benzyl (2R)-2-amino-4-methylpentanoate -Drug Synthesis Database

【结构式】

【分子编号】28648

【品名】benzyl (2R)-2-amino-4-methylpentanoate

【CA登记号】

【分子式】C₁₃H₁₉NO₂

【分子量】221.2994

【元素组成】C 70.56% H 8.65% N 6.33% O 14.46%

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：(II)

The esterification of D-leucine (I) with benzyl alcohol and HCl gives the corresponding ester (II), which is N-benzylated by reductocondensation with benzaldehyde and sodium cyanoborohydride yielding N-benzyl-D-leucine benzyl ester (III). The condensation of (III) with methyl phenyl phosphinyl chloride (IV) by means of N-methylmorpholine in dichloromethane affords the phosphinylamino derivative (V), which is treated with H2 over Pd/C in methanol to give N-benzyl-N-[methyl(phenyl)phosphinyl]-D-leucine (VI). The condensation of (VI) with O-benzylhydroxylamine (VII) by means of 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide (DEC) and HOBT in DMF yields the N-benzyl hydroxamic acid (VIII) as a diastereomeric mixture that is separated by flash chromatography providing the diastereomer (IX). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol.

参考文献中间体

合成目标

【1】 Elst, L.V.; et al.; A multinuclear MR study of Gd-EOB-DTPA: Comprehensive preclinical characterization of an organ specific MRI contrast agent. Magn Reson Med 1997, 38, 4, 604.
【2】 Taiwo, Y.O.; Pikul, S.; De, B.; McDow-Dunham, K.L. (The Procter & Gamble Co.); Phosphinic acid amides as matrix metalloprotease inhibitors. US 5830915; WO 9808853 .

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)	16010	D-leucine	328-38-1	C₆H₁₃NO₂	详情	详情
(II)	28648	benzyl (2R)-2-amino-4-methylpentanoate		C₁₃H₁₉NO₂	详情	详情
(III)	28643	benzyl (2R)-2-(benzylamino)-4-methylpentanoate		C₂₀H₂₅NO₂	详情	详情
(IV)	28644	methyl(phenyl)phosphinic chloride	5761-97-7	C₇H₈ClOP	详情	详情
(V)	28645	benzyl (2R)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-4-methylpentanoate		C₂₇H₃₂NO₃P	详情	详情
(VI)	28646	(2R)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-4-methylpentanoic acid		C₂₀H₂₆NO₃P	详情	详情
(VII)	14640	O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene	622-33-3	C₇H₉NO	详情	详情
(VIII)	28647	(2R)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-N-(benzyloxy)-4-methylpentanamide		C₂₇H₃₃N₂O₃P	详情	详情
(IX)	28649	(2R)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-N-(benzyloxy)-4-methylpentanamide		C₂₇H₃₃N₂O₃P	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXXIII)

Synthesis of dysinosin A: The reaction of the commercially available D-mannitol derivative (XXVII) with NaH and MeI in DMF gives the dimethoxy compound (XXVIII), which is hydrogenated with H2 over Pd/C in EtOH/EtOAc to yield the dimethoxy-D-mannitol (XXIX). The selective silylation of the primary OH groups of (XXIX) with Tbdps-Cl and imidazole affords the bis silyl ether (XXX), which is submitted to an oxidative cleavage of its vicinal diol group by means of Pb(OAc)4 to provide 2(R)-methoxy-3-(Tbdps-O)propanal (XXXI) (3). The oxidation of (XXXI) with NaClO2 gives the corresponding carboxylic acid (XXXII), which is condensed with D-leucine benzyl ester (XXXIII) by means of EDC and HOBt in dichloromethane to yield adduct (XXXIV). The reductive cleavage of the benzyl group of (XXXIV) with H2 over Pd/C in methanol affords the substituted leucine (XXXV), which is condensed with the perhydroindole intermediate (XIII) by means of Bop-Cl and DIEA in acetonitrile to provide the amide (XXXVI). The hydrolysis of the methyl ester group of (XXXVI) with LiOH in THF/MeOH gives the carboxylic acid (XXXVII), which is condensed with the aminoethyl-3-pyrroline intermediate (XXVI) by means of EDC and HOBt in dichloromethane to yield the amide intermediate (XXXVIII). The cleavage of the silyl ether group of (XXXVIII) by means of TBAF in THF affords the primary alcohol (XXXIX), which is treated with Pyr/SO3 and Bu2SnO to provide the sulfate ester (XL). Finally, this compound is fully deprotected by means of TFA in dichloromethane and purified by means of preparative HPLC to obtain the target dysinosin A (2).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; Piscopio, A.D.; Bertinato, P.; Chakraborty, T.K.; Minowa, N.; Koide, K.; Total Synthesis of Rapamycin. Chemistry (Weinheim) 1995, 1, 5, 318.
【2】 Hanessian, S.; Margarita, R.; Hall, A.; Johnstone, S.; Tremblay, M.; Parlanti, L.; Total synthesis and structural confirmation of the marine natural product Dysinosin A: A novel inhibitor of thrombin and Factor VIIa. J Am Chem Soc 2002, 124, 45, 13342.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	64913	methyl 5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-2-carboxylate	C₁₄H₂₅NO₆	详情	详情
(XXVI)	64925		C₁₇H₃₀N₄O₄	详情	详情
(XXVII)	64926		C₂₀H₂₂O₆	详情	详情
(XXVIII)	64927		C₂₂H₂₆O₆	详情	详情
(XXIX)	64928	2,5-bis(methyloxy)-1,3,4,6-hexanetetrol	C₈H₁₈O₆	详情	详情
(XXX)	64929	2,2,13,13-tetramethyl-6,9-bis(methyloxy)-3,3,12,12-tetraphenyl-4,11-dioxa-3,12-disilatetradecane-7,8-diol	C₄₀H₅₄O₆Si₂	详情	详情
(XXXI)	15026	(2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxypropanal	C₂₀H₂₆O₃Si	详情	详情
(XXXII)	64930	3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)propanoic acid	C₂₀H₂₆O₄Si	详情	详情
(XXXIII)	28648	benzyl (2R)-2-amino-4-methylpentanoate	C₁₃H₁₉NO₂	详情	详情
(XXXIV)	64931	phenylmethyl 2-{[3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)propanoyl]amino}-4-methylpentanoate	C₃₃H₄₃NO₅Si	详情	详情
(XXXV)	64932	N-[3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)propanoyl]leucine	C₂₆H₃₇NO₅Si	详情	详情
(XXXVI)	64933	methyl 1-(2-{[2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)acetyl]amino}-4-methylpentanoyl)-5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-2-carboxylate	C₃₉H₅₈N₂O₁₀Si	详情	详情
(XXXVII)	64934	1-(2-{[2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)acetyl]amino}-4-methylpentanoyl)-5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-2-carboxylic acid	C₃₈H₅₆N₂O₁₀Si	详情	详情
(XXXVIII)	64935		C₅₅H₈₄N₆O₁₃Si	详情	详情
(XXXIX)	64936		C₃₉H₆₆N₆O₁₃	详情	详情
(XL)	64937	2-{[(2-{1-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)({[(1,1-dimethylethyl)oxy]carbonyl}imino)methyl]-2,5-dihydro-1H-pyrrol-3-yl}ethyl)amino]carbonyl}-1-(4-methyl-2-{[2-(methyloxy)-2-(sulfonatooxy)acetyl]amino}pentanoyl)-5,6-bis{[(methyloxy)methyl]ox	C₃₉H₆₅N₆O₁₆S	详情	详情

Extended Information