WO2003089406A1 - Procede de preparation d'un produit intermediaire de cephalosporine et son utilisation pour la fabrication de composes de cephalosporine - Google Patents

Procede de preparation d'un produit intermediaire de cephalosporine et son utilisation pour la fabrication de composes de cephalosporine Download PDF

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Publication number
WO2003089406A1
WO2003089406A1 PCT/IB2002/004119 IB0204119W WO03089406A1 WO 2003089406 A1 WO2003089406 A1 WO 2003089406A1 IB 0204119 W IB0204119 W IB 0204119W WO 03089406 A1 WO03089406 A1 WO 03089406A1
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Prior art keywords
formula
process according
methyl
compound
chlorine
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PCT/IB2002/004119
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English (en)
Inventor
Pandurang Balwant Deshpande
Parven Kumar Luthra
Pratik Ramesh Sathe
Sivakumaran Sundaravadivelan
Praven Nagesh Ganesh
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Orchid Chemicals And Pharmaceuticals Limited
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Priority to AU2002337437A priority Critical patent/AU2002337437A1/en
Publication of WO2003089406A1 publication Critical patent/WO2003089406A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/14—Esters of phosphoric acids containing P(=O)-halide groups
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/095—Compounds containing the structure P(=O)-O-acyl, P(=O)-O-heteroatom, P(=O)-O-CN
    • C07F9/096—Compounds containing the structure P(=O)-O-C(=X)- (X = O, S, Se)

Definitions

  • the present invention relates to a process for the preparation of 4-halogeno-2- substituted imino-3-oxo-butyric acid of general formula (I)
  • Rt represents CH 3 , CR a R b COOR c where R and R b independently represent hydrogen or methyl and R c represents hydrogen or (C 1 -C 6 )alkyl;
  • X represents halogen such as chlorine or bromine.
  • the invention also discloses the activation of this acid and its further use in the preparation of cephalosporin antibiotic of formula (II) or its solvates in excellent yields and purity.
  • R 3 is carboxylate ion or COOR , where R d represents hydrogen, esters which form a prodrug or a counter ion which forms a salt.
  • US patent number 5,095,149 describes a process for the preparation of 4-halogeno- 2- methoxyimino-3-oxo-butyric acid of formula (I) by brominating the methoxy imino compound of general formula (III) by bromine in mixture of D?E and ethylene dichloride.
  • Ethylene dichloride is a toxic solvent and hence its use in the preparation of pharmaceuticals has to be avoided.
  • EP 0030294 discloses the condensation of the 4- halogeno-2-substituted imino-3-oxo-butyric acid represented by formula (I) with cephem carboxylic acids by using PC1 5 .
  • Another EP patent 0 842 937 discloses the formation of amide bond with cephem moiety by reacting with the thioester derivative of 4-chloro-2- methoxyimino-3-oxo-butyric acid.
  • the thioester was prepared by reacting 4-chloro-2- methoxyimino-3-oxo-butyric acid with 2,2'-dithio-bis-benzothiazole in the presence of triphenyl phosphine which is a costly material and its by product triphenyl phosphine oxide is also difficult to remove from the reaction mixture.
  • the primary objective of the invention is to provide a new process for the preparation of 4-halogeno-2-substituted imino-3-oxo-butyric acid of the general formula (I), which would be suitable for being used in the manufacture of cephalosporin antibiotic, which would be easy to implement in commercial scales.
  • Another objective of the present invention is to provide a process for the preparation of 4-halogeno-2-substituted imino-3-oxo-butyric acid of the general formula (I), in good yields with high purity.
  • Another objective of the present invention is to carry out the halogenation by photochemical irradiation which would give higher yield and halogenation can also be achieved in presence or absence of solvents thus making the process more environmental friendly.
  • Another objective of the present invention is to provide a process for the preparation of cephalosporin antibiotics e.g. cefotaxime, ceftriaxone, cefetamet, ceftiofur, cefditoren, cefpodoxime, ceftadizime, cefepime, cefixime, cefmenoxime, cefodizime, cefoselis, cefquinome, cefpirome, cefteram, cefuzonam etc. which comprises use of 4- halogeno-2-substituted imino-3-oxo-butyric acid of the general formula (I), prepared by the process of the present invention.
  • the present invention provides a process for the preparation of 4- halogeno-2-substituted imino-3-oxo-butyric acid of formula (I), which comprises hydrolysis and halogenation of the ester of formula (III) by photochemical irradiation in one pot using a halogenating agent in the absence or presence of a solvent at a temperature in the range of-20°C to 30°C.
  • the reaction is as shown in the Scheme-1 below:
  • Alk group represents (C ⁇ -C 4 )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso- butyl.
  • X represents halogen such as chlorine or bromine
  • Rt represents CH 3
  • R a and R b independently represent hydrogen or methyl and R c represents hydrogen or (C 1 -C 6 )alkyl and X' represents an activating group such as
  • Alk group represents (C ⁇ C 4 )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso- butyl.
  • the solvent used in step (i) is selected from diisopropyl ether, dichloromethane, acetic acid and mixtures thereof.
  • the halogenating agent used is chlorine or bromine.
  • the light source used for photochemical halogenation is IR or UV radiation, preferably UV radiation.
  • the activation in step (ii) is carried out using PC1 5 , DMF/POCl 3 , oxalyl chloride, SOCl 2 /DMF, diphenylchlorophosphoridate, dialkyl chlorophosphoridate, in the presence of a solvent selected from halogenated alkanes, ethyl acetate, tetrahydrofuran, aromatic hydrocarbons, acetone, acetonitrile, dialkylethers or mixtures thereof.
  • a solvent selected from halogenated alkanes, ethyl acetate, tetrahydrofuran, aromatic hydrocarbons, acetone, acetonitrile, dialkylethers or mixtures thereof.
  • condensation in step (iii) is carried out in the presence of a solvent selected from halogenated alkanes, ethyl acetate, tetrahydrofuran, aromatic hydrocarbons, acetone, acetonitrile, dialkylethers or mixtures thereof.
  • a solvent selected from halogenated alkanes, ethyl acetate, tetrahydrofuran, aromatic hydrocarbons, acetone, acetonitrile, dialkylethers or mixtures thereof.
  • the cyclisation in step (iv) is carried out using a mixture of water and organic solvent selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C C 3 )alcohol or mixtures thereof, in the presence of sodium acetate.
  • organic solvent selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C C 3 )alcohol or mixtures thereof, in the presence of sodium acetate.
  • the counter ion represented by R d is alkali metal, preferably sodium.
  • the compound of formula (I) obtained is a syn-isomer.
  • the compound of formula (V), when R represents trimethylsilyl the silylation is carried out by using silylating agent selected from N,O-bis-(trimethylsilyl)acetamide(BSA), hexamethyldisilazane (HMDS) , trimethylchlorosilane (TMCS), dichlorodimethylsilane.
  • tert-butyl 2-methoxyimino-3-oxobutyrate 100 gm was dissolved and chlorine gas was introduced into the solution at 0-5°C in the presence of ultraviolet radiation over a period of 18 hours. After completion of the introduction, water (150 ml) was added and then stirred to conduct the water washing to remove the inorganic by-products.
  • Step -I Silylation of 7-amino-3-[(2-furanylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid : Methylene dichloride (100 ml) was charged to the reaction flask followed by addition of 7-amino-3-[(2-furanylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid (10.0 g) and stirred at room temperature. N, O-bis- (trimethylsilyl) acetamide (BSA) (18.0 g) was added drop wise at room temperature and continued stirring for 2-3 hrs at the same temperature.
  • BSA O-bis- (trimethylsilyl) acetamide
  • Step -II Activation of 4-chloro-2-methoxyimino-3-oxobutyric acid with PCls Methylene dichloride (60 ml) was charged in the flask followed by addition of 4-chloro-2- methoxyimino-3-oxo-butyric acid (6.3 g) obtained in example 1 or 2 and stirred at - 40°C.
  • PC1 5 (7.3g) was added portion wise at -40°C and continued stirring for 1 hr at the same temperature.
  • Tetrahydrofuran (150 ml) and water (75 ml) were charged into the reaction flask followed by the addition of condensed product (15.0 g) obtained in step (III) above, thiourea(2.7 g) and sodium acetate (8.0 g). Stirred the reaction mixture at room temperature for 3 hrs. The progress of the reaction was monitored by HPLC. After completion of reaction, sodium chloride (145.0 g) was added to the reaction mixture and stirred at room temperature for 30 min. The tetrahydrofuran layer was separated and was added THF (240 ml), charcoal (5.0 g) stirred for 1 hr at room temperature.
  • Step -I Silylation of 7-amino-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-l,2,4-triazin-3- yl)thiomethyl]-3-cephem-4-carboxylic acid : Methylene dichloride (70 ml) was charged to the reaction flask followed by addition of 7- amino-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-l,2,4-triazin-3-yl) thio methyl ]- 3- cephem-4-carboxylic acid (5.0 g, 1.0 mol) and stirred at room temperature.
  • Step -III Condensation of activated 4-chloro-2-methoxyimino-3-oxo-butyric acid and silylated 7-amino-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-l,2,4-triazin-3-yl) thiomethyl]-3- cephem-4-carboxylic acid
  • Step -II Activation of 4-chloro-2-methoxyimino-3-oxobutyric acid with PCI 5 Methylene dichloride (30 ml) was charged in the flask followed by addition of 4-chloro-2- methoxyimino-3-oxo-butyric acid (7.2 gm, 1.1 mol) obtained in example 1 or 2 and stirred at - 30°C.
  • PCI 5 (9.3 gm, 1.1 mol) was added portion wise at -30°C and continued stirring for 1 hr at the same temperature.
  • Step -III Condensation of activated 4-chloro-2-methoxyimino-3-oxobutyric acid and silylated 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid
  • Step-II Activation of 4-chloro-2-methoxyimino-3-oxobutyric acid with DMF/POCI 3
  • a suspension of vilsmeir reagent prepared from POCI 3 (3.58 gm,1.4 mol) and DMF (1.71 gm, 1.4 mol) in acetonitrile (24 ml) was added 4-chloro-2-methoxyimino-3-oxo butyric acid (3.0 gm, 1.0 mol) obtained in example 1 or 2 under ice-cooling at 0-5°C.
  • the mixture was stirred at the same temperature for 30 minutes.
  • Step -III Condensation of activated 4-chloro-2-methoxyimino-3-oxobutyric acid and silylated 7-amino-3-[(2-furanylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid
  • Silylated 7- amino-3-[(2-furanylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid obtained in step (I) above was added to the activated acid solution obtained in step (II) above at -25°C.
  • the separated organic layer was washed with water (75 ml).
  • the organic solution was dried and condensed under reduced pressure to give 5.0 gm of the required product.
  • Tetrahydrofuran (50 ml) and water (25 ml) were charged into the reaction flask followed by the addition of condensed product (5.0 gm) obtained in step (III) above, thiourea(0.9 gm) and sodium acetate (2.8 gm). Stirred the reaction mixture at room temperature for 3 hrs. The progress of the reaction was monitored by HPLC. After completion of reaction, sodium chloride (48.0 gm) was added to the reaction mixture and stirred at room temperature for 30 min. The tetrahydrofuran layer was separated and was added THF (80 ml), charcoal (0.5 gm) stirred for 1 hr at room temperature.
  • Step-I Synthesis of diethyl -(4-chloro-2-methoxyimino-3-oxabutrate) phosphoridate 4-chloro-2-methoxyimino-3-oxobutyric acid (3.0 gm) obtained in example 1 or 2 was suspended in dichloromethane (24 ml) . Triethylamine (0.90 gm) was added into this solution and then diethylchlorophosphoridate (24.52 gm) was also added thereto over 20 minutes while maintaining the solution under nitrogen atmosphere at 0°C to 5°C. The mixture was stirred for 2 hours. After the reaction was completed, distilled water (25 ml) was added to the reaction solution and the mixture was stirred for 5 minutes.
  • Step -III Condensation of diethyl-(4-chIoro-2-methoxyimino-3-oxabutrate) phosphoridate and silylated 7-amino-3-[(2-furanylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid 5
  • the suspension of the activated reagent obtained in step (I) above was added to the silylated 7-amino-3-[(2-furanylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid obtained in step (II) above at -25°C.
  • ice-water (25 ml) was added.
  • the separated organic layer was washed with water (75 ml).
  • the organic solution was dried and condensed under reduced pressure to give 7.5 gm of the required 0 product.
  • Tetrahydrofuran (50 ml) and water (25 ml) were charged into the reaction flask followed by the addition of condensed product (5.0 gm) obtained in step (III) above, thiourea (0.9 gm) and sodium acetate (2.8 gm). Stirred the reaction mixture at room temperature for 3 hrs. The progress of the reaction was monitored by HPLC. After completion of reaction, sodium chloride (48.0 gm) was added to the reaction mixture and stirred at room temperature for 30 min. The tetrahydrofuran layer was separated and was added THF (80 ml), charcoal (0.5 gm) stirred for 1 hr at room temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'acide imino-3-oxo-butyrique 4-halogéno-2-substitué de formule (I), dans laquelle R1 représente CH3, CRaRbCOORc, où Ra et Rb représentent indépendamment hydrogène ou méthyle et Rc représente hydrogène, ou alkyle C1-C6, et X représente un halogène tel que le chlore ou le brome. L'invention concerne également l'activation de cet acide ainsi que son utilisation dans la préparation d'antibiotiques céphalosporaniques (II) présentant une pureté élevée avec un excellent rendement.
PCT/IB2002/004119 2002-04-19 2002-10-08 Procede de preparation d'un produit intermediaire de cephalosporine et son utilisation pour la fabrication de composes de cephalosporine WO2003089406A1 (fr)

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AU2002337437A AU2002337437A1 (en) 2002-04-19 2002-10-08 A process for the preparation of cephalosporin intermediate and its use for the manufacture of cephalosporin compounds

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IN305CH2002 2002-04-19
IN305/MAS/2002 2002-04-19

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Cited By (2)

* 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
CN102977123A (zh) * 2012-12-03 2013-03-20 邓世碧 一种头孢类化合物及其药学可接受盐

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0030294A2 (fr) * 1979-11-21 1981-06-17 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Procédé de préparation de dérivés de céphalosporine; intermédiaires et leur préparation
EP0324418A2 (fr) * 1988-01-14 1989-07-19 Takeda Chemical Industries, Ltd. Méthode pour la production de t-butyl-3-oxobutyrates et leur application
EP0416857A2 (fr) * 1989-09-04 1991-03-13 Wako Pure Chemical Industries Ltd Procédé de préparation d'acides gras 4-halogéno-2-alkoximino-3-oxo
US20020028931A1 (en) * 2000-08-14 2002-03-07 Ramesh Dandala Ceftiofur, its intermediate and a process for the preparation of the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0030294A2 (fr) * 1979-11-21 1981-06-17 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Procédé de préparation de dérivés de céphalosporine; intermédiaires et leur préparation
EP0324418A2 (fr) * 1988-01-14 1989-07-19 Takeda Chemical Industries, Ltd. Méthode pour la production de t-butyl-3-oxobutyrates et leur application
EP0416857A2 (fr) * 1989-09-04 1991-03-13 Wako Pure Chemical Industries Ltd Procédé de préparation d'acides gras 4-halogéno-2-alkoximino-3-oxo
US20020028931A1 (en) * 2000-08-14 2002-03-07 Ramesh Dandala Ceftiofur, its intermediate and a process for the preparation of the same

Cited By (4)

* 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
WO2005040175A3 (fr) * 2003-10-22 2005-07-28 Ranbaxy Lab Ltd Procede de preparation d'acides carboxyliques de type cephem
CN102977123A (zh) * 2012-12-03 2013-03-20 邓世碧 一种头孢类化合物及其药学可接受盐
CN102977123B (zh) * 2012-12-03 2015-04-29 邓世碧 一种头孢类化合物及其药学可接受盐

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