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【结 构 式】 
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【分子编号】21781 【品名】[(1R)-2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol 【CA登记号】 |
【 分 子 式 】C10H11N5O 【 分 子 量 】217.23044 【元素组成】C 55.29% H 5.1% N 32.24% O 7.37% |
合成路线1
该中间体在本合成路线中的序号：(XXXIV)An asymmetric synthesis of the (Z)(R)-enantioner has also been reported. Treatment of bromide (XXI) with NaOEt in Et2O provided ethyl methylenecyclopropanecarboxylate (XXII). Saponification of the ester group of (XXII) afforded racemic acid (XXIII) which, after activation as the mixed anhydride with isobutyl chloroformate, was coupled with (R)-phenylglycinol (XXIV) to yield a mixture of diastereomeric amides (XXV) and (XXVI). Chromatographic separation of the desired (R,R)-diastereoisomer (XXV) was followed by acid hydrolysis to furnish the (R)-acid (XXVII), which was subsequently esterified to (XXVIII) in ethanolic HCl. Addition of Br2 to (XXVIII) produced a mixture of (1S,2S)- and (1S,2R)-dibromoesters (XXIX). Further reduction of (XXIX) to alcohols (XXX) with DIBALH was followed by acetylation with Ac2O in pyridine yielding (XXXI). The alkylation-elimination procedure of the resulting bromides (XXXI) with adenine (V) afforded a mixture of (Z)(R) (XXXII) and (E)(R)- (XXXIII) olefins. Finally, deacetylation with ammonia in MeOH gave a mixture of the target (Z)(R)-compound and the corresponding E-isomer (XXXIV), which were not separed but used for analytical confirmation of the configuration of the title compound.
| 【1】 Qiu, Y.-L.; et al.; (Z)- and (E)-2-((Hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New nucleoside analogues with a broad-spectrum antiviral activity. J Med Chem 1998, 41, 1, 10. |
| 【2】 Qiu, Y.-L.; Hempel, A.; Camerman, N.; Camerman, A.; Geiser, F.; Ptak, R.G.; Breitenbach, J.M.; Kira, T.; Li, L.; Gullen, E.; Cheng, Y.C.; Drach, J.C.; Zemlicka, J.; (R)-(-)- and (S)-(+)-synadenol: Synthesis, absolute configuration, and enantioselectivity of antiviral effect. J Med Chem 1998, 41, 26, 5257. |
| 【3】 Zemilicka, J.; Qiu, Y.-L.; A new efficient synthesis of antiviral methylenecyclopropane analogs of purine nucleosides. Synthesis 1998, 10, 1447-1452. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 21768 | ethyl 2-bromo-2-methylcyclopropanecarboxylate | C7H11BrO2 | 详情 | 详情 | |
| (XXII) | 21769 | ethyl 2-methylenecyclopropanecarboxylate | C7H10O2 | 详情 | 详情 | |
| (XXIII) | 21770 | 2-methylenecyclopropanecarboxylic acid | C5H6O2 | 详情 | 详情 | |
| (XXIV) | 14576 | pentanimidamide | 109-51-3 | C5H12N2 | 详情 | 详情 |
| (XXV) | 21772 | (1R)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylenecyclopropanecarboxamide | C13H15NO2 | 详情 | 详情 | |
| (XXVI) | 21773 | (1S)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylenecyclopropanecarboxamide | C13H15NO2 | 详情 | 详情 | |
| (XXVII) | 21774 | (1R)-2-methylenecyclopropanecarboxylic acid | C5H6O2 | 详情 | 详情 | |
| (XXVIII) | 21775 | ethyl (1R)-2-methylenecyclopropanecarboxylate | C7H10O2 | 详情 | 详情 | |
| (XXIX) | 21776 | ethyl (1S)-2-bromo-2-(bromomethyl)cyclopropanecarboxylate | C7H10Br2O2 | 详情 | 详情 | |
| (XXX) | 21777 | [(1S)-2-bromo-2-(bromomethyl)cyclopropyl]methanol | C5H8Br2O | 详情 | 详情 | |
| (XXXI) | 21778 | [(1S)-2-bromo-2-(bromomethyl)cyclopropyl]methyl acetate | C7H10Br2O2 | 详情 | 详情 | |
| (XXXII) | 21779 | [(1R)-2-[(Z)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methyl acetate | C12H13N5O2 | 详情 | 详情 | |
| (XXXIII) | 21780 | [(1R)-2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methyl acetate | C12H13N5O2 | 详情 | 详情 | |
| (XXXIV) | 21781 | [(1R)-2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Addition of ethyl diazoacetate (II) to 2,3-dibromopropene (I) in the presence of dirhodium tetraacetate furnished ethyl 2-bromo-2-(bromomethyl)cyclopropane-1-carboxylate (III) as a mixture of cis- and trans-isomers. Subsequent condensation of the dibromo ester (III) with the sodium salt of adenine (IV) produced adduct (V) as a diastereomeric mixture. Then, elimination of HBr using potassium tert-butoxide gave olefin (VIa-b). Alternatively, a direct synthesis of (VIa-b) was carried out by reaction of adenine (IV) with dibromo ester (III) in the presence of K2CO3 in hot DMF. Reduction of ester (VIa-b) with diisobutylaluminum hydride afforded alcohol (VIIa-b) as a mixture of syn- and anti-isomers. Isolation of the desired syn-isomer (VIII) was achieved by conversion to the corresponding formamidines, followed by chromatographic separation. The formamidine function of (VIII) was then hydrolyzed with methanolic ammonia to yield the racemic synadenol (IX). Incubation of (IX) with adenosine deaminase converted the (S)-enantiomer to the hypoxanthine derivative (XI), which was separated from the unreacted (R)-synadenol (X) by column chromatography. Acetylation of alcohol (XI) with Ac2O in pyridine provided ester (XII). Chloropurine derivative (XIV) was then obtained by treatment of (XII) with N,N-dimethylamino(chloromethylene)ammonium chloride (XIII) in CHCl3. Finally, chloride displacement in (XIV) and simultaneous ester cleavage with methanolic ammonia in a pressure vessel gave rise to the title compound.
| 【1】 Drach, J.C.; Zemlicka, J.; Ptak, R.G.; Qiu, Y.-L. (University of Michigan; Wayne State University); 2-Hydroxy methylcyclopropylidenemethyl purines and -pyrimidines as antiviral agents. WO 0053603 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa),(IX) | 21754 | ethyl 2-[(Z)-(6-amino-9H-purin-9-yl)methylidene]cyclopropanecarboxylate | C12H13N5O2 | 详情 | 详情 | |
| (VIb) | 21755 | ethyl 2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropanecarboxylate | C12H13N5O2 | 详情 | 详情 | |
| (VIIa) | 21756 | [2-[(Z)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
| (VIIb) | 21757 | [2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
| (I) | 21748 | 2,3-dibromo-1-propene | 513-31-5 | C3H4Br2 | 详情 | 详情 |
| (II) | 15911 | Ethyldiazoacetate; ethyl 2-diazoacetate | 623-73-4 | C4H6N2O2 | 详情 | 详情 |
| (III) | 42613 | ethyl 2-bromo-2-(bromomethyl)cyclopropanecarboxylate | C7H10Br2O2 | 详情 | 详情 | |
| (IV) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (V) | 48356 | ethyl 2-[(6-amino-9H-purin-9-yl)methyl]-2-bromocyclopropanecarboxylate | C12H14BrN5O2 | 详情 | 详情 | |
| (VIII) | 21758 | N'-(9-[[2-(hydroxymethyl)cyclopropylidene]methyl]-9H-purin-6-yl)-N,N-dimethyliminoformamide | C13H16N6O | 详情 | 详情 | |
| (X) | 21781 | [(1R)-2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
| (XI) | 21759 | 9-[[(2S)-2-(hydroxymethyl)cyclopropylidene]methyl]-1,9-dihydro-6H-purin-6-one | C10H10N4O2 | 详情 | 详情 | |
| (XII) | 48357 | [(1S)-2-[(Z)-(6-oxo-1,6-dihydro-9H-purin-9-yl)methylidene]cyclopropyl]methyl acetate | C12H12N4O3 | 详情 | 详情 | |
| (XIII) | 17643 | (Chloromethylene)dimethylammonium chloride; N-(chloromethylene)-N-methylmethanaminium chloride | 3724-43-4 | C3H7Cl2N | 详情 | 详情 |
| (XIV) | 48358 | [(1S)-2-[(Z)-(6-chloro-9H-purin-9-yl)methylidene]cyclopropyl]methyl acetate | C12H11ClN4O2 | 详情 | 详情 |