Improvement On Synthesis Of Drug Intermediates Of Imidapril Tert-Butyl(4S)-1-methyl-2-oxoimidazolidine-4-carboxylate

Objective(4S)-1-methyl-2-oxoimidazolidine-4-carboxylate is the key intermediate for synthesis of imidapril,which was synthesized by use of L-asparagine as raw material,via amino protection,Hofmann rearrangement,esterification,N-methyl reaction and catalytic hydrogenation.In this synthesis process,the conditions were optimized for meeting the requirement of industrial production and eventually reduced the cost of imidapril.MethodsThis study was mainly contained five synthesis processes,and the processes as following described.N-(benzyloxycarbonyl)-L-asparagin(2)was synthesised by employ the DCM and water as solvent,where the raw material L-asparagine and sodium hydrogencarbonate were added.And then the Cbz-Cl was added in the reaction system before the reaction recovered to the room temperature for 18 h.(4S)-3-(benzyloxycarbonyl)-2-oxoimidazolidine-4-carboxylicacid(3)was prepared in this process.Bromine was added in the sodium hydroxide solution under 0 ?,when the mixed solution was stirred for minutes to clarification status,N-(benzyloxycarbonyl)-L-asparagin(2)was also added in the solution and then under 55 ? for 3 h.tert-Butyl(4s)-3-(benzyloxycarbonyl)-2-oxoimidazolidine-4-carboxylate(4)was synthesised by react with the t-Bu OH?pyridine and compound 3 under 0 ? in DCM solution the phosphorus oxychlorideare was added in the mixed solution and stirred for 30 min,and then recovered to the room temperature for 3 h.tert-Butyl(4S)-3-(Benzyloxycarbonyl)-1-methyl-2-oxoimidazolidine-4-carbox ylate(5)was obtained fromcompound 4,which was reacted in DCM and dimethyl sulfate as methyl donorat 40 ? for 8 h,and potassium carbonate solution as the base.(4s)-1-Methyl-2-oxoimidazolidine-4-carboxylate(6)was synthesised by use methanol as solvent,and which was reacted under the temperature is 25 ? and the hydrogen pressure is 1.5 MPa.The structures of the key intermediates and the target were confirmed by LC-MS and ~1H NMR,and the content were controlled by HPLC.ResultsCompound 2 was synthesized from L-asparagine,overall yield was 92.6% which was calculated by L-asparagine,increased 14.6%,purity of the target compound was 97.5%.Optimized conditions: The molar ratio of L-asparagine and Cbz-Cl was 1?1.1;The reaction temperature was 25 ?.Compound 3 was synthesized from compound 2,overall yield was 93.5%,purity of the target compound was 99.9%.Optimized conditions: the molar ratio of compound 2?sodium hydroxide and bromine was 1?3.3?1.08,the reaction time was 3 h,the temperature for add material is 0 and for separate out is 5 ? ?.In the synthesis process of compound 4,overall yield was 91%,increased 2%,purity of the target compound was 97.7%.Optimized conditions: The molar ratio of compound 3 and phosphorus oxychlorideare was 1?1.2,and the Trichloromethane was replace by DCM.In the synthesis process of compound 5,overall yield was 88.4%,increased 4.1%,purity of the target compound was 99.8%.Optimized conditions: the Acetone and THF was replaced with DCM as solvent,and iodomethane was replaced with dimethyl sulfate as methyl donor,whom was reacted at 40 ? for 8 h in potassium carbonate solution.In the synthesis process of compound 6,overall yield was 96.9%,purity of the target compound was 99.6%.Optimized conditions: the pressure of hydrogen was 1.5 MPa and The reaction temperature was 25 ?.The total yield which was around 67.49%,increased 14.62% compared with previous reported.The structures of the key intermediates and the target were confirmed by LC-MS and ~1H NMR.ConclusionsThese results have showed that the optimized progresses have various advantages such as soft conditions,higher yield,low-cost and convenient operation compared with the previous reported method.And more suit for the industrial production.