Preparation method of perindopril arginine salt of gamma-crystal form

A technology of perindopril arginine salt and perindopril, which is applied to the preparation methods of peptides, chemical instruments and methods, organic chemistry and other directions, and can solve the problems of prolonging the baking time, unfavorable suction filtration, reducing yield, etc. problem, to achieve the effect of easy suction filtration and separation

Active Publication Date: 2013-06-26
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 wi

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

Experimental program
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Effect test

Embodiment 1

[0023] Embodiment 1, the preparation of perindopril

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

Embodiment 2

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

[0026] Into a 150mL four-neck flask, add 5.0g (0.0136mol) perindopril, 2.13g (0.0122mol) L-arginine, and 10mL water, and stir until dissolved. Then, 100 mL of cyclohexane was added to the above solution, and the temperature was raised and refluxed to separate water. There was no more water entering the water separator. When the solvent was no longer layered, the water separation was completed, and the temperature was lowered. After cooling to room temperature, suction filtration was started, and the white powder solid (weight 6.36 g, yield 95.9%, HPLC content: 99.98%) obtained after the filter cake was dried after suction filtration was the perindopril of the final product γ crystal form Arginine salt, X-ray powder diffraction pattern is attached figure 1 , it can be seen that the product is perindopril arginine salt of γ crystal form. The cyclohexane in the filtrate obtained by suction filtra...

Embodiment 3

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

[0028] Add 5.0 g (0.0136 mol) of perindopril, 1.66 g (0.0095 mol) of L-arginine, and 5 mL of water to a 150 mL four-neck flask, and stir until dissolved. Then, 50 mL of cyclohexane was added to the above solution, and the temperature was raised and refluxed to separate water. There is no more water entering the water separator, and the water separation is completed when the solvent is no longer stratified, and the temperature begins to cool. Cool down to 30°C and start suction filtration. After suction filtration and drying of the filter cake, the obtained white powder solid (weight 4.80 g, yield 92.8%, HPLC content: 99.95%) is the final product of perindopril in γ crystal form Arginine salt, X-ray powder diffraction pattern with attached figure 1 Consistent. The 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, belonging to the technical field of medicine. Background technique [0002] Perindopril and its arginine salt are an angiotensin I converting enzyme inhibitor (CEI) mainly used for the treatment of arterial hypertension and heart failure. Perindopril arginine salt has high pharmaceutical value and good stability, chemical name: (2S)-2-[(1S)-ethyl ester butylamino]-1-oxo-propyl -(2S, 3As, 7aS) perhydroindole-carboxylic acid arginine salt, the structural formula is shown in formula (I): [0003] [0004] The preparation method of perindopril and its therapeutic use have been described in European patent specification EP0049658. International application WO2009157018 discloses perindopril arginine salt γ crystal form and its various preparation methods, wherein the described perindopril is dissolved in water, L-arginine is added, and then freeze-drying or sp...

Claims

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Application Information

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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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