肺动脉高压治疗药riociguat的合成

Synthesis of riociguat in the treatment of pulmonary hypertension

目的合成肺动脉高压治疗药物riociguat。方法以2-氟溴苄为起始原料合成2-氟苄肼(2);以草酸二乙酯为起始原料合成氰基丙酮酸乙酯的钠盐(3);2和3关环后再经过5步反应合成1-(2-氟苄基)-1H-吡唑并[3,4-b]吡啶-3-甲脒盐酸盐(9);以苯胺和丙二腈为起始原料合成苯偶氮丙二腈(10);9和10关环后再经过催化氢化、烷氧酰基化、甲基化得到目标化合物riociguat。结果与结论目标化合物和中间体的结构经MS、1H-NMR和13C-NMR确认,总收率为7.64%。

The synthesis of riociguat,a drug for curing pulmonary hypertension,has been accomplished via 13 steps according to the literature.The starting compounds,2-fluorobenzylhydrazine（2） and the sodium salt of ethyl cyanopyruvate（3） which were not commercially available were conveniently prepared from 2-fluorobenzylbromide and diethyl oxalate respectively.Condensation of 2 with 3 followed by a cyclization reaction and subsequently a series of functional group transforming reactions yielded 1-（2-fluorobenzyl）-1H-pyrazolo pyridine-3-carboximidamide hydrochloride（9）.Aniline was diazonium coupled with malononitrile to afford the key intermediate phenyldiazenyl malononitrile（10）.The pyrimidine ring was successfully formed by the cyclization of 9 with 10.Hydrogenation of the resulting compound followed by carbalkoxylation and methylation yielded the target compound riociguat.In our improved process,the amidine was salified with hydrogen chloride in ether to afford the amidine hydrochloride（9） to avoid the deconpositon of amine under neutral and basic conditons.Unlike the method reported in the literature,the amidine hydrochloride,instead of its free state reacted directly with phenyldiazenyl malononitrile to form the pyrimidine ring in 89.3% yield（lit.73%）.Hydrogenation of the azo compound（11） was carried out by using freshly prepared T-1 type Raney-Ni with the yield improved to 79.2%（lit.59%） and the time reduced to 12 h（lit.22 h）.The structure of the target compound and the intermediates were confirmed by MS,1H-NMR and 13C-NMR.The total yield was 7.64% which was comparable with that in the literature.