CN102703559B - 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 a kind of 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-preparation method of 3-cephem-4-carboxylate salt acidulants.
Background technology
7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylate salt acidulants is the key intermediate of cephalo Lorraine ester, cephalo Lorraine ester belong to the 5th generation the cephalosporins antimicrobial drug.This medicine is mainly used in treating 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 intermediate 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 is had relatively high expectations; make preparation cost higher, and its purity also difficulty reach higher standard, so more difficult suitability for industrialized production; cause the price height of cephalo Lorraine ester medicine, bring bigger economical load to the patient.
Summary of the invention
The objective of the invention is, a kind of 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl is provided]-preparation method of 3-cephem-4-carboxylate salt acidulants, make its reaction temperature and, production cost is low.
The present invention is achieved through the following technical solutions for achieving the above object: 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-preparation method of 3-cephem-4-carboxylate salt acidulants, comprise the steps:
1. prepare 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide: with phenol and 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide adds 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 that step is obtained in 1.]-3-cephem-4-carboxylic acid iodide add in the buffer salt solution; add the immobilized penicillin acylated enzyme hydrolysis; regulate pH to reacting completely by 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 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-mass volume ratio of 3-cephem-4-carboxylic acid benzhydryl ester iodide and phenol is: 1:0.5-5.
The crystallization solvent of described step described in 1. is any in ethyl 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 5%, 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-mass volume ratio of 3-cephem-4-carboxylic acid iodide and buffer salt solution is: 1:4-8; Immobilized penicillin acylated enzyme and 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-mass ratio of 3-cephem-4-carboxylic acid iodide is 0.2-2:1.
Described a kind of 7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-preparation method of 3-cephem-4-carboxylate salt acidulants, 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 30kg7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl down]-3-cephem-4-carboxylic acid benzhydryl ester iodide, 45-50 ℃ of following insulation reaction 3 hours is to reacting completely, add ethyl acetate 600L, stirred 1 hour, cool to 0-5 ℃ then, stirring and crystallizing 1 hour, filter, wash with ethyl 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 are that 7.8 phosphoric acid buffer adds in the reactor; stirring and transferring pH with 5% ammoniacal liquor down is 8.0-8.5; add the 15.3kg immobilized penicillin acylated enzyme; be warming up to 25-30 ℃ and begin reaction; transferring pH with 5% ammoniacal liquor is that 8.0-8.5 is to reacting completely; filter; wash lytic enzyme with phosphoric acid buffer; filtrate is cooled to 0-5 ℃; transferring pH with hydrochloric acid again is 1.3-1.5; continued stirring and crystallizing 1 hour; filter; washing; 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 15.3kg.
7 beta-aminos-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl with method preparation of the present invention]-3-cephem-4-carboxylate salt acidulants, the yield height, 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
A kind of 7 beta-aminos of the present invention-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-preparation method of 3-cephem-4-carboxylate salt acidulants, comprise the steps:
1. prepare 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid iodide: with phenol and 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide adds 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 that step is obtained in 1.]-3-cephem-4-carboxylic acid iodide add in the buffer salt solution; add the immobilized penicillin acylated enzyme hydrolysis; regulate pH to reacting completely by 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 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-mass volume ratio of 3-cephem-4-carboxylic acid benzhydryl ester iodide and phenol is: 1:0.5-5.
The crystallization solvent of step described in 1. is any in ethyl 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 5%, 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-mass volume ratio of 3-cephem-4-carboxylic acid iodide and buffer salt solution is: 1:4-8; Immobilized penicillin acylated enzyme and 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-mass ratio of 3-cephem-4-carboxylic acid iodide is 0.2-2:1.
7 beta-aminos of the present invention-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-preparation method of 3-cephem-4-carboxylate salt acidulants can have following several different methods:
Example 1:7 beta-amino-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-preparation method of 3-cephem-4-carboxylate salt acidulants, step is as follows:
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 down]-3-cephem-4-carboxylic acid benzhydryl ester iodide, 40-45 ℃ of following insulation reaction 3 hours to reacting completely, add the 6L ethyl acetate, 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: with 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl of 1.6Kg]-3-cephem-4-carboxylic acid iodide join in the 6.4L phosphoric acid buffer; phosphoric acid buffer pH value is 7.2; stir is 7-7.5 with 5% ammoniacal liquor adjust pH down; add the 320g immobilized penicillin acylated enzyme again; begin reaction after being warming up to 35-40 ℃; be 7-7.5 with 5% ammoniacal liquor adjust pH again; to reacting completely; filter; wash lytic enzyme with phosphoric acid buffer; filtrate is cooled to 15-20 ℃; be 0-0.5 with the hydrochloric acid adjust pH 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 1.15 Kg; total recovery: 82%, purity: 98%.
Example 2:7 beta-amino-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-preparation method of 3-cephem-4-carboxylate salt acidulants, step is as follows:
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 down]-3-cephem-4-carboxylic acid benzhydryl ester iodide, 55-60 ℃ of following insulation reaction 5 hours to reacting completely, add butylacetate 18L, stirred 1 hour, cool to 10-15 ℃ then, stirring and crystallizing 1 hour, filter, wash 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: with 1.7kg7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-to add 13.6L pH be in 8.5 the phosphoric acid buffer for 3-cephem-4-carboxylic acid iodide; stirring and transferring pH with 10% ammoniacal liquor down is 8.5-9.0; add the 3.4kg immobilized penicillin acylated enzyme; be warming up to 20 ~ 25 ℃ and begin reaction; transferring pH with 10% ammoniacal liquor is that 8.5-9.0 is to reacting completely; filter; wash lytic enzyme with phosphoric acid buffer; filtrate is cooled to 10-15 ℃; transferring pH with hydrochloric acid again is 2.5-3.0; continued stirring and crystallizing 1 hour; filter; washing; 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 1.17kg, total recovery: 83%, purity: 98%.
Example 3:7 beta-amino-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-preparation method of 3-cephem-4-carboxylate salt acidulants, step is as follows:
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 down]-3-cephem-4-carboxylic acid benzhydryl ester iodide, 50-55 ℃ of following insulation reaction 3 hours is to reacting completely, add propyl acetate 120L, stirred 1 hour, cool to 0 ~ 5 ℃ then, stirring and crystallizing 1 hour, 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 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 are that 7.8 phosphoric acid buffer adds in the reactor; stirring and transferring pH with 5% ammoniacal liquor down is 8.0 ~ 8.5; add the 3kg immobilized penicillin acylated enzyme; be warming up to 25 ~ 30 ℃ and begin reaction; transferring pH with 5% ammoniacal liquor is that 8.0-8.5 is to reacting completely; filter; wash lytic enzyme with phosphoric acid buffer; filtrate is cooled to 0-5 ℃; transferring pH with hydrochloric acid again is 1.3-1.5; continued stirring and crystallizing 1 hour; filter; washing; 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 3kg, total recovery: 85%, purity: 98%.
Example 4:7 beta-amino-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-preparation method of 3-cephem-4-carboxylate salt acidulants, step is as follows:
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 down]-3-cephem-4-carboxylic acid benzhydryl ester iodide, 45-50 ℃ of following insulation reaction 3 hours is to reacting completely, add ethyl acetate 600L, stirred 1 hour, cool to 0-5 ℃ then, stirring and crystallizing 1 hour, filter, wash with ethyl 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 are that 7.8 phosphoric acid buffer adds in the reactor; stirring and transferring pH with 5% ammoniacal liquor down is 8.0-8.5; add the 15.3kg immobilized penicillin acylated enzyme; be warming up to 25-30 ℃ and begin reaction, transferring pH with 5% ammoniacal liquor is that 8.0-8.5 is to reacting completely.Filter, wash lytic enzyme with phosphoric acid buffer, filtrate is cooled to 0-5 ℃, and transferring pH with hydrochloric acid again is 1.3-1.5, 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, total recovery: 87%, purity: 99%.
Claims (2)
1.7 beta-amino-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-preparation method of 3-cephem-4-carboxylate salt acidulants, it 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: with phenol and 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-3-cephem-4-carboxylic acid benzhydryl ester iodide adds 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 that step is obtained in 1.]-3-cephem-4-carboxylic acid iodide add in the buffer salt solution; add the immobilized penicillin acylated enzyme hydrolysis; regulate pH to reacting completely by 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 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-mass volume ratio of 3-cephem-4-carboxylic acid benzhydryl ester iodide and phenol is: 1:0.5-5;
The crystallization solvent of step described in 1. is any in ethyl 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 5%, 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-mass volume ratio of 3-cephem-4-carboxylic acid iodide and buffer salt solution is: 1:4-8; Immobilized penicillin acylated enzyme and 7 β-[(phenylacetyl) amino]-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-mass ratio of 3-cephem-4-carboxylic acid iodide is 0.2-2:1.
2. 7 beta-aminos according to claim 1-3-[4-(1-methyl-4-pyridine)-2-thiazole sulfenyl]-preparation method of 3-cephem-4-carboxylate salt acidulants, it 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 down]-3-cephem-4-carboxylic acid benzhydryl ester iodide, 45-50 ℃ of following insulation reaction 3 hours is to reacting completely, add ethyl acetate 600L, stirred 1 hour, cool to 0-5 ℃ then, stirring and crystallizing 1 hour, filter, wash with ethyl 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 are that 7.8 phosphoric acid buffer adds in the reactor; stirring and transferring pH with 5% ammoniacal liquor down is 8.0 ~ 8.5; add the 15.3kg immobilized penicillin acylated enzyme; be warming up to 25-30 ℃ and begin reaction; transferring pH with 5% ammoniacal liquor is that 8.0-8.5 is to reacting completely; filter; wash lytic enzyme with phosphoric acid buffer; filtrate is cooled to 0-5 ℃; transferring pH with hydrochloric acid again is 1.3-1.5; continued stirring and crystallizing 1 hour; filter; washing; 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 15.3kg.
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