34 results about "P-hydroxyphenylglycine methyl ester" patented technology

The invention relates to a method for comprehensively recovering effective ingredients in amoxicillin mother liquid prepared by an enzyme process. The method comprises the following steps: (1) concentrating the amoxicillin mother liquid, namely adjusting the pH value of the amoxicillin mother liquid prepared by the enzyme process to be 8.0-9.5, and performing nanofiltration and concentration to obtain concentrated mother liquid; (2) synthesizing amoxicillin under enzyme catalysis, namely adjusting the pH value of the concentrated mother liquid to be 5.8-7.0, and converting 6-APA (6-amino penicillanic acid) and D-methyl hydroxyphenyl glycinate into amoxicillin in the presence of immobilized penicillin acylase for synthesis; (3) preparing D-hydroxyphenyl glycine concentrated liquid by ultrafiltration and nanofiltration, namely separating after the enzyme catalysis reaction is ended to obtain amoxicillin crystals and secondary amoxicillin mother liquid, and performing ultrafiltration and nanofiltration on the secondary mother liquid to obtain the D-hydroxyphenyl glycine concentrated liquid; (4) crystallizing D-hydroxyphenyl glycine. According to the method, 6-APA and D-methyl hydroxyphenyl glycinate remained in the mother liquid are consumed through an indirect process of synthesizing amoxicillin under enzyme catalysis, the product quality of D-hydroxyphenyl glycine is improved, and the yield of D-hydroxyphenyl glycine is increased.

The invention relates to the medicine field, and especially relates to a synthetic method of D-p-hydroxyphenylglycine methyl ester. The invention provides a synthetic method by directly using d-p-hydroxyphenylglycine as an initial raw material without splitting and separation, a target compound D-p-hydroxyphenylglycine methyl ester can be obtained through one-pot synthesis, a technology process is shortened, and hydrolysis risk of ester in a long production process can be avoided. According to the invention, yield can reach more than 96%, the ee value of D-p-hydroxyphenylglycine methyl ester can reach more than 99%, and the quality index is excellent.

The invention relates to a method for synthesizing amoxicillin and generating a byproduct of a sodium phenylacetate solution by using a semi-direct method and belongs to the technical field of medicine preparation. The method comprises the following steps: splitting benzylpenicillin potassium into 6-APA (Amino Penicillanic Acid) and phenylacetic acid under the action of penicillin acylase, extracting a splitting solution with dichloromethane to separate 6-APA from the phenylacetic acid, putting ammonia water into an extraction water phase, adjusting the pH value of a material liquid to be neutral, removing the dichloromethane, putting the solid 6-APA into the obtained 6-APA dissolving liquid, and synthesizing the amoxicillin together with D-methyl p-hydroxyphenylglycinate under the actionof amoxicillin synthetase. A sodium phenylacetate solution can be prepared by alkalizing the dichloromethane obtained by extracting the splitting solution, the sodium phenylacetate solution can be directly applied to fermentation production of penicillin, the step of recycling the phenylacetic acid is avoided, and the production cost is reduced.

The invention provides a synthetic method of p-hydroxyphenylglycine methyl ester. The synthetic method comprises the following steps: (1) adding D-p-hydroxyphenylglycine into methanol, conducting uniform stirring, and then dropwise adding thionyl chloride at 30-50 DEG C to obtain a methanol solution of D-p-hydroxyphenylglycine methyl ester; (2) decompressing the methanol solution of D-p-hydroxyphenylglycine methyl ester to obtain methanol under the condition that a vacuum degree is less than or equal to 0.090 MPa, then adding water, performing stirring, and carrying out decolorizing with activated carbon under an acidic condition to obtain an aqueous solution of the D-p-hydroxyphenylglycine methyl ester; and (3) dropwise adding 15-20wt% of ammonia water into the aqueous solution of D-p-hydroxyphenylglycine methyl ester to adjust a pH value to 9-10, wherein the dropwise adding time of the ammonia water is 3-6 hours, subjecting D-p-hydroxyphenylglycine methyl ester to crystallization and precipitation, and finally, carrying out centrifugal separation to obtain a D-p-hydroxyphenylglycine methyl ester product. The D-p-hydroxyphenylglycine methyl ester prepared by the method disclosed by the invention is high in recovery rate and high in purity.

The invention discloses a preparation method of D-4-hydroxy-phenylglycinate and hydrochloride thereof. D-4-hydroxyphenylglycine is used as an initial raw material. The methyl D-4-hydroxy-phenylglycinate or the hydrochloride thereof is prepared by reacting the D-4-hydroxyphenylglycine with methanol or a methanol solution of hydrogen chloride under the existence of trimethylchlorosilane and by post-treatment. The preparation method has characteristics of easily available raw materials, simple operation, high yield, high product purity and little environment pollution, and is suitable for industrial production.

The present invention relates to a kind of synthesis method of amoxicillin production intermediate, use DL-p-hydroxyphenylglycine and methanol as raw materials, and use solid phosphoric acid as catalyst to synthesize D-p-hydroxyphenylglycine methyl ester, including preparation of solid phosphoric acid catalyst, DL-p-hydroxyphenylglycine Preparation of p-hydroxyphenylglycine methyl ester, hydrolysis of solid phosphoric acid catalyst, crystallization of D-p-hydroxyphenylglycine methyl ester and racemization of crystallization mother liquor in 5 parts. In the present invention, the solid phosphoric acid catalyst can be hydrolyzed into phosphoric acid after the esterification is completed, and forms a phosphoric acid double salt with DL-p-hydroxyphenylglycine methyl ester. ‑Resolving agent for methyl p-hydroxyphenylglycine. In the present invention, the synthesis and resolution of DL-p-hydroxyphenylglycine methyl ester is carried out in methanol aqueous solution, and the crystallization mother liquor is recycled, which greatly reduces the generation of waste liquid, and is a clean production process of D-p-hydroxyphenylglycine methyl ester.

The present invention relates to the field of compound synthesis and discloses a method for synthesizing D-para-hydroxyphenylglycine methyl ester. The method comprises the steps of: (1) in the presence of thionyl chloride, carrying out an esterification reaction of D-para-hydroxyphenylglycine resolving agent salt and methanol to obtain a D-para-hydroxyphenylglycine methyl ester resolving agent salt; (2) dropwise adding the D-para-hydroxyphenylglycine methyl ester resolving agent salt and an alkaline metal hydroxide to an aqueous D-para-hydroxyphenylglycine methyl ester solution at 10-15°C, controlling the pH value of the system at 6.5-7 during the dropwise addition, after completing the dropwise addition of the D-para-hydroxyphenylglycine methyl ester resolving agent salt, continuing the dropwise addition of the alkaline metal hydroxide until the pH value of the system is 7.5-8, then growing crystals under the conditions of a temperature of 10-15°C and the pH value of 7.5-8, and subsequently filtering the resultant crystallization liquid to obtain D-para-hydroxyphenylglycine methyl ester crystals and a mother liquor. With the adoption of the method provided by the present invention, D-para-hydroxyphenylglycine methyl ester can be produced with a higher yield.

The invention discloses a method for synthetizing amoxicillin through an enzymatic method. The method comprises the following steps: (1) immobilized penicillin G acylase is washed through distilled water and then soaked through hydrochloric acid; (2) Methyl p-hydroxyphenylglycinate and 6-APA are evenly mixed and then soaked through hydrochloric acid, and then purified water is added; (3) the immobilized penicillin G acylase, the Methyl p-hydroxyphenylglycinate and the 6-APA are mixed and then react to obtain an amoxicillin suspension; and (4) the amoxicillin suspension is cooled, hydrochloricacid is dripped till the solution is clear, gain growing is conducted after suction filtration, washing and drying are conducted, and then the amoxicillin product is obtained. In the reaction process,the immobilized penicillin G acylase is soaked by the hydrochloric acid for a short time, thus the reaction speed is increased, the reaction time is shortened, the yield of the product is increased,and the purity of the product is improved; and sucrose and histidine with the mass ratio being 3 to 1 are added in a reaction system, and thus the stability of the product is improved.

The invention discloses a synthesis method of p-hydroxyphenylglycine methyl ester. The method comprises the steps of: reacting p-hydroxyphenylglycine or salt thereof which is used as an initial raw material with methanol in the presence of solid acid; and treating so as to obtain p-hydroxyphenylglycine methyl ester. The preparation method of p-hydroxyphenylglycine methyl ester is available in raw material, simple and convenient to operate, low in cost, high in yield, high in product purity, and is suitable for commercial production.

The invention relates to a method for comprehensively recovering effective ingredients in amoxicillin mother liquid prepared by an enzyme process. The method comprises the following steps: (1) concentrating the amoxicillin mother liquid, namely adjusting the pH value of the amoxicillin mother liquid prepared by the enzyme process to be 8.0-9.5, and performing nanofiltration and concentration to obtain concentrated mother liquid; (2) synthesizing amoxicillin under enzyme catalysis, namely adjusting the pH value of the concentrated mother liquid to be 5.8-7.0, and converting 6-APA (6-amino penicillanic acid) and D-methyl hydroxyphenyl glycinate into amoxicillin in the presence of immobilized penicillin acylase for synthesis; (3) preparing D-hydroxyphenyl glycine concentrated liquid by ultrafiltration and nanofiltration, namely separating after the enzyme catalysis reaction is ended to obtain amoxicillin crystals and secondary amoxicillin mother liquid, and performing ultrafiltration and nanofiltration on the secondary mother liquid to obtain the D-hydroxyphenyl glycine concentrated liquid; (4) crystallizing D-hydroxyphenyl glycine. According to the method, 6-APA and D-methyl hydroxyphenyl glycinate remained in the mother liquid are consumed through an indirect process of synthesizing amoxicillin under enzyme catalysis, the product quality of D-hydroxyphenyl glycine is improved, and the yield of D-hydroxyphenyl glycine is increased.

The invention relates to a method for synthesizing cefprozil through an enzymatic method. According to the method, a cefprozil parent nucleus, D-para hydroxybenzene glycine methyl ester and / or D-para hydroxybenzene glycine ethyl ester, water and penicillin acylase react at the temperature of 10 DEG C-25 DEG C to obtain a crude cefprozil product and enzyme reaction mother liquor, the temperature is controlled to be 0 DEG C-15 DEG C, a pH value is controlled to be 0.2-0.8, N,N-dimethyl formamide is added, the mixture is stirred uniformly, a seed crystal is added for crystal growing, the pH value is adjusted to be 5.5-6.5, and the temperature is controlled to be 10 DEG C-30 DEG C to obtain a cefprozil N,N-dimethyl formamide compound; the temperature is controlled to be 0 DEG C-25 DEG C, water and the cefprozil N,N-dimethyl formamide compound are added into a reactor, the mixture is stirred for crystal transformation for 1-4.5 h, and then filtering, washing, swabbing-off and drying are carried out to obtain a finished cefprozil product. The cefprozil is high in product yield and high in purity, appearance is white, the preparing method is simple and easy to implement, the condition is mild, and the method is more suitable for industrial production.

The invention discloses a method for preparing amoxicillin or ampicillin in a full-water-phase through mode. The method includes the steps that a high-concentration penicillin GK or penicillin VK extracting solution is used as a raw material, immobilized penicillin G acylase or penicillin V acylase is used as an enzyme catalyst, a high-concentration 6-APA solution or crystal is obtained through full-water-phase operations such as catalytic cracking, separating, acidization, filtering, chromatography and concentration by nanofiltration, and then the amoxicillin or the ampicillin is synthesized by the solution or crystal and HPGME or phenylglycine methyl ester under the catalytic action of the immobilized penicillin synthetase. According to the method, water-phase reacting is conducted in the whole process, no organic solvent is used, and environmental pollution is reduced; besides, the special immobilized penicillin G acylase and the penicillin V acylase are used for cracking the high-concentration penicillin GK or VK extracting solution, and special macroporous absorption resin is used for separating and cracking products, so that the processing steps are greatly simplified, the production cost is lowered, the product yield is increased, and the industrial production requirement is met.

The invention relates to a preparation method for a crystal of L-p-hydroxyphenylglycine methyl ester. The preparation method comprises the following steps: (1) adding L-p-hydroxyphenylglycine methyl ester hydrochloride into a container filled with water, keeping solid-liquid ratio of solution within 0.08-0.15g / ml, stirring and dissolving under constant temperature at 25-40 DEG C, continuously stirring and then filtering and decolorizing; (2) pouring a filtrate into a crystallizer, stirring under constant temperature at 25-40 DEG C, adding alkali liquor into the crystallizer till pH of solutionis 5.0-5.8, adding a L-p-hydroxyphenylglycine methyl ester seed crystal and growing crystal for 1-3h; (3) continuing to add alkali liquor till pH of solution is 8.2-8.4, continuously cooling to 0-5 DEG C and growing crystal for 1-3h; (4) performing suction filtration, washing filter cake with water, and drying the acquired crystal product. The product acquired according to the invention is high in purity, large in grain size and high in liquidity; labor intensity of filtering and drying is low; the preparation method is easy for industrialization.

The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of cefpiramide side chain acid. Pyridine-3-formic acid and methyl p-hydroxyphenylglycinate are used as raw materials, and the cefpiramide side chain acid is obtained through chlorination, acylation, hydrolysis and crystallization. The synthesis method of the cefpiramide side chain acid is simple to operate, easily available in raw materials and low in cost, adopts a dichloromethane and N, N-dimethylacetamide mixed solvent as a solvent, greatly improves the product yield and stability, has good economic benefits, and is convenient for large-scale industrial production.

The invention discloses an HPLC method for determining the content of D(-)p-hydroxyphenylglycine in D(-)p-hydroxyphenylglycine methyl ester. The method is to prepare a solution of D(‑) p-hydroxyphenylglycine methyl ester with dilute acid solution, adopt a chemically bonded stationary phase chromatographic column, add organic base with buffer salt, and adjust pH to 0.8-12 with acid as buffer salt solution, buffered salt solution and organic phase modifier in an appropriate ratio for gradient elution, and then detect at an appropriate detection wavelength, flow rate and column temperature, and then calculate the sample content based on the spectrum. The method of the invention can effectively separate D(-)p-hydroxyphenylglycine methyl ester and D(-)p-hydroxyphenylglycine, and accurately measure the content of D(-)p-hydroxyphenylglycine. The method is simple, reliable and rapid , high sensitivity, good reproducibility and specificity, which established the foundation for the establishment of quality standards for D(‑) p-hydroxyphenylglycine methyl ester.

The invention discloses a preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production, and relates to a preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production. In the first step of reaction, methyl glyoxylate and phenol are used as raw materials, cheap S-(-)-arylethylamine is used as a chiral induction reagent, and (R)-2-(4-hydroxyphenyl)-2-(((S)-1-arylethyl) amino) methyl acetate hydrochloride (intermediate 1) is obtained through reaction. In the second reaction step, the intermediate 1 is subjected to hydrogenolysis of a protecting group under the Pd / C catalytic condition. The method provided by the invention has the main characteristics that 1, the process is simple, only two-step chemical reaction is adopted, and the production efficiency is high; and 2, a cheap chiral induction reagent S-(-)-arylethylamine is used for replacing an expensive resolution reagent chiral camphorsulfonic acid or chiral phenylethanesulfonic acid, so that the raw material cost and the production cost are greatly reduced;.