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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information