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【结 构 式】 
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【分子编号】55124 【品名】ethyl (E,4S)-4-[[(2S)-2-amino-3,3-dimethylbutanoyl](methyl)amino]-2,5-dimethyl-2-hexenoate 【CA登记号】 |
【 分 子 式 】C17H32N2O3 【 分 子 量 】312.45276 【元素组成】C 65.35% H 10.32% N 8.97% O 15.36% |
合成路线1
该中间体在本合成路线中的序号：(XIX)N-Boc-N-Methyl-L-valine (XII) was condensed with N,O-dimethylhydroxylamine by means of PyBOP as the coupling reagent. The resultant Weinreb amide (XIII) was then reduced to aldehyde (XIV) using LiAlH4. Wittig condensation of the valinal derivative (XIV) with (carbethoxyethylidene)triphenylphosphorane provided the unsaturated amino ester (XV). The N-Boc protecting group of (XV) was subsequently removed by treatment with trifluoroacetic acid, giving (XVI). Coupling of amino ester (XVI) with N-Boc-tert-leucine (XVII) was carried out via formation of the mixed anhydride of (XVII) with pivaloyl chloride. The resultant N-Boc dipeptide (XVIII) was further deprotected with trifluoroacetic acid, yielding (XIX). Coupling of dipeptide (XIX) with the N-Boc amino acid (IX) provided tripeptide (XX). The title compound was then obtained by sequential deprotection of the ethyl ester and N-Boc groups of (XX) using LiOH and trifluoroacetic acid, respectively.
| 【1】 Roberge, M.; Andersen, R.; Piers, E.; Nieman, J.; Coleman, J. (University of British Columbia); Hemiasterlin analogs. WO 9932509 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 55118 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoic acid | C17H25NO4 | 详情 | 详情 | |
| (XII) | 27154 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylbutyric acid | 45170-31-8 | C11H21NO4 | 详情 | 详情 |
| (XIII) | 55119 | tert-butyl (1S)-1-{[methoxy(methyl)amino]carbonyl}-2-methylpropyl(methyl)carbamate | C13H26N2O4 | 详情 | 详情 | |
| (XIV) | 55120 | tert-butyl (1S)-1-formyl-2-methylpropyl(methyl)carbamate | C11H21NO3 | 详情 | 详情 | |
| (XV) | 55121 | ethyl (E,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-2,5-dimethyl-2-hexenoate | C16H29NO4 | 详情 | 详情 | |
| (XVI) | 55122 | ethyl (E,4S)-2,5-dimethyl-4-(methylamino)-2-hexenoate | C11H21NO2 | 详情 | 详情 | |
| (XVII) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (XVIII) | 55123 | ethyl (E,4S)-4-[{(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}(methyl)amino]-2,5-dimethyl-2-hexenoate | C22H40N2O5 | 详情 | 详情 | |
| (XIX) | 55124 | ethyl (E,4S)-4-[[(2S)-2-amino-3,3-dimethylbutanoyl](methyl)amino]-2,5-dimethyl-2-hexenoate | C17H32N2O3 | 详情 | 详情 | |
| (XX) | 55125 | ethyl (6S,9S,12S,13E)-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-6-(1-methyl-1-phenylethyl)-4,7,10-trioxo-3-oxa-5,8,11-triaza-13-pentadecen-15-oate | C34H55N3O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)An alternative synthetic method employed the racemic amino acid (XXIX). The phenylpyruvic acid precursor (XXVII) was prepared from benzaldehyde (XXI) by several procedures. Condensation of benzaldehyde (XXI) with hydantoin (XXII) yielded the benzylidene hydantoin (XXIV), which was converted to (XXVII) by basic hydrolysis. Alternatively, aldehyde (XXI) was condensed with N-acetyl glycine or with the phosphonoacetate reagent (XXIII) to produce (XXV) or (XXVI), respectively. Basic hydrolysis of either (XXV) or (XXVI) led to the desired phenylpyruvic acid (XXVII). Dialkylation of keto acid (XXVII) with iodomethane and NaOH furnished the dimethyl derivative (XXVIII). Then, reductive amination of (XXVIII) with methylamine yielded the racemic amino acid (XXIX). Coupling of amino acid (XXIX) with the intermediate dipeptide (XIX) gave rise to tripeptide (XXX) as an epimeric mixture. After chromatographic isolation of the desired isomer, basic hydrolysis of the ethyl ester provided the title compound.
| 【1】 Zask, A.; Cheung, K.; Birnberg, G.; et al.; Synthesis and biological activity of analogs of the antimicrotubule agent HTI-286. Proc Am Assoc Cancer Res 2002, 43, Abst 3653. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 55124 | ethyl (E,4S)-4-[[(2S)-2-amino-3,3-dimethylbutanoyl](methyl)amino]-2,5-dimethyl-2-hexenoate | C17H32N2O3 | 详情 | 详情 | |
| (XXI) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (XXII) | 32482 | 2,4-imidazolidinedione | 461-72-3 | C3H4N2O2 | 详情 | 详情 |
| (XXIII) | 55126 | methyl 2-(acetyloxy)-2-(diethoxyphosphoryl)acetate | C9H17O7P | 详情 | 详情 | |
| (XXIV) | 55127 | 5-[(Z)-phenylmethylidene]-2,4-imidazolidinedione | C10H8N2O2 | 详情 | 详情 | |
| (XXV) | 55128 | 2-methyl-4-[(Z)-phenylmethylidene]-1,3-oxazol-5-one | C11H9NO2 | 详情 | 详情 | |
| (XXVI) | 55129 | methyl (Z)-2-(acetyloxy)-3-phenyl-2-propenoate | C12H12O4 | 详情 | 详情 | |
| (XXVII) | 55130 | 2-Oxophenylpropionic acid; Alpha-keto-DL-phenylalanine; Benzylglyoxylic acid; Phenylpyruvic acid | 156-06-9 | C9H8O3 | 详情 | 详情 |
| (XXVIII) | 55131 | 3-methyl-2-oxo-3-phenylbutanoic acid | C11H12O3 | 详情 | 详情 | |
| (XXIX) | 55132 | N-methyl-3-phenylvaline | C12H17NO2 | 详情 | 详情 | |
| (XXX) | 55133 | ethyl (E,4S)-4-[((2S)-3,3-dimethyl-2-{[3-methyl-2-(methylamino)-3-phenylbutanoyl]amino}butanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate | C29H47N3O4 | 详情 | 详情 |