A kind of preparation method of cilastatin sodium crude drug

A technology of cilastatin sodium and cilastatin, which is applied in the field of medicinal chemistry, can solve the problems of taking a long time, reducing the activity of raw materials, and consuming a long time, so as to avoid the reduction of chemical activity and improve the quality and yield , to avoid the effect of excessive losses

Active Publication Date: 2018-11-16
SHENZHEN HAIBIN PHARMA +1
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Problems solved by technology

[0006] In the first step, in the reaction of synthesizing cilastatin (VI), when the prior art is in industrial production, it takes a long time for the dissolution of various raw materials and the heating of the reactor, which greatly reduces the activity of the raw materials. After the reaction, each main raw material The residual amount is also relatively high, and some side reactions have also taken place during this period and generate impurities, which increases the impurity content in the reaction solution after the reaction is complete; the residual compound (Z)-7-chloro- 2-((S)-2,2-Dimethylcyclopropylformyl)-2-heptenoic acid has a large similarity with said cilastatin in terms of physical and chemical properties, making it difficult to compare its separation, resulting in an increased level of impurities in the product
[0007] In the prior art, the purification effect of the post-treatment production process of cilastatin is not good, and there are many steps, and part of the cilastatin will be lost in the post-treatment process of each step, which not only makes the yield of cilastatin low, And increased the production cost and the production cycle of cilastatin, also improved the workman's labor intensity simultaneously
[0008] In the second step, in the process of synthesizing cilastatin sodium, in the process of synthesizing cilastatin sodium by solvent method, not only sodium hydroxide needs to be completely dissolved in a certain amount of methanol, but also cilastatin needs to be dissolved in a certain amount. To dissolve in the methanol solution of cilastatin, it is necessary to slowly add methanol solution of sodium hydroxide to the methanol solution of cilastatin to adjust the pH value, which takes a long time for dissolution and a large amount of pH value adjustment time. In production, the pH value The value adjustment time is generally as high as 4-12h; during this process, cilastatin sodium will absorb too much moisture and it will take a long time to filter. In production, cilastatin sodium needs to be filtered after absorbing moisture More than 16h, cause the yield of cilastatin sodium to be on the low side and prolong the production cycle of cilastatin sodium simultaneously, increase the labor intensity of workers

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  • A kind of preparation method of cilastatin sodium crude drug
  • A kind of preparation method of cilastatin sodium crude drug
  • A kind of preparation method of cilastatin sodium crude drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Embodiment 1: the preparation of cilastatin sodium of the present invention

[0087] (1) Preparation of compound cilastatin shown in formula (VI):

[0088] At 0°C, add 15g of sodium hydroxide to 100g of water, stir for 10min, then add 10g of compound (Z)-7-chloro-2((S)-2,2-dimethylcyclo Propyl formamido)-2-heptenoic acid, stirred for 10min; at -5°C, 9g of cysteine ​​hydrochloride monohydrate was added, stirred for 10min, and the reaction started at 25°C until analyzed by HPLC, Complete the reaction when the normalized content of (Z)-7-chloro-2((S)-2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid in the resulting reaction solution is less than 5%. After cooling down to 25°C, add 300g of water to the solution, stir, and slowly add 6M hydrochloric acid solution to the solution to adjust the pH value to 1. Add the obtained solution to a Φ60*5.5m macroporous adsorption resin column HZ-820, first elute with water, and then change to acetone aqueous solution for elution...

Embodiment 2

[0091] Embodiment 2: the preparation of cilastatin sodium of the present invention

[0092] (1) Preparation of compound cilastatin shown in formula (VI):

[0093] At 10°C, add 9g of sodium hydroxide to 80g of water, stir for 10min, then add 10g of compound (Z)-7-chloro-2((S)-2,2-dimethylcyclo Propyl formamido)-2-heptenoic acid, stirred for 10min; at 10°C, 8.5g of cysteine ​​hydrochloride monohydrate was added, stirred for 10min, and the reaction started at 35°C until it was analyzed by HPLC The reaction is completed when the normalized content of (Z)-7-chloro-2((S)-2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid in the obtained reaction solution is less than 5%; After cooling down to 30° C., 250 g of water was added to the solution, stirred, and 6M hydrochloric acid solution was slowly added to the solution to adjust the pH value to 1.5. Add the obtained solution to a Φ35*3.5m macroporous adsorption resin column HZ-818, first elute with water, and then change to metha...

Embodiment 3

[0096] Embodiment 3: the preparation of cilastatin sodium of the present invention

[0097] (1) Preparation of compound cilastatin shown in formula (VI):

[0098] At 0°C, add 11g of sodium hydroxide to 70g of water, stir for 10min, then add 10g of compound (Z)-7-chloro-2((S)-2,2-dimethylcyclo Propyl formamido)-2-heptenoic acid, stirred for 10min; at 0°C, 8.3g of cysteine ​​hydrochloride monohydrate was added, stirred for 10min, and the reaction started at 45°C until it was analyzed by HPLC The reaction is completed when the normalized content of (Z)-7-chloro-2((S)-2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid in the obtained reaction solution is less than 5%; After cooling down to 5° C., 200 g of water was added to the solution, stirred, and 6M hydrochloric acid solution was slowly added to the solution to adjust the pH value to 2. Add the obtained solution to a Φ20*2.5m macroporous adsorption resin column HZ-816, first elute with water, and then change to methanol ...

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Abstract

The invention provides a preparation method of a cilastatin sodium active pharmaceutical ingredient. The preparation method comprises the following steps: (1) mixing alkali and reaction solvent, adding a compound (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropylformacyl)-2-heptenoic acid shown in Formula (V), then adding cysteine hydrochloride, reacting to obtain a reaction solution containing a compound cilastatin shown in Formula (VI); (2) purifying the reaction solution obtained in the step (1) through macroporous adsorption resin to obtain the compound cilastatin shown in Formula (VI); and (3) mixing sodium hydroxide and water, adding the cilastatin obtained in the step (2), regulating the pH value, and drying to obtain the compound cilastatin sodium shown in Formula (I). The preparation method is quick, efficient and suitable for industrial production; and the obtained cilastatin sodium active pharmaceutical ingredient is low in impurity content.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of cilastatin sodium bulk drug. Background technique [0002] Imipenem / cilastatin sodium is widely used as a broad-spectrum antibacterial drug. The chemical name of cilastatin sodium is [R-[R*,S*(Z)]]-7-[(2-amino-2-carboxyethyl)sulfur]-2-[[(2,2- Dimethylcyclopropyl)-carbonyl] amino]-2-sodium heptenoate, its chemical structure is as shown in formula (I), molecular formula is C 16 h 25 N 2 NaO 5 S, the molecular weight is 380.4. The combination of cilastatin sodium and carbapenem antibiotic imipenem (Imipenem) can inhibit the degradation of imipenem by renal dehydrodipeptidase and increase the concentration of imipenem in the urinary system, thereby Improve the activity of imipenem and reduce its nephrotoxicity. [0003] [0004] At present, the preparation method of cilastatin sodium is to make compound (Z)-7-chloro-2-((S)-2,2...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C323/59C07C319/14C07C319/28A61K31/198A61P31/04
CPCC07C319/14C07C319/28C07C323/59
Inventor 任鹏张鸣欧鹏赵勇邓华生
Owner SHENZHEN HAIBIN PHARMA
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