• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    1. METHOD FOR OBTAINING CRYSTALLINE HYDROCHLORIDE OR HYDROBROMIDAL OF BEER-ALOXYLETHYMETHYL ETHER
    公开号:SU1036250A1
    申请号:SU3238101
    申请日:1981-01-30
    公开日:1983-08-15
    发明作者:Скартаццини Риккардо
    申请人:Циба-Гейги Аг (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new salts of cephalosporins, namely, crystalline hydrochloride or pivaloyloxymethyl ester 7 / i-C2- (2-g-4-thiazolyl) -2-methoxyiminoacetamido 3-cephem-4-carboxylic acid hydrobromide, and can be used in medicine quality of medicinal substances. A known method for the preparation of crystalline pivagloyloxymethyl-7 / J-f2- {2-aminothiazol-4-yl) acetamido 3-3-1- (2-dimethylaminoethyl) -1 -1 tetrazol-5-ylthiomethyl-3-cephem-4carboxylic acid ester with a salt tartaric or citric acid, which is that pivaloyloxy-. (2-Aminothiazol4-yl) acetamido -3- / 1- (2-dimethylaminoethyl) -lH-tetrazol-5-ylthiomethyl3 .3-cefeme-4-carboxylic acid methyl ester. “Melt the reaction with saline or tartaric or lemon acid in the aqueous medium and from the reaction mixture crystallize the target product. 7p-G2 (2-aminothiazol-4-yl) acetamido-3-1 (2-dimethylaminoethyl) -1H-tetrazole-5ylthiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester is preferably reacted with a salt or an acid. The crystallization of the desired product from the reaction mixture can be carried out in the presence of acetone or carried out by concentrating or cooling the reaction mixture in the presence of ethanol or by concentrating and cooling the reaction mixture in the presence of sodium chloride 1. The purpose of the invention is to expand the arsenal of the antibacterial drugs obtained. in crystalline form and with increased stability. The above objective is achieved in that according to the process for the preparation of crystalline hydrochloride or hydrobromide of pivaloyloxymethyl ester of 7fb-2- (2-amino-4-thiazolyl) -2-methoxy-iminoacetamido-Z-cephem-4-carboxylic acid Pivaloyloxymethyl ester (2-amino- 4-thiazolyl) -2-methoxy iminoacetamdo} -3-cephem-4-carboxylic acid is reacted with (0.8-1.2 mol. Equivalents of chloride or hydrogen bromide in a solvent at (-10) to (+40) c and the resulting hydrochloride or hydrobromide is crystallized in a nonpolar solvent. Warping can be used in raw or purified form. Hydrogen chloride or methyl bromide is used in an aqueous or anhydrous form in an equivalent amount, i.e., depending on the purity of the base used, approximately 0.8-1 p2 (preferably 1-1.1) moles are added equivalent of chloride or methyl bromide .. Salt formation is carried out in water, or in an organic solvent, or in a mixture of them. Methylene chloride is preferably used as the organic solvent. Hydrogen chloride, you can enter t. same in solution. A solution of hydrogen chloride or methyl bromide can also be used in a diluted form, saturated or unsaturated. It is advisable to dissolve the base in methylene chloride and add the calculated amount of a solution of hydrogen chloride or hydrogen bromide in an organic solvent, as well as in methylene chloride. After adding chloride or hydrogen bromide, the solution containing the salt is concentrated by evaporation of the solvent and / or mixed with a non-polar solvent, for example diethyl ether, then after removing the soluble products, the hydrochloride or hydrobromide is precipitated. Depending on the purity of the used starting product, the salts precipitate in amorphous or already crystalline form. By cooling the precipitated solution, it is possible to carry out the precipitation completely. Salt formation is carried out at a temperature of approximately (-10) (+40) s (preferably about 030 ° C) t, especially at. High temperatures and excessive amounts of hydrogen chloride or hydrogen bromide should be kebeged, since in this case decomposition may occur. The precipitated salt is BEED, for example, by filtration or centrifugation, and washed with an incomplete solvent in which the crystals are insoluble or poorly soluble. If the quality of the precipitate in terms of the purity and shape of the crystals is still unsatisfactory, it can be improved by recrystallization. The first salt precipitate is purified by recrystallization from methylene chloride. While amorphous salts are readily soluble at room temperature or with slight heating. methylene chloride, the crystalline forms are practically insoluble. They are formed at low temperatures, at about 0-5 ° C. If necessary, the recrystallization process is repeated until a salt is obtained, the purity of which is suitable for analysis. Drying of the preparation is carried out efficiently under high vacuum at or near room temperature, in the appropriate case in the presence of drying agents.
    The crystalline salts of the invention can be used to prepare pharmaceutical preparations that contain an effective amount of the active substance, if appropriate in a mixture with. inorganic or organic, solid or liquid carriers used in pharmacopoeias that are particularly suitable for oral administration. For oral administration, tablets, capsule packets, gelatin capsules are used which contain the effective substance together with diluents, for example lactose, dextrose, mannitol sucrose, sorbitol, cellulose 15 and / or glycine and carriers, for example silica gel, talc, stearic acid or its salts, such as magnesium stearate or calcium and / or polyethylene glycol. Tablets also contain jn adhesives, e.g. magniyalkminy silicate, starches, like corn, wheat, -risovy or roots of arrowhead starch, gelatin, tragacanth, methylcellulose, cellulose natriykarboksimotil- 25 and / or polivinilpirrolidrn, and, if desired, thickeners, e.g. starch, agar, alginic acid or its salts, such as al gi: sodium, and / or foaming mixtures f. si, or absorption agents, colorants, flavoring substances and sweet substances. Candles are primarily fatty emulsions or suspensions.
    Pharmaceutical preparations can be stabilized and / or contain excipients, for example, conservatives, stabilizers, wetting and / or emulsifying agents, substances that promote solubility and / or buffers. The proposed pharmaceutical preparations, which, if desired, may contain other farme cological valuable substances, are prepared in the usual manner, for example, using conventional methods of mixing, dissolving or lyophilizing, and contain approximately 0.1-100% (preferably from 1-50%) , lyophilisates up to 100% active substance. Depending On the basis of the type and severity of the disease and the condition of the infected organism, a daily dose of approximately 0.5 to 5 g orally is used to treat warm-blooded animals with a weight of about 70 kg.
    Hydrochloride or hydrobromide of pivaloyloxymethyl ester is more complex than sodium salt of 7 / J-C2 (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-3-cephem-4- | (arbonic acid is 60 lots by the advantage that in animal experiments, such as rats, after oral administration, it is significantly better absorbed from the gastrointestinal tract and therefore in
    Medical trials are more effective when given orally. For example, pivaloyloxymethyl ether as a free base when given twice twice orally to mice against gram-positive cocci, like Staphylococcus aureus 10B and Streptococcus Aronson, has an ED of about 0.7-30 mg / kg, against enterobacteria, for example, Escherichia if 205, Escherichia coli 2018, Escherichia Coli 774, Salmonella Stanley | And Proteus Blinking 2359, Klebsjella Pneumonia 327, Proteus Mirabilis 774 EDgo about, .0-1-12 mg / kg, and against pseudsmonas, like Dsevdomonas aeroginosis mg / kg. The new salts of the ether are more fully absorbed compared to the free bases and, accordingly, have a higher chemotherapeutic efficacy, for example, against Streptococcus Aronson pyogenes, Escherichia coli 205 and 2018, Klebsiella pneumonia 327, blink proteus 2359, and pseudo mononas AORINOSIS ATS 12055.
    The following examples serve to illustrate the invention, where the temperatures are indicated in c, the Rf data from thin-layer chromatography, on a silica gel finished plate SL 354 from Antek, Birsfelden.
    Example. To a cooled to 0 ° C solution of 4.97 g of pivaloyloxymethyl ester (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-3 cefem-4-carboxylic acid (free base) in 50 ml of CHjCl, was added 61 ml of a 0.18 M solution HC1 in CHjClj (1 mol. Equivalent, obtained by passing dry gaseous hydrochloric acid, ode to dry CHjClj). After 10 minutes of stirring, the solution is mixed with diethyl ether, and a precipitate forms. The mixture is continued to stir for another 0.5 hour at, the precipitate is filtered off, washed with diethyl ether and dried under high vacuum at. The crude hydrochloride is thus obtained in the form of a light beige powder, which is dissolved in approximately 50 ml of CHjClg, somewhat evaporated and left to stand overnight at approximately + 5 ° C. The precipitated compound is filtered off, washed with a small amount of CHgClj and dynethnyl ether and dried as previously indicated. Colorless hydrochloridized piv alonloxy esters of 2- (2-amino-4-thiazolyl) -2methoxyiminoacetamido-3-cephem-4carboxylic acid, m.p. 187-191 C. rotf | f + Satl (, 689% in methanol) DS: Rf 0.29 (silica gel, ethyl acetate); UV spectrum (EtOH): maximum at 235 (6 16600), 245 (Sh and 296) Sh mm: IR spectrum (Nujol): absorption bands at 3240, 1778, 1757, 1750, 1738, 1658, 1626, 1590 , 1665 cm NMR spectrum: (DMSO. D 6; 100 mHz b 1.18, 9H / -C / CH3 / c /; s 3, 70.t, 2H (H-2); cGy, 98 S, ZN {OSN "); , 2H, d, cAi4.5 (H-6); сЛ5.96, ЗН (Ni -ОСНдО-), 63 t, 1Н (Н-3) (, 9 S, 1Н (thiazol-Н), сЛ9.56Ь, ЗН ((-NH-), 83 d, IH (CONH). Microanalysis. Found,%: C 42.79 H 4.44; N 13.30; S 11.71; C1 6.51. Calculated,%: C 42.74; H 4.53; N 13.12, - S 12.01; C1 6.64. X-ray powder pattern: sample is crystalline. 24 the strongest lines with d value of about 3.1 A correspond to the following interplanar spacing and relative intensity m id, intensity of 20.1 very strong 10.1 average, 8.6 strong 6.9 weak 6.7 average 6.3 very strong 5.34 weak 5,, 09 average 5.03 average 4.76 strong 4,64 very strong, 4.45 very weak 4,31 average 4,14sl BA 3, 89. Average 3.80 Very weak 3.73 Very strong 3.64 Average 3.55 ... Strong 3.46 Average 3,, and measure 2. To a cooled p 497 g of pivaloyloxymethyl ether 7 / L-C2 - (2-amino-4-thiazolyl) -2 methoxyiminoacetamido2-3-cephem-4carboxylic acid (free base) in 5 ml of CH2Cl2, add 2.72 ml of 0.46 M solution of HBr in CHjCl (about 1 , 25 equivalents; After 10 minutes of stirring, the solution is mixed with 35 ml of diethyl ether, and a precipitate forms. The mixture is kept stirring for another 0.5 h. The precipitate is filtered off, washed with ethyl ether and dried at the same time. The obtained slightly orange powder is dissolved in 2.5 ml of CH2Cl2, after which the product is recrystallized again. After adding 5 ml of CH2Cl2, stirred for 1 h while cooling with ice. Filtration, washing the resulting crystals with methylene chloride and Diethyl ether and drying under high vacuum yields hydrobromide, pivaloyloxymethyl ester 7 ((2-amino-4-thia-oolyl) -2-methoxyimino-acetamido-3-cephem-4-carboxylic acid, mp. (Decomposition) DS: Rf0, 31 (silica gel: ethyl acetate); UV spectrum (EtOH): maximum at 225 (E 17520), 231 (E-16920), 237 (16240), 243 (15600). And 249. (B 14420) mm IR spectrum (Nujol): absorption lines at 3245, 1776, 1757, 175.0, 1738, 1658, 1628, 1590, 1570, 1560 cm-, NMR spectrum (DMSO. D 6): 100 MHz. SG-. 1 , 18 S, 98 / -С / СНз / з /,, 70 t, 2Н (Н-2), сЛгЗ, 99 S, ЗН (AWW, h), 20 d, 2Н, 3 5.0 (Н-6) , сГ 5.86 m, ЗН (Н-7 and -O-CHO-O-),, 65 t, 1H (H-3),, 07 b, 3H (-NH-t7,, 84 d, (CONH).. X-ray diffraction diagram of the powder: a crystalline sample. 21 the strongest line with a d value of approximately more than 3.1 A corresponds to the following interplanar spacings and relative intensities m: Intensity Very strong Strong Medium Slab Medium Very strong Medium Strong II Slab Strong Medium Very strong Medium Strong Med. Capsules containing 0.25 g of 7 / J-C2- (2-amino-4-thiazolyl) -2-methoxy-amino-acetoacetate J3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride are prepared as follows. Composition (for 1000 capsules), g: 7 | 1-C2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride; 25000; corn starch 50,000; polyvinylpyrrolidone 15,000; magnesium stearate 5000; ethanol the rest 7 (4-G2- (2-amino-4-thiazolyl) 2-methoxyiminoacetamido 3-3-cephem-4carboxylic acid Hydrochloride pivaloyloxymethyl ester 7 (4-G2- (2-amino-4-thiazolyl)) is mixed with corn starch and moistened with a solution of polyvinylpyrrolidone in a 50 g ethanol; 3 mm and dried at. The dry granulate is sieved through a sieve with openings of 1 mm and mixed with 5 g of magnesium stearate. The mixture is fed in portions of 0.320 g into a stick capsule with a zero value. Example 4. Tablets containing 250 mg of hydrochloride pnyaloyl oxymethyl ether (2-a ino-4thiazolyl) -2-methoxyiminoacetamido 3-cephem-4-carboxylic acid, prepared as follows Composition (for 1 tablet), mg: pivaloyloxymethyl ester hydrochloride (2-amino-4-thiazolyl) -2-methoxyiminoacetamidor-3-cephem -4-carboxylic acid 250; microcrystalline cellulose 80; sodium carboxymethyl starch 10; magnesium stearate 3, talc 7; a total of 350. The effective substance is mixed with additives and pressed into tablets. To obtain dragees coated with film, the tablets are coated with 1 mg of aqueous varnish Instead of sodium carboxymethyl starch can be used Use sodium carboxymethylcellulose as well. In the same way, capsules and tablets are prepared with (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-3-ceph-4-carboxylic acid pivaloyloxymethyl-ester hydrobromide as an effective substance.
    权利要求:
    Claims (5)
    [1]
    1. METHOD FOR PRODUCING CRYSTALLINE HYDROCHLORIDE OR HYDROBROMIDE OF PIVALOYLXYMETHYL ETHER 7 / 3- [2 - (2 - AMINO-4 - THIAZOL IL) - 2 - METHOD IMINOACETAMIDO] -Z-4-CHELO and with the fact that pivaloyloxymethyl ether 7/3-f2 (2-amino-4-thiazolyl) -2-methoxyacetamido] -Z-cefem-4-carboxylic acid is reacted with 0.81.2 mol. equivalents of hydrogen chloride or bromide in a solvent. at a temperature in the range from -10 to + 40 ° C and the resulting hydrochloride or hydrobromide is crystallized in a non-polar solvent.
    [2]
    2. The method according to π. 1, characterized in that pivaloyloxymethyl ether 7 / 3- [2- (2-amino-4-thiazolyl) -
    2-methoxyiminoacetamido] 3-Cephem-4 carboxylic acid is reacted with 0.8-1.2 mol. equivalents of hydrogen chloride in a solvent at a temperature in the range from -10 to + 40 ° C and the resulting hydrochloride is crystallized in a non-polar solvent.
    [3]
    3. The method according to PP. 1 and 2, which entails that the interaction is carried out at 0 ° C.
    [4]
    4. Methods according to claims 1-3, characterized in that methylene chloride is used as a solvent.
    [5]
    5. The method according to claims 1 and 2, characterized in that diethyl ether is used as a non-polar solvent.
    equivalent of hydrogen chloride or bromide. The salt is formed in water, or in an organic solvent, or in a mixture thereof. The organic solvent used is predominantly methylene chloride. Hydrogen chloride may be added so ; same in solution. base gaseous.
    A solution of hydrogen chloride or bromide can also be used at times | diluted, saturated or unsaturated.
    It is advisable to dissolve the base in methylene chloride and add the calculated amount of a solution of hydrogen chloride or bromide in an organic solvent, as well as in methylene chloride.
    After the addition of hydrogen chloride or bromide, the solution containing the salt is concentrated by evaporation of the solvent and / or mixed with a non-polar solvent, for example diethyl ether, then after removal of the soluble hydro products. chloride or hydrobromide precipitated. Depending on the purity of the starting material used, the salts precipitate in an amorphous or already crystalline form. By cooling the deposition solution deposition can be performed floor 1 NOSTA.
    Salt formation is carried out at a temperature of about (-10) (+40) ° C (preferably about 030 ° C) / especially at 0 ° C. Avoid high temperatures and excessive amounts of hydrogen chloride or bromide, as in this case decomposition may occur. The precipitated salt is isolated, for example, by filtration or centrifugation, and washed with a non-polar solvent in which the crystals are insoluble or poorly soluble. If the quality of the precipitate with respect to the purity and shape of the crystals is still unsatisfactory, it can be improved by recrystallization. The first salt precipitate is purified by recrystallization from methylene chloride. While amorphous salts at room temperature or with gentle heating are readily soluble in. methylene chloride, crystalline forms are practically insoluble. They form at low temperatures, approximately at 0-5 ° C. If necessary, the recrystallization process is repeated until a salt is obtained whose purity is suitable for analysis.
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    同族专利:
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    IL62017D0|1981-02-27|
    AU6677981A|1981-08-06|
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    IE810176L|1981-08-01|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    PH17188A|1977-03-14|1984-06-14|Fujisawa Pharmaceutical Co|New cephem and cepham compounds and their pharmaceutical compositions and method of use|
    US4370326A|1977-09-13|1983-01-25|Fujisawa Pharmaceutical Co., Ltd.|Cephem compounds and composition|
    GB2025933B|1978-06-13|1982-10-27|Fujisawa Pharmaceutical Co|Cephem and cepham compounds|
    MA18686A1|1978-07-07|1980-10-01|Ciba Geigy Ag|AMINOTHIAZOLIC COMPOUNDS|
    JPS5543011A|1978-09-20|1980-03-26|Shionogi & Co Ltd|7-halothiazolylalkoxyiminoacetamido-3-cephem compound|
    JPS636552B2|1978-12-11|1988-02-10|Takeda Chemical Industries Ltd|
    JPS55151588A|1979-05-14|1980-11-26|Takeda Chem Ind Ltd|Preparation of cephalosporin salt crystal|EP0054512A3|1980-12-12|1983-08-03|Ciba-Geigy Ag|Cephalosporin esters, process for their preparation and pharmaceutical compositions containing them|
    US4400503A|1981-10-30|1983-08-23|Eli Lilly And Company|Purification of syn-7-[[ acetyl]amino]-3-methyl-3-cephem-4-carboxylic acid|
    US4594417A|1981-10-30|1986-06-10|Eli Lilly Company|Crystalline antibiotic salt|
    JPS60190783A|1983-12-21|1985-09-28|Sumitomo Seiyaku Kk|Cephem compound|
    US4683227A|1985-07-09|1987-07-28|Eli Lilly And Company|Antibiotic derivatives of 7β-[2-acetamide]-3-chloro-3-cephem-4-carboxylic acids and compositions and method of use thereof|
    JPH02101081A|1988-10-08|1990-04-12|Meiji Seika Kaisha Ltd|Crystalline dihydrochloride of cephalosporin derivative and production thereof|
    EP0638573A1|1993-08-10|1995-02-15|Lucky Ltd.|Crystalline hydrates of cephalosporin and process for preparation thereof|
    US20040067192A1|2002-10-07|2004-04-08|The Procter & Gamble Company|Conversion of sodium bromide to anhydrous hydrobromic acid and sodium bisulfate|
    PL1606293T3|2003-03-27|2010-01-29|Basilea Pharmaceutica Ag|Cephalosporin in crystalline form|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    CH83680|1980-02-01|
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