(2S)-2-amino-4-(tert-butoxy)-4-oxobutyric acid -Drug Synthesis Database

【结构式】

【分子编号】26564

【品名】(2S)-2-amino-4-(tert-butoxy)-4-oxobutyric acid

【CA登记号】3057-74-7

【分子式】C₈H₁₅NO₄

【分子量】189.21144

【元素组成】C 50.78% H 7.99% N 7.4% O 33.82%

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：(XVII)

Compound (XII) was protected as the tert-butyl carbamate (XIII) with Boc2O, and then coupled with piperidine using TBTU to give amide (XIV). The condensation of sulfonyl chloride (XVI) with L-aspartic mono tert-butyl ester (XVII) gave the N-sulfonylaspartate (XVIII). This was finally coupled with aminoamide (XV) by means of DCC and HOBt to yield the title compound.

参考文献中间体

合成目标

【1】 Jenneboer, A.J.s.M.; van Galen, P.J.M.; van Boeckel, C.A.A.; Rood, A.M.M.; Lucas, H.; Noach, A.B.J.; van Dinther, T.G.; Rewinkel, J.B.M.; 1-Aminoisoquinoline as benzamidine isostere in the design and synthesis of orally active thrombin inhibitors. Bioorg Med Chem Lett 1999, 9, 5, 685.
【2】 Van Galen, P.J.M.; Rewinkel, J.B.M.; Van Boeckel, C.A.A. (Akzo Nobel N.V.); Heterocyclic derivs. and their use as antithrombotic agents. EP 0975600; WO 9847876 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	30062	3-(1-amino-6-isoquinolinyl)alanine		C₁₂H₁₃N₃O₂	详情	详情
(XIII)	30063	3-(1-amino-6-isoquinolinyl)-N-(tert-butoxycarbonyl)alanine		C₁₇H₂₁N₃O₄	详情	详情
(XIV)	30064	tert-butyl 1-[(1-amino-6-isoquinolinyl)methyl]-2-oxo-2-(1-piperidinyl)ethylcarbamate		C₂₂H₃₀N₄O₃	详情	详情
(XV)	30065	2-amino-3-(1-amino-6-isoquinolinyl)-1-(1-piperidinyl)-1-propanone		C₁₇H₂₂N₄O	详情	详情
(XVI)	30066	4-Methoxy-2,3,6-trimethylbenzenesulfonyl chloride	80745-07-9	C₁₀H₁₃ClO₃S	详情	详情
(XVII)	26564	(2S)-2-amino-4-(tert-butoxy)-4-oxobutyric acid	3057-74-7	C₈H₁₅NO₄	详情	详情
(XVIII)	30067	(2S)-4-(tert-butoxy)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-4-oxobutyric acid		C₁₈H₂₇NO₇S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

4-Pentylbicyclo[2.2.2]octane-1-carboxylic acid (I) was converted to the corresponding acid chloride with SOCl2 and then coupled to L-aspartic acid beta-tert-butyl ester (II) to afford amide (III). Subsequent coupling of (III) with further L-aspartic acid beta-tert-butyl ester (II) in the presence of DCC and NHS produced diamide (IV). This was then condensed with (aminobutyl)diethylenetriamino-pentaacetic acid penta-tert-butyl ester (V) to provide (VI).

参考文献中间体

合成目标

【1】 Wallace, R.A.; Haar, J.P. Jr.; Miller, D.B.; Woulfe, S.R.; Polta, J.A.; Galen, K.P.; Hynes, M.R.; Adzamli, K.; Synthesis and preliminary evaluation of MP-2269: A novel, nonaromatic small-molecule blood-pool MR contrast agent. Magn Reson Med 1998, 40, 5, 733.
【2】 Woulfe, S.R. (Mallinckrodt Medical Inc.); Magnetic resonance blood pool agents. WO 9820908 .

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)	26563	4-pentylbicyclo[2.2.2]octane-1-carboxylic acid		C₁₄H₂₄O₂	详情	详情
(II)	26564	(2S)-2-amino-4-(tert-butoxy)-4-oxobutyric acid	3057-74-7	C₈H₁₅NO₄	详情	详情
(III)	26565	(2S)-4-(tert-butoxy)-4-oxo-2-[[(4-pentylbicyclo[2.2.2]oct-1-yl)carbonyl]amino]butyric acid		C₂₂H₃₇NO₅	详情	详情
(IV)	26566	(2S)-4-(tert-butoxy)-2-[((2S)-4-(tert-butoxy)-4-oxo-2-[[(4-pentylbicyclo[2.2.2]oct-1-yl)carbonyl]amino]butanoyl)amino]-4-oxobutyric acid		C₃₀H₅₀N₂O₈	详情	详情
(V)	26567	tert-butyl 9-[5-amino-1-(tert-butoxycarbonyl)pentyl]-6,12-bis[2-(tert-butoxy)-2-oxoethyl]-2,2-dimethyl-4-oxo-3-oxa-6,9,12-triazatetradecan-14-oate		C₃₈H₇₂N₄O₁₀	详情	详情
(VI)	26568	2-[N,N-Bis[2-[N,N-bis(tert-butoxycarbonylmethyl)amino]ethyl]amino]-6-[N-(4-pentylbicyclo[2,2,2]oct-1-ylcarbonyl)-(4-O-tert-butyl)-L-aspartyl-(4-O-tert-butyl)-L-aspartylamino]hexanoic acid tert-butyl ester; 2-[N,N-Bis[2-[N,N-bis(tert-butoxycarbonylmethyl)amino]ethyl]amino]-6-[N-(4-pentylbicyclo[2,2,2]oct-1-ylcarbonyl)-(4-O-tert-butyl)-L-aspartyl-(4-O-tert-butyl)-L-aspartylamino]hexanoic acid tert-butyl ester		C₆₈H₁₂₀N₆O₁₇	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Aspartic acid beta-tert-butyl ester (II) was silylated using bis(trimethylsilyl)acetamide and subsequently coupled with the hydroxysuccinimidyl ester of Z-valine (I) to furnish dipeptide (III) (1). This was converted to the corresponding mixed anhydride (IV) with isobutyl chloroformate and N-methylmorpholine. Reaction of anhydride (IV) with ethereal diazomethane, followed by treatment of the intermediate diazo ketone with HBr in HOAc, gave rise to the bromo ketone (V). Tetrafluorophenol (VI) was alkylated with bromide (V) to yield ether (VII). The ketone function of (VII) was then reduced to alcohol (VIII) employing NaBH4. Further hydrogenolysis of the benzyloxycarbonyl group of (VIII) provided amine (IX).

参考文献中间体

合成目标

【1】 Ternansky, R.J.; et al.; Structure-activity relationship of a series of oxamyl dipeptide caspase inhibitors developed for the treatment of stroke. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 75.
【2】 Karanewsky, D.S.; Ternansky, R.J. (Idun Pharmaceuticals, Inc.); C-Terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases. EP 1091930; WO 0001666 .

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)	49982	benzyl (1S)-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-methylpropylcarbamate		C₁₇H₂₀N₂O₆	详情	详情
(II)	26564	(2S)-2-amino-4-(tert-butoxy)-4-oxobutyric acid	3057-74-7	C₈H₁₅NO₄	详情	详情
(III)	49983	(2S)-2-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)amino]-4-(tert-butoxy)-4-oxobutyric acid		C₂₁H₃₀N₂O₇	详情	详情
(IV)	49984			C₂₆H₃₈N₂O₉	详情	详情
(V)	49985	tert-butyl (3S)-3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)amino]-5-bromo-4-oxopentanoate		C₂₂H₃₁BrN₂O₆	详情	详情
(VI)	49986	2,3,5,6-Tetrafluorophenol	769-39-1	C₆H₂F₄O	详情	详情
(VII)	49987	tert-butyl (3S)-3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoate		C₂₈H₃₂F₄N₂O₇	详情	详情
(VIII)	49988	tert-butyl (3S)-3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)amino]-4-hydroxy-5-(2,3,5,6-tetrafluorophenoxy)pentanoate		C₂₈H₃₄F₄N₂O₇	详情	详情
(IX)	49989	tert-butyl (3S)-3-[[(2S)-2-amino-3-methylbutanoyl]amino]-4-hydroxy-5-(2,3,5,6-tetrafluorophenoxy)pentanoate		C₂₀H₂₈F₄N₂O₅	详情	详情

Extended Information