3-methyl-2-oxopentanoic acid -Drug Synthesis Database

【结构式】

【分子编号】46950

【品名】3-methyl-2-oxopentanoic acid

【CA登记号】

【分子式】C₆H₁₀O₃

【分子量】130.1436

【元素组成】C 55.37% H 7.74% O 36.88%

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：(XXII)

The selective protection of the primary OH group of (XVII) with Tips-Cl and imidazole yields the silyl ether (XVIII), which is treated with TFA in dichloromethane to afford the carboxylic acid (XIX). The macrolactamization of (XIX) by means of EDC, HOAt and DIEA in DMF/dichloromethane provides the macrolactam (XX), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to furnish the aminophenol (XXI). The condensation of (XXI) with racemic 3-methyl-2-oxopentanoic acid (XXII) by means of EDC and HOAt in DMF/dichloromethane gives the amide (XXIII) as a diastereomeric mixture. The desilylation of (XXIII) by means of HF and pyridine gives the tetrahydroxy compound (XXIV), which is fully resilylated with Tes-OTf and lutidine in dichloromethane to yield the tetra-silyl ether (XXV).

参考文献中间体

合成目标

【1】 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	53353	tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1,3-dihydroxypropyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate	n/a	C₄₈H₅₇N₅O₁₃	详情	详情
(XVIII)	53354	tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate	n/a	C₅₇H₇₇N₅O₁₃Si	详情	详情
(XIX)	53355	(2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoic acid	n/a	C₅₃H₆₉N₅O₁₃Si	详情	详情
(XX)	53356	benzyl (10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-23-(benzyloxy)-10,11-dihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-ylcarbamate	n/a	C₄₈H₅₉N₅O₁₀Si	详情	详情
(XXI)	53357	2-[(10S,11R,12R,15S,18S)-18-amino-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-15-yl]acetamide	n/a	C₃₃H₄₇N₅O₈Si	详情	详情
(XXII)	46950	3-methyl-2-oxopentanoic acid		C₆H₁₀O₃	详情	详情
(XXIII)	53358	N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide	n/a	C₃₉H₅₅N₅O₁₀Si	详情	详情
(XXIV)	53359	N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-12-(hydroxymethyl)-9,14,17-trioxo-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide	n/a	C₃₀H₃₅N₅O₁₀	详情	详情
(XXV)	53360	N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-12-{[(triethylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide	n/a	C₅₄H₉₁N₅O₁₀Si₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXII)

参考文献中间体

合成目标

【1】 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	53353	tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1,3-dihydroxypropyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate	n/a	C₄₈H₅₇N₅O₁₃	详情	详情
(XVIII)	53354	tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate	n/a	C₅₇H₇₇N₅O₁₃Si	详情	详情
(XIX)	53355	(2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoic acid	n/a	C₅₃H₆₉N₅O₁₃Si	详情	详情
(XX)	53356	benzyl (10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-23-(benzyloxy)-10,11-dihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-ylcarbamate	n/a	C₄₈H₅₉N₅O₁₀Si	详情	详情
(XXI)	53357	2-[(10S,11R,12R,15S,18S)-18-amino-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-15-yl]acetamide	n/a	C₃₃H₄₇N₅O₈Si	详情	详情
(XXII)	46950	3-methyl-2-oxopentanoic acid		C₆H₁₀O₃	详情	详情
(XXIII)	53358	N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide	n/a	C₃₉H₅₅N₅O₁₀Si	详情	详情
(XXIV)	53359	N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-12-(hydroxymethyl)-9,14,17-trioxo-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide	n/a	C₃₀H₃₅N₅O₁₀	详情	详情
(XXV)	53360	N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-12-{[(triethylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide	n/a	C₅₄H₉₁N₅O₁₀Si₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

Bromination of N-phthaloyl tryptamine (I) with pyridinium tribromide provided the 2-bromo indole (II). Suzuki coupling of bromide (II) with phenylboronic acid (III) gave the 2-phenyl indole (IV). The phthaloyl group of (IV) was then removed by treatment with dimethylamine to furnish 2-phenyltryptamine (V). Then condensation of amine (V) with 3-methyl-2-oxovaleric acid (VI) using EDC and HOBt yielded the corresponding amide.

参考文献中间体

合成目标

【1】 Viziano, M.; Seneci, P.; Michelli, F.; Cavallini, P.; Zumerle, A.; Kennedy, G.; Winders, J.A.; Gevi, M.; Rodegher, P.; Studies on the novel anti-staphyloccal compound nematophin. Bioorg Med Chem Lett 2000, 10, 15, 1751.

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)	46946	2-[2-(1H-indol-3-yl)ethyl]-1H-isoindole-1,3(2H)-dione		C₁₈H₁₄N₂O₂	详情	详情
(II)	46947	2-[2-(2-bromo-1H-indol-3-yl)ethyl]-1H-isoindole-1,3(2H)-dione		C₁₈H₁₃BrN₂O₂	详情	详情
(III)	16593	Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide	98-80-6	C₆H₇BO₂	详情	详情
(IV)	46948	2-[2-(2-phenyl-1H-indol-3-yl)ethyl]-1H-isoindole-1,3(2H)-dione		C₂₄H₁₈N₂O₂	详情	详情
(V)	46949	2-(2-phenyl-1H-indol-3-yl)-1-ethanamine; 2-(2-phenyl-1H-indol-3-yl)ethylamine		C₁₆H₁₆N₂	详情	详情
(VI)	46950	3-methyl-2-oxopentanoic acid		C₆H₁₀O₃	详情	详情

Extended Information