Preparation method of N-carboxyalkyl dipeptide type angiotensin converting enzyme inhibitor
A technology of carboxyalkyl dipeptide type and angiotensin, which is applied in chemical instruments and methods, dipeptide, cardiovascular system diseases, etc., can solve the problem of overdose, and achieve the effect of simple and efficient process
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Embodiment 1
[0024] Preparation of (S)-N-((1-ethoxycarbonyl)-3-phenylpropyl)-L-alanine-N-carboxylic acid anhydride:
[0025] Dissolve 45 g (0.15 mol) of bis(trichloromethyl) carbonate and 27.9 g (0.1 mol) of (S)-N-((1-ethoxycarbonyl)-3-phenylpropyl)-L-alanine Add 180ml of anhydrous tetrahydrofuran, stir at 50°C until the reaction is complete, and then distill off tetrahydrofuran under reduced pressure. 90 ml of n-hexane was added to the residue, followed by stirring and crystallization. Filter and dry in vacuo to get (S)-N-((1-ethoxycarbonyl)-3-phenylpropyl)-L-alanine-N-carboxylic acid anhydride: melting point 68~72°C, [α] 25 D +11.0°-+13.0° (c=1, CH 3 CN).
Embodiment 2
[0027] Preparation of (S)-N-((1-ethoxycarbonyl)-butyl)-L-alanine-N-carboxylic acid anhydride:
[0028] Add (S)-N-((1-ethoxycarbonyl)-butyl)-L-alanine 4g (18.4mmol) and dichloromethane 20ml into a 100ml reaction flask, add bis(trichlorohydrin) carbonate at 20°C Methyl) ester 5.5g (18.4mol) and dichloromethane 20ml solution, stirred at reflux for 30h, concentrated to dryness. Add 20ml of dichloromethane, and then concentrate to dryness. The above operation was repeated twice to obtain an oily substance, which gradually solidified to obtain (S)-N-[(1-7,oxycarbonyl)-butyl)-L-alanine-N-carboxylic acid anhydride.
Embodiment 3
[0029] The preparation of embodiment 3 enalapril maleate:
[0030] Dissolve 17.3g (0.15mol) of L-proline, 6g (0.15mol) of sodium hydroxide and 15.9g (0.15mol) of sodium carbonate in 300ml of water, add (S)-N-((1-ethoxycarbonyl) - A solution of 30.5g (0.1mol) of -3-phenylpropyl)-L-alanine-N-carboxylic acid anhydride in 600ml of tetrahydrofuran, stirred at 5°C for 1h. The pH of the reaction solution was adjusted to 4.25 with 6 mol / L hydrochloric acid, and tetrahydrofuran was distilled off under reduced pressure. The resulting aqueous solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oil.
[0031] The above oil was dissolved in 100ml of acetonitrile at 60°C, a solution of 11.6g (0.1mol) of maleic acid in 180ml of acetonitrile at 60°C was added, and crystallized by cooling. Filter and recrystallize with water to obtain enalapril maleate, melting point 142-143°C, [α] 25 D -4...
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