Aprikalim, RP-52891, Aprim

阿普卡林Chemical Name: (-)-(1R,2R)-N-Methyl-2-(3-pyridinyl)tetrahydro-2H-thiopyran-2-carbothioamide 1-oxide
CAS No. 89544-10-5 (non-specific stereoch.), 92569-65-8 (trans-isomer)
项目整合开发状态: Phase II
项目研究机构: Aventis Pharma (Originator)
合成路线:The reaction of 3-(chloromethyl)pyridine (I) with thiourea (II) in ethanol gives S-(3-pyridylmethyl)isothiourea (III),which is condensed with 4-chlorobutyl bromide (IV) by means of NaOH in dichloromethane to yield 3-(4-chlorobutylsulfanylmethyl)pyridine (V).The careful oxidation of (V) with MCPBA in dichloromethane affords the corresponding sulfoxide (VI),which is cyclized by means of potassium tert-butoxide in THF,providing a mixture of cis- and trans-2-(3-pyridyl)tetrahydrothiopyran S-oxide (VII + VIII).This mixture can be separated by conventional methods; however,when this mixture (VII + VIII),or either (VII) or (VIII) separately,are treated with NaNH2 and methyl isothiocyanate,only the target (1RS,2RS)-compound is obtained.Alternatively,the mixture (VII + VIII) or either (VII) or (VIII) can also be treated with potassium tert-butoxide,CS2 and methyl iodide to yield the (1RS,2RS)-dithioester (IX),which is finally converted into the target compound by reaction with methylamine.

合成路线:The condensation of 2-(3-pyridinyl)tetrahydrothiopyran-2-carboxylic acid (I) with L-proline tert-butyl ester (II) by means of SOCl2 gives the corresponding amide as a diastereomeric mixture (S,S)-(III) + (R,S)-(III) that is separated by chromatography.The desired isomer (R,S)-(III) is hydrolyzed with conc.HCl to yield 2-(3-pyridinyl)tetrahydrothiopyran-2-carboxylic acid (R)-(IV),which is treated first with SOCl2 and methylamine,and then with Lawesson reagent or P2S5 to afford the thioamide (R)-(V).The reaction of (R)-(V) with methyl iodide,n-BuLi and H2S in pyridine provides the dithioester (R)-(VI),which is carefully oxidized with MCPBA in dichloromethane to provide the corresponding sulfoxide as a diastereomeric mixture (1R,2R)-(VII) + (1S,2R)-(VII) that is separated by chromatography.Finally,the desired isomer (1R,2R)-(VII) is treated with methylamine in ethanol to furnish the target thioamide.