SU1563595A3 - Method of producing a stable crystalline form of cephalosporins - Google Patents

Abstract

The invention relates to heterocyclic compounds, in particular, a method for the preparation of a stable crystalline form of cephalosporins of the formula O (O) CC = CY-CH ₂ -S-CH-N ...-C (O) -CH-NH ₂ .X, where Y-CH ₂ —N (CH ₃ ) —CH ₂ —CH ₂ —CH ₂ —CH ₂

X-HCL or HJ, which is used as an intermediate for conversion to cephalosporin antibiotics. The goal is to create new intermediates for a specified purpose. The synthesis is carried out by the interaction of compounds of the formulas CH ₂ -CH ₂ -CH ₂ -CH ₂ -N (CH ₃ ) -SI (CH ₃ ) ₃ and (H ₃ C) ₃ SI-O (O) CC = C [CH ₂ OC ( O) CH ₃ ] -CH ₂ -S-CH-NC (O) -CH-N H-SI (CH ₃ ) ₃ , in the medium of 1, 1, 2-trichlorotrifluoroethane. The resulting intermediate is treated with a lower alkanol to remove silyl groups and acidified with HCL or HJ. The method allows to obtain target compounds free from the impurity of the Δ ² isomer, the use of which simplifies the process of obtaining cephalosporin antibiotics by eliminating the release of carboxyl groups. 3 tab.

Description

The invention relates to a process for the preparation of a novel stable crystalline form of cephalosporins, namely, a hydroiodide or hydrochloride salt of the formula

X H2N

CH3

0I -sn2-p

(I)

sozg

where X is HC1 or HI,

which is free of impurity 4a-isomeu eu (I)

measure, and is used as an intermediate product for conversion to cephalosporin antibiotics with a wide spectrum of action.

The purpose of the invention is to obtain new stable crystalline salts of the cephalosporin series, which are used as intermediates for the synthesis of cephalosporin antibiotics and allow control of the latter.

ate

with

SP

s

(6R, 7E) -Trimethylsilyl-7- (trimethylsilyl) amino-3-acetoxymethyl-3-em-4-carboxylate (compound 1)

Method A. The Lriedrich’s flask and oven-dried flask is cooled to room temperature in a stream of dry nitrogen. Then, 50.0 g (184 mmol) of 7-aminocephalosporanic acid (7-ACC), purity jg 97.2%, and 400 ml of dry 1,1,2-trichloro-trifluoroethane (freon TF, dried with molecular sieves). 46.5 ml is added to the resulting slurry.

15635954

causing it to cool to room temperature.

1H-F spectral analysis (360 MHz) shows more than 95% conversion to the target product.

Method C. Dried in a furnace flask and refrigerator Friedrich cooled to room temperature in a stream of dry nitrogen. 10.0 g (36.7 mmol) of 7-ACC, purity 97.2%, and 80 ml of dry dichloromethane, dried on molecular sieves, are charged to the flask. 9.3 ml is added to the resulting slurry.

(222 mmol, 1.2 equivalents) 98% (44.1 mmol; 1.2 equivalents) 98% -20

1,1,1,3,3,3-hexamethyldisilazane (GaDS) and 0.80 ml (5.6 mmol, 0.03 equivalents) of iodotrimethylsilane (TMCI) with vigorous stirring with protection from moisture. This yulam is subjected to intensive boiling under reflux for 16–18 h, after which it is cooled to room temperature.

GN-NMR spectral analysis of the aliquots of the clouded reaction mixture shows more than 95% conversion to the target product.

NMR spectrogram (, 360 MHz, f): 0.23. (with ,, 9H, N- -Si (CH3) 3); 0.38 (s, 9H, -COO Si (CH3) 3); 1.51 (d, 1H, 13.6 Hz, NH-); 2.09 (p., GZ, -COOH3); 3.41 (d, W, 18.3 Hz, - "C-); 3.61 (d, 1H, 18.3 Hz, -SCHa); 4.80 (dd., 1H,

thirty

th HMDS and 0.16 ml (1.1 mmol; 0.03 equivalent) TMSI with vigorous stirring while protecting against moisture. The slurry is subjected to intensive boiling under reflux for 5 hours, after which the slightly clouded reaction mixture is cooled to room temperature.

H-NMR spectral analysis (CO2-G 360 MHz) shows a more than 95% conversion to the target product.

In the preparation of N-methyl-M-trimethylsilylpyrrolidinium iodide (compound 2), the kiln-dried flask is cooled in a stream of nitrogen supplied under an overpressure to room temperature. Then, 25 ml of dry freon TF, dried over molecular sieves, and 1.42 ml are charged into this flask.

4.5; 13.6 Hz, -COOH / NHSi (CH3) 3); 4.83 35 (10.0 mmol, 1.0 equivalent) TMSI.

40

(d., 1H, 13.2 Hz, -CHNOSOPCH3); 4.91 (d, 1H, 4.5 Hz, -COOH / NHSKCH / CH-); 5.11 (d., Ш, 13.2 Hz, -СН ОСОСНз).

Method B. The oven-dried flask and Friedrich cooler are cooled to room temperature in a stream of dry nitrogen. A flask was charged with 10.0 g (36.7 mmol) of 7-ACC, purity of 97.2%, and 80 ml of dry freon TF, dried on molecular sieves. 9.3 ml (44.1 mmol, 1.2 equivalents) of 98% -F HMDS and 44 ml (1.1 mmol of 0.03 equivalents) of a 0.025 M solution of hydrogen iodide hydrogen in freon are added to the prepared slurry. TF prepared by dissolving hydrogen iodide in dry TF freon and titrating the resulting saturated solution with phenolphthalein. This slurry is subjected to intensive boiling under reflux with vigorous stirring while protecting against moisture for 22 hours, after

The resulting solution is cooled to 0-5 ° C in a stream of dry nitrogen. A total of 1.04 ml (10.0 mmol, 1.0 equivalent) of dry 97% N-methylpyrrolidine, dried over molecular sieves, are added dropwise, and the resulting slurry is stirred at 0-5 C in a stream of nitrogen in for 30 minutes 45 After this time, the slurry is filtered under nitrogen overpressure on a Schlenk funnel and the collected solid material is washed with two 25-ml portions of fresh TF freon. The filter cake is partially dried under overpressure of a nitrogen stream for 15 minutes As a result of subsequent drying at room temperature and residual pressure of 0.05 mm Hg. Art. within 12 hours, 2.51 g (89% yield) of compound 2 is obtained as a colorless and extremely sensitive in air solid product. For numerical F-spectral analysis (, 360 MHz) shows more than 95% conversion to the target product.

Method C. Dried in a furnace flask and refrigerator Friedrich cooled to room temperature in a stream of dry nitrogen. 10.0 g (36.7 mmol) of 7-ACC, purity 97.2%, and 80 ml of dry dichloromethane, dried on molecular sieves, are charged to the flask. 9.3 ml is added to the resulting slurry.

(44.1 mmol; 1.2 equivalents) 98%

th HMDS and 0.16 ml (1.1 mmol; 0.03 equivalent) TMSI with vigorous stirring while protecting against moisture. The slurry is subjected to intensive boiling under reflux for 5 hours, 1 after which the slightly turbid reaction mixture is cooled to room temperature.

H-NMR spectral analysis (COgClg, 360 MHz) shows more than 95% conversion to the target product.

In the preparation of N-methyl-M-trimethylsilylpyrrolidinium iodide (compound 2), the kiln-dried flask is cooled in a stream of nitrogen supplied under an overpressure to room temperature. Then, 25 ml of dry freon TF, dried over molecular sieves, and 1.42 ml are charged into this flask.

(10.0 mmol, 1.0 equivalent) TMSI.

0

P

The resulting solution is cooled to 0-5 ° C in a stream of dry nitrogen. A total of 1.04 ml (10.0 mmol, 1.0 equivalent) of dry 97% N-methylpyrrolidine, dried over molecular sieves, are added dropwise, and the resulting slurry is stirred at 0-5 C in a stream of nitrogen in for 30 minutes 5 After this time, the slurry is filtered under nitrogen overpressure on a Schlenk funnel and the collected solid material is washed with two 25-ml portions of fresh TF freon. The filter cake is partially dried under overpressure of nitrogen flow for 15 minutes. As a result of subsequent drying at room temperature and a residual pressure of 0.05 mm Hg. Art. within 12 hours, 2.51 g (89% yield) of compound 2 is obtained as a colorless and extremely sensitive in air solid product. 44.49% iodine was calculated, 44.40% iodine was found (by chromatographic analysis of iodine ion).

In a separate experiment, the reaction was carried out in the same way, except that 0.40 ml (10.0 mmol; 1.0 equivalent) of methanol was added to the salt in Freon TF at 0-5 ° C. The resulting heterogeneous mixture was stirred at 0-5 ° C in a stream of nitrogen for 30 minutes. The slurry is filtered under anhydrous conditions on a P1penk funnel. The filter cake is washed with two 25 ml portions of fresh TF freon and dried at room temperature for 3 hours under a residual pressure of 0.05 mm Hg, 1.98 g (91% yield) of the isolated solid is identified. as N-methylpyrrolidinium hydroiodide with m.p. 80-82 ° C. An authentic sample of this salt is obtained independently by gasifying a solution of N-methylpyrrolidine (NML) in TF Freon with hydrogen iodide. M.p. the isolated solid is 83.5-85.5 ° C. The NMR spectrogram at 360 MHz of this material () corresponds to the spectrogram obtained for the salt isolated from the reaction mixture, the reaction in which is stopped with methanol. The NMR spectrogram at 360 MHz of the filtrate from the reaction terminated with methanol shows the presence of methoxymethylsilane and methyl iodide as the main components (total ratio 17: 1), as well as a small amount of hexamethyldisiloxane.

Example 1. (6R, 7K.) - 7-Amino-3- (1-methyl-1-pyrrolidinium) -methyl-Ce-3-em-4-carboxylate monohydrochloride (compound 3).

Method A. The oven-dried flask is cooled to room temperature in a stream of dry nitrogen. Then 15.7 ml (110 mmol; 1.5 equivalents) of TMSI and 140 ml of dry freon TF, dried over the molecules of the sieve, are charged to the flask. The resulting solution is cooled to 0-5 ° C and 10.7 ml (103 mmol 1.4 equivalent) of 97% NML are added dropwise in such a way as to maintain the reaction temperature below 0VC. After completion of the addition operation, the slurry is stirred at 0-5 ° C for 30 minutes in a stream of nitrogen. After this period of time, the slurry is heated to room temperature.

The reaction mixture containing compound 1, prepared according to method A using 20.0 g of 7-ACC, is added by means of a batch at a rate such that the NMP / TMSI slurry is at room temperature. The resulting heterogeneous mixture is stirred at room temperature for 14 days, periodically monitoring the progress of the reaction by high performance liquid chromatographic analysis. At the point where the 7-ACC percentage zone is less than 2% of the total peak zone, 6.0 ml (147 mmol; 2.0 equivalents) of methanol is added dropwise and stirring is continued for 30 minutes. The crude product is filtered, washed with 300 ml of fresh freon TF and partially dried with pumping the atmosphere for 15 minutes. Next, the product is dried in vacuum at room temperature for 16 hours

The crude product is used to prepare sludge in 80 ml of deionized water. The pH is lowered to 0.50 by adding dropwise concentrated hydrochloric acid with vigorous stirring. Bleaching coal (20% by weight of the amount of the crude product) is added and the mixture is stirred for 45 minutes. The slurry is subjected to vacuum filtration through diatomaceous earth and the filter layer is washed with deionized water. 900 ml of isopropyl alcohol (IPA) are added dropwise over 1 hour to the aqueous phase with moderate stirring. The resulting slurry is stirred at 25 ° C for 1 hour, cooled to 0-5 ° C and stirred for 1 hour. As a result of filtration, washing with cold (0-5 ° C) mixture of IPA with water in a ratio of 9: 1 in the amount 200 ml and 200 ml of acetone and drying at 25 ° C under vacuum for 16 hours gives 15.5 g (63% yield) of crystalline compound 3.

High-resolution liquid chromatographic data show 96.3% versus standard batch.

NMR spectrogram (D40,360 MHz, suppression of DaO: HjO, cf): 2.14-2.32 (envelope, 4H, -N (CHj) CHiCH, -);

.00 (s., NN, NCH3); 3.46-3.67 (m „, H, -N (CHs) CH7 CHtt SCH); 3.96 (d, W, 16.9 Hz, -SCH); 4.09 (d, IH, 13.9 Hz,); 4.73 (d, 1H, 13.9 Hz, -CCH4N-); 5.21 (d, 1H,

5.1 Hz, -COCHCHS-); 5.41 (d, 1H, 5.1 Hz, -COCHOHS-).

Method B. In addition to the one described in the slurry from a mixture of NML with TMSI and TFR at 0. 5 ° C, 0.50 g (7.3 mmol 0.10 equivalent) of imide-Zola is added. Such modification leads to a moderate increase in the reaction rate after the 7-ACC level reaches less than 2% of the total peak area of high-resolution liquid chromatography after 10 days. As a result of treating the reaction mixture in the same way as Method A, 14.7 g (60% yield) of crystalline compound 3 are obtained. Method C. Sludge (6R, 7K) -trimethyl-7-trimetal-1-silyl-7- (trimethyl - silyl) amino-3- (1-methyl-1-pyrrolidinium) -methyl-3-em-4 carboxylate iodide in TF freon, prepared according to method A using 20.0 g of 7-ACC, at 0-5 ° C in a stream of dry nitrogen, 10 ml (246 mmol 3.35 equivalents) of methanol are added dropwise over 5 minutes (the temperature does not rise to 9 ° C). The resulting slurry is stirred at 0-5 ° C for 15 minutes after completion of the addition operation. Then 50 ml of 3 N is added dropwise over 10 minutes. hydrochloric acid prepared by adding 250 ml of concentrated hydrochloric acid to 756 ml of deionized water. After completion of the addition operation, the cooling bath is removed and the mixture is stirred for 15 minutes. The phases are separated and the aqueous phase (the volume of which is brought to 100 ml) is stirred for 30 minutes at room temperature together with 4.0 g (20 mas.% Of the weight of the 7-ACC consumed) of the providing angle. Next, the slurry is filtered through 4.0 g of diatomaceous earth and the layer is washed with 10 ml of deionized water. The volume of water is brought to 1-00 ml,

The crystallization according to the first method is carried out as follows. 250 ml (5 volumes) of acetone are added to 50 ml of enriched water, and the addition is made dropwise, with

0

five

0

five

five

0

five

aim to precipitate the product. The resulting slurry is stirred with cooling with ice water for 1 hour, after which it is filtered with vacuum, washed with two portions of 40 ml of cold (0-5 ° C) mixture of acetone and water in a ratio of 5: 1 and 40 ml of acetone, partially dried with pumping the atmosphere for 15 minutes Next, the product is further dried, in vacuum at room temperature for 15 h, resulting in a gain of 4.48 g (37% yield, calculated on a 50% yield from theoretical, taking into account the flow rate of 20.0 g of 7-ACC) colorless crystalline compound 3.

The crystallization according to the second method is carried out as follows. 150 ml (3 volumes) of IPA are added dropwise to 50 ml of enriched water to precipitate the product. The resulting yula is stirred with cooling with ice-water for 1 h, after which it is filtered with vacuum, washed with two portions 40 ml of cold (0-5 ° C) mixture of IPA with water in the ratio of 9: 1 and 40 ml of acetone and subjected to partial drying with pumping of the atmosphere for 15 minutes. The product is further dried in vacuum at room temperature for 15 minutes, yielding 5.46 g (45% yield, if based on 50% yield from the theoretically possible in terms of consumption of 20.0 g of 7-ACC) is not quite white crystalline compound 3.

EXAMPLE 2: Preparation of Compound 3 by Successive Reactions (6R, 7K.) - Trimethylsilyl-7- (trimethylsilyl) -amino-3-acetoxymethyl-cem-3-em-4-to arboc silate (with combination 4) in freon TF with bromotrimethylsilane 5 NMP and aqueous hydrochloric acid.

To a stirred, slightly turbid reaction mixture of compound 4, prepared in accordance with method A of example 1 using 10.0 g of -7-ACC, in freon TF at room temperature in a stream of dry nitrogen in the form of a weak current for 1 min add 4 , 5 ml (42.2 mmol, 1.15 equivalents) of 98% bromotrimethylsilane. The progress of the reaction is monitored by H-NMR spectral analysis. After stirring for

90 min at room temperature, only traces of the reaction products (3-bromomethylcephelosporin and trimethylsilylacetone) are detected. The reaction mixture is carefully boiled under reflux in a stream of nitrogen, controlling the course of the reactions also by means of H-NMR spectral analysis. After 10 days in the reaction mixture, the starting materials remain the prevailing components. At best, analysis of the reaction mixture by means of H-NMR spectrograms at 360 MHz shows only a 15% conversion rate (from the total zone) to the target (6R, 7K) -trimethylsilyl-7- (trimethylsilyl) -amino-3- | bromomethyl cef-3-em-4-carboxylate.

Example 3: Preparation of Compound 3 by the successive reactions of Compound 4 in TF Freon with chlorotrimethylsilane, NML and aqueous hydrochloric acid solution.

The experimental procedure is similar to Example 2, except that 5.4 ml (42.2 mmol; 1.15 equivalents) of chloromethylsilane is used instead of bromomethylsilane. After boiling the reaction mixture under reflux for 10 days in a stream of nitrogen, analysis of this mixture by means of H-NMR spectrograms at 360 MHz shows the presence of chlorotrimethylsilane and 4 as the main components. In the best case, only 5% conversion is observed. zones) in the target (6R, 7B.) - trimethylsilyl-7- (trimethylsilyl) amino-3-chloromethyl-ceph-3-em-4-carboxylate.

EXAMPLE 4 (6R, 7K) -Amino-3- (1-methyl-1-pyrrolidinium) -methyl-3-em-4-carboxylate hydrochloride or hydroiodide according to a single vessel reaction scheme.

I

50.0 g (0.184 mol) of 7-ACC are added to 350 ml of CC12F CC1F2 (freon TF) in a stream of nitrogen. Moreover, 7-ACC is an extremely dusty solid substance that should be weighed in a hood or elsewhere where reliable ventilation is provided.

46.5 ml (0.22 mol, 1.2 equivalents) of HMDS is added to the stirred suspension of these materials in one portion. 0.78 ml (6.0 MMonbJ 0.03 equivalents) are added in one portion using a syringe

 .

ten

15

5635951i

(all operations with TMSI must be carried out with the creation of anhydrous conditions).

The resulting mixture is heated and refluxed for 7-10 hours. The reaction time is variable and depends on the presence of TMSI (or its reactive equivalent) as a catalyst. If the reaction mixture turns out to be viscous, an additional amount of TMCI allows for faster completion of the reaction. It is important to withstand vigorous reflux, since the removal of ammonia formed is the main driving force of this reaction. The reaction is monitored by NMR spectral analysis (when taking samples from the reaction mixture, it is important to observe anhydrous environmental conditions). The silylation reaction mixture is cooled to room temperature, further diluted with 150 ml of Freon TF and cooled to 5 ° with nitrogen flow. WITH.

With good stirring, for 26 minutes, 26.83 ml (0.25 mol; 1.4 equivalents) of NML was added, keeping the reaction temperature below 10 ° C. Increasing the temperature to a level greater than 10 ° C during the addition of the NML leads to

20

25

thirty

35

40

45

50

55

an increase in the amount of unwanted l -isomer relative to the normal ratio of isomers 1:26

In the form of a weak current for 10-15 minutes, 47.1 ml (0.33 mol} 1.8 equivalents) of TSHI are added to the well-stirred mixture at 5 ° C using a syringe. During the TMIC addition process, a slight exothermic temperature increase is observed. The reaction sludge is stirred at 5 ° C for 30 minutes in a stream of dry nitrogen. The resulting slurry is gently heated and stirred at 35-36 ° C for 1 hour. The substitution reaction is monitored by means of high-resolution liquid chromatographic analysis. Samples must be analyzed by high-performance liquid chromatography every 4-6 hours. During the course of this reaction, the reaction temperature, time, concentration and number of equivalents of TMSI, as well as the saturation of the medium, are important.

The volume of the reaction mixture and the speed of its mixing are constantly monitored. As necessary, an additional 100 ml of Freon TF is added. When the slurry becomes thick, in order to simplify mixing, it is necessary to add some CC12FCC1F2 to dilute it.

After completion of the reaction (less than 2% of 7-ACC according to high-resolution liquid chromatographic-FO analysis), the slurry is cooled in a stream of nitrogen to 5 ° C and added dropwise over an eight-minute period at 5 ° C 25 ml (0.615 mol) of methanol (before adding methanol, the sludge is so thick that lumps of material adhere to the walls of the reaction vessel, this makes it difficult to complete displacement with methanol; the quality and completeness of mixing throughout the reaction vessel should be determined HAND).

The slurry undergoes significant dilution; after the addition of methanol, it is further stirred for 15 minutes at 5-10 ° C.

The cooling bath is then removed and 125 ml of 3 N is added over 2 minutes with good stirring. hydrochloric acid solution prepared by adding 250 ml of concentrated hydrochloric acid solution to 756 ml of water. The reaction temperature rises to 12-15 ° C. The hydrolysis mixture can be so quickly heated to 20-25 ° C (not exceeding 25 ° C), after which it is further stirred for 15 minutes at 20-25 ° C.

The phases are separated and the organic phase (bottom layer) is back-extracted with 50 ml of water. This aqueous phase is used as a washing liquid during the final filtration of the enriched aqueous solution. 2S5 g of diatomaceous earth is added to the resulting enriched aqueous phase and then filtered through a layer of 7.5 g of pre-packed diatomaceous earth. The filter cake from diatomaceous earth is washed with an aqueous solution (back extraction) and then with 25 ml of deionized water. The combined enriched aqueous solution and wash liquid (in volume example

but 270 ml, reddish-brown color) is stirred for 30 min at 21-23 ° C together with 10 g of decolorizing charcoal. 2.5 g of diatomaceous earth is added to the mixture and stirring is continued for 5 minutes.

The carbon is removed by filtration through a filter from 7.5 g of the diatomaceous earth laid down. Charcoal Pie1

washed with 75 ml of water and further dried with pumping the atmosphere for 5 minutes.

If necessary, additional amounts of freon TF found in the lower part of the enriched aqueous solution are separated from the aqueous phase. In a clear aqueous solution, painted in orange color (in volume

0, about 350 ml, with a pH of 0.9-1.15), IPA is added dropwise to the cloud point (usually this requires the addition of 0.5 to 1.0 volume of isopropanol).

5 After the addition of IPA at 21-23 ° C for 15 minutes, the crystallization process is allowed to proceed. After the specified time has elapsed, additional IPA is added to the slurry for 45-60 minutes (a total of 1.2 mp IPA is added), and then the slurry is stirred, cooled to 0-5 ° C for 60 minutes.

The product is collected by filtration.

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the cake is washed in two portions of 100 ml of cold (0-5 ° C) mixture of IPA with water in the ratio of 9: 1 and 100 ml of acetone (the washing mixture is prepared by mixing 90 ml of isopropanol with 10 ml of water and cooling the mixture of 0-5 ° C in a bath of ice water). The product is dried by evacuating the atmosphere for 15 minutes. Next, the product is dried in vacuum to constant weight, to obtain 46-51 g (75-83% yield) crude mixture of hydrochloride and hydro-iodide salts of the indicated substance (compound (I)) in the form of a crystalline solid from off-white to white color. The activity yield is 60-63.3%.

In a separate experiment, the product was isolated as a pure hydroiodide salt by treating the slurry 125 ml 43 n. solution of hydroiodic acid instead of 125 ml of 3 N hydrochloric acid. As a result of treatment of the aqueous phase as described above, 44.3 g of a white crystalline hydroiodide salt are obtained. The reduced potential for high resolution liquid chromatography on a Chro-1 matrix is 105% versus the analytical standard hydrochloride salt. The yield of activity in terms of 7-ACC is 56.7%.

According to NMR spectral analysis, the purity of the product is over 95%. High-resolution liquid chromatographic analysis of potency 10

With good stirring over a 25-minute period, 475 ml of IPA is additionally added dropwise. Moreover, the total volume of IPA used for crystallization is 600 ml, which is 3.5 times the volume of the finally filtered water filtrate.

The resulting slurry is stirred with cooling in a bath of water with ice for 1 hour.

The slurry is filtered off and then successively washed with two portions of 750-800 µg / mg known-j5 mi 20 ml (the washing mixtures consist of an abrasive 3-form compound

from 108 ml of isopropanol and 12 ml of distilled water) with cold (0-5 ° C) mixture of isopropanol with a ratio of 9: 1 and 120 ml of acetone.

(I) in the form of hydrochloride. The purity zone is above 95%.

Example 5: Recrystallization 20 of compound 3 (compound (I) hydrochloride).

15.0 g (0.045 mol) of the crude hydrochloride of the compound (I), the number of moles of the hydrochloride used in the compound (25) given in terms of 100% purity, is added in one portion to 125 ml (3, 5 mol Ј 3.50 equivalent) 1 n. hydrochloric acid solution with good stirring, which is prepared by adding 83 ml of concentrated hydrochloric acid to 920 ml of distilled water. The resulting mixture is stirred at room temperature for 5 minutes. In a single portion, continuing with good mixing, a total of 8.0 g of decolorizing charcoal is added. The slurry is stirred for 45 minutes.

The coal slurry is filtered off by vacuum through a layer of 8.0 g of diatomaceous earth. This layer is washed with 35 ml of water and dried by pumping the atmosphere for 5 minutes.

The slightly clouded filtrate is subjected to final filtration by passing through a 5 micron milipore filter, obtaining a completely clear filtrate, similar in appearance to 50 with water (total volume 170 ml).

125 ml of IPA is added dropwise to the cloud point over 25 minutes with good agitation. Isopropanol added at the indicated point

from 108 ml of isopropanol and 12 ml of distilled water) with cold (0-5 ° C) mixture of isopropanol with a ratio of 9: 1 and 120 ml of acetone.

The filter cake is partially dried and the atmosphere is pumped out for 15 minutes. As a result of additional drying in vacuum (pumped out using a steam injector) for 15 hours at 40 ° C, 7.87 g (52% yield) of a snow white the action of electrostatic charge, crystalline hydrochloride of compound (I).

In tab. 1 shows analytical data consistent with the recrystallized hydrochloride of compound (I).

Table 1

35

According to the test data of this material, its potential is 99.5% against the standard liquid chromatographic high-resolution batch of the compound (I) hydrochloride. The Klettu number is equal to 3 (100.0 mg of the sample, diluted stop. The slurry is stirred at a volume of up to 10 ml in a volume flat temperature for 15 minutes, without Milli-Q water, filtered

moreover, during this time it is formed well through the sample preparative filter

high crystal seed layer for liquid chromatography with high

With good stirring over a 25 minute period, 475 ml of isopropyl alcohol is additionally added dropwise. Moreover, the total volume of IPA used for crystallization is 600 ml, which is 3.5 times the volume of the finally filtered water filtrate.

The resulting slurry is stirred with cooling in a bath of ice water for 1 hour.

The slurry is filtered off and then successively washed with two portions of 20 ml (the washing mixtures are

from 108 ml of isopropanol and 12 ml of distilled water) with cold (0-5 ° C) mixture of isopropanol with a ratio of 9: 1 and 120 ml of acetone.

The filter cake is partially dried by evacuating the atmosphere for 15 minutes, and as a result of additional drying in vacuum (pumped out using a steam injector) for 15 hours at 40 ° C., 7.87 g (52% yield) of snow white is obtained, electrostatic charge, crystalline hydrochloride of compound (I).

In tab. 1 shows analytical data consistent with the recrystallized hydrochloride of compound (I).

Table 1

25 30

35

According to the test data of this material, its potential is 99.5% against the standard liquid chromatographic high-resolution batch of the compound (I) hydrochloride. The Klett number by Mailek-ika resolution; bluish-light color; line length of about 1.2 cm).

Typically, the crude hydrochloride of compound (I), obtained by adding hydrochloric acid to the final mixture, contains some amount of the hydroiodide of compound (I), resulting from the presence of iodine in the intermediate product. Thus, although it is characterized by a high degree of antibacterial purity, in order to remove the hydroiodide of compound (I), the specified product should be recrystallized in the manner described.

The initially crystallized hydroiodide of compound (I), obtained by adding hydroiodic acid to the final reaction mixture, is free from the hydrochloride of compound (I). In this way, the hydroiodide of the compound (I) is obtained with a high degree of purity, therefore there is no need for its recrystallization.

PRI me R 6. Compound 4 of the formula

ngtch

0D-KHA

TMSN s

RAS-UPG 0 -NCO-iTHS

.ОАС

The oven-dried flask and Friedrich cooler are cooled to room temperature in a stream of dry nitrogen. Then, 10.0 g (36.7 mmol) of 7-ACC (purity 97.2%) and 70 ml of dry freon TF3 dried over molecular sieves were charged to the flask. B The resulting slurry was syringe with good mixing and 9.3 ml (44.1 mmol, 1.2 equivalents) of 98% HMDS and 0.16 ml (1.1 mmol $ 0.03 equivalents) of TMSI are added to protect against moisture penetration. This sludge is rapidly heated and maintained at a temperature of intensive boiling under reflux for 7–10 h, passing a weak stream of nitrogen through the system. Next, the reaction mixture is cooled to room temperature in a stream of dry nitrogen and diluted with 30 ml of fresh freon TF. H-NMR spectral analysis of the aliquot of a slightly turbid reaction mixture shows more than 95% conversion to the desired product.

five

0 5

Ijn s

 Hme

u I mon „

0

five

Q d§ „0

NMR spectrogram (CDaCl2, 360 MHz, G). 0.23 (s, 9H, N-Si (CH3) 3); 0.38 (s, 9H, -COOSi (CH3) 3); 1.51 (d, 1H, 13.6 Hz, NH-); 2.09 (s., GZ, -COCH3); 3.41 (d, 1H, 18.3 Hz, -SCH2-); 3.61 (d, 1H, 18.3 Hz, -SCH7); 4.80 (dd., 1H, 4.5 and 13.6 Hz, -COCH / NHS: (CH3) E); 4.83 (d, 1H, 13.2 Hz, -CH2OCOSCNE); 4.91 (d, 1H, 4.5 Hz, -COCH / NHS; (CH3) ESN-); 5.11 (d, 1H, 13.2 Hz, -CHNOSPCH3).

Example. (6R, 7K) -7-amino-3- (1-methyl-1-pyrrolidinium) -methylceph-3-em-4-carboxylate monohydroiodide (compound 5)

™ W

co2TMs i0 si

j I

 To a slightly turbid solution of compound 4 in freon TF prepared as described in example 6, at 0-5 ° C in a stream of dry nitrogen, add 5.35 ml (51, 4 mmolJ 1.4 equivalents) of dry 97% NML, dried over molecular sieves. A syringe is then added over about 5 minutes, continuing good mixing, 9.40 ml (66.1 mmol; 1.8 equivalents) of TMSI. During this addition, the reaction temperature is maintained at a lower level. The resulting slurry is stirred at 0-5 ° C for another 30 minutes. After this time, the sludge is placed in an oil bath, the temperature of which is carefully controlled in the range of 35-36 ° C. The progress of the reaction is monitored by high resolution liquid chromatographic analysis. After 45-48 hours, the reaction is complete (less than 2% of the 7-ACC zone) and the mixture is cooled to 0-5 ° C in a stream of dry nitrogen. With good stirring, a total of 5.0 ml (123 mmol; 3.35 equivalents) of methanol is added dropwise. The reaction temperature during the addition process is maintained at less than 10 ° C. The resulting slurry is stirred at 0-5 ° C for another 15 minutes. Then in one portion, 25 ml (75 mmol, 2.0 equivalents) of 3 N are added to the mixture. aqueous solution of hydroiodic acid. After completing this opera17

The additions of the cooling bath are removed and the two-phase mixture is quickly heated to 20-25 ° C. Intensive mixing is continued for 15 minutes. The phases are separated and the organic phase is back extracted with 10 ml of water. This backwash liquid is retained for further use.

The basic aqueous phase is stirred at 20-25 ° C for 10 minutes, together with 0.5 g of diatomaceous earth. The slurry is filtered through a layer of 1.5 g

18

ten

cooled to 0-5 ° C and allowed to stand for 1 hour. The slurry is filtered and washed with two portions of 20 ml of cold (0-5 ° C) mixture of iso-propanol and water in a volume ratio of 4: 1 and in two portions of 20 ml of acetone. The cake is partially dried by evacuating the atmosphere for 5 minutes. As a result of further drying in vacuum at 20–25 ° C to a constant weight, 8.94 g (57% yield of a white crystalline compound) are obtained. Data on liquid chromatography –nMijUyirvv v, W and i WJJLJnc 1 VI C1CL1

diatomaceous earth (preliminary analysis with a high solubility of 50 ml of water). This layer is then washed with a backwash aqueous liquid from the previous step, and then with 5 ml of water. The cake is partially dried by pumping the atmosphere for 5 minutes. A total of 2.0 g of decolorizing carbon is added and the slurry is stirred at 20-25 ° C for 30 minutes. After this time, 0.5 g of diatomaceous earth is added and stirring is continued for 5 minutes. The slurry is filtered through a layer of 1.5 g of diatomaceous earth (previously washed with 50 ml of water), then this layer is washed with 5 ml of water. The layer of diatomaceous earth is partially dried by pumping the atmosphere for 5 minutes. The filtrate is finally filtered through a 5 micron millipore filter.

The product is precipitated by adding dropwise 3.5 volumes of isopropanol to a clear amber-colored aqueous phase at 20-25 C. The slime formed

20

 25

thirty

96.3% of the standard batch products show a general ability.

NMR spectrogram (D20, 360 MHz, H20, J1 suppression): 2.14-2.32 (envelope, 4H, -NfCHaJCH Hi-); 3.0 (c.i ЗН, NCH3); 3.46-3.67 (m, 5H, -N (CH3) CH2 CH2, SCH-g); 3.96 (d, W, 16.9 Hz, -SCH); 4.09 (d, 1H, 13.9 Hz,); 4.73 (d, W, 13.9 Hz, CCHaN-); 5.21 (d, W, 5.1 Hz, -COCHCHS-); 5.41 (d, 1H, 5.1 Hz, -COCHCHS-).

X-ray powder analysis results for the compound of formula

.sg

35

+ vn

 +

C02 CH3

(1/26-HC1) m.p. 251 C (with decomp.) Are listed in Table. 2

1563595

18

0

cooled to 0-5 ° C and allowed to stand for 1 hour. The slurry is filtered and washed with two portions of 20 ml of cold (0-5 ° C) mixture of isopropanol and water in a volume ratio of 4: 1 and in two portions of 20 ml of acetone. The cake is partially dried by pumping the atmosphere for 5 minutes. As a result of further drying in vacuum at 20–25 ° C to constant weight, 8.94 g (57% yield) of a white crystalline compound 5 are obtained. Data on liquid chromatography t –nMijUyirvv v, f i j WJJLJnc 1 VI C1CL1

5 analysis with high resolution analysis with high resolution 20

25

thirty

96.3% of the standard batch is shown by common ability.

NMR spectrogram (D20, 360 MHz, H20, J1 suppression): 2.14-2.32 (envelope, 4H, -NfCHaJCH Hi-); 3.00 (c.i ЗН, NCH3); 3.46-3.67 (m, 5H, -N (CH3) CH2 CH2, SCH-g); 3.96 (d, W, 16.9 Hz, -SCH); 4.09 (d, 1H, 13.9 Hz,); 4.73 (d, W, 13.9 Hz, CCHaN-); 5.21 (d, W, 5.1 Hz, -COCHCHS-); 5.41 (d, 1H, 5.1 Hz, -COCHCHS-).

X-ray powder powder analysis results for the compound of formula

.sg

five

+ vn

 +

C02 CH3

(1/26-HC1) m.p. 251 C (with decomp.) Are listed in Table. 2

table 2

X-ray powder diffraction analysis for the compound form (1/26-HI) so pl. 222 ° C (with decomp.) Are listed in Table. 3

The compounds of formula (I) can easily be converted to broad-spectrum antibiotics by acidifying them with an acceptable side chain. For example, a compound of formula (I) (X is a hydrochloride salt of

cr

C-CONtt-rAH 3C

N

sozg

OCH3

N-acylation of 1-benzotriazolin (g) with 2- (2-aminothiazol-4-yl) 2-methoxyimino-i-acetate activated ether.

This reaction is easily carried out either in the presence of K, K7 Dimethylaniline in dimethylformamide at room temperature for 10-20 hours, or by dissolving Compound (I) in water and di

or hydroiodide; subjected to conversion to 7-Јo ((2-aminothiazol-4-yl) -oЈ- (2) methoxyiminoacetamido} -3-C (1-methyl-1-pyrrolidino) -methyl} -3-cephem-4-carboxylate

rW

sozg

methyl phrmamide and adding sodium bicarbonate with ice cooling, and then reaction at room temperature for about 30 minutes to 5 hours, or by dissolving the compound (I) in water, cooling the solution to 5-15 ° C, adding a dropwise solution of hydroxide rub up

41563595

pH values of 5.5-6.0, addition of tet pai hydrochloride, NaOH solution with pH adjustment to 6.7-6.9, addition of active ether reagent and reaction for 1 to 5 hours at room temperature.

Try on Conversion of compound (I), where X is HC1, to compound (II).

21.72 g (0.0612 mol) of the sample were combined, followed by stirring with 5.1 g of the product Di- for 10 minutes. Then the hardness of (I), where X is the hydrochloride, is dissolved in 190 ml of water at 25 ° C with stirring. Then the mixture is cooled to and its pH is adjusted to 2.5-5.8 (ranging from 5.7 to 5.7) J5 by adding dropwise 30.5 ml (0.061 mol; 1.0 equivalent) 2 n . sodium hydroxide solution. The total volume is 214 ml.

Then in three portions, add 20

Niemi Kalit1

These substances are separated by vacuum filtration and washed with two 5 ml portions of water.

The 314 ml of the resulting clear orange solution is acidified, with good stirring, to a pH of 3.7 (in the range of 3.5-4.0), adding dropwise 14.5 ml of 4N. sulfuric acid. At this point, the mixture becomes turbid, as the crystallization of the acidic sulfuric acid adduct of compound (II) begins.

Neither the temperature rises to 12-13 ° C, therefore, before adding each subsequent portion, it is lowered to 8-10 ° C. In total, the add-on time is 10 minutes. The pH of the mixture is adjusted to 5.8-6.1.

Next, the pH of the mixture was adjusted to 6.8 (in the range of 6.7-6.9) by adding dropwise 2.0 ml (0.004 mol) of 2N. sodium hydroxide solution.

A sample of 29.5 g (0.0927 ml) I-benzotriazole 2} -2- (2-aminothiazol-4-yl) -2-methoxyimino acetate active ether is added to the reaction mixture in five equal portions over 45 minutes. After the first portion of active ester has been added, the cooling bath is removed. The pH of the reaction mixture was again adjusted to 6.5 (range 6.5-6.7) after 5-10 minutes after completion of each operation for adding the active ester by adding 2 n dropwise to the mixture. sodium hydroxide solution.

The clear pale orange reaction mixture was stirred at 25 ° C for 2-3 hours. In the first 30 times, the pH was adjusted again to 6.5 (range 6.5-6.7) every 5-10 minutes by adding dropwise m 2 n. sodium hydroxide solution. During the rest of the reaction time, the pH is adjusted to 6.5 every 15 minutes, a total of 29.5 ml of 2N are added. sodium hydroxide solution (0.059 mol; 0.97 equivalent). The completion of the reaction is judged by high-resolution liquid chromatographic analysis.

22

Then the solids present in the reaction mixture were removed by filtration and washed with two 5 ml portions of water. The ethyl acetate is subjected to extraction with methyl isobutyl ketone (790 ml) and the aqueous layer is separated. The organic phase is washed with 64 ml of water and the aqueous phases.

together with 5.1 g of the product Di- for 10 minutes. Then twJ

20

thirty

35

five

40

45

0

five

Niemi Kalit1

These substances are separated by vacuum filtration and washed with two 5 ml portions of water.

The 314 ml of the resulting clear orange solution is acidified, with good stirring, to a pH of 3.7 (in the range of 3.5-4.0), adding dropwise 14.5 ml of 4N. sulfuric acid. At this point, the mixture becomes turbid, as the crystallization of the acidic sulfuric acid adduct of compound (II) begins.

Crystallization is continued for 10-15 minutes, after which the pH is adjusted to 3.0 (in the range of 2.9-3.1) by adding dropwise 7.5 ml of 4N. sulfuric acid. Next, the mixture is cooled to a temperature of from 0 to 5 ° C and the remaining 63.5 ml of 4N are added over a period of 20-30 minutes. sulfuric acid, as a result of which the pH value reaches the range of 1.3-1.5. After the addition of sulfuric acid is completed, the strain is stirred for 1 hour at 0-5 ° C.

The white crystalline product is removed by vacuum filtration and washed with 63.5 ml of 0.5N. sulfuric acid. The solid material is partially dried by evacuating the atmosphere for 15 minutes and then washed with two portions of 100 ml of acetone. The solid product is again partially dried by evacuating the atmosphere for 10 minutes, after which it is suspended for 1 hour in 400 ml of acetone with good mixing. The solid product is removed by vacuum filtration, washed with two portions of I00 ml of acetone and dried in vacuum (under a residual pressure of 10–15 mm Hg) at 35–40 ° C to constant weight for 3–6 hours.

28.79 g (yield 81.4%) of the product, the acidic sulfuric acid adduct of compound (II), is isolated in the form of slightly

23

exposed to electrostatic charge of a white crystalline solid.

EXAMPLE 9 Convert Compound (I), Where X is HI, to Compound (II)

The procedure of example 6 is repeated completely, except that in this case, the starting material is replaced with an equimolar amount of compound (I), where X is HI, resulting in a compound indicated in example 8.

Thus, the compounds of formula (I), when used as intermediates for the synthesis of cephalosporin antibiotics, simplify the process of obtaining the latter by eliminating the release steps of the carboxyl groups. The form, the invention

The method of obtaining a stable crystalline form of cephalosporins of the formula

s nz

X HfcN154359524

where X is HC1 or HI, which is practically free from admixture of the d-isomer,

distinguishing compound of the formula

co °

Yu

that

, dh g

QN-SUCH

15

20

treated with the compound of the formula

(CHjHSiHN-j-DL

 en

SO5KSNz) 3

25

in 1,1,2-trichlorotrifluoroethane (freon TF) followed by treatment with a lower alkanol to remove silyl groups and acidification with hydrochloric or hydroiodic acid to obtain the hydrochloride or hydroiodide salt.

Editor N. Bobkova

Compiled by N.Kapitanova Tehred M.Didyk

Order 1069

Circulation 327

VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk nab. 4/5

distinguishing compound of the formula

that

Yu

, dh g

QN-SUCH

treated with a compound of the formula

20

(CHjHSiHN-j-DL

 en

SO5KSNz) 3

in 1,1,2-trichlorotrifluoroethane (freon TF) followed by treatment with a lower alkanol to remove silyl groups and acidification with hydrochloric or hydroiodic acid to obtain the hydrochloride or hydroiodide salt.

Proofreader T.Malets

Subscription

Claims (1)

L isomer, characterized in that the compound of the formula SNS g , 0 Scr. treated with a compound of the formula 15 in 1,1,2-trichlorotrifluoroethane (freon TG) followed by treatment with lower 25 with an alkanol to remove the blueling groups and acidifying with hydrochloric or hydroiodic acid to obtain the hydrochloride or hydroiodide salt.