DK142702B - Process for the preparation of isoclavulanic acid derivatives. - Google Patents

Description

V R ^ Bby (11) SUBMISSION WRITING 142702 DENMARK m-a-s c 07 D 498/04 § (21) Application No. 57 ^ 8/75 (22) Filed on 17 · & eC. 1975 (24) Race day 17. deC. 1975 (44) The application presented and "

the writ of publication published on the 22nd aeC. Lyou

DIRECTORATE OF ._u ...

PATENT AND TRADEMARKET ™ ™ 1g? ^^ jQQ / ^ GB

Apr 14 1975a 15211/75, GB

(71) BEECHAM GROUP LIMITED, Beecham House, Great West Road, Brentford,

Middlesex TW8 9 ^ D, GB.

(7¾ Inventor: Thomas Trefor Howarth, Little Yard Cottage, North Breache Lane, Ewhurst, Surrey, GB: Irene Stirling, 147 Vale Road, Worcester Park, Surrey, GB.

(74) Plenipotentiary in the proceedings:

Plougmann & Vingtoft Patentbureau._ (54) Process for producing isoclavulanic acid derivatives.

The present invention relates to a particular process for the preparation of novel (3-lactam-containing compounds with β-lac-tamase inhibitory activity and, to some extent, antibacterial activity.

Danish Patent Application No. 1672/75 discloses clavulanic acid, which is a compound of the formula

H

in

! CH "0H

i i

COOH

2 142702 or salts or esters thereof. Clavulanic acid is a β-lactamase inhibitor and an antibacterial agent.

An additional group of compounds having β-lactamase inhibitory activity and antibacterial properties has now been found.

The present invention is based on this recognition and relates to

a process for preparing a compound of formula I

H

<-4λ '/ λ N. ch2oh 1

COOH

Here, a salt thereof having a base or a hydrogenolysable or hydrolysable ester thereof, the process of which is characterized in that a compound of formula VI

H

_U CH20H

WE

COOH

or a salt or ester of the above type is isomerized by contacting with a transition metal catalyst in the presence of hydrogen or by ultraviolet radiation.

whereupon, if desired, the carboxylic acid-derived function in the 2-position is converted to another carboxylic acid-derived function of the above-mentioned kind.

A particularly suitable group of the subject compounds are the pharmaceutically tolerable salts and esters.

142702 3

Such salts are e.g. sodium, potassium, calcium, magnesium, aluminum and usual substituted ammonium salts, especially salts having the general formula III

O + --NV ch 2 H t COO + M + where M + is a sodium or potassium ion.

Such salts can form hydrates.

Esters of the compound of formula I are those of general formula IV

RFV

CHOOH IV

o '; l

COOA

wherein A is such a group that COOA is a hydrogenolysable or hydrolysable ester group.

A is suitably an inert organic group having a maximum of 16 carbon atoms and in particular an inert organic group having a maximum of 12 carbon atoms.

Suitable substituents A are alkyl, alkenyl, alkynyl, aryl or aralkyl, all of which, if desired, can be substituted.

Suitable substituents which may be present in group A are halogen atoms or C 1-6 alkoxy, hydroxy, C 1-6 acyloxy or C 1-6 aryloxy.

Thus, A can be methyl, ethyl, n-propyl, isopropyl, straight or branched butyl, pentyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl, allyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclohexenyl, cyclohexadienyl, methylcyclopentyl, methylcyclohexyl, benzyl, benzhydryl, phenylethyl, naphthylmethyl, phenyl, naphthyl, propynyl, tolyl, 2-chloroethyl, 2,2,2-tri-chloroethyl, 2,2,2-trifluoroethyl , acetylmethyl, benzoylmethyl, 2-methoxyethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-piperidinoethyl, 2-morpholinoethyl, 3-dimethylaminopropyl, p-chlorobenzyl, p - methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, m-chlorobenzyl, 6-methoxynaphthyl-2-methyl, p-chlorophenyl or p-methoxyphenyl.

A preferred group of compounds of formula IV are those wherein A is a group having one of the subforms a) - d): -CA1A2 - X - CO - A3 a)

- | H - Z

0_ \ b)

ISLAND

4 - CHA A c) - A 6 d) 1 2 where A represents a hydrogen atom or a methyl group, A represents a hydrogen atom or an alkyl group of 1-4 carbon atoms, a phenyl group or a benzyl group, A represents an alkyl group, an aryl group or an aralkyl group having 7-11 carbon atoms, X represents oxygen or sulfur, Z represents a divalent organic group, A 4 represents a hydrogen atom or an inert aryl group, A5 represents an inert aryl group, and A carbon atoms optionally substituted with halogen atoms or with C 1-6 alkyl, C 1-6 acyl or C 1-6 acylated hydroxy.

In the sub-formulas listed above, A1 is suitably a hydrogen atom, A is a hydrogen atom or a methyl group, A is a methyl, tert-butyl or phenyl group, X is oxygen, Z is -CH = CH-, 142702.

X! ~ XC

OCH 3 4 A is hydrogen, phenyl, tolyl, halophenyl or methoxyphenyl, A8 is phenyl, tolyl, halophenyl or methoxyphenyl, and A8 is a hydrocarbon group having 1-6 carbon atoms optionally substituted with chlorine, bromine, iodine, trifluoromethyl, C ( CH3) 3, methoxy, acetyl, benzoyl or acetoxy.

A particularly preferred group of compounds of formula IV are those wherein A is a group having one of sub-formulas e) and f): A 7 - 9 - C - 0 - CO - A * e) i8 - CH - A12 i10-C = AU £> * 7 g where A represents a hydrogen atom or a methyl group, A represents g a hydrogen atom or a methyl, ethyl or phenyl group, A represents an alkyl group of 1-6 carbon atoms or a phenyl or benzyl group, A 8 represents -Cfc ^ Ct ^ -, -CH = CH-, X xc-xc ch3 and 3 11 12 and A and A denote oxygen or sulfur.

g In the sub-formulas (e) and (f) above, A is particularly conveniently a hydrogen atom, A is suitably a methyl, 11 12 ethyl, propyl, butyl or phenyl group, A and A are particularly suitably oxygen atoms, and A10 is particularly convenient for a group of 6,670,702 X. v / OCH or OCH3 Particularly suitable hydrogenolysable ester groups A are e.g. benzyl, naphthylmethyl, benzhydryl and trityl groups and their inert substituted derivatives such as 4-bromobenzyl, 3,4-dimethoxybenzyl, 6-methoxy-2-naphthylmethyl, 4,4-dimethoxybenzhydryl and 2-nitrobenzyl groups.

From the compounds of the process of the present invention, pharmaceutical compositions containing compounds of the general formula I may be prepared. Such preparations may also contain a pharmaceutically tolerable carrier.

The compositions in question are usually administered for administration to humans or other mammals, e.g. for usual treatment methods of bacterial diseases of the urinary tract, respiratory system and soft tissue, as well as diseases such as otitis media and mastitis.

Suitable formulations are e.g. tablets, capsules, creams, syrups, suspensions, solutions, reconstitutable powders and sterile forms suitable for injection or infusion. Such compositions may contain usual pharmaceutically tolerable substances such as diluents, binders, dyes, flavors, preservatives, disintegrants and similar substances in accordance with pharmaceutical practice.

The compound of formula I may be present in the composition as the sole therapeutic agent or together with other therapeutic agents such as penicillin or cephalosporin antibiotics.

The total amount of antibacterial agents present in unit dosage form will usually be between 50 and 1500 mg and will usually be between 100 and 1000 mg. However, injectable or infusible compositions may, if desired, contain greater amounts, e.g.

4 g or more active substance.

7 142702

Usually between 50 and 6000 mg of the compositions will be administered each day of treatment, preferably between 500 and 3000 mg of the compositions per day. However, for the treatment of severe systemic infections or infections caused by particularly stubborn organisms, larger doses may be used, in accordance with clinical practice.

In one aspect of the process of the present invention, the isomerization reaction is carried out by contacting a compound of formula VI with a transition metal catalyst in the presence of hydrogen.

If the isomerization reaction is carried out on an ester of the compound of formula VI, the final product will often be a compound of formula I or a salt thereof if the ester group present in the starting compound is a hydrogenolysable ester group.

A particularly suitable method for preparing the compound of formula I or a salt thereof is to bring compounds of general formula VII

H

in

'^ .0. CH-OH

- [\ = / J.-N \ / C) 'COOA' wherein COOA 'is a hydrogen-soluble ester group, in contact with a transition metal catalyst in the presence of hydrogen, wherein this reaction is carried out in the presence of a base to produce a salt of the compound of formula I.

A particularly suitable transition metal catalyst for carrying out the isomerization reaction is palladium, e.g. 10% palladium / coal.

In carrying out the isomerization reaction, the weight ratio of the transition metal catalyst to the compound of formula VI or VII will conveniently be less than 1: 3, e.g. 1: 2.5 - 1: 3. (in the present specification the term "the weight of the transition metal catalyst" also includes the weight of any carrier present for the transition metal catalyst). A particularly preferred variant of the process of the invention is that the transition catalyst is palladium and that the weight ratio of the catalyst to the starting material is less than 1: 3, as this results in reduced propensity for side reactions such as reduction of the C -,-group.

If the reaction is carried out in the presence of 1 atmosphere of hydrogen pressure, the reaction will usually be completed in less than 10 hours. Particularly long reaction times must be avoided as they may lead to an unacceptable reduction rate for the exocyclic double bond of compound I.

The reaction can be carried out at any non-extreme temperature, e.g. between -20 and + 100 ° C, e.g. between -5 and + 40 ° C such as between 0 and + 20 ° C.

The reaction is usually carried out in an organic solvent which is inert under the reaction conditions. Suitable solvents include lower alkanols such as ethanol, low boiling halohydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran.

It is to be understood that the compounds of formulas VI and VII are not always completely converted to the corresponding compounds of formula I, and that an equilibrium mixture of compounds VI and I or VII and I. often arises. usual way, e.g. by chromatography.

The ultraviolet irradiation of the starting materials is conveniently carried out on the benzyl ester of a compound of formula VI.

This reaction is usually carried out in a degassed organic solvent such as benzene, carbon tetrachloride, acetonitrile or other conventional solvents.

The reaction is usually carried out in an inert atmosphere, e.g. under argon or nitrogen.

9 U2702

The reaction is usually carried out at room temperature for convenience, but any non-extreme temperature, e.g. between -20 and + 80 ° C, although moderate temperatures are preferred, e.g. between 0 and + 30 ° C.

In accordance with conventional practice, a photosensitizer may be used, if desired, so agents such as dibenzyl, iodine, acetophenone or benzophenone may be used.

A wide or narrow ultraviolet spectrum can be used to induce the photolytic isomerization of the compound of formula VI. "Hanovia" ® low-pressure and medium-pressure mercury lamps have been found to give satisfactory results. When using such lamps, a silicon or glass water cooling sheath ("Pyrex" ®) can be used.

When a compound of formula VI is irradiated with ultraviolet light, the compound of formula I can be formed in admixture with the starting material or together with a number of other products. This mixture can be separated in the usual manner, e.g. by chromatography. It has been found that separation of the compound of formula I can often be conveniently carried out by column chromatography, e.g. by column chromatography on silica gel with an ethyl acetate / cyclohexane mixture.

The carboxylic acid-derived function at the 2-position of the compound of formula I can be converted to another carboxylic acid-derived function in the usual manner well known to those skilled in the art.

For example, when is a free carboxylic acid group at the 2-position, it can be converted to an ester group by reaction with an alcohol AOH, where A has the meaning given in formula IV, in the presence of a condensation promoting agent, e.g. dicyclohexylcarbodiimide, or by reaction with a diazo compound, e.g. diazomethane or it can be converted to a salt by treatment with a base, e.g. sodium or potassium hydrogen carbonate.

A salt of a compound of formula I may be converted to an ester by a conventional nucleophilic substitution reaction by reaction with a compound AQ wherein A has the definition of formula IV and Q is a good leaving group, e.g. Cl,

Br, I, OSO2CH3 or OSO2CgH4CH3.

142702

The process according to the invention is illustrated by the following examples:

Example 1.

H H

I T

l / \, CS20H, _ | / \ f y = j i [v =, di

J— "Ύ O Ύ 'CH2 ° H

I * I * C00CHoC0CcHt- '2 65 COOCH2COC6H5 (1) (2)

A diluted solution of 100 mg phenacylclavulanate (1) in 100 ml dry benzene was irradiated in a quartz vessel using a 450 watt "Hanovia" ® medium pressure mercury lamp (from Engelhard Hanovia Lamps,

Bath Road, Slough, Buckinghamshire, England) under nitrogen atmosphere for 3 hours. The solvent was removed by evaporation in vacuo and thin layer chromatography of the residue showed two components which were separated by silica gel chromatography with ethyl acetate / cyclohexane (1: 1) as eluant. The more polar component was investigated spectroscopically and found to be identical to the starting material.

The minor polar component was investigated by hplc (high pressure liquid chromatography) and found to be a mixture of two compounds which were separated by preparative hplc. The second eluted component was obtained in the form of a colorless oil in a yield of 151 by the theoretical and was added by spectroscopic examination to the structure shown as (2).

IR spectrum (film): 3480, 1790, 1750 and 1690 cm -1.

NMR Spectrum (CDCL3): 3.02 (1H, dd, J 17Hz, J '1Hz, 6β-Η); 3.52 (1H, dd, J 17Hz, J * 3Hz, 6a-H); 4.27 (2H, d, J 9Hz, CH 2 OH); 5.43 (1H, s, CHCO 2 R); 5.48 (1H, m, CHCH 2 OH); 5.52 (2H, s, CH 2 COPh); 5.73 (1H, dd, J 3Hz, J '1Hz, 5-H) and 7.7 (5H, m, aromatic -H).

Example 2.

11 142702

! f, _V ° \ / CHjOH _yO

f i y = \ + »i

0> -J, Y 0J- * Y CH 2 OH

•! COOCH2C6H5 COOCH2CgH5 (3) (4)

A solution of 300 mg of benzylclavulanate (3) in 300 ml of dry benzene was irradiated under nitrogen atmosphere in a quartz vessel using a "Hanovia" Photochemical "Reading Reactor" to give benzyl isoclavulanate (4) as a colorless oil and a 40% yield after column chromatography with ethyl acetate / cyclohexane (1: 2) as eluant. The lamp unit (from Engelhard Hanovia Lamps, Bath Road, Slough, Buckinghamshire, England) contains two low-pressure ultraviolet lamps of 45 watts each with an energy maximum at 254 nm.

IR spectrum (CH 2 Cl 2): 3550, 1795, 1740 and 1685 cm NMR spectrum (CDCl 3): 1.85 (1H, s, CH 2 OH); 2.98 (1H, dd, J 17Hz, J '1Hz, 6β-Η); 3.45 (1H, dd, J 17Hz, J '2.5Hz, 6a-H); 4.05 (2H, d, J 7Hz, CH 2 OH); 5.18 (2H, s, Ci 2 C 2) 5.32 (1H, s, CHCC> 2CH 2 C 6 H 5); 5.35 (1H, m, perturbed by signal at 5.32, CHCH₂OH); 5.63 (1H, dd, J 2.5Hz, J '1Hz, 5-H); 7.36 (5H, s, aromatic -H). Mass spectrum of this product showed a molecular ion at m / e 289.0949 (ci5Hy5N05 has a theoretical value of 289.0950).

12 142702

Example 3

H

, Η H

, _, CH OH l a i Λ 'CH OH!

COOCH "CfiHR" I

COOCH2C6H4Br COOCH2C6H4Br (3) (5) (6) 94 mg of benzyl clavulanate (3) in 8 ml of ethanol was hydrogenated over 30 mg of 10% palladium / carbon and 28 mg of sodium bicarbonate for 60 minutes. The catalyst was filtered off and washed with water, then the ethanol and the combined filtrates were evaporated. The residue was dissolved in 2.5 ml of dry dimethylformamide containing 245 mg of m-bromobenzyl bromide and the solution was allowed to stand at room temperature for 2 hours. The solution was fractionated on silica gel using first 1: 1 ethyl acetate-hexane and then ethyl acetate. Fractions 16 - 19 were evaporated to give 11 mg of p-bromobenzylisoclavulanate (5) in the form of thin bars of mp 134 - 134.5 ° C (of methylene chloride-carbon tetrachloride). Fractions 21-24 were evaporated to give 52 mg of p-bromobenzyl clavulanate (6) in the form of needles, mp 103 - 104 ° C (of methylene chloride-carbon tetrachloride).

The structures and absolute stereochemistry of the two products (5) and (6) were determined by X-ray analysis.

Example 4

13 142702 H f rh_ - * rfh J — NX / V, nH S ch2oh γ 'f CH ~ OH O' 2

0.2 I

in 'H00CHoC, H,' - + 2 6 5 COO Na (4) (7)

A mixture of 60 mg of benzyl isoclavulanate (4), 17.6 mg of sodium hydrogen carbonate and 20 mg of 10% palladium / carbon in ethanol was hydrogenated at 20 ° C and 1 atmosphere pressure for 105 minutes, followed by thin layer chromatography (ethyl acetate-cyclohexane the 1: 1 ratio showed that the reaction was complete. The catalyst was filtered off and washed with water and the filtrate and the combined washings were evaporated. The residue was treated twice with ethanol and evaporated, treated with acetone and evaporated and triturated with acetone / ether to give 30 mg of sodium isoclavulanate (7) as an off-white powder.

NMR Spectrum (D 2 O): 3.10 (1H, d, J 17.5Hz, δβ-CH); 3.64 (1H, dd, J 17.5Hz, J '3.0Hz); 4.18 (2H, d, J 7.5Hz, CH 2 <OH); 5.22 (2H, m, = CH-CH 2 OH, 3-CH); 5.86 (1H, d, J 3.0Hz, 5-CH).

The minimum inhibitory concentrations (MIC) in µg / ml of sodium isoclavulanate, ampicillin and combinations of sodium isoclavulanate with ampicillin against certain β-lactamase-producing organisms are given in Table I. The results were obtained by the microtiter technique with an inoculum obtained by overnight cultivation and then a 1: 500 dilution of the culture fluid was used.

14 142702 O + 1 tn β • h G s β β H m o • η β oi o M> h m μ td

Ml id H

Id S o µ tu --—____ 115.

µ ^ ® -3

? M

.5 +> +> J + G td ^ c c S C id

-ri ri i — I

7 ^ O Η £ β O 'Λ ^ H \> ro oj m pq TtO> Id "· g1 o β ho yj u cn * h \ u 0) Λ ogg so ω -η tu rtj nj Η Η cn η ο - ; - -µ μ ι ο m 6 η ns 3

Qi Η g td µ +> β h ++ + td ι — i td c ^ <UGC td + J Η Ή r-1 td tn 1-1 ^ _ C ΰ µ Η £> ω β tu a) -H \ td t- ~ m η h tn otnH 'S «H Η β O o oj> <U ft \ O ^ h td tj> Ό g tn η o G«! m h HU · Η (U OH Λ Λ tn η μ ------- td -η ω ο ι Εη ε tn ft g

Gtn G

Η β -Η Μ ft Μ -Ρ 4J + -µ id

βω <d C

C β G G <d <D -HH ΟΊ o 14-1 μ Η Η β * · * td β η ε> H m

β Η \ β H

H O O 'H

ε ω η β o \ β ft \ ο tn ο ε ω β ο <1 Η Η \ Ο__

U

Η Ο G

Η · Η μ> ι -) _ _ 1) ^ Η Ο Ο Η ft Η ° Ο -β β Ο mm Μ -μ · Η 8) ω ft> Β I Ό __ ^ _____ α ο η ε S Η ω η β Η Ο Ο 0 Γ "u ω ft Ο ω β tu υ β Η ω g ο ft η tu ω high -η> ι ω η ø G, β β ω ίβ β ft (UX! Ο tn β μ tu μ μ + J β Η 0) ο C0 β ft β

Claims (1)

A process for the preparation of isoclavulanic acid of the formula I H i 'O, rf v_ --- N \ / \ I 0 ^ CH 2 OH in A i t. COOH or a salt thereof with a base or a hydrogen-soluble or hydrolysable ester thereof, characterized in that a compound of formula VI