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【结 构 式】 
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【分子编号】18117 【品名】2-(1,3-benzodioxol-5-yl)acetic acid; 3,4-(Methylenedioxy)phenylacetic acid 【CA登记号】2861-28-1 |
【 分 子 式 】C9H8O4 【 分 子 量 】180.16012 【元素组成】C 60% H 4.48% O 35.52% |
合成路线1
该中间体在本合成路线中的序号：(XXI)Reaction of 2-(1,3-dioxol-5-yl)acetic acid (XXI) with pivaloyl chloride and TEA gives the corresponding anhydride (XXII), which is condensed with the chiral oxazolidinone (XXIII) by means of n-BuLi in THF to yield the amide (XXIV). Condensation of (XXIV) with 2-bromoacetic acid tert-butyl ester (XXV) by means of NaHMDS in THF affords the adduct (XXVI). Elimination of the chiral auxiliary of (XXVI) by means of LiOOH in THF/water provides the chiral succinic acid hemiester (XXVII) (93% ee), which is selectively reduced with BH3THF complex to give the 4-hydroxysuccinate (XXVIII). Reaction of succinate (XXVIII) with 4-chlorophenylsulfonyl chloride, TEA and DMAP in dichloromethane yields the sulfonate (XXIX), which is condensed with 4-methoxybenzaldoxime (XXX) by means of Cs2CO3 in hot acetonitrile to afford the oxime ether (XXXI). Transesterification of the tert-butyl ester of (XXXI) with trimethyl orthoformate and p-toluenesulfonic acid in hot methanol provides the methyl ester (XXXII), which is cyclized by means of trimethylsilyl triflate and tributylamine in dichloroethane to afford a 9:1 diastereomeric mixture of perhydro-1,2-oxazines (XXXIII) and (XXXIV) which is easily separated. The reductive N-O-bond cleavage of the major oxazine diastereomer (XXXIII) by means of Zn/HOAc or H2 over Pd/C gives the trisubstituted 4-aminobutanol (XXXV), which is cyclized by means of CBr4, PPh3 and TEA to yield chiral pyrrolidine (XXXVI) (4). Finally, pyrrolidine (XXXVI) is alkylated with N,N-dibutyl-2-bromoacetamide (XIII) followed by ester hydrolysis as before.
| 【1】 Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939. |
| 【2】 McLaughlin, M.A.; Wittenberger, S.J.; Preparation of endothelin antagonist ABT-627. Tetrahedron Lett 1999, 40, 7175. |
| 【3】 Winn, M.; et al.; 2,4-Diarylpyrrolidine-3-carboxylic acids-potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 1996, 39, 5, 1039. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 | |
| (XIII) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 | |
| (XXI) | 18117 | 2-(1,3-benzodioxol-5-yl)acetic acid; 3,4-(Methylenedioxy)phenylacetic acid | 2861-28-1 | C9H8O4 | 详情 | 详情 |
| (XXII) | 48688 | 1,3-benzodioxol-5-ylacetic 1,1-dimethylpropionic anhydride | C14H16O5 | 详情 | 详情 | |
| (XXIII) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (XXIV) | 48689 | (4S)-3-[2-(1,3-benzodioxol-5-yl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one | C15H17NO5 | 详情 | 详情 | |
| (XXV) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XXVI) | 48690 | tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutanoate | C21H27NO7 | 详情 | 详情 | |
| (XXVII) | 48691 | (2S)-2-(1,3-benzodioxol-5-yl)-4-(tert-butoxy)-4-oxobutyric acid | C15H18O6 | 详情 | 详情 | |
| (XXVIII) | 48692 | tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-hydroxybutanoate | C15H20O5 | 详情 | 详情 | |
| (XXIX) | 48693 | tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-[[(4-chlorophenyl)sulfonyl]oxy]butanoate | C21H23ClO7S | 详情 | 详情 | |
| (XXX) | 48694 | 4-methoxybenzaldehyde oxime | C8H9NO2 | 详情 | 详情 | |
| (XXXI) | 48695 | tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-([[(E)-(4-methoxyphenyl)methylidene]amino]oxy)butanoate | C23H27NO6 | 详情 | 详情 | |
| (XXXII) | 48696 | methyl (3S)-3-(1,3-benzodioxol-5-yl)-4-([[(E)-(4-methoxyphenyl)methylidene]amino]oxy)butanoate | C20H21NO6 | 详情 | 详情 | |
| (XXXIII) | 48697 | methyl (3R,4R,5S)-5-(1,3-benzodioxol-5-yl)-3-(4-methoxyphenyl)-1,2-oxazinane-4-carboxylate | C20H21NO6 | 详情 | 详情 | |
| (XXXIV) | 48698 | methyl (3S,5S)-5-(1,3-benzodioxol-5-yl)-3-(4-methoxyphenyl)-1,2-oxazinane-4-carboxylate | C20H21NO6 | 详情 | 详情 | |
| (XXXV) | 48699 | methyl (2R,3S)-2-[(R)-amino(4-methoxyphenyl)methyl]-3-(1,3-benzodioxol-5-yl)-4-hydroxybutanoate | C20H23NO6 | 详情 | 详情 | |
| (XXXVI) | 48700 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C20H21NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Esterification of 3,4-(methylenedioxy)phenylacetic acid (I) with methanol in the presence of sulfuric acid provided methyl ester (II). Fiedel Crafts acylation of (II) with 4-nitrobenzoic acid (III) under the action of P2O5 in refluxing dichloroethane yielded ketone (IV). This compound was refluxed with hydrazine hydrate in ethanol to afford benzodiazepinone (V). Finally, the nitro group was reduced by hydrogenation in acetic acid with Pd/C as the catalyst or with Raney-Ni and hydrazine to give the corresponding amine.
| 【1】 Wang, Y.; et al.; Synthesis of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones as novel and potent noncompetitive AMPA receptor antagonists. J Med Chem 1998, 41, 14, 2621. |
| 【2】 Xia, H.; Field, G.; Lan, N.C.; Wang, Y. (Acea Pharmaceuticals); Substd. 2,3-benzodiazepin-4-ones and the use thereof. EP 1021418; JP 2000506890; US 5891871; WO 9734878 . |
| 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) | 18117 | 2-(1,3-benzodioxol-5-yl)acetic acid; 3,4-(Methylenedioxy)phenylacetic acid | 2861-28-1 | C9H8O4 | 详情 | 详情 |
| (II) | 18118 | methyl 2-(1,3-benzodioxol-5-yl)acetate | C10H10O4 | 详情 | 详情 | |
| (III) | 18119 | 4-nitrobenzoic acid; p-nitrobenzoic acid | 62-23-7 | C7H5NO4 | 详情 | 详情 |
| (IV) | 18120 | methyl 2-[6-(4-nitrobenzoyl)-1,3-benzodioxol-5-yl]acetate | C17H13NO7 | 详情 | 详情 | |
| (V) | 18121 | 5-(4-nitrophenyl)-7,9-dihydro-8H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-one | C16H11N3O5 | 详情 | 详情 |