GB2300856A - Beta-lactam preparation - Google Patents

Beta-lactam preparation Download PDF

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GB2300856A
GB2300856A GB9510126A GB9510126A GB2300856A GB 2300856 A GB2300856 A GB 2300856A GB 9510126 A GB9510126 A GB 9510126A GB 9510126 A GB9510126 A GB 9510126A GB 2300856 A GB2300856 A GB 2300856A
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ceph
carboxylate
formula
sodium
tetrahydrofuran
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GB9510126D0 (en
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Michael Anthony Harris
Richard Neville Saunders
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Pfizer Ltd
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Pfizer Ltd
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    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/568—Four-membered rings
    • 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

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

Abstract

A compound of formula (I) or a salt thereof: wherein R is a substituent group, R 1 is hydrogen, methoxy or formamido; R 2 is an acyl group; CO 2 R 3 is a carboxy group or a carboxylate anion, or R 3 is a readily removable carboxy protecting group (such as a pharmaceutically acceptable in vivo hydrolysable ester group); and X is S,SO,SO 2 ,O or CH 2 , is prepared by base induced cyclisation of a compound of formula (II): ```where R' is alkyl or aryl, and R, R 1 , R 2 , R 3 , R 4 , X, and m are as defined in formula (I). A compound of formula (II) is prepared by reacting the corresponding novel compound in which the P(=O)(OR') 2 group is replaced by halogen with a phosphite of formula P(OR') 3 .

Description

Novel Process This invention relates to a novel process for preparing ss-lactam containing compounds.
The present invention provides a process for the preparation of a compound of formula (I) or a salt thereof:
wherein R is a substituent group, R1 is hydrogen, methoxy or formamido; R2 is an acyl group, in particular that of an antibacterially active cephalosporin; CO2R3 is a carboxy group or a carboxylate anion, or R3 is a readily removable carboxy protecting group (such as a pharmaceutically acceptable m vivo hydrolysable ester group); X is S,SO,SO2,O or CH2; and m is 1 or 2, which includes the step of base induced cyclisation of a compound of formula (II):
where R' is alkyl or aryl, and R, R1, R2, R3, R4, X, and m are as defined in formula (I).
The 3-position substituent group R in formula (I) is suitably an organic group, such as alkyl, e.g. methyl, or aryl, e.g. phenyl, or a cyclic ether group of the general formula:
where R4 represents hydrogen or up to four substituents selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, halogen, amino, alkylamino, acylamino, dialkylamino, C02R, CONR2, S02NR2 (where R is hydrogen or C16 alkyl), aryl and heterocyclyl, which may be the same or different and wherein any R4 alkyl substituent is optionally substituted by any other R4 substituent.
Compounds of formula (I) having such a cyclic ether group as substituent R are disclosed in WO 92/01696. The bonding carbon atom of such a cyclic ether moiety which links the ring to the cephalosporin nucleus in formula (I) is generally asymmetric. The present invention includes processes which produce either stereoisomer, as well as mixtures of both isomers.
In compounds of formula (I) wherein R1 is formamido, the formamido group can exist in conformations wherein the hydrogen atoms of the -NH-CHO moiety are cis- or eaLS-; of these the cis- conformation normally predominates.
Since the ss-lactam antibiotic compounds of the present invention are intended for use as therapeutic agents in pharmaceutical compositions, it will be readily appreciated that preferred compounds within formula (I) are pharmaceutically acceptable, LÇ are compounds of formula (Ia) or pharmaceutically acceptable salts or pharmaceutically acceptable in vivo hydrolysable esters thereof:
wherein R, R1, R2, R4, m and X are as defined with respect to formula (I) and the group C02R6 is CO2R3 where CO2R3 is a carboxy group or a carboxylate anion.
Those compounds of the formula (I) wherein R3 is a readily removable carboxy protecting group other than a pharmaceutically acceptable in. vivo hydrolysable ester or which are in non-pharmaceutically acceptable salt form are primarily useful as intermediates in the preparation of compounds of the formula (Ia) or a pharmaceutically acceptable salt or pharmaceutically acceptable in vivo hydrolysable ester thereof.
Suitable readily removable carboxy protecting groups for the group R3 include groups forming ester derivatives of the carboxylic acid, including in vivo hydrolysable esters. The derivative is preferably one which may readily be cleaved in vivo.
It will be appreciated that also included within the scope of the invention are salts and carboxy-protected derivatives, including in vivo hydrolysable esters, of any carboxy groups that may be present as optional substituents in compounds of formula (I) or (Ia). Also included within the scope of the invention are acid addition salts of any amino group or substituted amino group that may be present as optional substituents in compounds of formula (I) or (Ia).
Suitable ester-forming carboxyl-protecting groups are those which may be removed under conventional conditions. Such groups for R3 include benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2,2,2trichloroethyl, 2,2,2-tribromoethyl, butyl, 1-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, p-toluenesulphonylethyl, methoxymethyl, a silyl, stannyl or phosphorus- containing group, an oxime radical of formula -N=CHR7 where R7 is aryl or heterocyclic, or an in vivo hydrolysable ester radical such as defined below.
When used herein the term 'aryl' includes phenyl and naphthyl, each optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, C16 alkyl, phenyl, C16 alkoxy, hydroxy(Cl 6)alkyl, mercapto(C1 ,6)alkyl, halo(Cl 6) alkyl, hydroxy, amino, nitro, carboxy, C16 alkylcarbonyloxy, alkoxycarbonyl, formyl, or C16 alkylcarbonyl groups.
The terms '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, (C1-6)alkyl, (C1-6)alkoxy, halo(C1-6)alkyl, hydroxy, carboxy, carboxy salts, carboxy esters such as (C1 ,6)alkoxycarbonyl, (Cl 6)alkoxycarbonyl(Cl 6)alkyl, aryl, and oxo groups. Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. The term 'heteroaryl' as used herein means a heteroaromatic heterocyclic ring or ring system, suitably having 5 or 6 ring 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.
When used herein the terms 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.
When used herein the term 'halogen' refers to fluorine, chlorine, bromine and iodine.
A carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular R3 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.
Suitable and preferred examples of suitable pharmaceutically acceptable in vivo hydrolysable ester groups 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) disclosed in WO 92/01696.
Examples of suitable in vivo hydrolysable ester groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, a-acetoxyethyl, a-pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)prop- 1- yl, and (1 -aminoethyl)- carbonyloxymethyl; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, a-ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; dialkyl aminoalkyl especially di-loweralkylamino alkyl groups such as dimethyl aminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-(alkoxycarbonyl)-2-alkenyl groups such as 2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl; lactone groups such as phthalidyl and dimethoxyphthalidyl; and esters linked to a second Slactam antibiotic or to a ss-lactamase inhibitor. A preferred in vivo hydrolysable ester group is the pivaloyloxymethyl ester.
Suitable pharmaceutically acceptable salts of the carboxy group of the compound of formula (')include metal salts, eg aluminium, alkali metal salts such as sodium or potassium, especially sodium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)- amine, cycloalkylamines such as dicyclohexylamine, or with procaine, dibenzylamine, N,N-dibenzylethylene- diamine, lephenamine, N-methylmorpholine, Nethylpiperidine, N-benzyl- phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, ethylenediamine, or bases of the pyridine type such as pyridine, collidine or quinoline, or other amines which have been used to form salts with known penicillins and cephalosporins. Other useful salts include the lithium salt and silver salt. Salts within compounds of formula (I), may be prepared by salt exchange in conventional manner.
In compounds of formula (I) or (Ia), the group X may be sulphur or an oxidised sulphur atom, i.e. a sulphoxide (SO) or sulphone (SO2) group. When X is a sulphoxide group it will be understood that a- and isomers may exist; both such isomers are encompassed within the scope of the present invention. Examples of X include S, SO, S02 and CH2. Preferably X is sulphur or CH2.
Advantageously, R1 is hydrogen.
Suitably, a cyclic ether at the 3-position of the cephalosporin nucleus is unsubstituted or substituted by up to three substituents R4, selected from C1 6 alkyl, for example methyl, C1 6 alkoxy, for example methoxy, C1 6 alkoxycarbonyl for example methoxycarbonyl, C1 6 alkoxy C1 6 alkyl, for example methoxymethyl, and C1 6 alkanoyloxy C1-6 alkyl, for example acetoxymethyl. Preferably the cyclic ether at the 3-position of the cephalosporin nucleus is unsubstituted.
Preferably m in such a cyclic ether group is 1.
Preferably such a cyclic ether is bonded to the cephalosporin nucleus at a ring carbon adjacent to the oxygen heteroatom.
Suitable and preferred acyl groups R2 include those of formulae (a) - (f) disclosed in WO 92/1696.
A preferred group R2NH - in formula (I) is 2-(2-aminothiazol-4-yl)-2-(Z)- hydroxyiminoacetamino, or a group convertible thereto. For example such a conversion may be via formation of the corresponding 7-amino compound and reaction with the appropriate corresponding acid R2-OH. Such conversions are standard chemistry and are for example disclosed in WO 92/1696, see for example Example 3 steps (g), (h) and (i) thereof.
It will be appreciated that compounds of formula (I) wherein R2 is a group of formula (e) (or (f)) can exist as svn and an. (or E and Z) isomers or mixtures thereof.
Processes which yield either or both isomers are encompassed within the scope of this invention.
Preferably the compounds of formula (I) wherein R2 is a group of formula (e) have the svn configuration (i.e. have the group OA4 svn to the amide linkage) or are enriched in that isomer.
Similarly, when 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 Z-configuration is preferred.
Certain compounds of formula (I) include an amino group which may be 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. Examples of amino protecting groups include C1 6 alkanoyl; benzoyl; benzyl optionally substituted in the phenyl ring by one or two substituents selected from C14 alkyl, C14 alkoxy, trifluoromethyl, halogen, or nitro; C14 alkoxycarbonyl; benzyloxycarbonyl or trityl substituted as for benzyl above; allyloxycarbonyl,trichloroethoxycarbonyl or chloroacetyl.
Specific compounds of formula (Ia) include the following pharmaceutically acceptable carboxylic acids, salts and in-vivQ hydrolysable esters: Sodium (6B,7B)-7-[2- (2-aminothiazol-4-yl)-2- (Z)-methoxyiminoacetamido] -3-[(E)-tetrahydrofuran-2-yl]-ceph-3-em-$carboxylate.
Pivaloyloxymethyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2- (Z)- methoxyiminoacetamido]-3-[(RS)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate, Sodium (6JS,7B)-7-[2- (2-aminothi azol-4-yl)-2-(Z) -methoxyimino- acetamido]-3-[(RS)-tetrahydropyran-2-yl]ceph-3-em-4-carboxylate.
Pivaloyloxymethyl (6E,7E)-7- [2-(2-aminothiazol-4-yl)-2- (O-methoxy- iminoacetamido]-3-[(RS)-tetrahydropyran- 2-yl] ceph-3-em-4-carboxylate.
(6Er,7B)-7-[2-(2-aminothiazol-4-yl)-2-(O-hydroxyimino-acetamido] -3-[(E)- tetrahydrofuran-2-yl]ceph-3-em-4-carboxylic acid.
Sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido] 3-[(O-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Pivaloyloxymethyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z) methoxyiminoacetamido] -3-[(O-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Sodium (6R,7B)-7-[2-(2-aminothiazol4-yl)-2-(O-methoxyiminoacetSmido]- 3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Pivaloyloxymethyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z) methoxyiminoacetamido]-3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Sodium (6B,7R)-7-[2-(2-aminothiazol4-yl)-2-(Z)-methoxyiminoacetamido- 3- [CES)-tetrahydrofuran -3-yl] ceph-3-em-4-carboxylate.
Acetoxymethyl (6R,7O-7-[2-(2-aminothiazol4-yl)-2-(2)-methoxyirnino- acetamido-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]3-(5-methoxymethyltetrahydrofuran-2-yl)ceph-3-em-4-carboxylate.
Sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-(Z)-pent-2-enamido]-3-[(S)tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Sodium (6R,7R)-7-[2-(2-aminothiadiazol-4-yl)-2-(Z) methoxyiminoacetamido] -3-[CS)-tetrahydrofuran-2-yl] ceph-3-em-4-carboxylate.
(RS)-1-acetoxyethyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy iminoacetamido] -3-[(O-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
(6E,7O-7-[2-(2-aminothiazol-4-yl)-2-(O-carboxymethoxyimino acetamido] 3- [(BS)-tetrahydrofuran -2-yl]-ceph-3 -em4-carboxylic acid, disodium salt.
Sodium (6B,7B)-7-[(B)-2-amino-2-(4-hydroxyphenyl)acetamido]- 3- [c)-tetrahydrofuran-2-yl] ceph3 -em4-carboxylate.
Sodium (1S,6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z) methoxyimino acetamido] -3-[(O-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate-1-oxide.
Sodium 7-[2-(2-aminothiazol-4-yl)-2-(O-methoxyiminoacetamido]-3- (tetrahydrofuran-2-yl)-1-carba-1-dethiaceph-3-em-4-carboxylate.
Sodium (6E,7O-7-[2-(2-aminothiazol4-yl)-2-(O-methoxyiminoacetamido]- 3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate-1,1-dioxide.
(RS)-1-(propan-2-yl)oxycarbonyloxyethyl (6R,7R)-7-[2-(2-aminothiazol-4-yl) -2-(Z)-methoxyiminoacetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4carboxylate.
Sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido] 3-[(5R,5R)-5-methyltetrahydrofuran-2-yl)-ceph-3-em-4-carboxylate.
Sodium (6B,7B)-7-[2-(furan-2-yl)-2-(O-methoxyiminoacetamido] -3-[(S)- tetrahydrofuran-2-yl] ceph-3 -em-4-carboxylate.
Sodium (6B,7B)-7-[2-(2-aminothiazol-4-yl)-2-(O-methoxyiminoacetamido]- 3-[(S)-5,5-dimethyltetrahydrofuran-2-yl)-ceph-3-em-4-carboxylate.
Sodium (6B,7B)-7-[2-(2-arninothiazol-4-yl)-2-(O-methoxyiminoacetamido]- 3-[(5-methoxycarbonyltetrahydrofuran-2-yl)-ceph-3-em-4-carboxylate.
Sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido] 3-[-methyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
2-ethoxycarbonyl-(Z)-but-2-enyl (6,7E)-7-[2-(2-aminothiazol-4-yl)-2- (Z)- methoxyiminoacetomido]-3-[(S)-tetrahydrofuran-2-yl)-ceph-3-em-4-carboxylate.
In the compounds of formula (II), R3 is suitably a p-methoxybenzyl or benzhydryl group. R is suitably alkyl, preferably C14 alkyl, especially methyl.
Compounds of formula (I) can be prepared in the process of the invention by base included cyclisation of a compound of formula (II) by Wittig-type reaction, preferably a Wadsworth-Emmons cyclisation. The cyclisation is preferably effected by use of a base of formula M+ A-, where M is an alkali metal cation, and A- is a strongly basic counter anion, such as butyl lithium, sodium amide, sodium hydride, a sodium alkoxide, or an alkali metal carbonate, e.g. potassium carbonate. Preferably sodium hydride or potassium carbonate is used.
The cyclisation is suitably carried out in an organic solvent, e.g. a hydrocarbon such as toluene using sodium hydride, or acetone using potassium carbonate and will proceed to completion at room temperature but an elevated temperature may be preferable to speed the rate of reaction, and/or to take it to completion.
The temperature required to efffect cyclisation under these conditions is relatively low. Accordingly, fewer impurities or by-products are produced, affording an improved, minimal work-up.
Compounds of formula (I) prepared by the process of this invention may be used to prepare further compounds of formula (I), for example by replacement of protecting groups R3 with pharmaceutically acceptable salt cations, e.g. sodium, or pharmaceutically acceptable ester groups. Methods of achieving such replacement are described in WO 92101696.
The present invention also provides a process for the preparation of phosphonate compounds of formula (II) from compounds of formula (III):
wherein Y is halogen, the remaining substituents and m being as described for formula (I), by reaction of the compound of formula (III) with a phosphite of formula P(OR')3 where R' is as described in formula (II) above, for example in an Arbuzov type reaction. In this reaction the phosphite may suitably be used as the solvent.
Compounds of formula (III) can be prepared from the corresponding compound of formula (III) in which Y is -OH by treatment with a conventional halogenating agent such as thionyl chloride, e.g. in the presence of a base such as lutidine.
The preparation of compounds of formula (III) in which Y is -OH is described in WO 92/01696, e.g. on pages 25 and 26 and in Example 6(b) thereof.
Compounds of formula (11) in which Y is halogen are believed to be novel, and constitute a further aspect of this invention.
The above and other aspect of the processes of the present invention will now be illustrated further with reference to the following preparative example.
Example 1 4-Methoxybenzyl(6R)-7R)-7-phenylacetamino-3-[(RS)-tetrahydrofuran 2-yl]-ceph-3-em-4-carboxylate.
(a) 4-Methoxybenzyl(2RS)-2-chloro-2-[(3R)-4R)-3-phenyl-acetamino-4 [(RS)-tetrahydrofuran-2-yl-carbonyl methylthio]azetidin-2-on-1-yl]acetate (formula (m)).
4-Methoxybenzyl (2RS)-2-hydroxy-2-[(3R)-4R)-3-phenyl-acetamino-4-[(RS)tetrahydrofuran-2-yl]-carbonylmethylthio]azetidin-2-on-1-yl]acetate was prepared as in Example 6(b) of WO 92/01696. A solution of the compound (1.355g, 2.5mmol) in dry tetrahydrofuran (lOml) was cooled to -150C. 2,6-lutidine (0.267g, 2.5mmol) was added, followed dropwise by a solution of thionyl chloride (0.297g, 2.5mmol) in tetrahydrofuran (5ml). After the addition, the mixture was stirred for 15 minutes while the temperature rose to OOC. The lutidine hydrochloride was filtered off and the filtrate evaporated in vacuo to provide the title compound as a foam.
(b) Dimethyl (4-methoxybenzyloxycarbonyl) [(3B)-4B)-3-phenyl-acetamino 4-[(BS)-tetrahyd roxyfuran-2-yl-carbonyl methylthio]azetidin-2-on-1yl)methylphosphonate (formula (II).
The compound obtained in (a) above was dissolved in trimethylphosphite (lOml) and warmed to 900C for 30 minutes. Excess phosphite was removed in vacuo then the residue dissolved in ethyl acetate (20 ml) and washed with water (4 x lOml).
After drying over magnesium sulphate, the solution was concentrated and chromatographed on silica gel eluting with ethyl acetate to give the title compound as a pale yellow foam (0.712g, 45%).
(c) (4-Methoxybenzylcarbonyl) [(6E)-7B)-7-phenylacetamino-3-[(BS) tetrahydrofuran-2-yl]-ceph-3-em-4-carboxylate (formula (I)).
A solution of the compound obtained in (b) above (0.158g, 0.25mmol) in dry toluene (5ml) was added dropwise to a stirred suspension of sodium hydride (0.01g of 60% dispersion in oil, 0.25 mmol) in dry toluene (Sml). After stirring at ambient temperature for 1 hour the mixture was warmed to 800 for 1 hour then cooled and washed with water (2 x Sml). The pale yellow solution was dried (MgS04) and rapidly chromatographed on silica gel eluting with 25% hexane in ethyl acetate, to give the title compound (0.064g, 50%).

Claims (12)

at we shall claim may include the following:
1. A process for the preparation of a compound of formula (I) or a salt thereof:
wherein R is a substituent group, R1 is hydrogen, methoxy or formamido; R2 is an acyl group; CO2R3 is a carboxy group or a carboxylate anion, or R3 is a readily removable carboxy protecting group (such as a pharmaceutically acceptable in vivo hydrolysable ester group); X is S,SO,S02,0 or CH2; and m is 1 or 2, which includes the step of base induced cyclisation of a compound of formula (II):
where R' is alkyl or aryl, and R, R1, R2, R3, R4, X, and m are as defined in formula (I).
2. A process according to claim 1 wherein the 3-position substituent group R in formula (I) is an organic group.
3. A process according to claim 2 wherein the 3-position substituent group R in formula (I) is alkyl or aryl.
4. A process according to claim 2 wherein the 3-position substituent group R in formula (I) is a cyclic ether group of the general formula:
where R4 represents hydrogen or up to four substituents selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, halogen, amino, alkylamino, acylamino, dialkylamino, C02R, CONR2, S02NR2 (where R is hydrogen or C16 alkyl), aryl and heterocyclyl, which may be the same or different and wherein any R4 alkyl substituent is optionally substituted by any other R4 substituent.
5. A process according to any one of the preceding claims wherein the compound of formula (I) is selected from the compounds: Sodium (6Bw70-7-[2-(2-aminothiazol-4-yl)-2-(D-methoxyiminoacetamido] -3-[(E)-tetrahydrofuran-2-yl]-ceph-3-em-4-carboxylate.
Pivaloyloxymethyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2- (Z)- methoxyiminoacetamido]-3-[(RS)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(RS)-tetrahydropyran-2-yl)ceph-3-em-4-carboxylate.
Pivaloyloxymethyl (6E,7R)-7-[2-(2-aminothiazol-4-yl)-2- (O-methoxy- iminoacetamido]-3-[(RS)-tetrahydropyran-2-yl] ceph-3-em-4-carboxylate.
(6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido] -3-[(RS)tetrahydrofuran-2-yl]ceph-3-em-4-carboxylic acid.
Sodium (6B,70-7-[2-(2-aminothiazol-4-yl)-2-(0-methoxyimino acetamido] 3-[(0-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Pivaloyloxymethyl (6E7R)-7-[2-(2-aminothiazol4-yl)-2-(0 methoxyiminoacetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Sodium (6B,7B)-7-[2-(2-aminothiazol-4-yl)-2-(0-methoxyiminoacetamido]- 3- [(B)-tetrahydrofuran-2-yl] ceph-3-em-4-carboxylate.
Pivaloyloxymethyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z) methoxyiminoacetamido]-3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Sodium (6R,70-7-[2-(2-aminothiazol-4-yl)-2-(0-methoxyiminoacetamido- 3-[(RS)-tetrahydrofuran-3-yl]ceph-3-em-4-carboxylate.
Acetoxymethyl (6B,7ED)-7-[2-(2-aminothiazol4-yl)-2-(0-methoxyirnino- acetamido] -3-[(0-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido] 3-(5-methoxymethyltetrahydrofuran-2-yl)ceph-3-em4-carboxylate.
Sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-(Z)-pent-2-enamido]-3-[(S) tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Sodium (6R,7R)-7-[2-(2-aminothiadizol-4-yl)-2-(Z) methoxyiminoacetarmido] -3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
(RS)-1-acetoxyethyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy iminoacetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
(6R,70-7-[2-(2-aminothiazol4-yl)-2-(0-carboxymethoxyimino acetamido] 3-[(E)-tetrahydrofuran-2-yl]-ceph-3-em-4-carboxylic acid, disodium salt.
Sodium (6B,7B)-7-[(B)-2-amino-2-(4-hydroxyphenyl)acetamido]- 3-[(0-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
Sodium (1S,6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z) methoxyimino acetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate-1-oxide.
Sodium 7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3 (tetrahydrofuran-2-yl)- 1 -carba- 1 -dethiaceph-3-em4-carboxylate.
Sodium (6B,7R)-7-[2-(2-aminothiazol4-yl)-2-(0-methoxyiminoacetamido]- 3-[(0-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate- 1,1-dioxide.
(RS)-1-(propan-2-yl)oxycarbonyloxyethyl (6R,7R)-7-[2-(2-aminothiazol-4-yl) -2-(Z)-methoxyiminoacetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4carboxylate.
Sodium (6R,7B)-7-[2-(2-aminothi ol-4-yl)-2-(0-methoxyiminoacetamido] - 3-[(SR,SR)-5-methyltetrahydrofuran-2-yl)-ceph-3-em-4-carboxylate.
Sodium (6R,7B)-7-[2-(furan-2-yl)-2-GO-methoxyiminoacetamido] - 3-[() - tetrahydrofuran-2-yl]ceph-3-em4-carboxylate.
Sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]3-[(S)-5,5-dimethyltetrahydrofuran-2-yl]-ceph-3-em-4-carboxylate.
Sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]3-(5-methoxycarbonyltetrahydrofuran-2-yl)-ceph-3em4-carboxylate.
Sodium (6B,70-7-[2-(2-aminothi ol-4-yl)-2-(;Z)-methoxyiminoacetamido] 3-[-methyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate.
2-ethoxycarbonyl-(0-but-2-enyl (6B,7B)-7-[2-(2-aminothiazol4-yl)-2-(Z)- methoxyiminoacetomido] - 3- [ (S)-tetrahydrofuran-2-yl] ceph-3-em-4-carboxylate.
6. A process according to any one of the preceding claims wherein the cyclisation is effected by use of a base of formula M+ A-, where M is an alkali metal cation, and A- is a strongly basic counter anion
7. A process according to claim 6 wherein the base is selected from butyl lithium, sodium amide, sodium hydride, a sodium alkoxide, or an alkali metal carbonate.
8. A process according to claim 7 wherein the base is selected from sodium hydride and potassium carbonate.
9. A process according to claim 8 wherein the cyclisation is carried out in toluene as solvent using sodium hydride as the base, or in acetone as solvent using potassium carbonate as the base.
10. A process for the preparation of phosphonate compounds of formula (II) from compounds of formula (III):
wherein Y is halogen, the remaining substituents and m being as described for formula (I), by reaction of the compound of formula (III) with a phosphite of formula P(OR')3 where R' is as defined in formula (II) above.
11. A compound of formula (H) as defined in claim 10 in which Y is halogen.
12. A process according to any one of the preceding claims, substantially as hereinbefore described with reference to Example 1.
GB9510126A 1995-05-16 1995-05-16 Beta-lactam preparation Withdrawn GB2300856A (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002046198A1 (en) * 2000-12-04 2002-06-13 Pfizer Products Inc. Coupling process and intermediates useful for preparing cephalosphorins
WO2002046199A1 (en) * 2000-12-04 2002-06-13 Pfizer Products Inc. Process and ester derivatives useful for preparation of cephalosporins
WO2003053522A1 (en) * 2001-12-21 2003-07-03 Pfizer Products Inc. Methods of treating bacterial infections in dogs and cats
WO2005092900A1 (en) * 2004-03-09 2005-10-06 Pfizer Products Inc. PROCESS FOR PREPARING CEPHALOSPORIN INTERMEDIATES USING α-IODO-1-AZETIDINEACETIC ACID ESTERS AND TRIALKYLPHOSPHITES
CN108424418A (en) * 2017-02-15 2018-08-21 山东致纯医药科技有限公司 A kind of Flomoxef sodium impurity
WO2020008183A1 (en) 2018-07-02 2020-01-09 Norbook Laboratories Limited Intermediates in the synthesis of c3-substituted cephalosporins
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1424373A (en) * 1972-04-14 1976-02-11 Merck & Co Inc 7-azido-cephalosporin compounds and their preparation
WO1992001696A1 (en) * 1990-07-24 1992-02-06 Beecham Group Plc Cephalosporins and homologues, preparations and pharmaceutical compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1424373A (en) * 1972-04-14 1976-02-11 Merck & Co Inc 7-azido-cephalosporin compounds and their preparation
WO1992001696A1 (en) * 1990-07-24 1992-02-06 Beecham Group Plc Cephalosporins and homologues, preparations and pharmaceutical compositions

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002046198A1 (en) * 2000-12-04 2002-06-13 Pfizer Products Inc. Coupling process and intermediates useful for preparing cephalosphorins
WO2002046199A1 (en) * 2000-12-04 2002-06-13 Pfizer Products Inc. Process and ester derivatives useful for preparation of cephalosporins
WO2003053522A1 (en) * 2001-12-21 2003-07-03 Pfizer Products Inc. Methods of treating bacterial infections in dogs and cats
WO2005092900A1 (en) * 2004-03-09 2005-10-06 Pfizer Products Inc. PROCESS FOR PREPARING CEPHALOSPORIN INTERMEDIATES USING α-IODO-1-AZETIDINEACETIC ACID ESTERS AND TRIALKYLPHOSPHITES
CN108424418A (en) * 2017-02-15 2018-08-21 山东致纯医药科技有限公司 A kind of Flomoxef sodium impurity
WO2020008183A1 (en) 2018-07-02 2020-01-09 Norbook Laboratories Limited Intermediates in the synthesis of c3-substituted cephalosporins
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

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