methyl (4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxoheptanoate -Drug Synthesis Database

【结构式】

【分子编号】23510

【品名】methyl (4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxoheptanoate

【CA登记号】

【分子式】C₁₇H₂₃NO₅

【分子量】321.37336

【元素组成】C 63.54% H 7.21% N 4.36% O 24.89%

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：(XI)

Intermediate (VI) has been obtained as follows: The condensation of benzyloxycarbonyl-L-isoleucine (IX) with malonic acid monomethyl ester potassium salt (X) by means of carbonyldiimidazole (CDI) and MgCl2 in THF gives the ketoester (XI), which is reduced to the hydroxyester (XII) with NaBH4 in methanol. The methylation of (XII) with methyl iodide and silver oxide in DMF affords the N-methyl methoxyester (XIII). The hydrolysis of (XIII) with NaOH in dioxane/water followed by reesterification with isobutylene gives the tert-butyl ester (XIV), which is deprotected by hydrogenation over Pd/C, yielding the amino acid (XV). The condensation of (XV) with benzyloxycarbonyl-L-valine (XVI) by means of DCC in dichloromethane gives the protected dipeptide (XVII), which is debenzylated as usual, yielding (XVIII). The condensation of (XVIII) with N,N-dimethyl-L-valine (XIX) affords the tripeptide ter-butyl ester (XX). Finally, (XX) is hydrolyzed by treatment with trifluoroacetic acid to the free acid intermediate (VI).

参考文献中间体

合成目标

【1】 Tsukagoshi, S.; Sakakibara, K.; Gondo, M.; Natsume, T.; Mikami, T.; Kobayashi, M.; Miyazaki, K.; Synthesis and antitumor activity of novel dolastat. Chem Pharm Bull 1995, 43, 10, 1706.
【2】 Castañer, J.; Leeson, P.; Hoshi, A.; TZT-1027. Drugs Fut 1999, 24, 4, 404.
【3】 Sakakibara, K.; Gondo, M.; Miyazaki, K. (Teikoku Hormone Manufacturing Co., Ltd.); Novel tetrapeptide derivs.. EP 0598129; JP 1993503479; US 5654399; WO 9303054 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	15926	2-methyl-1-propene; isobutylene	115-11-7	C₄H₈	详情	详情
(VI)	23505	(3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid		C₂₂H₄₃N₃O₅	详情	详情
(IX)	23508	(2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid	3160-59-6	C₁₄H₁₉NO₄	详情	详情
(X)	23509	3-methoxy-3-oxopropanoate		C₄H₅O₄	详情	详情
(XI)	23510	methyl (4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxoheptanoate		C₁₇H₂₃NO₅	详情	详情
(XII)	23511	methyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylheptanoate		C₁₇H₂₅NO₅	详情	详情
(XIII)	23512	methyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-methoxy-5-methylheptanoate		C₁₉H₂₉NO₅	详情	详情
(XIV)	23513	tert-butyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-methoxy-5-methylheptanoate		C₂₂H₃₅NO₅	详情	详情
(XV)	23514	tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate		C₁₄H₂₉NO₃	详情	详情
(XVI)	18092	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid		C₁₃H₁₇NO₄	详情	详情
(XVII)	23516	tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate		C₂₇H₄₄N₂O₆	详情	详情
(XVIII)	23517	tert-butyl (3R,4S,5S)-4-[[(2S)-2-amino-3-methylbutanoyl](methyl)amino]-3-methoxy-5-methylheptanoate		C₁₉H₃₈N₂O₄	详情	详情
(XIX)	23518	(2S)-2-(dimethylamino)-3-methylbutyric acid		C₇H₁₅NO₂	详情	详情
(XX)	23519	tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate		C₂₆H₅₁N₃O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Protection of D-alloisoleucine (I) with Cbz-succinimide afforded benzyl carbamate (II). Activation of the carboxyl group of (II) as the pentafluorophenyl ester (III), followed by condensation with the lithium enolate of methyl acetate, gave beta-ketoester (IV). Stereoselective reduction of (IV) with KBH4 produced alcohol (V) as the major diastereomer. The hydroxyl group of (V) was protected as the triisopropylsilyl ether (VI), and then hydrolysis of the ester group of (VI) yielded carboxylic acid (VII).

参考文献中间体

合成目标

【1】 Liang, B.; et al.; The first total synthesis of (-)-tamadarin A. Org Lett 1999, 1, 8, 1319.

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)	32739	L-2-Amino-3-methylpentanoic acid; L-isoleucine	73-32-5	C₆H₁₃NO₂	详情	详情
(II)	23508	(2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid	3160-59-6	C₁₄H₁₉NO₄	详情	详情
(III)	37824	2,3,4,5,6-pentafluorophenyl (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoate		C₂₀H₁₈F₅NO₄	详情	详情
(IV)	23510	methyl (4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxoheptanoate		C₁₇H₂₃NO₅	详情	详情
(V)	37825	methyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylheptanoate		C₁₇H₂₅NO₅	详情	详情
(VI)	37826	methyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate		C₂₆H₄₅NO₅Si	详情	详情
(VII)	37827	(3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoic acid		C₂₅H₄₃NO₅Si	详情	详情

Extended Information