WO2006006040A2 - News diamine salts of cephalosporin antibiotics and their preparation - Google Patents
News diamine salts of cephalosporin antibiotics and their preparation Download PDFInfo
- Publication number
- WO2006006040A2 WO2006006040A2 PCT/IB2005/001888 IB2005001888W WO2006006040A2 WO 2006006040 A2 WO2006006040 A2 WO 2006006040A2 IB 2005001888 W IB2005001888 W IB 2005001888W WO 2006006040 A2 WO2006006040 A2 WO 2006006040A2
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- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- sodium
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- 0 **C1(C2SCC(*)=C(*)N2C1C=O)I Chemical compound **C1(C2SCC(*)=C(*)N2C1C=O)I 0.000 description 1
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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/48—Methylene radicals, substituted by hetero rings
- C07D501/50—Methylene radicals, substituted by hetero rings with the 7-amino radical acylated by an aliphatic carboxylic acid, which is substituted by hetero atoms
-
- 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
-
- 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
Definitions
- the present invention relates to an improved process for the preparation of cephalosporin antibiotics of formula (I)
- R represents hydrogen pharmaceutically acceptable alkali metal salts, or pharmaceutically acceptable esters, R 1 represents
- R 4 represents hydrogen or -CHO group
- R 5 represents hydrogen, trityl, CH 3 , CR a R b COOR c where R a and R b independently represent hydrogen or methyl and R c represents hydrogen or (C 1 -C 6 )alkyl
- Z represents hydrogen, C 1-6 alkyl, and substituted or unsubstituted aryl
- R 2 represents hydrogen or methoxy group
- the present invention also provides new salts of compound of formula (II)
- R 6 , R 7 may be identical or different and are each, independently of one another, represent a linear or branched alkyl having from 1 to 8 carbon atoms or together with the C atom to which they are bound form a 3- to 8- membered saturated ring which may be further substituted or substituted aryl ring;
- the present invention also provides a process for the preparation of compound of formula (I) using the new salts of formula (II).
- US patent No. 6,350,869 discloses the purification of impure cefdinir through the preparation of N,N-dicyclohexylamine salt of 7-[2-aminothiazol-4-yl-2- (z)-hydroxyimino acetamido]-3-vinyl-3-cephem-4-carboxylic acid and subsequent hydrolysis to get pure cefdinir.
- This process requires the preparation of crude cefdinir, conversion to N,N-dicyclohexylamine salt and then hydrolysis of the salt to get pure cefdinir, and therefore the overall yield is not attractive.
- US patent 5,705,496 discloses a process for preparing the benzathine salt of Cefonicid which comprises treating an aqueous solution or suspension of Cefonicid with an organic solvent and N,N'-dibenzylethylenediamine.
- US patent 5,026,843 discloses the process for the preparation of Ceftriaxone disodium hemiheptahydrate involving condensing 7-ACT with MAEM.
- the product formed is precipitated by using dibenzylethylenediamine and subsequently is treated with sodium ethylhexanoate in acetone.
- the main objective of the present invention is to provide new salts of compound of formula (H) 5 which are stable throughout the process for the preparation of cephalosporin antibiotics of the formula (I).
- Another objective of the present invention is to provide a process for the preparation of cephalosporin antibiotics of formula (I) using these new salts.
- Another objective of the present invention is to prepare cephalosporin antibiotics of formula (I) that are highly pure, high yielding and cost effective, which would be easy to implement on manufacturing scale.
- Still another objective of the present invention is to provide a process for the preparation of new salts of formula (II).
- R 6 , R 7 may be identical or different and are each, independently of one another, represent a linear or branched alkyl having from 1 to 8 carbon atoms or together with the C atom to which they are bound form a 3- to 8- membered saturated ring which may be further substituted or substituted aryl ring;
- the process is shown in the Scheme-I
- the base used in step (i) is selected from sodium hydroxide, sodium acetate, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate triethylamine, trimethylamine, N-methylpiperidine, diethylamine, tributylamine, pyridine, N-alkylanilines, N,N-diisopropylethylamine N-methylmorpholine, and the like or mixtures thereof.
- reaction in step (i) is carried out at a temperature ranging from -50 0 C to + 8O 0 C.
- the solvent used in step (i) is selected from ethanol, methanol, isopropanol, THF, cyclohexanol, acetonitrile, DMAc, DMF, N-methyl pyrrolidine, ethyl acetate, methylene dichloride, ethylene dichloride, acetone, toluene, tetrahydrofuran, xylene, water or mixtures thereof.
- active esters include benzothiazole, benzoxazole, benzotriazole or benzimidazole.
- M is selected from N,N'-Diisobutylethylenediamine, N,N'-Dicyclohexyllethylenediamine or N 5 N'- Di- (p-anisyl)lethylenediamine, N,N'-Dicyclopentylethylenediamine and N 9 N'- (p- tolyl)lethylenediamine
- the solvent used in step (ii) is selected from ethanol, methanol, isopropanol, acetonitrile, acetone, ethylacetate, THF, DMAc, DMF, water or mixtures thereof.
- the acid employed in step (iii) is selected from HCl, sulfuric acid, formic acid, acetic acid, perchloric acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, trifluoro acetic acid, UBK530 resin, cationic exchange resin or mixtures thereof.
- the sodium exchanging reagent is selected from sodium acetate, sodium citrate, sodium lactate, sodium ethylacetoacetate and sodium 2-ethylhexanoate and the solvent used for dissolving the reagent is selected from ethanol, methanol, isopropanol, acetonitrile, ethyl acetate, acetone, water or mixtures thereof.
- novel salts prepared in accordance with this invention is useful in the isolation of cephalosporin antibiotics such as Cefonicid ,Cefdinir ,Cefoxitin,Cefditoren,Cefixime ,Cefepime in pure and good yield.
- the starting material of formula (IV) is prepared by utilizing the scheme available in the prior art.
- N,N'-diisobutylethylenediamine salt of 7-D-mandelamido-3-(((l-sulfomethyl-lH- tetrazol-5-yl)thio)methyl)-3-cephem-4-carboxylic acid (2.0 g) was charged into a mixture of isopropyl alcohol (20 mL) and acetone (4 mL) followed by UBK-530 resin (5 g) and stirred the reaction mixture for 2-4 hours at 25-3O 0 C. The reaction mixture was filtered and washed the resin using acetone(10 mL).
- N j N'-dicyclohexylethylenediamine salt of 7-D-mandelamido-3-(((l-sulfomethyl- lH-tetrazol-5-yl)thio)methyl)-3-cephem-4-carboxylic acid (2.0 g) was charged into a mixture of isopropyl alcohol (20 mL) and acetone (4 mL) followed by UBK-530 resin (5 g) at 25-30°C and stirred for 2-4 hours , filtered the reaction mass and washed the resin with acetone (10 mL).
- Example 3 Step(i) N,N'-Di-(p-anisvDethvIenediamme salt of 7-D-mandelamido-3-(((l- suIfomethyI-JJ?-tetrazol-5-vI)thio)methvI)-3-cephem-4-carboxylic acid
- N,N'-di-(p-anisyl)ethylenediamine salt of 7-D-mandelamido-3-(((l-sulfomethyl- lH-tetrazol-5-yl)thio)methyl)-3-cephem-4-carboxylic acid (2.0 g) was charged into a mixture of isopropyl alcohol (20 mL) and acetone (4 mL) followed by UBK-530 resin (5 g) at 25-30°C and stirred for 2-4 hours. The reaction mixture was filtered, washed with acetone (10 mL).
- ethyl acetate layer was washed with 20% sodium chloride solution (20 g of NaCl in 100 ml of water) and separated.
- the ethyl acetate layer was added dropwise in 20 min at 32+2 0 C to a solution of N,N'-dicyclohexylethane- 1,2-diamine in a mixture of acetonitrile (300 ml) and methanol (50 ml) and stirred for 25 min.
- NjN'-dicyclohexylethane-l ⁇ -diammonium 7 ⁇ -[2-(2-amino-4- thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-vinyI-3-cephem-4-carboxylate from N,N'-dicyclohexylethane-l,2-diammonium 7 ⁇ -[2-(2-amino-4-thiazolyI)-2- (Z-trityloxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylate
- reaction mixture was heated to 60-62 0 C in 20 minutes, hydrochloric acid (34 ml, 1 : 1 v/v) and maintained at this temperature for 35 minutes.
- hydrochloric acid 34 ml, 1 : 1 v/v
- the carbon was filtered and the carbon bed was washed with acetone (100 ml).
- N,N'-dicyclohexyIethane-l,2-diammonium 7 ⁇ -[2-(2-amino-4-thiazolyl)- 2-(Z-hydroxyimino)acetamido]-3-vinyI-3-cephem-4-carboxyIate (20 gm) was added to a solution of acetone 80 ml in water 600 ml at 32-36 0 C, dissolved by hydrochloric acid (25 ml) at pH 1.25 to 1.75 in 5-10 minutes, and adjust the pH to 5.4-5.6 by ammonia (15 ml 15%). The aqueous solution was treated with carbon and EDTA at 30-34 0 C for 30 min.
- reaction mixture was acidified with cone. HCl (15-16mL) and maintained the reaction at 28-3O 0 C for about 2-3 hrs.
- mixture of Methylene dichloride and Tetrahydrofuran are charged and separated the aqueous layer.
- Aqueous layer pH was adjusted to 4.0 using 15 % ammonia solution at 28-30 °C for a period of 0.5-1.0 hour .
- the reaction mass solution was added to a solution of N,N'-diisopentylethylenediamine diacetate (20.2 g) in water (88 niL) in presence of Tetrahydrofuran and stirred well at 25-30°C for about 2-3 hours.
- Aqueous layer pH was adjusted to 4.0 using 15 % ammonia solution at 28-30 °C for a period of 0.5-1.0 hour .
- the reaction mass solution was added to a solution of N,N'-(p-tolyl)ethylenediamine diacetate (23 g) in water (92 mL) in presence of
- Cefdinir -DDA (10Og) was stirred in a mixture of acetone (20OmL) and water (3.0 Lt) at 35-38°C,pH of the solution was adjusted to 1.5 using 1: 1 HCl in 5-10 minutes then pH of the solution was readjusted to 6.0 using aqueous ammonia solution (70 mL) at 35-38 °C.
- carbon (1Og) was added stirred for 20 -25 minutes and filtered. pH of the clear filtrate was adjusted to 2.5 with 1:1 hydrochloric acid (5OmL) to precipitate Cefdinir. The precipitate was stirred for 3.0 hrs at 30-35 0 C, filterd and washed the wet cake with water (50OmL). Wet material is dried under vacuum to get 46.0 g of Cefdinir.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05759084A EP1765833A2 (en) | 2004-07-05 | 2005-07-04 | News salts in the preparation of cephalosporin antibiotics |
US11/631,595 US7741478B2 (en) | 2004-07-05 | 2005-07-04 | Salts in the preparation of cephalosporin antibiotics |
JP2007519899A JP4856795B2 (en) | 2004-07-05 | 2005-07-04 | Novel salts in the production of cephalosporin antibiotics. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN637CH2004 | 2004-07-05 | ||
IN637/CHE/2004 | 2004-07-05 |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2006006040A2 true WO2006006040A2 (en) | 2006-01-19 |
WO2006006040A3 WO2006006040A3 (en) | 2006-09-21 |
WO2006006040B1 WO2006006040B1 (en) | 2006-11-02 |
Family
ID=35784230
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2005/001888 WO2006006040A2 (en) | 2004-07-05 | 2005-07-04 | News diamine salts of cephalosporin antibiotics and their preparation |
Country Status (6)
Country | Link |
---|---|
US (1) | US7741478B2 (en) |
EP (1) | EP1765833A2 (en) |
JP (1) | JP4856795B2 (en) |
KR (1) | KR20070045195A (en) |
CN (1) | CN101031574A (en) |
WO (1) | WO2006006040A2 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7244842B2 (en) * | 2002-11-15 | 2007-07-17 | Orchid Chemicals & Pharmaceuticals Ltd. | Amorphous hydrate of a cephalosporin antibiotic |
US7250508B2 (en) | 2002-08-13 | 2007-07-31 | Sandoz Ag | Cefdinir intermediate |
US7405294B2 (en) * | 2002-10-01 | 2008-07-29 | Antibioticos S.P.A. | Intermediate cefdinir salts |
CN110204556A (en) * | 2019-07-16 | 2019-09-06 | 重庆医药高等专科学校 | (RS)-methoxyl group Cefoxitin preparation method |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006134607A1 (en) * | 2005-06-15 | 2006-12-21 | Hetero Drugs Limited | Cefdinir process |
KR101049912B1 (en) * | 2009-02-24 | 2011-07-19 | (주)닥터소프트 | Connection method between network systems |
CN105294734B (en) * | 2015-10-16 | 2018-02-13 | 华北制药河北华民药业有限责任公司 | A kind of method for preparing cefonicid dibenzylethylenediamsalt salt |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3129224A (en) * | 1962-11-23 | 1964-04-14 | Smith Kline French Lab | Antimicrobial 3-methyl-7-aminodecepha-losporanic acid derivatives |
US20050215781A1 (en) * | 2004-03-17 | 2005-09-29 | Orchid Chemicals & Pharmaceuticals Ltd. | Novel polymorph of cefdinir |
WO2005090360A1 (en) * | 2004-03-19 | 2005-09-29 | Orchid Chemicals & Pharmaceuticals Limited | Novel polymorph of cefdinir |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1348985A (en) * | 1970-06-16 | 1974-03-27 | Merck & Co Inc | Esters of cephalosporin compounds |
US4058661A (en) * | 1973-05-03 | 1977-11-15 | Merck & Co., Inc. | 7-Diacyl cephalosporins |
AT381495B (en) * | 1984-03-29 | 1986-10-27 | Biochemie Gmbh | METHOD FOR PRODUCING CEPHALOSPORINE DERIVATIVES |
IT1234385B (en) | 1989-05-23 | 1992-05-18 | Sbd Synthetic And Biolog Devel | IMPROVED PROCEDURE FOR THE PRODUCTION OF AN ANTIBIOTIC SUBSTANCE BELONGING TO THE CEPHALOSPORINE GROUP |
US5705496A (en) | 1994-03-24 | 1998-01-06 | Smithkline Beecham Corporation | Crystalline benzathine salt of cefonicid and its preparation |
AT405283B (en) | 1997-04-04 | 1999-06-25 | Biochemie Gmbh | 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 |
JP3933244B2 (en) * | 1997-04-04 | 2007-06-20 | 株式会社資生堂 | Alkylenediamine derivatives and anti-ulcer agents, antibacterial agents |
ITMI20022076A1 (en) * | 2002-10-01 | 2004-04-02 | Antibioticos Spa | INTERMEDIATE SALTS OF CEFDINIR. |
US20090036672A1 (en) * | 2002-10-01 | 2009-02-05 | Antibioticos S.P.A. | Intermediate cefdinir salts |
AU2003276525A1 (en) * | 2002-11-15 | 2004-06-15 | Orchid Chemicals And Pharmaceuticals Ltd | Novel amorphous hydrate of a cephalosporin antibiotic |
EP1848724A2 (en) * | 2005-10-31 | 2007-10-31 | Teva Pharmaceutical Industries Ltd | Process for the preparation of cefdinir |
-
2005
- 2005-07-04 KR KR1020077001291A patent/KR20070045195A/en not_active Application Discontinuation
- 2005-07-04 CN CNA2005800266146A patent/CN101031574A/en active Pending
- 2005-07-04 EP EP05759084A patent/EP1765833A2/en not_active Withdrawn
- 2005-07-04 WO PCT/IB2005/001888 patent/WO2006006040A2/en active Application Filing
- 2005-07-04 JP JP2007519899A patent/JP4856795B2/en not_active Expired - Fee Related
- 2005-07-04 US US11/631,595 patent/US7741478B2/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3129224A (en) * | 1962-11-23 | 1964-04-14 | Smith Kline French Lab | Antimicrobial 3-methyl-7-aminodecepha-losporanic acid derivatives |
US20050215781A1 (en) * | 2004-03-17 | 2005-09-29 | Orchid Chemicals & Pharmaceuticals Ltd. | Novel polymorph of cefdinir |
WO2005090360A1 (en) * | 2004-03-19 | 2005-09-29 | Orchid Chemicals & Pharmaceuticals Limited | Novel polymorph of cefdinir |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7250508B2 (en) | 2002-08-13 | 2007-07-31 | Sandoz Ag | Cefdinir intermediate |
US7825241B2 (en) | 2002-08-13 | 2010-11-02 | Sandoz Ag | Cefdinir intermediate |
US7405294B2 (en) * | 2002-10-01 | 2008-07-29 | Antibioticos S.P.A. | Intermediate cefdinir salts |
US7244842B2 (en) * | 2002-11-15 | 2007-07-17 | Orchid Chemicals & Pharmaceuticals Ltd. | Amorphous hydrate of a cephalosporin antibiotic |
CN110204556A (en) * | 2019-07-16 | 2019-09-06 | 重庆医药高等专科学校 | (RS)-methoxyl group Cefoxitin preparation method |
Also Published As
Publication number | Publication date |
---|---|
US20080306256A1 (en) | 2008-12-11 |
EP1765833A2 (en) | 2007-03-28 |
WO2006006040B1 (en) | 2006-11-02 |
JP4856795B2 (en) | 2012-01-18 |
CN101031574A (en) | 2007-09-05 |
WO2006006040A3 (en) | 2006-09-21 |
US7741478B2 (en) | 2010-06-22 |
JP2008505169A (en) | 2008-02-21 |
KR20070045195A (en) | 2007-05-02 |
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