- Preparation method of cefdiaxone pivoxil
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The invention relates to a preparation method of Cefditoren Pivoxil. The preparation method comprises steps as follows: 7-ACA (3-acetyloxymethyl-5-thio-7-amino-8-oxy-1-nitrogen heterobicyclic octyl-2-ene-2 carboxylic acid) is taken as a starting raw material and is subjected to iodination and Wittig reaction after silanization protection, and a Cefditoren parent nucleus 7-ATCA (7-amino-3-[(Z)-2-(4-methyl-5-thiazole) vinyl]-3-cephem-4-carboxylic acid) is generated; after amino protection of aminothiazole ethyl gallate, a compound 2 is produced from 7-ATCA under catalysis of AlMe3; the compound2 is subjected to an esterification reaction with iodomethyl pivalate under actions of a phase transfer catalyst and an acid adsorbent, the amino protection is removed, and a target product CefditorenPivoxil is obtained. According to the preparation method, reaction conditions are mild, product purity and yield are high, the process is stable, amplification is easy, and the method is applicable to industrial production.
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- Preparation method of high-purity cefditoren pivoxil
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The invention belongs to the technical field of medicines, and particularly relates to a preparation method of high-purity cefditoren pivoxil. The preparation method comprises following specific steps: controlling the temperature of cefditoren sodium (1) and iodomethyl pivalate (2) to be -30 DEG C to-35 DEG C for reaction to obtain a cefditoren pivoxil (3) solution; extracting with an organic phase/water mixed solvent, washing with a 0.1% sodium bicarbonate aqueous solution, crystallizing with an organic phase inert solvent, and carrying out ethyl acetate crystal transformation purification onan obtained crude product to obtain the high-purity cefditoren pivoxil of which the purity is greater than 99.5% and the individual impurity content is less than 0.1%, thereby reaching the USP bulk drug standard of the variety. The technical scheme discloses in the invention further provides a refining method of cefditoren pivoxil, a crystalline cefditoren pivoxil product is obtained by directlydissolving and crystallizing with ethyl acetate, and the refining method is simple to operate, easy to control, high in yield, good in quality and suitable for industrial production.
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Paragraph 0050-0075
(2020/01/25)
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- Preparation method of cefditoren pivoxil
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The invention relates to a preparation method of cefditoren pivoxil. The preparation method comprises the following steps: 7-aminocephalosporanic acid(ACA) is taken as a starting material and subjected to a series of reactions such as iodination and the like after silylation protection to generate parent nucleus for cefditoren, namely 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)ethenyl]-3-cephem-4-carboxylic acid (7-ATCA); the compound 7-ATCA firstly reacts with sodium iso-octoate to form sodium salt and then reacts with ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate to generate a compound 2,namely cefditoren sodium, under the catalysis of immobilized penicillin acylase; and then the cefditoren sodium reacts with iodomethyl pivalate to obtain a target product, namely cefditoren pivoxil.The preparation method is mild in reaction conditions, environmentally-friendly, high in conversion rate, simple in process, high in content of cis isomers, easy to enlarge and suitable for industrialproduction.
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- Method for synthesizing cefditoren pivoxil
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The invention relates to a method for synthesizing cefditoren pivoxil. The method comprises that D-7ACA reacts with an oxidizing reagent to produce a compound 1, the compound 1 is protected through silanization to produce a compound 2, 4-methylthiazole-5-methanol and NaI undergo an iodination reaction in the presence of a small amount of sulfuric acid for catalysis, triphenylphosphine is added into the reaction system and undergoes a reaction to produce a compound 3, the compound 3 is added into the compound 2 liquid and undergoes a reaction, the reaction product is concentrated, methanol anda small amount of concentrated hydrochloric acid are added into the concentrated product, the concentrated product is deprotected and crystallized to form cefditoren mother nucleuses, 7-ATCA and an AEactive ester undergo a reaction under alkaline conditions, the reaction product is crystallized to form a cefditoren sodium wet product, the cefditoren sodium wet product is added into iodomethyl pivalate and undergoes a reaction in the presence of a phase transfer catalyst and the product is crystallized to form a cefditoren pivoxil crude product. In preparation of the compound 1, cefditoren sodium and cefditoren pivoxil, single solvents are used and are easy to recover. The method has the advantages of simple operation, high product conversion rate, few impurities and low production cost and is suitable for industrial production of cefditoren pivoxil.
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Paragraph 0059; 0065-0068; 0074; 0075; 0081; 0082; 0088-0094
(2019/01/20)
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- A spore proper logical sequence of the ester preparation method
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The invention belongs to the technical field of medicines and particularly relates to a preparation method of cefditoren pivoxil. The preparation method particularly includes following steps: (1) carrying out a reaction between cefditoren mother nucleus 7ATCA and AE-activated ester with dichloromethane as a solvent under an alkaline condition at 0-5 DEG C; (2) performing extraction with pure water and adding a sodium iso-octoate/acetone solution to obtain cefditoren sodium; (3) carrying out a reaction between the cefditoren sodium and iodomethyl pivalate under the alkaline condition at -40 DEG C to obtain a cefditoren pivoxil solution; (4) adding pure water to separate out a crystal to obtain a crude product of the cefditoren pivoxil. The technical scheme also comprises steps of dissolving the crude product of the cefditoren pivoxil in a mixed solution including dichloromethane and anhydrous ethanol, washing the material solution with a 1% sodium bicarbonate solution and pure water, collecting an organic phase, and performing a pressure-reducing evaporate-drying process to obtain the cefditoren pivoxil being higher than 99% in purity and less in impurities. The preparation method is simple in operation, is easy to control, is high in yield, allows the raw material to be obtained easily and is suitable for industrialized large-scale production.
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Paragraph 0035; 0038; 0039; 0046; 0054; 0056; 0064
(2018/09/02)
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- A method for preparing spore proper logical sequenceester
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The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of cefditore. The method comprises the following steps that (1) under the photophobic condition, 7-ATCA and AE-active ester are added into methylene dichloride; catalysts are added; the temperature is lowered to 0 to 5 DEG C; triethylamine is added to obtain cefdiporen acid; a water solution of organic amine is added into organic solvents containing dissolved cefdiporen acid; crystal separation is carried out to obtain organic amine salts of the cefdiporen acid; (2) the organic amine salts of the cefdiporen acid take a reaction with iodomethyl pivalate under the existence of tetrabutylammonium bromide and sodium carbonate in N,N-dimethyl formamide to obtain the cefditore. The preparation method has the advantages that the organic amine salts of the cefdiporen acid are used; the defects of difficult storage and poor stability of the sodium salts of the cefdiporen acid are effectively avoided; E-shaped isomers are effectively removed; meanwhile, the esterification condition is optimized, so that the purity of final products is higher.
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Paragraph 0026; 0028
(2017/08/25)
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- Preparation method of cefditoren pivoxil
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The invention discloses a preparation method of an important antibiotic cefditoren pivoxil. The preparation method comprises that 7-ATCA as a raw material is bonded to an AE active ester under base catalysis so that cefditoren acid is obtained, the cefditoren acid and sodium bicarbonate undergo a reaction to produce a salt, and the salt and cefditoren pivoxil undergo a replacement reaction under alkaline conditions to produce 2, 2-dimethylpropionyloxy(6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methyl-1, 3-thiazolyl-5-yl)vinyl]-8-oxo-5-thia-1-azabicyalo[4. 2. 0]octyl-2-ene-2-formate. The preparation method has the advantages of low cost, simple operation, high purity, use of cheap and easily available raw materials, industrial production feasibility and small pollution.
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- A method for preparing esterspore proper logical sequence
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The invention relates to a preparation method of cephalosporin, particularly to a preparation method of cefditoren pivoxil. 7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl) vinyl]-3-cephem-4-carboxylic acid and 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic are taken as initial raw materials, and the cefditoren pivoxil is obtained through condensation and esterification reactions. The method is simple in process, high in yield, free of highly corrosive solvents and suitable for industrial production.
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Paragraph 0032-0036
(2017/01/12)
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- Method for preparing cefditoren pivoxil cephalosporins
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The invention discloses a method for preparing cefditoren pivoxil cephalosporins.The method comprises the following steps that 1, on the presence of TMEDA and sodium phosphate, 7-ATCA and MAEM are subjected to a contact reaction in THF, and a mixture containing cefditore is obtained, and the contact reaction temperature ranges from 0 to 25 DEG C; 2, the temperature is kept, TEA is added to the mixture containing cefditore obtained in the step 1, then iodomethyl pivalate is added to the mixture to be stirred for reacting, the product is poured into water after the reaction is finished, a saturated ammonium chloride solution is added, the pH is adjusted to be 5 to 5.3, filtering is carried out, and a filter cake obtained through filtering is recrystallized in methyl alcohol to obtain cefditoren pivoxil cephalosporins.According to the method, separation treatment is not needed in the intermediate steps, one-pot operation is easy, cost is reduced, the yield is high, the number of by-products is small, aftertreatment is easy, and the method is especially suitable for industrial popularization.
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Paragraph 0020; 0032
(2016/10/17)
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- NOVEL CRYSTALLINE FROM OF CEFDITOREN PIVOXYL AND PREPARATION METHOD THEREOF
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The present invention relates to: a novel crystal form of cefditoren pivoxil readily convertible into an amorphous form, to be used as an active ingredient of a drug, and having high cefditoren pivoxil purity; and a preparation method therefor. The novel crystal form of cefditoren pivoxil shows an XRD pattern having peaks at 2θ values of 8.500±0.2°, 10.535±0.2° and 16.400±0.2°.
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Paragraph 0046; 0047
(2016/12/26)
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- DEPLETION OF ISOMER IN CEPHALOSPORIN ANTIBIOTIC
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The present invention relates to the process for the depletion of E isomer of Cefditoren sodium of formula (I).
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Page/Page column 6
(2008/06/13)
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- DEPLETION OF E-ISOMERS IN PREPARATION OF Z-ENRICHED 3-(2-SUBSTITUTED VINYL) CEPHALOSPORINS
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The present invention relates to depleting E-isomers of 3-(2-substituted vinyl) cephalosporins from a Z/E mixture of the same by selective crystallization techniques. The present invention to Z-enriched compounds comprising less than 5 % E-isomer.
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Page/Page column 20
(2008/06/13)
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- PROCESS FOR SELECTIVE PREPARATION OF Z-ISOMER OF CEFDITOREN AND PHARMACEUTICALLY ACCEPTABLE SALTS AND ESTERS THEREOF
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The present invention relates to a selective process for preparation of Z-isomer of cefditoren of Formula I and pharmaceutically acceptable salts and esters thereof. cefditoren possesses a wide spectrum of antibacterial activity against Gram-positive and Gram-negative bacteria.
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Page/Page column 16-17
(2008/06/13)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF CEFDITOREN
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The present invention relates to an improved process for the preparation of Cefditoren of formula (I), the said process comprising the steps of: i) converting the compound of formula (II) to a compound of the formula (III) using TPP and sodium iodide in the presence of THF, water, and base; ii) reacting the compound of formula (III) with 4-methyl-5-formyl-thiazole to produce a compound of formula (IV); iii) deesterifying the compound of the formula (IV) to yield compound of formula (V); iv) converting the compound of formula (V) to compound of formula (VI) in the presence of a base and solvent; v) converting the compound of formula (VI) into compound of formula (VII) by enzymatic hydrolysis; and vi) reacting compound of formula (VII) with compound of formula (VIII) in the presence of solvent and base to produce compound of formula (I).
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- Synthesis and oral activity of pivaloyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3(Z)-(4-methylt hiazol-5-yl)vinyl-3-cephem-4 carboxylate (ME1207) and its related compound
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7-[2-(2-Aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3(Z)-(4-methylth iazol-5-yl)vinyl-3-cephem-4-carboxylic acid (11, ME1206) and its 3-trans isomer (13) were prepared to test antibacterial activity. These compounds exhibited excellent antibacterial activity against both gram-positive and gram-negative bacteria, including β-lactamase producing strains. The pivaloyloxymethyl esters (12 and 14) of the compounds (11 and 13) were prepared by esterification with pivaloyloxymethyl iodide. Among them, pivaloyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3(Z)-(4-methylt hiazol-5-yl)vinyl-3-cephem-4-carboxylate (12, ME1207) showed good urinary recovery after oral administration in mice.
- Sakagami,Atsumi,Yamamoto,Tamura,Yoshida,Nishihata,Fukatsu
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p. 2433 - 2436
(2007/10/02)
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