4-chloro-6-methyl-3-nitro-2(1H)-pyridinone -Drug Synthesis Database

【结构式】

【分子编号】23339

【品名】4-chloro-6-methyl-3-nitro-2(1H)-pyridinone

【CA登记号】

【分子式】C₆H₅ClN₂O₃

【分子量】188.57008

【元素组成】C 38.22% H 2.67% Cl 18.8% N 14.86% O 25.45%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VII)

Serinol (I) was protected with triphenylmethyl chloride giving the N-trityl derivative (II), which was O-methylated using CH3I and NaH to afford the bis(methyl ether) (III). Subsequent acid deprotection of the trityl group of (III) provided 1,3-dimethoxy-2-aminopropane (IV). The hydroxypyridone (V) was converted to the salt with cyclohexylamine (VI), and then treated with phosphoryl chloride to produce the 4-chloropyridone (VII), which was condensed with amine (IV) to yield the aminopyridone (VIII). Further treatment of (VIII) with phosphoryl chloride gave 2-chloropyridine (IX). The nitro group of (IX) was then reduced with iron powder and AcOH, and the resulting diamino pyridine (X) was treated with NaNO2 and AcOH to produce the triazolopyridine (XI). Finally, coupling of (XI) with 2-chloro-4,6-dimethylaniline (XII) in the presence of p-TsOH provided the title compound, which was isolated as the mesylate salt.

参考文献中间体

合成目标

【1】 Bakthavatchalam, R.; Arvanitis, A.G.; Beck, J.P.; Cain, G.A.; Chorvat, R.J.; Gilligan, P.J.; Olson, R.E. (DuPont Pharmaceuticals Co.); Arylamino fused pyridines and pyrimidines. EP 0935601; WO 9735539 .

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)	23333	2-amino-1,3-propanediol; serinol	534-03-2	C₃H₉NO₂	详情	详情
(II)	23334	2-(tritylamino)-1,3-propanediol		C₂₂H₂₃NO₂	详情	详情
(III)	23335	1,3-dimethoxy-N-trityl-2-propanamine		C₂₄H₂₇NO₂	详情	详情
(IV)	23336	1,3-dimethoxy-2-propanamine		C₅H₁₃NO₂	详情	详情
(V)	23337	4-hydroxy-6-methyl-3-nitro-2(1H)-pyridinone	4966-90-9	C₆H₆N₂O₄	详情	详情
(VI)	12294	Aniline; Phenylamine	62-53-3	C₆H₇N	详情	详情
(VII)	23339	4-chloro-6-methyl-3-nitro-2(1H)-pyridinone		C₆H₅ClN₂O₃	详情	详情
(VIII)	23340	4-[[2-methoxy-1-(methoxymethyl)ethyl]amino]-6-methyl-3-nitro-2(1H)-pyridinone		C₁₁H₁₇N₃O₅	详情	详情
(IX)	23341	2-chloro-N-[2-methoxy-1-(methoxymethyl)ethyl]-6-methyl-3-nitro-4-pyridinamine		C₁₁H₁₆ClN₃O₄	详情	详情
(X)	23342	2-chloro-N(4)-[2-methoxy-1-(methoxymethyl)ethyl]-6-methyl-3,4-pyridinediamine		C₁₁H₁₈ClN₃O₂	详情	详情
(XI)	23343	2-(4-chloro-6-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-3-methoxypropyl methyl ether		C₁₁H₁₅ClN₄O₂	详情	详情
(XII)	23344	2-chloro-4,6-dimethylaniline		C₈H₁₀ClN	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

4-Hydroxy-6-methyl-3-nitropyridone (I) is chlorinated to (II) by treatment with POCl3 in the presence of benzyltriethylammonium chloride. Alkylation of pyridone (II) with ethyl bromoacetate (III) and NaH leads to the pyridoneacetate (IV) (1). Displacement of the chloride group of (IV) with 2-mercaptobenzothiazole (V) affords the thioether (VI). After reduction of the nitro group of (VI) by catalytic hydrogenation, the resultant amine (VII) is protected as the di-Boc derivative (VIII) with di-tert-butyl dicarbonate and DMAP. Oxidation of the thioether (VIII) with KmnO4 gives the sulfone (IX), which is submitted to reductive cleavage with Zn/AcOH. Finally chlorination of the intermediate zinc sulfinate with NCS furnishes the sulfonyl chloride (X) (1,2).

参考文献中间体

合成目标

【1】 Sanderson, P.E.J.; Cutrona, K.J.; Savage, K.L.; Naylor-Olsen, A.M.; Bickel, D.J.; Bohn, D.L.; Clayton, F.C.; Krueger, J.A.; Lewis, S.D.; Lucas, B.J.; Lyle, E.A.; Wallace, A.A.; Welsh, D.C.; Yan, Y.; 3-Amino-4-sulfonylpyridinone acetamide and related pyridothiadiazine thrombin inhibitors. Bioorg Med Chem Lett 2003, 13, 8, 1441.
【2】 Sanderson, P.E.; Cutrona, K. (Merck & Co., Inc.); Thrombin inhibitors. EP 1117660; JP 2002525370; US 6117888; WO 0018762 .

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)	23337	4-hydroxy-6-methyl-3-nitro-2(1H)-pyridinone	4966-90-9	C₆H₆N₂O₄	详情	详情
(II)	23339	4-chloro-6-methyl-3-nitro-2(1H)-pyridinone		C₆H₅ClN₂O₃	详情	详情
(III)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(IV)	64710	ethyl 2-[4-chloro-6-methyl-3-nitro-2-oxo-1(2H)-pyridinyl]acetate		C₁₀H₁₁ClN₂O₅	详情	详情
(V)	24677	1,3-benzothiazol-2-ylhydrosulfide	149-30-4	C₇H₅NS₂	详情	详情
(VI)	64711	ethyl 2-[4-(1,3-benzothiazol-2-ylsulfanyl)-6-methyl-3-nitro-2-oxo-1(2H)-pyridinyl]acetate		C₁₇H₁₅N₃O₅S₂	详情	详情
(VII)	64712	ethyl 2-[3-amino-4-(1,3-benzothiazol-2-ylsulfanyl)-6-methyl-2-oxo-1(2H)-pyridinyl]acetate		C₁₇H₁₇N₃O₃S₂	详情	详情
(VIII)	64713	ethyl 2-[4-(1,3-benzothiazol-2-ylsulfanyl)-3-[bis(tert-butoxycarbonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate		C₂₇H₃₃N₃O₇S₂	详情	详情
(IX)	64714	ethyl 2-[4-(1,3-benzothiazol-2-ylsulfonyl)-3-[bis(tert-butoxycarbonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate		C₂₇H₃₃N₃O₉S₂	详情	详情
(X)	64715	ethyl 2-[3-[bis(tert-butoxycarbonyl)amino]-4-(chlorosulfonyl)-6-methyl-2-oxo-1(2H)-pyridinyl]acetate		C₂₀H₂₉ClN₂O₉S	详情	详情

Extended Information