CN102199164B - Method for preparing methoxy cephalosporin intermediate 7-MAC - Google Patents
Method for preparing methoxy cephalosporin intermediate 7-MAC Download PDFInfo
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- CN102199164B CN102199164B CN 201110082563 CN201110082563A CN102199164B CN 102199164 B CN102199164 B CN 102199164B CN 201110082563 CN201110082563 CN 201110082563 CN 201110082563 A CN201110082563 A CN 201110082563A CN 102199164 B CN102199164 B CN 102199164B
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Abstract
The invention relates to a method for preparing a methoxy cephalosporin intermediate 7-MAC, which comprises the following steps of: (1) dissolving 5-mercapto-1-methyltetrazole in acetonitrile, and adding ether solution of BF3 and cephalosporin C to obtain an intermediate IA; (2) dissolving the intermediate IA in dichloromethane, and adding diphenylidiazomethane to obtain an intermediate IB; (3) dissolving the intermediate IB in dichloromethane, and adding triphenylphosphine and a methoxy reagent to obtain an intermediate IC; and (4) breaking a 7-position amido bond of the intermediate IC under the action of acyltransferase of the cephalosporin. The method is simple and low in cost; the amido bond is cracked by an enzyme technology, the cracking yield is high, and the environment is protected; and the obtained product has high purity and excellent performance.
Description
Technical field
The invention belongs to methoxy cephalo intermediate field, particularly relate to the preparation method of a kind of methoxy cephalo intermediate 7-MAC.
Background technology
The methoxy cephalo is meant the cephalosporins that a trans methoxyl group is arranged on 7 bit aminos of cephalo parent nucleus, the existence of 7 methoxyl groups makes this type of cynnematin that the performance of stronger anti-β-Nei Xiananmei be arranged, and some bacteriums that produce β-Nei Xiananmei are had stronger antibacterial ability.This type of cynnematin mainly contains cefmetazole, cefotetan, cefbuperazone, cefminox etc.7-α-methoxyl group-7-amino-3-methyl four ammonia azoles thiomethyl Cephalosporanic acid benzhydryl esters (7-MAC) are the crucial parent nucleus of these cephalo products.The low pollution, the synthetic basis that provides of the innovation that low-cost synthetic 7-MAC can be this type of cephalo new drug, society and economic implications are great.7-MAC has following structure
The acquisition approach of 7-MAC mainly contains two kinds at present, a kind of is to be that raw material is synthetic from the methoxy cephamycin C, another kind is synthetic because methoxyl group cephamycin C source difficulty for raw material from 7 amino-3-acetoxyl group Cephalosporanic acid (7-ACA), and domestic 7-ACA is sufficient and cheap, therefore at present domestic mainly with this route acquisition 7-ACA, relevant patent has: Chinese patent publication number CN101117337A, CN101696213A etc.
Summary of the invention
Technical problem to be solved by this invention provides the preparation method of a kind of methoxy cephalo intermediate 7-MAC, and this method is simple, and cost is low, the efficient height; The purity height of products obtained therefrom, excellent performance.
The preparation method of the crucial parent nucleus 7-of a kind of methoxy cephalo of the present invention α-methoxyl group-7-amino-3-methyl four ammonia azoles thiomethyl Cephalosporanic acid benzhydryl esters (being called for short 7-MAC) comprising:
(1) intermediate compound I A (7-(D-5-amino-5-carboxyl valeryl amido)-3-(1-methyl isophthalic acid H-tetrazolium-5-thiomethyl)-3-cephalo west-4-carboxylic acid) is that the reaction of raw material and first sulphur tetrazole obtains with the cephalosporin
First mercapto tetrazole is dissolved in the acetonitrile, is cooled to 5 ℃-10 ℃, adds BF again
3Diethyl ether solution slowly is warming up to 28 ℃-30 ℃ after slowly repeatedly adding cephalosporin, adds catalyzer, insulated and stirred 2-3 hour, be chilled to 0 ℃-5 ℃, add entry and V-Brite B, regulate pH=3.5-4, stirred 3-4 hour about 5 ℃, filtration drying obtains intermediate compound I A;
(2) intermediate compound I B (7-(D-5-amino-5-carboxylic acid benzhydryl ester base valeryl amido)-3-(1-methyl isophthalic acid H-tetrazolium-5-thiomethyl)-3-cephalo west-4-carboxylic acid benzhydryl ester) obtains by intermediate compound I A and hexichol diazomethane reaction
Above-mentioned intermediate compound I A is dissolved in the methylene dichloride, and 20 ℃-25 ℃ add the hexichol diazomethane down, and room temperature reaction 3-4 hour, methylene dichloride was removed in decompression, and residue adds methyl alcohol, and filtration drying obtains intermediate compound I B;
(3) intermediate compound I C (7-(D-5-amino-5-carboxylic acid benzhydryl ester base valeryl amido)-7-methoxyl group-3-(1-methyl isophthalic acid H-tetrazolium-5-thiomethyl)-3-cephalo west-4-carboxylic acid benzhydryl ester) obtains by intermediate compound I B and methoxyl group reagent react
Above-mentioned intermediate compound I B is dissolved in the methylene dichloride cooling and adds triphenylphosphine for 0 ℃-2 ℃, keep 0 ℃-2 ℃ to stir 30-60 minute, add methoxyl group reagent, 4 ℃-5 ℃ were stirred 8.5-10 hour, added acetic acid in 20 minutes, added the aqueous solution of sodium chloride-containing, V-Brite B afterwards, system layering, the organic layer concentrating under reduced pressure, residue obtains intermediate compound I C with the mixing solutions recrystallization of methyl alcohol and hexanaphthene, oven dry;
(4) 7-MAC obtains by intermediate compound I C 7 amido linkage fractures under the effect of cynnematin acyltransferase
Above-mentioned intermediate compound I C adds phosphate buffered saline buffer, regulates pH=8.6-8.9, the system clarification; Add the cynnematin acyltransferase; 25 ℃-30 ℃ insulated and stirred 70-100 minute; elimination cynnematin acyltransferase; be cooled to 0 ℃-5 ℃, dichloromethane extraction, the layering organic phase is given up; add V-Brite B; regulate pH=5.5-6.0 and add crystal seed, continue to be adjusted to pH=3.5, the after-filtration drying obtained pure product in growing the grain 30-60 minute.
The mol ratio of first mercapto tetrazole and cephalosporin is 1: 1 in the described step (1).
Cephalosporin and BF in the described step (1)
3The molecular volume of diethyl ether solution is than being 1mol: 650ml.
The mol ratio of cephalosporin and V-Brite B is 3-4mol: 1mol in the described step (1).
Catalyzer is a methylsulfonic acid in the described step (1), with the mol ratio of cephalosporin be 1: 200.
Intermediate compound I A is 1mol: 2000ml with the molecular volume ratio of methyl alcohol in the described step (2).
The mol ratio of intermediate compound I B and triphenylphosphine is 1: 1.2 in the described step (3).
Intermediate compound I B is 1 with the molecular volume ratio of acetic acid in the described step (3): 200-300ml.
The mol ratio of intermediate compound I B and V-Brite B is 10: 1 in the described step (3).
Recrystallization solvent is the mixed solvent of methyl alcohol and hexanaphthene in the described step (3), and the volume ratio of methyl alcohol and hexanaphthene is 2: 1, and the mass volume ratio of middle intermediate compound I B and recrystallization solvent is 1-2g: 9ml.
The concentration of phosphate buffered saline buffer is 0.05mol/L in the described step (4).
The mass ratio of intermediate compound I C and cynnematin acyltransferase is 9-10 in the described step (4): 1.
The mol ratio of intermediate compound I C and V-Brite B is 7-8mol: 1-2mol in the described step (4).
The pH of reaction system is 8.8 in the described step (4).
Described step (1) uses strong aqua to regulate pH=3.5-4.0; PH=3.5 during described step (4) crystallization.
Beneficial effect
It is starting raw material that present method is selected the cephalosporin more more cheap than the 7-ACA of traditional method for use, has reduced cost, uses zymotechnic cracking amido linkage, cracking yield height, green non-pollution; The purity height of products obtained therefrom, excellent performance.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
(1) preparation of intermediate compound I A
12g first mercapto tetrazole is dissolved in the 400ml acetonitrile, is cooled to 5 ℃-10 ℃, adds BF3 diethyl ether solution 65ml again, slowly repeatedly adds cephalosporin 41.5g, adds catalyzer.Slowly be warming up to 28 ℃-30 ℃, insulated and stirred 2.2 hours is chilled to 0 ℃-5 ℃, adds entry 400ml, and V-Brite B 5g drips strong aqua and regulates pH=3.5, stirs 3 hours about 5 ℃.Filter, filter cake is washed with 100ml, and 100ml acetone is washed.40 ℃ of drying under reduced pressure obtain the 47g dry product.(purity 96.4%, method HPLC.)
(2) preparation of intermediate compound I B
The preparation of hexichol diazomethane
Weigh the 50g Benzophenonehydrazones, be dissolved in the mixing solutions of the N,N-DIMETHYLACETAMIDE of 30ml and 5ml water, 20 ℃ add iodine 10g potassiumiodide 16g, chloramine-T 12g, and insulated and stirred 1 hour adds methylene dichloride 50ml, water 10ml.2% aqueous sulfuric acid is regulated PH=2.0, and the layering organic phase is freezing stand-by.
Intermediate compound I A 47g is dissolved in the 100ml methylene dichloride, and 20 ℃ drip upward step organic phase down, room temperature reaction 3 hours, and the methylene dichloride that reduces pressure away, residue adds 400ml methyl alcohol, filters, and methyl alcohol is washed, the 61.0g of 40 ℃ of degree drying under reduced pressure (purity 95.6%, HPLC).
(3) preparation of intermediate compound I C
The preparation of methoxyl group reagent
Aluminum trichloride (anhydrous) 13g is dissolved in the 100ml methylene dichloride, cools to 10 ℃, and behind the dropping 200ml methyl alcohol, 33 ℃-34 ℃ were stirred 40 minutes, and were cooled to 15 ℃-20 ℃ in 20 minutes.Keep slowly adding sodium bicarbonate 25g below 25 ℃, stand-by.
Intermediate compound I B 61g is dissolved in the cooling of 500ml methylene dichloride and adds triphenylphosphine 26g for 0 ℃-2 ℃, keeps 0 ℃-2 ℃ to stir 30 minutes.4 ℃-5 ℃ were stirred 8.5 hours behind the methoxyl group reagent that the step prepares in the adding.Add 20ml acetic acid in 20 minutes.Add sodium chloride-containing 50g, the aqueous solution 500ml of V-Brite B 1.2g, system layering, organic layer concentrating under reduced pressure, residue volume ratio methyl alcohol: the mixing solutions 400ml recrystallization of hexanaphthene=2: 1, dry obtain product 54g (purity 96.2%, HPLC).
(4) preparation of 7-MAC
Intermediate compound I C 54g adds the phosphate buffer 1 000ml of 0.05mol/L, and the aqueous sodium hydroxide solution of 2mol/L is regulated pH=8.8, the system clarification.Add cynnematin acyltransferase 6g, 25 ℃ of insulated and stirred 70 minutes, elimination cynnematin acyltransferase; be cooled to 0 ℃-5 ℃; the 100ml dichloromethane extraction, the layering organic phase is given up, and adds V-Brite B 1.5g; hydrochloric acid is regulated pH=5.5 and is added crystal seed; continue to be adjusted to pH=3.5,30 minutes after-filtration of growing the grain, filter cake is washed with 100ml acetone; 35 ℃ of drying under reduced pressure obtain pure product 32g (purity 97.8%, HPLC).
Claims (6)
1. the preparation method of methoxy cephalo intermediate 7-α-methoxyl group-7-amino-3-methyl four ammonia azoles thiomethyl Cephalosporanic acid benzhydryl esters comprises:
(1) first mercapto tetrazole is dissolved in the acetonitrile, is cooled to 5 ℃-10 ℃, adds BF again
3Diethyl ether solution, slowly be warming up to 28 ℃-30 ℃ after slowly adding cephalosporin, add catalyzer, insulated and stirred 2-3 hour, be chilled to 0 ℃-5 ℃, add entry and V-Brite B, regulate pH=3.5-4,5 ℃-8 ℃ were stirred 3-4 hour, and filtration drying obtains intermediate compound I A7-(D-5-amino-5-carboxyl valeryl amido)-3-(1-methyl isophthalic acid H-tetrazolium-5-thiomethyl)-3-cephalo west-4-carboxylic acid; Wherein, cephalosporin, first mercapto tetrazole, BF
3Diethyl ether solution is 3mol:3mol:1950ml:1mol with the ratio of V-Brite B, and the mol ratio of catalyzer and cephalosporin is 1-2:200; (2) above-mentioned 7-(D-5-amino-5-carboxyl valeryl amido)-3-(1-methyl isophthalic acid H-tetrazolium-5-thiomethyl)-3-cephalo west-4-carboxylic acid is dissolved in the methylene dichloride, 20 ℃-25 ℃ add the hexichol diazomethane down, room temperature reaction 3-4 hour, methylene dichloride is removed in decompression, residue adds methyl alcohol, and filtration drying obtains intermediate compound I B7-(D-5-amino-5-carboxylic acid benzhydryl ester base valeryl amido)-3-(1-methyl isophthalic acid H-tetrazolium-5-thiomethyl)-3-cephalo west-4-carboxylic acid benzhydryl ester; Wherein, intermediate compound I A is 1mol-2mol:2000ml with the molecular volume ratio of methyl alcohol;
(3) above-mentioned 7-(D-5-amino-5-carboxylic acid benzhydryl ester base valeryl amido)-3-(1-methyl isophthalic acid H-tetrazolium-5-thiomethyl)-3-cephalo west-4-carboxylic acid benzhydryl ester is dissolved in 0 ℃-2 ℃ addings of methylene dichloride cooling triphenylphosphine, keep 0 ℃-2 ℃ to stir 30-60 minute, add methoxyl group reagent, 4 ℃-5 ℃ were stirred 8.5-10 hour, add acetic acid in 20 minutes, add sodium chloride-containing afterwards, the aqueous solution of V-Brite B, system layering, the organic layer concentrating under reduced pressure, residue obtains intermediate compound I C7-(D-5-amino-5-carboxylic acid benzhydryl ester base valeryl amido)-7-methoxyl group-3-(1-methyl isophthalic acid H-tetrazolium-5-thiomethyl)-3-cephalo west-4-carboxylic acid benzhydryl ester with the mixing solutions recrystallization of methyl alcohol and hexanaphthene, oven dry; Wherein, intermediate compound I B, triphenylphosphine, acetic acid are 1mol:1.2mol:200-300ml:0.1mol with the V-Brite B ratio;
(4) above-mentioned 7-(D-5-amino-5-carboxylic acid benzhydryl ester base valeryl amido)-7-methoxyl group-3-(1-methyl isophthalic acid H-tetrazolium-5-thiomethyl)-3-cephalo west-4-carboxylic acid benzhydryl ester adds phosphate buffered saline buffer, regulates pH=8.6-8.9, the system clarification; Add the cynnematin acyltransferase, 25 ℃-30 ℃ insulated and stirred 70-100 minute, elimination cynnematin acyltransferase, be cooled to 0 ℃-5 ℃, dichloromethane extraction, the layering organic phase is given up, add V-Brite B, regulate pH=5.5-6 and add crystal seed, continue to be adjusted to pH=3.5, the after-filtration drying obtained pure product 7-α-methoxyl group-7-amino-3-methyl four ammonia azoles thiomethyl Cephalosporanic acid benzhydryl esters in growing the grain 30-60 minute; Wherein, the mass ratio of intermediate compound I C and cynnematin acyltransferase is 9-10:1; The mol ratio of intermediate compound I C and V-Brite B is 7-8mol:1-2mol.
2. the preparation method of a kind of methoxy cephalo intermediate 7-α-methoxyl group according to claim 1-7-amino-3-methyl four ammonia azoles thiomethyl Cephalosporanic acid benzhydryl esters is characterized in that: catalyzer is a methylsulfonic acid in the described step (1).
3. the preparation method of a kind of methoxy cephalo intermediate 7-α-methoxyl group according to claim 1-7-amino-3-methyl four ammonia azoles thiomethyl Cephalosporanic acid benzhydryl esters, it is characterized in that: recrystallization solvent is the mixed solvent of methyl alcohol and hexanaphthene in the described step (3), the volume ratio of methyl alcohol and hexanaphthene is 2:1, and the mass volume ratio of intermediate compound I B and recrystallization solvent is 1-2g:9ml.
4. the preparation method of a kind of methoxy cephalo intermediate 7-α-methoxyl group according to claim 1-7-amino-3-methyl four ammonia azoles thiomethyl Cephalosporanic acid benzhydryl esters is characterized in that: the concentration of phosphate buffered saline buffer is 0.05mol/L in the described step (4).
5. the preparation method of a kind of methoxy cephalo intermediate 7-α-methoxyl group according to claim 1-7-amino-3-methyl four ammonia azoles thiomethyl Cephalosporanic acid benzhydryl esters is characterized in that: the pH of reaction system is 8.8 in the described step (4).
6. the preparation method of a kind of methoxy cephalo intermediate 7-α-methoxyl group according to claim 1-7-amino-3-methyl four ammonia azoles thiomethyl Cephalosporanic acid benzhydryl esters is characterized in that: described step (1) uses strong aqua to regulate pH=3.5-4; PH=3.5 during described step (4) crystallization.
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| WO2004069848A2 (en) * | 2003-01-28 | 2004-08-19 | Diversa Corporation | Amidases, nucleic acids encoding them and methods for making and using them |
| CN101117337A (en) * | 2006-08-03 | 2008-02-06 | 四平市精细化学品有限公司 | Method for preparing 7-alpha methoxy-7-amino-3-methyl amitrole sulfur methyl cepham alkanoates dimethyl |
| CN101696213A (en) * | 2009-10-28 | 2010-04-21 | 沧州那瑞化学科技有限公司 | Synthetic method of 7-MAC intermediate |
| CN101792455A (en) * | 2010-03-17 | 2010-08-04 | 河北九派制药有限公司 | Preparation method of high-purity 7-alpha-amino-7-methoxy-3-methyltetrazole thiomethyl cephalosporin benzyl ester |
| CN101792454A (en) * | 2010-03-17 | 2010-08-04 | 河北九派制药有限公司 | Preparation method of 7-alpha amino 7-methoxyl-3-methly tetrazole sulfur methyl cafe-benzyl alkanoic acid |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004069848A2 (en) * | 2003-01-28 | 2004-08-19 | Diversa Corporation | Amidases, nucleic acids encoding them and methods for making and using them |
| CN101117337A (en) * | 2006-08-03 | 2008-02-06 | 四平市精细化学品有限公司 | Method for preparing 7-alpha methoxy-7-amino-3-methyl amitrole sulfur methyl cepham alkanoates dimethyl |
| CN101696213A (en) * | 2009-10-28 | 2010-04-21 | 沧州那瑞化学科技有限公司 | Synthetic method of 7-MAC intermediate |
| CN101792455A (en) * | 2010-03-17 | 2010-08-04 | 河北九派制药有限公司 | Preparation method of high-purity 7-alpha-amino-7-methoxy-3-methyltetrazole thiomethyl cephalosporin benzyl ester |
| CN101792454A (en) * | 2010-03-17 | 2010-08-04 | 河北九派制药有限公司 | Preparation method of 7-alpha amino 7-methoxyl-3-methly tetrazole sulfur methyl cafe-benzyl alkanoic acid |
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