SU799667A3 - Method of preparing 3-methylenecephamsulfoxides - Google Patents

Abstract

3-Methylenecepham 1-sulphoxides of the formula <IMAGE> in which the substituents are defined in Claim 1 are prepared. These compounds are prepared by bringing about ring closure in a corresponding sulphinylazetidinone of the formula <IMAGE> in which X is chlorine or bromine, an alcohol or thioalcohol residue, an ester or a thioester residue, or an amino radical. If X is chlorine or bromine, the compound II is reacted with a Friedel-Crafts catalyst of the Lewis acid type, with a Friedel-Crafts catalyst of the Bronsted protonic acid type or with a metathetical cation former in a dry inert organic solvent, or is dissolved in an organic Bronsted acid. If X in compounds II is an alcohol, thioalcohol, ester or thioester residue or an amino radical, reaction is carried out with a Friedel-Crafts catalyst of the Bronsted protonic acid type in a dry inert organic solvent, or the compound is dissolved in an organic Bronsted acid. The resulting compounds can be used for the preparation of cephem antibiotics.

Description

This invention relates to a new process for the preparation of 3-methylene cephthalic oxides, which are used as intermediates in the synthesis of 3-oxycephamic or 3-halocephamic. A known method of producing 3-methylene cephams by converting a 3-acetoxymethyl or oxymethyl group by hydrolysis in a weakly basic phase or by treating with an appropriate ester, or by electrochemical reduction, or by reducing the chromium (II) salt or another reducing agent l and 2. A method for producing 3- methylene cephalum sulfoxides as a by-product in the synthesis of 7-acylamido-3-hydroxy-3-cepam-4-carboxylic esters by ozonolysis of 7-acylamido-3-exomethylene-cephamide-4-carboxylic esters by treating with ozone in an inert ohm solvent at a temperature of from -80 to the OS 13. The purpose of the invention - the improvement of yield W-metilenpefamsulfoksidov. This goal is achieved by the method of obtaining 3-methylene cephamsulfoxds of the general formula I, where R is a phthalimido group, N-phenoxy acetyl-M- (2,2,2-trichloroethoxycarbonyl) amino group, 2,2-dimethyl-SG-nitroso-5-oxo- 4-phenylimidazol-dinyl ilk 1 -mido group of the formula where the alkyl, 4-nitrobenzyloxy group or arylalkyl group of the formula “—f” -, where R is phenyl, phenoxy group or thienyl, Ry is a hydrogen atom or a protected hydroxyl or amino group, R. methyl, third -butyl, benzyl, 4-methoxybenzyl,, alkanoyloxymethyl, 2-iodoethyl, 4-nitrobenzyl, diphenylmethyl, phenacyl, 4-haloid natsil, dimethylallyl, or 2,2,2-trichloroethyl, zaklyuchakvdiys that connect 1ie- general formula II wherein R and Rj are as defined above and X is a chlorine or bromine atom, a group of formula OR | ,. in which R is a hydrogen atom or an alkyl, a group of the formula -SR-j in which R-y is alkyl or aryl, or a group of the formula E of which Rg is a hydrogen atom and B is a hydrogen atom, phenyl or represents a group of the formula in which -, alkylcarbonyl, al-. coxycarbonyl or tosyl, Rg - -COOR or -COR and RQ- -MHCOOR or -NHCOR, j h "in which R is C-C alkyl or phenyl or XM succinimido group, is reacted with a Friedol-Crafts catalyst of Lewis acid type either a strong acid or an anhydrous silver salt, or silver vi-toluenesulfonate in a dry aprotic organic solvent or dissolve a compound of general formula II in a strong organic acid at a temperature of 20115 ° C under the condition that X is a bromine atom, then the phthalimido group; when anhydrous silver p-toluenesulfonate or a Lewis acid is used, X is only a chlorine or boron atom, and the resulting free carboxylic acid is formed as a 4-carboxylic acid ester. Aluminum chloride, tin chloride, tin bromide, zinc chloride, cic pentachloride bromide, titanium tetrachloride, ferric chloride, gallium trichloride, zirconium tetrachloride, mercury chloride or chromium chloride are used as the catalyst. As . methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, sulfuric acid, phosphoric acid, polyphosphoric acid, perchloric acid, polyphosphoric acid, perchloric acid, chlorosulfonic acid, or fluorosulfonic acid are used as a medium for the use of a non-metallic acid by using a non-standard This reaction is in no noticeable reaction both with the reagents and with the obtained substances. Since the sulfinyl chlorides, which are the starting materials, like other acid-halide type reagents are sensitive to hydrolysis and to the effects of other protic compounds, for example alcohols or amines, get rid of moisture and other proton-containing compounds in the reaction medium. Thus, the use of a dry aprotic organic solvent is most preferred. The process is carried out under anhydrous conditions. Suitable solvents for this purpose include, for example, aromatic hydrocarbons, such as benzene, toluene, xylene, chlorobenzene or nitrobenzene, halogenated aliphatic hydrocarbons, such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, 2,2-trichloroethane, 1,1-dibromo-2-chloroethane and other solvents suitable for the Friedel Crafts reactions, including disulfides and nitromethanes. i The most preferred solvents are aromatic hydrocarbons and halogen-substituted aliphatic hydrocarbons; based on aromatic hydrocarbons - benzene or toluene; from among the halogen-substituted aliphatic hydrocarbons, methylene chloride, ethylene chloride or 1,1,2-trichloroethane. The time required for cyclization depends on the nature of the sulfinyl derivative, the acid used and the reaction temperature. Usually, azetydinone sulfinamide and sulfinamide derivatives are cyclized within 5-10 minutes at room temperature in methanesulfonic acid, while the cyclized dihydric sulfonic acid derivatives, esters and thioethers are completely complete in about 30 minutes at room temperature. The reaction is carried out at a temperature of 20-85 ° C, which depends primarily on the solubility and catalytic action of the particular cyclizing reagent used. To ensure that the cyclization reaction is complete, using at least a stoichiometric amount of catalyst, since the use of less than one molar equivalent of such reagents results in a reduction in the yield of 3-methylene sulfate sulfoxide and a portion of the sulfinyl chloride remains unreacted. Typically, the amount of catalyst used varies from slightly more than one equivalent to two equivalents per mole of sulfinyl chloride. Nuclear magnetic resonance (NMR) spectra are obtained on a Varian Associates t-60 spectrometer, in which tetramethylsilane is used as a reference. Chemical ssvsh-and are expressed in the value of {and x, COTTRPTGGvunhtsih parts mn million (ppm), and the coupling constants (I) - in hertz cycles in s). Example 1. Methyl 7-phthalimido-Z-methylene cephamic-4-carboxylate-1-oxide. A. Chloride tin. A mixture containing 18.8 g (50 kmol methyl sulfoxide 6-phthalimidopency lanate and 6.7 g (50) N-chloro succinimide in 1.1 dry carbon tetrachloride is heated under reflux for 70 minutes. The crude product is cooled to room temperature, filtered, washed with water (1 x 500 ml) and dried (MgS04). After that, the tal solution is distilled off in vacuum. The NMR spectra indicate that complete conversion to sulfinyl chloride occurs; NMR (COCU) f 1, 97 (broad), 3.86 (S. 3), 5.05 (broad) 5.2 (, Hz), 5.77 {d 1, 3 4 Hz), 5.9 (, 3 4 Hz ) and 7.83 (). Received sulfinilhlornd The solution is dissolved in dry) and added. 6 ml (150 mol) of anhydrous tin chloride. The resulting solution was mixed with BcooT for 45 minutes, washed with 1 and hydrochloric acid (2 X 200 ml) and dried (HgSO). Evaporation in a vacuum yielded 18.4 g (98.4%) of a mixture of P- and 5-sulfoxides (approximate 3: 2 according to NMR) in the form of a yellow foam. A part of this mixture was separated by chromatography over silica gel using chloroform ethyl acetate as a solvent. Fractions 6-10 contain pure P-sulfate oxide (340 mg), which is obtained by recrystallization from methylene chloride in cyclohexane: f „201-202 C: NMR (CDClt,) 3.62 and 4.12 (ABf, 2, I -14 Hz 3.85 ()., 88 (dt, I l, 5 Hz), 5.25 (broad), 5.58 (), 5.57 (d 1, I - 4.5 Hz) and 7.84 ( rn); mass spectrometry 374, 358, 346, 298, 287, 239, 220; IR spectrum1 ml (KBr) 1780 1745 and 1390 cm-1 Found,% C 54.41; H 4.06; N 7.26; O 25.59, - S 8.41 (371.37) Calculated,%: C 54, 54; H 3.77; N 7.48; O 25.64, - S 8.56 Factions 11–18 contain a mixture of Pu S - sulfoxides, and fractions 19-35 dgiot 210 mg S-sulfoxides, which are recrystallized from methylene chloride in cyclohexane: NMR (СDC Ц) 3.63 (), 3.82 (), .90 (d- | 1. - 4, 5 Hz), 5.32 (S.1), 5 , b (broad), 5.6. (, i 4.5 Hz), 5.77 () and 7.84 (mass spectrometry m / e 374, - 358, 346, 298, 287, 239 200 IR spectra (KBG) 1775, 1745, 1390, 1205, 1111, 1051, 730, and 715 cm; Found: C 54.33; H 3.76 / N 7.36 H Calculated,%: C 54.54; H 3, 77; N 7.48 B. Titanium tetrachloride. A solution containing 0.41 g of methyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate and 0, 12 ml of titanium tetrachloride, in 30 ml of dry 1,2-dichloroethane is heated under reflux for 30 minutes. The mixture is then cooled to room temperature, washed with 1N HCl and brine, and dried (NgSO4). Upon evaporation in vacuo, 0.34 g of methyl-7-phthalimido-3-methlenfate 1-4-carboxylate-1-oxide is obtained. C. Chloride A mixture containing 0.41 g of methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azvdcdinyl) -3-butenoate and 0.13 g of hypomini chloride is heated with a reflux condenser in 30 ml of dry 1,2-dichloroethane. The mixture is then cooled to the normal temperature, washed with 1N HCl and brine and dried (HgSO4). Upon evaporation in vacuo to completely distill off the solvent, 0.35 g of sulfoxide .3-methylene cephalum is obtained as a yellow foam. 0. Zinc bromide. A mixture containing 0.41 g of methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthal1 "odo-1-azetindinyl) -3-butenoate and 0.27 g of zinc bromide in dry methylene chloride , heated under reflux for 1 h. The mixture is cooled to room temperature, washed with 1 and. HC and dried (NgSO). When evaporating in vacuum to completely distilling off the solvent, a mixture of P- and S-3-methylcephamum sulfoxides is obtained as a yellow foam. E. Pentachloride sur. A solution containing 0.41 g of methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthal1 “Before -1-azetidnyl) -3-butenoate and 0.12 ml of antimony pentachloride is stirred at room temperature within 60 min. The reaction mixture is washed with 1N. HCl and brine, dried (NgSC.), And evaporated in vacuo to obtain a dry brine, thereby obtaining the desired 3-methylene cephum sulfoxide as a yellow foam. In order to confirm the presence of cefam sulfoxide, the reaction product is dissolved in 3 ml of dimethylformamide and 0.99 ml of phosphorus trichloride is reacted. The mixture was stirred at 0 ° C for 30 minutes. Poured onto crushed ice, found in water. The yellow precipitate obtained after this is collected by filtration and dried under vacuum. The NMR spectrum of the obtained product (0.15 g) shows that it is methyl-7-phthalimido-3-methylene cephamic-4-carboxylate: (COC1) 3.47, 3.96

(AB q 2, 1 17 Hz), 3.87 (, Cd-H), 5.20 (, I 4.5 Hz), 5.80 (d 1, I 4.5 Hz) and 7.83 ( m 4) ..

F. Mercury chloride.

A mixture containing 0.20 g of methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate and 0.14 g of mercury chloride in 10 ml of 1,2-dichloroethane , heated under reflux for 1 h. The mixture is cooled to room temperature, washed 1 and. HCl, dried (MgSO4), evaporated in vacuo to obtain a dry substance, and 0.14 g of 3-methylene cephum sulfooxide is obtained as a mixture of P and S sulfonic oxide isomers.

G, chloride glands and

The experiment was carried out according to the procedure described in paragraph F, but 0.08 g of ferric chloride was used as a catalyst instead of mercury chloride. The conversion of sulphinyl chloride to sulphonic acid, methylene cephamide 3, is confirmed by comparative thin film chromatography.

N. Zirconium tetrachloride. The experiment was carried out according to the procedure described in paragraph F, but 0.12 g of zirconium tetrachloride is used as a catalyst instead of mercury chloride. A clear conversion of sulfinyl chloride to sulfoxide 3-methylene cepham is confirmed by comparative thin-film chromatography. The NMR spectrum of the compound obtained is identical to the spectrum of the compound obtained in the studies described in paragraph A.

1. Polyphosphoric acid. Methyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl1-3-butenoate (, 0.20 g) is mixed with 27 g of polyphosphoric acid for 20 minutes. To the reaction mixture is added ice water and ethyl acetate (25 ml). The organic layer was separated and washed by water, followed by water, aqueous sodium bicarbonate and brine, dried (MgSO4) and evaporated in vacuo to dryness, yielding methyl 7 -phthalimido-3-methylene cephamic-4-carboxylate-1-oxide (.0.05 g) as a white foam. J. Sulfuric acid. A solution containing 0.20 g of methyl-3-methyl-2- (2-chlorosulfinyl) -4-oxo-3-phthalimido-1-azetidinyl), -3-butenoate and 2 drops of concentrated sulfuric acid in 10 ml of dry 1,2-dichloroethane, heated under reflux for 1 hour. The reaction mixture is cooled, washed with brine , dried (MgSO4), and evaporated in vacuo to obtain a dry substance in the form of 0.09 g of a colorless foam, the NMR spectrum of which shows that it is the required 3-methyl-sulfate sulfoxide.

K. Methanesulfonic acid. The experiment was performed according to the procedure described in H, but using 0.03 ml of methanesulfonic acid instead of sulfuric acid as a catalyst. The NMR spectra show that the required 3-methylene sulfate oxide as shown.

L. Trifluoroacetic acid. A solution containing 0.29 g of methyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate in 10 ml of trifluoroacetic acid is heated under reflux for 30 minutes and then evaporated in vacuo to dryness. The product is dissolved in 20 ml of ethyl acetate. The resulting solution was washed successively with an aqueous solution of sodium bicarbonate (SX), water and brine, dried (MgSO4) and evaporated in vacuo to a dry substance, yielding methyl 7-phthalimido-3-methylene cephamic-4-carboxylate-oxide.

M. Silver P-toluenesulfonate. Silver p-toluenesulfonate (0.80 g is added to a solution of methyl 3-methyl-2- (2-chlorosulfinyl-4. Oxo-3-phg. Limido-1-azetidinyl) -3-butenoate {1.0 g) in 75 ml of dry toluene. The reaction mixture is stirred at room temperature for 2.5 and then filtered. T. The filtrate was evaporated in vacuo to dryness, and the precipitate thus obtained was dissolved in 50 ml of ethyl acetate. The solution is dried under vacuum to dryness. According to the NMR spectra of the obtained product, it is established that it is methyl 7-phthalimido-3-methylene cephamic-4-carboxylate-1-oxide.

Example 2. Methyl-7-phthalimido-2, 2-dideuterio-3-methylene cephamic-4-carboxylate.

A mixture containing 3.76 g (10 mmol of methyl sulfoxide 6-phthalimidopenicillanate, 5 ml of deuterium oxide and 500 ml of dry carbon tetrachloride is heated under reflux for 3 hours. After that, the layers are separated and the organic layer is dried (MgSO4). evaporating in vacuum, 3.59 g of a white amorphous foam are obtained. The NMR spectra show the addition of deuterium (H) to only the k2O-methyl group and the presence of less than 29% residual hydrogen (n) in this group (by combining) Mass spectrometry data indicate the following distribution dey teri in the 2O1-methyl group: d, 5.8% d 20.5%; d241.3%; d 32.4 ± 2%. As a result of recrystallization from diethyl ether acetone, colorless prisms are obtained: Tchip 118-151c; mass spectrometry t / e 379, 378, 377, 376, 361, 360, 359, 358, 302, 301, 300 ,.

299, IR spectra (KBr) 180P, 1775 and 1725 cm; NMR {CO11з) cfl, 83 (): 5.86 (, I 4.5 Hz); 7.83 ().

Found,%: C 54.05; H 4.28; N 7.26; About 25.61 / S 8.53

G ,, N40j, S (376.387)

Calculated,%: C 54.25; H 4.28; N 7.44; About 25.50; S 8.52

A solution containing 0.57 g (.1.5 mmol) of methyl 28-methyl-2-trideuteriomethyl-6-phthalimidopenicillanate-1-oxide and 0.20 g (1.5 mol) of N-chlorosuccinimide is heated under reflux for 30 mi in 25 ml of dry 1,1,2-trichloroethane, cooled, washed with water (1 x 50 m brine (1 x 50 ml) and dried (MdSSC). Then the solvent is distilled off in a vacuum and get 0,69 g mixtures of R- and S-sulfinyl chlorides as a light yellow amorphous foam. Then the mixture is dissolved in 25 ml of dry mesgylene chloride and 0.20 g (1.7 mol) of anhydrous tin chloride is added. The mixture is stirred t for 50 minutes, washed with 1N hydrochloric acid, dried (HgSO4) and evaporated in vacuo, to give 0.57 g of a mixture of R- and S-sulfonic oxide as a yellow foam. The material thus obtained is dissolved in 4 ml of dry, N, N-dimethylformamide are cooled in an ice bath and 0.14 ml (1.6 mol) of phosphorus trichloride are then added.After 35 minutes, the crude mixture is poured onto crushed ice in water and stirred. filtered and dried in vacuo. The output is 0.38 g. In the NMR spectrum, the signals obtained are very weak, corresponding to the C2 position. theoretical NMR), while the signal corresponding to the C – j position of exomethylene is normal, indicating a selective combination of deuterium in position C. The results of mass spectrometric analysis give the desired distribution of deuterium (H) at do2.2%; d, 25.5%; d2.72.3% ± 2%. Upon recrystallization from cyclohexane methylene chloride, colorless crystals are obtained: T 198-201 C: (decomp.); mass spectrometry analysis m / e 360, 273, 174; IR spectra (KBr) 1770, 1740 and 1710 NMR (CDCl,) cG 3.80 (), 5.32 (), 5.46 (, I 4.5 Hz), 5.67 (d .. I. 4.5 Hz), 7.83 (t, 1).

Found,%: C 56.96; H.3.85; N 7.94

. (358, 372).

Calculated,%: C 56.98; H 3.94, N 7.82; O 22.32; S 8.95

Example 3. 4-Nitrobenzyl-7-phenoxy-acetamido-Z-methylene cephamic-4-carboxylate-1-oxide.

A. Chloride tin.

A mixture containing 6, O g (12 mmol)

4-nitrobenzene-6-phenoxy-acetamido-penicillanate-M-oxide and 500 ml of dry toluene are heated under reflux for 10 minutes using a Dean-Stark trap (Dean-Stark) to remove any traces of water. Then, 1.8 g of N-chlorosuccinimide is added, heating the mixture under reflux for 90 minutes and cooled to approximately 50 ° C. 1.8 ml of anhydrous tin chloride is added to the resulting sulfinyl chloride solution. The mixture was stirred at room temperature for 90 minutes. Then 100 ml of water and 100 ml of ethyl acetate were added. The organic layer is separated and washed (1N HCl, aqueous NaHCOj, brine) and dried (HgS04). Evaporation in vacuo to a solid gives a product, which crystallizes from ethyl acetate to give 2.16 g (36%). the product recovered. The sample is recrystallized from acetone ethyl acetate to obtain a large, t. 200-, 2010c; NMR (COCl,) df 3.5 and 3.75 (, I 14 Hz), 4.55 (), "|, 83 (. J 4.6 Hz), 5.3 (S.2), 5, 33 (), 5.5 (S.)), 5.78 (s; i). 5.9 and 6.1 (. 1 - 4.5 and 8.0 Hz), 6.98, 3 ().

Found,%: C 55.06; H 4.14; N 8.30, O 25.62; S 6.26 (.5) Calculated,%: C 55.31; H 4.24; N 8.41-, O 25.62; S 6,42 V. Zinc chloride.

4 Nitrobenzyl-3-yteyl-2- (2-chlorosul-2-oxo-3-phenoxy-acetamido-1-azetidinyl) -3-butenoate is obtained by heating under reflux a solution containing 1 g of sulfooxide 4-nitrobenzyl-6-phenoxy-acetamidopenenicillanate and 0 27 g of N-chlorosuccinimide in 40 ml of 1,1,2-trichloroethane, for 30 minutes. Then, 0.27 g of zinc chloride is added to the reaction mixture. After that, the mixture is heated under reflux for an additional 45 minutes. After cooling the mixture to room temperature, it is punched with 1N. HCl (2X), dried (evaporated in vacuo to obtain a dry substance. An NMR spectrum shows that the product is a BJm 4 -nitrobenzyl-7-phenoxyacetamido-3-methylencephamic-4-carboxyl at-1-oxide) C.C. Silver P-toluenesulfonate. A solution containing 1 g of 4-nitrobenzyl-6-phenoxy-acetamidopenicillanate-1-oxide and 0.27 g M of chlorosuccinimide in 10 ml of dry toluene is heated under reflux for 1 hour. To the hot solution is added P silver toluene sulfonate (0.61 g). The mixture is stirred for 45 minutes (until cooled to room temperature). Pe stock mixture is filtered.

washed with water (2X) and brine, dried (MgSO4) and evaporated in vacuo to obtain a dry substance, yielding 0.43 g of 4-nitrobenzyl-7-phenoxy-acetamido-3-methylene cephamic-4-carboxylate-1-oxide (with some impurities mi) in the form of a yellow foam.

Pr-meper 4, 4-Nitro-6-phthalimido-3-methylene-4-carboxylate-1-oxide.

To a solution containing 23.1 g of 4-nitrobeneyl-3-methyl-2- (2-chlorosulfft-IL-4-oxo-3-phalimido-1-azetidinyl 3-butenoate in 400 ml of dichloroethane, is added at room temperature Anhydrous tin chloride. As the reaction progresses, an increase in the precipitation of the precipitate is noted.After 45 minutes the reaction mixture is washed with 1. sulfuric acid, water, sodium bicarbonate solution and brine. The organic layer is dried and evaporated in vacuo to dryness, yielding 16.72 g (78%) of the desired product. Isomers of R- and S-sulfoxide are separated fractional crystallization from acetone and dichloroethane.

R-sulfoxide is obtained as colorless prisms that soften when completely melted by IR spectra (CDCl4) 1790, 1780, 1738 and .1723 cm; mass spectrometry t / e 495, 479, 367, 343; NMR (SOSC) HR, 5 and 4.10 (ABq.2 I - 13 Hz), 4.87 (.1 4.5 Hz), 5.33 (S), 5.57 (m2), 5.95 (d 1, 1 4.5 Hz), 7.4-8.4 (, Ar H).

Found,%: C 55.50; H 3.45; N 8.65; O 25.17; S 6.32 C, N N OgS (, 5) Calculated,%: C 55.76; H 3.46; N 3.48; O 25.83; S 6,47

S-sulfoxide was isolated in the form of colorless prisms: Tr, 190-192 C, - IR (TyP) 1780, 1775, 1741 and 1728 cm, NMR (sosi) rf 3.5 and 3.7 (., I. 15 Hz ), 4.9 (, 1 4.5 Hz), 5.34 (), 5.6 (), 5.6 (. 1- 4.5 Hz), 5.8 (5.1), 7.4-8.4 ( t 8).

Found,%: C 5.58; H 3.62; N 8, -25; O 25.19; S 6.18 С, Н N 0. S

Calculated,%: C 55.76, H 3.46) N 8.48; O 25.83, - S 6,, 47

Example 5. 2,2,2-Tri-chloroethyl-7-phenylacetamido-3-methylene cephamic-4-carboxylate-1-oxide.

A mixture of (1.0 g) 2, 2, 2-trichloroethyl-7-phenylacetamido-penicillanate-1-oxide, 0.5 g of N-succinimide and 80 ml of dry toluene is heated under reflux for 90 minutes, then cooled and washed ( water and brine). 0.28 ml of anhydrous tin chloride is added to the resulting sulfinyl chloride solution. The resulting mixture is stirred for 90 minutes. After washing (with water

and brine) the solvent is distilled off in vacuo to obtain a dry substance. The product is crystallized from ethyl acetate to obtain the desired product as colorless prisms; Mp 187-189c; NMR (SOSTS) 6 3.5 and 3.81 (ABq 2, T 14 Hz), 3.63 (S 2)

4.8 (), 2), 9 (d J, 1 4.5 Hz), 5.37 (S 1), 5.5 (), 5.82 (S 1),

5.9 and 6.07 (q1, I 4.5 and 10.0 Hz), 7.0 (d, NH. 1 10 Hz), 7.33 {Si5).

Example 6. Methyl-7- (2,2-dimethyl-3-nitroso-5-oxo-4-phenylamido-azolidin-1-y) -3-methylene cephamic-4-carboxylate-1-oxide.

A mixture of 0.896 g of N-nitroseghetacyline sulfoxide methyl ester and 0.536 g of M-chlorosuccinimide in 55 ml of dry benzene is heated in a reverse manner by refrigerating in a nitrogen atmosphere for about 1 h. . The resulting NMR spectra of the precipitate indicate that its structure is consistent with the required intermediate sulfinyl chloride. The remaining reaction mixture is cooled under a nitrogen atmosphere in an ice bath and 0.33 ml of tin chloride is added to it. Immediately after that, a light orange precipitate formed. After stirring the mixture for 2 hours and 15 minutes at room temperature, 5.5 ml of dimethylacetamide and 55 ml of ethyl acetate are added to it. The resulting solution was washed with water and brine, dried over CaSO4 and evaporated in vacuo to a solid, yielding 1.3 g of a yellow oily mass. The product is dissolved in methylene chloride and applied to 4 thin-layer chromatography plates, which are treated with a mixture of benzene and ethyl acetate (1: 1). Note two primary zones, one of which has a lower frequency value and corresponds to the connection specified in the header. Sulfur oxide 3-methylene cepham (mixture of R- and S-sulfoxide) is separated by extracting the marked zone with acetonitrile: NMR (CDClj) about 2.07, 6 years, dimethyl), 3.73 (, pine,), 4.7-5 , 6 (t) and 7.3 (S, ArN).

Example 7. 2, 2,2-Trichloroethyl-7-phenoxyacetamido-3-methylene cephamic-4-carboxylate-1-oxide,

A mixture containing 4.82 g (10 mmol 2, 2.2-trichloroethyl-6-phenoxy-acetamidopenicillanate-1-oxide, 150 ml of dry toluene and 2.0 (11 mol) N-chlorophthalimide is heated under reflux for 60 minutes using a Dean-Stark receiver. A 5 ml aliquot of the mixture / its NMR spectrum is evaporated, indicating complete conversion to a liquefied sulphinyl chloride. The sulphinyl chloride solution in toluene is cooled to approximately and 1.4 ml of tin chloride is added to it. The mixture is stirred for 60 min. and then washed; successively with 1N HC1, an aqueous solution of NaHCO and brine and dried (MHZOD.) After distilling off the solvent, 30 ml of chloroform is added to the residue and the insoluble phthalimide is filtered off. The filtrate is evaporated to dryness and the resulting yellow amorphous product is dried in vacuum. Yield: 3.4 g (70%) of the desired compound; NMR spectrum (CDCU) 3.56 and 3.80 (ABq 2. 1 1A Hz). 4. (), ij.T (mi2, CHaCU),, 89 (dl,, 5 D 5.33 (Si1), 5.48 (), 5.78 (), 5.9 and 6.07 (qi 1, 1 4.5 Hz), 6.8 7.4 (, ArH) and 8.1 (d, NH, T 10 Hz). Example 8. Methyl-7-phthalimido-3-methylene cephamic-4-carboxylate-1-oxide (from azetidine sulfonic acid). A.P phosphorus thioxide. A solution containing 0.10 g of methyl 3-methyl-2- 2-sulfino-4-oxo-3-phthalimido-1-azetidinyl) -3-butene and O i 04 g of phosphorus pentoxide in 20 m 1, 2 -dichloroethane, stirring at room temperature for 1 hour. Thin-layer chromatography of the mixture shows only the presence of traces of methylene sulfate oxide. The mixture is then heated under reflux for 30 minutes, cooled to room temperature, and combined with 25 ml of ethyl acetate and 50 ml of brine. The organic layer is separated, washed with aqueous sodium bicarbonate and brine, and dried (). After evaporation in vacuo to a solid, the desired product is obtained in the form of a white foam. B. Sulfuric acid. The experiment was carried out as described in Example 1 (J), but in the starting material, instead of sulfinyl chloride, 0.20 g methyl-3-methyl-2- (2-sulfino-4-oxo-3-phthalimido-1) is used. -azetidinyl) -3-butenoate and get 0.03 g of the desired substance C. Polyphosphoric acid. The experiment was carried out according to the method (Example 1), but methyl-3-methyl-2- (2-sulfino-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate was used instead of sulfinyl chloride as the starting material. As a result of the reaction, 0.10 g of the desired substance is obtained. 0. Trifluoroacetic acid. The experiment is carried out according to the method (Example 1 (L), but instead of the corresponding sulfinyl chloride, 0.20 g of methyl 3-methyl-2- (2-sulfino-4-oxo-3-phthalimido-1-azetidinyl) is used as a starting material. -3-butenoate. An NMR spectrum shows that the product contains the desired substance. Example 9. 4-Nitrobenzyl-3-methyl-2-2-chlorosulfinyl-4-oxo-3- (M-phenoxyacetyl-M- (2.2 , 2-trichloroethoxycarbonyl) -amino-1-azetidinyl-3-butenoate A mixture containing 4.855 g (10 mmol) of 4-nitrobenzyl-6-phenoxy-acetamido-2, 2-dimethylpenam-3-carboxylate, 16.94 g ( 80 mmol) 2,2,2-trichloroethyl chloride form, 18 ml of N, 0- (L i S-trimethylsilyl) -trifluoromethylacetamide and 20 ml of methylene chloride. The mixture is kept at room temperature overnight. The mixture is then heated under reflux for 7 hours, after which it is kept for After that, heating is continued for another 6 hours and the mixture is evaporated until a precipitate is obtained. The precipitate is dissolved in benzene, after which a large amount of heptane is added to the resulting solution. The resulting insoluble material is filtered off, dissolved in benzene, and chromatographed on silica gel using a mixture of benzene-ethyl acetate. 4-nitrobenzyl-6-n-phenoxy-acetyl-M- (2,2,2-trichloroethoxycarbonyl) -amino-2,2-dimethylrenam-3-carboxylate (4.76 g, 72%) is obtained as a product: NMR (COCU ) SU1,41 (S3), 1.62 (). 4.61 (), 4.84 (, I 12 Hz), 4.99 (oyl.I 1 12 Hz), 5.20 (). 5.30 (Si2), 5.56 (), 6.8-7.4 (m.5), 7.53 (di2, I 9 Hz) and 8.22 (. I 9 Hz). B. Preparation of sulfoxide. 2.54 g (3.84 mmol) of the above product was added to 75 ml of acetone. The mixture is cooled to -70 ° C and an excess of ozone is flowed into the mixture at a rate of about 1.17 mol per minute for 9 minutes, during which time the reaction mixture becomes frost. The mixture is kept at -70 ° C for 35 minutes, after which it is heated to room temperature. After distilling off the solvent in an acum, 2.76 g of 4-nitrobenzyl-6-N-phenoxy-acetyl-N- (2,2,2-trloroethoxycarbonyl) -amino-2,2-diethylpenam-3-carboxylate-1-oxide: MP ( CDCli,) (fl, 22 (). 1.62 (), 4.60 (S. 1), 4.78 (dl, 1 5 Hz),, 93 (), 5.26 (), 5.30 (), 5.93 (, 1 5 Hz), 6.9-7.4 (). 7.51 (, T 9 Hz) and 8.20 (, I 9 Hz). C. Preparation of sulfinyl chloride. K 40 ml of dry benzene was added 92 mg (about 1 mol) of the above product and 155 mg (about 1.2 mmol) of chlorosuccinimide. The resulting mixture was heated under reflux

for 1 h. An NMR spectrum of the reaction mixture indicates the presence of the title compound: NMR {COCl1 cf 1.92 (S 3), 4.89 (S 1), 4.96 (S.2), 5.05 (S .2), 5.23 (S 2), 5.26 (Sa), 5.34 (S. | 2), 5.64 (dil, I 5 Hz), 5.95 (, I 5 Hz), 6.10 - (, I 5 Hz), 6.8-7.5 {mi5), 7.56 (di2, 1 9 Hz) and 8.23 (, I 9 Hz).

D. Conversion to 4-nitrobenzyl-7-phenoxyacetyl- (2, 2, 2-trichloroethoxycarbonyl) amino-3-methylene cephamic-4-carboxylate-1-oxide.

To the reaction mixture, the preparation of which is described in paragraph C, cooled to room temperature, is added 390 mg (1.5 mmol) of tin chloride. The mixture was kept at room temperature for 75 minutes, after which 5 ml of methanol was added. Additionally, benzene is added to this and the resulting mixture is washed three times with a mixture of HCl and an aqueous solution of sodium chloride. The benzene layer is separated, dried over sodium sulfate and evaporated in vacuo to a dry substance. The residue is chromatographed over silica gel (15% water) using a gradient of benzoethyl acetate and 246 mg of sulforoxide exomethylene phase are obtained: NMR (CDCU) cf (Uz, 42 (.l 13-Hz), 3.98 (d 1, 13 Hz), 4 , 64, 1 b Hz ;, 4.9 (S. 2), 5.25 (S.2), 5.30 (S.2), 5.34 (S 1), 5.47 (), 6 , 04. (Dil, I 5 Hz), 6.8-7.4 (p1.5), 7.55 (, I 9 Hz) and 8.23 (, 1 9 Hz).

Example 10 4-Bromophenacyl-7-phenoxyacetamino-3-methylencepham-4-carboxylate-1-HPD.

To 200 ml of dried toluene is added. 5.6 g (10 mmol) of 4-bromophenacyl-6-phenoxy-acetamido-2, 2-dimethylpenam-3-carboxylate-1-oxide and 5.2 g. (50 mmol) sodium bisulfite. The mixture was heated under reflux and 1.5 g (11 mmol) of fsi-chlorosuccinimide was added. The resulting mixture was stirred and heated under reflux for 1 hour, cooled in an ice bath, after which 1.3 g (11 mmol) of tin chloride was added. The resulting mixture was stirred at room temperature for about 2 hours and then poured into a mixture of ethyl acetate and water. The organic layer is separated and washed successively with 5% hydrochloric acid, 5% sodium bicarbonate solution and brine. After that, the mixture is dried over magnesium sulfate. After evaporation in vacuo to obtain an almost dry substance, 1.75 g (31%) of the product crystallized and collected. The NMR spectra of the semi-finished product correspond to the structure of the title compound 11.

Found,%: C 51.03; H 3.91; N 5.10; Вг 14,46.

CaeHj N o Br

Calculated,%: C, 51.35; H 3.77, N 4.99; Вг 14,23

Example 11. 1-Oxide-7-phenoxyacetamido-3-methylene cephamic-4-carboxylic acid.

4. 95 g (10 mmol) of 4-methoxybenzyl-6-phenoxyacetamide 6-2, 2-dimethylpenam-3-carboxylate-1-oxide and 5.2 g (50 mmol) of sodium bisulfite are added to 200 ml of dried toluene. The mixture is heated under reflux and 1.5 g (11 mmolJ of N-succinimide) is added. The mixture is then stirred and heated under reflux for 1 h, cooled in an ice bath and 1.3 g (11 mmol) of tin chloride is added After this mixture is stirred at room temperature for about 2 hours and poured into a mixture of ethyl acetate and water. The organic layer is separated and washed successively with 5% hydrochloric acid and brine. Then the organic layer is extracted with 5% sodium bicarbonate solution. The extract is suspended with ethyl acetate. m and acidified to a pH of 2.5. The ethyl acetate layer is separated, washed with water, dried over magnesium sulfate and concentrated in vacuo to a small volume, from which 1.3 g (35%) of the substance are obtained as crystals. NMR spectra showed that they corresponded to the structure of the title compound.

H 4.64;

Found,%: C 52.99-, N 7.69

SbVa ° 6S

c 52.74; H 4.43, Calculated,%;

0 N 7.69 12. Benzhydryl-3Example

-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxy-acetamido-1-azetidyl "il-3-butenoate.

A. To 800 ml of dried toluene, add 20 g of benzhydryl-6-phenoxy-acetamido-2, 2-dimethylpenam-3-carboxylate-2-oxide. The mixture is heated to reflux in a system having a DinStark water trap designed to remove any azeotropic liquid. Then, 12.2 g of N-succinimide is added to the mixture. Heating with reflux is carried out for 1.5 hours. The NMR spectrum of the obtained product is taken, which correspond to the structure of the title compound: NMR (C OC) 5) (Y 1.88 (S3),

4.53 (5.2), 4.90 (Si G), 5.14 (),

5.54 (,), 6.24 (, I 4 and 8 Hz), 6.95), 7.15-7.4 () and 8.0 (, T 8 Hz).

B. Conversion to sulfos cis exomethylene. Azetidine sulfinyl chloride is cyclized with tin chloride to 1-oxide-7-phenoxy-acetamido-3-methylene cepha-4-carboxylic acid. Example 13, 2,2, 2-Trichlo-chloroethyl-3-methyl-2-2 chlorophenyl-4-oxo-3- (4-nitrobenzyloxycarbamido) -1-azetidinyl-3-butenoate, A, Prepare a mixture containing 300 ml 1,1,2-trichloroethane and 10/26 g 2,2,2-dimethylpenam-3-carboxylate 1-oxide. The mixture is heated under reflux to remove about 75 ml of solvent, allowing the reaction medium to dry. The mixture is then cooled and propylene oxide is added, after which 4 g of M-chlorosuccinimide is added. The temperature of the mixture is raised to 102 ° C and the mixture is heated with a reflux condenser for 2.5 hours. A sample of the reaction mixture is taken; the solvent is distilled off. The NMR spectrum of the precipitate corresponds to the structure of the compound indicated in the title: NMR (SOSTS) (L53 4.83 (, 5.25 (52), 5.0-5.4 (6.2 (, T 4 Hz), 7.55 (4, 2, Hz and 8.24 {d 2, 1 V Hz).,., B, Conversion to 2, 2, 2 -trichloroethyl-7- (4-nitrobenzyl-oxycarbamido) -3-methylenecepham-4- carboxylate.-1-oxide, Evaporate a portion representing about one third of the reaction mixture obtained in step A, and precipitate is dissolved in 100 ml of dried methylene chloride, To the resulting mixture is added 5 ml of tin chloride. according to the procedure described in Example 12, and 700 mg are obtained; si of 3-methylene cepham: NMR (CDCl,) (f 3.60, 3.88 (ABq2, 1.15 Hz), 4.82 (Si2), 4.94 (, 1 4.5 Hz), 5.23 (.), 5.40 (), 5.56 (), 5.83 (), 6.37 (d, l, I 10 Hz), 7.46 (di2, 1 9 Hz) and 8.20 ( , I 9 Hz.) Example 14, 4 -Nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-acetamido-1-azetidinyl) -3-butenoate, A, Toluene (500 ml) is heated in An installation with a Dean Stark trap designed to azeotropically remove any moisture. 1.0 g (2.4 mol) of 4-nitrobenzyl-6-acetamido-2, 2-dimethylpenam-3-carboxylate-1-oxide was added to the obtained dried toluene. The resulting mixture is again heated under reflux using a Dean-Stark water trap in order to remove the remaining amount of water. After this mixture is cooled and 400 m (2.9 mol) of N-chlorosuccinimide is added. The mixture is then heated under reflux for 1 hour. A sample of the reaction mixture is taken and the solvent is distilled off. The obtained product according to the NMR spectra corresponds to the structure of the title compound: NMR (CDC1, 1.86 (broad), 2.04, 2.09 (), 4.80 (), 5.2 (), 5.28 ( Si2), 5.63 (tL), 6.05 (, I 4 Hz) and 7.4-8.4 (q 4, AgN). B, Conversion to 4-nitrobeneyl-7-acetamido-3-methylene cephamide 4-carboxylate-1-oxide. The reaction mixture obtained in the tests described in point A is cooled in an ice bath and 1 ml of tin chloride is added to it. The mixture is held for 2 hours at room temperature, after which it is evaporated vacuum to dryness. The resulting precipitate is dissolved in ethyl the acetate / a mixture with ethyl acetate is washed once with a mixture of HC1 and an aqueous solution of sodium chloride and twice with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo to obtain a dry substance. The precipitate is dissolved in a minimum amount of ethyl acetate and after aging for nights collect the resulting crystals of sulfoxide 3-methylene cepham: NMR (CDC1,), cfl, 92 (5.3), 3.80 (width,), 5.00 (, 1 4 Hz), 5.32 (5.2-), 5.45-5.80 (w 5), 7.60 (d-, 2, I 8 Hz), 7.87 (dl, 1 9 Hz) and 8.20 (, 1 8 Hz), Prime, p 15. 4-Nitrobenzyl-7-phenoxy-acetamido-3-methylene cephamic-4-carboxylate- 1-oxide (isolation of the complex), toluene (750 ml) was refluxed using a Dean-Stark trap. To the dried toluene were added 35 ml of propylene oxide, 25 g of 4-nitrobenzyl-6-phenoxy-acetamidopenicillanate-1-oxide and 7 , 37 g of N-chlorosuccinimide. The reaction mixture is heated under reflux at 100 ° C for 2 hours, after which 120 ml of toluene are distilled off from the mixture. After cooling, 7.3 ml of tin chloride is added. Filtration of the mixture provides 17.1 g of an orange complex, which is dissolved in ethyl acetate and washed with an aqueous solution of HCl and brine. Dry the solution of ethyl acetate and evaporate in vacuo to obtain a solid, to give 6.9 g of the title compound. Example 16. Methyl-3-methyl-2- (2-bromosulf1: nyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate, A. A mixture containing 1.88 g of mei-6 -phthalimido-penenicillate -1-oxia and 890 mg of N-bromosuccinimide in 150 ml of carbon tetrachloride, are refluxed for 80 minutes. The reaction mixture is chlacd ;; t, washed with water and brine, extracts with anhydrous MgSO4 and evaporated in vacuo to obtain a dry substance, resulting in 1.82 g of the title compound: NMR (CDC1; j) f 1.98 (b S 3), 3.82 (, COOCH), 5.0–5.35 (), 5.8–6.2 (m 2, (h-lacquer H there)) and 7, 80 (br. Sf 4, AgN). B. Conversion of exomethylene cepham to sulfoxide. Azetidinone sulfinyl bromide obtained in the course of the research described in point A is dissolved in 20 ml of methylene chloride; 0.6 ml of tin chloride is added to the solution. incubation for 45 min at room temperature temperature, the reaction mixture is washed with water and brine, dried on anhydrous MgSO4 and evaporated in vacuo to obtain a dry substance - 1.15 methyl-7-phthalimido-3-methylene cephamic-4-carboxylate-1-oxide (mixture of isomero R and 5- sulfoxide). For the dominant isomer: NMR (CDCl,) (f 3.64, 4.20 (ABq; 2, 1 13.0 Hz,), 3.84 (S. COOCH), 4.90 (dl , 1 4.0 Hz, p) -la HAM), 5.3-5.7 {d 3), 5.97 (, T 4.0 Hz, p-lactam H) and 7.84 {br. S 4, A g N). Example 17. 4-Nitrobenzyl-3-methyl-2- (2-isopropylthiosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate. A. To a solution containing 10 g of 4-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate in 450 ml of toluene is added 1.8 ml of isopropylmercaptan and 3.5 ml of propylene oxide. The mixture was incubated for several days at room temperature and then evaporated in vacuo to dryness, yielding an oily liquid, which was chromatographed on a silica gel column using a toluene-ethyl acetate gradient. A total of 6.62 g of the title compound are isolated: NMR (COCl-j) 1.40 (d 6, 1 6.0 Hz SCH (Cn ,,.) I), 2.01 (S-, 3), 3.55 (m 1, SCH (CH-) 2), 4.60 (, CHi side chain), 5.1-5.4 (), 5.33 (, ether CHi), 6.20 (dd- il, 1 4.5 and 10.0 Hz, p-lactam H), 6.9-8.3 (m9, Arn) and 8, (d2, I 10.0 Hz, NH). B. Conversion to exomethylene cephamide. The title product (682 mg) was dissolved in 3.4 ml of methanesulfonic acid. After 30 minutes, the solution was poured through a separate flask containing ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer is separated, washed successively with an aqueous solution of sodium bicarbonate, water and p-salt (2X) and dried over anhydrous HgSO4. The product crystallizes from ethyl acetate when aged for hours. A total of 60 mg of 4-nitro-benzyl-7-phenoxy-acetamido-3-methylene cephamic-4-carboxylate-1-oxide is released. Example 18. 4-Nitrobenzyl-3-methyl-2- (2-tert-butylthiosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate. The experiment was carried out as described in Example 17, but using 2.4 ml of tert-butylmercaptan instead of isopropylmercap51an. After chromatography, 4.69 g of the title compound are isolated: NMR (CDCl-i,) (fl, 43 (, tert-butyl), 2.01 (), 4.57 (S-, 2, CH-side chain c), 5.0-5.4 (), 6.20 (ddil, 1 4.0 and 11.0 Hz, f-pactam H), 6.8-8.2 (m-f9, ArN) and 8.64 (dl, I 11.0 Hz, NH). B. Conversion of exomethylene cephamine sulfoxide. The title product (700 mg) was dissolved in 3.5 ml of methanesulfonic acid. According to the procedure described) in Example 17 (B) 190 mg of 4-nit-grobenzyl-7-phenoxyacetamido-3-methylene cepha-4-carboxylate-1-oxide. Example 19. 4-Nitrobenzyl-3-methyl-2- (2-methoxy-sulfinyl-4-oxo-3-phenoxy-acetamido-1-azetidinyl) -3-butenoate. To a solution containing 4-nitrobenzyl-3-methyl-2-1 2-chlorosulfinyl-4-oxo-3-phenoxy-acetamido-1-azetidinyl) -3-butenoate obtained from 10 g of 4-nitrobenneyl-6-phenoxyacetate-hydrophobiclimetrothylidyyyytlka – g. oxide and 2.68 g of N-chlorosuccinimide in 400 ml of toluene, 25 ml of dry methanol are added. The reaction mixture was stirred at room temperature overnight, and then washed successively with an aqueous solution of sodium bicarbonate (2X), water and brine (2X). After evaporation in vacuo to obtain a dry substance, 10 g of the pure substance indicated in the title was purified and chromatographic over washed acid with silica gel using a toluene-ethyl acetate gradient. The product is isolated as a mixture of the isomers of the R and S sulfonates. For the dominant isomer: NMR (CDCI ,,) (51/90 (), 3.74 (5, (3, OCH), 4.52 (5.2, CH2 side chain), 4.8-6.3 (mi5) , 5.32 (, ether CHj), 5.76 (, 1 5.0 and 9.0 Hz, p-lactam H) and 6.8-8.2 (, AH). B. Conversion to exomethylene acetate sulfoxide The title compound (590 mg) was dissolved in 2.0 ml of methanesulfonic acid.After aging for 30 minutes at room temperature, the mixture was treated according to the procedure described in 17 (B), at the same time 0.13 g (40%) 4-nitrobenzyl-7-phenoxyacetamido-3-methylene cephamic-4-carboxylate-1-oxide.

Example 20. 4 -Nitrobenzyl-3-methyl-2- (2-methyloxysulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate.

A. The experiment was carried out according to the procedure described

in Example 19, and 3.12 G7 (20 mmol), menitol is used instead of methanol. The resulting sulfinate ester is separated by chromatography on an acid washed silica gel column using a toluene / ethyl acetate gradient. The compound is isolated as a mixture of R- and S-sulfinate isomers. For the dominant isomer: NMR (CDCtb) 0.6-2.4, methyl H) 1.86 (), 3.98 (broad Si 1), 4.52

(S, side chain CHj.), 4.72 (d | l,: L 5, O Hz, I) -lactam H), 4.85, 2 (t.Z), 6.36 (, ester CHj) , 5.72

(dd.l, 1 5.0 and 9.0 Hz, fb-lactam H), 6.8-8.2 (, Arn) and 7.85 (,

1 9.0 Hz, NH).

B. Conversion to exomethylene cephamide.

The title compound (906 mg) was dissolved in 4.6 ml of methanesulfonic acid. After incubation at room temperature for 30 minutes, the reaction mixture is treated according to the described procedure. The conversion to 4-nitrobenzyl-7-phenoxy-acetamido-3-methylene cephamic-4-carboxylate-1-oxide is confirmed by the results of comparative thin-layer chromatography and NMR spectra.

Example 21. 4 -Nitrobenyl-3-3-methyl-2- (2-anilinsulfonyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate.

A. To a solution of 4-nitrobeneyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxy-acetamido-1-azetidinyl-3-butenoate obtained from 10 g

4-nitrobenzyl-6-phenoxy-acetamidopenicillanate-1-oxide and 2.68 g of N-chlorosuccinimide in 400 ml of toluene, 3.6 ml of aniline are added. After incubation at room temperature for 5 minutes, the reaction mixture was washed with water (2X) and brine, dried over anhydrous MgSOn and evaporated in vacuo to obtain a dry substance, while separating the title product: 4.5 (2, side chain CHj), 5, .34 (52, ether,), 6.0-5.3 (w3), 5.77 (dd, l, 5 and 10.0 Hz, | - lactam H) and 6, 8-8, 4 (, AH).

B. Conversion to exomethylene cephamide.

The title compound (2.07 g) was dissolved in 10 ml of methanesulfonic acid. After 30 minutes, the solution was slowly poured into a cooled mixture of saturated aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate layer is separated, washed successively with an aqueous solution of sodium bicarbonate (2x), water (2X) and brine (2X), dried over anhydrous MgSO4 and evaporated in vacuo to a dry product; 4-nitrobenzyl-7-phenoxy-acetamido-3-methylene-fem-4-to-arboxylate-1-oxide (373 mg, 21%) crystallizes from a solution of ethyl acetate as a solid.

Example 22. Methyl-3-methyl0 -2-2-M-succinimidosulfinyl-4-oxo-3-phenylacet1Mido-1-aetidinyl) -3-butenoate.

A. A solution (2.55 g, 7 mmol) of 4-nitrobenzyl-e-phenylacetate, 1mido-py15 of nicacylanate-1-oxide, 5.7 ml (34 mmol) of N-trimethylsilyl-succinimide and 0.81 ml of acetic acid in 41 p of dimethylacetamide are mixed for (3.5 hours at 105 ° C. after cooling

2Q of the reaction mixture was poured into a cooled mixture containing 50 ml of ethyl acetate and 150 ml of water. The water layer is extracted twice with ethyl acetate. The extracts made with ethyl acetate are combined, washed with water, dried over anhydrous Mg 50 d and evaporated in vacuo to obtain a dry substance, while separating 3.3 g of methyl 3-methyl-2- (2-M-succinimidothio- 4-oxo-3-phenylacetamido-1-azetidi 30 Nile -) - 3-butenoate: NMR (CD C)

(fl, 84 (S, 3) .2.78 (S, 4, succinimido;), 3.65 (, CH side chain,), 3.74 (Sj 3, COOCH,), 4.66 (), 5.05, 5 (, | b-lactam H + olefinic

5 CHj). 7f26 (, AHH) and 7.58 (dil, 1 8.0 Hz, NH).

The sulfanimide prepared according to the procedure described above is dissolved in 50 ml of methylene chloride and oxidized.

0 1.48 g of tyi-clabenzoic acid. After 1 h of incubation, the reaction mixture is washed successively with a saturated aqueous solution of sodium bicarbonate and water.

- and brine, dried over anhydrous HgSQf and evaporated in vacuo to give a dry product, which is the title substance: NMR (SOC), (f 1.86 (), 2.60 (, succinimido H), 3 , 54 (5, side

O chain CHi), 3.78 (, СООСН ,,), 4.85, 2 (), 5.7-5.9 (t 1, {b-lactam H), 7.04 (, 1 5 Hz, - lactam H) and 7.3 (S5, ArN).

B. The conversion of exo5 to methylene cepham to sulfoxide.

The title compound (469 mg, 1 MMOL1 J) was dissolved in 2.3 ml of methanesulfonic acid. After keeping for 30 minutes at room temperature

At temperature, the solution is slowly poured into a mixture of saturated aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate layer is separated, washed successively with an aqueous solution.

5 Sodium bicarbonate, water and brine, dried over anhydrous MgSO4 and evaporated in vacuo to a dry solid. The conversion to methyl-7-phenylacetam, co-3-methylene cephamic-4-carboxylate-1-oxide is confirmed by comparative thin-layer chromatography and NMR spectra.

Example 23. 4-Nitrobenzyl-3 methyl-2- 2- (L / H-dicarboethoxy-shchrasosulfinyl) -4-oxo-3-phenoxyacetamido-1-aetidinyl3-3-butenoaa.

A solution containing 10 g of 4-nitro-benzyl-6-feioxy-acetamido-penicillanate-1-oxide in 300 ml of dry 1,1,2-trichloroethane is heated under reflux and dried using a Dean-Stark trap. After approximately 50 ml of solvent is distilled, the mixture is cooled and bml of diethyl azodicarboxylate is added to it. The reaction mixture is heated under reflux for 45 minutes and then evaporated in vacuo to obtain a solid. The residue is triturated with hexane and the excess diethyl azodicarboxylate removed. Upon further drying, the title compound is obtained in the form of a yellow resin, which does not contain impurities, which is not purified prior to the conversion of exomethylenecephamine sulfoxide: NMR (SOSTS) cfl, 40 (t, 3, 1, 7 Hz, CHjCH), 1.95 {broad . S 3), 3.8-4.7), 6.0-5.6 () and 6.7-8.4 (Vni9, Arn).

B. Conversion to exomethylene sulfoxide.

1 g of the substance whose preparation is described in the same example (A) is dissolved in 20 ml of methanesulfonic acid. The mixture is stirred at room temperature for 20 minutes and then poured into an aqueous solution of sodium chloride. After that, the aqueous solution is extracted with 200 ml of ethyl acetate. The ethyl acetate extract was washed with an aqueous solution of sodium bicarbonate, dried (MgSOi) and evaporated in vacuo to a dry solid. The residue is purified by preparative thin layer chromatography using silica gel plates treated with 90% ethyl acetate-benzene. A total of 160 mg of 4-nitrobenzyl-7-phenoxyacetamido-3-methylene cepha-4-carboxylate-1-oxide was isolated.

Example 24. 4-Nitrobenzyl-3-methyl-2- 2- (N, L-dicarbo-tert-butoxy hydrazosulfinyl) -4-oxo-3-acetamido-1-aetidinyl} -3-butenoate.

A. In accordance with the procedure described in Example 23, 820 mg of 4-nit- - robeneyl-6-acetamido-penicillanate-1-oxide is reacted with 465 mg of di-tert-butylazodicarboxylate to give the title compound: NMR (CDCi ,) (fl, 50 (, tert-butyl

1.90 (width 3), 2.0, СН7, -С-Н-)

5.40 {5-, 2, ether СН2), 5.0-6.0 (t5 and 7.6-8.4 (, ArN).

B. Conversion to exomethylene sulfoxide.

The substance indicated in the title, obtained at the stage of the experiment described in paragraph A, is dissolved in 15 ml of methanesulfonic acid and, after 10 minutes at room temperature, poured into saturated aqueous sodium bicarbonate solution. The aqueous solution is extracted with ethyl acetate. The organic extract is washed with an aqueous solution of sodium bicarbonate, dried (IZO) and evaporated in vacuo / to dryness. Chromatographic purification of the residue yields 90 mg (12%) of 4-nitrobenzyl-7-acetamido-3-methylene cepha-4-carboxylate-1-oxide; NMR (SOSTS) d 2.04 O

(5i3, -CH, C-MH-), 3.66 (width B 2, C, -H), 4.90 (, 1 9.0 Hz, C-H), 5.26 (, C4- H-ester CHa) / 5.74 (2S, 2SP2), 5.92 (, I 4.0 and 8.0 Hz, C7-H), 6.97 (, 1 8.0 Hz, NH) and 7.4-8.4 (t | 4, Arn),

Example 25. Sulfoxide 2, 2, 2-trichlorostil-7 {2-thienyl acetamido) -3-methylene cephamic-4-carboxylate.

A solution of (1.4 g) 2,2, 2-trichloroethyl-6- (2-thienyl acetamido) peicants of the nicillanate 1-oxide and 525 mg of di-tert-butyl azodicarboxylate in 50 ml of 1,1,2-trichloroethane heated under reflux for 45 minutes Thereafter, the reaction mixture is cooled and evaporated in vacuo to obtain a solid. The precipitate thus obtained is dissolved in methanesulphonic acid and, after extraction at room temperature for 15 minutes, the acidic solution is extracted with ethyl acetate. The organic extract is washed with sodium bicarbonate solution, dried (.) And evaporated in vacuo to dryness, and 72 mg (7%) of the title compound is recovered: NMR {CDCU) (2.87 (bs. S-) 2 ,), 3.75 (, CH3 side chain), 4.80 C5i2, ether SNA), 5.28 (dl, 1. 4.0 Hz, Sat-H), 5.46, 5.77 (, I CH ,), 5.90 (, 1 4.0 and 8.0 Hz, C7-H) and 6.8-7.3 (, AH).

Example 26. 4-Nitrobenzyl-3 methyl-2- 2- (M, s-dibeisoylhydroazolyl-4-ox-3-phenoxyacetate UV-1-azetidin1-3-butenoate.

A. In accordance with the procedure described in approx. 23, 10 g of 4-nitrobenzyl-6-phenoxy-acetamidopenicillanate 1-oxide is reacted with 7.8 g of dibenzoyl diimide in dry 1,1,2-trichloroethane.

B, Conversion to exomethylene sulfoxide.

1/0 g of the crude substance obtained in the experiment described in point A is dissolved in 20 ml of methanesulfonic acid. After soaking for 20 minutes, the mixture was poured into 300 ml of saturated aqueous sodium bicarbonate solution. The aqueous solution is extracted with 200 ml of ethyl acetate and the organic extract is washed with aqueous sodium bicarbonate solution and dried (MgSO4) and evaporated in vacuo to obtain a dry substance. 4-n-trobenzyl-7-phenoxy-acetamido-3-methylene cephamic-4-carboxylate-1-oxnd (90 g, 40%) was isolated by preparative thin layer chromatography, Example 27. 4 -Nitrobenzyl-3-methyl-2- {2 -acetylhydroeosulfinyl) -4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate. A. To a solution of 4-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxy-acetamido-1-aetidinyl) -3 butenoate obtained from 50 g of 4-yl-robeyl-6-phenoxy-acetamidopenicillanate-1- oxide and 15 g of N-chlorosuccinimide in 1000 ml of 1,1,2-trichloroethane, 14.8 g of acetylhydraeid are added at room temperature. After stirring for about 30 minutes at room temperature, the reaction mixture is washed 3 times with portions (500 ml) of a saturated solution of sodium chloride, dried (MgSO4) and evaporated in vacuo to give a dry residue. The residue is dissolved in ethyl acetate. After cooling, 29.7 g (52%) of the title compound crystallized out in the refrigerator: NMR (SOSTS) (G US (5.6, + allnol CHj), 4.65 CS-i2, side chain C 4.9-5 , 4 (, 5.55 (% 2, ether, CH) and 6.8-8.4 (HI 9,). B. Conversion to sulfoxide exo methylende. 2.0 g of the title seiite is dissolved in 20 ml After incubation for 15 minutes at room temperature, the acidic solution is poured into a separate funnel containing 200 ml of ethyl acetate, 250 m of a saturated solution of sodium chloride and 250 ml of a solution of naciotic sodium bicarbonate. This is washed with sodium bicarbonate solution, dried (MgSO4) and evaporated in vacuo to dryness. The residue is dissolved in a minimal amount of ethyl acetate, and 879 mg crystallizes during the aging (51% 4-nitrobenzyl-7-phenoxyacetamido-3-methylene acetate -4-carboxyl silat-1-oxide Example 28. 4 -pitrobenzyl-3-methyl-2- (2-carbomethoxyhydrososulfonyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate. A. In accordance with the procedure described in Example 27, carbomethoxyhydrazide (4.5 g) is reacted with sulfinyl chloride, prepared from 15 g of 4-nitrobenzyl-6-phenoxyacetamido O penicillanate-1-oxide, and the above compound is obtained as yellow resins: NMR (COCI-), about 1.92 br.), 3.66 (, COOCH3), 4.56, side chain CHj), 4.8-5.6, ester CH, | L- lactam H, olefinic H) and 6.7-8.4 (, AVH). B. Conversion to exomethylene sulfoxide. In accordance with the procedure described in Example 27 (B), the title compound (640 mg) was cyclized in methanesulfonic acid {10 ml) and 240 mg (45%) of 4-ititrobenzyl-7-phenoxy-acetamido-3-methylene cephamide-4 were obtained. carboxylate 1-oxide. Example 29. 4-Nitrobenzyl-3-methyl-2- (2-tolisulfonylhydrazulfinyl-4-oxo-3-phenoxyacetic-4ido-1-azetidinyl) -3-butenoate. A. In accordance with the procedure described in Example 27 (B), tosyl hydrazide (18 g) is reacted with sulfinyl chloride prepared from 30 g of 4-nitrobenzyl-6-phenoxy-acetamidopenncylate-1-oxide, and the title compound is obtained in a yellow resin that does not crystallize. The compound obtained is cyclized in methanesulfonic acid (150 ml) and 7.0 g (23%) of 4-nitrobenzyl-7-feioxyacetamido-3-methylene cephamic-4-carboxylate-1-oxide are obtained. Example 30. 4-Nitrobenzyl-3-methyl-2- (2-aminosulfinyl-4-oxo-3-phenoxyacetamido-1-azendinyl) -3-butenoate. A. To a solution (5 g) of 4-nitrobenzyl-3-methyl-2- (2-chlorosulfnyl-4-oxo-3-phenox acetamido-1-azetidinyl) -3-butenoate in toluene is added a solution (5 g) sodium cyanate in 100 mp water. After aging at room temperature for 1 h, the organic layer was separated, dried (MgSO4) and evaporated in vacuo to dryness, thereby isolating a mixture containing the title column and 4-nitrobenzyl6-phenoxcacetamido-penenicillanate. For the title compound: NMR (SOSTS) f 1.96 (ei3), 4.55 (side chain CH + -S-NH), 4.88 (d, l, I - 4.5 Hz, p-lactam H), 5.0-5.5 CWi5), 5.72 (, 1 4.5 and 9.0 Hz, V-lactam H), 7.75 Cf1, T 9.0 Hz, H) and 6.9-8.4 (, AGN). Found,%: C 53.69; H 4.77; 10.62; S 5.90 C24V4 ° eS Calculated,%: C 53.48; "4.68; 10.85-, O 24.78; S 6.21 V. Conversion to ecomethylene sulfoxide. In accordance with the procedure described in Example 27 (B), the compound indicated in the Agolovke is cyclized in methanesulfonic acid to obtain 4-nitrobeneyl-7-phenoxy-acetamido-3-methylene cephamic-4-carboxylate-1-oxyl.

Example 31 2,2,2-Trichloroethyl-3-methyl-2-2-chlorosulfinyl-4-o-3- (2-tert-butylcarbonyl) Mino-2-phen lacetamido) X-azetindinyl -2-butenoate

A. A solution (2.85 g, 5 mmol) of 2, 2, 2-trichloroethyl-6- (2-tert-butoxycarbonylamino-2-phenylacetamido) -2,2-dimethylpenam-3-carboxylate-1-oxide in 175 ml toluene is subjected to aeotropic distillation of 50 ml of toluene from the mixture. To the dried solution, 0.685 g (5.5 mol) of N-chlorosuccinimide was added to the solution. The resulting mixture is boiled for 70 minutes, then cooled to room temperature, filtered, evaporated in vacuo to dryness to give the title product {contaminated with H-chlorosuccinimide): NMR (SOC) cf 1.40 (59, tert-butyl) , 1.95 (, CH (CH): CH2), 4.82ft) 5 2, ether CHi), 5.20 (IZ, CH (CH): CH2 + + CHCOOCHj CCli,). 5.38 {d 1, 1 4.5 Hz azetidinone), 5.80 (ml, azetiDINON) and 7.34 (S 5, ArN).

B. Cyclization in exomethylenes. The resulting product was dissolved in 100 ml of dry toluene and 1.0 ml of tin chloride was added. The resulting solution was stirred for 1 h, washed with brine, dried over magnesium sulfate and evaporated to dryness. The product is recrystallized from ethyl acetate a and no gives 2,2,2-trichloroethyl-7- (2-tert-butoxycarbonylamino-2-phenylacetamido) -3-methylene cephamic-4-carboxylate-1-oxide.

Example 32: 2,2, 2-Trichloroethyl-3-methyl-2- 2-sulfino-4-oxo-3- (2-tert-butoxycarbonylamino-2-phenyl acetamido) -1-azetidinyl-3-butenoate.

A. Sulfinyl chloride, obtained in the experiment described in example 31, is dissolved in 50 ml of acetone and 100 mp 1 n. HC1. The resulting solution was stirred for 2 hours at the temperature of the ice bath. The mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, and then extracted with an aqueous solution of sodium bicarbonate. The aqueous extracts are combined and layered with ethyl acetate.

The pH of the aqueous layer is adjusted to 2-1 n. hydrochloric acid. The ethyl acetate layer is separated. the brine was washed with brine, dried with hdzd and evaporated to dryness in vacuo to give 1.032 g of the title product: NMR (SDC)) cG 1.4 f 5.9, tert-butyl), 1.94, CHC (CHO sCH), 4.82 (2, CHjCCl), 5.22 (ri4, CH COO CH2CC3 + SNTCCH) ,,: CHO + azetidinone), 5.74 (dd-tl, 1 4.5 and 9.0 Hz, azetidinone), 7.34 (u5, Arn), 8.10 (bSl, 9.0 (bSl, SOOH).

B. Cyclization in exomethylenes.

A solution of the product (0.1 g) (point A) and 0.04 g of phosphorus pentoxide in 20 ml of 1,2-dichloroethane is stirred at room temperature for 1 hour. The mixture was boiled for 30 minutes, cooled to room temperature, combined with 25 ml of ethyl acetate and 50 ml of brine. The organic layer was separated, washed with brine, dried over MgSO4, evaporated to dryness, and 2.2,2-trichloroethyl-7- (2-4-butoxycarbonylamino-2-phenylacetamido) -3-methylene cephamide-4-carboxylate-1-oxide was obtained. ..

Example 33 2,2, 2-Triethyl-3-methyl-2-2-hydroxy-4-oxo-3-2-thienyl-estamido) -l-azethinyl-3-butenoate

A. Solution (3.5 g) 2, 2,2-trichloroethyl-6- (2-thienylacetamido) -2,2-dimethylpenam-3-carboxylate-1-oxide in 350 ml of toluene, dried by azeotropic distillation 100 ml of toluene from cMef si Then it is cooled and 1 g of N-chlorosuccinimide is added. The reaction mixture is boiled for 50 minutes, cooled.

and filtering 5 ml of the filtered solution was evaporated in vacuo to dryness and the title product was obtained: NMR (SOSTS) (f 1.87 (, CH (CH)%:: CH2.) 3.82 (, CHi side chain), 4.80 ( AB 2, I 13 Hz, CHiCCli,), 5.18 (lw-t3, CH (CHO iCHil, 5.50 (dil, 1 4.5 Hz, azetidinone) and 6.05 (W 1, azetidinone C -H ).

B. Cyclization on methylencepham. To the residue of the toluene solution

sulphinyl chloride product (item A is added 1.5 ml of stannous chloride). The mixture is stirred for 1 hour. 250 ml of ethyl acetate are added, the resulting solution is washed with three portions of 400 ml of brine, dried over MD50l, evaporated in vacuo to dryness. The product obtained is dissolved in 30 ml of ethyl acetate, recrystallized and separated to give 2,2,2-tri-chloroethyl-7- (2-thienyl-acetamido) -3-methyl-6-carboxylate-1-hydroxylate-1-hydroxy NMR (OM SOd-6 ) 3.38 (44 2, Cj-H), 3.8 (, side chain CHjl, 5.02 (, CH2CC1z) / 5.04 (с1 1, I 4.0 Hz, С (, - Н), 5.45, 8 (Wi4, 6.8-7.4 (“i3, thienyl} and 8.16 (, 1 80 Hz, NH).

Claims (3)

Invention Formula The method of obtaining 3-methnlencef 1 Sulfoxides of General formula I COOCg R -1, -C-C-alkyl, 4-nitrobenzyl hydroxy group or arylalkyl group of the formula R4-H, where 4 phenyl, phenoxy group or t-enyl, 515 is a hydrogen atom or beyond the “| , 4-1 "oxybenzyl, Cj-C alkanoyl oximbvl 2-iodoethyl, 4-nitrobenzyl, diphenylmethyl, phenacyl, 4-halo-hnvacil, di-methyl-alkyl or 2,2,2-trichloroethyl, characterized the yield of the target products, a compound of the general formula: Gl where 11 (and Ui are as defined above, and X is a chlorine or bromine atom, a group of the formula -ORfe, in which ftb is a hydrogen atom or C.-C.-. alkyl, by a group of the formula -, in which RT is alkyl or ari, or by a formula of formula 9 in which Rg is a hydrogen atom and Rq is a hydrogen atom, phenyl or represents a group of the formula in which C.-C alkylcarbonyl, alkoxycarbonyl or tosyl, R is COOR or -COV. and Rq is N HCOOR or -MHCOR, where K, alkyl or phenyl, or X-N -succinimido, is reacted with Friedl-Crafts catalyst such as Lewis acid or strong acid, or anhydrous silver salt, or silver I-toluene sulfonate in dry an aprotic organic solvent or a compound of the common form JJ And dissolves in a strong organic acid pr 20-115 ° C under the condition: when X is a bromine atom, then R. is a phthalimido group; chlorine or bromine atom, and forming 4karbonovuyu with free acid is recovered in the form of an ester. 2. The method according to claim 1, is also distinguished by the fact that aluminum chloride, or tin chloride, or tin bromide, or zinc chloride, or zinc bromide, or antimony pentachloride, or titanium tetrachloride, or ferric chloride are used as the catalyst. , or gallium trichloride, or zirconium tetrachloride, or mercury chloride, or stillage trichloride. 3. The method according to claim 1, characterized in that methanesulfonic acid or ethanesulfonic acid, or trifluoroacetic acid, or trichloroacetic acid, or dichloroacetic acid, or sulfuric acid, or phosphoric acid, or polyphosphoric acid, or chloric acid, or chlorosulfonic acid, or fluorosulfonic acid. Priority by featured. 12/24/744 when the phthalimido group, 2,2-dimethyl-3-nitroso-5-oxo-4-phenylimidazolidinyl or amido group of the formula I SOCHN-, where the alkyl of 4 is a nitrobenzyloxy group or arylalkyl group, where feIl, phenoxy group, or the arylalkyl group, where feIl; or hetero group, methyl, tert-butyl, benzyl, 4-methoxybenzyl, Ci-C, alkanoyloxymethyl, 2-yodztil, 4-nitrobenzyl, dipheiilyuyl, phenacyl, 4-halofenacnl, dimethylallyl or 2,2,2-trichlorostil; X is a chlorine atom or a hydroxyl group; the compound of the general formula II is reacted with a Friedel-Crafts catcher, such as a Lewis acid or a strong acid or an anhydrous silver salt, or silver h-toluene sulfonate in a dry aproton. organic solvent at a temperature of from 20 to 115 ° C. 11.19.75 when the phthalimido group, N-phenoxyacetyl-N- (2,2,2-tri-chloroethoxycarbonyl) -aminogropy, 2,2-dimethyl-3-nitroso-5-oxo-4-phenylimidazolidinyl or amido group of the formula O K NH R 4 an alkyl, 4-nitrobenzyloxy group or arylalkyl group of the formula T wherein 4 is phenyl, phenoxy group or thienyl and Rj is a hydrogen atom or a protected hydroxyl or amino group, 9 is methyl, t-butyl, benzyl, 4-methoxybenzyl, Cj-Ci alkanoyl-oximethyl, 2- Yaodztil, 4-nitrobenzyl, diphenylmethyl, phenacyl, 4-halophenacyl, methylmethyl, or 2,2,2-trichloroethyl; X is a chlorine or bromine atom, a group of the formula -ORb, where Rfe is a hydrogen atom or C -C alkyl, a group of the formula -SR-i, where R is, alkyl or aryl, or a group of the formula where Rg is a hydrogen atom and IQ is a hydrogen atom, phenyl or represents a group of the formula -NHRio where is -1C 3 alkylcarbonyl, alkoxycarbonyl or tosyl, or the group -CO (or -COR and R, is the group -1 HCOOR H or -NHCOR, where 8, is alkyl Cj-C or phenyl, or X is H-succinimido } the compound of formula 11 is reacted with a Friedel-Crafts catalyst such as a Lewis acid or a strong acid. or an anhydrous silver salt, or with silver I-toluenesulfonium in a dry aprotic organic solvent or dissolve a compound of general formula TI in a strong organic acid at a temperature of from 20 to silver toluensulfonate or Lewis acid, then X is a chlorine or bromine atom. Sources of information taken into account in the examination 1. Accepted for France  2190419, cl. And 61 to 21/00, 01.02.742. Accepted for France 2218877, cl. A 61 K 21/00, 09/20/74 5 1 3. Accepted for France No. 2207697, cl. A 61 to 21/00 06/21/74 (prototype).