EP1399429A1 - 1,3,4-oxadiazol-2-yl thioesters et leur utilisation pour l'acylation de 7-aminocephalosporines - Google Patents

1,3,4-oxadiazol-2-yl thioesters et leur utilisation pour l'acylation de 7-aminocephalosporines

Info

Publication number
EP1399429A1
EP1399429A1 EP01949861A EP01949861A EP1399429A1 EP 1399429 A1 EP1399429 A1 EP 1399429A1 EP 01949861 A EP01949861 A EP 01949861A EP 01949861 A EP01949861 A EP 01949861A EP 1399429 A1 EP1399429 A1 EP 1399429A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
cephalosporin
oxo
methoxyimino
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP01949861A
Other languages
German (de)
English (en)
Inventor
Pandurang Balwant Deshpande
Parven Kumar Luthra
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Orchid Pharma Ltd
Original Assignee
Orchid Chemicals and Pharmaceuticals Ltd
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
Application filed by Orchid Chemicals and Pharmaceuticals Ltd filed Critical Orchid Chemicals and Pharmaceuticals Ltd
Publication of EP1399429A1 publication Critical patent/EP1399429A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • 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

Definitions

  • the present invention relates to novel thioester derivatives of the general formula (I) prepared by the reaction of 4-halogeno-2-methoxyimino-3-oxo-butyric acid (II) with 5- substituted-l,3,4-oxadiazole-2-thiol of formula (III).
  • the invention also discloses the use of the new intermediate (I) for the preparation of cephalosporanic antibiotics (VI) in excellent yields and purity.
  • R ⁇ represents - C 4 alkyl or phenyl
  • Acid chlorides, anhydrides, esters, amide etc. are reported in the chemical literature for activation of carboxylic acid of formula (IV) . Activation in the form of acid chloride required protection and deprotection of NH 2 group.
  • US patent 4,767,852 discloses a process for production of cephems by acylating 7-amino- 3-cephem-4-carboxylic acid with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2- methoxyiminoacetate (MAEM).
  • US Pat.No.5,026,843 disclosed a process for preparing ceftriaxone disodium hemiheptahydrate by acylation of 7-amino-3-[[(2,5- dihydro-6-hydroxy-2-methyl-5-oxo-l,2,4-triazin-3yl)thio]methyl]3-cephem-4-carboxylic acid (ACT) by using MAEM as acylating agents in good yield and quality.
  • MAEM has become the standard acylating agent for the preparation of cephalosporins having an oximino group and a 2-aminothiazolyl group in 7-position of cephem compounds.
  • 0 842 937 discloses the formation of amide bond with cephem moiety by reacting with the thioester derivative prepared by using 2,2'-dithio-bis-benzothiazole.
  • the preparation of this active thioester involves use of same costly condensing agent triphenylphosphine (TPP) which has been mentioned earlier in the text.
  • TPP triphenylphosphine
  • 4-halogeno - 2 - methoxyimino-3-oxo-butyric acid represented by formula (II) also suffer with almost in same disadvantages which are commonly prevalent for 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (IV).
  • the primary objective of the invention is to provide new reactive thioester derivatives of 4- halogeno-2-methoxyimino-3-oxo-butyric acid of the general formula (I), which would be suitable for being used in the manufacture of cephalosporin antibiotics and would not be associated with the complexities mentioned above.
  • Another objective of the present invention is to provide a process for the preparation of above mentioned new thioesters (I) in good yields.
  • One more objective of the present invention is to provide a process for the preparation of cephalosporin antibiotics of the general formula (VI) from the said novel thioester derivatives.
  • Another objective of the present invention is to provide a process for the preparation of cephalosporin antibiotics e.g. cefotaxime, ceftriaxone, cefetamet, ceftiofur, cefpodoxime etc. which comprises condensation of new reactive derivatives (I) with cephem compounds (V) and insitu cyclisation with thiourea to obtain targeted antibiotics(VI) in excellent yields and purity.
  • Still another objective of the present invention is to produce cephalosporin antibiotics that are highly pure and free from toxic byproducts.
  • the present invention provides novel thioester derivatives of 4-halogeno-2-methoxyimino- 3-oxo-butyric acid of the general formula (I) also , the invention provides a method by which the said thioester derivatives can be prepared by reacting of 4-halogeno-2- methoxyimino-3-oxo-butyric acid of the general formula (II) with 2-mercapto-5- substituted- 1,3, 4-oxadiazole of the general formula (III) (preparation of m, J. Am. Chem.
  • the present invention provides new thioesters of 4-halogeno-2-methoxyimino-3-oxo- butyric acid of general formula (I).
  • the synthesis of compound (I) is achieved by preparing activated complex of 4-halogeno-2-methoxyimino-3-oxo-butyric acid (II) with DMF-POCI 3 followed by the reaction with thio-oxadiazoles of the general formula (III) in organic solvent in presence of an organic base at the temperature between -30°C and +20°C.
  • the reactive active ester is obtained quantitative yields (95-99%).
  • Ri represents C 1 -C alkyl or phenyl
  • the reactive thioester were characterized by NMR, IR and Mass spectra . A major side
  • X is chloro , bromo or iodo.
  • the organic solvent is selected from the group comprising dichloromethane, tetrahydrofuran, dioxane, N,N-dimethylformamide, acetonitrile and mixtures thereof.
  • the organic base is selected from the group comprising triethylamine, diethylamine, tributylamine, pyridine, N-alkylanilines, and mixtures thereof.
  • cephalosporin antibiotics obtained are of high purity (90-99%).
  • the method gives an excellent yield (70-95%) of cephalosporin without necessitating the protection of the amino group of the acylating agents, and the toxic byproduct 2-mercaptobenzothiazole is not produced.
  • the cephalosporin antibiotic were synthesized by following two methods: Method-I The reactive thioester (I) was reacted with 7-aminocephem compound (V)
  • Ri represents - alkyl or phenyl
  • R 2 represents H , CH 3 , CH 2 OCH 3 , CH 2 OCOCH 3 ,
  • R 3 is hydrogen, salt or carboxylic protecting group.
  • R is hydrogen or silyl. in organic solvent in the presence of base to obtained condensed product , which was not isolated and is directly cyclised with thiourea in mixture of water and a polar organic solvent like tetrahydrofuran, dimethylformamide, dioxane, alcohol to obtain desired cephalosporanic antibiotics of very good purity and excellent yields.
  • Method -II In this approach, starting from active ester of formula (I) final product was prepared in one pot reaction.
  • the process comprises cyclization of active ester in the first step and in same reactor addition of amino cephem compound in mixture of water and a polar organic solvent like tetrahydrofuran, dimethylformamide, dioxane, alcohols to obtain desired cephalosporanic antibiotics of equally good purity and yields as compared to first approach.
  • This approach provides a simple , cheap and commercially viable method without the necessity of isolating thioester and without producing any toxic byproduct namely 2-mercaptobenzothiazole.
  • the substituent R 2 in cephem compound (V) and (VI) represents hydrogen, methyl, acetyloxymethyl, methoxymethyl, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo- 1 ,2,4-triazine-3- thiol, furanyl-2-carbonyl thiol or a standard cephalosporin substituents.
  • R 3 in cephem compound (V) and (VI) represents hydrogen , salt or a ester group which can be easily removed e.g. p-methoxybenzyl , p-nitrobenzyl , diphenylmethyl , phenacyl , trimethylsilyl etc.
  • the organic base may be selected from the group consisting of triethylamine, N-methylmorpholine, pyridine, N-methylanilines, 1,5- diazabicyclo[4.3.0] non-5-ene, l,4-diazabicyclo[2.2.2]octane, 4-dimethylaminopyridine, and mixtures thereof.
  • the aqueous layer is subjected for charcoal treatment.
  • Thiourea (18.4g) and sodium acetate (4.2g) were added to the filtered aqueous layer and stirred for 1.0 hr to get the cefotaxime which was isolated with subsequent acidification of the aqueous layer with dil. HC1 at 10°C to pH 3.0.
  • the solid separated was filtered, washed with water and ethylacetate and then dried under vacuum at 40-45°C to get Cefotaxime, 40.9g (yield 98%).
  • Example -5 7-[[(Z)-2-(Aminothiazol-4-yl)-2-methoxyimino]acetamido]-3-methoxymethyl-3-cephem- 4-carboxylic acid [Cefpodoxime acid].

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

L'invention concerne des composés de la formule I suivante, dans laquelle X représente halogène et R1 alkyle ou phényle, que l'on utilise dans la préparation de céphalosporines de la formule VI par acylation et cyclisation de thiourée.
EP01949861A 2001-06-14 2001-06-14 1,3,4-oxadiazol-2-yl thioesters et leur utilisation pour l'acylation de 7-aminocephalosporines Withdrawn EP1399429A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2001/000113 WO2003004477A1 (fr) 2001-06-14 2001-06-14 1,3,4-oxadiazol-2-yl thioesters et leur utilisation pour l'acylation de 7-aminocephalosporines

Publications (1)

Publication Number Publication Date
EP1399429A1 true EP1399429A1 (fr) 2004-03-24

Family

ID=11076356

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01949861A Withdrawn EP1399429A1 (fr) 2001-06-14 2001-06-14 1,3,4-oxadiazol-2-yl thioesters et leur utilisation pour l'acylation de 7-aminocephalosporines

Country Status (2)

Country Link
EP (1) EP1399429A1 (fr)
WO (1) WO2003004477A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005040175A2 (fr) * 2003-10-22 2005-05-06 Ranbaxy Laboratories Limited Procede de preparation d'acides carboxyliques de type cephem
CN102993216A (zh) * 2013-01-06 2013-03-27 瑞普（天津）生物药业有限公司 盐酸头孢噻呋的一种制备方法
CN104876948A (zh) * 2015-05-28 2015-09-02 华北制药河北华民药业有限责任公司 一种头孢曲松钠的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI67385C (fi) * 1979-11-21 1985-03-11 Hoffmann La Roche Foerfarande foer framstaellning av (6r 7r)-7-(2-(2-amino-4-tiazolyl)-2-(z-metoxiimino)acetamido)-3-cefem-4-karboxylsyraderivat
CY1365A (en) * 1980-03-28 1987-08-07 Biochemie Gmbh New process for the production of cephalosporin antibiotics, and novel intermediates used in such process and their production
IN184690B (fr) * 1996-03-18 2000-09-23 Ranbaxy Lab Ltd
IT1286494B1 (it) * 1996-11-19 1998-07-15 Hichem Pharma S P A Procedimento per la preparazione di derivati cefalosporanici

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03004477A1 *

Also Published As

Publication number Publication date
WO2003004477A1 (fr) 2003-01-16

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