SU523640A3 - The method of obtaining penicillins or their salts, or their or isomers, or their diastereomers - Google Patents

Description

interact with

compound of general formula

X.CO-N-COHae or

111

ABOUT

IV R - N TSf-COHol

in which have the above

meanings

On -halogen,

in an anhydrous or aqueous solvent in the presence of a base. The products are isolated in free form or as a salt, as R or S isomers or diastereomers,

Nontoxic pharmaceutically tolerable salts include salts of the acidic carboxyl group, like sodium salts,

potassium, magnesium, calcium, aluminum, and non-toxic ammonium salts substituted with amines, such as di- and trinine alkylamines, procaine, dibenzylamine, N, K -dibenzylethylenediamine, M-benzyl - | V phenylstilamin, N-methyl - and M-ethylmorpholine, 1 - ephenamine, dehydroabiethylamine, N, M-bis dehydroabiethylethlenediamine, N is a lower alkylpiperidine, and other amines used to produce penicillin salts,

The term “lower alkyl” should be understood to mean an unbranched as well as a branched alkyl group with up to 4 carbon atoms. In other groups, the lower alkylamino nagfimer, expressed lower alkyl, refers only to the alkyl part of the corresponding group.

The compounds of the formula (J are preferably in the form of L RC: they are of formula P in the form of various crystals or salts for a year to be used as a starting material for carrying out the proposed method.

Configuration of asymmetric centers. Core 6 - aminopenicillanic acid in compounds of the formula Tt must be identical with the configuration of the corresponding asymmetric centers of 6-aminopenicillanic acid, obtained, for example, from penicillin-G using enzymes.

The reaction can be carried out, for example, in mixtures with water of organic solvents which are miscible with it, such as acetone, tetrahydro / urap, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide or from propanol. In this case, the pH value of the reaction mixture by adding alkali or using buffer solutions is maintained, for example, between 6.5-8.0. The proposed reaction can be carried out in a pH range of 4.5-9.0 or 2.0-3.0. Further, the reaction can

carried out in water-immiscible solvents, for example chloroform or methylene chloride, with the addition of triethylamine, diethylamine or N-ethylpiperidine. In addition, the reaction can be carried out in a mixture of water and a water-immiscible solvent, for example, ether, chloroform, methylene chloride, carbon disulfide, isobutyl methyl ketone, ethyl acetate, benzene. It is advisable to intensively stir and maintain the pH value by adding bases or using buffer solutions of 4.5-9.0 or 2.0-3.0.

The amount of base used depends on the pH value. In cases where the measurement and adjustment of the pH value is not carried out or this is impossible due to the lack of sufficient amounts of water in the solvent, then using a compound of the formula, preferably 2 L equivalent of base is added.

The reaction temperature may vary widely. In general, 1ppt at a temperature of approximately -20 to + 5 ° C, preferably from 0 to +20 ° C. In most cases, when carrying out the reactions, temperatures can be higher or lower than indicated in the examples. However, with significant pressure, side reactions occur to an increasing extent, reducing the yield or degrading the purity of the products. Excessively lowered reaction temperatures reduce the reaction rate, which reduces the yield of products.

The reaction can be carried out at normal pressure, as well as with reduced or elevated.

Reagents can be used in equimolar amounts for carrying out the proposed method. It may, however, be advisable to use one of the reagents in excess in order to facilitate purification or to obtain in pure form the desired peptides and increase the yield. The compound of the formula N can be used, for example, in excess of 0.1-0, 3M equivalents, while achieving a reduced decomposition of the reagents of the formulas or / or in a water-containing solvent mixture. The реаг excess of the reagent of formula / 7, following the best solubility in aqueous mineral acids, can be easily removed during the processing of the reaction mixture. On the other hand, it is also advisable to use the reagents of the formulas III or JV in excess, for example, 0,., 0 M equivalents. In this way, a better use of the formulas reagent and the compensation of decomposition of reagents of formulas III or (I) is carried out in water-containing solvents. Compounds of formulas W or // added in excess are quickly transformed into neutral amides, urea or thiourea, which can easily be removed, the purity of penicillins is almost not impaired. The processing of the initial mixture to obtain the proposed penidillins and their salts is carried out known for penicillins. New penicillins are characterized by strong anti bacterial properties. They are suitable for use in medicine and veterinary medicine for the liver and other diseases caused by bacteria, which are delayed by the corresponding postures of penicillin. New substances can be converted into conventional preparations in a known manner and used in the usual way. They are in pure form or in combination with a pharmaceutically neutral substance - filler in the usual way mocht be added to the preparations. Example. 2.0 weight. portions of the d-oC-ami nop-oxybenzylpenicillin trihydrate pac-jv are turned into 25 vol. 80% of the aqueous tetrahydrofuran tetras are added and the pH is adjusted to 8.5 by addition of triethylamine. While stirring, 0.7 parts by weight of 1-chlorocarbonyl-2-oxo-imidazoline is added in portions and the addition of triethylamine is maintained. pH 7-8. Additionally, stirring until the pH is constant, 20 vol. water, the tetrahydrofuran is removed with a rotary evaporator, the aqueous solution is extracted once with acetic ether, fresh acetic ether is added and, cooled with ice, acidified to pH 1.5 using dilute hydrochloric acid, and penicillin is obtained partly in the form of crystalline free acid, it is difficult to dissolve in water and in ethyl acetate. It is sucked off and washed in ode. The solution of ethyl acetate remaining in the mother solution is separated by stirring the aqueous phase, washed with a small amount of water, dried over MgSO4, and added 2.0 vol. Part 1 A1 of the sodium solution of 2–9 ethyl hexanoate in methanol containing ether, evaporated to dryness in vacuo, dissolved in a small amount of methanol and poured into 10 and a multiple of ice ether containing 1O% methanol. Sucked off, washed with methanol-containing ether and then pure ether and dried over paraffin chips in a vacuum desiccator. Output Oh, 3 wt. h. 12.5%. Sucked penshlline acid paci vorshot in 10 vol. including oimethylacetamide, add 4 vol. parts of a solution of sodium hydrochloride and pour in ice-cold ether (70 vol. h). The precipitate separated is filtered off and washed with methanol-containing ether and then pure ether and dried in a desiccator over P, Oy and paraffin chips. Output 1.9 weight. including (80%) D-Ci-f (2-oxy-imidaze-lidin-1-yl) - "arbenamine-Tt-hydroxybenzylpenicillin sodium, The thus obtained fractions of penidillin sodium sodium scopes were identical in the infrared spectrum test. The content of the | V-lactam is 88-90% (the content is determined by the infrared spectrum and the nuclear magnetic resonance spectrum). The bands of the IR spectrum: at 3280, 1765, 1722, 1660, 1605,1538.1330 and 1284 cm of 1 ewazelin oil). S1d-W of the W of the P-spectrum at G 2.7 (2K), 3.2 (2H), 4.5 (2H), 4.55 (1H) 5.8, (1H); 5.9-6.35 (2H), 6.4-6.8 (2H), 8.4 (3N) and 8.5 ppm (3N), 1-chlorocarbonyl-2-oxoimidazolidine. To the intensively stirred solution 3.5weight. including imidazolidone - (2) obtained by the method of Fisher and Koch, Ann - 232, p. 224 (1886), in 5Volume of h. absolute tetrahydrofuran is added dropwise 4 weight h, phosgene 10 vol, h, absolute tetrahydrofuran over 15 minutes. Then, at a temperature of 10 ° C, stir for 3 hours, a stream of dry air is passed through the reaction mixture in order to remove the hydrochloric acid formed and phosgene residues. Using a rotary evaporator, it is evaporated to dryness in vacuo and the solid residue is dried over concentrated sulfuric acid at approximately 12 Torr. Yield 93%; m.p. 150 C, after recrystallization from acetone-pentane, Calculated (%: C 32.3; H 3.4; N18.8; Ce 23.9. Found: C 32.3; H 4.5; Nl8.7 ; Ct23,9. Signals YaLSh spectrum at T 5.7 and 6.1 (2H) and 6.3 and 6.7 (2H), (acetone-d KaK solvent) is symmetrical And In -system. IR bands - spectrum at 3230, 1790, 1700, 1270 and 1150. Example 2. 2, O. of h.V-o6-amk- (1,4-cshshohexadien-1 yl) -methylpenicillin (epicillin) is suspended in 45 vol. aqueous tetragkrofrofuran. Then, stirring, add 1.4 card. parts. Midazolin - 2 - he - 1 carbonyl chloride while the addition of triethylamine is maintained at a pH of 7.5-8.0, then until Sewn until a further addition of triethylamine is required to maintain the pH value of 7.5-8.0. After diluting with tetrahydrofuran with about 80 parts by volume of water in a rotandone evaporator, ethyl ether is added to the remaining aqueous solution. acetic acid and, stirring, acidified with 2 standards, hydrochloric acid to achieve a pH value of 1.5. The greater amount of penicillin produced is released in the form of crystals. Output 1.2 wt. 43% of the theory of D-oL- (imidazolidin - 2 - it - 1 - ilcarboshshamino) -al- (l, 4 - cyclohexadnen-1-yl) - methylpenicillic acid. The content of li-lactam is 80%. Calculated with%: C 49.5; H 5.0; N14.4; S6,6, Naydenove: C 49.9; H 5.9; N14.2; 56.6. The IR spectral bands in the carbonyl region at 1785, 1730, 1680 and 1635 cm (nuzhol.) In order to convert penicillin to sodium salt, it is dissolved in methanol or dimethylacetamide with the greatest concentration possible, and the calculated amount of ether containing few percents is added. methanol, a solution of sodium-2-ethylhexanoate and then pour the mixture into approximately b-times the amount of simple ether. The sodium salt which separated was suction filtered, washed with methanol-containing ether, then ether, and dried. The signals of the spectrum of nuclear magnetic resonance are H, 4.1 (1H), 4.2-4.5 (4H), 5.0 (1H 5.7 (1H), 5.9-6.7 (4H), 7.3 (41 8.2–8.6 parts per million (6H). Example 3, Exposure to 1.65 parts by weight D — ° C —amino — AND-exibenzylpenicilline trihydrate with 0.74 weight.h, 1 -Chlorocarbonyl -2- "Jccccrropidine is prepared by the sodium salt B-cC 2-oxopyrrolidino -1nl9 -carbonylamins-p-hydroxybenzylpenicillin sodium by the method described in Example 1 described above. Yield 91%. Content of | 5-lactam is 91% nuclear magnetic resonance spectrum). The IR spectrum bands at ZZOO, 1772, 1716, 1669. 1610, 1532, and 127O cm (as needed). Sign Ly of the spectrum of nuclear magnetic resonance (in CD, OD) at G2.7 (2H), 3.15 (2H), (1H), 4.53 (2H), 5.8 (1H), 6.2 (2H) ; 7.4 (2H); 7.95 (2H); 8.4 (GH) and 8.47 ppm (GH), Example 4. The interaction of 1.25 parts by weight of B- oC-amino-L .- {1,4-cyclohexashen-1-yl) -methylpenicillin with 0.6 parts by weight of 1-chlorocarbonyl-2 oxopyrrolidine is prepared by the sodium salt D-° C - (2-oxopyrrolidine) method described in Example 1 1-yl) -carbonylamino - oi; - (1,4-cyclohexadiene-1-yl) -methylpenidillin. Yield 71%. The content of p-lactam is 87% (the content is determined with the help of willows of the acrospectrum and the spectrum of the nuclear magnetic resonance). The IR spectrum bands at 3304, 1773, 1665, 1610, 1530.1327, 1268, and 1232 cm (in the nuclean). The signals of the spectrum of nuclear magnetic resonance (in CD OH) with t 4,1 (1H), 4,3 (2H), 4,5 (2H), 5,0 (1H), 5,8 (1H); 6.2 (2H); 7.1-7.6 (6H), 7.7-8.2 (2H); 8.35 (ZN) and 8.45 ppm, (ZN). PRI me R 5. The interaction of 1.75 wt. hours) -o (-amino-1-oxybenzene-1-penicillin-hydrates with 0.96 parts by weight of 8 - chlorocarbonyl-NH-nponnn-N dimethyl ureas are prepared as described in example 1, sodium salt D - ob - C3 (dimethylaminocarbonyl) -3- (n-propyl) -ureido-p-oxybenzylpenicillin. Yield 86%. The content of ji-lactam is 91% (the content is determined using the infrared spectrum and the spectrum of nuclear magnetic resonance.) IR spectrum at 3260, 1760, 1635, 1500 , 1240 and 1126 cm (in a nuzhol). The signals of the spectrum of nuclear magnetic resonance (in CDjOTl) with G2.7 (2H), 3.17 (2H), 4.48 (2H), 4.55 (1H) ;, 5.8 (1H), 6.5 (2H), 7.03 (6H), 8.2-8.7 (2H), 8.4 (3N), 8.47 (3N) and 9, O parts per million (MN). Example 6. Interaction of 1.25 weight parts D - ° C -amino - ° C - (1.4% hexadene | 1 yl) -methylpenicillin with 0.77 weight parts. N-chlorocarbonyl - N - H - propyl - N-dimethyl-urea is prepared as described in Example 1 by the method of sodium salt TZOC. - 3-aminocarbonyl) -3- (n-shch) ureidoZ- | e1- (1,4-shshohexadiene-1 -yl) - methylpenicillin. Yield 76%. The content of p-lactam is 90% (the content is determined with the mini-infrared spectral and the spectrum of nuclear magnetic resonance.) The IR spectrum bands at 1762, 1680157О, 1204, 1125 and 963 cm1 are needed). The signals of the spectrum of sod-magnetic resonance (B C B j OB) at € 4.1 (1H), 4.25 (2H), 4.45 (2H), 5.05 (1H), 5.74 (1H) J 6.45 (2H); 7.0 (6H); 7.25 (4H), 8.2-8.8 (2H); 8.33 (3N); 8.4 (ZN) and 9.03h. on million (ZN).

Example 7. The interaction of 1.75 weight, including D-C-amino-t-oxybenzylpenicillin trihydrate with 0.75 weight. including N-chlorocarbonyl-N, M-dimethylurea is obtained by the sodium salt method described in Example 1

In "CH-methylaminocarbonyl) - 3 - methylureido iJ-Ti - hydroxybenzylpenicillin. Yield 82%.

The content of p-lactam is 90% (the content is determined using the infrared spectrum and the spectrum of nuclear magnetic resonance.

IR spectrum bands at 3240, 1755, 1672, 1605, 1500 and 13Sh

The signals of the spectrum of nuclear magnetic resonance (in SB, OT)) at Г2.75 (2Н); 3.2 (2H); 4.55 (2H); 4.65 (1H); 5.85 (1H); 6.85 (ЗН); 7.25 (ЗН); 8.4 (GZ) and 8.5 ppm (G).

Example The interaction of 1.25 weight. h D - oL -amino - oi. - (1,4-cyclohexadiene-1-yl) methylpenicillin with 0.56 wt. N-chlorocarbonyl-N, N-dimethylurea is obtained by the sodium salt of D - (methyl aminocarbonyl) -1 - (methyl) - ureido - oL - (1,4 - cyclohexadiene - 1 - yl) methylpenicillin, described in Example 1. Yield 85%.

The content of b-lactam is 87% (the content is determined by means of infrared speckgrum and a spectrum of nuclear magnetic resonance ;.

IR spectrum bands at 3260, 176О, 1675, 1604, 15ОО and 1310 (in the nuke).

Signals of the spectrum of nuclear magnetic resonance () with G4D (1H); 4.3 (2H); 4.5 (2H) g 5.1 (1H); 5.8 (1H); 6.8 (ЗН); 7.2 (M); 7.3 (4H); 8.35 (ZN) and 8.43 ppm. (ZN).

PRI me R 9. The interaction of 1.75 wt. Part D - oC -amine "p-hydroxybenzylpenicillin trihydrate with 0.85 weight.h. K-chlorocarbonyl N -methyl-N dimethylurea is prepared by the sodium salt B-o, (dimethylaminocarbonyl) -3Chmethyl) ureido-P. oxybenzylpenicillin described in example 1, Yield 91%.

The content of fi-lactam is 87% (the content is determined using the infrared spectrum and the spectrum of nuclear magnetic resonance),

The IR spectrum bands at 326О, 1760, 1670-1590, 1315, 1270-1230 and 1125 cm (in the nuke).

The signals of the spectrum of nuclear magnetic resonance (in CDjGD) at G2.7 (2H); 3.2 (2H); 4.5 (1H); 4.54 (2H); 5.8 (1W; 6.92 (ZN); 7.06 (6H); 8.4 (ZN) and 8.46 ppm) (ZN).

Example 1O. 1.25 interaction

weight. frequent B-ol.-amino-ot - (1,4-cyclohexadiene - 1 - yl) - methylpenicillin with 0.61 wt. Part of N-chlorocarbonyl-N-methyl-N, N-dimethylurea is obtained by the sodium salt B-oL- 3- (dimethylaminocarbonyl) -1 - 3- (methyl) -ureido 7-o (.- (1,4 - cyclohexadiene - 1 - yl) - methylpenicillin. Yield 85%.

The content of i-lactam is 90% (the content is determined with the help of the infrared spectrum and the spectrum of nuclear magnetic resonance.)

The bands of the infrared spectrum with the ZOO 1775, 169O-1610, 153O, 132O and 1140 cm (in the nuclean).

The signals of the spectrum of nuclear magnetic resonance at t (B СБ, ОТ)) 4,1 (1Н); 4.2 (2H); 4.45 (2H); 5.05 (1H); 5.8 (1H); 6.9 (3N); 7.02 (6H); 7.3 (4H); 8.36 (ZN) and 8.43 ppm. (ZN).

Example 11. The interaction of 1.75 weight. partly, D-oL-amino - p - hydroxybenzylpenicillin trihydrate with 0.82 wt. h, chloride

N-acetyl-H-methylcarbamic acid is prepared by the sodium salt D-oL- (3-acetyl-3-methylureido) -n-oxybenylpenicillin method described in Example 1. Yield 71%.

The content of p | -lactam is 84% (the content is determined using the infrared spectrum and the spectrum of nuclear magnetic resonance).

The bands of the infrared spectrum at 3220, 1758, 1678, 1602, 1508, 1306, 1235 cm (in a nuke).

The signals of the spectrum of nuclear magnetic resonance at T (c) 2.73, 3.2 (2H) j 4.55 (3N); 5.8 (1H); 6.75 (3N); 7.7 (ЗН); 8.42 (ZN) and 8.49 ppm. (ZN).

IR spectrum bands at 3220, 1758, 1678, 1602, 15О8, 13О6, 1235 (in the nuclean).

The signals of the spectrum of nuclear magnetic resonance () with G2,73 (2H); 3.2 (2H): 4.55 (3N); 5.8 (1H) 6.75 (3N); 7.7 (ЗН); 8.42 (ЗН); и8.49 h. per million (.ZN).

Example 12. The interaction of 1.25 weight. parts of G-dL-amino -.sz1CH1-, 4 - cyclohexadiene - 1 - yl) - methylpenicillin with 0.6 weight. including N-acetyl-H-methylcarbamic acid chloride is prepared by the sodium i) (3-acetyl 3-methylureido) -1 (1,4-cyclohexane diene-1-yl)-methylpenicillin salt described in Example 1. Yield 84%.

The content of p-lactam is 90% (the content is determined using the infrared spectrum and the spectrum of nuclear magnetic resonance).