SU993820A3 - Process for preparing 2-beta-chloromethyl-2alpha-methylpename-3alpha carboxylic acid sulfones or its salts (modifications) - Google Patents

Description

(5) METHOD FOR OBTAINING SULPHONES 2p-CHLOROMETHYL-2-6-METHYL-PEN-3 A-CARBIC ACID OR ITS COMPLEX ETHER, OR ITS SALTS (ITS OPTIONS)

12

This invention relates to a process for the preparation of new foam nocillin compounds, namely, sulfones 20-chloromethyl-2e (methyl peenes-3o-carboxylic acid or its esters or its salts (its variants). These compounds can be used in medicine.

A known method of producing peny -; - Q of cyllanic acid or its esters of esters or its salts consists in that 6-bromo-penicillanic acid or its salt is subjected to reduction by catalytic hydrogenolysis, 5 preferably in an inert solvent under hydrogen pressure from 1 to 5 kg / cm2. Or hydrogen at the time of isolation, and the desired product is isolated as the free acid or its salt jo or the free acid or its salt is converted to the ester l}.

A known method for the preparation of sulphone of lenicillanic acid or her. Compound esters or its salts by oxidation of sulfoxide of lenicillanic acid or its salt by treating with an oxidizing agent, such as metal permanganate, taken in an amount of 0.5 to 5 molar equivalents, preferably 1 molar equivalent, in a solvent medium at a temperature of from -20 to 50 ° C, preferably by either oxidation by treatment with an organic peracid, taken in an amount of from 1 to molar equivalents, preferably 1.2 molar equivalents in an organic solvent medium at a temperature of from -20 to 50 ° C; preferably, when the desired product is isolated in the form of the free acid, its salt or ester.

These compounds possess antibacterial activity, as well as the ability to protect cephalosporin and penicillin 3 row antibiotics under the influence of L-lactamase antibiotics, in particular, ampicillin, carbenicillin and cefazolin C2 J The purpose of the invention is to obtain new compounds that expand the arsenal of inhibitors / i-lactams. . This goal is achieved based on the known reactions of penicillin debromination by hydrogenolysis and the production of penicillin sulfone by the oxidation of sulfoxide. esters or its salts in that the compound of the general formula VJ (l, (l, kT "dOOR R is benzyl or substituted benzyl, is catalytically hydrogenated, followed by oxidation of the resulting hydrogenation product and release of the desired product in the form of freedoms The acid or its salt, or, if necessary, the free acid or its salt is esterified and the target product is isolated as its ester.Hydrogenation is predominantly carried out over a palladium catalyst Oxidation is usually carried out with an alkali metal permanganate or organic peracid. of the preparation of sulfones 2p-chloromethyl-2-6-meTylpenam-Zo-carboxylic acid or its staline esters or its salts is that the compound of the formula I dHzCJi, -cJ-ouizddis is oxidized with an oxidizing agent such as potassium permanganate or hydrogen peroxide and the resulting sulfone of the formula are reacted with a metal in an acid, such as zinc in Glacial acetic acid, to isolate the target product as free acid or its salt, or, if necessary, esterify the free acid or its salt and form of its ester. Typically, the solution in an inert solvent of a compound of the general formula where R is benzyl or substituted benzyl is stirred or shaken in an atmosphere of hydrogen or a mixture of hydrogen with an inert diluent such as nitrogen or argon in the presence of a catalytic amount of hydrogenation catalyst. Suitable for such hydrogenation solvents are lower alkanols such as methanol; esters such as tetrahydrofuran and dioxane; low molecular weight esters such as ethyl acetate and butyl acetate; water ;, and mixtures of these solvents. However, conditions are usually selected in which the starting material is soluble. Hydrogenation is usually carried out at a temperature in the range of about 0 to about 60 ° C and under pressure in the range of from about T to about 100 kg / cm2. The catalysts used in this hydrogenation reaction are noble metals such as nickel, palladium, platinum or rhodium. The catalyst is usually present in an amount of from about 0.01 to about 2.5% by weight, and preferably from about 0.1 to about 1.0% by weight, based on the weight of the compound of the general formula. It is often convenient to suspend the catalyst on an inert support; a particularly convenient catalyst is palladium suspended on an inert carrier such as coal. In addition, the reaction mixture is usually buffered in order to work at a pH in the range of from about to about 9, and

preferably, from 6 to 8. Usually use borate or phosphate buffer. The reaction takes about one hour.

The proposed method is illustrated by the examples below.

Skellisolve B is the petroleum ether fraction b.p. 606 ° C, which is a glle, is p-hexane (Skellisolve is a trademark of Skelly Oil Co.).

Example, Preparation of the potassium salt of 2/3-chloromethyl-2c6-methylpenes-Zo-carboxylic acid-sulfone (BL-P201.3).

a) Preparation of 5-sulfoxide 6c-bromopenicillanic acid)

30 g (37.5 mol) of N, N -dibenzylethylenediamine salt of Bd-bromopenicillanic acid are dissolved in 330 ml of methylene chloride. Stir and cool to 0 ° C.

Then 13 ml (156 mmol) of concentrated hydrochloric acid in methylene chloride-a solution are slowly added. The precipitation of the HCl salt of dibenzylethylenediamine (DBEDNA) occurs within a minute, the suspension is stirred at for 10 minutes.

In order to isolate the precipitate, the DBEDHS is filtered through a filter with diatomaceous earth (Dicalite), the filter cake is washed with 150 ml of methylene chloride (filtration should be carried out as quickly as possible) and the storage of the acidic methylene chloride solution is avoided for a long time, since there may be some difficulties during filtration associated with the nature of the precipitate, therefore it is useful to speed up the filtering of the suspension. The combined methylene chloride filtrates are washed with 60 ml of cold water, stirred for 5 minutes and the aqueous phase is drained, the pH of the wash is 2.0-2.3. A methylene chloride solution containing bo-bromopenicillanic acid is concentrated under reduced pressure to a volume of 65-80 ml, cooled and the solution is stirred at 5 ° C.

With vigorous stirring, 3 ml (86.9 mmol) of kQ% peracetic acid are carefully added over 30 minutes, the reaction is exothermic; maintain the temperature between using an ice bath. The sulfoxide begins to crystallize upon the addition of 0 ml of peracetic acid.

it is cooled and the suspension is stirred at, for 2 hours.

The white filter cake was filtered and washed in the following sequence: 10 ml of 5 ° C water, then 10 ml of methylene chloride, and finally .. 15 ml of heptane. It is dried (gel cake at 45 ° C in a temrostat to a constant weight of about 6-10 hours. Longer heating can cause a pinkish appearance. The weight of the compound is about 16.26 g, the yield is 73 ,. The reaction mixture and The target product is examined using thin-layer liquid chromatography: pa ({n4I, using 15 toluene C acetone as solvent system) 1 acetic acid (HAC) or 8 acetone (8 methanol) 3 toluene (HAC). The final product is analyzed with using NMR and IR.

b) Preparation of para-nitrobenzyl 6-oi-bromopenicillanate-S-sulfoxide (2)

To a solution of 12 g (0.0 mol) of B-bromopenicillanic acid 3-sulfoxide in 100 ml of acetone was added 7.5 g (0, mol) of potassium-2-ethylhexanoate. The resulting salt is collected by filtration, washed with cold acetone and air-dried, whereby 10 g of substance are obtained. The crystalline potassium salt was dissolved in 75 ml of dimethylacetamide. And 7.8 g (O, O mol) of p-nitrobenzyl bromide was added to the solution. This solution was stirred at 23 ° C for. The mixture was diluted with 500 ml of water and extracted with ethyl acetate. The ethyl acetate layer was washed four times with water and dried over anhydrous magnesium sulfate. The solvent is evaporated at (5 mm) to give an oil which crystallizes. Light local crystals of compound 2 are stirred until suspension in ether and filtered, resulting in 9 g (70% yield) of compound with TPA 12 -125 ° (with decomposition).

- Calculated,%: C 1.98; H N 6.52

Found: SL2,00; H 3, N 6.98

IR (KBG) 1800 (s), (s), (a), 1520 (s), (cf),. 1350 (s), 1060 (cf), (cf.) cm-

H-NMR (60 MHz, DMSO): SU, 22 (s, 3N /, 1.6 (s., 3N), if, 67 (s),

1H (5.2) d - 1-5 Hz (s, 1H), 5.45 (s-, 2H), 5.68 (d. Jl-5 Hz, 1H), 7.5-8.5 (m, AN), 5

c) Preparation of p-nitrobenzyl 2 / V-chloromethyl-2c6-methyl-6-bronpenam-3o carboxylate O).

A solution of 5 g (0.012 mol) of paranitrobenzyl & 5 bromopvnicillanate-57 sulfoxide (2 HV, 2Q ml of anhydrous dioxane is heated at reflux temperature under nitrogen for 1.5 hours with 1.5 g (0.012 mol) of quinoline and 1.6 g 5 (0.012 mol) of benzoyl chloride. The solution is diluted with 600 ml of water and extracted with ethyl acetate. The ethyl acetate extract is washed with 5% sodium bicarbonate solution, 5% phosphoric acid solution and finally with water. The organic layer is dried over anhydrous magnesium sulfate and evaporated to obtain an oil. at 35 ° C (15 mm). Oil crystallizes It is washed with ether 25 and finally with cold toluene, whereupon the compound (3) is obtained in the reagents, 3.5 g (65 ° yield), 130-135 ° C with decomposition.

Calculated: С 0.06; H 3.1 30 N 6.23

C..H..C18rN2 ° 5

Found, PP: C 40,19i H 3,12;

N 6.75

IR {KBG); 1792 (s), (c), 35 1610 (ate), 1520 (s), 1353 (s), 1280 (cf.), 1025 (ate), 990 (ate), 750 (cl) cm -one. NMR (60 MHz, DMSO), 45 (s, 3N), 3.5–4.3 (m, 2H), 5.05 (cj 1H.), 5.42 (s, 2H), 5.5 ( d J-1.5 Hz, 1H), 5.62 40 (d, J-1.5 Hz, UI), 7.5-8.5 (m, 4H).

d). Preparation of p-nitrobenzene. P 2-chloromethyl-2O-methylpenes-6c6-carboxylate-sulfoxide (4 X

A solution of 1 g (0.0022 mol) of para-nitrobenzyl Zr chloromethyl-2o (methyl-; -6-6-bromine-Zo-carboxylate t 3, dissolved in 50 ml of methylene chloride, is mixed with 473 mg (0.0022 mol) of methachloroperbenzoic acid. The solution is stirred at 23 ° C. for 3 hours, the methylene chloride is evaporated to 20 ml at 15 mm and 33 ° C, the resulting concentrated solution is diluted with 50 ml of heptane (Skellisolve B.) The solvent is decanted, and the residue is thoroughly stirred to give an ether slurry and compound (4) is soon crystallized, resulting in 250 mg (24 yield) of Tr 13b-137. ° with decomposition.

Calculated,%: C 38.68} H 3.02j Ы 6.02

S.M .. (, In

Found: I: C 39.14 H 3.13) N5.96

IR (KBg): 1800 (s), 1760 (s), 1520 (s), 1350 (s), 1200 (s), 1050 (s 830 (ate), 740 (ate) cm1

H-NMR (60 MHz, DMSO): cm, 32 (s, 3N-3.8-4.5 (m, 2H), 4.97 (s, 1H), 5.25 (d-JM, 5 Hz, 1H), 5.45 (s, 2H), 5, .6 (d, J-1.5 Hz, 1H), 7.8-8.5 (m, 4H).

e) Preparation of 2p-chloromethyl-2-methylpenes-Zsb-carboxylate-sulfone potassium salt (5), (B1.-P2013).

To a solution of 7 g (0.015 mol) para-nitrobenzyl 2 p-hl 6 rmet 1L-2o -methyl-6c1-bopenam-3o-carboxylate-0 sulfoxide (4) in 150 ml of ethyl acetate is added a suspension of 4 g of 301 palladium on diatomaceous earth (Celite) and 2.8 J- sodium bicarbonate in 150 ml of water. The resulting mixture is hydrogenated with 5 tons for 3 at 50 psi (3.5 kg / cm). The catalyst was removed by filtration, and the aqueous layer was separated and treated with 1.5 g of potassium permanganate in 50 ml of water. The mixture was stirred for 1 hour, after which 250 mg of sodium bisulfite was added. The mixture was filtered and the pH of the filtrate was adjusted to 2 with concentrated hydrochloric acid. The solution was lyophilized to obtain a white amorphous powder. The solid is extracted with ethyl acetate, evaporated to a volume of 20 ml, and diluted with 100 ml of heptane (Skellisolve B). A solid, hygroscopic 2-chloromethyl-2o -methylpenam-3o -carboxylic acid-sulfone is collected. The acid is dissolved in acetone, treated with solid potassium-2-ethylhexanoate. After filtration, a white crystalline precipitate of the salt is obtained. 170 mg of compound (5) with decomposition.

Calculated,%: C, 28.27; H 3.24; N 4; 12.

CgH ClKNOjSHjO

Found,%: C 28.27; H 3, B9; N 3.84

IR (KBr): 1790 (s), 1770 (cf.), 1620 (s), 1460 (cf.), 1370 (s). 1310 (s), 1200 (s), (s), 995 (cf. (cf.) cm-1 H-NMR (100 MHz, D-0), 68 (s, H 3.2-3.9 (m, Hz, J-- Hz, Hz 2n), C, Qk, (m, 2H), C, 3 (. S, 1H), 5.02 (dvd, J Hz, Hz, 1H). 2, Preparation of pivaloyloxymethyl 2-p-chlorophenyl-2c-methylpenam-3-carboxylate-sulphone 2/3-chloromethyl-2 1- "ethyl-phenam-3l-carboxylic acid-sulfone in dimethylformamide is treated with one equivalent of triethylamine and mixed to obtain the solution. Brmmethylpivalate (1 eq equivalent) in dimethylformamide is added, after which the mixture is peremana at room temperature. Then the mixture is purified by filtration, and semi % X Hz -ff dHzdi + Na (306; tBZ.-P2013) K. stirred suspension I, 6 (0.05 mol%) 8L-P20i3 (5) in 200 ml of acetone are added k ml of 10 aqueous solution of sodium iodide, and the resulting mixture is brought to a boil — under reflux on a steam Be. To this boiling under reflux, 1.8 ml (0.1 mol) of re-distilled chloromethyl pivalate (at 7 mm Hg) are added. right away The resulting mixture was stirred at reflux with reflux for 3 h, and then cooled to room temperature (22 ° C). The crystalline solid is collected by filtration, washed with 3X30 ml of acetone, and the combined filtrates are evaporated to an oil under vacuum at a temperature of less than 22 ° C. Then, the obtained oil was placed in 500 ml of ethyl acetate and washed once with water (200 ml), and once saturated with stirring c2 g of bleached charcoal and

993820

10 i + H20. + (IidH2-odd () TTj ciHzdi 0 d02 (iHj-ob-ci {dH3). The poured filtrate is poured into ice water. The solid that is separated out is filtered, washed with water and dried until the indicated compound is obtained (complex ether.) The corresponding acetoxymethyl, methoxymethyl, acetonyl, and phenacyl esters of the same cp is obtained by replacing in the above described method with a bronmethyl alkalate by an equivalent weight of chloromethyl acetate, chloromethyme methyl ester, chloroacetone and phenacyl bromide, respectively. lormethyl-2b6-methylphenam-Csb-carboxylate sulfone {BLP202). acetone. 0 0 x dT4 fjL-P2 (fO) while cooling (ice on the bath). After 20 minutes, the mixture is filtered through diatomaceous filtering material (Dicalite) with suction, and then this filter material is washed with I.XIOO ml of ethyl acetate. The combined filtrates are concentrated in vacuo at 22 ° C to an oil. Then this oil is further concentrated at a temperature of about 22 ° C and a pressure of less than 1 mm Hg to remove most of the residual chloromethyl pivalate. The remaining oil is triturated twice with 50 ml portions of h-pentane and left for two days in a cold room (about 10 ° C) in p-pentane. Then the solid crystalline mass is crushed into a solid powder under 40 ml of a 1: 1 mixture of ether p-pentane. The resulting product is filtered, washed with a mixture of ether - pentane (1: 1), then with pentane and dried in air. After drying in vacuo for h over P205, 13.37 g of pivaloyloxyX119 methyl 2p-chloromethyl-2o (methylpenam-3o (.- carboxylate sulfone (about 75% yield of Gc TPA 93-95 ° C, Calculated, C 4, 03, H5.27 / N 3.67 CW afNOlS Found,%; C if.ll; H 5.08, N 3.85. Example: Rekisylkalcization of potassium sulfone 2 / chloromethyl-2-6-methylphenam-3 "carboxylate (BL -P201 To a mixture of 20 ml of tt -butanol and one gram of BL-P2013 (5), add 1 ml of water, with shaking in a separating funnel, until a pale yellow solution is obtained. The clear solution is filtered through a fluted filter paper and the flask and filter shaft The paper was washed with a 9: 1 mixture of P-butanol - NlO (9 ml) and the combined filtrates were diluted with another 20 ml of P-butanol. The resulting solution was placed in a round bottom flask on a rotor0 ° CJ-OK

oh oh

t

- L-0-3

B 0 to the stirred mixture partially of the solution, partially suspension of compound 5 (BL-P2013) 2.3 g, (o, 0075 mol l) in 20 ml of dimethylformamide (DMF, dried for at least 3 weeks over 3 1.7 g (0.008 mol) of 3-bromophthalide (12) is added and the mixture is stirred for k hours at 22 ° C. The mixture is poured into a mixture of 200 ml of ice water and 200 ml of ice-cold ethyl acetate (washing the flask with a small quantity of ethyl acetate) and the resulting mixture is shaken, then the organic phase is separated and washed with SEB-P203b

de 0 evaporator and evaporated under reduced pressure to approximately half the initial volume. The white crystalline product is collected by filtration, washed with 6x10 ml of acetone and dried with air. Yield 810 mg. After vacuum drying for 6 hours, the pressure is less than 1 mm Hg. 800 mg of product is obtained with Tf, / 215 ° C (with decomposition), yield 80 °. Calculated,% C 29.67 H 3.39; N i, 63-, C1 in, 9Aj KF.HgO 5.56 CgHjClNOsSK-1H20 Found,% C 29.23} H 3.38; N i, it9i C1 10, K.F-H, O 5.7 This recrystallization procedure allows to obtain a crystalline monohydrate different from the starting material, which is practically anhydrous. EXAMPLE 5. Preparation of Phthalide 2p-chloromethyl-2o6-methylpenam-3o6-carboxylate sulfone. my portions of ice water (100 ml). The ethyl acetate phase is washed once with a saturated solution of aqueous N32804, dried on a cold nggd, filtered and evaporated to dryness in vacuum until no oil is obtained in the residue, which is triturated twice with methyl cyclohexane (25 ml), Twice with Skellisollev B (Teap 60 -68 ° C, generally P-hexane, 25 ml) and four times with 25 ml of n-hexane, to give 2.5 g of the compound as an almost solid after air drying. Then the product is dried

above P pressure less than 1 mm Hg. to obtain 2.5 g of compound 3 with T; d 10A ° C (with decomposition). Its purity is 85-95%; Calculated,%: C 51.615 N 3.79 $ N 3.77i Cl 9.53

Found,%: C 52.59} H, b7; N 3.21, C1 7.73 KP.N, 0 0.27

EXAMPLE 6 Preparation of pivaloyloxymethyl 2 | & chloromethyl-2-6-methylphenam-So1-carboxylate-sulfone.

A mixture of 2p-chloromethyl-2o sulphonhydrate (. -Met ilpenam-3o6-car (oxylate, potassium salt 1 g (0.0031 mol) and 1 g of molecular sieves is stirred in 15 ml of dimethy pharmamide) for 2 hours at 23 ° C. 70 mg (0.0031 mol) of beer was added to this mixture; loyloxymethyl chloride and stirring was continued for 18 hours. Molecular sieves were collected, the filtrate was diluted with 100 ml of water and extra ySf

 Cho.k

(D) To a stirred solution of 500 m BL-P2013 (potassium salt) in 15 ml of HgO and 10 ml of ethyl acetate is added 2N HCl to obtain a pH of 1 (this is done in an ice bath with vigorous stirring). Then, the resulting mixture is saturated, the aqueous layer is separated, and the organic phase is quickly dried on ice over filtered and 50 NaOH (sodium 2-ethylhexanoate) in a light P-butanol are added dropwise to a neutral reaction using wet indicator paper. The product does not crystallize upon scraping, and therefore it is concentrated in vacuo to an oil that is dissolved in acetone (5 ml), scrubbed again — no crystals, ether is added to the cloud point — no crystals. It is concentrated in vacuo on a rotor evaporator to gauze, which is dissolved in ethyl acetate, one drop of H2O is added — scratched — no crystals. Concentrated in vacuo, and then the residue was carefully triturated with 5 ml of p-butanol to give

bathed in ethyl acetate. Ethyl acetate. washed 9 times with water and dried over anhydrous magnesium sulphate. The solvent is removed at 30 ° C (15 mm), after which the oil remains, which is chromatographed on silica gel using silica CC-7 (methylene chloride 8, Ethyl acetate 2), and get 1 spot with Rf 5. The residue obtained by crystallization from heptane Skelly -. cojibB B is 100 mg (E 95 ° C) pivaloyloxymethyl 2/3-chloromethyl-2o-methylpenam-3 -carboxylate sulfone.

Calculated,%: С kk, Q3 Н 5.27, N 3.67

Found,%: C 4.20; H 5,

N 3.63

NMR and IR spectra correspond to

proposed by CTpyKtype.

PRI me R 7. Preparation of 2/3-chloromethyl-2-6-methylpenam-3o-carboxylate sulfone-sodium salt.

Oh oh

-K - OGN

ABOUT

dJNOg af 283.67} 200 mg of an amorphous white powder, washed with ether, dried in air and dried in vacuo over 24 hours, resulting in 180 mg of 2pglormethyl-2-methylpenes-ZOC-carboxylate-sulfone-sodium salt, decomposition temperature over 100 ° C (uncertain). Calculated,%: C 33.10; H 3.13; N k, B3 CgHgCIN05SNa Found,%: C 33.20; H 3.69; N C, KT-HjO, OC EXAMPLE 8 Preparation of 2/3-chloromethyl-2-6-methyl pen-ZOC-carboxylate sulfone, potassium salt (BL-P2013) K 10 l, water, 130 g (1 , 25 mol) of sodium hydrogencarbonate and 200 g of 10% Pd on BaSO add 271 g (0.55 mol) of p-nitrobenzyl-bs-bromo-2 chloromethyl-2-methylpen-M-3-carboxylate-sulfone dissolved in 5 l ethyl acetate. The resulting mixture is hydrogenated at a pressure of 1 kg. After 5 hours, the consumption of hydrogen becomes very slow. 15 . 99 200 g of 101 Pd on BaS04 are added and the resulting death is hydrogenated until a further noticeable decrease in the hydrogen uptake. The suspension is filtered through diatomaceous earth (Celite), the filter material ;; The mixture is washed with water and the aqueous phase is washed with 3 L of eipacetate. 3 L of ethyl acetate is added to the aqueous solution, and the mixture is adjusted to pH 1.5 with 150 ml of 12 and HC at 10 ° C. The organic phase was isolated and the aqueous solution was saturated and extracted with 2x1 L of ethyl acetate. The combined extracts are dried over magnesium sulphate, the drying agent is removed and 260 ml of 2N potassium-2-ethylhexanoic acid in butanol are added at 0 ° C. After stirring for 2 hours at 0 ° C, 2p-chloromethyl-2-methylpenam-3-carboxylate sulfone sodium salt (BL-P2013) is collected and dried in its room at room temperature. The output of 13.8 g (about 70%).

Oh oh

h,

rfScSf 2a

 CHi; - J., P l

800 mg (O, 00261 mol) of BL-P2013 in the form of a potassium salt is added to a mixture of 25 ml of etipacetate and 10 ml of water. After the solid part has completely dissolved, the mixture is treated dropwise with 5% aqueous phosphoric acid with vigorous shaking until a precipitate separates from the aqueous layer. The ethyl acetate layer was separated, then washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried agent is removed by filtration and washed with 10 ml of ethyl acetate (the washing solvent is combined with the original filtrate). Skellisolve B is then added to ethyl acetate until cloudy (approximately 10 ml). The resulting mixture is treated with 500 mg of activated carbon (Darko KB) Bg I dHzdi about "-% 0o

about o - .dHzdi

-3

CJOzH 016 EXAMPLE 9. Preparation of para-nitrobenzyl 6c (.-. Bromo-2p-chloromethyl-2-methylpenam-3-carboxylate sulfone) To 16 l of acetic acid, add 36.6 g (0.812 mol) of para- nitrobenzyl 6O1 bromo-2-chloromethyl-2methylpenam-3-carboxylate. To the solution thus obtained, stirred at room temperature, add a solution of 282 g (1.7.8 mol) of KMpOch in 26 l of water The resulting mixture was stirred at room temperature for 1 hour and H, 0 (37%} was added dropwise to obtain a colorless solution. Then 30 l of water was added, and the resulting mixture Mix for 1 h at room temperature and collect a crystalline precipitate, which is washed with l of water and 2X2 l of ethanol, and dried in vacuum at room temperature. Yield 297 g (7b%) o (.g) (0.5% + 75, 9. Example 10. Preparation of BL-P2013 as free acid and filtered. The filtrate is diluted with 15 ml of Skellisolve B, then seeded with BL-P2013 crystals as free acid. Approximately 3 hours at room temperature, the crystalline precipitate of the free acid is collected and dried in vacuum for 15 minutes over Ppo to obtain - -. - f 1 liter C- .. nor 323 mg (k6%) n odukta mp slow decomposition above 100 ° C. Calculated,%: C 35.89; H 3.77} N 5.23v C1 13.25 CeHjoCINOsS Found: C 35.88, H 3.91; N 5, + 1 i C1 13,52 This product loses stability when stored at 23 ° C for 7 days. Example 11. Preparation of 2-chloromethyl-2-methylpenam-3-carboxylate sulfone, potassium salt, (BL-P2013) OO .f dHzdi ShN, 1 /. jJ-VW dHs about - dOrK 3fSL P20l3 MB-305-77

To 600 ml of H20, Bg 30 Pd on Celite and 16 g (0.19 mol) of sodium bicarbonate are added. Then, 32 g (0.69 mol) of para-nitrobenzyl 6ot-bromo-2 (i-chloromethyl-2-methylpene-3-carboxylate sulfrxide) is dissolved in kOQ ml of ethyl acetate and added to the aqueous suspension. The semi-mixture is hydrogenated with a Paar apparatus under pressure 50 psi (3V5 kg / cm) for k hours. The resulting slurry is filtered through celite filter material on a sintered glass funnel, then the filter material is rinsed with 2xSO ml of H20 and the aqueous layer of combined filtrates and proqued is separated. The aqueous layer is washed 200 ml of diethyl ether, then dry up to 5 ° C and with stirring A solution of 12 g (0.076 mol) and 200 ml of H20 is added dropwise in 1/2 h, the pH being maintained between 7.5 and a, добав by adding kO% H-jPO. After the appearance of the pink color, after 5 min, the addition of KMnO4 is stopped The reaction mixture is mixed with a small amount (about 50 mg) of sodium bisulfite for 1/2 hour and then the suspension is filtered through a celite filter material. This filter material is washed with 2X50 ml. The combined filtrate and washings are exfoliated with 500 ml of ethyl acetate and, with stirring pH set 1.5 added 2 n. NA. The layers are separated and the aqueous layer is saturated with sodium sulfate. It is re-extracted 2) ((iOO ml of ethyl acetate, and then the combined ethyl acetate extracts are dried over sodium sulfate for 1/2 hour at 5 ° C. The sodium sulfate is removed by filtration, and the resulting filtrate is evaporated under reduced pressure to a residue. The residue is 16 grams of acetone and 1 bO ml of diethyl E (and 50% (by weight) of potassium-2-ethylhexanoate in H-butanol are added until the solution is neutralized on wet indicator paper. The potassium salt of BL-P2013 crystallizes, it is collected by filtration and washed with diethyl ether and dried. As a result oluchayut .16 g of 2-chloromethyl-2o {gMetilpenam Zo6-carboxylate potassium salt of sulfone (BL-P2013). Yield 76% (from Tm).

IR and NMR spectra correspond to the proposed structure.

Calculated,%: C 31.2; H 2.97} N 1.58

CdHqClKNO S

Found,%: C 31.18; H 2.98; N it, 51, HgO 0.93

EXAMPLE 12 Pivaloyloxymethyl-2 / chloromethyl-2-methylpenam-3-carboxylate sulfone (BL-P202j).

rY TCJHa.

About to a stirred suspension of 14.6 g (0 mol) of 2p-chloromethyl-2-methylpenam-3-carbrxylate potassium salt sulfonate (BL-P20T3) in 200 ml of acetone was added a ml of 10% aqueous solution of sodium iodide, and the resulting mixture until the mixture is boiled under reflux on a steam bath, H is immediately added to this suspension, boiling under reflux, 8 ml (0.1 mol liter) of distilled chloromethylpivalate KipZ at 7 mm Hg). The resulting mixture was stirred at reflux for 3 h and then cooled to room temperature.

Temperature 381.83 MB (22 ° С). The solid crystals are collected by filtration, washed with 3x30 ml of acetone and the combined filtrates are evaporated to an oil under reduced pressure at a temperature of less than 22 ° C. Then the oil is placed with 8,500 ml of ethyl acetate and washed once with water (200 bp), and once with a saturated solution of NanSO (200). Then the solution is quickly dried over, and it is mixed with 2 g of discolored carbon while cooling (ice on a bath). After 20 minutes, the resulting mixture was filtered through a Celite filter 9 valium material, and this material was washed with ml of ethyl acetate. The combined filtrates are concentrated under reduced pressure at up to May. Then this oil is concentrated further at a temperature of about 22 ° C and a pressure of less than 1 mm Hg. until most of the chlorine left to leave methylpivalate. The residual oil is then thoroughly triturated twice with 50 ml portions of n-heptane, and then left over the weekend at a temperature near under n-pentane. The resulting solid crystalline mass is then ground to powder under AO ml of a mixture of diethyl ether-p-pentane. The resulting product is collected by filtration, washed with diethyl ether, P-pentane ether (1: 1), and then with p-foam and dried with air. After drying under high vacuum over the top of P2O5, 13.37 g of pyvaloyloxymethyl 2p-chloromethyl-2-methyl-foam-3-carboxylate sulfone (BLv93-95 ° C. P2024) is obtained, about 75% with Tp; Cleaning BL -P202if. Approximately 3 g of crude BL-P202 (obtained by the method described above) is dissolved in 5 ml of ethyl acetate, placed on a column with silica gel, size is 5 0 cm (Nallicrodt CC7 and eluted with CH2C12 ethyl acetate:, volume ratio). Fractions containing a separate spot at RP 0 (thin layer liquid chromatography on silica gel plates with a mixture of l: CH2C12 ethyl acetate, Ij detection) are combined and concentrated under reduced pressure to 1.38 g of crystalline solid. A portion of this material (900 mg) was dissolved in 5 ml of ethyl acetate. The resulting solution is filtered, diluted almost to the cloud point with p-ether ether (Skellisolve B), and then stored at room temperature for 3 days. The resulting crystals are collected by filtration, washed with petrol with ether and dried, resulting in 5.0 mg of purified BL P202 with SO-UT C. Calculated,%: C, 03; H 5.27, N 3.67 C HjjTlNO-jS Found,%: C 44, P; H 5.08 j N 3.85. EXAMPLE 17. Preparation of ammonium salt BL-P2013. 020 1.BL-P2013 in free acid form (250 mg), dissolved in 20 ml of a mixture of acetone-methanol (1: 1 by volume), filtered to obtain a clear solution. 2. Anhydrous ammonium solution is obtained by adding 1 ml of ammonium hydroxide (30%, reagent grade wista) to 10 ml of the acetone-methanol mixture (1: 1 by volume), and then 1 g of anhydrous magnesium sulfate is added to this solution at weak stirring, and the resulting mixture is filtered through filter paper. The resulting filtrate is designated as anhydrous ammonium solution. 3. To the filtrate obtained according to method 1, approximately 2 ml of anhydrous ammonium solution are gradually added and mixed well, k. The mixture obtained according to method 3 is mixed with a portion in 100 ml of diethyl ether to precipitate the ammonium salt B-P2013. 5. The white ammonium salt is separated from the solvent and washed with 2 50 ml portions of each diethyl ether. 6. The recovered powder is dried at 35 ° C. in a vacuum oven overnight. 7. Test results: Calculated,%: C 33.7} H 4.6, N 9.8 Found, ° 4: C 33.66; H 4.63, N 10.12. Dried KF. Microscopic examination: the crystalline eco substance. PRI me R 14. Obtaining non-hygroscopic sodium salt BL, -P2013. 1. Dissolve 50 mg of the free acid BL-P2013 in 4 ml of a mixture of acetone and methanol (1: 1 by volume), filter until a clear solution is obtained. 2o Prepare a sodium-2-ethylhexanoate solution, dissolving 40 mg of sodium-2-ethylhexanoate in 10 ml of a mixture of acetone-methanol (1: 1 by volume) 3. To the filtrate (method 1) add 10 ml of solution (method 2) and mix well. 4. An ration of 10 ml of diethyl ether is mixed with the mixture obtained by method 3 to precipitate sodium salt of BL-P2013. 2199 5. The white salt is immersed in diethyl ether for 1-2 hours, and then separated from the solvent and washed with three portions of diethyl ether, 5 ml each. V / n Hw di V; i «nepeH / Jucma / rw NgO. YOGK-NgO

kOQ ml of BL-P2013 is dissolved in a minimum amount of acetone H20 (1: 1 by volume) and diluted with 10 ml of acetone, filtered, then diluted with acetone to a volume of about 25 ml, scraped, and after 30 minutes, the crystalline hydrate is collected by filtration, wash it well with acetone, then air dry, and then under vacuum at a pressure of less than 1 mm Hg. during the night. Exit 280 mg.

Calculated,%: C 29.67i H 3.39; N 4.63; C1 10, H, 0 5.55 C0H9C1NOSKH20

Found,%: C 29.32, - H 3.32 j H C, Cs. C1 11.31; H20 5.90.

Example 16. Preparation of NiN -dibenzylethylenediamine salt BLP2013.

BL-P2013 + 1/2 S, M-dibenzylethylenediamine diacetate recrystallization

acetone-ether 820 6. The recovered powder is dried at 30 ° C in a vacuum oven during the dark night. EXAMPLE 15 Recrystallization of BL-P2bl3. 0. о А PNf Н J-Jj C OfK-HzO

/ (

  YOGN- (bN5 (Ngda-s Ng

about

the goiter mg (0.001 mole BL-P2013 is dissolved in 7 ml and 180 mg (.0,0005 mole) N, N-dibeisylethylenediamine diacetate in 7 ml. H-O is added to the plant-35 thief in 7 ml. H-O. The resulting mixture is stirred and salt crystallizes, after stirring for about 10-15 minutes, the salt is collected by filtration and air dried, resulting in a BL, P-20133 N, N-dibenzylethylenediamine salt (300 mg). The resulting material is recrystallized.

They are dissolved in approximately 10 ml of boiling acetone and diluted with ether to a cloud point. You get 26O mg dried in air and in vacuum material.

Calculated,%: C 5t, 69i H S, 2; N 7.53) C1 9.55

Found,%: C 9.39; And 5,

N 7.05, Cl 8.96i H220 1.23 (KF).

Example 17. The preparation of chloromethyl ester BL-P2013.

ASf

(Jhtdi about

f3J6, J7)

7 To an intensively stirred mixture 15.25 g (O.OfI mol) BL-P2013 15), 15 g (0.15 mol) KHCOj and 1.7 g (0.005 mol) tetrabutylammonium acid sulfate (/ (ldrich Kem.Ko) mixed with 50 ml of water and 50 ml of CH2Cl2; a solution of 9.5 g (0.0575 mol) of C1CH2-0-S02t; l in 40 ml of CHjClj is added dropwise. The temperature rises to 26 ° C and after adding (which took about 15 minutes) the mixture was stirred for an additional 30 minutes. As the product crystallized, another (about 400 ml) was added to form a solution. The isolated layer of CHOCI and 50 ml of CH2C12 washings were combined, dried over magnesium sulfate with stirring And added 2 g of decolorized charcoal (Darko KB). After about 30 minutes the mixture was filtered, concentrated to about 50 ml and was added O, O

feedl

  -odHzdi? o to a stirred mixture of g (0.0159 mol) of BL-P2013 chloromethyl ester (7) in 25 ml of acetone was added 3 g (C ,, 02 mol) of sodium iodine. The resulting suspension is stirred for 17 h, and then cooled to 0 ° C. Two drops of valuable aqueous KHCO are added and the resulting mixture is slowly diluted dropwise with water for more than 10 minutes, until 50 ml is added. The suspension changes color from yellow to gray, then to purple and then to black, and then the crystals are immediately collected by filtration and

- J- tiHzdi

o / -d-odHiddiy

50

Lezlnm yftcyctfo ffc / f / fffma 99

,

Nai

d-odHzT o

eight

+ mll04-kn: 202

 o dH, di

 Cjl-odH ddi,

Part of .2 are 150 ml of isopropyl alcohol. The residue is then removed under reduced pressure. The resulting crystalline precipitate is collected by filtration, washed well with isopropyl alcohol and air dried. After drying in vacuum at a pressure of less than 1 mm Hg. Art. receive 8.5 g of chloromethyl-2 (3-chloro-meth-2-meth-yl-penam-3 ... - / -carboxylate-sulfone (7). Tal 116 C {decomposition at temperatures above 100 ° C, darkening). Elemental analysis for Calculated,%: C C, 18; H 3.5i; N, k3 C1 22, Found: C 3.16 J H 3.5, N, 47j C1 22.46; HgO 0.33 (KF): Purity grade: 90-95. EXAMPLE 18 Preparation of BL-P2313 Iodomethyl Ester wash with cold acetone - water (1: 2), then with isopropyl alcohol (3X10 ml), then with diethyl ether, and finally with p-pentane. After air drying, 5.55 g (91% yield) of BL-P2013 V8 iodomethyl ester is obtained. Тг7 / П8119 0 with decomposition. The purity of the product is about 90. Example 19. Preparation of N, N-dibenzylethylenediamine-2-chloromethyl-2o-methylpenes-2o-carboxylate sulfone. Stage 1. Compound 3 is dissolved in 1 l of acetic acid and, while stirring at 22 ° C, a saturated aqueous solution of KMnO4 is added dropwise, until a pink color appears (i.e., a dropwise filter is added). paper gives a pink color). Then, while cooling, N20 is added dropwise until a n is obtained. P1Osolutionary solution (with this (about 5 some white precipitate forms). The resulting solution is poured into 2.5 l of water and product i is extracted) Pj ml ethylate tata. Ethyl acetate is washed with 5 aqueous p: act thief of sodium bicarb sodium nitrate (i.e., there is no more bubbling when added), dried over sodium sulphate and evaporated; resulting in a residue of compound k. ITS is left for one day and then carefully grown with Skellisolve B to obtain 9.1 g of the compound. The output is 28 from the theoretical. Stage i3 4- -f2p0ux (/ g oy (,. G ciHzdi 1: 1ooh 5 (B1.-P2013) Dna 75 g of zinc powder is mixed to obtain a suspension with 5 ml of glacial acetic acid and cooled to 5 ° C. To this 3 g of a j (O, (U57 mol) solution in 15 ml of dimethylformamide is added and the resulting suspension is stirred for 2.5 h. Then the cnc is filtered off and the light yellow solution is poured into 80 ml of 5 aqueous hydrochloric acid. The mixture is extracted with 3x25 MP of ethyl acetate. The combined ethyl acetate extracts are extracted with 3 x 20 ml of 5% aqueous solution of sodium biconate and preserved after separation of ethyl acetate. The bicarbonate extracts are combined, placed under a layer of ethyl acetate, adjusted to pH 1.5 by adding 2N HCl and saturated with sodium sulfate. The ethyl acetate layer is separated and the aqueous phase is extracted with 2x30 ml of ethmioacetate. All ethyl acetate (combined, dried over sodium sulfate and evaporated to an oil (which was the free acid BL-P2013), and then dissolved and about 20 ml of acetic acid, to which is added 20 ml of diethyl ester-. Paragraphs. Then 50 Calyng-etiphexanoate (CEG) is added. In dry p-butenol, product 5 is crystallized to neutrality (BL-P2013). After stirring for about 75 hours, it is collected by filtration, resulting in 650 mg of compound 5 (yield 3). Step 3.50 mg of compound 5 is dissolved in d, 5 ml of water and 20 mg of N, N -dibenzylethylenediamine. (DBED) diacetate is added. DBED salt 5 crystallizes and is collected by filtration, washed with water and dried over P205 in vacuo to give N} N -dibenzyl tylenediamine-2p | -chloromethyl-2Y-methylpenam-3 (L-carboxylate-sulfone (DBED salt 5). Another part of the compound (5 mg) is dissolved in 3 ml of water, to which is added a solution of 270 mg DBED-diacene. Tata in 2 ml H20. When scraped, D6ED salt S crystallizes (430 mg). recrystallization From about 5 ml of boiling acetone ps 270 mg are obtained. . The results of biological tests. The product of Example 1, Compound 5, having the structure of OO fV (iH, (ii 6D5. Is referred to as BL-P2013. Although BL-P2013 itself is at best a very weak antibacterial agent, it inhibits p-lactamase and protects shiforand and amoxicillin against destruction by bacteria producing fb-lactamase ifn vitro and in vivo, when used in combination with these two agents.The proposed compounds are useful for oral or parenteral administration to increase the efficacy of α-lactam antibiotics against bacteria producing r - lactamase. In the calculation their weight should be from one to five parts, and preferably should be equal to the weight of the 3-lactam antibiotic. For example, these compounds, when used in the t: 1 ratio, show a marked increase in the activity of ceforadine and amo sicillin against anaerobic Bacteroides strains producing / 3-lac Tamase, for example, B. fragilis, B. thetaiotaomicron and other strains of this genus, as well as against resistant Staphylococus aureus. The compounds are administered either in a mixture or simultaneously with ft-lactam antibiotics. in doses within the specified range of ratios, with the antibiotic being administered in usual doses. The ability of the compounds increases the efficacy of β-lactam antibiotics against l3-producing lactam, amaz bacteria, and makes them valuable for co-administration with certain anti-lactam antibiotics in the treatment of bacterial diseases in mammals, in particular, humans. When treating bacterial diseases of a compound, it is possible to co-grind with β-lactam antibiotics, and thus administer two agents simultaneously. In addition, the compounds may be administered as independent agents during the course of treatment with β-lactam antibiotics. If a compound or its salt is used to increase the antibacterial activity of β-lactam antibiotics, it can be administered separately or preferably as part of a standard pharmaceutical carrier. and diluents. The compound, which is in the form of the free acid or a pharmaceutically acceptable salt thereof, can be administered orally or parenterally. A compound in the form of an ester, which is readily hydrolyzed in vivo, is best administered orally. Parenteral administration includes intramuscular, subcutaneous, intraperitoneal, and intravenous injections. If the compound is used in combination with a carrier or diluent, the carrier or diluent is selected based on the intended method of administration. For example, for oral administration, the compound can be used in the form of tablets 28 capsules, blocks, pellets, powders, syrups, elixirs, aqueous solutions and suspensions , and the like, according to standard pharmaceutical practice. The proportions of active ingredients and carrier will naturally depend on the chemical nature, solubility, stability and potency of the active ingredients, as well as on the required dosage. However, these pharmaceutical compositions may contain from about 5 to about 80 carriers. In the case of tablets for oral administration, carriers typically include lactose, sodium citrate, and phosphoric acid salts. Various disintegrants, such as starch, and lubricants such as magnesium stearate, sodium, and lauryl sulfate and talc are commonly used for tablets. Diluents such as lactose and high molecular weight polyethylene glycols are suitable for oral administration in the form of capsules. If suspensions are required for oral administration, the active ingredients are combined with emulsifying and suspending agents. If desired, sweetening and / or odorizing agents may be added. For parenteral administration, which includes intramuscular, intraperitoneal, sterile solutions of the active ingredients are usually prepared, and the pH of the solutions is appropriately adjusted and buffered. For intravenous use, the total concentration of the solutions should be controlled to create isotonic solutions. Although it is the physician who must determine the dosage required by the patient, the ratio of the daily dose of the compound or its salt and the / l-lactam antibiotic should be in the range of from about 1: 5 to 5: 1, and preferably 1: 1. Further, the daily dose of the oral administration of each component will be in the range of from about 10 to about 200 mg per kg of live weight, and the daily parenteral dose of each component will be from about 10 to about 100 mg per kg of live weight. These figures, however, are merely illustrative, and in some cases doses may be needed that go beyond these limits. 1. A process for the preparation of sulfones of 2-chloromethyl-2 | 1-methylpenamyl 3 -carboxylic acid of the formula. dHzdi Yne, (iooH. or its esters, or its salts, about aphids and with the fact that the compound of the general formula: 0-: xiHzdi trtf: -l3 ---. 0 dOOR where R is benzyl or substituted benzyl is catalytically hydrogenated, followed by oxidation of the product obtained; iodine and separation of the target product as the free acid; or its salt, if necessary, the free acid or its salt is esterified and the desired product is esterified as its ester 2. A method according to claim 1, wherein the hydrogenation is carried out over a palladium catalyst. The method according to claim 1, characterized in that the oxidation is carried out with an alkali metal permanganate or an organic peracid. k. A method for producing sulfones 2fV-chloromethyl-2OB-met ilpenam-3 o g of a carboxylic acid of the formula B.H.e. (JoOtt or its or its salts are distinguished by and, so that the formula -J dHjdi rnf-bnz X-OsF --- I (J-ixJHiCldiy "y is oxidized by an oxidizing agent such as potassium permanganate or hydrogen peroxide, and the resulting sulfone of the formula bp VdHzdi, -e-odHzcidia - o expose the interaction with the metal in the acid, for example, with zinc in glacial acetic acid, with the isolated Niemi desired product as the free acid I.LI salts thereof, or optionally the free acid or salt thereof is esterified and the desired product was isolated as the form of its ester. Sources of information taken into account in the examination 1. UK Patent No. 1072108, C 2 A, published. 1967. 2. If laid out for If 2B2kS3S, cl. C 07 199/00, published 1978

Claims (4)

The claims of bNe ‘<* 00Н or its esters, or its salts, characterized in that the compound of the formula 1. A method for producing sulfones of 2p-chloromethyl yl-2d-methane lpene mt 3d-carboxylic acid of the formula о о or its esters or its salts, except that the compound of the general formula 'dOOB where R is benzyl or substituted benzyl, is catalytically hydrogenated, followed by oxidation of the resulting hydrogenation product and isolation of the target. product in the form of a free acid or * its salt, or, if necessary, Free acid or its salt is esterified and the target product is isolated in the form of its ester 2. The method of y and s with. spend over rum. 3. S uch and drive or organic peracid. 4. Method for the production of sulfones 2Λ-chloromethyl yl-2d-meth-ilpenam-ZOb · carbon by π. 1, about t and h and -. in that hydrogenation with palladium catalysis25 E0 according to claim 1, the fact that the oxidation is pro ³⁵ • - & ·. .,. „· _ Method I with ⁵¹ alkali metal permanganate - (¾ I 0 is oxidized with such an oxidizing agent, potassium manganate or peroxide and the resulting sulfone 0 Oh PG2G'CH3 '' (J-odizddis о is reacted with a metal in an acid, for example, zinc in glacial acetic acid, with the isolation of the target product as a free acid or its salt, or, if necessary, free acid or its salt is esterified and secrete howl product in the form of its ester. yes, like the first hydroformic acid