SU700065A3 - Method of preparing 3-carbamoyloxymethyl-7-aminothiazolyl acetamidoceph-3-em-4-carboxylic acid derivatives in the form of syn-isomers or their salts - Google Patents

Description

aqueous 3-carbamoyloxymethyl-7 furyl (thienyl or phenyl) acetamido cef 3-om-4-carboxylic acid, which has physiological activity, by acylation of 3 carbamoyl-7-aminocef 3-em-4-carboxylic acid 1,

The aim of the invention is to synthesize new cephalosporin derivatives that expand the range of agents that affect the living organism.

The proposed method consists in the fact that the compound of the General formula

NHR,

.hh

(1 / x

15H-J - j%

, OC- "H

N I OR

II o

(3)

where R. is a group removed by acidic hydrolysis or hydrogenolysis, or chloroacetyl; 1 - has the indicated values, in the form of the sii-isomer, is treated with an acidic agent of hydrolysis or hydrogenolysis or thiourea and isolates the target product in the form of free acid or its salt (alkali metal, magnesium alkaline earth metal or oxidized Organic base.

 as an acidic agent of hydrolysis, the action of which is subjected to, if necessary, the products of the General Formula 3, trifluoroacetic, formic or acetic acid can be called.; These acids. can be used anhydrous or in the absence of water. As an agent for hydrogenolysis, one can name the system zinc-acetic acid.

Preferably, such an acidic agent of adrolysis is used as a neutral and trifluoroacetic acid, aqueous formic acid or aqueous acetic acid, in order to remove the tertiary butoxycarbonyl JL and trityl groups.

A predominantly zinc-acetic acid system is used to remove the trichloroethyl group, and catalytic hydrogenation is used to remove the benzyl, dibenzyl, and carbobenzshuxyx group.

The salt formation of the products of general formula 1 can be carried out, for example, by acting on the acid of a mineral base {sodium hydroxide or potassium hydroxide or sodium carbonate acid) or an organic base, such as triethylamine.

The salt formation is preferably carried out in a solvent or in a mixture of solvents (water7 methanol, ethanol, acetone, dioxane).

The following examples describe methods for the preparation of both target and starting products.

Example 1. 3-Carbamoyloxymethyl-7-2 (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetamido1 cef-3-em-4-carboxylic acid.

A. Sodium salt of 3-hydroxymethyl-7-G2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetamido1 cef-3-em-4-carboxylic acid.

Mix under nitrogen atmosphere 85 ml

5 methanol and 1.7 g of diethylamine salt of 3-acetoxymethyl-7- 2- (2-tritylamino-4.-Thiazolyl) -2- {methoxyimino} acetamido1 cef-3-em-4-carboxylic acid Solution is brought to -25 ° C and added over

0 2 min. 380 g sodium methoxide. While stirring at -20 ° C for 4 hours and 30 minutes, 126 g of sodium methoxide is added and the mixture is stirred for an additional 4 hours. Saturated with ice,

5 then. Poured at -20 ° C in 680 ml of ether.

After standing overnight in the refrigerator, it is dried and washed with ether. Get

0 A, 89 g of white matter from 210230 ° С with decomposition.

B. 3-Carbamoyloxymethyl-7- 2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetammon cep-3 em-4 cap 5 lateral acid

30 ml of methylene chloride and 0.75 ml of trichloroacetyl isocyanate are mixed under nitrogen. Maintain the temperature O- and add

 4 min 1.5 g of the product obtained in stage A.

After the half of the obtained product has been injected (0.25 ml of trichloroethyl eocyclic sulfate is added, at the end of the introduction another 0.25 ml is added again

5 After 10 minutes of stirring at 0-5 ° C, 1 ml of methanol is added and the mixture is concentrated almost to dryness in vacuo. It is again dissolved in 30 ml of methanol and a solution of 915 mg is added.

0 Sodium carbonate acid in 22.5 water, the Mass is stirred for 3 hours at room temperature, decanted, concentrated, acidified to pH 2 with normal hydrochloric acid, the precipitate taken up, washed with water, then ether, stirred in ether and dried in a vacuum .

600 mg of solid are obtained, m.p. 210 ° C (decomposition),, 0.28 (ethyl acetate: ethanol, salt, Sr2: 1).

Diethylamine salt 3 of acetoxymethyl-7-G2- {2-tritylamino-4-thiazo-5-lyl) -2- (methoxyimino) acetamido); 1ef-3H-4-carboxylic acid is prepared as follows.

2- (2-Amino-4-thiazolyl) -2-methoxyiminoethyl acetate. Load 1 g} (- chloro-o (- methoxyimino ethyl acetate, 3 ml of absolute ethanol and 0.42 g of crushed urea and mix at room temperature for about 2 hours. Dilute 60 ml of ether, crystallize the resulting hydrochloride, mix, dehydrate, wash, dry and 685 mg of hydrochloride are obtained. Dissolve them in 4 ml of water at 50 ° C, add potassium acetate to obtain a pri 6 value, free amine crystallizes. Cool, dry, wash with water, dry and get 27Q mg of the expected product, m.p. 161 ° C:

2- (2-Trithylamino-4-thiazolyl) -2-methoxyimino ethyl acetate.

4.6 g of the product obtained at the preceding stage, a solution of yutpri 30 ° C B 92 ml of methylene chloride. The mixture is cooled to -10 ° C, 2.9 ml of triethylamine are added, it is cooled to -35 ° C, and 6.1 g of toityl chloride is added in 15 minutes. leave the mixture to reach room temperature for 2 hours and 30 minutes. Washed with water, then 0.5 n. hydrochloric acid and sodium acetate in water. Dry, concentrate, absorb with ether, concentrate again, dissolve in methanol, add water and ether, leave to crystallize, dehydrate, wash with ether and obtain 6.15 g of the expected product, m.p. .

2- (2-Trithylamino-4-thiazolyl) -2-methoxyiminoacetic acid.

7.01 g of the obtained ester is dissolved in 35 ml of dioxane, brought to 110 ° C in an oil bath and 9 ml of 2N sodium hydroxide solution are added over 5 minutes, washed with reflux for 30 minutes with stirring. The sodium salt crystallizes. Cool, dehydrate, wash with dioxane, then with ether and obtain 5.767 g of salt. The mother liquor is concentrated and another 1.017 g is obtained; a total of 6.784 g of salt is collected.

3.06 g of salt in 65 ml of methylene chloride and 6.5 ml of 2N are added. hydrochloric acid, washed with water, dried and concentrated to dryness to obtain a quantitatively free acid.

Diethylamine salt of 3-acetoximethyl-7-E2- {2-tritylamino-4-thiazolyl -2-methoxyiminoacetamido cef-3-em-4-carboxylic acid.

The acid obtained in the previous step from 153.6 g of sodium salt is dissolved in 450 ml of methylene chloride in an inert atmosphere.

Cool in an ice bath. 36 g of dicyclohexylcarbodimide are added. Stir for 40 min at 5 ° C and 30 min at. Dehydrated precipitated dicyclohexyl urea. g Cool at between the temperature of the precursor solution and at -1 CGS, a solution of 40.8 g of 7-aminocephalosporanic acid in 600 ml of methylene chloride and 41 ml of triethylamine is added to it. The mixture was allowed to reach room temperature, transferred, washed twice with 1N. hydrochloric acid and 3 times with water. Dry, concentrate, absorb with ethyl acetate and evaporate to dryness 15. The product is dissolved in 350 ml of ether, then 33 ml of diethylamine, stirred for 20 minutes, filtered, the filtrate is concentrated and about 2.5 liters of ether are added. Stir, drain and obtain 110.3 g of the expected salt.

The Jf-Chloro-c-methoxyiminoethyl acetyl acetate used previously is prepared as follows. 25 Take 22.5 g of y-chloro-yc-oxyimino ethyl acetylacetate in 100 ml of methylene chloride. Place a fresh solution of diazometa30 (21.6 g / l or 275 ml) with stirring and slowly add it with stirring. Leave the solution for 5 minutes and destroy the excess diazomethane with a small amount of alumina. Concentrate, then purify by elution with 2x of oxo of silicon with methylene chloride. 11.93 g of the expected product are obtained.

Example 2. 3-Carbamoyloxymethyl-7- 2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acet.amido cef-3-e-4-carboxylic acid.

A. Sodium salt of 3-hydroxymethyl-7-C2- (2-tritylamino-4-thiazolyl) -2- (methyloxyimino) acetamido3 cef-3-em-4-carboxylic acid. 5. a) In a nitrogen atmosphere, 15 ml of dry methanol and 272 mg of 7-aminocephalosporanic acid are mixed. The temperature is adjusted before and 136 mg of sodium methylate 0 are added 3 times. Stir for 7 hours and 30 minutes at -15 ° C, then use the product directly during the synthesis.

b) 1 g of sodium salt of 5 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid and 8 ml of methylene chloride, 1 ml of ether and 4 ml of 1N hydrochloric acid are added. Stir until dissolved, decant Q and re-extract with methylene chloride. It is washed with water, dried and evaporated to dryness.

The product obtained is again dissolved in 4 MP of dry methylene chloride, 235 mg of dicyclohexylcarbodiimide is added, the mixture is stirred at room temperature for 30 minutes, the resulting dicyclohexylurea is dehydrated and washed with methylene chloride.

c) Solution b is added to product a, pre-saturated with ice. Stir for 30 minutes at, then leave overnight at ° C. The product is precipitated by the addition of zopropyl ether. 800 mg of product are obtained, identical to the product obtained in stage A of prier 1..

B. 3-Carbamoyloxymethyl-7-t2- (2-Trithylamino-4-thiazolyl) -2- (label-aimino) acetamido1-cef-3-em-4-carboxylic acid.

The process is carried out analogously to stage B of Example 1 to obtain the indicated product.

Example 3. 3-Carbamoyloxymethyl-7-2 {2-tritylamino-4-thiazolyl) -2 (methoxyimino) acetamido def-3-em-4-carbanoic acid.

2- (2-Trithylamino-4-thiazolyl) -2-methoxnimoacetic acid, obtained as previously described, from 1.81 g of its sodium salt, is dissolved in 20 ml of dry chloroform, by adding 0.48 g of dicyclohexylcarbodiimide and stirring 45 min at room temperature. The urea formed is dehydrated, cooled to -10-sec, and a solution of 0.5 g of 3-carbamoyloxymethyl-7 aminoceph-3-em-4-carboxylic acid in 8 ml of chloroform and 0.5 ml of triztilamine is added.

After standing overnight, the mixture was extracted with 4% sodium bigarbonate solution. The aqueous solution is washed with ether, then acidified to pH 2, the precipitate is dried, washed with water and ether, dried, and the product is identical to that obtained in Example 1.

Example 4. 2- {2-AMINO-4-thiazolyl) -2- (methoxyimino) ethyl acetate syn-isomer.

Mix 1 g of 3-chloro-o-methoxyiminoethyl acetyl acetate 3 ml of absolute ethanol and 0.42 g of ground thiourea. The mixture is stirred at room temperature for approximately 2 hours. Dissolve 60 Mji zfir, the hydrochloride obtained crystallizes, the yoke is stirred, dried, washed, dried and obtained 685 g of hydrochloride, which is dissolved in 4 ml of water at 50 ° C, potassium acetate is added to obtain pH. 6, the free amine crystallizes. The mixture is cooled, dehydrated, washed with water, dried and obtained from 270 MI as expected; the product, m.p. 161 ° with ..

2- (2-Chloroacetamido-4-thiazolyl); -2- (methT-Symino) ethyl acetate, syng-isomer.

Mix it up. 45.8 g of 2 - (2-amino-4 - thiazolyl) -2- (methoxyimino) ethyl acetate, syn-isomer, and 200 ivui of methylene chloride. 20 ml are distilled off for drying, cooled to 10 ° C and 50 ml of pyridine are added. 41 g of monochloroacetic anhydride are added and slightly heated to dissolve. Leave for 6 hours at 20 ° C under nitrogen, add 5 ml under stirring and pour into 300 ml of 2 hydrochloric hydrochloric acid. Decanted, extracted with methylene chloride, washed with water, acidic sodium carbonate, water, dried, passed through activated carbon, concentrated and 300 L of isopropyl ether added. The product crystallized. It is concentrated to a thick paste, cooled, dehydrated, washed with isopropyl ether, dried and 45.4 g of product are obtained, m.p. 113s,

Get a clean sample of the curry, talization from a mixture of methylene chloride and isopropyl ether, so pl. 118 ° C.

2- (2-Chloroacetamido-4-thiazolyl) -2- (methoxyimino) acetic acid, syn-isomer.

46 g of the product obtained in the previous step are introduced in 250 ml of absolute ethanol. 30 ml of pure sodium liquor are added under nitrogen. The product is dissolved, the sodium salt begins to crystallize, and then the medium sets. After 16 h, the mixture is dehydrated and washed with ethanol. The resulting salt is dissolved in water, cooled, and SO is added with a ml of 2N. hydrochloric acid saturated with sodium chloride, extracted with ethyl acetate containing 10% ethanol. It is dried, passed through activated carbon, distilled under vacuum, water is removed with benzene, taken up in methylene chloride, distilled to dryness, taken up in methylene chloride, cooled, dried, washed with methylene chloride, dried, and 34.5 g of the expected product is obtained, t. square Purify the product by recrystallization from a mixture of acetone and isopropyl ether.

Found,%: C 34.8; H 2.8;

N 14.8; C # 12.6; S 11.5.

 (they say, v. 277.68)

Calculated,%: C 34.60; H 2.90;

N 15.13; SS 12.77; S 11.55.

3-Acetoxymethyl-7- (2-chloroacetamido-4-thiazolyl) 2- (methoxyimino; acetamido cef-3-em-4-carboxylic acid, syn-isomer.: Enter 15.3 g of the product obtained in the previous step, in 80 ml of methylene chloride. At 5, 8 ml of triethylamine are added. At OC and in the atmosphere of ayoto, input of 3.8 MP of thionyl chloride and 26 ml of methylene chloride. CMBCJ ost & is for 15 min at, then, 7 ml triethylamine ,, Vvod d. at 0 ° C and E, nitrogen atmosphere 13.6 g of 7-aminocephalosporanic acid in 100 ml of methylene chloride and 14 ml of triethylamine. Increase the temperature to 20 ° C, mix 1 This solution is distilled to dryness in vacuum at 30-35 ° C. The residue is dissolved in 250 ml of water, passed through activated carbon, 5 ml of 2N hydrochloric acid are added, the precipitate is dried, washed with water. The resulting crude product is suspended in 80 ml of ethanol. At 5 ° C, 7 ml of triethylamine is added. The product is added immediately with stirring and at 15 ml of 4 N sulfuric acid, the product crystallizes. After 15 minutes, dehydrated, washed with ethanol, kneaded, then with ether, dried in vacuum and get 18.6 g of the expected product, L. jj 26t. (1%, in dkmetilformamkde). 3-OKSIMRTIL-7-C2- {2 hLoratdeta ™ mido 4-tia5colk) 2 (methoxyimino). Acetag -.mdo cef-3-e.m-4-carboxylic acid., Sc.: 1-: h: Somers Mix 240 ml of distilled water at 37 ° C and 40 g of defatted seedlings; mix for 30 minutes at, centrifuge and obtain a float mass (205 cm) at pH 6, S, enter into 96 ml of distilled water 1.6 g -3-acatoxymethyl-7-2- (2-chloroacet M11DO-4-tha-oolyl) -2- {methoxyimino) a; A./1ido cef-3-em 4 - carboxylic acid, syn-eomer. A suspension of pH 4.3 was obtained, which was adjusted to pH 6.7 by the addition of 11.9 mp 0.2 n.e. potassium. The solution becomes a pro. 4HHf4. Introduced with stirring, under and under a nitrogen atmosphere, 192 cm of the fresh enzyme solution described earlier, then preduction. acidic solution with pH 6.7. The value of KN is maintained by 6.5 automatically adding 0.2 n. caustic potash. Control the reaction by chromatography in a thin layer. The reaction is stopped after 4 hours, centrifuged at 5 ° C, the residue is triturated in 19 ml of ice-water, then centrifuged at for 30 tJOiH, the floating mass is combined and concentrated to 61 ml. Dobyle J9T 168 ml of acetone, “to precipitate proteins, filtered, washed with kneading 3 times with 16 ml of a solution of water and acetone (1: 2.5). The filtrate and washings were combined and 640 mg of carbon black was added, stirred for 1 hour at room temperature, then filtered, washed; 1 was mixed with a mixture of water and acetone, the washings were combined and the filtrate was concentrated in a water bath, then 5 ml was added formic acid. Crystallization occurs. The mixture is left overnight at 5 ° C and the crystals are dried over, washed with water, and 76.1 g of the expected product are obtained, which is recrystallized as follows. 727.4 ml of the obtained product is added to 28 ml of distilled water. 134 mg of acidic Kap6q-. sodium acetate, stirred, the insoluble part was separated, again ... 50 mg of sodium carbonate was added, stirred for 15 minutes, 142 mg of carbon black was added, stirred for 30 minutes at room temperature, filtered, washed 3 times with 2 ml of water. The washings were combined with the wash and the filtrate, 1 ml of acetic acid was added, followed by 0.5 ml of formic acid, and the product slowly crystallized. It is dehydrated, washed with distilled water, and 635.9 mg of product is obtained after drying. fiCjjj, 63.4 (0.5%, in i acidic sodium carbonate with 0.5 M). Nuclear magnetic resonance (dimethyl sulfo; led, 60 MHz) -: 7.48 protons in the thiazole cycle, 3.91 ppm methoxyoxime, 4.28 ppm of methylene group. 3-Carbamyloxymethyl-7-: 2- {2-chloroacetamido-4-thiazolyl) -2-jMethoxyimino) acetamido cef-3-em-4-carboxylic acid, sin-isomept Mix 1.56 g of 3-hydroxymethyl-7 2- (2-chloroacetamido-4-thiazolyl) (methoxyimino) acetamido cef-3-em-4-carboxylic acid, syn-isomer obtained in the previous step, 18 ml of pyridine and 60 ml of tetrahydrofuran. The temperature is adjusted to -25 ° C and 3 ml of trichloroacetyl isocyanate are added at one time. The temperature rises to, then drops again. Pour 600 ml of the solution saturated with acid sodium carbonate into water for half dilution, stir at room temperature, extract 4 times with 25 ml of ethyl acetate. Each extract is washed with 125 ml of a solution of sodium hydrogencarbonate, saturated and half diluted. Combine all the basic water basics, bring them to a neutrally neutral state of 2 n. hydrochloric acid, is folded. two times (250 ml)

with ethyl acetate, washed with saturated sodium chloride solution, extracted again with tetrahydrofuran, and washed again. The organic phases are combined, washed with salt water, dried, evaporated under reduced pressure, the resulting rubber is triturated with ether, stirred at room temperature, dried, rinsed, dried, and 1.020 g of a white powder are obtained, mp. 24bS (with decomposition), Rif 0,37 (ethyl acetate: acetic acid: water, 80: 15: 5),

: Example 5. 3-Carbamoyloxymethyl-7- 2- (2-amino-4-thiazolyl) -2- {methoxyimino) acetamido cef-3-em; 4-carboxylic acid.

500 mg of the product obtained in Example 1 and 5 ml of 8% acetic acid in water are mixed. After stirring: ayut 2 h 30 min at 50 ° C, cool T to room temperature and precipitate by adding 40 ml of ether. Dehydrate, wash with ether, and make 1T 290 mg of solid contaminated cream.

Dissolve 270 JMr of the previous product in 4 ml-8% acetic acid in water. 4 ml of ethyl acetate are added, filtered, washed with a mixture of 8% acetic acid in water: ethyl acetate (1: 1), the filtrate is stirred with 270 mg of silicon dioxide. After filtration and washing, it is precipitated by adding ether, dehydrated and washed with ether. Obtain 136 mg of product, so pl. 260 ° C, Rf 0.35 {ethyl acetate: ethanol: water 6: 2: 2).

Example 6. 3-Carbamoyloxymethyl 7 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido cef-3-em-4-carboxylic acid, syn-isomer ,. 950 mg of the product obtained in the previous stage, and 171 mg of thiourea in 2 ml of distilled water are taken. Place in ice and bath and inject 190 mg of potassium hydrogen carbonate several times. The mixture was kept at room temperature and left for 5 hours 30 minutes with stirring, then 6.7 ml of water was added and formic acid was added until neutral. The mixture is triturated in ice-water, hydrated, washed with 3.8 ml of water With 10% formic acid, absorbed 1.5 ml with 7 ml of water, kept on ice and triethylamine added for better dissolution. 0.6 ml of formic acid is injected, dehydrated with 3.8 ml of water; s with 10% formic acid over 2 times and dark brown rubber is removed. The aqueous phases are combined, treated and 10.25 g of ammonium sulfate, the precipitate is dried out, kneaded in water, then in ether, dried, and 470 m of solution is obtained, and the ammonium sulfate mother liquors receive an additional 52 mg.

The product is purified as follows. 46 mg of the crude product containing formic acid and 0.12 ml of absolute ethanol with 0.1 mmol of pyridine are stirred at room temperature for 2 hours. Dehydrate, rinse with absolute ethanol, dry and get 32 mg of purified white powder,

Nuclear magnetic resonance (60 Mgd, dimethyl sulfoxide) jrpm 6.75 protons in thiazole, 6.58 of the OCONH2 group.

Example 7. Sodium salt of 3-carbamoyloxymethyl-7- 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido cef-3-em - 2-carboxylic acid, syn-isomer.

92 mg of 3-carbamoyloxymethyl-7-C2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamidoDece-3-em-4-carboxylic acid, synisomer obtained in Example 5, in O, 2 ml are added. distilled water. 12 mg of sodium hydrogencarbonate are re-added in small amounts. The solution gradually dissolves. It is absorbed by 2.4 ml of acetone and triturated. The formation of rubber is observed, which decant, flow and absorb 2.4 liters of acetone, triturate and mix for 10 minutes at room temperature. Fraction A is obtained. 2.4 ml of acetone is added to the mother liquors, triturated and stirred for 10 minutes at room temperature. Fraction B is obtained. Combine fractions D and B and subsequently mixed with 0.2 G 4 L of ethanol, 0.2 MP of isopropyl ether and 0.2 ml of acetone. Placed in a drying oven until a constant weight is reached and 65 mg of white powder is obtained, m.p. 272C, R 0.16 (eluen: ethyl acetate: acetic acid: water 80; 15: 5).

Claims (1)

1. US patent 3,974,153, cl. 260-243 C, published. 08.08.76. 15