CA1121360A - .beta.-LACTAM COMPOUNDS - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

.beta.-LACTAM COMPOUNDS

A process for the preparation of a compound of the formula (I):

(I) wherein R1 is a CH2CH3 or CH2CH2CH3 group of a salt or ester thereof, which process comprises the reduction of an ester of a compound of the formula (II):

Description

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This application is a division of Canadian Patent Application Serial No. 308,302, filed July 27, 1978.
The present invention relates to a process for the preparation of certain ethers of clavulanic acid, to chemical intermediates in the process, to a process for the preparation of these inter-mediates, and to pharmaceutical compositions containing them.
Ethers of clavulanic acid are disclosed in Belgian Patent No:
847045, Japanese Patent Application No: 122725/76 and U.S. Patent Application Serial No: 786345. U.S~ Application Serial No. 786345 corresponds to Canadian Patent Applications Nos. 263105 and 298622.
It has been found that ethyl and propyl ethers of clavulanic acid and derivatives thereof can conveniently be prepared via the vinyl and propenyl ethers of clavulanic acid.
Accordingly, the present invention provides a process for the preparation of the compounds of the formula (I):

H

-- ~CH20R1 ~ _N ~ (I) `CO2H

and salts and esters thereof wherein Rl is a CH2CH3 or CH2CH2CH3 group, which process comprises the reduction of an ester o~
a compound of the formula (II):

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` r ` CH OR (II) ` C02H

wherein R2 is a CH-CH2 or CH=CH-CH3 group and there-after or simultaneously if desired converting the thus-formed ester of the compound of the formula (I~
to the corresponding acid or a sal-t thereof.

Most suitably, -the reaction is performed on an ester of the compound of the formula (II) wherein R2 is a CH=CH2 group.

The reduction reaction is normally effected by hydro-genation in -the presence of a catalys-t such as a trans-ition metal catalyst, such as platinium oxide, pallad-ium or the like. An approximately atmospheri.c pressure of hydrogen is generally most convenient for laboratory use, but sub-atmospheric pressures may also be employed, so long as ex-treme conditions are avoided.

If a compound of the formula (I) ~er se or a salt thereof is required, this may be obtained by de-esteri-fying a suitable ester of the compound, for example, by the hydrolysis of a methoxymethyl or like ester or by the hydrogenation of a benzyl, p-methoxybenzyl or like ester optionally in the presence of a base, for example, as described in Belgian Patent No: 847045.

If desired, the hy~rogenation o~ the vinyl or propenyl group and hydrogenolysis of the ester may occur at the same time, by selecting a suitable catalyst and solvent, for example, by using a tetrahyd-rofuran - containing solvent sys-tem and by using a palladium or mixed platin-ium oxide/palladium catalyst.

The compounds oE the Eormula (Il) and salts and esters thereof form the invention of the aforementioned parent patent application.
Preferably, R2 i~ a CH-CH2 group.

Suitable es-ters of the compounds of the formula (II) include those wherein the esterifying moiety is a group A1 or CHA2A3 wherein A1 is an allcyl group of 1 8 carbon atoms optionally substituted by halogen or by a group of the formula oA4, oCoA4, SA4, So2A4 herein A4 i,5 a hydrocarbon group o~ up to 6 carbon atoms; A is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl group optionally substituted by halogen or by a group A5 or oA5 where A5 is an alkyl group of up to 6 carbon atoms; and A3 is a phenyl group optionally substituted by halogen or nitro or by a group A5 or oA5 where A5 is an alkyl group.

Preferably, the ester of the compound of the formula (II) is such that the corresponding ester of the compound of the formula (I) is a readily hydrolysable or hydro-genolysable ester. Suitable esters of this type include the methoxymethyl~ ethoxymethyl, benzyl, methoxybenzyl, nitrobenzyl and the like esters.

A particularly preferred ester of the compounds of the formula (II) is the p~nitrobenzyl ester.

Suitable salts of the compounds of the formula (II) include alkali metal~ alkaline earth metal and ammonium and substitu~ed ammonium salts.

Preferably, the salt is a pharmaceu-tically aeceptable salt.

The above novel compounds possess useful ~-lactamase inhibi-tory proper-ties whlch allow them to be utilised in antibaeterial compositions. Aeeordingly, there is provided a pharmaceu-tical composition whieh eomprises a compound of the formula (II) or a pharmaeeutieally accep-table salt or ester thereof and a pharmaceutically acceptable carrier.

The aforementioned compositions may be utilized as deseribed in the aforementioned pa-tent speeifieations and may advantageously contain a penicillin or cephalosporin.

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There is also provided a process for the prepara-tion of the compounds of -the formula (II) and salts and esters thereof which process comprises the reaction of an ester of clavulanic acid with a compound of the formula (III) or (IV):

R3 - 0 - CH = CH2 (III) R~ - 0 - CH = CH - CH3 (IV) wherein R3 is an alkyl group of up to 6 carbon atoms, in the presence of mercuric ions as catalyst, and thereafter~
if desired, de-esterifying the resulting ester of the compound of the formula (II).

Most sui-tably, R3 in formulae (III) and (IV) is an ethyl group.

Most suitably, -the catalyst is mercuric acetate or mercuric trifluoroacetateO

The reaction may take pl.ace in an inert organic solvent, or if a large excess of the compound of the formula (III) or (IV) is used, this may act as solvent.

The reaction may be effected at a non~e~treme temperature such as about -10 to 60C, for example from about 0 to 30C.Low temperatures in this range are preferred when using a compound of the fromula (IV).
Compounds of the formula (II) and salts thereof may ~e formed by cleavage of the corresponding p-nitrobenzyl ester. This cleavage may be effected using a reducing agent which reduces the nitro group to an amino group, for example, as described in Dutch Patent Application No: 7702027. An example of a suitable reducing agent * correspvnds to Belgian Patent Mo. 851821.

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_ 6 _ is iron powder/ammonium chloride solution.

The follo~ing Examples illustrate this invention~

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Example 1 Benzyl 9-0-vinylclavulanate H H
F I-- ~ ~2H~~

Co2cH2c6H5 C02CH2C6H5 Mercuric acetate (50 mg) was added to a solution of benzyl clavulanate (1g) in ethyl vinyl ether (10 ml).
The solution was refluxed for 6 hours, then allowed to stand at room tempera-ture for 72 hours. The solvent was removed under vacuum and the product purified by colwnn chromatography (Kieselgel G, cyclohexane:e-thyl acetate 3:1). Yield 0.676g. I.r:~ max (film) 1805, 1750, 1700, 1638, 1620 cm 1. N.m.r.: ~ (CDCl3) 3.00 (1H, d, J 17Hz), 3.43 (1H, dd, J 3Hz and 17 Hz), 3.95 (1H, dd, J 7Hz and 3Hz), 4.13 (1H, dd, J 3 and 14Hz), 4.26 (2H, d, J 7Hz), 4.81 (1H, broad t~ J 7Hz), 5.05 (1H, s), 5.13 (2H, s), 5.64 (1H, d? J 3Hz), 6-33 (1H~
dd, J 14 and 7Hz), 7.27 (5H, s).

. , .;

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_ 8 -Example 2 Benzyl 9-0-ethylclavulanate H H

~ C~ 6~5 ~o~2c r~

A solu-tion of benzyl 9-0-vinylclavulana-te (81 mg) in ethy]. acetate (10 ml) was hydrogena-ted over Adams catalyst (10 mg) for 2 hours at room temperature and pressure. The solution was filtered and the ~iltrate evaporated, and the product separated from starting material by column chromatography (Kieselgel, cyclo-hexane:ethyl acetate 3:1). Yield 54.8 mg~

I.r~rmax(film) 1805, 1750, 1700cm 1.
N.m.r.~(CDCl3) 1.16 (3H, t, J 7Hz), 2.98 (1H, d9 J
17Hz), 3.37 (2H, q, J 7Hz), 3.41 (1H, dd, J 3 and 17Hz), 4.00 (2H, d, J 7Hz), 4.79 (1H, t, J 7Hz), 5.04 (1H, s), 5.14 (2H, s) 5.62 (1H, d, J 3Hz), 7.29 (5H, s).

Exa~le 3 .
Me-thoxvmethyl 9-0-vinylclavulanate H H
~ OH 2 5 ~ O--CH=CH2 `C02CH20CH3 C02CH20CH3 A mixture of methoxymethyl clavulanate (972 mg), e-thyl vinyl ether (10 ml) and mercuric ace-tate (50 mg) was heated at reflux, with stirring, for 3~ hours. The mixture was allowed to stand at room temperature 5 overnight, a further portion oP methyl vinyl ether (3ml) was added, and the mixture was refluxed for a fur-ther hour. The solvent was removed under vacuum, and the product was isolated using column chromatography-(Kieselgel 60, cyclohexane:ethyl acetate 3~1) Yield 10 550 mg as a pale yellow oil.

I.r:~ max (film) 1810, 1755, 1700, 1635, 1620 cm 1 N-m-r- ~ (CDCl3) 3.05 (1H, d, J 17Hz), 3.44 (3H, s), 3.48 (1H, dd, J 3 and 17Hz), 4.97 (1H, dd, J 2 and 7Hz), 4.16 (1H, dd, J 2 and 14Hz), 4.31 (2H, d, J 7Hz), 15 4.90 (1H, broad t, J 7Hz), 5.06 (1H, broad s), 5.22 (1H, d, J 5Hz), 5.33 (1H, d, J 5Hz), 5.68 (1H, d, J
3Hz), 6.36 (1H, dd, J 7 and 14 Hz).

(i ... .

' ~ ' ~z~3~3~

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Example 4 .
Benzyl 9-0-pro~en~Icla~ulanate H~ H

~ ~ t ~ _ r~l ~ 0 _ CH=CHCH3 0 ~`` C N
C02CH2C6H5 H3 "C02CH2C6H5 A stirred solution of benzyl cla~ulanate (578 mg) in ethyl propenyl ether (5 ml) was cooled to 0C and treat-ed with mercuric trifluoroacetate (20 mg). After 2 hours at 0C, -the mixture was allowed to warm to room temperature for 16 hours. The solvent was remcved under reduced pressure and -the product was isolated by column chroma-tography (Kieselgel 60, cyclohexane:
ethyl acetate 4:1) Yield 246 mg as a pale yellow oil.

I.r:~ max (film) 1800, 1750, 1695, 1670 cm 1.

N.m.r : ~ (CDCl3) 1.45 - 1.65 (3H, m), 2.99 (1H, d, J
17HZ), 3.44 (1H, dd, J 3 and 17Hz), 4.1 - 4.5 and 4.6 -4.95 (4H, m), 5 05 (1H, s), 5.13 (2H, s), 5.62 (1H, d, J 3Hz), 5.8 - 6.2 (1H, m)~ 7.28 (5H, s).

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Benzyl 9-0-propy~ clavulanate H~ H
~ ~ 3 F 1- ~ -CH2CH2CH3 `C02CH2C6H5 C02CH2C6H5 A solution of benzyl 9-0-propenylclavulanate (42.2 mg) in ethyl acetate (3ml) was hydrogenated over Adams catalyst (10 mg~ for 3 hours at room tempera-ture and pressure. The solution was filtered and evaporated to yield the title compound (40.9 mg).

1 spot by t.l.c (cyclohexaneoethyl ace-ta-te 3:1) I-R- max(film) 1805, 1755 and 1700cm~1 N.m.rO (CDCl3) 0.88 (3H, t, J 7Hz) 1.55 (2H, sextet J 7Hz). 2.99 (1H9 d, J 17Hz), 3.27 (2H, t, J 7Hz), 3.42 (1H, dd, J 3 and 17Hz), 3.99 (2H, d, J 7Hz), 4.78 ~1H, broad t, 7Hz), 5.04 (1H, s), 5.14 (2H, s), 5.62 (1H, d, J 3Hz), 7.78 (5H, s).

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12 _ Example 6 .
Sodium 9-0-propyl clavulanate H H
,O ~
_ CH,= CHCH3 ~)~0 -CH2CH2CH~5 ~0 CH C H 0 ~

2 2 6 5 ` C02IJa A solution of benzyl 9-0-propenylclavulanate (117 mg) in tetrahydrofuran (4 ml) was hydrogenated over 10%
palladium on charcoal (40 mg) at room temperature and presssure for 10 minutes. The solution was filtered 5 through celite and the residue washed with tetrahydro-furan. The combined filtrates were treated with a solution of sodium bicarbonate (29.9 mg) in distilled water (4 ml). The tetrahydrofuran was then removed on a rotary evaporator. The residual aqueous solution 10 was extracted twice with ethyl acetate and filtered through celite. The solution was evaporated on a rotary evaporator and the residue dried over phosporus pent-oxide to yield the title compound (77.5 mg).
N.m.r. (D20) 0.84 (3H, t, J 7Hz), 1.53 (2H, sextet~
J 7Hz), 3.05 (1H, d, J 17Hz), 3.41 (2H, t, J 7Hz), 3.54 (1H, dd, J 3 and 17Hz), 4.07 (2H, d, J 7Hz), 4.86 (1H, broad t, J 7Hz), 4.91 (1H, s), 5.69 (1H, d, J 3Hz).

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Example 7 .
Pivaloylox~meth~l 9-0-vin~lclavulanate H` H

OH ~ O-CH=CH2 N ~
~02CH20-CO-c(c~3)3 " C02CH20-CO-c(cH~3 A mixture of pivaloyloxymethyl clavulana-te (700 mg of crude material) ethyl vinyl ether (5 ml) and mercuric acetate (50 mg) was refluxed for 6 hours and left to stand at room temperature overnight. The solvent was removed under vacuum and the product isolated by column chromatography (Kieselgel 60~ cyclohexane:ethyl acetate 3:1). Yield 19 mg.

I.r:~ max (film) 1810, 1760, 1700, 1635, 1620 cm 1 N.m.r.~ ~ (CDCl3) 1.19 (9H, s), 3.02 (1H, d, J 17Hz), 3.46 (1H, dd, J 3 and 17Hz), 3.96 (1H, dd, J 2.5 and 7Hz), 4.05 - 4.35 (3H, m), 4.84 (1H, broad t, J 7Hz), ~5.04 (1H, broad s), 5.66 (1H, d, J 3Hz)~ 5.71 (1H, d, J 5Hz), 5.78 (1H, d, J 5Hz)~ 6.35 (1H, dd, J 7 and 14Hz).

3~0 q~ - 1 L~ - .

Example 8 Methyl 9-0-vin~clavulanate H C2H5~ H

~OH + ¦ ¦ ~ yO~ CH=CH2 ` C02CH3 ' C2CH3 A mixture of methyl clavulanate (426 mg), ethyl vinyl ether (5 ml) and mercuric acetate (25 mg) was heated at reflux for 4 hours. The solvent was removed on a rotary evaporator and the produc-t purified by column chromato-5 graphy. (Kieselgel, cyclohexane:ethyl acetate 1:1) Yield 168 mg.

I.r.:~ ma~ (film) 1800, 1750~ 1700~ 1632~ 1618 cm 1.

N.m.r: ~ (CDCl3) 3.02 (1H~ d, J 17Hz) ~ 3.46 (1H~ dd, J
3 and 17Hz) ~ 3.74 (3H~ s) ~ 3.97 (1H~ dd, J 3 and 7Hz)

4.16 (1H~ dd~ J 3 and 14Hz) ~ 4.28 (2H~ d~ J 8Hz) 4.85 (1H, broad t9 J 8Hz), 5.04 (1H, s~ ~ 5.66 (1H, d~
J 3Hz) ~ 6.36 (1H~ dd, J 7 and 14Hz) .

Analysis: Found C 55.19, H5.70, N 5. 93%
C11H13N05 requires C 55.23~ H 5.48~ N 5.860/o.
j',,,', ( .

~1 ~13~0 Example 9 -Nitrobenzyl 9-0-vinyl-clavulanate p-Nitrobenzyl clavulana-te (3.34g) was dis-solved in dry tetrahydrofuran (30ml). Ethyl vinyl ether (50ml) and mercuric acetate (0.5g) were added to this solution and the resulting mixture was stirred and refluxed (bath temperature 40-50) with exclusion of moisture for 24 hours. The mixture was filtered and the solvent was evaporated from the filtrate to yield a bright yellow gum. The gum was chromatographed on silica gel (25 g) using ethyl acetate/petroleum ether (b.p. 60-80). The appropriate fractions, which were recognised using -t.l.c., were combined and the solvent was evaporated to give the title compound as a pale yellow gum (270mg). [~]20 = + 31.6 (c 1.09 CHC13).
~ max (CHCl3): 1802, 1750, 1700, 1620, 1615, 1525, 1350 cm 1 ~ (CDC13)~ 3.07 (1H, d, J 16Hz), 3 51 (1H, dd, J 16 and 2Hz), 3.95-4.15 (2H, m) 4.32 (2H, d, J 8Hz), 4.88 (1H, t, J 8Hz), 5.15 (1H, br.s), 5.28 (2H, s),

5.70 (1H, d, J 2Hz), 6.39 (1H, dd, J 14 and 7Hz), 7.49 ~2H, d, J 8.5Hz), 8.22 (2H, d, J 8.5Hz).

, ` ~ .

` ~ Z ~ 3 Example 10 Lithium 9-0-vinyl-clav~lanate H H
0 - CH = ~~ ~ 0-CH=CH2 N ~ ~ N-~
C02CH~>No2 C02Li p-Ni-trobenzyl 9-0-vinyl-clavulanate (190mg) was dissolved in tetrahydrofuran (6ml~ and to the result-ing stirred solution 1M ammonium chloride solution (6ml) and iron powder (0.8g) were added. The mix-ture was stirred for 20 minutes and then more iron powder (0.8g) and 1M ammonium chloride solu-tion (0.5ml) were added.
The mixture was stirred for a further 15 minutes and was then diluted with ethyl acetate (100ml). The resulting mixture was stirred rapidly while hydrogen sulphide was bubbled through it for 5 minutes. The mixture was filtered and the solid was washed well with water. The aqueous layer of the filtrate was saturated wi-th sodium chloride and the mixture was filtered again. The filtrate was treated wi-th 1N HCl (3ml), was shaken, and the layers were separated. The organic layer was dried (sodium sulphate) and filtered. The resulting solution was extracted with 1/15 ~ phosphate buffer (pH 7; 3 x 30ml).
The combined extracts were overlayed with ethyl acetate (50ml) and were treated with 1N HCl (5ml). The mixture was shaken and the layers were separated. The organic layer was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure. The resulting residue was immediately dissolved in -tetrahydrofuran (5ml). This .

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~Z:~3~3 solution was diluted with water (5ml) and the pH wasadjusted to 7 by dropwise addition of 0.1M lithi~
hydroxide solution (ca 2ml). The neu-tralised solution was ~iltered and the solvent was evaporated from the filtrate under reduced pressure. The resulting residue was stirred with a mix-ture of acetone (3ml) and ether (6ml). The resulting solid was collected by filtration, washed with ether, and dried in vacuo.
The title compound was thus obtained as a very pale yellow powder which appeared to be 70-80%
pure as judged by t.l.c. and n.m.r.
~ max (KBr): 1770, 1690, 1610 cm 1. ~(D20); inter alia:
3.02 (1H, d, J 17Hz), 3.50 (1H) dd, J 17 and 2.5Hz), 4.00-4.25 (2H, m), 5.68 (1H, d, J 2.5Hz), 6.42 (1H, dd, J 14 and 7Hz).

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Demonstration of ~-Lactamase Inhibi'tory Activit~
The minimum inhibitory concentrations (MIC) of certain compounds of this invention and of ampicillin, alone or in the presence of compounds of the invention, were determined in vitro for a range of micro-organisms.
The results are shown in Table 1.

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Table 1 Compound of Conc. MIC Ampicillin Example No. ~g/m] ~g/ml . ....................... _ l . SAR KA PM EC
8 5 0.6 3.18 8 1 1.25 3.1 62.5 16 0 250 62.5500250 Compound alone 125500 250 500 0.08 3.12 2 4 1 0.3 3.12 8 8 _ 0 ~ 10001000 1 ~2000 2000 Compound alone 15.631.2 62.5 31.2 SAR : Staphylococcus aureus Russell XA : Klebsiella aerogenes E70 PM : Proteus mirabilis C889 EC : E. coli JT39

Claims (10)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula (I):

(I) wherein R1 is a CH2CH3 or CH2CH2CH3 group of a salt or ester thereof, which process comprises the reduction of an ester of a compound of the formula (II):

(II) wherein R2 is a CH=CH2 or CH=CH-CH3 group and thereafter is desired converting the thus-formed ester of the compound of the formula (I) to the corresponding acid or a salt thereof.

2. A process as claimed in claim 1 wherein R2 is a CH=CH2 group.

3. A process as claimed in claim 2 wherein the reduction is effected by hydrogenation in the presence of a transition metal catalyst.

4. A process as claimed in claim 3 wherein the catalyst is platinum oxide or palladium.

5. A process as claimed in claim 1, 2 or 3 for the preparation of a compound of the formula (I) or a salt thereof wherein the methoxymethyl ester of the compound of the formula (I) is de-esterified by hydrolysis.

6. A process as claimed in claim 1 for the preparation of a compound of the formula (I) or a salt thereof wherein the benzyl or p-methoxybenzyl ester of the compound of the formula (I) is de-esterified by hydrogenolysis, optionally in the presence of a base.

7. A process as claimed in claim 6 wherein the hydrogen-ation of the vinyl or propenyl group and hydrogenolysis of the ester occur at the same time.

8. A process for the preparation of benzyl 9-0-ethylclavu-lanate which comprises hydrogenating a solution of benzyl 9-0-vinylclavulanate in ethyl acetate over Adams catalyst and separating the required product.

9. A process for the preparation of benzyl 9-0-propyl clavulanate which comprises hydrogenating benzyl 9-0-propenyl-clavulanate in ethyl acetate over Adams catalyst and separating the required product.

10. A process for the preparation of sodium 9-0-propyl-clavulanate which comprises hydrogenating benzyl 9-0-propenyl-clavulanate in tetrahydrofuran over 10% palladium on charcoal, treating the product with sodium bicarbonate and separating the required product.