摘要
4-氟-2-甲氧基硝基苯(2)经Pd/C催化还原得4-氟-2-甲氧基苯胺(3),3在≤0℃温度下经硝化得4-氟-2-甲氧基-5-硝基苯胺(4);由于降低了反应温度(文献为≤10℃),故成功避免了产品碳化,从而简化了后处理。此外,N-甲基吲哚(5)与2,4-二氯嘧啶缩合得3-(2-氯嘧啶-4-基)-1-甲基吲哚(6),通过改变加料顺序(先使2,4-二氯嘧啶和无水三氯化铁充分络合后再加入5),使该反应杂质明显减少,收率达70%。4和6缩合后,经氨化得N'-(2-二甲胺基乙基)-2-甲氧基-N'-甲基-N-[4-(1-甲基吲哚-3-基)嘧啶-2-基]-5-硝基苯-1,4-二胺(8),8经水合肼/三氯化铁还原硝基(文献用铁粉)得N^1-甲基-N^1-(2-二甲胺基乙基)-5-甲氧基-N^4-[4-(1-甲基吲哚-3-基)嘧啶-2-基]苯-1,2,4-三胺(9),后处理更加便捷,同时也减少了"三废"污染。9再经酰化、消除及成盐制得甲磺酸奥希替尼,总收率40.8%(以2计),纯度99.7%。
4-Fluoro-2-methoxyaniline （3） was prepared from 4-fluoro-2-methoxynitrobenzene （2） via Pd/C catalytic reduction, then 3 was subjected to nitration in the temperature of ≤ 0 ℃ to give 4-fluoro-2-methoxy-5-nitroaniline （4）. Because of the lower reaction temperature than that（ ≤ 10 ℃ ） in the literature, carbonization
could be avoided, and the work-up was simplified. Meanwhile, N-methylindole （5） reacted with the complex of 2,4-dichloropyrimidine and anhydrous ferric chloride via Friedel-Crafts arylation to afford 3-（2-chloropyrimidin-4-yl）-1-methylindole （6）, the formation of impurities was reduced and the yield was increased from 45% to 70% since the charging sequence was changed. Then 4 reacted with 6 via condensation followed by amination to prepare N＇-[2-
（dimethylamino）ethyl]-2-methoxy-N＇-methyl-N-[4-（1-methyl-1H-indol-3-yl）pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine （8）, which was subjected to nitro-reduction to give N1-methyl-N1-[2-（dimethylamino）ethyl]-5-methoxy-N4-[4-（1-methyl-1H-indol-3-yl）pyrimidin-2-yl]benzene-1,2,4-triamine （9）. In this step, hydrazine hydrate/ferric chloride was used instead of iron powder which was used in the literature to simplify the work-up and reduce pollution. After acylation of 9, eliminate and salt formation, osimertinib mesylate was obtained with an overall yield of 40.8% （based on 2） and purity of 99.7% .
出处
《中国医药工业杂志》
CAS
CSCD
北大核心
2017年第4期483-487,共5页
Chinese Journal of Pharmaceuticals
关键词
甲磺酸奥希替尼
非小细胞肺癌
合成
osimertinib mesylate
non-small cell lung cancer
synthesis
