US 12,005,059 B2
Nemonoxacin malate active pharmaceutical ingredient with low combination impurities, and a preparation method thereof
Li Sheng, Zhejiang (CN); Gang Fan, Zhejiang (CN); Dadong Shen, Zhejiang (CN); Guofeng Wu, Zhejiang (CN); Xufeng Wu, Zhejiang (CN); Haoling Gao, Zhejiang (CN); and Lanfang Zhu, Zhejiang (CN)
Assigned to ZHEJIANG MEDICINE CO., LTD. XINCHANG PHARMACEUTICAL FACTORY, Shaoxing (CN)
Filed by ZHEJIANG MEDICINE CO., LTD. XINCHANG PHARMACEUTICAL FACTORY, Zhejiang (CN)
Filed on Dec. 12, 2022, as Appl. No. 18/079,019.
Claims priority of application No. 202111250494.5 (CN), filed on Oct. 26, 2021.
Prior Publication US 2023/0201189 A1, Jun. 29, 2023
Int. Cl. A61K 31/4709 (2006.01)
CPC A61K 31/4709 (2013.01) 14 Claims
 
1. A method for preparing a nemonoxacin malate API, comprising the following steps:
1) Providing a C1-C3 alcohol/water mixed solvent in which nemonoxacin free base and D,L-malic acid are dissolved, the temperature of the mixed solvent is 50° C.-65° C.,
wherein, a feeding mole ratio of the D,L-malic acid to the nemonoxacin free base is 0.95:1.0-1.2:1.0, the use amount of the C1-C3 alcohol/water mixed solvent is 8-14 times the weight of the nemonoxacin free base, and a weight ratio of the water to the C1-C3 alcohol is 0.4-0.7:1;
2) Performing cooling crystallization on a mixed solution obtained in the step 1), and then performing solid-liquid separation, washing and drying on a precipitated solid, so as to obtain the nemonoxacin malate API;
the cooling crystallization refers to direct cooling crystallization; and the direct cooling crystallization comprises: cooling the mixed solution to room temperature, and then performing cooling to −10° C.-20° C. by means of an ice bath for crystallization; or
the cooling crystallization refers to gradient cooling crystallization, the gradient cooling crystallization comprises the following steps:
(i) cooling the mixed solution to 35° C.-45° C., then holding the temperature and performing stirring for 0.5-6 h;
(ii) cooling filtrate obtained in the step (i) to −10° C.-20° C. for crystallization;
(iii) filtering the filtrate after the crystallization, washing a filter cake with ethanol, and then performing vacuum drying on the filter cake at 20° C.-65° C. so as to obtain the nemonoxacin malate API.