Refining method of avibactam sodium intermediate

A technology of avibactam sodium and a purification method, applied in the field of drug synthesis, can solve the problems of limited removal of impurities, large ring-opening impurities, inability to guarantee high purity and the like

Pending Publication Date: 2021-09-14
SICHUAN KELUN PHARMA RES INST CO LTD +1
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  • Claims
  • Application Information

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Problems solved by technology

[0007] Both routes involve the key avibactam sodium intermediate 1(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carba In the preparation of amides, since the subsequent conversion of the ester functional group of the starting material involves alkaline conditions, there is isomerization, and the main isomer impurity A will be produced during the preparation of intermediate 1, which is similar in structure and property to intermediate 1. Purification is difficult, and impurities are easily transferred to the raw material drug in the follow-up, which affects the safety of medication
In addition, because the bridged ring structure is unstable under acid and alkali conditions, it will also produce polar ring...

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  • Refining method of avibactam sodium intermediate
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  • Refining method of avibactam sodium intermediate

Examples

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preparation example 1

[0045] Preparation Example 1: Preparation of Avibactam Sodium Intermediate 1 Crude Product:

[0046] The crude product of avibactam sodium intermediate 1 was prepared with reference to the method disclosed in Example 3c of patent document CN201280029765.7 (page 30 of the description).

[0047] The obtained avibactam sodium intermediate 1 crude product is carried out HPLC purity detection, and its total purity is 88.37%, and impurity A content is 2.33%, and impurity B content is 0.66%, and total impurity content is 11.63%, as shown in table 1 Show. The obtained avibactam sodium intermediate 1 is used in the following examples or test examples as the avibactam sodium intermediate 1 crude product.

[0048] Table 1 Avibactam sodium intermediate 1 crude product HPLC detection result

[0049]

[0050]

Embodiment 1

[0051] Embodiment 1: the refining of avibactam sodium intermediate 1

[0052] Step (1): Take 20g of the crude product of avibactam sodium intermediate 1 (based on the pure product of avibactam sodium intermediate 1), add 60mL of dichloromethane, and heat up to 35-45°C under stirring;

[0053] Step (2): Add 180mL of methyl tert-butyl ether dropwise, dropwise for 0.5-1h, solids precipitate out, cool down to -10-0°C, stir for 1-2h, filter with suction, wash with 20mL of methyl-tert-butyl ether , and dried to obtain 19.0 g of avibactam sodium intermediate 1 (yield 95%).

[0054] The refined product of avibactam sodium obtained in this embodiment was detected by HPLC, and the experimental data are shown in Table 2. The total purity is 99.92%, impurity A is not detected, the content of impurity B is 0.011%, and the content of other single impurities is less than 0.03%, meeting the pharmaceutical requirement of less than 0.10%.

[0055] The avibactam sodium intermediate 1 refined p...

Embodiment 2

[0068] Embodiment 2: the refining of avibactam sodium intermediate 1

[0069] Step (1): Take 20g of the crude product of avibactam sodium intermediate 1 (based on the pure product of avibactam sodium intermediate 1), add 80mL of dichloromethane, and heat up to 35-45°C under stirring;

[0070] Step (2): Add 200mL of methyl tert-butyl ether dropwise, dropwise for 1-1.5h, solids precipitate out, cool down to -10-0°C, stir for 1-2h, suction filter, 40mL of methyl tert-butyl ether Washing, drying to obtain 18.6g avibactam sodium intermediate 1 (yield 93%).

[0071] The refined product of avibactam sodium obtained in this embodiment was detected by HPLC, and the experimental data are shown in Table 5. The total purity is 99.97%, the content of impurity A is 0.017%, the content of impurity B is 0.0095%, and other single impurities are not detected.

[0072] The avibactam sodium intermediate 1 refined product HPLC detection result that table 5 embodiment 2 makes

[0073] ...

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Abstract

The invention discloses a refining method of an avibactam sodium intermediate 1. The method comprises the step of refining a crude product of the avibactam sodium intermediate 1 in a good solvent dichloromethane and poor solvent methyl tert-butyl ether system to obtain the high-purity avibactam sodium intermediate 1. According to the refining method provided by the invention, the content of an isomer impurity A and a ring-opening impurity B can be effectively reduced, the purity is improved, the total purity of the refined avibactam sodium intermediate 1 is greater than 99.9%, the isomer impurity A and the ring-opening impurity B are both less than 0.05%, the other single impurities are all less than 0.10%, the reagents are conventional and easy to obtain, the operation is simple and safe and the method is very suitable for industrial amplification under conventional production conditions.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, in particular to avibactam sodium intermediate 1(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane -The refining method of 2-carboxamide, especially a method for reducing the content of isomer impurity A and / or ring-opening impurity B in avibactam sodium intermediate 1. Background technique [0002] Avibactam sodium (Avibactam) is a novel non-β-lactam structure β-lactamase inhibitor developed by Novexel. Avibactam sodium belongs to diazabicyclooctone compound, which itself does not have obvious antibacterial activity, but acts by inhibiting β-lactamase. Avibactam sodium can inhibit type A (including ESBL and KPC), part of type C and part of type D β-lactamases. Therefore, when used in combination with penicillium, cephalosporin and carbapenem antibiotics, it has broad-spectrum antibacterial activity, especially against Escherichia coli and Klebsiella pneumoniae containing ...

Claims

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Application Information

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IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 李发光李海望杨光吴蕾姜珊肖宇陈文博胡佰艳王丽李贺扬吴灵静王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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