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【结 构 式】 
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【分子编号】18799 【品名】4-(2-bromoethoxy)benzaldehyde 【CA登记号】52191-15-8 |
【 分 子 式 】C9H9BrO2 【 分 子 量 】229.07326 【元素组成】C 47.19% H 3.96% Br 34.88% O 13.97% |
合成路线1
该中间体在本合成路线中的序号：(VI)The target compound was obtained by several related ways. Indolylethanol (III) was either prepared by alkylation of indole (I) with methyl bromoacetate, followed by reduction of the resulting indolylacetate (II) with LiAlH4 or by alkylation of (I) with 2-bromoethanol. Alkylation of (III) with 4-fluorobenzaldehyde (IV) in the presence of NaH or condensation with 4-hydroxybenzaldehyde (V) under Mitsunobu conditions provided ether (VII). Alternatively, (VII) was prepared by alkylation of indole (I) with 4-(bromoethoxy)benzaldehyde (VI). Then, Knoevenagel condensation of aldehyde (VII) with 2,4-thiazolidinedione (VIII) in the presence of piperidinium benzoate in refluxing toluene with azeotropic removal of water yielded benzylidene compound (IX). Reduction of the olefinic double bond by either hydrogenation in the presence of an excess of Pd/C or by chemical reduction with Mg in MeOH provided the target benzyl compound. Alternatively, indolylethanol (III) was condensed with hydroxybenzyl compound (X) in the presence of tributyl phosphine and 1,1'-(azodicarbonyl)dipiperidine (ADDP) in benzene to give (XI), which was finally deprotected by hydrogenation in the presence of an excess of Pd/C in dioxan.
| 【1】 Lohray, B.B.; et al.; Novel indole containing thiazolidinedione derivatives as potent euglycemic and hypolipidaemic agents. Bioorg Med Chem Lett 1997, 7, 7, 785. |
| 【2】 Rao, K.N.; Reddy, A.K.; Reddy, P.G.; Vikramadityan, R.K.; Madhavan, G.R.; Bhushan, V.; Rajagopolan, R.; Mamidi, R.N.V.S.; Rajesh, B.M.; Jajoo, H.K.; Rao, B.P.; Murali, N.; Chakrabarti, R.; Subramaniam, S.; Lohray, B.B.; Novel euglycemic and hypolipidemic agent. J Med Chem 1998, 41, 10, 1619. |
| 【3】 Fujita, T.; Fujimoto, K.; Yoshioka, T.; Yanagisawa, H.; Fujiwara, T.; Horikoshi, H.; Oguchi, M.; Wada, K. (Sankyo Co., Ltd.); Heterocyclic cpds. having antidiabetic activity, their preparation and their use. CA 2146701; EP 0676398; JP 1995330728; US 5624935; US 5834501; US 5962470; US 6117893 . |
| 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) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (II) | 18795 | methyl 2-(1H-indol-1-yl)acetate | C11H11NO2 | 详情 | 详情 | |
| (III) | 18796 | 2-(1H-indol-1-yl)-1-ethanol | C10H11NO | 详情 | 详情 | |
| (IV) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (V) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VI) | 18799 | 4-(2-bromoethoxy)benzaldehyde | 52191-15-8 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 18800 | 4-[2-(1H-indol-1-yl)ethoxy]benzaldehyde | C17H15NO2 | 详情 | 详情 | |
| (VIII) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (IX) | 18802 | 5-((E)-[4-[2-(1H-indol-1-yl)ethoxy]phenyl]methylidene)-1,3-thiazolidine-2,4-dione | C20H16N2O3S | 详情 | 详情 | |
| (X) | 18803 | 5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione | C29H23NO3S | 详情 | 详情 | |
| (XI) | 18804 | 5-[4-[2-(1H-indol-1-yl)ethoxy]benzyl]-3-trityl-1,3-thiazolidine-2,4-dione | C39H32N2O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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3
该中间体在本合成路线中的序号：(XI)In a related method, 4-(2-bromoethoxy)benzaldehyde (XI) was subjected to a Horner-Emmons reaction with phosphonate (II) to produce the unsaturated ester (XIIa-b), which was further hydrogenated to afford (XIII). Alkylation of phenoxazine (XIV) with bromide (XIII) gave adduct (VIII) (1,2). In a different reaction sequence, bromoaldehyde (XI) was initially condensed with phenoxazine (XIV), producing adduct (XV). This was subjected to Horner-Emmons condensation with (II) to give the unsaturated ester (XVIa-b), which was then hydrogenated to (VIII). Alternatively, double-bond reduction of (XVI) by means of Mg in MeOH gave rise to the transesterified methyl ester (IX). Ester hydrolysis as above provided acid (X).
| 【2】 Kalchar, S.; Lohray, V.B.; Lohray, B.B.; Chakrabarti, R.; Bajji, A.C.; Ramanujam, R. (Dr. Reddy's Research Foundation); Novel tricyclic cpds. and their use in medicine; process for their preparation and pharmaceutical compsns. containing them. EP 1049684; JP 2001519422; WO 9919313 . |
| 【3】 Rajagopalan, R.; Ashok, C.B.; Shivaramayya, K.; Gurram, R.M.; Lohray, B.B.; Paraselli, B.R.; Rajan, C.; Lohray, V.B. (Dr. Reddy's Research Foundation); Novel tricyclic cpds. and their use in medicine; process for their preparation and pharmaceutical compsn. containing them. EP 1155006; WO 0050414 . |
| 【1】 Lohray, B.B.; et al.; (-)-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid[(-)DRF 2725]: A dual PPAR agonist with potent antihyperglycemic and lipid modulating activity. J Med Chem 2001, 44, 16, 2675. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIa) | 51686 | ethyl (E)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxy-2-propenoate | C15H19BrO4 | 详情 | 详情 | |
| (XIIb) | 51687 | ethyl (Z)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxy-2-propenoate | C15H19BrO4 | 详情 | 详情 | |
| (XVIa) | 51689 | ethyl (E)-2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]-2-propenoate | C27H27NO5 | 详情 | 详情 | |
| (XVba) | 51690 | ethyl (Z)-2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]-2-propenoate | C27H27NO5 | 详情 | 详情 | |
| (II) | 51675 | ethyl 2-(diethoxyphosphoryl)-2-ethoxyacetate | C10H21O6P | 详情 | 详情 | |
| (VIII) | 51679 | ethyl 2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propanoate | C27H29NO5 | 详情 | 详情 | |
| (IX) | 51680 | methyl 2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propanoate | C26H27NO5 | 详情 | 详情 | |
| (X) | 51681 | 2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propionic acid | C25H25NO5 | 详情 | 详情 | |
| (XI) | 18799 | 4-(2-bromoethoxy)benzaldehyde | 52191-15-8 | C9H9BrO2 | 详情 | 详情 |
| (XIII) | 51688 | ethyl 3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate | C15H21BrO4 | 详情 | 详情 | |
| (XIV) | 51684 | 2,3,5,6-Dibenzo-1,4-oxazine; Phenoxazine | 135-67-1 | C12H9NO | 详情 | 详情 |
| (XV) | 51685 | 4-[2-(10H-phenoxazin-10-yl)ethoxy]benzaldehyde | C21H17NO3 | 详情 | 详情 |