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【结 构 式】 
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【分子编号】42613 【品名】ethyl 2-bromo-2-(bromomethyl)cyclopropanecarboxylate 【CA登记号】 |
【 分 子 式 】C7H10Br2O2 【 分 子 量 】285.9632 【元素组成】C 29.4% H 3.52% Br 55.88% O 11.19% |
合成路线1
该中间体在本合成路线中的序号：(I)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 |
合成路线2
该中间体在本合成路线中的序号：(III)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 |