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【结 构 式】 
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【分子编号】43331 【品名】methyl 4-methyl-3-oxopentanoate 【CA登记号】42558-54-3 |
【 分 子 式 】C7H12O3 【 分 子 量 】144.17048 【元素组成】C 58.32% H 8.39% O 33.29% |
合成路线1
该中间体在本合成路线中的序号：(I)The hydrolysis of the ketoester (I) with NaOH gives the corresponding ketoacid (II), which is condensed with 4-nitrobenzaldehyde (III) by means of pyridine to yield the hydroxyketone (IV). The reaction of (IV) with acetic anhydride and pyridine affords the acetoxy compound (V), which is dehydrated by means of hot pyridine to provide the enone (VI). The condensation of (VI) with benzyl acetate (VII) by means of LDA gives 3-hydroxy-3-isopropyl-5-(4-nitrophenyl)-4-pentenoic acid benzyl ester (VIII), which is fully hydrogenated with H2 over Pd(OH)2 to yield the amino acid (IX). Finally, (IX) is treated with acetic anhydride to afford the target 5-(4-acetamidophenyl)-3-hydroxy-3-isopropylpentanoic acid intermediate (X).
| 【1】 Deering, C.F.; et al.; Application of the Schöpf method to optimization of the synthesis of 3-[2-(p-N-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid: Simultaneous reduction of three functional groups to maximine yield and throughput. Org Process Res Dev 2000, 4, 6, 596. |
| 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) | 43331 | methyl 4-methyl-3-oxopentanoate | 42558-54-3 | C7H12O3 | 详情 | 详情 |
| (II) | 50030 | 4-methyl-3-oxopentanoic acid | C6H10O3 | 详情 | 详情 | |
| (III) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (IV) | 50031 | 1-hydroxy-4-methyl-1-(4-nitrophenyl)-3-pentanone | C12H15NO4 | 详情 | 详情 | |
| (V) | 50032 | 4-methyl-1-(4-nitrophenyl)-3-oxopentyl acetate | C14H17NO5 | 详情 | 详情 | |
| (VI) | 50033 | (E)-4-methyl-1-(4-nitrophenyl)-1-penten-3-one | C12H13NO3 | 详情 | 详情 | |
| (VII) | 35457 | benzyl acetate | 140-11-4 | C9H10O2 | 详情 | 详情 |
| (VIII) | 50034 | benzyl (E)-3-hydroxy-3-isopropyl-5-(4-nitrophenyl)-4-pentenoate | C21H23NO5 | 详情 | 详情 | |
| (IX) | 50035 | 3-(4-aminophenethyl)-3-hydroxy-4-methylpentanoic acid | C14H21NO3 | 详情 | 详情 | |
| (X) | 50036 | 3-[4-(acetamido)phenethyl]-3-hydroxy-4-methylpentanoic acid | C16H23NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Catalytic hydrogenation of methyl isobutyrylacetate (I) in the presence of chiral ruthenium catalyst afforded the (S)-hydroxy ester (II). Subsequent alkylation of the lithium enolate of (II) with 3-bromo-2-methyl-1-propene (III) proceeded with diastereoselectivity, yielding (IV). The olefin double bond of (IV) was then hydrogenated over Pd/C to provide the saturated compound (V). After basic hydrolysis of the methyl ester group of (V), the resultant carboxylic acid (VI) was coupled to O-tetrahydropyranylhydroxylamine (VII) to furnish the tetrahydropyranyl-protected hydroxamate (VIII). Conversion of (VIII) into the corresponding mesylate, followed by cyclization under basic conditions, gave rise to the azetidinone (IX). Further azetidinone ring opening under conditions of basic hydrolysis generated the N-hydroxyaminoacid derivative (X). This was converted to the formamide (XI) upon treatment with formic acetic anhydride in pyridine.
| 【1】 Chan, J.H.; Bubacz, D.G.; Andersen, M.W.; McDougald, D.L.; Stanford, J.B.; Andrews, R.C.; Gaul, M.D.; Rabinowitz, M.H.; Musso, D.L.; Cowan, D.J.; Wiethe, R.W. (GlaxoSmithKline plc); Reverse hydroxamate derivs. as metalloprotease inhibitors. EP 1019386; JP 2001513767; WO 9838179 . |
| 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) | 43331 | methyl 4-methyl-3-oxopentanoate | 42558-54-3 | C7H12O3 | 详情 | 详情 |
| (II) | 52102 | methyl (3S)-3-hydroxy-4-methylpentanoate | C7H14O3 | 详情 | 详情 | |
| (III) | 40015 | 3-bromo-2-methyl-1-propene | 1458-98-6 | C4H7Br | 详情 | 详情 |
| (IV) | 52103 | methyl (2R)-2-[(1R)-1-hydroxy-2-methylpropyl]-4-methyl-4-pentenoate | C11H20O3 | 详情 | 详情 | |
| (V) | 52104 | methyl (2R,3R)-3-hydroxy-2-isobutyl-4-methylpentanoate | C11H22O3 | 详情 | 详情 | |
| (VI) | 52105 | (2R,3R)-3-hydroxy-2-isobutyl-4-methylpentanoic acid | C10H20O3 | 详情 | 详情 | |
| (VII) | 52106 | 2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine | C5H11NO2 | 详情 | 详情 | |
| (VIII) | 52107 | (2R,3R)-3-hydroxy-2-isobutyl-4-methyl-N-(tetrahydro-2H-pyran-2-yloxy)pentanamide | C15H29NO4 | 详情 | 详情 | |
| (IX) | 52108 | (3R,4S)-3-isobutyl-4-isopropyl-1-(tetrahydro-2H-pyran-2-yloxy)-2-azetidinone | C15H27NO3 | 详情 | 详情 | |
| (X) | 52109 | (2R,3S)-2-isobutyl-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)amino]pentanoic acid | C15H29NO4 | 详情 | 详情 | |
| (XI) | 52110 | (2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutyl-4-methylpentanoic acid | C16H29NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)2,6-Dichlorobenzaldehyde (I) was converted to oxime (II) and then chlorinated with N-chlorosuccinimide to afford the oximidoyl chloride (III). The cycloaddition reaction between ketoester (IV) and the nitrile oxide resulting from (III) in the presence of NaOMe gave rise to the isoxazole system (V). The ester group of (V) was then reduced to alcohol (VI) employing diisobutylaluminium hydride. Subsequent coupling of alcohol (VI) with 2-chloro-4-hydroxybenzaldehyde (VII) under Mitsunobu conditions provided ether (VIII). Phosphonate (X) was prepared by heating methyl 3-(bromomethyl)benzoate (IX) with triethyl phosphite at 185 C. Horner-Emmons condensation of aldehyde (VIII) with phosphonate (X) in the presence of NaH in THF furnished the stilbene derivative (XI). The methyl ester group of (XI) was finally hydrolyzed by means of LiOH in aqueous THF.
| 【1】 Lehmann, J.; Stimmel, J.B.; Blanchard, S.G.; Kliewer, S.A.; Willson, T.M.; Parks, D.J. (Glaxo Group Ltd.); Assays for ligands for nuclear receptors. WO 0037077 . |
| 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) | 27507 | 2,6-dichlorobenzaldehyde | 83-38-5 | C7H4Cl2O | 详情 | 详情 |
| (II) | 43329 | 2,6-dichlorobenzaldehyde oxime | C7H5Cl2NO | 详情 | 详情 | |
| (III) | 43330 | 2,6-dichloro-N-hydroxybenzenecarboximidoyl chloride | C7H4Cl3NO | 详情 | 详情 | |
| (IV) | 43331 | methyl 4-methyl-3-oxopentanoate | 42558-54-3 | C7H12O3 | 详情 | 详情 |
| (V) | 43332 | methyl 3-(2,6-dichlorophenyl)-5-isopropyl-4-isoxazolecarboxylate | C14H13Cl2NO3 | 详情 | 详情 | |
| (VI) | 43333 | [3-(2,6-dichlorophenyl)-5-isopropyl-4-isoxazolyl]methanol | C13H13Cl2NO2 | 详情 | 详情 | |
| (VII) | 43334 | 2-chloro-4-hydroxybenzaldehyde | C7H5ClO2 | 详情 | 详情 | |
| (VIII) | 43335 | 2-chloro-4-[[3-(2,6-dichlorophenyl)-5-isopropyl-4-isoxazolyl]methoxy]benzaldehyde | C20H16Cl3NO3 | 详情 | 详情 | |
| (IX) | 20392 | methyl 3-(bromomethyl)benzoate | 1129-28-8 | C9H9BrO2 | 详情 | 详情 |
| (X) | 43336 | methyl 3-[(diethoxyphosphoryl)methyl]benzoate | C13H19O5P | 详情 | 详情 | |
| (XI) | 43337 | methyl 3-[(E)-2-(2-chloro-4-[[3-(2,6-dichlorophenyl)-5-isopropyl-4-isoxazolyl]methoxy]phenyl)ethenyl]benzoate | C29H24Cl3NO4 | 详情 | 详情 |