(2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid -Drug Synthesis Database

【结构式】

【分子编号】31819

【品名】(2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid

【CA登记号】16937-99-8

【分子式】C₁₁H₂₁NO₄

【分子量】231.29208

【元素组成】C 57.12% H 9.15% N 6.06% O 27.67%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(XII)

Protection of the carboxyl group of Boc-L-threonine (I) with [2-(chloromethoxy)ethyl]trimethylsilane (SEM-Cl) (II) by means of Li2CO3 affords protected threonine (III). Separately, Z-L-tyrosine (IV) is treated with dimethyl sulfate and KOH in THF with tetrabutylammonium hydrogen sulfate as a catalyst to furnish N,O-dimethyl-L-tyrosine (V), which is then converted into secondary amine (VI) by coupling with protected threonine (III) either by means of 2,4,6-trichlorobenzoyl chloride in THF and DMAP in benzene or with isopropenyl chloroformate, Et3N and DMAP, followed by elimination of the carbobenzyloxy group by hydrogenation over Pd/C. Coupling of Z-L-leucine (IX) to L-proline methyl ester (X) by means of DCC, HOBt and NMM in CH2Cl2, followed by hydrolysis with LiOH, affords Z-leucylproline (VII), which is then coupled to amine (VI) by means of BOPCl and Et3N in CH2Cl2, and then subjected to deprotection with hydrofluoric acid in acetonitrile affording intermediate (VIII).

参考文献中间体

合成目标

【1】 Hamada, Y.; Shioiri, T.; Anti-tumor active cyclic peptide derived from marine organism: Synthesis, conformation and bioactivity. Kagaku Zokan 1990, 118, 31.
【2】 Harris, B.D.; et al.; Synthetic studies of didemnins. II. Approaches to statine diastereomers. Tetrahedron Lett 1987, 28, 25, 2837.
【3】 Hamada, Y.; et al.; Efficient total synthesis of didemnins A and B. J Am Chem Soc 1989, 111, 2, 669.

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)	50775	(2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid		C₁₁H₂₁NO₄	详情	详情
(II)	44205	(2-ethoxy-2-oxoethyl)lithium		C₄H₇LiO₂	详情	详情
(III)	50776	ethyl (4R,5S)-4-[(tert-butoxycarbonyl)amino]-5-methyl-3-oxoheptanoate		C₁₅H₂₇NO₅	详情	详情
(IV)	50777	tert-butyl (1R,2S)-1-formyl-2-methylbutylcarbamate		C₁₁H₂₁NO₃	详情	详情
(V)	50778	ethyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate		C₁₅H₂₉NO₅	详情	详情
(VI)	50779	2,2,2-trichloro-1-ethanol		C₂H₃Cl₃O	详情	详情
(VII)	50780	2,2,2-trichloroethyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate		C₁₅H₂₆Cl₃NO₅	详情	详情
(VIII)	50781	2,2,2-trichloroethyl (3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoate		C₁₀H₁₈Cl₃NO₃	详情	详情
(IX)	50782	(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid		C₁₆H₂₃NO₅	详情	详情
(X)	50783	2,2,2-trichloroethyl (3S,4R,5S)-4-[[(2S,3R)-2-amino-3-(benzyloxy)butanoyl]amino]-3-hydroxy-5-methylheptanoate		C₂₁H₃₁Cl₃N₂O₅	详情	详情
(XI)	50788	(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid		C₁₂H₂₃NO₄	详情	详情
(XII)	31819	(2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid	16937-99-8	C₁₁H₂₁NO₄	详情	详情
(XIII)	50787	2,2,2-trichloroethyl (6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-[[tert-butyl(dimethyl)silyl]oxy]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate		C₃₉H₆₆Cl₃N₃O₈Si	详情	详情
(XIV)	50784	2,2,2-trichloroethyl (6R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R)-1-hydroxyethyl]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate		C₃₂H₆₀Cl₃N₃O₈Si	详情	详情
(XV)	50747	(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid		C₁₉H₂₁NO₅	详情	详情
(XVI)	39328	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid		C₁₇H₁₇NO₅	详情	详情
(XVII)	50785	2,2,2-trichloroethyl (5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oate		C₄₆H₇₁Cl₃N₄O₁₀Si	详情	详情
(XVIII)	50786	(5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oic acid		C₄₄H₇₀N₄O₁₀Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Removal of the Boc protecting group of (V) with trifluoroacetic acid was followed by coupling with N-Boc-D-leucine (VI) in the presence of HATU to provide (VII). The deprotection-coupling procedure was repeated using N-Boc-L-aspartic acid gamma-benzyl ester (VIII), N-Boc-L-valine (X), and N-Boc-D-Leucine yielding the depsipeptide resins (IX), (XI) and (XII), respectively.

参考文献中间体

合成目标

【1】 Yanai, M.; Suguroi, T.; Solid-phase synthesis of cyclooctadepsipeptide N-4909 using a cyclization-cleavage method with oxime resin. J Antibiot 1999, 52, 9, 835.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	31816	(3S)-3-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoyl]oxy)-13-methyltetradecanoic acid		C₂₆H₄₉NO₆	详情	详情
(VI)	31819	(2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid	16937-99-8	C₁₁H₂₁NO₄	详情	详情
(VII)	31817	(6R,9S,12S)-6-isobutyl-2,2-dimethyl-9-[(1S)-1-methylpropyl]-12-(10-methylundecyl)-4,7,10-trioxo-3,11-dioxa-5,8-diazatetradecan-14-oic acid		C₃₂H₆₀N₂O₇	详情	详情
(VIII)	25219	(2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid	7536-58-5	C₁₆H₂₁NO₆	详情	详情
(IX)	31821	(6S,9R,12S,15S)-6-[2-(benzyloxy)-2-oxoethyl]-9-isobutyl-2,2-dimethyl-12-[(1S)-1-methylpropyl]-15-(10-methylundecyl)-4,7,10,13-tetraoxo-3,14-dioxa-5,8,11-triazaheptadecan-17-oic acid		C₄₃H₇₁N₃O₁₀	详情	详情
(X)	19733	(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid		C₁₀H₁₉NO₄	详情	详情
(XI)	31822	(6S,9S,12R,15S,18S)-9-[2-(benzyloxy)-2-oxoethyl]-12-isobutyl-6-isopropyl-2,2-dimethyl-15-[(1S)-1-methylpropyl]-18-(10-methylundecyl)-4,7,10,13,16-pentaoxo-3,17-dioxa-5,8,11,14-tetraazaicosan-20-oic acid		C₄₈H₈₀N₄O₁₁	详情	详情
(XII)	31823	(6S,9S,12S,15R,18S,21S)-12-[2-(benzyloxy)-2-oxoethyl]-6,15-diisobutyl-9-isopropyl-2,2-dimethyl-18-[(1S)-1-methylpropyl]-21-(10-methylundecyl)-4,7,10,13,16,19-hexaoxo-3,20-dioxa-5,8,11,14,17-pentaazatricosan-23-oic acid		C₅₄H₉₁N₅O₁₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

Alkylation of benzyl N-allylcarbamate (I) with 5-bromo-1-pentene (II) in the presence of NaH provides the aza diene derivative (III). Cyclization of (III) under olefin metathesis conditions, employing a ruthenium catalyst, gives rise to the tetrahydroazepine (IV). Oxidation of (IV) with m-chloroperbenzoic acid yields epoxide (V), which is subsequently converted into the trans azido alcohol (VI) upon ring opening with NaN3 and NH4Cl. Azide (VI) is reduced to the corresponding amine (VII) by using 1,3-propanedithiol. Acylation of the racemic trans amino alcohol (VII) by N-Boc-L-leucine (VIII) produces a diastereomeric mixture of amides, which are separated by column chromatography. The desired isomer (IX) is then subjected to catalytic hydrogenolysis of the N-carbobenzoxy group to afford azepine (X). Then, acylation of (X) with 3-(2-pyridyl)phenylacetic acid (XI) furnishes amide (XII).

参考文献中间体

合成目标

【1】 Cummings, M.D.; Veber, D.F.; Yamashita, D.; Ru, Y.; Marquis, R.W. Jr.; Thompson, S.K. (SmithKline Beecham Corp.); Protease inhibitors. EP 1158986; WO 0038687 .

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)	49723	benzyl allylcarbamate		C₁₁H₁₃NO₂	详情	详情
(II)	49724	1-Bromo-4-Pentene; 5-Bromo-1-pentene; 4-Penten-1-yl Bromide	1119-51-3	C₅H₉Br	详情	详情
(III)	49725	benzyl allyl(4-pentenyl)carbamate		C₁₆H₂₁NO₂	详情	详情
(IV)	49726	benzyl 2,3,4,7-tetrahydro-1H-azepine-1-carboxylate		C₁₄H₁₇NO₂	详情	详情
(V)	49727	benzyl 8-oxa-3-azabicyclo[5.1.0]octane-3-carboxylate		C₁₄H₁₇NO₃	详情	详情
(VI)	57657	benzyl (3S,4S)-4-azido-3-hydroxy-1-azepanecarboxylate		C₁₄H₁₈N₄O₃	详情	详情
(VII)	57658	benzyl (3S,4S)-4-amino-3-hydroxy-1-azepanecarboxylate		C₁₄H₂₀N₂O₃	详情	详情
(VIII)	31819	(2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid	16937-99-8	C₁₁H₂₁NO₄	详情	详情
(IX)	57659	benzyl (3S,4S)-4-({(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl}amino)-3-hydroxy-1-azepanecarboxylate		C₂₅H₃₉N₃O₆	详情	详情
(X)	57660	tert-butyl (1S)-1-({[(3S,4S)-3-hydroxyazepanyl]amino}carbonyl)-3-methylbutylcarbamate		C₁₇H₃₃N₃O₄	详情	详情
(XI)	50904	2-[3-(2-pyridinyl)phenyl]acetic acid		C₁₃H₁₁NO₂	详情	详情
(XII)	57661	tert-butyl (1S)-1-{[((3S,4S)-3-hydroxy-1-{2-[3-(2-pyridinyl)phenyl]acetyl}azepanyl)amino]carbonyl}-3-methylbutylcarbamate		C₃₀H₄₂N₄O₅	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

N-Boc-L-Leucine (I) is activated as the corresponding succinimidyl ester (II) upon treatment with N-hydroxysuccinimide and EDC. Coupling of active ester (II) with (S)-alpha-amino-gamma-butyrolactone (III) affords amide (IV). After N-Boc group deprotection of (IV) under acidic conditions, the resultant amine (V) is condensed with phenyl isothiocyanate to furnish thiourea (VI). Finally, reduction of the lactone function of (VI) with DIBAL gives rise to the target cyclic hemiacetal compound.

参考文献中间体

合成目标

【1】 Nakamura, M.; Yamaguchi, M.; Sakai, O.; Inoue, J.; Exploration of cornea permeable calpain inhibitors as anticataract agents. Bioorg Med Chem 2003, 11, 7, 1371.

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)	31819	(2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid	16937-99-8	C₁₁H₂₁NO₄	详情	详情
(II)	64224	tert-butyl (1S)-1-{[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}-3-methylbutylcarbamate		C₁₅H₂₄N₂O₆	详情	详情
(III)	64228	(3S)-3-aminodihydro-2(3H)-furanone;L-homoserine lactone;(S)-3-aminodihydrofuran-2(3H)-one		C₄H₇NO₂	详情	详情
(IV)	64225	tert-butyl (1S)-3-methyl-1-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)butylcarbamate		C₁₅H₂₆N₂O₅	详情	详情
(V)	64226	(2S)-2-amino-4-methyl-N-[(3S)-2-oxotetrahydro-3-furanyl]pentanamide		C₁₀H₁₈N₂O₃	详情	详情
(VI)	64227	(2S)-2-[(anilinocarbothioyl)amino]-4-methyl-N-[(3S)-2-oxotetrahydro-3-furanyl]pentanamide		C₁₇H₂₃N₃O₃S	详情	详情

Extended Information