DK146853B - PROCEDURE FOR N-DEACYLATION OF 7-ACYLAMIDO-3-HYDROXYMETHYL CEPHALOSPORIN COMPOUNDS FOR THE CREATION OF 7-AMINO-3-CHLORMETHYLPHALOSPORINES - Google Patents

Description

(19) DENMARK

Ig (12) PUBLICATION OF 146853 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Patent Application No .: 4087/74 (51) Lnt.CI.3: C 07 D 501/04 (22) Filing Date: 31 Jul 1974 (41) Alm. available: 02 Feb 1975 (44) Submitted: 23 Jan 1984 (86) International Application No: - (30) Priority: 01 Aug 1973 GB 36497/73 (71) Applicant: 'GLAXO LABORATORIES LIMITED; Greenford, GB.

(72) Inventor: Colin 'Roblson; GB, Derek 'Walker; GB.

(74) Clerk: Office of Industrial Energetic (54) Process for N-deacylation of 7-acylamino-do-3-hydroxymethylcephalosporin compounds to form 7-amino-3-chloromethylcephalosporins

The present invention relates to a particular method for N-deacylation of 7-acylamido-3-hydroxymethylcephalo-sporin compounds to form 7-amino-3-chloromethylcephalo-sporins which are valuable as intermediates in the preparation of cephalosporin antibiotics.

One can encounter 3-hydroxymethylcephalosporins both as starting materials and as intermediates in the synthesis of ce-Ώ phalosporin antibiotics, and an example of such a 3-hydroxylmethyl compound is deacetylcephalosporin C, i.e. (6R, 7R) -7-JO (R-5-Amino-5-carboxypentanamido) -3-hydroxymethylceph-3-em-4-carboxylic acid, which is an important component of fermentation cephalosporin supplements C. In converting such compounds into c ephalo sporin antibodies, it is in many cases necessary to deacylate and subsequently reacylate the 7-amino group to form the desired 7-acylamido group in the antibiotic and the ability to N -Deacylating 3-hydroxymethylcephalo-sporins effectively is therefore of little importance in cephalosporin chemistry.

An N-deacylation technique that has been widely proposed for the treatment of i. 3-Acyloxycephalosporins are the so-called imide halide technique which involves reacting a carboxyl protected cephalosporin with an imide halide forming agent, converting the resulting imide halide to an imino ether and cleaving the ether, for example by hydrolysis or alcoholysis to produce -sporin. Given the prior publications of this technique, all of which have indicated the necessity of deactivating reactive groups already present in the cephalosporin molecule, one would not expect this technique to be used for N-deacylation of 3-hydroxymethylcephalosporins. Thus, for example, British Patent No. 1,041,985, which describes an imide halide technique for N-deacylation of cephalosporin C derivatives with an esterified hydroxymethyl group at the 3-position or a lactone group formed by reaction between a 3-hydroxymethyl group and the 4-carboxy group, states that the free amino groups and carboxy groups present in the cephalosporin molecule should be blocked before the deacylation reaction. This need to block such active substituents is reiterated in British Patents Nos. 1,119,806, 1,227,014 and 1,244,191, and is particularly emphasized in British Patent Nos. 1,239,814. All of the aforementioned patents relate to the deacylation of cephalosporin compounds containing 3-acyloxymethyl groups or 3-methyl groups or a lactone group between position 3 and position 4, i.e., groups which do not participate in the deacylation reaction, and thus there is no prior indication of reactive substituents. such as 3-hydroxy methyl groups which are not inert to the reaction conditions may be present.

In addition, the prior art relating to the imide halide technique indicates that the presence of alcohols should be avoided by winning the step in which the imide halide is formed. It is thus stated, for example, in the above-mentioned British No. 1,227,014 that this step should be carried out in a non-hydroxylated anhydrous organic liquid solvent, while British Patent No. 1,239,814 in connection with usable solvents states that if chloroform is used in This step, it should be free of alcohol. For this reason, 3-hydroxy-methylcephalosporins would not be expected to be useful as starting materials in the imide halide process, given the potential for the alcoholic 3-substituent to be mixed into the imide halide formation.

However, it has now surprisingly been found that 3-hydroxymethylcephalosporins can be successfully N-deacylated using the imide technique described above and that the reaction proceeds in good yield and is accompanied by conversion of the 3-hydroxymethyl group to a 3-halo methyl group, a steps that are really desirable for a variety of reasons. The deacylation is substantially free of the reactions arising from the presence of an active alcoholic hydroxyl group in the substituent at the 3-position, such as reaction of 3-hydroxyl groups with the intermediate imide halide groups or with other reactive centers in the cephalosporin molecule, reactions which could actually have been expected given the prior art. In addition, it has been found that the 3-halo-methylcephalosporin product is stable under reaction conditions, and that side reactions involving the 3-halo-methyl side chain are minimal, despite the known tendency of such compounds to undergo nucleophilic substitution of the halogen substituent. in the group in the 3 position.

The process of the invention is therefore characterized by a) reacting an ester derivative of the 7-acylamido-3-hydroxymethyl-cephalosporin compound of the general formula

RCONH - T O

! IN

t

(F - CH 2 OH

COOR1 wherein RCO- is a carboxylic acyl group, R1 is a carboxyl blocking group in the form of an ester-forming residue of an alcohol or phenol R 1 OH with 1-20 carbon atoms and the broken line between positions 2, 3 and 4 indicates that the compound may be a ceph-2 em or ceph-3 em compound or a mixture thereof, with the imide halide forming agent phosphorus pentachloride in the presence of base, b) contacting the product thus formed with an imino-forming compound and c ) cleaves the resulting product by hydrolysis or alcoholysis. Thereby, a corresponding 7-amino-3-chloromethylcephalosporin, a compound of the general formula H2H -] - 1

I-N & -CH-Cl II

Cf COOR1 where R 1 and the broken line have the above meanings.

A) Reaction with the imidehalide forming agent

This reaction is carried out in the presence of a rabbit, for example an organic rabbit, which advantageously has a pKb measured in water at 25 ° C in the range 4-6. Examples of suitable organic rabbits are tertiary amines such as, for example, N, N-disubstituted anilines such as Ν, Ν-dimethylaniline or Ν, Ν-diethylaniline, and pyridine-type heterocyclic gases, e.g., pyridine, quinoline, collidine, lutidine or a picoline.

The reaction is conveniently carried out in solution in an inert organic solvent such as a chlorinated hydrocarbon, for example methylene chloride, 1,2-dichloroethane or 1,1-dichloroethane.

As phosphorus pentachloride is added as the imide halide forming agent, the reaction is conveniently carried out by allowing phosphorus trichloride and chlorine to act on each other in the selected reaction medium to develop in situ phosphorus pentachloride, then adding 7-acylamido-3-hydroxymethylcephalosporine solution, in the same solvent. On the other hand, if the base used in the imide halide formation step is inert to the action of phosphorus pentachloride, with pyridine being an example of a suitable inert base for this purpose, a phosphorus pentachloride base complex can be prepared, e.g. in situ by reacting the chlorine with a mixture of phosphorus trichloride and the base, after which the resulting complex is used to treat the 7-acylamido-3-hydroxymethylcephalosporin compound. Where phosphorus pentachloride is used directly, it is conveniently used in finely divided form, for example with a particle size of approx. 10 mesh. At least one mole and desirably at least two moles of imidhalo gem * rider flour Rpsmi dl et. Should be used. Phosphorus pentachloria may conveniently be used in excess and amounts of up to 20 molar excess may be used. It will be uneconomical to use large excess and it is preferred to work with the cephalosporin compound and the phosphorus pentachloride in molar ratios of, for example, between 1: 1 and 1:10, preferably between 1: 2 and 1: 5 · The temperature of the reaction of the phosphorus pentachloride with the cephalosporin may be between -50 ° C and + 50 ° C. The optimum temperature will at least to some extent depend on the reactants used. It is advantageous to work in the temperature range between -30 and + 30 ° C, for example between -10 and + 20 ° C.

B) Reaction with the imino-forming compound

The imino-forming compound is advantageously a lower alkanol, i.e. an alkanol having up to 6 carbon atoms, for example methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, with methanol being particularly suitable for this purpose. Other useful imino-forming compounds are diols of the general formula HO-R -OH, wherein R is a divalent alkylene group or cycloalkylene group having 2,3 or 4 carbon atoms in the carbon chain connecting the oxygen atoms. Examples of such diols are ethylene glycol, propane-1,2-diol and propane-1,3-diol, and the various butane diols such as butane-1,3-diol.

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The iminoether-forming compound can be used in substantially molar excess, for example in an amount of up to 75 or possibly even 100 mole excess relative to the cephalosporin compound.

Although the imino-ether compound can be added to the reaction solution, it is preferred to add the reaction solution to the imino-ether compound because this technique allows for better control of the reaction system on a large scale.

Advantageously, the reaction is carried out in the presence of a substantially anhydrous acid, e.g., hydrogen chloride or concentrated sulfuric acid or p-toluenesulfonic acid.

The temperature during the reaction can generally be between -50 and + 40 ° C, for example between -30 and + 30 ° C, since the optimum temperature depends at least to some extent on the reactants used.

C) Cleavage

The product of step B may be cleaved to form the desired 7-amino compound by hydrolysis, for example, by contacting the reaction solution with water or an aqueous medium, or by alcoholysis, for example, using a lower alkanol such as methanol. It is desirable to carry out the cleavage under acidic conditions, which will often occur as a result of the earlier steps, since this tends to end the reaction. If additional acid is needed, examples of useful acids include mineral and organic acids such as hydrochloric acid, p-toluenesulfonic acid, nitric acid, phosphoric acid, sulfuric acid and formic acid.

It is convenient to carry out this reaction with water, (e.g., at a temperature between -5 and + 30 ° C), ensuring that the preceding steps are carried out in such a way that sufficient acid is obtained from it. The 7-amino compound can then be recovered by raising the pH of the reaction solution and isolating the compound by evaporating the solvent from the reaction solution.

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However, in many cases it may be preferable to convert the 7-amino product resulting from the cleavage, in situ by halogen exchange, acylation, reaction with a nucleophile and / or deesterification in known manner. Thus, for example, the reaction solution resulting from the cleavage can be treated directly with an acylating agent to introduce the 7-acyl group desired in the final product. This avoidance of isolation of 7-aminocephalosporins may be advantageous because 7-amino-3-halomethyl compounds are generally less stable than their 7-acylamido side pieces and are therefore more difficult to purify and require greater care in the treatments.

The acyl moiety of the acylamido group at the 7-position of the starting material used cephalosporin, ie. the group RCO-in Formula I may generally be any of the very numerous carbocyclic amide-forming acyl groups listed in the cephalosporin literature, provided that reactive substituents such as amino groups, carboxy groups and hydroxy groups are already deactivated by substitution. In particular, the RCO-group may be a carboxylic acyl group having 1-20 carbon atoms. Specific examples of acyl groups are listed below which do not appear to be exhaustive.

(i) rUC H co- where Ru is an aryl group (carbocyclic or heterocyclic), cycloalkyl group, substituted aryl group, substituted cycloalkyl group, cycloalkadienyl group or non-aromatic heterocyclic or mesoionic group and n is the number 0 or an integer 1 -4. Examples of such a group are phenylacetyl; thien-2 and -3-ylacetyl; 3- and 4-isoxazolylacetyl, both substituted and unsubstituted; pyridylacetyl, tetrazolylacetyl or sydnonacetyl. If n is different from 0, especially in cases where n = 1, the α-carbon atom in the acyl group may be substituted by, for example, an esterified hydroxy group (e.g., an acyloxy group) or a blocked amino group (e.g., an amino group substituted by any one). preferably of the blocking groups listed below); Examples of α-substituted acyl groups of this type include esterified 2-hydroxy-2-phenylacetyl and N-blocked 2-amino-2-phenylacetyl.

(ii) C H ~, -, C0-, where n is 0 or integers 1-7 · n 2n + l

The alkyl group may be straight or branched and may be substituted by, for example, a cyano group, blocked carboxy group (e.g. esterified carboxy group such as an alkoxycarbonyl group), esterified hydroxy group, blocked amino group or blocked carboxycarbonyl group (-CO.COOH). Examples of such groups are formyl, glutaroyl and N-blocked (e.g. N-ethoxycarbonyl) R-5-amino-5-carboxypentanoyl.

Rv (iii) RuZC-CO-, where Ru has the one specified in (i)

Rw is meaning and furthermore may be a benzyl group and wherein Rv and Rw which may be the same or different each are a hydrogen atom or a phenyl group, benzyl group, phenethyl group or lower alkyl group and where Z is an oxygen atom or sulfur atom. Examples of such a group are phenoxyacetyl and pyridylthioacetyl.

For example, amino groups present in the acyl moiety can be protected by being substituted by a mono- or divalent blocking group, and of the examples of suitable groups are acyl groups such as lower alkanoyl, e.g., acetyl; substituted lower alkanoyl, for example lower haloalkanoyl such as phenylacetyl; and aroyl such as benzoyl or phthaloyl; further, lower alkoxycarbonyl groups such as ethoxycarbonyl, isobutyloxycarbonyl or t-butoxycarbonyl and substituted lower alkoxycarbonyl groups, e.g. lower haloalkoxycarbonyl such as 2,2,2-trichloroethoxycarbonyl; aryl (lower alkoxycarbonyl) groups such as benzyloxycarbonyl; sulfonyl groups such as lower alkylsulfonyl groups such as methanesulfonyl or arylsulfonyl groups such as benzenesulfonyl or p-toluenesulfonyl; ylidene groups can be formed by reaction with an aldehyde or ketone forming a schiffic base, e.g., benzaldehyde, salicylic aldehyde or acetoacetic acid ester; and divalent groups such that nitrogen atoms form part of a dihydropyridine ring (protecting groups of the latter type may be obtained, for example, by reaction with formaldehyde and a β-keto ester, for example, acetoacetic acid ester as described in British Patent No. 771,694.

For example, hydroxyl groups present in the acyl moiety can be protected by substitution with carboxylist or sulfonic acyl groups in a similar manner to amino groups.

Carboxyl groups which may be present in the acyl moiety may be protected by esterification, for example, to introduce a carboxyl-blocked group as defined above.

Valuable starting materials of the process are 3-hydroxymethylcephalosporin compounds formed by fermentation, in particular according to the invention desacetylcephalosporin C in N-blocked and esterified form.

In general, the carboxyl blocking groups introduced to the carboxyl group at the 4 position or introduced to protect introduced carboxyl groups in the side chain at the 7 position in the starting material may be any C- q alcoholic or phenolic group described in the literature. regarding esterification of β-lactam antibiotics and their precursors.

A particularly preferred class of carboxyl blocking groups are those of formula CH-34 wherein R is a hydrogen atom or an organic group and R is a 344 organic group, or wherein R or R together and together with the carbon atom to which they are attached form a cyclic organic group. group. Thus, for example, R 1 and R 2 may be carbocyclic aryl groups such as phenyl or naphthyl; 5- or 6-membered heterocyclic rings containing one or more of the atoms 0, N and S (e.g. thien-2-yl, fur-2-yl or pyridin-2-yl); aralkyl groups, eg those containing a monocyclic aryl group and 1-6 carbon atoms in the alkyl moiety such as benzylj heterocyclic substituted alkyl groups, e.g. those containing 1-6 carbon atoms in the alkyl moiety, e.g. thien-2-ylmethyl or fur-2-ylmethyljalkyl groups e.g. -6 carbon atoms such as methyl, ethyl, n-propyl and isopropyl; cycloalkyl groups, for example, having 5-7 carbon atoms in the ring, eg cyclopentyl or cyclohexyl; unsaturated analogs to said groups such as, for example, carbocyclic or heterocyclic aralkenyl groups, lower alkenyl groups (e.g. 2-6 carbon atoms such as vinyl or allyl); and cycloalkenyl groups, for example, containing 5-7 carbon atoms such as cyclohexyl or cyclopentadienyl; or any of the aforementioned groups substituted by one or more halogen atoms, cyano groups, nitro groups, alkyl groups, alkylsulfonyl groups or alkoxy groups which the latter groups may contain, for example, 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, ethoxy , isopropoxy or methylsulfonyl. Optionally, R and R may also form, together with the associated carbon atom, a cycloaliphatic group having 5-20 carbon atoms, e.g., a cycloalkyl group (e.g., containing 5-7 carbon atoms such as cyclopentyl or cyclohexyl) or a cycloalkenyl group (e.g., having 5-7 carbon atoms such as cyclohexenyl or cyclopentyl) ) j or a heterocyclic group having at least one 5- or 6-membered heterocyclic ring containing one or more of the atoms 0, N and S, e.g., a monocyclic group such as pyranyl or piperidinyl.

Preferred carboxyl blocking groups of these types are because of this ease, after which they can later be cleaved by, for example, acid hydrolysis, carbocyclic and heterocyclic aralkyl groups having 1 or 2 aryl groups bonded to the C1 atom in a lower alkyl moiety (e.g. with 1-6 carbon atoms) and examples of such groups are benzyl, 1-phenylethyl, naphthylphenylmethyl, di- (thien-2-yl) -methyl, phenyl- (thien-2-yl) -methyl and substituted versions of such groups, e.g. -tolyl) -methyl and (ρίπε toxyphenyl) -phenylmethyl; it will be understood that this list is not exhaustive. Particularly valuable for the reasons stated, the invention is one or more carboxyl blocking groups of the compound I diphenylmethyl.

The chloromethyl group at the 3-position may, optionally after halogen exchange, be converted to the group desired in a given cephalosporin antibiotic, for example, by nucleophilic replacement of the halogen atom or by reaction with a compound containing a nucleophilic carbon atom, nitrogen atom, oxygen atom or sulfur atom as described in British U.S. Patent No. 1,241,657 or Belgian Patent No. 755,256 to form a compound wherein the methyl group at the 3-position is substituted with the rest of a nucleophile.

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Conversion of the halo methyl group 13 position will normally be performed after reacylation of the 7-amino group in the cephalosporin compound to avoid undesired side reactions involving this amino group.

The products obtained by the process according to the invention are of considerable value as synthetic intermediates in the cephalosporin chemistry due to the presence of a 3- 'cyclophenyl group which can be converted to such groups as acetoxymethyl, pyridinium methyl, 5-methyl-1,3,4-methyl. thiadiazol-2-ylthiomethyl and 1-methyl- and 1-phenyltetrazol-5-ylthiomethyl taken in such cephalosporin antibiotics as cephalotine, cephaloridine, cephazoline and cephamandole, and the presence of a 7-amino group which can be acylated to form an appropriate 7-acyl amido group for such antibiotic compounds. Since the 3-hydroxymethyl compounds used as starting materials can be obtained at a relatively low cost from, for example, fermentation soups for cephalosporin C, the process of the present invention is extremely valuable for the economic synthesis of various cephalosperin antibiotics from naturally occurring cephalosporin compounds.

The process according to the invention will now be described in more detail by some examples.

In these, the reactions were monitored by NMR spectroscopy which showed formation - and upon further in situ disappearance - of a free amino group corresponding to formation - and reacylation of the 7-aminocephalosporin compound. The reactions were also monitored by thin layer chromatography. The isolated intermediate of Example 3 gave a reddish-purple spot with an R R value of 0.45, and this characteristic spot was also seen in all the examples where in situ conversion was done, showing formation of the same intermediate (the product of Example 9 is a phenylmethyl ester and not a diphenyl ester, but it does not affect the R The thin layer chromatography was performed on silica plates using a 2: 1 benzene / ethyl acetate elution system.

Example 1 12 (146R) a) (6R, 7R) -7- / R-5-carboxy-5- (3,5-diethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridin-1-yl) -pentanamido7-3-hydroxymethylceph -3-em-4-carboxylic acid bis-diphenylmethyl ester

To a solution of potassium (6R, 7R) -7- (R-5-amino-5-carboxypentanamido) -3-hydroxymethylceph-3-em-4-carboxylate (70µg, 12g, 20mmol) was added containing 18.7 ml (249 mmol) of 37% formaldehyde solution and 25> 2 ml (199 mmol) of ethyl azidoacetate separately over an hour at 5 ° C. The pH of the solution was maintained at 7.0 by the addition of 25% aqueous potassium phosphate solution. After a further 30 minutes of stirring, the solution was extracted with 200 ml of dichloromethane. Then, 150 ml of dichloromethane containing 10 g (52 mmol) of diphenyl diazomethane was added to the aqueous solution and the mixture was stirred for 45 minutes during which time the pH was adjusted to 2.0 with orthophosphoric acid. After separation, the solvent layer was washed with 200 ml of water, 200 ml of 5% sodium bicarbonate solution and 200 ml of water. After drying over magnesium sulfate, the solution was concentrated in vacuo to a volume of 75 ml to give a solution of the title compound.

b) Diphenylmethyl (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-carboxylate

The 75 ml solution obtained in Example 1 (a) was added to a pre-made mixture of 9 * 2 g (43 mmol) of phosphorus pentachloride and 3.5 ml (44 mmol) of pyridine in 50 ml of dichloromethane at -5 ° C. The mixture was stirred for 15 minutes during which time the temperature reached 15 °. The solution was cooled to -10 ° C, 40 ml of methanol was added and the solution was stirred for 15 minutes at 15 ° C. The solution was washed with 50 ml of water, 100 ml of 5% aqueous sodium bicarbonate solution and 100 ml of water.

After drying over magnesium sulfate, the solvent was removed in vacuo. The gum thus obtained was redissolved in 5 ml of dichloromethane and 75 ml of ether was added. The product was filtered off and redissolved in 50 ml of dichloromethane. This solution contained the title compound, which was confirmed by TLC and NMR data, and subjected to further reactions without isolating the compound.

Example 2 a) (6R, 7R) -7- (R-5-benzoylamino-5-carboxypentanamido) -3-hydroxy-methylceph-3-em-4-carboxylic acid bis-diphenylmethyl ester

To a solution of potassium (6R, 7R) -7- (R-5-amino-5-carboxypentanamido) -3-hydroxymethylceph-3-em-4-carboxylate (70% pure, 6.0g, 10mmol) in 150 ml of water was added a mixture of 3.5 ml (30 mmol) of benzoyl chloride and 5 ml of acetone.

The mixture was stirred for 1 1/2 hours at room temperature keeping the pH of 8.5 by adding 50% sw / r aqueous potassium phosphate (v / r: weight / volume, i.e., the ratio of solid to liquid units as between grams and ml ). The pH was adjusted to 5.0 with orthophosphoric acid and the solution extracted with 100 ml of chloroform to remove benzoic acid and benzoyl chloride.

90 ml of ethyl acetate containing 5 g (26 mmol) of diphenyl-diazomethane, 50 ml of dichloromethane and 10 ml of ethanol were added to the aqueous solution and the mixture was stirred for 45 minutes during which time the pH was adjusted to 2.0 with orthophosphoric acid.

After separation, the solvent layer was washed with 100 ml of 5% v / r aqueous sodium bicarbonate solution and 100 ml of water. The solvent was removed in vacuo and the rubber dissolved. in 25 ml of isopropanol at 30 ° C. 10 ml of petroleum ether (b.p. 30-40 ° C) was added and the solution cooled to -5 ° C. The product was washed with 15 ml of petroleum ether and dried in vacuo at room temperature to give 10.5 g of the title compound.

Thin layer chromatography on silica gel GF254 plates using chloroform / acetone / acetic acid 80: 20: 1 as wetting agent showed that the product was essentially the title compound with traces of impurity, b) The following compounds were prepared by the example of 2 (a), replacing the benzoyl chloride with isobutyl chloroformate, 2,2,2-trichloroethyl chloroformate and benzenesulfonyl chloride, respectively: 1) (6R, 7R) -7- (R-5-carboxy-5-isobutyloxycarbonylamino-pentanamido) -hydroxymetylceph-3-em-4-carboxylic acid bis-difenylmetylester; 2) (6R, 7R) -7 - [(5-carboxy-5- (2,2,2-trichloroethoxycarbonylamino) -pentanamido] -3-hydroxymethylceph-3-em-4-carboxylic acid bis-diphenylmethyl ester ; 3) (6R, 7R) -7- (R-5-benzenesulfonylamino-5-carboxypentanamido) -3-hydroxymethylceph-3-em-4-carboxylic acid bis-diphenylmethyl ester.

c) Diphenylmethyl (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-carboxylate

To a slurry of 9.2 g (43 mmol) of phosphorus pentachloride in 40 ml of dichloromethane was added 3.5 ml (44 mmol) of pyridine in 10 ml of dichloromethane. The mixture was stirred for 15 minutes and then cooled to -5 ° C. To this mixture was added a solution of 15.0 g (about 5 mmol) (6R, 7R) -7- (R-5-benzoylamino-5-carboxypentanamido) -3-hydroxymethylceph-3-em. 4-carboxylic acid bis-diphenylmethyl ester in 50 ml of dichloromethane. The mixture was stirred for 15 minutes during which time the temperature reached 15 ° C. The solution was cooled to -10 ° C, 40 ml of methanol was added and the solution was stirred for 15 minutes at 15 ° C.

The resulting solution was washed with 50 ml of water, 100 ml of 5% aqueous sodium bicarbonate and 100 ml of water. TLC and NMR data indicated that the title compound was present in the solution which is further reacted without isolation of the 7-amino compound.

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Example 3

Diphenylmethyl (6R, 7R) -7-amino-3-chloromethylceph-3-em-4-carboxylate

To a slurry of 5.0 g (23 mmol) of phosphorus pentachloride in 20 ml of dichloromethane was added 2.1 ml (26 mmol) of pyridine in 6 ml of dichloromethane. The mixture was stirred for 15 minutes and then cooled to -5 ° C. To this mixture was added a solution of 5.5 g (about 7 mmol) (6R, 7R) -7- (R-5-benzoylamino-5-carboxypentanamido) -3-hydroxymethylceph-3-em-4-carboxylic acid bis -diphenylmethyl ester in 20 ml of dichloromethane. The mixture was stirred for 15 minutes during which time the temperature reached 15 ° C. The solution was cooled to -10 ° C, 15 ml of methanol was added and the solution was stirred for 15 minutes at 15 ° C. The resulting solution was washed with 100 ml of water, 100 ml of 5% aqueous sodium bicarbonate solution and 100 ml of water. After drying, the solvent is removed in vacuo. The gum thus obtained was dissolved in benzene / ethyl acetate 5: 1 and eluted on a silica gel column of 30 g with benzene / ethyl acetate first 5: 1 and 2: 1 as eluent. Fractions containing the title compound were evaporated in vacuo and the resulting foam was treated with petroleum ether (bp 40-60 ° C) to give 0.5 g of the title compound.

The structure as the title compound was confirmed by TLC, NMR and IR data. Thus, the NMR spectrum (10% CDCl 3) showed the following Τ 'values: 1.65 (NH ^), 2.65 (phenyl ring), 3.03 (ester-CH), 4.72 (Cg-H; O ?-5), 5.54 (C3-CH2), and 6.26 (02- ^). IR (nujol): 1775 (β-lactam) and 1715 ciri (-C00CHPh2).

Example 4

Diphenylmethyl (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-carboxylate To a slurry of 9.2 g (43 mmol) of phosphorus penta-chloride in 40 ml of dichloromethane was added 3, 5 ml (44 mmol) of pyridine in 10 ml of dichloromethane. The mixture was stirred for 15 minutes and then cooled to -5 ° C. To this mixture was added a solution of 5.7 g (about 7 mmol) (6R, 7R) -7- (R-5-benzenesulfonylamino-5-carboxypentanamido) -3-hydroxymethylceph-3-em - 4-carboxylic acid bis-diphenylmethyl ester in 50 ml of dichloromethane. The mixture was stirred for 15 minutes during which time the temperature reached 15 ° C. The solution was cooled to -10 ° C, 40 ml of methanol was added and the solution was stirred for 15 minutes at 15 ° C. The resulting solution was washed with 100 ml of water, 100 ml of water aqueous overnight in solution and 100 ml of water. This solution was subjected to further reactions without isolation of the title 7-amino compound, the presence of which was confirmed by TLC and NMR data.

Example 5

Difenylmetyl- (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-Karb-oxylate

To a slurry of 9.2 g (43 mmol) of phosphorus pentachloride in 40 ml of dichloromethane was added 3.5 ml (44 mmol) of pyridine in 10 ml of dichloromethane. The mixture was stirred for 15 minutes and cooled to -5 ° C. To this mixture was added a solution of 10 g (about 9 mmol) of (6R, 7R) -7- (R-5-carboxy-5-isobutyloxy-carbonylaminopentanamido) -3-hydroxymethylceph-3-em-4-carboxylic acid. acid bis-diphenylmethyl ester in 50 ml of dichloromethane. The mixture was stirred for 15 minutes during which time the temperature reached 15 ° C. The solution was cooled to -10 ° C, 40 ml of methanol was added and the solution was stirred for 15 minutes at 15 ° C.

The resulting solution was washed with 50 ml of water, 100 ml of 5% aqueous sodium bicarbonate solution and 100 ml of water. The solution contained the title compound, the structure of which was confirmed by IR and NMR data. The solution was subjected to further reactions without isolation of the 7-amino compound.

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Example 6

Difenylmetyl- (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-carboxylate

To a slurry of 9.2 g (43 mmol) of phosphorus pentachloride in 40 ml of dichloromethane was added 3.5 ml (44 mmol) of pyridine in 10 ml of dichloromethane. The mixture was stirred for 15 minutes and then cooled to -5 ° C. To this mixture was added a solution of 6.5 g (about 8 mmol) of (6R, 7R) -3-hydroxymethyl-7_ (R_5-carboxy-5-trichloroethoxycarbonylaminopentanamido) -ceph-3_em-4-carboxylic acid bis-diphenylmethyl ester in 50 ml of dichloromethane. The mixture was stirred for 15 minutes during which time the temperature reached 15 ° C. The solution was cooled to -10 ° C, 40 ml of methanol was added and the solution was stirred for 15 minutes at 15 ° C. The resulting solution was washed with 100 ml of water, 100 ml of 5% aqueous sodium bicarbonate solution and 100 ml of water.

IR and NMR data confirmed that the solution contained the title compound; this was not isolated, but the solution was subjected to further reactions.

Example 7

Difenylmetyl- (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-karboxyiat

To a slurry of 13.0 g (62 mmol) of phosphorus pentachloride in 40 ml of dichloromethane was added 5 ml (62 mmol) of pyridine in 10 ml of dichloromethane. The mixture was stirred for 15 minutes at 20 ° C and then cooled to -5 ° C. To this mixture was added a solution of 20 mmol (6R, 7R) -7- [ft-5-carboxy-5- (2,2,2-trichloroethyloxycarbonylamino) -pentanamido7-3-hydroxymethylceph-3-em-4-carboxylic acid -bis-diphenylmethyl ester in 75 ml of dichloromethane. The mixture was stirred for 15 minutes during which time the temperature reached 15 ° C. The solution was cooled to -10 ° C, 70 ml of methanol was added and the solution was stirred at 15 ° C for 15 minutes and then washed with 100 ml of water. It was confirmed by IR and NMR data that the solution contained the title compound; this was not isolated, but subjected to additional reactants in situ.

Example 8 18 146853

Difenylmetyl- (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-carboxylate

A slurry of 15 g, 62 mmol of phosphorus pentachloride in 20 ml of dichloromethane was added to a solution of 17.5 g, 18 mmol (6R, 7R) -7- / R-5-carboxy-5- (2,2,2-trichloroethoxycarbonylamino). -pentanamido7-3-hydroxymethylceph-3-em-4-carboxylic acid bis-diphenylmethyl ester in 75 ml of dichloromethane containing 8 ml, 63 mmol of dimethylaniline The mixture was stirred for 15 minutes at 15 ° C and then cooled to -10 ° C. 75 ml of methanol were added and the solution was stirred for 15 minutes at 15 ° C and then washed with 2 x 100 ml of water The solution was subjected to further reactions without isolation of the one present there (confirmed by IR and NMR data) in the title -amino.

Example 9 1-Phenylethyl (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-carboxylate 10 g, ca. 10 mmol (6R, 7R) -7- / R-5-carboxy-5- (2,2,2-trichloroethoxycarbonylamino) -pentanamido7-3-hydroxymethylceph-3-em-4-carboxylic acid bis-1-phenylethyl ester was reacted in accordance with the process described in Example 7 to obtain a solution containing the title compound, the structure of which was thus confirmed by IR and NMR data. The solution was subjected to further reaction without isolation of the 7-amino compound.

Example 10

Diphenyl (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-carboxylate 18 g, 20 mmol (6R, 7R) -7- / R-5-carboxy-5- (2, 2,2-Trichloroethoxycarbonylamino) -pentanamido 7-3-hydroxymethylceph-3-em-4-carboxylic acid bis-diphenylmethyl ester was reacted in accordance with the process described in Example 7 with the difference that the imide halide forming agent was a slurry of 4.25 g (20 mmol) of phosphorus pentachloride and 1.7 ml (21 mmol) of pyridine in 50 ml of dichloromethane and the decomposition was carried out with 20 ml of butane-1,3-diol in 30 ml of dichloromethane instead of methanol, a solution was obtained containing the title compound whose structure as such was confirmed by IR and NMR data. The compound was further reacted without being isolated.

Example 11

Diphenylmethyl (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-carboxylate 12.9 g (16.6 mmol) (6R, 7R) -7- (R-5-carboxylic acid) 5-Ethoxy-carbonylaminopentamino-3-hydroxymethylceph-3-em-4-carboxylic acid bis-diphenylmethyl ester was reacted according to the method described in Example 7, with the exception that decomposition was carried out by 20 ml of butane-1,3-diol in 30 ml of dichloromethane instead of methanol; a solution was obtained containing the title compound. IR and NMR data confirmed the structure of the product as the indicated compound and it was further reacted without being isolated.

Example 12

Diphenylmethyl (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-carboxylate 3.9 g (7.5 mmol) diphenylmethyl (6R, 7R) -3-hydroxymethyl-7- ( thien-2-ylacetamido) ceph-3-em-4-carboxylate in 30 ml of dichloromethane was reacted in the manner described in Example 7, with the exception that the amounts of reagents indicated in Example 7 were halved; a solution was obtained containing the title compound whose structure was confirmed by IR and NMR data. The 7-amino compound is further reacted without isolation.

Example 13

Difenylmetyl- (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-carboxylate

A solution of 19 g (20 mmol) (6R, 7R) -7- / R-5-carboxy-5- (2,2,2-ethoxycarbonylamino) -pentanamido7-3-hydroxymethylceph-3-em-4-carboxylic acid bis-diphenylmethyl ester in 50 ml of dichloromethane was treated with 13 g (62 mmol) of phosphorus pentachloride and 5 ml (62 mmol) of pyridine and then with methanol, as described in Example 7.

The resulting dichloromethane solution of diphenylmethyl (6R, 7R) -7-amino-3-chloromethylceph-3-em-4-carboxylate was then dried over magnesium sulfate and further reacted without isolation of the compound whose structure was confirmed by IR and NMR data.

Example 14

Diphenylmethyl (6R, 7R) -7-amino-3-chloropmethylceph-3-em-4-carboxylate 1.28 g of phosphorus pentachloride was slurried in 8 ml of dichloromethane and added over 2 minutes at 15-20 ° C. , 5 ml of pyridine in 2 ml of dichloromethane. The slurry was stirred for 15 minutes and cooled to 5 ° C and a suspension of 1.0 g of diphenylmethyl (6R, 7R) -3-hydroxymethyl-7- (2- (thien-2-yl) -acetamido) -ceph was added. -3-em-4-carboxylate in 8 ml of dichloromethane over 5 minutes. After stirring for 15 minutes, the temperature was 15 ° C. The mixture was cooled to -10 ° C and added to 2 ml of cold butane-1,3-diol in 7 ml of diisopropyl ether. The mixture was stirred for 10 minutes at 0-8 ° C, 7.5 ml of water and 20 ml of diisopropyl ether were added and the solution grafted. A gum was obtained which was separated by decantation and dissolved in dichloromethane; to the solution was added the upper (organic) layer of the decanted liquid. The combined organic liquids were washed with 25 ml 1N aqueous sulfuric acid, 50 ml 5% aqueous sodium bicarbonate and 100 ml brine. The organic liquids were then dried over magnesium sulfate and the solvent removed under reduced pressure to give an oil which was dissolved in the least possible amount of dichloromethane and chromatographed on silica gel (column of 12.5 cm), eluting successively with benzene / ethyl acetate 4: 1 and benzene / ethyl acetate 2: 1. After thin layer chromatography of the eluted fractions, those containing the title compounds were combined; they were evaporated under reduced pressure and degassed to 0.6 g of the title compound as a foam. Thin layer chromatography showed that the product was free of contaminants.