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【结 构 式】 
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【药物名称】PMT-13 【化学名称】5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzyl]thiazolidine-2,4-dione 【CA登记号】199113-95-6, 199114-09-5 (sodium salt) 【 分 子 式 】C19H21N3O4S 【 分 子 量 】387.46092 |
【开发单位】Dr. Reddy's Research Foundation (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARgamma Agonists |
合成路线1
2-Ethyl-6-methyl-3,4-dihydropyrimidin-4-one (I) is alkylated with 4-(2-bromoethoxy)benzaldehyde (II) in the presence of NaH and LiBr to afford (III). Subsequent Knoevenagel condensation of benzaldehyde (III) with thiazolidine-2,4-dione (IV) employing piperidine/benzoic acid leads to the benzylidene thiazolidinedione (V), which is finally reduced to the title benzyl thiazolidinedione by catalytic hydrogenation over Pd/C.
| 【1】 Madhavan, G.R.; Chakrabarti, R.; Vikramadithyan, R.K.; Mamidi, R.N.V.S.; Balraju, V.; Rajesh, B.M.; Misra, P.; Kumar, S.K.B.; Lohray, B.B.; Lohray, V.B.; Rajagopalan, R.; Synthesis and biological activity of novel pyrimidinone containing thiazolidinedione derivatives. Bioorg Med Chem 2002, 10, 8, 2671. |
| 【2】 Lohray, V.B.; Lohray, B.B.; Ramanujam, R.; Chakrabarti, R.; Gurram, R.M.; Paraselli, R.B.; Pakala, S.K.S. (Dr. Reddy's Research Foundation); Heterocyclic cpds., process for their preparation and pharmaceutical compsns. containing them and their use in the treatment of diabetes and related diseases. EP 0958296; US 5885997; US 5985884; US 6372750; US 6573268; WO 9741097 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 63395 | 2-ethyl-6-methyl-4(3H)-pyrimidinone | C7H10N2O | 详情 | 详情 | |
| (II) | 18799 | 4-(2-bromoethoxy)benzaldehyde | 52191-15-8 | C9H9BrO2 | 详情 | 详情 |
| (III) | 63396 | 4-({2-[2-ethyl-4-methyl-6-oxo-1(6H)-pyrimidinyl]ethyl}oxy)benzaldehyde | C16H18N2O3 | 详情 | 详情 | |
| (IV) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (V) | 63397 | 5-{[4-({2-[2-ethyl-4-methyl-6-oxo-1(6H)-pyrimidinyl]ethyl}oxy)phenyl]methylidene}-1,3-thiazolidine-2,4-dione | C19H19N3O4S | 详情 | 详情 |
合成路线2
In an alternative procedure, pyrimidinone (I) is alkylated with 4-(2-bromoethoxy)nitrobenzene (II) to produce (III). Reduction of nitro compound (III) by catalytic hydrogenation affords aniline (IV). After diazotization of amine (IV), the resultant diazonium salt is coupled to ethyl acrylate in the presence of CuI, yielding the 2-bromo-3-arylpropionate (V). Cyclization of bromo ester (V) with thiourea (VI) furnishes the iminothiazolidinone (VII), which is finally hydrolyzed under acidic conditions to the target thiazolidinedione.
| 【1】 Lohray, V.B.; Lohray, B.B.; Ramanujam, R.; Chakrabarti, R.; Gurram, R.M.; Paraselli, R.B.; Pakala, S.K.S. (Dr. Reddy's Research Foundation); Heterocyclic cpds., process for their preparation and pharmaceutical compsns. containing them and their use in the treatment of diabetes and related diseases. EP 0958296; US 5885997; US 5985884; US 6372750; US 6573268; WO 9741097 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 63395 | 2-ethyl-6-methyl-4(3H)-pyrimidinone | C7H10N2O | 详情 | 详情 | |
| (II) | 63398 | 1-[(2-bromoethyl)oxy]-4-nitrobenzene; 2-bromoethyl 4-nitrophenyl ether | 13288-06-7 | C8H8BrNO3 | 详情 | 详情 |
| (III) | 63399 | 2-ethyl-6-methyl-3-{2-[(4-nitrophenyl)oxy]ethyl}-4(3H)-pyrimidinone | C15H17N3O4 | 详情 | 详情 | |
| (IV) | 63400 | 3-{2-[(4-aminophenyl)oxy]ethyl}-2-ethyl-6-methyl-4(3H)-pyrimidinone | C15H19N3O2 | 详情 | 详情 | |
| (V) | 63401 | ethyl 2-bromo-3-[4-({2-[2-ethyl-4-methyl-6-oxo-1(6H)-pyrimidinyl]ethyl}oxy)phenyl]propanoate | C20H25BrN2O4 | 详情 | 详情 | |
| (VI) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VII) | 63402 | 2-ethyl-3-[2-({4-[(2-imino-4-oxo-1,3-thiazolidin-5-yl)methyl]phenyl}oxy)ethyl]-6-methyl-4(3H)-pyrimidinone | C19H22N4O3S | 详情 | 详情 |