ethyl 2-oxopropanoate; Ethyl pyruvate -Drug Synthesis Database

【结构式】

【分子编号】12135

【品名】ethyl 2-oxopropanoate; Ethyl pyruvate

【CA登记号】617-35-6

【分子式】C₅H₈O₃

【分子量】116.11672

【元素组成】C 51.72% H 6.94% O 41.34%

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：(V)

The cyclization of methyl 2-aminobenzoate (I) with 2,5-dimethoxytetrahydrofuran (II) in refluxing acetic acid gives methyl 2-(pyrrol-1-yl)benzoate (III), which by reduction with LiAlH4 in ether is converted into 2-(pyrrol-1-yl)benzyl alcohol (IV). The cyclization of (IV) with ethyl 2-oxopropionate (V) by means of butyllithium and tetramethylethylenediamine (TMEDA) in THF affords 4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylic acid ethyl ester (VI), which is hydrolyzed with NaOH in refluxing ethanol to the corresponding free acid (VII). The condensation of (VII) with 1-(piperidin-4-yl)-2,3-dihydro-1H-benzimidazol-2-one (VIII) by means of carbonyldiimidazol (CDI) in THF gives 1-[1-(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-ylcarbonyl) piperidin-4-yl]-2,3-dihydro-1H-benzimidazol-2-one (IX), which is finally reduced with LiAlH4 in THF, and treated with maleic acid in acetone.

参考文献中间体

合成目标

【1】 Robinson, C.; Robinson, K.; Castaner, J.; Zaldaride Maleate. Drugs Fut 1996, 21, 7, 719.
【2】 Wasley, J.W.F.; Norman, J. (Novartis AG); Pyrrolo[1,2-a][4,1]benzoxazepins, process for their preparation, pharmaceutical compsns. containing them as well as therapeutic use. EP 0233483; JP 1987169791; JP 1995089966; US 4758559 .

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)	11161	methyl 2-aminobenzoate; Methyl anthranilate	134-20-3	C₈H₉NO₂	详情	详情
(II)	12132	2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether	696-59-3	C₆H₁₂O₃	详情	详情
(III)	12133	methyl 2-(1H-pyrrol-1-yl)benzoate		C₁₂H₁₁NO₂	详情	详情
(IV)	12134	[2-(1H-Pyrrol-1-yl)phenyl]methanol		C₁₁H₁₁NO	详情	详情
(V)	12135	ethyl 2-oxopropanoate; Ethyl pyruvate	617-35-6	C₅H₈O₃	详情	详情
(VI)	12136	ethyl 4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylate		C₁₆H₁₇NO₃	详情	详情
(VII)	12137	4-Methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylic acid		C₁₄H₁₃NO₃	详情	详情
(VIII)	12138	1-(4-Piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one; 4-(2-Keto-1-benzimidazolinyl)piperidine	20662-53-7	C₁₂H₁₅N₃O	详情	详情
(IX)	12139	1-[1-[(4-Methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)carbonyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one		C₂₆H₂₆N₄O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Condensation of dichloronitrotoluene (I) with diethyl oxalate in the presence of KOEt afforded phenylpyruvate (II), and subsequent reductive cyclization gave indole-2-carboxylate (VI). Alternatively, condensation of 3,4-dichlorophenyl hydrazine (III) with ethyl pyruvate (IV) provided hydrazone (V). Then, Fischer indole synthesis with p-TsOH in refluxing toluene yielded a mixture of 5,6-dichloroindole (VI) and the corresponding 4,5-dichloroindole. Ester reduction using LiAlH4 in THF afforded alcohol (VII), which was subsequently oxidized to aldehyde (VIII) with MnO2 in Et2O. Condensation of (VIII) with phosphonate (IX) in the presence of NaH provided E-indolylpropenoate (X). Then, the sequence of DIBAH reduction, followed by oxidation of the resulting allyl alcohol (XI) with MnO2 in EtOAc furnished aldehyde (XII).

参考文献中间体

合成目标

【1】 Consolandi, E.; Nadler, G.; Gagliardi, S.; et al.; 5-(5,6-Dichloro-2-indolyl)-2-methoxy-2, 4-pentadienamides: Novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. J Med Chem 1998, 41, 10, 1568.
【2】 Farina, C.; Gagliardi, S.; Parini, C.; Pinza, M.; Nadler, G.M.M.G.; Morvan, M.J.-M. (SmithKline Beecham SpA); Indole derivs. useful in the treatment of osteoporosis. JP 1998512251; WO 9621644 .

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)	19088	1,2-dichloro-4-methyl-5-nitrobenzene		C₇H₅Cl₂NO₂	详情	详情
(II)	19089	ethyl 3-(4,5-dichloro-2-nitrophenyl)-2-oxopropanoate		C₁₁H₉Cl₂NO₅	详情	详情
(III)	19090	1-(3,4-dichlorophenyl)hydrazine		C₆H₆Cl₂N₂	详情	详情
(IV)	12135	ethyl 2-oxopropanoate; Ethyl pyruvate	617-35-6	C₅H₈O₃	详情	详情
(V)	19092	ethyl 2-[(Z)-2-(3,4-dichlorophenyl)hydrazono]propanoate		C₁₁H₁₂Cl₂N₂O₂	详情	详情
(VI)	19093	ethyl 5,6-dichloro-1H-indole-2-carboxylate		C₁₁H₉Cl₂NO₂	详情	详情
(VII)	19094	(5,6-dichloro-1H-indol-2-yl)methanol		C₉H₇Cl₂NO	详情	详情
(VIII)	19095	5,6-dichloro-1H-indole-2-carbaldehyde		C₉H₅Cl₂NO	详情	详情
(IX)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(X)	19097	ethyl (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenoate		C₁₃H₁₁Cl₂NO₂	详情	详情
(XI)	19098	(E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propen-1-ol		C₁₁H₉Cl₂NO	详情	详情
(XII)	19099	(E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenal		C₁₁H₇Cl₂NO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

Diazotization of 3,5-dichloroaniline (I), followed by reduction of the resultant diazonium salt provides hydrazine (II). Subsequent reaction of 3,5-dichlorophenylhydrazine (II) with ethyl pyruvate (III) under Fischer reaction conditions gives rise to indole (IV). Vilsmeier formylation of (IV) using N-methylformanilide and phosphoryl chloride produces aldehyde (V). This is reductively aminated with methyl glycinate and NaBH(OAc)3 to afford aminoester (VI). Condensation of (VI) with phenyl isocyanate, followed by cyclization in the presence of Et3N leads to hydantoin (VII). Finally, ester (VII) is hydrolyzed employing LiOH to furnish the target indolecarboxylic acid.

参考文献中间体

合成目标

【1】 Jansen, M.; Potschka, H.; Brandt, C.; Loscher, W.; Dannhardt, G.; Hydantoin-substituted 4,6-dichloroindole-2-carboxylic acids as ligands with high affinity for the glycine binding site of the NMDA receptor. J Med Chem 2003, 46, 1, 64.

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)	26542	3,5-dichloroaniline	626-43-7	C₆H₅Cl₂N	详情	详情
(II)	28066	1-(3,5-dichlorophenyl)hydrazine	39943-56-1	C₆H₆Cl₂N₂	详情	详情
(III)	12135	ethyl 2-oxopropanoate; Ethyl pyruvate	617-35-6	C₅H₈O₃	详情	详情
(IV)	32142	ethyl 4,6-dichloro-1H-indole-2-carboxylate		C₁₁H₉Cl₂NO₂	详情	详情
(V)	32144	ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate		C₁₂H₉Cl₂NO₃	详情	详情
(VI)	64389	ethyl 4,6-dichloro-3-({[2-(methyloxy)-2-oxoethyl]amino}methyl)-1H-indole-2-carboxylate		C₁₅H₁₆Cl₂N₂O₄	详情	详情
(VII)	64390	ethyl 4,6-dichloro-3-[(2,4-dioxo-3-phenyl-1-imidazolidinyl)methyl]-1H-indole-2-carboxylate		C₂₁H₁₇Cl₂N₃O₄	详情	详情

Extended Information