【结 构 式】 |
【分子编号】28119 【品名】(2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyric acid 【CA登记号】 |
【 分 子 式 】C17H26O5 【 分 子 量 】310.39044 【元素组成】C 65.78% H 8.44% O 25.77% |
合成路线1
该中间体在本合成路线中的序号:(VII)Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII).
【1】 Mealy, N.E.; Castañer, R.M.; Silvestre, J.S.; Castañer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139. |
【2】 Rigollier, P.; Stutz, S.; Goeschke, R.; Yamaguchi, Y.; Maibaum, J.; Wood, J.; Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.230. |
【3】 Göschke, R.; Maibaum, J.K.; Schilling, W.; Stutz, S.; Rigollier, P.; Yamaguchi, Y.; Cohen, N.C.; Herold, P. (Novartis AG); Delta-amino-gamma-hydroxy-omega-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500; EP 0678503; JP 1996053434; JP 1996081430; US 5559111; US 5627182; US 5646143 . |
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) | 28115 | 5-(hydroxymethyl)-2-methoxyphenol | 4383-06-6 | C8H10O3 | 详情 | 详情 |
(II) | 17319 | 1-bromo-3-methoxypropane; 3-bromopropyl methyl ether | C4H9BrO | 详情 | 详情 | |
(III) | 28116 | [4-methoxy-3-(3-methoxypropoxy)phenyl]methanol | 172900-74-2 | C12H18O4 | 详情 | 详情 |
(IV) | 28117 | 3-[5-(bromomethyl)-2-methoxyphenoxy]propyl methyl ether | 172900-73-1 | C12H17BrO3 | 详情 | 详情 |
(V) | 28131 | (4S)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
(VI) | 28118 | (4S)-4-benzyl-3-[(2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanoyl]-1,3-oxazolidin-2-one | C27H35NO6 | 详情 | 详情 | |
(VII) | 28119 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyric acid | C17H26O5 | 详情 | 详情 | |
(VIII) | 28120 | 3-[5-[(2R)-2-(bromomethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether | 172900-69-5 | C17H27BrO3 | 详情 | 详情 |
(IX) | 10296 | (R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine; (3R)-3-Isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether; (2R)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine | 109838-85-9 | C9H16N2O2 | 详情 | 详情 |
(X) | 28121 | (2R,5S)-2-isopropyl-3,6-dimethoxy-5-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,5-dihydropyrazine | C26H42N2O5 | 详情 | 详情 | |
(XI) | 28122 | methyl (2S,4S)-2-[(tert-butoxycarbonyl)amino]-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate | C25H41NO7 | 详情 | 详情 | |
(XII) | 28123 | tert-butyl (1S,3S)-1-formyl-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentylcarbamate | C24H39NO6 | 详情 | 详情 | |
(XIII) | 28124 | [(2S)-2-[(benzyloxy)methyl]-3-methylbutyl](bromo)magnesium | C13H19BrMgO | 详情 | 详情 | |
(XIV) | 28125 | tert-butyl (1S,4S)-4-[(benzyloxy)methyl]-2-hydroxy-1-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-5-methylhexylcarbamate | C37H59NO7 | 详情 | 详情 | |
(XV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
(XVI) | 28126 | tert-butyl (4S,5S)-5-[(2S)-2-[(benzyloxy)methyl]-3-methylbutyl]-4-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C40H63NO7 | 详情 | 详情 | |
(XVII) | 28127 | tert-butyl (4S,5S)-5-[(2S)-2-(hydroxymethyl)-3-methylbutyl]-4-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C33H57NO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VII)The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in MeOH to yield the target amino alcohol. An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol.
【1】 Mealy, N.E.; Castañer, R.M.; Silvestre, J.S.; Castañer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139. |
【2】 Rüeger, H.; Maibaum, J.; Stutz, S.; Spindler, F.; Göschke, R.; A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. Tetrahedron Lett 2000, 41, 51, 10085. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VII) | 28119 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyric acid | C17H26O5 | 详情 | 详情 | |
(XIX) | 28129 | 3-amino-2,2-dimethylpropanamide | 324763-51-1 | C5H12N2O | 详情 | 详情 |
(XXVIII) | 50572 | (2S,4S)-4-isopropyl-5-oxotetrahydro-2-furancarbonyl chloride | C8H11ClO3 | 详情 | 详情 | |
(XXIX) | 50573 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methyl-1-butanol | C17H28O4 | 详情 | 详情 | |
(XXX) | 50574 | 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)benzene; 3-[5-[(2R)-2-(chloromethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether | 324763-39-5 | C17H27ClO3 | 详情 | 详情 |
(XXXI) | 50575 | (3S,5S)-3-isopropyl-5-[(3S)-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentanoyl]dihydro-2(3H)-furanone | C25H38O6 | 详情 | 详情 | |
(XXXII) | 50576 | (3S,5S)-5-[(1R,3S)-1-hydroxy-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C25H40O6 | 详情 | 详情 | |
(XXXIII) | 50577 | (3S,5S)-5-[(1S,3S)-1-hydroxy-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C25H40O6 | 详情 | 详情 | |
(XXXIV) | 50578 | (3S,5S)-5-[(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C25H39N3O5 | 详情 | 详情 | |
(XXXV) | 50579 | (2S,4S,5S,7S)-N-(4-amino-2,2-dimethyl-4-oxobutyl)-5-azido-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide | C31H53N5O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VII)The condensation of benzaldehyde (I) with ethyl isovalerate (II) by means of hexyl lithium and DIA in THF gives the hydroxyester (III), which is acylated with Ac2O and DMAP in THF to yield the acetoxy derivate (IV). The elimination reaction in (IV) by means of t-BuOK in THF affords the unsaturated ester (V), which is hydrolyzed with KOH in ethanol to provide the unsaturated free acid (VI). Finally, this compound is enantioselectively reduced with H2 over several chiral Rh catalysts {[Rh(NBD)2BF4, [Rh(NBD)(OCOCF3)2], [Rh(NBD)Cl2], etc} to give the target intermediate 2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]propionic acid (VII). (see scheme 26758001a, intermediate (VII)).
【1】 Herold, P.; Stutz, S. (Speedel Pharma Inc.); Preparation of (R)-2-alkyl-3-phenylpropionic acids. WO 0202500 . |
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) | 61620 | 4-Methoxy-3-(3-methoxypropoxy)benzaldehyde | 172900-75-3 | C12H16O4 | 详情 | 详情 |
(II) | 61621 | propyl 3-methylbutanoate | C8H16O2 | 详情 | 详情 | |
(III) | 61622 | propyl 2-{hydroxy[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-methylbutanoate | C20H32O6 | 详情 | 详情 | |
(IV) | 61623 | propyl 2-{(acetyloxy)[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-methylbutanoate | C22H34O7 | 详情 | 详情 | |
(V) | 61624 | propyl (E)-2-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-propenoate | C20H30O5 | 详情 | 详情 | |
(VI) | 61626 | (E)-2-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-propenoic acid | C17H24O5 | 详情 | 详情 | |
(VII) | 28119 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyric acid | C17H26O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(IX)
【1】 Rueger H, Stutz S, Goschke R, et al. 2000. A convergent synthesisi approach towards CGP60536B, a nonpeptide orally potent renin inhibitory, via an enantiomerically pure keto lactone intermediate. Tetrahedron Lett, 41(51): 10085~10089 |
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) | 28131 | (4S)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
(II) | 50566 | (4S)-4-benzyl-3-[(2S)-2-isopropyl-4-pentenoyl]-1,3-oxazolidin-2-one | C18H23NO3 | 详情 | 详情 | |
(III) | 50567 | (3S)-5-(hydroxymethyl)-3-isopropyldihydro-2(3H)-furanone | C8H14O3 | 详情 | 详情 | |
(IV) | 50569 | (4S)-4-isopropyl-5-oxotetrahydro-2-furancarbonyl chloride | C8H11ClO3 | 详情 | 详情 | |
(V) | 67008 | benzyl (2S,4R)-4-isopropyl-5-oxotetrahydro-2-furancarboxylate | C15H18O4 | 详情 | 详情 | |
(VI) | 50570 | benzyl (2S,4S)-4-isopropyl-5-oxotetrahydro-2-furancarboxylate | C15H18O4 | 详情 | 详情 | |
(VII) | 50571 | (2S,4S)-4-isopropyl-5-oxotetrahydro-2-furancarboxylic acid | C8H12O4 | 详情 | 详情 | |
(VIII) | 50572 | (2S,4S)-4-isopropyl-5-oxotetrahydro-2-furancarbonyl chloride | C8H11ClO3 | 详情 | 详情 | |
(IX) | 28119 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyric acid | C17H26O5 | 详情 | 详情 | |
(X) | 50573 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methyl-1-butanol | C17H28O4 | 详情 | 详情 | |
(XI) | 50574 | 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)benzene; 3-[5-[(2R)-2-(chloromethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether | 324763-39-5 | C17H27ClO3 | 详情 | 详情 |
(XII) | 50575 | (3S,5S)-3-isopropyl-5-[(3S)-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentanoyl]dihydro-2(3H)-furanone | C25H38O6 | 详情 | 详情 | |
(XIII) | 50576 | (3S,5S)-5-[(1R,3S)-1-hydroxy-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C25H40O6 | 详情 | 详情 | |
(XIV) | 50578 | (3S,5S)-5-[(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C25H39N3O5 | 详情 | 详情 | |
(XV) | 28129 | 3-amino-2,2-dimethylpropanamide | 324763-51-1 | C5H12N2O | 详情 | 详情 |
(XVI) | 50579 | (2S,4S,5S,7S)-N-(4-amino-2,2-dimethyl-4-oxobutyl)-5-azido-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide | C31H53N5O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(VIII)
【1】 Dorg H, Zhang ZL, Huang JH, et al. 2005. Practical synthesisi of an orally active renin inhibitory aliskiren. Tetrahedron Lett, 46(37): 6337~6340 |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXV) | 67017 | 2-cyano-2-methylpropanamide | 7505-93-3 | C5H8N2O | 详情 | 详情 |
(I) | 18455 | 3-hydroxy-4-methoxybenzaldehyde; Isovanillin | 621-59-0 | C8H8O3 | 详情 | 详情 |
(II) | 67010 | 3-methoxypropyl methanesulfonate | C5H12O4S | 详情 | 详情 | |
(III) | 61620 | 4-Methoxy-3-(3-methoxypropoxy)benzaldehyde | 172900-75-3 | C12H16O4 | 详情 | 详情 |
(IV) | 28116 | [4-methoxy-3-(3-methoxypropoxy)phenyl]methanol | 172900-74-2 | C12H18O4 | 详情 | 详情 |
(V) | 28117 | 3-[5-(bromomethyl)-2-methoxyphenoxy]propyl methyl ether | 172900-73-1 | C12H17BrO3 | 详情 | 详情 |
(VI) | 28131 | (4S)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
(VII) | 28118 | (4S)-4-benzyl-3-[(2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanoyl]-1,3-oxazolidin-2-one | C27H35NO6 | 详情 | 详情 | |
(VIII) | 28119 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyric acid | C17H26O5 | 详情 | 详情 | |
(IX) | 50573 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methyl-1-butanol | C17H28O4 | 详情 | 详情 | |
(X) | 28120 | 3-[5-[(2R)-2-(bromomethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether | 172900-69-5 | C17H27BrO3 | 详情 | 详情 |
(XI) | 67009 | (S)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine | 134870-62-5 | C11H20N2O2 | 详情 | 详情 |
(XII) | 67011 | 3,6-diethoxy-2-isopropyl-5-(2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutyl)-2,5-dihydropyrazine | C28H46N2O5 | 详情 | 详情 | |
(XIII) | 67012 | ethyl 2-amino-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanoate | C21H35NO5 | 详情 | 详情 | |
(XIV) | 28122 | methyl (2S,4S)-2-[(tert-butoxycarbonyl)amino]-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate | C25H41NO7 | 详情 | 详情 | |
(XV) | 67013 | tert-butyl (1-hydroxy-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexan-2-yl)carbamate | C24H41NO6 | 详情 | 详情 | |
(XVI) | 28123 | tert-butyl (1S,3S)-1-formyl-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentylcarbamate | C24H39NO6 | 详情 | 详情 | |
(XVII) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
(XVIII) | 14560 | Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene | 3587-60-8 | C8H9ClO | 详情 | 详情 |
(XIX) | 23285 | (4R)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
(XX) | 67014 | 4-benzyl-3-(2-((benzyloxy)methyl)-3-methylbutanoyl)oxazolidin-2-one | C23H27NO4 | 详情 | 详情 | |
(XXI) | 67015 | (R)-2-((benzyloxy)methyl)-3-methylbutanoic acid | C13H18O3 | 详情 | 详情 | |
(XXII) | 67016 | 2-((benzyloxy)methyl)-3-methylbutan-1-ol | C13H20O2 | 详情 | 详情 | |
(XXIII) | 66991 | (R)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene | C13H19BrO | 详情 | 详情 | |
(XXIV) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
(XXVI) | 67018 | benzyl (3-amino-2,2-dimethyl-3-oxopropyl)carbamate | C13H18N2O3 | 详情 | 详情 | |
(XXVII) | 28129 | 3-amino-2,2-dimethylpropanamide | 324763-51-1 | C5H12N2O | 详情 | 详情 |
(XXVIII) | 28125 | tert-butyl (1S,4S)-4-[(benzyloxy)methyl]-2-hydroxy-1-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-5-methylhexylcarbamate | C37H59NO7 | 详情 | 详情 | |
(XXIX) | 67019 | tert-butyl (6-hydroxy-8-(hydroxymethyl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-yl)carbamate | C30H53NO7 | 详情 | 详情 | |
(XXX) | 67004 | tert-butyl (1-(4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate | C30H49NO7 | 详情 | 详情 | |
(XXXI) | 67020 | tert-butyl (8-((1-amino-2-methyl-1-oxopropan-2-yl)carbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-yl)carbamate | C34H59N3O8 | 详情 | 详情 |