A-85380-[18F]-F, [18F]-F-A-85380, -Drug Synthesis Database

【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 合成路线2 合成路线3

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.

参考文献中间体

【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.

参考文献中间体

【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.

参考文献中间体

【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	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