Preparation method of perindopril arginine salt of gamma-crystal form

A technology of perindopril arginine salt and perindopril, applied in peptide preparation methods, chemical instruments and methods, organic chemistry, etc., can solve the problems of prolonging the drying time, unfavorable suction filtration, and reducing yield, etc. problem, to achieve the effect of high yield

Active Publication Date: 2014-12-17
NINGBO MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the second and third preparation methods above, water participates in the reaction. During the post-treatment suction filtration process, the target product will wrap water molecules and form a spherical shape, which is not conducive to suction filtration, and will also reduce the yield and prolong the subsequent drying. time

Method used

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  • Preparation method of perindopril arginine salt of gamma-crystal form
  • Preparation method of perindopril arginine salt of gamma-crystal form
  • Preparation method of perindopril arginine salt of gamma-crystal form

Examples

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Effect test

Embodiment 1

[0023] Example 1. Preparation of Perindopril

[0024] Dissolve 60.0g of perindopril tert-butylamine salt in 240mL of water, add 240mL of dichloromethane, stir at 25-30℃, then add 2.0mol / L hydrochloric acid dropwise to the above solution to adjust the pH of the water phase It is 3.8-4.4, finally separated, extracted with dichloromethane, and concentrated under reduced pressure to obtain perindopril.

Embodiment 2

[0025] Example 2. Preparation of perindopril arginine salt (I) in γ crystal form

[0026] Add 5.0g (0.0136mol) of perindopril, 2.13g (0.0122mol) of L-arginine, and 10mL of water to a 150mL four-neck flask, and stir until it is clear. Then add 100 mL of cyclohexane to the above solution, start to heat up and reflux to separate water, no more water enters in the water separator, water separation is completed when the solvent is no longer stratified, and the temperature begins to drop. After cooling down to room temperature, start suction filtration. After suction filtration, the white powder solid (weight 6.36g, yield 95.9%, HPLC content: 99.98%) obtained after drying the filter cake is the final product of perindopril γ crystal form Arginine salt, X-ray powder diffraction pattern see attached figure 1 It can be seen that the product is perindopril arginine salt of γ crystal form. Cyclohexane in the filtrate obtained by suction filtration can be recovered by simple distillation. ...

Embodiment 3

[0027] Example 3. Preparation of perindopril arginine salt (I) in γ crystal form

[0028] Add 5.0g (0.0136mol) of perindopril, 1.66g (0.0095mol) of L-arginine, and 5mL of water to a 150mL four-necked flask, and stir until it is clear. Then, 50 mL of cyclohexane was added to the above solution, and the temperature was increased to reflux to separate water. There is no more water in the water separator, the water separation is completed when the solvent is no longer stratified, and the temperature starts to drop. The temperature is lowered to 30°C and suction filtration is started. The white powder solid (weight 4.80g, yield 92.8%, HPLC content: 99.95%) obtained after suction filtration and drying of the filter cake is the final product of perindopril γ crystal form Arginine salt, X-ray powder diffraction pattern and attached figure 1 Consistent. Cyclohexane in the filtrate obtained by suction filtration can be recovered by simple distillation.

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Abstract

The invention discloses a preparation method of perindopril arginine salt of a gamma-crystal form. The preparation method comprises the following steps of: dissolving perindopril and L-arginine in water; adding an organic solvent after stirring and dissolving the perindopril and L-arginine; heating up the mixture until the mixture is refluxed; distributing water by utilizing a water distributor until no water enters the water distributor; cooling a reaction liquid to the room temperature for carrying out suction filtration; and drying the filter cake to obtain the perindopril arginine salt of the gamma-crystal form. According to the preparation method of the perindopril arginine salt of the gamma-crystal form disclosed by the invention, the organic solvent is added for refluxing and distributing water; the water is extracted by the solvent, so that no water exists in the reaction liquid, and therefore, the water molecule is not packaged by the target product to form a spherical shape, and the suction filtration and separation are easy; and meanwhile, the water is separated out, the yield of the product is 92% or higher.

Description

Technical field [0001] The invention relates to a preparation method of perindopril arginine salt of γ crystal form, and belongs to the technical field of medicine. Background technique [0002] Perindopril and its arginine salt are angiotensin I converting enzyme inhibitors (CEI), mainly used to treat arterial hypertension and heart failure. Perindopril arginine salt has extremely high pharmaceutical value and good stability. The chemical name is: (2S)-2-[(1S)-carbethoxybutylamino]-1-oxo-propyl -(2S, 3As, 7aS) perhydroindole-arginine carboxylate, the structural formula is shown in formula (I): [0003] [0004] The preparation method and therapeutic use of perindopril have been described in European Patent Specification EP0049658. International application WO2009157018 discloses the perindopril arginine salt γ crystal form and its various preparation methods. The perindopril is dissolved in water, L-arginine is added, and then freeze-dried or spray-dried. The solvent is removed...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/062C07K1/02
Inventor 张立兵焦华高贵冯胜波
Owner NINGBO MENOVO PHARMA
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