SU974936A3 - Process for producing pename derivatives - Google Patents

Abstract

1481807 Cephem derivatives PFIZER Inc 14 Oct 1974 [17 Oct 1973] 44350/74 Heading C2C The invention comprises compounds of the formula and the salts thereof, wherein T is a tetrazoyl group which is either wherein R is an acyl group of the formula A is H, CH 3 COO, l-methyl-tetrazolyl-5-thio or 2 - methyl - 1,3,4 - thiadiazolyl - 5 - thio; R 1 is H, (C 3 -C 6 ) alkanoyloxymethyl, 1 - (C 4 -C 7 ) alkanoyloxyethyl, CH 3 OCH 2 - or phthalidyl and Rll is the same as R 1 or is a tetrazolyl cephem nitrogen protecting group or precursor thereof and is selected from and wherein R 6 is (C 1 -C 3 ) alkyl or phenyl, R 7 is OH, CH 3 O, (C 2 -C 4 ) alkanoyloxy or benzyloxy, R 8 is H, OH, F, Cl, Br, I, CH 3 , CH 3 O, (C 2 -C 4 ) alkanoyloxy, phenyl or benzyloxy, R 9 and R 10 are each H or CH 3 and X is O or S; Ar is cyano, bromo, phenyl, mono- or disubstituted phenyl where each substituent is hydroxy, fluoro, chloro, bromo, amino, methoxy, or methyl, phenoxy, phenylthio, pyridylthio, thienyl, 2- methyl - 1,3,4 - thiadiazol - 5 - ylthio, 1 - tetrazolyl, (C 1 -C 12 ) alkyl, (C 2 -C 12 ) alkenyl, (C 3 - C,) cycloalkyl, (C 5 -C 8 ) cycloalkenyl, cycloheptatrienyl, 1,4 - cyclohexadienyl, 1 - amino (C 4 -C 7 ) cycloalkyl, 5 - methyl - 3 - phenyl - 4- isoxazolyl; 5 - methyl - 3 - (o - chlorophenyl)- 4 - isoxazolyl, 5 - methyl - 3 - (2,6 - dichlorophenyl) - 4 - isoxazolyl, 5 - methyl - 3 - (2- chloro - 6 - fluorophenyl) - 4 - isoxazolyl, 2- (C 1 -C 4 ) alkoxy-1-naphthyl, sydnonyl, furyl, pyridyl, thiazolyl, isothiazolyl, pyrimidinyl, triazolyl, imidazolyl, pyrazolyl, substituted phenoxy, substituted phenylthio, substituted pyridylthio, substituted thienyl, substituted furyl, substituted pyridyl, substituted tetrazolyl, substituted thiazolyl, substituted isothiazolyl, substituted pyrimidinyl, substituted triazolyl, substituted imidazolyl or substituted pyrazolyl, each substituted moiety being substituted by up to two of fluoro, chloro, bromo, hydroxy, hydroxymethyl, amino, N,N-di (C 1 - C 4 ) alkylamino, (C 1 -C 4 ) alkyl, aminomethyl, aminoethyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkylthio, 2-aminoethoxy and N-(C 1 -C 4 ) alkylamino, Q is hydrogen, hydroxy, azido, amino or carboxy ; n is an integer of 0 or 1; provided that when Ar is pyridylthio, phenoxy, phenylthio, 2 - methyl - 1,3,3 - thiadiazol - 5 - ylthio, bromo or cyano and n is 1, Q is hydrogen or carboxy. They may be obtained by (1) acylating a compound of Formula I wherein R is replaced by H with an acid halide, an activated ester or a mixed anhydride of a carboxylic acid, or a mixture of a carboxylic acid and a carbodiimide to give R as an acyl group of the above formula; and (2) reacting a compound of Formula I where T is replaced by -CONHR 2 wherein R 2 is selected from groups of Formulµ III and IV above, with a chlorinating agent to produce an imino chloride followed by reaction with an azide to form a tetrazolyl group, optionally replacing the R 2 group by treatment with a mixture of CF 3 COOH and anisole. Pharmaceutical compositions comprise the compounds of Formula I above as antibacterial agents together with a pharmaceutical carrier, and may be administered orally, e.g. by way of animal feed supplements, or parenterally.

Description

The invention relates to the production of new derivatives of foam, which can be used as intermediates for the synthesis of antibacterial compounds, valuable as an additive to animal feed, as therapeutic agents in the fight against infectious diseases caused by gram-positive and gram -negative bacteria, to as a means of sterilizing hospital rooms.

Various penam derivatives are known having a carboxyl group L1J -15 at position 3 of the foam ring. or broadcast £ 2].

It is known that the reaction of an alkali metal azide with an iminohalide results in the corresponding tetrazole [3]. 20

The purpose of the invention is the development of a method for obtaining a previously unknown row of foam having a tetrazolyl group in the 3 “position, directly attached to the ring of the foam.

This goal is achieved based on the known reaction [3] a method for producing derivatives of foam of the General formula

or with ?

(W 5 or —CH ₂ CH ₂ Y! In which is a hydrogen atom, Cp. 4. Alkyl;

974936: 4 each of R. and R. - oxy "7 2- group TS_ ₄ alkoxy, benzyloxy; R4. a hydrogen atom or methyl; ^R 5 ^C 4-4 “ ^alkyl ί 5

Y-Cg ^ g-alkoxycarbonyl, which consists in the fact that 6-triphenylmethylaminopenicillanic acid is reacted with an appropriate amine selected from cadaver

where the radicals have the indicated meanings, at a temperature of (~ 30) “(+ 30) ° С or with an isocyanot of the formula jq о

_{0 = c} = tg-s where 'the radicals have the indicated values 25, at a temperature of 0 0 ^σ 0, followed by treatment of the corresponding 6-triphenylmethylamino-3 “carbamoylpenam with phosphorus or phosgene or thionyl chloride JO in the presence of 1-3 mol of teric amine at a temperature of (-20) ~ 30 ° C and the resulting iminochloride is reacted with an azide of an alkali metal or tetramethylguanidinium at a temperature of 0 ~ 30 ° C. ^,5

In the examples illustrating the invention, the following abbreviations are adopted: s-singlet; d-doublet; t-triplet; sq quartet; m-multiplet.

PRI me R -1. 6- (Triphenylmethyl- ¹⁰ amino) -2,2-dimethyl-3 1- (4-methoxybenzyl) -tetrazol-5 ^_ yl] foams.

A, 6- (Triphenylmethylamino) -2,2-dimethyl-3- £ H- (4-methoxybenzyl) ^ carbamoylpenam. ⁴⁵

In a stirred suspension (86.4 g, 0.8 mol) of 6-aminopenicillanic acid in 600 ml of anhydrous chloroform, 11.2 ml (0.4 mol) of triethylamine are added and transferred at room temperature to a clear solution (about 15 minutes) . 134.9 g (0.44 mol) of triphenylmethyl chloride of 90% purity 55 'at room temperature are added to the resulting solution in portions over 25 minutes. Stirring is continued for another 64 hours, then 5.6 ml of triethylamine are added. Ras creates cooled to 0-5®S and then dropwise during 30 minutes, poured · 'ice-cooled solution (38 ml, 0.4 mol) of ethyl chloroformate in 80 ml of chloroform ι, maintaining the reaction temperature in the range ^of 4-9 Permesha'vayut C. for another 15 minutes, then for 30 minutes at 4 "C 9 ^F, fed below solvent surface 54.2 ml (0.4 mol) 4tmetoksibenzilamina. Stirred for another half hour at 3-6 ° C, then for 20 minutes allow the reaction mass to warm to 20 ° C. The reaction mixture is washed with water, then brine. After that, it was dried using magnesium sulfate to obtain a chloroform solution of 6- (triphenylmethylamino) -2,2-dimethyl ~ 3 £ M- (4-methylbenzyl) carbamoyl-penam.

B. 6- (Triphenylmethylamino) -2,2dimethyl ~ 3 ^_ £ 1 - (4-methoxybenzyl) -tetrazol-5-yl] foams.

In a chloroform solution prepared by the described method containing .6'9 ^ 4 g. (0.120 mol) 6- (triphenylmethylamino) -2,2-dimethyl-3 - [, \ - (4-me ~ toxibenzyl) carbomoyl] penam, volume 133.3 ml, another 132.7 ml of chloroform is added, then 29.1 ml (O. ZbOmol) of pyridine. The solution was cooled to 0 ° C, then 26.22 g (0.126 mol) of phosphorus pentachloride were added over 15 minutes with stirring. Stirring continues. 10 min at 10 ° C, then

1.5 hours at room temperature, an iminochloride solution is obtained. To 1/6 • an aliquot of this solution is poured

4.85 ml. (0.06 mol) of pyridine, then 2.42 ml (0, V mol) of methanol at 25 ° C with stirring. Stir for another 15 minutes and add 2.03 g (0.038 mol) of ammonium chloride, then 2.59 g (0.039 mol) of 95% sodium azide. The reaction mixture was stirred at room temperature for 4 hours. After this, 400 ml of water and 200 ml of chloroform were poured, separated into layers. The organic phase is washed with water, dried using magnesium sulfate and evaporated in vacuo to a small volume. This final chloroform solution was poured dropwise with stirring into a large volume of diisopropyl ether and filtered after 30 minutes. precipitate formed. 6.1 g are obtained.

6- (triphenylmethylamino) -2,2-dimethyl-3 “£ 1 - (4-methoxybenzyl) tetrazol-5 ~ yl) penam. The IR spectrum (KW tablet) shows an absorption band at 1790 cm * ' ¹ '. (beta-lactam); The NMR spectrum (CDCl ^) shows absorption at 7.25 (aromatic hydrogens), 5.40 S (wide benzyl hydrogen), 5.05 (C-3 hydrogen), 4.50-3.30 (C-5 hydrogens) and C-6), 3.70 (methoxy hydrogens), 3.50-3.1CL (wide peak, H), 1.50 (C-2 methyl hydrogen) and 0.75 (C * hydrogen -2 methyl).

PRI me R 2. 6- (Triphenylmethylamino) -2,2-dimethyl-3 ^ £ 1 - (4-benzyl'oxybeneyl) -tetrazole-5 “Il penam.

A. 6- (triphenylmethylamino) -2,2-di-15 methyl-3 ~ [M- (4-benzyloxybenzyl)] carbomyl foams.

Into a stirred solution (20 g)

6-triphenylmethylaminopenicillanic acid in 140 ml of acetone at 0-5 ° C 20 poured 6.08 ml of triethylamine, then 5.78 ml of isobutylchloroformate. After 10 minutes, the mixture was filtered directly into a stirred solution (9.28 g) -. 4-benzyloxybenzylamine in 25 100 ml of water and 300 ml of acetone at room temperature. The resulting mixture was stirred for 4 minutes, then 500 ml of water was added. Stirred for another 7 minutes, then the reaction mixture was extracted with 30 ether. The ether extract was dried with anhydrous magnesium sulfate and evaporated to dryness in vacuo. The resulting crude product was dissolved in 200 ml of ether and poured dropwise into 2500 ml of hexane over 35 10 minutes. The precipitate formed is filtered off to give 21.5 g of 6- (triphenylmethylamino) -

2,2-dimethyl-3 “[M- ^ benzyloxybenzyl) carbomyl J-foams. 40

B. .6- (triphenylmethylamino) -2,2-dimethyl-3-chloro- [M- (4-benzyloxybenzyl) aminomethyl to foams.

Into a stirred solution (2 g) of amide c. 45 10 ml of dry chloroform at 0-5 ° C is poured 0.99 ml of pyridine, then 5.42 ml of a 2.26 M solution of phosgene in chloroform. The reaction mixture was stirred at room temperature. _m Then it is evaporated to dryness under vacuum, a viscous resin is obtained, which is extracted with 100 ml of ether. The ether extract was filtered, the filtrate was evaporated, and the iminochloride was obtained as a yellow $ ₅ foam.

C. 6- (Triphenylmethylamino) -2,2-dimethyl-3 * (1 - (4-benzyloxybenzyl) tetrazol-5-yl} foams.

The described iminochloride is dissolved in 8 ml of dry N, N-dimethylformamide. 249 mg of potassium azide was added to the resulting solution, and the turbid solution was stirred for 2.25 hours at room temperature. The solvent is distilled off at room temperature under high vacuum, a brown gum is prepared, distributed between 60 ml of water and 150 ml of ether. The ether phase is separated, washed with saturated brine, dried with anhydrous sodium sulfate, and evaporated to dryness in vacuo. Receive 980 mg of 6- (triphenylmethylamino) · -

2,2-dimethyl ~ 3 ~ £ 1 - (4 benzyloxybenzyl) tetrazol-5-yl] penam. NMR spectrum (CDClj) shows absorption bands at 7.30 (m, aromatic hydrogens), 5.46 (q, benzyl hydrogens) 5.05 (s, hydrogen C-3), 5.00 (C. , benzyl hydrogens), 4.40 (m, hydrogens C-5 and C-6), 1.40 (s., hydrogen C-2) and 0.70 (s., hydrogen C-2).

Example 3. 6- (Triphenylmethylamino) -2,2-dimethyl-3 ~ (1-furfuryltetrazol-5-yl) foams.

A. 6- (Triphenylmethylamino) -2,2-dimethyl-3- (N-furfurylcarbamoyl) foam.

In a stirred suspension (216 g, 1 mol) of 6-aminopenicillanic acid in 1500 ml of chloroform, 2278 ml (2 mol) of triethylamine are poured at 25 ~ 30 ° C. In the resulting solution, add in portions over 25 minutes) 0 g (1.1 mol) of triphenylmethyl chloride at 25 ~ 30 ^s C. Continue to stir for another 44 hours at room temperature,

A portion of 522 ml (0.25 mol) of the indicated solution of 6- (triphenylmethylamino) -penicillanic acid was cooled to 4 ° C and 3.5 ml of triethylamine were added. With vigorous stirring at 5 ° C, 23.75 ml of ethyl chloroformate are added. Stirred for another half hour at 6 ° C, then 8.43 ml of furfurylamine was fed below the surface of the liquid. Then, in a similar manner, three more servings of furfurylamine (5.90, 4.22 and 3.54 ml) are poured at 10 minute intervals. The total volume of the infused “furfurylamine reaches 22.09 ml (0.25 mol), during the entire period of the infusion of the amine, the temperature is maintained at about 6 ° C. At the end of the tide, the amine was removed from the cooling bath and the reaction mixture was stirred for 45 minutes at 25 ° C. Then washed successively with three portions of water and one portion of brine. Then dried at

Ί 974936 8 power of anhydrous magnesium sulfate. 610 ml of a " chlorofrrmno " solution are obtained.

6- (triphenylmethylamino) -2,2-dimethyl3,3 * (M-urfurylcarbomoyl) penam. The NMR spectrum of the solution shows up to 5 ppm at 7.3 ppm. (17 N, m), 6.2 ppm.

(1 N, m), 4.35 ppm. (3 N, m), 4.05 ppm. (2 N, s), 1.6 ppm. (3 N, s) and 1.35 (3 N, s).

I Q

C. 6 ~ (Triphenylmethylamino) -2,2-dimethyl-3 ~ (1-furfuryltetrazol-5 ^_ yl) foams.

In a stirred solution of 3.05 g _ (5, 6 mol) of 6- (triphenylmethylamino) 2,2-dimethyl-3 ~ [Y-furfurylcarbamoyl). Penam in 8 ml of chloroform at 0 ° C. is added 1.35 ml (17 mol) pyridine, then 2.64 ml of a 4.33 M solution of phosgene ₍ in chloroform. Continue stirring for 1 h at 25 ° C. Chloroform, an excess of ²⁰ phosgene and pyridine are distilled off under vacuum, the residue is dissolved in 5 ml of chloroform. The solution is cooled to 0 ° C and then, in a few small portions: 2.25 g (14.4 mol) of azide are added; ²⁵ yes tetrometoylguan ~ idinium: continue stirring for 15 minutes at room temperature, 20 ml of chlorofor are added ma, then 30 ml of water and adjusted the pH to 6.5. Separate the chloroform layer / ³⁰ washed with water, then brine, dried over magnesium sulfate. The solvent is distilled off in vacuo to give 3.37 g of a dark red foam. It is dissolved in a small amount of chloroform 35 and absorbed in a column of chromatographic silica gel, elute with chloroform, evaporate the appropriate fractions in vacuo to give 6- (triphenylmethylamino) -2,2-dimethyl-3 “(1-fur · ⁴⁰ furyltetrazole ~ 5yl) foams. I MR - spectrum: product (CDClj) is detected - absorption at 7.40 ppm (m, 16 n), 6.40 ppm. (m, 2H), 5.50 ppm. (s, 2H),

5.20 ppm (s. 1H), 4.90 ppm. (m, 2H), 1.60 ppm. (s, ZN) and 0.80 ppm. (s, zn).

PRI me R 4. L- (triphenylmethylamino) -2,2-dimethyl-3 ^- (1-methylfurfuryl-tetrazol-5-yl) foams are obtained by the method described in example 3, but they take 5 ymerto fur-50 furylamine 5 methylfurfurylamine. The NMR spectrum (CDCl ^) of the product shows absorption at 7.36 ppm. (m, 15H), 6.33 ppm. (m, Щ), 5.93 ppm. (m, 1H),

5.50 ppm (s, 2H), 5.20 ppm. (s, 2H), 55

4.50 ppm (m, 2H), 3.23 ppm. (d, 1H),

2.26 ppm (s, ZN), 1.63 ppm. (s, ZN) and 0.90 ppm. (m, ZN) I.

EXAMPLE 5. 6- (Triphenylmethyl ^; but) -2,2-dimethyl-3- [1 - (2,4-dimethoxybenzyl) tetraZol-5 ~ yl] foams are obtained in 46% yield from 6 - (triphenylmethylamino) penicillanic acid, replacing the furfurylamine of Example 3 with 24-dimethoxybenzylamine. The crude product is purified by recrystallization from a mixture of methylene chloride and methanol. . NMR spectrum of the product (CDClg) shows absorption at 6.40 ppm. (m, 16H), 6.45 ppm. (m, 2H), 5.40 ppm. (s, 2H), 4.5 ppm. (m, 2H), 3.75 ppm. (s, ZN), 3.70 ppm (s, ZN), 1.55 ppm (s, ZN). and 0.90 ppm (s, ZN).

Example 6 .. 6- (triphenylmethyl-. Amino) -2,2-dimethyl-3 [1 (4-hydroxybenzyl) tetrazol-5-ylZpenam.

A, b- (Triphenylmethylamino) -2,2dimethyl-3 ~ GN- (4-hydroxybenzyl) carbamoyl foams.

! Into a mixed suspension! (43.2 g, 0.2 mol) of 6-aminopenicillanic acid in 300 ml of chloroform add (pour) 55.6 ml (0.40 mol) of triethylamine, then 61.2 g (0.22 mol) of triphenylmethyl chloride at room temperature. Stirring is continued for an additional 48 hours at room temperature.

120 ml of the chloroform solution obtained by the described method containing 0.06 mol of 6- (triphenylmethylamino) penicillate triethylammonium are taken. 40. ml of chloroform is diluted and 1.67 ml (0.012 mol) of triethylamine are added. The mixture is cooled to 4 ° C. in an ice bath, then 6.84 ml of ethyl chloroformite are added in one go with stirring. Stirring is continued for another half an hour while cooling in an ice bath and 7.5 (0.0 mol) _ 4-hydroxybenzylamine is added. Stirring is continued for 10 minutes while cooling in an ice bath, then 1 hour without cooling. The chloroform solution is washed with water, then brine, and then dried with anhydrous sodium sulfate. The solvent was distilled off in vacuo to give the crude amide. The crude amide is dissolved in 50 ml of chloroform.m and absorbed in a chromatographic / silica gel column. The column is eluted with chloroform, taking 400 ml of the fraction. Fractions 9-15 were combined and evaporated to give an oil which solidified upon trituration with methylene chloride. Then triturated with ether to give 12.63 g of 6- (triphenylmethylamino) -2,2-dimethyl ~ 3- £ N-,

IS (4-hydroxybenzyl1 carbamoyl 'penam, mp 166-168 ° C (decomp.). The IR spectrum of the product (solution in CHCl-j) shows absorption at 1785 cm ⁷ · ¹ (betalactam) and 1675 cm * ( amide 1). The Nuclear resonance spectrum (CDC1%) exhibits β absorption at 7.60-6.40 ppm (m, 20H, aromatic and amide hydrogens), 4.704.10 ppm (m, 5H, C- 5 and C-6, hydrogens of benzylmethylene and C-3), ⁰ (2.98 ppm (d, 1 N, amine nitrogen), 1.64 ppm s, 3H, methyl C-2 hydrogens and 1.31 ppm s, ZN, methyl hydrogen (C-2).

B. ^ - (Triphenylmethylamino -2,2-dimethyl-3 ^_ D- (4-hydroxybenzyl) tetrazol-5 ~ yl) foams.

To a stirred solution of 1.69 g (3 mol) of 6-triphenylmethylamino) -2,2 dimethyl ~ 3 ~ EI ^- (4-hydroxybenzyl carbomoyl] penam (obtained in step A), 1 ml (12 mol) of pyridine is added to 9 ml of chloroform. The solution is cooled ... 4 ° C in an ice bath and 0.80 ml of chlorotrimethylsilane is added. ^! The solution is stirred for 40 minutes at room temperature and again cooled to 4 ° C. 1.5 ml of 4.3 I phosgene solution are added in chloroform (6.45 mol) and the cooling bath is removed, stirred for another 1-5 hours and the volatile components are distilled off under vacuum.

The oily residue is dissolved in 6 ml of chloroform and the solution is cooled to 4 ⁱⁿ C in an ice bath. Q95 g (6 mol) of tetramethylguanidinium azide was added to the stirred solution and stirring continued for another Th. at room temperature. Then add 25 ml of water, then 1N sodium hydroxide is enough to bring the pH of the aqueous phase to 10. ' The chloroform layer is separated, washed with water, dried with sodium sulfate, evaporated to dryness in vacuo. The oily residue (2.3 g) was dissolved in a small volume of chloroform and absorbed in a column with 30 g of chromatographic silica gel. Elute with chloroform, taking fractions of 50 ml each. The 13–19 fractions were combined and evaporated in vacuo to give 0.71 g of 6- (triphenylmethylamino) -2,2-dimethyl-3 ~ {1 - 4-hydroxybenzyl tetrazol-5 ^_ ylZpenam. The IR spectrum (CHCl ^) exhibits absorption at 1780 cm '(beta-lactam). The NMR spectrum (CDC1 $) shows absorption at 7.80-.6.67 ppm. (m, 2QH, apo35 hydrogens

974936.10 magic and phenolic), 5.66-5.10 ppm. (q, 2H, hydrogens of benzylmethylene), 5.02 ppm. (s, 1H, C-3 hydrogen) 5.60.-4.20 ppm (m, 2H, C-5 hydrogen ^{and with} “6), 3.10 ppm. (d, 1H, amine hydrogen), 1.44 ppm, (s, 3Н, methyl C-2 hydrogens).

PRI me R 7. 6- (Triphenylmethylamino) -2,2-dimethyl ~ 3 ~ [1- (4-acetaxzbenzyl tetrazole-5-ml foam,

1.69 g (3 mol) of 6- (triphenylmethylamino) 2, 2-dimethyl-3-tN- (4-hydroxybenzyl) carbamoyl penam are added to a stirred solution of 9 ml of chloroform 1 ml (.12 mol) of pyridine. The solution was cooled to 4 ° C in an ice bath and 2.35 mg of acetyl chloride was slowly added. The solution is stirred for 2 hours at room temperature and again cooled to 4 ° C. 1.5 ml of a 4.3 M solution of phosgene in chloroform (6.45 mol) are added and the cooling bath is removed. Stirring is continued for another 1.5 hours, then the volatile components are distilled off under vacuum. The residue was dissolved in 6 ml of chloroform, the solution was cooled to 4 ° C in an ice bath, 0.95 g (6 mol) of tetramethylguanidinium azide were added to the "stirred" solution and stirred for another 1 h at room temperature. Pour 25 ml of water, then 1 N. sodium hydroxide to bring the pH of the aqueous phase to 10. The chloroform layer is separated, washed with water, dried with sodium sulfate, evaporated to dryness in vacuo. Get crude_6- (triphenylmethylamino) -2,2-dimethyl-3-G ¹ · ~ (4-acetoxybenzyl) tetra--] zol-5 “yl] foams, which are purified by chromatography.

By the described method, but replacing acetyl chloride with an equimolar amount of formic acetic anhydride and chloromethyl methyl ether, 6- (triphenylmethylamino) -2,2-dimethyl-3 Li ~ (4-formyloxybenzyl) tertazole ~ 51penam and 6- (triphenylmethylamino), respectively, are obtained 2-dimethyl-3-L1-E4- (methoxy · [methoxybenzyl) tetrazol-5 ~ yl] foams.

An example. In a stirred solution of 1.69 g (3 mol) obtained by the method described in Example 6, 6 (triphenylmethylamino) ~ 2,2-dimethyl-3 f'J- (4-hydroxybenzyl) carbamoyl) penam pour 1 ml of 9 ml of chloroform ( 12 mol) of pyridine. The solution was cooled to 4 ° C in an ice bath and fl, 80 ml of chlorotrimethylsilane was added. The solution is stirred to 4C. They are surging. ^υ 974936

1.5 ml of a 4.3 M solution of phosgene in chloroform (6.45 mol) and the cooling bath is removed. Stirred for another hour and a half and volatile components are distilled off under vacuum. The oily residue is dissolved in 6 ml of chloroform and the solution is cooled to 4 ° C in an ice bath. 0.95 g (6 mol) of tetramethylguanidinium azide was added to the stirred solution and stirred for 1 h at room temperature. I pour '25 ml of water, then 1 n. sodium hydroxide to adjust the pH of the aqueous phase to 10. The chloroform layer is removed, washed with water, dried with sodium sulfate and evaporated to dryness in vacuo. The crude 6- (triphenylmethylamino) -2,2-dimethyl-3 ^_ “fl- (4-trimethylsilyloxybenzyl) tetrazol-5 ~ yl] is obtained. Netsam which is purified by chromatography on silica gel using chloroform as eluent.

PRI me R 9 · 6- (Triphenylmethylamino) -2,2-dimethyl ~ 3 ~ [1 ^_ (ethylcarbonyl) tetrazol-5yl] foams.

A. 6- (Triphenylmethylamino) -2,2-dimethyl-3 {(H “EToxycarbonylcarbamoyl) foams.

1.15 g (10 mol) of ethoxycarbonyl isocyanate dissolved in 5 ml of acetonitrile are added to a stirred solution (4.58 g, 10 mol) of 6- (triphenylmethylamino) penicillanic acid and 1.45 ml (10 mol of triethylamine in 75 ml of acetonitrile). * the solution is stirred for 16 hours at 2 ° C, then the solvent is distilled off in vacuo. The residue is dissolved in chloroform, the chloroform solution is washed successively with water, sodium bicarbonate solution and sodium chloride solution. Then the chloroform solution is dried with anhydrous magnesium sulfate and evaporated in vacuo The residue is redissolved in chloroform, the resulting solution is washed with dilute hydrochloric acid, dried with magnesium sulfate and evaporated again to dryness. A crude product is obtained, which is purified chromatographically using silica gel as an adsorbent and eluting with chloroform containing 4 vol .. ethanol. 2.54 g (48% yield) of 6- (triphenylmethylamino) -2,2-dimethyl-3 (N-tooxycarbonylcarbamoyl) penam are obtained.

B. 6- (Triphenylmethylamino) -2,2-dimethyl-3 “[1- (ethoxycarbonyl) -tetrazole“ 5 ~ yl] foams.

to

IS

In a stirred solution of 529 mg (1 mmol) of 6- (triphenylmethylamino) -2 ^ 2-dimethyl-3 “[N - (ethoxycarbonyl) carbamoyl] penam and 240 mg (3 mmol) of pyridine in 25 ml of methylene chloride, 208 mg (1 mmol) of phosphorus pentachloride at 0 ° C. The reaction mixture was stirred for 0.5 hours at 0 ° C and 2 hours at 25 ° C. The solvent and excess pyridine are distilled off under vacuum and the residue is dissolved in 15 “ml of chloroform. This solution is cooled to 0 ° C and 0 ^ 47 g (3 mmol) of tetramethylguanidinium azide are added in several small portions. Stirring is continued for 2 hours at room temperature, then 15 ml of chloroform and then 30 ml of water are added to the reaction mixture. Adjust the pH to

6.5 and the chloroform layer is separated. The chloroform solution is washed with water, then with brine and dried with anhydrous sodium sulfate. The solvent is distilled off under vacuum, untreated • 6- (triphenylmethylamino) -2,2-dimethyl-3 ^_ [1- (ethoxycarbonyl) tetrazol-5 ~ yl] foams, which are purified by chromatography using silica gel.

Example. 6- (Triphenylmethylamino) -2,2-dimethyl-3 ~ [1- (2-methoxycarbonylethyl) tetrazol-5-yl] foams.

A. 6- (Triphenylmethylamino) -2,2-dimethyl ~ 3 [H- (2-methoxycarbonylethyl) carbomoyl] foams.

- Into a stirred solution of 35 g

6- (triphenylmethylamino) penicillanic acid in 250 ml of dry, without ethanol impurity, chloroform is added 11.7 ml of triethylamine at 0 ~ 3 ° С. The resulting solution is then poured dropwise with stirring and 0-6 ° C into a second solution prepared from

7.3 ml of ethyl chloroformate in 155 ml of dry, ethanol-free, chloroform. Stir for another 10 minutes. A chloroform solution of mixed 6- (triphenylamino) penicillanic acid anhydride is obtained.

In another flask, a solution of methyl ester of beta-alanine is prepared by adding 11.7 ml of triethylamine to a suspension of 10.73 g of beta-alanine methyl ester hydrochloride and 2 g of anhydrous sodium sulfate in 115 ml of dry, ethanol-free, chloroform at 10 ^f C. Stir for another 10 minutes.

The last solution of the amino ester is poured dropwise with stirring at 3 ~ 6 ° С into the solution of the obtained mixed anhydride. At the end of the infusion, continue to mix for another 2 hours.

A method of obtaining derivatives of the foam formula

Then the reaction solution is washed successively with three portions of water and one portion of brine. The solution was dried with anhydrous sodium sulfate and evaporated in vacuo to give 40.1 g of crude 6- (triphenyl but) -2,2-dimethyl-3 * £ N- (2-methoxycarbonylethyl) carbamoyl] penam as a glassy solid, so pl. 60-70 ° C. It is purified by extraction in boiling ether, treating the filtered solution with activated carbon and reprecipitating by pouring in 'petroleum ether.

. . . ²⁰

C. 6- (Triphenylmegilamino) -2,2-dimethyl-3 ~ G 1 (2-methoxycarbonylethyl) tetrazol-5 ^_ yl) foams.

In a stirred solution (2 g) of the amide obtained in stage A in 5 ml of dry ethanol-free impurity, chloroform is added at 0 ^° C with 1.36 ml of pyridine, then a solution of 620 mg of phosgene in 4 ml of dry, without ethanol admixture. ' chloroform. The solution was stirred for 2.5 hours at room temperature, then the solvent was distilled off in vacuo. The residue was dissolved in 9 ml of dry (ethanol-free) chloroform and 580 mg of tetramethylguanidinium azide were added. The reaction mixture was stirred for 45 minutes and another 200 mg of tetramethylguanidinium azide was added. The reaction mixture was stirred for 18 hours until conversion to tetrazole was complete. Then, a saturated solution of sodium bicarbonate is poured into the reaction solution in an amount sufficient to bring the pH of the aqueous phase to 7.6. The chloroform layer is separated, washed with water at pH 5, washed with water at pH 7 ”, dried with anhydrous sodium sulfate and evaporated in vacuo. 2.19 g of a crude product is obtained, which is recrystallized from methanol and 1.11 g (yield 48%) of a product is obtained with mp. 100-105 ° C, NMR spectrum (CDCl ^) detects absorption at 7.40 ppm (m, 15 N), 5.15 ppm. (C, - 1 H), 3.80 ppm. (m, 4 N),

3.70 ppm (s, 3 N), 3, S. ppm (t, 2Нр5

1.70 ppm · (s, 3 N) and 1.17 ppm.

(s, ZN) and indicates the solvation methanol content in the product.

zo ma where or

Claims (3)

397 each of R, j, and 1C is hydroxy, C, d-alkoxy, benzyloxy; R is a hydrogen atom or methyl zinc; Y-C2, g alkoxycarbonyl I which consists in the fact that 6-triphenylmethylaminopenicilic acid is reacted with a corresponding amine selected from the group. H O -Rn% T.CHR, H; OC .-. Ht35av J, HiNCRsCHjY, where the radicals have the indicated values, at a temperature of (-30) - ((-30) C or with isocyanot formulas where the radicals have the specified values. , at a temperature of O-ZOCH with the subsequent treatment of the corresponding 6-triphenylmethylamino 3-carbamoylpenam obtained by phosphorus or phosphonate with phosphorus or phosgene or thionyl chloride in the presence of 1–3 molar amine at a temperature of (–20) -ZOCH and obtained at the same time, an NHLOL procedure is determined by a procedure in the presence of 1–3 molar amine or tetramethylguanidini at a temperature of 0-30 ° C. In the examples, The following abbreviations are accepted: c-singlet; d-doublet; t triplet; q-quartet; m-multiplet. Pr and MB p. 1. 6- (Triphenylmethylamino) -2,2-dimethyl-3- 1 (4-methoxyben zyl) -tetrazol-5-yl 1penam. A. 6- (Triphenylmethylamino) -2,2-dimethyl-3-M- (4-methoxybenzyl) carbamoyl gg B stirred suspension (86.4 g, 0 , 8 mol) of 6-aminopenicillanic acid in 600 ml of anhydrous chloroform are poured 11.2 ml (0.4 mol) of triethylamine and transferred at room temperature until a clear solution is formed (about 15 minutes). 13.9 g (O, 44 mol) of triphenylmethyl chloride of 90% purity at room temperature are added in portions to the resulting solution in 25 minutes at room temperature. Stirring is continued for another 64 hours, then 5.6 ml of triethylamine are added. Ras: 4 the cools are cooled before and then dropwise for 30 minutes a solution of an cooled (38 ml, 0.4 mol) ethyl chloroformate in 80 ml i of chloroform is poured in, keeping the temperature of the reaction mixture in the range of -E C. then for 30 minutes at, below the surface of the solvent, serve ml (0.4 mol) of 4methoxybenzylamine. Stir for another half hour at 3 b C, then for 20 minutes let the reaction mass warm to 20 ° C. The reaction mixture is washed with water, then brine. After that, it is dried using magnesium sulfate and a chloroform solution of 6-Gtriphenylmethylamino) -2,2-dimethyl-sGN (methylbenzyl) carbamoyl penam, B. b- (Triphenylmethylamino) -2,2-dimethyl-S-E (4-methoxybenzyl) - tetrazol-5-yl foams. In prepared as described in the chloroform solution containing b91Gg. THEN, 120 mol) b-Ttriphenylmethylamino) -2,2-dimethyl-3-rN-r -methoxybenzyl) carboyl 1penam with a volume of 133.3 ml, another 132 7 ml of chloroform are added, then 29.1 ml (O ZbO mol) of pyridine. The solution is cooled to 0 ° C. Then, within a period of 15 minutes, 26 22 g (o, 2b mol) of phosphorus pentachloride ppm chloride / o, mg, stirring are added. Stirring is continued for another 10 minutes at S, then 1, 5 hours at room temperature, a solution of imino chloride is obtained. To 1/6 aliquot of this solution is added m (0.06 mol) pyridine, then. , 42 ml (0.06 mol) of methanol at C and stirring. The mixture was stirred for J5 min and 2.03 g (0.038 mol) of ammonium chloride were introduced, for 2.59 g (0.039 mol) of 95% azide three. The reaction mixture is stirred at room temperature for k hours. After this, 00 ml of water and 200 ml of chloroform are poured, and the layers are separated. The organic phase is washed with water, dried using magnesium sulfate and evaporated under vacuum to a small volume. This final chloroform solution is added dropwise with stirring to a large volume of diisopropyl ether and the precipitate formed is filtered off after 30 minutes. 6.1 g of 6- (triphenylmethylamino) -2,2-dimethyl-3 1- (4-methoxybenzyl) tetrazol-5-yl penam are obtained. The IR spectrum (KBG tablet) detects the absorption band at 1790 cm (beta-lactam); The NMR spectrum (CDCl) detects absorption at 7.25 (aromatic hydrogens), kO (benzyl wide hydrogen), 5.05 (hydrogen C-3), t, 50-3.30 (C-5 hydrogens and C –6), 3.70 (methoxy hydrogens), 3.50–3.10, (broad peak, H), 1.50 (C-2 hydrogen, methyl) and 0.75 (C-2 hydrogen, methyl) . PRI me R 2  6- (Triphenylmethylamino) -2,2-dimethyl-SQ 1 (-benzyloxyb enzyl 1-tetrazol-5-yl foams.  BUT.  6- (triphenylmethylamino) -2,2-di methyl-3-CH- (-benzyloxybenzyl) carbomyl foams.  To a stirred solution (20 g) of 6-triphenylmethylaminopenicillanoic acid in ml of acetone, 6.08 ml of triethylamine are added, followed by 5.78 ml of isobutyl chloroformate.  After 10 minutes, the mixture was filtered directly into a stirred solution (9.28 g) -. A-benzyloxybenyl (in 100 ml of water and 300 ml of acetone at room temperature.  The resulting mixture is stirred for min, then 500 ml of water is added.  Stir for another 7 minutes, then extract the reaction mixture with ether.  The ether extract is dried with anhydrous magnesium sulphate and evaporated to dryness under vacuum.  The resulting crude product is dissolved in 200 ml of ether and added dropwise over 10 minutes to 2500 ml of hexane.  The precipitate is filtered off and 21.5 g of b- (triphenylmethylamino) 2,2-dimethyl-3-tN - (- benzyl hydroxybenzylcarbomyl3 foams are obtained.  B. 6- (triphenylmethylamino) -2, 2-dimethyl-3-chloro-H1- (-benzyloxybenzyl) aminomethyl foams.  In the stirred solution (2 g) obtained by the described method amide c.  10 ml of dry chloroform at 0-5 ° C is poured 0.99 ml of pyridine, then 5.2 ml of a 2.26 M solution of phosgene in chloroform.  The reaction mixture is stirred at room temperature.  Then evaporated to dryness under vacuum, a viscous gum is obtained, which is extracted with 100 ml of ether.  The ether extract is filtered, the filtrate is evaporated, and the imino chloride is obtained as a yellow foam.  C. 6- (Triphenylmethylamino) -2,2-dimethyl- 3t 1 (-lenzyloxybenzyl) tetrazol-5-yl 1penam.  6 The iminochloride described is dissolved in 8 ml of dry N, N-dimethylformamide.  Mg of potassium azide was added to the resulting solution and the turbid solution was stirred for 2.25 hours at room temperature.  The solvent is distilled off at room temperature under high vacuum, a brown gum is obtained, distributed between 60 ml of water and 150 ml of ether.  The ether phase is separated, washed with saturated brine, dried with anhydrous sodium sulfate, and evaporated to dryness under vacuum.  980 mg of 6- (triphenylmethylamino) -2, 2-dimethyl-3-1- (+ benzenexybenzyl) tetrazol-5-yl penam are obtained.  The NMR spectrum (CDCli) show absorption bands at 7. 30 (m , aromatic hydrogens), 5, “b (sq. , benzyl hydrogens) 5.05 (s. , C-3), 5.00 (C. , benzyl hydrogens), i (, (m , hydrogens C-5 and C-6), 1.0 (s. , hydrogen C-2) and 0.70 (C. , hydrogen C-2).  PRI me R 3.  6- (Triphenylmethylamino) -2,2-dimethyl-3- (1-furfuryltetrazol-5-yl) foams.  L.  6- (Triphenylmethylamino) -2,2-DI-methyl-3- (H-furfurylcarbamoyl) foams.  In a stirred suspension (216 g, 1 mol) of 6-aminopenicillanic acid in 1500 ml of chloroform, 2278 ml (2 mol) of triethylamine are poured at 25-30 ° C.  The resulting solution is introduced in portions over 25 MVin 306 g (1.1 mol) of triphenylmethyl chloride at 25-30 °.  Continue to stir for another kk h at room temperature. A portion of 522 ml (0.25 mol) of the indicated solution of 6- (triphenylmethylamino) -penicillanic acid is cooled to ° C and 3.5 ml of triethylamine are added.  Under vigorous stirring at 5-10 ° C, 23.75 ml of ethyl chloroformate are added.  Stir for another half an hour at, then below the surface of the liquid serves 8.43 ml of furfuryl.  Then, in a similar manner, at 10-minute intervals, furfuryl amine (5.90, k, 22 3.5 ml) is added further.  The total volume of the added furfurylamine reaches 22.03 ml (0.25 mol), and during the entire period of the influx of amine, the temperature is maintained at about.  At the end of the inflow of amine, the cooling bath is removed and the reaction mixture is stirred for i5 min at.  Then it is washed successively with three portions of water and one portion of brine.  It is then dried with the strength of anhydrous magnesium sulphate.  610 ml of chloroform solution of 6- (triphenylmethylamino) -2,2-dimethyl3, 3 (H-furfurylcarboyl) penam solution is obtained.  The NMR spectrum of the solution showed an absorption at m. d, (17 N, m), 6.2 m. d (1 N, m), 35 m d, (3 N, m), Go5m. d.  (2 N, s), 1.6 m. d.  (3 N, s) and 1.35 V.  Sriphenylmethylamino) -2,2-di, 1.  . , - -, methyl-3- (1-furfuryltetrazol-5-yl) peV Mixable solution of 3.05 g G5.6 mol) 6- (three | phenylmethylamino) 2, 2-dimethyl-3-H-furfurylcarbamoyl). panama in 8 ml of chloroform with 1 35 ml of C 7 mol) pyridine, then 2.6A ml of a 4.33 M solution of phosgene in chloroform are added.  Continue to stir for 1 h at.  Chloroform, excess phosgene and pyridine are distilled off under vacuum, o. The stalk is dissolved in 5 ml of chloroform.  The solution is cooled before and then 2.25 g (14.4 moles) of the TeRP methylutylNuIdIonazide azide are added in several small portions. Continue to mix for 15 minutes at room temperature, add 20 ml of chloroform, then 30 ml of water and adjust the pH to 6.5.  The chloroform layer is separated. washed with water, then with brine, dried over magnesium sulphate.  The solvent is distilled off in vacuo to give 3.37 g of a dark red foam.  It is dissolved in a small volume of chloroform and absorbed in a column of chromatographic silica gel.  Elute with chloroform, evaporate the appropriate fractions under vacuum, to obtain 6- (three phenylmethylamino) -2 2-dimethyl-3- (L-furyltetrazol-5-yl) foams.  NMR spectrum; of the product (CDCl1) exhibit absorption at 7.40 m. d.  (m, 16 n), 6.40 m. d.  (m, 2H), 5.50 m. d.  (with „2Н), 5.20 m. d.  (with.  1H), 4.90 m. d ,, (m, 2H), 1.60 m d.  (s, ZN) and 0.80 m „d.  (s, zn).  PRI me R 4.  B- (triphenylmethylamino) -2,2-dimethyl-3- (1-methylfurfu (:) yltetrazol-5-yl) foams are prepared by the method described in Example 3, but 5-methylfurfurylamine is taken by furfurylamine.  The NMR spectrum (CDCl) of the product shows an absorption at 7.36 m. d.  (m, 15H) 6.33 m. d.  (m, III), 5. 93 m. d.  (m, W), 5.50 m. d.  (s, 2H), 5.20 m. d.  (s, 2H), 4.50 m. d.  (m, 2H), 3.23 m. d.  (d, 1H), 2.26 m. d.  (s, ZN), 1.63 m. l  (s, ZN) and 0.90 m. d.  (m, ZN).  68 fT p and me 5.  6- (Triphenylmethylamino) -2,2-dimethyl-3-1-C2,4-dimethox1 benzyl) tetraZol-5-ylPenam is obtained with the yield from 6- (triphenylmethylamino) penicillanic acid, replacing the furfurylamine of example 3 with 2j-dimethoxybenzylamine .  The crude product is purified by recrystallization from a mixture of methylene chloride and meta ° - the MR-spectrum of the product (CDClI) detects absorption at b. cho m d.   , “H), S. fO m d.  s, 2H), L, 5 m. d.  (m, 2H), 3.75 m d.  (s, ZSP, 3.70 m. d.  (s, ZN), 1.55 m d.  (s, ZN), and 0.90 m. d.  (s, zn).  EXAMPLE D 6. , 6 ;;; GHriftrniptipaminoU. 2,2-dim e il-s 1 - - 5a T-.  zil) tetra; ash-5-ylZpenam.  i, 5- (Triphenylmethylamino) -2,2d "ethyl-3-H-C -oxybenzyl) carbamoyl foams.  In intermittent vzve. cc (3.2 g, 0.2 mol) of 6-aminopenicillanic acid in 300 ml of chloroform is added (poured) to 55.6 ml (0.40 mol) of triethylamine, then 61.2 g (0. 22 mol) triphenylmethyl chloride at room temperature.  Stirring is continued for another 48 h at room temperature.  120 ml of a chloroform solution prepared as described and containing 0.06 mol of triethylammonium 6- (triphenylmethylamino) penicillate obtained are taken.  Diluted 40.  ml of chloroform and poured 1.67 ml (0.012 mol) of triethylamine.  The mixture is cooled to an ice bath, then 6.84 ml of ethyl chloroformate are added in one step.  with stirring.  Continue to mix for another half an hour while cooling on noGban and the yield is 7.5 (0.0b mol) of 4-hydroxybenzylamine.  Continue to stir for 10 minutes while cooling in an ice bath, then for 1 hour without cooling.  The chloroform solution is washed with water, then brine, then dried with anhydrous sodium sulfate.  The solvent is oggry south under vacuum, the crude amide is obtained.  The crude amide is dissolved in 50 ml of chloroform and absorbed in a column of xr. Omatographic silica gel.  The column was eluted with chloroform, and 400 ml of the fraction was collected.  Fractions 9-15 are combined and evaporated to give an oil, which is said to be milled with methylene chloride.  Then fray with ether, get 12,63 g of 6- (triphenylmethylamino) -2,2-dimethyl-Z-C N C -oxybenzyl) carbamoylpenam, t. square  1b6-1b8s (rzzlozh. ).  The IR spectrum of the product (solution in aiCl3) detects absorption at 1785 cm (beta-lactam) and 1675 cm (amide 1).  YANRspectr (CE) C1%) detects -absorption at Y. bean.  m, d  (m, 20H, aromatic hydrogen and amide), (,. lO m d.  (m, 5H, C-5 and C-6 hydrogens are benzylmethylene and C-3), 2.98 m. d.  (d, 1 N, amine nitrogen), 1.64 m. d.  s, ZN, methyl hydrogens C-2 and 1.31 m. d.  c, 3N, methyl hydrogens C-2).  AT.  6- (Triphenylmethylamino -2,2-dimethyl- 3 D (hydroxybenzyl) tetrazol-5 yl) foams.  In a stirred solution of 1, b9 g (3 mol) of 6-triphenylmethylamino) -2,2 dimethyl-3-Ef f (4-hydroxybenzyl carbamoyl penam (obtained in stage A) in 9 ml of chloroform, 1 ml (12 mol) of pyridine is added.  The solution is cooled to C ° C in an ice bath and tide. They are 0.80 MLhortrimethylsilane, the solution is stirred for 0 min at room temperature and cooled again to.  1.5 ml of a 4.3 M solution of phosgene in chloroform (6.45 mol) are poured in and the cooling bath is removed.  The mixture is stirred for another 1-5 hours and the volatile components are distilled off under vacuum. The oily residue is dissolved in 6 ml of chloroform and the solution is cooled to C in an ice bath.  Q95 g (6 mol7 of tetramethylguanidine azide) is added to the stirred solution and stirring is continued for another 1 h.  at room temperature.  Then 25 ml of water is poured, then 1N sodium hydroxide is sufficient to bring the pH of the aqueous phase to 10.  The chloroform layer is separated, washed with water, dried with sodium sulfate, evaporated to dryness under vacuum.  The oily residue (2.3 g) is dissolved in a small volume of chloroform and. absorbed in a column with 30 g of chromatographic silica gel.  Elute with chloroform, 50 ml fractions of bira.  Fractions 13-19 are combined and evaporated in vacuo to give 0.71 g of 6- | triphenylmethylamino) -2,2-dimethyl-3-11-4-hydroxybenzyl tetrazol-5 or zpenam.  IR specimen (QiCl) detects absorption at 1780 cm Sbet-lactam).  The NMR spectrum (CDC1,) detects absorption at 7.80. 6, B7 m. d.  (m, 2QH, aromatic and phenolic hydrogens), 5.66-5.10 m. d.  (sq.  2H, benzylmethylene hydrogens), 5.02 m. d.  (s, 1H, hydrogen C-3) 5.60. -4.20 m. d. (m, 2H, hydrogen C-5 and C-6), 3.10 m. d.  (d, 1H, hydrogen amine), 1. ts4 m d.  (s, 3N, methyl hydrogens C-2).  PRI me R 7.  6- (Triphenylmethylamino) -2,2-dimethyl-3- 1- (4-acetax. benzyl tetrazole-5-ml foams.  In a mixed solution of 1.6E g (3 mol) of b- (triphenylmethylamino) 2,2dimethyl-3-tN- (4-hydroxybenzyl) carbamoyl penam in 9 ml of chloroform, 1 ml (12 mol) of pyridine is added.  The solution is cooled to an ice bath and slowly adds 235 mg of acetyl chloride.  The solution is stirred for 2 hours at room temperature and cooled to 4 ° C.  1.5 m-P of a 4.3 N solution of phosgene in chloroform (6.45 mol) is poured in and the cooling bath is removed.  Continue to stir for another 1.5 h, then the volatile components are distilled off under vacuum.  The residue is dissolved in 6 ml of chloroform, the solution is cooled to 4 ° C in an ice bath.  The mixed solution was added 0.95 g (6 f-jul) of lzide tetramethylguanidine and stirred for another 1 h at room temperature.  25 ml of water are poured, then 1N.  sodium hydroxide to bring the p11 in the bottom phase to 10.  The chloroform layer is separated, washed with water, dried with sodium sulfate, evaporated to dryness under vacuum.  Untreated 6- (triphenylmethylamino) -2,2-dimethyl-3 C1- (4-acetoxybenzyl) tetra-sol-5 yl foams are obtained, which is purified by chromatography.  By the described method, but replacing acetyl chloride with an equimolar amount of formic acetic anhydride and chloromethyl methyl ether, respectively, 6- (triphenylmethylamino -2,2-dimethyl-ss1 14-formyloxybenzyl) tertazol-51penam and 6 (triphenylmethylomethanylmethanoylmethanylmethanylmethanylmethanylmethanylmethanylmethanylmethanyl -3 L1 L4- (methoxyl (methoxybenzyl) tetrazol-5-yl foams.  Froze  In a stirred solution of 1, b9 g (3 mol) obtained using the method described in example 6 of example 6 (triphenylmethylamino -2,2-dimethyl-3 pb (4-hydroxybenzyl) carbamoyl penam in 9 ml of chloroform, 1 ml of U2 mol) of pyridine is added.  The solution is cooled to an ice bath and 0.80 ml of chlorotrimethylsilane is added.   stirred to 4 C.  Surging.  97 1.5 ml, 3 M phosgene solution in chloroform (6.5 mol) and the cooling bath removed.  The mixture is stirred for an additional hour and a half and the volatile components are distilled off under vacuum.  The oily residue is dissolved in 6 ml of chloroform and the solution is cooled to an ice bath.  0.95 g (6 mol) of tetramethylguanidine azide is introduced into the stirred solution and stirred for 1 hour at room temperature.  I pour in 25 ml of water, then 1 n.  caustic soda to bring the pH of the aqueous phase to 10.  The chloroform layer is removed, washed with water, dried with sodium sulfate and evaporated to dryness under vacuum.  Untreated 6- (triphenylmethylamino) -2,2-Dimethyl-3 -f1- (4-trimethylsilyloxybenzyl) tetrazol-B-ylJ is obtained. ffyonan ,.  which is purified chromatographically on silica gel using chloroform as eluent. P r and m 6 p 9- 6- (Triphenylmethylamino) -2,2-dimethyl-3 C1- (ethylcarbonyl) tetrazol-5-yl foams.  BUT.  6- 1 Triphenylmethylamino) -2,2-dimethyl-3- {(M-ethoxycarbonylcarbamoyl) foams.  In the stirred solution (if, 58 g  10 mol) 6- (triphenylmethylamino) penicillanoic acid and 1.5 ml (10 mol of triethylamine in 75 ml of acetonitrile) add 1.15 g (10 mol) of ethoxycarbonyl isocyanate dissolved in 5 ml of acetonitrile.  The resulting solution is stirred for 16 hours at which time, then the solvent is distilled off under vacuum.  The residue is dissolved in% chloroform, the xjidroform solution is washed successively with water, sodium bicarbonate solution and sodium chloride solution.  The chloroform solution is then dried with anhydrous magnesium sulphate and evaporated in vacuo.  The residue was redissolved in chloroform, the resulting solution was washed with dilute hydrochloric acid, dried with magnesium sulfate, and again evaporated to dryness.  A crude product is obtained which is purified; romatographically using silica gel as an adsorbent and heat up chloroform containing k vol. .  ethanol.  2.5 g (yield (8) of 6- (triphenylmethylamino) -2,2-dimethyl-3 (N-toxycarbonylcarbamoyl) penam are obtained.  AT.  6-gtriphenylmethylamino) -2,2-dimethyl-3-C1 (ethoxycarbonyl) -tetrazol-5-yl foams.  A stirred solution of 529 mg (1 mmol) of 6- (triphenylmethylamino) -2i2-dimethyl-3-H- (ethoxycarbonyl) carbamoyl Zpenam and 240 mg (3 mmol) of pyridine in 25 ml of methylene chloride is added 208 mg (1 mmol) of pentyl chloride phosphorus at, the reaction mixture is stirred for 0.5 h at and 2 h at 25 ° C.  The solvent and excess pyridine were removed under vacuum and the residue was dissolved in 15 h of chloroform.  This solution is cooled to 0 ° C and g (3 mmol) of tetramethylguanidine azide is added in small portions.  Continue to stir for 2 hours at room temperature, then 15 ml of chloroform is added to the reaction mixture and then 30 ml of water.  The pH is adjusted to 6.5 and the chloroform layer is separated.  The chloroform solution is washed with water, then brine, and dried with anhydrous sodium sulfate.  The solvent is distilled off under vacuum, the crude 6- (triphenylmethylamino) -2,2-dimethyl-3-. 1 (ethoxycarbonyl) tetrazol-5-yl foams, which are purified chromatographically using silica gel.  I'll try it on.  6- (Triphenylmethylamino) -2,2-dimethyl-3-E1- (2-methoxycarbonylstil) tetrazol-5-yl foams.  BUT.  6- (Triphenylmethylamino) -2,2-dimethyl-3-C - (2-metaxycarbonylstil) carbomoyl foams.  In a stirred solution of 35 g of 6- (triphenylmethylamino) penicillanic acid in 250 ml of dry, without chloroform, the addition of ethanol.  11.7 ml of triethylamine at.  The resulting solution is then added dropwise with stirring and into the second solution prepared from 7.3 ml of ethyl chloroformate in 155 ml of dry, ethanol-free, chloroform.  Continue to mix for another 10 minutes.  A chloroform solution of b- (triphenylamino) penicillanic acid mixed anhydride is obtained.  In another flask, cook. a solution of methyl ester-beta-alanine by adding 11.7 ml of triethylamine to a suspension of 10.73 g of beta-alanine methyl ester hydrochloride and 2 g of anhydrous sodium sulfate in 115 ml of dry, without admixture of ethanol, chloroform at.  Stir for another 10 minutes.  The last solution of amino ether is added dropwise with stirring at 396 936 Research Institute at 3-6 ° C to a solution of the resulting mixed anhydride.  At the end of the tide continue to mix for another 2 hours.  The reaction solution is then washed successively with three portions of water and one portion of brine.  The solution is dried with anhydrous sodium sulfate and evaporated in vacuo to give 0.1 g of crude 6- (triphenylamino) -2,2-dimethyl-3- H- (2-methoxycarbonylethyl) carbamoyl penam as a glassy solid, t. pl, bo-woC.  It is purified by extracting in boiling ether, by treating the OTBio solution with activated charcoal and reprecipitation by pouring in petroleum ether.   .  . 20 V.  6 (Trife is methylmethylamino) -2, 2-dimethyl-3-C 1 - (2-methoxycarbonylethyl) tetrazol-5-yl foams.   To a stirred solution (2 g) of the amide obtained in stage A in 5 ml of dry ethanol, chloroform, is added with 1.36 ml of pyridine, then a solution of 620 mg of phosgene in ml dry, without ethanol: chloroform.  The solution is stirred for 2.5 hours at room temperature, then the solvent is distilled off under vacuum.  The residue is dissolved in 9 ml of dry (without ethanol impurity) chloroform and 580 mg of tetramethylguanidine azide are added.  The reaction mixture is stirred for 5 minutes and another 200 mg of tetramethylguanidine azide is added.  The reaction mixture is stirred for 18 hours until the conversion to tetrazole is complete.  A sufficient amount of saturated sodium bicarbonate is then added to the reaction solution in an amount sufficient to bring the pH of the aqueous phase to 7.6.  The chloroform layer is separated; WATER WATER at pH 5, washed with water at pH 7.  dried with anhydrous sodium sulphate and evaporated in vacuo.  Obtain 2.19 g of the crude product, which is recrystallized from methanol and receive 1.11 g (yield 4Q%) of the product with t. square  100-105 0, NMR spectrum (CDCl1) detects absorption at 7.0 m. d.  (m, 15 N), 5I5m. d, (C, 1 H), 3.80 m d.  (m, it N), 3.70 m. d.  (s, 3 H), 3.10 m. d.  (t, 2Hj; 55-3 1,70 m. d.  (s, 3 H) and 1.17 m. d.  . Fo (s, ZN) and indicates the content of the solvation methanol product. goma v o 6 k so tp h pr dy of d u va Formula of the invention. Method of obtaining derivatives of foam.  General formulas with CH (CgHsbcm-pYY-CH.  f-iT -% -: i- / - о J Tjf U / 1U - with STEREEN which R - is a hydrogen atom, С -4, alkyl; each of R.  and hydroxy, alkoxy, benzyloxy; Rd is a hydrogen atom or methyl; -ylkyl; Y-Cj. j is alkoxycarbonyl, in which the riphenylmethylaminopenicillan lot is reacted with an appropriate amine selected from 0 t H NCHiCHR HiNGH CBiY temperature (-30) - (+30) C or with an anatom of formula.  the radicals are indicated; this is the temperature followed by treatment of the corresponding 6-triphenylmethylaminoarbamoylpeneam obtained with phosphorus chloride or phosgene, or thionylchloride in the presence of 1-3 mol of the tertiary nomina at (-20) -30 С 1597 93616 and the resulting iminochloride 1, US Patent N 328 ““ f6, subjected to interaction with azide .kl. 260-239.1, publ. 1969. alkali metal or tetramethylgua-2, US Patent No. W 87073, cl. 2bOnidini at a temperature of 0-30 S.239-1, published. 19b9. Ishtoniki information, .Heteixxyclic concurs. NJ., taken into account in the examination-p, yo.   3. Jijrton L. The Qiemistry of