FI67553B - PROCEDURE FOR FRAMSTATING AV ENHANCED THERAPEUTIC 2BETA-CHLORMETHYL-2ALFA-METHYLPENAM-3ALFA-CARBOXYLSYRASULFONE SATER OCH ESTRAR DAERAV - Google Patents

Description

67553

This invention relates to 2 / - - chloromethyl-2H-methylpenam-3-carboxylic acid sulfone, its salts and esters. The present invention relates to 2 /> -chloromethyl-2'-methylpenam-3-carboxylic acid sulfone, pharmaceutically acceptable acceptable salts or readily hydrolyzable esters useful as β-lactamase inhibitors.

The efficacy of certain β-lactam antibiotics against β-lactamase-producing bacteria has led to intensive research into β-lactamase inhibitors. Clavulanic acid is an example of a compound that is currently the subject of intensive research. EP Patent Application 15,927 discloses a β-lactamase inhibitor having the structural formula in the acid form as follows 0.

H H! * H0N -— 1 _____, 'S • -. <' CH3 20 “il CH3 N --------:

0 COOH

The structural formula of the β-lactamase-25 inhibitor described in U.S. Patent Nos. 4,036,847, 4,009,159, 3,993,646, 3,989,685 and 3,954,732 is

H H

, .CH_C1 h2n “T-- I '<2 il’ CH3 A --- N ----— 30 <f

COOH

U.S. Patent No. 4,155,912 discloses a 2-penem-3-carboxylic acid compound having the formula - “ΤΓ _ 2,67553, s Γ (ο \

COOH

5 and esters and salts; see also Farmdoc Abstracts 82090A, 10336B and 44337B.

A compound (part number CP-45899) having the structural formula 10 (K ^ 0 S ^ CHO 3! I! "" S / - N -------- wherein COOH 1 5 is an irreversibly β-lactamase inhibitor , with excellent solution stability, has weak antibacterial activity and potentiates the in vitro and in vivo activity of ampicillin against β-lactamase-producing species ^ Ä.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 Famdoc Abstracts 89627A and 73866B.7.

The present invention relates to a process for the preparation of 2β-chlorometh-25-yl-2-methylpenen-3β-carboxylic acid sulfone of the formula ° XN // ° ch9ci -r * 30! CH3 / $> - N ------ i 1

0 COOH

and pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof.

67553

The aforementioned pharmaceutically acceptable salts include non-toxic metal salts such as sodium, potassium, calcium and magnesium salts, ammonium salt and substituted ammonium salts, e.g. non-toxic amines such as trialkylamines, dibutylamine, e.g. -phenethylamine, 1-ephenamine, N, N'-dibenzylethylenediamine, dehydroabietylamine. Salts of N, N'-bis (dehydroabietyl) ethylenediamine, N- (lower) alkylpiperidine (e.g. N-ethyl-10-piperidine) and other amines used to prepare pharmaceutically acceptable salts of penicillins and cephalosporins.

As used herein, the term "physiologically hydrolyzable esters" refers to pharmaceutically acceptable esters known to hydrolyze to the free acid in vivo. Examples of suitable physiologically hydrolyzable esters are phenacyl, acetoxymethyl, pivaloyloxymethyl, N-acetoxyethyl, <% acetoxybenzyl, N-pivaloyloxyethyl, phthalidyl (3-phthalidyl), indan-20-yl (5-indanyl), methoxymethyl, benzoxymethyl, benzyl -ethylbutyryloxymethyl, propionyloxymethyl, valeryloxymethyl and isobutyryloxymethyl.

The process according to the invention is characterized in that a) an ester of the formula 0 t is catalytically hydrogenated

Br | FH2C1 '"' i f ™ 3 äo N —Λ c„ y 1 wherein R is benzyl or substituted benzyl, and the hydrogenated product is oxidized, or b) an ester of formula --- "τ 4 675S3

O

'aCH ^ Cl Br ^ S 2 "I;' CH3 N ---- i.

"C-OCH" CCl ~ 5 0 II 2 3 o is oxidized to the ester sulfone of formula O. .0 ^ "kCH Cl 10 Br ._ ^ S ^ 2«! i CH3 f-- N-1 ~ C-OCHCH3.

° l | 2 3

O

And the resulting ester sulfone is reacted with a metal and an acid, preferably zinc and glacial acetic acid, to give a compound of formula I or a salt thereof, and c) process option a) or b) esterifies the compound of formula I or a salt thereof, if desired.

In process variant a), the protecting group R, which is a benzyl group or a substituted benzyl group, in particular 4-nitrobenzyl, is removed by hydrogenation. The hydrogenation is conveniently carried out in an inert solvent under a hydrogen atmosphere, or in a mixture of hydrogen and an inert gas such as nitrogen or argon in the presence of a catalyst. Suitable solvents include lower alkanols such as methanol; ethers such as tetrahydrofuran and dioxane; lower esters such as ethyl acetate and butyl acetate; water; and mixtures of these solvents; conditions under which the starting material is dissolved are usually selected. The hydrogenation is usually carried out at a temperature of about 0 to 60 ° C and a pressure of about 1 to 100 kg / cm 2.

The catalysts used are of the type commonly used in the art for such hydrogenation. Typical examples are precious metals such as palladium, platinum and 35 roidum, as well as nickel. The catalyst is usually present in an amount of about 0.01 to 2.5% by weight, preferably about 0.1 to 1.0% by weight, based on the amount of the compound of formula A. The catalyst is often supported on a suitable inert support; a particularly suitable catalyst is, for example, 5 palladium suspended on carbon. In addition, it is customary for the reaction mixture to be buffered so that it is carried out at a pH of about 4-9, preferably 6-8. Borate and phosphate buffers are commonly used. A typical reaction time is about one hour.

10 Various oxidants that are known in the art to be used to oxidize sulfides to sulfones are useful in process option b). Particularly suitable reagents are early metal permanganates, e.g. potassium permanganate, and organic peracids, e.g.

15 3-Chloroperbenzoic acid.

The following examples are provided to illustrate the preparation of typical compounds of this invention.

6 67553

Example 1

Preparation of potassium 2β-chloromethyl-2β-methylpenam-3-ylate sulphone (BL-P2013) 5 2 0

BrBr „_ ^ N '' CO h ^ --- N ------------ k CO -CH ^ rT \ 10 \ V_- / '- No V 2

1 2 O V

1, Br _ ^ s. ^ H2Cl Hr. . ^> V ''! Γ j CH3 <ä-- I 3

J_N__]. J - N

° "" c02-ch2 / c> 020 '"2-ch2 ^ VnO2 4 3 20 H2

V

f 0 ^. s aCH_C1 .S ci 25, -r -'- o KMn:,>. —F · '«,

o- "co2h | / -N--; co2K

! i 5,5 6-bromopenicillanic acid-S-sulfoxide (1) 30 g (37.5 mmol) 6 oi. -bromipen in fathers acid-N, N'-dibenzylethylenediamine salt / G. Cignarella et al., J.

Org. Chem. 27, 2668 (1962) and E. Evrard, Nature 201, 1124 35 (1964) / are dissolved in 330 ml of methylene chloride. The solution 7 67553 is cooled to 0 ° C and 13 ml (156 mmol) of concentrated hydrochloric acid are slowly added. The dibenzylethylenediamine HCl salt (DBED.HCl) precipitates after stirring for 10 minutes at 0-5 ° C. The DBED.HCl precipitate is filtered through a pad of diatomaceous earth and washed with 150 ml of methylene chloride. The combined methylene chloride filtrate and washings are washed with 60 mL of cold water, and concentrated in vacuo to 65-80 mL. The solution is stirred and cooled to 5 ° C. 13 ml (86.9 mmol) of 40% peracetic acid are added with gentle stirring over 30 minutes with vigorous stirring. The reaction is exothermic, and the temperature of the mixture is maintained in an ice bath with cooling between 15-18 ° C. After the addition of 10 ml, the sulfoxide begins to crystallize. The mixture is cooled and stirred at 0-5 ° C for two 15 hours, then the precipitate is filtered and washed in the following order: 10 ml of water at 5 ° C, 10 ml of methylene chloride at 0-5 ° C, and finally with 15 ml of heptane. The precipitate is dried at 45 ° C. 16.26 g of the title compound are obtained, yield 73.24%.

20 p-Nitrobenzyl-6α-bromopenicillanate-S-sulfoxy di (2)

To a solution of 12 g (0.04 mol) of 6α-bromopenicillanic acid S-sulfoxide in 100 ml of acetone is added 7.5 g (0.041 mol) of potassium 2-ethylhexanoate. The salt 25 is filtered, washed with cold acetone and air dried. The obtained potassium salt (10 g) is dissolved in 75 ml of dimethylacetamide, and 7.8 g (0.04 mol) of p-nitrobenzyl bromide are added to the solution. The solution is stirred at 23 ° C for 24 hours, diluted with 500 ml of water and extracted with ethyl acetate. The extract is washed four times with water, dried over anhydrous magnesium sulfate and evaporated at 35 ° C (15 mm Hg) to an oil which crystallizes on standing. The light brown crystals are slurried in ether and filtered to give the title compound 9 g (70%), m.p. 124-125 ° C 35 (decomposes).

67553 8

Analysis:

Calculated for J-Br 2 O 2 S: C, 41.98; H, 3.05; N, 6.52 Found: C, 42.00; H, 3.48; N, 6.98.

Δ IR (KBr); 1800 (s), 1740 (s), 1610 (w), 1520 (s), 1450 (m), 1350 (s), 1060 (m), 740 (n) cm -1 1H-NMR (60 mHz) , DMSO): δ 1.22 (s, 3H), 1.6 (s, 3H), 4.67 (s, 1H), 5.2 (d, J / -1-5 Hz, 1H), δ .45 (s, 2H), 5.68 (d, J 1 -5 Hz, 1H), 7.5-8.5 (m, 4H) .p-nitrobenzyl-2β-chloromethyl-2-methyl- 6-bro-10 mipenam-3'-carboxylate (3)

A solution of 5 g (0.012 mol) of p-nitrobenzyl-6α-bromopenicillanate S-sulfoxide (2) in 1.5 g (0.012 mol) of quinoline and 1.6 g (0.012 mol) of benzoyl chloride in 120 ml: in dry dioxane, reflux under nitrogen for 4 hours. 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 at 35 ° C (15 mm Hg) to an oil which crystallizes. The crystals are washed with ether and finally with cold toluene to give 3.5 g (65%) of the title compound, 130-135 ° C (decomposes).

Analysis: Calculated for C 18 H 18 Cl 2 Br 2 O 3 S: C, 40.06; H, 3.14; N, 6.23 Found: C, 40.19; H, 3.12; N, 6.75.

IR (KBr); 1792 (s), 1740 (s), 1610 (w), 1520 (s), 1353 (s), 1280 (m), 1025 (w), 990 (w), 750 (w) cm -1.

Δ NMR (60 MHz, DMSO): δ 1/45 (s, 3H), 3.5-4.3 (n, 2H), 5.05 (s, 1H), 5.42 (s, 2H), 5.5 (d, J ~ 1.5 Hz, 1H), 5.62 (d, J ~ 1.5 Hz, 1H), 7.5-8.5 (m, 4H).

p-Nitrobenzyl-6β-bromo-2β -chloromethyl-2β -methylpenam-3β * -carboxylate sulfoxide (4) 35 To a solution of 1 g (0.0022 moles) of p-nitrobenzyl-3β -chloromethyl-2-methyl-6H-bromopenam-3α-9,67553 carboxylate (3) dissolved in 50 ml of methylene chloride, 473 mg (0.0022 mol) of m-chloroperoxybenzoic acid are added. The solution is stirred at 23 ° C for 3 hours, then the solution is evaporated to 20 ml of 15 mm Hg under vacuum at 33 ° C, and the concentrated solution is diluted with 50 ml of heptane ("Skel-lysolve B"). The solvent is decanted and the residue is slurried in ether to give the crystalline title compound, 250 mg, 24%; mp. 136-137 ° C (decomposes).

Analysis: Calculated for 10 H 2 Cl 2 Cl 2 O 2 S: C, 38.68; H, 3.02; N, 6.02 Found: C, 39.14; H, 3.13; N, 5.96.

IR (KBr): 180 ° (s), 1760 (s), 1520 (s), 1350 (s), 12CO (s), 1050 (m), 230 (w) cm -1. 1 H-NMR (60 mHz, DNSO): </> 1.32 (S, 3H), 3.8-4.5 (m, 2H), 4.97 (s, 1H), 5.25 (D, J ~ 1 , 5

Hz, 1H), (s, 3H), 3.8-4.5 (m, 2H), 4.97 (s, 1H), 5.25 (d, J ~ 1.5 Hz, 1H), δ .45 (s, 2H), 5.6 (d, J ~ 1.5 Hz, 1H), 7.8-8.5 (m, 4H).

Potassium 2β-chloromethyl-2β-methylpenam-3β-carb-20 oxylate sulfone (5) (BL-P2013)

To a solution of 7 g (0.015 mol) of p-nitrobenzyl-2β -chloromethyl-2β-methyl-6β-bromopenam-3β-carboxylate sulfoxide (4) in 150 ml ethyl acetate, a suspension of 4 g of 30% palladium-silicon ("Celite") and 2.8 g of sodium hydrogen carbonate in 150 ml of water is added. The mixture is hydrogenated for 3 hours at a pressure of 345 kPa. The catalyst is filtered off and the aqueous layer is separated and treated with 1.5 g of potassium permanganate in 50 ml of water. The mixture is stirred for 1 hour, 250 mg of sodium hydrogen sulfite are added to the mixture, the mixture is filtered, and the pH of the filtrate is adjusted to pH 2 with concentrated hydrochloric acid. Freeze-drying the solution gives a white amorphous powder. It is extracted with ethyl acetate, the extract is evaporated to 20 ml and then diluted with 100 ml of heptanes ("Skellysolve B"). 35 A white, hygroscopic solid 2 β-chloromethyl-2-methylpenam-3-carboxylic acid sulfone was collected.

10 67553

The acid is dissolved in acetone and solid potassium 2-ethylhexanoate is added to the solution to give 170 mg of a crystalline white salt, mp> 140 ° C (dec).

Analysis: Calculated for C 9 H 7 ClNO 5 S · 2H 2 O: C, 28.27; H, 3.24; N, 4.12 Found; C, 28.27; H, 3.69; N, 3.84.

IR (KBr); 1790 (s), 1770 (m), 1620 (s), 1460 (m), 1370 (s), 1310 (s), 1200 (s), 1140 (s), 955 (m), 740 (n) cm "1. 1 H-NMR δ (100 mHz, D 2 O): δ 1.68 (s, 3H), 3.2-3.9 (m, J ~ 2Hz, J ~ 4

Hz, J '(6 Hz, 2H), 4.0-4.4 (m, 2H), 4.3 (s, 1H), 5.02 (dd, J ~ 4 Hz), J - 2 Hz, 1 H).

Example 2

Pivaloyloxymethyl-2β-chloromethyl-2-methyl-penam-3-carboxylate sulfone

To a mixture of 2N-chloromethyl-2'-methylpenam-3β-carboxylic acid sulfone in dimethylformamide is added with stirring an equivalent amount of triethylamine. Bromomethyl pivalate (1 equivalent) in di-20 methylformamide is then added. The resulting mixture is stirred at room temperature. The mixture is then filtered and the filtrate is poured into ice-water. The separated solid is collected by filtration, washed with water and dried to give the title ester.

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

Example 3

Pivaloyloxymethyl-2β-chloromethyl-2H-methyl-penam-3'-carboxylate sulfone BL-2024

II

11 67553

_ ^ st ° / H3 O

I [V, li \ jij I CH 2 Cl + Nai + 1 ^ O + Clti ^ -O-C — C (CH 2)

5 ™ (306) CO2'K

acetone (BL-P2013) 10 Q .0 ____ ^ S \ 3 i rCH2C10

V N II

CO 2 CH 2 -O-CC (CH 3) (BL-P 2 O 24) To a stirred suspension of 14.6 g (0.0487 moles) of BL-P 2 O 3 (5) in 200 ml of acetone was added 4 ml of 10% aqueous sodium iodide solution and the mixture was heated to boiling in a water bath. To the boiling suspension was added 14.8 ml (0.1 mol) of redistilled chloromethyl pivalate (b.p. 34 ° C / 7 mmHg) in one portion. The mixture was stirred under reflux for three hours, then cooled to room temperature (22 °). The crystalline solids were collected by filtration, washed with 3 x 30 mL of acetone, and the combined filtrates were evaporated to an oil in vacuo at <22 ° C. the oil was then dissolved in 500 ml of ethyl acetate and washed once with water (200 ml) and once with saturated Na 2 SO 4 with stirring under cooling (ice bath) with 2 g of decolorizing carbon.

After 20 minutes, the mixture was filtered through a pad of diatomaceous earth (Dica-35 lite) with suction and the pad was washed with 4 x 100 mL of 117553 ethyl acetate. The combined filtrates were concentrated in vacuo at 22 ° C to an oil, then the oil was further concentrated. at about 22 ° C and <1 nunHgrn in vacuo to remove most of the remaining chloromethylpiperate 5. The residual oil was then triturated twice with 50 mL portions of n-pentane and then left in the cold room over the weekend (about 10 ° C). C) to n-pentane The solid crystalline mass was then crushed to a solid powder under a mixture of 4: 1 ether and 10 n-pentane, the product was filtered, washed with ether-pentane (1: 1), then with pentane and air dried. Drying in vacuo for 4 hours at Ρ20 ^: η gave 13.37 g of pivaloyloxymethyl-2 β-chloromethyl-2J'-methylpenen-3Λ-carboxylate sulfone (yield about 75%), mp 93-95 ° C.

Analysis:

Calcd for 1 H 2 ClNO 2 S: C, 44.03; H, 5.27; N, 3.67;

Found: C, 44.11; H, 5.08; N, 3.85.

20 Example 4

Recrystallization of potassium-2β -chloromethyl-2H-methylpenam-3d-carboxylate sulfone (BL-P2013)

To a mixture of 20 ml of 25 n-butanol and 1 g of BL-P2013 (5) in a separatory funnel was added 1 ml portions of water and shaken until a pale yellow solution was obtained. The clear solution was filtered through pleated filter paper and the flask and filter paper were washed with about 10 mL of n-butanol-H 2 O (9: 1), the combined filtrates were diluted with 20 mL of n-butanol. The resulting solution was placed in a round bottom flask on a rotary evaporator and evaporated in vacuo to approximately half its original volume. The off-white crystalline product was filtered, washed 6 times with 10 ml of acetone and dried over mass. Yield 810 mg. Drying for 6 hours on P 2 O 3 in I3 67553 <1 nunHg vacancies gave 800 mg of product, m.p. 215 ° C (decomposes) (yield 80%).

Analysis:

Calculated for C 9 H 9 ClNO 2 SK. 1 → 0: 5 C, 29.67; H, 3.39; N, 4.63; Cl, 10.94, K.F.H 2 O, 5.56;

Found: C, 29.23; H, 3.38; N, 4.49; Cl, 10.74; K.F.H 2 O, 5.74.

This recrystallization process gives a crystalline monohydrate which differs from the starting material which is essentially anhydrous.

Example 5 15.

/ - \ O

// \ __ ς! + N-bromosuccinimide. -azoisobutyronitrile CC14 20

A

v 25 f ~ Y / w * 30 Recrystallized phthalide (50 g, 0.375 moles) and recrystallized N-bromosuccinimide (0.375 moles) were refluxed as described in U.S. Patent 3,860,579 for 4.5 hours in 1 liter of CCl 4. containing about 100 mg of ot-azoisobutyronitrile.

The mixture was cooled to about 15 ° C and filtered to remove the succinimide, which was also washed with about 100 mL of CCl 4 and filtered. The combined CCl 4 phases were concentrated in vacuo to about 150 mL to give solid 3-bromophthalide which was collected by filtration, washed with about 50 mL of CCl 4 and dried in air to give 54 g of product weighing boiling cyclohexane. after recrystallization 50 g, m.p. 84-86 ° C.

10 O., 0> S \ CH Cl ^ € ΗΒξ —r 0 I "" CH3 * f V ^ c7 X - N ______ \ __ / λ '/% ^ -' 012

0 C-OK

15 5 II

- 0 DMF 22 ° C.

V

20

O O

Is ^ CH2C1 m rcH3 i l /} - N - * *

2 5 0 'C-O-CH

Il O I BL-P2036 °>: ~ kj

Il * dl 13 0

To a stirred mixture of compound 5 (BL-P 2 O 3; 2.3 g, 0.0075 mol) in 20 mL of dimethylformamide (DMF; dried for at least 3 weeks on a 3A ° molecular sieve) was added 1.7 times. g (0.008 mol) of 3-bromophthalide (12) and the mixture was stirred for 4 hours at 22 ° C. The resulting mixture was poured into a mixture of 200 ml of ice-cold water and 200 ml of ice-cold 67553 ethyl acetate (the flask was rinsed with a small amount of ethyl acetate), and the mixture was shaken. The organic solvent phase was then separated and washed with seven portions of ice-cold water (100 ml). The ethyl acetate phase was washed once with saturated aqueous Na 2 SO 4, dried over cold Na 2 SO 4, filtered and evaporated to dryness in vacuo to give a residue which was triturated twice with methylcyclohexane (25 ml), twice Bkel. (b.p. 60-68 ° C, mainly n-hexane) 10 (25 ml) and four times 25 ml of n-hexane to give 2.5 g of compound 13 as an off-white solid after air drying. This product was then dried over P 2 O 2 under less than 1 mmHg to give 2.5 g of compound 13, m.p. 104l! (Decomposed). Its estimated purity was 85-95%.

Analysis:

Calcd for C 18 H 18 ClNO 2 S: C, 51.61; H, 3.79; N 3.77; Cl, 9.53;

Found: C, 52.59; H, 4.67; N, 3.21; Cl, 7.73; 20 K.F.H 2 O, 0.27.

Example 6

Pivaloyloxymethyl-2β-chloromethyl-2β-methylpenen-3β-carboxylate sulfone

A mixture of 1 g (0.0031 mol) of potassium 2β-25 chloromethyl-2 rt-methylpenam-3 rt carboxylate sulfonic hydrate and 1 g of 3A molecular sieve was stirred in 15 ml of dimethylacetamide for 2 hours at 23 ° C. :in. To this mixture was added 470 mg (0.0031 mol) of pivaloyloxymethyl chloride, and stirring was continued for 18 hours. The molecular sieve was filtered and the filtrate was diluted with 100 ml of water and extracted with ethyl acetate. The ethyl acetate was washed nine times with water and dried over anhydrous magnesium sulfate. The solvent was removed at 3 ° C (15 mm) to leave an oil which was chromatographed on silicon-35 acid using CC-7 (methylene chloride 8, 16 67553 ethyl acetate 2) to give a spot, Rf 5. The resulting residue was crystallized from heptane. ("Skellysolve B") in a yield of 100 mg (m.p. 94-95 ° C) of pivaloyloxymethyl-2/3-chloromethyl-2-methylpenam-3- * carboxylate-5-sulfon.

Analysis:

Calculated: C, 44.03; H, 5.27; N, 3.67.

Found: C, 44.20; H, 5.24; N, 3.63.

NMR and IR spectra were consistent with structure.

10 Example 7

Sodium 2-Q-chloromethyl-2-methylpenen-3 <* - carboxylate sulfone 15

NaEH ^ CH ^ Cl> S \> CH2C1 H + x (2)> _ -ν '7τγ> [f 3 // N -: ¾ q ^ COpNa 20 "" <: ο2κ 0 2

CgHgClNO 2 SNa (306) (289.67) To a stirred solution of 500 mg of BL-P 2 O 3 (potassium salt) in 5 mL of H 2 O and 10 mL of ethyl acetate was added 2N HCl until the pH was 1. (HCl addition was performed in an ice bath with vigorous stirring).

The mixture was then saturated with Na 2 SO 4, the aqueous layer was separated and the organic phase was dried over Na 2 SO 4 in an ice bath, filtered, and 50% sodium 2-ethylhexanoate (NaEH) in dry n-butanol was added dropwise to the neutral reaction (moist pH paper). The product did not crystallize on scraping and the solution was concentrated in vacuo to an oil which was dissolved in acetone (5 mL), the solution was scraped - no crystals, ether was added to the cloud point.

II

17 67553 up to tea - no crystals. The solution was concentrated in vacuo on a rotary evaporator. To an oil which was dissolved in ethyl acetate, a drop of water was added, scraped off - no crystals. The solution was concentrated in vacuo, the residue triturated with 5 ml of n-butanol to give 200 mg of an amorphous white powder, washed with ether, air dried, dried in vacuo over P 2 O 4 for 24 hours. The final yield was 180 mg of sodium 2R-clocremethyl-2-methylpenam-3α-carboxylate sulfone; dispersion point-10 te> 100 °, indeterminate.

Analysis:

Calcd for C 9 H 11 ClNO 2 SNa: C, 33.10; H, 3.13; N, 4.89;

Found: C, 33.2C; H, 3.69; N, 4.44; K.F.H 2 O, 4.04.

1 5 Example 8

Potassium-2 β-chloromethyl-2-methylpanan-3-carboxylate sulfone (BL-P2013)

To a mixture of 10 liters of water, 130 g (1.25 moles) of sodium bicarbonate and 200 g of 10% 20 Pd / BaSO 4 were added 272 g (0.565 moles) of p-nitrobenzyl-11-6d-bromine. 2 β-Chloromethyl-2-methylpenen-3-carboxylate sulfone dissolved in 5 liters of ethyl acetate. The mixture was hydrogenated at 40 ° C under a pressure of 98 kPa. After 5 hours, hydrogen uptake slowed, 25,200 g of 10% Pd-BaSO 4 was added to the mixture, and the mixture was hydrogenated when no significant hydrogen absorption was observed.

The slurry was filtered through a pad of diatomaceous earth ("Celite"), the pad was washed with water and the aqueous phase was washed with 3 liters of ethyl acetate. To the aqueous solution was added 3 liters of ethyl acetate, and the pH of the mixture was adjusted to 1.5 with 150 ml of 12 N HCl at 10 ° C. The organic phase was separated and the aqueous solution was saturated with Na 2 SO 4 .10H 2 O and extracted twice with 1 liter of ethyl acetate. The combined extracts were dried over magnesium sulfate. The desiccant was removed and at 0 ° C 260 ml of a 2-butanol solution of potassium 2-ethylhexanoate were added.

Γ 18 67553

After stirring for 2 hours at 0 ° C, potassium 2β-chloromethyl-2-methylpenam-3β-carboxylate sulfone (BL-P 2 O 3) was collected and dried in vacuo at room temperature. Yield: 134.8 g (about 70%).

5 Example 9

p-nitrobenzyl 6 - * - bromopenicillinate sulfoxide O

10 t Π Γ + (ίου + BrCH2 \ λΝ ° 2 / // N-- o C02K (216), 5 12961 O ^ f

Br 1 20 ^ s x., / ^ / “N ---- O CO2CH2_ ^ ^> NO2 25 (431.28)

Method: To 200 ml of N, N-dimethylacetamide were added 44 g (0.148 mol) of 6α-bromopenicillanic acid sulfoxide followed by 20.5 ml (0.148 mol) of triethylamine and 38.2 g (0.177 mol) of p-nitrobenzyl bromide. Stirred for 20 hours at 22 ° C.

The reaction mixture was poured into 1 L of H 2 O and extracted with 3 x 300 mL of methylene chloride. The combined methylene chloride-355 ride extracts were washed with 200 ml of 5% aqueous sodium hydrogencarbonate solution and dried for half an hour at 5 ° C with 19,67553 sodium sulfate. The solution was filtered and evaporated in vacuo. The residue was diluted with ether and the solid was collected by filtration to give, after drying, 54 g of p-nitrobenzyl 6-bromopenicillinate-5 sulfoxide. Yield 85%. NMR was consistent with structure. The yield of this step was the same as in the K-salt esterification. The advantage is that it is not necessary to prepare the K-salt (in the preparation of the K-salt the yield is 85-90%).

Example 10 Preparation of 10β-nitrobenzyl-6α-bromopenicillinate sulfoxide To 4.375 liters of N, N-dimethylacetamide was added 873.0 g (2.95 moles) of 6β-bromopenicillanic acid sulfoxide, and then added with stirring and maintaining the internal temperature. Below 0 ° C, 293 g (2.95 moles) of triethylamine followed by 764 g (3.54 moles) of p-nitrobenzyl bromide. The mixture was stirred at room temperature for 5 hours, then allowed to stand overnight.

The reaction mixture was poured into 20 liters of water and extracted with 3 x 7 liters of methylene chloride. The combined organic extracts were washed with 5x7 liters of water and then with 7 liters of 5% aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate.

The magnesium sulfate was filtered off and the solution was evaporated, 4 liters of diethyl ether were added to the crystalline residue, and the crystals were collected to give, after drying at room temperature, 1171 g (92%) of p-nitrobenzyl 6 * -bromopenicillanate sulfoxide. Br 18.48% (calculated 18.53%), λ x (0.25% MeOH) + 162 °.

Example 11 Preparation of BL-P2013-free acid 20 67553 k /> \ / I --- / 5 CH2C1 H.PO. _> s »CH2C1, -N -T CH3 -> ΓΎ? CH3

5 0 C02®K® // - 1 »" "C0? H

To a mixture of 25 ml of ethyl acetate and 10 ml of water was added 800 mg (0.00261 mol) of the potassium salt of BL-P2013. The dissolved mixture of all solids was treated by adding dropwise a 50% aqueous solution of phosphoric acid with vigorous shaking until no more material precipitated from the aqueous layer. The ethyl acetate layer was separated, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and washed with 10 ml of ethyl acetate. (The washing solvent was combined with the original filtrate). "Skellysol-ve B" was then added to the ethyl acetate to the cloud point (about 10 mL). The mixture was treated with 500 mg of activated carbon ("Darko KB") and filtered. The filtrate was diluted with 15 ml of "Skellysolve B", then crystals of BL-P2013-free acid were added as seed. After about 3 hours at room temperature, the crystalline precipitate of the free acid was collected and dried in vacuo (15 min) at -20 ° C to give 323 mg (46%) of product; mp. slowly decomposing above 100 °.

Analysis:

Calculated for C 9 H 11 ClNO 2 S: C, 35.89; H, 3.77; N, 5.23; Cl, 13.25;

Found: C, 35.88; H, 3.91; N, 5.41; Cl, 13.52.

30 This product was found to be unstable when stored for seven days at 23 ° C.

Example 12 6 d-Bromopenicillanic acid sulfoxide li 67553 21 p - 0 ΐ

5 Brs ·. Br. ,, ^ S

II X (C6B5CH;! MHCH2) 2 - * j Γ Y

/ N ^ - / γ — N ^ 0 C09H 0 ^

U 2 U CO2

J 2

Mp. 800.64 Mp * 296.14

To 3 liters of methylene chloride was added 300 g (0.75 moles) of 6'-bromopenicillanic acid N, Ν1-dibenzylethylenediamine salt and the resulting suspension was cooled to 15 ° C. 130 ml of concentrated HCl were then added dropwise over 15 minutes with good stirring. The slurry was stirred at 5 ° C for 2 hours. It was then filtered through a pad of diatomaceous earth ("Celite") and the filter cake was washed with 3 x 250 mL of methylene chloride.

The combined methylene chloride solutions were washed with 2 x 500 mL of 10% and dried over sodium sulfate for 15 minutes. The sodium sulfate was removed by filtration and the filtrate was evaporated in vacuo to about 750 ml.

This solution was cooled to 5 ° C and 130 ml of 40% peracetic acid was added dropwise with vigorous stirring to maintain the temperature between 5-12 ° C. The addition caused a rather exothermic reaction. After the addition was complete, the slurry was stirred at 5 ° C for 2 hours and the product was collected by filtration and washed with 100 mL of cold IVO (5 °) and 100 mL of cold methylene chloride (5 °). 126 g (57%) of 6'X-bromopenicillanic acid sulfoxide were obtained, m.p. 129 ° C. IR and NMR spectra were consistent with the desired product.

ΊΤ 22 67553

Analysis:

Calcd for C 9 H 11 BrNO 2 S: C, 32.44; H, 3.40; N, 4.73;

Found: C, 32.3C; H, 3.35; N, 4.71; H 2 O, 2.18.

5 Potassium 6a-bromopenylsilanate sulfoxide

O O

10] —---------> J-

0 '"CO, H", CO 2 K

2 Mp. 334.24

To three liters of acetone were added 126 g (0.43 moles) of 6,9-brompenicillanic acid sulfoxide and 162 ml of a 50% by weight solution of potassium 2-ethylhexanoate in n-butanol.

After stirring for 1 h at 22 ° C, the product was filtered, washed with 2 x 250 mL of acetone and dried. 127 g (90%) of potassium 6-bromocenicillanate sulphoxide were obtained, m.p. 185 ° C. The IR and NMR spectra were consistent with the desired structure.

Analysis:

Calculated for C 9 H 9 BrKNO 2 S: C, 28.75; H, 2.71; N, 419;

Found: C, 29.03; H, 2.78; N, 4.04.

25 p-Nitrobenzyl-6 <* -bromopenicillanate sulfoxide? ? γΓϊ · ___ r ~ "% 0 k w / r \

o CO 2 K O CO CH - (f V / -NO

2 2 \ - / 2

Mp. 431.28 35 23 67553

To a liter of Ν, Ν-dimethylacetamide was added 14b g (0.43 moles) of potassium 6ίλ-bromopenicillanate sulfoxide, and then 115 g (0.53 moles) of p-nitrobenzyl bromide was added thereto with stirring at 22 ° C. The mixture was stirred at 22 ° C for 20 hours.

The reaction mixture was poured into 3 liters of H 2 O and extracted with 3 x 1500 mL of ethyl acetate. The combined ethyl acetate extracts were washed with 2 x 500 mL of 5% aqueous sodium bicarbonate and dried over sodium sulfate for 10 1/2 hours. The sodium sulfate was filtered off and the filtrate was evaporated in vacuo to a residue to which was added 1 liter of diethyl ether which caused the product to crystallize. The crystals were collected by filtration, washed with 2 x 100 ml of diethyl ether and dried to give 15,162 g (87%) of p-nitrobenzyl-6-bromopenicillanate sulfoxide, m.p. 111 °. The IR and NMR spectra were of the desired structure.

Analysis:

Calculated for gBr 2 O 5 S: 20 C, 41.78; H, 3.51; N, 6.50;

Found: C, 41.66; H, 3.45; N, 6.85; H 2 O, 0.69.

p-Nitrobenzyl 6-o-bromo-2/3-chloromethyl-2-ethyl-penenam-3''-carboxylate 25

O

Br ,,> S Br v - / '· 3 ^ AH2C1 -γ ____) Pj_j ch3 30 / _ N' '// co2ch ^ 3-no2 o' c ° 2ch2mo2

Mp. 446.71

To a liter of p-dioxane was added 70 g (0.16 moles) of 35 p-nitrobenzyl 6β-bromopenicillanate sulfoxide followed by 21.2 ml (0.10 moles) of benzoyl chloride and 21.8 ml (0.19 moles) of benzoyl chloride. ) quinoline, The reaction mixture was refluxed for 4 hours, then cooled to 22 ° C, poured into 2500 ml of 1N Orta and extracted with 3 x 5,800 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 300 mL of 5% aqueous sodium bicarbonate, 300 mL of 5% aqueous phosphoric acid, and 300 mL of 10%. The ethyl acetate solution was dried over sodium sulfate for 1/2 hour and the sodium sulfate was removed by filtration. The filtrate was evaporated in vacuo to a residue which was redissolved in a liter of ethyl acetate and evaporated again in vacuo to a residue. 1 liter of diethyl ether was then added and the product was collected by filtration to give 41 g (57%) of 15 p-nitrobenzyl 6 - (.-Bromo-2 β-chloromethyl-2% methyl-penam-3-carboxylate, m.p. 132 The IR and NMR spectra were of the desired structure.

Analysis:

Calcd for J 2 H 2 BrCl 2 Cl 2 S: 20 C, 40.06; H, 3.14; N, 6.23;

Found: C, 40.62; H, 3.11; N, 6.13.

p-Nitrobenzyl-6-ol-bromo-2H-chloromethyl-2- (3-methylpenam-3-ol carboxylate sulfoxide 25

O

f

Br%,> S \> CH2C1 Β »,, _ / S VCH2C1 f TCH3 _i, | "™ 3 J— - ^ /} λ i N ~, —v 30 O CO2CH2- <'J} ~ NO2 0 CO2CH2 ^ j) -NO2

Mp. 465.71 I! To 1,755 ml of methylene chloride was added 51 g (0.11 moles) of p-nitrobenzyl 6-bromo-2β-chloromethyl-2β-methylpenam-3-ol carboxylate, followed by 23 g (0.12 moles) of m-chloroperoxybenzoic acid. The solution was stirred at 22 ° C for 2 hours, then the solution was evaporated in vacuo to a wet residue. The residue was stirred with 4 liters of diethyl ether for 1 hour and then allowed to stand at 10 ° C for 20 hours. The product crystallized and was collected by filtration, washed with 2 x 200 ml of diethyl ether and dried to give 39 g of p-nitrobenzyl-6β-bromo-2β-chloromethyl-2β-methylpenam-3-ol. carboxylate sulfoxide (75%), m.p. 132 ° C. The IR and NMR spectra were of the desired structure.

Analysis: Calculated for C 18 H 18 BrClN 2 O 9 S: C, 38.69; H, 3.03; N, 6.07;

Found: C, 38.98; H, 3.04; N, 5.84; H 2 O, 0.35.

Potassium-2β-chloromethyl-2,3-methylpenen-3β-carboxylate sulfone (BL-P2013) 20 ° C)

ΒΓ '' v ._ / S \ | ^ CH2C1 _> S

, i-JS- * -> Π rCH3

25 0 CO2CH2 // _ ^ \ - NO2 '' ^ CO2K

BL-P2013 Mp. To 305.77 mL of H 2 O was added 8 g of 30%

Pd / Celite catalyst and 16 g (0.19 moles) of sodium bicarbonate. 32 g (0.69 mol) of p-nitrobenzyl-6x-bromo-2β-chloromethyl-2α-methylpenam-3α-carboxylate sulfoxide were then dissolved in 400 ml of ethyl acetate 35 and added to an aqueous slurry. The mixture was hydrogenated on a Parr apparatus at 345 kPa at 22 ° C for 4 hours. The slurry was filtered through a thin pad of Celite in a sintered glass funnel, the pad was washed with 2 x 50 mL of HoO, and the aqueous layer of the combined filtrate and washings was separated.

The aqueous layer was washed with 200 mL of diethyl ether, then cooled to 5 ° C, and a solution of 12 g (0.076 moles) of KMnO 2 in 200 mL of H 2 O was added dropwise with stirring over 1/2 hour, maintaining the pH between 7 , 5-8.0 by adding 40% H 2 PO 4. When the rose-red color 10 persisted for 5 minutes, no more KMnO 2 solution was added.

The reaction mixture was stirred with a small amount (about 50 mg) of sodium hydrogen sulfite for 1/2 hour, and then the slurry was filtered through a pad of Celite. The mattress was washed with 2 x 50 mL H 2 O. A 500 ml layer of ethyl acetate was poured onto the combined filtrate and washings and the pH was adjusted, with stirring, to 1.5 by the addition of 2-norm. HCl. The layers were separated and the aqueous layer was saturated with sodium sulfate. It was re-extracted with 2 x 400 ml of ethyl acetate and the combined ethyl acetate extracts were dried over sodium sulfate for 1/2 hour at 5 ° C. The sodium sulfate was removed by filtration and the filtrate was evaporated in vacuo to a residue. That residue was dissolved in 160 ml of acetone and 160 ml of diethyl ether and a 50% by weight solution of potassium 2-ethylhexanoate in n-butanol were added until the solution was neutral on moist pH paper. The separated crystalline potassium salt of BL-P2013 was collected by filtration, washed with diethyl ether and dried. Yield 16 g of potassium 2'-chloromethyl-2-methyllipenam-3 (β-carboxylate sulfone (BL-P2013)) (76%), mp 202 [deg.] C. IR and NMR the spectra 30 were of the desired structure.

Analysis:

Calculated for C 9 H 9 ClNCO, -S: C, 31.42; H, 2.97; N, 4.58;

Found: C, 31.18; H, 2.98; N, 4.51; H 2 O, 0.93.

Il 5 27 67553

Example 13

Piyloxyloxymethyl-2β-chloromethyl-2β-methyl-penam-3β-carboxylate sulfone (BL-P2024) 0 0 0 "/ CH 3

// N V / CO K ^ '"CO CH OCOCfCHJ

10 o o BL-P2024 Mp. 381.83

To a stirred suspension of 14.6 g (0.0487 15 moles) of potassium 2β-chloromethyl-2 ° C-methylpenam-3 carboxylate sulfone (BL-P2013) in 200 mL of acetone was added 4 mL of 10% sodium iodide. aqueous solution and the mixture was heated to boiling in a water bath. To this boiling suspension was added 14.8 mL (0.1 mol) of redistilled chloromethyl pivalate (b.p. 34 ° C / 7 mmHg) in one portion. The mixture was stirred at reflux for three hours and then cooled to room temperature (22 ° C). The crystalline solids were collected by filtration, washed with 3 x 30 ml of acetone and the combined filtrates evaporated in vacuo at 25 <22 ° C to an oil, the oil was then dissolved in 500 ml of ethyl acetate and washed once with water (200 ml) and once with saturated Na 2 SO 4. ^ solution (200 ml). The solution was then dried briefly with Na 2 SO 4 by stirring under cooling (in an ice bath) with 2 grams of decolorizing carbon. After 20 minutes, the mixture was filtered through a pad of Celite and the pad was washed with 4 x 10 mL of ethyl acetate. The combined filtrates were concentrated in vacuo at 22 ° C to an oil Γ ~ ο 67553 si. the oil was then further concentrated at about 22 ° C and <1 mmHg to remove residual chloromethyl pivalate. The residual oil was then triturated with two 50 ml portions of n-pentane and then left for about the end of week 5 to about 10 ° C under n-pentane. The solid crystalline mass formed was then decomposed into a powder under a mixture of 40 ml of a mixture of diethyl ether and n-pentane (4: 1). The product was filtered, washed with diethyl ether-n-pentane (1: 1) followed by n-pentane 10 and air dried. After drying under high vacuum for 4 hours under P 2 O 3, 13.37 g of pivaloyloxymethyl-2β-chloromethyl-2-methylpenam-3α-carboxylate sulfone (BL-P 2 O 24) were obtained in a yield of about 75%. mp. 93-95 ° C.

15 Cleaning the BL-P2024

About 3 g of crude BL-P2024 (obtained as described above) was dissolved in 5 ml of ethyl acetate, the solution was applied to a 4.5 x 40 cm silica gel column (Mallinckrodt CC-7) and eluted with a mixture of 20: 4 by volume. : 1 CH2Cl2 and ethyl acetate. Fractions to give a single spot at 0.84 (TLC on silica gel plates with CH 2 Cl 2 / ethyl acetate 4: 1, δ-detection) were combined and concentrated in vacuo to 1.38 g of crystalline material. A portion of this material (900 mg) was dissolved in 5 mL of ethyl acetate; the resulting solution was filtered, diluted to near cloud point with petroleum ether ("Skellysolve B") and then kept at room temperature for three days. The formed crystals were collected by filtration, washed with petroleum ether and dried to give 560 mg of purified BL-P2024, m.p. 100-101 ° C.

Analysis:

Calculated for c- | 4H20ClNO7S: C, 44.03; H, 5.27; N, 3.67; Found: C, 44.11; H, 5.08; N, 3.85.

29

Example 14 Preparation of 67553 ammonium salt of BL-P2013 1. Free BL-P2013 acid (250 mg) dissolved in 20 ml of acetone-methanol (1: 1 by volume) was filtered to give a clear solution.

2. To 10 ml of acetone-methanol solvent (1: 1 by volume) was added 1 ml of ammonium hydroxide (30%, reagent grade), 1 g of anhydrous magnesium sulfate was added to the solution with stirring, and the mixture was filtered through filter paper; 10 filtrates were referred to as "anhydrous ammonium solution".

3. To the filtrate obtained in step 1, about 2 ml of "anhydrous ammonium solution" was gradually added and mixed well.

4. 100 ml of diethyl ether was mixed with the mixture obtained in step 3 to precipitate the ammonium salt of BL-P2013.

5. The white ammonium salt was isolated from the solvent and washed with two 50 mL portions of diethyl ether.

6. The isolated powder was dried at 35 ° C in a vacuum oven overnight.

7. Analytical values were as follows: Calculated,%: C 33.7; H 4.6; N 9.8;

Found: C, 33.66; H 4.63; N 10.12; dry (KF)

Microscopic examination: crystalline matter.

Example 15

Preparation of non-hygroscopic sodium salt of BL-P2013 1. Dissolve 50 mg of free BL-P2013 acid in 4 ml of acetone / methanol (1: 1 by volume). The solution is filtered to give a crude solution.

2. Prepare sodium 2-ethylhexanoate solution 30 by dissolving 40 mg of sodium 2-ethylhexanoate in 10 ml of acetone / methanol (1: 1 by volume).

3. To the filtrate of step 1 add 10 ml of the solution of step 2; mixed.

4. 10 ml of diethyl ether is mixed with the mixture of step 3 to precipitate the sodium salt of BL-P2013.

30 67553 5. The white salt is kept in diethyl ether for 1-2 hours and then isolated from the solvent and washed with three 5 ml portions of diethyl ether.

6. The isolated powder is dried at 30 ° C in a vacuum oven overnight.

Example 16 Recrystallization of BL-P2013 10 O /? Recrystallization of ^ 0 __> SyCH2C1 ^ ^ S / ^ H2Cl T Γ "CH3 H2O-acetone j CH3 j? - N -1 ,, -N -1,

"CO-K-H-O / '' -CO-K-H-O

O 2 2 o 2 2 BL-P 2 O 3 (400 mg) was dissolved in a minimum amount of acetone / H 2 O (1: 1 by volume) and the solution was diluted with 10 mL of acetone, filtered, then diluted with acetone to about 25 mL, scraped , and after 30 minutes, the crystalline hydrate was filtered, washed well with acetone, air dried, and then dried overnight under vacuum at <1 mmHg. Yield 280 mg.

25 Analysis:

Calculated for C 9 H 9 ClNOSK.H 2 O: C, 29.67; H, 3.39? N, 4.63; Cl, 10.94; Η2 <0.55;

Found: C, 29.32; H, 3.32; N, 4.44; Cl, 11.31; H 2 O, 30 5.90.

Example 17 N, N'-Dibenzylethylenediamine salt of BL-P2013

II

31 67553 BL-P2013 + 1/2 Ν, Ν'-dibenzylethylenediamine diacetate recrystallization from acetone-ether / \ 5 / ^ s ^ ° ^ .ch2ci \ / | -r \ \ q 2. ό 5 2 2, o \ 302 mg (0.001 mL) of BL-P2013 was dissolved in 7 mL of H 2 O and added to a solution of 180 mg (0.0005 moles) of Ν, Ν'-dibenzylethylenediamine diacetate in 7 mL of H 2 O. ta. The mixture was stirred and the salt crystallized, and after stirring for about 10-15 minutes, the salt was collected by filtration and air-dried to give the N, N1-dibenzylethylenediamine salt of BL-P2.013 (300 mg). The material was recrystallized by dissolving it in about 10 ml of boiling acetone and diluting with ether to cloud point. 260 mg of air-dried and then vacuum-dried material were obtained.

Analysis:

Calculated: C, 51.69; H, 5.42; N, 7.53; Cl, 9.55;

Found: C, 49.39; H, 5.49; N, 7.05; Cl, 8.96; H 2 O, 1.23 (KF).

Example 18 Chloromethyl ester of BL-P2013 32 67553

O O

aPH2C1 + C1CH0 “0-S00Cl

Vxf * 2 2 <=> Γ '-CH + (CH3CH2CH2CH2) 4N HS04 _N __ [5 o COOK + 3 KHCO3 (305.7)

1 CH2C12 HO V

1 0 _ ^ Si ^ H2Cl I TCH3. N-1 M ^ C-OCHoCl O.2

O

15 (316.17) 7

To a vigorously stirred mixture of 15.25 g (0.05 moles) of BL-P 2 O 3 (5), 15 g (0.15 moles) of KHCO 3 and 1.7 g (0.005 moles) of tetrabutylammonium hydrogen-20 sulfate (Aldrich Chem. Co.) in a mixture of 50 ml of water and 50 ml of CH 2 Cl 2 was added dropwise a solution of 9.5 g (0.0575 moles) of ClCH 2 -O-SO 2 Cl in 40 ml of CH 2 Cl 2. The temperature rose to 26 ° C and after the addition (which took about 15 minutes) the mixture was stirred for a further 25 minutes. As the product separated as crystals, more CH 2 Cl 2 (ca. 400 mL) was added to give a solution. The separated CH 2 Cl 2 layer and 50 mL of CH 2 Cl 2 wash were combined, dried over MgSO 4, and treated with decolorizing carbon (2 g) ("Darco KB"). After about 30 minutes, the mixture was filtered, concentrated to about 50 mL, and isopropyl alcohol (150 mL) was added. The remainder of the CH2Cl2 was then removed in vacuo. The resulting crystalline precipitate was filtered, washed well with isopropyl alcohol and air dried. After drying in vacuo at less than 1 mmHg, 8.5 g of chloromethyl-2β-chloromethyl-2β-methylpenal 33 6 7 5 5 3 mi-3 o-carboxylate sulfone were obtained (7). Sp. 116 ° C (decomposes, darkens above 100 ° C).

Analysis:

Calcd for C 9 H 11 Cl 2 NO, -S: 5 C, 34.18; H, 3.51; N, 4.45; Cl, 22.43;

Found: C, 34.16; H, 3.45; N, 4.47; Cl, 22.46; H 2 O, 0.33 (KF).

Estimated purity between 90-95%.

Iodomethyl ester of B1-P2013 10 \ ff .CH-Cl n 0 _> s 2 \ // £ H Cl '"' CH, NaI. - ^ * S / 15 JN-1 |" 'CH3 O C-OCH " Cl /) - N- \

I 2 o "c-OCH, I

o I 2

7 8 O

To a stirred mixture of 5 g (0.0159 mol) of chloromethyl ester of BL-P2013 (7) in 25 ml of acetone was added 3 g (0.02 mol) of sodium iodide. The resulting slurry was stirred for 17 hours, then the mixture was cooled to about 0 ° C. Two drops of saturated aqueous KHCO 3 were added, and the mixture was slowly diluted by dropwise addition of 50 mL of water over ten minutes. The slurry suddenly changed color from yellow to gray, purple, black, and therefore the crystals were immediately collected by filtration and washed with cold acetone / water (1: 2), isopropyl alcohol (3 x 10 mL), diethyl ether, and finally n- pentane, and air-dried to give 5.55 g (91% yield) of iodomethyl ester of BL-P2013 (8), m.p. 118-119 ° C with decomposition. The purity was estimated to be 90%.

τ ~ 34 67553

Example 19

Improved Synthesis of BL-P2013 This method simplifies the preparation of BL-P2013 because it eliminates previously used catalytic reduction.

Step 1 0 f

Br „ς 10 - / s ^ I + CH2CCl_ + dicyclohexyl-1-N-k, I carbodiimide

COOH OH

Pyridine CH2Cl2

V

O

v / V

i-1 to L

'j 6-och0cci,

o il 2 J

o 25 (See Cephalosporins and Penicillins Strain 633, edited by Edwin H. Flynn, Academic Press, New York, 1972).

6 cx-Bromopenicillanic acid sulfoxide, (1) (30 g, 30 0.1 mol) was dissolved in a liter of dry CH 2 Cl 2 and then 16.2 ml (0.2 mol) of pyridine and 29.8 g (0 mol) of pyridine were added. , 2 moles) of trichloroethanol. 20 g (0.1 mol) of dicyclohexylcarbodiimide were then added and the mixture was stirred at 22 ° C for 16 hours. The mixture crystallized from dicyclo-35hexylurea; upon completion of crystallization, it was removed by filtration. The filtrate was washed with 200 ml of 5% aqueous sodium hydrogen carbonate solution, 200 ml of 10% phosphoric acid and 100 ml of saturated aqueous sodium sulfate solution. The organic phase was dried over sodium sulfate at 5 ° C for 30 minutes, filtered and evaporated to an oil. Diethyl ether was added and product 2 crystallized on scraping (27 g, 63% yield).

Step 2 10 o i * O - '"' 1 15 Quinoline

V

o

Br * * * ch2ci 1 I | CH3 20 hN — l X C-OCH-CCl _ 3 o II 2 3

O

Compound 2 (26.5 g, 0.062 mol) was dissolved in 500 ml of p-dioxane and 8.5 ml (0.078 mol) of benzoyl chloride and 8.75 ml (0.078 mol) of quinoline were added. The solution was boiled for four hours and then poured into 1100 ml of water and the product 3 was extracted with 2 x 400 ml of ethyl acetate. The ethyl acetate extracts were combined, washed successively with 200 ml of 5% aqueous sodium hydrogen carbonate solution, 200 ml of 5% aqueous phosphoric acid and 200 ml of saturated aqueous sodium sulfate solution, dried for for 40 minutes with sodium sulfate (oil) at 5 ° C and 35 h. , which was used as a "67553 36" follower, in the reaction.

Step 3 3 + KMnO 4 + H 2 O 2 5 in glacial acetic acid

V

10 \\ // ° £ H? C1 I "" CH3 J_N___i 1 U '' '' C-OCH-CCl., 15 ö II 2 3 0

The product 3 obtained in the previous step was dissolved in 1 L of glacial acetic acid and, with stirring at 22 ° C, a saturated aqueous solution of KMnO 4 was added dropwise until the rose-red color persisted (i.e., a drop instilled on a piece of filter paper gave a rose-colored spot). 30% H 2 O 2 was then added dropwise with cooling until the solution was clear; there was a little white precipitate in it. The solution was poured into 2.5 liters of water and the product 4 was extracted with 3 x 500 ml of ethyl acetate. The ethyl acetate extracts were washed with 5% aqueous sodium bicarbonate until neutral (i.e., no more bubbling occurred upon addition), dried over sodium sulfate and evaporated to dryness to give residue 4. It was allowed to stand at 10 ° C for one day and then triturated with "Skellysolve B" to give 9.1 g of solid compound 4. For steps 2 and 3, the total yield was 28% of theory.

67553 37

Lie 4 5 i. + (X) Zn in acetic acid

+ (T) KEH

10 V

O. / P

_Jsl / H2C1

I p j / '-' CH3 1 (BL-P2013I

) / - n — 4.

15 o '"cook (See U.S. Patent 4,164,497) 20

Zinc dust (3.75 g) was slurried in 5 ml of glacial acetic acid and cooled to 5 ° C. To this mixture was added a solution of compound 4 (3 g, 0.0057 mol) in 15 ml of dimethylformamide, and the resulting slurry was stirred at 25 ° C for 2.5 hours.

The zinc was then filtered off and the pale yellow solution was poured into 80 ml of 5% aqueous hydrochloric acid, and the mixture was extracted with 3 x 25 ml of ethyl acetate. The combined ethyl acetate extracts were extracted 3 x 20 with 30 mL of 5% aqueous sodium bicarbonate, saving the ethyl acetate phase after separation.

The bicarbonate extracts were combined, drained under a pad of ethyl acetate, adjusted to pH 1.5 with 2N HCl and saturated with sodium sulfate.

The ethyl acetate portion was separated and the aqueous phase was extracted with 2 x 30 mL of ethyl acetate.

38 67553

All the above ethyl acetate phases were combined, dried over sodium sulfate and evaporated to an oil (free of BL-P2013 acid) which was dissolved in about 20 ml of acetone, to which was then added 20 ml of diethyl ether. 50% Potassium 2-ethylhexanoate (KEH) in dry n-butanol was then added until the mixture was neutral. Product 5 (BL-P2013) crystallized apart. After stirring for 0.5 h at 22 ° C, the product was collected by filtration to give 650 10 mg of compound 5 (yield 37%).

A 50 mg portion of compound 5 was dissolved in 0.5 ml of water, and 20 mg of N, N'-dibenzylethylenediamine (DBED) diacetate was added to the solution. The DBED salt of compound 5 crystallized apart, was collected by filtration, washed with water and dried over P 2 O 4 in vacuo to give N, N'-dibenzylethylenediamine-2 β-chloromethyl-2-methyl-p-Nam-3-carboxylate salfonone (5 DBED salts of the free acid).

Another portion of compound 5 (450 mg) was dissolved in 3 mL of water, to which was added a solution of 270 mg of DBED-diacetate in 2 mL of H 2 O. Upon scraping, the DBED salt of compound 5 crystallized apart (430 mg). Recrystallization from about 5 ml of boiling acetone gave 270 mg.

Biological information

The product of Example 1, compound 5, having the structure-25 formula

Qx // 0% t> CH2Cl \ n / -N - 1

30 0 C02K

hereinafter referred to as BL-P2013.

Although BL-P2013 alone is at best a very weak antibacterial agent, it inhibits β-lactams and prevents the degradation of cephoranide and amoxicillin by β-lactamase-producing bacteria.

II

39 67553 in Virto and in vivo when used with these two substances.

table 1

Antibacterial activity of the new sulfone 5 MIC (ug / ml)

Organism Γ BL-P2013 Ampicillin] __ —.-, S. pneumoniae A-9585 16 0.004 10 s. Pyogenes A-9604 63 0.004 S. aureus A-9537> 125 0.16 S. aureus + 50% Serum A-9537 > 125 0.06 S. aureus Pen-

Res A-9606> 125> 125 S. aureus Meth-

Res A15097> 125 125 S. faecalis A20688> 125 0.13 20 e. Coli A15119> 125 1 E. coli A20341-1> 125> 125 K. pneumoniae A15130> 125 125 K. pneumoniae A20468> 125> 125 25 'P mirabilis A-9900> 125 0.13 P. vulgaris A21559> 125 125 P. morganii A15153> 125> 125 30 P. rettgeri A21203> 125 4 S. marcescens A20019> 125 16 E. cloacae A-9659> 125 63 E cloacae A-9656> 125> 125 35 p, aeruginosa A-9843A> 125> 125 P. aeruginosa A21213> 125> 125 40 r ~ 67553

Table 2

Action of cephoranide and amoxicillin against Bacteroides alone and in combination with BL-P2013 5 MIC Jug / ml) +)

Organism / lactate- Kefo- Cephoranide- EL-P Amoxicillin- Amoxy-t maasi ranidi + BL-P2013 2013 + BL-P2013 herring- (1: 1) (1: 1) B.fragilis A21916 + j 63 2> 125 2 8 A22053 + i 32 4 63 2 8 A22021 +32 2 32 _2_ 4 A21875 +32 4 63 2 8 A22534 +> 125 32 125 J6> 125, c A22697 + 63 8 63 2 8 A22693 + I 63 4 63 2 16 A22694 + 125 16 63 2 16 A22695 +> 125 _1_6_ 32 4 125 A22696 +> 125 _3_2_ 63 8> 125 2Q A22533 +> 125 _3_2_ 32 32> 125 A22535 +> 125 32 125 32> 125 A22.792 + > 125 8 32 4 125 A22793 +32 4 32 2 8 A22794 +32 4 32 2 8 25 A22795 +63 4 32 4 16 A22797 +63 4 63 2 16 A22798 +32 4 63 2 8 B.theta- iotaomicron 3Q A22277 + 125 4 63 2 16 A22279 + 125 8 63 4 16 41 6755 3

Table 2 (continued)

Effect of cefaroanide and amoxicillin against Bacteroldes alone and in combination with BL-P2013 (5 μg / ml)

Organism -lact- Kefo- Kefananide BL-P Amoxisil- Amoxisil-maase ranide + BL-P2013 2013 line line (1: 1) + BL-P2013 (1: 1) 10 ''

Bacteroid species A20934 + 32 4 32 2 8 A21959 + 63 A 32 2 16 A20929 + 63 4 32 2 16 15 A21954 + 63 16 63 2 16 A20933 + 63 B5 63 _4_ 8 A20930 + 125 8 125 4 32 A20931 + 63 4 32 2 16 A20927-1 + 0,5 1 63 0,13 0,13 20 A20935 + 2 2 125 0,13 0,13 25 -good interaction ----- marginal interaction +) Minimum contraceptive concentration (MIC ) as determined by the agar-agar dilution method using 50-fold dilutions of 24-hour cultures inoculated on a Steer 30 planter. The experimental medium contained Brucella Agar as well as 5% lacquered sheep blood and 10 micrograms / ml vitamin K.

42 67553

Table 3

Therapeutic efficacy of amoxicillin as a combination of BL-P2013 in mice infected for the experiment with a strain producing Staphylo-5 coccus aureus coc / β-lactamase.

Organism Test dose PD - .. / treatment (mg / kg) Number of organisms Amoxicillin (A) BIHP2013 (B) A + B (1: 1)

10 _amount) _IM PO_IM PO IM PO

S. aureus 5 x 10®> 800> 800> 50> 200 6.3 44 A-9606 5 x 10®> 800> 800> 50> 200 19 77 7 x 10®> 800 -> 50 9.6 - 15

Treatment schedule:

The test compound was administered 0 and 2 hours after infection.

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Claims (3)

A process for the preparation of the antibacterial 2β-chloromethyl-2α-methylpenen-3α-carboxylic acid sulfone having the formula%, _S * \ / H2Cl1 T'CH3 1 To prepare J-N-1'O COOH and its pharmaceutically acceptable salts and physiologically hydrolyzable esters, characterized in that a) a catalytic ester of formula 1 CH-Cl Br. 20 1 [C »3 I A y N V, i o co2r! wherein R is benzyl or substituted benzyl, and the hydrogenated product is oxidized, or b) an ester of the formula 0 1 ^ CH-Cl Br'T ~ 1 ^ 'A 30 o ^ C-OCH-CC1_11 2 3 o is oxidized to the ester sulfone of formula II 67553 oo ^ // Br // »^ * '/ - ^ c Λ-N" C-OCH-CCl .. 5 <J „2 3 O and the resulting ester sulfone is reacted with a metal and an acid , preferably with zinc and glacial acetic acid to give a compound of formula I or a salt thereof, and c) the compound of formula I or a salt thereof obtained by process option a) or b) is esterified, if desired, 54-67553 For use as an antibacterial agent 2 cx - methylpenam-3α -carboxylicsyrosulfon with the formula 5 0 0 _CH2d! Esters with formula 15 4s CH „C1 Brs__s 2] f '" CH3 jr— N -L 1 * K CO-R 20 0 2 1 color R är benzyl eller substituerad b enzymes and oxides with hydrated products, or b) oxides with esters of formula 25 0 _s * Γ '"' 'CK-. MY. ^ C-OCH-CCl-0 I, 2 3 30 0 to estersulfone with the formula 0 / P ^ ^ ^ H0C1 sr, \ F Ί-CH 35 1 J_N - AO 'C-OCH-CCl- Il 2 3 o 11