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WO1996017847A1 - Procede de preparation de cephalosporines et analogues - Google Patents

Procede de preparation de cephalosporines et analogues Download PDF

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Publication number
WO1996017847A1
WO1996017847A1 PCT/GB1995/002783 GB9502783W WO9617847A1 WO 1996017847 A1 WO1996017847 A1 WO 1996017847A1 GB 9502783 W GB9502783 W GB 9502783W WO 9617847 A1 WO9617847 A1 WO 9617847A1
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formula
group
compound
alkyl
acid
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George Burton
Antoinette Naylor
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Pfizer Corp Belgium
Pfizer Corp SRL
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Pfizer Corp Belgium
Pfizer Corp SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; 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
    • C07D463/00—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D463/02—Preparation
    • C07D463/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D463/08—Modification of a carboxyl group directly attached in position 2, e.g. esterification
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to novel processes for the preparation of cephalosporins. These cephalosporins have antibacterial properties, and are therefore of use in the treatment of bacterial infections in humans and animals caused by a wide range of organisms.
  • the invention also relates to novel intermediates formed in the course of the process.
  • R2 is an acyl group, in particular that of an antibacterially active cephalosporin;
  • R3 is a pharmaceutically acceptable in, vivo hydrolysable ester group;
  • R 4 represents hydrogen or up to four substituents selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, halogen, amino, alkylamino, acylamino, dialkylamino, CO2 . CONR2, SO2N 2 (where R is hydrogen or C .Q alkyl), aryl and heterocyclyl, which may be the same or different and wherein any R 4 alkyl substituent is optionally substituted by any other
  • R 4 substituent; X is S,SO,S ⁇ 2,0 or CH2; m is 1 or 2; and n is 0.
  • PCT/GB91 01228 also discloses process for the preparation of compounds of formula (I).
  • the present invention provides a process for the preparation of compounds of formula (I) as defined above, wherein an acid of formula (II): 96/17847
  • Rl, R 4 , X, m and n are as defined in formula (I) above, and R21 is a group R2 as defined above or an amino-substituting or amino-protecting group different to R2, is reacted with a compound of formula (III):
  • Y is a halide radical, in an organic solvent which is at least partially immiscible with water, in the presence of an aqueous phase containing a base and a phase-transfer catalyst, to form a compound of formula (IV):
  • R*, R ⁇ , R ⁇ t ⁇ t m and n are as defined above; and then if R21 is different to R , converting the compound of formula (IV) into a compound of formula (I) as defined above; and thereafter if necessary or desired, carrying out one or more of the following steps:
  • the conversion of the compound of formula (IV) into a compound of formula (I) may for example be carried out by removal of the group R 1 and its replacement by hydrogen so as to form a 7-amino analogue of the compound of formula (IV), followed by reaction of this 7-amino analogue with an acid of formula (V):
  • the compound of formula (IV) may be converted into a compound of formula (VI):
  • Rl, R3, R 4 , X, m and n are as defined above, and A" is a counter anion, followed by reaction of the compound of formula (VI) with an acid of formula (V) as defined above.
  • the bonding carbon atom of the cyclic ether moiety which links the ring to the cephalosporin nucleus is generally asymmetric.
  • the present invention includes either stereoisomer, as well as mixtures of both isomers.
  • the formamido group can exist in conformations wherein the hydrogen atoms of the -NH-CHO moiety are £i ⁇ - or trans-: of these the £i ⁇ . conformation normally predominates.
  • 'aryl' includes phenyl and naphthyl, each optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, C ⁇ _g alkyl, phenyl, Cj.g alkoxy, hydroxy(C ⁇ _g)alkyl, mercapto(C ⁇ _g)alkyl, halo(C ⁇ -g) alkyl, hydroxy, amino, nitro, carboxy, Cj.g alkylcarbonyloxy, alkoxycarbonyl, formyl, or
  • heterocyclyl' and 'heterocyclic' as used herein include aromatic and non-aromatic, single and fused, rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three groups selected from halogen, (C ⁇ .g)alkyl, (C ⁇ -g)alkoxy, halo(C ⁇ - g)alkyl, hydroxy, carboxy, carboxy salts, carboxy esters such as (C ⁇ __ g)alkoxycarbonyl, (C ⁇ _g)alkoxycarbonyl(C ⁇ _g)alkyl, aryl, and oxo groups.
  • Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
  • the term 'heteroaryl' refers to heteroaromatic heterocyclic rings suitably having 5 or 6 atoms in each ring.
  • a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
  • Compounds within the invention containing a heterocyclyl group may occur in two or more tautometric forms depending on the nature of the heterocyclyl group; all such tautomeric forms are included within the scope of the invention.
  • 'alkyl' 'alkenyl', 'alkynyl' and 'alkoxy include straight and branched chain groups containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl and butyl.
  • a particular alkyl group is methyl.
  • 'halogen' refers to fluorine, chlorine, bromine and iodine
  • 'halide' is used correspondingly.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups R ⁇ include those which break down readily in the human body to leave the parent acid or its salt.
  • Suitable ester groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v):
  • R a is hydrogen, C ⁇ _g alkyl, C3.7 cycloalkyl, methyl, or phenyl
  • R D is C . ⁇ alkyl, C ⁇ _g alkoxy, phenyl, benzyl, C3.7 cycloalkyl, C3.7 cycloalkyloxy, C ⁇ .g alkyl C3.7 cycloalkyl, 1-amino C ⁇ .g alkyl, or l-(C ⁇ -g alkyDamino C ⁇ .g alkyl; or R a and R ⁇ together form a 1,2-phenylene group optionally substituted by one or two methoxy groups;
  • R c represents C ⁇ .g alkylene optionally substituted with a methyl or ethyl group and R ⁇ and R e independently represent C ⁇ .g alkyl;
  • f represents C ⁇ .g alkyl;
  • R ⁇ represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, C ⁇ .g alky
  • suitable in vivo hydrolysable ester groups R ⁇ include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, ⁇ -acetoxy ethyl, ⁇ -pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)prop- 1- yl, and (l-aminoethyl)carbonyloxymethyl; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, ⁇ -ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-(alkoxycarbonyl)-2-alkenyl groups such as
  • a further suitable pharmaceutically acceptable in vivo hydrolysable ester group R3 is that of the formula:
  • R ⁇ is hydrogen, C ⁇ .g alkyl or phenyl.
  • a preferred in vivo hydrolysable ester group is the pivaloyloxymethyl ester.
  • the group X may be sulphur or an oxidised sulphur atom, i.e. a sulphoxide (SO) or sulphone (SO2) group.
  • SO sulphoxide
  • SO2 sulphone
  • X examples include S, SO, SO2 and CH2.
  • X is sulphur or CH2.
  • R is hydrogen
  • the cyclic ether at the 3-position of the cephalosporin nucleus is unsubstituted or substituted by up to three substituents, R 4 , selected from C ⁇ _g alkyl, for example methyl, C ⁇ .g alkoxy, for example methoxy, C ⁇ .g alkoxycarbonyl for example methoxycarbonyl, C ⁇ .g alkoxy C ⁇ .g alkyl, for example methoxymethyl, and C ⁇ .g alkanoyloxy C ⁇ .g alkyl, for example acetoxymethyl.
  • R 4 selected from C ⁇ _g alkyl, for example methyl, C ⁇ .g alkoxy, for example methoxy, C ⁇ .g alkoxycarbonyl for example methoxycarbonyl, C ⁇ .g alkoxy C ⁇ .g alkyl, for example methoxymethyl, and C ⁇ .g alkanoyloxy C ⁇ .g alkyl, for example acetoxymethyl.
  • R 4 selected from C ⁇ _g alkyl,
  • n 1
  • the cyclic ether is bonded to the cephalosporin nucleus at a ring carbon adjacent to the oxygen heteroatom.
  • the cyclic ether at the 3-position is a tetrahydrofuran-2-yl group, particularly an (S)-tetrahydrofuran-2-yl group.
  • Suitable acyl groups R include those of formulae (a) - (0:
  • A is C ⁇ .g alkyl, substituted C ⁇ .g alkyl, C3.g cycloalkyl, cyclohexenyl, cyclohexadienyl, an aromatic (including heteroaromatic) group, such as phenyl, substituted phenyl, thienyl, pyridyl, or an optionally substituted thiazolyl group, a C ⁇ .g akylthio group or C ⁇ .g alkyloxy;
  • Xx is a hydrogen or halogen atom, a carboxylic acid, carboxylic ester, sulphonic acid, azido, tetrazolyl, hydroxy, acyloxy, amino, ureido, acylamino, heterocyclylamino, guanidino or acylureido group;
  • A2 is an aromatic group, for example a phenyl, 2,6-dimethoxyphen
  • A4 is hydrogen, C ⁇ .galkyl, C3.8 cycloalkyl, C3.8 cycloalkyl(C ⁇ .g)alkyl, C ⁇ .g alkoxycarbonyl(C ⁇ .g) alkyl, C2-g alkenyl, carboxy(C ⁇ .g)alkyl, C2-g alkynyl, aryl or C ⁇ .galkyl substituted by up to three aryl groups.
  • R is a group (a)
  • Ax is C ⁇ .g alkyl, C3 «g cycloalkyl, cyclohexenyl, cyclohexadienyl, phenyl, substituted phenyl such as hydroxyphenyl, thienyl or pyridyl; and
  • X is a hydrogen or halogen atom, or a carboxy, carboxylic ester, azido, tetrazolyl, hydroxy, acyloxy, optionally protected amino, ureido, guanidino or acylureido group.
  • R ⁇ is a group of formula (d)
  • A2 is phenyl
  • X3 is oxygen
  • p is O.
  • R2 is a group of formula (e) or (f) suitable values for the group A3 include those commonly found in antibacterially active cephalosporins containing a hydroxyimino, substituted hydroxyimino or vinyl group in the side chain attached to position 7 of the cephalosporin nucleus, for example phenyl, thien-2-yl, thien-3-yl, fur-2-yl, fur-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 5-amino-l,2,4-thiadiazol-3-yl and 2-aminothiazol-4-yl in each of which the amino group is optionally protected.
  • suitable values for the group A3 include those commonly found in antibacterially active cephalosporins containing a hydroxyimino, substituted hydroxyimino or vinyl group in the side chain attached to position 7 of the cephalosporin nucleus, for example phenyl, thien-2-
  • Preferred groups for A3 include phenyl, 2-aminothiazol-4-yl, fur-2-yl, thien-2-yl, 2-(2-chloroacetamido)thiazol-4-yl, 2-tritylamino-thiazol-4-yl, 5-amino-l,2,4-thiadiazol-3-yl and 4-aminopyrimid-2-yl.
  • a particularly preferred group for A3 is 2-aminothiazol-4-yl.
  • Suitable values for the group A4 include hydrogen, methyl, ethyl, cyclopropylmethyl, triphenylmethyl (trityl), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, carboxymethyl, carboxypropyl and i-butoxycarbonylmethyl.
  • Preferred values for A4 in compounds of formula (I) include methyl and hydrogen. 6/17847
  • the compounds of the invention wherein R is a group of formula (e) have the svn configuration (i.e. have the group OA4 syn to the amide linkage) or are enriched in that isomer.
  • R2 is a group of formula (f)
  • the group A4 is preferably cis to the amide linkage, i.e. when group (f) is 2-amino-thiazol-4-yl, the ⁇ -configuration is preferred.
  • Certain compounds of formula (I), may, and compounds of formulae (II) and (IV) do include an amino group which is protected.
  • Suitable amino protecting groups are those well known in the art which may be removed under conventional conditions without disruption of the remainder of the molecule.
  • amino protecting groups such as R 1 include C ⁇ .g alkanoyl, benzoyl, phenylacetyl, benzyl optionally substituted in the phenyl ring by one or two substituents selected from C ⁇ .4 alkyl, C ⁇ .4 alkoxy, trifluoromethyl, halogen, or nitro; C ⁇ .4 alkoxycarbonyl; benzyloxycarbonyl or trityl substituted as for benzyl above; allyloxycarbonyl,trichloroethoxycarbonyl or chloroacetyl.
  • An example of a group R21NH is phenylacetamido.
  • Formula (I) includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • Acids of formula (II) above may be prepared from known (see PCT/GB 91/01228) compounds of formula (VII):
  • R*, R , R 4 , X, m and n are as defined above, and R ⁇ l is a carboxylate-protecting group, by removal of the group R ⁇ l to leave a carboxylic acid group.
  • Suitable readily removable carboxylate protecting groups R ⁇ l include groups forming ester derivatives of the carboxylic acid, including in, vivo hydrolysable esters.
  • the derivative may be one which may readily be cleaved in vivo.
  • Suitable ester-forming carboxylate-protecting groups are those which may be removed under conventional conditions.
  • a carboxylic acid group may be regenerated from any of the above esters by usual methods appropriate to the particular R ⁇ l group, for example, acid- and base- catalysed hydrolysis, or by enzymically-catalysed hydrolysis, or by hydrogenolysis under conditions wherein the remainder of the molecule is substantially unaffected.
  • R ⁇ l is a 4-methoxybenzyl group
  • the carboxylic acid group may be regenerated by reaction of the compound of formula (VII) with aluminium chloride in the presence of anisole, in an organic solvent such as dichloromethane, for example at -50°C to 0°C.
  • the acid (II) so formed may then be purified by formation of the sodium salt in aqueous solution, acidification and extraction of the acid (II) so formed into an organic solvent such as dichloromethane.
  • a suitable organic solvent is dichloromethane.
  • the base may for example be an inorganic base, such as a Group I or II metal hydroxide, carbonate or bicarbonate, or a Group II metal oxide, such as sodium or potassium hydroxide, carbonate or bicarbonate, calcium or magnesium oxide, carbonate or hydroxide etc.
  • Organic bases such as organic amines, for example triethylamine or pyridine may also be used.
  • the phase transfer catalyst and the base may be the same compound, or a separate base and catalyst may be used. Suitable phase-transfer catalysts include quarternary ammonium salts, for example those of formula (VIII):
  • Y" is an anion
  • *0 and R ⁇ are C ⁇ . ⁇ g organic groups
  • R*2 is a C ⁇ _ ⁇ o alkyl group
  • R 1 ⁇ i s a C ⁇ .g alkyl group
  • R 1 *, R* and R 1 ⁇ and the nitrogen to which they are attached can form a pyridine system.
  • Suitable examples of the groups R*0 and R 1 are C ⁇ . ⁇ g straight chain alkyl groups, and, more generally, C ⁇ _ ⁇ g hydrocarbon groups which may contain one or more hetero atoms and which are joined to nitrogen through saturated carbon atoms.
  • the anion Y" may be an inorganic anion, provided it is in practice inert under the reaction conditions, for example a halide such as chloride, bromide or iodide.
  • the anion Y" may be a hydroxide ion, so that the compound (VIII) may function both as a base and as the phase transfer catalyst, and so that a separate base in the aqueous phase may not be necessary.
  • phase-transfer catalyst may be a tetrabutylammonium salt, for example a halide, used in combination with a separate base.
  • the catalyst is tetrabutylammonium hydroxide, functioning both as the catalyst and as a base.
  • the compound (III) may be any halide of the group R ⁇ , for example a chloride, bromide or iodide. Conveniently the compound (III) may be pivaloyloxymethyl iodide, to introduce a pivaloyloxymethyl group R ⁇ into the compound (IV). If Y is an iodide radical it is desirable to include a reducing agent such as a metabisulphite into the aqueous phase as a stabiliser.
  • a reducing agent such as a metabisulphite into the aqueous phase
  • Conversion of the compound (IV) into the ammonium salt (VI) may be carried out by removal of the amino-substituting or amino-protecting group R 1 to leave an N ⁇ 2 group, followed by formation of the salt.
  • Removal of R 1 may be achieved by the Delft procedure commonly used in ⁇ -lactam chemistry. Suitable reaction conditions include treatment with phosphorus pentachloride and and H-methylmorpholine at reduced temperatures, e.g. -20°C to + 10°C. The 7-amino compound so produced may then be reacted with the acid HA to form the salt (VI).
  • the anion A " in (VI) may be any in practice inert inorganic or organic anion which is known to form salts with 7-amino cephem compounds, for example halide (e.g.
  • the acid HA and the 7-amino compound may be reacted together in an organic solvent such as ethyl acetate.
  • Acids of formula (V) are known (see for example PCT/GB 91/01228), or may be prepared by methods known in the art, or methods analogous to such processes. Suitable processes include those described for example in GB 2107307, GB 1536281, and GB 1508064.
  • a reactive H-acylating derivative of the acid (V) may be employed in the process. The choice of reactive derivative will of course be influenced by the chemical nature of the substituents of the acid.
  • Suitable N-acylating derivatives include an acid halide, preferably the acid chloride or bromide or alternatively a symmetrical or mixed anhydride.
  • the acylation may be effected in the presence of an acid binding agent for example, tertiary amine (such as pyridine or dimethylaniline), molecular sieves, an inorganic base (such as calcium carbonate or sodium bicarbonate) or an oxirane, which binds hydrogen halide liberated in the acylation reaction.
  • the oxirane is preferably a (C ⁇ _ g)-l,2-alkylene oxide - such as ethylene oxide or propylene oxide.
  • the acylation reaction using an acid halide may be carried out at a temperature in the range -50°C to +50°C, preferably -20°C to +20°c, in aqueous or non-aqueous media such as water, acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1,2-dichloroethane, or mixtures thereof.
  • the reaction may be carried out in an unstable emulsion of water-immiscible solvent, especially an aliphatic ester or ketone, such as methyl isobutyl ketone or butyl acetate.
  • the acylation with acid halide or anhydride is suitably carried out in the presence of a basic catalyst such as pyridine or 2,6-lutidine.
  • Acid halides may be prepared by reacting the acid (V) or a salt or a reactive derivative thereof with a halogenating (eg chlorinating or brominating) agent such as methane sulphonyl chloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride or phosgene.
  • a halogenating agent eg chlorinating or brominating
  • Suitable mixed anhydrides are anhydrides with, for example, carbonic acid monoesters, trimethyl acetic acid, thioacetic acid, diphenylacetic acid, benzoic acid, phosphorus acids (such as phosphoric, phosphorous, and phosphinic acids) or aromatic or aliphatic sulphonic acids (such as E-toluenesulphonic acid or methanesulphonic acid).
  • Alternative H-acylating derivatives of acid (V) are the acid azide, or activated esters such as esters with 2-mercaptopyridine, cyanomethanol, E-nitrophenol, 2,4-dinitrophenol, thiophenol, halophenols, including pentachlorophenol, monomethoxyphenol, N-hydroxy succinimide, H-hydroxybenzotriazole, or 8-hydroxyquinoline; or amides such as ⁇ -acylsaccharins, j -acylthiazolidin-2-thione or H-acylphthalimides; or an alkylidene iminoester prepared by reaction of the acid (V) with an oxime.
  • esters such as esters with 2-mercaptopyridine, cyanomethanol, E-nitrophenol, 2,4-dinitrophenol, thiophenol, halophenols, including pentachlorophenol, monomethoxyphenol, N-hydroxy succinimide, H-hydroxybenzotriazole, or 8-hydroxyquinoline
  • reactive ⁇ -acylating derivatives of the acid (V) include the reactive intermediates formed by reaction in situ with a condensing agent such as a carbodiimide, for example, N.,N-diethyl-, dipropyl- or diisopropylcarbodiimide, ⁇ ,H'-di-cyclohexyl-carbodiimide, or ⁇ -ethyl-H'-[3-(dimethylamino)propyl]- carbodiimide; a suitable carbonyl compound, for example, N.,H'-carbonyldiimidazole or £ H'-carbonyldi- triazole; an isoxazolinium salt, for example, -ethyl-5-phenylisoxazolinium-3-sulphonate or N-t-butyl-5- methylisoxazolinium perchlorate; or an N-alkoxycarbonyl 2-alkoxy-l,2-dihydroquinoline
  • condensing agents include Lewis acids (for example BBr3 - CgHg); or a phosphoric acid condensing agent such as diethylphosphorylcyanide.
  • the condensation reaction is preferably carried out in an organic reaction medium, for example, methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxan or tetrahydrofuran.
  • a further method of forming the H-acylating derivative of the acid of formula (V) is to treat the acid of formula (V) with a solution or suspension preformed by addition of a carbonyl halide, preferably oxalyl chloride, or a phosphoryl halide such as phosphorus oxychloride, to a halogenated hydrocarbon solvent, preferably dichloromethane, containing a lower acyl tertiary amide, preferably ⁇ .H-dimethylformamide.
  • the ⁇ -acylating derivative of the acid of formula (V) so derived may then be caused to react with a compound of formula (II).
  • the acylation reaction may conveniently be carried out at -40° to +30°C, if desired in the presence of an acid binding agent such as pyridine.
  • a catalyst such as 4-dimethylaminopyridine may optionally also be added.
  • a preferred solvent for the above acylation reaction is dichloromethane.
  • the optional reduction step, the optional conversion of R2 to a different R ⁇ and X to a different X, and the optional formation of a salt may be carried out using methods well known in the art of cephalosporin and penicillin chemistry. 96/1784
  • the group X when the group X is S, SO, or SO2, the group X may be converted into a different group X by methods of oxidation or reduction well known in the art of cephalosporin and penicillin synthesis, as described, for example, in EP-A-0 114 752.
  • sulphoxides in which X is SO
  • a suitable oxidising agent for example an organic peracid such as m-chloroperbenzoic acid.
  • a reduction step is generally effected by processes well known in the art of ⁇ -lactam chemistry, for example using phosphorus trichloride in dimethylformamide.
  • Deprotection may be carried out by any convenient method known in the art such that unwanted side reactions are minimised. Separation of unwanted by-products may be carried out using standard methods.
  • Aluminium trichloride (1.526g, 11.4mmol) was added to anisole (10ml) in dichloromethane (20ml) at ⁇ -20°C and stirred 0.25h. The mixture was cooled to -40°C and 4-methoxybenzyl (6 ⁇ ,7 ⁇ )-7- ⁇ henylacetamido-3-[(S)- tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate ( 1.893g, 3.7mmol) in dichloromethane (30ml) added. Stirred 0.25h at -40°C then sodium bicarbonate (4.188g, 50mmol) in 0.1M pH7 sodium phosphate buffer
  • Phosphorus pentachloride (1.887g, 9.2mmol) in dichloromethane (47ml) was added to pivaloyloxymethyl (6i2,7_R)-7-phenylacetamido-3-[(S')- tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (3.082g, 6.14mmol) and -V-methylmorpholine (1.4ml, 12.3mmol) in dichloromethane (50ml) at ⁇ -20°C. Stirred O. ⁇ h at -7.5+5°C then methanol (15ml) added quickly, stirred 0.75h then water (50ml) added and stirred vigorously for lh.
  • Phosphorus pentachloride (1-69g, 7.14mmol) in dichloromethane (37ml) was added to pivaloyloxymethyl (6-R,7-R)-7-phenylacetamido-3-[(-5)- tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (2.387g, 4.75mmol) and _V-methylmorpholine (1.05ml, 9.55mmol) in dichloromethane (40ml) at ⁇ -20°C. Stirred O. ⁇ h at -7.5+5°C then methanol (10ml) added quickly, stirred 0.75h then water (20ml) added and stirred vigorously for lh.
  • Aluminium trichloride ( ⁇ 52mg, 4.1 ⁇ mmol) was added to anisole (4ml) in dichloromethane (8ml) at ⁇ -20°C and stirred 0.25h. The mixture was cooled to -40°C and 4-methoxybenzyl (6i2,7S)-7-phenylacetamido-3-[(S)- tetrahydrofuran-2-yl]-l-carba-l-dethiaceph-3-em-4-carboxylate (700mg,
  • pivaloyloxymethyl iodide prepared from pivaloyloxymethyl chloride (744mg) and sodium iodide ( ⁇ 95mg) in acetone (3ml)] added. The reaction was stirred overnight and maintained at 0 pH6. ⁇ with 10% tetrabutylammonium hydroxide.
  • Methanesulphonyl chloride (6 ⁇ l, 0.84mmol) was added to 2-(2- 0 aminothiazol-4-yl)-2-( )-methoxyiminoacetic acid (169mg, 0.84mmol) and diisopropylethylamine (147 ⁇ l, 0.84mmol) in DMF (7ml) at ⁇ -40°C.

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

Abstract

L'invention concerne un procédé de préparation de composés de céphalosporines de la formule (I). Dans cette formule, R1 représente un hydrogène, un méthoxy ou un formamido; R2 représente un groupe acyle en particulier celui d'une céphalosporine ayant une activité antibactérienne; R3 représente un groupe ester acceptable sur le plan pharmaceutique et hydrolysable in vivo; R4 représente un hydrogène ou jusqu'à quatre substituants choisis parmi alkyle, alcényle, alcynyle, alcoxy, hydroxy, halo, amino, alkylamino, acylamino, dialkylamino, CO¿2?R, CONR2, SO2NR2 (où R représente un hydrogène ou un alkyle C1-6), aryle et hétérocyclyle, lesdits substituants pouvant être identiques ou différents et où un substituant R?4¿ alkyle quelconque peut être substitué par un substituant R4 quelconque; X représente S, SO, SO¿2?, O ou CH2; m est égal à 1 ou 2; et n est égal à 0. Le procédé consiste à faire réagir l'acide carboxylique correspondant avec un composé de la formule R?3¿-Y, où Y représente un radical halogénure, en présence d'une phase aqueuse contenant une base et un catalyseur de transfert de phase. On peut ensuite éliminer les groupes protecteurs, convertir les groupes X et R2 et former des sels.
PCT/GB1995/002783 1994-12-09 1995-11-29 Procede de preparation de cephalosporines et analogues Ceased WO1996017847A1 (fr)

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GB9424847.3 1994-12-09
GBGB9424847.3A GB9424847D0 (en) 1994-12-09 1994-12-09 Novel process

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WO1996017847A1 true WO1996017847A1 (fr) 1996-06-13

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014421A1 (fr) * 1996-10-02 1998-04-09 Daiichi Pharmaceutical Co., Ltd. Procede d'esterification de composes carboxyliques
ES2155349A1 (es) * 1997-10-08 2001-05-01 J K Ind Ltd Procedimiento de preparacion de un antibiotico de cefalosporina oralmente activo, cefixime.
EP1178049A1 (fr) * 2000-08-03 2002-02-06 Pfizer Inc. Procédé pour la préparation de composés de céphalosporine et produits intermédiaires pour la synthèse de ces composés
WO2002046198A1 (fr) * 2000-12-04 2002-06-13 Pfizer Products Inc. Procede de couplage et produits intermediaires utiles pour la preparation de cephalosporines
WO2002046199A1 (fr) * 2000-12-04 2002-06-13 Pfizer Products Inc. Procede et derives d'ester utiles pour la preparation de cephalosporines
WO2003053522A1 (fr) * 2001-12-21 2003-07-03 Pfizer Products Inc. Procedes de traitement d'infections bacteriennes chez les chats et les chiens

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0395219A2 (fr) * 1989-03-30 1990-10-31 Beecham Group p.l.c. Céphalosporines et leurs homologues, procédé pour leur préparation et compositions pharmaceutiques
WO1992001695A1 (fr) * 1990-07-24 1992-02-06 Beecham Group Plc Cephalosporines et homologues, preparations et compositions pharmaceutiques
WO1992004353A1 (fr) * 1990-09-10 1992-03-19 Beecham Group Plc Derives de cephalosporine et leurs homologues
WO1993011131A1 (fr) * 1991-12-03 1993-06-10 Smithkline Beecham Plc Composes de cephalosporine
WO1994000457A1 (fr) * 1992-06-26 1994-01-06 Smithkline Beecham P.L.C. Alphalosporines et cephalosporines 1-carba-1-dethia

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0395219A2 (fr) * 1989-03-30 1990-10-31 Beecham Group p.l.c. Céphalosporines et leurs homologues, procédé pour leur préparation et compositions pharmaceutiques
WO1992001695A1 (fr) * 1990-07-24 1992-02-06 Beecham Group Plc Cephalosporines et homologues, preparations et compositions pharmaceutiques
WO1992001696A1 (fr) * 1990-07-24 1992-02-06 Beecham Group Plc Cephalosporines et homologues, preparations et compositions pharmaceutiques
WO1992004353A1 (fr) * 1990-09-10 1992-03-19 Beecham Group Plc Derives de cephalosporine et leurs homologues
WO1993011131A1 (fr) * 1991-12-03 1993-06-10 Smithkline Beecham Plc Composes de cephalosporine
WO1994000457A1 (fr) * 1992-06-26 1994-01-06 Smithkline Beecham P.L.C. Alphalosporines et cephalosporines 1-carba-1-dethia

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014421A1 (fr) * 1996-10-02 1998-04-09 Daiichi Pharmaceutical Co., Ltd. Procede d'esterification de composes carboxyliques
ES2155349A1 (es) * 1997-10-08 2001-05-01 J K Ind Ltd Procedimiento de preparacion de un antibiotico de cefalosporina oralmente activo, cefixime.
EP1178049A1 (fr) * 2000-08-03 2002-02-06 Pfizer Inc. Procédé pour la préparation de composés de céphalosporine et produits intermédiaires pour la synthèse de ces composés
US6825344B2 (en) 2000-08-03 2004-11-30 Pfizer Inc. Process for the preparation of cephalosporin compounds and synthetic intermediates
US7355040B2 (en) 2000-08-03 2008-04-08 Desmond John Best Process for the preparation of cephalosporin compounds and synthetic intermediates
WO2002046198A1 (fr) * 2000-12-04 2002-06-13 Pfizer Products Inc. Procede de couplage et produits intermediaires utiles pour la preparation de cephalosporines
WO2002046199A1 (fr) * 2000-12-04 2002-06-13 Pfizer Products Inc. Procede et derives d'ester utiles pour la preparation de cephalosporines
WO2003053522A1 (fr) * 2001-12-21 2003-07-03 Pfizer Products Inc. Procedes de traitement d'infections bacteriennes chez les chats et les chiens

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