The crystalline acid salt additive pure diastereomers of 1-(2,2-dimethylpropionic)-ethyl ester 3-cefem-4-carboxylic acids and methods for their production


C07D501/34 - with the 7-amino radical acylated by carboxylic acids containing hetero rings

 

(57) Abstract:

The inventive crystalline acid salt additive pure diastereomers of 1-(2,2-dimethylpropionic)-ethyl ester 3-cefem-4-carboxylic acid of General formula (II), where X is the anion of a physiologically safe one - or polybasic inorganic or organic acid, and group = NOH is in the SYN-position, get chromatographic separation of the mixture of diastereomers of the formula (III) or by dissolving a mixture of crystalline acid additive salts of diastereomers General formula (II) in dimethylformamide or dimethylacetamide and then adding the resulting solution in the 5-50-fold volume of the solvent and crystallization of the less polar I-S diastereoisomer, as well as by treatment of a solution of a mixture of diastereomers of the formula (IV) an aqueous or organic solution of the acid components with subsequent deposition of pure diastereomers and converting it into the target products. Formula (II), (III), (IV) listed in the description. 4 S. and 2 C.p. f-crystals, 1 table.

The invention relates to crystalline, rezorbiruetsa in the gut salts of diastereomers of 1-(2,2-dimethylpropionic)ethyl ester of 7-[2-(2-aminothiazol-4-yl)-2-the treatment.

In the patent application Germany N 3804841 (European patent A-A) describes esters of 7-[2-(2-aminothiazol-4-yl)-2-(z)-oximino-acetamido]-3-methoxymethyl-3-cefem-4-carboxylic acid. Of particular interest is the ester of formula I, as it is good for intestinal resorbed different kinds of animals and after resorbtive due to autogenic enzymes again quickly and completely breaks down to is antibiotic active cephalosporin with a free carboxyl group.

In the patent application Germany N 3919259 (European patent A-0402806) describes stoichiometric, crystalline salt of ester of the formula I and sulphonic acids, which on the basis of its high stability have advantages in comparison with the free bases of formula I.

An ester of formula I has an asymmetric carbon atom in the I-position of the ethyl ester groups. Described in the patent application Germany N 3919259 salts are in the form of mixtures of diastereomers.

Comparable mixture of diastereomers exist in the case of cefotiam-exetel, cefuroxim-aksetila, cefpodoxim-proxetil and VMF 28271.

According to previous experiments on the mechanism of intestinal resorbtive such esters ceph is irRemote. This could experimentally show for the diastereomers of cefotiam-exetel (T. Nishimura and others The Journal of Antibiotics, so XI (1987), 81-90).

So very unexpectedly found that the salt separated diastereomers of the formula I possess a distinct difference in intestinal resorption, so it is better resorbable the diastereoisomer has a higher biocosmology than the mixture of diastereomers described in the patent application Germany N 3919259.

The object of the present invention are therefore diastereomers pure salt of General formula II, in which the group z N-OH is in the SYN-position. Preferred is less polar of the two diastereomers with (IS)-configuration in the ester portion, which has a higher biocosmology.

< / BR>
In the General formula II HX denotes a one - or polybasic acid, and X may be inorganic or organic, physiologically safe anion.

As the inorganic acid HX denotes, for example, a stoichiometric amount of HCl, HBr, HY, HBF4, HNO3, HClO4H2SO4or H3PO4. As organic acids HX denotes an aliphatic or aromatic sulfonic acids. The inorganic acid is HCl, offacility, p-toluensulfonate and 4-ethylbenzonitrile preferred. Especially preferred benzosulfimide, p-toluensulfonate and 4-ethylbenzonitrile.

The subject invention are methods of obtaining diastereomeric compounds of General formula II, which are distinguished by the fact that

get the connection formulas

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the diastereomers separated using chromatography, triteleia group otscheplaut receive the addition products of acids

or

from the mixture of diastereomers of formula II by crystallization allocate the enrichment of the less polar diastereoisomer,

or

receive an intermediate stage of the formula IV in the form of separated diastereomers:

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and transferred to the separated diastereoisomers of formula II.

Obtaining required in method 1 mixture of diastereomers of the formula III are described in the patent application Germany N 3804841.

Separation of the diastereomers is carried out by chromatography on silica gel with a solvent of toluene and ethyl acetate. The ratio of toluene and acetic ether is widely variable and ranges from 3:1 to 20:1, preferably the area from 10: 1 to 15:1. One part of the partial use a mixture of 20-80 parts of silica gel to rmula III was transferred to the salt of formula II by methods that already described for the mixture of diastereoisomers in patents Germany N 3804841 and N 3919259.

On the way 2 get the less polar diastereoisomer of formula II by crystallization of the mixture of diastereomers of organic solvents.

Under normal conditions, the recrystallization of the substance in the solvent, dissolve by heating to boiling. Compounds of formulas I and II differ in these conditions. However, following the path allows recrystallization of salts.

One part of the mixture of diastereoisomers first dissolved in 1 to 5 parts, preferably 1-2 parts of an organic solvent, such as, for example, dimethylformamide or dimethylacetamide. Thus, the obtained solution was added dropwise in 5-50-fold volume of an organic solvent (e.g., alcohol, ester, simple ester, ketone, nitrile), as, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, ethyl acetate, butyl acetate, acetone, diethyl ether, diisopropyl ether and acetonitrile. It is particularly preferred 10-20 times the volume of n-propanol, isopropanol and n-butanol.

The duration of the addition can be from 10 minutes to two hours, preferably from 30 minutes to triostat 0 -40oC, preferably 20-25oC.

Thus, the obtained salt emit the usual laboratory methods, such as, for example, filtration and in high vacuum (< 1 Torr) in the presence of a desiccant, such as phosphorus pentoxide, freed from adhering solvent.

By repetition of the above process have the diastereoisomer with high intestinal resorption of the formula II (HX p-toluene-acid) in pure form.

According to method 3 receives the connection of the formula IV, which is described in the patent of Germany N 3804841, in the form of a mixture of diastereoisomers.

The diastereomers can be divided by the crystallization of salts of the formula

< / BR>
In the General formula V HY denotes a one - or polybasic acid, and Y may be an inorganic or organic anion.

As the inorganic acid HY denotes, for example, HCl, HBr, HJ, HNO3, HClO4, HSCN, H2SO4or H3PO4. As the organic acid HY take into account aliphatic, respectively aromatic sulfonic acids, carboxylic acid and phosphonic acid. For example, you can use the following organic acids: benzosulfimide, p-translatability, 4-biphenylcarboxylic, naphthalene-1,5-disulfonate, methansulfonate, econsultation, dodecylsulfonate, camphorsulfonate, oxalic acid.

The preferred acid components should be considered HCl, HBr, benzosulfimide, p-toluensulfonate, 4-ethylbenzonitrile and 4-biphenylcarboxylic.

Getting salt of formula V is carried out by combining a solution of a mixture of diastereoisomers of formula IV and acidic components HY. As organic solvents can be used, for example, simple and complex esters, alcohols, ketones, hydrocarbons, NITRILES and halogenated hydrocarbons, and mixtures thereof. Preferred solvents are, for example, benzene, toluene, ethyl acetate, butyl acetate, methanol, ethanol, n-propanol, isopropanol, tert-butanol, diisopropyl ether, acetonitrile, dichloromethane, acetone and mixtures thereof.

As solvents for inorganic acids can be used, besides water, if an organic solvent miscible with water. Solutions of HCl and HBr in organic solutions can be obtained, for example, by introducing hydrogen chloride or bromoiodide or from acetylchloride, phosphorus is eromero is the ratio of the founding of the formula IV and acid components. For one equivalent of the mixture of diastereomers need to use 0.2 to 2, preferably 0.3 to 1 equivalent of the acid components.

Additive acid components is carried out at room temperature. Depending on the acid components and solvent for completeness of precipitation is stirred for an additional up to 10 hours. If necessary for completeness of precipitation must be cooled to temperatures from room temperature to -78oC.

Obtained after filtering off the salt, if necessary, purified further by crystallization. For this purpose apply the above solvents and their mixtures. The optimal choice of the solvent depends on the acid components. So, for example, salts of p-toluenesulfonic acid suitable methanol, ethanol, n-propanol and isopropanol.

The method differs in that the deposition of diastereomers of General formula IV is carried out in two consecutive partial stage. So, for example, by combining a solution of a mixture of diastereoisomers of formula IV with a solution of acid components HY first precipitated harder soluble diastereoisomer of General formula V, is separated by filtration and then from the solution after filtering off precipitated easier rest be the same or different, moreover, the sequence of adding various acidic components HY any. So, for example, by suitable selection of the acid components HY first, you can besiege the more polar diastereoisomer of General formula IV or more non-polar diastereoisomer of General formula IV in the form of harder soluble salts.

By the choice of acid components both diastereoisomer of formula V can be obtained in pure form. For example, when using hydrogen chloride or bromoiodide get the more polar diastereoisomer, while the use of benzosulfimide, 4-ethylbenzonitrile, biphenylcarboxylic or p-toluenesulfonic acid gives less polar diastereoisomer.

Alternative mixture of diastereomers of the formula IV can also be obtained from compounds of the formula

< / BR>
The group R1this means conventional in the chemistry of peptides for protective amino group, such as formyl group, tert-butoxycarbonyl group, phenoxyacetyl group, phenylacetylene group, allyloxycarbonyl group, benzyloxycarbonyl group and 4-nitrobenzisoxazole group.

Cleavage of the protective groups is in itself known methods. So, formeln the St group and phenylacetylene group can be split, for example, using pentachloride phosphorus or enzyme using penicillinases. If allyloxycarbonyl group removal can be accomplished using Pd(P(C6H5)3)4. Benzyloxycarbonyloxy group and 4-nitrobenzenesulfonyl group can be removed hydrolytically.

When removal phenoxyacetyl group or phenylacetylene group using pentachloride phosphorus in continuous processing in an enriched form get the more polar diastereoisomer as hydrochloride, when processing are undeleted mixed anhydrides esters of phosphoric acid, which slowly release hydrogen chloride.

Proceeding from compounds of formula VI can also come to diastereomeric pure compounds of the formula V in that first carry out the separation of the diastereomers and then otscheplaut protective group. Separation of diastereoisomers may be achieved by crystallization or chromatography, and the exact conditions depend on the protective group R1. If R1means, for example, phenoxyacetyl group, the diastereomers can also be split by chromatography on silica gel using a mixture of organic solvents.

Diastereomer mixture of Schiff's bases of the formula VII is divided either by chromatography, for example on silica gel or by fractional crystallization. Reverse splitting of Schiff's bases to pure diastereomers of formula IV is in itself known methods, for example by acid hydrolysis or by using the Girard-T reagent.

Based on diastereomeric pure salts of the formula V by known methods get diastereomeric the base of the formula IV and translate them, as described in patents Germany N 3804941 and N 3919259, diastereomeric salt of formula II.

The usefulness of the present invention is increased intestinal resorption of the less polar diastereoisomer of formula II, as shown in table salt, p-toluenesulfonic acid.

The table shows the detected number (0-24 hours) 7-[2-(2-aminothiazol-4-yl)-2-(z)-oxyimino-acetamido]-3-methoxymethyl-3-cefem-4-carboxylic acid in the urine of dogs (n 4) after oral administration of p-toluensulfonate 1-(2,2-dimethyl-propionate (dose: 10 mg/kg per antibacterial active biologically active substance). Number of biologically active substances in the urine is determined microbiologically using diffusion test in agar when using Mueller-Minton agar (with 10% sheep blood) and Streptococcus pyogenes A 77 as the test microorganism.

Proposed in the invention compounds of General formula II are introduced orally in the form of conventional pharmaceutical compositions, as, for example, capsules, tablets, powders, syrups or suspensions. The dose depends on age, symptoms and body weight of the patient, and the duration of treatment. However, as a rule, it is from about 0.1 g to about 5 g per day, preferably about 0.2 g to about 3 g per day. The compounds are preferably administered in divided doses, for example, 2-4 times a day, and a single dose may contain, for example, 50-500 mg of biologically active substances.

Oral compositions may contain conventional carriers and/or diluents. So, for example, capsules or tablets are taking into consideration a binder, such as gelatin, sorbitol, polyvinylpyrrolidone or carboxymethyl cellulose, diluents, such as lactose, sugar, starch, calcium phosphate or polyethylene glycol, lubricants, such as talc or magnesium stearate. For liquid compositions, Mapusa examples of implementation obtained according to the invention diastereomers pure salts of the compounds of formula 1,1-(2,2-dimethylpropionic)-ethyl ester of 7-[2-(2-aminothiazol-4-yl)-2-(z)-oximino-acetamido] -3-methoxymethyl-3-cefem-4-carboxylic acid serve for further explanation of the invention, however, they do not limit the scope of protection.

Exemplary embodiment 1.

Preliminary stage. The acid chloride of 2-(2-tritylimidazole-4-yl)-2-(z)-trisiloxane-acetic acid (trityl-triphenylmethyl).

To a solution of 42 g (54 mmol) triethylammonium salt of 2-(2-tritylimidazole-4-yl)-2-(z)-trisiloxane acetic acid in 400 ml of anhydrous methylene chloride at -70oC for 30 minutes was added dropwise 11.4 g (55 mmol) of pentachloride phosphorus dissolved in 200 ml of anhydrous methylene chloride, so that the internal temperature did not exceed 50oC. After following 60 minutes at -70oC, the solvent is removed in vacuo, and the bath temperature should not exceed 30oC. Then briefly dried under high vacuum. Thus, the obtained crude product is dissolved in 100 ml of anhydrous methylene chloride and used for acylation.

Stage 1. 1-(2,2-dimethylpropionic)-ethyl ester-3-methoxymethyl-7-[2-(2-tritylimidazole-4-yl)-2-(z)-trityloxy-monoacetate]-3-cefem-4-carboxylic acid.

To a suspension of 14 g (57 mmol) of 7-amino-3-methoxymethyl-3-cefem-4-carboxylic acid in 160 ml of anhydrous methylene chloride at 0oC slowly add 9.5 mg (RA 2,2-dimethylpropionic acid, stirred for further 30 minutes at 0oC and then left to warm to room temperature for 30 minutes. After cooling again to 0oC was added dropwise crude acid chloride - 2(2-tritylimidazole-4-yl)-2-(z)-tricalciumphosphate acid (approximately 54 mmol) dissolved in 100 ml of methylene chloride, and then stirred for another 2 hours at 0oC. the Reaction mixture was concentrated in vacuo and the residue treated with ethyl acetate. Washed sequentially with 5% aqueous sodium thiosulfate solution, then saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, the organic phase is dried over sodium sulfate and concentrated in vacuo to dryness. The crude product is purified by chromatography on silica gel (35-70 , column: 50 cm x 8.5 cm, toluene/ethyl acetate 5/1). Output: 36.5 g (66%). The diastereomers are in the ratio 1/1.

Stage 2. Chromatographic separation of the diastereomers.

17 g of a mixture of diastereoisomers chromatographic on silica gel (35-70 , column: 46 cm x 7.5 cm) using a mixture of toluene/ethyl acetate (15/1) and with a flow rate of 50 ml/min After concentration in vacuo get 6 g of the nonpolar diastereoisomer of 1 and 4.5 g of the polar diastereoisomer 2.

Diastereomers>), 1,50 (doublet 3H, OCH(CH3)O) 3,20 (singlet, 3H, OCH3), 3,57 (AB-system, 2H, SCH2), 4.5 (singlet, 2H, CH2O) a 5.25 (doublet, 1H, H-6), of 5.89 (double doublet, 1H, H-7), 6,59 (singlet, 1H, thiazole-H), 6.89 in (quadruplet, 1H, och(CH3)O, 7,12-7,37 (multiplet, 3 HE, aromatic H), 8,75 (singlet, 1H, NH), 9,90 (doublet, 1H, amide NH).

The diastereoisomer 2:

Rf (toluene/ethyl acetate 5/1): 0,40;

1H-NMR (CDCl3, 270 MHz): d 1,22 (singlet, N, C(CH3)3), and 1.56 (doublet, 3H, OCH(CH3)O) 3,30 (singlet, 3H, OCH3), 3,39 (AB-system, 2H, SCH2), 4,27 (singlet, 2H, CH2O) of 5.05 (doublet, 1H, H-6), 6,04 (double doublet, 1H, H-7), 6,41 (singlet, 1H, thiazole-H), 6.75 in (singlet, 1H, NH),? 7.04 baby mortality (quadruplet, 1H, OCH(CH3)O), 7,10-7,44 (multiplet, 3 HE, aromatic H).

Stage 3. 1-(2,2-dimethylpropionic)-ethyl ester of 7-[2-(2-aminothiazol-4-yl)-2-(z)-oxigenoterapia] -3-methoxymethyl-3-cefem-4-carboxylic acid

The diastereoisomer 1. A solution of 6 g (5.9 mmol) of diastereoisomer 1 of stage 2 in 15 ml of formic acid dropwise mixed with 3 ml of water. First is stirred for 90 minutes at room temperature and then for 30 minutes at 0oC. Precipitated in the sediment triphenylcarbinol sucked off and optionally washed with a small amount of formic acid with water (5/1). United fil and sodium establish a pH-value equal 3. The organic phase is separated, washed with twice 50 ml of water and again mixed with 50 ml of water. By adding 40% aqueous solution of sodium hydroxide establish a pH-value of 6.5, and the internal temperature should not exceed 10oC. After separation of the organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated in vacuo to a quarter of the original volume. The thus obtained solution was added dropwise to 150 ml of diisopropyl ether. Later, following 60 minutes of stirring at room temperature, the product is sucked off, washed with diisopropyl ether, and dried first 18 hours in air and then in vacuo over phosphorus pentoxide. Yield: 1.7 g (54%).

1H-NMR (DMCO-d6, 270 MHz): d 1,15 (singlet, N, C(CH3)3), 1,48 (doublet, 3H, OCH(CH3)O) 3,20 (singlet, 3H, OCH3), 3,55 (AB-system, 2H, SCH2), 4,13 (singlet, 2H, CH2O) to 5.21 (doublet, 1H, H-6), 5,85 (double doublet, 1H, H-7), 6,65 (singlet, 1H, thiazole-H), 6.87 in (quadruplet, 1H, och(CH3)O), 7,11 (singlet, 2H, NH2), for 9.47 (doublet, 1H, amide NH), 11,28 (singlet, 1H, NOH).

The diastereoisomer 2. Similarly injected into the interaction of 4.5 g (44 mmol) obtained in step 2 of diastereoisomer 2. Yield 1.7 g (71%).

Stage 4. p-Toluensulfonate 1-(2,2-dimethylpropionic)-ethyl ester of 7-[2-(2-aminothiazol-4-yl)-2-(z)-oxigenoterapia] -3-methoxymethyl-3-cefem-4-carboxylic acid

The diastereoisomer 1. A suspension of 1 g (of 1.85 mmol) diastereoisomer 1 of stage 3 in 35 ml of n-propanol is mixed with 383 mg (2 mmol) of the monohydrate of p-toluenesulfonic acid in 1 ml n-propanol. The solid is dissolved and, after a few minutes, starts yet to crystallize the salt. At room temperature and stirred for further 1 hour, then the product is sucked off and washed with 5 ml n-propanol and 10 ml of diisopropyl ether. First dried for 18 hours in air and then in a high vacuum over calcium chloride and paraffin. Output: 1,09 g (83%).

[]2D0= +48,8+48,8oC (C 1, methanol), so pl. above 200oC (decomposition).

1H-NMR (DMCO-d6, 270 MHz): 1,15 (singlet, N, (CH3)3), 1,48 (doublet, 3H, OCH(CH3)O) to 2.29 (singlet, 3H, aryl-CH3), 3,20 (singlet, 3H, OCH3) and 3.59 (AB-system, the em 1H, OCH(CH3)O) 7,08-7,15 and 7,45-7,52 (2 x multiplet, 2 x 2H, aromatic H), 8,0-8,8 (broadened, 3H, NH3), 9,67 (doublet, 1H, amide NH), 12,04 (singlet, 1H, NOH).

The diastereoisomer 2. On the basis of 1.6 g (2.5 mmol) of diastereoisomer 2 of stage 3 by crystallization from 15 ml of n-propanol are salt of p-toluenesulfonic acid.

Yield: 1.4 g (66%).

[]2D0= +12,7(C 1, methanol). So pl. above 200oC (decomposition).

1H-NMR (DMCO-d6, 270 MHz): 1,17 (singlet, N, C(CH3)3), 1,49 (doublet, 3H, OCH(CH3)O) to 2.29 (singlet, 3H, aryl-CH3), 3,21 (singlet, 3H, OCH3), 3,57 (AB-system, 2H, SCH2), 4,13 (singlet, 2H, CH2O) 5,22 (doublet, 1H, H-6), of 5.82 (double doublet, 1H, H-7), 6,85 (singlet, 1H, thiazole-H) 6,94 (quadruplet, 1H, SLEEP(CH3)O) 7,08-7,16 and 7,45-7,52 (2 x multiplet, 2 x 2H, aromatic H), 8.4 to 8.9 in (broadened, 3H, NH3), 9,68 (doublet, 1H, amide NH), 12,12 (singlet, 1H, NOH).

Exemplary embodiment 2. p-Toluensulfonate 1-(2,2-dimethylpropionic)ethyl ester of 7-[2-(2-aminothiazol-4-yl)-2-(z)-oxigenoterapia]-3-methoxymethyl-3-cefem-4-carboxylic acid (diastereoisomer 1).

50 g (70 mmol) of p-toluensulfonate 1-(2,2-dimethylpropionic)-ethyl ester of 7-[2-(2-aminothiazol-4-yl)-2-(z)-oxigenoterapia)-3-methoxy ml of dimethylacetamide. Within 1 hour the solution was added dropwise to 450 ml of n-propanol. For completeness crystallization stirred for further 4 hours at room temperature, the product is sucked off, washed successively with n-propanol and diisopropyl ether and dried first in air and then in vacuo over phosphorus pentoxide. Output: 29,5 g (59% diastereoisomer 1/diastereoisomer 2 79/21).

After three subsequent kristallizatsii from, depending on the circumstances, 65 ml of dimethylacetamide and 450 ml of n-propanol receive 8 g (25%) of diastereoisomer 1 with more than 97% purity.

Spectral data match those of diastereoisomer 1 in embodiment 1. The ratio of diastereomers is determined using liquid chromatography high pressure (Lichrospher 60, RP-select B, 125 x 4 mm, methanol/water 5/6 with 0.12% of ammonium dihydrophosphate, pH 2.3, flow rate 1 ml/min, detection at A 228 nm, retention times of the diastereoisomer 1 14, 6 min; diastereoisomer 2 of 11.7 min).

Exemplary embodiment 3.

Stage 1. 3-Methoxymethyl-7-phenoxyacetamide-3-cefem-4-carboxylate sodium. The sodium salt is obtained from the carboxylic acid (Fujimoto and others J. Antibiotics XL (1987) 370-84).

50,3 g (133 mmol) of carboxylic acid and 11.7 g (140 mmol) of sodium bicarbonate of paramashiva">

1H-NMR (D2O, 270 MHz): d 3,28 (singlet, 3H, OCH3), 3,42 (AB-system, 2H, SCH2), 4,16 (AB-system, 2H, CH2O), 4,72 (AB-system, 2H, OCH2CO), 5,12 (doublet, 1H, H-6), 5,67 (doublet, 1H, H-7), 6,98-7,12 and 7,32-7,42 (2 x multiplet, 5H, aromatic H).

Stage 2. 1-(2,2-dimethylpropionic)ethyl ester of 3-methoxymethyl-7-phenoxyacetamide-3-cefem-4-carboxylic acid.

42.8 g (107 mmol) of 3-methoxymethyl-7-phenoxyacetamide-3-cefem-4-carboxylate sodium in 430 ml of anhydrous dimethylformamide is mixed with 25.7 g (100 mmol) of 1-itatiaia ether of 2,2-dimethylpropionic acid. The reaction mixture was stirred for further 1 hour at room temperature and then poured into a mixture of 2.5 liters of water and 1.5 l of ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuum. Output: 50,3 g (98% diastereoisomer 1/diastereoisomer 2 50/50).

Stage 3. Chromatographic separation of the diastereomers. Share obtained in stage 2 mixture of diastereomers using medium pressure chromatography (silica gel 35-70 , 1 g of substance on 40 g of silica gel, toluene/ethyl acetate/diisopropyl ether 120/15/6).

The diastereoisomer 1.

1<>) and 3.59 (AB-system, 2H, SCH2), 4,14 (singlet, 2H, CH2O) to 4.52 (doublet, 2H, OCH2CO), 5,18 (doublet, 1H, H-6), 5,78 (double doublet, 1H, H-7), 6.87 in (quadruplet, 1H, OCH(CH3)O) and 6.9-7.0 and 7,25-7,32 (2 x multiplet, 5H, aromatic H), 9,13 (doublet, 1H, amide NH).

The diastereoisomer 2.

1H-NMR (DMCO-d6, 270 MHz): d 1,17 (singlet, N, C(CH3)3), 1,49 (doublet, 3H, OCH(CH3)O) 3,22 (singlet, 3H, OCH3), 3,60 (AB-system, 2H, SCH2), 4,13 (singlet, 2H, CH2O) to 4.52 (doublet, 2H, OCH2CO), 5,18 (doublet, 1H, H-6), 5,75 (double doublet, 1H, H-7), 6,90-6,99 (multiplet, 4H, aromatic h, och(CH3)O), 7,20-7,32 (multiplet, 2H, aromatic H), 9,12 (doublet, 1H, amide NH).

Stage 4. 1-(2,2-dimethylpropionic)ethyl ester of 7-amino-3-methoxymethyl-3-cefem-4-carboxylic acid.

p-Toluensulfonate of diastereoisomer 1.

The solution 3,93 g (7.8 mmol) of diastereoisomer 1 stage 3 and 1.07 ml (8,45 mmol) N,N-dimethylaniline in 39 ml of anhydrous methylene chloride at -40oC dropwise mixed with 1,94 g (to 9.32 mmol) pentachloride phosphorus in 32 ml of anhydrous methylene chloride, and the internal temperature should not exceed -25oC. for 2 hours left to stand to raise the temperature to -10oC and then in one portion add to 19.4 ml Isuzu ethyl acetate and the organic phase as quickly as possible is separated. The aqueous phase is extracted again with ethyl acetate. Then the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to dryness. The residue is dissolved in 5 ml ethyl acetate and mixed with a solution of 1.47 g (7,74 mmol) of the monohydrate of p-toluenesulfonic acid in 10 ml of ethyl acetate. The product is sucked off, washed with ethyl acetate and dried in vacuum over phosphorus pentoxide. Output: to 2.57 g (61%).

1H-NMR (DMCO-d6, 270 MHz): d 1,15 (singlet, N, C(CH3)3), 1,48 (doublet, 3H, OCH(CH3)O) to 2.29 (singlet, 3H, aryl-CH3), 3,23 (singlet, 3H, OCH3), 3,69 (AB-system, 2H, SCH2), 4,16 (singlet, 2H, CH2O), 5,24 and 5,28 (2 x double, 2 x 1H, H-6 and H-7), 6,89 (quadruplet, 1H, OCH(CH3)O), 7,12 (doublet, 2H, aromatic H), 7,49 (doublet, 2H, aromatic H), 8,88 (singlet, 2H, NH2).

Hydrochloride diastereoisomer 2.

On the basis of 506 g (1 mmol) of diastereoisomer 2 stage 2, similarly carry out the removal phenoxyacetyl group. The diastereoisomer 2 crystallizes in the form of a hydrochloride of ethyl acetate. Output: 223 mg (55%).

1H-NMR (DMCO-d6, 270 MHz): d 1,17 (singlet, N, C(CH3)3), 1,49 (doublet, 3H, OCH(CH3)O), 3,24 (singlet, 3H, OCH3), 3,68 (AB-system, 2H, SCH2).

Stage 5. 1-(2,2-dimethylpropionic)-ethyl ester 3-methoxymethyl-7-[2-(2-tritylimidazole-4-yl)-2-(z) -trailokyanath-3-cefem-4-carboxylic acid (diastereoisomer 1).

1.5 g (2,75 mmol) tosilata of diastereoisomer 1 of stage 4 are suspended in 100 ml of ethyl acetate and 30 ml of water. Under vigorous stirring at 0oC using saturated solution of sodium bicarbonate establish a pH-value of 6.5. The organic phase is successively washed with 30 ml of water and saturated sodium chloride solution, dried over sodium sulfate and stirred under vacuum to dryness. Output: 1,03 g (98%).

As described in the embodiment 1 of 1.81 g (2.3 mmol) triethylammonium salt of 2-(2-tritylimidazole-4-yl)-2-(z)-trisiloxane-acetic acid is transferred to the acid chloride acid.

To a solution of 880 mg (2.3 mmol) of ester in 10 ml of anhydrous methylene chloride at -5oC was added dropwise to the acid chloride acid in 8 ml of anhydrous methylene chloride. After 2 hours, treated as described in example 1. After chromatography of the crude product using a mixture of toluene with ethyl acetate (5/1) get diastereomers pure product. Yield: 2.38 g (99%).

Spectral data sootvetstvuem.

Exemplary embodiment 4. 1-(2,2-dimethylpropionic)-ethyl ester of 7-amino-3-methoxymethyl-3-cefem-4-carboxylic acid, tosylate of diastereoisomer 1 and hydrochloride diastereoisomer 2.

As described for stage 4 in embodiment 3, the separation phenoxyacetyl groups are based on 3.03 g (6 mmol) of 1-(2,2-dimethylpropionic)-ethyl ester 3-methoxymethyl-7-phenoxy-acetamido-3-cefem-4-carboxylic acid (diastereoisomer 1/diastereoisomer 2 52/48). The dried organic phase is concentrated to a volume of 10 ml by cooling to 0oC diastereoisomer 2 precipitated as hydrochloride and sucked off (output: 759 mg, 31% ). The mother liquor is mixed with 1.13 g (5.9 mmol) of the monohydrate of p-toluenesulfonic acid in 5 ml of ethyl acetate. Precipitated precipitated salt of toluenesulfonic acid is sucked off, washed with a small amount of ethyl acetate and dried in vacuum over phosphorus pentoxide. Output: 667 mg (23%).

The content of diastereoisomer 1 according to liquid chromatography high pressure is over 97% (liquid chromatography high pressure: Lichrospher 100 RP-18,5 , 125 x 4 mm, flow rate 1 ml/min, detection at A 254 nm, water/methanol 52/48 with 0.1% ammonium acetate, retention time: diastereoisomer 1 of 12.1 min, deserialize.

Exemplary embodiment 5. 1-(2,2-dimethylpropionic)-ethyl ester of 7-amino-3-methoxymethyl-3-cefem-4-carboxylic acid, p-toluensulfonate of diastereoisomer 1.

Suspension 4,88 g (20 mmol) of 7-amino-3-methoxymethyl-3-cefem-4-carboxylic acid in 200 ml of anhydrous methylene chloride at 0oC is mixed with 3,12 ml (21 mmol) of DBU. To slightly turbid yellow solution add 4,99 g (24 mmol) of 1-bromatologia ether of 2,2-dimethylpropionic acid and then stirred for 3 hours at room temperature. The reaction solution was poured onto 600 ml of saturated sodium hydrogen carbonate solution and 800 ml of methylene chloride. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated in vacuum. The crude product (9.3 g) was dissolved in 15 ml ethyl acetate and mixed with 1.9 g (10 mmol) of the monohydrate of p-toluenesulfonic acid in 10 ml of ethyl acetate. Precipitated precipitated product is sucked off, washed with diisopropyl ether and dried in vacuum. Output: 3,95 g (36% diastereoisomer 1 /diastereoisomer 2 85/15).

Recrystallization of the salt from n-propanol gives the pure diastereoisomer 1, which transform as described hereinafter.

Exemplary embodiment 6. 1-(2,2-dimethylpropionic)-ethyl ester of 7-amino-3-methoxymethyl-3-cefem-osushestvleniya 5, from 4,88 g (20 mmol) of 7-amino-3-methoxymethyl-3-cefem-4-carboxylic acid get crude product. The thus obtained oil was dissolved in 20 ml ethyl acetate and mixed with a freshly prepared solution of 0.65 ml (9.2 mmol) of acetylchloride and 1.07 ml (18.4 mmol) of ethanol in 5 ml of ethyl acetate. Phase precipitate in an ice bath hydrochloride is sucked off, washed with ethyl acetate and dried. Output: to 2.57 g (32% diastereoisomer 1/diastereoisomer 2 22/78).

The filtrate is mixed with a solution of 1.75 g (9.2 mmol) of the monohydrate of p-toluenesulfonic acid in 8 ml of ethyl acetate and the precipitation is sucked off. Output: 1,15 g (16% diastereoisomer 1/diastereoisomer 2 97/3).

Spectral data correspond to those of the embodiment 3.

An example of implementation 7.

Stage 1: 1-(2,2-dimethylpropionic)-ethyl ester 3-methoxymethyl-7-[(nafti-2-yl)methyladenosine]-3-cefem-4-carboxylic acid.

As described in embodiment 5, of 2.44 g (10 mmol) of 7-amino-3-methoxymethyl-3-cefem-4-carboxylic acid get crude ester. The thus obtained oil was dissolved in 30 ml of anhydrous methylene chloride and mixed with a solution of 1.56 g (10 mmol) of naphthalene-2-carbaldehyde in 40 ml of toluene. After 3 hours of standing at room temperature vacuume dry.

Stage 2. Chromatographic separation of the diastereomers.

The crude product from stage 1 chromatographic on 500 g of silica gel (pH 7.5). For this purpose the sales silica gel (35-70 ) is suspended in water and mixed with dilute sodium hydroxide solution up until the pH remains constant at a 7.5. The silica gel was sucked off, washed with methanol and dried 18 hours at 110oC and a pressure of 20 Torr. Using a mixture of toluene/ethyl acetate (20/1) elute first 1,7 (33%) of diastereoisomer 1 and then of 1.65 g (32%) of diastereoisomer 2. The diastereoisomer 1 crystallizes from methanol in colourless needles with so pl. 110oC.

The diastereoisomer 1:

1H-NMR (CDCl3, 270 MHz): d 1,22 (singlet, N, (CH3)3), 1,58 (doublet, 3H, CH-CH3), 3,22 (singlet, 3H, OCH3), 3,57 (singlet, 2H, SCH2), or 4.31 (AB-system, 2H, CH2O) to 5.21 (doublet, 1H, H-6), 5,50 (double doublet, 1H, H-7), 6,99 (quadruplet, 1H, CH-CH3), 7.62mm (MC, 2H, aromatic H), 7,88 (MS, 3H, aromatic H), 8,03 (MS, 3H, aromatic H), 8,78 (doublet, 1H, CH-N).

The diastereoisomer 2:

1H-NMR (CDCl3, 270 MHz): d 1,22 (singlet, N, C(CH3)3), 1,58 (doublet, 3H, CH-CH3), 3,32 (singlet, 3H, OCH3), 3,52 (singlet, 2H, SCH2), 4.26 deaths (AB-system, 2H, CH2O), 5,26 (doublet, 1H, e), 8,02 (MS, 3H, aromatic H), 8,75 (doublet, 1H, CH=N).

Cleavage of the Schiff's bases to pure diastereomers of 1-(2,2-dimethylpropionic)-ethyl ester of 7-amino-3-methoxymethyl-3-cefem-4-carboxylic acid is carried out using Girard T reagent similar literary techniques (e.g., violence begets violence, and others The Journal of Antibiotics XI, I(II), 1988, 1602-1616).

1. The crystalline acid salt additive pure diastereomers of 1-(2,2-dimethylpropionic)-ethyl ester 3-cefem-4-carboxylic acid of General formula I

< / BR>
where X is the anion of a physiologically safe one - or polybasic inorganic or organic acid, and group N HE is in the SYN-position.

2. Salt under item 1, characterized in that it is difficult-essential parts have a configuration (IS).

3. Salt under item 1 or 2, characterized in that the NC benzosulfimide, a pair of toluensulfonate or 4-ethylbenzonitrile.

4. A method of obtaining a crystalline acid additive salts pure diastereomers of General formula II, wherein a mixture of diastereomers formula III

< / BR>
subjected to chromatographic separation of the pure diastereomers with the subsequent removal trailing protective groups and translation recip is audica fact, the mixture of the crystalline acid additive salts of diastereomers of General formula II is dissolved in dimethylformamide or dimethylacetamide, followed by a gradual addition of the resulting solution at 5 to 50-fold volume of a solvent selected from the group consisting of (C1-C4-alkanol, (C1C4)- alkyl acetate, di(C2C3)- alkilany ether, acetone or acetonitrile, with stirring, crystallization and allocation enrichment acid additive salt, less polar 1S-diastereoisomer.

6. The method according to p. 4, characterized in that the solution of the mixture of diastereomers of formula IV

< / BR>
processed water or organic acidic components WELL, where Y is an organic or inorganic anion, followed by precipitation of the less soluble diastereoisomer of General formula V

< / BR>
where Y has the value

additional processing after the deposition of acidic component HY', where Y' is an organic or inorganic anion, and Y and Y' can be equal or different,

deposition of more soluble diastereoisomer of General formula V'

< / BR>
where y' has a specified value,

and converting the received

 

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39 cl, 3 tbl, 25 ex

FIELD: organic chemistry, pharmaceutical composition.

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26 cl, 518 ex, 3 tbl

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11 cl, 7 tbl, 353 ex

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26 cl, 6 tbl, 114 ex

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