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【结 构 式】 
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【分子编号】51681 【品名】2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propionic acid 【CA登记号】 |
【 分 子 式 】C25H25NO5 【 分 子 量 】419.47724 【元素组成】C 71.58% H 6.01% N 3.34% O 19.07% |
合成路线1
该中间体在本合成路线中的序号：(X)Several related procedures have been described for the synthesis of the title compound. The Horner-Emmons reaction of 4-benzyloxybenzaldehyde (I) with triethyl 2-ethoxyphosphonoacetate (II) afforded the unsaturated ester (IIIa-b) as a mixture of E/Z isomers. Simultaneous double-bond hydrogenation and benzyl group hydrogenolysis in the presence of Pd/C furnished phenol (IV). Alternatively, double-bond reduction by means of magnesium in MeOH was accompanied by transesterification, yielding the saturated methyl ester (V). Further benzyl group hydrogenolysis of (V) over Pd/C gave phenol (VI). The alkylation of phenols (IV) and (VI) with the phenoxazinylethyl mesylate (VII) provided the corresponding ethers (VIII) and (IX), respectively. The racemic carboxylic acid (X) was then obtained by hydrolysis of either ethyl- (VIII) or methyl- (IX) esters under basic conditions.
| 【1】 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 . |
| 【2】 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 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 50411 | ethyl (E)-3-[4-(benzyloxy)phenyl]-2-ethoxy-2-propenoate | C20H22O4 | 详情 | 详情 | |
| (IIIb) | 51683 | ethyl (Z)-3-[4-(benzyloxy)phenyl]-2-ethoxy-2-propenoate | C20H22O4 | 详情 | 详情 | |
| (I) | 29179 | 4-(Benzyloxy)benzaldehyde | 4397-53-9 | C14H12O2 | 详情 | 详情 |
| (II) | 51675 | ethyl 2-(diethoxyphosphoryl)-2-ethoxyacetate | C10H21O6P | 详情 | 详情 | |
| (IV) | 51682 | ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate | C13H18O4 | 详情 | 详情 | |
| (V) | 51676 | methyl 3-[4-(benzyloxy)phenyl]-2-ethoxypropanoate | C19H22O4 | 详情 | 详情 | |
| (VI) | 51677 | methyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate | C12H16O4 | 详情 | 详情 | |
| (VII) | 51678 | 2-(10H-phenoxazin-10-yl)ethyl methanesulfonate | C15H15NO4S | 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 |
合成路线2
该中间体在本合成路线中的序号：(X)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 |
合成路线3
该中间体在本合成路线中的序号：(X)Resolution of the racemic acid (X) was carried out via activation as the mixed anhydride (XVIII) upon treatment with pivaloyl chloride (XVII) and triethylamine. Anhydride (XVIII) was then condensed with (S)-2-phenylglycinol (XIX), producing a separable mixture of diastereomeric amides. Isolation of the desired (S,S)-isomer (XX) by silica gel chromatography, followed by amide hydrolysis under acidic conditions, furnished the target (S)-enantiomer.
| 【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 |
|---|---|---|---|---|---|---|
| (X) | 51681 | 2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propionic acid | C25H25NO5 | 详情 | 详情 | |
| (XVII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XVIII) | 51691 | 1,1-dimethylpropionic 1-ethoxy-2-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propionic anhydride | C30H33NO6 | 详情 | 详情 | |
| (XIX) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (XX) | 51692 | (2S)-2-ethoxy-N-[(1S)-2-hydroxy-1-phenylethyl]-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propanamide | C33H34N2O5 | 详情 | 详情 |