CN114874232A - 一种含有乙基萘结构的噻吩并嘧啶酮类化合物的制备方法与应用 - Google Patents
一种含有乙基萘结构的噻吩并嘧啶酮类化合物的制备方法与应用 Download PDFInfo
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- CN114874232A CN114874232A CN202210532237.9A CN202210532237A CN114874232A CN 114874232 A CN114874232 A CN 114874232A CN 202210532237 A CN202210532237 A CN 202210532237A CN 114874232 A CN114874232 A CN 114874232A
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- dihydrothiophene
- dimethylformamide
- amino
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- 238000002360 preparation method Methods 0.000 title claims abstract description 58
- -1 thienopyrimidinone compound Chemical class 0.000 title claims abstract description 31
- ZMXIYERNXPIYFR-UHFFFAOYSA-N 1-ethylnaphthalene Chemical group C1=CC=C2C(CC)=CC=CC2=C1 ZMXIYERNXPIYFR-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 claims abstract description 46
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 claims abstract description 45
- 229940116269 uric acid Drugs 0.000 claims abstract description 45
- 239000003814 drug Substances 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- ZYHQTNIEECNQIN-UHFFFAOYSA-N C1=CC(C(=O)OC)C(N)S1 Chemical compound C1=CC(C(=O)OC)C(N)S1 ZYHQTNIEECNQIN-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 12
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 claims description 11
- JGNFTGRANYCGMM-UHFFFAOYSA-N methyl 3-amino-2,3-dihydrothiophene-2-carboxylate Chemical compound COC(=O)C1SC=CC1N JGNFTGRANYCGMM-UHFFFAOYSA-N 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- UTVNSHXHFRIXMM-UHFFFAOYSA-N ethyl 1-bromocyclobutane-1-carboxylate Chemical compound CCOC(=O)C1(Br)CCC1 UTVNSHXHFRIXMM-UHFFFAOYSA-N 0.000 claims description 10
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 10
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 9
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 9
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 9
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 9
- LHZSKEFBVKPQRL-UHFFFAOYSA-N 4-bromo-n-methylnaphthalen-1-amine Chemical compound C1=CC=C2C(NC)=CC=C(Br)C2=C1 LHZSKEFBVKPQRL-UHFFFAOYSA-N 0.000 claims description 8
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 claims description 7
- XXSPGBOGLXKMDU-UHFFFAOYSA-M 2-bromo-2-methylpropanoate Chemical compound CC(C)(Br)C([O-])=O XXSPGBOGLXKMDU-UHFFFAOYSA-M 0.000 claims description 6
- MONMFXREYOKQTI-UHFFFAOYSA-M 2-bromopropanoate Chemical compound CC(Br)C([O-])=O MONMFXREYOKQTI-UHFFFAOYSA-M 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 5
- 235000011009 potassium phosphates Nutrition 0.000 claims description 5
- FHXASJKBBLIBAQ-UHFFFAOYSA-N 1-bromo-4-(bromomethyl)naphthalene Chemical compound C1=CC=C2C(CBr)=CC=C(Br)C2=C1 FHXASJKBBLIBAQ-UHFFFAOYSA-N 0.000 claims description 4
- LVBIDTYBTJQDHZ-UHFFFAOYSA-N 1-bromo-4-(isothiocyanatomethyl)naphthalene Chemical compound C1=C(C2=C(C(=C1)CN=C=S)C=CC=C2)Br LVBIDTYBTJQDHZ-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 4
- IDRVLLRKAAHOBP-UHFFFAOYSA-N 1-bromo-4-methylnaphthalene Chemical compound C1=CC=C2C(C)=CC=C(Br)C2=C1 IDRVLLRKAAHOBP-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 238000001308 synthesis method Methods 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 238000005642 Gabriel synthesis reaction Methods 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000006698 hydrazinolysis reaction Methods 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- BYXYCUABYHCYLY-UHFFFAOYSA-N isoindole-1,3-dione;potassium Chemical compound [K].C1=CC=C2C(=O)NC(=O)C2=C1 BYXYCUABYHCYLY-UHFFFAOYSA-N 0.000 claims 1
- 239000007787 solid Substances 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 41
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 34
- 238000002844 melting Methods 0.000 description 32
- 230000008018 melting Effects 0.000 description 32
- 238000004611 spectroscopical analysis Methods 0.000 description 31
- 238000010438 heat treatment Methods 0.000 description 18
- 230000000694 effects Effects 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
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- 201000001431 Hyperuricemia Diseases 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
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- MJYRSXGQXVUCRL-UHFFFAOYSA-N (4-cyclopropylnaphthalen-1-yl)methanamine Chemical compound C1C(C2=C3C=CC=CC3=C(CN)C=C2)C1 MJYRSXGQXVUCRL-UHFFFAOYSA-N 0.000 description 4
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- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 4
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- PQUSVJVVRXWKDG-UHFFFAOYSA-N methyl 2-bromo-2-methylpropanoate Chemical compound COC(=O)C(C)(C)Br PQUSVJVVRXWKDG-UHFFFAOYSA-N 0.000 description 4
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Abstract
本发明涉及一种含有乙基萘结构的噻吩并嘧啶酮类化合物及其制备方法和应用。所述化合物具有式I或Ⅱ所示的结构。本发明还涉及含有式I或式Ⅱ结构化合物的制备方法以及药物组合物。本发明还提供上述化合物在制备降尿酸的药物中的应用。
Description
技术领域
本发明属于有机化合物合成与医药应用技术领域。具体而言,本发明涉及一种含有乙基萘结构的噻吩并嘧啶酮类化合物及其制备方法或含有它们的药物组合,以及其在医药上的用途。
背景技术
高尿酸血症(HUA)是指正常嘌呤饮食状态下,非同日两次空腹血尿酸水平:男性血尿酸>420μmol/L,女性血尿酸>360μmol/L。痛风是指血尿酸浓度超过6.8mg/dL,由单钠尿酸盐(MSU)沉积所致的晶体相关性关节病,与嘌呤代谢紊乱或尿酸排泄减少所致的高尿酸血症直接相关,特指急性特征性关节炎和慢性痛风石疾病。痛风与高尿酸血症都与人体内的尿酸水平有关。正常成年人每日约产生尿酸750mg,其中1/3经肠道分解代谢,2/3经肾脏排泄,从而维持体内尿酸水平的稳定。目前治疗痛风的药物主要有两类:一类是抑制尿酸生成的黄嘌呤氧化酶抑制剂,另一类是促进尿酸排泄的URAT1抑制剂。尿酸转运蛋白1(URAT1)位于人肾近端小管上皮细胞的刷状缘上,主要介导尿酸在肾脏的重吸收,其基因突变所导致的URAT1活性增加或基因表达增加是高尿酸血症的重要发病机制之一。Lesinurad是一种用于治疗高尿酸血症和痛风的URAT1抑制剂,其治疗剂量大且具有严重的毒副作用。因此,对其进行进一步地结构修饰,有望获得具有更优活性及安全性且具有自主知识产权的新型降尿酸药物。
发明内容
针对现有技术的不足,本发明提供了一种基于含有乙基萘结构的噻吩并嘧啶酮骨架的新型URAT1抑制剂的制备方法,本发明还提供了上述化合物作为降尿酸药物的活性筛选结果及其应用。
本发明的技术方案如下:
一、含有乙基萘结构的噻吩并嘧啶酮类化合物
本发明的含有乙基萘结构的噻吩并嘧啶酮类化合物,或其药学上可接受的盐,具有如下通式I或Ⅱ所示的结构:
其中,R为烷烃或取代烷烃,所述取代基为C1-C10的烷烃;R1为烷烃或取代烷烃,所述取代基为C1-C10的烷烃;R2为甲基或乙基或氢;Ar为取代的芳香环,所述的取代基为环丙基或溴。
根据本发明优选的,R为亚甲基,R1为亚甲基、异丙基、叔丁基、环丁基,Ar为1-环丙基-4-萘或1-溴-4-萘。
根据本发明进一步优选的,含有乙基萘结构的噻吩并嘧啶酮类化合物是下列之一:
表1.化合物1-32的结构式
二、含有乙基萘结构的噻吩并嘧啶酮类化合物的制备方法
本发明含有乙基萘结构的噻吩并嘧啶酮类化合物类衍生物的制备方法为如下方法之一:
(1)化合物1~16的合成:
首先以1-溴-4-甲基萘为起始原料,在过氧化二苯甲酰的催化作用下,在正己烷中与N-溴代丁二酰亚胺反应,生成1-溴-4-(溴甲基)萘(L-B)。L-B在DMF中与邻苯二甲酰亚胺钾发生取代反应,生成中间体2-((4-溴萘-1-基)甲基)异吲哚啉-1,3-二酮(L-C)。L-C在水合肼作用下,于乙醇溶液中发生Gabriel Synthesis肼解反应生成关键中间体(4-溴萘-1-基)甲胺(L-D)。L-D在三乙胺的存在下,于二氯甲烷中与N,N'-硫羰基二咪唑(TCDI)反应生成1-溴-4-(异硫氰酸甲基)萘(LR-1)。LR-1在DMF中与2-氨基-2,3-二氢噻吩-3-羧酸甲酯或3-氨基-2,3-二氢噻吩-2-羧酸甲酯反应,然后在NaOH作用下环合生成对应的巯基(LR-SH或RL-SH)。在DMF中,LR-SH或RL-SH在碳酸钾的催化作用下与不同的溴取代酯反应,生成1~8。1~8在四氢呋喃和甲醇的混合溶液中用氢氧化锂水解得到9~16。
路线一:
试剂及条件:(i)N-溴代丁二酰亚胺,过氧化二苯甲酰,正己烷,70℃;(ii)邻苯二甲酰亚胺钾盐,N,N-二甲基甲酰胺,100℃;(iii)水合肼,乙醇,回流;(iv)N,N'-硫羰基二咪唑,三乙胺,N,N-二甲基甲酰胺,室温;(v)2-氨基-2,3-二氢噻吩-3-羧酸甲酯或3-氨基-2,3-二氢噻吩-2-羧酸甲酯,氢氧化钠,N,N-二甲基甲酰胺,100℃;(vi)溴乙酸甲酯或2-溴丙酸甲酯或2-溴异丁酸甲酯或1-溴环丁烷羧酸乙酯,碳酸钾,N,N-二甲基甲酰胺,50℃;(vii)氢氧化锂,四氢呋喃,甲醇,室温;
(2)化合物17~32的合成
化合物17~32的合成方法与路线一中化合物1~16的制备所描述的合成方法相似,只是(4-溴萘-1-基)甲胺与环丙基硼酸在磷酸钾与四三苯基膦钯的催化下反应生成(4-环丙基萘-1-基)甲胺(LH-1)。LH-1在三乙胺的存在下,在二氯甲烷中与N,N'-硫羰基二咪唑反应生成1-环丙基-4-(异硫氰酸甲基)萘(LH-2)。LH-2在DMF中与2-氨基-2,3-二氢噻吩-3-羧酸甲酯或3-氨基-2,3-二氢噻吩-2-羧酸甲酯反应,然后在NaOH作用下环合生成相应的巯基(LH-SH或HL-SH)。LH-SH或HL-SH在DMF中在碳酸钾的催化作用下与不同的酯反应,生成17~24。17~24在四氢呋喃和甲醇的混合溶液中用氢氧化锂水解得到25~32。
路线二:
试剂及条件:(i)N-溴代丁二酰亚胺,过氧化二苯甲酰,正己烷,70℃;(ii)邻苯二甲酰亚胺钾盐,N,N-二甲基甲酰胺,100℃;(iii)水合肼,乙醇,回流;(iv)环丙基硼酸,磷酸钾,四三苯基膦钯,甲苯,氮气,100℃;(v)N,N'-硫羰基二咪唑,三乙胺,N,N-二甲基甲酰胺,室温;(vi)2-氨基-2,3-二氢噻吩-3-羧酸甲酯或3-氨基-2,3-二氢噻吩-2-羧酸甲酯,氢氧化钠,N,N-二甲基甲酰胺,100℃;(vii)溴乙酸甲酯或2-溴丙酸甲酯或2-溴异丁酸甲酯或1-溴环丁烷羧酸乙酯,碳酸钾,N,N-二甲基甲酰胺,50℃;(viii)氢氧化锂,四氢呋喃,甲醇,室温;
本发明所述的室温是指20-30℃。
三、含有乙基萘结构的噻吩并嘧啶酮类化合物的应用
本发明公开了一类含有乙基萘结构的噻吩并嘧啶酮类化合物降血尿酸活性筛选结果及其用于制备降尿酸药物的首次应用。通过实验证明本发明的含有乙基萘结构的噻吩并嘧啶酮类化合物可作为降血尿酸药物应用。具体地说,可作为降血尿酸化合物用于制备降尿酸药物。本发明还提供上述化合物在制备降尿酸药物中的应用。
目标化合物的降尿酸活性:
对按照上述方法合成的32个化合物(化合物的结构式见表1),并对其进行了降尿酸活性筛选,它们的降尿酸活性数据列于表2和表3中,以Lesinurad为阳性药物。
由表2和表3可以看出有16个化合物表现出较好的降尿酸活性,降尿酸活性均优于阳性对照药物Lesinurad或与Lesinurad相当。其中化合物9、10、13、25和29在动物体内活性测试中,血尿酸下降率均超过60%,显示出优异的降尿酸活性,可作为制备降尿酸的药物。
因此,本发明中含有乙基萘结构的噻吩并嘧啶酮类化合物是一类结构新颖的具有降血尿酸活性的化合物,可作为降尿酸的候选药物加以利用,用于制备降尿酸的药物。
一种降尿酸药物组合物,包括本发明的含有乙基萘结构的噻吩并嘧啶酮类化合物和一种或多种药学上可接受的载体或赋形剂。
具体实施方式
通过下述实例有助于理解本发明,但是不能限制本发明的内容,在下列实例中,所有目标化合物的编号与表1相同。
化合物1-16的合成路线:
试剂及条件:(i)N-溴代丁二酰亚胺,过氧化二苯甲酰,正己烷,70℃;(ii)邻苯二甲酰亚胺钾盐,N,N-二甲基甲酰胺,100℃;(iii)水合肼,乙醇,回流;(iv)N,N'-硫羰基二咪唑,三乙胺,N,N-二甲基甲酰胺,室温;(v)2-氨基-2,3-二氢噻吩-3-羧酸甲酯或3-氨基-2,3-二氢噻吩-2-羧酸甲酯,氢氧化钠,N,N-二甲基甲酰胺,100℃;(vi)溴乙酸甲酯或2-溴丙酸甲酯或2-溴异丁酸甲酯或1-溴环丁烷羧酸乙酯,碳酸钾,N,N-二甲基甲酰胺,50℃;(vii)氢氧化锂,四氢呋喃,甲醇,室温。
化合物L-B的制备
将N-溴代丁二酰亚胺(9.70g,54.80mmol)、过氧化二苯甲酰(0.22g,0.91mmol)混合置于250mL圆底烧瓶中,加入100mL正己烷,然后将原料1-溴-4-甲基萘(10.00g,45.66mmol)滴加到烧瓶中,加热到70℃反应12h;TLC监测反应完全。停止加热,待反应液冷却至室温后,过滤收集滤饼。将滤饼置于250mL烧杯中,加入100mL饱和NaHCO3水溶液搅拌10min后过滤,重复上述操作两次。收集滤饼,将滤饼置于100mL烧瓶中,加入50mL正己烷加热至回流,加热1h后停止加热,冷却至室温后过滤,收集滤饼真空干燥得淡黄色粉末,收率68.3%,熔点:102~104℃。ESI-MS:m/z 299.02[M-H]-,C11H8Br2[299.99].
化合物L-C的制备
将1-溴-4-(溴甲基)萘(9.00g,30.10mmol)加入到250mL圆底烧瓶中,再加入约50mL DMF使其溶解,接着将邻苯二甲酰亚胺(4.41g,30.10mmol)溶于50mL DMF中滴加至烧瓶中。加热至100℃,搅拌12h后TLC监测,待反应结束后减压旋蒸除去溶剂。往烧瓶中加入150mL水,搅拌10min后过滤,收集滤饼,重复上述操作两次。最后将滤饼置于250mL烧瓶中,加入100mL乙醇加热至回流,搅拌1h后停止加热,冷却至室温后过滤,将滤饼真空干燥后得白色固体,收率65.4%,熔点:175~177℃。ESI-MS:m/z 367.02[M+H]+,C19H12BrNO2[366.21].
化合物L-D的制备
将L-C(7.00g,19.11mmol)置于250mL烧瓶中,然后加入100mL无水乙醇,加热至回流后将水合肼(1.91g,38.22mmol)滴加至烧瓶中,反应12h后TLC检测反应完全。停止加热冷却至室温后过滤,收集滤液减压蒸除溶剂后向残余物中加入100mL DCM,用饱和NaCl水溶液(50mL×3)洗涤,将有机相用无水硫酸钠干燥2h后减压蒸除溶剂得黄色油状物,收率70.5%。ESI-MS:m/z 235.26[M-H]-,C11H10BrN[236.11].
化合物LR-1的制备
将(4-溴萘-1-基)甲胺(3.00g,12.71mmol)和三乙胺(2.57g,25.42mmol)置于250mL烧瓶中,然后溶于40mL THF中,将N,N'-硫羰基二咪唑(3.39g,19.05mmol)溶于50mLTHF中缓慢滴加至烧瓶中,室温下搅拌4h。TLC检测反应完全,用饱和NaCl水溶液(50mL×3)洗涤,将有机相用无水硫酸钠干燥后经柱层析(EA:PE=1:10)得到中间体溴-4-(异硫氰酸甲基)萘(LR-1),收率62.7%,熔点:87~89℃。ESI-MS:m/z 277.23[M-H]-,C12H8BrNS[278.16].
化合物LR-SH的制备
将中间体LR-1(2.00g,7.19mmol)与2-氨基-2,3-二氢噻吩-3-羧酸甲酯(1.70g,10.78mmol)溶于50mL DMF中,100℃下搅拌12h。TLC监测反应完全后停止加热,冷却至室温后减压浓缩。向浓缩液中加入10mL无水乙醇,有固体析出,加热至回流,1h后停止加热,冷却至室温,将固体过滤。将固体置于100mL烧瓶中,加入20mL 1mol/L NaOH溶液,加热至100℃,4h后停止加热,冷却至室温。此时有少量絮状物析出,过滤,用2mol/L HCl将滤液pH调至3左右,析出大量白色固体,此时缓慢过滤,滤饼再用水(10mL×2)洗涤,真空干燥得中间体3-((4-溴萘-1-基)甲基)-2-巯基噻吩并[2,3-d]嘧啶-4(3H)-酮(LR-SH),收率51.5%,熔点:225~227℃。ESI-MS:m/z 402.48[M-H]-,C17H11BrN2OS2[403.31].
化合物RL-SH的制备
制备方法同LR-SH,只是LR-1(2.00g,7.19mmol)与3-氨基-2,3-二氢噻吩-2-羧酸甲酯(1.70g,10.78mmol)反应,最后得到RL-SH,收率65.2%,熔点:207~209℃。ESI-MS:m/z402.45[M-H]-,C17H11BrN2OS2[403.31].
实施例1.化合物1的制备
将LR-SH(0.18g,0.45mmol)用10mL DMF溶解于25mL圆底烧瓶中,后加入K2CO3(0.09g,0.67mmol)。室温下活化15min,然后将溴乙酸甲酯(0.08g,0.54mmol)逐滴加入其中,加热至50℃,4h后TLC监测。待反应完全后,停止加热,向反应液中加入50mL NaCl水溶液与50mL乙酸乙酯,萃取分液后有机相用饱和NaCl水溶液(20mL×3)洗涤,有机相用无水硫酸钠干燥、过滤。滤液减压浓缩后经柱层析(EA:PE=1:5)得到产物后乙酸乙酯重结晶,白色固体,收率56.4%,熔点:157~159℃。化合物1的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.43–8.29(m,1H),8.30–8.17(m,1H),7.81(s,1H),7.80(s,1H),7.79(s,1H),7.56(d,J=5.7Hz,1H),7.41(d,J=5.7Hz,1H),6.77(d,J=7.8Hz,1H),5.82(s,2H),4.08(s,2H),3.67(s,3H).13C NMR(150MHz,DMSO-d6)δ168.89,163.22,157.84,157.70,131.81,131.62,131.34,130.14,128.57,128.20,127.76,124.10,123.74,122.78,122.45,121.85,120.37,52.96,45.12,34.48.ESI-MS:m/z 973.56[2M+Na]+,C20H15BrN2O3S2[475.38].
实施例2.化合物2的制备
操作同实施例1,不同的是LR-SH(0.18g,0.45mmol)与2-溴丙酸甲酯(0.09g,0.54mmol)反应,乙酸乙酯重结晶,白色固体,收率63.9%,熔点:188~190℃。化合物2的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.39–8.29(m,1H),8.30–8.18(m,1H),7.81(d,J=3.2Hz,1H),7.80(s,1H),7.79(d,J=1.9Hz,1H),7.57(d,J=5.8Hz,1H),7.41(d,J=5.8Hz,1H),6.74(d,J=7.8Hz,1H),5.77(s,2H),4.53(q,J=7.3Hz,1H),3.66(s,3H),1.47(d,J=7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ171.91,163.13,157.64,157.25,131.70,131.58,131.24,130.16,128.63,128.23,127.75,124.11,123.88,122.55,122.47,121.84,120.49,53.14,45.31,44.42,16.91.ESI-MS:m/z 490.47[M+H]+,C21H17BrN2O3S2[489.40].
实施例3.化合物3的制备
操作同实施例1,不同的是LR-SH(0.18g,0.45mmol)与2-溴异丁酸甲酯(0.10g,0.54mmol)反应,乙酸乙酯重结晶,白色固体,收率57.7%,熔点:182~184℃。化合物3的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.33–8.28(m,1H),8.28–8.21(m,1H),7.82(d,J=3.9Hz,1H),7.80(d,J=3.1Hz,1H),7.80–7.77(m,1H),7.55(d,J=5.7Hz,1H),7.40(d,J=5.8Hz,1H),6.71(d,J=7.8Hz,1H),5.73(s,2H),3.67(s,3H),1.58(s,6H).13C NMR(150MHz,DMSO-d6)δ173.56,162.92,157.58,157.12,131.72,131.62,131.34,130.18,128.60,128.20,127.75,124.08,123.79,122.48,122.45,121.82,120.50,53.82,53.21,45.31,26.04.ESI-MS:m/z 504.64[M+H]+,C22H19BrN2O3S2[503.43].
实施例4.化合物4的制备
操作同实施例1,不同的是LR-SH(0.18g,0.45mmol)与1-溴环丁烷羧酸乙酯(0.11g,0.54mmol)反应,乙酸乙酯重结晶,白色固体,收率59.1%,熔点:165~167℃。化合物4的波谱数据:1H NMR(600MHz,DMSO-d6)δ8.33(dd,J=7.1,2.6Hz,1H),8.26(dd,J=7.1,2.7Hz,1H),7.85–7.75(m,3H),7.52(d,J=5.8Hz,1H),7.38(d,J=5.7Hz,1H),6.72(d,J=7.8Hz,1H),5.75(s,2H),4.13(q,J=7.1Hz,2H),2.80(dd,J=12.3,8.0Hz,2H),2.23(ddd,J=13.3,9.0,5.9Hz,2H),2.10–1.97(m,2H),1.13(t,J=7.1Hz,3H).13C NMR(150MHz,DMSO-d6)δ172.00,163.21,157.60,157.53,131.78,131.63,131.33,130.11,128.61,128.21,127.76,124.12,123.69,122.46,122.39,121.84,120.45,61.70,54.15,45.36,31.89,17.23,14.50.ESI-MS:m/z530.88[M+H]+,C24H21BrN2O3S2[529.47].
实施例5.化合物5的制备
操作同实施例1,不同的是RL-SH(0.18g,0.45mmol)与溴乙酸甲酯(0.08g,0.54mmol)反应,乙酸乙酯重结晶,白色固体,收率67.7%,熔点:150~152℃。化合物5的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.40–8.32(m,1H),8.27(s,1H),8.25(d,J=5.4Hz,1H),7.81(d,J=2.3Hz,1H),7.80(s,1H),7.79(s,1H),7.33(d,J=5.3Hz,1H),6.76(d,J=7.8Hz,1H),5.84(s,2H),4.08(s,2H),3.66(s,3H).13C NMR(100MHz,DMSO-d6)δ169.00,158.69,157.66,156.22,137.12,131.75,131.59,131.40,130.16,128.61,128.22,127.76,125.02,124.12,122.75,121.86,118.95,52.95,45.11,34.47.HR-MS:m/z 476.9764[M+H]+,C20H15BrN2O3S2[475.38].
实施例6.化合物6的制备
操作同实施例1,不同的是RL-SH(0.18g,0.45mmol)与2-溴丙酸甲酯(0.09g,0.54mmol)反应,乙酸乙酯重结晶,白色固体,收率69.8%,熔点:168~170℃。化合物6的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.36–8.29(m,1H),8.27(d,J=5.3Hz,1H),8.26–8.23(m,1H),7.81(d,J=3.0Hz,1H),7.80(s,1H),7.79(d,J=1.7Hz,1H),7.33(d,J=5.3Hz,1H),6.74(d,J=7.8Hz,1H),5.79(s,2H),4.56(q,J=7.3Hz,1H),3.66(s,3H),1.47(d,J=7.3Hz,3H).13C NMR(150MHz,DMSO-d6)δ171.94,158.12,157.61,156.19,137.07,131.70,131.61,131.34,130.13,128.57,128.19,127.75,124.92,124.06,122.61,121.87,119.10,53.06,45.28,44.45,17.03.HR-MS:m/z 490.9914[M+H]+,C21H17BrN2O3S2[489.40].
实施例7.化合物7的制备
操作同实施例1,不同的是RL-SH(0.18g,0.45mmol)与2-溴异丁酸甲酯(0.10g,0.54mmol)反应,乙酸乙酯重结晶,白色固体,收率62.1%,熔点:187~189℃。化合物7的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.34–8.29(m,1H),8.27(d,J=2.4Hz,1H),8.25(d,J=4.5Hz,1H),7.82(q,J=2.6,1.7Hz,1H),7.81(d,J=2.9Hz,1H),7.80–7.75(m,1H),7.24(d,J=5.3Hz,1H),6.71(d,J=7.8Hz,1H),5.76(s,2H),3.67(s,3H),1.59(s,6H).13C NMR(100MHz,DMSO-d6)δ173.68,157.99,157.53,156.07,137.25,131.66,131.58,131.39,130.19,128.64,128.23,127.75,124.62,124.10,122.44,121.83,118.98,53.63,53.18,45.34,25.97.HR-MS:m/z 505.0080[M+H]+,C22H19BrN2O3S2[503.43].
实施例8.化合物8的制备
操作同实施例1,不同的是RL-SH(0.18g,0.45mmol)与1-溴环丁烷羧酸乙酯(0.11g,0.54mmol)反应,乙酸乙酯重结晶,白色固体,收率71.7%,熔点:156~158℃。化合物8的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.45–8.31(m,1H),8.29–8.25(m,1H),8.23(d,J=5.3Hz,1H),7.82(s,1H),7.81(s,1H),7.80(s,1H),7.20(d,J=5.3Hz,1H),6.72(d,J=7.9Hz,1H),5.77(s,2H),4.12(q,J=7.1Hz,2H),2.90–2.70(m,2H),2.29–2.16(m,2H),2.11–1.93(m,2H),1.11(t,J=7.1Hz,3H).13C NMR(150MHz,DMSO-d6)δ172.07,158.41,157.56,156.32,137.06,131.76,131.62,131.41,130.10,128.61,128.22,127.76,124.72,124.11,122.48,121.86,118.98,61.62,54.08,45.37,31.88,17.26,14.44.HR-MS:m/z529.0250[M+H]+,C24H21BrN2O3S2[528.02].
实施例9.化合物9的制备
将化合物1(80mg,0.17mmol)溶于5mL甲醇和2.5mL四氢呋喃的混合溶液中,将适量的LiOH溶于1mL水中,逐滴加入到混合溶液中。室温下搅拌反6h后TLC监测,待反应完全后,加入5mL水,减压旋蒸除去混合液的甲醇和四氢呋喃,然后缓慢向剩余溶液中滴加1mol/LHCl,滴加过程中有固体析出,将pH调至3左右至固体不再增多,过滤,用5mL水冲洗滤饼,真空干燥后乙酸乙酯重结晶,白色固体,收率71.1%,熔点:210~212℃。化合物9的波谱数据:1HNMR(600MHz,DMSO-d6)δ8.35(d,J=8.4Hz,1H),8.25(d,J=7.5Hz,1H),7.84–7.73(m,3H),7.55(dd,J=5.8,1.4Hz,1H),7.40(dd,J=5.7,1.4Hz,1H),6.77(d,J=7.8Hz,1H),5.82(s,2H),4.00(s,2H).13C NMR(150MHz,DMSO-d6)δ169.38,163.35,158.23,157.77,131.81,131.62,131.41,130.14,128.57,128.20,127.76,124.11,123.61,122.80,122.42,121.80,120.31,45.14,35.13.HR-MS:m/z 460.9471[M-H]-,C19H13BrN2O3S2[461.35].
实施例10.化合物10的制备
操作同实施例9,不同的是水解的是化合物2(80mg,0.16mmol),白色固体,收率83.6%,熔点:223~225℃。化合物10的波谱数据:1H NMR(400MHz,DMSO-d6)δ13.04(s,1H),8.41–8.29(m,1H),8.30–8.18(m,1H),7.56(d,J=5.8Hz,1H),7.41(d,J=5.9Hz,1H),6.75(d,J=7.8Hz,1H),5.98–5.67(m,2H),4.48(q,J=7.3Hz,1H),1.48(d,J=7.3Hz,3H).13CNMR(150MHz,DMSO-d6)δ172.57,163.27,157.73,157.59,131.74,131.62,131.35,130.13,128.57,128.19,127.76,124.07,123.70,122.63,122.42,121.80,120.47,45.28,45.14,17.51.ESI-MS:m/z 476.47[M+H]+,C20H15BrN2O3S2[475.38].
实施例11.化合物11的制备
操作同实施例9,不同的是水解的是化合物3(80mg,0.16mmol),白色固体,收率89.8%,熔点:139~141℃。化合物11的波谱数据:1H NMR(400MHz,DMSO-d6)δ12.79(s,1H),8.34–8.29(m,1H),8.28–8.22(m,1H),7.55(d,J=5.8Hz,1H),7.40(d,J=5.8Hz,1H),6.71(d,J=7.8Hz,1H),5.75(s,2H),1.58(s,6H).13C NMR(100MHz,DMSO-d6)δ174.44,162.97,157.66,157.41,131.71,131.59,131.44,130.15,128.61,128.21,127.74,124.12,123.71,122.45,122.38,121.77,120.46,53.88,45.33,26.12.ESI-MS:m/z 490.73[M+H]+,C21H17BrN2O3S2[489.40].
实施例12.化合物12的制备
操作同实施例9,不同的是水解的是化合物4(80mg,0.15mmol),白色固体,收率73.9%,熔点:196~198℃。化合物12的波谱数据:1H NMR(400MHz,DMSO-d6)δ12.75(s,1H),8.37–8.30(m,1H),8.29–8.19(m,2H),7.80(dd,J=8.0,4.6Hz,3H),7.21(d,J=5.3Hz,1H),6.75(d,J=7.8Hz,1H),5.78(s,2H),2.80(dt,J=12.9,8.5Hz,2H),2.30–2.16(m,2H),2.02(ddd,J=14.2,10.5,3.9Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.62,158.77,157.62,156.44,136.99,131.74,131.59,131.49,130.15,128.61,128.21,127.74,124.88,124.15,122.60,121.79,118.94,54.20,45.46,31.93,17.36.ESI-MS:m/z 523.02[M+Na]+,C22H17BrN2O3S2[499.99].
实施例13.化合物13的制备
操作同实施例9,不同的是水解的是化合物5(80mg,0.17mmol),白色固体,收率67.2%,熔点:170~172℃。化合物13的波谱数据:1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),8.40–8.32(m,1H),8.26(d,J=1.9Hz,1H),8.25(d,J=2.8Hz,1H),7.84–7.80(m,1H),7.80(d,J=3.2Hz,1H),7.78(d,J=5.0Hz,1H),7.35(d,J=5.3Hz,1H),6.77(d,J=7.8Hz,1H),5.84(s,2H),4.02(s,2H).13C NMR(100MHz,DMSO-d6)δ169.55,159.01,157.73,156.32,137.01,131.75,131.59,131.45,130.14,128.59,128.21,127.76,125.04,124.11,122.78,121.82,118.89,45.13,35.06.ESI-MS:m/z 460.95[M-H]-,C19H13BrN2O3S2[461.35].
实施例14.化合物14的制备
操作同实施例9,不同的是水解的是化合物6(80mg,0.16mmol),白色固体,收率82.4%,熔点:182~184℃。化合物14的波谱数据:1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.29–8.22(m,1H),8.19(d,J=5.1Hz,1H),7.75(dd,J=7.4,2.0Hz,1H),7.72(d,J=3.6Hz,1H),7.70(s,1H),7.30(d,J=5.2Hz,1H),6.68(d,J=7.8Hz,1H),5.73(s,2H),4.46(q,J=7.3Hz,1H),1.42(d,J=7.3Hz,3H).13C NMR(150MHz,DMSO-d6)δ172.66,158.51,157.70,156.32,136.97,131.71,131.60,131.44,130.13,128.58,128.20,127.76,125.00,124.07,122.64,121.81,119.01,45.27,45.23,17.69.HR-MS:m/z 474.9621[M+H]-,C20H15BrN2O3S2[475.38].
实施例15.化合物15的制备
操作同实施例9,不同的是水解的是化合物7(80mg,0.16mmol),乙白色固体,收率73.1%,熔点:177~179℃。化合物15的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.35–8.28(m,1H),8.27–8.23(m,1H),8.20(d,J=5.2Hz,1H),7.81(d,J=6.2Hz,1H),7.79(s,1H),7.77(d,J=3.0Hz,1H),7.37(d,J=5.3Hz,1H),6.65(d,J=7.8Hz,1H),5.85(s,2H),1.75(s,6H).13C NMR(150MHz,DMSO-d6)δ174.54,162.20,158.01,156.61,136.25,132.36,131.79,131.57,130.10,128.45,128.04,127.71,125.17,124.14,122.43,121.41,118.38,62.51,45.24,26.81.HR-MS:m/z 490.9913[M+H]+,C21H17BrN2O3S2[489.40].
实施例16.化合物16的制备
操作同实施例9,不同的是水解的是化合物8(80mg,0.15mmol),白色固体,收率63.4%,熔点:182~184℃。化合物16的波谱数据:1H NMR(400MHz,DMSO-d6)δ12.68(s,1H),8.37–8.29(m,1H),8.29–8.24(m,1H),8.23(d,J=5.3Hz,1H),7.85–7.80(m,1H),7.80(d,J=3.2Hz,1H),7.78(d,J=3.0Hz,1H),7.21(d,J=5.3Hz,1H),6.74(d,J=7.8Hz,1H),5.77(s,2H),2.80(dt,J=12.9,8.5Hz,2H),2.23(dt,J=12.7,8.3Hz,2H),2.03(dtd,J=15.5,8.2,7.7,4.6Hz,2H).13C NMR(150MHz,DMSO-d6)δ173.62,158.76,157.63,156.43,136.93,131.76,131.61,131.49,130.12,128.59,128.20,127.74,124.87,124.11,122.63,121.81,118.96,54.21,45.44,31.96,17.35.HR-MS:m/z 502.9924[M+H]+,C22H17BrN2O3S2[501.41].
化合物17~32的合成路线:
试剂及条件:(i)N-溴代丁二酰亚胺,过氧化二苯甲酰,正己烷,70℃;(ii)邻苯二甲酰亚胺钾盐,N,N-二甲基甲酰胺,100℃;(iii)水合肼,乙醇,回流;(iv)环丙基硼酸,磷酸钾,四三苯基膦钯,甲苯,氮气,100℃;(v)N,N'-硫羰基二咪唑,三乙胺,N,N-二甲基甲酰胺,室温;(vi)2-氨基-2,3-二氢噻吩-3-羧酸甲酯或3-氨基-2,3-二氢噻吩-2-羧酸甲酯,N,N-二甲基甲酰胺,氢氧化钠,100℃;(vii)溴乙酸甲酯或2-溴丙酸甲酯或2-溴异丁酸甲酯或1-溴环丁烷羧酸乙酯,碳酸钾,N,N-二甲基甲酰胺,50℃;(viii)氢氧化锂,四氢呋喃,甲醇,室温
化合物LH-1的制备
中间体(4-溴萘-1-基)甲胺(L-D)的制备如化合物1~16的合成方法所得。将L-D(5.00g,21.17mmol)、环丙基硼酸(2.37g,27.53mmol)、K3PO4(22.47g,105.88mmol)、四三苯基膦钯(1.71g,1.48mmol)依次加入到250mL烧瓶中,加入100mL甲苯与4mL水,N2氛围中,加热至100℃,12h后TLC监测反应完毕,将反应液冷却至室温后过滤,将滤液减压蒸除溶剂,残余物加入100mL乙酸乙酯溶解,然后用饱和NaCl水溶液(50mL×3)洗涤,有机相用无水硫酸钠干燥2h后过滤。滤液经减压浓缩后经柱层析(EA:PE=1:1)得到中间体4-环丙基萘-1-甲胺(LH-1),为黄色油状物,收率71.9%。ESI-MS:m/z 196.36[M-H]-,C14H15N[197.28].
化合物LH-2的制备
将4-环丙基萘-1-甲胺(2.00g,10.138mmol)和三乙胺(2.05g,20.276mmol)置于250mL烧瓶中,然后溶于50mL THF中,将TCDI(2.71g,15.20mmol)溶于50mL THF后缓慢滴加至烧瓶中,室温下搅拌4h。TLC检测反应完全,反应液用饱和NaCl水溶液(50mL×3)洗涤,将有机相用无水硫酸钠干燥后经柱层析(EA:PE=1:10)得到淡黄色粉末,收率74.2%,熔点:75~77℃。ESI-MS:m/z238.41[M-H]-,C15H13NS[239.33].
化合物LH-SH的制备
制备方法同LR-SH,只是LH-2(2.00g,8.37mmol)与2-氨基-2,3-二氢噻吩-3-羧酸甲酯(1.78g,12.56mmol)反应,最终得白色固体,收率62.0%,熔点:183~185℃。ESI-MS:m/z 363.56[M-H]-,C25H22N2O3S2[364.48].
化合物HL-SH的制备
制备方法同LR-SH,只是LH-2(2.00g,8.37mmol)与3-氨基-2,3-二氢噻吩-2-羧酸甲酯(1.78g,12.56mmol)反应,最终得白色固体,收率62.4%,熔点:167~169℃。ESI-MS:m/z 363.49[M-H]-,C25H22N2O3S2[364.48].
实施例17.化合物17的制备
将LH-SH(0.20g,0.55mmol)用10mL DMF溶解于25mL圆底烧瓶中,后加入K2CO3(0.11g,0.82mmol)。加热至50℃活化15min,然后将溴乙酸甲酯(0.10g,0.66mmol)逐滴加入其中,继续加热4h后TLC监测。待反应完全后,停止加热,冷却至室温后将溶液蒸干。残余物用20mL乙酸乙酯溶解,用饱和NaCl溶液洗涤(10mL×3),有机相用无水硫酸钠干燥、过滤。滤液减压浓缩后经柱层析(EA:PE=1:5)得到化合物后,乙酸乙酯重结晶,白色固体,收率66.7%,熔点:158~160℃。化合物17的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.56–8.46(m,1H),8.33–8.19(m,1H),7.77–7.70(m,1H),7.69(d,J=3.3Hz,1H),7.55(d,J=5.8Hz,1H),7.40(d,J=5.8Hz,1H),7.16(d,J=7.5Hz,1H),6.70(d,J=7.5Hz,1H),5.80(s,2H),4.08(d,J=2.3Hz,2H),3.67(s,3H),2.39(td,J=8.5,4.2Hz,1H),1.12–0.92(m,2H),0.79–0.56(m,2H).13C NMR(150MHz,DMSO-d6)δ173.69,158.20,157.52,156.02,138.94,137.05,133.59,130.54,128.78,126.82,126.63,125.50,124.57,123.66,123.28,121.11,119.02,53.12,45.58,26.02,13.24,7.04.ESI-MS:m/z 435.32[M-H]-,C23H20N2O3S2[436.54].
实施例18.化合物18的制备
操作同实施例17,不同的是LH-SH(0.20g,0.55mmol)与2-溴丙酸甲酯(0.11g,0.66mmol)反应,白色固体,收率60.6%,熔点:142~144℃。化合物18的波谱数据:1H NMR(600MHz,DMSO-d6)δ8.45–8.37(m,1H),8.17–8.10(m,1H),7.64–7.61(m,1H),7.61–7.59(m,1H),7.47(d,J=5.8Hz,1H),7.32(d,J=5.8Hz,1H),7.08(d,J=7.5Hz,1H),6.59(d,J=7.5Hz,1H),5.68(s,2H),4.45(q,J=7.3Hz,1H),3.59(s,3H),2.30(td,J=8.5,4.3Hz,1H),1.39(d,J=7.3Hz,3H),0.96(dt,J=9.0,2.9Hz,2H),0.60(td,J=5.6,3.6Hz,2H).13C NMR(150MHz,DMSO-d6)δ171.93,163.09,157.65,157.45,138.99,133.60,130.57,128.60,126.83,126.62,125.51,123.73,123.65,123.26,122.42,121.21,120.50,53.08,45.52,44.41,16.95,13.24,7.04.ESI-MS:m/z 450.62[M+H]+,C24H22N2O3S2[450.11].
实施例19.化合物19的制备
操作同实施例17,不同的是LH-SH(0.20g,0.55mmol)与2-溴异丁酸甲酯(0.12g,0.66mmol)反应,白色固体,收率74.4%,熔点:174~176℃。化合物19的波谱数据:1H NMR(600MHz,DMSO-d6)δ8.54–8.47(m,1H),8.21(d,J=5.6Hz,1H),7.73–7.65(m,2H),7.54(d,J=5.7Hz,1H),7.38(d,J=5.8Hz,1H),7.17(d,J=8.5Hz,1H),6.64(d,J=8.8Hz,1H),5.72(s,2H),3.67(s,3H),2.39(ddd,J=13.8,8.5,5.4Hz,1H),1.59(s,6H),1.07–1.01(m,2H),0.70–0.66(m,2H).13C NMR(150MHz,DMSO-d6)δ173.61,162.86,157.58,157.32,138.95,133.61,130.57,128.69,126.81,126.62,125.50,123.68,123.65,123.27,122.41,121.10,120.50,53.75,53.18,45.55,26.06,13.23,7.04.ESI-MS:m/z 464.85[M+H]+,C25H24N2O3S2[464.12].
实施例20.化合物20的制备
操作同实施例17,不同的是LH-SH(0.20g,0.55mmol)与1-溴环丁烷羧酸乙酯(0.14g,0.66mmol)反应,白色固体,收率55.6%,熔点:160~162℃。化合物20的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.57–8.42(m,1H),8.29–8.17(m,1H),7.70(dd,J=6.4,3.3Hz,2H),7.51(d,J=5.7Hz,1H),7.36(d,J=5.8Hz,1H),7.16(d,J=7.4Hz,1H),6.65(d,J=7.4Hz,1H),5.73(s,2H),4.12(q,J=7.1Hz,2H),2.89–2.71(m,2H),2.39(h,J=5.7Hz,1H),2.23(dq,J=13.4,7.8,7.2Hz,2H),2.10–1.90(m,2H),1.13(t,J=7.1Hz,3H),1.04(d,J=6.7Hz,2H),0.67(d,J=5.3Hz,2H).13C NMR(100MHz,Chloroform-d)δ172.51,163.45,158.20,157.39,138.98,133.87,130.64,127.94,126.12,125.79,125.50,123.55,122.74,122.44,121.48,121.13,120.50,61.80,54.26,45.22,32.07,17.27,14.26,13.33,6.36.ESI-MS:m/z 490.81[M+H]+,C27H26N2O3S2[490.14].
实施例21.化合物21的制备
操作同实施例17,不同的是HL-SH(0.20g,0.55mmol)与溴乙酸甲酯(0.10g,0.66mmol)反应,白色固体,收率70.9%,熔点:160~162℃。化合物21的波谱数据:1H NMR(600MHz,DMSO-d6)δ8.48–8.39(m,1H),8.19–8.15(m,2H),7.65–7.57(m,2H),7.25(d,J=5.2Hz,1H),7.08(d,J=7.5Hz,1H),6.62(d,J=7.5Hz,1H),5.74(s,2H),4.00(s,2H),3.59(s,3H),2.30(td,J=8.4,4.3Hz,1H),0.99–0.92(m,2H),0.62–0.56(m,2H).13C NMR(150MHz,DMSO-d6)δ169.00,158.87,157.67,156.18,139.01,136.92,133.61,130.61,128.74,126.83,126.60,125.51,124.98,123.66,123.28,121.43,118.99,52.89,45.34,34.48,13.25,7.05.ESI-MS:m/z436.79[M+H]+,C23H20N2O3S2[436.09].
实施例22.化合物22的制备
操作同实施例17,不同的是HL-SH(0.20g,0.55mmol)与2-溴丙酸甲酯(0.11g,0.66mmol)反应,白色固体,收率66.6%,熔点:114~116℃。化合物22的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.46–8.40(m,1H),8.19(d,J=5.3Hz,1H),8.17–8.13(m,1H),7.67–7.59(m,2H),7.26(d,J=5.3Hz,1H),7.09(d,J=7.5Hz,1H),6.59(d,J=7.5Hz,1H),5.70(s,2H),4.48(q,J=7.3Hz,1H),3.59(s,3H),2.35–2.25(m,1H),1.40(d,J=7.3Hz,3H),1.01–0.90(m,2H),0.61(t,J=4.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.04,158.32,157.60,156.16,138.98,137.03,133.58,130.52,128.66,126.85,126.65,125.52,124.91,123.67,123.30,121.17,119.058,53.06,45.54,44.38,16.98,13.26,7.04.ESI-MS:m/z450.67[M+H]+,C24H22N2O3S2[450.11].
实施例23.化合物23的制备
操作同实施例17,不同的是HL-SH(0.20g,0.55mmol)与2-溴异丁酸甲酯(0.12g,0.66mmol)反应,白色固体,收率62.7%,熔点:114~116℃。化合物23的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.55–8.45(m,1H),8.25(d,J=5.3Hz,1H),8.24–8.18(m,1H),7.75–7.65(m,2H),7.24(d,J=5.3Hz,1H),7.17(d,J=7.5Hz,1H),6.63(d,J=7.5Hz,1H),5.74(s,2H),3.67(s,3H),2.44–2.33(m,1H),1.59(s,6H),1.07–0.98(m,2H),0.71–0.63(m,2H).13C NMR(150MHz,DMSO-d6)δ168.94,163.18,158.03,157.71,138.99,133.61,130.63,128.65,126.83,126.60,125.52,123.67,123.63,123.30,122.42,121.41,120.36,52.94,45.34,34.46,13.26,7.04.ESI-MS:m/z 464.66[M+H]+,C25H24N2O3S2[464.12].
实施例24.化合物24的制备
操作同实施例17,不同的是HL-SH(0.20g,0.55mmol)与1-溴环丁烷羧酸乙酯(0.14g,0.66mmol)反应,白色固体,收率59.4%,熔点:184~186℃。化合物24的波谱数据:1H NMR(600MHz,Chloroform-d)δ8.58–8.49(m,1H),8.17–8.06(m,1H),7.76(d,J=5.3Hz,1H),7.69–7.62(m,2H),7.20–7.11(m,2H),6.80(d,J=7.4Hz,1H),5.87(s,2H),4.21(q,J=7.1Hz,2H),2.96–2.81(m,2H),2.38–2.31(m,1H),2.25(dd,J=21.4,7.2Hz,2H),2.12(p,J=8.2Hz,2H),1.23(t,J=7.1Hz,3H),1.06(dd,J=8.5,4.2Hz,2H),0.79–0.69(m,2H).13CNMR(150MHz,Chloroform-d)δ172.60,158.32,158.03,156.22,138.98,134.42,133.89,130.70,128.11,126.10,125.76,125.47,124.41,123.51,122.76,121.30,119.49,61.59,54.13,45.21,32.03,17.24,14.17,13.31,6.36.ESI-MS:m/z 490.95[M+H]+,C27H26N2O3S[490.14].
实施例25.化合物25的制备
将化合物17(80mg,0.18mmol)溶于5mL甲醇和2.5mL四氢呋喃的混合溶液中,将适量的LiOH溶于1mL水中,逐滴加入到混合溶液中。室温搅拌,TLC监测反应完全,加入5mL水,减压旋蒸除去混合液的甲醇和四氢呋喃,然后缓慢向剩余溶液中滴加1mol/L HCl,滴加过程中有固体析出,将pH调至3左右至固体不再增多,过滤,用5mL清水洗涤滤饼,真空干燥后将目标化合物乙酸乙酯重结晶,白色固体,收率81.4%,熔点:150~152℃。化合物25的波谱数据:1H NMR(400MHz,DMSO-d6)δ12.97(s,1H),8.53–8.41(m,1H),8.22–8.15(m,1H),7.63(d,J=3.8Hz,1H),7.63–7.60(m,1H),7.60(s,1H),7.47(dd,J=5.8,2.6Hz,1H),7.32(d,J=5.7Hz,1H),7.08(t,J=6.1Hz,1H),6.62(d,J=7.4Hz,1H),5.75(d,J=15.1Hz,2H),3.93(d,J=2.6Hz,2H),2.30(ddd,J=13.8,8.5,5.4Hz,1H),0.96(ddd,J=8.4,5.2,1.9Hz,2H),0.59(td,J=5.9,4.1Hz,2H).13C NMR(100MHz,DMSO-d6)δ169.48,163.33,158.43,157.79,138.93,133.59,130.60,128.69,126.84,126.61,125.52,123.67,123.55,123.31,122.37,121.34,120.27,45.36,35.22,13.27,7.03.ESI-MS:m/z 420.75[M-H]-,C22H18N2O3S2[422.07].
实施例26.化合物26的制备
操作同实施例25,不同的是水解的是化合物18(80mg,0.18mmol),白色固体,收率81.1%,熔点:109~111℃。化合物26的波谱数据:1H NMR(600MHz,DMSO-d6)δ8.45–8.40(m,1H),8.15(dt,J=7.8,2.6Hz,1H),7.65–7.59(m,2H),7.48(d,J=5.8Hz,1H),7.32(d,J=5.8Hz,1H),7.07(d,J=7.5Hz,1H),6.60(d,J=7.5Hz,1H),5.69(s,2H),4.40(q,J=7.3Hz,1H),2.31(td,J=8.4,4.3Hz,1H),1.40(d,J=7.3Hz,3H),0.99–0.93(m,2H),0.60(td,J=5.8,3.9Hz,2H).ESI-MS:m/z 435.46[M-H]-,C23H20N2O3S[436.54].
实施例27.化合物27的制备
操作同实施例25,不同的是水解的是化合物19(80mg,0.17mmol),白色固体,收率58.0%,熔点:120~122℃。化合物27的波谱数据:1H NMR(400MHz,DMSO-d6)δ12.84(s,1H),8.51–8.46(m,1H),8.24–8.20(m,1H),7.71–7.65(m,2H),7.54(d,J=5.8Hz,1H),7.38(d,J=5.8Hz,1H),7.15(d,J=7.4Hz,1H),6.64(d,J=7.5Hz,1H),5.73(s,2H),2.40–2.35(m,1H),1.58(s,6H),1.05–1.01(m,2H),0.68–0.65(m,2H).13C NMR(100MHz,DMSO-d6)δ174.49,162.92,157.66,157.62,138.87,133.57,130.54,128.78,126.83,126.64,125.50,123.69,123.63,123.29,122.33,121.02,120.44,53.82,45.56,26.13,13.26,7.03.ESI-MS:m/z472.79[M+Na]+,C24H22N2O3S2[450.11].
实施例28.化合物28的制备
操作同实施例25,不同的是水解的是化合物20(80mg,0.16mmol),白色固体,收率83.6%,熔点:194~196℃。化合物28的波谱数据:1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),8.50(d,J=7.8Hz,1H),8.23(d,J=8.0Hz,1H),7.75–7.65(m,2H),7.51(d,J=6.0Hz,1H),7.36(dd,J=5.8,1.8Hz,1H),7.15(d,J=6.4Hz,1H),6.67(d,J=7.6Hz,1H),5.73(s,2H),2.78(d,J=12.7Hz,2H),2.41–2.35(m,1H),2.21(dd,J=13.1,7.8Hz,2H),2.12–1.97(m,2H),1.04(d,J=8.8Hz,2H),0.66(dd,J=10.4,4.9Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.64,163.30,158.05,157.68,138.89,133.59,130.58,128.73,126.84,126.64,125.51,123.72,123.52,123.30,122.33,121.14,120.41,54.14,45.68,31.90,17.32,13.28,7.02.ESI-MS:m/z 484.86[M+Na]+,C25H22N2O3S2[462.11].
实施例29.化合物29的制备
操作同实施例25,不同的是水解的是化合物21(80mg,0.18mmol),白色固体,收率95.6%,熔点:180~182℃。化合物29的波谱数据:1H NMR(600MHz,DMSO-d6)δ8.47–8.38(m,1H),8.20–8.17(m,1H),8.16(d,J=5.2Hz,1H),7.62(d,J=3.8Hz,1H),7.61(d,J=3.3Hz,1H),7.27(d,J=5.2Hz,1H),7.07(d,J=7.5Hz,1H),6.63(d,J=7.5Hz,1H),5.75(s,2H),3.93(s,2H),2.30(td,J=8.4,4.3Hz,1H),0.99–0.93(m,2H),0.60(td,J=5.9,4.1Hz,2H).13C NMR(150MHz,DMSO-d6)δ169.49,159.32,157.75,156.31,138.95,136.79,133.61,130.61,128.82,126.82,126.59,125.51,125.02,123.66,123.30,121.42,118.88,45.35,35.38,13.25,7.03.ESI-MS:m/z 842.70[2M-H]-,C22H18N2O3S2[422.07].
实施例30.化合物30的制备
操作同实施例25,不同的是水解的是化合物22(80mg,0.18mmol),白色固体,收率67.1%,熔点:106~108℃。化合物30的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.46–8.40(m,1H),8.16(dd,J=12.1,4.6Hz,2H),7.67–7.58(m,2H),7.29(d,J=5.3Hz,1H),7.07(d,J=7.5Hz,1H),6.59(d,J=7.4Hz,1H),5.71(s,2H),4.44(q,J=7.2Hz,1H),2.32(td,J=8.5,4.3Hz,1H),1.41(d,J=7.3Hz,3H),1.02–0.90(m,2H),0.63–0.55(m,2H).13C NMR(100MHz,DMSO-d6)δ172.81,158.76,157.70,156.30,138.91,136.88,133.58,130.52,128.75,126.84,126.63,125.52,125.00,123.66,123.31,121.18,118.97,45.33,17.76,13.27,7.04.ESI-MS:m/z 870.75[2M-H]-,C23H20N2O3S2[436.09].
实施例31.化合物31的制备
操作同实施例25,不同的是水解的是化合物23(80mg,0.17mmol),白色固体,收率65.7%,熔点:117~119℃。化合物31的波谱数据:1H NMR(400MHz,DMSO-d6)δ8.52–8.47(m,1H),8.22(dd,J=10.7,4.7Hz,2H),7.72–7.66(m,2H),7.25(d,J=5.2Hz,1H),7.15(d,J=7.7Hz,1H),6.64(d,J=7.5Hz,1H),5.75(s,2H),2.39(dd,J=10.2,4.9Hz,1H),1.60(s,6H),1.05(dd,J=8.2,5.6Hz,2H),0.67(t,J=5.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ174.56,158.69,157.62,156.13,138.86,136.92,133.57,130.52,128.91,126.83,126.64,125.50,124.70,123.70,123.30,121.05,118.93,47.53,45.58,26.15,13.26,7.03.ESI-MS:m/z 898.71[2M-H]-,C24H22N2O3S2[450.11].
实施例32.化合物32的制备
操作同实施例25,不同的是水解的是化合物24(80mg,0.16mmol),白色固体,收率59.7%,熔点:194~196℃。化合物32的波谱数据:1H NMR(600MHz,DMSO-d6)δ12.65(s,1H),8.44–8.41(m,1H),8.17–8.15(m,1H),7.65–7.60(m,2H),7.44(d,J=5.8Hz,1H),7.29(d,J=5.8Hz,1H),7.08(dd,J=6.4,4.0Hz,2H),6.61(d,J=7.5Hz,1H),5.66(s,2H),2.71(dt,J=13.3,9.1Hz,2H),2.33–2.29(m,1H),2.14(ddd,J=13.3,8.9,6.3Hz,2H),2.00–1.90(m,2H),0.97–0.95(m,2H),0.61(dt,J=5.6,2.9Hz,2H).13C NMR(150MHz,DMSO-d6)δ173.60,163.28,158.02,157.68,138.92,133.61,130.63,128.75,126.81,126.60,125.50,123.69,123.45,123.26,122.33,121.23,120.45,54.12,45.66,31.95,17.31,13.25,7.03.ESI-MS:m/z 461.23[M-H]-,C25H22N2O3S2[462.58].
实施例33.目标化合物的体内降尿酸活性试验
测试材料和方法:
(1)实验动物:雄性昆明小鼠,由山东大学实验动物中心提供。
(2)样品处理:待测化合物临用前,用DMSO和CMC-Na配成适当的浓度。
(3)造模药物:次黄嘌呤、氧嗪酸钾。
(4)阳性对照药:Lesinurad。
(5)测试方法:每组灌胃次黄嘌呤0.2mL,皮下注射氧嗪酸钾0.2mL,灌胃药物0.2mL并开始计时,在给药4小时后摘眼球取血,30分钟凝血后离心,取上清液血清。用尿酸仪检测血清中的尿酸浓度。
血尿酸浓度下降率(DR)=(造模值-实验值)/(造模值-空白值)×100%,其下降率数值越大说明其活性越好。
表2.化合物1~16的结构及降尿酸的活性
表3.化合物17~32的结构及降尿酸的活性
结论:由表2和表3可以看出,有16个化合物呈现出降尿酸活性,降尿酸活性均优于阳性对照药物Lesinurad或与Lesinurad相当。其中化合物9、10、13、25和29在动物体内活性测试中,血尿酸下降率均超过60%,显示出优异的降尿酸活性,可作为降尿酸候选药物。
Claims (6)
2.如权利要求1所述的含有乙基萘结构的噻吩并嘧啶酮类化合物,其特征在于,R为亚甲基,R1为亚甲基、异丙基、叔丁基、环丁基,Ar为1-环丙基-4-萘或1-溴-4-萘。
4.如权利要求3所述的含有乙基萘结构的噻吩并嘧啶酮类化合物的制备方法,其特征在于,为如下方法之一:
(1)化合物1~16的合成:
首先以1-溴-4-甲基萘为起始原料,在过氧化二苯甲酰的催化作用下,在正己烷中与N-溴代丁二酰亚胺反应,生成1-溴-4-(溴甲基)萘(L-B);L-B在DMF中与邻苯二甲酰亚胺钾发生取代反应,生成中间体2-((4-溴萘-1-基)甲基)异吲哚啉-1,3-二酮(L-C);L-C在水合肼作用下,于乙醇溶液中发生Gabriel Synthesis肼解反应生成关键中间体(4-溴萘-1-基)甲胺(L-D);L-D在三乙胺的存在下,于二氯甲烷中与N,N'-硫羰基二咪唑(TCDI)反应生成1-溴-4-(异硫氰酸甲基)萘(LR-1);LR-1在DMF中与2-氨基-2,3-二氢噻吩-3-羧酸甲酯或3-氨基-2,3-二氢噻吩-2-羧酸甲酯反应,然后在NaOH作用下环合生成对应的巯基(LR-SH或RL-SH);在DMF中,LR-SH或RL-SH在碳酸钾的催化作用下与不同的溴取代酯反应,生成1~8;1~8在四氢呋喃和甲醇的混合溶液中用氢氧化锂水解得到9~16;
路线一:
试剂及条件:(i)N-溴代丁二酰亚胺,过氧化二苯甲酰,正己烷,70℃;(ii)邻苯二甲酰亚胺钾盐,N,N-二甲基甲酰胺,100℃;(iii)水合肼,乙醇,回流;(iv)N,N'-硫羰基二咪唑,三乙胺,N,N-二甲基甲酰胺,室温;(v)2-氨基-2,3-二氢噻吩-3-羧酸甲酯或3-氨基-2,3-二氢噻吩-2-羧酸甲酯,氢氧化钠,N,N-二甲基甲酰胺,100℃;(vi)溴乙酸甲酯或2-溴丙酸甲酯或2-溴异丁酸甲酯或1-溴环丁烷羧酸乙酯,碳酸钾,N,N-二甲基甲酰胺,50℃;(vii)氢氧化锂,四氢呋喃,甲醇,室温;
(2)化合物17~32的合成
化合物17~32的合成方法与与路线一中化合物1~16的制备所描述的合成方法相似,只是(4-溴萘-1-基)甲胺与环丙基硼酸在磷酸钾与四三苯基膦钯的催化下反应生成(4-环丙基萘-1-基)甲胺(LH-1);LH-1在三乙胺的存在下,在二氯甲烷中与N,N'-硫羰基二咪唑反应生成1-环丙基-4-(异硫氰酸甲基)萘(LH-2);LH-2在DMF中与2-氨基-2,3-二氢噻吩-3-羧酸甲酯或3-氨基-2,3-二氢噻吩-2-羧酸甲酯反应,然后在NaOH作用下环合生成相应的巯基(LH-SH或HL-SH);LH-SH或HL-SH在DMF中在碳酸钾的催化作用下与不同的酯反应,生成17~24;17~24在四氢呋喃和甲醇的混合溶液中用氢氧化锂水解得到25~32;
路线二:
试剂及条件:(i)N-溴代丁二酰亚胺,过氧化二苯甲酰,正己烷,70℃;(ii)邻苯二甲酰亚胺钾盐,N,N-二甲基甲酰胺,100℃;(iii)水合肼,乙醇,回流;(iv)环丙基硼酸,磷酸钾,四三苯基膦钯,甲苯,氮气,100℃;(v)N,N'-硫羰基二咪唑,三乙胺,N,N-二甲基甲酰胺,室温;(vi)2-氨基-2,3-二氢噻吩-3-羧酸甲酯或3-氨基-2,3-二氢噻吩-2-羧酸甲酯,氢氧化钠,N,N-二甲基甲酰胺,100℃;(vii)溴乙酸甲酯或2-溴丙酸甲酯或2-溴异丁酸甲酯或1-溴环丁烷羧酸乙酯,碳酸钾,N,N-二甲基甲酰胺,50℃;(viii)氢氧化锂,四氢呋喃,甲醇,室温。
5.权利要求1-3任一项所述的含有乙基萘结构的噻吩并嘧啶酮类化合物在制备降尿酸的药物中的应用。
6.一种降尿酸药物组合物,包含权利要求1-3任一项所述的含有乙基萘结构的噻吩并嘧啶酮类化合物和一种或多种药学上可接受载体或赋形剂。
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