WO1998045299A1 - Crystalline amine salt of cefdinir - Google Patents

Crystalline amine salt of cefdinir Download PDF

Info

Publication number
WO1998045299A1
WO1998045299A1 PCT/EP1998/001953 EP9801953W WO9845299A1 WO 1998045299 A1 WO1998045299 A1 WO 1998045299A1 EP 9801953 W EP9801953 W EP 9801953W WO 9845299 A1 WO9845299 A1 WO 9845299A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
salt
dicyclohexylamine
cefdinir
Prior art date
Application number
PCT/EP1998/001953
Other languages
French (fr)
Inventor
Hubert Sturm
Siegfried Wolf
Johannes Ludescher
Original Assignee
Biochemie Gesellschaft Mbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to IL13175598A priority Critical patent/IL131755A0/en
Application filed by Biochemie Gesellschaft Mbh filed Critical Biochemie Gesellschaft Mbh
Priority to DE69816056T priority patent/DE69816056T2/en
Priority to AU74288/98A priority patent/AU731413B2/en
Priority to CA002283718A priority patent/CA2283718A1/en
Priority to BR9809745-8A priority patent/BR9809745A/en
Priority to PL98335620A priority patent/PL335620A1/en
Priority to AT98921425T priority patent/ATE244249T1/en
Priority to JP54235898A priority patent/JP3421354B2/en
Priority to US09/381,947 priority patent/US6350869B1/en
Priority to SK1343-99A priority patent/SK134399A3/en
Priority to EP98921425A priority patent/EP0973779B1/en
Publication of WO1998045299A1 publication Critical patent/WO1998045299A1/en
Priority to NO994466A priority patent/NO994466D0/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to intermediates in the purification of cefdinir, i.e. 7-(Z)-[2-(2-aminothiazol-4-yl)-2-hydroxyirmnoacetarnido]-3-vinyl-3-cephem-4-carboxylic acid of formula
  • Cefdinir may be used, e.g. in form of a monohydrate, as a pharmaceutical, e.g. antibiotic; see e.g. Y.Inamoto,Toshiyuki Chiba,Toshiaki iamimura und Takao Takaya, J.Antibiotics Vol XII, No 6, 829, (1988).
  • Cefdinir may be obtained in impure form according to known production processes. It was now surprisingly found that impure cefdinir may be purified via the formation of a salt, e.g. in crystalline form, thereof.
  • the present invention provides a compound of formula I in the form of a salt, e.g. crystalline, with dicyclohexylamine.
  • a compound of formula I in the form of a salt with dicyclohexylamine may be produced as follows:
  • Cefdinir e.g. in the form of a solvate, such as a hydrate, e.g. in impure form, e.g. as obtained in a production process of cefdinir, such as a mixture of cefdinir and impurities, e.g. such as a mixture of by-products originating from the production process of cefdinir and cefdinir; may be treated in the presence of a solvent, e.g. in dissolved or suspended form, with dicyclohexylamine.
  • a solvent includes any solvent which is inert towards cefdinir or towards cefdinir in the form of a salt with dicyclohexylamine, e.g.
  • a polar organic solvent such as amides, e.g. dimethylformamide; alcohols, e.g. methanol oder ethanol; ketones, e.g acetone; e.g. in combination with water and water.
  • a solvent system e.g. mixtures of individual solvents, e.g. as described above may be used.
  • a preferred solvent system may be e.g. acetone/water, including e.g. a ratio of about 100:1 such as 50:1, e.g. 20:1 to 1:5; such as 10:1 to 1:3, e.g. 5:1 to 2:1, e.g. about 1:1.
  • Per equivalent of cefdinir about one equivalent or more, such as 5; e.g.
  • a compound of formula I in the form of a salt with dicyclohexylamine may crystallize e.g. from a reaction solution, or, e.g. a suspension of a compound of formula I in a solvent may be converted into a crystall suspension of a compound of formula I in the form of a salt with dicyclohexylamine.
  • An anti-solvent may be added to the reaction mixture, e.g. in order to complete crystallization.
  • An anti-solvent includes solvents wherein a compound of formula I in the form of a salt with dicyclohexylamine is insoluble or soluble only to a small extent if added to the solution or suspension of a compound of formula I in the form of a dicyclohexylamine, e.g. apolar solvents; e.g. ethers, such as diethylether, tetrahydrofurane; or a ketone, e.g. acetone.
  • a compound of formula I in the form of a salt with dicyclohexylamine may be isolated from the reaction mixture, e.g. as conventional, e.g. by filtration, centrifugation.
  • a compound of formula I in the form of a salt with dicyclohexylamine may be obtained in pure form, e.g. in 98% purity and more, such as 99% to 100% purity; e.g. the amount of impurities present in cefdinir in impure form used for salt formation may be decreased; e.g. impurities of 10% and more in cefdinir in impure form may be decreased to impurities of 1 % and less, e.g. 0 to 1 % in cefdinir in the form of a salt with dicyclohexylamine.
  • a compound of formula I in the form of a salt with dicyclohexylamine may be further purified by re-suspension or re-dissolution as described above, e.g. in an (anti) solvent (system), e.g. as described above.
  • the present invention provides a process for the production of a compound of formula I in the form of a salt with dicyclohexylamine, e.g. in crystalline form, comprising treating a compound of formula I, e.g. in form of a solvate, such as a hydrate, in a solvent with dicyclohexylamine and isolating a compound of formula I in the form of a salt with dicyclohexylamine, e.g. in crystalline form.
  • Cefdinir in free form e.g. in the form of a solvate, such as a hydrate, e.g. monohydrate and in purified form, e.g. in respect with impure cefdinir used for the formation of a salt of a compound of formula I with dicyclohexylamine
  • a compound of formula I in the form of a salt with dicyclohexylamine e.g. as conventional for setting free a compound which is in the form of a salt, e.g. in the form of an amine salt; e.g. by adjusting an appropriate pH, e.g. 1.5 to 4, such as 2 to 3; of a mixture, e.g.
  • cefdinir in the form of a salt with dicyclohexylamine with a solvent, e.g. in the presence of water, preferably in water, e.g. by addition of an acidic agent, such as an organic or inorganic acid, preferably an inorganic acid, e.g. sulphuric acid.
  • Cefdinir e.g. in the form of hydrate, e.g. monohydrate may crystallize and may be isolated, e.g. as conventional, e.g. by filtration, centrifugation.
  • a compound of formula I may be obtained according to the process of the present invention as such or in the form of a solvate, e.g. a hydrate, e.g. a monohydrate.
  • a compound of formula I obtained according to the process of the present invention as such may be converted into a compound of formula I in the form of a solvate, e.g. a hydrate, such as a monohydrate and vice versa.
  • the present invention provides a process for the production of a compound of formula I, e.g. in form of a solvate, such as a hydrate, e.g. monohydrate comprising converting a compound of formula in the form of a salt with dicyclohexylamine, e.g. in crystalline form, into a compound of formula I, e.g. in the form of a solvate, and isolating a compound of formula I, e.g. in the form of a solvate.
  • a solvate such as a hydrate, e.g. monohydrate
  • the present invention provides a process for the purification of cefdinir in a mixture of a compound of formula I with impurities, comprising forming a salt of a compound of formula I with dicyclohexylamine; and converting a compound of formula I in the form of a salt with dicyclohexylamine, e.g. in crystalline form, into a compound of formula I, e.g. in the form of a solvate, and isolating a compound of formula I, e.g. in the form of a solvate.
  • a compound of formula I in the form of a salt with dicyclohexylamine is useful in the purification of cefdinir in impure form.
  • the present invention provides the use of a compound of formula I in the form of a salt with dicyclohexylamine, e.g. in crystalline form in the purification of a mixture of a compound of formula I with impurities.
  • a compound of formula I in the form of a salt with dicyclohexylamine may be in acrystalline form; cefdinir in the form of a salt may be obtained in surprising high purity, e.g. 98% purity and more, e.g. 98% to 100%;- production of the salt is simple; cefdinir obtained from the salt may be surprisingly pure, e.g. 98% and more, e.g. 99% to 100%. It is surprising that cefdinir under the basic conditions of the salt formation according to the present invention is stable, because from e.g. Yoshihiko Okamoto et al., J.
  • cefdinir may be instable in a basic environment; it was e.g. found that cefdinir in the presence of other amines, e.g. tert.- octylamine under similar conditions may be, e.g. heavily, degraded.
  • the present invention provides crystalline 7-(Z)-[2-(2-aminothiazol-4-yl)-2- hydroxyiminoacetarnido]-3-vinyl-3-cephem-4-carboxylic acid.dicyclohexylammonium salt of formula
  • the mixture obtained is stirred for ca.90 minutes at 0° and added under stirring to a mixture of 44.55 g of NaHCO3, 600 ml of water und 100 ml of dichloromethane of a temperature of 5°.
  • the pH of the mixture obtained is adjusted to a pH of ca. 7.2 - 7.3 with a saturated aqueous solution of NaHCO3.
  • the phases formed are separated.
  • To the aqueous phase 300 ml of water are added and 28.7 g of NH4CI.
  • the pH of the mixture obtained is adjusted to pH 8 by addition of an aqueous 10% K2CO3 solution and the mixture is stirred for ca. 80 minutes.
  • a solution is obtained.
  • the pH of the solution obtained is adjusted to pH 3 by addition of 5m sulphuric acid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cefdinir in the form of a salt with dicyclohexylamine, a process for its production and its use in the purification of impure cefdinir.

Description

CRYSTALLINE AMINE SALT OF CEFDINIR
The present invention relates to intermediates in the purification of cefdinir, i.e. 7-(Z)-[2-(2-aminothiazol-4-yl)-2-hydroxyirmnoacetarnido]-3-vinyl-3-cephem-4-carboxylic acid of formula
Figure imgf000003_0001
Cefdinir may be used, e.g. in form of a monohydrate, as a pharmaceutical, e.g. antibiotic; see e.g. Y.Inamoto,Toshiyuki Chiba,Toshiaki iamimura und Takao Takaya, J.Antibiotics Vol XII, No 6, 829, (1988).
Cefdinir may be obtained in impure form according to known production processes. It was now surprisingly found that impure cefdinir may be purified via the formation of a salt, e.g. in crystalline form, thereof.
In one aspect the present invention provides a compound of formula I in the form of a salt, e.g. crystalline, with dicyclohexylamine.
A compound of formula I in the form of a salt with dicyclohexylamine may be produced as follows:
Cefdinir, e.g. in the form of a solvate, such as a hydrate, e.g. in impure form, e.g. as obtained in a production process of cefdinir, such as a mixture of cefdinir and impurities, e.g. such as a mixture of by-products originating from the production process of cefdinir and cefdinir; may be treated in the presence of a solvent, e.g. in dissolved or suspended form, with dicyclohexylamine. A solvent includes any solvent which is inert towards cefdinir or towards cefdinir in the form of a salt with dicyclohexylamine, e.g. a polar organic solvent, such as amides, e.g. dimethylformamide; alcohols, e.g. methanol oder ethanol; ketones, e.g acetone; e.g. in combination with water and water. A solvent system, e.g. mixtures of individual solvents, e.g. as described above may be used. A preferred solvent system may be e.g. acetone/water, including e.g. a ratio of about 100:1 such as 50:1, e.g. 20:1 to 1:5; such as 10:1 to 1:3, e.g. 5:1 to 2:1, e.g. about 1:1. Per equivalent of cefdinir about one equivalent or more, such as 5; e.g. 3, such as 2 equivalents of dicyclohexylamine may be used, e.g. combined with the mixture of impure cefdinir in a solvent. A compound of formula I in the form of a salt with dicyclohexylamine may crystallize e.g. from a reaction solution, or, e.g. a suspension of a compound of formula I in a solvent may be converted into a crystall suspension of a compound of formula I in the form of a salt with dicyclohexylamine. An anti-solvent may be added to the reaction mixture, e.g. in order to complete crystallization. An anti-solvent includes solvents wherein a compound of formula I in the form of a salt with dicyclohexylamine is insoluble or soluble only to a small extent if added to the solution or suspension of a compound of formula I in the form of a dicyclohexylamine, e.g. apolar solvents; e.g. ethers, such as diethylether, tetrahydrofurane; or a ketone, e.g. acetone. A compound of formula I in the form of a salt with dicyclohexylamine may be isolated from the reaction mixture, e.g. as conventional, e.g. by filtration, centrifugation.
A compound of formula I in the form of a salt with dicyclohexylamine may be obtained in pure form, e.g. in 98% purity and more, such as 99% to 100% purity; e.g. the amount of impurities present in cefdinir in impure form used for salt formation may be decreased; e.g. impurities of 10% and more in cefdinir in impure form may be decreased to impurities of 1 % and less, e.g. 0 to 1 % in cefdinir in the form of a salt with dicyclohexylamine. A compound of formula I in the form of a salt with dicyclohexylamine may be further purified by re-suspension or re-dissolution as described above, e.g. in an (anti) solvent (system), e.g. as described above.
In another aspect the present invention provides a process for the production of a compound of formula I in the form of a salt with dicyclohexylamine, e.g. in crystalline form, comprising treating a compound of formula I, e.g. in form of a solvate, such as a hydrate, in a solvent with dicyclohexylamine and isolating a compound of formula I in the form of a salt with dicyclohexylamine, e.g. in crystalline form.
Cefdinir in free form, e.g. in the form of a solvate, such as a hydrate, e.g. monohydrate and in purified form, e.g. in respect with impure cefdinir used for the formation of a salt of a compound of formula I with dicyclohexylamine, may be obtained from a compound of formula I in the form of a salt with dicyclohexylamine, e.g. as conventional for setting free a compound which is in the form of a salt, e.g. in the form of an amine salt; e.g. by adjusting an appropriate pH, e.g. 1.5 to 4, such as 2 to 3; of a mixture, e.g. a solution, of cefdinir in the form of a salt with dicyclohexylamine with a solvent, e.g. in the presence of water, preferably in water, e.g. by addition of an acidic agent, such as an organic or inorganic acid, preferably an inorganic acid, e.g. sulphuric acid. Cefdinir, e.g. in the form of hydrate, e.g. monohydrate may crystallize and may be isolated, e.g. as conventional, e.g. by filtration, centrifugation. A compound of formula I may be obtained according to the process of the present invention as such or in the form of a solvate, e.g. a hydrate, e.g. a monohydrate. A compound of formula I obtained according to the process of the present invention as such may be converted into a compound of formula I in the form of a solvate, e.g. a hydrate, such as a monohydrate and vice versa.
In another aspect the present invention provides a process for the production of a compound of formula I, e.g. in form of a solvate, such as a hydrate, e.g. monohydrate comprising converting a compound of formula in the form of a salt with dicyclohexylamine, e.g. in crystalline form, into a compound of formula I, e.g. in the form of a solvate, and isolating a compound of formula I, e.g. in the form of a solvate.
In another aspect the present invention provides a process for the purification of cefdinir in a mixture of a compound of formula I with impurities, comprising forming a salt of a compound of formula I with dicyclohexylamine; and converting a compound of formula I in the form of a salt with dicyclohexylamine, e.g. in crystalline form, into a compound of formula I, e.g. in the form of a solvate, and isolating a compound of formula I, e.g. in the form of a solvate.
A compound of formula I in the form of a salt with dicyclohexylamine is useful in the purification of cefdinir in impure form.
In another aspect the present invention provides the use of a compound of formula I in the form of a salt with dicyclohexylamine, e.g. in crystalline form in the purification of a mixture of a compound of formula I with impurities.
The present invention has several surprising advantages:
A compound of formula I in the form of a salt with dicyclohexylamine may be in acrystalline form; cefdinir in the form of a salt may be obtained in surprising high purity, e.g. 98% purity and more, e.g. 98% to 100%;- production of the salt is simple; cefdinir obtained from the salt may be surprisingly pure, e.g. 98% and more, e.g. 99% to 100%. It is surprising that cefdinir under the basic conditions of the salt formation according to the present invention is stable, because from e.g. Yoshihiko Okamoto et al., J. of Pharmaceutical Sciences, Vol 85, No 9, 976, (1996) it is known that cefdinir may be instable in a basic environment; it was e.g. found that cefdinir in the presence of other amines, e.g. tert.- octylamine under similar conditions may be, e.g. heavily, degraded.
In another aspect the present invention provides crystalline 7-(Z)-[2-(2-aminothiazol-4-yl)-2- hydroxyiminoacetarnido]-3-vinyl-3-cephem-4-carboxylic acid.dicyclohexylammonium salt of formula
Figure imgf000006_0001
In the following examples, which illustrate the invention more fully but do in no way limit its scope, all temperatures are given in degrees Celsius. Purity of a compound obtained is determined by HPLC.
Example 1
7-(Z)-[2-(2-Arainothiazol-4-yl)-2-hydroxyiminoacetarrιido]-3-vinyl-3-cephem-4-carboxy lie acid in form of a salt with dicyclohexylamine
10 g of crude cefdinir, e.g. as obtained in a cefdinir production process, in 50 ml of water and 50 ml of acetone are treated under stirring with 5 ml of dicyclohexylamine. A solution is obtained and 7-(Z)-[2-(2-Aπ nothiazol-4-yl)-2-hydroxyimino-acetamido]-3-vinyl-3-cephem-4- carboxylic acid in form of a salt with dicyclohexylamine crystallizes. 250 ml of acetone are added to the crystall suspension which is stirred for ca. 30 minutes at room temperature. The crystalls are filtrated off, washed with acetone and dried. Crystalline 7-(Z)-[2-(2- Aminothiazol-4-yl)-2-hydroxyiminoacetarnido]-3-vinyl-3-cephem-4-carboxylic acid in form of a salt with dicyclohexylamine in a purity of 98.6 % is obtained. Mp: 175° (decomposition).
αH-NMR ( DMSO-d6): 9.41 (d, 1H, J = 8.1 Hz, NH); 7.12 (s, 2H, NH2); 6.99 (dd, 1H, J = 11.4 and 17.7 Hz, CH = CH2); 6.64 (s, 1H, thiazol); 5.60 (dd, 1H, J = 4.8 and 8.1 Hz, H7); 5.15 (d, 1H J = 17.7 Hz, CH = CH2); 5.04 (d, 1H, J = 4.8 Hz, He); 4.94 (d, 1H, J = 11.4 Hz, CH = CH2); 3.52, 3.39 (AB d, 1H, J = 17 Hz, H2); 3.21 (m, 2H); 2.05 (m, 4H); 1.8 (m, 4H); 1.6 (m, 2H); 1.2 - 1.4 (m, 10H).
Example 2
7-(Z)-[2-(2-An-άnotMazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid in the form of a monohydrate
10 g of 7-(Z)-[2-(2-Aιrύnothiazol-4-yl)-2-hydroxyirrunoacetamido]-3-vinyl-3-cephem-4- carboxylic acid in form of a salt with dicyclohexylamine, obtained according to Example 1 are dissolved in 175 ml of water at a temperature of ca. 35-40° and treated with active charcoal. Active charcoal is filtrated off and the pH of the solution obtained is adjusted to pH 2.5 by addition of 5ml of sulphuric acid at ca. 35°. 7-(Z)-[2-(2-Aminothiazol-4-yl)-2-hydroxyimino- acetamido]-3-vinyl-3-cephem-4-carboxylic acid in the form of a monohydrate precipitates, is filtrated off, washed with water and dried. 7-(Z)-[2-(2-Aminothiazol-4-yl)-2-hydroxyimino- acetamido]-3-vinyl-3-cephem-4-carboxylic acid in the form of a monohydrate in a purity of 99% is obtained.
Example 3
Production of crude cefdinir
40 g of 7-amino-3-vinyl-3-cephem-4-carboxylic acid in 400 ml of dichloromethane are treated with 55.7 ml of N,O-bistrimethyl-silylacetamid. The mixture obtained is stirred for ca. 2 hours at room temperature, cooled to 0° and treated with 52.2 g of 2-(Z)-(2-aminothiazol-4- yl)-2-acetoxyiminoacetic acid chloride in the form of a hydrochloride in small portions. The mixture obtained is stirred for ca.90 minutes at 0° and added under stirring to a mixture of 44.55 g of NaHCO3, 600 ml of water und 100 ml of dichloromethane of a temperature of 5°. The pH of the mixture obtained is adjusted to a pH of ca. 7.2 - 7.3 with a saturated aqueous solution of NaHCO3. The phases formed are separated. To the aqueous phase 300 ml of water are added and 28.7 g of NH4CI. The pH of the mixture obtained is adjusted to pH 8 by addition of an aqueous 10% K2CO3 solution and the mixture is stirred for ca. 80 minutes. A solution is obtained. The pH of the solution obtained is adjusted to pH 3 by addition of 5m sulphuric acid. 7-(Z)-[2-(2-aιmno-thiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem- 4-carboxylic acid precipitates, is filtrated off, washed with water and dried. 7-(Z)-[2-(2-amino- thiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid in a purity of 94.3 % is obtained.

Claims

Patent claims
1. A compound of formula
Figure imgf000009_0001
in the form of a salt with dicyclohexylamine.
2. A process for the production of a compound of formula I as defined in claim 1 in the form of a salt with dicyclohexylamine comprising treating a compound of formula I in a solvent with dicyclohexylamine and isolating a compound of formula I in the form of a salt with dicyclohexylamine.
3. A process for the production of a compound of formula I as defined in claim 1 comprising converting a compound of formula I in the form of a salt with dicyclohexylamine into a compound of formula I and isolating a compound of formula I.
4. A process for the purification of a compound of formula I as defined in claims 1 in a mixture of a compound of formula I with impurities, comprising forming a salt of a compound of formula I with dicyclohexylamine; and converting a compound of formula I in the form of a salt with dicyclohexylamine into a compound of formula I and isolating a compound of formula I.
5. A process according to any one of claims 3 to 4 comprising converting a compound of formula I in the form of a salt with dicyclohexylamine into a compound of formula I in the form of a solvate.
6. A process according to any one of claims 3 to 5 comprising isolating a compound of formula I in the form of a solvate.
7. Use of a compound of claim 1 in the purification of a mixture of a compound of formula I with impurities.
8. A compound of formula I as defined in claim I in the form of a salt with dicyclohexylamine according to any one of claims 1 to 7, which is in crystalHne form.
9. Crystalline 7-(Z)-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid.dicyclohexylammonium salt of formula
Figure imgf000010_0001
PCT/EP1998/001953 1997-04-04 1998-04-02 Crystalline amine salt of cefdinir WO1998045299A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
PL98335620A PL335620A1 (en) 1997-04-04 1998-04-02 Crystalline cephdynir and amine salt
DE69816056T DE69816056T2 (en) 1997-04-04 1998-04-02 CRYSTALLINE AMINE SALT FROM CEFDINIR
AU74288/98A AU731413B2 (en) 1997-04-04 1998-04-02 Crystalline amine salt of cefdinir
CA002283718A CA2283718A1 (en) 1997-04-04 1998-04-02 Crystalline amine salt of cefdinir
BR9809745-8A BR9809745A (en) 1997-04-04 1998-04-02 Crystalline amine salt of cefdinir
IL13175598A IL131755A0 (en) 1997-04-04 1998-04-02 Crystalline amine salt of cefdinir
AT98921425T ATE244249T1 (en) 1997-04-04 1998-04-02 CRYSTALLINE AMINE SALT OF CEFDINIR
SK1343-99A SK134399A3 (en) 1997-04-04 1998-04-02 Cefdinir in the form of a salt with dicyclohexylamine, a process for its production and its use
US09/381,947 US6350869B1 (en) 1997-04-04 1998-04-02 Crystalline amine salt of cefdinir
JP54235898A JP3421354B2 (en) 1997-04-04 1998-04-02 Crystalline cefdiniramine salt
EP98921425A EP0973779B1 (en) 1997-04-04 1998-04-02 Crystalline amine salt of cefdinir
NO994466A NO994466D0 (en) 1997-04-04 1999-09-15 Crystalline amine salt of cefdinir

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT0057097A AT405283B (en) 1997-04-04 1997-04-04 NEW CRYSTALLINE 7- (Z) - (2- (2-AMINOTHIAZOL-4-YL) -2-HYDROXYIMINOACETAMIDO) -3-VINYL-3-CEPHEM-4- CARBONIC ACID DICYCLOHEXYLAMMONIUM SALTS AND METHODS FOR THE PRODUCTION THEREOF
ATA570/97 1997-04-04

Publications (1)

Publication Number Publication Date
WO1998045299A1 true WO1998045299A1 (en) 1998-10-15

Family

ID=3494111

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/001953 WO1998045299A1 (en) 1997-04-04 1998-04-02 Crystalline amine salt of cefdinir

Country Status (18)

Country Link
US (1) US6350869B1 (en)
EP (1) EP0973779B1 (en)
JP (1) JP3421354B2 (en)
KR (1) KR100442717B1 (en)
CN (1) CN1139596C (en)
AT (2) AT405283B (en)
AU (1) AU731413B2 (en)
BR (1) BR9809745A (en)
CA (1) CA2283718A1 (en)
DE (1) DE69816056T2 (en)
HU (1) HUP0002987A3 (en)
ID (1) ID22536A (en)
IL (1) IL131755A0 (en)
NO (1) NO994466D0 (en)
PL (1) PL335620A1 (en)
SK (1) SK134399A3 (en)
TR (1) TR199902406T2 (en)
WO (1) WO1998045299A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098884A1 (en) * 2001-06-05 2002-12-12 Hanmi Pharm. Co., Ltd. Crystalline acid salts of cefdinir and process for preparing cefdinir using same
WO2004035800A2 (en) * 2002-10-01 2004-04-29 Antibioticos S.P.A. Intermediate cefdinir salts
WO2006053625A1 (en) * 2004-11-19 2006-05-26 Antibioticos S.P.A. Crystalline form of cefdinir ammonium salt as an intermediate for the preparation of pure cefdinir
WO2006117794A1 (en) * 2005-05-02 2006-11-09 Hetero Drugs Limited A novel crystalline form of cefdinir
WO2011078819A1 (en) * 2009-12-25 2011-06-30 Mahmut Bilgic Amine salts of cefdinir
US8614315B2 (en) 2009-12-25 2013-12-24 Mahmut Bilgic Cefdinir and cefixime formulations and uses thereof

Families Citing this family (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080113025A1 (en) * 1998-11-02 2008-05-15 Elan Pharma International Limited Compositions comprising nanoparticulate naproxen and controlled release hydrocodone
ITMI20020913A0 (en) * 2002-04-29 2002-04-29 Acs Dobfar Spa NEW CRYSTALLINE FORM OF CEFDINIR
DE60336331D1 (en) 2002-08-13 2011-04-21 Sandoz Ag A CEFDINIR INTERMEDIATE PRODUCT
AU2003276525A1 (en) * 2002-11-15 2004-06-15 Orchid Chemicals And Pharmaceuticals Ltd Novel amorphous hydrate of a cephalosporin antibiotic
ITMI20022724A1 (en) * 2002-12-20 2004-06-21 Antibioticos Spa CRYSTALLINE SALTS OF CEFDINIR.
CA2520083A1 (en) * 2003-03-24 2004-10-07 Acs Dobfar S.P.A. Novel crystal of 7-[2-[(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) and method for preparation thereof
WO2004104010A1 (en) * 2003-05-20 2004-12-02 Ranbaxy Laboratories Limited Crystalline form of cefdinir
US20050137182A1 (en) * 2003-06-02 2005-06-23 Ramesh Dandala Novel crystalline form of cefdinir
US20040242556A1 (en) * 2003-06-02 2004-12-02 Ramesh Dandala Novel crystalline form of cefdinir
US20050059818A1 (en) * 2003-09-12 2005-03-17 Duerst Richard W. Polymorph of a pharmaceutical
US20050059819A1 (en) * 2003-09-12 2005-03-17 Duerst Richard W. Cefdinir pyridine salt
US20050113355A1 (en) * 2003-09-12 2005-05-26 Duerst Richard W. Cefdinir pyridine salt
US20060211676A1 (en) * 2004-03-16 2006-09-21 Devalina Law Crystalline anhydrous cefdinir and crystalline cefdinir hydrates
US20050209211A1 (en) * 2004-03-16 2005-09-22 Devalina Law Trihemihydrate, anhydrate and novel hydrate forms of Cefdinir
US20060142261A1 (en) * 2004-03-16 2006-06-29 Devalina Law Crystalline anhydrous cefdinir and crystalline cefdinir hydrates
US20060142563A1 (en) * 2004-03-16 2006-06-29 Devalina Law Crystalline anhydrous cefdinir and crystalline cefdinir hydrates
WO2005090360A1 (en) * 2004-03-19 2005-09-29 Orchid Chemicals & Pharmaceuticals Limited Novel polymorph of cefdinir
US20060069079A1 (en) * 2004-09-27 2006-03-30 Sever Nancy E Stable amorphous cefdinir
US20050245738A1 (en) * 2004-05-03 2005-11-03 Lupin Ltd Stable bioavailable crystalline form or cefdinir and a process for the preparation thereof
WO2006010978A1 (en) * 2004-06-30 2006-02-02 Wockhardt Limited Cefdinir polymorphic forms, and imidazole salt
EP1765833A2 (en) 2004-07-05 2007-03-28 Orchid Chemicals and Pharmaceuticals Limited News salts in the preparation of cephalosporin antibiotics
WO2006018807A1 (en) * 2004-08-16 2006-02-23 Ranbaxy Laboratories Limited Crystalline forms of cefdinir
MX2007006018A (en) * 2004-11-30 2007-06-07 Astellas Pharma Inc Novel oral pharmaceutical suspension of cefdinir crystal.
GB2421024A (en) * 2004-12-07 2006-06-14 Sandoz Ag Cefdinir crystalline form C
EP1899356A1 (en) * 2005-06-15 2008-03-19 Hetero Drugs Limited Cefdinir process
CN1903860B (en) * 2005-07-25 2012-01-18 四川抗菌素工业研究所有限公司 Technology of preparing high purity cefotamei sodium by solvent process and its medical use
JP2008526782A (en) * 2005-10-31 2008-07-24 テバ ファーマシューティカル インダストリーズ リミティド Cefdinir cesium salt crystals
US20070128268A1 (en) * 2005-12-07 2007-06-07 Herwig Jennewein Pharmaceutical compositions comprising an antibiotic
CN101481383B (en) * 2008-12-31 2012-01-11 杭州奥默医药技术有限公司 Cefdinir acid type double salt compound and preparation
CN102010427B (en) * 2010-11-19 2012-09-12 苏州中联化学制药有限公司 Method for preparing cefdinir
CN101974020B (en) * 2010-11-19 2012-09-12 苏州中联化学制药有限公司 Method for synthesizing cefdinir
CN103012433B (en) * 2012-12-13 2015-06-24 珠海保税区丽珠合成制药有限公司 Preparation method of cefdinir crystal form B
CN108546270B (en) * 2017-05-31 2019-11-08 郑州大学第一附属医院 The method for preparing Cefdinir
CN107286148B (en) * 2017-06-20 2019-10-15 广州市桐晖通医药科技有限公司 A kind of preparation method of Cefdinir and its new midbody compound
CN111635419B (en) * 2020-07-13 2022-05-24 广药白云山化学制药(珠海)有限公司 Method for treating cefdinir refined mother liquor

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1038529A (en) * 1964-03-14 1966-08-10 Fujisawa Pharmaceutical Co 7-(ª‡-substituted acylamino) cephalosporanic acid and derivatives thereof
US4559334A (en) * 1983-08-26 1985-12-17 Fujisawa Pharmaceutical Co., Ltd. 7-Substituted-3-vinyl-3-cephem compounds and processes for production of the same
EP0304019A2 (en) * 1987-08-19 1989-02-22 Fujisawa Pharmaceutical Co., Ltd. Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer)
WO1997007121A1 (en) * 1995-08-14 1997-02-27 Biochemie Gesellschaft Mbh Purification process
WO1997024358A1 (en) * 1995-12-27 1997-07-10 Hanmi Pharmaceutical Co., Ltd. Process for preparation of cefdinir

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993016084A1 (en) * 1992-02-05 1993-08-19 Biochemie Gesellschaft M.B.H. Process for the purification of a 3-cephem-4-carboxylic acid derivative
US5750682A (en) * 1994-07-22 1998-05-12 Antibioticos S.P.A. Glutaryl 7-ACA derivatives and processes for obtaining them
AT404251B (en) * 1996-08-14 1998-10-27 Biochemie Gmbh NEW CRYSTALLINE SALT FROM CEFIXIM

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1038529A (en) * 1964-03-14 1966-08-10 Fujisawa Pharmaceutical Co 7-(ª‡-substituted acylamino) cephalosporanic acid and derivatives thereof
US4559334A (en) * 1983-08-26 1985-12-17 Fujisawa Pharmaceutical Co., Ltd. 7-Substituted-3-vinyl-3-cephem compounds and processes for production of the same
EP0304019A2 (en) * 1987-08-19 1989-02-22 Fujisawa Pharmaceutical Co., Ltd. Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer)
WO1997007121A1 (en) * 1995-08-14 1997-02-27 Biochemie Gesellschaft Mbh Purification process
WO1997024358A1 (en) * 1995-12-27 1997-07-10 Hanmi Pharmaceutical Co., Ltd. Process for preparation of cefdinir

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098884A1 (en) * 2001-06-05 2002-12-12 Hanmi Pharm. Co., Ltd. Crystalline acid salts of cefdinir and process for preparing cefdinir using same
WO2004035800A2 (en) * 2002-10-01 2004-04-29 Antibioticos S.P.A. Intermediate cefdinir salts
WO2004035800A3 (en) * 2002-10-01 2004-08-26 Antibioticos Spa Intermediate cefdinir salts
US7405294B2 (en) 2002-10-01 2008-07-29 Antibioticos S.P.A. Intermediate cefdinir salts
WO2006053625A1 (en) * 2004-11-19 2006-05-26 Antibioticos S.P.A. Crystalline form of cefdinir ammonium salt as an intermediate for the preparation of pure cefdinir
WO2006117794A1 (en) * 2005-05-02 2006-11-09 Hetero Drugs Limited A novel crystalline form of cefdinir
WO2011078819A1 (en) * 2009-12-25 2011-06-30 Mahmut Bilgic Amine salts of cefdinir
US8614315B2 (en) 2009-12-25 2013-12-24 Mahmut Bilgic Cefdinir and cefixime formulations and uses thereof

Also Published As

Publication number Publication date
KR100442717B1 (en) 2004-08-02
KR20010005907A (en) 2001-01-15
AU731413B2 (en) 2001-03-29
DE69816056D1 (en) 2003-08-07
EP0973779B1 (en) 2003-07-02
TR199902406T2 (en) 2000-02-21
HUP0002987A3 (en) 2001-04-28
HUP0002987A2 (en) 2001-02-28
JP2000514833A (en) 2000-11-07
SK134399A3 (en) 2000-05-16
IL131755A0 (en) 2001-03-19
ATA57097A (en) 1998-11-15
ID22536A (en) 1999-11-04
BR9809745A (en) 2000-06-20
DE69816056T2 (en) 2004-04-15
AT405283B (en) 1999-06-25
CN1139596C (en) 2004-02-25
NO994466L (en) 1999-09-15
NO994466D0 (en) 1999-09-15
AU7428898A (en) 1998-10-30
JP3421354B2 (en) 2003-06-30
US6350869B1 (en) 2002-02-26
ATE244249T1 (en) 2003-07-15
PL335620A1 (en) 2000-05-08
CA2283718A1 (en) 1998-10-15
EP0973779A1 (en) 2000-01-26
CN1251590A (en) 2000-04-26

Similar Documents

Publication Publication Date Title
EP0973779B1 (en) Crystalline amine salt of cefdinir
EP0968214B1 (en) Purification process
WO1999051607A2 (en) Process for purification of a cephalosporin derivative
US4003896A (en) Method of preparing a sparingly soluble complex of cephalexin
US5639877A (en) Intermediates in the synthesis of cephalosporins
US6835829B2 (en) Purification process
EP2218723A2 (en) Processes for the preparations of cefepime
JP2609039B2 (en) New production method of ceftriaxone
JPH069647A (en) New cephalosporin intermediate
EP0531981A1 (en) Process for the preparation of a cephalosporin antibiotic
CA1236089A (en) Ceftazidime
US20060149055A1 (en) Process for the manufacture of cefpodoxime proxetil
NO301766B1 (en) Process for Preparation of a Cephalosporin Antibiotic Using the Syn-Isomer of a Thiazole Intermediate
KR20020033616A (en) Crystalline Beta-Lactam Intermediate
US6313289B1 (en) Purification process
WO2010089729A1 (en) Processes for the preparation of cefozopran, its salts and polymorphic forms thereof
JP4616844B2 (en) Production process of intermediates for use in the synthesis of cephalosporin
US4659812A (en) Cephalosporin intermediates
KR960011779B1 (en) Novel process for preparing crystalline hydrate of cephalosporin
US4304909A (en) Process for producing 7-(D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl)acetamido)-3-(5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl)-.DELTA.3 -cephem-4-carboxylic acid and a pharmaceutically acceptable salt thereof
KR960011778B1 (en) Novel process for preparing crystalline hydrate of cephalosporin
US5138049A (en) Cephalosporin derivative
KR960011780B1 (en) Novel process for preparing crystalline hydrate of cephalosporine
CA1133470A (en) Cephapirine esters, salts thereof and processes for producing the same
HU197579B (en) Process for production of derivatives of cefem carbonic acid

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 131755

Country of ref document: IL

Ref document number: 98803850.1

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1998921425

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 74288/98

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 337555

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 1199900726

Country of ref document: VN

ENP Entry into the national phase

Ref document number: 2283718

Country of ref document: CA

Ref document number: 2283718

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 09381947

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 1999/02406

Country of ref document: TR

ENP Entry into the national phase

Ref document number: 1998 542358

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 134399

Country of ref document: SK

Ref document number: PA/a/1999/009045

Country of ref document: MX

Ref document number: PV1999-3506

Country of ref document: CZ

Ref document number: 1019997008984

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 1998921425

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV1999-3506

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1019997008984

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 74288/98

Country of ref document: AU

WWR Wipo information: refused in national office

Ref document number: PV1999-3506

Country of ref document: CZ

WWG Wipo information: grant in national office

Ref document number: 1998921425

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 1019997008984

Country of ref document: KR