SU1170972A3 - Method of producins derivatives of 1,1-dioxide 6-aminoalkyl-penicillanic acid or their additive salts with p-toluenesulfoacid - Google Patents

Abstract

The title compds. I and II [ R=H; n=1; Q=benzyl, o-, m-, phydroxybenzyl, penethyl, 2-, 3-, 4-picolyl; R1=H, ester! were prepd. Thus, 108.73g benzyl-6,6-dibromo-penicillanate in 600 ml THF (-78≰C) was reacted with 83.5 ml 2.9 M-methylmagnesium in ether soln., mixed with 27 g benzyloxycarboxy amido methyl acetate in 200 ml THF for 10 min., and treated with 14.52 ml acetic acid to give 113 g benzyl-6-α-bromo-6-β-(benzyloxycarbonyl-amino methyl) penicillanate.

Description

11.01.82 - at 8 ,, - hydrogen atom,. and Rj has the indicated values, 11.06.82 — with R — methyl h 1 1170972 and B has the indicated values, 21.10.82 — with R, is a hydrogen atom or methyl, and R is methylene.

I

The invention relates to a process for the preparation of new derivatives of 1,1-dioxide 6-aminoalkylpenicillan. acids or their salts with p-toluenesulfonic acid, which have the properties of inhibitor / s-lactamase and can be used in combination with the known (s) lactam antibiotics to enhance the effectiveness of their action.

The purpose of the invention is to obtain new compounds that enhance the efficacy of β-lactam antibiotics.

Unless otherwise specified, the PMR spectra are recorded at 60 MHz.

Example 1. Benzyl-6-o-bromo-6- / z- (benzyloxycarbonylaminomethyl) penicillanate and 6- / 5-bromo-6-o (- (benzyloxycarbonylaminomethyl) -penicillanate.

To a solution of benzyl-6,6-dibromopenicillanate (108.73 g 0.242 mol) in 600 ml of tetrahydrofuran (THF), cooled to -78 ° C, is added an ether solution of methylmagnesium bromide (83.5 ml, 2.9 M). After stirring for 15 minutes at -78 ° C, a solution of benzyloxycarboxamidomethyl acetate (27 g, 0.121 mol) in 200 ml of dry THF is added over 10 minutes. After stirring for an hour, the reaction is quenched by adding 14.52 ml of acetic acid. The resulting mixture is allowed to warm to room temperature and the volatile portion is removed under vacuum at a temperature below. Ethyl acetate was added to dissolve the residue, the resulting solution was washed with water (100 ml), an aqueous solution of CaNOS3 (100 ml) and 2400 ml of water, then dried over Na-SQj and concentrated in vacuo to obtain 113 g of an oily product. The oil is chromatographed on a column with 1.2 kg of silica gel, zlyuiruyu her first with 6 liters of a mixture of 1: 1 hexane: chloroform, and then chloroform. The first 6 l of the eluate is drained. The eluate is then collected in 25 ml portions. Fractions 181-190 concentrate. PMR spectrum

the residue in CDCl2 corresponds to benzyl-L1C1 bromo-6-y9- (benzyloxycarbonylaminomethyl) penicillanate: cA / TMS: 1.37 (ZN, s), 1.57 (ZN, s), 3.86 (2H, d., Hz ), 4.42 (1H, s),

5.06 (2H, s), 5.12 (2H, s), 5.52 (1H, s), 7.25 (UN, s). Fractions No. 201-249 concentrate.

The spectrum of this residue in CDCl corresponds to (:- (benzyloxycarbonylaminomethyl) penicillanate: (H / TMS: 1.36 (GH, s), 1.60 (GH, s), 3.90 (32H, d, 2 Hz) , 4.47 (1H, s), 5.07 (2H, s), 5.14 (2H, s), 5.40 (1H, t, J 6.2), 5.47 (1H, s) , 7.28

(5H, s), 7.30 (5H, s).

The products of fractions 171-240 are combined and concentrated to obtain 22 g of foam, which is used in Example 2.

Example 2. Benzyl-6- - (benzshloxycarbonylaminomethyl) penicillanate.

To a solution of the product (mixture of zpimers) of the previous example (22 g,

0.0413 mol) in 100 ml of benzene, tri-n-butyl tin hydride (32.7 ml, 0.124 mol) was added. The resulting mixture was heated under reflux in a nitrogen atmosphere for 2 hours, concentrated in vacuo to an oil, which was triturated with 4x100 ml of hexane. The resulting viscous oil is transferred to 70 ml of ether, from which the indicated product crystallizes within an hour (8.1 g in two portions).

PMR spectrum (CDCl5) (/ TMC: 1.37 (ZN, s), 1.57 (ZN, s), 3.58 (ZN, m), 4.34 (1H, s), 5.04 (2H , s), 5.12 (2H, s), 5.33 (1H, d, Hz), 7.32

(YUN, s).

Example 3. Benzylb- - (benzyloxycarbonylaminomethyl) penicillanate and 1-UZ-oxydg-benzyl-6 - (benzyloxycarbonylmethyl) penicillanate l-rf-Oxide. To a solution of the product of the previous example (A, 54 g, 0.01 mol) in 70 ml of ethylacetate was added m-chloroperbenzoic acid (2.02 g, 0.01 mol) in 30 ml of ethyl acetate. The resulting mixture is stirred for 30 minutes at room temperature, washed with 1x50 ml of saturated NaHCOj and 2) with 50 ml of HjO, dried over and concentrated in vacuo to a viscous oil. The oil is dissolved in 50 ml of ether and 10 ml, and as a result of ei-oxide crystallization caused by scraping, 2.2 g of product are obtained with a mp. 123124 C. PMR (CDClp c / / TMS: 1.22 (ZN, s), 1.51 (ZN, s), 3.7 (ZN, m), 4.34 (1H, s), 4.63 (1H, d, Hz), 5.11 (2H, s), 5.22 (2H, s), 5.50 (IH, m) 7.34 (5H, s), 7.40 (5H, s). Concentration of the mother liquor to dryness in vacuum yields the indicated y, α-oxide in the form of a petroleum oil (2.5 g). IIMP (CDC1,) "l / TMS: 1.05 (3N, s), 1.60 (3N, s), 3.8 (3N, m), 4.63 (1H, s), 4.73 (1H, d, Hz), 5.13 (2H, s), 5.23 (2H, KB), 5.70 (1H, m) 7.35 (5H, s), 7.39 (5H, s). Example 4, 1- | 9-Oxide-banzyl6-o (- (benzyloxycarbonylaminomethyl) penicillanate. To the specified - To the oxide of the previous example (2.3 g, 9 mmol), 1,5-diazabicyclo 4.3 non-5-ene (DBN, 0.607 g, 4.9 mmol) was added to 100 ml of CHCPj. the mixture is stirred at room temperature for 15 minutes, diluted with 50 ml of 1N HC and the aqueous layer is extracted. The organic layer is washed with 2x50 ml of H ,, 0, dried on anhydrous Na2SO4 and concentrated in vacuo to give an oil 2.3 The oil is chromatographed on a column of silica gel (100 g), eluting with a 4: 1 mixture of CHC, ethyl acetate per fraction of 20 ml. Fractions 41-70 are combined and concentrated to give the product as a viscous oil (0.9 g). PMR (SVS1z) / TMS: 1.03 (ZN, s), 1.60 (ZN, s), 3.67 (ZN, m), 4.46 (1H, s), 4.88 (1H, m ), 5.08 (2H, s), 5.17 (2H, KB), 5.39 (1H, m), 7.32 (5H, s), 7.37 (5H, s). Example 5. 1,1-Dioxide-benzyl-6- (benziloxycarbonylaminomethyl) -penicillanate. To a solution of the product of Example 2 (8.0 g, 0.0766 mol) in 200 ml of ethyl acetate cooled to m-chloroperbenzoic acid (10.68 g, 0.0528 mol) is added. The resulting mixture is warmed to room temperature, stirred for 6 hours, cooled again to 0-5 ° C and diluted with 50 ml of saturated NaHSO. The organic layer was washed with 2 50 ml of saturated NaHCOj and ml of HjO, dried over and concentrated in vacuo to a viscous oil (8.6 g). The oil is chromatographed on 250 g of silica gel, eluting with a 19: 1 CHCfj mixture of ethyl acetate into 25 mp fractions. Fractions 44-150 are combined and concentrated in vacuo to yield the product as a white greous foam (7.6 g). PMR (SOSG) сЛ / (ТМС: 1.25 (ЗН, s), 1.49 (ЗН, с), 3.98 (ЗН, m), 4.45 (1Н, s), 4.59 (1Н , d, Hz), 5.09 (2H, s), 5.19 (2H, KB), 5.36 (1H, shir), 7.36 (YN, s). Example 6. 1.1-Dioxide benzyl6-o - (benzyloxycarbanilaminomethyl) penicillanate. In Example 4, the dioxide of the previous example (3.3 g, 6.79 mmol) is converted into the indicated product (3.1 g, crude) and purified on a chromatographic column on 150 g of silica gel, eluting its 1: 9 mixture of ethyl acetate: CHCf3 into fractions of 20 ml. Fractions 26-37 are combined and concentrated in vacuo to give a purified product as a viscous oil, which crystallizes on standing (1, 9 g, mp. 112-113s). PMR (CDCl,) (/ - / TMS: 1.20 (ZN, s), 1.49 (ZN, s), 3.65 (ZN, m), 4.32 (1H, s), 4.59 (1H, m), 5.07 (2H, s), 5.14 (2H, KB), 5.30 (1H, broad), 7.32 (YUN c). The indicated product can also be obtained by further oxidation of the product of example 4 with an excess of m-chloroperbenzoic acid according to example 5. Example 7. 1,1-Dioxide 6- / J (aminomethyl) penicillanic acid. Product of example 5 (1, 9 g), T1F (40 ml), (40 ml) and 10% Pd / C (1.9 g) are combined and hydrirun T at 50 psi (3.5 kg / cm) for 1 hour.

The catalyst was removed by filtration, and THF was removed from the filtrate in vacuo. The aqueous layer was washed with 30 ml of ethyl acetate, freeze dried to obtain a white powder, and the first portion of crystals (0.26 g) was obtained by thoroughly rubbing the powder with 5 mp water. A second batch (0.14 g) is obtained by adding 10 ml of acetone to the mother liquor, and a third (0.35 g) by evaporating the second mother liquor to 2 ml and adding 50 ml of acetone. Total yield of 0.75 g.

PMR (250 MHz, VgO) SL / DSS: 1.47 (ZN, s), 1.59 (ZN, s), 3.74 (2H, m), 4.36 (1H, td, 55 Hz) , 4.45 (1H, s), 5.17 (1H, d, Hz),

Example 8. 1,1-Dioxide (aminomethyl) -penicillanic acid. o In Example 7, the product indicated in Example 6 (1.7 g) was converted to the product indicated in this example, the crystalline product was obtained directly by concentration in vacuo, followed by extraction with ethyl acetate (0.7 g).

PMR (250 MHz,) / D1SS: 1.44 (ZN, s), 1.59 (ZN, s), 3.63, (2H, d, 5 Hz), 4.07. (1H, td, : i 2.5.5 Hz), 4.31 (1H., s), 5.06 (1H, d,).

Example 9. Benzyl-6-β-bromo-6- trifluoromethanesulfo-yloxymethyl penicillanate

To a solution of trifluoromethanesulfonic anhydride (3.15 ml) in methylene chloride (20 ml), a solution of benzyl-6; 3-bromo-6- - (hydroxymethyl) penicillanate (6.232 g, 15.6 mmol) and pyridine (1 , 89 ml) in methylene chloride (20 ml), the mixture is stirred and cooled in an ice bath for 45 minutes. The methylene chloride is evaporated under reduced pressure and the residue is partitioned between ethyl acetate and water. doi The ethyl acetate phase is separated into the aqueous phase and extracted with an additional portion of ethyl acetate. The combined ethyl acetate solutions are washed first with sodium bicarbonate solution at pH 8.3 and then with brine. After drying over anhydrous sodium sulfate, the solution was extruded under reduced pressure to give the product as an orange solid (8.296 g).

PMR (CDCl1) G / TMS: 1.41 (s, ZN), 1.63 (s, ZN), 4.51 (s, 1H), 4.87 (s, 2H), 5.14 (s, 2H), 5.44 (s, 1H), 7.30 (s, 5H).

Example 10. Benzyl-6- / -azidomethyl-6-bromopenicillanate.

Tetramethylguanidinium azide (2.96 g, 18.7 mmol) is added to a solution of benzyl-6-bromo-6- / -trifluoromethylsulfonyloxymethyl penicillanate (8.296 g, 15.6 mmol) in chloroform (50 ml) at 10 ° C. The reaction mixture stirred for one hour, then 5 reduced to one third and filtered through a layer of silica gel. This layer was eluted with 10% ethyl acetate / chloroform (100 ml) and the resulting eluate was evaporated to give 0 amber oil (6.744 g).

PMR (CDCl) SL / TMS: 1.38, (s, 3N),

1.61 (s, .ЗН), 3.96 (s, 2H), 4.53

(s, 1H), 5.17 (s, 2H), 5.40 (s, 1H),

7.34 (s, 5H).

Example 11, Benzyl 6-o-bromo-6-β-trifluoromethanesulfonyloxymethyl penicillanate.

In accordance with the procedure of Example 9, benzyl-6-o / -bromo-6-oxymethyl penicillanate (0.584 g,

1.4 mmol) in methylene chloride. (4 ml) containing pyridine (0.17 ml), reacted with a solution of trifluoromethanesulfonic anhydride (0.42 ml) in 3 ml of methylene chloride to obtain the product as an amber oil (641 mg).

PMR (CDCl1) (L / TMS: 1.43 (s, NN),

1.62 (s, 3N), 4.52 (s, 1H), 4.88 (sq. 2H), 5.19 (s, 1H), 5.62 (s, 1H),

7.35 (s, 5H).

Example 12. Benzyl-6-o / -bromo-6 - /} - azidomethylpenicillat ..

To a solution of benzyl-6-o-bromo-6- / 3 trifluoromethanesulfonyloxymethyl penicillanate (641 mg, 1.2 mmol) in 10 ml of chloroform was added tetramethylguanidinium azide (229 mg of 1.2 mmol) at. The reaction mixture is stirred under reduced pressure. The oily residue is filtered through a pad of silica gel and eluted from it with a mixture of 10% ethyl acetate / chloroform. After evaporation of the eluate, the product is obtained as an amber oil (420 mg).

MPR (CDClj) o / TMS: 1.43 (s, ZN), 1.61 (s, ZN), 3.91 (s, 2H), 4.48

(s, Ai, 5.15 (s, 1H), 5.57 (s, 1H), 7.37 (s, 5H).

Example 13. Benzyl-6-1o - (ami styen) -6-y-bromopenicillanate.

Hydrogen sulfide is bubbled into a rapidly stirred solution of benzyl-6-o-azidomethyl-6-β-bromopeiacyllanate (54.1 mg, 1.3 mmol) and triethylamine (0.71 ml, D eq) in chloroform (10 ml for 1 h). Then the reaction mixture is evaporated in vacuo to a red oil. NMR data shows that the residue contains the desired product with an admixture of triethylamine.

PNR (CDC1,) SL / TMS: 1.39 (s, ZN), 1.64 (s, ZN), 3.35 (s, 2H), 4.51 (s, 1H), 5.16 (s , 2H), 5.35 (s, 1H), 7.33 (s, 5H).

Example 14. Benznp-6-z-bromo-6-o-benzyloxycarbonylaminomethyl penicillanate.

A solution of pyridine (0.14 ml) and ben, zyl-6-o-aminomethyl-6- / 5-bromopenicillanate (239 mg, 0.6 mmol) in methylene {chloride (5 mp) is added via syringe over 5 minutes to a solution of benzyl chloroformate in methylene chloride (5 ml) and the reaction mixture is stirred on an ice bath in a nitrogen atmosphere for 75 minutes. The reaction mixture is evaporated in vacuo, the residue is placed in a mixture of ethyl acetate / water. The pH was adjusted to 2.9 with dilute hydrochloric acid, the ethyl acetate phase was isolated and extracted with dilute sodium bicarbonate solution (pH 8.1), washed with brine and sugate over anhydrous sodium sulfate. After evaporation under reduced pressure, 312 mg is obtained, which is placed in chloroform and chromatographed on a silica gel column (15 g, 14x20 cm column), and then eluted from it with a mixture of 5% ethyl acetate / chloroform. Collect fractions of 4 ml. Fractions 1427 were combined and evaporated under reduced pressure to obtain the product (168 mg).

The DEM (CDCl), SL / TMS corresponds to the indicated product and is identical to the spectrum of the compound obtained in Example 1.

Example 15. Benzsh1-6- / z- (benzyloxycarbonylaminomethyl) penicillanate.

A solution of three (n-butyl) tinhydride (0.25 ml) and benzyl-6- / 1-bromo-6oi- (benzyloxycarbonnelah labeled) pe, nicillanate (168 mg, 0.31 mmol) in j-benzene (4 ml) kip t t with. reflux for 2 hours. Then the benzene is evaporated in vacuo and the residue is triturated with hexane (ml), the residue is placed and the mixture is ethyl acetate / water, the ethyl acetate phase is separated, washed with brine and dried with anhydrous sodium sulfate. After evaporation in vacuo, 101 mg of an oil is obtained, which is chromatographed on a column of silica gel (4 g, see column), adjusted with chloroform and eluted with a mixture of 5% ethyl acetate / chloroform. Fractions of 4 ml are collected. Fractions 3-5 are combined and evaporated to yield the indicated product (66 mg, PMR spectrum is identical to the spectrum of the product of example 2).

Example 16. Benzyl-6-o (benzyloxycarbonylaminomethyl) penicillanate and benzyl-6- (benzyloxycarbonylaminomethyl) penicillanate.

Benzyl-6-c-iodopenicillanate is dissolved in 75 ml of dry tetrahydrofuran and cooled to -78 ° C under a dry nitrogen atmosphere. Methyl magnesium bromide (5.6 ml of ZM in ether) is added dropwise. After stirring for an additional 15 minutes, benzyloxycarbonylaminomethyl acetate (1.87 g) in 25 m tetrahydrofuran is added at a time. After another 15 minutes of stirring at -78 ° C, acetic acid (2 ml) was added, the mixture was heated to 0 ° C and evaporated in vacuo. The residue is partitioned between 250 ml of ethyl acetate and 50 ml of water. The organic layer is taken up, rinsed with 1 ml of saturated NaHCOj and brine, dried over. and evaporated in vacuo to an oil (7.3 g). The oil is chromatographed on 250 g of silica gel, eluting with a 1:10 mixture of ethyl acetate: chloroform in 20 ml fractions. Fractions 20-24 contain 1.3 g of a by-product (oil), fractions 25-34 contain 0.62 g of a mixture of these products according to 1SR . Fractions 35-60 contain 2.2 g of a mixture of 3: 1 mixture of the indicated products.

Example 17 “Benzyl-bs-broMo-6- / i- (1K-tri-fluoromethanesulfon-1-coxistil) penicillanate. Benzyl-6-oC-bromo-6- (3- (Sh-hydroxyethyl) -peiicillanate (20.28 g, 0.0489 mol) is dissolved in 400 ml of CHjCl and cooled in an acetone-ice bath. Pyridine (7, 91 ml, 2 eq.), And then trifluoromethanesulfonic anhydride (11.58 ml, 1.4 eq.) Dropwise maintaining the temperature of ± 5 ° C. The resulting mixture was stirred at 0 ° C for 30 minutes, diluted. washed successively with saturated NaHCO, NdO and saturated NaCl, evaporated in vacuo and diluted with 1: 1 hexane, causing crystallization of the indicated product 18.71 g. NDP (CDClj) cA / TMS: 1.42 (ЗН, s), 1.55 (ZN, d, Hz), 1.66 (ZN, s), 4.58 (1H, s), 5.20 (2H, s), 5.34 (1H, KB, Hz), 5.56 ( 1H, c), 7.38 (5H, s). Example 18. Benzyl-6-C-bro-6- / J- (1 S-azidoethyl) penicillanate. The product described in the previous example (34.4 g, 0.0628 mol) was dissolved in 400 ml of CHgCKj. Tetrabutylammonium azide (25.0 g, 1.4 eq.) In 100 ml is added dropwise and the mixture is stirred for one hour at. Stripped in vacuum, and the residual oil is filtered through 500 g of silica gel on a sintered glass funnel, eluting with 2 L of CH J Clj. After evaporation, the product is obtained in the form of a pale yellow oil, 27 g, PMR (CDClj) (/ - / TMS: 1.40 (ЗН, s), 1.53 (ЗН, д, 3 Hz), 1.57 (ZN, 4.10 (1H, KB,, 3), 4.47 (1H, s) 5.19 (2H, s), 5.61 (1H, s), 7.34 (5H, s). Example 19 Benzyl 6- (5- (13-amino-ethyl) -6-o (-bromopenicillanate. The product indicated in the previous example (27.0 g, 0.0613 mol) was dissolved in 300 ml of CHSS). Triethylamine ( 35 ml, 4 eq), and then HS is bubbled through the reaction mixture for 3.5 hours. The reaction mixture is flushed with nitrogen for half an hour and the vacuum is evaporated in CHS. The residue is obtained, the oil is partitioned between ether and 1N HC (200 ml Ether The fresh layer is extracted with ml of fresh 1N NSK. The combined aqueous layers are diluted with ethyl acetate and the pH of the two-phase system is adjusted to 8.5. The organic layer is concentrated and extracted to obtain the product as an oil (6.34 g). The organic ether layer is diluted with leaves and The pH is adjusted to 8.5. The ether layer is isolated and evaporated to obtain an additional amount of product, 6.0 g. PMR (CST) / TMS: 1.28 (G, d, 3 Hz), 1.40 (G, с), 1.58 (ЗН, с), 3.34 (1Н, KB, 3 Hz), 4.45 (1H, s), 5.16 (2H, s), 5.54 (1H, s ), 7.33 (5H, s). Example 20. Benzyl-6-UZ- (15benznloxycarbonylaminoethyl) -6-oi bromopenicillanate. The benzyl chloroformate (5.10 ml, 1.2 eq.) Is dissolved in 20 ml in an acetone-ice bath. A solution of the product indicated in the previous example (12.34 g, 0.02980 mol) in 50 ml of CHjCPj containing diisopropylethylamine (7.78 ml, 1.5 eq.) Is added dropwise, maintaining the temperature 0-5 ° C with ice water baths. The reaction mixture is stirred for 20 minutes, stripped in vacuo, diluted with ethyl acetate and water (the pH is maintained at 8.2) and the pH is adjusted to 2.0 with diluted HC. The organic layer is separated, washed and then with saturated NaC and evaporated to give the product as a pale yellow oil. 17 g. PMR (CDClI) (L / TMS: 1.35 (G), 1.38 (G, d ), 1.55 (3N, s), 4.26 (1H, m), 4.45 (1H, s), 4.97 (1H, d), 5.08 (1H, s), 5 , 14 (2H, s), 5.53 (1H, s), 7.33 (YUN, s). Example 21. Benzyl 6- / 9- (18 benzyloxycarbonylaminoethyl) penicillanate. Target product of example 20 (16.33 g , 0.0298 mol) is dissolved in 200 ml of benzene. Three-n-butyl-tin hydride (23.5 ml, 3 eq.) Is added and the mixture is refluxed for 3 hours. The benzene is removed in vacuum, the product is crystallized from the residue, ext ow hexane 9.26 g. PMR (CDClj) (L / TMS: 1.39 (ZN, d, Hz), 1.40 (ZN, s), 1.63 (ZN, s), 3.62 (1H , dd, 11 Hz), 4.12 (1H, m), 4.39 (1H, s), 4.81 (1H, d, Hz), 5.08 (2H, s), 5, 17 (2H, s), 5.32 (1H, d, Hz), 7.32 (5H, s), 7.36 (5H, s).

Example 22. 1,1-Dioxide-benzyl-6- / e- (1 S-benzyloxycarbonylaminoethyl) -penicillanate.

In Example 5, the product of the previous example (4.0. G, 0.0085 mol) was converted to the indicated product, 4.25 g was isolated as a white foam.

PMR (SOS1) (G / TMS: 1.21 (ZN, s), 1.33 (ZN, d, Hz), 1.48 (ZN, s), 4.20 (1H, m), 4.35 (1H, m), 4.40 (1H, s), 4.53 (W, d, 5 Hz), 5.08 (2H, s), 5.17 (2H, q), 5.45 ( 1H, d, Hz), 7.30 (5H, s), 7.35 (6H, s).

Example 23. 1,1-Dioxide 6- / 3 (18-aminoethyl) penicillanic acid.

Using 180 mg of 5% Pd / C as a catalyst, the compound of the previous example (175 mg) was converted to the indicated product by the method of Example 7. After removing the catalyst, the combined mother liquor and washing with tetrahydrofuran / H, O were evaporated with tetrahydrofuran in vacuo, the product was dried by freezing water overnight.

IR spectrum (KVg): 1765 cm

 PMR (TO) L / DDS: 1.47 (ZN, s), 1.53 (ZN, d), 1.60 (ZN, s), 4.35 (2H, m), 4.37 (1H, c), 5.12 (1H, d, J Hz).

Example 24. Benzyl-1,1-dioxide 1 - (1- (15-benzyloxycarbonylaminoethyl) penicillanate.

The product indicated in Example 22 (4.25 g, 0.0085 mol) was dissolved in 100 ml (0.96 ml, 1 eq.) Added dropwise, the mixture was stirred for 3 minutes at, then quenched, added to 1 ml (2 eq. of glacial acetic acid. The quenched mixture is diluted with CH2Ct2, evaporated (t sequentially HC (pH 2.5), water and saturated NaCl solution and evaporated in vacuo to give the crude compound as a white foam, 4, 5 g. After chromatography on a silica gel column using a 9: 1 mixture: ethyl acetate as the eluent, the purified product is obtained as a white foam, 2.83 g.

PMR (CDClI) // TMS: 1.21 (ZN, s), 1.33 (ZN, D, Hz), 1.51 (ZN, s), 3.78 (1H, dv, d, 4 Hz) 4.27

(1H, m), 4.36 (1H, s), 4.56 (1H, d Hz), 5.09 (2H, s), 5.16 (2H, q) 7.3 (1CH, s) .

Example 25o 1,1-Dioxide (1S-aminoethyl) penicenzanoic acid

5% Pd / C (4.5 g) are suspended in 50 ml and pre-hydrogenated for 1.5 hours at 25, 50 psi (3.5 kg / cm). The product indicated in the previous example (2.83 g) was dissolved in 50 ml of ethyl acetate, added to a pre-hydrogenated aqueous suspension of the catalyst and hydrogenated at 25 °, 5b psi (3.5 kg / cm) for 0.5 h. The catalyst is isolated by filtration. The aqueous layer was isolated. The product is crystallized in three portions (total weight 1.1 g) as the aqueous layer is concentrated.

PMR () o / DDS: 1.47 (ZN, s), 1.52 (ZN, d), 1.62 (ZN, s), 4.05 (2H, m), 4.28 (1H, s ), 5.10 (1H, d).

IR (KBG): 1787 cm

Example 26. Benzyl-6- -bromo-6-o1 - (1-trifluoromethylsulfonyloxyethyl) -penicillanate.

In example 17, benzyl-6- / 3-bromo-6- (1-hydroxymethyl) penicillanate / mixture of epimers on the side chain (8.9 g, 0.0214 mol) is converted to the compound indicated in the title. When adding a 1: 1 mixture of hexane: ether, the first portion (4.7 g) crystallizes, which is mainly the 1R side chain epimer. If desired, this epimer is treated in Examples 25-30 until the product specified in Example 3.2 is obtained. The second portion of the solid product (2.40 g) and the third portion (1.60 g) are a mixture of the side chain epimers indicated in the title of the product, preferably the side chain epimer IS.

PMR (CDCl) sL / TMS: 1.41 (ZN, s), 1.65 (ZN, s), 1.78 (ZN, d, 5 Hz) 4.56 (1H, s), 5.22 (2H, s), 5.37 (1H, q, 5 Hz), 5.48 (1H, s), 7.4 (5H, s).

Example 27. Benzyl-6-o / - (1azIdoetch1) -6- (y-bromopenicillanate.

The second and third portions (mainly IS epimer of the side chain) of the product indicated in the previous example (4.0 g, 0.0073 mol) are converted into the product indicated in the title of this example h (mostly 1C epimer of the side chain) as in the example 18. The product is isolated as a pale yellow oil, 2.91 g.

PMR (CDCl1) (L / TMS: 1.40 (3N, s), 1.56 (3N, d, 5 Hz), 4.00 (1H,

B, 5 Hz), 4.48 (1H, s), 5.16 (2H, s), 5.34 (1H, s), 7.32 (5H, s).

PREMIER 28. Benzyl-6-o6- (1Kminoethyl) -6- / E-bromopenicillanate and enzyl-6-1 (- (18-amino-ethyl) -6-beta-5 bromopenicillanate,

The product of the previous example (mainly 1R side chain epimer, 9-1 g, 0.0066 mol) is converted to the product indicated in example 19, After removal of CHCfj, which is used as a reaction solvent, the line is distributed between ether and 1N . ECt (200 ml). The ether layer was extracted and extracted with ml of 1N. 5 carried The combined aqueous layers were diluted with etipacetate and the pH was adjusted to 8.5. The aqueous layer was isolated and extracted with fresh etilacetate. The ethyl acetate layers were combined and evaporated to obtain a mixture of products (mainly 1 R, isomer) as an oil, 1.53 g. The isomers were separated on a chromatographic column on 200 g of silica gel, eluting with a 25 1: 1 mixture of CHjCfj: ethyl acetate, control of those (3: 2: ethlo1acetate). The pure high mobility fractions (RP 0.52) are combined and evaporated to give the 1S isomer (0.172 g), 30 which is converted, if desired, in Examples 20-23 into the product specified in Example 25. The middle fractions give a mixture of the products indicated in titles (0.45 g), which, if desired, 35 are rechromatographed to obtain an additional amount of pure products. Pure, less mobile fractions (RJ 0.47) are combined to give the side chain epimer 40 1R, 0.674 g

PMR (CDClj) A / TMS: 1.29 (ZN, d, Hz), 1.38 (ZN, s), 1.64 (ZN, s), 3.29 (1H, KB Hz), 4.51 (1H, s), 5.17 (2H, s), 5.38 (1H, s), 45 7.33 (5H, s).

Example 29. Benzsh1-6-bromo-6-X (1R-benzyloxycarbonylamino3TH) i) -penicillanate.

In example 20, the product indicated 50 in the preceding example 1R side chain (0.674 g, 0.0016 mol) is converted into the product indicated in the title of this example, 0.877 g

P 0.85 (1: 1 CH Ct ethyl acetate). 55 Example 30. Benzsh1-6- / z- (1Kbenzyloxycarbrynyl-aminoethyl) penicillanate.

In example 21, the product specified in the previous example (0.877 g, 0.0016 mol) is converted into the product indicated in the given title. After evaporation with benzene as a solvent, the residue was triturated with MP with hexane to give the crude product as an oil (627 mg). The oil is chromatographed on silica gel, eluting with 19: 1 chloroform: ethyl acetate to obtain a purified product of 569 mg.

PMR (CDCl1) (L / TMS: 1.10 (3N, d, 5 Hz), 1.36 (3N, s), 1.60 (3N, s), 3.41 (1H, dv, d, , 11 Hz), 4.16 (1H, m), 4.43 (1H, s), 5.08 (2H, s), 5.13 (2H, s), 5.32 (1H, d, Hz ), 7.29 (5H, s), 7.33 (5H, s)

Example 31 1,1-Dioxide of benzyl-6 - /} - t (1H-benzyloxycarbonylamino-, ethyl) -penicillanate.

In example 5, the product specified in the previous example (0.569 g, 0.0012 mol) is converted into the product indicated in the title of this example, 0.681 g.

PMR (CDCl,) (L / TMS: 1.22 (ZN, s), 1.27 (ZN, d), 1.47 (ZN, s), 3.94 (1H, dd, 12 Hz ), 4.42 (1H, s) 4.48 (2H, m), 5.04 (2H, s), 5.13 (2H, KB), 5.40 (1H, d), 7.27 ( 5H, c), 7.32 (5H, s).

Example 32 1,1- Dioxide 6- / 5 (1R-aminoethyl) penicillanic acid.

Using 400 mg of 5% Pd / C, the product indicated in the previous example (202 mg) is converted into the product indicated in the title of this example, 50 mg, IR (KBG) 1788 cm

PMR (DGO) / DCC: 1.45 (ZN, s), 1.51 (ZN, d), 1.57 (ZN, s), 4.27 (1H, m), 4.33 (1H, s ), 4.85 (1H, m),

5.15 (1H, d, Hz).

Example 33. 1-Dioxide of benzyl-6-o- (1B-benzyloxycarbonylaminoethyl) -penicillanate.

In example 24, using a mixture of 19: 1 CHCBj: ethyl acetate as eluent during chromatography, the product indicated in example 40 (368 g) is converted to the product indicated in the title of this example, 285 mg.

PMR (CDClj) g / TMS: 1.23 (ZN, s), 1.33 (ZN, d, 5 Hz), 1.50 (ZN, s), 3.61 (1H, dd, 9 Hz), 4.28 (1H, m), 4.34 (1H, s), 4.67 (1H, d, Hz), 4.98 (1H, d), 5.07 (2H, s) , 5.18 (2H, KB), 7.30 (5H, s), 7.35 (5H, s). Example 34, 1, 1-Dioxide-6- (1P-aminoethyl) penicillanic acid. In example 32, the product specified in the previous example (285 m is converted into the product specified in the title of this example (132 mg), IR (KBG) 1768 cm. PMR (D20). Л / ТМС: 1.47 (ЗН, с ), 1.54 (ZN, d), 1.61 (ZN, s), 4.03 (2H, m), 4.44 (1H, s), 5.10 (1H, d Example 35. 1.1- Dioxide 6 (benzyloxycarbonylaminomethyl) chillanic acid. Method A. The product indicated in example 6 (11.2 g) in 70 ml THF and 50 ml HjO in the presence of 6 g 10% Pd / C was partially hydrogenated at 50 psi (3.5 kg / cm) for 30 minutes. The catalyst is removed by filtering on the cake of diatomaceous earth with THF from the filtrate into the vacuum and the aqueous residue trap 100 of ethyl acetate. The organic layer is separated, dried (NajSO) and evaporated to obtain the product as a foam, 3.0 g. PMR (CO1) | / TMS: 1.40 (G, s), 1.55 (G, s ), 3.70 (3N, m), 4.31 (1H, s), 4.58 (1H, m), 5.04 (2H, s, 7.24 (5H, s). The aqueous layer is concentrated to crystalline 1,1-dioxide (aminomethyl) penicillan acid, 3.1 g, the PMR spectrum is completely identical to the spectrum of the fully hydrogenated product of example 8. Method B. The product indicated in example 8 (3.0 g, 11.45 mol), dissolved in 100 ml of a 1: 1 mixture of H20: methanol. The pH is adjusted and maintained at 8.3-8.7 as chloroformate (1.79 g, 12.59 mol) is added dropwise within a few minutes. After a brief stirring, the pH is adjusted to 6.0 with 1N. HC and THF are removed by distillation in vacuo. The aqueous residue is extracted with 30 ml of ethyl acetate and the extracts are drained. Fresh ethyl acetate (50 ml) was added, the pH was adjusted to 1.8 with 1N. HC, suitable layers are extracted with 50 ml of fresh acetate. The combined organic layer and the extract are washed with 1 to 50 ml of saturated NaCl, dried (Na-2SO) 4 is evaporated in vacuo to yield 7216 product as a foam, 3.7 g, the PMR product is completely identical to the PMR spectrum of the product obtained according to method A. Example 36. 1,1-Dioxide of pivaloyloxymethyl-6-o - (benzyloxycarbonylaminomethyl) penicillanate. The product indicated in the previous example (6.75 g, 17 mmol), and N, N diisopropylamine (3.34 ml, 18.7 mmol) was dissolved in dimethylformamide (50 ml), chloromethyl pivalate (2.72 ml, 18.7 mmol), the resulting mixture is left under stirring at room temperature for 20 hours. The reaction mixture is diluted with ethyl ether (300 ml), washed with water (MP), dried (Na2SO) H, evaporated in vacuo to an oil. The oil is dissolved in 100 MP ether, washed with 3x50 ml, dried () and concentrated in vacuo to give a purified product as a viscous oil, 4.4 g. PMR (CDCl,) TMS: 1.20 (9H, s), 1.34 (ZN, s), 1.51 (ZN, s), 3.64 (ZN, m), 4.31 (1H, s), 4.60 (1H, d), 5.04 (2H , c), 5.71 (2H, q), 7.24 (5H, s). Example 37. P-Toluenesulfonate salt of .1,1-pivaloyloxymethyl-b-tz Chaminomethyl-penicillanate dioxide. The product mentioned in the previous example (1.8 g, 3, -53 mmol) is hydrogenated in a mixture of 40 ml of THF and 20 ml per 1.8 g of 10% Pd / C in the presence of pyridine p-toluenesulfonate (1.77 g, 7.06 mmol) at a pressure of 50 psi (3.5 kg / cm) for 1.5 hours. The catalyst is removed by filtration on diatomaceous earth, the filtrate is stripped with THF under vacuum, during which time the product crystallizes. 1.2 g, m.p. 214-215 C (with decomposition). PMR (DMSO-d) TMS: 1.16 (9H, s), 1.32 (ZN, s), 1.48 (ZN, s), 2.28 (ZN, s), 3.34 (2H, m), 3.82 (1H, m), 4.60 (1H, s), 5.14 (1H, d, Hz), 5.75 (2H, AV kV), 7.23 (4H, AV k ). Elemental analysis for C H Calculated: C 48.16; L1 5.88; N 5.11. Found: C 48.3i; H 6.1i; N 5.08. Example 38. Chloromethyl-6d- (2-azido-2-phenylacetamido) .1 Phenylanate.

J7

A solution of 12.0 g (0.03 mol) of sodium salt (2-azido-2-fench1 acet amido) penicillanic acid, 25 ml of water is combined with 100 ml of methylene chloride and 10.17 g (0.03 mol) of tetrabutylammonium hydrogen sulphate . The pH of the mixture (3.0) is adjusted to pH 7.5 with sodium bicarbonate, the organic layer is filtered and the aqueous layer is extracted with 2,100 ml of methylene chloride. The combined o: organic layers are dried () and the solvent is evaporated to a solid residue. The residue was triturated with ethyl acetate (300 ml), filtered, the filter cake washed with ethyl acetate and then with ethyl ether, and dried under a nitrogen atmosphere to obtain 16.5 g (89%) of the tetrabutylammonium salt.

A mixture of 12.32 g (0.02 mol) of this salt was combined with 70 ml of chloro-methane, and the mixture was stirred overnight at room temperature. The reaction mixture is concentrated to dryness and the residue is purified by chromatography on 600 g of silica gel, eluted with a 1: 1 mixture. ethyl acetate / hexane (by volume) to yield 8.1 g (95%) of the desired chloromethyl ester as a pale yellow viscous oil.

IMP (SVS1z): 1.58 (s, ZN), 1.68 (s, ZN), A, 45 (s, 1H), 5.1 (s, 1H), 5.5-5.9 (dv D. dm, 4H), 7.2 (d, 1H) and 7.4 (s, 5H) md.

Example 39. Iodomethyl-6D- (2-azido-2-phenylacetamido) penicillanate.

The product indicated in the previous example (1.45 g, 0.00342 mol) in 3 ml of acetone is purged with nitrogen for 3 minutes. NaJ (2.55, 0.01714 mol) was added and the resulting solution was stirred for 16 hours at room temperature. The reaction mixture is clarified by filtration, the resulting filtrate is concentrated in vacuo and the residue is taken up in 75 ml and filtered. The CHCl j filtrate is washed with 2 x 30 ml of saturated NaCP, dried (Na, j S04) n is concentrated to give the product as a foam, 1.23 g

PNR (CDCl.,) TMSDmd): 1.53 (GD, s 1.64 (GH, s), 4.37 (1H, s), 5.05 (1H, s), 5.56 (2H, m , ,, 11 Hz), 5.87 (2H, AB KB), 7.31 (5H, s).

170972

18

Example 40. 6-h) - (Benzyloxy carbonylaminomethyl) -1,1-dioxopenicillanoyloxymethyl-6-Cd- (2-azidophenylacetamido)} penicyl lamate.

J The product indicated in Example 16 (0.56 g, 1.43 mmol) was dissolved in 50 ml. (20 ml) was added and the pH was adjusted to 8.6 with 1N NaOH. NaHCO (0.121 g, 1.43 mmol) was added, and then tetrabutylammonium acid sulphate (0.488 g 1.43 mmol) was added in portions, maintaining the pH to 8.0-8.3, adding 1N. NaOH almost to the very end of the addition, when

15 pH is reduced to 7.0. After stirring the mixture for 15 minutes, the layers are separated. The aqueous layer is extracted with 1 ml of fresh CHjCfj. Combined organic layer and extract.

20 was dried (Na2SO.) And concentrated in vacuo to yield tetrabutylammonium-1, 1-dioxide 6-alpha (benzo-1oxycarbonylaminomethyl) penicillanate as a foam. The latter is dissolved in

5 with 20 ml of acetone and added to a solution of the title product of the previous example (0.714 g, 1.43 mmol) in 15 ml of acetone, the resulting mixture is stirred for 1 h at a room temperature, concentrated in vacuo and the resulting residue is suspended in 30 ml of ethyl acetate to obtain crystalline tetrabutylammonium iodide (0.42 g). The resulting filtrate is evaporated to a foam (1.2 g) which is then chromatographed on 100 g of silica gel, eluting with 20% addetate / CHC {20 ml fractions. The pure product fractions (R 0.22 on TLC with the same eluent) are combined and concentrated in vacuo to give a pure product as a foam, 0.61 g.

PMR (CDClj) L (ppm): 1.33 (ZN, s), 1.48 (ZN, s), 1.52 (ZN, s), 1.59 (ZN, s), 3.65 (ZN , m), 4.33 (1H, s), 4.42 (1H, s), 4.61 (1H, s, br), 5.05 (ZN, s): 5.58 (5H, m) , 7.24 (5H, s), 7.32 (5H, s).

Example. 41. The di (p-toluenesulfonate) salt of 6-alpha- (amino-methyl) -1,1-dioxopenicillanoyloxymethyl-6- (D-2-amino-2-phenylacetamido) penicillanate.

Pd / C (10%, 2 g) is preliminarily 5 hydrogenated in 20 ml of water. A solution of the title product of the previous example (0.96 g, 1.226 mmol) in 30 ml of THF and then pyrich di-p-toluenesulfonate (0.615 g, 2.452 mmol) is added, the mixture is hydrogenated for 1.5 h at 50 psi (3.5 kg / cm). The catalyst was removed by filtration through diatomaceous earth, washing with THF and. The THF is then removed from the combined filtrate and the washings are concentrated in vacuo. The aqueous residue is extracted with ml of ethyl acetate and freeze-dried to obtain the title product, 0.66 g with an admixture of unreacted compound. Fresh 10% Pd / C (1.0 g) in O ml HjO is preliminarily hydrogenated again. The impurity containing product (0.5 g) is dissolved in 30 ml of THF and then added to the pre-reduced catalyst slurry. Fresh pyridine-p-toluenesulfonate (0.315 g) was added and the mixture was hydrogenated at 50 p (3.5 kg / cm) for 1.5 hours. The catalyst was removed, the product was isolated, as described earlier, 0.5 g NDP (lTMSO-D4) TMS, G (250 MHz): 1.35 (6H, width C), 1.47 (6H, s), 2.30 (6H, s), 3.38 (2H, m ), 3.94 m), 4.45 (1H, s), 4.72 (1H, s) (1H, shir, s), 5.31 (1H, imp.s) 5.08 (1H, d , Hz), 5.60 (1H, m) 5.45 (1H, 5.93 (2H, m), 7.32 (8H, AB square), 7.4 (5H, m). Example 42. 1 , 1-dioxid-1, - (dioxypenicillanoyloxymethyl-6-oi (benzyloxy, Icarbonylaminomethyl) penicillanate. The product indicated in Example 16 (0.5 g, 1.26 mmol) was dissolved in HjO (10 ml) and the pH of your product was 5 MP CHjCfj was adjusted to 8 , 6 1 N. NaOH-Na HCOj (0.106 g, 1.26 mmol), and then tetrabutylammonium acid sulphate (0.428 g, 1.26 mmol) is added, the pH, which drops to 5.0, is adjusted to 7.5 with 1N NaOH. After mixing at room temperature, the organic layer is concentrated for 30 minutes, dried (NajSO4), and concentrated in vacuo to obtain tetrabuthtammonium-6-o (benzyloxycarbonylaminomethyl) penicillanate 1,1 dioxide as a foam. The solution is dissolved in 20 ml of acetone. 1,1-Dioxide of iodomethyl penicillanate (0.47 g) in 15 ml of acetone is added, the mixture is stirred in those; Chencé for 5 minutes and then concentrated in vacuo. The residue is suspended in 7220 with 30 ml of eipacetate and crystalline tetrabutylammonium iodide (0.33 g) is isolated by filtration. The filtrate is concentrated in vacuo. The residue was suspended in 30 units of ethyl acetate and the crystalline tetrabutylammonium iodide (0.33 g) was filtered by filtration. The obtained filtrate is concentrated in vacuo to obtain a product in the form of a foam, 0.82 g. PMR (CBC1) TMS, (m): 1.40 (3N, s), 1.42 (3N, s), 1.58 (6H , c), 3.41 (2H, m), 3.69 (3N, m), 4.40. (2H, s), 4.58 (2H, m), 5.08 (2H, s), 5.59 (W, m), 5.86 (2H, s), 7.29 (5H, s) . Example 43. The T-toluenesulfonate salt of 1,1-dioxide, 1,1-dioxopenicillanoyloxymethyl-6-o (aminomethyl) penicillanate. Pd / C (10%, 1.2 g) is pre-hydrogenated in 10 ml of HjO. Pyridinium tosylate (0.482 g, 1.92 mmol) is added and then a solution of the product in the title of the previous example in 30 ml of THF is added, followed by hydrogenation at 50 psi (3.5 kg / cm) for one hour. The catalyst was removed by filtration on diatomaceous earth, washing with THF / HO. THF was removed from the combined filtrate by washing, and the filtrate was concentrated in vacuo. The aqueous residue is extracted with 1 x S0 ml of ethyl acetate. The organic layer is dried () and concentrated to obtain 60 mg of solid product. The aqueous layer is concentrated to 10 ml. The crystalline product is isolated by filtration, 100 mg, m.p. 228-229С (with decomposition). PMR (DMSO-d) (G (250 MHz): 1.35 (ZN, s), 1.37 (ZN, s), 1.49 (ZN, s), 1.50 (ZN, s), 2 , 29 (ZN, s), 3.29 (1H, dd,, 7, 16.6 Hz), 3.39 (2H, m), 3.72 (1H, ds.d, 6, 16 , 6 Hz), 3.92 (1H, m), 4.60 (1H, s), 4.77 (1H, s), 5.21 (2H, m), 5.96 (2H, s), 7.31 (4H, AB, q) Elemental analysis for C "AND N. C 44.17, H 4.89, Calculated N 6.18. Found: C 45.53, H 4.76, N 6, 10. The aqueous mother liquor is freeze dried to obtain 160 mg of solid product, which is suspended in a small amount of water.

filtered, washed with a small amount of ethyl acetate and dried to obtain an additional 70 mg of purified product with identical mp, and a spectrum of the NDP.

Example 44.1,1-Chloromethyl-6-b1 dioxide ((benzyloxycarbonylaminomethyl) penicillanate.,

In example 40, the product specified in example 16 (0.396 g 1.0 mmol), turn it. tetrabutylammonium salt. The latter is dissolved in 30 ml of bromochloromethane and stirred at room temperature for 18 hours, concentrated in vacuo to a foam, and chromatographed on 50 g of silica-gel with 20% ethyl acetate / CHC as eluent in 20 ml fractions. Fractions 6-10 are combined and concentrated in vacuo to a foam, 0.25. g, RI 0.7 on those with the same eluent.

PMR (SVS1z) TMS, cG (ppm): 1.37; (ZN, s), 1.54 (ZN, s), 3.70 (ZN, m), 4.38 (W, s), 4, 67 (1H, brs),

5.07 (2H, s), 5.66 (1H, d, Hz), 5.70 (2H, AB KB), 7.33 (5H, s).

Example 45: 1,1-Dioxide iodo methyl 6-o - (benzyloxycarbonylaminomethyl) -penenilane.

The product indicated in the previous example (0.25 g, 0.563 mol) was dissolved in 15 ml of acetone and purged with nitrogen. NaJ (0.42 g,

2.8 mmol) and the resulting mixture is stirred for 17 h, and then concentrated in vacuo. The hard part is thoroughly triturated with CHCEj, the insoluble part is removed from the filtrate

and the product was concentrated from the filtrate by concentration in vacuo to a foam, 0.23 g.

nMP (CDClI) TMS, cl (MD): 1.39 (ZN, s), 1.55 (ZN, s), 3.64 (ZN, m), 4.28 (1H, s), 4.59 (1H, shir, s), 5.04 (2H, s), 5.48 (1H, m), 5.83 (2H, AB KB), 5.23 (5H, s).

P. Example 46. Methylene bis- (6o (- (benzyloxycarbonyl aminomethyl)} - 1, 1-docoxopenicillanate.

7097222

The product indicated in Example 16 (0.17 g, 0.429 mmol) is converted to its tetrabutylammonium salt (0.27 g) by the method of Example 49. The latter is dissolved in 10 ml of acetone and added to the solution of the previous example. product (0.23 g, 0.429 mmol) in 10 ml of acetone. The mixture was stirred for 15 minutes, concentrated to a foam in vacuum, and the foam was suspended in 20 ml of ethyl acetate. The suspension was filtered to obtain tetrabutylammonium iodide (110 mg) and

15, the resulting filtrate was concentrated in vacuo to give the product as a foam, 0.28 g.

PMR (CDCl,) TMS, ((ppm): 1.36 (6H, s), 1.52 (6H, s), 3.73 (6H, m),

20 4.40 (2H, s), 4.69 (2H, br. S), 5.08 (4H, s), 5.77 (4H, m), 7.28 (YUN, s).

Example 47. Bis-p-toluenesulfonate salt of methylene bis-6-ot5 (aminomethyl) -1,1-dioxopenicillanate.

I

According to the method of example 43, the product specified in the previous

0 example. After removing the catalyst in THF, the water residue is extracted with 3x20 ml of ethyl acetate and freeze dried to obtain the title product (0.19 g).

PMR (DMSO-d) TMS, s (250 MHz): 1.37 (6H, s), 1.50 (6H, s), 2.31 (6H, s), 3.40 (4H, m), 3.94 (2H, m), 4.77 (2H, s), 5.30 (2H, m), 5.98 (2H, m), 7.32 (8H, ABq).

0 Antibacterial activity was investigated by adding the compound of formula 1 or (j to the Cefaperone Antibiotic Known (CEF). The effectiveness of the separate antibiotic Cefaperzon and its mixtures with the compound of Formula 1 and ij is expressed as the minimum inhibitory concentration (MIC) in mg / ml. Test results are given in the table.

200

6.25 + 6.25 50

6.25 + 6.25 200

100 +100

0.39 + 0.39 0.78 + 0.78

0.39 + 0.39 0.78 - f 0.78

25 +25 25 + 25

Claims (1)

The method of obtaining derivatives 6-aminoalkylpenicillanic acid 1,1-dioxide of formula 1 or II or their additive salts with p-toluensulfonate, namely, that the compound of formula III or IV where has the indicated meanings, "= 2, P _g -methylene or η = 1, K ₃ -benzip, pivaloyloxymethyl, 1,1-dioxopenicillanoyl oxymethyl or a radical of formula B S-Sosh b n SNS ch ₃ δΙΙ "1170972 where is a hydrogen or methyl atom, η = 2 Βχ is methylene or / η = 1, a hydrogen atom, pivaloyloxymethyl, 1,1-dioxopenicilla 'noyloxymethyl or a radical of formula A subjected to hydrogenation with hydrogen in the presence of a palladium-carbon catalyst in an aqueous organic medium at ambient temperature and in the case of the addition of salts with k-toluenesulfonic acid, in the presence of pyridinium tosylate. Priority by featured. > 11.01.82 - at δ · ,, - a hydrogen atom, P = 1 and I ₂ has the indicated values, 11.06.82 - at d ₇ - methyl, p = 1 1170972 and has the indicated values, 10/21/82 - when x, is a hydrogen atom or methyl, <η = 2 and x ₂ is methylene. . one