ethyl 2,4-dioxopentanoate -Drug Synthesis Database

【结构式】

【分子编号】42500

【品名】ethyl 2,4-dioxopentanoate

【CA登记号】615-79-2

【分子式】C₇H₁₀O₄

【分子量】158.154

【元素组成】C 53.16% H 6.37% O 40.47%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

Total synthesis: Reaction of ethyl acetopyruvate (I) with triethyl orthoformate gives compound (II), which is then treated with cyanoacetamide to yield 3-cyano-4-methyl-6-(carbethoxy)-2(1H)-pyridone (III). The reaction of (III) with methyl acrylate (A) gives compound (IV), which is sequentially submitted to decarboxylation, ketalization and treatment with diethylcarbonate, giving the functionalized tetrahydroindolizine (V). Ethylation of (V) followed by reduction in the presence of acetic anhydride gives the amide (VI), which is reacted with sodium nitrite, refluxed in CCl4, hydrolyzed and acidified to give the tricyclic compound (VII). The DIBAL reduction of (VII) and subsequent elimination of the hydroxyl group gives the cyclic enol ether (VIII). Asymmetric dihydroxylation of compound (VIII) with (DHQD)2PHAL, K2OsO4 and K3Fe(CN)6 in t-BuOH gives the diol (IX). The oxidation and deketalization of compound (IX) gives (S)-hydroxylactone (X). Finally, Friedlander condensation of the lactone (X) with 3-[N-isopropyl-N-(carbobenzyloxy)amino]-1-(2-aminophenyl)propan-1-one (B) followed by deprotection gives CKD-602.

参考文献中间体

合成目标

【1】 Hong, C.I.; Kim, J.K.; Ahn, S.K.; CKD-602. Drugs Fut 2000, 25, 12, 1243.
【2】 Kim, J.M.; Jew, S.; Kim, M.G.; Kim, H.-J.; Hah, J.M.; Ok, K.; Cho, Y.; Enantioselective synthesis of 20(S)-camptothecin using sharpless catalytic asymmetric dihydroxylation. Tetrahedron Asymmetry 1995, 6, 6, 1245.
【3】 Jew, S.-S.; Kim, H.-J.; Kim, M.G.; et al.; Synthesis and antitumor activity of 7-substituted 20(RS)-camptothecin analogues. Bioorg Med Chem Lett 1996, 6, 7, 845.

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)	42500	ethyl 2,4-dioxopentanoate	615-79-2	C₇H₁₀O₄	详情	详情
(II)	42501	ethyl (Z)-4-ethoxy-2-oxo-3-pentenoate		C₉H₁₄O₄	详情	详情
(III)	15637	ethyl 5-cyano-4-methyl-6-oxo-1,6-dihydro-2-pyridinecarboxylate		C₁₀H₁₀N₂O₃	详情	详情
(IV)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(V)	15639	methyl 6-cyano-1-hydroxy-7-methyl-5-oxo-3,5-dihydro-2-indolizinecarboxylate		C₁₂H₁₀N₂O₄	详情	详情
(VI)	15642	2-[6'-Cyano-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]acetic acid ethyl ester		C₁₅H₁₆N₂O₅	详情	详情
(VII)	15644	2-[6'-(Acetamidomethyl)-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester		C₁₉H₂₆N₂O₆	详情	详情
(VIII)	42502			C₁₅H₁₇NO₅	详情	详情
(IX)	42503			C₁₅H₁₇NO₄	详情	详情
(X)	42504			C₁₅H₁₉NO₆	详情	详情
(XI)	10841	(4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione		C₁₃H₁₃NO₅	详情	详情
(XII)	42505	benzyl 3-(2-aminophenyl)-3-oxopropyl(isopropyl)carbamate		C₂₀H₂₄N₂O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Ethyl 2,4-dioxopentanoate (V) was converted into the O-methyloxime (VI) and subsequently cyclized with 4-methoxyphenylhydrazine (VII) to furnish pyrazole (VIII) (1,2). Optionally, ester (VIII) was hydrolyzed and then converted to acid chloride (IX) by treatment with oxalyl chloride (1). Biphenylamine (IV) was coupled with ester (VIII) in the presence of trimethylaluminium (2) or, alternatively, with acid chloride (IX) (1) to give amide (X). The N-tert-butyl group of (X) was finally removed by refluxing in trifluoroacetic acid.

参考文献中间体

合成目标

【1】 Galemmo, R.A. Jr.; Fevig, J.; Lam, P.Y.; et al.; New functional groups for interaction with the S1 pocket of factor Xa: The discovery of 1-(4-methoxyphenyl)pyrazole inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 290.
【2】 Dominguez, C.; Fevig, J.M.; Galemmo, R.A. Jr.; Pinto, D.J.P.; Pruitt, J.R.; lma, P.; Quan, M.L.; Han, Q. (DuPont Pharmaceuticals Co.); Inhibitors of factor Xa with a neutral P1 specificity group. US 5998424; WO 9857937 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	23363	4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide		C₁₆H₂₀N₂O₂S	详情	详情
(V)	42500	ethyl 2,4-dioxopentanoate	615-79-2	C₇H₁₀O₄	详情	详情
(VI)	44129	ethyl 2-(methoxyimino)-4-oxopentanoate		C₈H₁₃NO₄	详情	详情
(VII)	12688	4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine	3471-32-7	C₇H₁₀N₂O	详情	详情
(VIII)	44130	ethyl 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxylate		C₁₄H₁₆N₂O₃	详情	详情
(IX)	44131	1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carbonyl chloride		C₁₂H₁₁ClN₂O₂	详情	详情
(X)	44132	N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxamide		C₂₈H₃₀N₄O₄S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Cyclization of ethyl 2,4-dioxovalerate (I) with 3-(trifluoromethyl)phenylhydrazine (II) in a refluxing mixture of HOAc and 2-methoxyethanol produced pyrazole ester (III). After saponification of the ethyl ester group of (III), the resulting carboxylic acid (IV) was coupled to 5-aminoisoquinoline (V) by using O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate to furnish the corresponding amide.

参考文献中间体

合成目标

【1】 Kordik, C.P.; Rosenthal, D.I.; Luo, C.; Reitz, A.B.; Vaidya, A.H.; Crooke, J.J.; Zanoni, B.C.; Lovenberg, T.W.; Wilson, S.J.; Pyrazolecarboxamide human neuropeptide Y5 receptor ligands with in vivo antifeedant activity. Bioorg Med Chem Lett 2001, 11, 17, 2287.
【2】 Kordik, C.P.; Lou, C.; Zanoni, B.; et al.; Pyrazole-based antagonists of the human neuropeptide-Y5 (NPY5) receptor. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 304.
【3】 Reitz, A.B.; Lovenberg, T.W.; Kordik, C.P. (Ortho-McNeil Pharmaceutical, Inc.); Pyrazole carboxamides useful for the treatment of obesity and other disorders. WO 0069849 .

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)	42500	ethyl 2,4-dioxopentanoate	615-79-2	C₇H₁₀O₄	详情	详情
(II)	44088	1-[3-(trifluoromethyl)phenyl]hydrazine	368-78-5	C₇H₇F₃N₂	详情	详情
(III)	44089	ethyl 5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate		C₁₄H₁₃F₃N₂O₂	详情	详情
(IV)	44090	5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylic acid		C₁₂H₉F₃N₂O₂	详情	详情
(V)	44091	8-isoquinolinylamine; 8-isoquinolinamine		C₉H₈N₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

3-Amino-2-naphthoic acid (I) is diazotized with NaNO2/HCl, and the obtained diazonium salt is then isolated as the corresponding tetrafluoroborate (II). Subsequent thermal decomposition of the diazonium tetrafluoroborate (II) in refluxing xylene leads to 3-fluoro-2-naphthoic acid (III). After chlorination of (III) with oxalyl chloride, the resultant acid chloride (IV) is treated with NaN3 to produce the acyl azide (V), which undergoes Curtius rearrangement to the amine (VI) in refluxing aqueous DMF. Diazotization of (VI), followed by reduction with SnCl2 gives rise to hydrazine (VII). Treatment of ethyl 2,4-dioxovalerate (VIII) with O-methylhydroxylamine gives oxime (IX), which is then condensed with hydrazine (VII), yielding the intermediate pyrazole (X).

参考文献中间体

合成目标

【1】 Jia, Z.J.; et al.; Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors: Part 1: Structure-activity relationships of the substituted 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides. Bioorg Med Chem Lett 2002, 12, 12, 1651.
【2】 Wang, L.; Zhu, B.-Y.; Li, W.; Zhang, P.; Huang, W.; Song, Y.; Goldman, E.; Zuckett, J.; Scarborough, R. (Millennium Pharmaceuticals, Inc.); Benzamides and related inhibitors of factor Xa. EP 1216228; EP 1216231; WO 0119788; WO 0119798 .

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)	47431	3-amino-2-naphthoic acid	5959-52-4	C₁₁H₉NO₂	详情	详情
(II)	57028			C₁₁H₇BF₄N₂O₂	详情	详情
(III)	57029	3-fluoro-2-naphthoic acid		C₁₁H₇FO₂	详情	详情
(IV)	57030	3-fluoro-2-naphthoyl chloride		C₁₁H₆ClFO	详情	详情
(V)	57031	3-fluoro-2-naphthoyl azide		C₁₁H₆FN₃O	详情	详情
(VI)	57032	3-fluoro-2-naphthalenamine; 3-fluoro-2-naphthylamine		C₁₀H₈FN	详情	详情
(VII)	57033	1-(3-fluoro-2-naphthyl)hydrazine		C₁₀H₉FN₂	详情	详情
(VIII)	42500	ethyl 2,4-dioxopentanoate	615-79-2	C₇H₁₀O₄	详情	详情
(IX)	44129	ethyl 2-(methoxyimino)-4-oxopentanoate		C₈H₁₃NO₄	详情	详情
(X)	57034	ethyl 1-(3-fluoro-2-naphthyl)-3-methyl-1H-pyrazole-5-carboxylate		C₁₇H₁₅FN₂O₂	详情	详情

Extended Information