allyl (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoate -Drug Synthesis Database

【结构式】

【分子编号】18903

【品名】allyl (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoate

【CA登记号】

【分子式】C₁₉H₃₃NO₆

【分子量】371.47416

【元素组成】C 61.43% H 8.95% N 3.77% O 25.84%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VI)

Title compound can be prepared either by bacterial fermentation or by chemical synthesis. Thus, the compund was isolated from cultures of Nostoc sp. GSV 224, growing in the presence of 2,2-dimethyl-b-alanine. After lyophilization and extraction with CH3CN-CH2Cl2, the extract was subjected to several chromatographic purifications to provide the pure compound. Alternatively, 2,2-dimethyl-b-alanine tert-butyl ester (I) was deprotected with trifluoroacetic acid, and the resulting carboxylic acid (II) was treated with di tert-butyl oxalate (III) in the presence of NaOH to afford carbamate (IV). Subsequent coupling with allyl (S)-2-hydroxy-4-methylpentanoate (V) using DCC and DMAP gave ester (VI). The allyl ester was then cleaved by treatment with Pd(Ph3P)4 and morpholine in THF at r.t., and the resulting acid (VII) was coupled with compound (VIII) in the presence of DCC and DMAP to afford (IX). After deprotection of the trichloroethyl ester group by treatment with Zn in AcOH and subsequent cleavage of the N-Boc group with trifluoroacetic acid, the resulting amino acid compound (XI) was cyclized using pentafluorophenyl diphenyl phosphinate (FDPP) to furnish (XII). Finally, epoxidation with meta-chloroperbenzoic acid provided a mixture of diastereomeric epoxides that were separated by reverse phase HPLC.

参考文献中间体

合成目标

【1】 Shih, C.; Gossett, L.S.; Gruber, J.M.; Grossman, C.S.; Andis, S.L.; Schultz, R.M.; Worzalla, J.F.; Corbett, T.H.; Metz, J.T.; Synthesis and biological evaluation of novel cryptophycin analogs with modification in the beta-alanine region. Bioorg Med Chem Lett 1999, 9, 1, 69.
【2】 Moore, R.E.; Patel, V.F.; Ray, J.E.; Toth, J.E. (Eli Lilly and Company; University of Hawaii; Wayne State University); Pharmaceutical cpds.. EP 0850057; JP 2000501067; WO 9707798; WO 9708334 .
【3】 Shih, C. (Eli Lilly and Company; University of Hawaii; Wayne State University); Pharmaceutical cpds.. EP 0869786; JP 2000502351; WO 9723211 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	18898	tert-butyl 3-amino-2,2-dimethylpropanoate	C₉H₁₉NO₂	详情	详情
(II)	18899	2,2-dimethyl-beta-alanine	C₅H₁₁NO₂	详情	详情
(III)	18900	tert-butyl 2-(tert-butoxy)-2-oxoacetate	C₁₀H₁₈O₄	详情	详情
(IV)	18901	N-(tert-butoxycarbonyl)-2,2-dimethyl-beta-alanine	C₁₀H₁₉NO₄	详情	详情
(V)	18902	allyl (2S)-2-hydroxy-4-methylpentanoate	C₉H₁₆O₃	详情	详情
(VI)	18903	allyl (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoate	C₁₉H₃₃NO₆	详情	详情
(VII)	18904	(2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid	C₁₆H₂₉NO₆	详情	详情
(VIII)	18905	2,2,2-trichloroethyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-[[(2E,5S,6R,7E)-5-hydroxy-6-methyl-8-phenyl-2,7-octadienoyl]amino]propanoate	C₂₇H₂₉Cl₄NO₅	详情	详情
(IX)	18906	2,2,2-trichloroethyl (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oate	C₄₃H₅₆Cl₄N₂O₁₀	详情	详情
(X)	18907	(10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oic acid	C₄₁H₅₅ClN₂O₁₀	详情	详情
(XI)	18908	(2R)-2-[[(2E,5S,6R,7E)-5-([(2S)-2-[(3-amino-2,2-dimethylpropanoyl)oxy]-4-methylpentanoyl]oxy)-6-methyl-8-phenyl-2,7-octadienoyl]amino]-3-(3-chloro-4-methoxyphenyl)propionic acid	C₃₆H₄₇ClN₂O₈	详情	详情
(XII)	18909	(3S,10R,16S)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone	C₃₆H₄₅ClN₂O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Synthesis of intermediate 2(S)-[3-(tert-butoxycarbonylamino)-2,2-dimethylpropionyloxy]-4-methylpentanoic acid (VIII): The reaction of 3-amino-2,2-dimethyl-1-propanol (I) with Boc2 and Et3N in methanol gives the carbamate (II), which is oxidized with NaIO4 in CCl4/acetonitrile/water yielding 3-(tert-butoxycarbonylamino)-2,2-dimethylpropionic acid (III). The esterification of 2(S)-hydroxy-4-methylpentanoic acid (IV) with allyl bromide (V), NaHCO3 and tetrabutylammonium chloride in dichloromethane/water affords the corresponding allyl ester (VI). The esterification of hydroxyester (VI) with amino acid (II) by means of DCC and DMAP in dichloromethane provides the corresponding diester (VII), which is finally treated with Pd(PPh3)4 and morpholine in THF to furnish the intermediate 2(S)-[3-(tert-butoxycarbonylamino)-2,2-dimethylpropionyloxy]-4-methylpentanoic acid (VIII).

参考文献中间体

合成目标

【1】 WO 9640184 .

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)	42783	3-amino-2,2-dimethyl-1-propanol	26734-09-8	C₅H₁₃NO	详情	详情
(II)	42784	tert-butyl 3-hydroxy-2,2-dimethylpropylcarbamate		C₁₀H₂₁NO₃	详情	详情
(III)	18901	N-(tert-butoxycarbonyl)-2,2-dimethyl-beta-alanine		C₁₀H₁₉NO₄	详情	详情
(IV)	42785	(2S)-2-hydroxy-4-methylpentanoic acid	13748-90-8	C₆H₁₂O₃	详情	详情
(V)	11720	4-Bromo-1-butene	5162-44-7	C₄H₇Br	详情	详情
(VI)	18902	allyl (2S)-2-hydroxy-4-methylpentanoate		C₉H₁₆O₃	详情	详情
(VII)	18903	allyl (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoate		C₁₉H₃₃NO₆	详情	详情
(VIII)	18904	(2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid		C₁₆H₂₉NO₆	详情	详情

Extended Information