benzyl (2S)-2-amino-3-methylbutanoate -Drug Synthesis Database

【结构式】

【分子编号】41936

【品名】benzyl (2S)-2-amino-3-methylbutanoate

【CA登记号】

【分子式】C₁₂H₁₇NO₂

【分子量】207.27252

【元素组成】C 69.54% H 8.27% N 6.76% O 15.44%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IV)

The reaction of 2-bromo-4'-methylbiphenyl (I) with 14C labeled cuprous cyanide in refluxing DMF gives 4'-methylbiphenyl-2-carbonitrile (II), which is brominated with NBS and AIBN in refluxing CCl4 to yield the bromomethyl derivative (III). The condensation of (III) with L-valine benzyl ester (IV) by means of DIEA in hot DMF affords the N-substituted valine (V), which is acylated with pentanoyl chloride (VI) and DIEA to provide the N-acylated valine (VII). The cyclization of the cyano group of (VII) with tributyltin azide at 140 C furnishes the tetrazol derivative (VIII) which is finally debenzylated by hydrogenation with H2 over Pd/C in dioxane.

参考文献中间体

合成目标

【1】 Moenius, T.; et al.; Carbon-14 labelling of Diovan(TM) in its valine-moiety. J Label Compd Radiopharm 2000, 43, 13, 1245.

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)	41935	2-bromo-4'-methyl-1,1'-biphenyl		C₁₃H₁₁Br	详情	详情
(II)	13929	2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile	114772-53-1	C₁₄H₁₁N	详情	详情
(II)	45264	4'-methyl[1,1'-biphenyl]-2-carbonitrile		C₁₄H₁₁N	详情	详情
(III)	15332	4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl	114772-54-2	C₁₄H₁₀BrN	详情	详情
(III)	45265	4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile		C₁₄H₁₀BrN	详情	详情
(IV)	41936	benzyl (2S)-2-amino-3-methylbutanoate		C₁₂H₁₇NO₂	详情	详情
(V)	41937	benzyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl]amino]-3-methylbutanoate; N-[(2'-cyanobiphenyl-4-yl)methyl]-L-valine benzyl ester	137864-23-4	C₂₆H₂₆N₂O₂	详情	详情
(V)	45266	benzyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl]amino]-3-methylbutanoate		C₂₆H₂₆N₂O₂	详情	详情
(VI)	15116	pentanoyl chloride; valeryl chloride	638-29-9	C₅H₉ClO	详情	详情
(VII)	41938	benzyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl](pentanoyl)amino]-3-methylbutanoate		C₃₁H₃₄N₂O₃	详情	详情
(VII)	45267	benzyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl](pentanoyl)amino]-3-methylbutanoate		C₃₁H₃₄N₂O₃	详情	详情
(VIII)	41939	benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate		C₃₁H₃₅N₅O₃	详情	详情
(VIII)	45268	benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate		C₃₁H₃₅N₅O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

The reaction of 14C labeled chiral bromoacetyl sultam (I) with benzophenoneimine (II) in hot acetonitrile gives the substituted benzophenoneimine (III), which is estereoselectively alkylated with isopropyl iodide (IV) and n-BuLi in THF yielding the labeled L-valine derivative (V). The hydrolysis of (V) with HCl in THF affords the valine derivative (VI) with a free amino group that is protected with Boc2O in THF providing the carbamate (VII). The basic hydrolysis of (VII) with LiOH in THF gives the labeled N-(tert-butoxycarbonyl)-L-valine (VIII), which is esterified with Bn-OH, EDC and DMAP in dichloromethane yielding the protected benzyl ester (IX). Treatment of (IX) with TFA in dichloromethane affords L-valine benzyl ester (X), which is condensed with the bromomethylbiphenyl (XI) by means of DIEA in hot DMF to give the N-alkylated valine ester (XII). The acylation of (XII) with pentanoyl chloride (XIII) by means of DIEA in toluene yields the N-disubstituted valine ester (XIV), which is finally deprotected by hydrogenation with H2 over Pd/C in EtOH.

参考文献中间体

合成目标

【1】 Moenius, T.; et al.; Carbon-14 labelling of Diovan(TM) in its valine-moiety. J Label Compd Radiopharm 2000, 43, 13, 1245.

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)	41945	(1S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione		C₁₂H₁₈BrNO₃S	详情	详情
(I)	45269	(1S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione		C₁₂H₁₈BrNO₃S	详情	详情
(II)	32024	diphenylmethanimine	1013-88-3	C₁₃H₁₁N	详情	详情
(III)	41946	(1S)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione		C₂₅H₂₈N₂O₃S	详情	详情
(III)	45270	(1S)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione		C₂₅H₂₈N₂O₃S	详情	详情
(IV)	19369	2-iodopropane	75-30-9	C₃H₇I	详情	详情
(V)	41940	(1S)-4-[(2S)-2-[(dibenzylene)amino]-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione		C₂₈H₃₄N₂O₃S	详情	详情
(V)	45271	(1S)-4-[(2S)-2-[(dibenzylene)amino]-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione		C₂₈H₃₄N₂O₃S	详情	详情
(VI)	41941	tert-butyl (1S)-1-[[(1S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate		C₂₀H₃₄N₂O₅S	详情	详情
(VI)	45272	(1R)-4-[(2S)-2-amino-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione		C₁₆H₂₇NO₃S	详情	详情
(VII)	41947	tert-butyl (1S)-1-[[(1S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate		C₂₀H₃₄N₂O₅S	详情	详情
(VII)	45273	tert-butyl (1S)-1-[[(1S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate		C₂₀H₃₄N₂O₅S	详情	详情
(VIII)	19733	(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid		C₁₀H₁₉NO₄	详情	详情
(VIII)	45274	(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid		C₁₀H₁₉NO₄	详情	详情
(IX)	41942	benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate		C₁₇H₂₅NO₄	详情	详情
(IX)	45275	benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate		C₁₇H₂₅NO₄	详情	详情
(X)	41936	benzyl (2S)-2-amino-3-methylbutanoate		C₁₂H₁₇NO₂	详情	详情
(X)	45276	benzyl (2S)-2-amino-3-methylbutanoate		C₁₂H₁₇NO₂	详情	详情
(XI)	15538	5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole	124750-51-2	C₃₃H₂₅BrN₄	详情	详情
(XII)	41943	benzyl (2S)-3-methyl-2-([[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate		C₄₅H₄₁N₅O₂	详情	详情
(XII)	45277	benzyl (2S)-3-methyl-2-([[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate		C₄₅H₄₁N₅O₂	详情	详情
(XIII)	15116	pentanoyl chloride; valeryl chloride	638-29-9	C₅H₉ClO	详情	详情
(XIV)	41944	benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate		C₅₀H₄₉N₅O₃	详情	详情
(XIV)	45278	benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate		C₅₀H₄₉N₅O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XIII)

In a similar fashion, N-Boc-L-phenylalanine (XI) is coupled with L-valine benzyl ester (XIII) to furnish the protected dipeptide (XIV). Debenzylation of (XIV) with H2 and Pd/C leads to acid (XV), which is then condensed with tripeptide (XII) to yield, after deprotection with formic acid, the pentapeptide derivative (XVI).

参考文献中间体

合成目标

【1】 Rawale, S.; Hrihorczuk, L.M.; Wei, W.-Z.; Zemlicka, J.; Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by Beta-glucuronidase. J Med Chem 2002, 45, 4, 937.

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)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(XII)	65159	benzyl (2S)-2-{[(2S,3R)-2-{[(2S)-2-amino-3-phenylpropanoyl]amino}-3-(benzyloxy)butanoyl]amino}-4-methylpentanoate		C₃₃H₄₁N₃O₅	详情	详情
(XIII)	41936	benzyl (2S)-2-amino-3-methylbutanoate		C₁₂H₁₇NO₂	详情	详情
(XIV)	65162	benzyl (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-methylbutanoate		C₂₆H₃₄N₂O₅	详情	详情
(XV)	65163	(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-methylbutanoic acid		C₁₉H₂₈N₂O₅	详情	详情
(XVI)	65161	benzyl (2S,5S,8S,11S,14S)-14-amino-8-benzyl-5-[(1R)-1-(benzyloxy)ethyl]-2-isobutyl-11-isopropyl-4,7,10,13-tetraoxo-15-phenyl-3,6,9,12-tetraazapentadecan-1-oate		C₄₇H₅₉N₅O₇	详情	详情

Extended Information