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【结 构 式】 
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【分子编号】22692 【品名】dimethyl 3-oxopentanedioate 【CA登记号】1830-54-2 |
【 分 子 式 】C7H10O5 【 分 子 量 】174.1534 【元素组成】C 48.28% H 5.79% O 45.93% |
合成路线1
该中间体在本合成路线中的序号：(X)The condensation of dimethylacetone-1,3-dicarboxylate (X) with ethanolamine (XI) yields methyl 3-(methoxycarbonylmethyl)-3-(2-hydroxyethylamino)acrylate (XII), which is cyclized with bromoacetaldehyde diethylacetal (XIII) affording methyl 1-(2-hydroxyethyl)-3-methoxycarbonylpyrrol-2-acetate (XIV). Acylation of (XIV) with methanesulfonyl chloride (XV) and triethylamine in CH2Cl2 yields the corresponding mesylate (XVI), which by treatment with methyl iodide in refluxing acetonitrile is converted into methyl 1-(2-iodoethyl)-3-methoxycarbonylpyrrole-2-acetate (XVII). The cyclization of (XVII) with NaH in DMF yields dimethyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (XVIII), which is hydrolyzed with KOH in refluxing methanol - water to the corresponding diacid (XIX). Partial esterification of (XIX) with isopropanol and HCl gives isopropyl 1,2-dihydro-3H-7-carboxypyrrolo[1,2-a]pyrrole-1-carboxylate (XX), which is decarboxylated by heating at 270 C affording isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXI). Benzoylation of (XXI) with N,N-dimethylbenzamide (XXII) and POCl3 in refluxing CH2Cl2 yields isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXIII), which is finally hydrolyzed with K2CO3 or NaOH in methanol - water.
| 【1】 Blancafort, P.; Serradell, M.N.; Hillier, K.; Castaner, J.; BPPC. Drugs Fut 1981, 6, 11, 669. |
| 【2】 Muchowski, J.M.; Kluge, A.F. (Roche Bioscience); 1,2-Dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids derivatives and process for the production thereof. DE 2731678; ES 460706; ES 470214; FR 2358406; FR 2375234; GB 1554075 . |
| 【3】 Arrigoni-Martelli, E.; Castaner, J.; Blancafort, P.; Serradell, M.N.; RS-37,619. Drugs Fut 1983, 8, 10, 871. |
| 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) | 22692 | dimethyl 3-oxopentanedioate | 1830-54-2 | C7H10O5 | 详情 | 详情 |
| (XI) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (XII) | 30764 | dimethyl (E)-3-[(2-hydroxyethyl)amino]-2-pentenedioate | C9H15NO5 | 详情 | 详情 | |
| (XIII) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (XIV) | 30765 | methyl 1-(2-hydroxyethyl)-2-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate | C11H15NO5 | 详情 | 详情 | |
| (XVI) | 30766 | methyl 2-(2-methoxy-2-oxoethyl)-1-(2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl)-1H-pyrrole-3-carboxylate | C14H21NO5S | 详情 | 详情 | |
| (XVII) | 30767 | methyl 1-(2-iodoethyl)-2-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate | C11H14INO4 | 详情 | 详情 | |
| (XVIII) | 30768 | dimethyl 2,3-dihydro-1H-pyrrolizine-1,7-dicarboxylate | C11H13NO4 | 详情 | 详情 | |
| (XIX) | 30769 | 2,3-dihydro-1H-pyrrolizine-1,7-dicarboxylic acid | C9H9NO4 | 详情 | 详情 | |
| (XX) | 30770 | 1-(isopropoxycarbonyl)-2,3-dihydro-1H-pyrrolizine-7-carboxylic acid | C12H15NO4 | 详情 | 详情 | |
| (XXI) | 30771 | isopropyl 2,3-dihydro-1H-pyrrolizine-1-carboxylate | C11H15NO2 | 详情 | 详情 | |
| (XXII) | 30757 | N,N-dimethylbenzamide | 611-74-5 | C9H11NO | 详情 | 详情 |
| (XXIII) | 30772 | isopropyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate | C18H19NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Synthesis of intermediate (I): 1a) Dimethyl acetonedicarboxylate (IV) is treated with MgCl2 and triethylamine, giving the corresponding magnesium complex (V), which by cyclocondensation with chloroacetyl chloride and thiourea yields methyl 2-(2-aminothiazol-4-yl)-3-hydroxy-4-(methoxycarbonyl)-2-butenoate (VI). The reduction of (VI) with NaBH4 affords dimethyl 2-(2-aminothiazol-4-yl)-3-hydroxyglutarate (VII), which by successive treatments with benzyloxycarbonyl chloride (to protect the amino group), and with mesyl chloride - triethylamine (to dehydrate the OH group) is converted to methyl 2-[2 (benzyloxycarbonylamino)thiazol-4-y]-4-(methoxycarbonyl)-2-butenoate (VIII). The hydrolysis of (VIII) with aqueous NaOH in toluene gives the corresponding diacid (IX), which is selectively esterified with benzyl alcohol in acidic medium yielding (I). 1b) The reaction of methyl 2-(2-aminothiazol-4-yl)acetate (X) with beozyloxycarbonyl chloride and NaHCO3 gives the protected compound (XI), which is condensed with methyl 3-methoxyacrylate (XII) by means of sodium methoxide in DMF to yield dimethyl ester (VIII), already obtained.
| 【1】 Yoshioka, M.; Synthetic studies related to oral beta-lactam antibiotics. Pure Appl Chem 1987, 59, 8, 1041. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 | |
| 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 | |
| (I) | 22689 | (Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid | C23H20N2O6S | 详情 | 详情 | |
| (IV) | 22692 | dimethyl 3-oxopentanedioate | 1830-54-2 | C7H10O5 | 详情 | 详情 |
| (V) | 22693 | Bis(3-Hydroxy-2-pentenoic acid dimethyl ester) magnesium salt | C14H18MgO10 | 详情 | 详情 | |
| (VI) | 22694 | dimethyl (E)-2-(2-amino-1,3-thiazol-4-yl)-3-hydroxy-2-pentenedioate | C10H12N2O5S | 详情 | 详情 | |
| (VII) | 22695 | dimethyl 2-(2-amino-1,3-thiazol-4-yl)-3-hydroxypentanedioate | C10H14N2O5S | 详情 | 详情 | |
| (VIII) | 22696 | dimethyl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioate | C18H18N2O6S | 详情 | 详情 | |
| (IX) | 22697 | (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioic acid | C16H14N2O6S | 详情 | 详情 | |
| (X) | 22698 | methyl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)acetate | 64987-16-2 | C6H8N2O2S | 详情 | 详情 |
| (XI) | 22699 | methyl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)acetate | C14H14N2O4S | 详情 | 详情 | |
| (XII) | 22700 | methyl (E)-3-methoxy-2-propenoate | 34846-90-7 | C5H8O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Mannich reaction of dimethyl 3-oxoglutarate (I) with methylamine and two equivalents of 2-pyridinecarboxaldehyde (II) gave piperidinone (III). Then, a further Mannich reaction with formaldehyde and methylamine furnished the bicyclic compound.
| 【1】 Kogel, B.; et al.; HZ2, a selective kappa-opioid agonist. CNS Drug Rev 1998, 4, 1, 54. |
| 【2】 Samhammer, A.; et al.; Synthesis, stereochemistry and analgesic activity of 3,7-diazabicyclo[3.3.1]nonan-9-ones and 1,3-diazaadamantan-6-ones. Arch Pharm 1989, 322, 9, 551. |
| 【3】 Haller, R.; Unholzer, H.; Stereochemistry of 3-oxa-7-aza- and 3,7-diazabicyclo[3.3.1]nonan-9-ones. Arch Pharm 1972, 305, 11, 855. |
合成路线4
该中间体在本合成路线中的序号：(I)Aldol condensation between dimethyl 1,3-acetonedicarboxylate (I) and 3,5-heptanedione (II) produced dimethyl 4,6-diethyl-2-hydroxy-1,3-benzenedicarboxylate (III). After conversion of phenol (III) to the corresponding aryl triflate (IV), Suzuki coupling with 4-fluorobenzeneboronic acid (V) yielded the biphenyl derivative (VI). The diisopropyl compound (VII) was then obtained by methylation of (VI) at the benzylic position using iodomethane and LDA. Partial reduction of diester (VII) with Red-Al?gave rise to the hydroxy ester (VIII), which was further oxidized to aldehyde (IX) by treatment with pyridinium chlorochromate. Wittig reaction of aldehyde (IX) with ethyl triphenylphosphonium bromide furnished the propenyl compound (X)
| 【2】 Schmidt, G.; Wolanin, D.J.; Bischoff, H.; Schoen, W.R.; Angerbauer, R.; Schmidt, D.; Kramss, R.H.; Wohlfeil, S.; Brandes, A.; Muller-Gliemann, M.; Lease, T.G.; Ladouceur, G.H.; Osterhout, M.H.; Hertzog, D.L.; Cook, J.H. II (Bayer AG; Bayer Corp.); Substd. pyridines and biphenyls as anti-hypercholesterinemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents. WO 9804528 . |
| 【1】 Wolanin, D.J.; Schoen, W.R.; Kramss, R.H.; Lease, T.G.; Ladouceur, G.H.; Osterhout, M.H.; Hertzog, D.L.; Cook, J.H. II (Bayer AG; Bayer Corp.); Substd. biphenyls. US 6218431 . |
| 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) | 22692 | dimethyl 3-oxopentanedioate | 1830-54-2 | C7H10O5 | 详情 | 详情 |
| (II) | 39689 | 3,5-heptanedione | 7424-54-6 | C7H12O2 | 详情 | 详情 |
| (III) | 60521 | dimethyl 4,6-diethyl-2-hydroxyisophthalate | C14H18O5 | 详情 | 详情 | |
| (IV) | 60522 | dimethyl 4,6-diethyl-2-{[(trifluoromethyl)sulfonyl]oxy}isophthalate | C15H17F3O7S | 详情 | 详情 | |
| (V) | 38403 | 4-fluorophenylboronic acid | 1765-93-1 | C6H6BFO2 | 详情 | 详情 |
| (VI) | 60523 | dimethyl 3,5-diethyl-4'-fluoro[1,1'-biphenyl]-2,6-dicarboxylate | C20H21FO4 | 详情 | 详情 | |
| (VII) | 60524 | dimethyl 4'-fluoro-3,5-diisopropyl[1,1'-biphenyl]-2,6-dicarboxylate | C22H25FO4 | 详情 | 详情 | |
| (VIII) | 60525 | methyl 4'-fluoro-6-(hydroxymethyl)-3,5-diisopropyl[1,1'-biphenyl]-2-carboxylate | C21H25FO3 | 详情 | 详情 | |
| (IX) | 60526 | methyl 4'-fluoro-6-formyl-3,5-diisopropyl[1,1'-biphenyl]-2-carboxylate | C21H23FO3 | 详情 | 详情 | |
| (X) | 60527 | methyl 4'-fluoro-3,5-diisopropyl-6-[(E)-1-propenyl][1,1'-biphenyl]-2-carboxylate | C23H27FO2 | 详情 | 详情 |