SU406362A1 - METHOD OF OBTAINING AMIDINOPENYCILLANIC ACID DERIVATIVES - Google Patents

Description

1.; I

This invention relates to a process for the preparation of new penicillic acid derivatives with biological activity.

A known method for the preparation of derivatives of B-iminopenicilli anOBOY. Acids with aliphatic or aromatic aldehyde.

The proposed method for obtaining derivatives of a.M1Idinopenica illa, NOVA acid of general form | Mules

where R and Kg are unsubstituted or substituted al-α1T, ical radicals containing 1-7 atoms of y 1 Hydrogen, phenyl, betazyl or / g-chlorobenzyl, -cyclopentyl, cy-clohexyl, cycloheptyl, cyclohexylmethyl or bornyl, furfuryl, or RI and R2 in in addition to atOMO: M of nitrogen is pyrrolidyl, piperidyl, methylpiperidyl, hexahydroazepinyl, hexahydroazocinyl, 1,2,3,4-tetratidoroisoquinonyl-2-yl, 4methylpiper: azinyl-1 -yl, 4; piperazinyl;

Ks - unsubstituted or substituted hydroxyl, or their salts is based on the known p | reaction and consists in the fact that the compound of the general formula

SNS

 N /

sn,

SOBZ

where Rs is the above values, or its silyl derivative is treated reactively with an amide or thioamide derivative of the general formula

Bf ..

.C-CH

vG

20

In which RI and On - as stated above;

R is oxygen or sulfur, followed by cleavage of the protective group, if it is 25, and release of the products in free form or in the form of salt, or by splitting with a complex effusive group by known methods.

The reaction is carried out in an inert organic polymer solvent, for example, in ether or

., iri-cooling and IB presence; at least "one equivalent of a tertiary, for example, trimethylamine, tr. diethylamin, M, M-diisopropylethylamine or N-methylmorpholine.

: As reactionary: amide derivative of amide or thioamide, acetal, acid halide or amide dialkyl sulfate is usually used. Using two or more equivalents of tertiary am.ide, the resulting amidinolenicenicillic acid derivative can be converted to a salt.

B: pvm: the reaction depends on the use of my reactants, temperature and solvents. If KS is a hydroxyl in the INITIAL compound, then it is recommended to protect the carboxyl group by z, to obtain a complex trimethylsilyl or di-methylsilyl diester. It is recommended that this reaction be carried out using acetal amide as a reagent. The preparation of silyl ethers of 6-AMINOPENITS-ILLOBOIC acid is known from Lithuanian (cataracts. The silyl esters of 6-aminone-nicyclic acid are recommended to be cleaved by hydrolysis or by alcoholysis under mild conditions.

The reaction products are very high and are separated by conventional methods, both in the free state and in the form of salts, for the preparation of which pharmaceutically acceptable acids are used, such as hydrochloric, phosphoric, nitric, p-toluenesulfonic, acetic, propionic, lemon, wine and. Maleinovuyu. IF RS is hydroxyl, the reaction products can be isolated in the form of a phion or in the form of a salt, nanorime, p in the form of alkali metal, ammonium or amine salts, or salts with strong acid.

Derivatives of amidiopenicillanic acid, depending on the available substituents, can be isolated in the form of various Isomeric forms.

Free acids (Cs OH) can also be obtained from certain esters by enzymatic hydrolysis or hydrogenolI3101M under microgap conditions or by other methods known from the literature.

The starting materials (amines) are formed by the esterification of b-a. Minonenicillanic acid, or its b-triphenyl methyl derivatives, from which the | T1-три T triphenylmethyl group after the reaction, "does not affect the lactase ring. They can also be obtained by esterification of penicillins commonly used in the IB industry, after which the acyl residue is cleaved off by chemical or farm enzymes, but they can be used.

Halides of amides, most often chlorine or bromohydrin, are obtained by treating amides with halogenating agents, preferably those that produce gaseous by-products during the reaction 0, for example, phylogen, halide oxalic acid, tonsonyl halide. The reaction is carried out in an inert organic solvent, for example, in ether or

in toluene, IB of which halo danhydride amide is in most cases dissolved, and can be filtered after the reaction is complete. Amide.h dyumohydrides are hygroscopic and comparatively unstable, so they are recommended to be used in the next stage without purification.

Acidic complex amides of dialkyl sulfates can be obtained by treating amides with dialkyl sulfato, preferably dimethyl sulfate, under known conditions. When treating complex acidic amides of the dialkylsulyphate. A lower sodium alcoholate, for example, sodium methyl acetate, acidic acetals of the amides of the general formula are formed.

B1

-N-CH-ilJPa) (

in which RI and Na are as above; RG is lower alkyl.

Acid thioamides, for example (p-haloalkylthioamides, are prepared when used in haloalkyl, for example, iodide alkyl, according to x and amides.

In all the preservatives, 1 ml chloroform, containing alcohol, is used.

EXAMPLE 1. Trimethylaceto.xymethyl-6 (hexahydro-3-azepine - 1-yl) methyl methyamine penicillat.

To a solution of 12.7 g of M-formylhex of 1-tethylenimine (m.p. 111-120 C / ilO mm) in 250 ml of dry ether with re-masking and cooling drop by M (add a solution of 8.5 ml of oxalic acid chloride e 50 ml of dry ether, mix up. overnight, the a-nida chloride is filtered off, washed with sulim ether and placed in a desiccator.

27.5 g / g-toluenesul (background, trimethylacetoxymethyl-6-amine O (penicilate is suspended in 1500 l / l of ethyl acetate with continuous re-mixing and cooling in an ice bath, 950 ml of ice-cold 2% -n an aqueous solution of a 1B sodium bicarbonate, the ethyl acetate layer is separated, stirred with 750 ml of ice water containing 25 ml of 2% WATER. Sodium bicarbonate solution, dissolved over magnesium sulfate at 0 ° C, filtered and evaporated dry under vacuum. A solution of 15.5 ml of dry triethylamine in 75 ml of dry chloroform is added to the residue, and 10% are added at -20 ° C g of the obtained chlorohydride am.d., dissolved in 75 ml of dryOlO chloroform, is kept for 0.5 hour at -20 ° C and heated to 0 ° C for 15 minutes, the solution is evaporated to dryness in vacuum, the residue is kept with 750 ml of ether, hlarhydrate triethylamine and the filtrate are evaporated to dryness in a vacuum, the precipitate is recrystallized. From a mixture of 200 ml of acetone and 150 mg of water, then from cyclohexane and obtain analytically pure target product, so pl. 118.5 - 119.5 ° C; H-231 ° (, 96% ethanol). Pr-imer 2. Chlorohydrate trimethylacetoximet; il-6- (M, N - dimethylformamidino-M) penicillat. A solution of 5; 8 g of chlorodimethylformam Idinyl chloride IB 40 ml of dry chloroform is added dropwise at () - (-40) ° C and stirring to a solution of 13.3 g of trimethylacetoxymethyl-6-aminopenicillate and 12.4 ml of t-diethyl mine in 75 ml of dry chloroform are heated to 0 ° C 1B for 1 hour, packed in vacuum and the residue is treated with 200 ml of dry ether. After separation of the triethylamine hydrochloride, the filtrate is evaporated in vacuo, the oily residue is dissolved in 40 ml of isoprotanol, at a temperature of 0 ° C and 4 ml of 9N are added dropwise. solution of hydrogen chloride / in isopropanol And then 150 ml of ether. After filtration, washing with ether and recrystallization from an acetone-ether mixture, an analytically pure product is obtained, mp. 146 ° C; and about + 209 ° (, 96% ethanol). Example 3. O. oxalate schianomethyl-b- (N, iSj diethylformamidINo-M) -l & nitsillat. To a stirred suspension of 43.3 g of 6-aminopenicillic acid in 400 ml of di, methylformamide, 35 ml of triethylamine and 25.5 ml of chloroacetonitrile are added at room temperature, stirred for 24 hours, diluted with 400 ml of ethylacetate and filtered. The precipitate was diluted with 800 ml of ethyl acetate, extracted with 4X200 ml of water, dried with magnesium sulfate, filtered, burnt off, and 320 ml of a 0.5 7W solution of l-toluenesulfonic acid in ethyl acetate were added, the precipitate was filtered and the solution was washed with ethyl acetate and ether. After recrystallization, colorless analytically c. Pure cya-yumethyl-6-amino, nenicillat, t.nl. Is obtained from a mixture of methanol and ethyl acetate. 154.5-156 ° C (decomp.); Mo + 146 ° С (, 96% ethanol). A solution of 1.7 ml of 1-chlorohydride n, and veliic acid in 10 ml of dry ether is slowly added with 0 ° C and stirred to a solution of 2.2 ml of diethylformamide in 50 ml of dry ether, stirred for 45 minutes, quickly filtered on a suction filter, wash the precipitate with dry ether and store in a desiccator. Chlorodiethylformamidinyl chloride is obtained. Cyanoalkyl - 6 - a minute of opacification, in an analogous to Example 1, out of 4.7 g of its p-toluenesulfonate, is dissolved in 15 ml of dry chloroform, 3.1 ml of dry triethylamine are added. and cooled to -30 ° C. While stirring slowly, a solution of 1.7 g of crude acid chloride in 15 ml of dry chloroform is added, the mixture is heated to 0 ° C for 45 minutes, the solution is evaporated in vacuo and the residue B is dissolved. 200 {liter of ether. After filtration and evaporation of the filtrate in vacuo, dissolve the ocTHTOiK in 200 ml of ether and filter through a micronized earth ("Dicalite). While stirring, a solution of 0.85 g of anhydrous solution, abelboi acid in 50 ml of ether is added to the filtrate, the top layer of liquid is decanted, the precipitate is mixed with a new portion of ether, filtered, recrystallized. From an acetone-ether mixture, an analytically pure target is obtained. 1 Tr. O (Du | CT, mp. 121-122.5 °; a D ° + 214 ° (, 96% Ethanol). Example 4. y-phenylpropyl hydrochloride 6- (hexahydro-1H-azepine -1-yl) methylamino nonnicylate. To a stirred suspension of 21.6 g of 6-aminopenicillan acid in 200 ml of dimethylformamide D0 | Baval at room temperature 11.4 ml of triethylamine and 22.0 g of y-bromoNepropane, stirred for 18 hours, 200 ml of ethyl acetate were added and filtered. The filtrate was diluted with 400 ml of ethyl acetate, extracted with 4X100 ml of water and dried over magnesium sulfate. After evaporation in vacuo of oil The pure residue is dissolved with stirring and cooling with a mixture of 200 ml of water and 200 ml of ether with dilute hydrochloric acid to a pH of 3-4. The aqueous phase is separated, dried under sodium bicarbonate to pH 7.5 and extracted by ether. After drying, the ether is evaporated in vacuo to give an oily residue of an incomplete 7-phenylP (ropyl-6-aminopenicillat. 2.2 g of the resulting crude product and 2.0 ml of dry triethylamine are dissolved in 5 ml of dry chloroform, cooled to -60 ° With stirring, a solution of 1.2 g of amide hydrochloride amide (see Example 1) is added slowly iB 10 ml of dry chloroform, heated to 0 ° C for 1 hour, evaporated in Vacuum, triturated with 80 ml of ether, the precipitate is filtered off , the filtrate is extracted with 80 ml of water while stirring and cooling with ice. The pH of the aqueous phase is up to 3. The aqueous phase is separated off, alkalized with patriotal bicarbonate and extracted with ether. After drying, the ether is evaporated in vacuo. The oily residue is dissolved in 10 ml of isopropanol and treated with 0.35 mL of 9 k. a solution of dry hydrogen chloride in isopropanol with stirring and cooling with ice. The precipitate is filtered off and washed with a small amount of isopropanol. After a two-fold recrystallization from a mixture of methanol - ether, an analytical pure pure product is obtained, so pl. 163.5 ° C; OD-f 20G (., 96% ethanol). Example 5. 6- (Hexahydro-1H-azepin-1yl) -methyleneamino-penicillanava zslota. A solution of 4.6 g of chloroamide amide (see solution 1) in 20 ml of dry chloroform is slowly added, and while stirring and cooled to -70 ° C, 7.2 g of trimethylsilyl-6a minopec and 3.5 are added to a solution ml of triethylamine in 50 ml of dry chloroform, heated to 0 ° C for 30 minutes, evaporated to dryness in vacuum and triturated with dry, ,m ether. The filtrate is broken up with 200 ml of ether, filtered off: And washed with dry ether. The filtrate is added with 200 ml of ether, while stirring and 2.8 ml of butao is added dropwise at 0 ° C, it is stirred for 15 minutes, the precipitate is filtered off, washed with ether and dried. A white amorphous powder, obtained in water, is obtained. With XipovviaTorpa; fad on paper paper number 1 in the system n-butanol-ethanol-water (4: 1: 5) R / was 0.5.

Ex. 6. Hydrochloride buty L-6- {N, N diethylformam Idino-M) -pe, n: 1 cill.

To a stirred suspension of 21.7 g of 6-aminopenylillanic acid in 200 ml of dimethylformamide at 16.5 ml of ethylamine, 21.4 ml of n-butyl bromide and a catalytic amount of triethylammon monodide are added at room temperature. stir for 24 hours at room temperature. add 200 ml of ethyl acetate and filter. The precipitate is washed with ethyl acetate, (the filtrate is diluted with 400 ml of EBIT, extracted with 4X100 ml of water and dried over matt sulfate. After evaporation in a vacuum, the reddish oil is mixed with ice and cooled with ice and 250 ml of water , the pH was adjusted to 3.5, slowly adding dilute hydrochloric acid, the aqueous phase was separated, filtered, the syrup, bicarbonate m / b to pH 7.5 and extracted with 200 ml of ether. After drying “Adduct magnesium sulfate ether layer with cooling and stirring is treated with a solution of 9.5 g of l-toluenesulfonic acid in 250 ml of ether, the precipitate is filtered off and drawn in ether, mp 139-140 ° C.

Butyl-6-a-minopenicyl acetate, prepared analogously to example 1 from 4.9 g of p-toluenesulfonate, is dissolved in 3.1 ml of dry chlorofor, ma, 3.1 ml of dry triethylamine are added, cooled to -30 ° C, at {-20) - (- 30) ° C and mixing slowly. The solution is 1.7 g of chlorine. diethylformamidine chloride in 15 ml of chloroform and heated for 45 minutes to 0 ° C. The solution is evaporated in vacuo, the residue is triturated in 200 ml of ether, the T1 trimethylammonium chloride is filtered off, the filtrate is evaporated in a vacuum, a solution of 1000 t of residue in 00 ml of water is added and diluted with hydrochloric acid, pH 3.5. After filtering through Dicalite, sodium bicarbonate is added to ipH 7.5. The oil phase is extracted with 200 ml of ether, dried, ay and evaporated in vacuo. To the residue was added 10 ml of isopropanol, while cooling and stirring I injected 8.5 ml. After dissolving dry hydrogen chloride in isopropanol, 150 ml of ether are added, and the product is separated off with a tin. 126-130 ° C, which is recrystallized from a mixture of acetone - sufir and isopropanol - ether. T. pl. target

product 140.5 141 ° C; and about + 241 ° (, 96% ethanol).

Example 7. Hydrochloride trimethylacetox methyl-6- (L, N - (dimethylformamidino-K) penicillat.

Pa-3,3, g three.methylacetyl-6-a1-aminopenicillate and 1.2 g of 1,1-dimethoxytrimethylamine in 30 ml of ether. Slowly evaporated for 1 hour at room temperature and 3 hours at 40 ° C. The oily residue is dissolved in dilute hydrochloric acid (pH 3), filtered, sodium bicarbonate (up to rP 7.5) is added to the filtrate, the base is treated with ether. O: M, dried and evaporated. The oily residue was dissolved in 10 ml of isopropanol, and 0.36 ml of 8.5N was added. solution of dry hydrogen chloride in nzopropaiol and then 100 ml of ether. T. pl. 143-146 ° C. The IR spectrum is identical to a similar pattern.

5 Example 8. Trimethylacetoxymethyl-6 (hexahydro-1H-azepium - 1-yl) -methyleneamino penicillat.

To a solution of 3.3 g of trimethylacetylb-amnopenicillat and 1.7 g of N, N-diisonropylethyl0 per 35 ml of dry chlorofor, and 1 g at 0 ° C are added 2.5 g of dimethyl sulfate complex with N-formylhexylmethylamine, incubated 20 hour at O-5 ° C, evaporated, the residue is recrystallized from cm-ace A. acetone - water and get the target product, so pl. 115-117 ° C. The IR spectrum is similar to a similar sample.

Example 9. Chlorohydrate of trimethylacetoxymethyl-6- (hexahydro-1H-azepin-1-yl) -methylenes: but-penny, tsillata.

36 g of the free base are suspended in 165 ml of iso-propanol with stirring and cooled with ice and 9.7 ml of 8.5N are added. The solution of dry hydrogen chloride in isopropanol, then 350 ml of ether, is filtered, recrystallized. Called from a mixture of methanol - di 1zo, propyl e - firm and get analytically pure product, so pl. 172-173 ° C; a about + 219 °, 0.1 n. hydrochloric acid). Example 10. Trimetry acetyl 6- (hexahydro-1H-azepi.n-1-yl) methylamino-1-penicillate iodide.

To a solution of 2.6 g of the above-mentioned hydrochloride. In 15 ml of water is added 0.8 g of iodide of dl in 5 ml of water. The siege is sucked off, washed with water and dried. After recrystallization from a mixture of isoiro.pa | Nol - ether and ethanol - ether, an analogue pure product was obtained, t. Pl. 1S3-il54 ° C; + 182 ° (, 96% -. Ny ethanol).

Example P. / J, /, -Tri-.chloroethyl-6- (hexahydro-1H-azepin-1-yl) -Met1IlenaMINO-penny .cillat.

To a solution of ill, l 3 p phosphorous phosphorus in PO ml of dry chloroform, 12 ml of quinoline are added with stirring. At -20 ° C. Add 14.8 g, 1, -trichloroethylbenzylphencyllate, mix for 20 min at -15 ° C, add 37 ml for 2-3 min at -40 ° C

n-propanol, and incubated for 15 min at this temperature. Under stirring and cooling with ice, the solution is poured into a mixture of 330 ml of petroleum eff., 88 ml of a saturated organic sodium chloride solution and

16 ml of water, inoculated with seed and mixed for 30 minutes. The aqueous phase is removed, the precipitate is separated, washed with a small amount of isopropanol with ether and the chlorohydrate (3, / 3, / 3-trichloroethyl-b-amINnopenicillat) is obtained, 153 ° (0.1N hydrochloric acid ). An analytically pure compound is obtained by the interaction of the free base, the preparation of the base and the treatment with sodium bicarbonate, with hydrogen chloride in isopropanol. After recrystallization from ethanol-ether, m.p. 153.5-155.5 ° C; + 160 ° (, 0.1 N hydrochloric acid). Dissolving 1.0 g of chloramide (see Example 1) in 15 ml of pure chloroform at -20 ° C and stirring was slowly added to a solution of 1.9 g of the resulting blended ester and 2.2 ml of trierylamine in 15 ml of pure chloroform, heated to 0 ° C for 45 minutes, the solution is evaporated in a vacuum, the residue is triturated with 100 ml of ether and the precipitate is filtered off. The filtrate is evaporated in vacuo, the thick residue is triturated with 50 ml of WODA, precipitated, filtered, and recrystallized from a mixture of acetone-water and isopropiol-water. T.; pl. 99 - .101 ° C; + 214 ° (s-, 96% ethanol). Example 12. Hydrate rat-6 (M, N-di-to-butylformal L-shindo-NO-penicillus: HOBOY acid. A solution of 4.9 g of N- (dimethoxy: methyl) -di.but.ylamine IB 100 ml of dry spirit. and at -3.0 ° C and. stirring, slowly add to a solution of 7.0 g of trimethylsilyl-b-amino acid. Formula IB 500 ml of ether, add in 30 minutes to 0 ° C, add 25 ml of water over 10 minutes, the combined aqueous phases are freeze-dried, the rubbed solid particles are rubbed with 10 ml of water at 0 ° C, filtered and dried in air. mp 106 ° C (decomp.) + 26 D (0.1 N salt) on acid). Example 13. Dihydr.at chlorhydrate 6 (teksahidro-1H - azepin-1-yl) methyleneamino penicillanic acid. A solution of 4.3 g of benzyl-6- (hexahydro-1H-azepin-1-yl) - methyleneamino-penicillat IB chlorine hydrate with 70 ml of methanol is hydrogenated for 21 minutes on a catalyst — pallium. Carbon dioxide (10%, 4.3 d) At coM | natal temperature and hydrogen generation 1 atm. After separation of the catalyst, the filtrate is evaporated in vacuo, the oily residue is diluted in 28 ml of 95% isolropanol, filtered through Dicalite, etched with 15 ml of isopropanol, 50 ml of diisopropyl ether are added, the precipitate is filtered off, washed with diisopropyl ether and dried "and air. T. pl. 87-89 ° C (decomp.) + 238 ° (water). Example 14. Trimethylaceto.kaimethyl-6 (.hexahydro-1H - azenin-1-yl) methyleneamino penicillum at. To a solution of 2.9 g of N-thioformatexamethylamine in 10 ml of dry ether, 1.4 ml of methyl iodide are added with stirring and cooling, stirred for 30 minutes and filtered. The precipitate of a complex of methyl iodide with N-thioformalhexamethylenim. The other is washed with ether and placed in a desiccator. T. ll. 120-122 ° C. To an ice-cooled solution of 3.3 g of trimethylacetylmethyl-6-aminopenicillat and 1.7 ml of N, -di.isopropylethylamine in 35 ml of pure chloroforma, add 2.9 g of the obtained complex, incubate for 20 hours at-5 ° C, vacuum the solution in vacuo, recrystallize the residue from acetone-water to obtain the desired product, so pl. 119-120 ° C. The IR spectrum is identical to a similar pattern. Measures 15-46. Similarly to the above examples, compounds of the following formula are obtained. S./CH, K, TSN, VG ,, and SSH-K. listed in the table. In all experiments, (OOC1) 2 was used for halogenation. It was used in 47. Di6-dihydrate of 6- (hexahydro-1Nazepin-1-th l) methylene amino - penicillan acid. Dimethyl acetal aldehyde 1-hexamethylenimides. Nocarboxylic acid is obtained from a complex of N-formOl-hexamethylenimine with dimethyl sulfate by reaction with sodium methoxide. T. Kip. 83-84 ° C / 12 mm. A solution of 4.1 g of acetic amide acetal in 100 ml of dry ether at -130 ° C and stirred is slowly added to a solution of 6.8 g of trimethylsilyl-6-aM (Inopenicillat in 500 ml of ether, matured to 0 ° C for 30 minutes, add 300 ml of water, mix for 10 minutes, separate the aqueous phase, extract and absorb with ether and freeze dry. The solid product is recrystallized FROM methanol-acetone, mp 135-142 ° C (decomp.). Ex. 48. 6 - {(Hexatidro-1H-azepine .1-yl) -methylamino.o-penny.cylan.-hydroxy acid. 6.7 g of benzyl-6- (hexa hydrochloride) | Hydro1P-azepIN - -yl) -methylene.mino-penises. Lata is added to 550 ml of ethyl acetate while stirring and cooling, while stirring and cooling, in an ice bath, add a solution of 14.3 g of sodium bicarbonate in 400 ml of water, separate the organic phase and the extract; then 350 ml of water. Drying the organic and the phases are evaporated in 1B of suum. The oily residue is dissolved in 1:50 ml of Methanol and hydrogenated for 15 minutes in the presence of a catalyst, palladium on carbon (10%, 11.4 g) at room temperature and pressure V0. Gain 1 atm. The catalyst from the filter is washed with methanol, the filter is filtered into vacuum, the oily residue is recrystallized from a mixture of 15 ml of methanol and 190 ml of acetone. The precipitate is filtered off by washing with 2X10 ml of acetone and dried in a vacuum desiccator. T. pl.

23

156 ° C (dec); + 285 ° (, 0.1N salt per acid).

Example 49. Chlorine acetoxymethyl. T6- (N, N - dimethylfcrm.a.midino-M) -1peNICILLAT hydrate.

Aceto-methyl-b-aminopeniadilate, obtained "3 5.1 g of its d-t-oluol sulfo" ata by the method of Example 1, is dissolved in 30 ml of dry chloroformMB to: 2.8 ml of dry thi | EthylM and "a and cooled to -40 ° C. With stirring and -20 ° C, a solution of 1.3 3 chlorine | Dimethyl-1L | formamidinium chloride is added in 15 ml of dry chloroform, heated to 0 ° C for 45 min, the solution is evaporated in a vacuum and the residue is dissolved in 200 ml of ether . After filtration at 0 ° C, Q ml 8N is added with stirring. solution of dry hydrogen chloride in isopropanol and get a morphic product.

PRIMER 50. Three, megilacetoxymethyl-6 (H-ztil-M- / 3-ethoxyeth; ilfOr moms; idino - N) -ne Nitsillat.

M-Ethyl-M-β-ethoxyethylformaMid is obtained from the corresponding a.min: and. Chloral. T. Kip. 102- 04 ° C / 11 mm.

3.4 ml of oxalic acid chlorohydride, dissolved in 20 ml of dry ether, three 0 ° C and slowly added to a solution of 5.8 g (il-M-ethoxyethyl form: mida in a salt) dry ef.ira. After stirring at room temperature for 1 hour, the ether is decanted, and the mild chloramide is triturated twice with ether. "" wound in a desiccator. Chloro- (ethyl - p-ethoxyethyl) -forms or x and l are obtained.

5 g of crude chloramide-dissolved in 30 ml of dry chloroform, is added dropwise to a solution of 6.6 g of tp: and methylacetyl-6-am1 1-penopenicill-ata and 7 ml of trietclamine in 30 ml of dry chloroform at (-30) - ( -40) ° C and stirring. The temperature is raised to 0 ° C for 45 minutes, the solution is evaporated in a vacuum, the residue is treated with 400 ml of ether, the triethylamine hydrochloride is separated, the filtrate is evaporated In a vadouume, the oily residue is dissolved in 350 ml of dilute hydrochloric acid to pH 3, filter through Dicalite, alkalinize the filter with sodium bicarbonate to pH 7.5 and extract with ether. After drying, the ether is removed in vacuo to give a non-crystallizing oily residue.

Example 51. Trimethylethoxymethyl-6 (N-5-ethyl-N- / 3-cyanoethyl form. Amidino-N-): heH-Cyclate.

N-B util-ft-f or m i m idop r they, and tril p formylirovaniem, 8- -butylamino1Proionitrile chloral. T. Kip. 114-115 ° C / 0.4 mm.

1.7 ml of oxalic acid chloride is dissolved in 10 ml of dry ether, and at a temperature of 0 ° C and added with stirring to a solution of 3.1 g of K-butyl-p-formamidopropionic acid, IL in 30 ml of dry ether, alternator, The mixture is allowed to stand for 2 hours at room temperature, the ether is decanted, the oily chlorine, (butyl-p-cyanoethyl) -amidinium chloride, is treated twice with fresh portions of ether and stored in a desiccator.

A solution of 2.3 3 crude chloramide in

15 ml of dry chloroform (-20) - (-30) ° C and stirring are added dropwise to a solution of 3.3 g of trimethylacetylmethyl-b-aminopenicillat and 3.1 ml of triethylamine in dry chloroform, incubated for 30 min. At -20 ° С

and heated to 0 ° C for 15 minutes. The solvent is removed in vacuo, the residue is triturated with 200 ml of ether, the triethylammonium chloride is separated, the filtrate is concentrated in vacuo to a volume of 50, extracted with 75 ml of hydrochloric acid (-). The aqueous phase is filtered through Dicalite, alkalinized to, 5, the oily product is extracted with ether, the ether phase is dried and evaporated in vacuo. The residue is | Nek; oil being deployed. EXAMPLE 52. Methyl three-Cetho.xymethyl-6 (M-methyl-H - “arbomethoxymethylformamidino1) PbNICILLAT.

3.0 g of phosgene in 6 ml of dry. Benzene is slowly added to the p-solution of 2.0 g of N-formyl-1-methylthly; q.nat in 15 ml of dry benz: 0l at 0 ° C and mixed; overnight at room temperature and evaporated in va; cuum. Oily residue of chlorophor (methyl 1carbomethoxymethyl) -formamidinium chloride twice

ground with ether: m and stored in a desiccator.

A solution of 2.4 g of crude chloravide in

15 ml dry chloroform slowly add. to a solution .3, .3 g of trimethylacetylmethyl-6 aminopenicillat and -3.4 ml of triethylamine in

, 15 ml of dry chloroform at (-20) -

(-i30) ° C and moving, heated to 0 ° C

for 45 minutes and remove the solvent in

vacuum.

The residue is treated with 200 ml of ether, the precipitate is filtered off, the filtrate is concentrated in vacuo to a volume of 50 ml, extracted with 75 ml of dilute hydrochloric acid (pH 3), and the aqueous phase is filtered through Dicalite.

Add Sodium bicarbonate is added up to; 5, the resulting oil is treated with etheriol1, the ether phase is dried and evaporated to obtain a non-crystallizable oil.

Subject invention

1. A method for preparing amidinopenicillanic acid derivatives of general formula

-N-ttC N-lf CH5

vG

Nh

WITH,

ABOUT

60 where RI and R2 are unsubstituted or substituted aliphatic radicals containing 1-7 carbon atoms, phenyl, benzyl or p-chloro. Benzyl, Cyclopentil, cyclohexyl, cyclohexylmethyl, dicloheptyl or bornyl, furfuryl,

65 or RI and R2 together with the nitrogen atom form

15

pyrrolidyl, piperidyl, methylpiperidyl, hexa-adazazepinyl, hexahydroazocinyl, 1, 2, 3, 4-tet | r.ag, idroiz10.CHi.ol, yl-2-yl, 4-methylpiperazinyl-1 -yl, 4-morpholium, 4-d methylcarbam, and il il er 3 and “.and l;

Cs is a substituted ill unsubstituted hydroxyl, or their salts, characterized in that the compound of the general formula

,

Claims (3)

1 T sn. owls where Cs has the values indicated above, or its silyl derivative is treated with a reactive amide or thiomide derivative: Bix , sixteen where RI | and R2 - as above; R4 - oxygen lly sulfur, followed by cleavage of the protective silyl group, if about a) has synga, and release of the products in free form, or in the form of salt, or by splitting of the ester soil are known, by means of methods. 2. Demolished by l. 1, characterized in that Acetal is used as a reactive amide or thioamide, halide anhydride or complex dialkyl sulfate amide. 3. C | poso; b according to claim 1, characterized in that the protective silyl groups are cleaved off with hydrolysis or alcoholysis. Priority from 11.11.69, per N ° 55209/69 (Velikob | ritani), on the basis of: R4-oxygen. Priority from 08.06.70, for application No. 33211/70 (| UK), by / attribute: R4 - oxygen OR sulfur.