【结 构 式】 |
【分子编号】21753 【品名】ethyl 2-[(6-amino-9H-purin-9-yl)methyl]-2-bromocyclopropanecarboxylate 【CA登记号】 |
【 分 子 式 】C12H14BrN5O2 【 分 子 量 】340.17966 【元素组成】C 42.37% H 4.15% Br 23.49% N 20.59% O 9.41% |
合成路线1
该中间体在本合成路线中的序号:(VI)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 |