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【结 构 式】

【药物名称】A-85380-[18F]-F, [18F]-F-A-85380

【化学名称】3-[Azetidin-2(S)-ylmethoxy]-2-(18-fluoro)pyridine

【CA登记号】205594-65-6

【 分 子 式 】C9H11FN2O

【 分 子 量 】181.20082

【开发单位】Commissariat a l'Energie Atomique (Originator)

【药理作用】DIAGNOSTIC AGENTS, Drugs Acting on Acetylcholine Receptors (Nicotinic)

合成路线1

Title radiolabeled compound has been obtained by several related procedures. Protection of (S)-2-azetidinecarboxylic acid (I) with tert-butyl dicarbonate provided carbamate (II), which was reduced to alcohol (III) using borane-dimethyl sulfide in THF at -78 C (1, 3). Subsequent coupling of (III) with 3-hydroxy-2-nitropyridine (IV) under Mitsunobu conditions gave ether (V). Introduction of the 18F in (IV) was performed by means of [18F]KF-Kryptofix K222 complex in DMSO, either by conventional heating at 150 C or by microwave activation yielding (VI). The resulting radiolabeled fluoropyridine (VI) was finally deprotected with trifluoroacetic acid in CH2Cl2.

1 Dolle, F.; et al.; Synthesis of 2-[18F]fluoro-3-[2(s)-azetidnylmethoxy]pyridine, a higly potent radioligand for in vivo imaging central nicotinic acetylcholine receptors. J Label Compd Radiopharm 1998, 41, 451-463.
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) 26204 (2S)-2-azetidinecarboxylic acid; (S)-(-)-Azetidine carboxylic acid 2133-34-8 C4H7NO2 详情 详情
(II) 26205 (2S)-1-(tert-butoxycarbonyl)-2-azetidinecarboxylic acid C9H15NO4 详情 详情
(III) 26206 tert-butyl (2S)-2-(hydroxymethyl)-1-azetidinecarboxylate C9H17NO3 详情 详情
(IV) 26207 2-nitro-3-pyridinol 15128-82-2 C5H4N2O3 详情 详情
(V) 26208 tert-butyl (2S)-2-[[(2-nitro-3-pyridinyl)oxy]methyl]-1-azetidinecarboxylate C14H19N3O5 详情 详情
(VI) 26209 tert-butyl (2S)-2-[[(2-fluoro-3-pyridinyl)oxy]methyl]-1-azetidinecarboxylate C14H19FN2O3 详情 详情
(VI) 26215 tert-butyl (2S)-2-[[(2-fluoro-3-pyridinyl)oxy]methyl]-1-azetidinecarboxylate C14H19FN2O3 详情 详情

合成路线2

In an alternative procedure, Mitsunobu coupling of alcohol (III) with 3-hydroxy-2-iodopyridine (VII) provided ether (VIII). The iodo atom of (III) was then displaced using [18F]KF-Kryptofix K222 complex in DMSO to provide radiolabeled precursor (VI), which was finally deprotected with trifluoroacetic acid.

1 Hrti, A.; et al.; Synthesis of a radiotracer for studying nicotinic acetylcholine receptors: 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]A85380). J Label Compd Radiopharm 1998, 41, 309-318.
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) 26206 tert-butyl (2S)-2-(hydroxymethyl)-1-azetidinecarboxylate C9H17NO3 详情 详情
(VI) 26209 tert-butyl (2S)-2-[[(2-fluoro-3-pyridinyl)oxy]methyl]-1-azetidinecarboxylate C14H19FN2O3 详情 详情
(VI) 26215 tert-butyl (2S)-2-[[(2-fluoro-3-pyridinyl)oxy]methyl]-1-azetidinecarboxylate C14H19FN2O3 详情 详情
(VII) 26210 2-iodo-3-pyridinol 40263-57-8 C5H4INO 详情 详情
(VIII) 26211 tert-butyl (2S)-2-[[(2-iodo-3-pyridinyl)oxy]methyl]-1-azetidinecarboxylate C14H19IN2O3 详情 详情

合成路线3

In a related procedure, 2-fluoro-3-hydroxypyridine (IX) was treated with dimethylamine to provide (dimethylamino)pyridine (X). This was coupled to alcohol (III) to give ether (XI). Alternatively, (XI) was prepared by coupling fluoropyridine (IX) with alcohol (III) and subsequently treated with dimethylamine. Quaternization by means of methyl trifluoromethanesulfonate produced trimethylammonium derivative (XIII). Further displacement in (XIII) using [18F]KF-Kryptofix K222 complex provided radiolabeled fluoropyridine (VI), which was finally deprotected as above.

1 Dollé, F.; et al.; Synthesis and nicotinic acetylcholine receptor in vivo binding properties of 2-fluoro-3-[2(S)-2azetidinylmethoxylpyridine: A new positron emission tomography ligand for nicotinic receptors. J Med Chem 1999, 42, 12, 2251.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI),(XII) 26215 tert-butyl (2S)-2-[[(2-fluoro-3-pyridinyl)oxy]methyl]-1-azetidinecarboxylate C14H19FN2O3 详情 详情
(III) 26206 tert-butyl (2S)-2-(hydroxymethyl)-1-azetidinecarboxylate C9H17NO3 详情 详情
(VI) 26209 tert-butyl (2S)-2-[[(2-fluoro-3-pyridinyl)oxy]methyl]-1-azetidinecarboxylate C14H19FN2O3 详情 详情
(IX) 26212 2-fluoro-3-pyridinol C5H4FNO 详情 详情
(X) 26213 2-(dimethylamino)-3-pyridinol C7H10N2O 详情 详情
(XI) 26214 tert-butyl (2S)-2-([[2-(dimethylamino)-3-pyridinyl]oxy]methyl)-1-azetidinecarboxylate C16H25N3O3 详情 详情
(XIII) 26216 3-[[(2S)-1-(tert-butoxycarbonyl)azetidinyl]methoxy]-N,N,N-trimethyl-2-pyridinaminium trifluoromethanesulfonate C18H28F3N3O6S 详情 详情
Extended Information