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【结 构 式】 
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【分子编号】35086 【品名】1-benzyl 4-(tert-butyl) (2R,3S)-2-isobutyl-3-(3-[[(4-nitrophenoxy)carbonyl]oxy]propyl)butanedioate 【CA登记号】 |
【 分 子 式 】C29H37NO9 【 分 子 量 】543.61412 【元素组成】C 64.07% H 6.86% N 2.58% O 26.49% |
合成路线1
该中间体在本合成路线中的序号：(V)Alkylation of diethyl malonate (II) with 5-(4-chlorophenyl)pentyl bromide (I) gives diethyl 5-(4-chlorophenyl)pentyl malonate (III). Intermediate (III) is hydrolyzed to the monoester (IV), followed by condensation with paraformaldehyde in pyridine/piperidine to yield ethyl 7-(4-chlorophenyl)-2-methyleneheptanoate (V), which is oxidized with m-chloroperbenzoic acid. Alternatively, intermediate (IV) can be prepared by condensation of 4-chlorocinnamaldehyde (VI) with diethyl ethylidenemalonate (VII) to yield intermediate (VIII) and subsequent hydrogenation.
| 【1】 Eistetter, K.; Wolf, H.P.O.; Synthesis and hypoglycaemic activity of phenylalkyloxirane carboxylic acid derivatives. J Med Chem 1982, 25, 22, 109-113. |
| 【2】 Eistetter, K.; Rapp, E. (Byk Gulden Lomberg Chemische Fabrik GmbH); Substd. oxiranecarboxylic acids, their use and medicaments containing them. US 4324796 . |
| 【3】 Kohl, B.; Eistetter, K.; Amschler, H.; Ludwig, G.; Wolf, H.P.O. (Byk Gulden Lomberg Chemische Fabrik GmbH); Phenylalkyloxirane carboxylic acids, preparation and therapeutical use. EP 0071175 . |
| 【4】 Wolf, H.P.O.; Eistetter, K.; POCA. Drugs Fut 1983, 8, 5, 428. |
| 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) | 36082 | 1-(5-bromopentyl)-4-chlorobenzene | C11H14BrCl | 详情 | 详情 | |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (III) | 36083 | diethyl 2-[5-(4-chlorophenyl)pentyl]malonate | C18H25ClO4 | 详情 | 详情 | |
| (IV) | 36085 | 7-(4-chlorophenyl)-2-(ethoxycarbonyl)heptanoic acid | C16H21ClO4 | 详情 | 详情 | |
| (V) | 35086 | 1-benzyl 4-(tert-butyl) (2R,3S)-2-isobutyl-3-(3-[[(4-nitrophenoxy)carbonyl]oxy]propyl)butanedioate | C29H37NO9 | 详情 | 详情 | |
| (VI) | 36087 | (E)-3-(4-chlorophenyl)-2-propenal | C9H7ClO | 详情 | 详情 | |
| (VII) | 36088 | (E)-2-(ethoxycarbonyl)-2-butenoic acid | C7H10O4 | 详情 | 详情 | |
| (VIII) | 36084 | (2E,4E,6E)-7-(4-chlorophenyl)-2-(ethoxycarbonyl)-2,4,6-heptatrienoic acid | C16H15ClO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Condensation of 4-methylpentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone using n-BuLi afforded the N-acyloxazolidinone (III). Asymmetric alkylation of (III) with tert-butyl bromoacetate and LDA gave (IV), and subsequent removal of the chiral auxiliary by hydrolysis with lithium peroxide yielded (R)-2-isobutylsuccinic acid mono tert-butyl ester (V). This was further alkylated with allyl bromide (VI) and LDA to provide the (R,R)-2,3-disubstituted succinate (VII). Epimerization of (VII) to the required (2R,3S)-isomer (VIII) was accomplished by treatment with LDA and Et2AlCl. Benzyl ester (IX) was then prepared by reaction of (VIII) with benzyl bromide and DBU. Hydroboration of the olefinic double bond of (IX) by means of 9-borabicyclononane, followed by oxidative treatment with H2O2 gave rise to the primary alcohol (X). This was converted to carbonate (XI) upon reaction with p-nitrophenyl chloroformate and N-methylmorpholine (NMM). Coupling of (XI) with lysine derivative (XII) then yielded carbamate (XIII).
| 【1】 Xue, C.-B.; Cherney, R.J.; DeCicco, C.P.; Degrado, W.F.; He, X.; Hodge, C.N.; Jacobson, I.C.; Magolda, R.L.; Arner, E.C.; Duan, J.; Nelson, D.J. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0863885; JP 2000502050; WO 9718207 . |
| 【2】 Nelson, D.; Magolda, R.L.; Jacobson, I.C.; He, X.; Arner, E.; Cherney, R.J.; Duan, J.; Xue, C.-B.; Decicco, C.P.; Degrado, W.F. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0981521; WO 9851665 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 | |
| 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 | |
| (I) | 25390 | 4-methylpentanoyl chloride | 38136-29-7 | C6H11ClO | 详情 | 详情 |
| (II) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (III) | 25391 | (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (IV) | 25392 | tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate | C22H31NO5 | 详情 | 详情 | |
| (V) | 25393 | (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid | C12H22O4 | 详情 | 详情 | |
| (VI) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VII) | 35082 | (2R,3R)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid | C15H26O4 | 详情 | 详情 | |
| (VIII) | 35083 | (2R,3S)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid | C15H26O4 | 详情 | 详情 | |
| (IX) | 35084 | 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-isobutylbutanedioate | C22H32O4 | 详情 | 详情 | |
| (X) | 35085 | 4-benzyl 1-(tert-butyl) (2S,3R)-2-(3-hydroxypropyl)-3-isobutylbutanedioate | C22H34O5 | 详情 | 详情 | |
| (XI) | 35086 | 1-benzyl 4-(tert-butyl) (2R,3S)-2-isobutyl-3-(3-[[(4-nitrophenoxy)carbonyl]oxy]propyl)butanedioate | C29H37NO9 | 详情 | 详情 | |
| (XII) | 35087 | methyl (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoate | C15H22N2O4 | 详情 | 详情 | |
| (XIII) | 35088 | 17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-19-methyl-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaicosane-5,16,17-tricarboxylate | C38H54N2O10 | 详情 | 详情 |