LU83071A1 - CHEMICALS - Google Patents

Description

JT

The present invention relates to 2ß-chloromethyl-2a-methylpename-3a-carboxylic acid sulfone, a pharmaceutically acceptable salt or a corresponding readily hydrolyzed ester which is useful as a β-lactamase inhibitor.

The presumed association between resistance shown by ß-lactam antibiotics against certain bacteria and the ability of these bacteria to produce ß-lactamases has led to an intensive search for ß inhibitors. -lactamase. Clavulanic acid is an example of such a compound currently being studied in detail. Another β-lactamase inhibitor has the following formula in acid form: 15. ? 2 H H Γ Œ H ~ N — f-- 2 I ^ H3 J - * - {

COOH

20 and is the subject of European patent application 2927 published on July 11, 1979 *

The compound of formula: 25

H H

Ξ 1.-CH, Cl H, N - if 2 2 ^ —CH3) - ^ - i.

Q COOH

30 'is described in the patents of the United States of America "No. 4.036.84-7, 4.009.159, 3 * 993 * 646, 3 * 989 * 685 and 3 * 954 * 732.

* · US Pat. No. 4,155,912 describes 2-penem-3-carboxylic acid derivatives of the formula: JT '2,

COOH

as well as the esters and the salts, about which one can also refer to Farmdoc Abstracts ^ 82090A, 10336B and 44337B.

10 The compound (bearing the number CP-45899) of formula:> V ^ CH3

i5 è ~ n — I

COOH

is an irreversible ß-lactamase inhibitor with excellent solution stability. It has a weak antibacterial activity and potentiates the in vitro and in vivo activities of ampicillin with regard to the strains producing ß-lactamase [A. R. English et al., Antimicrobial Agents and Chemotherapy, 14-, 414-419 (1978), Aswapokee et al., J. Antibiotics 31 (12), 1238-1244 (Dec. 1978) and Derwent's Farmdoc Abstracts 25 89627 and 73866B].

It has been reported by B. Baltzer et al., "Mutual ^ Pro-Drugs of ß-Lactam Antibiotics and ß-Lactamase Inhi bitors" J. Antibiotics, 33 (10), 1183-1192 (1980) that the principle of combining a tarnished ß-lac-JO cycle antibiotic with a ß-lactamase inhibitor in a single molecule functioning as a drug precursor for the two active constituents is illustrated by the combined esters 3 and 4 in which ampicillin and mecil-liname, respectively, are combined with penicillanic acid sulfone 33 which is a ß-lactamase inhibitor. It has been shown that in humans these esters are absorbed excellently in the gastrointestinal tract and hydrolyzed after absorption with simultaneous release of the active ingredients. As a result, high blood and tissue levels of antibiotic and β-lactamase inhibitor are reached which have a balanced ratio. The advantages offered by "mutual drug precursors" over simple combinations are considered.

Esters 5 and 4 mentioned are those answered, with the formulas: 10 Ο-ξ “-" p, 2 ÿ — N - // ^ 0 o o 'co ° K J? Co * T' NV * '

pr k nrxf K

- * C0 —0 θ '? 'CO-O

0 or 20 —-

It is indicated in the document GB 2044255 published on October 15, 1980 that the invention described eon-25 identifies hitherto unknown compounds of general formula:

H H

E1_ÇH-C0-NH! - »" ÎP: 0 ▼

u H C — 0 — CH — A

n il 1 * 0 1 55 where R- ^ represents a phenyl, 4-hydroxyphenyl, 1,4-cyclohexadienyl or 5-thienyl radical; R2 represents a primary amino or carboxyl radical; R ^ represents a

J

4 hydrogen atom or a lower alkyl, aryl or aralkyl radical and A represents a radical of a ß-lactamase inhibitor containing a ß-lactam ring, in addition to a carboxyl radical, A being united via the radical 5 carboxyl.

These new compounds are useful for the treatment of bacterial infections and are, in particular, highly active against bacteria producing β-lactamase. Reference can also be made to this subject 10 at armdoc Abstracts 607730 and 607760.

^ The subject of the invention is therefore the acid of formula:

O O

___________ V // CH_Cl _ / 2 15 f '"CH3

Cr tzOOH

or a pharmaceutically acceptable salt of the acid or an easily hydrolyzed ester of the acid.

The above-mentioned pharmaceutically acceptable salts include non-toxic metal salts, such as sodium, potassium, calcium and magnesium salts, ammonium salt and substituted ammonium salts, such as amine salts non-toxic such as trialkylamines (for example triethylamine), procaine, dibenzylamine, III-ben-zyl-β-phenethylamine, 1-ephenamine, ΪΓ, Ν'-diben-zylethylenediamine, dehydroabietylamine, Ν, ΙΓ'-30 bis (dehydroabiethyl) ethylenediamine, U-alkyl (lower) piperidines (e.g. h-ethylpiperidine) and other amines which have been used to form pharmaceutically acceptable salts of penicillins and cephalosporins. The especially preferred salts are the alkali metal salts, i.e. the sodium and potassium salts, in addition to the ammonium salt.

For the purposes of the invention, "physiologically hydrolyzed esters" means pharmaceutically acceptable esters which are known to hydrolyze to free acids in vivo. Examples of suitable physiologically hydrolyzed esters are esters comprising a phenacyl, ace-toxymethyl, pivaloyloxymethyl, cx-acetoxyethyl, <x-acetoxybenzyl, a-pivaloyloxy ethyl, phthalidyl (3-phthali-dyl), indanyl (5-) radical. indanyl), methoxymethyl, methylated benzoyloxy-h, tx-ethylbutyryloxymethyl, propionyloxymethyl, valeryloxymethyl, isobutyryloxymethyl, 6 - [(R) -2-amino-2-phenylac etamido] -3,3-dimethyl-7-oxo-4- thia-l-azabicy-clo [3.2.0] heptane-2-carbonyloxymethyl and 6 - [(R) -2-ami-no - 2-p -hydr oxyphenyl ac et amido] -3,3-dimethyl-7- oxo-4-thia-1-azabicyclo [3 -2.0] heptane-2-carbonyloxymethyl.

Preferred esters are the esters comprising an acetoxymethyl, pivaloyloxymethyl, methoxymethyl, phthalidyl, 5-indanyl, 6 - [(R) -2-amino-2-phenylacetami-do] -3, 3-dimethyl-7-oxo-4 ~ radical. thia-l-azabicyclo [3.2.0] hepta-ne-2-carbonyloxymethyl and 6 - [(R)] - 2-amino-2-p-hydroxy-20 phenylacet amido] -3, 3-dimethyl-7-oxo -4-thia-l-azabicy- clo [3 -2.0] heptane-2-carbonyloxym ethyl.

The invention also relates to the process for producing the desired acid of formula: 25 0 0,.

- CB, C1 r— / NC 2 I CH3

-‘EooH

30 or a pharmaceutically acceptable salt of this acid, according to which, in successive stages, a) is subjected to catalytic hydrogenation, for example by means of a catalytic precious metal such as palladium, an ester of formula: 6 X CH Cl

V (> W

5 Γ CH3 ^ Λ — N ** 1

O- C02R

where E "* · represents a benzyl or substituted benzyl radical; cb) the hydrogenated product is subjected to oxidation to form the desired acid or its salt, then, if desired, c) esterified acid or salt to produce an easily hydrolyzed ester of the acid.

The subject of the invention is also the process for producing the desired acid of formula:

O O

20 .CH Cl γι '> 3 25 or a pharmaceutically acceptable salt of this acid, according to which, at successive stages, a) is oxidized, for example by means of EMnO 4, Έ.2Έ2 or a similar peroxide or well dJun peracide, an ester of formula: 50

Br? a CHpCl

% / J

I-f '"" CBj J_H-1

• 35- 0 C-OCVS

0 7 to form an ester sulfoxide of formula: 0 0

Br JpE2C1

5 VTiC

JN — k 0 C-OCHgCCl ^ 0 10 then b) reacting this sulfoxide ester with a metal in an acid, such as zinc in glacial acetic acid, to produce the desired acid or salt, then , if desired, c) esterifying the acid or its salt to produce an easily hydrolyzed ester of the acid,

Many oxidants known for the oxidation of sulfides to sulfones are suitable. However, particularly suitable reagents are the permanganates of alkali metals, such as potassium permanganate, and organic peracids, such as 3 “chloroperbenzoic acid.

Particularly useful protecting radicals R · * "are the benzyl radical and substituted benzyl radicals and especially the 4-nitrobenzyl radical.

Benzyl and substituted benzyl radicals can be conveniently removed by catalytic hydrogenation.

In this case, a solution of the compound of formula A, where 1 ~ R represents a benzyl or substituted benzyl radical, in an inert solvent is stirred in a hydrogen atmosphere or with hydrogen mixed with an inert diluent such as nitrogen or argon, in the presence of a catalytic amount of a hydrogenation catalyst. Solvents suitable for such hydrogenation are the lower alkanols, such as methanol, ethers, such as tetrahydrofuran and dioxane; low molecular weight esters, such as ethyl acetate and butyl acetate, water and mixtures of these various solvents. However, it is usual to choose conditions under which the starting compound is soluble. The hydrogenation is carried out ha-5 bitude at a temperature of about 0 to 60 ° G under a pressure of about 101 to 10100 kPa. The catalysts used for this hydrogenation are of the kind known for such a transformation, typical examples being the noble metals, such as nickel, palladium, platinum and rhodium. The catalyst is usually taken in an amount of about 0.01 to 2.5% by weight and preferably about 0.1 to 1.0% by weight, based on the compound of formula A. It is often Advantageous to deposit the catalyst on an inert support and a particularly convenient catalyst is palladium deposited on an inert support such as carbon. In addition, it is common to buffer the reaction mixture to work at a pH of about 4 to 9 and preferably 6 to 8. Borate and phos-20 phage buffers are in common use. The reaction normally takes about 1 hour.

A subject of the invention is also the esters of formula: CH3 25 R — CH — CO -im ^ y / ^ T ¥ "> 50

Vf, cv, J

"" 'CH, CH_

"/ ~ Ïï —h ^ I

'55 O C-0

II

O

9 where E represents: 5 C) '' CV, 0'O “* 0 where E ^ represents a hydrogen atom or a hydroxyl radical and E represents a hydrogen or chlorine atom or a hydroxyl, methyl radical or methoxy, and preferably the ester of formula: 10 / = v CH ^ 0 0 f 1 7 "CH. ch 20 I2 ο. c-0

II

O

and the ester of formula: y = v ch ^ 25 HO-Ù y- CH-CO-NH ^ 'v.j | —F> ol

* r ^ Z

30 0. 0 \ sxC> CËLC1? r-ryl k

35 I

^ 0 · € -0

II

O

as well as the process for producing such an ester, according to which an acid is reacted with a solution of a compound of formula: 10 CH3 5 R— ÇH: -

jXjS

H * - !. ^ 0 Y

vc ^ * 3 10 ir 0 0 y 'CÏLC1 9 t — ΓΊΖ 1 ΓΟΗ, CH, ^ - »- \ 3 2 15 0 C-0

II

0 where R represents: - - »ooo- · υ ·" Ύ where R represents a hydrogen atom or a hydroxyl radical and Ήτ represents a hydrogen or chlorine atom or a hydroxyl, methyl or methoxy radical; 1 2

R represents an alkyl, aralkyl or aryl radical; R

represents a hydrogen atom or an alkyl, aralkyl or aryl radical and R represents an alkyl, aralkyl, aryl, alkoxy, aralcoxy, aryloxy or -RR R ^ radical, where R and R- ^ each represent a hydrogen atom or an alkyl, aralkyl or aryl or Men radical, taken together with the nitrogen atom, represent a piperidino or morpholino radical, which reaction by means of the acid is preferably carried out in an organic solvent such as l acetone or chloroform or in an aqueous or partially aqueous solution and preferably at a pH of 1 to 5 at room temperature.

It is further preferred that in formula 11 of the radical protecting the amino function, R "*" represents 2 a methyl radical, R represents a hydrogen atom and Ir represents a methoxy, ethoxy or methyl radical, which requires use methyl 5-acetoacetate, ethyl acetoacetate or acetylacetone For the removal of the protective radical of the α-amino function, it is preferable to use a strong mineral acid, such as hydrochloric acid, or X formic acid.

The subject of the invention is also, as a new intermediary, an ester of formula:

I '^ CH

15 Λ_I. 3 U „

HORN

where R represents a benzyl or substituted benzyl radical -20 and preferably p-nitrobenzyl, as well as the process for preparing this ester, according to which a compound of formula is heated, preferably under reflux:

Br '? / at? . yw

TT

J-Π.

and '' C-OR

u „

; O

where R represents a benzyl or substituted benzyl radical and preferably p-nitrobenzyl, in an inert anhydrous organic solvent, preferably dioxane, in the presence of a large and preferably equimolar amount of a weak tertiary amine, preferably the quinoline, and an acid chloride, preferably benzoyl chloride, until substantial completion of the reaction.

A further object of the invention is, as a new intermediary, an ester of formula:

O

Br i jf »Cl 5 TT T- · J — 1, —K r where R represents a benzyl or substituted benzyl radical 10 and preferably p-nitrobenzyl, as well as the process for preparing this ester, according to which a solution is oxidized , in an inert solvent, preferably methylene chloride, of a compound of formula:

Br „* CHpCl 15 4-_2 I '' ch

—K

0 'C-OR

Where R represents a benzyl or substituted benzyl and preferably p-nitrobenzyl radical, at approximately room temperature, by means of a peracid, preferably m-chloroperoxybenzoic acid.

The subject of the invention is also, as a new intermediate, the ester of formula: 0 0

Br ^ // jPE2C1 i ^ 30 6% 0 Ç-OCHgCCl ^ 0 as well as the process for its preparation, according to which a solution in an inert solvent, preferably methylene chloride, of a compound is oxidized formula: 13

Br? * CHpCl Γ ^ 0¾ 2 5 J ~ * - * 0 'Ç-OCHgCCl ^

O

little. near at room temperature by means of an oxidizing agent such as potassium permanganate, hydrogen peroxide or a similar peroxide or preferably a peracid, advantageously m-chloroperoxÿbenzoic acid.

"Skellysolve B" is a fraction of petroleum ether boiling from 60 to 68 ° 0 and consisting essentially of n-hexane, sold by the company Skelly

Oil Co.

The examples below illustrate the preparation of representative compounds forming the subject of the invention without limiting the latter.

2 ° EXAMPLE 10-

Preparation of 2b-chloromethyl-2a-methyl-pename-3cc-potassium carboxylate sulfone (BL-P2013) 25

0 O

Br - î Br, S fa '30 -rTY _VkY ώ N ^ COnH <J N ^ 2n υ C02-CH2 35 1 2 14- Ο -5 Br, jPH, C1 Br, S. »CH, C1

Yc „3„ _ Y-f | CH3 ^ -N- \ f— \ /? - N-b 0 C02-CH2- (O) -M2 <J 602 "CH2 H2 φ i ψ 1 n02 15

“Q O. yO

î "Xs /. CHLCl

Z - "- to, H V

20 2 κ 5 (BL-P2013) 25 S-sulfoxide of 6 "-bromopenicillanic acid (1) 1. 30 g (37.5 mmol) of the salt of N, N'-dibenzyl ethylenediamine acid 6a- are dissolved bromopenicillanic [G. Cignarella et al., J. Org. Chem. 2 £, 2668 (1962) and E. Evrard, Nature 201, 1124- (1964-)] in 330 ml of methylene chloride. Stir and cool to 0 ° C.

2. Add in 13 ml (156 mmol) of concentrated hydrochloric acid to the tt methylene chloride solution. Diben-zylethylenediamine hydrochloride is precipitated in 1 minute. The suspension was stirred at 0-5 ° C for 10 minutes.

3. The precipitated amine hydrochloride is separated by filtration on a pre-filled filter with diatomaceous earth ("Dicalite" brand). The filter cake is washed with 150 ml of methylene chloride. Filtration should be completed as quickly as possible. Care should be taken to avoid long-term storage of the acid solution in methylene chloride. Some filtration difficulties may result from the fineness of the precipitate. A filter aid added to the suspension can be useful.

4-. The methylene chloride filtrates are mixed and washed with 60 ml of cold water. The mixture is stirred for 5 minutes and the aqueous phase is discarded. The pH of the wash water is 2.0 to 2.5.

5 * The solution of 6a-hromopeicillinic acid in methylene chloride is concentrated under reduced pressure to a volume of 65 to 80 ml. The solution is cooled to 5 ° C with stirring.

6. With vigorous stirring, carefully add 15 ml (86.9 mmol) of 40% peracetic acid in 50 minutes. The reaction is exothermic. By cooling in an ice bath, the temperature is maintained between 15 and 18 ° C. The sulfoxide begins to crystallize after adding 10 ml of peracetic acid. Stir and cool the suspension to 0-5 ° C for 2 hours.

7. The suspension is filtered and the snow white cake is washed in the following order: 10 ml of water at 5 ° 0, 10 ml of methylene chloride at 0-5 ° C, finally 15 ml of heptane.

8. The filter cake is dried at 45 ° C in an air oven to constant weight, a period of 6 to 50 10 hours should be sufficient. Longer heating may cause a pink reflection to appear. The weight of compound 1 is 16.26 g, ie a yield of 73.24%.

ff 9. The state of the reaction mixture and of the final product can be observed by thin layer chromatography in the systems 15 toluene / 4 acetone / 1 acetic acid or else 8 acetone / 8 methano] / 3 toluene / 1 acetic acid . The final product is analyzed by nuclear magnetic resonance spectroscopy and infrared spectroscopy.

P-Nitrobenzyl 6oi-bromopenicillinate S-sulfoxide (|) 5 7.5 g (* fl mmol) of potassium 2-ethylhexanoate are added to a solution of 12 g (* f0 mmol) of S-sulfoxide 6oc-bromopenicillanic acid in 100 ml of acetone. The salt is collected by filtration, washed with cold acetone and dried in air 10 to obtain a total amount of 10 g. The crystalline potassium salt is dissolved in 75 ®1 of dimethylacetamide and 7.8 g (0.04 mole) of p-nitrobenzyl bromide are added to the solution. The solution is stirred at 25 ° C for 24 hours. The mixture is diluted with 15,500 ml of water and extracted with ethyl acetate. The extract in ethyl acetate is washed 4 times with water and dried over anhydrous magnesium sulfate. The solvent is evaporated off at 35 ° C (2000 Pa) to obtain an oil which crystallizes. Clear clear yellow crystals of Compound 2 are dispersed in ether, then

collect them by filtration to obtain a quantity of 9 g (7QP / o) EF · 124-125 ° C with decomposition. Analysis for C ^^ H ^^ BrN ^ OgS

Calculated: C, 41.98; H, 3.05; N, 6.52% Found: C, 42.00; H, 3.48; H, 6.98%

Infrared spectrum (KBr): 1800 (1?), 1740 (F), 1610 (f), 1520 (F), I45O (m), I35O (F), 1060 (m), 740 (m) cm-1.

Nuclear magnetic resonance spectrum H (60 MHz, DMSO): S 1.22 (s, 3H), 1.6 (s, 3H), 4.67 (s, 1H), r ~ 5.2 (d, Jn / 1-5 Hz, 1H), 5.4-5 (s, 2H), 5.68 (d, Jn ^ l-5 Ξζ, ΙΗ), 7.5-8.5 (m, 4H).

25-Chloromethyl-2a-methyl-6-bromopenam-3a-p-nitrobenzyl carboxylate (J1

A solution of 5 g (12 mmol) of p-nitrobenzyl 6oc-bromopenicillanate S-sulfoxide (2) in 120 ml of anhydrous dioxane in the presence of 1.5 g is heated at reflux in a nitrogen atmosphere for 4 hours.

IV

(12 mmoleg) of quinoline and 1.6 g (12 mmol) of benzoyl chloride. The solution is diluted with 600 ml of water and extracted with ethyl acetate. The extract in ethyl acetate is washed with a 5% solution of sodium bicarbonate, a solution of 5% phosphoric acid and finally water. The organic layer is dried over magnesium sulfate and evaporated to 35 ° G (2000 Pa) in an oil. The crystal oil reads and the crystals are collected which are washed with ether 10 and finally with cold toluene, to obtain 3.5 S - (65%) of the compound 3L, melting at 130-135 ° C with decomposition. tion.

Analysis for C ^ H ^ ClBrï ^ O ^ S

Calculated: C, 40.06; H, 3.14; N, 6.23% Found: C, 40.19; H, 3.12; N, 6.75%

Infrared spectrum (KBr): 1792 (1), 1740 (1), 1610 (f), 1520 (10, 1353 (1), 1280 (m), 1025 (f), 990 (f), 750 (f) year -1. Nuclear magnetic resonance spectrum (60 MHz, HMSO): 3 1.45 (s, 3H), 3.5-4.3 (rn, 2H), 5.05 (s, 1H), 5.42 (s, 2H), 20 5.5 (d, J ^ l, 5 Ηζ, ΙΗ), 5.62 (d, 1 ^ 1.5 Ηζ, ΙΗ), 7.5- 8.5 (m, 4H ).

23-chloromethyl-2a-methylpenam-6a-carboxy-late p-nitrobenzyl sulfoxide

A solution of 1 g (2.2 mmol) of p-nitrobenzyl 3P-chloromethyl-2a-methyl-6a-bromopenam-3oc-carboxylate (3.) in 50 ml of methylene chloride is stirred with 473 mg (2 , 2 mmol) of m-chloroperoxy-benzoic acid. The solution is stirred for 3 hours at 23 ° C. The methylene chloride is evaporated to 50 20 ml at 2000 Pa at 33 ° C and the concentrated solution is diluted with 50 ml of heptane ("Skellysolve B"). The solvent is decanted and the residue is dispersed in ether to rapidly crystallize the compound (4) melting at 136-137 ° 0 with decomposition and obtained in an amount of 250 mg (yield 24%).

18

Analysis for C ^ H ^ BrCl ^ OgS

Calculated: 0.38.68; H, 3.02; N, 6.02%

Found: 0.39.14; H, 3.13; N, 5.96%

Infrared spectrum (KBr): 1800 (F), 1760 (F), 1520 (F), 5 1350 (19, 1200 (F), 1050 (m), 830 (f), 740 (f) cm "1.

Nuclear magnetic resonance spectrum H (60 MHz, DMSO): δ 1.32 (s, 3H), 3.8-4.5 (m, 2H), 4.97 (s, 1H), 5.25 (d , Jo / 1.5 Hz, 1H), 5.45 (s, 2H), 5.6 (d, J ^ l, 5 Ηζ, ΙΗ), 7.8-8.5 (m, 4H).

10 2ß-chloromethyl-2a-methylpename-3a-car'boxy- ~ late potassium sulfone (%) (BL-P2013)

A suspension of 4 g of 30% palladium on diatomaceous earth ("Celite") and 2.8 g of sodium bicarbonate in 150 ml of water is added to a solution of 7 g (15 mmol) of 2β-chloro-methyl-2a-methyl-6oc-bromopenam-3oc-p-ni-trobenzyl sulfoxide (4) sulfoxide in 150 ml of ethyl acetate. The mixture is hydrogenated for 3 hours under 3 ^ 5 kPa.

The catalyst is filtered off and the aqueous layer is collected to which 1.5 g of potassium permanganate in 50 ml of water are added. The mixture is stirred for 1 hour and 250 mg of sodium bisulfite is added thereto. The mixture is filtered and the filtrate is adjusted to pH 2 with concentrated hydrochloric acid. The solution is lyophilized to obtain a white amorphous powder. The solid is extracted with ethyl acetate, the extract is evaporated to 20 ml and the residue is diluted with 100 ml of heptane ("Skellysolve B"). 2ß-chloro-methyl-2a-me-30-thylpenam-3 "· -carboxylic acid hygroscopic white sulfone is collected.

The acid is dissolved in acetone and solid potassium 2-ethylhexanoate is added thereto. A precipitate of a white crystalline salt is obtained, which is collected by filtration to obtain 170 mg of the compound, melting above 140 ° C. with decomposition.

19

Analysis for CgH ^ OlKNO ^ S.

Calculated: C, 28.27; H, 3.24; H, 4.12%

Found: C, 28.27; H, 3.69; H, 3.84%

Infrared spectrum (KBr): 1790 (F), 1770 (m), 1620 (3?), 5 1460 (m), 1370CF), 1310 (1), 1200 (11), 1140 (51), 933 (m) , 740 (m) cm '' · ''.

Nuclear magnetic resonance spectrum H (100MHz, D ^ O): δ 1.68 (s, 3H), 3.2-3.9 (m, J ^ / 2 Hz, <Κ / 4 Hz, JA / 6 Hz , 2H), * 4.0-4.4 (m, 2H), 4.3 (s, 1H), 5.02 (dd, J ^ 4 Hz), 10 J (\ j 2 Ηζ, ΙΗ).

- EXAMPLE 20-

Pivaloyloxymethyl 2P-chloromethyl-2a-methylpenam-5a-carboxy-sulfone sulfone

2P-chloromé-13 thyl-2a-methylpéname-3a-carboxylic acid sulfone is mixed in dimethyl sulfoxide with 1 equivalent of triethylamine and the whole is stirred for dissolution. Then 1 equivalent of bromomethyl pivalate in dimé-thylformamide is added. The resulting mixture is stirred at room temperature. The mixture is then clarified by filtration and the filtrate is poured into ice water. The precipitated solid is collected by filtration, which is washed with water and dried to obtain the desired ester.

The acetoxymethyl, methoxymethyl, acetonyl and phenacyl radical esters of the same acid are prepared by replacing, in the above process, bromomethyl pivalate with an equimolar amount of chloromethyl acetate, chloromethyl methyl ether. ", chloroacetone and phenacyl bromide, respectively.

33 20 EXAMPLE 3.-

Sulfone de 2ß-chIoromethyl-2a-methyl'pename-5a-car'boxy-late of pivaloyloxymethyl BL-P2024 5 O o

_O

> CH2C1 + NaI + H 0 + ciCH2-0-C-C (CH3) 3 10. O (306> co2-K ~ (BL-P2013)

O O

V / vCH3 15, -

acetone V

-> 1 CH ^ Cl

Λ i R

Ζ_Λ 0 C02CH2-0-C-C (CH3) 3 20 (BL-P2024)

Add 4 ml of a 10% aqueous solution of sodium iodide to a stirred suspension of 14.6 g (48.7 mmol) of BL-P2013 (j?) In 200 ml of acetone and carry the mixture at reflux in a steam bath. 14.8 ml (0.1 mole) of redistilled chloromethyl pivalate (m.p. 34 ° C at 933 Pa) are added to the refluxing suspension at reflux once. the mixture is stirred at reflux for 3 hours, then it is cooled to room temperature (22 ° C.) The crystalline solids are collected by filtration and washed 3 times with 30 ml of acetone, after which the filtrates are combined and they are evaporated under vacuum below 22 ° C. in an oil. The oil is then taken up in 500 ml of ethyl acetate and the solution is washed once with 200 ml of water and once with saturated sodium sulphate, while stirring with 2 g of discolored charcoal, under cooling in an ice bath After 20 minutes, the mixture is filtered through diatomaceous earth (Dicalite) by vacuum, after what we wash the Dicalite 4 times with 100 ml of ethyl acetate. The filtrates are combined and concentrated at 22 ° C under vacuum to an oil. The oil is further concentrated at about 22 ° C below 133 Pa to remove most of the residual chloromethyl pivalate. The remaining oil is then triturated twice in 30 ml of 10 n-pentane and it is left to stand over the weekend in a cold room (approximately 10 ° C.) under a layer of n-pentane. The resulting crystalline solid mass is then crushed into a solid powder under 4-0 ml of a 4: 1 mixture of ether and n-pentane. The product is collected by filtration, washed with a 1: 1 ether-pentane mixture, then with pentane, after which it is air dried. After drying under vacuum for 4 hours in the presence of PgO 4, 13.37 g of pivaloyloxymethyl 2P-chloromethyl-2a-methylpenam-3a-carboxylate sulfone (yield of about 75%) are obtained, melting at 93-95 °. vs.

Analysis for O ^ î ^ qCINO ^ S

Calculated: C, 44.03; H, 3.27; N, 3.67%

Found: 0.44.11; H, 3.08; N, 3.83% 25 EXAMPLE 4, -

Recrystallization of the sulfone from potassium 2p-chloromethyl-2a-methylpenam-3a-carboxylate (BL-P2015) 'Water is added, 1 ml at a time, with stirring to a mixture of 20 ml of n -buta-30 nol and 1 g of compound BL-P2013 (J?) in a separatory funnel until a pale yellow solution is formed. The clear solution is filtered through pleated filter paper, then the ampoule and the filter paper are washed with about 10 ml of a 9: 1 mixture of n-butanol and water, after which the filtrates are combined and dilutes them with another 20 ml of n-butanol. The resulting solution is introduced into the round bottom flask of a rotary evaporator and evaporated under reduced pressure to approximately half the initial volume. The snow white crystals of the product are collected by filtration and washed 6 times with 10 ml of acetone and dried in air. 810 mg are thus obtained. After 6 hours of drying under vacuum on Po0, - below 2 3

133 Pa, 800 mg (80% yield) of the compound, melting at 215 ° C. with decomposition, are obtained. f- Analysis for CgH ^ ClNO ^ SK.IHgO

Calculated: C, 29.67; H, 5.39; N, 4.63; Cl, 10.94; K.P.HgO, 5.56%

Found: 0.29.23; H, 3.38; N, 4.49; Cl, 10.74 ‘E.P.HgO, 5.74%

This recrystallization technique gives a crystalline monohydrate which is different from the starting compound, which is essentially anhydrous.

EXAMPLE 5. "

0 S

3n ™ 0-Ü-C1 Clg. > CICHg-O-C-Cl 3 light

+ C1S0, H

3 1 0 C1CEL-0-S-C1 c. ψ 6 0 25 ~

See Chemical Abstracts 22, 2427 and 22, 3828; besides GB 299064.

ClSO ^ CELCl ^ O o ^ 0 0 - ^ i> </ CHgC1 r-ZV4 “r ~ r Z ™, i ch3 3 X-N ---% 35 </ ~ H- COOK. C-OCH ^ Cl 5 1 23 * c Naï acetone 0 Ψ0 .CH2C1

r — f H

* I 'CH, J - 1 3

10 0 t-0CHoI

Il à- 0 8 15 20 8 + f === \ λ S ^ ° ¾ - \ J ~ C H-CO-Μ ^ -γ ^ CHj J% ook 25 ": H (\ c [OCH ^ 9 (" EUA patent 3.316.24-7) 55 "30 24- Q-ch-co-kh ^ Y ^ 5 ^ o ^ —Vo vf> HC-c ^ 1 1

OCHj O

10 - 0 -0 X / V1! - /> CH,

—K 5 I

15 0 ii 0 o H + 20 ψ 25 J - "- K ^. MH2 o c = 0 30 0 • il 0 0 - / Νζ CHp 1 'CH, 2 33' x ^" k,> 2-? 0 C-0

II

0 25 a) A solution of chloromethyl chlorosulfate (0.115 mmol) in 40 ml of dichloromethane, while maintaining the reaction temperature under 30 ° C., is added dropwise to a solution of the compound (0.1 mol) and potassium bicarbonate (0.3 mole) in 200 ml of a 1: 1 mixture of dichloromethane and water containing tetrabutylammonium hydrogen sulfate (0.01 mole). At the end of the addition, the mixture is stirred at room temperature for 30 minutes, then the organic phase is separated and the aqueous phase is extracted with "dichloromethane (50 ml). The organic phases are combined and they are dried over sodium sulphate, then they are evaporated under vacuum to obtain a residue which is dissolved in 150 ml of ether, after addition of diatomaceous earth, the insoluble materials are separated by filtration and the filtrate is evaporated under vacuum to obtain compound 2.- b) 1.6 g of bis-chloromethyl sulfate are added to a suspension of compound £ (1.5 g) in dimethylformamide (12 ml) and the mixture is stirred for 45 minutes at room temperature After dilution with ethyl acetate (50 ml), the mixture is washed with water and then with aqueous sodium bicarbonate, after which it is dried and evaporated under vacuum to obtain compound 2. in the form of an oil.

c) 7 mmol of triethylamine and 30 mmol of chloroiodomethane are added to a solution of 5 mmol of compound 5. 7> 5 ml of dimethylformamide, then the mixture is stirred for 4 hours at room temperature. After dilution with 30 ml of ethyl acetate, the mixture is washed 3 times with 10 ml of water, then with 5 ml of saturated aqueous sodium chloride, after which the mixture is dried and evaporated in vacuo to obtain compound 2. in the form of an oil.

d) 1.5 mol of chloroiodomethane is added to a mixture of 0.15 mol of compound J 2, 0.15 mol 26 of silver nitrate and 7.5 g of silver oxide in 7 ^ 0 ml of acetonitrile. After 48 hours of stirring at room temperature, the silver salts are filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 200 ml of ethyl acetate and the solution is washed with saturated aqueous sodium chloride, filtered, dried and evaporated in vacuo to give the compound 2 · "The compound 2 of other intermediate compounds, as well as the final products of the invention, if desired, by column chromatography on "Sephadex" LH20 using a chloroform: hexane 65:35 mixture as eluent, for example , or by silica gel column chromatography, for example Mallinckrodt CC-7 ™ using mixtures hexane-ethyl acetate 3: 2, ethyl acetate-petroleum ether 8: 2, 7: 3 ? 1: 9 or 15:83? 4: 6 or 3: 1 ethyl acetate-n-hexane? 3: 1 hexane-ethyl acetate? 1: 1 or 1: 4 or cyclohexane acetate ethyl 1: 1.

20 Thin-layer chromatography is also useful. "Sephadex" is epichlorohydrin, ether chloride hydrochloride 2- (diethylamino) ethyl-2-Ê [2 - (diethylamino) -ethyl ^ diethylammonio ^ ethyl crosslinked dex-trane (Merck Index, ninth edition, n ° 7337). A solution of 0.2 mole of compound 2 and 0.3 mole of sodium iodide in 150 ml of acetone is stirred for 18 hours at room temperature. The resulting suspension is cooled to about 0 ° C and 'approximately adjusts to pH 7-2 by addition, with stirring, of saturated aqueous sodium bicarbonate. After discoloration by careful addition of 0.5 M aqueous sodium thiosulfate, 150 ml of water are added dropwise to the stirred mixture in order to precipitate the solid compound 8 which is collected by filtration and then washed with a 1: 1 acetone-water mixture (2 x 20 ml), isopropanol (2 x 20 ml) and ether (2 x 20 ml), then dry.

Ampicillin is converted to compound 227 by means of methyl acetoacetate, as described in United States Patent No. J.316.247. 0.3 mole of compound 8 is then added at 5 ° C. to a stirred solution of 0.57 mole of compound 9 in 1 liter of 5-dimethylformamide. After 15 minutes of stirring at 5 ° 0, the reaction mixture is poured into an ice-cold stirred mixture of 4 liters of ethyl acetate and 2 liters of saturated aqueous calcium chloride. The organic phase is separated, washed with saturated aqueous calcium chloride (2 x 500 ml), filtered and evaporated to about 1 liter under vacuum to obtain a concentrated solution of compound 10. add 500 ml of water and 500 ml of n-butanol to this concentrate, then dropwise 4 U hydrochloric acid with stirring until the radical protecting the amino function is removed, so as to obtain a solution of compound 11. At the end of the addition of acid, 1 liter of ether and 50,000 ml of water are added to the stirred mixture, after which the aqueous phase is separated and the organic phase is extracted only with 800 ml of water. The aqueous extracts are combined and washed with 1 liter of ether, then 640 g of sodium chloride and 2 liters of dichlorome-thane are added thereto, after which the mixture is stirred for 15 minutes. The organic phase is separated and the aqueous phase is extracted with 1 liter of dichloromethane, after which the organic extracts are combined and dried over magnesium sulfate, then evaporated to about 600 ml under reduced pressure to obtain a concentrated solution of compound 11. By adding 200 ml of 2-butanone to the concentrate, then cooling, the sulfone of 2p-chloromethyl-2a-methylpenen-3a-carboxy-oxy late of 6 is precipitated in the solid state - [(P) -2-amino-2-phenylacetamido] -3,3-d.imethyl- 7-oxo-4-thia-l-azabicyclo [3.2.0] heptane-2-carbonyloxy-35 methyl (11) which is collected by filtration.

28 EXAMPLE 6.-

2p-chloromethyl-2a-methylpenam-5a sulfone - car'bo: 6-C (R) -2-amino-2 ~ xy-late ~ p-hydroxyphenylacetamido] -5.5-dimethyl-7-oxo-4-thia -l-aza'bicycloC3 "2.0]] ieptane-2-car-5 bonyloxymethyl of formula: / = \ CH ^ HO ^ 10 ^ KH2 0 c = 0 15 0 Ο o ^ O CH2C1

j = Ch P

20 0 ^ ΐ-o

II

0

Qu obtains this compound by replacing the ampicillin used in Example 5 with amoxicillin.

EXAMPLE 7.- a) CHp // \ J. + N-Bromosuccinimide cx-azo-isobutyronitrile>, Δ4 CHBr * (S-ζ 29

Gum indicated in United States Patent No. 3,860,579 d or heated under reflux for 4.5 hours 50 g (0.375 mole) of recrystallized phthalide and 0.375 mole of H-bromosuccinimide recrystallized in the presence of approximately 100 mg of oc-azobutyronitrile in 1 liter of carbon tetrachloride. The mixture is cooled to around 15 ° C and filtered to separate the succinimide, which in turn is washed with 100 ml of carbon tetrachloride which is separated by filtration. The carbon tetrachloride solutions are mixed and concentrated in vacuo to about 150 ml to obtain the solid 3-bromophthalide which is collected by filtration, which is washed with about 50 ml of carbon tetrachloride and which air dried to obtain 15 54- g of the compound, the weight of which reduces to 50 g after recrystallization from boiling cyclohexane, the melting point being 84 ~ 86 ° Co t>) OO · V // CHBr CH_C1 ^ \ -] ^>; · RC <J-H-1 ^ == / "0 12

σ C-OK

ii 5 0

oc DMF

-7 22 ° C.

O O

> S CH_C1 3 °, _ / \ / 2 '' jCR3. J — N- ÎT ° 7CHBL-P2036 O 0 13 0 35 30

1.7 S (8 mmol) of 3-bromophta-lide (12) are added to a partial solution and stirred partial suspension of compound j5 (BL-P2013; 2.3 g, 7.6 moles) in 20 ml of dimethylformamide (dried for 3 weeks on 3A molecular sieve) and the mixture is stirred for 4 hours at 22 ° C. The resulting mixture is poured into a mixture of 200 ml of ice water and 200 ml of ice-cold ethyl acetate (by rinsing the flask with a little ethyl acetate), then the mixture is stirred . The organic phase is then separated and washed 7 times with 100 ml of ice water. The organic phase is washed again with saturated aqueous sodium sulfate, then it is dried in the cold over sodium sulfate, filtered and evaporated to dryness under vacuum, 13 to obtain, as residue, an oil which we grind

2 times in 25 ml of cyclohexane, 2 times in 25 ml of "Skellysolve B" (P, bp 60-68 ° C, essentially n-hexane) and 4 times in 25 ml of n-hexane, to obtain 2, 5 g of compound 11 in the form of a solid almost white after air drying. The product is then dried over ï ^ O ^ under a pressure below 133 Pa to obtain 2.5 g of compound 13. melting at 104 ° C with decomposition. Estimated purity is 85-93% Analysis for C ^ H ^ CINO ^ S

23 Calculated: G, 50.61; H, 3.79; N, 3.77; 01, 9.33% Found: C, 52.59; H, 4.67; N, 3.21; Cl, 7.73;% k.i.h2o, 0.27 EXAMPLE 8, -

Pivaloyloxymethyl d3 25-chloromethyl-2a-methylpenam-5a-carboxy-late sulfone d3

A mixture of 1 g (3.1 mmol) of 2P-chloromethyl-2a-methylene-3-namene-3 "sulfone potassium carboxylate and 1 g of molecular sieve 3A to 15 ml of agar is incorporated by stirring. dimethylacetamide 33 for 2 hours at 23 ° C. 47Ο mg (3.1 mmol) of pivaloyloxymethyl chloride are added to this mixture and stirring is continued for 18 hours. The molecular sieve is separated and the filtrate is diluted with 100 ml of water, then it is extracted with ethyl acetate. The extract in ethyl acetate is washed 9 times with water. , then dried over anhydrous magnesium sulfate. The solvent is removed at 30 ° C (2000 Pa) to obtain an oil which is chromatographed on silicar CO-7 silica (methylene chloride 8, ethyl acetate 2) giving a spot with an Rf of 0, 5 *

The residue is crystallized from heptane ("Skelly-10 solve B") to obtain 100 mg of pivaloyloxy-methyl 2β-chloro-methyl-2a-methylpenam-3a-carboxylate melting at 94--95 ° C .

Analysis

Calculated: C, 44.03; H, 5.27; F, 3.67% Found: C, 44.20; H, 5.24; F, 3.63%

The nuclear magnetic resonance spectrum and the infrared spec-spectrum are compatible with the structure. EXAMPLE 9.-

23-Chloromethyl-2o sulfone: -methylpenam-3 (^ - csû? Boxy-20 late sodium CH Cl / Cn2C1 25 I-S NJch2 H + NaEH | - ^

Z-4 — i ^ <rN ~ V

2 CoEUClNOcSNa- '(306> (289.67) 30

2 F hydrochloric acid is added to a stirred solution of 500 mg of BL-P2013 (potassium salt) in 5 ml of water and 10 ml of ethyl acetate until the pH or 1 (operation 35 is carried out with vigorous stirring in an ice bath). The sodium sulphate mixture is then saturated, the aqueous layer is separated and the organic phase is dried briefly in ice on sodium sulphate, after which it is collected by filtration and added dropwise to it. Sodium 2-ethylhexanoate at 50% in anhydrous n-butanol until the paper 5 pH wet. The product does not crystallize during the scraping of the wall of the container and the mixture is then concentrated under vacuum in an oil which is dissolved in 3 ml of acetone, the scraping of the walls does not induce crystallization and a contribution of ether up to cloud point 10 also does not induce crystallization.

- The mixture is concentrated in vacuo on a rotary evaporator to obtain an oil which is dissolved in ethyl acetate and to which a drop of water is added without scraping showing crystals.

. The mixture is concentrated in vacuo and the residue is triturated with 5 ml of n-butanol to obtain 200 mg of an amorphous white powder which is washed with ether, dried in air and it is dried under vacuum under P ^ O ^ for 24 hours. Finally, 180 mg of sodium 2P-chloromethyl-2a-methylpenam-3oc-carboxylate sulfone are obtained, the ill-defined decomposition point of which is greater than 100 ° C.

Analysis for CgH ^ ClNO ^ SlTa

Calculated: C, 33.10; H, 3.13; N, 4.89% Found: C, 33.20; H, 3.69; N, 4.44;

HgO according to K.P., 4.04% EXAMPLE 10.-

Potassium 23-chloromethyl-2-methylpenam-3-carboxylate sulfone (BL-P2013) 30 g (1.25 mol) of sodium hydrogen carbonate and 200 g of 10% palladium on barium sulfate are added. 10 liters of water and 272 g (0.565 mol) of p-nitrobenzyl 6a-bromo-2p-chloromethyl-2-methylpenam-3-carboxylate sulfone are dissolved in 5 μl of ethyl acetate. The whole is mixed and the hydrogenation is carried out at 40 ° C. under a pressure of 101 kPa. After 5 hours, the absorption of hydrogen 33 becomes very slow and 200 g of 10% palladium on barium sulfate are added, after which the hydrogenation is continued until the absorption of hydrogen becomes imperceptible.

The suspension is filtered through diatomaceous earth ("Celite"), the filter cake is washed with water and the aqueous phase is washed with 3 liters of ethyl acetate. 3 liters of ethyl acetate are added to the aqueous solution and the pH of the mixture is brought to 10 1.5 using 150 ml of 12 N hydrochloric acid at 10 ° 0. The organic phase is separated and the aqueous solution is saturated with sodium sulfate decahydra-t, after which the extraction is carried out 2 times with 1 liter of ethyl acetate. The extracts are combined and dried over magnesium sulfate. The drying agent is separated and 260 ml of 2N potassium 2-ethylhexa-noate are added in butanol at 0 ° 0 <,

After 2 hours of stirring at 0 ° C., the potassium 25-chloromethyl-2-methylpenam-3-carboxylate sulfone (BL-P2013) is collected and dried under vacuum at room temperature. , 8 g (yield of about 70%) of this compound.

EXAMPLE 11, -

N-nitrobenzyl ea-bromonenicillanate sulfoxide 23 0

'T

r ~%> #. <ai6> (296) · »0 bVy ^

35 V N-i / = V

° C020V <\ / ¾

(431.28) "—J

34

44 g (0.148 mole) of 6a-bromopenicillanic acid sulfoxide are added, then 20.5 ml (0.148 mole) of triethylamine and 38.2 g (0.177 mole) of p-nitrobenzyl bromide to 200 ml of N, N -dimethylacetamideo 5 The mixture is stirred at 22 ° 0 for 20 hours.

The reaction mixture is poured into 1 liter of water which is extracted 3 times with 300 ml of methylene chloride. The extracts in methylene chloride are combined and washed with 200 ml of 5% aqueous solution of sodium bicarbonate, after which they are dried over sodium sulfate at 5 ° 0 for 30 minutes .

The solution is filtered and evaporated in vacuo to obtain a residue. The residue is diluted with ether and the solid is collected by filtration to obtain, after drying, 54 g of p-nitrobenzyl 6α-bromopeniaillanate sulfoxide. The yield is 85%.

The nuclear magnetic resonance spectrum is compatible with the assigned structure.

The yield achieved at this stage is the same as for the esterification of the potassium salt. The advantage is that there is no need to prepare the potassium salt. (This operative phase is done with a yield of 85 to 90%).

EXAMPLE 12 Preparation of p-nitrobenzyl 6α-bromopenicillanate sulfoxide

87,350 g (2.95 moles) of 6oc-bromopenicillanic acid sulfoxide (S) are added to ^ -, 375 liters of N, N-dimethylacetamide, then added, with stirring and maintaining the temperature of the system at- below 35 ° C, 293 g (2.95 moles) of triethylamine, then 764 g (3 »54 moles) of p-nitrobenzyl bromide. The mixture is stirred at room temperature for 5 hours and left to stand overnight.

The reaction mixture is poured into 20 liters of water which is extracted 3 times with 7 liters of methylene chloride. The organic extracts are combined and washed 5 times with 7 liters of water, then 1 time with 7 liters of a 5% aqueous solution of sodium bicarbonate, after which they are dried over anhydrous magnesium sulfate.

5 Separate the magnesium sulfate by filtration and evaporate the solution to obtain a crystalline residue, add 4 liters of diethyl ether to the residue and collect the crystals to obtain, after drying at room temperature, 1171 g (yield 10% (92%) of p-ni- * trobenzyl 6oc-bromopenicillanate sulfoxide.

On analysis, the compound reveals a bromine content of 18.48% (calculated value 18.53%) and an oc ^ rotary power of + 162 ° (0.25% in methanol).

EXAMPLE Preparation of p-nitrobenzyl 6u-bromo-2g-chloromethyl-2-methylpenam-5-carboxylate sulfone

364.6 g (0.812 mole) of p-ni-20 trobenzyl 6a-bromo-23-chloromethyl-2-methylpenam-3-carboxylate are added to 16 liters of acetic acid. The resulting solution is stirred at room temperature and a solution of 282 g (1.78 mole) of potassium permanganate in 26 liters of water is added dropwise over 3 hours. The mixture is then stirred at room temperature for 1 hour and hydrogen peroxide is added dropwise at 37 ° / ° until a colorless solution is obtained. 30 liters of water are then added, after which the mixture is stirred for 1 hour at room temperature and the crystalline precipitate is separated therefrom, which is washed 3 times with 5 liters of water and 2 times with 2 liters of ethanol before drying it under vacuum at room temperature.

297 g are thus obtained (yield of 76%) of the compound having a rotary power of + 75 ° to 9 ° (0.5% in methylene chloride).

36 EXAMPLE 14 -.-

PreparatiorL of 1 "free acid BL-P2013

V V

5 I 'f N> CH2C1 H, P04 _ ^ S ^ yOHgCl li_] ΰ03 ^' ->.

uC02 K '' COgH

800 mg (2.61 mmol) of potassium salt-10 of BL-P2013 is added to a mixture of 25 ml of ethyl acetate and 10 ml of water. After complete dissolution of the solid, 50% aqueous phosphoric acid is added dropwise to the mixture, with vigorous stirring, until the end of precipitation from the aqueous layer. The phase formed is separated by ethyl acetate, then washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent is separated by filtration and washed with 10 ml of ethyl acetate. The wash liquors are mixed with the initial filtrate. "Skellysolve B" is then added to the ethyl acetate up to the cloud point (approximately 10 ml). 5OO mg of activated charcoal ("Darko KB") is added to the mixture and the whole is filtered. The filtrate is diluted with 15 ml of "Skellysolve B", then it is seeded with crystals of BL-P2013 in the form of free acid. After about 3 hours at room temperature, the crystalline free acid precipitate is collected and dried under vacuum for 15 minutes on P ^ Oj- to obtain 323 mg 30 (yield of 4-6%) of the fluxing compound. above 100 ° C with slow decomposition.

Analysis for CqH ^ qCINO ^ S

Calculated: C, 35.89; H, 3.77; N, 5.23; ci, 13.25% Found: C, 35.88; H, 3.91; N, 5.4-1; Cl, 13.52% 35 This compound is found to be unstable during 7 days of storage at 23 ° C.

37 EXAMPLE 15.-

6a-bromopenicillanic acid diacid

- - O

5 +

Br, Br,

□ X / <(csvw) s—> Jj ^ X

Ό ^ C02I O '^ C02H

10 I_ —1 2 PM 800.64 PM 296; 14

300 g (0.75 mole) of N, N'-dibenzylethylenediamine salt of 6a-bromopenicillanic acid are added to 3 liters of methylene chloride and the suspension is cooled to 5 ° 0. Then 130 ml of concentrated hydrochloric acid are added thereto, dropwise and with vigorous stirring, over 15 minutes. The suspension is stirred at 5 ° C for 2 hours. It is then filtered on diatomaceous earth ("Celite"), then the filter cake is washed 3 times with 250 ml of methylene chloride.

The methylene chloride solutions are combined and washed twice with 500 ml of water, then dried over sodium sulfate for 15 minutes. The sodium sulfate is separated by filtration and the filtrate is evaporated under reduced pressure until ^. about 750 ml.

The solution is cooled to 5 ° 0 and with vigorous stirring, 130 ml of 40% peracetic acid is added dropwise to it, while maintaining the temperature between 5 and 12 ° C. The addition is very exothermic. At the end of the addition, the suspension is stirred at 5 ° 0 for 2 hours, then the product is isolated by filtration and washed with 5 ml of cold water (5 ° 0) and 100 ml of chloride cold methylene (5 ° C). 126 g (57% yield) of 6oc-bromopenicillanic acid sulfoxide, thus melting at 129 ° 0, are thus obtained. The infrared spectrum and the nuclear magnetic resonance spectrum are compatible with the structure of the desired product.

Analysis for CgH- ^ BrNO ^ S

Calculated: C, 32.44; H, 3.40; 35Γ, 4.73% 3 Found: C, 32.30; H, 3.33; N, 4.71% H2O, 2.18

Potassium 6a-bromopenicillanate sulfoxide 0 0 io Br '"'„ ___) \ —f ^ Y / J — J ~

6 ^ C02H ^ COgK

MP 334.24. 126 g (0.43 mole) of 6oc-bromopenicillanic acid sulfoxide and 162 ml of 50% by weight potassium 2-ethylhexa-noate in butanol are added to 3 liters of acetone. After 1 hour of stirring at 22 ° C., the product is collected by filtration, washed twice with 250 ml of acetone and dried. 127 S (90% yield) of potassium 6a-bro-mopenicillanate sulfoxide, melting at 185 ° C., are thus obtained. The infrared spectrum and the nuclear magnetic resonance spectrum are compatible with the desired structure.

25 Analysis for CgH ^ BrKNO ^ S

Calculated: C, 28.75; H, 2.71; N, 4.19% „Found: C, 29.03; H, 2.78; N, 4.04%

P-nitrobenzyie 6a-bromopenicillanate sulfoxide 30 ο o Y> + a4 * -7 “" "C02K - Yo2 QK2- (2) ~ m2 35 PM 431.28 59

149 S (0.43 mole) of potassium 6a-bromopenicillanate sulfoxide is added to 1 liter of ΕΓ, ΙΤ-dimethylacetamide, then, with stirring, 115 g (0.53 mole) of p-nitrobenzyl bromide at 22 ° vs. The mixture is stirred at 22 ° C for 20 hours

The reaction mixture is poured into 3 liters of water which is extracted 3 times with 1500 ml of ethyl acetate. The extracts are combined with ethyl acetate and washed twice with 500 ml of 10 to 5% aqueous sodium bicarbonate solution, then dried for 30 minutes over sodium sulfate. The sodium sulfate is separated by filtration and the filtrate is evaporated under reduced pressure to obtain a residue to which 1 liter of diethyl ether is added to crystallize the product. The crystals are collected by filtration, washed twice with 100 ml of diethyl ether and dried to obtain 162 g (87%) of p-nitrobenzyl 6α-bromopenicillanate sulfoxide, melting at 111 ° C. The infrared spectrum and the nuclear magnetic resonance spectrum are compatible with the desired structure.

Analysis for C15H16Brïï2 ° 6S

Calculated: C, 41.78; H, 3.51; N, 6.50

Found: C, 41.66; H, 3.45; N, 6.85; 25 HpO according to KP 0.69 6a-Br omo -2 β - chloromethyl -2 -m et hylp ename -3 -c arboxyl at e of p-nitrobenzyl 30 f Br * yS ^ Cl% _ / -NI -> I CE ?

\ "<h * —S

Γ * 35 PM 449.71 40

70 g (0.16 mole) of p-nitrobenzyl 6a-bromopenicillanate sulfoxide are added, then 21.2 ml (0.10 mole) of benzoyl chloride and 21.8 ml (0.19 mole) of quinoline to 1 liter of p-dioxanre. The reaction mixture was heated at reflux for 4 hours, then cooled to 22 ° C, poured into 2500 ml of water and extracted all 3 times with 800 ml of ethyl acetate. The extracts are combined with ethyl acetate and washed with 300 ml of 5% aqueous sodium bicarbonate solution, 300 ml of 3% aqueous phosphoric acid and 300 ml of water. The ethyl acetate solution is dried for 30 minutes over sodium sulfate, then the sodium sulfate is separated by filtration. The filtrate is evaporated under reduced pressure to obtain a residue which is redissolved in 1 liter of ethyl acetate, after which the solution is evaporated again under reduced pressure to obtain a residue. 1 liter of diethyl ether is added to the residue and the product is collected by filtration to obtain 41 g 20 (yield of 57%) of p-nitrobenzyl 6a-bromo-2p-chloromethyl-2-methyl-penam-3-carboxylate melting at 132 ° C. The infrared spectrum and the nuclear magnetic resonance spectrum are compatible with the desired structure.

25 Analysis for C ^ H ^ BrClT ^ O ^ -S

Calculated: C, 40.06; H, 3.14; N, 6.23%

Found: C, 40.62; H, 3.11; N, 6.13% 30 35 41

P-nitrobenzyl 6a-bromo-23-chloromethyl-2-methylpenam-3-carboxylate sulfoxide

O

~ - Λ * CH0C1

5 \ SS ^ C1 v Vi ^^ CH

^ I ^ CH5 0 ^ \ ch2; - φ no2 EM 465.71 15 51 δ (0.11 mole) of p-nitro-benzyl 6a-bromo-2ß- chloromethyl-2-methylpenam-3-carboxylate are added, then 23 g (0.12 mole) m-chloroperoxy-benzoic acid to 1200 ml of methylene chloride. The solution was stirred at 22 ° C for 2 hours and evaporated under reduced pressure to obtain a wet residue. This is stirred with 4 liters of diethyl ether for 1 hour, then allowed to stand at 10 ° C for 20 hours. The crystallized product is collected by filtration, which is washed twice with 200 ml of diethyl ether and dried to obtain 39% (75% yield) of 6a-bromo-2P-chloromethyl-2 sulfoxide. - · p-nitrobenzyl methylpenam-3-carboxylate melting at * 132 ° 0. The infrared spectrum and the nuclear magnetic resonance spectrum are compatible with the desired structure.

Analysis for C ^ K ^ BrClNgOgS

Calculated: C, 38.69; H, 3.03; N, 6.07%

Found: 0.38.98; H, 3.04; N, 5.84% H2O, 0.35 35 4-2

Sulfone of 2p-chloromethyl-2-methylpenam-3-carbox, potassium y-late (BL-P2Q13) - 00 5 B? > s> ch2ci ^ S <^ CH2C1 "-f ^ - * rT_f'CH3

O ^ 02CH2 ^ 3 “N02 ^% C02K

'-' BL-P2013 10 PM 305.77

8 g of 30% palladium on "Celite" and 16 g (0.19 mole) of "sodium bicarbonate are added to 600 ml of water. 32 g (0.069 mole) of 6oc sul-oxide are then dissolved. -bromo-2ß-chloromethyl-2-methylpename-3-p-nitrobenzylcarboxylate in 4-00 ml of ethyl acetate and the solution is added to the aqueous dispersion The mixture is hydrogenated in a Parr apparatus under 3 ^ 5 kPa at 22 ° C for 4- hours The suspension is filtered through a thin layer of "Celite" in a sintered glass filter, then the filter cake is washed twice with 50 ml of water, after which the aqueous layer is separated from the mixture of filtrates and washing liquors, the aqueous layer is washed with 200 ml of di-ethyl ether, then cooled to 5 ° C. and with stirring, added dropwise 30 minutes, a solution of 12 g (0.076 mole) of potassium permanganate in 200 ml of water while maintaining the pH between 7.5 and 8.0 by adding phosphoric acid at 4-0%. 30 pink persis ration for 5 minutes, the addition of the potassium permanganate solution is stopped. The reaction mixture is stirred with a small amount (about 50 mg) of sodium bisulfite for 30 minutes, then the suspension is filtered through a layer of nelite, t. The filter cake is washed twice with 50 ml of water. The filters and washing liquors are combined and covered with 500 ml of ethyl acetate and, with stirring, the pH is adjusted to 1.5 using 2N hydrochloric acid. The layers are separated and saturates the aqueous layer of sodium sulfate. It is extracted back with 2 times 400 ml of ethyl acetate, then the extracts are combined in ethyl acetate and they are dried over sodium sulphate for 30 minutes at 3 ° 0. The sodium sulfate is separated by filtration and the filtrate is evaporated under reduced pressure to obtain a residue. This residue is dissolved in 160 ml of acetone and 160 ml of diethyl ether, then a 50% by weight solution of potassium 2-ethyl hexanoate in n-butanol is added until the solution is neutral. wet pH paper. The potassium salt of BL-P2013 is crystallized, collected by filtration, washed with diethyl ether and dried. 16 g (76% yield) are thus obtained of potassium 2P-chloromethyl-2-methyl-pename-3-carboxylate sulfone, melting at 202 ° C.

The infrared spectrum and the nuclear magnetic resonance spectrum are compatible with the desired structure.

Analysis for CgH ^ ClKNO ^ S

Calculated: C, 31.42; H, 2.97; N, 4-, 58%

Found: C, 31.18; H, 2.98; H, 4.51% 25 H2O, 0.93 EXAMPLE 16.-

Pivaloyloxr / m ethyl 2P-chloromethyl-2-methylpenam-3-carboxylate sulfone (BL-P2024) 0 0 0 0 50 yS ^ / CHgCl n_r * -> rCn / ^ / C02K (f ^ COgCHgOCOCiCH ^ BL-P2024 33 PM 381.83 '14

4 ml of a 10% aqueous solution of sodium iodide are added to a stirred suspension of 14.6 g (48ÿ7 mmol) of potassium 2p-chloromethyl-2-methylpé-name-3-carboxylate sulfone (BL -P2013) in 200 ml of acetone and the mixture is brought to reflux in a water bath. 14.8 ml (0.1 mol) of redistilled chloromethyl pivalate (m.p. 34 ° c at 933 Pa) are added to the boiling suspension at reflux. The mixture was stirred at reflux for 3 hours, then re-cooled to room temperature (22 ° C). The crystalline solids are collected by filtration, which are washed 3 times with 30 ml of acetone, after which the mixture of filtrates is evaporated under reduced pressure below 22 ° C to obtain an oil. The oil is taken up in 13,500 ml of ethyl acetate and the solution is washed once with 200 ml of water and once with 200 ml of saturated sodium sulphate solution. The solution is then briefly dried over sodium sulfate, while stirring with 2 g of bleaching charcoal under cooling in an ice bath. After 20 minutes, the mixture is filtered on a layer of "Celite" and the filter cake is washed with 4 times 100 ml of ethyl acetate. The mixture of filtrates is concentrated at 22 ° C under reduced pressure to obtain an oil. The oil 23 is further concentrated at about 22 ° C below 133 ° C to remove most of the residual chloromethyl pivalate. The residual oil is then triturated 2 times

ί N

with 50 ml of n-pentane, after which it is left to stand over the weekend at approximately 10 ° C. under a layer of n-pentane. The resulting solid crystalline mass is crushed into a powder under 40 ml of a 4: 1 mixture of diethyl ether and n-pentane. The product is collected by filtration, washed with a 1: 1 mixture of diethyl ether and n-pentane, then with n-penta-35 ne5 after which it is air dried. After drying under high vacuum for 4 hours on ^ 2 ^ 5 '011 13.37 S (yield of about 75%) of sulfone of pivaloyloxy-methyl 2ß-chloro-45-methyl-2-methylpenam-3-carboxylate ( BL-P2024) melting at 93-95 ° C.

BL-P2024 purification

Approximately 3% of crude BL-P2024 (obtained 5 as described above) is dissolved in 5 ml of ethyl acetate, then the solution is poured onto a column of 4.5 cm x 40 cm of silica gel ( Mallinckrodt CC-7) which is eluted with a 4: 1 volume mixture of methylene chloride and ethyl acetate. The fractions giving a single spot of one of 0.84 are combined (chromatography in a flash layer on silica gel plates eluted with a 4: 1 mixture of methylene chloride and ethyl acetate, detection by Ig) and concentrated under reduced pressure to obtain 1.38 g of a crystalline solid. A 900 mg fraction of this solid is dissolved in 5 ml of ethyl acetate and the solution is filtered, then it is diluted approximately to the cloud point with petroleum ether ("Skellysolve B" ), after which it is stored at room temperature for 3 days. The crystals which have formed are collected by filtration and washed with petroleum ether, then dried to obtain 560 mg of purified BL-P2024, melting at 100-101 ° C.

Analysis for C ^ zj ^ oCOlMV ^ Computed: C, 44.03; H, 5.27; N, 3.67%

Found: C, 44.11; H, 5.08; N, 3.85% EXAMPLE 17.-

Preparation of the ammonium salt of BL-P2015 1. A solution of 250 mg of the free acid form of BL-P2013 is filtered in 20 ml of a 1: 1 mixture by volume of acetone and methanol to obtain a clear solution.

"2. An anhydrous ammonium solution is prepared by adding 1 ml of ammonium hydroxide (30%, for 35 laboratory operations) to 10 ml of a 1: 1 mixture by volume of acetone and methanol, then adding to this solution 1 g of anhydrous magnesium sulphate with moderate stirring, after which the mixture is filtered on filter paper, the filtrate being called hereinafter "anhydrous ammonium solution".

3. About 2 ml of the "anhydrous ammonium solution" are gradually added and carefully mixed with the filtrate obtained in 1.

40 ml of diethyl ether are mixed with the mixture obtained in 3 to precipitate the ammonium salt of BL-P2013.

10 5 · The white ammonium salt is isolated from the soil. before and washed twice with 50 ml of diethyl ether than each time.

6. The resulting powder is dried at 35 ° 0 in the vacuum oven overnight.

; 15 7- Analysis

Calculated: Ç, 33.7; H, 4.6; N, 9.8%

Found: Ç, 33.66; H, 4.63; N, 10.12% Anhydrous according to K.F.

Microscopic appearance: crystalline substance.

20 EXAMPLE 18, -

Preparation of the sodium salt of non-hygroscopic BL-P2013 1. 50 μg of the free acid form of BL-P2013 are dissolved in 4 ml of a 1: 1 mixture by volume of acetone and methanol. The mixture is filtered to obtain a clear solution.

2. A solution of sodium 2-ethylhexanoate II is prepared by dissolving 40 mg of sodium 2-ethylhexanoate in 10 ml of a 1: 1 mixture by volume of acetone and methanol.

3- Add the 10 ml of solution obtained in 2 to the filtrate obtained in 1 and mix everything carefully.

4. 10 ml of diethyl ether are mixed with the mixture obtained in 3 to precipitate the sodium salt of BL-P2013.

5 · The white salt is left to stand in diethyl ether 47 for 1 to 2 hours, then it is separated from the solvent and washed 3 times with 5 ml of diethyl ether each time.

6. The resulting powder is dried at 30 ° C in the vacuum oven overnight.

EXAMPLE 19.-

Recrystallization of Β1-Ρ2013; 0 0 0 0 in CH2C1 recrystal- ^ <^ * CH0C1.-R- * · 'ia liaation. , - \ CIb I CH5 / 8 "“ s'-V ** 'C0gK * Hg0 13 400 mg of BL-P2013 is dissolved in a minimum quantity of a 1: 1 mixture by volume of acetone and water and dilute the solution with 10 ml of acetone, then filter and dilute again with acetone to about 25 ml, after which the container wall is scraped off and, after 30 minutes, collects by filtration the crystalline hydrate which is washed carefully with acetone, then dried in air and then under vacuum below 133 Pa overnight. 280 mg of the compound are obtained.

25 Analysis for CgHgClIfOSE.E ^ O

Calculated: C, 29.67; H, 3.39; N, 4.63; Cl, 10.94;

HgO, 5.55%

Found: C, 29.32; H, 3.32; N, 4.44; Cl, 11.31; H2O, 5.90% 30 35 48 EXAMPLE 20.-

IT salt, N * -dibenzylethylenediamine from BL-P2013 BL-P2013 + 1/2 Diacetate from N, N'-dibenzylethylenedLamine 5% 5 ^ ° * CE2C1 ^ \ - recrystallization / N / ώ \ -> / T "'CH * \ acetone-ether / 12 I / "'cOgH.CgH ^ HgHH-CH ^ - 10 · \ / 2

306 mg (l mmol) of BL-P2013 are dissolved in 7 ml of water and the solution is added to a solution of 180 mg (0.5 mmol) of N, N'-dibenzylethylenediamine diacetate in 7 hlL of water. The mixture in which the salt crystallizes is stirred and after approximately 10 to 15 minutes of stirring, the salt is collected by filtration, then it is dried in air to obtain 300 mg of Ν, Ν'-dibenzylethylenediamine salt from BL -P2013. The salt is recrystallized by dissolving it in about 10 ml of boiling acetone and diluting the solution with ether to the cloud point. 260 mg of the air-dried and vacuum-dried compound are thus obtained.

Analysis Computed: C, 51.69; H, 5.42; N, 7.53; 01, 9.53% Found: 0.49.39; H, 5.49; N, 7.05; 01, 8.96% Β ^, Ο according to E.P., 1.23 EXAMPLE 21, -

BL-P2015 3 ° 0 0 V chloromethyl ester ^ CHgCl + CICHg-O-SOgCl

-Y [4CH_ + (CHjCHgCHgCHg ^ lhtaOjP

qT - "-" "COOK + 3 KHC03 35 (305.7) 5, 49 ch2ci2, Ho0 V 2 0 0 JßKf h2ci 5 I TcH, jr — KK, 0 C-0CHoCl V 2 0 * · (516.17) 10 - 1. A solution of 9.5 g (57.5 mmol) of ClCl 4 -O-SO 4 in 40 ml of methylene chloride is added dropwise to a vigorously stirred mixture of 15.25 g (50 mmol) of BL-P2013 (£), 15 g (0.15 mol) of EHGO ^ and 1.7 g (5 mmol) of tetrabutyl ammonium hydrogen sulphate (Company Aldrieh Chem. Co.) in a mixture of ^ 0 ml of water and 50 ml of methylene chloride, the temperature rises to 26 ° C. and, at the end of the addition (which takes place in about 15 minutes), 20 the mixture is stirred for another 30 minutes. As the product crystallizes, an additional 400 ml of methylene chloride are added to obtain a solution. The layer formed by methylene chloride is separated and mixed with 50 ml. of a washing liquor comprising methylene chloride, then the whole is dried by stirring with magnesium sulfate and o n add 2 g of bleaching charcoal ("Darco KBU). After about 30 minutes, the mixture is filtered, concentrated to about 50 ml and 150 ml of isopropanol are added. The rest of the methylene chloride is removed under reduced pressure. The resulting crystalline precipitate is collected by filtration, which is washed thoroughly with isopropanol and dried in air. After drying under vacuum below 35,133 Pa, 8.5 g of chloromethyl-2-chloromethyl-2-methylpenam-3-carboxylate sulfone (2) are obtained, melting at 116 ° C. (with decomposition and darkening at 50 above 100 ° C).

Analysis for C ^ H ^ C ^ NO ^ S

Calculated: C, 34.18; H, 3.51; N, 4.43; 01, 22.43% Found: C, 34.16; H, 3.45; N, 4.47; 01, 22.46;% 5 I ^ O according to K.E., 0.33

The estimated purity is 90 to 95% ·

BL-P2013 iodomethyl ester 0 0 0 0 .CH-Cl 10> t / 2, -> </ 1Α-4Λ jr * - \ </ C-OCHgCl 0 8 Ç-OCHgl 70 0 15

3 g (20 mmol) of sodium iodide are added to a stirred mixture of 5 g (15.9 mmol) of BL-P2013 chlo-romethyl ester (2) in 25 ml of acetone. The resulting suspension was stirred for 17 hours, then cooled to about 0 ° 0. 2 drops of saturated aqueous potassium bicarbonate solution are added, then the mixture is slowly diluted dropwise with water over 10 minutes until a supply of 50 ml. The suspension suddenly turns yellow to gray and purple, then to black, and the crystals are then collected immediately by filtration and washed with a cold 1: 2 mixture of acetone and water, 3 times 10 ml d isopropanol, diethyl ether and finally n-pentane, before drying them in air to obtain 5.55 g (91% yield) of the iodomethyl ester of BL-P2013 (8) melting at 118-119 ° 0 with decomposition.

The estimated purity is around 90%.

55 51

Sulfone of 2S-chlopomethyl-2aHoaethvlnénamer5ff ~~ lfo ~: ^ '^ late de 6 - [(R) -2-amino-2-phenylac6tamido] 7-oxo-4-thia-l-azabicyclo Γ 5.2.0] heptane- 2 ^ cgJ''bP ”iglg.:Sy-methyl (11) ^ / - \ s cil3 1+ '<f V-CH-CO-MHirj- ^ ^ / CH ^

Cr N ^ COOK

V ^ N 9 10 (Däne salt of ampicilli-

II; born; voj_r "E0U.A patent

HGV jp n ° 3.316.247) 15 ocîb ψ 20 CH3 fH-co-®-y-f S <CHj 1 Vo N 0

25 H-, C —C

^ Il f HC J) OCH ^ 0 30 - 0 0 r1 vCH2C1 _ / v / 0¾ I ^ CH, | 2

J — K-L 'I

çy * c - o

II

0 H + v 35 52 / = \ S / ¾ 5 Y __ / Γ '* CH-> _N__p nh2 O c «0

10 'W

• 11 0 0 - CH Cl

- / CH

• "i = i-4 CH5 i 0 c-0

II

0

4.08 g (10 mmol) of BL-P2013 iodomethyl ester is added to a stirred, ice-cold mixture of 5 ^ 6 g (10 mmol) of the above ampicillin salt ÿ (solvated with 1 molecule of i-sopropanol) in 60 ml of acetone and the resulting almost clear solution is stirred for 5 hours by re-drawing the ice bath after 30 minutes. „Most of the acetone is then removed in vacuo on a rotary evaporate, then the resulting concentrated solution is dissolved in 200 ml of cold ethyl acetate, after which this solution is washed twice with ^> 0 ml of ice water and twice with 100 ml of saturated aqueous sodium sulfate. The ethyl acetate solution is dried over sodium sulfate, filtered and most of the ethyl acetate is removed in vacuo on a rotary evaporator. The residue is triturated twice with 200 ml of dry diethyl ether, then the resulting solids are collected by filtration to obtain 5 * 5 g of compound 10 in the form of a pink powder. This powder is incorporated into a stirred mixture of 5 ml of water, 50 ml of n-butanol and 20 ml of ethyl acetate to which 6N hydrochloric acid is added dropwise until whether the pH is 2.5 · Occasionally 1 or 2 drops of hydrochloric acid are added to maintain the pH at 2.2-2.5 for 45 minutes. When the pH stops rising, 100 ml of diethyl ether are added to the mixture with good stirring. The aqueous phase is separated and mixed with a second 25 ml aqueous extract of the organic phase. The aqueous solution is extracted 1 time with 50 ml of diethyl ether and the ethereal extract is discarded.

The aqueous layer is then stirred vigorously under a 100 ml layer of 2-butanone (methyl ethyl; ketone), while sodium sulfate is added to saturate the aqueous layer. The 2-butanone layer is separated, dried for 30 minutes over sodium sulfate in an ice bath, filtered and concentrated in vacuo almost to dryness. The residual oil is triturated to a solid under n-butanol, then the solid is washed thoroughly with ether and then with n-pentane, after which it is dried first in air and then under vacuum on PgO ^ below 133 la to obtain 1.6 g of 6 - [(R) -2-amino-2-phenylacetamido] - 3,3 - 2P-chloromethyl-2-methylpenam-25 3a sulfone -dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carbonylmethyl in crude form. The infrared spectrum and the nuclear magnetic resonance spectrum are compatible with the structure of the compound (II) which is however not of high purity. It is estimated that this solid contains at least 40% by weight and can be up to 80% by weight of sulfone of 2ß-chloromethyl-2oc-m é thy lp ename -3 cxr- c arboxyl at e de 6 - [(R ) -2-amino-2-phenyl-acetamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo- "35 [3-2.0] heptane-2-carbonyloxymethyl0 54 EXAMPLE 22.-

Improved synthesis route of BL-P2013

This procedure simplifies the preparation of BL-P2013 by eliminating the catalytic reduction previously carried out.

Stage 1 0

Br “î c 10 + CHpCC-L · + Dicyclohexyl- i_N - *%. Lr 2 carbodiimide

$ COOH 0H

i Pyridine CHpClp 13 Ψ 0 20 0 tî-OCHgCClj 0 (See page 633 of Gephalosporins and Penicillins by Edwin H. Flynn, Academie Press, New York, 1972).

25 30 g (0.1 mole) of acid sulfoxide 6a ~ hromopenicillanic (1} are dissolved in 1000 ml of dry methylene chloride, then 16.2 ml (0.2 mole) of pyridine is added to the solution and 29.8 g (0.2 mole) of trichloroethanol, then 20 g (0.1 mole) of dicyclohexylcarbodiimide are added and the mixture is stirred at 22 ° G for 16 hours. The dicyclohexylurea begins to precipitate and it finally eliminated by filtration. The filtrate is washed with 200 ml of 5% aqueous sodium bicarbonate 200 ml of 10% phosphoric acid and 100 ml of saturated aqueous sodium sulfate. The organic phase is dried to 5 ° 0 for 30 minutes on sodium sulfate which is separated by filtration, after which the organic phase is evaporated to an oil 55. Diethyl ether is added and, by scraping, the product 2 is crystallized (obtained in quantity of 27 g, i.e. with a yield of 27%).

5 Stage 2 s * O-

Quinoline Ψ 15 Br ° .CILC1, \ ^% / \ / A CH ^ ^

—W

0 'C-OCH ^ CCl H ^ 3 20 °

26.5 g (62 mmol) of compound 2 are dissolved in 500 ml of p-dioxane and 8.5 ml (78 mmol) of benzoyl chloride and 8.75 ml (78 mmol) of quinoline are added to the solution. . The solution is heated to reflux; for 4- hours, then it is poured into 1100 ml of water, after which the product 3 is extracted into 2 times 300 ml of ethyl acetate. The extracts are mixed in ethyl acetate, washed successively with 200 ml of 5% aqueous sodium bicarbonate> 200 ml of 5% phosphoric acid and 200 ml of saturated aqueous sodium sulfate, after which they are dried over sodium sulphate at 5 ° C. for 30 minutes and evaporated to an oil (3) which is used as it is for the following reaction.

56

Stage 3 2. + KMn04 + H202 5 in glacial acetic acid Ψ 0 0 10 Br N \ // / H2C1 yWL i J — 11 - '% 0 C-OCHgCCl ^; 15 0

The compound 3, obtained in the preceding stage, is dissolved in 1000 ml of glacial acetic acid and, with stirring at 22 ° G, a saturated aqueous solution of potassium permanganate juice-20 with a persistent pink color (c (i.e. a drop on a piece of filter paper gives a pink spot). -Under cooling,. then 30% hydrogen peroxide is added dropwise until a clear solution containing a little white precipitate is obtained. The solution is poured into 2500 ml of water and the product 4 is extracted into 3 times $ 00 ml of ethyl acetate. The ethyl acetate extract is washed with 5% aqueous sodium bicarbonate until neutral (i.e. until effervescent), then dried over sulfate of sodium and it is evaporated to obtain compound 4 in the form of a residue.

The residue is left to stand at 10 ° C. for 1 day, then it is triturated with "Skellysolve B" to obtain 9.1 g of solid 4. The yield is 28% of the theoretical value 55 in stages 2 and 3 considered together.

57

Stage 4 it + (i) Zn in acetic acid + (2) 2 ”potassium ethylhexanoate 5

\ K

- [| CEj 5 (BL-P2015) -%

O COOK

> 15 (See "U.S. Patent No. 4,164,497)

3.75 S of zinc dust are dispersed in 5 ml of glacial acetic acid and the dispersion is cooled to 5 ° G · A solution of 3 g of compound 4 (5.7 mmol) in 15 ml is added to this mixture of dimethyl-20 formamide and the resulting suspension is stirred at 5 ° G for 2 hours and 30 minutes.

The zinc is separated by filtration and the pale yellow solution is poured into 80 ml of 5% aqueous hydrochloric acid. The mixture is extracted 3 times with 25 ml of ethyl acetate. The extracts are mixed in ethyl acetate and they are extracted, in turn, with 3 times 20 ml of "5% aqueous sodium bicarbonate, the ethyl acetate phase being preserved after separation.

The bicarbon extracts are combined, covered with a layer of ethyl acetate, brought to 1.5% by addition of 2 B "hydrochloric acid and saturated with sodium sulfate. the ethyl acetate phase and the aqueous phase is extracted twice with 30 ml of ethyl acetate.

All the extracts are mixed in ethyl acetate, dried over sodium sulfate and evaporated to an oil (which is the free acid form of BL-P2013) which is dissolved in about 20 ml acetone, solution to which 20 ml of diethyl ether are added. Then 50% potassium 2-ethylhexanoate 50% in dry n-hutanol is added until neutral.

The product £ (BL-P2013) is deposited in crystals. After 30 minutes of stirring at 22 ° C., the crystals are collected by filtration to obtain 6 ^ 0 mg of the compound £ * (yield of 37%) · 50 mg of the compound j are dissolved. in 0.5 ml of water and 20 mg of N, N'-dibenzyl-ethylenediamine diacetate are added. The dibenzylethylenediamine salt of. compound ^ is deposited in crystals which are collected by filtration, then washed with water and dried over P205 under vacuum to obtain the sulfone of 25-chloromethyl-2-methylpenam-3 -carboxylate of N ", h'-dibenzylethyl-lenediamine (salt of Ν, Ν'-dibenzylethylenediamine of free acid%).

Another 40 mg sample of compound £ is dissolved in 3 ml of water and 270 mg of N, N'-dibenzylethylenediamine diacetate in 2 ml of water is added to the solution. By scraping, 43Ο mg of the salt of K,]! '- dibenzylethylenediamine of the compound J is crystallized. By recrystallization from 100 ml of boiling acetone, 270 mg of the compound are isolated.

30 ”35 59 EXAMPLE 25

23-chloromethyl-2a-iiiethylpéiiame-3a-carboxylate sulfone of 6 - [(P) -2-amino-2-p-hydroxyphenylacetamido] - 3,3-dimethyl-7-oxo-ip-thia- l-aza'bic; 7clo [3 »2« OJheptane-5 2-carlonylox: methyl of formula:. — s CH3 ho- \ t-cn-co-m-rrH ^

! 0 'J — N-K

m2 o c = o i54 0 0 0 X / 5 ^ 1 - {^ CH, ^ 20

II

0

This compound is prepared by replacing the ampicillin in the process of Example 21 with the corresponding Däne salt of 25 amoxicillin. Biological data.

The compound of Example 1 or compound corresponding to the formula: 50 Vf / H2cl -S '' '' O'CHj

g "lo2K

is hereinafter called compound BL-P2013.

Although at best it is a very weak antibacterial agent, the compound BL-P2013 inhibits β-lactamases and protects ceforanide and amoxicillin against destruction in vitro and in vivo by bacteria producing ß-lactamase 5 when combined with these two agents.

TABLE I

Antibacterial activity of the new sulfone.

ICD (^ ug / ml) 10 Organism ------ BL-P2013 Ampicillin S. pneumoniae A-9585 16 0.00½ S. pyogenes A-960 * +. 63 0.00½ S. aureus A-9537> 125 0.16. 15 S. aureus + $ 50 serum A-9537> 125 0.06 S. aureus Pen- Res A-9606> 125> 125 S. aureus Meth- Res Al5097> 125 125 S. faecalis A20688> 125 0.13 E. coli Al5119> 125 1 20 E. coli A203lfl-1> 125> 125 K. pneumoniae A15130> 125 125 K. pneumoniae A20½68> 125> 125 P. mirabilis A-99 ° 0> 125 0.13 P. vulgaris A21559> 125 125 25 P. morganii A15153> 125> 125 P. rettgeri A21203> 125 1+ S. marcescens A20019> 125 16 E. clcacae A-9659> 125 63 E. clcacae A-9656> 125> 125 30 p · aeruginosa A- 981 + 3A> 125> 125 P. aeruginosa A21213> 125> 125 35 61

TABLE II

Antibacterial activity of ceforamlde and amoxicillin alone and in combination with the compound BL-P2013 5 Beta- CIM (/ jg / ml) *

Lact organism -___________________________ amase Cefo- Céforanide Arnoxi- ranide + BL - P2013 BL-P c illine Amoxi- (1: 1) 2013 + BL-P c illine 2013 (1: 1) 10 --—----- ------- B. fragilis A21916 +63 2> 125 2 8 A22053 + 32 k 63 2 8 A22021 + 32 2 32 _2_> + 15 A21875 + 32 k 63 2 8 A2253 ^ - +> 125 32 125 16 > 125 A22697 +63 8 63 2 8 A22693 +63 k 63 2 16 A2269 ^ + 125 16 63 2 16 20 A22695 +> 125 _16_ 32 k I25 A22696 +> 125 _32_ 63 8> 125 A22533 + Π25 _32_ 32 32> 125 A22535 +> 125 22 125 22> 125 A22792 +> 125 8 32 k 125 25 A22793 +32 k 32 2 8 A2279 ^ +32 k 32 2 8 A22795 +63 k 32 k 16 A22797 +63 k 63 2 16 A22798 +32 k 63 2 8 30 B. thetaio-taomicron A22277 + 125 k 63 2 16 A22279 + 125 8 63 k 16

Bacteroides 35 species A2093 ^ - +32 k 32 2 8 A21959 +63 k 32 2 16 62 TABLE II (continued)

Antibacterial activity of ceforamide and amoxicillin in isolation and in combination with the compound BL-P2013 5 Beta- CIM (; ug / ml) *

Lact organism -______________ amase Cefo- Céforanide Amoxi- banide + BL-P2013 BL-P cillin Amoxi- (1: 1) 2013 + BL-P cilline 2013 - (1: 1) 10_______________

Bacteroides species A209 29 + 63 k 32 2 16 A2l95b- + 63 16 63 2 16 15 A20933 + 63 16 63 _k_ 8 A20930 + 125 8 125 k 32 A20931 + 63 k 32 2 16 A20927-1 - 0.5 1 63 0 , 13 0.13 A20935 - 2 2 125 0.13 0.13 20______ _ good synergy.

--- marginal synergy X The minimum inhibitory concentration (MIC) is determined by dilution on agar using cultures of 21 25 diluted diluted 50 times with 1; Steer inoculator. The test medium is formed of Brucella agar supplemented with% lacquered sheep blood and 10 ^ ug / ml of vitamin K.

30 35 63

TABLE III

Therapeutic efficacy of amoxicillin in combination with compound BL-P2013 in mice experimentally infected with a strain of staphylococcus aureus producing ß-lactamase.

not . DP infection? / treatment (mgÆg)

Organism (nCffibre - 1 - ^ - of organizations) Amox ic i 1 -

Heine (A) BL-P2013 (B; A + B {1: 1)

10 IM PO IM PO IM PO

O

S. aureus 5 x 10> 800> 300> 50> 200 6.3 è-è- A-9606 5 x 108> 800> 800> 50> 200 19 77 7 X 108> 800 -> 90 - 9.6 - 15 --- ---------

Dosage: administration of the drug 0 and 2 hours after infection.

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72

The compounds of the invention are therefore useful, for oral or parenteral administration, for improving the effectiveness of antibiotics with a ß-lactam cycle against bacteria producing ß-lactamase. On a weight basis, the dose is one fifth to five times that of β-lactam ring antibiotics and is preferably equal to the latter. For example, the compounds of the invention, as illustrated above, administered in a 1: 1 ratio, clearly improve the activity of ceforanide and amoxicillin against the strains producing anaerobic β-lactamase from Bacteroides, as fragilis and thetaiotaomicron, in addition to other species of this genus, as well as against the resistant forms of Staphylococcus aureus. The compounds of the invention are administered in admixture with, or at the same time as, the β-lactam ring antibiotic in a dose establishing the ratio indicated with the known and usual dose of the antibiotic.

Therefore, the ability of the compounds of the invention to improve the efficacy of a β-lactam ring antibiotic against certain bacteria producing ß-lactamase makes them attractive for simultaneous administration with certain ring antibiotics. Β-lactam in the treatment of infections by bacteria in mammals and, in particular, humans. For the treatment of infection with bacteria, a compound of the invention may be mixed with the β-lactam ring antibiotic and the two agents may thus be administered simultaneously. Alternatively, a compound of the invention may be administered separately during treatment with an ß β-lactam ring antibiotic.

When a compound of the invention or a salt thereof is used to enhance the antibacterial effect of a β-lactam ring antibiotic, it can be administered as such or, preferably, with diluents or conventional pharmaceutical excipients. A compound of the invention in the form of a pharmaceutically acceptable acid or salt can be administered orally or parenterally and a compound of the invention in the form of an ester which is readily hydrolyzed in vivo is most favorably administered by the oral.

By parenteral administration is meant intramuscular, subcutaneous, intraperitoneal or intravenous administration.

When a compound of the invention is used with a diluent or excipient, this is chosen according to the mode of administration intended. For example, for oral administration, the compound may be presented in the form of tablets, capsules, lozenges, lozenges, powders, syrups, elixirs, solutions or suspensions aqinuse s , etc. according to current pharmaceutical practice. The ratio between the active constituents and the excipient obviously depends on the chemical nature, the solubility, the stability and the effectiveness of the active principles, as well as on the dose envisaged, nevertheless, these pharmaceutical compositions are likely to contain about 5 to 80% of excipient. In the case of tablets for oral use, common excipients are in particular lactose, sodium citrate and phosphates. Various disintegrating agents, such as starch and lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are frequently used in tablets. For oral administration in the form of capsules, useful diluents are lactose and high molecular weight polyethylene glycols. In aqueous suspensions * administered orally, the active ingredients are combined with emulsifiers and 55 suspending agents. If desired, certain sweetening and / or flavoring agents may be added. For parenteral, in particular intramuscular, intraperitoneal, subcutaneous or intravenous administration, the active ingredients are usually presented in the form of sterile solutions, the pH of which is advantageously adjusted by means of a buffer. For intravenous administration, the total concentration of solutes should make the composition isotonic.

Although the physician ultimately decides - the dose administered to his patient, the ratio between the daily dose of a compound of the invention or its salt and the daily dose of a ß-lactam antibiotic is normally about 1: 5 to -5; 1 and preferably about 1: 1. In addition, the daily dose of each active ingredient is normally about. About 10 to 200 mg per kg of body weight for oral administration and about 10 to 100 mg per kg of body weight for parenteral administration. These values are, however, only indicative and it may sometimes be necessary to administer doses falling outside these limits.

The invention is capable of industrial application.

25 30 35

Claims (29)

75 1. The acid of formula: O O V // ς CH Cl -Y Ή 'CH3 σ £ ooh 3 ·. 10 or a pharmaceutically acceptable salt of this acid or physiologically hydrolyzable ester of this acid. 2, - Ester according to claim 1 selected from the class consisting of esters containing phenacyl, acetoxymethyl, pivaloyloxymethyl, α-aceto-toxyethyl, oc-acetoxybenzyl, oc-pivaloyloxyethyl, 3-phthalidyl, 5-i & danyl, methoxymethyl, benzoyloxymethyl -thyle, oc- ethylbutyryloxymethyl, propionyloxymethyl, valeryloxymethyl, isobutyryloxymethyl, 6 - [(R) -2-ami-no-2-phenylacetamido] -3,3-dimethyl-7-oxo-4-thia-l-aza-20 bicyclo [3.2.0] heptane-2-carbonyloxymethyl or 6 - [(R) ~ 2-amino-2-p-hydroxyphenylacetamido] -3,3-dimethyl-7-oxo 4-thia-l-azabicyclo [3.2. 0] heptane-2-carbonyloxymethyl. 3 · - Ester according to claim 2, which is the radical ester 6 - [(R) -2-amino-2-phenylacetamido] -25 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carbonyloxymethyl. 4 -.- Ester according to claim 2, which is the radical ester 6 - [(R) -2-amino-2-p-hydroxyphenylaceous-tamido] -3,3-dimethyl-7-oxo-4-thia -1-azabicyclo [3-2.0] -30 heptane-2-carbonylmethyl. 5 · - Ester of formula: * 1 35 76 CH ^ r__CH — CO -NH *** ._ J. '<1, 5 </ - \ 0 c = o - o ° 10 _> t.C!, £ C1 | ’Γ pcn CH? / -N — k 3 I2 o C-0 II 0 15 where R represents: »O · O- Ο- Ό-“ where R-1 represents a hydrogen atom or a 2 hydroxyl radical and R represents an atom of hydrogen or chlorine or a hydroxyl, methyl or methoxy radical. 6. Process for the preparation of the compounds according to Claims 1 to 4, characterized in that, at successive stages, ** 'a) an ester of formula is subjected to catalytic hydrogenation: 30 O X CH Cl * Vy S co2r! 1 where R represents a benzyl or substituted benzyl radical; b) the hydrogenated product is subjected to oxidation to form the desired acid or its salt, then, if desired, c) the acid or salt is esterified to produce an easily hydrolyzed ester. acid. 7 · - Process according to claim 6, characterized in that the hydrogenation is carried out using a palladium catalyst. "" 8. A process according to claim 6, characterized in that the oxidation is carried out using an alkali metal permanganate or an organic peracid. 9 · - A process for preparing the compounds according to claims 1 to 4, characterized in that, at successive stages, a) one oxidizes, for example by means of KMnO ^, ^ 2 ^ 2 or ^ ·, υη peroxide analog or else of a peracid, an ester of formula: 20 Br? * CHgCl% _ I CH ^ / Un-1 * 0 'C-OCHgCCl ^ 0 25 to form a sulfoxide ester of formula: 0 0 \ // JSH-d Br V //> 2 // N% 0 C-OCHgCCl ^ 0 then, 35 b) this sulfoxide ester is reacted with a metal in an acid, such as zinc in glacial acetic acid, to produce the desired acid or salt, 78 then, if desired, c) esterifying the acid or its salt to produce an easily hydrolyzed ester of the acid. 10.- Process for the preparation of the following compounds before claim 5, characterized in that an acid is reacted with a solution of a compound of formula: CH ^ 10 R — CH-C0 ~ NHÄ »n __ ^ * S \ / 'NI [" CHj R ^ CHJ Nk 2. ii' ° "<> 0 R- ° ^ '• 5 15 & 0 0 V *' CH.C1 ? Γ ÇH2 Jr — K -1 ,,? J 20. e —-. 0 II 0 where R represents: O · 'Cy ό U- * 4 f ^ where R represents a hydrogen atom or a hydroxyl radical and R ^ represents a hydrogen atom or chlorine or a hydroxyl, methyl or methoxy radical; R ^ 2 represents an alkyl, aralkyl or aryl radical; R represents a hydrogen atom or an alkyl, aralkyl or aryl radical and R represents an alkyl radical, * - 45 yy aralkyl, aryl, alkoxy, aralkoxy or aryloxy or -MR, where R ^ and R ^ each represent an atom d hydrogen or an alkyl, aralkyl or aryl radical, or else, taken together with the nitrogen atom, represent a piperidino or morpholino radical, which reaction with the acid is carried out in an organic solvent or in solution aqueous or partially aqueous at room temperature. II. - Process according to claim 10, characterized in that R ^ represents a methyl radical, R represents a hydrogen atom and R ^ represents a ^ methoxy, ethoxy or methyl radical. 12. A process according to claim 10, characterized in that the reaction is carried out in acetone or chloroform. IJ. - Process according to claims 10 to 12, characterized in that the reaction is carried out at a pH 13 of 1 to 5. 14. Pharmaceutical composition for improving the efficacy of antibiotics with a ß-lactam cycle against bacteria producing ß-lactamase, characterized in that it comprises, as active principle, the free acid or pharmaceutically acceptable salt of a compound according to claim 1 in the presence of a vehicle or excipient. 15. Antibacterial composition, characterized in that it comprises, as active principle, an ester according to any one of claims 2 to 5. 16. Antibacterial composition, characterized in that it comprises, as active principles, the free acid or pharmaceutically acceptable salt of the acid according to claim 1 inhibiting ß-lactamase in mixture with an antibiotic with a ß-lactam cycle in presence of a vehicle or excipient. 17 · - Composition according to Claim 16, * characterized in that the antibiotic with a β-lactam cycle is ceforanide, ampicillin or amoxicil-33 line. 18.- Composition according to Claims 16 and 17, characterized in that the ratio of the main / 80 active pes is from 1: 5 to 5: 1 · 19. “Composition according to Claims 16 and 17, characterized in that the ratio of active ingredients is approximately 1: 1. 20. A method for improving the efficacy of ß-lactam ring antibiotics against bacteria producing ß-lactamase, characterized in that a free acid or pharmaceutically acceptable salt of a compound is administered according to claim 1. 10 21. A method of treating infectious diseases, characterized in that an effective antibacterial amount of an ester is administered according to any one of claims 2 to 5 · 22. A method of treating bacterial diseases, characterized in that an effective antibacterial amount of the free acid or pharmaceutically acceptable salt of the acid according to claim 1 is administered together with a ß-cycle antibiotic -lactam. 23. A method according to claim 22, characterized in that the β-lactam ring antibiotic is ceforanide, ampicillin or amoxicillin. 24, - Process according to claim 22 or 23, characterized in that the ratio of the active principles administered is approximately 1: 5 to 5: 1 · 23. The method of claim 22 or 23, characterized in that the ratio of active ingredients ~ is about 1: 1. 26.- Ester of formula: 30 Br ^! Cfl3 o ^ -N-W-oa 35 Ö where R represents a benzyl or p-nitrobenzyl radical. ί 81 27. Ester of formula: n, JL / CH2cl 5. I fCH3 / —N γοκ ^ where R represents a benzyl, p-nitrobenzyl or 10 ß, β, β-trichlorethyl radical. 28 - The ester according to claim 27, in the formula of which R represents a ß, ß, ß-trichlo-roethyl radical. 29 · - Ester of formula: O O Brùs' JC H-Cl VV "bC [CH3 20 rY N ^ 0 C-OCH CCL il 2 "5 .0 30.- Process for the preparation of a compound according to claim 26, characterized in that a compound of formula 23 is heated: _ 0 Br ', ^ _ |> S \ / Vor U II 0 i where R represents a benzyl or substituted benzyl radical, in an inert anhydrous organic solvent, in the presence of a large and equimolar amount of a weak tertiary amine and an acid chloride; until substantial completion of the reaction. 82 31.- Process for the preparation of a compound according to Claims 27 and 28, characterized in that a solution, in an inert solvent, of a compound of formula: 5 Br _ CH Cl J- - is oxidized 0 G-OH „II 10 o where R represents a benzyl or substituted benzyl radical, at room temperature by means of a peracid. - ·> 32.- Process for preparing the following compound; 15 before claim 29, characterized in that oxidizes a solution, in an inert solvent, of a compound of formula: Br? * CHpCl \ _ / y 20 d "" CE, —K O7 C- OCHjjCCl ^ 0 23. approximately at room temperature, using an oxidant such as KMnO ^, H ^ O ^ or a similar peroxide or else a peracid. 4 to 30