(6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-5,6-dihydro-2H-pyran-2-one -Drug Synthesis Database

【结构式】

【分子编号】17462

【品名】(6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-5,6-dihydro-2H-pyran-2-one

【CA登记号】

【分子式】C₂₅H₂₀FNO₂

【分子量】385.4377432

【元素组成】C 77.9% H 5.23% F 4.93% N 3.63% O 8.3%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XLIV)

Elimination of thiophenol from (XLIII) by means of CaCO3 in refluxing toluene gives the unsaturated lactone (XLIV) with the (E)-vinylene bond. The alpha,beta-epoxidation of the unsaturated lactone (XLIV) with H2O2 and NaOH in methanol/dichloromethane affords the monoepoxy lactone (XLV) regioselectively, which is finally submitted to a regioselective ring opening with diphenyl diselenide and NaBH4 in THF.

参考文献中间体

合成目标

【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859.
【2】 Kamikubo, T.; Takano, S.; Sugihara, T.; Suzuki, M.; Ogasawara, K.; Enantioconvergent synthesis of a promising HMG-CoA reductase inhibitor NK-104 from both enantiomers of epichlorohydrin. Tetrahedron Asymmetry 1993, 4, 2, 201-4.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XLIII)	17457	(6S)-6-[2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-(phenylsulfinyl)ethyl]-5,6-dihydro-2H-pyran-2-one	C₃₁H₂₆FNO₃S	详情	详情
(XLIV)	17462	(6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-5,6-dihydro-2H-pyran-2-one	C₂₅H₂₀FNO₂	详情	详情
(XLV)	17463	(1R,4S,6R)-4-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-3,7-dioxabicyclo[4.1.0]heptan-2-one	C₂₅H₂₀FNO₃	详情	详情
(XLVI)	64696	(4R,6S)-6-{(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl}-4-hydroxytetrahydro-2H-pyran-2-one	C₂₅H₂₂FNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Isonipecotic acid (I) was protected with benzyl chloroformate and the resultant 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (II) was subsequently converted to the corresponding acid chloride (III) by treatment with SOCl2. Coupling of acid chloride (III) with 4-(tert-butoxycarbonylamino)piperidine (IV) afforded the piperidinyl amide (V), which was further reduced with BH3 to the piperidinylmethyl piperidine (VI). Aminopiperidine (VII), obtained by acidic cleavage of the N-Boc group of (VI), was then coupled with 4-amino-5-chloro-2-methoxybenzoic acid (VIII) to provide amide (IX). Deprotection of the N-benzyloxycarbonyl group was carried out by means of methanesulfonic acid in the presence of anisole to give (X). Acylation of piperidine (X) with the protected aminoacid (XI) yielded amide (XII). Then, selective reduction of the aliphatic amide function, followed by deprotection of the amino group provided the title compound.

参考文献中间体

合成目标

【1】 Harada, H.; et al.; Novel N-[1-(1-substituted 4-piperidinylmethyl)-4-piperidinyl]benzamides as potent colonic prokinetic agents. Bioorg Med Chem Lett 2002, 12, 6, 967.
【2】 Kato, S.; Yoshida, N.; Harada, H.; Toyotomi, Y.; Morikage, S. (Dainippon Pharmaceutical Co., Ltd.); Benzamido derivs. and medicinal compsns. containing the same. JP 1999001472 .

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)	17462	(6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-5,6-dihydro-2H-pyran-2-one		C₂₅H₂₀FNO₂	详情	详情
(II)	56082	Z-Isonipecotic acid	10314-98-4	C₁₄H₁₇NO₄	详情	详情
(III)	35165	benzyl 4-(chlorocarbonyl)-1-piperidinecarboxylate		C₁₄H₁₆ClNO₃	详情	详情
(IV)	41601	tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine	73874-95-0	C₁₀H₂₀N₂O₂	详情	详情
(V)	56548	benzyl 4-({4-[(tert-butoxycarbonyl)amino]-1-piperidinyl}carbonyl)-1-piperidinecarboxylate		C₂₄H₃₅N₃O₅	详情	详情
(VI)	56549	benzyl 4-({4-[(tert-butoxycarbonyl)amino]-1-piperidinyl}methyl)-1-piperidinecarboxylate		C₂₄H₃₇N₃O₄	详情	详情
(VII)	56550	benzyl 4-[(4-amino-1-piperidinyl)methyl]-1-piperidinecarboxylate		C₁₉H₂₉N₃O₂	详情	详情
(VIII)	12419	4-Amino-5-chloro-2-methoxybenzoic acid	7206-70-4	C₈H₈ClNO₃	详情	详情
(IX)	56551	benzyl 4-({4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinyl}methyl)-1-piperidinecarboxylate		C₂₇H₃₅ClN₄O₄	详情	详情
(X)	56552	4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide		C₁₉H₂₉ClN₄O₂	详情	详情
(XI)	56553	N-Carbobenzoxy-4-amino-n-butyric acid; N-Carbobenzoxy-gamma-aminobutyric acid	5105-78-2	C₁₂H₁₅NO₄	详情	详情
(XII)	56554	benzyl 4-[4-({4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinyl}methyl)-1-piperidinyl]-4-oxobutylcarbamate		C₃₁H₄₂ClN₅O₅	详情	详情

Extended Information