Ep 2385054 B1

(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:

+ + + + 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:

3 EP 2 385 054 B1

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 potassium 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

[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, sodium 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, ammonium propionate, and ammonium butyrate. [0019] In a class ofthis embodiment, the cefdinir sulfatedouble salt comprises (- )-(6R, 7R)- 7- ((Z)- 2- (2- aminothiazole- 4- yl)- 2- hydroxyimino- acetylamino)- 8- oxo- 3- vinyl- 5- thia- 1- azabicyclo (4.2.0) oct- 2- ene- 2- carboxylic acid sodium hydrogen sulfate, (- )- (6R, 7R)- 7- ((Z)- 2- (2- aminothiazole- 4- yl)- 2- hydroxyimino- acetylamino)- 8- oxo- 3- vinyl- 5-

5 EP 2 385 054 B1

thia- 1- azabicyclo (4.2.0) oct- 2- ene- 2- carboxylic acid potassium hydrogen sulfate, (- )- (6R, 7R)- 7- ((Z)- 2- (2- aminothiazole-4- yl)- 2- hydroxyimino- acetylamino)-8- oxo- 3- vinyl- 5- thia- 1- azabicyclo (4.2.0) oct- 2- ene- 2- carboxyl ic acid ammonium hydrogen sulfate, and (- )- (6R, 7R)- 7- ((Z)- 2- (2- aminothiazole- 4- yl)- 2- hydroxyimino- acetylamino)- 8- oxo- 3- vinyl- 5- thia- 1- azabicyclo (4.2.0) oct- 2- ene- 2- carboxylic acid cesium hydrogen sulfate. The cefdinir sulfate 5 double salt further comprises (- )- (6R, 7R)- 7- ((Z)- 2- (2- aminothiazole- 4- yl)- 2- hydroxyimino- acetylamino)- 8- oxo- 3- vinyl- 5- thia- 1- azabicyclo (4.2.0) oct- 2- ene- 2- carboxylic acid sodium hydrogen (0.5) sulfate (1.5), (- )- (6R, 7R)- 7- ((Z)- 2- (2- aminothiazole- 4- yl)- 2- hydroxyimino- acetylamino)- 8- oxo- 3- vinyl- 5- thia- 1- azabicyclo (4.2.0) oct- 2- ene- 2- carboxylic acid potassium hydrogen (0.5) sulfate (1.5), (- )- (6R, 7R)- 7- ((Z)- 2- (2- aminothiazole- 4- yl)- 2- hydroxyimino- acetylamino)- 8- oxo- 3- vinyl- 5- thia- 1- azabicyclo (4.2.0) oct- 2- ene- 2- carboxylic acid ammonium 10 hydrogen (0.5) sulfate (1.5), and (- )- (6R, 7R)- 7- ((Z)- 2- (2- aminothiazole- 4- yl)- 2- hydroxyimino- acetylamino)- 8- oxo- 3- vinyl- 5- thia- 1- azabicyclo (4.2.0) oct- 2- ene- 2- carboxylic acid cesium hydrogen (0.5) sulfate (1.5) . [0020] In a class of this embodiment, the cefdinir phosphate double salt comprises (- )- (6R, 7R)- 7- ((Z)- 2- (2- aminothiazole-4- yl)- 2- hydroxyimino- acetylamino)-8- oxo- 3- vinyl- 5- thia- 1- azabicyclo (4.2.0) oct- 2- ene- 2- carboxyl ic acid sodium dihydrogen phosphate, (- )- (6R, 7R)- 7- ((Z)- 2- (2- aminothiazole- 4- yl)- 2- hydroxyimino- acetylamino) 8- 15 oxo- 3- vinyl- 5- thia- 1- azabicyclo (4.2.0) oct- 2- ene- 2- carboxylic acid potassium dihydrogen phosphate, and (- )- (6R, 7R)- 7- ((Z)- 2- (2- aminothiazole- 4- yl)- 2- hydroxyimino- acetylamino)- 8- oxo- 3- vinyl- 5- thia- 1- azabicyclo (4.2.0) oct- 2- ene- 2- carboxylic acid ammonium dihydrogen phosphate, and (- )- (6R, 7R)- 7- ((Z)- 2- (2- aminothiazole- 4- yl)- 2- hydroxyimino- acetylamino)- 8- oxo- 3- vinyl- 5- thia- 1- azabicyclo (4.2.0) oct- 2- ene- 2- carboxylic acid cesium dihydrogen phosphate. 20 [0021] Advantages of the invention are summarized below. [0022] The cefdinir sulfate double salt and cefdinir phosphate double salt have good stability, good solubility, and thus the bioavailability thereof have been enhanced greatly. The double salts can be administered orally or by injection. [0023] The melting point of the double salts is still under study. Above 203°C, the double salts turn yellow, above 270°C, turn brown, and at 303°C, the salts don’t disappear. The sodium cefdinir disclosed in CN 1,415,615A turns yellow 25 at about 160°C, and turns black at 190°C and finally disappear. Obviously, in contrast to the prior art, the double salts of the invention have better stability. [0024] Cefdinir has a broad antimicrobial spectrum and good antibacterial activity against gram- positive and -negative bacteria, e.g., Moraxella catarrhalis, Klebsiella pneumoniae, proteobacteria, and Escherichia coli. Furthermore, cefdinir is stable to β-lactamase and can kill some bacteria capable of synthesizing enzyme. With good water solubility, the 30 double salts can be prepared into solid formulations or injections. [0025] The method for producing the double salts has a stable process and high manufacturing feasibility. The compound (double salts) has good solubility and high bioavailability, and exhibits high activity and high efficiency in clinical practice. [0026] For further illustrating the invention, experiments detailing a cefdinir double salt and preparation method thereof 35 are described below. It should be noted that the following examples are intended to describe and not to limit the invention.

Example 1

[0027] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield 40 a uniform mixture. 0.496 g of sulfuric acid was diluted with 10 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture under an ice bath condition. After the solution was clear, 0.273 g of sodium methoxide was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir sodium hydrogen sulfate obtained. The yield was 99%, with a content of 98.7% and purity 45 greater than or equal to 99%.

Example 2

[0028] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield 50 a uniform mixture. 0.496 g of sulfuric acid was diluted with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture under an ice bath condition. After the solution was clear, 0.1365 g of sodium methoxide was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir sodium hydrogen (0.5) sulfate (1.5) obtained. The yield was 98.1%, with a content of 98.4% 55 and purity greater than or equal to 99%.

6 EP 2 385 054 B1

Example 3

[0029] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.496 g of sulfuric acid was diluted with 10 mL of anhydrous methanol, and the resulting solution was 5 dripped slowly into the uniform mixture under an ice bath condition. After the solution was clear, 0.355 g of potassium methoxide was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir potassium hydrogen sulfate obtained. The yield was 98%, with a content of 98.3% and purity greater than or equal to 99%. 10 Example 4

[0030] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous acetone were added and stirred to yield a uniform mixture. 0.496 g of sulfuric acid was diluted with 10 mL of anhydrous acetone, and the resulting solution was 15 dripped slowly into the uniform mixture under an ice bath condition. After the solution was clear, 0.1775 g of potassium methoxide was added and allowed to react for 15 min. Subsequently, acetone was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir potassium hydrogen (0.5) sulfate (1.5) obtained. The yield was 96.5%, with a content of 97.1% and purity greater than or equal to 99%. 20 Example 5

[0031] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.496 g of sulfuric acid was diluted with 10 mL of anhydrous methanol, and the resulting solution was 25 dripped slowly into the uniform mixture under an ice bath condition. After the solution was clear, 0.086 g of ammonia gas was inflated and allowed to react under sealing condition for 15 min. Subsequently, methanol was distilled off at 30°C under reduced pressure. The solution was concentrated, crystallized with hexane using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir ammonium hydrogen sulfate obtained. The yield was 96.4%, with a content of 98.6% and purity greater than or equal to 99%. 30 Example 6

[0032] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.496 g of sulfuric acid was diluted with 10 mL of anhydrous ethanol, and the resulting solution was 35 dripped slowly into the uniform mixture under an ice bath condition. After the solution was clear, 0.043 g of ammonia gas was inflated and allowed to react under sealing condition for 15 min. Subsequently, ethanol was distilled off at 30°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir ammonium hydrogen (0.5) sulfate (1.5) obtained. The yield was 96.7%, with a content of 97.7% and purity greater than or equal to 99%. 40 Example 7

[0033] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.516 g of sodium hydrogen sulfate was mixed with 30 mL of anhydrous ethanol, and the resulting 45 solution was dripped slowly into the uniform mixture. After the solution was clear, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir sodium hydrogen sulfate obtained. The yield was 97%, with a content of 98.4% and purity greater than or equal to 99%.

50 Example 8

[0034] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.689 g of potassium hydrogen sulfate was mixed with 30 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, methanol was distilled off at 35°C 55 under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir potassium hydrogen sulfate obtained. The yield was 97%, with a content of 98% and purity greater than or equal to 99%.

7 EP 2 385 054 B1

Example 9

[0035] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.582 g of ammonium hydrogen sulfate was mixed with 30 mL of anhydrous methanol, and the 5 resulting solution was dripped slowly into the uniform mixture. After the solution was clear, methanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir ammonium hydrogen sulfate obtained. The yield was 98%, with a content of 98.7% and purity greater than or equal to 99%.

10 Example 10

[0036] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.496 g of phosphoric acid was diluted with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture under an ice bath condition. After the solution was clear, 0.273 g of sodium 15 methoxide was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir sodium dihydrogen phosphate obtained. The yield was 96%, with a content of 98.5% and purity greater than or equal to 99%.

20 Example 11

[0037] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.4966 g of phosphoric acid was diluted with 10 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture under an ice bath condition. After the solution was clear, 0.355 g of potassium 25 methoxide was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir potassium dihydrogen phosphate obtained. The yield was 96.8%, with a content of 98.7% and purity greater than or equal to 99%.

30 Example 12

[0038] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous acetone were added and stirred to yield a uniform mixture. 0.4966 g of phosphoric acid was diluted with 10 mL of anhydrous acetone, and the resulting solution was dripped slowly into the uniform mixture under an ice bath condition. After the solution was clear, 0.086 g of ammonia 35 gas was inflated and allowed to react for 25 min under sealing condition. Subsequently, acetone was distilled off at 30°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir ammonium dihydrogen phosphate obtained. The yield was 92.4%, with a content of 98.6% and purity greater than or equal to 99%.

40 Example 13

[0039] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.607 g of sodium dihydrogen phosphate was mixed with 40 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, methanol was distilled off at 45 35°C under reduced pressure. The solution was concentrated, crystallized with hexane using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir sodium dihydrogen phosphate obtained. The yield was 96.8%, with a content of 98.7% and purity greater than or equal to 99%.

Example 14 50 [0040] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of dimethylformamide (DMF) were added and stirred to yield a uniform mixture. 0.607 g of sodium dihydrogen phosphate was mixed with 40 mL of DMF, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, DMF was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with hexane using a dropping funnel, and stirred to yield 55 a solid. The solid was dried and cefdinir sodium dihydrogen phosphate obtained. The yield was 96.7%, with a content of 97.5% and purity greater than or equal to 99%.

8 EP 2 385 054 B1

Example 15

[0041] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.688 g of potassium dihydrogen phosphate was mixed with 30 mL of anhydrous ethanol, and the 5 resulting solution was dripped slowly into the uniform mixture. After the solution was clear, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir potassium dihydrogen phosphate obtained. The yield was 93.6%, with a content of 98.7% and purity greater than or equal to 99%.

10 Example 16

[0042] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of dimethylsulfoxide (DMSO) were added and stirred to yield a uniform mixture. 0.688 g of potassium dihydrogen phosphate was mixed with 30 mL of DMSO, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, DMSO was distilled off at 35°C under 15 reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir potassium dihydrogen phosphate obtained. The yield was 95.4%, with a content of 97.2% and purity greater than or equal to 99%.

Example 17 20 [0043] To a 100 mL reaction flask, 2.0 g of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.582 g of ammonium dihydrogen phosphate was mixed with 30 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred 25 to yield a solid. The solid was dried and cefdinir ammonium dihydrogen phosphate obtained. The yield was 96.4%, with a content of 98.7% and purity greater than or equal to 99%.

Example 18

30 [0044] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.496 g of sulfuric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of sodium ethoxide was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir 35 sodium hydrogen sulfate obtained. The yield was 98.2%, with a content of 98.3% and purity greater than or equal to 99%.

Example 19

[0045] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to 40 yield a uniform mixture. 0.496 g of sulfuric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 2.53 mmol of potassium propoxide was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir potassium hydrogen (0.5) sulfate (1.5) obtained. The yield was 98.3%, with a content of 98.8% and purity greater 45 than or equal to 99%.

Example 20

[0046] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous acetone were added and stirred to 50 yield a uniform mixture. 0.496 g of sulfuric acid was mixed with 10 mL of anhydrous acetone, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of cesium butoxide was added and allowed to react for 15 min. Subsequently, acetone was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir cesium hydrogen sulfate obtained. The yield was 97.3%, with a content of 98.5% and purity greater than or equal to 99%. 55 Example 21

[0047] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous acetone were added and stirred to

9 EP 2 385 054 B1

yield a uniform mixture. 0.496 g of sulfuric acid was mixed with 10 mL of anhydrous acetone, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 2.53 mmol of potassium isopropoxide was added and allowed to react for 15 min. Subsequently, acetone was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was 5 dried and cefdinir potassium hydrogen (0.5) sulfate (1.5) obtained. The yield was 96.5%, with a content of 97.1 % and purity greater than or equal to 99%.

Example 22

10 [0048] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.496 g of sulfuric acid was mixed with 10 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 2.53 mmol of ammonia water was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 30°C under reduced pressure. The solution was concentrated, crystallized with hexane using a dropping funnel, and stirred to yield a solid. The solid was 15 dried and cefdinir ammonium hydrogen sulfate obtained. The yield was 96.4%, with a content of 98.6% and purity greater than or equal to 99%.

Example 23

20 [0049] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.496 g of sulfuric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of sodium tert- butoxide was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and 25 cefdinir sodium hydrogen sulfate obtained. The yield was 98.6%, with a content of 97.3% and purity greater than or equal to 99%.

Example 24

30 [0050] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.496 g of sulfuric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 2.53 mmol of potassium acetate was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and 35 cefdinir potassium hydrogen (0.5) sulfate (1.5) obtained. The yield was 95.3%, with a content of 97.8% and purity greater than or equal to 99%.

Example 25

40 [0051] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous acetone were added and stirred to yield a uniform mixture. 0.496 g of sulfuric acid was mixed with 10 mL of anhydrous acetone, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of cesium propionate was added and allowed to react for 15 min. Subsequently, acetone was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and 45 cefdinir cesium hydrogen sulfate obtained. The yield was 96.3%, with a content of 98.4% and purity greater than or equal to 99%.

Example 26

50 [0052] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous acetone were added and stirred to yield a uniform mixture. 0.496 g of sulfuric acid was mixed with 10 mL of anhydrous acetone, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 2.53 mmol of sodium isopropoxide was added and allowed to react for 15 min. Subsequently, acetone was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and 55 cefdinir sodium hydrogen (0.5) sulfate (1.5) obtained. The yield was 96.5%, with a content of 97.1 % and purity greater than or equal to 99%.

10 EP 2 385 054 B1

Example 27

[0053] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.496 g of sulfuric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution 5 was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of sodium tert- butyrate was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir sodium hydrogen sulfate obtained. The yield was 96.6%, with a content of 96.7% and purity greater than or equal to 99%. 10 Example 28

[0054] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.496 g of phosphoric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution 15 was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of sodium ethoxide was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir sodium dihydrogen phosphate obtained. The yield was 96.8%, with a content of 97.5% and purity greater than or equal to 99%. 20 Example 29

[0055] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.4966 g of phosphoric acid was mixed with 10 mL of anhydrous methanol, and the resulting 25 solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of potassium propoxide was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir potassium dihydrogen sulfate obtained. The yield was 97.3%, with a content of 96.5% and purity greater than or equal to 99%. 30 Example 30

[0056] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous acetone were added and stirred to yield a uniform mixture. 0.4966 g of phosphoric acid was mixed with 10 mL of anhydrous acetone, and the resulting 35 solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of ammonia water was added and allowed to react for 25 min. Subsequently, acetone was distilled off at 30°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir ammonium dihydrogen phosphate obtained. The yield was 95.4%, with a content of 96.6% and purity greater than or equal to 99%. 40 Example 31

[0057] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.496 g of phosphoric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution 45 was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of cesium butoxide was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir cesium dihydrogen phosphate obtained. The yield was 96.8%, with a content of 97.5% and purity greater than or equal to 99%. 50 Example 32

[0058] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.4966 g of phosphoric acid was mixed with 10 mL of anhydrous methanol, and the resulting 55 solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of potassium isopropoxide was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir potassium dihydrogen phosphate obtained. The yield was 97.5%, with a content of

11 EP 2 385 054 B1

97.3% and purity greater than or equal to 99%.

Example 33

5 [0059] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.496 g of phosphoric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of sodium tert- butoxide was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was 10 dried and cefdinir sodium dihydrogen phosphate obtained. The yield was 98.1%, with a content of 97.6% and purity greater than or equal to 99%.

Example 34

15 [0060] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.4966 g of phosphoric acid was mixed with 10 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of potassium acetate was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The 20 solid was dried and cefdinir potassium dihydrogen phosphate obtained. The yield was 93.6%, with a content of 96.3% and purity greater than or equal to 99%.

Example 35

25 [0061] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.4966 g of phosphoric acid was mixed with 10 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of sodium acetate was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The 30 solid was dried and cefdinir sodium dihydrogen phosphate obtained. The yield was 92.6%, with a content of 97.3% and purity greater than or equal to 99%.

Example 36

35 [0062] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.496 g of phosphoric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of sodium tert-propionate was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The 40 solid was dried and cefdinir sodium dihydrogen phosphate obtained. The yield was 95.2%, with a content of 98.6% and purity greater than or equal to 99%.

Example 37

45 [0063] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.4966 g of phosphoric acid was mixed with 10 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of potassium butyrate was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The 50 solid was dried and cefdinir potassium dihydrogen phosphate obtained. The yield was 92.6%, with a content of 98.3% and purity greater than or equal to 99%.

Example 38

55 [0064] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.4966 g of phosphoric acid was mixed with 10 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of cesium butyrate was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 40°C under reduced pressure. The

12 EP 2 385 054 B1

solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir potassium dihydrogen phosphate obtained. The yield was 92.6%, with a content of 97.3% and purity greater than or equal to 99%.

5 Example 39

[0065] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 0.496 g of phosphoric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of sodium tert- hydroxide was added 10 and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir sodium dihydrogen phosphate obtained. The yield was 97.2%, with a content of 96.2% and purity greater than or equal to 99%.

15 Example 40

[0066] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.4966 g of phosphoric acid was mixed with 10 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of potassium hydroxide 20 was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir potassium dihydrogen phosphate obtained. The yield was 90.6%, with a content of 97.7% and purity greater than or equal to 99%.

25 Example 41

[0067] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 0.4966 g of phosphoric acid was mixed with 10 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of cesium hydroxide was 30 added and allowed to react for 15 min. Subsequently, methanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir cesium dihydrogen phosphate obtained. The yield was 89.6%, with a content of 98.3% and purity greater than or equal to 99%.

35 Example 42

[0068] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 5.06 mmol of sulfuric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of sodium tert- butoxide was added 40 and allowed to react for 15 min. Subsequently, ethanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir sodium hydrogen sulfate obtained. The yield was 96.2%, with a content of 98.5% and purity greater than or equal to 99%.

45 Example 43

[0069] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous methanol were added and stirred to yield a uniform mixture. 5.06 mmol of sulfuric acid was mixed with 10 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of potassium hydroxide 50 was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir sodium hydrogen sulfate obtained. The yield was 90.6%, with a content of 97.7% and purity greater than or equal to 99%.

55 Example 44

[0070] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to yield a uniform mixture. 5.06 mmol of sulfuric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution

13 EP 2 385 054 B1

was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of cesium hydroxide was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir cesium hydrogen sulfate obtained. The yield was 87.6%, with a content of 98.7% and purity greater 5 than or equal to 99%.

Example 45

[0071] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous methanol were added and stirred 10 to yield a uniform mixture. 5.06 mmol of sulfuric acid was mixed with 10 mL of anhydrous methanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of ammonium acetate was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir ammonium hydrogen sulfate obtained. The yield was 91.6%, with a content of 98.7% and 15 purity greater than or equal to 99%.

Example 46

[0072] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to 20 yield a uniform mixture. 5.06 mmol of sulfuric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of ammonium propionate was added and allowed to react for 15 min. Subsequently, ethanol was distilled off at 40°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir ammonium hydrogen sulfate obtained. The yield was 89.6%, with a content of 98.1% and purity greater 25 than or equal to 99%.

Example 47

[0073] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to 30 yield a uniform mixture. 0.496 g of phosphoric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of ammonium acetate was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir ammonium dihydrogen phosphate obtained. The yield was 94.2%, with a content of 97.6% and purity greater 35 than or equal to 99%.

Example 48

[0074] To a 100 mL reaction flask, 5.06 mmol of cefdinir and 20 mL of anhydrous ethanol were added and stirred to 40 yield a uniform mixture. 0.496 g of phosphoric acid was mixed with 10 mL of anhydrous ethanol, and the resulting solution was dripped slowly into the uniform mixture. After the solution was clear, 5.06 mmol of ammonium acetate was added and allowed to react for 15 min. Subsequently, methanol was distilled off at 35°C under reduced pressure. The solution was concentrated, crystallized with petroleum ether using a dropping funnel, and stirred to yield a solid. The solid was dried and cefdinir ammonium dihydrogen phosphate obtained. The yield was 89.2%, with a content of 98.6% and purity 45 greater than or equal to 99%.

Industrial applicability

[0075] Cefdinir is hard soluble in water. The solubility of the compounds of the invention has been increased by 100 50 times. Table 1 lists the solubility of the compounds of the invention.

Table 1 No. Compound Solubility

55 1 Cefdinir sodium hydrogen (0.5) sulfate (1.5) Soluble 2 Cefdinir potassium hydrogen (0.5) sulfate (1.5) Soluble 3 Cefdinir ammonium hydrogen (0.5) sulfate (1.5) Soluble

14 EP 2 385 054 B1

(continued) No. Compound Solubility 4 Cefdinir sodium hydrogen sulfate Slightly soluble 5 5 Cefdinir potassium hydrogen sulfate Slightly soluble 6 Cefdinir ammonium hydrogen sulfate Slightly soluble 7 Cefdinir sodium dihydrogen phosphate Slightly soluble 8 Cefdinir potassium dihydrogen phosphate Slightly soluble 9 Cefdinir ammonium dihydrogen phosphate Slightly soluble 10

[0076] Beagles, half male and half female, with body weight of 10 kg, were starved for 12 hrs and only water fed. The compounds of the invention were formulated into capsules containing 200 mg of cefdinir and fed to beagles by intragastric administration. The control group was administered with conventional cefdinir capsules. 3 hrs later, the beagles were

15 fed with common food. At 0 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, and 10 h after intragastric administration, 0.5 mL of venous blood was collected respectively to measure the concentration of cefdinir. The results are listed in Table 2.

Table 2 Bioavailability comparison between compounds of the invention and conventional cefdinir capsule

20 Bioavailability Drugs Cmax (mg/mL) Time to peak (h) AUC (0-10) (mg·h/mL) percentage increase Conventional cefdinir 21.80 3 102.11 / capsule Cefdinir sodium 65.43 3 255.27 149% 25 hydrogen sulfate Cefdinir sodium 50.23 3 239.96 135% hydrogen (0.5) sulfate (1.5)

30 Cefdinir potassium 54.13 2.5 261.41 156% hydrogen sulfate Cefdinir potassium 47.65 3 213.40 109% hydrogen (0.5) sulfate (1.5) 35 Cefdinir ammonium 43.63 3 202.18 98% hydrogen sulfate Cefdinir ammonium 34.12 2.5 160.31 57% hydrogen (0.5) sulfate (1.5) 40 Cefdinir sodium 27.28 2.5 123.55 20% dihydrogen phosphate Cefdinir potassium 30.37 3 152.15 49% dihydrogen phosphate

45 [0077] As shown in Table 2, the bioavailability of the compounds of the invention has been improved by 20% compared with that of conventional cefdinir capsules. The largest increase was 156%. [0078] The production process of cefdinir sodium hydrogen sulfate of Example 1 and cefdinir potassium hydrogen sulfate of Example 3 is stable and thus the bioavailability thereof has improved a lot. 50

Claims

1. A cefdinir acid double salt represented by Formula I 55

15 EP 2 385 054 B1

15 characterized in that

M represents Na+, K+, NH4+, or Cs+; 2- 3- Y represents SO4 or PO4 ; and 20 2- 1) when Y represents SO4 :

when m = 1, then n = 1; when m = 0.5, then n = 1.5; and 25 3- 2) when Y represents PO4 : when m = 1, then n = 2.

2. A method for producing the cefdinir acid double salt of claim 1, comprising contacting cefdinir with an acid and an alkali or ammonium compound, or contacting cefdinir with an acid salt; characterized in that when the acid or acid 30 salt comprises a sulfate group, the product is a cefdinir sulfate double salt; when the acid or acid salt comprises a phosphate group, the product is a cefdinir phosphate double salt.

3. The method of claim 2, characterized in that the alkali compound is selected from the group consisting of sodium methoxide, potassium methoxide, cesium methoxide, sodium ethoxide, potassium ethoxide, cesium ethoxide, so- 35 dium propoxide, potassium propoxide, cesium propoxide, sodium butoxide, potassium butoxide, cesium butoxide, sodium isopropoxide, potassium isopropoxide, cesium isopropoxide, sodium tert- butoxide, potassium tert- butoxide, cesiumtert- butoxide, sodium acetate, potassium acetate, cesium acetate, sodium propionate, potassium propionate, cesium propionate, sodium butyrate, potassium butyrate, cesium butyrate, sodium hydroxide, potassium hydroxide, and cesium hydroxide. 40 4. The method of claim 2, characterized in that the ammonium compound is selected from the group consisting of ammonia, ammonia water, ammonium acetate, ammonium propionate, and ammonium butyrate.

5. The compound of claim 1, characterized in that the compound is: 45

16 EP 2 385 054 B1

17 EP 2 385 054 B1

25 or

40 6. The compound of claim 1, characterized in that the compound is:

18 EP 2 385 054 B1

25 or

7. A method for preparing the compound of claim 5, the method comprising: 40 mixing cefdinir and an equimolar amount of sulfuric acid; adding an alkali compound at a molar ratio of said alkali compound to cefdinir being 0.5:1 or 1:1 to obtain a product, wherein said alkali compound is sodium methoxide, potassium methoxide, cesium methoxide, sodium ethoxide, potassium ethoxide, cesium ethoxide, sodium propoxide, potassium propoxide, cesium propoxide, 45 sodium butoxide, potassium butoxide, cesium butoxide, sodium isopropoxide, potassium isopropoxide, cesium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, cesium tert-butoxide, sodium acetate, potassium acetate, cesium acetate, sodium propionate, potassium propionate, cesium propionate, sodium butyrate, potassium butyrate, cesium butyrate, sodium hydroxide, potassium hydroxide, or cesium hydroxide; and concentrating, crystallizing with ether, petroleum ether, or hexane, filtering, and drying the product. 50 8. A method for preparing the compound of claim 5, the method comprising:

mixing cefdinir and an equimolar amount of sulfuric acid; adding ammonium acetate, ammonia gas, or ammonia water to obtain a product, wherein a molar ratio of 55 ammonium acetate, ammonia gas, or ammonia water to cefdinir is 0.5: 1 or 1:1; concentrating, crystallizing with ether, petroleum ether, or hexane, filtering, and drying the product to yield cefdinir ammonium hydrogen sulfate.

19 EP 2 385 054 B1

9. A method for preparing the compound of claim 5, the method comprising mixing cefdinir and an equimolar amount of sodium hydrogen sulfate, potassium hydrogen sulfate, or ammonium hydrogen sulfate to obtain a product, concentrating, crystallizing with ether, petroleum ether, or hexane, filtering, and drying the product.

5 10. A method for preparing the compound of claim 6, the method comprising:

mixing cefdinir and an equimolar amount of phosphoric acid, adding an alkali compound at a molar ratio of said alkali compound to cefdinir being 1:1 to obtain a product, wherein said alkali compound is sodium methoxide, potassium methoxide, cesium methoxide, sodium ethoxide, 10 potassium ethoxide, cesium ethoxide, sodium propoxide, 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, sodium acetate, potassium acetate, cesium acetate, sodium propionate, potassium propionate, cesium propionate, sodium butyrate, potassium butyrate, cesium butyrate, sodium hydroxide, potassium hydroxide, or cesium hydroxide; and 15 concentrating, crystallizing with ether, petroleum ether, or hexane, filtering, and drying the product.

11. A method for preparing the compound of claim 6, the method comprising:

mixing cefdinir and an equimolar amount of phosphoric acid, 20 adding ammonium acetate, ammonia gas, or ammonia water at a molar ratio of said ammonium acetate, ammonia gas, or ammonia water to cefdinir being 1:1, and concentrating, crystallizing with ether, petroleum ether, or hexane, filtering, and drying the product.

12. A method for preparing the compound of claim 6, the method comprising mixing cefdinir and an equimolar amount 25 of sodium dihydrogen phosphate, potassium dihydrogen phosphate, or ammonium dihydrogen phosphate to obtain a product, concentrating, crystallizing with ether, petroleum ether, or hexane, filtering, and drying the product.

Patentansprüche 30 1. Cefdinir- Säure- Doppelsalz, das durch die folgende Formel I dargestellt ist:

dadurch gekennzeichnet, dass

50 + + + + M für Na , K , NH4 oder Cs steht; 2- 3- Y für SO4 oder PO4 steht; und

2- 1) wenn Y für SO4 steht:

55 wenn m = 1 ist, dann n = 1 ist; wenn m = 0,5 ist, dann n = 1,5 ist; und

3- 2) wenn Y für PO4 steht: wenn m = 1 ist, dann n = 2 ist.

20 EP 2 385 054 B1

2. Verfahren zum Herstellen des Cefdinir- Säure-Doppelsalzes nach Anspruch 1, umfassend das Inkontaktbringen von Cefdinir mit einer Säure und einer Alkali- oder Ammoniumverbindung oder Inkontaktbringen von Cefdinir mit einem Säuresalz; dadurch gekennzeichnet, dass, wenn die Säure oder das Säuresalz eine Sulfatgruppe umfasst, das Produkt ein Cefdinir-Sulfat-Doppelsalz ist; wenn die Säure oder das Säuresalz eine Phosphatgruppe umfasst, das 5 Produkt ein Cedfinir-Phosphat-Doppelsalz ist.

3. Verfahren nach Anspruch 2, dadurch gekennzeichnet, dass die Alkaliverbindung ausgewählt ist aus der Gruppe bestehend aus Natriummethoxid, Kaliummethoxid, Cäsiummethoxid, Natriumethoxid, Kaliumethoxid, Cäsiumeth- oxid, Natriumpropoxid, Kaliumpropoxid, Cäsiumpropoxid, Natriumbutoxid, Kaliumbutoxid, Cäsiumbutoxid, Natri- 10 umisopropoxid, Kaliumisopropoxid, Cäsiumisopropoxid, Natrium- tert- butoxid, Kalium- tert- butoxid, Cäsium- tert- butoxid, Natriumacetat, Kaliumacetat, Cäsiumacetat, Natriumpropionat, Kaliumpropionat, Cäsiumpropionat, Natri- umbutyrat, Kaliumbutyrat, Cäsiumbutyrat, Natriumhydroxid, Kaliumhydroxid und Cäsiumhydroxid.

4. Verfahren nach Anspruch 2, dadurch gekennzeichnet, dass die Ammoniumverbindung ausgewählt ist aus der 15 Gruppe bestehend aus Ammoniak, Ammoniakwasser, Ammoniumacetat, Ammoniumphosphat und Ammoniumbu- tyrat.

5. Verbindung nach Anspruch 1, dadurch gekennzeichnet, dass die Verbindung Folgendes ist:

21 EP 2 385 054 B1

oder 50

22 EP 2 385 054 B1

6. Verbindung nach Anspruch 1, dadurch gekennzeichnet, dass die Verbindung Folgendes ist:

50 oder

23 EP 2 385 054 B1

7. Verfahren zum Herstellen der Verbindung nach Anspruch 5, wobei das Verfahren Folgendes umfasst:

15 Mischen von Cefdinir und einer äquimolaren Menge Schwefelsäure; Zugeben einer Alkaliverbindung in einem Molverhältnis der Alkaliverbindung zu Cefdinir von 0, 5: 1 oder 1: 1, um ein Produkt zu erhalten, wobei die Alkaliverbindung Natriummethoxid, Kaliummethoxid, Cäsiummethoxid, Natriumethoxid, Kaliumethoxid, Cäsiumethoxid, Natriumpropoxid, Kaliumpropoxid, Cäsiumpropoxid, Natrium- butoxid, Kaliumbutoxid, Cäsiumbutoxid, Natriumisopropoxid, Kaliumisopropoxid, Cäsiumisopropoxid, Natrium- 20 tert- butoxid, Kalium- tert- butoxid, Cäsium- tert- butoxid, Natriumacetat, Kaliumacetat, Cäsiumacetat, Natrium- propionat, Kaliumpropionat, Cäsiumpropionat, Natriumbutyrat, Kaliumbutyrat, Cäsiumbutyrat, Natriumhydroxid, Kaliumhydroxid oder Cäsiumhydroxid ist; und Konzentrieren, Kristallisieren mit Ether, Petroleumether oder Hexan, Filtern und Trocknen des Produkts.

25 8. Verfahren zum Herstellen der Verbindung nach Anspruch 5, wobei das Verfahren Folgendes umfasst:

Mischen von Cefdinir und einer äquimolaren Menge Schwefelsäure; Zugeben von Ammoniumacetat, Ammoniakgas oder Ammoniakwasser zum Erhalt eines Produktes, wobei das Molverhältnis von Ammoniumacetat, Ammoniakgas oder Ammoniakwasser zu Cefdinir 0,5:1 oder 1:1 ist; 30 Konzentrieren, Kristallisieren mit Ether, Petroleumether oder Hexan, Filtern und Trocknen des Produktes, so- dass Cefdinir-Ammoniumwasserstoffsulfat hervorgebracht wird.

9. Verfahren zum Herstellen der Verbindung nach Anspruch 5, wobei das Verfahren das Mischen von Cefdinir und einer äquimolaren Menge Natriumwasserstoffsulfat, Kaliumwasserstoffsulfat oder Ammoniumwasserstoffsulfat zum 35 Erhalt eines Produktes, Konzentrieren, Kristallisieren mit Ether, Petroleumether oder Hexan, Filtern und Trocknen des Produktes umfasst.

10. Verfahren zum Herstellen der Verbindung nach Anspruch 6, wobei das Verfahren Folgendes umfasst:

40 Mischen von Cefdinir und einer äquimolaren Menge Phosphorsäure; Zugeben einer Alkaliverbindung in einem Molverhältnis der Alkaliverbindung zu Cefdinir von 1: 1, um ein Produkt zu erhalten, wobei die Alkaliverbindung Natriummethoxid, Kaliummethoxid, Cäsiummethoxid, Natriumethoxid, Kaliumethoxid, Cäsiumethoxid, Natriumpropoxid, Kaliumpropoxid, Cäsiumpropoxid, Natriumbutoxid, Kalium- butoxid, Cäsiumbutoxid, Natriumisopropoxid, Kaliumisopropoxid, Cäsiumisopropoxid, Natrium- tert- butoxid, 45 Kalium- tert- butoxid, Cäsium- tert- butoxid, Natriumacetat, Kaliumacetat, Cäsiumacetat, Natriumpropionat, Kaliumpropionat, Cäsiumpropionat, Natriumbutyrat, Kaliumbutyrat, Cäsiumbutyrat, Natriumhydroxid, Kalium- hydroxid oder Cäsiumhydroxid ist; und Konzentrieren, Kristallisieren mit Ether, Petroleumether oder Hexan, Filtern und Trocknen des Produktes.

50 11. Verfahren zum Herstellen der Verbindung nach Anspruch 6, wobei das Verfahren Folgendes umfasst:

Mischen von Cefdinir und einer äquimolaren Menge Phosphorsäure; Zugeben von Ammoniumacetat, Ammoniakgas oder Ammoniakwasser in einem Molverhältnis des Ammoniu- macetats, Ammoniakgases oder Ammoniakwassers zu Cefdinir von 1:1, und 55 Konzentrieren, Kristallisieren mit Ether, Petroleumether oder Hexan, Filtern und Trocknen des Produktes.

12. Verfahren zum Herstellen der Verbindung nach Anspruch 6, wobei das Verfahren das Mischen von Cefdinir und einer äquimolaren Menge Natriumdiwasserstoffphosphat, Kaliumdiwasserstoffphosphat oder Ammoniumdiwasser-

24 EP 2 385 054 B1

stoffphosphat zum Erhalt eines Produktes, Konzentrieren, Kristallisieren mit Ether, Petroleumether oder Hexan, Filtern und Trocknen des Produktes umfasst.

5 Revendications

1. Double sel d’acide de cefdinir représenté par la formule I

caractérisé en ce que 25 + + + + M représente Na , K , NH4 , ou Cs ; 2- 3- Y représente SO4 ou PO4 ; et

1) lorsque Y représente SO42- : 30 lorsque m = 1, alors n = 1 ; lorsque m = 0,5, alors n = 1,5 ; et

3- 2) lorsque Y représente PO4 : lorsque m = 1, alors n = 2. 35 2. Procédé de production du double sel d’acide de cefdinir selon la revendication 1, comprenant la mise en contact de cefdinir avec un acide et un composé alcalin ou d’ammonium, ou la mise en contact de cefdinir avec un sel d’acide ; caractérisé en ce que lorsque l’acide ou le sel d’acide comprend un groupe sulfate, le produit est un double sel de sulfate de cefdinir ; lorsque l’acide ou le sel acide comprend un groupe phosphate, le produit est un 40 double sel de phosphate de cefdinir.

3. Procédé selon la revendication 2, caractérisé en ce que le composé alcalin est sélectionné dans le groupe constitué par le méthoxyde de sodium, le méthoxyde de potassium, le méthoxyde de césium, l’éthoxyde de sodium, l’éthoxyde de potassium, l’éthoxyde de césium, le propoxyde de sodium, le propoxyde de potassium, le propoxyde de césium, 45 le butoxyde de sodium, le butoxyde de potassium, le butoxyde de césium, l’isopropoxyde de sodium, l’isopropoxyde de potassium, l’isopropoxyde de césium, le tert- butoxyde de sodium, le tert-butoxyde de potassium, le tert- butoxyde de césium, l’acétate de sodium, l’acétate de potassium, l’acétate de césium, le propionate de sodium, le propionate de potassium, le propionate de césium, le butyrate de sodium, le butyrate de potassium, le butyrate de césium, l’hydroxyde de sodium, l’hydroxyde de potassium et l’hydroxyde de césium. 50 4. Procédé selon la revendication 2, caractérisé en ce que le composé d’ammonium est sélectionné dans le groupe constitué par l’ammoniac, l’eau ammoniacale, l’acétate d’ammonium, le propionate d’ammonium et le butyrate d’ammonium.

55 5. Composé selon la revendication 1, caractérisé en ce que le composé est :

25 EP 2 385 054 B1

26 EP 2 385 054 B1

50 6. Composé selon la revendication 1, caractérisé en ce que le composé est :

27 EP 2 385 054 B1

50 7. Procédé de préparation du composé selon la revendication 5, le procédé comprenant :

le mélange de cefdinir et d’une quantité équimolaire d’acide sulfurique ; l’ajout d’un composé alcalin selon un rapport molaire dudit composé alcalin au cefdinir qui est 0,5: 1 ou 1: 1 pour 55 obtenir un produit, dans lequel ledit composé alcalin est le méthoxyde de sodium, le méthoxyde de potassium, le méthoxyde de césium, l’éthoxyde de sodium, l’éthoxyde de potassium, l’éthoxyde de césium, le propoxyde de sodium, le propoxyde de potassium, le propoxyde de césium, le butoxyde de sodium, le butoxyde de potassium, le butoxyde de césium, l’isopropoxyde de sodium, l’isopropoxyde de potassium, l’isopropoxyde de césium,

28 EP 2 385 054 B1

le tert-butoxyde de sodium, le tert-butoxyde de potassium, le tert-butoxyde de césium, l’acétate de sodium, l’acétate de potassium, l’acétate de césium, le propionate de sodium, le propionate de potassium, le propionate de césium, le butyrate de sodium, le butyrate de potassium, le butyrate de césium, l’hydroxyde de sodium, l’hydroxyde de potassium ou l’hydroxyde de césium ; et 5 la concentration, la cristallisation avec un éther, de l’éther de pétrole ou de l’hexane, la filtration et le séchage du produit.

8. Procédé de préparation d’un composé selon la revendication 5, le procédé comprenant :

10 le mélange de cefdinir et d’une quantité équimolaire d’acide sulfurique ; l’ajout d’acétate d’ammonium, d’ammoniac gazeux ou d’eau ammoniacale pour obtenir un produit, dans lequel le rapport molaire de l’acétate d’ammonium, de l’ammoniac gazeux ou de l’eau ammoniacale au cefdinir est 0,5:1 ou 1:1; la concentration, la cristallisation avec un éther, de l’éther de pétrole ou de l’hexane, la filtration et le séchage 15 du produit pour donner un hydrogénosulfate d’ammonium de cefdinir.

9. Procédé de préparation du composé selon la revendication 5, le procédé comprenant le mélange de cefdinir et d’une quantité équimolaire d’hydrogénosulfate de sodium, dhydrogénosulfate de potassium ou d’hydrogénosulfate d’ammonium pour obtenir un produit, la concentration, la cristallisation avec un éther, de l’éther de pétrole ou de 20 l’hexane, la filtration et le séchage du produit.

10. Procédé de préparation du composé selon la revendication 6, le procédé comprenant :

le mélange de cefdinir et d’une quantité équimolaire d’acide phosphorique ; 25 l’ajout d’un composé alcalin selon un rapport molaire dudit composé alcalin au cefdinir qui est 1: 1 pour obtenir un produit, dans lequel ledit composé alcalin est le méthoxyde de sodium, le méthoxyde de potassium, le méthoxyde de césion, l’éthoxyde de sodium, l’éthoxyde de potassium, l’éthoxyde de césium, le propoxyde de sodium, le propoxyde de potassium, le propoxyde de césium, le butoxyde de sodium, le butoxyde de potassium, le butoxyde de césium, l’isopropoxyde de sodium, l’isopropoxyde de potassium, l’isopropoxyde de césium, le 30 tert-butoxyde de sodium, le tert- butoxyde de potassium, le tert- butoxyde de césium,l’acétate de sodium, l’acétate de potassium, l’acétate de césium, le propionate de sodium, le propionate de potassium, le propionate de césium, le butyrate de sodium, le butyrate de potassium, le butyrate de césium, l’hydroxyde de sodium, l’hydroxyde de potassium ou l’hydroxyde de césium ; et la concentration, la cristallisation avec un éther, de l’éther de pétrole ou de l’hexane, la filtration et le séchage 35 du produit.

11. Procédé de préparation d’un composé selon la revendication 6, le procédé comprenant :

le mélange de cefdinir et d’une quantité équimolaire d’acide phosphorique ; 40 l’ajout d’acétate d’ammonium, d’ammoniac gazeux ou d’eau ammoniacale selon un rapport molaire de l’acétate d’ammonium, de l’ammoniac gazeux ou de l’eau ammoniacale au cefdinir de 1:1;et la concentration, la cristallisation avec un éther, de l’éther de pétrole ou de l’hexane, la filtration et le séchage du produit.

45 12. Procédé de préparation du composé selon la revendication 6, le procédé comprenant le mélange de cefdinir et d’une quantité équimolaire d’hydrogénosulfate de sodium, d’hydrogénosulfate de potassium ou d’hydrogénosulfate d’ammonium pour obtenir un produit, la concentration, la cristallisation avec un éther, de l’éther de pétrole ou de l’hexane, la filtration et le séchage du produit.

29 EP 2 385 054 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• CN 1415615 [0005] • KR 20070088757 [0005] • CN 1251590 [0005] • DE 60311869 [0005] • CN 1512996 [0005] • CN 1415615 A [0023] • US 4559334 A [0005]