Study on the Synthesis Process of 2-Butyl-4-chloro-5-formy-limidazole
|Keywords||2-butyl-4-chloro-5-formy-limidazole Pinner Vilsmeier reagent chroloformylation|
2-Butyl-4-chloro-5-formy-limidazole is A key intermediate of Losartan. It was synthesized from valeronitrile by Pinner reaction, neutralization by CH3ONa, amination and Vilsmeier reaction with POCl3 and DMF. The suitable technical conditions for synthesizing the target compound were investigated in detail. The results were as follows:1. The suitable technical conditions for synthesizing methyl pentanimidate were:the mole ratio of valeronitrile, methanol and HCl 1:1.3:1.4, venting HCl at 0℃for 2 hours, holding reaction temperature 15℃for 12 hours, neutralized at 0℃. Then 0.932 yield of methyl pentanimidate was obtained.2. The suitable technical conditions for synthesizing (pentanimidoylamino)acetic acid were: the mole ratio of glycine and valeronitrile 1:1, the temperature 20℃, the reaction time 2 hours. Then 0.842 yield of (pentanimidoylamino)acetic acid was obtained.3. We substituded CH3ONa for NaOH to neutralize hydrochloride to get methyl pentani-midate. And then the synthesis route was simplified:methyl pentanimidate getted above can directly react with glycine without further purification and the yield was increased.4. The suitable technical conditions for synthesizing 2-Butyl-4-chloro-5-formy-limidazole by Vilsmeier reaction were:the mole ratio of (pentanimidoylamino)acetic acid, POC3 and DMF 1:2.8:3.0, adding DMF at 60℃, holding reaction temperature 100℃for 2 hours. Then 0.83 yield of 2-Butyl-4-chloro-5-formy-limidazole was obtained. The total yield was increased from 55% up to 69%.5. We investigated the effect of toluene’s reuse times on 2-Butyl-4-chloro-5-formy-limidaz-ole’s yield and how to deal with the byproduct HCl and the waste water containing H3PO4.