氘代丁苯那嗪合成工艺优化

Improved Synthesis of Deutetrabenazine

盐酸多巴胺、三乙胺和甲酸乙酯反应得N-[2-(3,4-二羟基苯基)乙基]甲酰胺(9)。9和三氯氧磷在乙酸乙酯中脱水形成6,7-二羟基-3,4-二氢异喹啉(11)。11和三苯基膦、氘代甲醇、偶氮二甲酸二异丙酯在四氢呋喃中反应得6,7-二(甲氧基-d_(3))-3,4-二氢异喹啉(6),此步骤通过采用氯化锌和调节后处理时反应体系的pH值可革除柱色谱纯化。6和(2-乙酰基-4-甲基戊基)三甲基碘化铵(7)在碳酸钾作用下反应得氘代丁苯那嗪(1)粗品,再经甲醇重结晶即可得纯品,总收率约49%,纯度99.6%。优化后的工艺简便,无需柱色谱纯化。

Dopamine hydrochloride(8) reacted with triethylamine and ethyl formate to get N-[2-(3,4-dihydroxyphenyl)ethyl]formamide(9).The dehydration reaction occurred between compound 9 and phosphorus oxychloride in ethyl acetate to obtain 6,7-dihydroxy-3,4-dihydroisoquinoline(11).Compound 11 reacted with triphenylphosphine,deuterated methanol and diisopropyl azodicarboxylate in tetrahydrofuran to obtain 6,7-bis(methoxy-d_(3))-3,4-dihydroisoquinoline(6),in which column chromatography can be eliminated by using zinc chloride and adjusting pH value of the reaction solution in the work-up.Compound 6 reacted with (2-acetyl-4-methylpentyl)trimethyl-1-aminium iodide(7) in the presence of potassium carbonate to obtain crude deuterated tetrabenazine(1).After recrystallization from methanol,the purity of deutetrabenazine reached to 99.6%.In this route,experimental operations were simplified and the column chromatography was avoided.