CN102703559A - Preparation method for 7 beta-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazole sulfenyl]-3-cephem-4-carboxylate acidification matter - Google Patents
Preparation method for 7 beta-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazole sulfenyl]-3-cephem-4-carboxylate acidification matter Download PDFInfo
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Abstract
The invention provides a preparation method for a 7 beta-amino-3-[4-(1-methyl-4- pyridinium)-2-thiazole sulfenyl]-3-cephem-4-carboxylate acidification matter. The preparation method comprises the following steps of: (1) preparation of 7 beta-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridinium)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide: adding phenol and 7 beta-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridinium)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide to a reaction vessel, then adding a crystallization solvent for crystallization to obtain the 7 beta-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridinium)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide; and (2) preparation of the 7 beta-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazole sulfenyl]-3-cephem-4-carboxylate acidification matter, adding the 7 beta-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridinium)-2-thiazole sulfenyl]-3-cephem-4- carboxylic acid iodide to a saline solution, acidifying and crystallizing after enzyme hydrolysis to obtain the 7 beta-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazole sulfenyl]-3-cephem-4-carboxylate acidification matter. The preparation method is mild in reaction and low in production cost.
Description
Technical field
The present invention relates to medicine, is the preparation method of a kind of 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants.
Background technology
[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants is the key intermediate of cephalo Lorraine ester to 7 beta-aminos-3-, cephalo Lorraine ester belong to the 5th generation the cephalosporins antimicrobial drug.This medicine is mainly used in treatment bacterial enteritis, acute bacterial skin infections and various skin histology infection etc.Because this medicine is the exploitation of Japanese military field drugmaker, U.S. a company just obtains the power list marketing in October, 2010, therefore; The disclosed technology contents of midbody for cephalo Lorraine ester is less, though, partial content is disclosed in periodical and Phosphonocephem compound patent; But its yield is lower, generally about 65%; Because reaction conditions has relatively high expectations, make preparation cost higher, and its purity also difficulty reach higher standard; So more difficult suitability for industrialized production causes the price of cephalo Lorraine ester medicine high, brings bigger economical load to the patient.
Summary of the invention
The objective of the invention is, the preparation method of a kind of 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants is provided, make its reaction temperature with, production cost is low.
The present invention is for realizing above-mentioned purpose, and realize through following technical scheme: the preparation method of 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants comprises the steps:
1. prepare 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide: phenol and 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide are added in the reaction vessel; After insulation reaction is complete; Add the crystallization solvent and carry out crystallization, obtain 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide:
（Ⅱ） （Ⅲ） ；
2. prepare 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants: 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide that step is obtained in 1. add in the buffer salt solution; Add the immobilized penicillin acylated enzyme hydrolysis; Regulate pH to reacting completely through ammoniacal liquor; The acidifying crystallization obtains 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants:
（I）。
Described step 1. in the mass volume ratio of 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide and phenol be: 1:0.5-5.
The crystallization solvent of described step described in 1. is any in ETHYLE ACETATE, propyl acetate or the butylacetate, and the volume ratio of phenol and crystallization solvent is 1:5-15.
The insulation reaction temperature of described step described in 1. is: 40-60 ℃, the reaction times is: 3 ~ 5 hours, recrystallization temperature was 0-20 ℃.
The ammonia concn of described step described in 2. is that the mass volume ratio of 5%, 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide and buffer salt solution is: 1:4-8; The mass ratio of immobilized penicillin acylated enzyme and 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide is 0.2-2:1.
The preparation method of described a kind of 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants comprises following preparation process:
1. prepare 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide: 60L phenol is added in the reaction vessel; Stir and add 30kg7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide down; 45-50 ℃ of following insulation reaction added ETHYLE ACETATE 600L to reacting completely in 3 hours, stirred 1 hour; Cool to 0-5 ℃ then; Stirring and crystallizing 1 hour is filtered, and washs with ETHYLE ACETATE; 40 ℃ of following vacuum-dryings 8 hours, obtain 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide 23kg;
2. prepare 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants: with 23kg7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide and 138L pH is that 7.8 phosphoric acid buffer adds in the reactor drum, stirs and uses 5% ammoniacal liquor to transfer pH to be 8.0-8.5 down, adding 15.3kg immobilized penicillin acylated enzyme; Be warming up to 25-30 ℃ and begin reaction, use 5% ammoniacal liquor transfer pH as 8.0-8.5 to reacting completely, filter; Wash lytic enzyme with phosphoric acid buffer; Filtrating is cooled to 0-5 ℃, uses hydrochloric acid to transfer pH to be 1.3-1.5 again, continues stirring and crystallizing 1 hour; Filter; Washing 40 ℃ of following vacuum-dryings 8 hours, obtains 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants 15.3kg.
7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants with method preparation of the present invention; Yield is high; Can reach about 85%; Product purity is greater than 97%, and have the reaction conditions gentleness, simple to operate, side reaction is few, low cost and other advantages, is specially adapted to suitability for industrialized production.
Embodiment
The preparation method of a kind of 7 beta-aminos of the present invention-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants comprises the steps:
1. prepare 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide: phenol and 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide are added in the reaction vessel; After insulation reaction is complete; Add the crystallization solvent and carry out crystallization, obtain 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide:
（Ⅱ） （Ⅲ） ；
2. prepare 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants: 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide that step is obtained in 1. add in the buffer salt solution; Add the immobilized penicillin acylated enzyme hydrolysis; Regulate pH to reacting completely through ammoniacal liquor; The acidifying crystallization obtains 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants:
（I）。
Step 1. in the mass volume ratio of 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide and phenol be: 1:0.5-5.
The crystallization solvent of step described in 1. is any in ETHYLE ACETATE, propyl acetate or the butylacetate, and the volume ratio of phenol and crystallization solvent is 1:5-15.
The insulation reaction temperature of step described in 1. is: 40-60 ℃, the reaction times is: 3-5 hour, recrystallization temperature was 0-20 ℃.
The ammonia concn of step described in 2. is that the mass volume ratio of 5%, 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide and buffer salt solution is: 1:4-8; The mass ratio of immobilized penicillin acylated enzyme and 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide is 0.2-2:1.
The preparation method of 7 beta-aminos of the present invention-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants can have following several different methods:
The preparation method of example 1:7 beta-amino-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants, step is following:
1. prepare 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide: 120L phenol is added in the reaction vessel; Stir and add 2.4g7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide down; To reacting completely, add 6L ETHYLE ACETATE 40-45 ℃ of following insulation reaction 3 hours, stir after 66 minutes; Cool to 15-20 ℃; Stir 1 hour complete to crystallization, filter, wash with propyl acetate; 40 ℃ of following vacuum-dryings 8 hours, obtain 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide 1.6Kg;
2. prepare 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants: 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide of 1.6Kg are joined in the 6.4L phosphoric acid buffer, and phosphoric acid buffer pH value is 7.2, stirs down and uses 5% ammoniacal liquor adjust pH to be 7-7.5; Add the 320g immobilized penicillin acylated enzyme again, begin reaction after being warming up to 35-40 ℃, use 5% ammoniacal liquor adjust pH to be 7-7.5 again; To reacting completely, filter, wash lytic enzyme with phosphoric acid buffer; Filtrating is cooled to 15-20 ℃; Use the hydrochloric acid adjust pH to be 0-0.5 again, continued stirring and crystallizing 1 hour, filter, wash; 40 ℃ of following vacuum-dryings 8 hours; Obtain 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants 1.15 Kg, total recovery: 82%, purity: 98%.
The preparation method of example 2:7 beta-amino-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants, step is following:
1. prepare 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide: 1.2L phenol is added in the reaction vessel; Stir and add 2.4kg7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide down; To reacting completely, add butylacetate 18L 55-60 ℃ of following insulation reaction 5 hours, stirred 1 hour; Cool to 10-15 ℃ then; Stirring and crystallizing 1 hour is filtered, and washs with butylacetate; 40 ℃ of following vacuum-dryings 8 hours, obtain 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide 1.7kg.
2. prepare 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants: it is in 8.5 the phosphoric acid buffer that 1.7kg7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide is added 13.6L pH, stirs and uses 10% ammoniacal liquor to transfer pH to be 8.5-9.0 down, adding 3.4kg immobilized penicillin acylated enzyme; Be warming up to 20 ~ 25 ℃ and begin reaction, use 10% ammoniacal liquor transfer pH as 8.5-9.0 to reacting completely, filter; Wash lytic enzyme with phosphoric acid buffer; Filtrating is cooled to 10-15 ℃, uses hydrochloric acid to transfer pH to be 2.5-3.0 again, continues stirring and crystallizing 1 hour; Filter; Washing 40 ℃ of following vacuum-dryings 8 hours, obtains 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants 1.17kg; Total recovery: 83%, purity: 98%.
The preparation method of example 3:7 beta-amino-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants, step is following:
1. prepare 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide: 12L phenol is added in the reaction vessel; Stir and add 6kg7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide down; 50-55 ℃ of following insulation reaction added propyl acetate 120L to reacting completely in 3 hours, stirred 1 hour; Cool to 0 ~ 5 ℃ then; Stirring and crystallizing 1 hour is filtered, and washs with propyl acetate; 40 ℃ of following vacuum-dryings 8 hours, obtain 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide 4.5kg.
2. prepare 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants: with 4.5kg7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide and 27L pH is that 7.8 phosphoric acid buffer adds in the reactor drum, stirs to use 5% ammoniacal liquor to transfer pH down to be 8.0 ~ 8.5, to add the 3kg immobilized penicillin acylated enzyme; Be warming up to 25 ~ 30 ℃ and begin reaction, use 5% ammoniacal liquor transfer pH as 8.0-8.5 to reacting completely, filter; Wash lytic enzyme with phosphoric acid buffer; Filtrating is cooled to 0-5 ℃, uses hydrochloric acid to transfer pH to be 1.3-1.5 again, continues stirring and crystallizing 1 hour; Filter; Washing 40 ℃ of following vacuum-dryings 8 hours, obtains 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants 3kg; Total recovery: 85%, purity: 98%.
The preparation method of example 4:7 beta-amino-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants, step is following:
1. prepare 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide: 60L phenol is added in the reaction vessel; Stir and add 30kg7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide down; 45-50 ℃ of following insulation reaction added ETHYLE ACETATE 600L to reacting completely in 3 hours, stirred 1 hour; Cool to 0-5 ℃ then; Stirring and crystallizing 1 hour is filtered, and washs with ETHYLE ACETATE; 40 ℃ of following vacuum-dryings 8 hours, obtain 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide 23kg.
2. prepare 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants: with 23kg7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide and 138L pH is that 7.8 phosphoric acid buffer adds in the reactor drum; Stir and use 5% ammoniacal liquor to transfer pH to be 8.0-8.5 down; Add the 15.3kg immobilized penicillin acylated enzyme; Be warming up to 25-30 ℃ and begin reaction, use 5% ammoniacal liquor transfer pH as 8.0-8.5 to reacting completely.Filter, wash lytic enzyme with phosphoric acid buffer, filtrating is cooled to 0-5 ℃; Use hydrochloric acid to transfer pH to be 1.3-1.5 again, continued stirring and crystallizing 1 hour, filter; Washing 40 ℃ of following vacuum-dryings 8 hours, obtains 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants 15.3kg; Total recovery: 87%, purity: 99%.
Claims (6)
1.7 the preparation method of beta-amino-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants is characterized in that: comprise the steps:
1. prepare 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide: phenol and 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide are added in the reaction vessel; After insulation reaction is complete; Add the crystallization solvent and carry out crystallization, obtain 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide:
（Ⅱ） （Ⅲ） ；
2. prepare 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants: 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide that step is obtained in 1. add in the buffer salt solution; Add the immobilized penicillin acylated enzyme hydrolysis; Regulate pH to reacting completely through ammoniacal liquor; The acidifying crystallization obtains 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants:
（I）。
2. the preparation method of 7 beta-aminos according to claim 1-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants is characterized in that: step 1. in the mass volume ratio of 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide and phenol be: 1:0.5-5.
3. the preparation method of 7 beta-aminos according to claim 1-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants; It is characterized in that: the crystallization solvent of step described in 1. is any in ETHYLE ACETATE, propyl acetate or the butylacetate, and the volume ratio of phenol and crystallization solvent is 1:5-15.
4. the preparation method of 7 beta-aminos according to claim 1-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants; It is characterized in that: the insulation reaction temperature of step described in 1. is: 40-60 ℃; Reaction times is: 3-5 hour, recrystallization temperature was 0-20 ℃.
5. the preparation method of 7 beta-aminos according to claim 1-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants; It is characterized in that: the ammonia concn of step described in 2. is that the mass volume ratio of 5%, 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide and buffer salt solution is: 1:4-8; The mass ratio of immobilized penicillin acylated enzyme and 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide is 0.2-2:1.
6. the preparation method of 7 beta-aminos according to claim 1-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants is characterized in that: comprise following preparation process:
1. prepare 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide: 60L phenol is added in the reaction vessel; Stir and add 30kg 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide down; 45-50 ℃ of following insulation reaction added ETHYLE ACETATE 600L to reacting completely in 3 hours, stirred 1 hour; Cool to 0-5 ℃ then; Stirring and crystallizing 1 hour is filtered, and washs with ETHYLE ACETATE; 40 ℃ of following vacuum-dryings 8 hours, obtain 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide 23kg;
2. prepare 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants: with 23kg7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide and 138L pH is that 7.8 phosphoric acid buffer adds in the reactor drum, stirs to use 5% ammoniacal liquor to transfer pH down to be 8.0 ~ 8.5, to add the 15.3kg immobilized penicillin acylated enzyme; Be warming up to 25-30 ℃ and begin reaction, use 5% ammoniacal liquor transfer pH as 8.0-8.5 to reacting completely, filter; Wash lytic enzyme with phosphoric acid buffer; Filtrating is cooled to 0-5 ℃, uses hydrochloric acid to transfer pH to be 1.3-1.5 again, continues stirring and crystallizing 1 hour; Filter; Washing 40 ℃ of following vacuum-dryings 8 hours, obtains 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants 15.3kg.
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| CN104725425A (en) * | 2015-04-09 | 2015-06-24 | 山东罗欣药业集团股份有限公司 | Preparation method for ceftaroline fosamil |
| CN104892674A (en) * | 2015-06-18 | 2015-09-09 | 河北大学 | Preparation method of ceftaroline fosamil |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104718216A (en) * | 2012-10-19 | 2015-06-17 | 桑多斯股份公司 | Novel process for preparing ceftaroline fosamil |
| CN104718216B (en) * | 2012-10-19 | 2017-09-22 | 桑多斯股份公司 | Prepare the new method of Ceftaroline Fosamil |
| CN104725425A (en) * | 2015-04-09 | 2015-06-24 | 山东罗欣药业集团股份有限公司 | Preparation method for ceftaroline fosamil |
| CN104725425B (en) * | 2015-04-09 | 2017-01-04 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Ceftaroline Fosamil |
| CN104892674A (en) * | 2015-06-18 | 2015-09-09 | 河北大学 | Preparation method of ceftaroline fosamil |
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| CN102703559B (en) | 2013-09-11 |
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