DK144066B - METHOD OF ANALOGY FOR THE PREPARATION OF DEOXYCLAVULANIC ACID DERIVATIVES - Google Patents

Description

(19) DENMARK

Iff <, 2> submission script η4066 Β

DIRECTORATE OF THE PATENT-OQ TRADE MARKET

(21) Application No. 1565/76 (61) IntCI * C 07 [) (22) Filing Day 51 · Mar. 1976 98 / 0A (24) Race day 51 · roar. 1976 (41) Aim. available Oct. 15 1976 (44) Presented 50 · Nov. 1 981 (86) International Application No. "(86) International Filing Day - (85) Continuation Day ~ (62) Master Application No. ~

(30) Priority 1 ^. April 1975, 152Ο9 / 75, GB 27-Sep. 1975, 3967i / 75 QB

(71) Applicant BEECHAM GROUP LIMITED, Brentford, GB.

(72) Inventor Thomas Trefor Howarth, GB: Jennifer Goodacre, qb: r

John Ponsford, GB. is (74) Plougmann & Vngtoft's Patent Office.

(54) Analogous process for the preparation of deoxyclavulanic acid derivatives.

The present invention relates to an analogous process for the preparation of novel β-lactam-containing compounds of general formula III

H

—Γ ° \ / CH 3] Q 0 i

£> COOR

D

ISLAND

Wherein R represents H, R or CHR R, wherein R represents a hydrocarbon group of 1-9 carbon atoms optionally monosubstituted with halogen, C1-6 alkoxy, C2-7 acyl, hydroxy or C 1-6 acyloxy, and 3 R 2 and R 3 optionally represent with halogen, C 1-6 alkyl or C 1-6 alk oxy monosubstituted phenyl, or a pharmaceutically tolerable salt of the compound wherein R is hydrogen, with bases which compounds should be used for antibacterial therapy.

Danish Patent Application No. 1672/75 discloses that the compound of formula I

H

; ch2oh i

COOH

and salts and esters thereof have antibacterial and β-lactamase inhibitory effect. The compound of formula I is called clavulanic acid. Acylated derivatives of the above compounds are described in Danish Patent Application No. 4738/75 and in Danish Patent Application No. 5748/75 isoclavulanic acid and salts and esters thereof, which isoclavulanic acid having formula II

rix

X CHOOH

0 '2 S

COOH

Isoclavulanic acid and acylated clavulanic acid derivatives as well as salts and esters thereof also have antibacterial and β-lactamase inhibitory effect. A further group of compounds with valuable antibacterial and β-lactamase - inhibitory effect has now been found.

The present invention is based on this recognition and, as mentioned, relates to an analogous process for the preparation of compounds of general formula III

3 144066 '/% —Γ ° \ = ™ J-Ν \ / ο χ

COOR

1 2 3 1 wherein R represents Η, R or CHR R, wherein R represents a hydrocarbon group of 1-9 carbon atoms optionally monosubstituted with halogen, C acyloxy, 2 3 1-0 2-7 x_0 and R and R optionally represent with halogen, C 1-6 alkyl or C 1-6 alkoxy monosubstituted phenyl, or a pharmaceutically tolerable salt of the compound wherein R is hydrogen, with bases, which method is peculiar to a corresponding

compound of the general formula X

H

_

\ s = a = sCH-CH ~ OR6 X

\ \

COOR

wherein R is as defined above and R® is a hydrogen atom or an acyl group or, if R is hydrogen, a salt of the kind set forth in the preamble of claim 1, hydrogenated and then, if desired, a recovered ester of formula III is hydrolyzed in the presence of a base to form a pharmaceutically tolerable salt with bases of the acid of formula III, and / or a recovered acid of the general formula III or a salt thereof thereof reacted with an alcohol of the formula R'OH or with a compound of formula R'Q, wherein R 'is as defined above for R except H, and Q represents a leaving group, or a recovered acid of formula III is treated with a diazo compound of formula R'N2 wherein R' has the meaning given above.

The stereochemistry at the carbon atoms 2 and 5 of compounds of formula III is the same as that found in naturally occurring penicillins.

The acid of formula IV

4 144066 Η -1/0 £ Η ~ .jxy%

COOH

IV

is a therapeutic agent, but generally the pharmaceutically tolerable salts thereof are preferred because of their better stability.

Suitable salts of the compounds of formula III include usual pharmaceutically tolerable salts such as sodium, potassium, calcium, magnesium and ammonium salts and in the usual manner substituted ammonium salts formed with benzylpenicillin such as 1-ephenamine, procaine, benzathine and similar salts.

Particularly suitable salts of deoxyclavulanic acid are e.g. the sodium and potassium salts as these salts are convenient to use for e.g. injection.

When comparing the results obtained using phenacyldeoxyclavulanate and sodium deoxyclavulanate, respectively, it is seen that the salt form is most active. Therefore, it is advantageous to prepare a salt form, and a preferred variant of the process according to the invention therefore assumes that the compound of formula X is in the form of a salt.

Suitable esters of formula III are those having the general formula VIII

5 144066 Η I n CH- rfv- /

I> = CH VIII

Or R 2 COOR 'wherein R 1 is as defined in the definition of Formula X and is such an organic group that the alcohol R'OH is pharmaceutically tolerable.

It is believed that the antibacterial effect of the esters of deoxy-clavulanic acid is due to their ability to act as "pro-drugs" for deoxyclavulanic acid and its salts. Thus, preferred esters are those which can be converted to the corresponding acid or salts thereof under physiological conditions.

Suitable groups R 'are alkyl, alkenyl, alkynyl, aryl and arylalkyl, all of which, if desired, may be substituted in the manner described above.

Preferably, the group R 'is theoretically derived from an alcohol R'OH which is pharmaceutically tolerable. Suitable groups R 'include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, vinyl, allyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclohexadienyl, methylcyclopentyl, methylcycloentyl, methylcyclohexyl , cyclohexylmethyl, benzyl, benzhydryl, phenylethyl, phenyl, propynyl, tolyl, 2-chloroethyl, acetylmethyl, benzoylmethyl, 2-methoxyethyl, p-chlorobenzyl, p-methoxybenzyl, p-bromobenzyl, m-chlorobenzyl, p-chlorophenyl and p methoxyphenyl.

Pharmaceutical compositions may be prepared which contain a compound of formula III and a pharmaceutically tolerable carrier. Such compositions advantageously contain a pharmaceutically tolerable salt or a pharmaceutically tolerable in vivo hydrolysable ester of formula III.

6 144066

It is particularly suitable that the pharmaceutical composition contains a pharmaceutically tolerable salt of the compound of formula III.

The present compositions are usually designed for administration to humans and other mammals, e.g. for use in the usual way of treating bacterial infectious diseases of the urinary tract, respiratory tract and soft tissue, and for treating diseases such as otitis media in humans and mastitis in domestic animals.

The compound of formula III may be present in the composition as the sole therapeutic agent, or it may occur together with other therapeutic agents, e.g. another β-lactam antibiotic. Suitable other β-lactam antibiotics for use in such preparations include not only those known to be sensitive to β-lactamases, but also those which have some intrinsic resistance to β-lactams. Thus, other suitable β-lactam antibiotics for use in compositions of this type are e.g. benzylpenicillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, hetacillin, ampicillin, amoxycillin, ticarcillin, cephaloridine, cephalothin, cephalexin, cephaloglycine, cephamandole and in vivo ester hydrolyses phenyl-, tolyl- and 5-indanyl esters of carbenicillin and ticarcillin, the acetoxymethyl ester of benzyl-penicillin and acetoxymethyl, pivaloyloxymethyl and phthalidyl esters of ampicillin, amoxycillin, cephaloglycine, cephalexin salts and the like.

When the compound of formula III is present in a pharmaceutical composition together with another β-lactam antibiotic, the ratio of the compound of formula III or its salt or ester to the other β-lactam antibiotic may be e.g. be between 20: 1 and 1: 5, e.g. between 10: 1 and 1: 3, and the ratio may advantageously be between 5: 1 and 1: 2, e.g. between 3: 1 and 1: 1.

The total amount of the antibacterial agents present in any unit dosage form will usually be between 50 and 1500 mg, usually between 100 and 1000 mg. However, injectable or infusible compositions may, if desired, contain greater amounts, e.g. 4 g or more active substance. Usually between 50 and 6000 mg of the present compositions should be administered on each treatment day, but preferably between 500 and 3000 mg of the compositions should be administered daily. Generally, a daily dose of not more than 2000 mg of a compound of formula III, e.g. 100 - 1000 mg.

In the process of the invention for the preparation of compounds of formula III it is often particularly convenient to use

C

a compound of formula X, wherein R is a hydrogen atom, when using a lighter reaction is obtained. It is also often convenient to use a compound of formula X in the form of a salt thereof, as the salt form of the final product, as stated above, has a slightly more potent effect than esters.

The hydrogenation reaction of the process according to the invention is often carried out in the presence of a catalyst containing a transition metal, e.g. palladium or platinum oxide. A particularly suitable catalyst is activated carbon palladium, e.g. 10% palladium on activated charcoal.

The catalyst used is suitably present in highly active form, e.g. one obtained by using a fresh portion of catalyst.

It is most convenient that the weight of catalyst present (as a total of 10% palladium / activated carbon or the like) is at least 1/3 of the weight amount of the compound of formula X or a salt or ester thereof, since this way, the best yield of the desired compound is ensured. Advantageously, at least as much catalyst as a compound of formula X is present, especially for those compounds where R 1 is hydrogen.

The process of the invention usually takes place at non-extreme temperature. Eg. the reaction can take place in a lower alkanol at a temperature between -10 and + 50 ° C, usually between 0 and 25 ° C, e.g. between 5 and 20 ° C.

The process of the invention usually takes place in an inert solvent such as a lower alkanol, water or an aqueous alkanol. It is particularly convenient that the solvent used is a lower alkanol such as methanol or ethanol. For those compounds of formula X wherein R 2 is hydrogen, water-miscible ethers such as tetrahydrofuran may also be used, but such ether solvents are not generally useful when an acyl group is used.

Elevated, medium or low hydrogen pressure can be used in this reaction. It is generally preferred to use hydrogen at atmospheric pressure or at pressures slightly above atmospheric pressure.

A preferred form of the process of the invention consists in the hydrogenation of clavulanic acid or a salt or a hydrogenolysable ester thereof in the presence of a palladium catalyst. Such a process leads to the preparation of a compound of formula IV or a salt thereof. If a salt is desired and the clavulanic acid is not already in salt form, a base such as sodium hydrogen carbonate may be used in the reaction medium.

The nature of an acyl group R®, which may occur in a compound of formula X, is relatively immaterial as long as it does not lead to rapid degradation of the compound of formula X. Suitable acyl derivatives are disclosed in Danish Patent Application No. 4738/75 .

/ Γ Particularly suitable acyl groups r contain up to 9 carbon atoms and may be optionally substituted by e.g. halogen, C 1-6 alkoxy, C 2-6 alkoxycarbonyl, C 1-6 acyloxy or hydroxy. It is particularly desirable that such acyl groups be unsubstituted or only substituted with non-reactive groups.

Esters of formula III can be prepared by reacting a recovered acid of formula III or a salt thereof with an alcohol R'OH or a compound of formula R'Q, wherein R 1 has the meaning given for R other than H and Q is a well split unit, e.g. a chlorine, bromine or iodine atom, an activated ester group, a sulfone ester such as a mesylate or tosylate group or other usual well-leaving group. Alternatively, the acid of formula III obtained can be treated with a diazo compound R'N2 such as diazomethane.

9 "144066

The reaction with R'Q is usually carried out in an organic solvent with a relatively high dielectric constant, e.g. dimethylformamide, acetone, dioxane or tetrahydrofuran, and at a non-extreme temperature, e.g. between -5 and + 100 ° C, usually between +5 and 30 ° C, e.g. at room temperature.

The reaction between an acid of formula III and a diazoalkane is a mild method of preparing alkyl or aralkyl esters.

The diazotization may be carried out under usual reaction conditions, e.g. at a non-extreme temperature and in a usual solvent. Such reactions are usually carried out between -5 and + 100 ° C, usually between 5 and 30 ° C, e.g. at room temperature. Suitable solvents for this reaction include lower alkanols such as methanol and ethanol and solvents such as tetrahydrofuran or dioxane. Ethanol has been found to be a particularly valuable solvent for this reaction. The reaction of an acid of formula III with an alcohol in the presence of a condensation promoter will normally take place in an inert organic solvent such as dichloromethane or acetonitrile. This reaction is usually carried out at room temperature or lower temperature, e.g. between -10 and + 22 ° C, usually between -5 and + 18 ° C, e.g. first at 0 ° C and then gradually heating to approx. 15 ° C. The condensation promoting agent used is usually an agent which removes water from the reaction mixture. Suitable agents are e.g. carbodiimides, carbodiimidazoles or similar reagents. Dicyclohexylcarbodiimide has been found to be a particularly suitable condensation enhancer for this process.

Salts of the compounds of formula III can be prepared by hydrolysis of an ester of formula III. This can generally be accomplished by holding the ester of formula III in an aqueous medium which is maintained at a pH of approx. 7-9, for up to 1 hour. Certain reactive esters such as the pivaloyloxymethyl and acetoxymethyl esters hydrolyze in a few minutes when kept in an aqueous medium having a pH of approx. 6-8 to give acids which can then be neutralized to form salts with the fumble III.

10 U4066

The process according to the invention is further illustrated by the examples below

Example 1.

Natriumdeoxyclavulanat.

H

I h

, -U-o% OH

220 mg of benzylclavulanate in 20 ml of ethanol is hydrogenated over 70 mg of 10% palladium / carbon and 60 mg of sodium bicarbonate for 60 minutes. The catalyst is filtered off and washed with water and then ethanol and the combined filtrates are evaporated. This substance is chromatographed on a 4: 1: 1.75 silica gel column with n-butanol / ethanol / water and the fastest-running component is isolated. The solvents are removed under low pressure to give the sodium salt of deoxy-clavulanic acid.

IR Spectrum (KBr): 1780, 1700 and 1605 cm -1. NMR Spectrum (D 2 O): 1.52 (3H, dd, J 7Hz, J'1, 5Hz); 2.98 (1H, d, J 18Hz, δβ-CH)} 3.52 (1H, dd, J 18Hz, J '2.5Hz, 6a-CH); 4.5 - 4.9 (m, disturbed by HOD tip); 5.64 (1H, d, J 2.5Hz, 5-CH).

[The sodium salt of clavulanic acid is also obtained from the column by further elution].

Example 2.

11 144066

Natriumdeoxyclavulanat.

H

I H

'CH-OH' ^ jXx ”1 'o s \'

COOCH2CgH5 COOH

NaHCO3 1 J- j. O, CH,

N

OONa 8.25 g of benzylclavulanate are dissolved in 75 ml of tetrahydrofuran. To this solution is added 8.25 g of 10% palladium / activated charcoal and the mixture is hydrogenolysed at room temperature under vigorous shaking and using 1 atmosphere hydrogen pressure for 30 minutes. The suspension is filtered and the filtrate is treated with a solution of 2.39 g of sodium bicarbonate dissolved in the least amount of water. The solution is evaporated under reduced pressure on a rotary evaporator at room temperature and the residue is triturated with acetone and ether to give 4.7 g of a pale yellow solid. This salt is identical to that of Example 1 and has the same physical data.

12 144066

Example 3

Natriumdeoxyclavulanat.

H

CHO-CO-CHO-O-C / -Ht rT w2265 h (T + Z Z, Pa / c COOCH2C6H5 NaHCO3 and to the solution are added 56 mg of sodium hydrogen carbonate and 47 mg of 10% palladium / activated charcoal. The solution is hydrogenated at room temperature (corresponding to 18 ° C) for 15 minutes. dryness to give a quantitative yield of contaminated sodium deoxyclavulanate. .

Example 4

p-Brombenzyldeoxyclavulanat.

? ! CH

Γ ~ Κ °, CH3 Br-C6H4-CH2Br / 3 J-Lr - \ \ COONa 'cooch 2 “Q ~ Br 144066 13

A solution of 50 mg of p-bromobenzyl bromide is added to a solution of 10 mg of sodium deoxyclavulanate in 0.5 ml of dimethylformamide and the mixture is kept at room temperature (about 18 ° C) for 2 hours. The reaction mixture is fractionated on silica gel eluting with ethyl acetate / hexane in a ratio of 1: 4 to give, after evaporation, p-bromobenzyl dioxyclavulanate (in the form of an oil).

IR Spectrum (CHCl3): 1790, 1740, and 1695 cm -1 NMR Spectrum JCDC13): 1.62 (3H, dd, J 7Hz, J * 1.4Hz, CH 2.95 (1H, dd, J 17Hz, J '1.0Hz, 6p-CH); 3.48 (1H, dd, J 17Hz, J '2.6Hz, 6a-CH); 4.58 (1H, dq, J 7Hz, J 1Hz, = CHCH 3); 5.03 (1H, dd, J 1.4Hz, J '1.0Hz, 3-CH); 5.12 (2H, s, CO 2 CH 2 -); 5.65 (1H, dd, J 2.6Hz, J '1.0Hz, 5-CH); 3.38 (4H, ABq, J 8.5Hz, aromatic protons).

Example 5

Methyldeoxyclavulanat.

1.45 g of benzyl clavulanate in 40 ml of methanol is hydrogenated over 0.4 g of 10% palladium / carbon at room temperature and atmospheric pressure for 30 minutes. The catalyst is filtered off and the filtrate is cooled to 0 ° C and treated with an excess amount of ethereal diazomethane. The solvent is evaporated and the oil recovered from the residue is fractionated on silica gel with ethyl acetate / hexane as the eluent. As the first eluted product, 365 mg of methyl deoxyclavulanate is obtained.

IR Spectrum (CHCl-J: v = 1800, 1745 and 1700 cm

J IClaX

NMR Spectrum (CDCl 3): δ = 1.68 (3H, dd, J 7.5 and 1.5Hz, = CH-CH 3), 3.07 (1H, d, J 17Hz, ββ-CH), 3.59 ( 1H, dd, J 17 and 2.5Hz, 6a-CH), 3.84 (3H, S, COOCH3), 4.71 (1H, dq, J 7.5 and 1.5Hz, = CH-CH3), 5.08 (1H, m, 3-CH), 5.76 (1H, d, J 2.5Hz, 5-CH); M + = 197.0688.

Λ

Example 6

14 144066

Phenacyldeoxyclavulanat.

-yO / CH3 / 0. / CH3 __II / + CcHr-COCHoBr -Jj /

6 5 2 Y

COONa COOCH2COPh 0.2 g phenacyl bromide is added to a solution of 0.2 g sodium deoxyclavulanate in 5 ml dimethylformamide and the mixture is stirred at room temperature for 3 hours. The solvent is removed and the residue is dissolved in ethyl acetate, washed with water, dried and evaporated. Gradient chromatography on silica gel using cyclohexane / ethyl acetate as the eluant yields the product which, by recrystallization of ether, gives 0.15 g of colorless crystals.

Mass measurement shows a molecular ion at m / e 301.

IR Spectrum (nujol): ν max = 1798, 1755 and 1702 cm NMR Spectrum (CDCl 3): δ = 1.7 (3H, dd, J 7 and 1.5 Hz, = CHCH 3), 3.0 ( 1H, dd, J 17 and 1Hz, ββ-CH), 3.5 (1H, dd, J 17 and 3Hz, βα-CH), 4.81 (1H, m, CHCH 3) 5.17 (1H, m, 3-CH), 5.4 (2H, s, CH 2 COh), 5.7 (1H, dd, J 3 and 1 Hz, 5-CH), 7.7 (5H, m, ArH).

Pharmacology.

Sodium deoxyclavulanate did not appear to induce any obvious toxic effects on mice when the compound was administered intraperitoneally at a dose of 500 mg / kg.

The antibacterial and synergistic properties of sodium deoxyclavulanate are illustrated by the following results obtained in vitro: 15 U4066

Organism Minimum inhibitory concentration of sodium deoxyclavulanate (µg / ml)

Bacillus subtilis A 62.5

Enterobacter clodbae NI 125

Escherichia coli 10418 62.5

Klebsiella aerogenes A 62.5

Proteus mirabilis C 977 125

Pseudomonas aeruginosa A 1000

Salmonella typhimurium CT10 125

Serratia marcescens US 39 125

Staphylococcus aureus Oxford 15.6

Staphylococcus aureus Russell 31

Organism Minimum inhibitory concentration (µg / ml) ampicillin in the presence of various concentrations of sodium deoxyclavulanate (yug / ml) _ 0__1__5__20_

Staphylococcus aureus Russell 500 0.8 0.08 *

Klebsiella aerogenes E70> 500 0.8 0.2 - 0.4 0.1 - 0.02 * Inhibition was induced by sodium deoxyclavulanate alone at this concentration.

Comparison of antibacterial activity and synergistic effect of sodium clavulanate (C) and sodium deoxyclavulanate (D), respectively. The following results have been obtained in vitro: 16 144066

Antibacterial effect:

Organic MIC (/ µg / ml) __ __D__C_

Escherichia coli JT4 62 31

Escherichia coli JT410 125 31

Klebsiella aerogenes E70 125 125

Proteus mirabilis C889 62 31

Pseudomonas aeruginosa

Dalgleish 61-125 125-250

Staphylococcus aureus

Russell 62 31

Synergistic effect:

Organism | MIC_ Ampicillin (, ua / ml) _ + D (/ Ug / ml) + C (/ Ug / ml) _ __1 '5 alone 1' 5

Staphylococcus aureus

Russell 0.8 0.16 250 0.4 0.16

Klebsiella aerogenes E70 6.0 6 ', G 500 6.0 1.6

Escherichia coli 'JT4> 500 500> 2000 600 125

Proteus mirabilis__250_62> 500 250_3Γ_

The minimum inhibitory concentrations (MIC) in vitro have been determined for ampicillin alone, phenacyldeoxyclavulanate alone and ampicillin in the presence of 5 µg / ml phenacyldeoxyclavulanate.

The results are given in the table below: MIC (yug / ml)

Staphylococcus Klebsiella aureus Russell aerogenes E70 1) Ampicillin 500 500 2) Phenacyldoxyclavulanate 125 125 3) 1) + 5 µg / ml 2) 0.2 31 The table below gives the I5Q values (µg / ml) for some representative compounds of the formula III: 17 144066 o \

COOR

I50 (/ u? / Ml) R Staphylococcus Escherichia Klebsiella

Russell coli JT4 E.70 CH2COC6H5 0.27 0.2 0.14 CH3 1.0 4.8 1.9 CH2CgH5 0.6 14 0.4 Ι_Λ is the concentration of the clavulanic acid derivative that causes you a 50% inhibition of purified β-lactamase produced by a bacterial strain.

The percent inhibition of β-lactamase is calculated as follows using that of Batchelor et al., Proc. Roy.

Soc., B 154, 498 (1961), described hydroxylamine experiments wherein the inhibition is determined colorimetrically or spectrophotometrically:

Absorption of standard penicillin blind minus absorption of control sample (uninhibited reaction) = X.

Absorption of test (inhibited reaction) minus absorption of the control sample (uninhibited reaction) = Y.

Y

Percent inhibition = - - 100 Λ

To obtain the IQ value, the inhibitor preparation is diluted until 50% inhibition of the β-lactamase inactivation of standard penicillin is achieved.

Claims (2)

18 144066 Patent Claims. An analogous process for the preparation of deoxyclavulanic acid derivatives of the general formula III H 'OH., Γ-K ° \ / II) = CH III' 'λ \ \ COOR 1 2 3 1 wherein R represents H, R or CHR R, wherein R represents a hydrocarbon group having 1-9 carbon atoms optionally monosubstituted with halogen, C1-6 alkoxy, C2-6 acyl, hydroxy or C1-6 acyloxy, and R2 and R3 optionally with halogen, C C 1-6 alkyl or C 1-6 alkoxy monosubstituted phenyl, or a pharmaceutically tolerable salt of the compound wherein R is hydrogen, with bases, characterized in that a corresponding compound of the general formula XHIT \ === CH-CH, OR6 x N \ / COOR g wherein R is as defined above and R represents a hydrogen atom or an acyl group or, if R is hydrogen, a salt of the kind set forth in the preamble of the claim, hydrogenated and then, if desired, a recovered ester of formula IXI is hydrolyzed in the presence of a base to form a pharmaceutically tolerable salt with bases of the acid having Formula III, and / or a recovered acid of general formula III or a salt thereof, is reacted with an alcohol of formula R'OH or with a compound of formula R'Q, wherein R 'has the meaning given above for R except H and Q represent a leaving group or a recovered acid of formula III is treated with a diazo compound of formula R'N2 wherein R 'has the meaning given above.