methyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoate -Drug Synthesis Database

【结构式】

【分子编号】15884

【品名】methyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoate

【CA登记号】

【分子式】C₂₇H₃₆FNO₅

【分子量】473.5849832

【元素组成】C 68.48% H 7.66% F 4.01% N 2.96% O 16.89%

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：(IX)

The compound can be obtained in a multistep synthesis as outlined in Scheme 18923701a. The cyclization of ethyl 3-amino-4-methylpent-2-enoate and 4-(ethoxycarbonyl)-5-(4-fluorophenyl)-2-methylpent-4-en-3-one (II) in a conventional dihydropyridine synthesis gives the dihydropyridine (III), which is oxidized to the symmetric penta-substituted pyridine (IV). After selective monoreduction with Red-Al the pyridine alcohol (V) is methylated to (VI). The second ester group is converted to the aldehyde (VII) in a two-step reduction/oxidation procedure. trans-Selective Wittig-Horner reaction with diethyl 2-(cyclohexylamino)vinylphosphonate affords the alpha,beta-unsaturated aldehyde (VIII). The condensation of (VIII) with methyl acetoacetate and subsequent erythro-selective reduction with triethylborane and NaBH4 results in the racemic dihydroxyester (IX). The reaction of (IX) with (S)-(+)-phenylglycinol yields the two diastereomeric (S)-(+)-phenylglycinolamides which can be separated on a silical gel column. After hydrolysis of the phenylglycinolamide (X) the sodium salt of the (+)-enantiomer is obtained.

参考文献中间体

合成目标

【1】 Angerbauer, R.; Fey, P.; Hubsch, W.; Philipps, T.; Bischoff, H.; Petzinna, D.; Schmidt, D.; Thomas, G. (Bayer AG); Substituted pyridines. AU 8928617; EP 0325130; JP 1989216974; US 5006530; US 5169857 .
【2】 Angerbauer, R.; Fey, P.; Hubsch, W.; Philipps, T.; Bischoff, H.; Petzinna, D.; Schmidt, D.; Thomas, G. (Bayer AG); Substituted pyridyl-dihydroxy-heptenoic acid and its salts. DE 4040026; EP 0491226; JP 1992308573; US 5177080 .
【3】 Bischoff, H.; Ritter, W.; Steinke, W.; Angerbauer, R.; BAY W 6228. Drugs Fut 1994, 19, 6, 537.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	42234	Diethyl 2-(cyclohexylamino)vinylphosphonate	C₁₂H₂₄NO₃P	详情	详情
(I)	15876	ethyl (E)-3-amino-4-methyl-2-pentenoate	C₈H₁₅NO₂	详情	详情
(II)	15877	ethyl (Z)-3-(4-fluorophenyl)-2-isobutyryl-2-propenoate	C₁₅H₁₇FO₃	详情	详情
(III)	15878	diethyl 4-(4-fluorophenyl)-2,6-diisopropyl-1,4-dihydro-3,5-pyridinedicarboxylate	C₂₃H₃₀FNO₄	详情	详情
(IV)	15879	diethyl 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-pyridinedicarboxylate	C₂₃H₂₈FNO₄	详情	详情
(V)	15880	ethyl 4-(4-fluorophenyl)-5-(hydroxymethyl)-2,6-diisopropylnicotinate	C₂₁H₂₆FNO₃	详情	详情
(VI)	15881	ethyl 4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)nicotinate	C₂₂H₂₈FNO₃	详情	详情
(VII)	15882	4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)nicotinaldehyde	C₂₀H₂₄FNO₂	详情	详情
(VIII)	15883	(E)-3-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]-2-propenal	C₂₂H₂₆FNO₂	详情	详情
(IX)	15884	methyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoate	C₂₇H₃₆FNO₅	详情	详情
(X)	15885	(3R,5S,6E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]-3,5-dihydroxy-N-[(1S)-2-hydroxy-1-phenylethyl]-6-heptenamide	C₃₄H₄₃FN₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

In an alternative approach, the racemic dihydroxymethyl ester (IX) is converted to the racemic lactone (XI), which can be separated into the pure enantiomers on a large-scale chromatography using the newly developed chiral phase Baychiral PM. Finally, the (+)-lactone (XII) is hydrolyzed to BAY W 6228.

参考文献中间体

合成目标

【1】 Angerbauer, R.; Bischoff, H.; Bömer, B.; Fey, P.; Grosser, R.; Hübsch, W.; Lange, W.; Lautz, J.; Philipps, T.; Schmidt, D.; Stereoselective biological activity of the synthetic HMG-CoA reductase inhibitor BAY W 6228. 2nd Eur Med Chem Conf (March 31-April 4, Bad Nauheim) 1993, 1993.
【2】 Bischoff, H.; Ritter, W.; Steinke, W.; Angerbauer, R.; BAY W 6228. Drugs Fut 1994, 19, 6, 537.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	15884	methyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoate	C₂₇H₃₆FNO₅	详情	详情
(XI)	64684	(rac)-[(4R,6S)-6-{(E)-2-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]ethenyl}-4-hydroxytetrahydro-2H-pyran-2-one]	C₂₆H₃₂FNO₄	详情	详情
(XII)	15886	(4R,6S)-6-[(E)-2-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]ethenyl]-4-hydroxytetrahydro-2H-pyran-2-one	C₂₆H₃₂FNO₄	详情	详情
(XIII)	15888	(4S,6R)-6-[(E)-2-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]ethenyl]-4-hydroxytetrahydro-2H-pyran-2-one	C₂₆H₃₂FNO₄	详情	详情

Extended Information