SU425402A3 - METHOD FOR OBTAINING DERIVATIVES OF 7-AMINOCEPHALOSPORANIC ACID - Google Patents

Description

one

The invention relates to methods for producing new 7-aminocephalosporanic acid derivatives with pharmacological activity exceeding the activity of similar compounds very similar in structure.

The proposed method for the preparation of 7-aminocephalosporanic acid derivatives of the general formula

l SHCHgCO-NH

iM J-CHgRj

g with 00 and

where RI is a five-membered heterocyclic residue containing at least two heteroatoms — nitrogen, sulfur or oxygen — that in position 5 can be unsubstituted or replaced by a mercapto group, and in other positions it can also be unsubstituted or substituted by lower alkyl and in which the carbon of the five-membered ring at position 2 or 3, located between two heteroatoms, is bonded to the sulfur atom of the mercto-acetyl group;

Kg - hydroxy group, free or esterified with carboxylic or thiocarboxylic acid to ester, N-substituted

a carbamoyloxy group in which oxygen atoms can be replaced by sulfur atoms, or a residue of a quaternary ammonium salt,

based on the well-known reaction of mercaptan with haloalkyl.

The method consists in the fact that 7-halogenoacetylamino cephalosporanic acid of the general formula

HalCHjCO-M-pV

0

with the UN

where R2 has the indicated meanings;

Hal is a halogen atom, is reacted with a mercapto compound of the formula RjSH

where RI has the indicated meanings.

The process is preferably carried out in an inert solvent, such as methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, dimethylformamide, acetonitrile, in the presence of an acid binding agent, such as a weak inorganic base, such as carbonate, bicarbonate, alkali metal acetate or tertiary amine, preferably ethyldiisopropylamine

(basis of Gunig).

The reaction is usually carried out at room temperature for several hours. You can carry out the process at a lower or higher temperature.

Products are isolated in a known manner in free form or as an alkali or alkaline earth metal salt. If R2 is a hydroxy group, an esterified carboxylic or thiocarboxylic acid ester, this group can be converted into N-substituted carbamoyloxy group, in which the oxygen atoms can be replaced by sulfur atoms, or a quaternary ammonium salt.

Example 1. 3.93 g (10 mmol) of bromoacetyl-7-aminocephalosporanic acid are dissolved in 20 ml of methylene chloride, and 3.45 ml (20 mmol) of N-ethyldiisopropylamine are added. Then a solution of 1.37 g (12 mmol) of 2-mercapto-1-methylimidazole in 20 ml of methylene chloride is added, and another 10 ml of methylene chloride is rinsed.

After 7 hours, the solvent was removed in vacuo and 10 ml of methanol and 1.65 ml of glacial acetic acid were added to the remaining oil, after a short time the crystals precipitated, they were filtered off under suction, washed with methanol, and gave almost pure 7- 1-methylimidazolyl- (2) - mercapto-acetylamino cephalosporanic acid, so pl. 177-179 ° С (decomposition) in a sealed capillary.

The product is converted to a crystalline sodium salt as follows. 2.9 g are mixed with 60 ml of methanol and then 3.75 ml of 3 M methanolic sodium cc-ethylhexanoate are added. With stirring and short heating in a water bath having a temperature of 30 ° C, first the dissolution takes place and then the sodium salt crystallizes. The mixture is concentrated in vacuo to approximately 15 ml, left to stand for 1 hour at -20 ° C, filtered under suction, washed with a mixture of tetrahydrofuran and methanol (1: 1) and dried in vacuo. The sodium salt is readily soluble in water, + + 107 ± 1 ° (s 1; NgO).

The UV spectrum (in water) shows a maximum at Z 256 mcq (e 12800), so pl. 150-154 ° C (with decomposition), Rfsa 0.04; RfipiX 0.35.

Example 2. 3.93 g (10 mmol) of bromoacetyl-7-aminocephalosporanic acid was dissolved in 15 ml of methylene chloride, and 3.45 ml (20 mmol) of N, N-diisopropylethylamine was added. A solution prepared by dissolving 1.23 g (12 mmol) of 2-mercaptoimidazoline in 20 ml of dimethylformamide with 10 ml of methylene chloride is added to it. Additionally washed with 5 ml of methylene chloride.

After 6 hours, the methylene chloride is removed under vacuum, obtained by means of a water-jet pump, and then dimethylformamide is distilled as completely as possible under a vacuum of about 0.3 mm Hg. Art. and at a temperature of 30 ° C. As a result, 10.7 g of a thick oil is formed.

By adding 100 ml of tetrahydrofuran, a viscous mass is obtained, which is vigorously stirred. The residue is filtered and triturated with an additional 50 ml of tetrahydrofuran, sucked off and washed with a small amount of tetrahydrofuran and then with hexane. After drying in vacuo, 6.75 g of a yellowish powder are obtained. 4.5 g of this crude product is dissolved in

13.5 ml of dimethylformamide and diluted with 13.5 ml of methanol. The solution is stirred with a spatula tip with activated carbon at room temperature for 5 minutes, then filtered through a layer of diatomaceous earth.

the soil and filter are washed with 6 ml of a mixture of dimethylformamide and methanol (1: 1). The filtrate and washings were combined and 165 ml of tetrahydrofuran was added, and a light yellow precipitate formed. Leave it to stand.

1 hour at - 20 ° C. It is then filtered off under suction and the residue is washed well with a mixture of methanol and tetrahydrofuran (1: 4.5), tetrahydrofuran, and finally hexane. After drying, 7-imidazolinyl (2) -mercaptoacetylamino-cephalosporanic acid is obtained in the form of an almost colorless amorphous powder, which is homogeneous according to thin-layer chromatography, Rf52 0.05; RfjoiA 025, so pl. (sealed capillaries)

213-216 ° С (decomposition), and + 143 ± 2 ° (in water, s 0.5).

Example 3. 3.93 g of bromoacetyl-7-aminocephalosporanic acid is dissolved in

27 ml of methylene chloride, added 3.45 ml of S, M-diisopropylethylamine. A solution prepared by dissolving 1.43 g of 2-mercaptothiazoline in 2 ml of dimethylformamide is then added, followed by dilution with 8 ml of methylene chloride. Additionally wash off with 10 ml of methylene chloride.

After 7 hours, the solvent is removed first in the vacuum obtained using a water-jet pump and then at about 0.3 mm.

Hg Art. (in a water bath at 30 ° С). Get 7 g of thick oil.

6.3 g of this crude product is taken up with 27 ml of 10% potassium dihydrogen phosphate solution. By adding 0.3 ml 2 n. soda solution

The pH is adjusted to 5. Then the solution is poured into a separating funnel and it is extracted with 55 ml of methylene chloride and then 90 ml of ethyl acetate. The organic phases are washed twice with 45 ml of phosphate each.

buffer (pH 5), and discard them. Then all the aqueous phases are combined and 180 ml of ethyl acetate are separated, after which the pH is adjusted by adding 11 ml of 1N. hydrochloric acid to 2.9 and saturate the aqueous phase with common salt. The mixture was shaken well, the phases were separated and the aqueous phase was extracted twice more using 90 ml of ethyl acetate. The organic phases are washed with additional 45 ml of a saturated solution of common salt;

sodium sulfate. combined and evaporated

them under vacuum to dryness. The amorphous residue is recrystallized from 6 ml of a mixture of ethyl acetate and tetrahydrofuran (9: 1) almost completely.

The crystals (1.76 g) are filtered under suction and washed with ethyl acetate, they are cleaned, the solution in 15 ml of tetrahydrofuran is mixed by stirring the tip of the spatula with activated carbon at room temperature and the filter through a layer of diatomaceous earth. The filtrate is washed with 5 ml of tetrahydrofuran, the solvent is removed in vacuo and the amorphous residue is crystallized from 5 ml of a mixture of ethyl acetate and tetrahydrofuran (9: 1). The crystals are filtered under suction, washed with ethyl acetate and dried under high vacuum. Pure 7-thiazolinyl- (2) -mercapto-acetylamino cephalosporanic acid is obtained, m.p. (sealed capillaries) 131 –138 ° С (decomposition).

To obtain the sodium salt, 1.6 g of the acid is suspended in 32 ml of methanol, and 2.1 ml of ZM of methanolic sodium ethyl hexanate are added to the suspension. The resulting solution is concentrated in vacuo to a volume of 8-10 ml and left to stand for about 2.5 hours at - 20 ° C. It is then filtered on suction and washed with sodium salt crystals and 12 ml of a mixture of methanol and ethyl acetate (1: 1), 5 ml of a mixture of ethyl acetate and hexane.

Sodium salt melts at 185-189 ° C (during decomposition), 4-120 ± G (in water, s l), Rf52 0.26; Rfiou 0.55.

Example 4. 3.93 g of bromoacetyl-7-aminocephalosporanic acid was dissolved in 20 ml of methylene chloride, and 3.45 ml of diisopropylethylamine was added. Then, a solution prepared by dissolving 1.22 g of 3-mercapto-1,2,4-triazole in 10 ml of dimethylformamide and diluting with 10 ml of methylene chloride is introduced. Wash with an additional 10 ml of methylene chloride.

After 7 hours, the solvent is distilled off, first in the vacuum obtained by means of a water-jet pump, and then at about 0.2 mm Hg. Art. (in a water bath having a temperature of 30-40 ° C), as a result, 10.5 g of brownish oil remain. This crude product is dissolved in 20 ml of a 10% potassium dihydrogen phosphate solution. Added 0.9 ml 2 n. The soda solution is adjusted to pH 5. Then the solution is extracted in a separating funnel with 80 ml of methylene chloride and 30 ml of ethyl acetate. The organic phases are washed twice using 20 ml of phosphate buffer (pH 5) each. The combined aqueous phases were then separated with 300 ml of ethyl acetate and the pH was adjusted to 2.9 by adding 1.0 ml of concentrated hydrochloric acid. As a result, a colorless viscous mass forms that fills both phases. The entire contents of the separatory funnel are filtered overnight through a glass filter and the residue is further washed with 100 ml of ethyl acetate. By repeated trituration of this precipitate with tetrahydrofuran (approximately 150 ml), an almost pure and crystallized 2,4-triazolyl- (3) -mercaptoacetylamino cephalosporanic acid can be isolated from the solution. The filtrate containing both phases is separated and still crystallized is obtained from it. 2.5 g of the combined crude crystallisate is dissolved in 30 ml of a mixture of tetrahydrofuran and methanol (1: 1), the solution is stirred with activated carbon at room temperature, filtered through a layer of diatomaceous carbon dioxide

3 ml of the above mixture and 5 ml of methanol are washed with a filter. Then, the filtrate is concentrated in a vacuum to approximately 5 ml, and crystals immediately precipitate after infection with a crystal, m.p. 149-151 ° С (during decomposition).

1.55 g of acid are suspended in 50 ml of methanol and 1.85 ml of ZM methanol / sodium ethyl hexanate are added. A clear solution is concentrated in a vacuum in about 10-12 ml,

from which crystals slowly form. Add another 2.5 ml of tetrahydrofuran and leave the solution to stand for 2 hours at -20 ° C. Then filtered on suction and washed the residue successively with a mixture of methanol and tetrahydrofuran (1: 1), tetrahydrofuran, ethyl acetate and hexane.

Pure sodium salt melts at 220-230 ° C (upon decomposition); + FROM ± 1 °; Rf520.21; Rfioi A. 0.5.

Example 5. 39.3 mg of bromoacetyl-7-aminocephalosporanic acid is dissolved in 0.2 ml of methylene chloride, added 25.8 mg of N, .N-diisopropylethylamine. Then a solution prepared by dissolving 17.4 mg is introduced.

2-mercapto-4,5-dimethylthiazole in 0.05 ml of dimethylformamide and dilution of 0.15 ml of methylene chloride. Wash off an additional 0.05 ml of methylene chloride.

After 7 hours, the solvent was removed in vacuo at 0.3 mm Hg. Art. (on a water bath having a temperature of 30 ° C) and processing the evolving oil further, as described in Example 3. 5-dimethylthiazolyl (2) is obtained - mercapto-acetylamino-pephalosporanic acid, Rf52 0.35; Rfioia. 0.6.

Example 6. 393 mg (1.0 mmol) of bromanetyl-7-amine, Cecephalosporanic acid, dissolved in 2.0 ml of methylene chloride, was added

258 mg .N, iN-diisopropylethylamine. A solution prepared by dissolving 180 mg of 2,5-dimercapto-1,3,4-thiadiazole in 0.5 ml of dimethylformamide is then added, followed by dilution with 2.2 ml of methylene chloride. Wash off with additional 1 ml of methylene chloride.

After 6 hours, the solvent is distilled off, first in the vacuum obtained by means of a water-jet pump, and then at about 0.2 mt.

Hg Art. (in a water bath having a temperature of 30 ° C), approximately 1.1 g of a yellowish oil remains. This crude product is taken up with 10 ml of a 10% potassium dihydrogen phosphate solution and added 0.3 ml of 2N. soda solution.

the solution is adjusted to pH 5. Then it is extracted in a separatory funnel successively with 20 ml of methylene chloride and 30 ml of ethyl acetate. The organic phases are washed twice using 10 ml of phosphate buffer (pH 5) each. The aqueous phases are then combined and separated with 40 ml of ethyl acetate. By adding 2.7 ml of 1N. hydrochloric acid is adjusted to pH 2.9 and the aqueous phase is saturated with common salt. After vigorous stirring, the phases are separated and the aqueous solution is further extracted twice more using 20 ml of ethyl acetate. The organic phases are washed three times with 8 ml of saturated sodium chloride solution, then dissolved in sodium sulfate, filtered and evaporated to dryness in vacuo. The residue is recrystallized from a mixture of ethyl acetate and tetrahydrofuran (9: I). 7- 5-Mercapto-1,3,4-thiadiazolyl - (2) -mercaptoacetylamino cephalosporanic acid melts at 130-142 ° C during decomposition (sealed capillaries), Rf52 0.36; Rfjoj 0.6.

Example 7. 1.97 g of bromoacetyl-7-aminocephalosporanic acid was dissolved in 50 ml of methylene chloride, adding 1.29 g (1.73 ml) of N, N-diisopropane. Teal Mine The solution was then introduced which was prepared by dissolving 0.975 g of 2-mercaptobenzimidazole in 5 ml of dimethylformamide and diluting with 10 ml of methylene chloride. Additionally rinse 5 ml of methylene chloride.

After 5 hours, the solvent is distilled off, first in the vacuum obtained using a water-jet pump and then at about 0.2 mm Hg. Art. (water bath has a temperature of 30 ° C). The light brown oil which is separated out is absorbed by 10 ml of 10% aqueous solution of potassium dihydrogen phosphate and added 0.5 ml of 2N. The soda solution is adjusted to pH 5. Then it is extracted twice in a separatory funnel using 100 ml of ethyl acetate each time and the extracts are washed twice using 5 ml of phosphate buffer (pH 5). The aqueous phases are combined, dividing them with 250 ml of ethyl acetate and, adding 9 ml of 1N. hydrochloric acid, pH adjusted to 2.5. A gummy mass is formed, most of which consists of the desired product. Separate and shift it with hexane, from the solid residue thus obtained, extracted with 7-Gbenzimidazolyl- (2) -mercaptoacetylamino-cephalosporanic acid with tetrahydrofuran. The biphasic filtrate obtained after separation of the viscous mass is saturated with sodium chloride. After vigorous stirring, the organic phase is separated, the aqueous solution is extracted twice more with 100 ml of ethyl acetate, and the three aqueous phases are washed with 10 ml of saturated sodium chloride solution, dissolved in sodium sulfate, filtered and the combined organic solutions are concentrated in vacuo to a volume of approximately 10 ml. moreover, most of the 7-benzimidazolyl- (2) -mercaptoacetylamino-cephalosporanic acid crystallizes.

m.p. 135-145 ° C (with decomposition), Rf52 0.35; RfjoM 0.6.

Example 8. 11.75 g of H- (dezacetoxymethyl) 3-benzoylthiomethyl-7-bromoacetylaminocephalosporanic acid was dissolved in 75 ml of dimethylformamide, added 9.75 ml of N-ethyldiisopropylamine. Then, a solution of 3.58 g of 2-mercaptothiazoline in 25 ml of dimethylformamide is introduced and, in the absence of light, left to stand at room temperature. After 20 hours, most of the solvent is distilled off in vacuo (0.5-1 mm Hg) and the oily residue evolved is taken up in 250 ml of phosphate buffer (pH 6) and 250 ml of acetic ester. The pH of the aqueous phase is then adjusted to 6 and the phases are separated. The organic phase is discarded, the pH is adjusted to 2.3 with aqueous hydrochloric acid and saturated with sodium chloride. Extraction is carried out using 1000, 250 and 250 ml of acetic ester. The acetic ester extracts are washed with a saturated solution of sodium chloride, dissolved with sodium sulfate and filtered through a column of 75 g of silica gel. From the combined filtrates, 11 g of solids are obtained. The latter is chromatographed on a column with 520 g of silica gel using chloroform and mixtures of chloroform and acetone. For chloroform-acetone (9: 1), the eluates yield 7.6 g of amorphous 3- (deacetoxymethyl) -3-benzoylthiomethyl-7-thiazolinyl- (2) -mercaptoacetylamino cephalosporanic acid, which can be converted to a crystalline sodium salt with the structure

l

Z-SNGSO-in

bNxA

cHgScoceHg ioONa

using sodium a-ethylhexanate, Rf52 0.50, I 240 nm (e 19200) and I 274 nm (e 20000).

The 3- (deacetoxymethyl) -3-benzoylthiomethyl-7-bromoacetylaminocephalosporanic acid used as the starting material can be prepared as follows. A solution of 17.5 g of 3- (deacetoxymethyl) -3-benzoylthiomethyl) -7-aminocephalosporanic acid (cf. Belgian patent No. 650444) and 12.5 ml of triethylamine in 1 liter of dimethylformamide are added dropwise over 1 hour to a well displaced and having a temperature of minus 13 -minus 15 ° C solution of 9.2 ml of bromoacetyl bromide in 100 ml of methylene chloride under nitrogen atmosphere.

The temperature is allowed to rise slowly to 10 ° C over 90 minutes and is maintained

30 min. Then most of the solvent is distilled off in vacuum at 0.5-1 mm Hg. Art. with the help of a cooler - dry ice and acetone. The oily product is poured onto a phosphate buffer (pH 6) and mixed with 1 liter of acetic ester. On the border of both phases

a viscous mass is formed, which is separated by filtration and centrifugation. The pH of the aqueous phase is then adjusted to 2, the latter is saturated with sodium chloride and the organic phase is separated. The aqueous phase is extracted with an additional 600 and 400 ml of acetic ester. After washing with a saturated solution of sodium chloride, the organic phases are dried over sodium sulfate and filtered successively through a column of 100 ml of silica gel. The filtrates are concentrated in vacuo to dryness, 30 ml of ethanol is added to the residue and it is recrystallized at -20 ° C. 7.8 g of 3- (deacetoxymethyl) -3-benzoylthiomethyl-7-bromoacetylaminocephalosporanic acid are obtained, m.p. 137-138 ° C, Rf52 0.55.

Sodium salt in the UV spectrum in water: Yamax 243 im (e 16,800) and I, “axi 275 nm (e 20600), 47 ± 1 ° c 1, in a 0.1 M solution of sodium bicarbonate - acetone (1: 1).

Example 9. 4.73 g of H- (dezacetoxymethyl) 3-benzoylthiomethyl-7-thiazolinyl- (2) -mercaptoacetylamino cephalosporanic acid (sodium salt) was dissolved in 35 ml of pyridine and then 35 ml of dioxane was added. Next, 20.9 ml of a 40% mercury perchlorate solution are introduced and allowed to react to the solution, moving it strongly for 45 min at 45 ° C (under nitrogen atmosphere). Cool, add 11.1 ml of thiobenzoic acid and shake for 5 minutes. The solvent is distilled off in a vacuum and the solution of the residue is stirred in 140 ml of water with activated carbon. The filtrate is washed twice with 90 ml of toluene twice, using 55 ml of Arnberlit LA-2 in 115 ml of toluene, and twice using 90 ml of toluene. The aqueous phase is then filtered through a column that contains from the bottom up 8.5 ml of Sephadex CM C-25 (H + form), 34 ml Alox, 8.5 ml Zeo-Karb 226 (H + form), 34 ml Alox, 8.5 ml of Dowex-1 (acetate form) and 8.5 ml of Sephadex CM C-25 (H + form). Celite, the organic phases and the column are extracted an additional two times, using 30 ml of water each, and the column is eluted; in addition, another 200 ml of water are eluted. The combined eluates are concentrated in vacuo, a small amount is removed by viscous filtration and evaporated to dryness. The residue is digested with 10 ml of alcohol to obtain pure 3- (deacetoxymethyl) -3-pyridinomethyl-7-thiazolinyl- (2) -mercaptoacetylamino cephalosporanic acid, -j-41 ± + 1 ° (in water; UV spectrum in water; 1 max 257 MMK (E 13000), K, (,, d 0.18.

Example 10. 2.95 g of sodium salt of 7-thiazolinyl- (2) -mercaptoacetylamino-cephalosporanic acid (cf. Example 3) are dissolved in 150 ml of water. The solution is heated to 37 ° C and 0.7 ml 0.1 n. The caustic soda is adjusted to pH 7.5. Then mixed with 60 mg of acetyl esterase (from Bacillus subtilis ATCC 6633, cf. English patent No. 1 080 904) in 2 ml of water and an automatic LA titrator

continuously neutralize the resulting acetic acid with 0.1N. sodium hydroxide (pH adjusted to 7.3). After 4 hours the reaction is over. The pH is adjusted to 6.5, the solution is filtered through a G 4 glass filter and freeze dried. 3.18 g of a yellowish gum of sodium salt of 7-thiazolinyl- (2) -mercapto-acetylamino-O-deacetylcephalosporanic acid are obtained.

This crude product is dissolved directly in a mixture of 30 ml of absolute dimethylformamide and 8.5 ml of triethylamine, 5.05 ml of p-chloroethyl isocyanate is added to it and stirred for 30 minutes at room temperature. The solvent is then removed under high vacuum and the gummy brownish residue is triturated three times using 150 ml of absolute ether. The ether-soluble residue is taken up in 75 ml.

10% phosphate buffer (pH 6.7) and separated with 500 ml of acetic ester. By adding 30 ml of 2 n. hydrochloric acid is adjusted to a pH of the aqueous phase to 2.5. After vigorous agitation, the phases are separated and the aqueous phase is then extracted with another 300 and 200 ml of acetic ester. The organic phases are washed twice with 50 ml of a saturated solution of common salt, dried with sodium sulfate and evaporated to dryness in vacuo. The resulting resin crystallizes after adding a small amount of acetone. Filter on suction and wash the crystals with a mixture of equal parts of acetone and ether. Crude crystallized can be cleaned further, added 1.2 ml 3 n. methanol solution of sodium aethylhexanate to suspension in 18 ml of methanol, clarified the mixture with a small amount of diatomaceous earth, condensing in vacuum

to about 8 ml and recrystallization of the pure sodium salt of O-desacetyl-0- (ip-chloroethylcarbamoyl) -7-thiazolinyl- (2) -mercaptoacetylamino-cephalosporanic acid at -15 ° C. It has in the UV spectrum yamaks

255 nm (, e 10850, in water), and +99 + 1 °. The following data were obtained by thin layer chromatography: for the Rhz system, 0.35; for the Rfioj system, 0.55; and for the acetic acid ester — pyridine — ice on acetic acid — water system (62: 21: 6: 11) Rf 034.

Subject invention

Claims (4)

1. A process for the preparation of 7-amipocephalosporanic acid derivatives of general formula RiSHCHgCO-NH 60 CH, R . From the UN where RI is a five-membered heterocyclic residue of 65 tatok containing at least two heteroatoms MOB is nitrogen, oxygen, or sulfur, which in position 5 can be unsubstituted or substituted by mercaptogranes, and in other positions it can be unsubstituted or substituted by lower alkyl and in which the carbon atom of the five-membered ring in position 2 or 3 is between two heteroatoms linked to the sulfur atom of the mercaptoacetyl group; R2 is a hydroxy group, free or esterified with a carboxylic or thiocarboxylic acid ester, an iN-substituted carbamoyloxy group in which the oxygen atoms can be replaced by sulfur atoms, or a residue of a quaternary ammonium salt, characterized in that 7-halogenacetylamino cephalosporanic acid of general formula NHi CH, R H / 2 2 J.: IoH 12 where R2 has the indicated meanings; Hal is a halogen atom, is reacted with a mercapto compound of the formula RiSH, where RI has the indicated meanings, followed by isolating the products in free form or in the form of an alkali or alkaline earth metal salt or, if R2 is an hydroxy group, esterified with a carboxylic or thiocarboxylic acid, into an ester, the known methods convert this group to an N-substituted carbamoyloxy group, in which the atoms oxygen can be replaced by sulfur atoms, or in a quaternary ammonium salt. 2. The method according to p. 1, about tl and h and y and with the fact that the process is conducted in an inert solvent. 3. The method according to paragraphs. 1 and 2, characterized in that the process is carried out in the presence of an acid binding agent. 4. The method according to paragraphs. 1, 2 and 3, characterized in that the process is carried out at ambient temperature.