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【结 构 式】 
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【分子编号】34409 【品名】(1S,2S)-2-(methylamino)-1-phenyl-1-propanol 【CA登记号】90-82-4 |
【 分 子 式 】C10H15NO 【 分 子 量 】165.23524 【元素组成】C 72.69% H 9.15% N 8.48% O 9.68% |
合成路线1
该中间体在本合成路线中的序号：(XXI)The cyclization of the intermediate 3-(6-butyl-3-formylpyridin-2-yl)-2(E)-propenoic acid tert-butyl ester (VI) with the chiral auxiliary (XV) by means of AcOH gives the chiral oxazolidine (XVI), which is enantioselectively condensed with the intermediate 3-(2-bromo-5-methoxyphenyl)-2(S)-methyl-1-propanol tert-butyldimethylsilyl ether (XIV) by means of n-BuLi to yield the adduct (XVII). Elimination of the chiral auxiliary with citric acid affords the aldehyde (XVIII), which is treated with 1,3-benzodioxol-5-ylmagnesium bromide (XIX) to provide the corresponding secondary alcohol (XX). Alternatively, the cyclization of the intermediate 3-(6-butyl-3-formylpyidin-2-yl)-2(E)-propenoic acid tert-butyl ester (VI) with the chiral auxiliary (XXI) by means of AcOH gives the chiral oxazolidine (XXII), which is enantioselectively condensed with the intermediate 3-(2-bromo-5-methoxyphenyl)-2(S)-methyl-1-propanol tert-butyldimethylsilyl ether (XIV) by means of n-BuLi to yield the adduct (XXIII). Elimination of the chiral auxiliary with citric acid affords the previously reported aldehyde (XVIII).
| 【1】 Song, Z.J.; et al.; Practical asymetric synthesis of an endothelin receptor antagonist. J Org Chem 1999, 64, 26, 9658. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 27564 | tert-butyl (E)-3-(6-butyl-3-formyl-2-pyridinyl)-2-propenoate | C17H23NO3 | 详情 | 详情 | |
| (XIV) | 27567 | 4-bromo-3-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)phenyl methyl ether | C17H29BrO2Si | 详情 | 详情 | |
| (XV) | 38554 | (1S,2R)-1-(methylamino)-2,3-dihydro-1H-inden-2-ol | C10H13NO | 详情 | 详情 | |
| (XVI) | 38555 | tert-butyl (E)-3-[6-butyl-3-(3-methyl-2,3-dihydro-1,3-benzoxazol-2-yl)-2-pyridinyl]-2-propenoate | C24H30N2O3 | 详情 | 详情 | |
| (XVII) | 38556 | tert-butyl (3R)-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]-3-[6-butyl-3-(3-methyl-2,3-dihydro-1,3-benzoxazol-2-yl)-2-pyridinyl]propanoate | C41H60N2O5Si | 详情 | 详情 | |
| (XVIII) | 27569 | tert-butyl (3R)-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]-3-(6-butyl-3-formyl-2-pyridinyl)propanoate | C34H53NO5Si | 详情 | 详情 | |
| (XIX) | 27570 | 1,3-benzodioxol-5-yl(bromo)magnesium | C7H5BrMgO2 | 详情 | 详情 | |
| (XX) | 38557 | tert-butyl (3R)-3-[3-[(R)-1,3-benzodioxol-5-yl(hydroxy)methyl]-6-butyl-2-pyridinyl]-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]propanoate | C41H59NO7Si | 详情 | 详情 | |
| (XXI) | 34409 | (1S,2S)-2-(methylamino)-1-phenyl-1-propanol | 90-82-4 | C10H15NO | 详情 | 详情 |
| (XXII) | 27566 | tert-butyl (E)-3-[6-butyl-3-[(4S,5S)-3,4-dimethyl-5-phenyl-1,3-oxazolidin-2-yl]-2-pyridinyl]-2-propenoate | C27H36N2O3 | 详情 | 详情 | |
| (XXIII) | 27568 | tert-butyl (3R)-3-[6-butyl-3-[(4S,5S)-3,4-dimethyl-5-phenyl-1,3-oxazolidin-2-yl]-2-pyridinyl]-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]propanoate | C44H66N2O5Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXIX)Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX).
| 【1】 Mealy, N.E.; Castañer, R.M.; Silvestre, J.S.; Castañer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139. |
| 【2】 Carey, J.S.; Sandham, D.A.; Taylor, R.J.; Fassler, A.; A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41, 51, 10091. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 |
| (XXXVI) | 50580 | (E)-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-propenoic acid | C14H18O5 | 详情 | 详情 | |
| (XXXVII) | 50581 | 3-[4-methoxy-3-(3-methoxypropoxy)phenyl]propionic acid | C14H20O5 | 详情 | 详情 | |
| (XXXVIII) | 50582 | 3-[4-methoxy-3-(3-methoxypropoxy)phenyl]propanoyl chloride | C14H19ClO4 | 详情 | 详情 | |
| (XXXIX) | 34409 | (1S,2S)-2-(methylamino)-1-phenyl-1-propanol | 90-82-4 | C10H15NO | 详情 | 详情 |
| (XL) | 50583 | N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-N-methylpropanamide | C24H33NO5 | 详情 | 详情 | |
| (XLI) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (XLII) | 50584 | (2R)-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-N,3-dimethylbutanamide | C27H39NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The acylation of (S,S)-pseudoephedrine (I) with butyric anhydride (II) gave the corresponding butyramide (III), which was asymmetrically alkylated with m-methoxybenzyl bromide (IV) in the presence of LDA and LiCl in THF at low temperature to produce the (S,S,R) isomer (V). Amide hydrolysis of (V) to provide the (R)-carboxylic acid (VI) was effected according to a described procedure by treatment with methanesulfonic acid in boiling THF, and then with lithium borohydride and tetrabutylammonium hydroxide. Further treatment of (VI) with ethereal diazomethane afforded the methyl ester (VII). This was submitted to acyloin condensation using Na metal and trimethylsilyl chloride to form the corresponding acyloin as the bis(silyl) ether (VIII). Double cyclization of (VIII) using TiCl4 at low temperature yielded the required tetrahydrochrysene system with minimal epimerization. The major cis isomer (IX) was then isolated by flash chromatography. Finally, deprotection of the methyl ethers of (IX) with BBr3 furnished the title bis-phenolic compound.
| 【1】 Meyers, M.J.; et al.; Estrogen receptor subtype-selective ligands: Asymmetric synthesis and biological evaluation of cis- and trans-5,11-dialkyl-5,6,11,12-tetrahydrochrysenes. J Med Chem 1999, 42, 13, 2456. |
| 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) | 34409 | (1S,2S)-2-(methylamino)-1-phenyl-1-propanol | 90-82-4 | C10H15NO | 详情 | 详情 |
| (II) | 25047 | butyric anhydride | 106-31-0 | C8H14O3 | 详情 | 详情 |
| (III) | 34402 | N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylbutanamide | C14H21NO2 | 详情 | 详情 | |
| (IV) | 34403 | 1-(bromomethyl)-3-methoxybenzene; 3-(bromomethyl)phenyl methyl ether | C8H9BrO | 详情 | 详情 | |
| (V) | 34404 | (2R)-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-2-(3-methoxybenzyl)-N-methylbutanamide | C22H29NO3 | 详情 | 详情 | |
| (VI) | 34405 | (2R)-2-(3-methoxybenzyl)butyric acid | C12H16O3 | 详情 | 详情 | |
| (VII) | 34406 | methyl (2R)-2-(3-methoxybenzyl)butanoate | C13H18O3 | 详情 | 详情 | |
| (VIII) | 34407 | 3-[(2R,3E,5R)-2-ethyl-5-(3-methoxybenzyl)-3,4-bis[(trimethylsilyl)oxy]-3-heptenyl]phenyl methyl ether; (E)-4,5-bis[(1R)-1-(3-methoxybenzyl)propyl]-2,2,7,7-tetramethyl-3,6-dioxa-2,7-disila-4-octene | C30H48O4Si2 | 详情 | 详情 | |
| (IX) | 34408 | (5R,11R)-5,11-diethyl-8-methoxy-5,6,11,12-tetrahydro-2-chrysenyl methyl ether; (5R,11R)-5,11-diethyl-2,8-dimethoxy-5,6,11,12-tetrahydrochrysene | C24H28O2 | 详情 | 详情 |