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【结 构 式】

【分子编号】25586

【品名】ethyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate

【CA登记号】

【 分 子 式 】C10H14N2O3S

【 分 子 量 】242.29884

【元素组成】C 49.57% H 5.82% N 11.56% O 19.81% S 13.23%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

Michael addition of acrylonitrile (II) to 2-methyl-3-aminopropionitrile (I) gave dinitrile (III), which was cyclized to piperidone (IV) under Thorpe-Ziegler conditions. After protection of (IV) as the carbamate (V), hydrolysis of the nitrile with 85% H2SO4 provided ketoamide (VI). This was converted to enamine (VII) by condensation with benzylamine in refluxing xylene. Subsequent treatment of (VII) with H2S in DMF, followed by bromine in AcOH furnished isothiazole (VIII). The ethoxycarbonyl group of (VIII) was then replaced for a tert-butoxycarbonyl group by hydrolysis with HBr in AcOH to (IX), and then reaction with Boc2O to give a N,O-di-Boc intermediate, which was further treated with K2CO3 in MeOH to afford (X). After alkylation of the hydroxyl group of (X) with propargyl bromide (XI), the tert-butyl carbamate was removed with ethereal HCl to yield the racemic isothiazolopyridine (XII). Finally, the (S)-(+)-enantiomer of (XII) was resolved by crystallization as the diastereomeric salt with D-(+)-dibenzoyltartaric acid and, after liberation of the base with NaOH, was isolated as the fumarate salt.

1 Pedersen, H.; et al.; Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline. Bioorg Med Chem 1999, 7, 5, 795.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(I) 25580 3-amino-2-methylpropanenitrile C4H8N2 详情 详情
(II) 10847 Acrylonitrile 107-13-1 C3H3N 详情 详情
(III) 25581 3-[(2-cyanoethyl)amino]-2-methylpropanenitrile C7H11N3 详情 详情
(IV) 25582 5-methyl-4-oxo-3-piperidinecarbonitrile C7H10N2O 详情 详情
(V) 25583 ethyl 3-cyano-5-methyl-4-oxo-1-piperidinecarboxylate C10H14N2O3 详情 详情
(VI) 25584 ethyl 3-(aminocarbonyl)-5-methyl-4-oxo-1-piperidinecarboxylate C10H16N2O4 详情 详情
(VII) 25585 ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate C17H23N3O3 详情 详情
(VIII) 25586 ethyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate C10H14N2O3S 详情 详情
(IX) 25587 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol C7H10N2OS 详情 详情
(X) 25588 tert-butyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate C12H18N2O3S 详情 详情
(XI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XII) 25589 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl 2-propynyl ether C10H12N2OS 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VIII)

Michael addition of acrylonitrile (II) to 2-methyl-3-aminopropionitrile (I) gave dinitrile (III), which was cyclized to piperidone (IV) under Thorpe-Ziegler conditions. After protection of (IV) as the carbamate (V), hydrolysis of the nitrile with 85% H2SO4 provided ketoamide (VI). This was converted to enamine (VII) by condensation with benzylamine in refluxing xylene. Subsequent treatment of (VII) with H2S in DMF, followed by bromine in AcOH furnished isothiazole (VIII). The ethoxycarbonyl group of (VIII) was then replaced for a tert-butoxycarbonyl group by hydrolysis with HBr in AcOH to (IX), and then reaction with Boc2O to give a N,O-di-Boc intermediate, which was further treated with K2CO3 in MeOH to afford (X). After alkylation of the hydroxyl group of (X) with propargyl bromide (XI), the tert-butyl carbamate was removed with ethereal HCl to yield the racemic isothiazolopyridine (XII). Finally, the (R)-(-)-enantiomer of (XII) was resolved by crystallization as the diastereomeric salt with L-(-)-dibenzoyltartaric acid and, after liberation of the base with NaOH, was isolated as the fumarate salt .

1 Pedersen, H.; et al.; Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline. Bioorg Med Chem 1999, 7, 5, 795.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(I) 25580 3-amino-2-methylpropanenitrile C4H8N2 详情 详情
(II) 10847 Acrylonitrile 107-13-1 C3H3N 详情 详情
(III) 25581 3-[(2-cyanoethyl)amino]-2-methylpropanenitrile C7H11N3 详情 详情
(IV) 25582 5-methyl-4-oxo-3-piperidinecarbonitrile C7H10N2O 详情 详情
(V) 25583 ethyl 3-cyano-5-methyl-4-oxo-1-piperidinecarboxylate C10H14N2O3 详情 详情
(VI) 25584 ethyl 3-(aminocarbonyl)-5-methyl-4-oxo-1-piperidinecarboxylate C10H16N2O4 详情 详情
(VII) 25585 ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate C17H23N3O3 详情 详情
(VIII) 25586 ethyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate C10H14N2O3S 详情 详情
(IX) 25587 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol C7H10N2OS 详情 详情
(X) 25588 tert-butyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate C12H18N2O3S 详情 详情
(XI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XII) 25589 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl 2-propynyl ether C10H12N2OS 详情 详情
Extended Information