# US 12,005,059 B2 · Nemonoxacin malate active pharmaceutical ingredient with low combination impurities, and a preparation method thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,005,059 B2 - Document ID: US12005059B2 - Status: Granted - Kind: B2 - Application number: 18/079,019 - Filed: 2022-12-12 - Published: 2023-06-29 - Granted: 2024-06-11 - Earliest claimed: 2021-10-26 - Assignees: Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory - Applicants: Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory - Inventors: Li Sheng; Gang Fan; Dadong Shen; Guofeng Wu; Xufeng Wu; Haoling Gao; Lanfang Zhu - Web page: https://patentgrep.com/patent/US12005059B2 ## CPC - A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract Provided in the present disclosure are a nemonoxacin malate active pharmaceutical ingredient with low combination impurities, and a preparation method thereof, specifically, provided in the present disclosure is a method for preparing the nemonoxacin malate active pharmaceutical ingredient, the method includes the following steps: 1) providing a C1-C3 alcohol/water mixed solvent in which nemonoxacin free base (Formula II) and D,L-malic acid are dissolved; and 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 active pharmaceutical ingredient. ## Claims ### Claim 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. ### Claim 2 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein the temperature of the mixed solvent is 55° C.-60° C. ### Claim 3 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein the use amount of the C1-C3 alcohol/water mixed solvent is 10-12 times the weight of the nemonoxacin free base. ### Claim 4 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein a weight ratio of water to C1-C3 alcohol is 0.5-0.6:1. ### Claim 5 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein the feeding mole ratio of the D,L-malic acid to the nemonoxacin free base is 0.98:1.03-1.05:1.0. ### Claim 6 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein before cooling crystallization, the method further comprises the following step: using activated carbon to decolorize the mixed solution. ### Claim 7 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein performing cooling to −10° C.-10° C. by means of an ice bath for crystallization. ### Claim 8 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein performing cooling to −5° C.-5° C. by means of an ice bath for crystallization. ### Claim 9 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein holding the temperature and performing stirring for 1-4.5 h. ### Claim 10 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein holding the temperature and performing stirring for 1-3 h. ### Claim 11 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein cooling filtrate obtained in the step (i) to −10° C.-10° C. for crystallization. ### Claim 12 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein cooling filtrate obtained in the step (i) to −5° C.-5° C. for crystallization. ### Claim 13 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein performing vacuum drying on the filter cake at 30-60° C. so as to obtain the nemonoxacin malate API. ### Claim 14 (depends on 1) The method for preparing the nemonoxacin malate API according to claim 1, wherein performing vacuum drying on the filter cake at 40-50° C. so as to obtain the nemonoxacin malate API.