Ton-grade perindopril tert-butylamine synthesis process
A synthesis process, the technology of perindopril, which is applied in the preparation methods of peptides, chemical instruments and methods, organic chemistry, etc., can solve the problems such as the inability to improve the yield, and achieve the requirements of low equipment and equipment, high yield and easy raw materials. the effect
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Embodiment 1
[0018] Example 1: Preparation of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (3).
[0019] (S)-indoline-2-carboxylic acid (2, Shanghai Bi De Pharmaceutical Technology Co., Ltd., purity 99.1%, 180kg, 1104mol), methanol (1080kg) and 5% rhodium carbon (19.2kg) or 7% Palladium carbon was added to the hydrogenation kettle, the temperature was controlled at 50°C, the pressure was 2.5MPa, and the reaction was carried out for 6 hours, but the reaction was shortened or extended for several hours. After hydrogenation, cool to 35°C, press filter, wash the filter cake with water (40kg), and concentrate the filtrate to dryness at 60°C under reduced pressure. Add dioxane (1900kg) and water (180kg) to the residue, heat up to 85°C, stir until the solid dissolves, cool down and crystallize for 2-3 hours, shake off the filter, and dry the filter cake under reduced pressure at 45-55°C for 2 hours , then heated to 85°C and dried under reduced pressure for about 14 h to obtain white solid 3 (1...
Embodiment 2
[0020] Example 2: Preparation of (2S,3aS,7aS)-benzyl octahydroindole-2-carboxylate p-toluenesulfonate (4).
[0021]Add 3 (90kg, 533mol), p-toluenesulfonic acid monohydrate (112kg, 589mol), benzyl alcohol (144kg, 1333mol) and toluene (840L) into the reactor, heat up to 110°C, and reflux for about 14h. After the reaction, it was cooled to about 60°C, and concentrated to dryness under reduced pressure. Add ethyl acetate (900L), lower the temperature to about 5°C, crystallize for 2h, shake off the filter, dry the filter cake at room temperature under reduced pressure for 2h, then raise the temperature to 65°C and dry under reduced pressure for 20h to obtain a white solid 4 (218kg, 95% ), purity 98.40% [HPLC peak area normalization method: chromatographic column Shimpack CLC-ODS column (6.0mm * 150mm, 5 μ m); mobile phase A is a buffer solution (sodium dihydrogen phosphate 1.38g is dissolved in water 1000ml, with Concentrated phosphoric acid adjusted to pH2.7), B is acetonitrile, ...
Embodiment 3
[0022] Example 3: Preparation of N-[(S)-1-ethoxycarbonylbutyl]-(S)-alanine (6).
[0023] Add L-norvaline (5, 150 kg, 1282 mol) and absolute ethanol (1200 L) to the reaction kettle, control the temperature at 5°C, slowly add thionyl chloride (190 kg, 1 597 mol) dropwise, After about 9 hours of dripping. Raise the temperature to 60°C and keep the reaction for about 4 hours. After the reaction, it was concentrated to dryness under reduced pressure at 45-55°C. Water (800 L), absolute ethanol (900 L), sodium pyruvate (160 kg, 1 455 mol) and 7% palladium carbon (11.5 kg) were successively added to the concentrate, and at room temperature and a pressure of 0.4 MPa, , hydrogenation reaction about 16 h. After the hydrogenation was completed, press filter, and the filtrate was adjusted to pH 3.5-4.0 with concentrated hydrochloric acid (5-15 L). Control the temperature not to be higher than 60 °C, distill the solvent under reduced pressure until a large amount of solids are precipita...
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