32 results about "Cefcapene" patented technology

The invention belongs to the technical field of antibiotic drug synthesis, in particular to a synthesis methodof cefcapene pivoxil hydrochloride. The invention is mainly used for process improvement and optimization of cefcapene pivoxil, and the advantage of the synthesis process of cefcapene pivoxil are obvious; new catalytic agents are used, such as phenol, boric acid and other reagents, thereby improving the product quality, increasing the yield, simplifying the operating steps and realizing greater productivity effect and social effect.

The invention belongs to the technical field of antibiotic synthesis, and relates to a preparation method for cefcapene pivoxil hydrochloride. The preparation method comprises the following steps: (1) reacting 7-ACA with sodium hydroxide in a solution with quaternary ammonium salt under the temperature of (-5 DEG C)-5 DEG C to generate 7-DACA; (2) adding (cefcapene pivoxil side chain acid, compound 5) into the solution containing 7-DACA, diisopropylamine and phenyltriethylammonium chloride under the temperature of 0-10 DEG C to react with a methylsufonyl chloride reaction solution under the temperature of (-15 DEG C)-0 DEG C to obtain a compound (4); reacting the compound 4 and chlorosulfonyl isocyanate to obtain a compound (3); further reacting the compound (3) with iodomethyl pivalate to obtain a compound (2); removing the protection base of the compound (2) in a hydrochloric acid methanol solution to obtain the cefcapene pivoxil hydrochloride (compound 1).

The invention discloses a synthetic method of cefcapene pivoxil hydrochloride. The synthetic method comprises following steps: 7-aminocephalosporanic acid (7-ACA) is taken as a raw material, and is subjected to 'one-pot reaction' so as to realize 3-esterolysis, and 7-amino protection is carried out; an obtained product is subjected to 'one-pot reaction' so as to realize 3-amidation, and 7-deprotection is carried so as to obtain an important intermediate of cefcapene pivoxil; the intermediate and a derivative of cefcapene pivoxil with an acid side chain are subjected to condensation, and an obtained cefcapene pivoxil precursor with a 4-acid group is subjected to esterification and acidification so as to obtain cefcapene pivoxil hydrochloride finished products. According to the synthetic method, 'atom economy' principle is fully used so as to shorten reaction route, and increase reaction total yield; and it is beneficial for synthetic technology improvement and optimization of cefcapene pivoxil hydrochloride.

The invention relates to a cefcapene pivoxil hydrochloride and a method for preparing an intermediate of cefcapene pivoxil hydrochloride, the method is characterized in that 7-DACA (iii) is taken as a raw material, and is performed condensation reaction with cefcapene pivoxil hydrochloride side chain acid (iv) and a carbamylated reagent to obtain tertbutyloxycarbonyl cefcapene acid sodium salt (vi), an amino protective group is removed to obtain the cephalospene acid (ii), then performed esterification reaction with iodomethyl pivalate, salifying with hydrochloric acid to obtain the cefcapene pivoxil hydrochloride hydrate (i) (a flow chart is shown as follows). The preparation method has the advantages of cheap raw material, easy raw material acquisition, less reaction step, high yield and high purity of intermediate and product, and is suitable for industrial production.

The invention relates to a preparation method of cefcapene diisopropylamine salt. The preparation method comprises the following steps: (1) obtaining acylate 3 by using cefcapene side chain acid 2 in the presence of an acylation reagent namely SOCl2 and an acid-binding agent namely triethylamine; (2) obtaining a condensation product 5 by using acylate 3 and a 7-HACA raw material 4 in the presence of triethylamine and a catalyst namely 4-dimethylaminopyridine; (3) enabling the condensation product 5 to react with chlorosulfonic acid isocyanate to obtain a 3-bit aminoacyl ester compound 6; (4) performing salt formation on the compound 6 and diisopropylamine to obtain cefcapene diisopropylamine salt 1. According to the preparation method disclosed by the invention, thionyl chloride is used as the acylation reagent, and triethylamine is used as the acid-binding agent so as to reduce the cost; 4-dimethylaminopyridine with the catalyst amount is added in the step (2) to ensure that the reaction is performed more completely and the reaction time is shortened; the preparation method is simple and convenient in whole route operation, and is convenient for large-scale production.

The invention provides a method for synthesizing an intermediate of cefcapene pivoxil, and the intermediate is 7-beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-buteneacyl] amino-3-hydroxymethyl-3-cephem-4-carboxylic acid shown in formula (I). The invention particularly provides the method for preparing the 7-beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-buteneacyl] amino-3-hydroxymethyl-3-cephem-4-carboxylic acid shown in the formula (I) by a hydrolysis reaction of 7-beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-buteneacyl] amino-3-acetyloxymethyl-3-cephem-4-carboxylic acid shown in formula (II) under an alkaline condition. Through use of the method, reaction steps ate reduced, the operation is convenient, and the preparation cost is reduced.

The invention belongs to the field of chemical synthesis of antibiotics, and in particular discloses a synthesis and purification method of t-butyloxycarboryl cefcapene diisopropylammonium which is used as a key intermediate of cefcapene pivoxil hydrochloride hydrate. The method comprises the following steps: carrying out an acylation reaction on D-7ACA and side chain acid under the actions of triethylamine and phosphorus oxychloride, purifying to obtain an acylation reaction feed liquid to be directly reacted with chlorosulfonyl isocyanate, carrying out water washing, drying and dropwise adding diisopropylamine to form salt and concentrating after the reaction is quenched, and performing crystallization by using a poor solvent of a target product to ensure that the pH of the feed liquid is weak acidic or neutral in the whole post-processing process so as to improve the stability of the feed liquid, thereby solving the problem of impurity increase caused by the prolonged subsequent processing time in large-scale production, and further improve the yield, thereby being especially suitable for industrialized mass production.

A process for producing cefcapene pivoxil methanesulfonate and, with the use thereof as an intermediate, corresponding hydrochloride. There is provided methanesulfonate of the compound of the formula ().

The invention relates to a preparation method of cefcapene pivoxil hydrochloride and a synthesis intermediate cefcapene pivoxil sulfonate. According to the invention, a sulfonic acid derivative V is used to perform a de-Boc reaction with cefcapene pivoxil tert-butoxycarbonyl as shown in a formula II to obtain the cefcapene pivoxil sulfonate as shown in a formula IV, and the cefcapene pivoxil sulfonate is then transferred into the cefcapene pivoxil hydrochloride as shown in the formula I. The method provided by the invention is mild in reaction conditions and simple and convenient to operate, meets requirements of environmental protection, and green and safe production; and the prepared cefcapene pivoxil sulfonate is high in purity, can be further transferred into the cefcapene pivoxil hydrochloride, with a purity of more than 99.5 % and high product quality.

The invention relates to a crystallization method of cefcapene ester hydrochloride monohydrate, which belongs to the field of medicine. The method comprises the following steps: adding solvents into cefcapene ester hydrochloride for dissolution; adding active carbon for decolourization; carrying out filtration and washing; adding hydrochloric acid water solution into obtained filter liquid for carrying out crystallization; filtering crystals; respectively washing the crystals by water and ethyl acetate; and carrying out drying to obtain the cefcapene ester hydrochloride monohydrate. The method of the invention can use a single solvent of methanol for crystallization to improve the recovery yield and reduce the production cost, and can also use mixed solvents of the methanol and ketone for crystallization to improve the quality of finished product. Low-temperature active carbon is used for decolourization, and the impurity control in the operation process can be ensured at the same time of ensuring the product quality (the control on the color grade, the endotoxin and the like). The baking temperature is reduced, the baking time is shortened, and the quality such as the color grade, the impurity content and the like of the products can be reached. The invention has the advantages of simplicity, easy implementation, low cost, good crystallization clarity, good color grade and easy control on the impurities of the finished products, is suitable for large-scale popularized application, and has obvious economic benefits.

The invention relates to a cefcapene pivoxil hydrochloride composition and a preparation method thereof. The composition consists of a tablet core and a coating layer, wherein the tablet core contains cefcapene pivoxil hydrochloride, a filler, a disintegrating agent, an antisticking agent and a lubricating agent; the grain diameter of the cefcapene pivoxil hydrochloride serving as a raw material is less than 100 micrometers; and the antisticking agent is in an amount which is 3 to 15 percent of the weight of the tablet core. The prepared cefcapene pivoxil hydrochloride tablets have excellent disintegrative property and dissolution of over 75 percent.

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of a cefcapene pivoxil E-type isomer. According to the preparation method, an organic solution of a cefcapene pivoxil raw material is heated and refluxed to obtain the E-type isomer of the cefcapene pivoxil, the cefcapene pivoxil raw material comprises the cefcapene pivoxil and / or inorganic salt of the cefcapene pivoxil, and the heat preservation temperature of heating and refluxing is larger than or equal to 40 DEG C. According to the preparation method provided by the invention, the cefcapene pivoxil E-type isomer is successfully prepared by heating and refluxing the cefcapene pivoxil solution when the holding temperature is greater than or equal to 40 DEG C, and the yield of the cefcapene pivoxil E-type isomer is high.

The invention relates to the technical field of medicine, in particular to a cefcapene pivoxil hydrochloride granule and a preparation method thereof. The cefcapene pivoxil hydrochloride granule comprises cefcapene pivoxil hydrochloride, microcrystalline cellulose, mannitol, croscarmellose sodium, hydroxypropyl methylcellulose, talcum powder and steviosin. The obtained cefcapene pivoxil hydrochloride granule is good in stability, rapid in disintegration, good in taste and good in curative effect, and has an obvious anti-inflammatory effect which is remarkably higher than inflammatory effect inthe prior art.

The invention provides cefcapene pivoxil granules. The cefcapene pivoxil granules comprise medicine-containing granules and essence, wherein the medicine-containing granules consist of a core part anda coating layer wrapping the core part; the cefcapene pivoxil granules comprise the following components in percentage by weight: 97-99% of the medicine-containing granules and 1-3% of the essence, wherein the medicine-containing granules comprise the following components in percentage by weight: 0.5-5% of the coating layer and the balance of the core part, and the coating layer consists of a coating agent; and the core part comprises the following components in percentage by weight: 14-15% of cefcapene pivoxil, 10-30% of a disintegrating agent, 30-70% of a flavoring agent, 4-10% of a suspending agent and 1-10% of a pH regulating agent, wherein the pH regulating agent is one or more of citric acid, malic acid, tartaric acid and lactic acid. The cefcapene pivoxil granules prepared by the preparation method disclosed by the invention are good in solubility, appropriate in release speed, good in stability and good in taste.

The invention relates to a preparation method of a cefcapene lactone compound or a hydrochloride thereof, and belongs to the technical field of synthesis of drug-related impurities. In order to solvethe problems of few synthesis routes and low yield in the prior art, the invention provides a preparation method of a cefcapene lactone compound or a hydrochloride thereof. The method comprises the following steps: carrying out a condensation reaction on (Z)-2-(2-tert-butyloxycarbonylaminothiazole-4-yl)-2-pentenoic acid and hydroxymethyl-7-aminocephalosporanic acid in an organic solvent in the presence of an organic alkali I, continuously adding an organic alkali II to adjust the pH value to 9.0-9.5 after the reaction is finished, and performing lactonization to obtain a compound represented by a formula IV; performing a deprotection reaction on the compound represented by the formula IV in a non-water-soluble organic solvent under the action of a Lewis acid to obtain a compound represented by a formula I; and carrying out a reaction on the compound represented by the formula I and hydrochloric acid to obtain a cefcapene lactone compound hydrochloride when the cefcapene lactone compound hydrochloride is synthesized. The synthetic route is easy to operate, and the yield and the purity are high.

The invention relates to a method for preparing beta-lactam derivative through enzymatic reaction. The method for preparing beat-lactam derivative through enzymatic reaction comprises the step of synthesizing a compound shown in a formula I by virtue of an enzymatic reaction, and the compound can be used for preparing antibacterial cefcapene pivoxil, wherein R is the conventional amino protection groups like a t-butyloxycarboryl group. A biological enzyme catalyst used in the enzymatic reaction is immobilized deacetyl esterase, and the method for synthesizing the compound shown in the formula I has the advantages of mild conditions, low cost and environmental friendliness, and is easy to operate.

The invention discloses a cefcapene pivoxil hydrochloride composition which is obtained by tabletting cefcapene pivoxil hydrochloride, starch, hydroxy propyl cellulose, carboxymethyl starch sodium, magnesium stearate and medical film coating premixed excipients. The cefcapene pivoxil hydrochloride composition has the benefits that the dissolution of the cefcapene pivoxil hydrochloride composition reaches above 90 percent, the use effect of the cefcapene pivoxil hydrochloride composition is improved, and the utilization rate of drugs can be effectively improved.

The invention relates to the technical field of medicines, in particular to cefcapene pivoxil hydrochloride hydrate composition tablets. The cefcapene pivoxil hydrochloride hydrate composition tablets comprise the following components in part by weight: 100 parts of cefcapene pivoxil hydrochloride hydrate, 30 parts of microcrystalline cellulose, 22 parts of mannitol, 22 parts of hydroxyl cellulose, 1.5 parts of magnesium stearate and 0.5 to 1 part of lactose. Compared with a positive medicinal control group, the cefcapene pivoxil hydrochloride hydrate composition tablets have the advantage that a medicinal effect is improved obviously.

The invention relates to the technical field of synthesis of related impurities of medicines, and provides a synthesis method of cefcapene acid. The method comprises the following steps: taking BCN as a raw material, neutralizing diisopropylamine salt in BCN with acid to obtain desalted BCN, then removing a BOC protecting group to obtain a cefcapene acid crude product, then purifying with alkali to remove salt formed by cefcapene acid and inorganic acid and alkali-soluble impurities, and finally cooling and crystallizing under an acidic condition, so that the acid-soluble impurities are left in mother liquor, and the separated crystal is high-purity cefcapene acid. The synthesis method provided by the invention is high in production efficiency, the purity of the obtained product is more than 98%, the high-purity cefcapene acid can be used as a reference substance for analyzing the key impurity in the cefcapene pivoxil hydrochloride, and the method plays a positive role in quality control of the cefcapene pivoxil hydrochloride.

The invention discloses a cefcapene pivoxil hydrochloride synthesis method, and belongs to the technical field of synthesis of cephalosporin medicines. The cefcapene pivoxil hydrochloride synthesis method comprises the following steps: (1) using BCN as a starting material, reacting with an inorganic acid aqueous solution in a solvent to obtain a dissolved clarified solution, standing, layering, abandoning a water layer, collecting an organic layer comprising a compound I, and drying; (2) adding a formic acid and a concentrated hydrochloric acid, reacting at the temperature of 0-5 DEG C, washing with water after finishing reacting, layering, and collecting an organic layer comprising a compound II; (3) adding a sodium bicarbonate aqueous solution and iodomethyl pivalate, maintaining the pHvalue to 5-6, layering after finishing reacting, collecting the organic layer, adding ethanol, washing with water, layering, additionally adding the ethanol in the organic layer, regulating the pH value to 7-8 by using an inorganic base, layering, and collecting an organic layer comprising a compound III; and (4) conducting vacuum concentration until no liquid drop is distilled, adding a solvent,adding a diluted hydrochloric acid, regulating the crystallization, cooling, growing the crystal, conducting suction filtration, and drying to obtain cefcapene pivoxil hydrochloride. The process of the method is simple, the reaction condition is mild, the method is environmentally friendly, the yield is high, the purity is high, and the method is easy for industrial production.

The invention discloses a method for preparing an important third-generation oral cephalosporin antibiotic, namely cefcapene pivoxil hydrochloride. BCN is dissolved in dichloroethane and is in docking with 4-side-chain iodomethyl pivalate, then 7-amino BOC protection is removed by means of an ethyl acetate solution of hydrogen chloride, amino hydrochloride is generated directly, finally amino hydrochloride and a diluted hydrochloric acid aqueous solution are recrystallized in methyl alcohol, and white crystal of Cefcapene pivoxil hydrochloride with one molecular of water is obtained. According to the method, the number of synthesis steps is small, cost is low, materials in use are cheap and easy to obtain, industrial production is benefited, and pollution is little.

The invention belongs to the technical field of antibiotic drug synthesis, and relates to a method for synthesizing cefcapene pivoxil hydrochloride by an enzymic method, the method comprises the following steps: treating a compound shown in a formula (IV) with acid and alkali in sequence to obtain a compound shown in a formula (III), performing enzymolysis on the compound shown in the formula (III) to obtain a compound shown in a formula (II), the enzyme used for enzymolysis being IPA-750 enzyme; and (2) in the presence of an acid-binding agent, carrying out esterification reaction on the compound as shown in the formula (II) and iodomethyl pivalate, and salifying with hydrochloric acid to obtain the compound cefcapene pivoxil hydrochloride as shown in the formula (I). The invention also provides a synthetic intermediate for synthesizing cefcapene pivoxil hydrochloride by an enzymic method. According to the method for synthesizing the cefcapene pivoxil hydrochloride through the enzyme method and the synthetic intermediate of the cefcapene pivoxil hydrochloride, the reaction conditions are milder, and the obtained product is higher in purity and more environmentally friendly.