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【结 构 式】 
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【分子编号】69370 【品名】6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione 【CA登记号】 |
【 分 子 式 】C7H8O3 【 分 子 量 】140.13872 【元素组成】 C 60% H 5.75% O 34.25% |
合成路线1
该中间体在本合成路线中的序号：(XLVI)In an alternative method to intermediate (XI), dehydration of caronic acid (XLV) by heating with Ac2O and H2SO4 in toluene at 190 °C produces caronic anhydride (XLVI) , which is then condensed with benzylamine in tert-butyl methyl ether at 170-180 °C to yield the bicyclic imide (XLVII). Subsequent reduction of imide (XLVII) with LiAlH4 in refluxing THF followed by debenzylation of the obtained pyrrolidine derivative (XLVIII) by catalytic hydrogenation over Pd/C in AcOH furnishes 6,6-dimethyl-3-azabicyclo[3.1.0]hexane (XLIX) .
Alternatively, caronic anhydride (XLVI) is reacted with NH4OH in H2O at 155 °C or THF at 180 °C to give 6,6-dimethyl-3-azabicyclo[3.1.0]-hexane-2,4-dione (L), which can also be prepared by debenzylation of intermediate (XLVII) with H2 in the presence of Pd/C or Pt/C. Reduction of imide (L) with LiAlH4 in refluxing THF then yields the bicyclic amine (XLIX). This secondary amine is converted to the corresponding imine (LII) by chlorination with NaClO in methyl tertbutyl ether, followed by treatment of the intermediate chloramine (LI) with NaOH in the presence of Bu4NOH or NBC in MeOH , or alternatively by direct oxidation of amine (XLIX) with K2S2O8 in the presence of AgNO3 and NaOH in acetonitrile. Addition of sodium bisulfite to the imine (LII) produces the racemic sulfonate (LIII), which upon cyanation with NaCN yields the α-amino nitrile (LIV). After methanolysis of nitrile (LIV) with HCl in MeOH/MTBE, resolution of the racemic amino ester employing di-p-toluoyl-D-tartaric acid in MeOH affords intermediate (XI) .
| 【3】 Smith, J.P. Treatment options for patients with hepatitis C: Role of pharmacists in optimizing treatment response and managing adverse events. Pharmacotherapy 2008, 28(9): 1151-61. |
| 【1】 Kwok, D.-L., Lee, H.-C., Zavialov, I.A. (Schering Corp.). Dehydrohalogenation process for the preparation of intermediates useful in providing 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane compounds. WO 2009073380. |
| 【2】 Berranger, T., Demonchaux, P. (Schering Corp.). Process for the preparation of 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane compounds utilizing bisulfite intermediate. WO 2008082508. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 69339 | methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate HCl salt | 565456-77-1 | C9H15NO2.HCl | 详情 | 详情 |
| (XLV) | 69369 | 3,3-dimethylcyclopropane-1,2-dicarboxylic acid | 497-42-7 | C7H10O4 | 详情 | 详情 |
| (XLVI) | 69370 | 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione | C7H8O3 | 详情 | 详情 | |
| (XLVII) | 69371 | 3-benzyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione | C14H15NO2 | 详情 | 详情 | |
| (XLVIII) | 69372 | 3-benzyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane | C14H19N | 详情 | 详情 | |
| (XLIX) | 69373 | 6,6-dimethyl-3-azabicyclo[3.1.0]hexane | C7H13N | 详情 | 详情 | |
| (L) | 69374 | 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione | C7H9NO2 | 详情 | 详情 | |
| (LI) | 69375 | 3-chloro-6,6-dimethyl-3-azabicyclo[3.1.0]hexane | C7H12ClN | 详情 | 详情 | |
| (LII) | 69376 | 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene | C7H11N | 详情 | 详情 | |
| (LIII) | 69377 | sodium 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-sulfonate | C7H12NNaO3S | 详情 | 详情 | |
| (LIV) | 69378 | 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile | C8H12N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XLVI)In a further process, the proline analogue (XI) is prepared starting from ethyl chrysanthemate (LV). Oxidative cleavage of the isobutenyl side-chain of compound (LV) with KMnO4 followed by alkaline hydrolysis of the ethyl ester group provides caronic acid (XLV) as a mixture of cis- and trans-isomers. Diacid (XLV) is then converted to the bicyclic anhydride (XLVI) using either trifluoroacetic anhydride or acetic anhydride as dehydrating reagents. Ring opening opening of anhydride (XLVI) with allyl alcohol and quinidine, followed by resolution with (R)-(+)-α-methylbenzylamine gives the chiral monoallyl ester (LVI), which is subsequently coupled with ammonium bicarbonate by means of di-tert-butyl dicarbonate and pyridine to afford the amide ester (LVII). After reduction of compound (LVII) with LiAlH4, the resulting amino alcohol (LVIII) is protected as the benzyl carbamate (LIX) by treatment with benzyl chloroformate and K2CO3. The primary alcohol (LIX) is then oxidized to aldehyde (LX) by means of sodium hypochlorite and a catalytic amount of TEMPO. Cyclization of aldehyde (LX) with AcOH in EtOH followed by replacement of the EtOH solvent with THF gives a mixture of the bicyclic hemiaminal (LXI) and its O-ethyl derivative (LXII), which, without separation, is treated with cyanotrimethylsilane and boron trifluoride etherate to afford nitrile (LXIII). Addition of NaOMe to the nitrile (LXIII) followed by aqueous hydrolysis of the obtained imidate (LXIV) provides ester (LXV), which can be alternatively obtained by treatment of nitrile (LXIII) with acetyl chloride in MeOH, followed by addition of water. Finally, the benzyl carbamate (LXV) is then deprotected by hydrogenation over Pd/C to yield the cyclopropanefused prolinate ester (XI) .
| 【1】 Park, J., Sudhakar, A., Wong, G.S. (Schering Corp.). Process and intermediates for the preparation of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo-[3,1,0]hexane-2-carboxylates or salts thereof. JP 2007520434, US 2005059648, WO 2004113295. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 69339 | methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate HCl salt | 565456-77-1 | C9H15NO2.HCl | 详情 | 详情 |
| (XLV) | 69369 | 3,3-dimethylcyclopropane-1,2-dicarboxylic acid | 497-42-7 | C7H10O4 | 详情 | 详情 |
| (XLVI) | 69370 | 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione | C7H8O3 | 详情 | 详情 | |
| (LV) | 69379 | Ethyl chrysanthemumate;ethyl 2,2-dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropanecarboxylate | 97-41-6 | C12H20O2 | 详情 | 详情 |
| (LVI) | 69380 | 3-((allyloxy)carbonyl)-2,2-dimethylcyclopropanecarboxylic acid | C10H14O4 | 详情 | 详情 | |
| (LVII) | 69381 | allyl 3-carbamoyl-2,2-dimethylcyclopropanecarboxylate | C10H15NO3 | 详情 | 详情 | |
| (LVIII) | 69382 | (3-(aminomethyl)-2,2-dimethylcyclopropyl)methanol | C7H15NO | 详情 | 详情 | |
| (LIX) | 69383 | benzyl ((3-(hydroxymethyl)-2,2-dimethylcyclopropyl)methyl)carbamate | C15H21NO3 | 详情 | 详情 | |
| (LX) | 69384 | benzyl ((3-formyl-2,2-dimethylcyclopropyl)methyl)carbamate | C15H19NO3 | 详情 | 详情 | |
| (LXI) | 69385 | benzyl 2-hydroxy-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate | C15H19NO3 | 详情 | 详情 | |
| (LXII) | 69386 | benzyl 2-ethoxy-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate | C17H23NO3 | 详情 | 详情 | |
| (LXIII) | 69387 | benzyl 2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate | C16H18N2O2 | 详情 | 详情 | |
| (LXIV) | 69388 | benzyl 2-(imino(methoxy)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate | C17H22N2O3 | 详情 | 详情 | |
| (LXV) | 69389 | 3-benzyl 2-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate | C17H21NO4 | 详情 | 详情 |