ethyl 4-methyl-3-oxopentanoate -Drug Synthesis Database

【结构式】

【分子编号】19408

【品名】ethyl 4-methyl-3-oxopentanoate

【CA登记号】7152-15-0

【分子式】C₈H₁₄O₃

【分子量】158.19736

【元素组成】C 60.74% H 8.92% O 30.34%

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：(II)

The condensation of 4-fluorobenzaldehyde (I) with 4-methyl-3-oxopentanoic acid ethyl ester (II) by means of piperidine/AcOH in refluxing benzene gives the corresponding benzylidene derivative (III), which is cyclized with S-methylisothiourea (IV) and oxidized with DDQ, affording the pyrimidine derivative (V). The oxidation of (V) with m-chloroperbenzoic acid (m-CPBA) gives the expected methanesulfonyl derivative (VI), which is treated first with methylamine and then with methanesulfonyl chloride to provide the N-methylmethanesulfonamide (VII). The reduction of the ester group of (VII) with DIBAL in toluene, followed by selective oxidation of the resulting alcohol with TPAP, affords the aldehyde (VIII), which is submitted to a Wittig condensation with the phosphorane (IX) in acetonitrile to give the protected heptenoate (X). The deprotection of (X) with FH and the controlled reduction of the resulting keto alcohol with Et2BOMe and NaBH4 affords the chiral dihydroxyheptenoate (XI), which is hydrolyzed with NaOH in ethanol, yielding the corresponding sodium salt (XII). Finally, this compound is treated with calcium chloride.

参考文献中间体

合成目标

【1】 Watanabe, M.; et al.; Synthesis and biological activity of methanesulfonamide pyrimidine- and N-methanesulfonyl pyrrole-substituted 3,5-dihydroxy-6-heptenoates, a novel series of HMG-CoA reductase inhibitors. Bioorg Med Chem 1997, 5, 2, 437.
【2】 Castañer, J.; Graul, A.; ZD-4522. Drugs Fut 1999, 24, 5, 511.
【3】 Hirai, K.; Ishiba, T.; Koike, H.; Watanabe, M. (Shionogi & Co. Ltd.); Pyrimidine derivs. as HMG-CoA reductase inhibitors. EP 0521471; JP 1993178841; US 5260440 .

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)	12337	4-fluorobenzaldehyde	459-57-4	C₇H₅FO	详情	详情
(II)	19408	ethyl 4-methyl-3-oxopentanoate	7152-15-0	C₈H₁₄O₃	详情	详情
(III)	15877	ethyl (Z)-3-(4-fluorophenyl)-2-isobutyryl-2-propenoate		C₁₅H₁₇FO₃	详情	详情
(IV)	10272	[[Amino(imino)methyl]sulfanyl]methane	2986-19-8	C₂H₆N₂S	详情	详情
(V)	23879	ethyl 4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfanyl)-5-pyrimidinecarboxylate		C₁₇H₁₉FN₂O₂S	详情	详情
(VI)	23880	ethyl 4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfonyl)-5-pyrimidinecarboxylate		C₁₇H₁₉FN₂O₄S	详情	详情
(VII)	23881	ethyl 4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinecarboxylate		C₁₈H₂₂FN₃O₄S	详情	详情
(VIII)	23882	N-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-2-pyrimidinyl]-N-methylmethanesulfonamide	147118-37-4	C₁₆H₁₈FN₃O₃S	详情	详情
(IX)	23884	methyl (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-oxo-6-(triphenylphosphoranylidene)hexanoate	147118-35-2	C₃₁H₃₉O₄PSi	详情	详情
(X)	23883	methyl (3R,6E)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-5-oxo-6-heptenoate	147118-38-5	C₂₉H₄₂FN₃O₆SSi	详情	详情
(XI)	23885	methyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoate	147118-40-9	C₂₃H₃₀FN₃O₆S	详情	详情
(XII)	23887	sodium (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoate	147098-18-8	C₂₂H₂₇FN₃NaO₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Cyclization of ethyl 4-methyl-3-oxopentanoate (I) with guanidine carbonate (II) in boiling EtOH gave 2-amino-4-hydroxy-6-isopropylpyrimidine (III), which was converted to the corresponding chloropyrimidine (IV) by means of POCl3. Boronic ester (VI) was prepared by lithiation of 1-bromo-4-fluoronaphthalene (V) with n-butyllithium, followed by reaction with trimethyl borate. Subsequent coupling of chloropyrimidine (IV) with boronic ester (VI) in the presence of tetrakis(triphenylphosphine)palladium yielded the target naphthylpyrimidine.

参考文献中间体

合成目标

【1】 Berger, J.; Flippin, L.A.; Greenhouse, R.; Jaime-Figueroa, S.; Liu, Y.; Miller, A.K.; Putman, D.G.; Weinhardt, K.K.; Zhao, S.-H. (F. Hoffmann-La Roche AG); Aryl pyrimidine derivs.. EP 0901474; US 5863924; WO 9744326 .

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)	19408	ethyl 4-methyl-3-oxopentanoate	7152-15-0	C₈H₁₄O₃	详情	详情
(II)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(III)	30387	2-amino-6-isopropyl-4-pyrimidinol		C₇H₁₁N₃O	详情	详情
(IV)	30388	4-chloro-6-isopropyl-2-pyrimidinylamine; 4-chloro-6-isopropyl-2-pyrimidinamine		C₇H₁₀ClN₃	详情	详情
(V)	30389	1-bromo-4-fluoronaphthalene	341-41-3	C₁₀H₆BrF	详情	详情
(VI)	30390	dimethyl 4-fluoro-1-naphthylboronate		C₁₂H₁₂BFO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

Acid chloride (II) (prepared from 4-bromophenylacetic acid (I) and SOCl2), was condensed with ethyl isobutyrylacetate (III) in the presence of NaH in toluene to yield diketoester (IV). Further reaction of (IV) with hydrazine monohydrate in AcOH gave pyrazole (V). The subsequent N-alkylation of (V) with propyl iodide and NaH provided a 3:1 mixture of regioisomers (VI) and (VII), which were separated by silica gel chromatography. The major isomer (VI) was coupled with arylboronic acid (VIII) in the presence of CsF and Pd(PPh3)4 to provide biphenyl compound (IX). The title compound was then obtained by simultaneous cleavage of the ethyl ester and the N-trityl group on heating with hydroethanolic KOH.

参考文献中间体

合成目标

【1】 Almansa, C.; Gonzales, C.; Torres, M.C.; Carceller, E.; Bartroli, J. (J. Uriach & Cia., SA); New pyrazole derivs. as angiotensin II antagonists. EP 0721454; ES 2105939; JP 1997504804; WO 9604273 .

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)	14247	2-(4-Bromophenyl)acetic acid; p-Bromophenylacetic acid; 4-Bromophenylacetic acid	1878-68-8	C₈H₇BrO₂	详情	详情
(II)	19407	2-(4-bromophenyl)acetyl chloride		C₈H₆BrClO	详情	详情
(III)	19408	ethyl 4-methyl-3-oxopentanoate	7152-15-0	C₈H₁₄O₃	详情	详情
(IV)	19409	ethyl 2-[2-(4-bromophenyl)acetyl]-4-methyl-3-oxopentanoate		C₁₆H₁₉BrO₄	详情	详情
(V)	19410	ethyl 5-(4-bromobenzyl)-3-isopropyl-1H-pyrazole-4-carboxylate		C₁₆H₁₉BrN₂O₂	详情	详情
(VI)	19411	ethyl 5-(4-bromobenzyl)-3-isopropyl-1-propyl-1H-pyrazole-4-carboxylate		C₁₉H₂₅BrN₂O₂	详情	详情
(VII)	19412	ethyl 3-(4-bromobenzyl)-5-isopropyl-1-propyl-1H-pyrazole-4-carboxylate		C₁₉H₂₅BrN₂O₂	详情	详情
(VIII)	19413	2-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)phenylboronic acid		C₂₆H₂₁BN₄O₂	详情	详情
(IX)	19414	ethyl 3-isopropyl-1-propyl-5-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-pyrazole-4-carboxylate		C₄₅H₄₄N₆O₂	详情	详情

Extended Information