SB-737552, S-8510, -Drug Synthesis Database

【结构式】

【药物名称】SB-737552, S-8510

【化学名称】2-(3-Isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine monophosphate monohydrate

【CA登记号】151224-83-8 (anhydrous), 151466-23-8 (anhydrous), 151466-25-0 (anhydrous, maleate salt (1:1)), 151225-40-0 (anhydrous, monoHCl s

【分子式】C₁₂H₁₅N₄O₇P

【分子量】358.24975

【开发单位】Shionogi (Originator), GlaxoSmithKline (Codevelopment)

【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Vascular Dementia, Treatment of, GABA(A) BZ Site Receptor Inverse Agonists

合成路线1 合成路线2 合成路线3

合成路线1

3-Nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridine (III) was prepared by heating tetrahydropyranone (I) with dinitropyridone (II) in methanolic ammonia following a reported procedure. Hydrogenation of the nitro derivative (III) and protection of the resulting amine (IV) with trichloroacetyl chloride afforded the trichloroacetamide (V). Oxidation of the pyridine ring of (V) with 3-chloroperoxybenzoic acid gave the N-oxide (VI). Nitration of the pyridine ring of (VI) with fuming nitric acid, followed by amide hydrolysis with ammonium hydroxide provided the 3-amino-4-nitropyridine N-oxide (VII). Reduction of the N-oxide and 4-nitro groups of (VII) was accomplished in a single step by hydrogenation in the presence of Raney-nickel to furnish the bicyclic diaminopyridine (VIII). Subsequent monoacylation of (VIII) with isoxazole-3-carbonyl chloride (IX) followed by thermal cyclization provided the desired imidazopyranopyridine compound (1,2), which was finally isolated as the title phosphate salt

参考文献中间体

【1】 Takada, S.; Sasatani, T.; Chomei, N.; Adachi, M.; Fujishita, T.; Eigyo, M.; Murata, S.; Kawasaki, K.; Matsushita, A.; Synthesis and structure-activity relationships of fused imidazopyridines: A new series of benzodiazepine receptor ligands. J Med Chem 1996, 39, 14, 2844.
【2】 Takada, S.; Sasatani, T.; Chomei, N.; Adachi, M.; Matsushita, A. (Shionogi & Co. Ltd.); Condensed imidazopyridine derivs. with psychotropic activity. EP 0556008; JP 1993286973; US 5378848; US 5461062 .

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)	31563	tetrahydro-4H-pyran-4-one	29943-42-8	C₅H₈O₂	详情	详情
(II)	59825	1-methyl-3,5-dinitro-2(1H)-pyridinone		C₆H₅N₃O₅	详情	详情
(III)	59826	3-nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridine		C₈H₈N₂O₃	详情	详情
(IV)	59827	7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-amine; 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-ylamine		C₈H₁₀N₂O	详情	详情
(V)	59828	2,2,2-trichloro-N-(7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl)acetamide		C₁₀H₉Cl₃N₂O₂	详情	详情
(VI)	59829	3-[(2,2,2-trichloroacetyl)amino]-7,8-dihydro-5H-pyrano[4,3-b]pyridin-1-ium-1-olate		C₁₀H₉Cl₃N₂O₃	详情	详情
(VII)	59830	3-amino-4-nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-1-ium-1-olate		C₈H₉N₃O₄	详情	详情
(VIII)	59831	3-amino-7,8-dihydro-5H-pyrano[4,3-b]pyridin-4-ylamine; 7,8-dihydro-5H-pyrano[4,3-b]pyridine-3,4-diamine		C₈H₁₁N₃O	详情	详情
(IX)	59832	3-isoxazolecarbonyl chloride		C₄H₂ClNO₂	详情	详情

合成路线2

In a related procedure, the pyranopyridine (III) was oxidized to the corresponding N-oxide (X) with 3-chloroperoxybenzoic acid, and the nitro group of (X) was subsequently reduced to amine (XI) by catalytic hydrogenation over Pd/C. Acylation of (XI) with isoxazole-3-carbonyl chloride (IX) provided amide (XII). After pyridine ring nitration with fuming nitric acid to afford (XIII), its N-oxide function was reduced by treatment with phosphorus tribromide. The resultant nitro amide (XIV) was then hydrogenated to the corresponding amino amide derivative (XV), which was finally cyclized in hot ethyleneglycol to the target imidazopyranopyridine

参考文献中间体

【1】 Takada, S.; Sasatani, T.; Chomei, N.; Adachi, M.; Matsushita, A. (Shionogi & Co. Ltd.); Condensed imidazopyridine derivs. with psychotropic activity. EP 0556008; JP 1993286973; US 5378848; US 5461062 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(III)	59826	3-nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridine	C₈H₈N₂O₃	详情	详情
(IX)	59832	3-isoxazolecarbonyl chloride	C₄H₂ClNO₂	详情	详情
(X)	59833	3-nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-1-ium-1-olate	C₈H₈N₂O₄	详情	详情
(XI)	59834	3-amino-7,8-dihydro-5H-pyrano[4,3-b]pyridin-1-ium-1-olate	C₈H₁₀N₂O₂	详情	详情
(XII)	59835	3-[(3-isoxazolylcarbonyl)amino]-7,8-dihydro-5H-pyrano[4,3-b]pyridin-1-ium-1-olate	C₁₂H₁₁N₃O₄	详情	详情
(XIII)	59836	3-[(3-isoxazolylcarbonyl)amino]-4-nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-1-ium-1-olate	C₁₂H₁₀N₄O₆	详情	详情
(XIV)	59837	N-(4-nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl)-3-isoxazolecarboxamide	C₁₂H₁₀N₄O₅	详情	详情
(XV)	59838	N-(4-amino-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl)-3-isoxazolecarboxamide	C₁₂H₁₂N₄O₃	详情	详情

合成路线3

In a different synthetic strategy, dienamine (XVIII) was obtained by heating the tetrahydropyranone enamine (XVI) with the (aminomethylene)oxazolone (XVII) in the presence of Ac2O in toluene. Thermal cyclization of (XVIII) in hot N-methylpyrrolidinone gave rise to the pyridopyranone (XIX). Upon chlorination of pyridone (XIX) with POCl3 in the presence of DMF, a simultaneous displacement of the benzoyl group occurred, leading to the formamidino derivative (XX), which was further hydrolyzed to the 3-amino-4-chloropyridine (XXI) under acidic conditions. Acylation of amine (XXI) with acid chloride (IX) afforded the corresponding amide (XXII). This was converted to the required amidine (XXIII) by chlorination with PCl5, followed by treatment with isopropanolic ammonia. Finally, the tricyclic imidazo-fused compound was obtained by thermal cyclization of the chloro amidine (XXIII) in NMP at 215 C

参考文献中间体

【1】 Adachi, M.; Chomei, N.; Takada, S.; Intramolecular transfer of an alkenyl group in enamines: Application to synthesis of [b]-fused pyridines. Tetrahedron Lett 1996, 37, 49, 8871.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	59832	3-isoxazolecarbonyl chloride	C₄H₂ClNO₂	详情	详情
(XVI)	59839	4-(3,6-dihydro-2H-pyran-4-yl)morpholine	C₉H₁₅NO₂	详情	详情
(XVII)	59840	4-[(E)-aminomethylidene]-2-phenyl-1,3-oxazol-5(4H)-one	C₁₀H₈N₂O₂	详情	详情
(XVIII)	59841	4-[(E)-(3,6-dihydro-2H-pyran-4-ylamino)methylidene]-2-phenyl-1,3-oxazol-5(4H)-one	C₁₅H₁₄N₂O₃	详情	详情
(XIX)	59842	N-(4-oxo-1,5,7,8-tetrahydro-4H-pyrano[4,3-b]pyridin-3-yl)benzamide	C₁₅H₁₄N₂O₃	详情	详情
(XX)	59843	N'-(4-chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl)-N,N-dimethyliminoformamide	C₁₁H₁₄ClN₃O	详情	详情
(XXI)	59844	4-chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-amine; 4-chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-ylamine	C₈H₉ClN₂O	详情	详情
(XXII)	59846	N-(4-chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl)-3-isoxazolecarboxamide	C₁₂H₁₀ClN₃O₃	详情	详情
(XXIII)	59845	N'-(4-chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl)-3-isoxazolecarboximidamide	C₁₂H₁₁ClN₄O₂	详情	详情

Extended Information