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【结 构 式】 
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【分子编号】21769 【品名】ethyl 2-methylenecyclopropanecarboxylate 【CA登记号】 |
【 分 子 式 】C7H10O2 【 分 子 量 】126.1552 【元素组成】C 66.65% H 7.99% O 25.36% |
合成路线1
该中间体在本合成路线中的序号：(XXII)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：(II)Zinc-catalyzed debromination of dibromo compound (I) afforded the methylene cyclopropane (II). After reduction of the ester group of (II) with LiAlH4, the resulting alcohol (III) was converted to acetate ester (IV) with Ac2O in pyridine. The carbene generated from ethyl diazoacetate in the presence of rhodium catalyst was then added to the olefinic double bond of (IV) to furnish the spirocyclopentane derivative (V) as a mixture of four stereoisomers. Hydrolysis of (V) with NaOH gave rise to the corresponding mixture of stereoisomeric hydroxy acids, which were partially separated by column chromatography to provide a mixture of proximal (VI) and medial-syn (VII) isomers. Acetylation of alcohols (VI) and (VII) gave the corresponding mixture of diastereoisomeric acetates (VIIIa-b). Curtius rearrangement of (VIIIa-b) employing diphenylphosphoryl azide in tert-butanol produced the tert-butyl carbamates (IXa-b). After deacetylation of (IX) using K2CO3 in aqueous MeOH, separation of the isomers by means of column chromatography furnished the desired medial-syn carbamate (X). Removal of the Boc group o (X) was accomplished with HCl in methanol to give the corresponding amine hydrochloride (XI). The purine derivative (XIV) was obtained by alkylation of amine (XI) with 4,6-dichloro-5-nitropyrimidine (XII), followed by treatment of the crude nitro amine (XIII) with SnCl2 and triethyl orthoformate. Cloropurine (XIV) was then converted into adenine derivative (XV) by ammonolysis with methanolic ammonia at 100 C in an autoclave. This was finally coupled with phenyl chlorophosphoroalaninate (XVI) to furnish the title compound.
| 【1】 Guan, H.-P.; Drach, J.C.; Cheng, Y.-C.; Kern, E.R.; Ksebati, M.B.; Zemlicka, J.; Spiropentane mimics of nucleosides: Analogues of 2'-deoxyadenosine and 2'-deoxyguanosine. Synthesis of all stereoisomers, isomeric assignment, and biological activity. J Org Chem 2000, 65, 5, 1280. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 42603 | (1S,3S,4S)-4-[(acetoxy)methyl]spiro[2.2]pentane-1-carboxylic acid | C9H12O4 | 详情 | 详情 | |
| (VIIIb) | 42604 | (1S,3S,4R)-4-[(acetoxy)methyl]spiro[2.2]pentane-1-carboxylic acid | C9H12O4 | 详情 | 详情 | |
| (IXa) | 42605 | [(1R,3S,4S)-4-[(tert-butoxycarbonyl)amino]spiro[2.2]pent-1-yl]methyl acetate | C13H21NO4 | 详情 | 详情 | |
| (IXb) | 42606 | [(1S,3S,4S)-4-[(tert-butoxycarbonyl)amino]spiro[2.2]pent-1-yl]methyl acetate | C13H21NO4 | 详情 | 详情 | |
| (I) | 42613 | ethyl 2-bromo-2-(bromomethyl)cyclopropanecarboxylate | C7H10Br2O2 | 详情 | 详情 | |
| (II) | 21769 | ethyl 2-methylenecyclopropanecarboxylate | C7H10O2 | 详情 | 详情 | |
| (III) | 42598 | (2-methylenecyclopropyl)methanol | C5H8O | 详情 | 详情 | |
| (IV) | 42599 | (2-methylenecyclopropyl)methyl acetate | C7H10O2 | 详情 | 详情 | |
| (V) | 42600 | ethyl 4-[(acetoxy)methyl]spiro[2.2]pentane-1-carboxylate | C11H16O4 | 详情 | 详情 | |
| (VI) | 42601 | (1S,3S,4S)-4-(hydroxymethyl)spiro[2.2]pentane-1-carboxylic acid | C7H10O3 | 详情 | 详情 | |
| (VII) | 42602 | (1S,3S,4R)-4-(hydroxymethyl)spiro[2.2]pentane-1-carboxylic acid | C7H10O3 | 详情 | 详情 | |
| (X) | 42607 | tert-butyl (1S,3S,4R)-4-(hydroxymethyl)spiro[2.2]pent-1-ylcarbamate | C11H19NO3 | 详情 | 详情 | |
| (XI) | 42608 | [(1R,3S,4S)-4-aminospiro[2.2]pent-1-yl]methanol | C6H11NO | 详情 | 详情 | |
| (XII) | 15284 | 4,6-dichloro-5-nitropyrimidine | 4316-93-2 | C4HCl2N3O2 | 详情 | 详情 |
| (XIII) | 42609 | [(1R,3S,4S)-4-[(6-chloro-5-nitro-4-pyrimidinyl)amino]spiro[2.2]pent-1-yl]methanol | C10H11ClN4O3 | 详情 | 详情 | |
| (XIV) | 42610 | [(1R,3S,4S)-4-(6-chloro-9H-purin-9-yl)spiro[2.2]pent-1-yl]methanol | C11H11ClN4O | 详情 | 详情 | |
| (XV) | 42611 | [(1R,3S,4S)-4-(6-amino-9H-purin-9-yl)spiro[2.2]pent-1-yl]methanol | C11H13N5O | 详情 | 详情 | |
| (XVI) | 42612 | methyl 2-[[chloro(phenoxy)phosphoryl]amino]propanoate | C10H13ClNO4P | 详情 | 详情 |