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【结 构 式】 
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【分子编号】46786 【品名】3,5-dimethylphenol 【CA登记号】108-68-9 |
【 分 子 式 】C8H10O 【 分 子 量 】122.1668 【元素组成】C 78.65% H 8.25% O 13.1% |
合成路线1
该中间体在本合成路线中的序号：(I)Coupling of 2,5-dimethylphenol (I) with methyl 3,3-dimethylacrylate (II) by means of methanesulfonic acid yields dihydrocoumarin (III), which is reduced with LiAlH4 in THF to provide alcohol (IV). Selective O-protection at the primary hydroxy group of (IV) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and Et3N in dichloromethane affords compound (V), which is then coupled with Boc-Ala-OH (VI) by means of EDC and DMAP in dichloromethane to give ester (VII). O-Deprotection of (VII) with HOAc in THF/H2O furnishes alcohol (VIII), which is then oxidized by means of pyridinium chlorochromate (PCC) in dichloromethane, giving aldehyde (IX). Compound (IX) is further oxidized with NaClO2 and sodium sulfite (Na2CO3) in H2O and NaH2PO4 in acetonitrile to yield propionic acid (X), whose Boc group is removed by treatment with TFA in dichloromethane, furnishing hydrochloride (XI). Coupling of (XI) with PEG thiazolidinethione (T-PEG) (XII) (1) by means of DIEA in dichloromethane gives PEG-alaninyl derivative (XIII), which is finally condensed with daunorubicin hydrochloride (XIV) by means of EDC · HCl, HOBt and NMM in dichloromethane to afford the target product.
| 【1】 Greenwald, R.B.; et al.; PEG thiazolidine-2-thione, a novel reagent for facile protein modification: Conjugation of bovine hemoglobin. Bioconjugate Chem 1996, 7, 6, 638. |
| 【2】 Choe, Y.H.; Shum, K.; Conover, C.D.; Greenwald, R.B.; Wu, D.; Royzen, M.; Drug delivery systems based on trimethyl lock lactonization: Poly(ethylene glycol) prodrugs of amino-containing compounds. J Med Chem 2000, 43, 3, 475. |
| 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) | 46786 | 3,5-dimethylphenol | 108-68-9 | C8H10O | 详情 | 详情 |
| (II) | 24113 | methyl 3-methyl-2-butenoate; Methyl 3,3-dimethylacrylate | 924-50-5 | C6H10O2 | 详情 | 详情 |
| (III) | 46787 | 4,4,5,7-tetramethyl-2-chromanone | C13H16O2 | 详情 | 详情 | |
| (IV) | 46788 | 2-(3-hydroxy-1,1-dimethylpropyl)-3,5-dimethylphenol | C13H20O2 | 详情 | 详情 | |
| (V) | 46789 | 2-(3-[[tert-butyl(dimethyl)silyl]oxy]-1,1-dimethylpropyl)-3,5-dimethylphenol | C19H34O2Si | 详情 | 详情 | |
| (VI) | 26450 | Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid | 15761-38-3 | C8H15NO4 | 详情 | 详情 |
| (VII) | 46790 | 2-(3-[[tert-butyl(dimethyl)silyl]oxy]-1,1-dimethylpropyl)-3,5-dimethylphenyl (2S)-2-[(tert-butoxycarbonyl)amino]propanoate | C27H47NO5Si | 详情 | 详情 | |
| (VIII) | 46791 | 2-(3-hydroxy-1,1-dimethylpropyl)-3,5-dimethylphenyl (2S)-2-[(tert-butoxycarbonyl)amino]propanoate | C21H33NO5 | 详情 | 详情 | |
| (IX) | 46792 | 2-(1,1-dimethyl-3-oxopropyl)-3,5-dimethylphenyl (2S)-2-[(tert-butoxycarbonyl)amino]propanoate | C21H31NO5 | 详情 | 详情 | |
| (X) | 46793 | 3-[2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]oxy)-4,6-dimethylphenyl]-3-methylbutyric acid | C21H31NO6 | 详情 | 详情 | |
| (XI) | 46794 | 3-(2-[[(2S)-2-aminopropanoyl]oxy]-4,6-dimethylphenyl)-3-methylbutyric acid | C16H23NO4 | 详情 | 详情 | |
| (XII) | 46795 | 2-(2-methoxyethoxy)-1-(2-thioxo-1,3-thiazolidin-3-yl)-1-ethanone | C8H13NO3S2 | 详情 | 详情 | |
| (XIII) | 46796 | 3-[2-[((2S)-2-[[2-(2-methoxyethoxy)acetyl]amino]propanoyl)oxy]-4,6-dimethylphenyl]-3-methylbutyric acid | C21H31NO7 | 详情 | 详情 | |
| (XIV) | 18598 | 2-methyl-8-quinolinol | 826-81-3 | C10H9NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)3,5-Dimethylphenol (I) was alkylated with ethyl 4-bromobutyrate (II) to provide the (dimethylphenoxy)butyrate ester (III), which was hydrolyzed under basic conditions to yield acid (IV). This was sulfonated with chlorosulfonic acid, and the resultant sulfonyl chloride (V) was condensed with Boc-diaminopropanoic acid (VI) to afford sulfonamide (VII). Coupling of (VII) with mono-benzyloxycarbonyl ethylenediamine (VIII) furnished amide (IX). Then, acid cleavage of the Boc protecting group of (IX) provided amine (X).
| 【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeles with in-111 for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 88. |
| 【2】 Rajopadhye, M.; Harris, T.D.; Cheesman, E.H. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. WO 0035488 . |
| 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) | 46786 | 3,5-dimethylphenol | 108-68-9 | C8H10O | 详情 | 详情 |
| (II) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (III) | 50998 | ethyl 4-(3,5-dimethylphenoxy)butanoate | C14H20O3 | 详情 | 详情 | |
| (IV) | 50999 | 4-(3,5-dimethylphenoxy)butyric acid | C12H16O3 | 详情 | 详情 | |
| (V) | 51000 | 4-[4-(chlorosulfonyl)-3,5-dimethylphenoxy]butyric acid | C12H15ClO5S | 详情 | 详情 | |
| (VI) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (VII) | 51001 | 4-(4-[[((1S)-1-[[(tert-butoxycarbonyl)amino]methyl]-2-methoxy-2-oxoethyl)amino]sulfonyl]-3,5-dimethylphenoxy)butyric acid | C21H32N2O9S | 详情 | 详情 | |
| (VIII) | 51002 | benzyl 2-aminoethylcarbamate | C10H14N2O2 | 详情 | 详情 | |
| (IX) | 51003 | methyl (2S)-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate | C31H44N4O10S | 详情 | 详情 | |
| (X) | 51004 | methyl (2S)-3-amino-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]propanoate | C26H36N4O8S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The reductocondensation of N-Boc-piperidin-4-one (I) with 3,4-dichloroaniline (II) by means of NaHB(OAc)3 in dichloroethane gives the secondary amine (III), which is acylated with chloroacetyl chloride (IV) by means of K2CO3 in dichloromethane to yield the chloroacetamide (V). The reaction of (V) with 3,5-dimethylphenol (VI) by means of Cs2CO3 in acetonitrile affords the aryl ether (VII), which is finally Boc deprotected with TFA in dichloromethane to provide the title trisubstituted acetamide.
| 【1】 Pirlot, N.; Balançon, L.; Berton, O.; Genicot, C.; Lamberty, Y.; Quéré, L.; Pasau, P.; Lallemand, B.; Talaga, P.; Ryckmans, T.; First dual NK1 antagonists-serotonin reuptake inhibitors: Synthesis and SAR of a new class of potential antidepressants. Bioorg Med Chem Lett 2002, 12, 2, 261. |
| 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) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (II) | 23629 | 3,4-dichloroaniline | 95-76-1 | C6H5Cl2N | 详情 | 详情 |
| (III) | 54455 | tert-butyl 4-(3,4-dichloroanilino)-1-piperidinecarboxylate | C16H22Cl2N2O2 | 详情 | 详情 | |
| (IV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (V) | 54456 | tert-butyl 4-[3,4-dichloro(2-chloroacetyl)anilino]-1-piperidinecarboxylate | C18H23Cl3N2O3 | 详情 | 详情 | |
| (VI) | 46786 | 3,5-dimethylphenol | 108-68-9 | C8H10O | 详情 | 详情 |
| (VII) | 54457 | tert-butyl 4-{3,4-dichloro[2-(3,5-dimethylphenoxy)acetyl]anilino}-1-piperidinecarboxylate | C26H32Cl2N2O4 | 详情 | 详情 |