(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoic acid -Drug Synthesis Database

【结构式】

【分子编号】50772

【品名】(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoic acid

【CA登记号】

【分子式】C₁₅H₂₁NO₄

【分子量】279.33608

【元素组成】C 64.5% H 7.58% N 5.01% O 22.91%

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：(XXXIV)

Protection of ethyl lactate (XXX) with tert-butyldimethylsilyl chloride in DMF in the presence of imidazole provides derivative (XXXI), which is then converted into dipeptide (XXXII) by first hydrolysis with LiOH in THF/H2O followed by coupling with L-proline methyl ester (X) by means of DCC, HOBt and NMM. Next, hydrolysis of the methyl ester of (XXXII) with LiOH in THF/H2O yields carboxylic acid (XXXIII). Esterification of Z-D-N-Me-Leu (XXXIV) with 2-(trimethylsilyl)ethanol (XXXV) by means of EDCI, DMAP and Et3N in DMF furnishes leucine derivative (XXXVI), whose Z protecting group is removed by hydrogenation over Pd/C in MeOH/AcOEt to afford secondary amine (XXXVII). Coupling of carboxylic acid (XXXIII) with amine (XXXVII) is then performed by means of BOPCl, Et3N. Treatment with tetrabutylammonium fluoride in DMF allows protecting group removal to provide carboxylic acid derivative (XXXVIII), which is then attached to macrocycle (XXIX) by means of BOP and NMM in CH2Cl2 to furnish the target didemnin.

参考文献中间体

合成目标

【1】 Li, W.-R.; et al.; Total synthesis and structural investigations of didemnins A, B, and C. J Am Chem Soc 1990, 112, 21, 7659.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	29552	methyl (2S)-2-pyrrolidinecarboxylate	2133-40-6	C₆H₁₁NO₂	详情	详情
(XXIX)	50769	ethyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoate		C₁₁H₂₄O₃Si	详情	详情
(XXX)	16659	ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate	687-47-8	C₅H₁₀O₃	详情	详情
(XXXI)	50769	ethyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoate		C₁₁H₂₄O₃Si	详情	详情
(XXXII)	50770	methyl (2S)-1-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylate		C₁₅H₂₉NO₄Si	详情	详情
(XXXIII)	50771	(2S)-1-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylic acid		C₁₄H₂₇NO₄Si	详情	详情
(XXXIV)	50772	(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoic acid		C₁₅H₂₁NO₄	详情	详情
(XXXV)	20323	2-(trimethylsilyl)-1-ethanol	2916-68-9	C₅H₁₄OSi	详情	详情
(XXXVI)	50773	2-(trimethylsilyl)ethyl (2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoate		C₂₀H₃₃NO₄Si	详情	详情
(XXXVII)	50774	2-(trimethylsilyl)ethyl (2R)-4-methyl-2-(methylamino)pentanoate		C₁₂H₂₇NO₂Si	详情	详情
(XXXVIII)	37840	(2R)-2-[([(2S)-1-[(2S)-2-hydroxypropanoyl]pyrrolidinyl]carbonyl)(methyl)amino]-4-methylpentanoic acid		C₁₅H₂₆N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Coupling of benzyloxy isovalery propionic acid (Bzl-Hip-OH) (I) with leucine trimethylsilylethyl ester (II) by means of HOBt and DCC followed by hydrogenation over Pd/C in isopropanol for benzyl protecting group removal provides dipeptide (III), which is then converted into compound (V) by first coupling to Boc-Sta(TBDMS)-OH (IV) by means of DMAP and DCC followed by removal of the TMSe group by means of TBAF. Coupling between Z-D-N-MeLeu-OH (VI) and H-Thr-OTMSe (VII) by means of N-hydroxysuccinimide (NHS) and EDC yields protected dipeptide (VIII), which is then condensed with dipeptide (IX) by means of DMAP and DCC and then treated with HCl in EtOAc for Boc removal to afford tetrapeptide (X) (in turn, dipeptide (IX) can be obtained by coupling between Boc-Pro-OH (XI) and Me2Tyr-ONb (XII) by means of EDC followed by p-nitrobenzyl removal by hydrogenation over Pd/C in HOAc). Coupling of tetrapeptide (X) with compound (V) by means of EDC, HOBt leads to formation of linear peptide (XIII), which is partially deprotected by treatment with TBAF and TFA and then cyclized by means of HOBt, EDC and NMM, providing macrolide (XIV).

参考文献中间体

合成目标

【1】 Rinehart, K.L.; et al.; Total synthesis of didemnins A, B, and C. J Am Chem Soc 1987, 109, 22, 6846.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	50799	(2S,4S)-4-(benzyloxy)-2,5-dimethyl-3-oxohexanoic acid	C₁₅H₂₀O₄	详情	详情
(II)	50800	2-(trimethylsilyl)ethyl (2S)-2-amino-4-methylpentanoate	C₁₁H₂₅NO₂Si	详情	详情
(III)	50801	2-(trimethylsilyl)ethyl (2S)-2-[[(2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino]-4-methylpentanoate	C₁₉H₃₇NO₅Si	详情	详情
(IV)	50802	(3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-methylheptanoic acid	C₁₉H₃₉NO₅Si	详情	详情
(V)	50803	(6R,7S,11S,13S,16S)-7-[[tert-butyl(dimethyl)silyl]oxy]-16-isobutyl-11-isopropyl-2,2,13-trimethyl-6-[(1S)-1-methylpropyl]-4,9,12,14-tetraoxo-3,10-dioxa-5,15-diazaheptadecan-17-oic acid	C₃₃H₆₂N₂O₉Si	详情	详情
(VI)	50772	(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoic acid	C₁₅H₂₁NO₄	详情	详情
(VII)	50804	2-(trimethylsilyl)ethyl (2S,3R)-2-amino-3-hydroxybutanoate	C₉H₂₁NO₃Si	详情	详情
(VIII)	50805	2-(trimethylsilyl)ethyl (2S,3R)-2-([(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-3-hydroxybutanoate	C₂₄H₄₀N₂O₆Si	详情	详情
(IX)	50806	(2S)-2-[[[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid	C₂₁H₃₀N₂O₆	详情	详情
(X)	50807	2-(trimethylsilyl)ethyl (2S,3R)-2-([(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-3-[((2S)-3-(4-methoxyphenyl)-2-[methyl[(2S)pyrrolidinylcarbonyl]amino]propanoyl)oxy]butanoate	C₄₀H₆₀N₄O₉Si	详情	详情
(XI)	16734	(2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid	C₁₀H₁₇NO₄	详情	详情
(XII)	50808		C₁₁H₁₄NNbO₃	详情	详情
(XIII)	50809	2-(trimethylsilyl)ethyl (2S,3R)-2-([(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-3-[[(2S)-2-[[((2S)-1-[(2S,5S,7S,11S,12R)-11-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-7-isopropyl-5,16,16-trimethyl-12-[(1S)-1-methylpropyl]-4	C₇₃H₁₂₀N₆O₁₇Si₂	详情	详情
(XIV)	50810	benzyl (1R)-1-[([(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin	C₅₇H₈₄N₆O₁₄	详情	详情

Extended Information