4-hydroxy-3-pyridinesulfonic acid -Drug Synthesis Database

【结构式】

【分子编号】28520

【品名】4-hydroxy-3-pyridinesulfonic acid

【CA登记号】

【分子式】C₅H₅NO₄S

【分子量】175.16504

【元素组成】C 34.28% H 2.88% N 8% O 36.54% S 18.31%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VI)

The reaction of 4-hydroxypyridine-3-sulfonic acid (VI) with POCl3 and PCl5 gives 4-chloropyridine-3-sulfonyl chloride (VII), which is treated with ammonia at room temperature yielding the sulfonamide (VIII). The resulting sulfonamide (VIII) was heated with ammonia to afford 4-aminopyridine-3-sulfonamide (IX), which is cyclized with urea (X) to provide the pyridothiadiazinone (XI). The reaction of (XI) with P2S5 in pyridine gives the corresponding thione (XII), which is methylated with methyl iodide to furnish the methylsulfanyl compound (XIII). Finally, this compound (XIII) is condensed with the chiral intermediate (R)(-)-1,2-dimethylpropylamine (R)(-)-(I) to afford the chiral (R)(-)-target compound. The condensation of the intermediate methylsulfanyl compound (XIII) with the chiral intermediate (S)(+)-1,2-dimethylpropylamine (S)(+)-(I) to afford the chiral (S)(+)-target compound.

参考文献中间体

合成目标

【1】 Pirotte, B.; et al.; 3-(Alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides as powerful inhibitors of insulin release from rat oancreatic B-cells: a new class of potassium channel openers?. J Med Chem 1993, 36, 21, 3211-13.
【2】 de Tullio, P.; Khelili, S.; Lebrun, P.; et al.; Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2'-butylamino)-4H- and 3-(3'-methyl-2'-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers. Bioorg Med Chem 1999, 7, 8, 1513.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(R)(-)-(I)	38922	(1R)-1,2-dimethylpropylamine; (2R)-3-methyl-2-butanamine		C₅H₁₃N	详情	详情
(S)(+)-(I)	38923	(1S)-1,2-dimethylpropylamine; (2S)-3-methyl-2-butanamine		C₅H₁₃N	详情	详情
(VI)	28520	4-hydroxy-3-pyridinesulfonic acid		C₅H₅NO₄S	详情	详情
(VII)	28521	4-chloro-3-pyridinesulfonyl chloride		C₅H₃Cl₂NO₂S	详情	详情
(VIII)	22151	4-chloro-3-pyridinesulfonamide		C₅H₅ClN₂O₂S	详情	详情
(IX)	38924	4-amino-3-pyridinesulfonamide		C₅H₇N₃O₂S	详情	详情
(X)	19310	urea	57-13-6	CH₄N₂O	详情	详情
(XI)	38925	1lambda(6)-pyrido[4,3-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione		C₆H₅N₃O₃S	详情	详情
(XII)	38926	3-thioxo-3,4-dihydro-2H-pyrido[4,3-e][1,2,4]thiadiazine-1,1(2H)-dione		C₆H₅N₃O₂S₂	详情	详情
(XIII)	38927	3-(methylsulfanyl)-2H-pyrido[4,3-e][1,2,4]thiadiazine-1,1(4H)-dione		C₇H₇N₃O₂S₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Coupling of N-Boc-p-nitrophenylalanine (I) with 4-(2-fluoroethyl)piperidine (II) by means of 2-benzotriazolyl-1,1,3,3-tetramethyluronium tetrafluoborate (TBTU) gave amide (III) which, after acidic deprotection provided aminoamide (IV). 4-Chloropyridine-3-sulfonyl chloride (VI), generated from 4-hydroxy pyridine-3-sulfonic acid (V) by chlorination with PCl5/POCl3, was coupled with amine (IV) to afford sulfonamide (VII). Further condensation of (VII) with L-phenylalaninol (VIII) produced aminopyridine (IX). Conversion of the alcohol group of (IX) to the corresponding mesylate, followed by displacement with morpholine furnished the N-substituted morpholine (X). The nitro group of (X) was finally reduced to the target aniline by hydrogenation over Pd/C.

参考文献中间体

合成目标

【1】 Ambler, J.; Baker E; Brown, L.; Butler, P.; Farr, D.; Dunnet, K.; Le Grand, D.; Janus, D.; Jones, D.; Menear, K.; Mercer, M.; Smith, G.; Talbot, M.; Tweed, M.; The discovery of orally available thrombin inhibitors: Studies towards the optimisation of CGH1668. Bioorg Med Chem Lett 1998, 8, 24, 3583.

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)	28516	(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propionic acid		C₁₄H₁₈N₂O₆	详情	详情
(II)	28517	4-(2-fluoroethyl)piperidine		C₇H₁₄FN	详情	详情
(III)	28518	tert-butyl (1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethylcarbamate		C₂₁H₃₀FN₃O₅	详情	详情
(IV)	28519	(2S)-2-amino-1-[4-(2-fluoroethyl)-1-piperidinyl]-3-(4-nitrophenyl)-1-propanone		C₁₆H₂₂FN₃O₃	详情	详情
(V)	28520	4-hydroxy-3-pyridinesulfonic acid		C₅H₅NO₄S	详情	详情
(VI)	28521	4-chloro-3-pyridinesulfonyl chloride		C₅H₃Cl₂NO₂S	详情	详情
(VII)	28522	4-chloro-N-[(1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide		C₂₁H₂₄ClFN₄O₅S	详情	详情
(VIII)	28523	(2S)-2-amino-3-phenyl-1-propanol; L-phenylalanilol; (S)-2-amino-3-phenyl-1-propanol	5267-64-1	C₉H₁₃NO	详情	详情
(IX)	28524	4-[[(1S)-1-benzyl-2-hydroxyethyl]amino]-N-[(1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide		C₃₀H₃₆FN₅O₆S	详情	详情
(X)	28525	4-[[(1S)-1-benzyl-2-(4-morpholinyl)ethyl]amino]-N-[(1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide		C₃₄H₄₃FN₆O₆S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

The reaction of 4-hydroxypyridine-3-sulfonic acid (I) with POCl3 and PCl5 gives 4-chloropyridine-3-sulfonyl chloride (II), which is treated with ammonia at room temperature yielding the sulfonamide (III). The resulting sulfonamide (VIII) was heated with ammonia to afford 4-aminopyridine-3-sulfonamide (IV), which is cyclized with urea (V) to provide the pyridothiadiazinone (VI). The reaction of (XI) with P2S5 in pyridine gives the corresponding thione (VII), which is methylated with methyl iodide to furnish the methylsulfanyl compound (VII) (2). Finally, this compound (VIII) is condensed with the chiral intermediate (R)(-)-1-methylpropylamine (R)(-)-(IX) to afford the chiral (R)(-)-target compound. The condensation of the intermediate methylsulfanyl compound (VIII) with the chiral intermediate (S)(+)-1-methylpropylamine (S)(+)-(IX) to afford the chiral (S)(+)-target compound.

参考文献中间体

合成目标

【1】 Pirotte, B.; et al.; 3-(Alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides as powerful inhibitors of insulin release from rat oancreatic B-cells: a new class of potassium channel openers?. J Med Chem 1993, 36, 21, 3211-13.
【2】 de Tullio, P.; Khelili, S.; Lebrun, P.; et al.; Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2'-butylamino)-4H- and 3-(3'-methyl-2'-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers. Bioorg Med Chem 1999, 7, 8, 1513.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(R)(-)-(IX)	38928	(1R)-1-methylpropylamine; (2R)-2-butanamine		C₄H₁₁N	详情	详情
(S)(+)-(IX)	38929	(1S)-1-methylpropylamine; (2S)-2-butanamine		C₄H₁₁N	详情	详情
(I)	28520	4-hydroxy-3-pyridinesulfonic acid		C₅H₅NO₄S	详情	详情
(II)	28521	4-chloro-3-pyridinesulfonyl chloride		C₅H₃Cl₂NO₂S	详情	详情
(III)	22151	4-chloro-3-pyridinesulfonamide		C₅H₅ClN₂O₂S	详情	详情
(IV)	38924	4-amino-3-pyridinesulfonamide		C₅H₇N₃O₂S	详情	详情
(V)	19310	urea	57-13-6	CH₄N₂O	详情	详情
(VI)	38925	1lambda(6)-pyrido[4,3-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione		C₆H₅N₃O₃S	详情	详情
(VII)	38926	3-thioxo-3,4-dihydro-2H-pyrido[4,3-e][1,2,4]thiadiazine-1,1(2H)-dione		C₆H₅N₃O₂S₂	详情	详情
(VIII)	38927	3-(methylsulfanyl)-2H-pyrido[4,3-e][1,2,4]thiadiazine-1,1(4H)-dione		C₇H₇N₃O₂S₂	详情	详情

Extended Information