- Preparation method of medicinal tebipenem pivoxil
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The invention discloses a preparation method of medicinal tebipenem pivoxil, which comprises the following steps: taking MAP and YKTP-1 as raw materials, sequentially carrying out condensation, reduction and substitution reaction, and purifying the material after the substitution reaction twice to obtain the medicinal tebipenem pivoxil. A primary purification process comprises the following steps: adding ethyl acetate into the material after the substitution reaction, conducting filtering, adding water into the filtrate, adjusting the pH value, carrying out liquid separation to obtain a water layer, adjusting the pH value of the water layer, conducting extracting with ethyl acetate to obtain an organic layer, washing the organic layer, conducting drying, decolorizing and filtering, carrying out vacuum concentration on the filtrate, conducting crystallizing and centrifuging, leaching a filter cake with ethyl acetate, and conducting drying in vacuum to obtain YKTP-4; and a secondary purification process comprises the following steps: mixing YKTP-4 with ethyl acetate, adding activated carbon, conducting stirring, conducting filtering to obtain filtrate, concentrating the filtrate to YKTP-4 under reduced pressure, conducting crystallizing and centrifuging, leaching a filter cake with ethyl acetate, and performing vacuum drying to obtain the medicinal tebipenem pivoxil.
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Paragraph 0059; 0061-0062; 0072; 0074-0075; 0086; 0088-0089
(2021/05/19)
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- Preparation method for tebipenemoic acid
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The invention discloses a preparation method for a tebipenem pivoxil intermediate shown as a formula 1-tebipenemoic acid, and belongs to the field of medicinal chemistry. The method takes a compound Ias an initial raw material, takes SiO2 or montmorillonite KSF supported perfluorosulfonic acid resin pyridine salt as a catalyst, and takes dichloroethane/acetonitrile as a solvent, reaction with a compound II in the presence of organic base can be performed, so that tebipenemoic acid can be prepared through one pot. Compared with the prior art, the adopted synthetic process is less in syntheticstep, simple in operation and post-treatment, strong in operationality, low in product cost and suitable for industrial production; and a used soil acid reagent is cheap in price, easy in obtaining and pollution free, has no corrosiveness, and can be recycled. The tebipenem pivoxil intermediate is shown as the formula 1.
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Paragraph 0046-0060
(2019/05/08)
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- Tebipenem pivoxil and synthetic method thereof
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The invention provides tebipenem pivoxil and a synthetic method thereof. The invention relates to the technical field of drug synthesis. The synthetic method comprises the three-step synthetic reactions of condensation of a main ring and a tebipenem side chain, a TB-1 hydrogenation reduction reaction, and a reaction of a TB-2 intermediate and iodomethyl pivalate. The preparation method of tebipenem pivoxil provided by the invention is simple and convenient in preparation process, suitable for industrial production, and relatively high in yield; processing operations, such as column chromatography, which are required to be adopted by traditional synthesis are eliminated; a reasonable synthetic route is designed; the reaction time is effectively shortened; the post-processing process is simplified.
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Paragraph 0053-0083
(2019/07/04)
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- Preparation method of high-purity tebipenem pivoxil crystals
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The invention discloses a preparation method of high-purity tebipenem pivoxil crystals. The method comprises the following steps: adding a first solvent to crude tebipenem pivoxil, and performing stirring to obtain a primary dissolved product; adding a second solvent dropwise to the primary dissolved product at a reaction temperature, and then performing stirring for crystallization, wherein the first solvent contains water; the second solvent is acetonitrile; the reaction temperature is 0-60 DEG C. The tebipenem pivoxil crystals with high purity and low solvent residue content can be preparedwith the method.
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Paragraph 0021
(2019/01/17)
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- A method for preparing for than peinan
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The invention discloses a preparation method of tebipenem. The method comprises the following step of: performing a catalytic hydrogenation reaction on a compound II and hydrogen gas in an organic solvent or a mixed solution of water and an organic solvent under the catalyzing actions of a palladium catalyst, a nickel catalyst and a platinum catalyst to obtain tebipenem, wherein R is a carboxyl protecting group which can be prepared into carboxylic acid ester together with carboxyl in the carbapenem industry and can be removed without cusing variations of other parts in the molecule. The preparation method disclosed by the invention has high yield and simple post-treatment; and in a preferred post-treatment method, a carbapenem crystal with high yield and high purity can be obtained.
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Paragraph 0040; 0041
(2017/02/17)
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- Preparation method of tebipenem pivoxil
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The invention provides a preparation method of tebipenem pivoxil, and relates to the technical field of pesticide synthesis. The preparation method of the tebipenem pivoxil comprises the following steps that 1-(4,5-dihydro-2-thiazolyl) azetidine-3-thiol hydrochloride and 1 beta-methyl vinyl phosphate are used as raw materials to take a reaction under the existence of diisopropylethylamine, and an acetonitrile water solution is used for washing to obtain an intermediate I; the intermediate I, an n-butyl alcohol water solution, a palladium-carbon catalyst and sodium bicarbonate take a mixed reaction, and treatment is performed to obtain an intermediate II; the intermediate II and chloromethyl pivalate take a reaction through phase transfer catalyst catalysis under the existence of diisopropylethylamine and dimethylformamide to obtain an intermediate III; the intermediate III and a sodium bicarbonate water solution are mixed, ethyl acetate is added, and reaction and refining are performed to prepare the tebipenem pivoxil. The preparation method has the advantages that the purity and the yield of the intermediates are obviously improved; the purity of the final product of the tebipenem pivoxil reaches 99.21 to 99.78 percent; the yield reaches 88.7 to 92.1 percent.
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Paragraph 0042
(2017/05/12)
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- A process for the preparation of antibacterial drug
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The invention discloses a preparation method of an antibacterial medicament tebipenem pivoxil. (4R,5R,6S)-3-((diphenyl-phosphoroso-carbonyl)oxyl)-6-((R)-1-ethoxyl)-4-methyl-7-carbonyl-1-azabicyclo[3.2.0]heptane-2-alkenyl-2-carboxylic acid p-nitro ester(6-MAP(I)) serving as a raw material reacts with 1-(4,5-dihydro-2-thiazolinyl)-3-sulfydryl azetidine hydrochloride (II) in the presence of alkali to obtain (4R,5S,6S)-3-((1-(4,5-dihydro-2-thiazolinyl)-3-azetidine) sulfenyl)-6-((R)-1-ethoxy)-4-methyl-7-oxygen-1-azabicyclo[3.2.0]heptane-2-alkenyl-2-carboxylic acid p-nitro ester (III); the protecting group of the compound (III) is removed under the catalytic hydrogenation condition to obtain (4R,5S,6S)-3-((1-(4,50dihydro-2-thiazolinyl)-3-azetidine)sulfenyl)-6-((R)-1-ethoxy)-4-methyl-7-oxygen-1-azabicyclo[3.2.0]heptane-2-alkenyl-2-carboxylic acid (IV); and the compound (IV) reacts with chloromethyl pivalate and sodium iodide or potassium iodide in the presence of alkali to obtain tebipenem pivoxil (V). According to the preparation method, the selected initial raw materials are low in price and easily available, so that the synthesizing route is simplified, the raw material utilization and total yield can be improved; and the intermediate substance obtained in the reaction is purified by using a re-crystallization method with high yield, less three wastes are generated in the reacting process, and the low cost is advantageous to industrial production.
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- A method for preparing than peinan thai
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The present invention relates to a preparation method of an improved carbapenem compound tebipenem (shown as a formula 2). The method employs a tebipenem intermediate I as a raw material to conduct a hydrogenated deprotection reaction in a reaction solvent of a single solvent water in the presence of alkali and catalyst. The method of the invention adopts the single solvent water as the reaction solvent, and is economical, safe, environment-friendly, and more suitable for industrial scale operation.
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Paragraph 0036-0038
(2017/01/09)
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- Syntheses and pharmacokinetic studies of prodrug esters for the development of oral carbapenem, L-084
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We discovered an orally active carbapenem, L-084, through pharmacokinetic studies on various prodrug esters of (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl- 2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-1-carbapen-2-em-3-carboxylic acid (LJC11,036). L-084 showed a strong antimicrobial activity against Gram-positive and Gram-negative bacteria and exhibited the highest intestinal absorption among synthesized prodrugs of LJC11,036. Japan Antibiotics Research Association.
- Isoda, Takeshi,Ushirogochi, Hideki,Satoh, Koichi,Takasaki, Tsuyoshi,Yamamura, Itsuki,Sato, Chisato,Mihira, Ado,Abe, Takao,Tamai, Satoshi,Yamamoto, Shigeki,Kumagai, Toshio,Nagao, Yoshimitsu
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p. 241 - 247
(2007/10/03)
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