methyl (5R)-5-hydroxy-2-[(1S)-1-(3-nitrophenyl)propyl]-3-oxo-5-phenethyloctanoate -Drug Synthesis Database

【结构式】

【分子编号】21167

【品名】methyl (5R)-5-hydroxy-2-[(1S)-1-(3-nitrophenyl)propyl]-3-oxo-5-phenethyloctanoate

【CA登记号】

【分子式】C₂₆H₃₃NO₆

【分子量】455.55116

【元素组成】C 68.55% H 7.3% N 3.07% O 21.07%

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：(XIII)

1) The condensation of 1-phenylhexan-3-one (I) with ethyl acetate by means of butyllithium and diisopropylamine in THF gives racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ethyl ester (II), which is hydrolyzed with NaOH in methanol to the corresponding free acid (III). The optical resolution of (III) with (1R,2S)-(-)-norephedrine (IV) followed by treatment with aqueous HCl yields the chiral (R)-acid (V), which is treated with 4-biphenylyloxymethyl chloride (VI) and diisopropylethylamine in toluene affording the protected ester (VII). The reduction of the ester group of (VII) with diisobutylaluminum hydride (DIBAL) in toluene gives the monoprotected diol (VIII), which is oxidized at the primary hydroxy group with 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy radical (TEMPO) and NaOCl yielding the corresponding aldehyde (IX). The condensation of (IX) with (R)-3-(3-nitrophenyl)pentanoic acid methyl ester (X) by means of sodium hexamethyldisilazide (NaHMDS) in THF gives the hydroxyester (XI) as a mixture of four diastereomers. This mixture is oxidized with pyridinium chlorochromate (PCC) in dichloromethane to afford the ketoester (XII) also as a mixture of two diastereomers. Elimination of the biphenylyloxymethyl protecting group with H2SO4 in methanol yields the hydroxy ketoester (XIII).

参考文献中间体

合成目标

【1】 Fors, K.S.; et al.; A convergent, scalable synthesis of HIV protease inhibitor PNU-140690. J Org Chem 1998, 63, 21, 7348.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	17491	ethyl acetate	141-78-6	C₄H₈O₂	详情	详情
(I)	17233	1-phenyl-3-hexanone		C₁₂H₁₆O	详情	详情
(II)	21156	ethyl 3-hydroxy-3-phenethylhexanoate		C₁₆H₂₄O₃	详情	详情
(III)	21157	3-hydroxy-3-phenethylhexanoic acid		C₁₄H₂₀O₃	详情	详情
(IV)	13355	2-Amino-1-phenyl-1-propanol; (1S,2R)-(+)-Norephedrine	37577-28-9	C₉H₁₃NO	详情	详情
(IV)	21158	(1R,2S)-2-amino-1-phenyl-1-propanol		C₉H₁₃NO	详情	详情
(V)	21159	(3R)-3-hydroxy-3-phenethylhexanoic acid		C₁₄H₂₀O₃	详情	详情
(VI)	21160	[1,1'-biphenyl]-4-yl chloromethyl ether; 4-(chloromethoxy)-1,1'-biphenyl		C₁₃H₁₁ClO	详情	详情
(VII)	21161	([1,1'-biphenyl]-4-yloxy)methyl (3R)-3-[([1,1'-biphenyl]-4-yloxy)methoxy]-3-phenethylhexanoate		C₄₀H₄₀O₅	详情	详情
(VIII)	21162	(3R)-3-[([1,1'-biphenyl]-4-yloxy)methoxy]-3-phenethyl-1-hexanol		C₂₇H₃₂O₃	详情	详情
(IX)	21163	(3R)-3-[([1,1'-biphenyl]-4-yloxy)methoxy]-3-phenethylhexanal		C₂₇H₃₀O₃	详情	详情
(X)	21164	methyl (3S)-3-(3-nitrophenyl)pentanoate		C₁₂H₁₅NO₄	详情	详情
(XI)	21165	methyl (5R)-5-[([1,1'-biphenyl]-4-yloxy)methoxy]-3-hydroxy-2-[(1S)-1-(3-nitrophenyl)propyl]-5-phenethyloctanoate		C₃₉H₄₅NO₇	详情	详情
(XII)	21166	methyl (5R)-5-[([1,1'-biphenyl]-4-yloxy)methoxy]-2-[(1S)-1-(3-nitrophenyl)propyl]-3-oxo-5-phenethyloctanoate		C₃₉H₄₃NO₇	详情	详情
(XIII)	21167	methyl (5R)-5-hydroxy-2-[(1S)-1-(3-nitrophenyl)propyl]-3-oxo-5-phenethyloctanoate		C₂₆H₃₃NO₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

The hydroxy ketoester (XIII) (Scheme 24009402a), which is cyclized by means of NaOH in methanol/water affording the dihydropyranone (XIV). The reduction of the nitro group of (XIV) with hydrogen over Pd/C in THF gives the corresponding aniline (XV), which is finally amidated with 5-(trifluoromethyl)pyridine-2-sulfonyl chloride and pyridine in DMSO.

参考文献中间体

合成目标

【1】 Fors, K.S.; et al.; A convergent, scalable synthesis of HIV protease inhibitor PNU-140690. J Org Chem 1998, 63, 21, 7348.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	21167	methyl (5R)-5-hydroxy-2-[(1S)-1-(3-nitrophenyl)propyl]-3-oxo-5-phenethyloctanoate	C₂₆H₃₃NO₆	详情	详情
(XIV)	21168	(6R)-4-hydroxy-3-[(1R)-1-(3-nitrophenyl)propyl]-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one	C₂₅H₂₉NO₅	详情	详情
(XV)	17236	(6R)-3-[(1R)-1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one	C₂₅H₃₁NO₃	详情	详情
(XVI)	17237	5-(trifluoromethyl)-2-pyridinesulfonyl chloride	C₆H₃ClF₃NO₂S	详情	详情

Extended Information