(19) TZZ ¥Z_T (11) EP 2 385 054 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 501/22 (2006.01) A61K 31/546 (2006.01) 02.10.2013 Bulletin 2013/40 A61P 31/04 (2006.01) (21) Application number: 09836052.2 (86) International application number: PCT/CN2009/076164 (22) Date of filing: 29.12.2009 (87) International publication number: WO 2010/075765 (08.07.2010 Gazette 2010/27) (54) CEFDINIR ACID DOUBLE SALT AND ITS PREPARATION CEFDINIRSÄURE-DOPPELSALZ UND SEINE ZUBEREITUNG DOUBLE SEL D’ACIDE DE CEFDINIR ET SA PRÉPARATION (84) Designated Contracting States: • YU, Baochun AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Zhejiang 310011 (CN) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL • YE, Tianjian PT RO SE SI SK SM TR Zhejiang 310011 (CN) • YU, Meiping (30) Priority: 31.12.2008 CN 200810164211 Zhejiang 310011 (CN) (43) Date of publication of application: (74) Representative: Hryszkiewicz, Danuta 09.11.2011 Bulletin 2011/45 Kancelaria Patentowa Matthias Scholl, Inc. (73) Proprietor: Zhejiang Adamerck Biopharmlabs Inc. Ul. Jana z Kolna 38 Zhejiang 310011 (CN) 75-204 Koszalin (PL) (72) Inventors: (56) References cited: • QI, Youmao EP-A2- 0 304 019 WO-A1-02/098884 Zhejiang 310011 (CN) WO-A1-2004/056835 CN-A- 1 251 590 • YE, Fengqi CN-A- 1 415 615 CN-A- 101 481 383 Zhejiang 310011 (CN) US-A- 4 559 334 •JIE,Qing Zhejiang 310011 (CN) Remarks: • QI, Yingbei Thefile contains technical information submitted after Zhejiang 310011 (CN) the application was filed and not included in this • ZHANG, Fengmin specification Zhejiang 310011 (CN) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 385 054 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 385 054 B1 Description [0001] The invention relates to a compound and method for producing the same, and more particularly to a cefdinir acid double salt, a preparation method, and use thereof. 5 [0002] Cefdinir was first synthesized by Fujisawa Company, Japan, in 1988 by modifying the structure of cefixime. It is the third generation of oral cephalosporin. The vinyl group linked to a mother ring carbon of cephalosporin improves the oral absorption rate thereof. The hydroxyl amino group and ammonia thiophene group at the side chain not only enhance the antibacterial activity against gram-negative bacteria and the stability of β-lactamase, but also improve the antibacterialactivity against gram- positivebacteria, particularly against Staphylococcus aureus. The cefdinir preparations 10 were first approved for sale in Japan in December, 1991, with a brand name of Cefzon, and then were sold in USA in December, 1997, with a brand name of Omnicef, and in Korea in 1999. Tianjin Centralpharm Co., Ltd. and Tianjin Institute of Pharmaceutical Research have cooperatively developed the production and synthesis of cefdinir and the dosage form of capsules and granules are obtained. The capsules have a brand name of Cefdinir Capsules, approved for sale in 2001 in China. 15 [0003] With a broad antimicrobial spectrum, high activity, good drug resistance, cefdinir is very excellent in the third generation of cephalosporin. However, it has obvious disadvantages such as low solubility and low bioavailability. Study shows that capsule cefdinir has a bioavailability of 16-20%, and for a liquid suspension, the bioavailability is merely 25%. Low bioavailability wastes drug resources, and the antibiotic residues easily cause side effect, e.g., intestinal flora disturbance and diarrhea. Furthermore, cefdinir is insoluble in water, and thus it cannot be prepared into an injection 20 directly. [0004] To solve the above disadvantages, a large number of researches have been conducted. Since the chemical structure of cefdinir includes carboxylic acids and amino group, a basic salt or acid salt thereof has been disclosed. [0005] Chinese Pat. CN 1,415,615 discloses sodium cefdinir and a preparation method thereof. Chinese Pat. CN 1,251,590 discloses a salt synthesized by cefdinir and dicyclohexylamine. Chinese Pat. CN 1,512,996 discloses sulfate 25 or mesylate cefdinir. U.S. Pat. 4,559,334 discloses the following cefdinir salt: sodium, potassium, calcium, magnesium, ammonium, organic ammonium, hydrochloric acid, sulfuric acid, bromated, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzoic acid, arginine, aspartic acid, glutamic acid. KR20070088757 discloses a method for producing cesium cefdinir to purify cefdinir. DE60311869 discloses a method for producing phosphate cefdinir to purify cefdinir. 30 [0006] Cefdinir basic salts have poor stability. [0007] The cefdinir salts recited in the above patents mainly target the purification of cefdinir. Currently, no cefidinir acid double salts or the benefits thereof have been reported. [0008] In view of the above- described problems, it is one objective of the invention to provide a cefdinir acid double salt. [0009] It is another objective of the invention to provide a method for producing a cefdinir acid double salt. 35 [0010] To achieve the above objectives, in accordance with one embodiment of the invention, there is provided a cefdinir acid double salt represented by Formula I: 40 45 50 + + + + 2- [0011] wherein M represents Na , K , NH4 , or Cs ; and 1) when Y represents SO 4 and m = 1, n = 1; when m = 0.5, 55 2- n = 1.5; 2) when Y represents PO 4 , m = 1, n = 2. [0012] In accordance with another embodiment of the invention, there is provided a method for producing the cefdinir acid double salt. The method comprises contacting cefdinir with an acid and an alkali or ammonium compound, or contacting cefdinir with an acid salt. When the acid or acid salt comprises a sulfate group, the product is a cefdinir sulfate 2 EP 2 385 054 B1 double salt. When the acid or acid salt comprises a phosphate group, the product is a cefdinir phosphate double salt. [0013] In a class of this embodiment, the cefdinir sulfate double salt is prepared as follows. 1) Cefdinir and equimolar sulfuric acid is mixed, and then an alkali compound with a molar ratio to cefdinir of 0.5: 1 or 1:1 is added. The resultant product is concentrated, crystallized with ether, filtered, and dried to yield cefdinir sodium hydrogen (1 or 0.5) sulfate (1 5 or 1.5), cefdinir potassium hydrogen (1 or 0.5) sulfate (1 or 1.5), or cefdinir cesium hydrogen (1 or 0.5) sulfate (1 or 1.5). 2) Cefdinir and equimolar sulfuric acid is mixed, and then ammonium acetate, ammonia gas, or ammonia water with a molar ratio to cefdinir of 0.5: 1 or 1: 1 is added. The resultant product is concentrated, crystallized with ether, filtered, and dried to yield cefdinir ammonium hydrogen (1 or 0.5) sulfate (1 or 1.5). 3) Cefdinir and equimolar sodium hydrogen sulfate, potassium hydrogen sulfate, or ammonium hydrogen sulfate is mixed. The resultant product is concentrated, 10 crystallized with ether, filtered, and dried to yield a cefdinir sulfate double salt. [0014] In a class of this embodiment, the cefdinir sulfate double salt is represented by the following formulas: 15 20 25 30 35 40 45 50 55 3 EP 2 385 054 B1 5 10 15 20 25 30 35 40 45 [0015] In a class of this embodiment, the cefdinir phosphate double salt is prepared as follows. 1) Cefdinir and equimolar phosphoric acid is mixed, and then an alkali compound with a molar ratio to cefdinir of 1: 1 is added. The resultant product is concentrated, crystallized with ether, filtered, and dried to yield cefdinir sodium dihydrogen phosphate, cefdinir potas- sium dihydrogen phosphate, or cefdinir cesium dihydrogen phosphate. 2) Cefdinir and equimolar phosphoric acid is mixed, and then ammonium acetate, ammonia gas, or ammonia water with a molar ratio to cefdinir of 1: 1 is added. The 50 resultant product is concentrated, crystallized with ether, filtered, and dried to yield cefdinir ammonium dihydrogen phosphate. 3) Cefdinir and equimolar sodium dihydrogen phosphate, potassium dihydrogen phosphate, or ammonium dihydrogen phosphate is mixed. The resultant product is concentrated, crystallized with ether, filtered, and dried to yield cefdinir sodium dihydrogen phosphate, cefdinir potassium dihydrogen phosphate, or cefdinir ammonium dihydrogen phosphate. 55 [0016] In a class of this embodiment, the cefdinir phosphate double salt is represented by the following formulas: 4 EP 2 385 054 B1 5 10 15 20 25 30 35 40 45 [0017] In a class of this embodiment, the alkali compound is selected from the group consisting of sodium methoxide, potassium methoxide, cesium methoxide, sodium ethoxide, potassium ethoxide, cesium ethoxide, sodium propoxide, 50 potassium propoxide, cesium propoxide, sodium butoxide, potassium butoxide, cesium butoxide, sodium isopropoxide, potassium isopropoxide, cesium isopropoxide, sodium tert-butoxide, potassium tert- butoxide, cesium tert-butoxide, so- dium acetate, potassium acetate, cesium acetate, sodium propionate, potassium propionate, cesium propionate, sodium butyrate, potassium butyrate, cesium butyrate, sodium hydroxide, potassium hydroxide, and cesium hydroxide. [0018] In a class of this embodiment, the ammonium compound is selected from the group consisting of ammonia, 55 ammonia water, ammonium acetate,