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【结 构 式】 
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【分子编号】21757 【品名】[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：(X)The addition of ethyl diazoacetate (II) to 2,3-dibromopropene (I) catalyzed by dirhodium tetraacetate in CH2Cl2 yielded a mixture of E- (III) and Z- (IV) cyclopropanes. Alkylation of adenine (V) with the mixture of bromoesters (III) and (IV) in the presence of either NaH in DMF at r.t. or K2CO3 at 80 C provided the diastereomeric (cyclopropylmethyl)adenines (VI). Elimination of HBr was carried out with potassium tert-butoxide in cold DMF or with NaH in THF to yield an unseparable mixture of Z- (VII) and E- (VIII) methylene cyclopropanes. Alternatively, simultaneous alkylation of adenine (V) and elimination of HBr to give (VII) + (VIII) was effected using K2CO3 in DMF at 100 C. Reduction of the ester groups of (VII) and (VIII) with DIBALH afforded a mixture of the racemic (Z) title compound (IX) and its its E-isomer (X). The unseparable mixture of (IX) and (X) was treated with dimethylformamide dimethylacetal in DMF to give the corresponding (dimethylamino)methylene derivatives that allowed a chromatographic separation. The desired racemic (Z)-isomer (XI) was further deprotected in methanolic ammonia to furnish racemic (IX) (1). Optical resolution was then achieved on treatment with adenosine deaminase, to produce the (Z)(S)-(+)-hypoxanthine derivative (XII) that was separated chromatographically from the unchanged (Z)(R)-(-)-isomer, the target 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 |
|---|---|---|---|---|---|---|
| (I) | 21748 | 2,3-dibromo-1-propene | 513-31-5 | C3H4Br2 | 详情 | 详情 |
| (II) | 21749 | Diazoacetic acid ethyl ester; Diazoacetic acid ethyl ester | C4H7N2O2 | 详情 | 详情 | |
| (III) | 21750 | ethyl (1S,2R)-2-bromo-2-(bromomethyl)cyclopropanecarboxylate | C7H10Br2O2 | 详情 | 详情 | |
| (IV) | 21751 | ethyl (1S,2S)-2-bromo-2-(bromomethyl)cyclopropanecarboxylate | C7H10Br2O2 | 详情 | 详情 | |
| (V) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (VI) | 21753 | ethyl 2-[(6-amino-9H-purin-9-yl)methyl]-2-bromocyclopropanecarboxylate | C12H14BrN5O2 | 详情 | 详情 | |
| (VII) | 21754 | ethyl 2-[(Z)-(6-amino-9H-purin-9-yl)methylidene]cyclopropanecarboxylate | C12H13N5O2 | 详情 | 详情 | |
| (VIII) | 21755 | ethyl 2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropanecarboxylate | C12H13N5O2 | 详情 | 详情 | |
| (IX) | 21756 | [2-[(Z)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
| (X) | 21757 | [2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
| (XI) | 21758 | N'-(9-[[2-(hydroxymethyl)cyclopropylidene]methyl]-9H-purin-6-yl)-N,N-dimethyliminoformamide | C13H16N6O | 详情 | 详情 | |
| (XII) | 21759 | 9-[[(2S)-2-(hydroxymethyl)cyclopropylidene]methyl]-1,9-dihydro-6H-purin-6-one | C10H10N4O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)A related synthesis for the racemic compound (IX) has been reported. This involves initial reduction of the diasteromeric esters (III) and (IV) to the corresponding alcohols (XIII) with DIBALH. The hydroxyl group of (XIII) was then protected as either the benzoate ester (XIV) with benzoyl bromide in pyridine, or as the methoxymethyl (MOM) ether, using chloromethyl methyl ether and diisopropyl ethylamine, which furnished dibromo- (XV) along with bromochlorocompound (XVI). The alkylation-elimination reaction of dibromide (XIV) using adenine (V) and K2CO3 in DMF at 95 C gave an unseparable mixture of Z- (XVII) and E- (XVIII) methylene cyclopropanes. The benzoate esters (XVII) + (XVIII) were then deprotected in methanolic ammonia to afford a mixture of the target racemic Z-olefin (IX) and its E-isomer (X). In contrast, the alkylation-elimination products (XIX) and (XX) from the MOM-protected halides (XV) + (XVI) could be separed by chromatography. Deprotection of the desired Z-isomer (XX) with methanolic HCl provided racemic (IX).
| 【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 |
|---|---|---|---|---|---|---|
| (III) | 21750 | ethyl (1S,2R)-2-bromo-2-(bromomethyl)cyclopropanecarboxylate | C7H10Br2O2 | 详情 | 详情 | |
| (IV) | 21751 | ethyl (1S,2S)-2-bromo-2-(bromomethyl)cyclopropanecarboxylate | C7H10Br2O2 | 详情 | 详情 | |
| (IX) | 21756 | [2-[(Z)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
| (X) | 21757 | [2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H11N5O | 详情 | 详情 | |
| (XIII) | 21760 | [2-bromo-2-(bromomethyl)cyclopropyl]methanol | C5H8Br2O | 详情 | 详情 | |
| (XIV) | 21761 | [2-bromo-2-(bromomethyl)cyclopropyl]methyl benzoate | C12H12Br2O2 | 详情 | 详情 | |
| (XV) | 21762 | 1-bromo-1-(bromomethyl)-2-[(methoxymethoxy)methyl]cyclopropane; [[2-bromo-2-(bromomethyl)cyclopropyl]methoxy]methyl methyl ether | C7H12Br2O2 | 详情 | 详情 | |
| (XVI) | 21763 | 1-bromo-1-(chloromethyl)-2-[(methoxymethoxy)methyl]cyclopropane | C7H12BrClO2 | 详情 | 详情 | |
| (XVII) | 21764 | [2-[(Z)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methyl benzoate | C17H15N5O2 | 详情 | 详情 | |
| (XVIII) | 21765 | [2-[(E)-(6-amino-9H-purin-9-yl)methylidene]cyclopropyl]methyl benzoate | C17H15N5O2 | 详情 | 详情 | |
| (XIX) | 21766 | 9-([2-[(methoxymethoxy)methyl]cyclopropylidene]methyl)-9H-purin-6-ylamine; 9-([2-[(methoxymethoxy)methyl]cyclopropylidene]methyl)-9H-purin-6-amine | C12H15N5O2 | 详情 | 详情 | |
| (XX) | 21767 | 9-([2-[(methoxymethoxy)methyl]cyclopropylidene]methyl)-9H-purin-6-amine; 9-([2-[(methoxymethoxy)methyl]cyclopropylidene]methyl)-9H-purin-6-ylamine | C12H15N5O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIIb)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 |