- 150000002367 halogens Chemical class 0.000 claims description 96
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 60
- 229910052739 hydrogen Inorganic materials 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 55
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 52
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 43
- 150000002431 hydrogen Chemical class 0.000 claims description 39
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 36
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- 229910052760 oxygen Inorganic materials 0.000 claims description 30
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 27
- 239000001301 oxygen Substances 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 15
- 125000000468 ketone group Chemical group 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 239000000370 acceptor Substances 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
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- 125000003342 alkenyl group Chemical group 0.000 claims 4
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- 201000008482 osteoarthritis Diseases 0.000 claims 1
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 287
- 239000002585 base Substances 0.000 description 204
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 190
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 180
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 172
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 159
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 91
- 235000010290 biphenyl Nutrition 0.000 description 86
- 238000006243 chemical reaction Methods 0.000 description 84
- 238000005160 1H NMR spectroscopy Methods 0.000 description 79
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 74
- 239000012044 organic layer Substances 0.000 description 70
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 66
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
- 239000012043 crude product Substances 0.000 description 62
- 235000011054 acetic acid Nutrition 0.000 description 55
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 53
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 53
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 50
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 50
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 46
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 45
- 238000001914 filtration Methods 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 44
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
- 239000012265 solid product Substances 0.000 description 43
- 239000007787 solid Substances 0.000 description 41
- 238000003756 stirring Methods 0.000 description 40
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 39
- 239000003208 petroleum Substances 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 37
- 235000019441 ethanol Nutrition 0.000 description 36
- 238000004809 thin layer chromatography Methods 0.000 description 33
- 238000001514 detection method Methods 0.000 description 32
- 108091008680 RAR-related orphan receptors Proteins 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 31
- 238000001035 drying Methods 0.000 description 30
- 239000002994 raw material Substances 0.000 description 30
- 239000000741 silica gel Substances 0.000 description 30
- 229910002027 silica gel Inorganic materials 0.000 description 30
- 229960001866 silicon dioxide Drugs 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 29
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 28
- 238000000605 extraction Methods 0.000 description 25
- 229910052757 nitrogen Inorganic materials 0.000 description 25
- 238000000926 separation method Methods 0.000 description 25
- 239000000243 solution Substances 0.000 description 23
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
- 239000003921 oil Substances 0.000 description 18
- 235000019198 oils Nutrition 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
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- 235000002639 sodium chloride Nutrition 0.000 description 16
- 235000011121 sodium hydroxide Nutrition 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
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- 230000006837 decompression Effects 0.000 description 13
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- 238000000034 method Methods 0.000 description 11
- 102000013691 Interleukin-17 Human genes 0.000 description 10
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- 150000004702 methyl esters Chemical class 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 8
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- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 8
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 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 7
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- CRZQGDNQQAALAY-UHFFFAOYSA-N Methyl benzeneacetate Chemical compound COC(=O)CC1=CC=CC=C1 CRZQGDNQQAALAY-UHFFFAOYSA-N 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
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- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 5
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- UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于化学医药技术领域,涉及具有通式I结构的联芳基脲类羧酸化合物或其盐、其制备方法、其药物组合物,和在制备治疗与RORγt有关的疾病的药物中用途。本发明经研究,结果显示,所述化合物可有效抑制RORγt蛋白受体,从而调控Th17细胞的分化,抑制IL‑17的产生,可进一步制备RORγt介导的炎症相关类疾病的治疗药物,用于治疗多发性硬化、类风湿关节炎、胶原诱导性关节炎、银屑病、炎症性肠病、脑脊髓炎、克隆疾病、哮喘、癌症等炎症相关类疾病。
Description
技术领域
本发明属于化学医药技术领域,涉及具有通式I的具有RORγt抑制活性的联芳基脲类羧酸衍生物及其制备方法,还涉及该联芳基脲类羧酸类化合物在用于制备治疗与RORγt有关的疾病药物的用途。
背景技术
视黄酸受体相关孤儿受体(retinoic acid recetor-related orphanreceptors,RORs),又称为NF1R,属于配体依赖的转录因子核受体超家族的一员。RORs亚家族主要包括RORα、RORβ和RORγ这三个成员。RORγ存在两种不同的亚型:RORγ1和RORγt(也称作RORγ2),其中RORγ1分布于骨骼肌、胸腺、睾丸、胰腺、前列腺、心脏和肝脏等处,而RORγt仅表达于某些免疫细胞中。
Littman等最早报道RORγt对于初始CD4+T细胞分化成Th17细胞是必需的。经抗原刺激的Thp细胞向Th17细胞分化过程中,在IL-6、IL-21和TGF-β等细胞因子作用下诱导表达RORγt。从RORγt缺失小鼠中分离出来的Thp细胞,向Th17细胞株分化的能力明显降低。这些都表明RORγt是促进Th17细胞分化的关键调节因子。
Th17细胞是辅助性T细胞的一种,会产生IL-17及其他促炎性细胞因子。Th17细胞在许多小鼠自身免疫性疾病模型中均发挥了关键的作用,如实验性变态反应性脑脊髓炎(EAE)和胶原诱导性关节炎(CIA)动物模型。此外,在一些人类自身免疫性疾病包括类风湿性关节炎(RA)、多发性硬化(MS)、银屑病(Psoriasis)和炎症性肠病(IBD)中,均能检测到IL-17水平的提高。自身免疫性疾病病人的组织和外周血液样本中所发现的Th17细胞数量均增多。因此,Th17细胞或其产生的细胞因子IL-17与炎症及自身免疫性疾病的发病机制有紧密联系。
2015年1月,由诺华公司开发的通过特异性阻断IL-17治疗银屑病的单克隆抗体Cosentyx(Secukinumab/AIN457),已获FDA批准上市,这是治疗银屑病类药物市场中首个作用于IL-17的药物。这也强调了IL-17信号通路在炎性疾病中的重要性,并且展示了通过RORγt抑制剂而影响IL-17信号通路而治疗炎性疾病的潜在可能性。
因此,RORγt可作为治疗自身免疫性疾病药物的新靶点,寻找RORγt小分子调节剂并将其用于RORγt介导的炎症和自身免疫性疾病的治疗将具有重要意义。
发明内容
本发明的目的是提供具有通式I的联芳基脲类羧酸化合物及其药学上可接受的盐:
其中:
A表示苯基或杂芳基;
B表示苯基或杂芳基;
R1任选自氢、甲基、卤素、氰基、羟基、-CF3、-CHF2、-CH2F;
R1'任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2;
R2任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、羧基或氰基取代的杂芳基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2中的一个或两个;
R3、R4各自独立地选自氢、C1-C3烷基、卤素取代的C1-C3烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基;
R5、R6各自独立地选自氢、卤素、氰基、C1-C3烷基、-(CH2)nOH、卤素取代的C1-C3烷基、C1-C3烷氧基、卤素取代的C1-C3烷氧基、C3-C6环烷基、C3-C6氧或氮杂环烷基,且R5、R6也可以连接成C3-C6环;
R7任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、羧基或氰基取代的杂芳基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2;
Y选自共价键、-NRa-、-O-、-NRaCRa1Ra2-、-OCRa1Ra2-、-(CRa1Ra2)n-、-C(O)NRa-;
Ra、Ra1、Ra2各自独立地选自氢、氰基、C1-C3烷基、-(CH2)nOH或卤素;
m、r、t、n、s各自独立地选自0~2中的任一整数值。
优选地,A为苯基,s为1且R6为H,结构如通式II所示:
其中:
B表示苯基或杂芳基;
R1任选自氢、甲基、卤素、氰基、羟基、-CF3、-CHF2、-CH2F;
R1'任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2;
R2任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、羧基或氰基取代的杂芳基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2中的一个或两个。
R3、R4各自独立地选自氢、C1-C3烷基、卤素取代的C1-C3烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基;
R5任选自氢、卤素、氰基、C1-C3烷基、-(CH2)nOH、卤素取代的C1-C3烷基、C1-C3烷氧基、卤素取代的C1-C3烷氧基、C3-C6环烷基、C3-C6氧或氮杂环烷基;
R7任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、羧基或氰基取代的杂芳基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2;
Y选自共价键、-NRa-、-O-、-NRaCRa1Ra2-、-OCRa1Ra2-、-(CRa1Ra2)n-、-C(O)NRa-;
Ra、Ra1、Ra2各自独立地选自氢、氰基、C1-C3烷基、-(CH2)nOH或卤素;
m、r、t、n各自独立地选自0~2中的任一整数值。
进一步优选地,A为苯基,B为苯基或六元杂芳基,R5为H,结构如通式III所示:
其中:
R1任选自氢、甲基、卤素、氰基、羟基、-CF3、-CHF2、-CH2F;
R1'任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2;
R2任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、羧基或氰基取代的杂芳基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2中的一个或两个。
R3、R4各自独立地选自氢、C1-C3烷基、卤素取代的C1-C3烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基;
R5任选自氢、卤素、氰基、C1-C3烷基、-(CH2)nOH、卤素取代的C1-C3烷基、C1-C3烷氧基、卤素取代的C1-C3烷氧基、C3-C6环烷基、C3-C6氧或氮杂环烷基;
R7任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、羧基或氰基取代的杂芳基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2;
Y选自共价键、-NRa-、-O-、-NRaCRa1Ra2-、-OCRa1Ra2-、-(CRa1Ra2)n-、-C(O)NRa-;
Ra、Ra1、Ra2各自独立地选自氢、氰基、C1-C3烷基、-(CH2)nOH或卤素;
r、m、n、t各自独立地选自0~2中的任一整数值。
更进一步优选地:
r为1或2;当r为1时R2选自-Cl、-F、-CF3、-OCF3、氰基、C1-C3烷基任意一个;当r为2时R2选自-Cl、-F、-CF3、-OCF3、氰基、C1-C3烷基任意两个。
R7任选自氢、卤素、氰基、羟基、C1-C6烷基;
最优选地,本发明提供的联芳基脲类羧酸化合物包括但不限于以下具体化合物实例:
本发明还提供了一种制备联芳基脲类羧酸类化合物的方法,其包括以下合成方案:
合成方案1:
1.式1-1所示化合物与1-2所示化合物跟Pd2(dba)3,磷酸钾或碳酸钾,叔丁基四氟硼酸盐,在微波中110℃反应得1-3所示化合物;
2.式1-3所示化合物在SnCl2,盐酸的乙醇溶液中60℃反应得1-4所示化合物;
3.式1-4所示化合物与中间体A跟三光气,N,N-二异丙基乙胺在0℃到室温的条件下反应得1-5所示化合物;
4. 1-5所示化合物在氢氧化锂或氢氧化钠的乙醇/水溶液中室温反应得1-a所示目标化合物。
合成方案2:
1.式2-1所示化合物在NaH或K2CO3作用下,与卤代烷在室温作用下得2-2所示化合物;
2.式2-2所示化合物与中间体A跟三光气,N,N-二异丙基乙胺在0℃到室温的条件下反应得式2-3所示化合物;
3.式2-3所示化合物在氢氧化锂或氢氧化钠的乙醇/水溶液中室温反应得式2-a所示目标化合物‘
除非另有说明,上述合成方案中所述基团、术语的含义与通式I、II、III化合物中的含义相同。
上述合成方案只是列举了本发明中部分化合物的制备方法,按照本领域的公知技术,技术人员在上述合成方案的基础上,采用类似的方法也可合成本发明的化合物。
本发明所述的“化合物”,包括所有立体异构体、几何异构体、互变异构体和同位素。
本发明所述的“化合物”,可以是不对称的,例如,具有一个或多个立体异构体。除非另有说明,所有立体异构体都包括,如对映异构体和非对映异构体。本发明中含有不对称碳原子的化合物,可以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分,或通过使用手性原料或手性试剂合成。
本发明所述的“化合物”,还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
本发明还包括所有同位素的原子,无论是在中间体或最后的化合物。同位素的原子包括具有相同的原子数、但不同质量数的。例如,氢的同位素包括氘和氚。
本发明中,除特殊说明外,所用的术语具有如下含义:
术语“卤素”是指氟、氯、溴或碘,优选氟或氯。
术语“氰基”,指-CN。
术语“羟基”,指-OH。
术语“羧基”,指-COOH。
术语“烷基”,指由碳原子和氢原子组成的直链或支链的饱和烃基团,如C1-C20烷基,优选为C1-C6烷基,例如甲基、乙基、丙基(包括正丙基和异丙基)、丁基(包括正丁基、异丁基、仲丁基或叔丁基)、戊基(包括正戊基、异戊基、新戊基)、正己基、2-甲基己基等。所述烷基可以是非取代的、或是被一个或多个取代基所取代,取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基。
术语“环烷基”,指全部为碳的单环、稠合、螺环或桥环的环,如环丙基、环丁基、环戊基、环戊烯基、环己基、螺[3.4]辛烷基、二环[3.1.1]己烷基。
术语“杂环烷基”,指含1个或多个N、O或S的杂原子的单环或稠合的环。典型地为含1个或多个N、O或S的杂原子的5-6元杂环基,例如哌嗪子基、吗啉代基、哌啶子基、吡咯烷基及其衍生物。
术语“芳基”,指具有完全共轭的π电子体系的全碳单环或稠合环,通常具有6-14个碳原子,优选具有6-12个碳原子,最优选具有6个碳原子。芳基可以是非取代的、或被一个或多个取代基所取代,取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、芳烷基、氨基、卤素、磺酰基、亚磺酰基、磷酰基。非取代的芳基的实例包括但不限于苯基、萘基和蒽基。
术语“杂芳基”是指5-12个环原子的单环或稠合环,其中含有1-4个选自N、O、S的环原子,其余环原子为C,且具有完全共轭的π-电子体系,包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、三唑基、四氢吡咯基。杂芳基可以是非取代的或取代的,所述的取代基包括但不限于烷基、烷氧基、芳基、芳烷基、氨基、卤素、羟基、氰基、硝基、羰基和杂脂环基。
术语“脲”,指式-N(RaRb)-C(=O)-NRcRd的基团,其中Ra、Rb、Rc、Rd独立地选自氢、烷基、环烷基、杂环、芳基或杂芳基等。
术语“共价键”,指原子间通过共用电子对所形成的相互作用。
“治疗”意味着对哺乳动物体内疾病的任何治疗,包括:(1)防止疾病,即造成临床疾病的症状不发展;(2)抑制疾病,即阻止临床症状的发展;(3)减轻疾病,即造成临床症状的消退。
本发明还提供了一种药物组合物,包含如前所述的化合物或其药学上可接受的盐作为活性成份,以及一种或多种药学上可接受的载体。
本发明所述的“药物组合物”,指一种或多种本发明的化合物或其盐与在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体的制剂。药物组合物的目的是有利于对有机体给药输送。
术语“药学上可接受的载体”,指与活性成份共同给药的、且有利于活性成份给药的物质,包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。例如包括但不限于碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
本发明所述的药物组合物,可配制成固态、半固态、液态或气态制剂,如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
本发明所述的药物组合物,可以采用本领域熟知的方法制造,如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
本发明所述的化合物或其药学上可接受的盐或其药物组合物的给药途径,包括但不限于口服、直肠、透黏膜、经肠给药,或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。
对于口服给药,可以通过将活性化合物与本领域熟知的药学上可接受的载体混合,来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等,以用于对患者的口服给药。例如,用于口服给药的药物组合物,可采用如下方式获得片剂:将活性成分与一种或多种固体载体合并,如果需要将所得混合物制粒,并且如果需要加入少量的赋形剂加工成混合物或颗粒,以形成片剂或片芯。片芯可与任选适合肠溶的包衣材料结合,加工成更有利于有机体(例如人)吸收的包衣制剂形式。
本发明还提供了如前所述的联芳基脲类羧酸类化合物或其药学上可接受的盐或在制备RORγt受体抑制剂方面的应用。
本发明同时还提供了一种如前所述的化合物或其药学上可接受的盐或它们的药物组合物作为RORγt受体抑制剂在制备用于治疗或预防与RORγt相关的疾病的药物中的用途。
优选的,前述与RORγt受体相关的疾病选自多发性硬化、类风湿关节炎、胶原诱导性关节炎、银屑病、炎症性肠病、脑脊髓炎、克隆疾病、哮喘、癌症等炎症相关类疾病。癌症优选前列腺癌。
本发明提供了一类具有通式I结构特征的联芳基脲类羧酸化合物。经研究发现,该类化合物可有效抑制RORγt蛋白受体,从而调控Th17细胞的分化,抑制IL-17的产生,可作为治疗RORγt介导的炎症相关类疾病的治疗药物。
具体实施方式
以下结合具体实施例,对本发明的技术方案做进一步的描述,但是本发明的保护范围并不限于这些实施例。凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
本发明提供的目标化合物制备方法中,柱层析色谱采用乳山太阳干燥剂有限公司生产的硅胶(300-400目);薄层色谱采用GF254(0.25毫米);核磁共振色谱(NMR)使用Varian-400核磁共振仪测定;液质连用(LC/MS)使用Agilent Technologies 6120液质联用仪。
此外,凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明,本发明使用的原料都是市售原料、无需进一步纯化可以直接使用。
实施例1:4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯甲酸
(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)benzoic acid)
步骤1:4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯甲酸甲酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),DCM(5mL),DIEA(120mg,0.93mmol)冰浴搅拌5分钟,然后加入三光气(33mg,0.11mmol),继续冰浴反应30分钟,然后加入4-氨甲基苯甲酸甲酯(56mg,0.34mmol)继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(石油醚:乙酸乙酯=10:1)分离得白色固体80mg,产率50.3%。1H NMR(400MHz,CDCl3)δ7.86(d,J=8.1Hz,2H),7.82(s,1H),7.49–7.41(m,1H),7.39(s,2H),7.36–7.30(m,2H),7.22(d,J=8.1Hz,2H),7.17(d,J=7.6Hz,1H),6.06(s,1H),4.36(d,J=4.9Hz,2H),3.88(s,3H).MS(ESI)m/z:512.7(M-1).
步骤2:4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯甲酸
往25mL单口瓶中加入4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基-4-基]脲)甲基)苯甲酸甲酯(80mg,0.16mmol),氢氧化锂(19mg,0.48mmol),乙醇(1mL),水(0.3mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调pH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物粗产物,经制备板多次分离得白色固体产物18mg,产率24.3%.1HNMR(400MHz,CD3OD)δ8.01(d,J=8.2Hz,2H),7.60(s,2H),7.52(t,J=7.0Hz,1H),7.47–7.39(m,4H),7.30(d,J=7.5Hz,1H),4.48(s,2H).MS(ESI)m/z:496.7(M-1).。
实施例2:2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
(2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid)
步骤1:2-溴-1,3-二氯-5-硝基苯
往单口瓶中加入2,6-二氯-4-硝基苯胺(5g,24mmol),溴化铜(16g,72mmol)和乙腈(50mL),冰浴搅拌下滴加叔丁基亚硝酸酯(7.46g,72mmol),然后室温搅拌反应6小时,反应毕,加入水(100ml),用乙酸乙酯萃取(100mLx2),饱和氯化钠(100mL),无水硫酸钠干燥,加压浓缩得橙色固体6.3克,产率97%。
步骤2:4-溴-3,5-二氯苯胺
室温下,往单口瓶中加入2-溴-1,3-二氯-5-硝基苯(1g,4mmol),乙醇(6mL),四氢呋喃(1mL),浓盐酸(1mL),氯化亚锡((3.78g,16mmol)。然后加热到50℃搅拌反应2小时。反应毕,冷却到室温,旋干溶剂,然后加入2N的氢氧化钠水溶液,乙酸乙酯(100mlx3)萃取,合并有机层,干燥,加压浓缩得粗产品0.86克,产率96.7%。
步骤3:2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺
往微波管中加入4-溴-3,5-二氯苯胺(200mg,0.83mmol),(2-(三氟甲氧基)苯基)硼酸(342mg,1.66mmol),三叔丁基膦四氟硼酸盐(96mg,0.33mmol),Pd2(dba)3(304mg,0.33mmol),饱和碳酸钠(1.245ml,2.49mmol),1,4-二氧六环(4mL),微波120℃反应4小时。反应毕旋干溶剂,加水,乙酸乙酯萃取,合并有机层,减压旋干溶剂,硅胶柱分离(展开剂乙酸乙酯:石油醚=0:100-10:90)得黄色固体产物136mg,产率59.9%。
步骤4:2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(40mg,0.12mmol),DCM(3mL),DIEA(31mg,0.24mmol)冰浴搅拌5分钟,然后加入三光气(15mg,0.05mmol),继续冰浴反应30分钟,然后加入4-氨甲基苯乙酸甲酯(27mg,0.15mmol),继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(二氯甲烷:甲醇=50:1)分离得白色固体2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯25mg,产率38.5%。1H NMR(400MHz,CDCl3)δ7.60(s,1H),7.48-7.42(t,J=7.1Hz,1H),7.42(s,2H),7.39–7.31(m,2H),7.24-7.22(d,J=6.5Hz,1H),7.20–7.11(m,4H),5.66(s,1H),4.27-4.25(d,J=5.2Hz,2H),3.71(s,3H),3.63(s,2H),1.87(s,1H).MS(ESI)m/z:527.1(MH+).
步骤5:2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
往25mL中加入2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯(25mg,0.047mmol),氢氧化钠(5.7mg,0.14mmol),乙醇(2mL),水(0.5mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调pH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物2-(4-((3-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯基]-4-基)脲)甲基)苯基)乙酸18mg,产率75.0%。1H NMR(400MHz,CD3OD)δ7.59(s,2H),7.54-7.51(t,J=7.1Hz,1H),7.44-7.39(m,2H),7.33–7.25(m,5H),4.39(s,2H),3.59(s,2H).MS(ESI)m/z:513.1(MH+).。
实施例3:2-(4-((3-(2-氯-6-氰基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
(2-(4-((3-(2-chloro-6-cyano-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid)
步骤1:3-氯-5-氰基-2-溴苯
往25mL单口瓶中加入2-氨基-3-氯-5-硝基苄腈(3g,15mmol),溴化铜(4g,18mmol),乙腈(50mL),冰浴搅拌5分钟后,称取正戊基亚硝酸酯(6.76g,57.8mmol)于乙腈(20mL)中,冰浴下滴加入反应液中,然后继续冰浴反应30分钟,自然升温到室温,反应过夜。加入水(100mL),乙酸乙酯(100mLx3)萃取,再水(100mL)洗,饱和氯化钠(100mL)洗,无水硫酸钠干燥,旋干溶剂,粗产品经硅胶柱分离得黄色固体3-氯-5-氰基-2-溴苯2.3g,产率58.4%。1HNMR(400MHz,CDCl3)δ8.52(d,J=2.4Hz,1H),8.41(d,J=2.4Hz,1H).
步骤2:6-氯-4-硝基-2’(三氟甲氧基)-[1,1’-联苯基]-2-甲腈
往微波管中加入2-溴-3-氯-5-硝基苄腈(300mg,1.15mmol),2-三氟甲氧基苯硼酸(355mg,1.72mmol),Pd2(dba)3(11mg,0.012mmol),三叔丁基磷四氟硼酸盐(10mg,0.033mmol),三水合磷酸钾(897mg,3.45mmol),1,4-二氧六环/H2O(10mL/1mL)。氮气鼓泡5分钟,然后微波100℃反应1.5小时,饱和氯化铵(20mL)洗涤。硅胶柱分离(石油醚:乙酸乙酯=30:1)得黄色固体产物6-氯-4-硝基-2’(三氟甲氧基)-[1,1’-联苯基]-2-甲腈270mg,产率68.7%。1H NMR(400MHz,CDCl3)δ8.59-8.58(d,J=2.1Hz,1H),8.54-8.53(d,J=2.1Hz,1H),7.65-7.62(t,J=7.1Hz,1H),7.55–7.45(m,2H),7.37-7.35(d,J=7.5Hz,1H).
步骤3:4-氨基-6-氯-2’-(三氟甲氧基)-[1,1联苯基]-2-甲腈
往25mL单口瓶中加入6-氯-4-硝基-2’(三氟甲氧基)-[1,1’-联苯基]-2-甲腈(265mg,0.77mmol),二水合氯化亚锡(524mg,2.31mmol),乙醇(20mL),浓盐酸(2mL),60℃加热反应3小时,TLC检测已反应完成,冷却到室温,加入2N的氢氧化溶液调PH值到碱性,乙酸乙酯(20mLx3)萃取,合并有机层,饱和氯化钠(30mL)洗涤,旋干溶剂得白色固体产物4-氨基-6-氯-2’-(三氟甲氧基)-[1,1联苯基]-2-甲腈240mg,产率99.6%。1H NMR(400MHz,CDCl3)δ7.51-7.48(t,J=7.0Hz,1H),7.43–7.36(m,2H),7.34-7.33(d,J=6.3Hz,1H),6.99(d,J=2.3Hz,1H),6.92(d,J=2.3Hz,1H),2.96(s,2H).
步骤4:2-(4-((3-(2-氯-6-氰基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯
往25mL单口瓶中加入4-氨基-6-氯-2’-(三氟甲氧基)-[1,1-联苯基]-2-甲腈(80mg,0.26mmol),DCM(4mL),DIEA(67mg,0.52mmol)冰浴搅拌5分钟,然后加入三光气(29.7mg,0.10mmol),继续冰浴反应30分钟,然后加入4-氨甲基苯乙酸甲酯(50mg,0.28mmol)继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(石油醚:乙酸乙酯=10:1)分离得白色固体2-(4-((3-(2-氯-6-氰基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯38mg,产率28.8%。1H NMR(400MHz,CDCl3)δ7.87–7.78(m,2H),7.54–7.47(m,2H),7.41-7.37(t,J=7.2Hz,2H),7.31-7.29(d,J=6.5Hz,1H),7.21–7.16(m,4H),5.70(s,1H),4.29-4.28(d,J=5.2Hz,2H),3.67(s,3H),3.62(s,2H).MS(ESI)m/z:518.2(MH+).
步骤5:2-(4-((3-(2-氯-6-氰基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
往25mL单口瓶中加入2-(4-((3-(2-氯-6-氰基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯(38mg,0.014mmol),一水合氢氧化锂(9.2mg,0.22mmol),乙醇(1mL),水(0.3mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物2-(4-((3-(2-氯-6-氰基-2’-(三氟甲氧基)-[1,1’-联苯]-4-脲)甲基)苯基)乙酸27mg,产率72.9%。1H NMR(400MHz,CD3OD)δ7.93-7.92(d,J=2.1Hz,1H),7.87-7.86(d,J=2.1Hz,1H),7.61-6.57(t,J=11.1,4.6Hz,1H),7.51–7.44(m,2H),7.43–7.38(m,1H),7.32–7.26(m,3H),7.25-7.23(d,J=11.0Hz,1H),4.39(s,2H),3.59(s,2H).MS(ESI)m/z:504.1(MH+).。
实施例4:2-(4-((3-(2-氯-6-甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
(2-(4-((3-(2-chloro-6-methyl-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid)
步骤1:2-溴-1-氯-3-甲基-5-硝基苯
往25mL三口瓶中加入2-氯-6-甲基-4-硝基苯胺(500mg,2.68mmol),溴化铜(718mg,3.22mmol),乙腈(8ml),冰浴搅拌5分钟,另取叔丁基亚硝酸酯(470mg,4.02mmol)用乙腈(2mL)溶解,然后滴加到三口瓶中,自然升温到室温,反应过夜。加入H2O(20mL),乙酸乙酯(20mLx3)萃取,合并有机层,饱和氯化钠(20mL)洗涤,旋干溶剂得黄色固体产物2-溴-1-氯-3-甲基-5-硝基苯650mg,产率96.7%。1H NMR(400MHz,CDCl3)δ8.17(s,1H),8.01(s,1H),2.57(s,3H).
步骤2:4-溴-3-氯-5-甲基苯胺
往25mL单口瓶中加入2-溴-1-氯-3-甲基-5-硝基苯(640mg,2.56mmol),二水合氯化亚锡(2.25g,10mmol),浓盐酸(0.5mL),乙醇(10mL),四氢呋喃(4mL),60℃加热搅拌反应2小时,自然冷却到室温,加入水(30mL),20%氯化钠(50mL),乙酸乙酯(50mLx3)萃取,合并有机层,有机层用饱和氯化钠(50mL)洗涤,无水硫酸钠干燥,过滤,旋干溶剂得黄色固体产物4-溴-3-氯-5-甲基苯胺540mg,产率95.9%。1H NMR(400MHz,CDCl3)δ6.65(d,J=2.3Hz,1H),6.47(s,1H),3.65(s,2H),2.34(s,3H).MS(ESI)m/z:220.0(MH+).
步骤3:2-氯-6-甲基-2’-(三氟甲氧基)-[1,1’-联苯基]-4-胺
往微波管中加入4-溴-3-氯-5-甲基苯胺(500mg,2.3mmol),2-三氟甲氧基苯硼酸(710mg,3.5mmol),Pd2(dba)3(210mg,0.23mmol),叔丁基磷四氟硼酸盐(200mg,0.7mmol),碳酸钠(730mg,6.9mmol),1,4-二氧六环/水(10mL/1mL)。氮气鼓泡5分钟,然后微波120℃反应3小时,饱和氯化铵(50mL)洗涤,硅胶柱分离(石油醚:乙酸乙酯=20:1-10:1)得黄色固体产物2-氯-6-甲基-2’-(三氟甲氧基)-[1,1’-联苯基]-4-胺190mg,产率27.8%。MS(ESI)m/z:302.1(MH+).MS(ESI)m/z:220.0(MH+).
步骤4:2-(4-((3-(2-氯-6-甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸乙酯
往25mL单口瓶中加入2-氯-6-甲基-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(30mg,0.1mmol),DCM(1mL),DIEA(26mg,0.2mmol)冰浴搅拌5分钟,然后加入三光气(12mg,0.04mmol),继续冰浴反应30分钟,然后加入4-氨甲基苯乙酸甲酯(22mg,0.12mmol)继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(二氯甲烷:甲醇=20:1)分离得白色固体2-(4-((3-(2-氯-6-甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸乙酯31mg,产率62.0%。1H NMR(400MHz,CDCl3)δ7.45–7.38(m,1H),7.38–7.30(m,3H),7.22–7.11(m,6H),5.65(s,1H),4.28(s,2H),3.68(s,3H),3.60(s,2H),1.95(s,3H).MS(ESI)m/z:507.2(MH+).
步骤5:2-(4-((3-(2-氯-6-甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
往25mL单口瓶中加入2-(4-((3-(2-氯-6-甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯(30mg,0.059mmol),氢氧化钠(7.1mg,0.177mmol),乙醇(1mL),水(0.3mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物2-(4-((3-(2-氯-6-甲基-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸23mg,产率79.3%。1H NMR(400MHz,CD3OD)δ7.55(s,1H),7.51-7.47(t,J=7.6,6.4Hz,1H),7.43–7.38(m,2H),7.33–7.22(m,5H),7.19(s,1H),4.39(s,2H),3.59(s,2H),2.00(s,3H).MS(ESI)m/z:493.1(MH+).。
实施例5:2-(4-((3-(2-氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
(2-(4-((3-(2-chloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid)
步骤1:2-二氯-2’-(三氟甲氧基)-[1,1’-联苯基]-4-胺
往微波管中加入4-氯-3-溴苯胺(500mg,2.43mmol),2-三氟甲氧基苯硼酸(649mg,3.15mmol),Pd2(dppf)Cl2(69mg,0.12mmol),碳酸钾(1.01g,7.29mmol),乙腈/水(4mL/1mL)。氮气鼓泡5分钟,然后微波100℃反应2小时,饱和氯化铵(20mL)洗涤。硅胶柱分离(石油醚:乙酸乙酯=10:1-5:1)得黄色油状物2-二氯-2’-(三氟甲氧基)-[1,1’-联苯基]-4-胺610mg,产率88.5%。1H NMR(400MHz,CDCl3)δ7.42–7.35(m,1H),7.36–7.28(m,3H),7.06-7.04(d,J=8.2Hz,1H),6.81-6.80(d,J=1.9Hz,1H),6.64-6.62(d,J=8.2Hz,1H),3.57(s,2H).MS(ESI)m/z:288.0(MH+).
步骤2:2-(4-((3-(2-氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯
往25mL单口瓶中加入2-氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.34mmol),二氯甲烷(4mL),DIEA(129mg,1mmol)冰浴搅拌5分钟,然后加入三光气(35mg,0.12mmol),继续冰浴反应30分钟,然后加入4-氨甲基苯乙酸甲酯(73mg,0.34mmol)继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(石油醚:乙酸乙酯=2:1)分离得白色固体2-(4-((3-(2-氯-2’-(三氟甲氧基)-[1,1’-联苯基]-4-脲)甲基)苯基)乙酸甲酯31mg,产率18.1%。MS(ESI)m/z:493.1(MH+).
步骤3:2-(4-((3-(2-氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
往25mL单口瓶中加入2-(4-((3-(2-氯-2’-(三氟甲氧基)-[1,1’-联苯基]-4-脲)甲基)苯基)乙酸甲酯(30mg,0.06mmol),氢氧化钠(7.3mg,0.18mmol),乙醇(2mL),水(0.5mL),室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物23mg,产率79.3%.1H NMR(400MHz,CD3OD)δ7.71-7.70(d,J=1.9Hz,1H),7.50-7.47(t,J=7.6,1H),7.42-7.36(m,3H),7.35–7.23(m,6H),7.18-7.16(d,J=8.4Hz,1H),4.40(s,2H),3.60(s,2H).MS(ESI)m/z:479.1(MH+).。
实施例6:2-(4-((3-(2,6-二氟-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
(2-(4-((3-(2,6-difluoro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid)
步骤1:2,6-二氟-2’-(三氟甲氧基)-[1,1’-联苯基]-4-胺
往微波管中加入4-溴-3,5-二氟苯胺(500mg,2.4mmol),2-三氟甲氧基苯硼酸(590mg,2.9mmol),Pd2(dppf)Cl2(98mg,0.12mmol),碳酸铯(2.35g,7.2mmol),乙腈/水(10mL/1mL)。氮气鼓泡5分钟,然后微波100℃反应1小时,饱和氯化铵(20mL)洗涤。硅胶柱分离(石油醚:乙酸乙酯=50:1)得黄色油状物2,6-二氟-2’-(三氟甲氧基)-[1,1’-联苯基]-4-胺460mg,产率66.3%。1H NMR(400MHz,CDCl3)δ7.47–7.28(m,4H),6.29-6.27(d,J=9.1Hz,2H),3.67(s,2H).MS(ESI)m/z:290.1(MH+).
步骤2:2-(4-((3-(2,6-二氟-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯
往25mL单口瓶中加入2,6-二氟-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(20mg,0.069mmol),DCM(1mL),DIEA(18mg,0.03mmol)冰浴搅拌5分钟,然后加入三光气(10mg,0.11mmol),继续冰浴反应30分钟,然后加入4-氨甲基苯乙酸甲酯(16mg,0.11mmol)继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(石油醚:乙酸乙酯=2:1)分离得白色固体2-(4-((3-(2,6-二氟-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯7mg,产率20.6%。1H NMR(400MHz,CDCl3)δ7.49–7.37(m,2H),7.38–7.30(m,3H),7.21–7.13(m,4H),7.02-7.00(d,J=9.4Hz,2H),5.46-5.43(t,J=5.2Hz,1H),4.28(d,J=5.3Hz,2H),3.70(s,3H),3.63(s,2H).MS(ESI)m/z:495.2(MH+).
步骤3:2-(4-((3-(2,6-二氟-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
往100mL单口瓶中加入2-(4-((3-(2,6-二氟-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯(7mg,0.014mmol),氢氧化钠(17mg,0.042mmol),乙醇(1mL),水(0.3mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物2-(4-((3-(2,6-二氟-2’-(三氟甲氧基)-[1,1’-联苯基]-4-脲)甲基)苯基)乙酸5mg,产率73.5%。1H NMR(400MHz,CD3OD)δ7.58–7.47(m,1H),7.47–7.37(m,3H),7.29(q,J=10.6,4H),7.17(d,J=9.9Hz,2H),4.39(s,2H),3.59(s,2H).MS(ESI)m/z:481.2(MH+).。
实施例7:2-(4-((3-(2,6-二氯-2'-(二氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
(2-(4-((3-(2,6-dichloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid)
步骤1:2,6-二氯-2’-(二氟甲氧基)-[1,1’-联苯基]-4-胺
往微波管中加入4-溴-3,5-二氯苯胺(500mg,2.07mmol),2-二氟甲氧基苯硼酸酯(672mg,2.49mmol),Pd2(dba)3(378mg,0.4mmol),三叔丁基磷四氟硼酸盐(180mg,0.62mmol),碳酸铯(2.02g,6.01mmol),1,4-二氧六环/水(13mL/2mL)。氮气鼓泡5分钟,然后微波120℃反应3小时。饱和氯化铵(20mL)洗涤。硅胶柱分离(石油醚:乙酸乙酯=10:1-5:1)得黄色油状物2,6-二氯-2’-(二氟甲氧基)-[1,1’-联苯基]-4-胺140mg,产率15.5%。1HNMR(400MHz,CDCl3)δ7.44-7.40(t,J=6.8Hz,1H),7.31-7.27(t,J=8Hz,1H),7.25–7.20(m,2H),6.72(s,2H),6.55-6.18(t,J=74.1Hz,1H),3.86(s,2H).
步骤2:2-(4-((3-(2,6-二氯-2'-(二氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯
往25mL单口瓶中加入2,6-二氯-2'-(二氟甲氧基)-[1,1'-联苯基]-4-胺(50mg,0.11mmol),二氯甲烷(2mL),DIEA(63mg,0.49mmol)冰浴搅拌5分钟,然后加入三光气(19.5mg,0.066mmol),继续冰浴反应30分钟,然后加入4-氨甲基苯乙酸甲酯(35mg,0.197mmol)继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(二氯甲烷:甲醇=50:1)分离得黄色油状物2-(4-((3-(2,6-二氯-2'-(二氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯33mg,产率49.3%。1H NMR(400MHz,CDCl3)δ7.68(s,1H),7.44-7.40(t,J=7.8Hz,1H),7.35(s,2H),7.30-7.26(t,J=8.0Hz,1H),7.24-7.21(d,J=8.2Hz,1H),7.20–7.08(m,5H),6.53-6.18(t,J=74.0Hz,1H),5.77(d,J=5.1Hz,1H),4.24-4.22(d,J=5.3Hz,2H),3.68(s,3H),3.60(s,2H).MS(ESI)m/z:509.1(MH+).
步骤3:2-(4-((3-(2,6-二氯-2’-(二氟甲氧基)-[1,1’-联苯基]-4-基)脲)甲基)苯基)乙酸
往25mL单口瓶中加入2-(4-((3-(2,6-二氯-2’-(二氟甲氧基)-[1,1’-联苯基]-4-基)脲)甲基)苯基)乙酸甲酯(33mg,0.065mmol),氢氧化钠(7.78mg,0.19mmol),乙醇(2mL),水(0.5mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物2-(4-((3-(2,6-二氯-2’-(二氟甲氧基)-[1,1’-联苯基]-4-基)脲)甲基)苯基)乙酸30mg,产率90.9%。1H NMR(400MHz,CD3OD)δ7.57(s,2H),7.47-7.44(t,J=7.2Hz,1H),7.31–7.25(m,5H),7.24-7.20(t,J=8.0Hz,2H),6.85-6.8(t,J=73.9Hz,1H),4.38(s,2H),3.59(s,2H).MS(ESI)m/z:495.1(MH+).。
实施例8:2-(4-((3-(2'-(二氟甲氧基)-2,6-二甲基-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
(2-(4-((3-(2'-(difluoromethoxy)-2,6-dimethyl-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid)
步骤1:2-(2-(二氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊烷
往100mL三口瓶中加入2-二氟甲氧基溴苯(2g,9mmol)频那联硼酯(4.6,18mmol),乙酸钾(3.62g,36mmol),Pd(dppf)Cl2(73mg,0.09mmol),1,4-二氧六环(100mL),加热到120℃搅拌反应过夜。冷却到室温,加入水(50mL),乙酸乙酯(50mLx3)萃取,合并有机层,饱和氯化钠(100mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,用硅胶柱分离(石油醚:乙酸乙酯=50:1)得橙色固体2-(2-(二氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊烷2.1g,产率86.7%。1H NMR(400MHz,CDCl3)δ7.76-7.75(d,J=6.3Hz,1H),7.47-7.43(t,J=6.9Hz,1H),7.26-7.22(d,J=7.2Hz,1H),7.15(d,J=8.2Hz,1H),6.52(t,J=75.5Hz,1H),1.35(s,12H).
步骤2:4-溴-3,5-二甲基苯胺
往25mL单口瓶中加入3,5-二甲基苯胺(2g,16.5mmol),乙腈(80ml),冰浴搅拌5分钟,然后用乙腈(20mL)溶解NBS(3.94g,21.6mmol),滴加入单口瓶中,滴加毕,继续冰浴反应2小时,反应毕,加入水(50mL),乙酸乙酯(100mLx3)萃取,合并有机层,旋干溶剂过硅胶柱(石油醚:乙酸乙酯=10:1-4:1)得白色固体4-溴-3,5-二甲基苯胺2.3g,产率69.7%。1HNMR(400MHz,CDCl3)δ6.44(s,2H),3.45(s,2H),2.31(s,6H).MS(ESI)m/z:200.1(MH+).
步骤3:2’-(二氟甲氧基)-2,6-二甲基-[1,1’-二联苯基]-4-胺
往微波管中加入4-溴-3,5-二甲基苯胺(293mg,1.46mmol),2-二氟甲氧基苯硼酸酯(330mg,1.2mmol),Pd2(dba)3(110mg,0.12mmol),叔丁基磷四氟硼酸盐(104mg,0.36mmol),碳酸铯(1.17g,3.6mmol),1,4-二氧六环/水(4mL/1mL)。氮气鼓泡5分钟,然后微波120℃反应3小时。饱和氯化铵(20mL)洗涤。硅胶柱分离(石油醚:乙酸乙酯=10:1-4:1)得黄色油状物2’-(二氟甲氧基)-2,6-二甲基-[1,1’-二联苯基]-4-胺62mg,产率15.6%。1HNMR(400MHz,CDCl3)δ7.3,7-7.33(t,J=7.6,1H),7.30–7.21(m,2H),7.17(dd,J=7.3,1.1Hz,1H),6.48(s,2H),6.45-6.07(t,J=74.6Hz,1H),3.50(s,2H),1.95(s,6H).MS(ESI)m/z:264.1(MH+).
步骤4:2-(4-((3-(2'-(二氟甲氧基)-2,6-二甲基-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯
往25mL单口瓶中加入2,6-二甲基-2'-(二氟甲氧基)-[1,1'-联苯基]-4-胺(30mg,0.11mmol),DCM(2mL),DIEA(28mg,0.22mmol)冰浴搅拌5分钟,然后加入三光气(13mg,0.044mmol),继续冰浴反应30分钟,然后加入4-氨甲基苯乙酸甲酯(25mg,0.14mmol)继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(二氯甲烷:甲醇=20:1)分离得黄色油状物2-(4-((3-(2'-(二氟甲氧基)-2,6-二甲基-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯43mg,产率81.1%。1H NMR(400MHz,CDCl3)δ7.37-7.35(t,J=7.6Hz,1H),7.27-7.19(m,7H),7.10-7.08(d,J=7.3Hz,1H),7.01(s,1H),6.44-6.07(t,J=74.2Hz,1H),5.55(d,J=5.4Hz,1H),4.37-4.35(d,J=5.4Hz,2H),3.68(s,3H),3.61(s,2H),1.94(s,6H).MS(ESI)m/z:469.2(MH+).
步骤5:2-(4-((3-(2'-(二氟甲氧基)-2,6-二甲基-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
往25mL单口瓶中加入2-(4-((3-(2'-(二氟甲氧基)-2,6-二甲基-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯(43mg,0.092mmol),氢氧化钠(11mg,0.28mmol),乙醇(3mL),水(1mL)室温反应1小时,TLC检测原料已反应完,用2N的盐酸调pH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物2-(4-((3-(2'-(二氟甲氧基)-2,6-二甲基-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸36mg,产率84.0%。1H NMR(400MHz,CD3OD)δ7.42-7.39(t,J=7.0Hz,1H),7.34–7.23(m,6H),7.13-7.12(m,3H),6.79-6.42(t,J=74.4Hz,2H),4.38(s,2H),3.59(s,2H),1.95(s,6H).MS(ESI)m/z:455.2(MH+).。
实施例9:2-(4-((3-(2-(1-甲基-1H-吡唑-4-基)-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
(2-(4-((3-(2-(1-methyl-1H-pyrazol-4-yl)-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid)和
2-(4-((3-(2'-(1-甲基-1H-吡唑-4-基)-6'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
(2-(4-((3-(2'-(1-methyl-1H-pyrazol-4-yl)-6'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid)
步骤1:1-溴-2-氯-4硝基苯
往25mL单口瓶中加入2-氯-4-硝基苯胺(5g,28.9mmol),溴化铜(7.73g,34.7mmol),乙腈(80mL),冰浴搅拌5分钟后,称取正戊基亚硝酸酯(6.76g,57.8mmol)于乙腈(20mL)中,冰浴下滴加入反应液中,然后继续冰浴反应30分钟,自然升温到室温,反应过夜。加入水(100mL),乙酸乙酯(100mLx3)萃取,再水(100mL)洗,饱和氯化钠(100mL)洗,无水硫酸钠干燥,旋干既得黄色固体1-溴-2-氯-4硝基苯5.68g,产率82.9%。
步骤2:2-氯-4-硝基-2'-(三氟甲氧基)-1,1'-联苯
往微波管中加入1-溴-2-氯-4-硝基苯(1g,0.42mmol),2-三氟甲氧基苯硼酸(1.05g,0.51mmol),Pd2(dppf)Cl2(160mg,0.02mmol),碳酸铯(2.77g,1.26mmol),CH3CN/H2O(12mL/3mL)。氮气鼓泡5分钟,然后微波100℃反应2小时。加入乙酸乙酯(20mL),饱和氯化铵(20mL)洗涤,旋干溶剂,粗产品经硅胶柱分离(石油醚:乙酸乙酯=30:1)得黄色油状物物2-氯-4-硝基-2'-(三氟甲氧基)-1,1'-联苯1.47g,产率99.3%。1H NMR(400MHz,CDCl3)δ8.38-8.37(d,J=2.1Hz,1H),8.21-8.18(dd,J=8.4,2.2Hz,1H),7.56–7.47(m,2H),7.45–7.39(m,2H),7.37–7.30(m,1H).
步骤3:4,4,5,5-四甲基-2-(4-硝基-2'-(三氟甲氧基)-[1,1'-联苯]-2-基)-1,3,2-二氧硼戊环
往微波管中加入2-氯-4-硝基-2'-(三氟甲氧基)-1,1'-联苯(500mg,1.55mmol),联硼酸频那醇酯(800mg,4.65mmol),Pd2(dba)3(115mg,0.13mmol),醋酸钾(465mg,4.65mmol),x-phos(240mg,0.5mmol),1,4-二氧六环(15mL)。氮气鼓泡5分钟,然后微波90℃反应2小时。加入乙酸乙酯(20mL),饱和氯化铵(20mL)洗涤,旋干溶剂,粗产品经硅胶柱分离(石油醚:乙酸乙酯=6:1)得黄色油状物物4,4,5,5-四甲基-2-(4-硝基-2'-(三氟甲氧基)-[1,1'-联苯]-2-基)-1,3,2-二氧硼戊环130mg,产率20.2%。
步骤4:1-甲基-4-(4-硝基-2'-(三氟甲氧基)-[1,1'-联苯]-2-基)-1H-吡唑和1-甲基-4-(4'-硝基-6-(三氟甲氧基)-[1,1'-联苯]-2-基)-1H-吡唑
往微波管中加入4,4,5,5-四甲基-2-(4-硝基-2'-(三氟甲氧基)-[1,1'-联苯]-2-基)-1,3,2-二氧硼戊环(100mg,0.2mmol),4-溴-1-甲基-1H-吡唑(47mg,0.29mmol),四三苯基磷钯(22mg,0.014mmol),碳酸钠(80mg,0.75mmol),1,4-二氧六环/H2O(4mL/1mL)。氮气鼓泡5分钟,然后微波90℃反应1.5小时,饱和氯化铵(20mL)洗涤。硅胶柱分离(石油醚:乙酸乙酯=1:1)得两种黄色油状物各为15mg和20mg。
步骤5:2-(1-甲基-1H-吡唑-4-基)-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺和2'-(1-甲基-1H-吡唑-4-基)-6'-(三氟甲氧基)-[1,1'-联苯基]-4-胺
往25mL单口瓶中加入1-甲基-4-(4-硝基-2'-(三氟甲氧基)-[1,1'-联苯]-2-基)-1H-吡唑(15mg,0.04mmol),一水合氯化亚锡(37mg,0.16mmol),乙醇(2mL),浓盐酸(0.25mL),70℃加热反应三小时,TLC检测已反应完成,冷却到室温,加入2N的氢氧化溶液(10mL),乙酸乙酯(20mLx3)萃取,合并有机层,饱和氯化钠(30mL)洗涤,旋干溶剂得白色固体产物2-(1-甲基-1H-吡唑-4-基)-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺12.5mg。
往25mL单口瓶中加入1-甲基-4-(4'-硝基-6-(三氟甲氧基)-[1,1'-联苯]-2-基)-1H-吡唑(20mg,0.05mmol),一水合氯化亚锡(37mg,0.16mmol),乙醇(2mL),浓盐酸(0.25mL),70℃加热反应三小时,TLC检测已反应完成,冷却到室温,加入2N的氢氧化溶液(10mL),乙酸乙酯(20mL x3)萃取,合并有机层,饱和氯化钠(30mL)洗涤,旋干溶剂得白色固体产物2'-(1-甲基-1H-吡唑-4-基)-6'-(三氟甲氧基)-[1,1'-联苯基]-4-胺16mg。
步骤6:2-(4-((3-(2-(1-甲基-1H-吡唑-4-基)-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯和2-(4-((3-(2'-(1-甲基-1H-吡唑-4-基)-6'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯
往25mL单口瓶中加入2-(1-甲基-1H-吡唑-4-基)-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(12.5mg,0.037mmol),DCM(2ml),DIEA(9.5mg,0.074mmol)冰浴搅拌5分钟,然后加入三光气(4.4mg,0.015mmol),继续冰浴反应30分钟,然后加入4-氨甲基苯乙酸甲酯(7.39mg,0.04mmol)继续冰浴反应30分钟,然后室温反应过夜。加入H2O(10mL),二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(石油醚:乙酸乙酯=1:1)分离得白色固体2-(4-((3-(2-(1-甲基-1H-吡唑-4-基)-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯12mg,产率60.0%。1H NMR(400MHz,CDCl3)δ7.47(s,1H),7.39–7.28(m,2H),7.25–7.16(m,7H),7.17–7.09(m,2H),7.04(s,1H),6.89(s,1H),5.64(s,1H),4.33(s,2H),3.67(s,3H),3.66(s,3H),3.58(s,2H).MS(ESI)m/z:539.2(MH+).
往25mL单口瓶中加入2'-(1-甲基-1H-吡唑-4-基)-6'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(16mg,0.048mmol),DCM(2mL),DIEA(13mg,0.096mmol)冰浴搅拌5分钟,然后加入三光气(5.7mg,0.019mmol),继续冰浴反应30分钟,然后加入4-氨甲基苯乙酸甲酯(9.46mg,0.053mmol)继续冰浴反应30分钟,然后室温反应过夜。加入H2O(10mL),二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(石油醚:乙酸乙酯=1:1)分离得白色固体2-(4-((3-(2'-(1-甲基-1H-吡唑-4-基)-6'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯10mg,产率38.7%。1H NMR(400MHz,CDCl3)δ7.46–7.28(m,4H),7.25–7.12(m,6H),7.11–7.01(m,3H),6.78(s,1H),5.47(s,1H),4.38(s,2H),3.69(s,3H),3.68(s,3H)3.61(s,2H).MS(ESI)m/z:539.2(MH+).
步骤7:2-(4-((3-(2-(1-甲基-1H-吡唑-4-基)-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸和2-(4-((3-(2'-(1-甲基-1H-吡唑-4-基)-6'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸
往25mL单口瓶中加入2-(4-((3-(2-(1-甲基-1H-吡唑-4-基)-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯(12mg,0.022mmol),氢氧化钠(1.92mg,0.04mmol),乙醇(1mL),水(0.3mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物2-(4-((3-(2-(1-甲基-1H-吡唑-4-基)-2’-(三氟甲氧基)-[1,1’-联苯基]-4-基)脲)甲基)苯基)乙酸10mg,产率85.6%。1H NMR(400MHz,CD3OD)δ7.61-7.60(d,J=2.0Hz,1H),7.43-7.42(d,J=6.1Hz,1H),7.39–7.33(m,1H),7.32–7.25(m,6H),7.23-7.22(d,J=4.7Hz,2H),7.15-7.13(d,J=8.4Hz,1H),6.97(s,1H),4.40(s,2H),3.75(s,3H),3.59(s,2H).MS(ESI)m/z:525.2(MH+).
往25mL单口瓶中加入2-(4-((3-(2'-(1-甲基-1H-吡唑-4-基)-6'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸甲酯(10mg,0.018mmol),氢氧化钠(1.92mg,v0.04mmol),乙醇(1mL),水(0.3mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调pH3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物2-(4-((3-(2’-(1-甲基-1H-吡唑-4-基)-6’-(三氟甲氧基)-[1,1’-联苯基]-4-基)脲)甲基)苯基)乙酸5mg,产率51.2%。1H NMR(400MHz,CD3OD)δ7.61(d,J=1.9Hz,1H),7.45-7.42(t,J=10.9,4.6Hz,1H),7.37-7.33(t,J=7.5Hz,1H),7.32–7.25(m,7H),7.22(s,1H),7.15-7.14(d,J=8.3Hz,1H),6.97(s,1H),4.39(s,2H),3.73(s,3H),3.57(s,2H)。MS(ESI)m/z:525.2(MH+).。
实施例10:2-(4-((3-([1,1'-联苯]-4-基)脲基)甲基)苯基)乙酸(2-(4-((3-([1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid)
步骤1:4-胺甲基苯乙酸甲酯
往25mL单口瓶中加入P-氰基苯乙酸甲酯(200mg,1.14mmol),甲醇(2mL),Pd/C少许,浓盐酸2滴,充氢气球。室温搅拌反应三小时。TLC检测反应已完成,过滤,旋干得白色固体产物4-胺甲基苯乙酸甲酯178mg,产率74.2%。1H NMR(400MHz,DMSO)δ8.22(s,2H),7.44(d,J=8.1Hz,2H),7.30(d,J=8.1Hz,2H),3.98(s,2H),3.71(s,2H),3.61(s,3H).MS(ESI)m/z:180.1(MH+).
步骤2:2-(4-((3([1,1’-联苯基-4-基]脲)甲基)苯基)乙酸甲酯
往25mL单口瓶中加入(4-(氨甲基))苯乙酸甲酯(76mg,0.45mmol),二氯甲烷(2mL),DIEA(116mg,0.90mmol),冰浴搅拌5分钟,然后加入三光气(44mg,0.15mmol),继续冰浴反应30分钟,然后加入4-联苯胺(80mg,0.45mmol)继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(石油醚:乙酸乙酯=1:1)分离得白色固体2-(4-((3([1,1’-联苯基-4-基]脲)甲基)苯基)乙酸甲酯60mg,产率37.9%。1H NMR(400MHz,CDCl3)δ7.55-7.50(m,3H),7.45-7.39(m,2H),7.37-7.30(m,2H),7.27-7.25(m,2H),7.22-7.20(m,3H),4.40(s,2H),3.68(s,3H),3.61-3.60(d,J=2.6Hz,2H).MS(ESI)m/z:374.9(MH+).
步骤3:2-(4-((3([1,1’-联苯基-4-基]脲)甲基)苯基)乙酸
往25mL单口瓶中加入2-(4-((3([1,1’-联苯基-4-基]脲)甲基)苯基)乙酸甲酯(60mg,0.16mmol),氢氧化钠(19mg,0.48mmol),乙醇(2mL),H2O(1mL),室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,用乙酸乙酯(20mLx3)萃取,有机层旋干得白色固体2-(4-((3([1,1’-联苯基-4-基]脲)甲基)苯基)乙酸40mg,产率87.7%。1H NMR(400MHz,DMSO)δ8.68(s,1H),7.60-7.58(d,J=7.2Hz,2H),7.54-7.52(d,J=8.8Hz,2H),7.49-7.47(d,J=8.8Hz,2H),7.42-7.48(t,J=7.7Hz,2H),7.29-7.27(t,J=7.3Hz,1H),7.25-7.21(q,J=6.3Hz,3H),7.17(s,1H),6.64(s,1H),4.27(d,J=5.8Hz,2H),4.18(d,J=4.8Hz,1H),3.52(s,2H).MS(ESI)m/z:361.0(MH+).。
实施例11:2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)丙酸
(2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)propanoic acid)
步骤1:2-(4-氰基苯基)异丙酸甲酯
往25mL单口瓶中加入对氰基苯乙酸甲酯(300mg,0.86mmol),四氢呋喃(2mL),冰浴搅拌10分钟,然后加入NaH(81mg,1.02mmol,60%),继续冰浴反应十分钟。然后加入碘甲烷(243mg,0.86mmol),继续冰浴搅拌反应1小时,反应毕,加水淬灭反应,用2M的盐酸溶液调pH到3,乙酸乙酯(10mLx3)萃取,合并有机层,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产品,粗产品过柱(乙酸乙酯:石油醚=1:10)得白色油状产物190mg,产率58.6%。1HNMR(400MHz,CDCl3)δ7.62(d,J=8.3Hz,2H),7.41(d,J=8.1Hz,2H),3.78(q,J=7.1Hz,1H),3.67(s,3H),1.51(d,J=7.2Hz,3H).MS(ES)m/z:190.0(MH+).步骤2:2-(4-氨甲基苯基)异丙酸甲酯
往25mL单口瓶中加入2-(4-氰基苯基)丙酸甲酯(190mg,1.0mmol),甲醇(10mL),四氢呋喃(2mL),氨水(0.5mL,28%),Raney Ni(100mg)。反应液室温搅拌30分钟,硅藻土过滤,旋干溶剂得无水固体产物140mg,产率72.9%。MS(ES)m/z:194.1(MH+).
步骤3:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)异丙酸甲酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),DCM(4mL),DIEA(120mg,0.93mmol)冰浴搅10分钟,然后加入三光气(35mg,0.11mmol),继续冰浴反应30分钟,然后加入2-(4-氨甲基苯基)异丙酸甲酯((71mg,0.37mmol),继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(二氯甲烷:甲醇=20:1)分离得白色固体65mg,产率38.7%。1HNMR(400MHz,CDCl3)δ7.99(d,J=5.7Hz,1H),7.48–7.41(m,1H),7.41(s,2H),7.33(t,J=7.6Hz,2H),7.21–7.10(m,5H),6.11–6.01(m,1H),4.26(d,J=5.6Hz,2H),3.69(d,J=7.2Hz,1H),3.61(s,3H),1.44(d,J=7.2Hz,3H).MS(ES)m/z:540.7(MH+).
步骤4:2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)异丙酸
往25mL单口瓶中加入2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)异丙酸甲酯(65mg,0.12mmol),一水合锂氧化钠(15mg,0.36mmol),乙醇(2mL),四氢呋喃(2mL),水(0.3mL),室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物35mg,产率56.4%。1H NMR(400MHz,CD3OD)δ7.58(s,2H),7.50(td,J=8.1,1.4Hz,1H),7.43–7.35(m,2H),7.31–7.23(m,5H),4.37(s,2H),3.69(q,J=7.1Hz,1H),1.43(d,J=7.1Hz,3H).MS(ES)m/z:526.8(MH+).。
实施例12:2-(4-((3-(2,6-氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2,2-二氟乙酸
(2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)-2,2-difluoroacetic acid)
步骤1:2-(4-氰基苯基)-2,2-二氟乙酸乙酯
往25mL单口瓶中加入4-碘苄腈(940mg,4.21mmol),DMSO(10mL),2-溴-2,2-二氟乙酸乙酯(940mg,4.63mmol),铜粉(539mg),65℃加热反应18小时后,冷却到室温,加入水(40mL),乙酸乙酯(20mLx3)萃取,合并有机层,旋干过硅胶柱分离(石油醚:乙酸乙酯=200:1)得无水液体2-(4-氰基苯基)-2,2-二氟乙酸乙酯670mg,产率70.8%。1H NMR(400MHz,CDCl3)δ7.75(q,J=8.5Hz,4H),4.31(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H).
步骤2:2-(4-(氨基甲基)苯基)-2,2-二氟乙酸乙酯
往25mL单口瓶中加入Raney Ni少许,2-(4-氰基苯基)-2,2-二氟乙酸乙酯(200mg),无水乙醇(4mL),盐酸的乙醚溶液(0.5mL),充氢气球,室温反应10分钟,TLC检测原料已反应完,硅藻土过滤,旋干,粗产物过柱(二氯甲烷:甲醇=10:1)得橙黄色固体2-(4-(氨基甲基)苯基)-2,2-二氟乙酸乙酯100mg,产率49.2%。MS(ESI)m/z:230.1(MH+).
步骤3:2-(4-((3-(2,6-氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2,2-二氟乙酸乙酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(00mg,0.31mmol),DCM(4mL),DIEA(120mg,0.93mmol)冰浴搅10分钟,然后加入三光气(35mg,0.11mmol),继续冰浴反应30分钟,然后用DMF(1mL)溶解2-(4-(氨基甲基)苯基)-2,2-二氟乙酸乙酯(85mg,0.37mmol),加入到反应液中,继续冰浴30分钟。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(二氯甲烷:甲醇=20:1)分离得白色固体30mg,产率16.8%。1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.50(d,J=7.9Hz,2H),7.46(s,2H),7.45–7.40(m,1H),7.36–7.28(m,5H),7.20(d,J=7.0Hz,1H),6.09(s,1H),4.38(d,J=5.1Hz,2H),4.25(q,J=7.1Hz,2H),1.29–1.25(m,4H).MS(ESI)m/z:574.7(M-1).
步骤4:2-(4-((3-(2,6-氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2,2-二氟乙酸
往25mL单口瓶中加入2-(4-((3-(2,6-氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2,2-二氟乙酸乙酯(30mg,0.035mmol),氢氧化锂(4.27mg,0.1mmol),乙醇(2mL),水(0.5mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调pH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物2-(4-((3-(2,6-氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2,2-二氟乙酸25mg,产率71.4%。1H NMR(400MHz,CD3OD)δ7.62–7.55(m,4H),7.55–7.49(m,1H),7.49–7.43(m,3H),7.40(t,J=7.6Hz,2H),7.30(t,J=10.1Hz,1H),4.46(s,2H).MS(ESI)m/z:548.8(MH+).。
实施例13:2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯氧基)乙酸
(2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenoxy)acetic acid)
步骤1:2-(4-氰基苯氧基)乙酸甲酯
往50mL单口瓶中依次加入4-氰基苯酚(1.32g,11mmol),2-溴乙酸甲酯(2g,13mmol),碳酸钾(4.15g,33mmol),乙腈(25mL),70℃加热反应1.5小时,反应完成后,冷却,过滤,旋干溶剂得白色固体产物2-(4-氰基苯氧基)乙酸甲酯2.28g,产率100%。1H NMR(400MHz,CDCl3)δ7.62-7.60(d,J=8.9Hz,2H),6.97-6.96(d,J=8.9Hz,2H),4.69(s,2H),3.82(s,3H).
步骤2:2-(4-(氨甲基)苯氧基)乙酸甲酯
往25mL单口瓶中加入2-(4-氰基苯氧基)乙酸甲酯(500mg,2.62mmol),甲醇(10mL),浓盐酸(1mL),然后加入Pd/C(50mg),插上氢气球,室温反应二小时,用硅藻土过滤,滤液旋干得黄色固体2-(4-(氨甲基)苯氧基)乙酸甲酯560mg,产率92.7%。1H NMR(400MHz,DMSO)δ8.28(s,3H),7.42-7.40(d,J=8.5Hz,2H),6.98-6.96(d,J=8.6Hz,2H),4.83(s,2H),3.94(s,2H),3.69(s,3H).步骤3:2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯氧基)乙酸乙酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(60mg,0.1mmol),DCM(4mL),DIEA(72mg,0.56mmol)冰浴搅拌5分钟,然后加入三光气(22mg,0.074mmol),继续冰浴反应30分钟,然后加入2-(4-(氨甲基)苯氧基)乙酸甲酯(44mg,0.20mmol)继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(展开剂石油醚:乙酸乙酯=1:1)分离得白色固体2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯氧基)乙酸乙酯38mg,产率37.6%。1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.49–7.37(m,3H),7.38–7.30(m,2H),7.21-7.19(d,J=6.6Hz,1H),7.10-7.07(d,J=8.4Hz,2H),6.75-6.73(d,J=8.5Hz,2H),5.89(s,1H),4.58(s,2H),4.22(d,J=3.6Hz,2H),3.78(s,3H).MS(ESI)m/z:541.0(M-1).
步骤4:2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯氧基)乙酸
往25mL单口瓶中加入2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯氧基)乙酸乙酯(38mg,0.07mmol),氢氧化锂(8.8mg,0.21mmol),乙醇(1mL),水(0.3mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物2-(4-((3-(2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯]-4-基)脲基)甲基)苯氧基)乙酸34mg,产率91.2%。1H NMR(400MHz,CD3OD)δ7.58(s,2H),7.52(t,J=7.1Hz,1H),7.41(dd,J=15.3,7.8Hz,2H),7.28(t,J=7.1Hz,3H),6.95–6.87(m,2H),4.67(d,J=22.3Hz,2H),4.33(s,2H),3.77(s,1H).MS(ESI)m/z:529.0(M-1).。
实施例14:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)-3-甲基脲基)甲基)苯基)乙酸
(2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-methylureido)methyl)phenyl)acetic acid)
步骤1:2,6-二氯-N-甲基-2’-(三氟甲氧基)-[1,1’-联苯]-4-胺
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),四氢呋喃(1mL),多聚甲醛(17mg,0.45mmol),乙酸(2滴),室温搅拌反应2小时,然后加入氰基硼氢化钠(30mg,0.9mmol),继续室温反应过夜。反应毕,加入水(20mL),乙酸乙酯(20mLx3)萃取,合并有机层,饱和氯化钠(30mL)洗涤,旋干溶剂,粗产物过硅胶柱(石油醚:乙酸乙酯=20:1)得白色油状物2,6-二氯-N-甲基-2’-(三氟甲氧基)-[1,1’-联苯]-4-胺45mg,产率26.9%。1H NMR(400MHz,CDCl3)δ7.47–7.40(m,1H),7.39–7.32(m,2H),7.31–7.27(m,1H),6.63(s,2H),2.85(s,3H).MS(ESI)m/z:336.0(MH+).
步骤2:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)-3-甲基脲基)甲基)苯基)乙酸甲酯
往25mL单口瓶中加入2,6-二氯-N-甲基-2’-(三氟甲氧基)-[1,1’-联苯]-4-胺(45mg,0.14mmol),二氯甲烷(4mL),DIEA(54mg,0.42mmol)冰浴搅拌5分钟,然后加入三光气(16mg,0.05mmol),继续冰浴反应30分钟,加入二氯甲烷(10mL),饱和氯化铵(10mL)洗涤,有机层旋干溶剂,真空干燥,所得产物用四氢呋喃(2mL)溶解,然后加入4-氨甲基苯乙酸甲酯(30mg,0.14mmol),DIEA(54mg,0.28mmol),60℃加热反应过夜,旋干溶剂,粗产物用制备板(石油醚:乙酸乙酯=2:1)分离得白色固体产物2-(4-((3-(2,6-二氯-2’-(三氟甲氧基)-[1,1’-联苯基]-4-基)-3甲基脲)甲基)苯基)乙酸甲酯52mg,产率72.2%。MS(ESI)m/z:541.1(MH+).
步骤3:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)-3-甲基脲基)甲基)苯基)乙酸
往25mL单口瓶中加入2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)-3-甲基脲基)甲基)苯基)乙酸甲酯(50mg,0.09mmol),氢氧化钠(11mg,0.27mmol),乙醇(1mL),水(0.3mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调pH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物42mg,产率86.2%。1H NMR(400MHz,CD3OD)δ7.55(t,J=7.1Hz,1H),7.48(s,2H),7.44(t,J=7.6Hz,2H),7.33–7.21(m,5H),4.36(s,2H),3.57(s,2H),3.31(s,3H).MS(ESI)m/z:526.7(MH+).。
实施例15:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)-1-甲基脲基)甲基)苯基)乙酸
(2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1-methylureido)methyl)phenyl)acetic acid)
步骤1:2-(4-(溴甲基)苯基)乙酸
往100mL单口瓶中加入对甲基苯乙酸(3.88g,25.9mmol),NBS(4.83g,27.2mmol),AIBN(42mg,0.26mmol),四氯化碳(50mL),90℃加热反应4小时。减压旋干溶剂,过柱(乙酸乙酯:石油醚=1:4)得白色固体产物2.28g,产率40.8%。1H NMR(400MHz,DMSO)δ12.31(s,1H),7.25(d,J=7.6Hz,2H),7.11(d,J=7.5Hz,2H),4.56(s,2H),3.44(s,2H).MS(ESI)m/z:228.9(MH+).
步骤2:2-(4-((甲基氨基)甲基)苯基)乙酸
往25mL单口瓶中加入甲胺乙醇溶液(0.5mL),然后称取2-(4-(溴甲基)苯基)乙酸(1g,4.4mmol)溶于二氯甲烷(4mL)中,室温下滴加入反应液中,滴加毕,继续室温反应1小时,旋干溶剂,产物直接用于下一步反应。MS(ESI+)m/z:180.1((MH+).
步骤3:2-(4-((甲基氨基)甲基)苯基)乙酸乙酯
步骤2中所得的2-(4-((甲基氨基)甲基)苯基)乙酸用甲醇(5mL)溶解,加入氯化亚砜(0.5mL),室温反应半小时,旋干溶剂,加入水(20mL),用饱和碳酸钠调pH到8,乙酸乙酯(20mLx3)萃取,无水硫酸钠干燥,有机层旋干过硅胶柱(石油醚:乙酸乙酯=10:1到4:1)得白色油状物120mg。(ESI+)m/z:194.1((MH+).
步骤4:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)-1-甲基脲基)甲基)苯基)乙酸乙酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),二氯甲烷(5ml),DIEA(120mg,0.93mmol)冰浴搅10分钟,然后加入三光气(35mg,0.11mmol),继续冰浴反应30分钟,然后加入2-(4-((甲基氨基)甲基)苯基)乙酸乙酯(72mg,0.37mmol)继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(二氯甲烷:甲醇=20:1)分离得白色固体70mg,产率41.9%。1HNMR(400MHz,CDCl3)δ7.51(s,2H),7.48–7.42(m,1H),7.36(t,J=7.0Hz,2H),7.33–7.28(m,2H),7.28–7.26(m,3H),6.43(s,1H),4.58(s,2H),3.70(s,3H),3.64(s,2H),3.05(s,3H).(ESI+)m/z:540.7((MH+).
步骤5:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)-1-甲基脲基)甲基)苯基)乙酸
往25mL单口瓶中加入2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)-1-甲基脲基)甲基)苯基)乙酸乙酯(73mg,0.13mmol),氢氧化钠(16mg,0.39mmol),乙醇(2mL),四氢呋喃(1mL),水(0.3mL)室温反应2小时,加压旋掉乙醇,加入水(5mL),用2N的盐酸调PH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物45mg,产率61.6%。1HNMR(400MHz,CD3OD)δ7.63(s,2H),7.48(t,J=7.8Hz,1H),7.42–7.32(m,2H),7.29–7.18(m,5H),4.56(s,2H),3.56(s,2H),2.94(s,3H).(ESI+)m/z:526.8((MH+).。
实施例16:2-(6-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)吡啶-3-基)乙酸
(2-(6-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)pyridin-3-yl)acetic acid)
步骤1:2-(6-氯吡啶-3-基)乙酸乙酯
往100mL单口瓶中加入2-(6-氯吡啶-3-基)乙酸(4g,22.4mmol),乙醇(20mL),浓硫酸(0.4mL),加热到90℃反应过夜,反应毕,冷却到室温,用饱和碳酸氢钠中和,乙酸乙酯萃取,合并有机层,加压旋干溶剂,硅胶柱分离(石油醚:乙酸乙酯=5:1)得无色油状物3.75g,产率87.2%。1H NMR(400MHz,CDCl3)δ8.28(d,J=1.5Hz,1H),7.61(dd,J=8.2,2.1Hz,1H),7.29(d,J=8.2Hz,1H),4.16(q,J=7.1Hz,2H),3.59(s,2H),1.25(t,J=7.1Hz,3H).
步骤2:2-(6-氰基吡啶-3-基)乙酸乙酯
往25mL的微波管中加入2-(6-氯吡啶-3-基)乙酸乙酯(2g,10.8mmol),氰化锌(1.88g,0.5mmol),四三苯基膦钯(1.2g,0.054mmol),DMF(10ml),微波155℃反应2小时,硅胶柱分离(石油醚:乙酸乙酯=10:1-5:1)得白色固体产物930mg,产率48.9%。MS(ESI)m/z:189.0(M+1).
步骤3:2-(6-(氨基甲基)吡啶-3-基)乙酸乙酯
往25mL单口瓶中加入2-(6-氰基吡啶-3-基)乙酸乙酯(200mg),甲醇(2mL),浓盐酸(10滴),Pd/C(20mg),通氢气球,室温反应10分钟,TLC检测原料已反应完,硅藻土过滤,滤液碱压旋干,直接用于下一步反应。MS(ESI)m/z:195(M+1).
步骤4:2-(6-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)吡啶-3-基)乙酸乙酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.3mmol),DCM(4mL),DIEA(120mg,0.93mmol)冰浴搅10分钟,然后加入三光气(35mg,0.11mmol),继续冰浴反应10分钟,然后加入2-(6-(氨基甲基)吡啶-3-基)乙酸甲酯(57mg,0.37mmol)继续冰浴30分钟。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(二氯甲烷:甲醇=20:1)分离得白色固体20mg,产率11.9%。
步骤5:2-(6-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)吡啶-3-基)乙酸
往25mL单口瓶中加入2-(6-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)吡啶-3-基)乙酸乙酯(20mg,0.037mmol),氢氧化锂(4.54mg,0.11mmol),乙醇(1mL),水(0.3mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物15mg,产率78.9%。1H NMR(400MHz,CD3OD)δ8.42(s,1H),7.76(dd,J=8.0,1.8Hz,1H),7.60(s,2H),7.55–7.48(m,1H),7.45–7.36(m,3H),7.29(dd,J=7.6,1.7Hz,1H),4.51(s,2H),3.65(s,2H).MS(ESI)m/z:513.8(M+1).。
实施例17:2-(6-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)吡啶-3-基)异丙酸
(2-(6-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)pyridin-3-yl)propanoic acid)
步骤1:2-(6-氰基吡啶-3-基)异丙酸乙酯
往25mL干燥的三口瓶中加入2-(6-氰基吡啶-3-基)乙酸乙酯(300mg,1.7mmol),四氢呋喃(2mL),冰浴搅拌5分钟,然后分批加入NaH(75mg,1.87mmol),冰浴继续搅拌15分钟,另取碘甲烷(241mg,1.7mmol),用四氢呋喃(1mL)稀释,加入到反应液中,冰浴继续搅拌反应30分钟。反应毕,加水淬灭反应,乙酸乙酯萃取,有机层合并,减压压旋干溶剂,硅胶柱分离(石油醚:乙酸乙酯=5:1)得无水油状物140mg,产率43.5%。MS(ESI)m/z:205.1(M+1)。步骤2:2-(6-(氨基甲基)吡啶-3-基)异丙酸乙酯
往25mL单口瓶中加入2-(6-氰基吡啶-3-基)异丙酸乙酯(140mg),甲醇(2mL),浓盐酸(5滴),Pd/C(15mg),通氢气球,室温反应30分钟,TLC检测原料已反应完,硅藻土过滤,滤液碱压旋干,直接用于下一步反应。MS(ESI)m/z:209.1(M+1)。
步骤3:2-(6-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)吡啶-3-基)异丙酸乙酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),DCM(4mL),DIEA(120mg,0.93mmol)冰浴搅10分钟,然后加入三光气(35mg,0.11mmol),继续冰浴反应30分钟,然后加入2-(6-(氨基甲基)吡啶-3-基)异丙酸乙酯(77mg,0.37mmol)继续冰浴30分钟,然后室温反应过夜。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(二氯甲烷:甲醇=20:1)分离得白色固体10mg,产率5.81%。MS(ESI)m/z:555.8(M+1)。
步骤4:2-(6-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)吡啶-3-基)异丙酸
往25mL单口瓶中加入2-(6-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)吡啶-3-基)乙酸乙酯(10mg,0.018mmol),氢氧化锂(2.17mg,0.053mmol),乙醇(1mL),水(0.3mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,用用乙酸乙酯(10mLx3)萃取,有机层旋干得白色固体产物5mg,产率52.6%。1H NMR(400MHz,CD3OD)δ8.46(s,1H),7.81(d,J=7.8Hz,1H),7.60(s,2H),7.52(t,J=8.1Hz,1H),7.48–7.37(m,3H),7.30(d,J=7.4Hz,1H),4.51(s,2H),3.79(d,J=6.7Hz,1H),1.50(d,J=7.1Hz,3H).MS(ESI)m/z:527.8(M+1)。
实施例18:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)2-甲基苯基)乙酸
(2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)-2-methylphenyl)acetic acid)
步骤1:4-溴-2-甲基苯乙酸甲酯
往25mL的单口瓶中加入4-溴-2-甲基苯乙腈(1g,4.1mmol),甲醇(10mL),冰浴下加入氯化亚砜(5mL),冰浴反应20分钟,然后室温反应过夜,反应毕,过滤,旋干溶剂得无色油状物630g,产率54.3%。1H NMR(400MHz,CDCL3)δ7.33(s,1H),7.28(d,J=8.1Hz 1H),7.06(d,J=8.1Hz,1H),3.69(s,3H),3.59(s,2H),2.28(s,3H).MS(ESI)m/z:242.9(MH+).
步骤2:4-氰基-2-甲基苯乙酸甲酯
往20mL微波管中加入4-溴-2-甲基苯乙酸乙酯(620mg,2.55mmol),氰化锌(448mg,3.83mmol),N,N-二甲基甲酰胺(10mL),氮气鼓泡5分钟,然后加入四三苯基磷钯(301mg,0.26mmol),然后微波155℃反应2小时,反应毕,冷却到室温,乙酸乙酯萃取三次,合并有机层,再用水洗5次,最后用饱和氯化钠洗涤,有机层减压旋干溶剂,粗产物用硅胶柱分离(石油醚:乙酸乙酯=8:1-5:1)得无色油状物350mg,产率71.5%。1H NMR(400MHz,CDCL3)δ7.46(d,J=8.2Hz,2H),7.30(d,J=7.7Hz,1H),3.70(s,3H),3.69(s,2H),2.34(s,3H).MS(ESI)m/z:190.1(MH+).
步骤3:4-氨甲基-2-甲基苯乙酸甲酯
往25mL单口瓶中加入4-氰基-2-甲基苯乙酸甲酯(200mg,1.06mmol),甲醇(2mL),氨水(5drops,28%),Raney Ni,通氢气球,室温搅拌反应20分钟,硅藻土过滤,旋干溶剂得无色油状物110mg,产率53.9%。MS(ESI)m/z:194.1(MH+).
步骤4:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)2-甲基苯基)乙酸甲酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),二氯甲烷(4mL),N,N-二异丙基乙胺(120mg,0.93mmol),氮气保护,冰浴搅5分钟,然后加入三光气(35mg,0.11mmol),冰浴反应10分钟,然后加入4-氨甲基-2-甲基苯乙酸甲酯(66mg,0.37mmol),继续冰浴30分钟。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(石油醚:乙酸乙酯=3:1-2:1)分离得白色固体产物70mg,产率41.7%。MS(ESI)m/z:540.8(MH+).
步骤5:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)2-甲基苯基)乙酸
往25mL单口瓶中加入3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)2-甲基苯基)乙酸甲酯(80mg,0.15mmol),氢氧化锂(18mg,0.45mmol),乙醇(2mL),水(0.5mL),室温反应3小时,TLC检测原料已反应完,用2N的盐酸调PH到3,有白色固体析出,过滤,真空干燥得白色固体产物65mg,产率95.5%。1H NMR(400MHz,CD3OD)δ7.59(s,2H),7.52(td,J=7.8,1.3Hz,1H),7.43(d,J=7.4Hz,1H),7.39(d,J=8.4Hz,1H),7.29(d,J=7.6Hz,1H),7.20–7.14(m,2H),7.12(d,J=8.1Hz,1H),4.35(s,2H),3.62(s,2H),2.31(s,3H).MS(ESI)m/z:526.8(MH+).。
实施例19:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)2-氟苯基)乙酸
2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)-2-fluorophenyl)acetic acid
步骤1:4-溴-2-氟苯乙酸甲酯
往25mL的单口瓶中加入4-溴-2-氟苯乙腈(1g,4.67mmol),甲醇(10mL),冰浴下滴加入氯化亚砜(5mL),冰浴反应20分钟,然后室温反应过夜,反应毕,过滤,旋干溶剂得无色油状物1g,产率86.9%。1H NMR(400MHz,CDCL3)δ7.49(t,J=7.7Hz,1H),7.07(dd,J=9.3,1.7Hz,1H),6.95(d,J=8.2Hz,1H),3.70(s,3H),3.59(s,2H).MS(ESI)m/z:245.9(MH+).
步骤2:4-氰基-2-氟苯乙酸甲酯
往20mL微波管中加入4-溴-2-氟苯乙酸乙酯(1.7g,6.68mmol),氰化锌(1.21g,10.3mmol),N,N-二甲基甲酰胺(10mL),氮气鼓泡5分钟,然后加入四三苯基磷钯(795mg,0.69mmol),微波155℃反应1.5小时,反应毕,冷却到室温,乙酸乙酯萃取三次,合并有机层,再用水洗5次,最后用饱和氯化钠洗涤,有机层减压旋干溶剂,粗产物用硅胶柱分离(石油醚:乙酸乙酯=8:1-5:1)得无色油状物730mg,产率55.3%。1H NMR(400MHz,CDCL3)δ7.59(t,J=7.3Hz,1H),7.19(d,J=8.7Hz,2H),3.72(s,3H),3.69(s,2H).MS(ESI)m/z:194.1(MH+).
步骤3:4-氨甲基-2-氟苯乙酸甲酯
往25mL单口瓶中加入4-氰基-2-氟苯乙酸甲酯(160mg,0.81mmol),甲醇(4mL),氨水(5drops,28%),Raney Ni,通氢气球,室温搅拌反应1小时,硅藻土过滤,旋干溶剂得无色油状物140mg,产率85.9%。1H NMR(400MHz,CDCLl3)δ7.29(d,J=7.7Hz,1H),7.02(d,J=8.1Hz,1H),6.99(d,J=11.1Hz,1H),3.88(s,2H),3.70(s,3H),3.60(s,2H),1.78(s,2H).MS(ESI)m/z:198.1(MH+).
步骤4:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)2-氟苯基)乙酸甲酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),二氯甲烷(4mL),N,N-二异丙基乙胺(120mg,0.93mmol),氮气保护,冰浴搅5分钟,然后加入三光气(35mg,0.11mmol),冰浴反应10分钟,然后加入4-氨甲基-2-氟苯乙酸甲酯(73mg,0.37mmol),继续冰浴30分钟。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(展开剂二氯甲烷:甲醇=20:1)分离得白色固体产物80mg,产率40.8%。1H NMR(400MHz,CDCL3)δ7.85(s,1H),7.44(m,1H),7.38(s,2H),7.34(d,J=7.9Hz,2H),7.22–7.16(m,2H),6.95–6.92(m,1H),6.90(d,J=6.1Hz,1H),6.00(d,J=2.8Hz,1H),4.32(d,J=3.0Hz,2H),3.68(s,3H),3.58(s,2H).MS(ESI)m/z:544.8(MH+).
步骤5:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)2-氟苯基)乙酸
往25mL单口瓶中加入3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)2-氟苯基)乙酸甲酯80mg,0.15mmol),氢氧化锂(18mg,0.45mmol),乙醇(4mL),水(1mL),室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,有白色固体析出,过滤,真空干燥得白色固体产物70mg,产率89.7%。1H NMR(400MHz,CD3OD)δ7.58(s,2H),7.54–7.49(m,1H),7.43(d,J=7.6Hz,1H),7.40(s,1H),7.37(d,J=3.7Hz,1H),7.34(d,J=7.9Hz,1H),7.31–7.26(m,1H),7.08(t,J=9.7Hz,2H),4.44(s,2H),3.61(s,2H).MS(ESI)m/z:530.8(MH+).。
实施例20:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)2-氯苯基)乙酸
2-(2-chloro-4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid
步骤1:4-溴-2-氯苯乙酸甲酯
往25mL的单口瓶中加入4-溴-2-氯苯乙酸(1g,4.02mmol),甲醇(10mL),加入氯化亚砜(0.5mL),65℃反应3小时,反应毕,旋干溶剂得无色油状物900mg,产率84.9%。1H NMR(400MHz,CDCL3)δ7.56(d,J=1.9Hz,1H),7.37(dd,J=8.2,1.9Hz,1H),7.16(d,J=8.2Hz,1H),3.73(s,2H),3.71(s,3H).
步骤2:4-氰基-2-氯苯乙酸甲酯
往20mL微波管中加入4-溴-2-氯苯乙酸甲酯(1g,3.84mmol),氰化锌(539mg,4.61mmol),N,-二甲基甲酰胺(10mL),氮气鼓泡5分钟,然后加入四三苯基磷钯(222mg,0.19mmol),然后微波155℃反应1.5小时,反应毕,冷却到室温,乙酸乙酯萃取三次,合并有几层,再用水洗5次,最后用饱和氯化钠洗涤,有机层减压旋干溶剂,粗产物用硅胶柱分离(石油醚:乙酸乙酯=8:1-5:1)得无色油状物350mg,产率48.8%。1H NMR(400MHz,CDCL3)δ7.69(s,1H),7.53(d,J=1.3Hz,1H),7.42(d,J=7.9Hz,1H),3.84(s,2H),3.73(s,4H).
步骤3:4-氨甲基-2-氯苯乙酸甲酯
往25mL单口瓶中加入4-氰基-2-氯苯乙酸甲酯(350mg,1.67mmol),甲醇(2mL),氨水(5drops,28%),Raney Ni,通氢气球,室温搅拌反应1小时,硅藻土过滤,旋干溶剂得无色油状物,直接用于下一步反应。MS(ESI)m/z:214.0MH+).
步骤4:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)2-氯苯基)乙酸甲酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),二氯甲烷(4mL),N,N-二异丙基乙胺(120mg,0.93mmol),氮气保护,冰浴搅5分钟,然后加入三光气(35mg,0.11mmol),冰浴反应10分钟,然后加入4-氨甲基-2-氯苯乙酸甲酯(71mg,0.37mmol),继续冰浴30分钟。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(石油醚:乙酸乙酯=3:1-2:1)分离得白色固体产物90mg,产率51.7%。MS(ESI)m/z:560.7(MH+).
步骤5:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)2-氯苯基)乙酸
往25mL单口瓶中加入3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)2-氯苯基)乙酸甲酯(47mg,0.084mmol),氢氧化锂(11mg,0.25mmol),乙醇(4mL),水(1mL),室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,有白色固体析出,过滤,真空干燥得白色固体产物35mg,产率76.1%。1H NMR(400MHz,CD3OD)δ12.51–12.29(m,1H),9.18(s,1H),7.64(s,2H),7.57(t,J=7.0Hz,1H),7.47(t,J=7.0Hz,2H),7.39–7.35(m,1H),7.33(d,J=7.9Hz,2H),7.20(d,J=9.0Hz,1H),7.04(s,1H),4.28(d,J=5.8Hz,2H),3.66(s,2H).MS(ESI)m/z:546.7(MH+).。
实施例21:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)3-甲基苯基)乙酸
(2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)-3-methylphenyl)acetic acid)
步骤1:4-溴-3-甲基苯乙酸甲酯
往25mL的单口瓶中加入4-溴-3-甲基苯乙腈(1g,4.76mmol),甲醇(10mL),冰浴下加入氯化亚砜(5mL),冰浴反应20分钟,然后室温反应过夜,反应毕,过滤,旋干溶剂得无色油状物1g,产率64.1%。1H NMR(400MHz,CDCL3)δ7.47(d,J=8.1Hz,1H),7.15(s,1H),6.96(dd,J=8.2,1.6Hz,1H),3.69(s,3H),3.55(s,2H),2.38(s,3H).
步骤2:4-氰基-3-甲基苯乙酸甲酯
往20mL微波管中加入4-溴-3-甲基苯乙酸乙酯(1g,4.1mmol),氰化锌(722mg,6.2mmol),N,N-二甲基甲酰胺(10mL),氮气鼓泡5分钟,然后加入四三苯基磷钯(237mg,0.21mmol),微波155℃反应1.5小时,反应毕,冷却到室温,乙酸乙酯萃取三次,合并有几层,再用水洗5次,最后用饱和氯化钠洗涤,有机层减压旋干溶剂,粗产物用硅胶柱分离(石油醚:乙酸乙酯=10:1)得无色油状物360mg,产率46.2%。1H NMR(400MHz,CDCL3)δ7.55(d,J=7.9Hz,1H),7.24(s,1H),7.19(d,J=8.0Hz,1H),3.71(s,3H),3.64(s,2H),2.53(s,3H).MS(ESI)m/z:190.1(MH+).
步骤3:4-氨甲基-3-甲基苯乙酸甲酯
往25mL单口瓶中加入4-氰基-3-甲基苯乙酸甲酯(350mg,1.85mmol),甲醇(5mL),氨水(5drops,28%),Raney Ni,通氢气球,室温搅拌反应1小时,硅藻土过滤,旋干溶剂得无色油状物340mg,产率95.2%。MS(ESI)m/z:194.1(MH+).
步骤4:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)3-甲基苯基)乙酸甲酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),二氯甲烷(4mL),N,N-二异丙基乙胺(120mg,0.93mmol),氮气保护,冰浴搅5分钟,然后加入三光气(35mg,0.11mmol),冰浴反应10分钟,然后加入4-氨甲基-3-甲基苯乙酸甲酯(72mg,0.37mmol),继续冰浴30分钟。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(石油醚:乙酸乙酯=5:1-3:1)分离得白色固体产物90mg,产率53.5%。MS(ESI)m/z:538.8(M-1).
步骤5:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)3-甲基苯基)乙酸
往25mL单口瓶中加入3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)3-甲基苯基)乙酸甲酯(90mg,0.17mmol),氢氧化锂(21mg,0.51mmol),乙醇(4mL),水(1mL),室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,有白色固体析出,过滤,真空干燥得白色固体产物37mg,产率42.0%。1H NMR(400MHz,DMSO)δ14.32–13.80(m,1H),9.06(s,1H),7.64(s,2H),7.60–7.54(m,1H),7.48(t,J=7.0Hz,2H),7.41–7.35(m,1H),7.18(d,J=8.3Hz,1H),7.08–7.02(m,2H),6.83(t,J=5.6Hz,1H),4.26(d,J=5.6Hz,2H),3.49(s,2H),2.27(s,3H).MS(ESI)m/z:527.0(MH+).。
实施例22:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)3-氟苯基)乙酸
(2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)-3-fluorophenyl)acetic acid)
步骤1:4-溴-3-氟苯乙酸甲酯
往25mL的单口瓶中加入4-溴-3-氟苯乙酸(1g,4.3mmol),甲醇(10mL),冰浴下加入氯化亚砜(0.5mL),室温反应3小时,反应毕,过滤,旋干溶剂得无色油状物1.3g,直接用于下一步反应。1H NMR(400MHz,CDCL3)δ7.49(t,J=7.7Hz,1H),7.08(dd,J=9.3,1.8Hz,1H),6.95(dd,J=8.2,1.4Hz,1H),3.71(s,3H),3.59(s,2H).
步骤2:4-氰基-3-氟苯乙酸甲酯
往20mL微波管中加入4-溴-3-氟苯乙酸乙酯(1.3g,5.3mmol),氰化锌(924mg,7.89mmol),N,N-二甲基甲酰胺(10mL),氮气鼓泡5分钟,然后加入四三苯基磷钯(613mg,0.53mmol),然后微波155℃反应1.5小时,反应毕,冷却到室温,乙酸乙酯萃取三次,合并有几层,再用水洗5次,最后用饱和氯化钠洗涤,有机层减压旋干溶剂,粗产物用硅胶柱分离(石油醚:乙酸乙酯=8:1-5:1)得白色固体620mg,产率60.2%。1H NMR(400MHz,CDCL3)7.58(t,J=7.2Hz,1H),7.18(d,J=8.7Hz,2H),3.72(s,3H),3.69(s,2H).MS(ESI)m/z:194.1(MH+).
步骤3:4-氨甲基-3-氟苯乙酸甲酯
往25mL单口瓶中加入4-氰基-3-氟苯乙酸甲酯(350mg,1.78mmol,甲醇(4mL),氨水(5drops,28%),Raney Ni,通氢气球,室温搅拌反应2小时,硅藻土过滤,旋干溶剂得无色油状物300mg,产率84.0%。MS(ESI)m/z:198.1(MH+).
步骤4:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)3-氟苯基)乙酸甲酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),二氯甲烷(4mL),N,N-二异丙基乙胺(120mg,0.93mmol),氮气保护,冰浴搅5分钟,然后加入三光气(35mg,0.11mmol),冰浴反应10分钟,然后加入4-氨甲基-3-氟苯乙酸甲酯(73mg,0.37mmol),继续冰浴30分钟。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(石油醚:乙酸乙酯=5:1)分离得白色固体产物85mg,产率50.3%。1HNMR(400MHz,CDCL3)δ7.46–7.42(m,3H),7.39–7.33(m,2H),7.24(dd,J=7.8,1.7Hz,2H),7.11(s,1H),7.02–6.93(m,2H),4.40(s,2H),3.72(s,3H),3.63(s,2H)..MS(ESI)m/z:544.8(MH+).
步骤5:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)3-氟苯基)乙酸
往25mL单口瓶中加入3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)3-氟苯基)乙酸甲酯(85mg,0.16mmol),氢氧化锂(20mg,0.48mmol),乙醇(5mL),水(1mL),室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,有白色固体析出,过滤,真空干燥得白色固体产物45mg,产率54.2%。1H NMR(400MHz,DMSO)δ12.40(s,1H),9.13(s,1H),7.64(s,2H),7.57(t,J=7.8Hz,1H),7.48(t,J=7.0Hz,2H),7.40–7.35(m,1H),7.29(t,J=7.9Hz,1H),7.07(t,J=9.5Hz,2H),6.95(t,J=5.9Hz,1H),4.32(d,J=5.7Hz,2H),3.57(s,2H).MS(ESI)m/z:530.8(MH+).。
实施例23:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)丙酸
(3-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)propanoic acid)
步骤1:4-氰基苯丙酸甲酯
往25mL单口瓶中加入4-氰基苯丙酸(1g,5.7mmol),甲醇(10mL),室温下滴加入氯化亚砜(0.5mL),室温搅拌反应3小时,反应毕,减压旋干溶剂,粗产物用乙酸乙酯(20mL)溶解,饱和氯化钠洗涤,有机层用无水硫酸钠干燥,过滤,减压旋干溶剂得无色油状物960mg。1H NMR(400MHz,CDCL3)δ7.57(d,J=8.2Hz,2H),7.30(d,J=8.1Hz,2H),3.66(s,3H),3.00(t,J=7.6Hz,2H),2.64(t,J=7.6Hz,2H).MS(ESI)m/z:190.1(MH+).
步骤2:4-氨甲基苯丙酸甲酯
往25mL单口瓶中加入4-氰基苯丙酸甲酯(500mg,2.65mmol),甲醇(5mL),氨水(5drops,28%),Raney Ni,通氢气球,室温搅拌反应3小时,反应毕,硅藻土过滤,旋干溶剂,得粗产物,用硅胶柱分离(二氯甲烷:甲醇=50:1-25:1)得白色固体产物126mg,两步产率24.7%。MS(ESI)m/z:194.1(MH+).步骤3:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)丙酸甲酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),二氯甲烷(4mL),N,N-二异丙基乙胺(120mg,0.93mmol),氮气保护,冰浴搅拌5分钟,然后加入三光气(35mg,0.11mmol),冰浴反应10分钟,然后加入4-氨甲基苯丙酸甲酯(66mg,0.37mmol),继续冰浴30分钟,室温反应1小时。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(3x10mL)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用硅胶柱(石油醚:乙酸乙酯=3:1-2:1)分离得白色固体110mg,产率59.4%。1H NMR(400MHz,CDCL3)δ7.87(s,1H),7.48–7.41(m,1H),7.40(s,2H),7.34(d,J=7.5Hz,2H),7.18(dd,J=6.5,5.2Hz,1H),7.11(d,J=8.1Hz,2H),7.06(d,J=8.1Hz,2H),6.00(d,J=1.0Hz,1H),4.26(s,2H),3.62(s,3H),2.86(t,J=7.7Hz,2H),2.56(t,J=7.7Hz,2H).MS(ESI)m/z:540.8(MH+).
步骤4:3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)丙酸
往25mL单口瓶中加入3-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)丙酸甲酯(110mg,0.2mmol),氢氧化锂(26mg,0.6mmol),乙醇(4mL),水(1mL),室温搅拌反应1小时,TLC检测原料已反应完,用2N的盐酸调PH到3,有白色固体析出,过滤,真空干燥得白色固体产物90mg,产率84.1%。1H NMR(400MHz,CD3OD)δ7.58(s,2H),7.51(t,J=11.1,4.6Hz,1H),7.45–7.37(m,2H),7.29(d,J=7.7Hz,1H),7.26(d,J=8.0Hz,2H),7.21(d,J=8.0Hz,2H),4.36(s,2H),2.90(t,J=7.6Hz,2H),2.58(t,J=7.6Hz,2H).MS(ESI)m/z:526.9(MH+).。
实施例24:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2-羟基乙酸
(2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)-2-hydroxyacetic acid)
步骤1:4-溴苯基-2-羟基乙酸甲酯
往25mL的单口瓶中加入:4-溴苯基-2-羟基乙酸(2g,8.66mmol),甲醇(10mL),冰浴下加入氯化亚砜(0.5mL),65℃反应2小时,反应毕,旋干溶剂,粗产物用乙酸乙酯20(mL)溶解,饱和氯化钠洗涤,有机层减压旋干得白色固体2.1g,产率99%。1H NMR(400MHz,CDCL3)δ7.49(d,J=8.4Hz,2H),7.30(d,J=8.4Hz,2H),5.14(s,1H),3.76(s,3H).
步骤2:4-氰基苯基-2-羟基乙酸甲酯
往20mL微波管中加入4-溴苯基-2-羟基乙酸甲酯(1g,4.1mmol),氰化锌(720mg,6.1mmol),N,N-二甲基甲酰胺(10mL),氮气鼓泡5分钟,然后加入四三苯基磷钯(240mg,0.2mmol),微波155℃反应1.5小时,反应毕,冷却到室温,乙酸乙酯萃取三次,合并有几层,再用水洗5次,最后用饱和氯化钠洗涤,有机层减压旋干溶剂,粗产物用硅胶柱分离(石油醚:乙酸乙酯=3:1-2:1)得黄色油状物450mg,产率38.5%。1H NMR(400MHz,CDCL3)δ7.67(d,J=8.2Hz,2H),7.58(d,J=8.2Hz,2H),5.25(s,1H),3.79(s,3H).MS(ESI)m/z:192.0(MH+).
步骤3:4-氨甲基苯基-2-羟基乙酸甲酯
往25mL单口瓶中加入4-氰基苯基-2-羟基乙酸甲酯(200mg,1.05mmol),甲醇(2mL),氨水(10drops,28%),Raney Ni,通氢气球,室温搅拌反应2小时,硅藻土过滤,旋干溶剂得无色油状物,130mg,产率63.7%。MS(ESI)m/z:196.2(MH+).
步骤4:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2-羟基乙酸甲酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),二氯甲烷(4mL),N,N-二异丙基乙胺(120mg,0.93mmol),氮气保护,冰浴搅5分钟,然后加入三光气(35mg,0.11mmol),冰浴反应10分钟,然后加入4-氨甲基苯基-2-羟基乙酸甲酯(72mg,0.37mmol),继续冰浴30分钟。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(10mLx3)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用制备板(石油醚:乙酸乙酯=10:1-1;1)分离得白色固体产物40mg,产率23.8%。MS(ESI)m/z:542.8(MH+).
步骤5:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2-羟基乙酸
往25mL单口瓶中加入2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2-羟基乙酸甲酯(40mg,0.07mmol),氢氧化锂(9mg,0.21mmol),乙醇(2mL),水(0.5mL),室温反应3小时,TLC检测原料已反应完,用2N的盐酸调PH到3,有白色固体析出,过滤,得粗产,用制备板进一步分离得白色固体产物7mg,产率17.9%。1H NMR(400MHz,CD3OD)δ7.58(s,2H),7.55–7.42(m,3H),7.42–7.36(m,2H),7.33(s,2H),7.28(d,J=7.4Hz,1H),4.40(s,2H),2.03(s,1H).MS(ESI)m/z:526.8(M-1).。
实施例25:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2-氟乙酸
步骤1:4-溴苯基-2-氟乙酸甲酯
往25mL单口瓶中加入4-溴苯基-2-氟乙酸甲酯(1g,4.1mmol)(实施例56,步骤1),二氯甲烷(10mL),冰浴搅拌5分钟后滴加入双(2-甲氧基乙基)氨基三氟化硫(1.35g,6.1mmol),然后室温反应过夜。冰浴冷却,然后加入饱和碳酸氢钠淬灭反应,二氯甲烷(3x20mL)萃取,饱和氯化钠洗涤,有机层减压旋干溶剂,硅胶柱分离(石油醚:乙酸乙酯=4:1)得无色液体720mg,产率72%。1H NMR(400MHz,CDCl3)δ7.54(d,J=7.7Hz,2H),7.34(d,J=7.7Hz,2H),5.75(d,J=47.3Hz,1H),3.78(s,3H).
步骤2:4-氰基苯基-2-氟乙酸甲酯
往20mL微波管中加入4-溴-2-氯苯乙酸甲酯(600mg,2.4mmol),氰化锌(426mg,3.6mmol),N,N-二甲基甲酰胺(10mL),氮气鼓泡5分钟,然后加入四三苯基磷钯(138mg,0.12mmol),微波155℃反应1.5小时,反应毕,冷却到室温,乙酸乙酯萃取三次,合并有机层,再用水洗5次,最后用饱和氯化钠洗涤,有机层减压旋干溶剂,粗产物用硅胶柱分离(石油醚:乙酸乙酯=10:1)得黄色色油状物270mg,产率49.4%.
步骤3:4-氨甲基苯基-2-氟乙酸甲酯
往25mL单口瓶中加入4-氰基苯基-2-氟乙酸甲酯(100mg,0.52mmol),甲醇(2mL),浓盐酸(5滴),Raney Ni,通氢气球。反应液室温搅拌10分钟,硅藻土过滤,旋干溶剂得黄色固体,产物直接用于下一步反应。MS(ESI)m/z:198.1(MH+).
步骤4:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2-氟乙酸甲酯
往25mL单口瓶中加入2,6-二氯-2'-(三氟甲氧基)-[1,1'-联苯基]-4-胺(100mg,0.31mmol),二氯甲烷(4mL),N,N-二异丙基乙胺(120mg,0.93mmol),氮气保护,冰浴搅5分钟,然后加入三光气(35mg,0.11mmol),冰浴反应10分钟,然后加入4-氨甲基苯基-2-氟乙酸甲酯(72mg,0.37mmol),继续冰浴30分钟。加入H2O(10mL),饱和氯化铵洗涤,二氯甲烷(3x10mL)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,滤液旋干得粗产物,粗产物用硅胶柱分离(石油醚:乙酸乙酯=4:1-2;1)分离得白色固体20mg,产率11.8%。1H NMR(400MHz,CDCL3)δ7.73(s,1H),7.48–7.40(m,3H),7.37–7.30(m,4H),7.28–7.26(m,1H),7.25(s,1H),7.19(d,J=7.7Hz,1H),7.15(s,1H),5.97(t,J=5.5Hz,1H),5.76(d,J=47.6Hz,1H),4.36(d,J=5.4Hz,2H),3.74(s,4H).MS(ESI)m/z:544.7(M-1).
步骤5:2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2-氟乙酸
往25mL单口瓶中加入2-(4-((3-(2,6-二氯-2'-(三氟甲基)-[1,1'-联苯]-4-基)脲基)甲基)苯基)-2-氟乙酸甲酯(20mg,0.037mmol),氢氧化锂(4.6mg,0.11mmol),乙醇(2mL),水(0.5mL)室温反应2小时,TLC检测原料已反应完,用2N的盐酸调PH到3,有白色固体析出,过滤,真空干燥得白色固体产物13mg,产率97.4%.1H NMR(400MHz,CD3OD)δ7.59(s,2H),7.51(t,J=7.9Hz,1H),7.49–7.43(m,2H),7.43–7.36(m,4H),7.29(d,J=7.6Hz,1H),5.82(d,J=48.2Hz,1H),4.43(s,2H).MS(ESI)m/z:528.7(M-1).。
实施例26:体外测定化合物对RORγ受体的亲和力试验
对本发明的化合物采用荧光共振能量转移(FRET)实验测定化合物对RORγ蛋白受体的亲和能力;该亲和能力采用半数抑制率(IC50)表示。
实验方法:
1.RORγ基础缓冲液的配制
准备100mL基础缓冲液,加入10mL DTT,混合均匀备用;
2.化合物溶液的配制
化合物均为7.5mM起3倍稀释10个浓度;
3.蛋白溶液混合物的配制
a.配制40nM的B-RORγLBD和20nM的SA-APC溶液,混合均匀,室温孵育15分钟,然后加入400nM生物素,混合均匀,室温孵育10分钟;
b.配制40nM的Bioin-SRC1和10nM的SA-eu溶液,混合均匀,室温孵育15分钟,然后加入200nM生物素,混合均匀,室温孵育10分钟;
c.将上述两个混合溶液1:1混合,室温孵育5分钟;
d.在384孔板中每孔加入0.1μM替代激动剂N-(2-氯-6-氟苯基)-N-((20-甲氧基-[1,10-联苯基]-4-取代)甲基)苯磺酰胺,25μLB-RORγLBD/SA-APC和Bioin-SRC1/SA-eu混合液及受试化合物,1000rpm离心1分钟,室温下孵育1小时。在Envision微孔板检测仪上读取数据,计算IC50值。测定结果显示:本发明的化合物对RORγ蛋白受体具有较好的亲和能力(如表1所示)。
表1实施例化合物的RORγ结合活性测定
·IC50值为至少两次独立试验的平均值。
·+++表示IC50<500nM;++表示IC50范围为500-5000nM;+表示IC50范围为5000nM-50μM;-表示未测试。
实施例27:Th17细胞分化抑制实验
实验方法:分离小鼠脾脏CD4+T细胞并将细胞分化至Th17。CD4+T细胞在anti-CD3(0.25μg/mL),anti-CD28(1μg/mL),anti-IL4(2μg/mL),anti-IFNγ(2μg/mL),TGF-β(5ng/mL),IL6(20ng/mL)环境下培养,同时加入化合物,96小时后分析Th17的分化效率。收集细胞前加入PMA 50ng/mL,离子霉素500ng/mL刺激4小时,用细胞内染色和流式细胞仪的方法检测IL-17的比例。同时我们用Live/Dead Cell Dye(Invitrogen)染色的方法,分析细胞的存活率,判断药物对细胞是否有毒性,测定化合物浓度为0.3μM时对Th17细胞分化IL-17的抑制率,测定结果显示:本发明部分化合物具有较好的抑制Th17细胞分化的能力(如表2所示)。
表2Th17细胞分化抑制实验测定
·+++表示%inh@0.3μM在70-100之间;++表示%inh@0.3μM在40-70之间;+表示%inh@0.3μM在0-40之间;-表示未测试。
Claims (17)
1.具有通式I的联芳基脲类羧酸衍生物或其药学上可接受的盐
其中:
A表示苯基或杂芳基;
B表示苯基或杂芳基;
R1任选自氢、甲基、卤素、氰基、羟基、-CF3、-CHF2、-CH2F;
R1'任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2;
R2任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、羧基或氰基取代的杂芳基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2中的一个或两个;
R3、R4各自独立地选自氢、C1-C3烷基、卤素取代的C1-C3烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基;
R5、R6各自独立地选自氢、卤素、氰基、C1-C3烷基、-(CH2)nOH、卤素取代的C1-C3烷基、C1-C3烷氧基、卤素取代的C1-C3烷氧基、C3-C6环烷基、C3-C6氧或氮杂环烷基,且R5、R6也可以连接成C3-C6环;
R7任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、羧基或氰基取代的杂芳基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2;
Y选自共价键、-NRa-、-O-、-NRaCRa1Ra2-、-OCRa1Ra2-、-(CRa1Ra2)n-、-C(O)NRa-;
Ra、Ra1、Ra2各自独立地选自氢、氰基、C1-C3烷基、-(CH2)nOH或卤素;
m、r、t、s、n各自独立地选自0~2中的任一整数值。
2.根据权利要求1所述的联芳基脲类羧酸衍生物或其药学上可接受的盐,其特征在于,其中A为苯基。
3.根据权利要求1-2所述的联芳基脲类羧酸衍生物或其药学上可接受的盐,其特征在于,其中s为1。
4.根据权利要求1-3所述的联芳基脲类羧酸衍生物或其药学上可接受的盐,其特征在于,其中R6为H。
5.根据权利要求1-4所述的联芳基脲类羧酸衍生物或其药学上可接受的盐,其特征在于,所述联芳基脲类羧酸衍生物或其药学上可接受的盐具有通式II的结构,
其中:
B表示苯基或杂芳基;
R1任选自氢、甲基、卤素、氰基、羟基、-CF3、-CHF2、-CH2F;
R1'任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2;
R2任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、羧基或氰基取代的杂芳基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2中的一个或两个。
R3、R4各自独立地选自氢、C1-C3烷基、卤素取代的C1-C3烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基;
R5任选自氢、卤素、氰基、C1-C3烷基、-(CH2)nOH、卤素取代的C1-C3烷基、C1-C3烷氧基、卤素取代的C1-C3烷氧基、C3-C6环烷基、C3-C6氧或氮杂环烷基;
R7任选自氢、卤素、氰基、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C(O)ORa或环烷基取代的C1-C6烷基、C3-C6环烷基、C3-C6氧或氮杂环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C3烷氧基取代的C1-C3烷基、苯基、取代的苯基、苯氧基、取代的苯氧基、杂环基、杂环氧基、杂芳基、杂芳氧基、C2-C6烯基、卤素取代的芳香酮基、羧基或氰基取代的杂芳基、-(CH2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2;
Y选自共价键、-NRa-、-O-、-NRaCRa1Ra2-、-OCRa1Ra2-、-(CRa1Ra2)n-、-C(O)NRa-;
Ra、Ra1、Ra2各自独立地选自氢、氰基、C1-C3烷基、-(CH2)nOH或卤素;
m、r、t、n各自独立地选自0~2中的任一整数值。
6.根据权利要求1-5所述的联芳基脲类羧酸衍生物或其药学上可接受的盐,其特征在于,其中B为苯基或六元杂芳基。
7.根据权利要求1-6所述的联芳基脲类羧酸衍生物或其药学上可接受的盐,其特征在于:其中R1'选自氢、-OCF3、-OCHF2、-CF3、杂芳基。
8.根据权利要求1-7所述的联芳基脲类羧酸衍生物或其药学上可接受的盐,其特征在于:其中m为0。
9.根据权利要求1-7所述的联芳基脲类羧酸衍生物或其药学上可接受的盐,其特征在于:其中m为1且R1选自-Cl、-F、-CH3。
10.根据权利要求1-9所述的联芳基脲类羧酸衍生物或其药学上可接受的盐,其特征在于:其中r为1且R2选自-Cl、-F、-CF3、-OCF3、C1-C3烷基、氰基、杂芳基中的任意一个。
11.根据权利要求1-9所述的联芳基脲类羧酸衍生物或其药学上可接受的盐,其特征在于:其中r为2且R2任选自-Cl、-F、-CF3、-OCF3、C1-C3烷基、氰基中的任意两个。
12.根据权利要求1-11所述的联芳基脲类羧酸衍生物或其药学上可接受的盐,其特征在于:其中R7任选自氢、卤素、氰基、羟基、C1-C6烷基;
13.根据权利要求1-12任一所述的联芳基脲类羧酸衍生物或其药学上可接受的盐,其特征在于:选自如下化合物:
14.一种作为RORγt受体抑制剂的药物组合物,包含如权利要求1-13所述化合物或其药学上可接受的盐作为活性成份,以及一种或多种药学上可接受的载体。
15.如权利要求1-13所述化合物或其药学上可接受的盐在制备RORγt受体抑制剂中的应用。
16.如权利要求1-13所述化合物或其药学上可接受的盐在制备用于治疗或预防与RORγt受体相关的疾病的药物中的用途。
17.如权利要求16所述的用途,其特征在于:所述的疾病选自多发性硬化、类风湿关节炎、胶原诱导性关节炎、银屑病、炎症性肠病、脑脊髓炎、克隆疾病、哮喘、癌症等炎症相关类疾病。
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