CN101974020B - Method for synthesizing cefdinir - Google Patents
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Abstract
The invention relates to a method for synthesizing cefdinir. The process comprises the following steps of: after 7-amino-3-vinyl-3-cephem-4-carboxylic acid and 2-(2-aminothiazole-4-radical)-2-(Z)-(acetoxyimido) acetylbenzothiazolethioester undergo acylation reaction to generate acetyl cefdinir, converting the obtained acetyl cefdinir into acetyl cefdinir dicyclohexylamine salt by simple salifying reaction, and hydrolyzing the salt to obtain the cefdinir. Compared with the prior art, the method not only improves the purity of the finally obtained cefdinir product, but also improves the yield of the cefdinir product; the obtained product can be directly used as a raw medicament for clinic; and moreover, the method also has the advantages of simple operation, quick reaction, short production period, low production cost and the like.
Description
Technical field
The invention belongs to technical field of medicine synthesis, particularly the compound method of cefdinir.
Background technology
Cefdinir belongs to third generation cephalosporin class microbiotic; Chemistry [6R-[6 α by name; 7 β (z)]]-7-[[(2-amino-4-thiazolyl)-(oximido) ethanoyl] amino]-3-vinyl-8-oxygen-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, structure is suc as formula shown in (I).By the development of Japanese Fujisawa Pharmaceutical Co., Ltd, obtain drugs approved by FDA in December, 1997 at first in Japan's listing in 1991.The clinical treatment that mainly is applicable to acute episode of chronic bronchitis, bacterial pneumonia, upper respiratory tract infection, skin and soft tissue infection etc.
According to existing bibliographical information, the compound method of cefdinir can reduce three types basically, that is: the amino directly transformation method of chloride method, active ester method and 7-.Wherein:
The method of the synthetic cefdinir of chloride method has been described among Japanese Patent such as JP02-000790 and the JP04-173781; The deficiency that this method exists is: can not obtain the Z-isomer of e.e.＞99%, and also there is bigger security risk in acyl chlorides in industrial production with in using.
Adopting the synthetic a large amount of cefotaxime series cynnematins that comprise cefdinir of active ester method, is a kind of method that extensively adopts at present.Because active ester is active lower than acyl chlorides, and isomerized probability takes place when having reduced acylation reaction, the generation of impurity E-isomer has reduced.Using more active ester at present is the cynnematin side chain that mercaptobenzothiazole is modified.
In patent US6093814 and WO97/24358, described with 7-amino-3-vinyl-3-cephem-4-carboxylicesters and carboxylic acid derivative through acylation reaction; React with nitrosification agent again; After final and thiocarbamide carries out condensation reaction formation thiazole ring; Obtain cefdinir ester midbody, get cefdinir through deprotection again.This method requires low-temperature anhydrous operation, and reaction conditions is strict, and the intermediate product separation difficulty, and the entire reaction step is more, and yield is very low.
Introduced in the U.S. Pat 20060040915 and used the cefdinir active ester of oxime hydroxyl with trityl as protecting group, condensation reaction is carried out very smoothly, has obtained highly purified cefdinir midbody.But this midbody removes the process of trityl as protecting group with duration (acidolysis needs several hours), and product yield is lower, impurity is more.
In order to overcome the many defectives in the cefdinir synthesis technique, development in recent years the cefdinir active ester (CAEM) of a kind of oxime hydroxyl with the ethanoyl protection, its structure is suc as formula shown in (II).And ethanoyl protection base all is easy to hydrolysis under acidity or alkaline condition, and yield and quality product are improved.
Adopt the existing a large amount of bibliographical information of the synthetic cefdinir of CAEM (II); 7-AVCA and CAEM have been described in the mixed solvent of THF/water like US2004242557 and WO2006134607; After carrying out acylation reaction under the organic bases effect; The deacetylate that under alkaline condition, directly is hydrolyzed protection, crystallization obtains the cefdinir bullion.Yet also there is its deficiency in this method, and the cefdinir content in crude product and the purity that are mainly reflected in gained are all lower, also needs the further refining cefdinir bulk drug product of clinical application that just can obtain supplying.
Summary of the invention
Technical problem to be solved by this invention is the deficiency that overcomes prior art, and a kind of compound method of cefdinir of simple to operate, quick, the with low cost and good product quality of reaction is provided.
For solving above technical problem, the present invention takes following technical scheme:
A kind of compound method of cefdinir, it comprises the steps:
(1), make 7-amino-3-vinyl-3-cephem-4-carboxylic acid and 2-(thiazolamine-4-yl)-2-(Z)-(acetyl oxygen imido grpup) acetyl benzothiazole thioesters generation acylation reaction generate the acetyl cefdinir;
(2), make the reaction of gained acetyl cefdinir and dicyclohexyl amine generate acetyl cefdinir dicyclohexyl amine salt;
(3), make acetyl cefdinir dicyclohexyl amine salt hydrolytic reactions generate said cefdinir, the synthetic route of said compound method is following:
According to an aspect of the present invention; The said acylation reaction of step (1) in solvent and organic bases in the presence of carry out; Solvent is the mixed solvent of organic solvent or organic solvent and water; Wherein organic solvent can be for being selected from N, the combination of one or more in dinethylformamide, DMAC N,N, methyl alcohol, ethanol, Virahol, acetone, methylene dichloride, THF, the 2-methyltetrahydrofuran.After acylation reaction finished, adding sour neutralization reaction solution was 2.5～3.5 to pH, extraction afterwards, and collected organic layer obtains containing the solution of acetyl cefdinir, is used for next step reaction.Preferably, in the step (1) used organic bases for being selected from triethylamine, diethylamine, Tributylamine, tetramethyl guanidine, 1,8-diazacyclo [5,4,0] hendecene-7 (DBU), 1, the combination of one or more in 5-diazabicyclo [4.3.0] nonene-5 (DBN).According to another preferred aspect, gained contains the solution of acetyl cefdinir before being used for next step reaction, earlier through activated carbon decolorizing.
According to the present invention, the reaction of step (2) is conventional acid-base reaction, can under the processing condition of routine, carry out.A concrete embodiment is: dicyclohexyl amine is joined in the solution that contains the acetyl cefdinir that step (1) obtains; Under 0～50 ℃ of temperature; Stirring reaction 10-20 minute, be cooled to-5 ℃～5 ℃ then, stirred 0.5～2 hour; Filter, the gained solid is said acetyl cefdinir dicyclohexyl amine salt through washing with at the dry solid that obtains off-white color or white below 35 ℃.
According to the present invention, the said hydrolysis reaction of step (3) both can carry out under acidic conditions, also can under alkaline condition, carry out.
According to a concrete aspect of the present invention; The said hydrolysis reaction of step (3) carries out under acidic conditions; Practical implementation is following: step (2) gained acetyl cefdinir dicyclohexyl amine salt joined is selected from mixed solutions that one or more solvent and one or more acid that are selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetate, the trifluoroacetic acid of combination in methyl alcohol, ethanol, Virahol, acetone, acetonitrile and the water form, and complete in 0 ℃～40 ℃ following stirring reaction to hydrolysis of temperature.After hydrolysis reaction finished, the alkaline solution that adds 1wt%～10wt% was regulated pH to 5～6, adds activated carbon decolorizing, filters, and regulated filtrating pH to 2.5～3.5, and crystallization separates, and drying obtains said cefdinir.Wherein, used alkaline solution can be selected from a kind of in ammonia soln, sodium carbonate solution, sodium hydrogen carbonate solution, sodium hydroxide solution, solution of potassium carbonate, potassium bicarbonate solution, the potassium hydroxide solution.
According to another concrete aspect of the present invention; The said hydrolysis reaction of step (3) carries out under alkaline condition; Practical implementation is following: step (2) gained acetyl cefdinir dicyclohexyl amine salt is joined in the solution that one or more and the water that are selected from yellow soda ash, sodium hydrogencarbonate, sodium hydroxide, salt of wormwood, saleratus, Pottasium Hydroxide, the potassium acetate forms; Keep pH 7.5～9.0, complete in 15 ℃～40 ℃ following stirring reaction to hydrolysis of temperature.After hydrolysis reaction is complete, regulate pH to 5～6, add activated carbon decolorizing, filter, regulate pH to 2.5～3.5 of filtrating, crystallization separates, and drying obtains said cefdinir.
Because the employing of technique scheme, the present invention compared with prior art has the following advantages:
The present invention is after obtaining the acetyl cefdinir; Direct hydrolysis does not obtain cefdinir, but is translated into acetyl cefdinir dicyclohexyl amine salt through simple salt-forming reaction earlier, again this salt hydrolysis is obtained cefdinir; Compared with prior art; Not only improved the cefdinir product gas purity of final acquisition, and improved the yield of cefdinir product simultaneously, products obtained therefrom can directly supply clinical use as bulk drug; In addition, the present invention also has simple to operate, reacts quick, with short production cycle and advantage such as production cost is low.
Embodiment
The used main raw material material of the present invention 7-amino-3-vinyl-3-cephem-4-carboxylic acid and 2-(thiazolamine-4-yl)-2-(Z)-(acetyl oxygen imido grpup) acetyl benzothiazole thioesters all can be through being purchased acquisition; Or through known method preparation, they will use " 7-AVCA " and " CAEM " expression respectively hereinafter.
The acetyl cefdinir that the present invention relates to is the compound of formula (II) expression, and its chemical name is " 7-[[(2-amino-4-thiazolyl)-(acetyl oxygen oximido) ethanoyl] amino]-3-vinyl-3-cephem-4-carboxylic acid ".This compound is known.
The acetyl cefdinir dicyclohexyl amine salt that the present invention relates to, its structural formula is seen formula (III), is (class) white solid.
The IR Characterization data are (cm as follows
-1): 3437,3360,3122 (the NH stretching vibration is secondary amide, amino); 3100～3000 (=C-H); 2937,2858 (saturated CH); 1770 (C=O, beta-lactam, ethanoyl), 1662 (C=O, secondary amide; C=N, the ethanoyl oxime); 1624 (C=C replaces alkene); 1624,1385 (C=O, carboxylate salts); 1578 (NH flexural vibration, amine salt, secondary amine salt); 1578,1533,1347 (ring stretching vibration, thiazole rings); 1203,1030 (C-O, esters); 999,920 (CH flexural vibration, single alkene that replace).
Below in conjunction with concrete embodiment the present invention is done further detailed explanation, but the invention is not restricted to these embodiment.
Embodiment 1
According to the compound method of the cefdinir of present embodiment, concrete steps are following:
(1), acylation reaction: 7-AVCA 20g and CAEM 39g are joined among the THF 150ml, add entry 50ml again, stir, cool to 15～20 ℃, in 45 minutes, drip triethylamine 18g, regulate pH 8.0～8.5, insulated and stirred 3～4h.Sampling detects 7-AVCA residual＜3g/l (HPLC), acylation reaction end.In acylation reaction liquid, add methylene dichloride 200ml, stirred 15 minutes, add entry 100ml again, stirred 15 minutes.Leave standstill, layering, water layer extracts with methylene dichloride 100ml * 2, and collected organic layer is used the 100ml water extraction.Combining water layer adds ETHYLE ACETATE 200ml, drips the about 9ml of concentrated hydrochloric acid, regulates pH 2.8～3.2, stirs 15 minutes.Leave standstill, layering, water layer is with ETHYLE ACETATE 100ml * 2 extractions, collected organic layer.Organic layer is told organic layer with saturated sodium-chloride water solution 100ml washing.Organic layer adds gac 2g, is incubated 20～25 ℃, stirs 30 minutes, filters, an amount of ETHYLE ACETATE washing charcoal layer.Merging filtrate;
(2), salt-forming reaction: in the filtrating of step (1) gained, add dicyclohexyl amine 24ml, stirred 15 minutes, cool to 0 ℃, stirred 1 hour.Filter, ETHYLE ACETATE 100ml washing is no more than 35 ℃ of dryings, obtains 49g off-white color solid acetyl cefdinir dicyclohexyl amine salt.Calculated yield is 94%, purity: 99.3%, and wherein acetyl cefdinir weight content is 65.9%, the dicyclohexyl amine weight content is 32.4%.
(3), hydrolysis reaction: get step (2) gained acetyl cefdinir dicyclohexyl amine salt 20g, join in the 50ml methyl alcohol, stir and be cooled to 0～5 ℃, add the 5ml vitriol oil,＜10 ℃ of stirring reaction 1～2h; Hydrolysis is complete, is added dropwise to about 400ml 3% sodium hydrogen carbonate solution, regulates pH to 5.0, adds the 2.5g gac; Stir, filter, washing, filtrating is warming up to 35～40 ℃; Regulate pH to 3 with 2N sulfuric acid, filter, washing, drying; Obtain the 12g solid phase prod, survey purity 99.6%, wherein the cefdinir weight content 97.8%, yield 91%.
Products obtained therefrom has been carried out performance test, specific as follows:
Optical value :-62.6 °.
Ultimate analysis (C14H13N5O5S2): C, 42.1%; H, 3.4%; N, 17.5%.Theoretical value: C, 42.5%; H, 3.3%; N, 17.7%.
Infrared (cm
-1): 3300 (OH), 3090 (NH), 2980 (CH), 1775 (C=O, beta-lactams), 1690 (CONH), 1620 (CO, COOH), 1520 (NH), 1400 (CO, COOH), 1350 (NH
2).
The hydrogen spectrum (δ, DMSO-d6): 3.56,3.78 (2H, C-2), 5.21 (1H, d, C-6); 5.32 (1H, d ,-CH=CH2), 5.63 (1H, d ,-CH=CH2), 5.79-5.84 (1H; M, C-7), 6.68 (1H, s, Basedol-H), 6.89-6.98 (1H, m;-CH=CH2), 7.15 (2H ,-NH2), 9.79 (1H, d ,-NH-).
Embodiment 2
Present embodiment provides a kind of compound method of cefdinir; Detailed process is following: triethylamine 10g was joined in 20 minutes in the suspension of the 20g 7-AVCA that cools to 15 ℃ and 150ml DMF; Stirred 5 minutes; Add 39g CAEM, be incubated 15～20 ℃, stir fully up to the 7-AVCA conversion.After reacting completely, add entry 100ml and ETHYLE ACETATE 250ml, regulate pH 2.8～3.2 with concentrated hydrochloric acid.Layering, organic layer washs with 20% sodium chloride solution 100ml, and layering added dicyclohexyl amine 24ml in organic layer in 30 minutes, can be observed crystallization and occurred.Stirred 15 minutes, and cooled to 0 ℃, stirred 1 hour.Solids filtered, ETHYLE ACETATE 100ml washing, drying obtains 47.5g acetyl cefdinir dicyclohexyl amine salt.Yield 93%.Purity: 99.6%, acetyl cefdinir content: 66.5%, dicyclohexyl amine content: 32.6%.Gained acetyl cefdinir dicyclohexyl amine salt is through obtaining cefdinir with embodiment 1 identical hydrolysis reaction.
Embodiment 3
Present embodiment provides a kind of preparation process of acetyl cefdinir dicyclohexyl amine salt, and is specific as follows: 7-AVCA 20g and CAEM 37g are joined among the methylene dichloride 200ml, stir; Cool to 0～10 ℃; In 45 minutes, drip tetramethyl guanidine 14g, insulated and stirred 2～3h.Sampling detects 7-AVCA residual＜3g/l (HPLC), acylation reaction end.In acylation reaction liquid, add ETHYLE ACETATE 200ml, water 100ml drips the about 10ml of concentrated hydrochloric acid, regulates pH 2.8～3.2, stirs 15 minutes.Leave standstill layering, collected organic layer.Organic layer is told organic layer with saturated sodium-chloride water solution 100ml washing.Organic layer adds gac 2g, is incubated 20～25 ℃, stirs 30 minutes, filters, an amount of ETHYLE ACETATE washing charcoal layer.Merging filtrate added dicyclohexyl amine 24ml in 30 minutes, stirred 15 minutes, cooled to 0 ℃, stirred 1 hour.Solids filtered, ETHYLE ACETATE 100ml washing is no more than 35 ℃ of dryings, obtains 49g off-white color acetyl cefdinir dicyclohexyl amine salt.Yield 94%.Purity: 99.1%, acetyl cefdinir content: 65.7%, dicyclohexyl amine content: 33.1%.
Embodiment 4
A kind of compound method of cefdinir, detailed process is following: get embodiment 1 gained acetyl cefdinir dicyclohexyl amine salt 20g, add the 100ml deionized water, drip the K of 20wt%
2CO
3Solution, control pH8.0～8.2 and at 15～20 ℃ of following hydrolysis 30min.It is complete that sampling detects hydrolysis.Drip the 10wt% sulphuric acid soln, regulate pH about 5～6, add the 2g gac, in 20～25 ℃ of stirring 30min, filter breeze, collect filtrating, filtrating is warming up to 30～40 ℃, and the dilute sulphuric acid of dropping 10wt% is regulated pH to 2.5～2.8, stirs 30min.Be cooled to 0 ℃, stir 1h, filter, washing, 40～45 ℃ of vacuum-dryings, cefdinir 10.6g, yield 80.5%, cefdinir weight content 97.2%, purity 99.2%, optical value-62.6 °.
More than the present invention has been done detailed description; Its purpose is to let the personage that is familiar with this art can understand content of the present invention and implements; Can not limit protection scope of the present invention with this; All equivalences of doing according to spirit of the present invention change or modify, and all should be encompassed in protection scope of the present invention.
Claims (10)
1. the compound method of a cefdinir, it is characterized in that: said compound method comprises the steps:
(1), make 7-amino-3-vinyl-3-cephem-4-carboxylic acid with (Z)-2-(thiazolamine-4-yl)-2-acetyl oxyimino group thioacetic acid (S-2-benzothiazole) ester generation acylation reaction generation acetyl cefdinir;
(2), make the reaction of step (1) gained acetyl cefdinir and dicyclohexyl amine generate acetyl cefdinir dicyclohexyl amine salt;
(3), make acetyl cefdinir dicyclohexyl amine salt hydrolytic reactions generate said cefdinir,
The synthetic route of said compound method is following:
2. the compound method of cefdinir according to claim 1 is characterized in that: the said acylation reaction of step (1) in solvent and organic bases in the presence of carry out, said solvent is the mixed solvent of organic solvent or organic solvent and water; Wherein organic solvent is for being selected from N, the combination of one or more in dinethylformamide, DMAC N,N, methyl alcohol, ethanol, Virahol, acetone, methylene dichloride, THF, the 2-methyltetrahydrofuran; After acylation reaction finishes; Adding sour neutralization reaction solution is 2.5～3.5 to pH, extraction afterwards, collected organic layer; Obtain containing the solution of acetyl cefdinir, be used for next step reaction.
3. the compound method of cefdinir according to claim 2; It is characterized in that: organic bases used in the step (1) is for being selected from triethylamine, diethylamine, Tributylamine, tetramethyl guanidine, 1; 8-diazacyclo [5; 4,0] hendecene-7,1, the combination of one or more in 5-diazabicyclo [4.3.0] nonene-5.
4. the compound method of cefdinir according to claim 2 is characterized in that: the solution that gained contains the acetyl cefdinir in the step (1) is before being used for next step reaction, through activated carbon decolorizing.
5. the compound method of cefdinir according to claim 2; It is characterized in that: the detailed process of step (2) is: dicyclohexyl amine is joined in the said solution that contains the acetyl cefdinir, and under 0～50 ℃ of temperature, stirring reaction 10-20 minute; Be cooled to-5 ℃～5 ℃ then; Stirred 0.5～2 hour, and filtered, the gained solid is said acetyl cefdinir dicyclohexyl amine salt through washing with at the dry solid that obtains off-white color or white below 35 ℃.
6. according to the compound method of the described cefdinir of each claim in the claim 1 to 5; It is characterized in that: the said hydrolysis reaction of step (3) carries out under acidic conditions; Detailed process is: step (2) gained acetyl cefdinir dicyclohexyl amine salt joined is selected from mixed solutions that one or more solvent and one or more acid that are selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetate, the trifluoroacetic acid of combination in methyl alcohol, ethanol, Virahol, acetone, acetonitrile and the water form, and complete in 0 ℃～40 ℃ following stirring reaction to hydrolysis of temperature.
7. the compound method of cefdinir according to claim 6 is characterized in that: after step (3) hydrolysis reaction finishes, add alkaline solution adjusting pH to 5～6 of 1wt%～10wt%; Add activated carbon decolorizing; Filter, regulate filtrating pH to 2.5～3.5, crystallization; Separate, drying obtains said cefdinir.
8. the compound method of cefdinir according to claim 7 is characterized in that: described alkaline solution is to be selected from a kind of in ammonia soln, sodium carbonate solution, sodium hydrogen carbonate solution, sodium hydroxide solution, solution of potassium carbonate, potassium bicarbonate solution, the potassium hydroxide solution.
9. according to the compound method of the described cefdinir of each claim in the claim 1 to 5; It is characterized in that: the said hydrolysis reaction of step (3) carries out under alkaline condition; Detailed process is: step (2) gained acetyl cefdinir dicyclohexyl amine salt is joined in the solution that one or more and the water that are selected from yellow soda ash, sodium hydrogencarbonate, sodium hydroxide, salt of wormwood, saleratus, Pottasium Hydroxide, the potassium acetate forms; Keep pH7.5～9.0, complete in 15 ℃～40 ℃ following stirring reaction to hydrolysis of temperature.
10. the compound method of cefdinir according to claim 9 is characterized in that: after step (3) hydrolysis reaction is complete, regulate pH to 5～6; Add activated carbon decolorizing, filter, regulate filtrating pH to 2.5～3.5; Crystallization separates, and drying obtains said cefdinir.
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| CN103183687A (en) * | 2011-12-30 | 2013-07-03 | 山东天绿制药有限公司 | Phase transfer catalysis method for preparing cefdinir |
| CN102659817B (en) * | 2012-05-08 | 2014-07-02 | 浙江普洛得邦制药有限公司 | Preparation method of cefdinir |
| CN106279207A (en) * | 2016-08-15 | 2017-01-04 | 苏州中联化学制药有限公司 | A kind of synthetic method of cefdinir |
| CN106749333B (en) * | 2016-12-29 | 2019-05-14 | 江苏豪森药业集团有限公司 | The preparation method of Cefdinir |
| CN108546270B (en) * | 2017-05-31 | 2019-11-08 | 郑州大学第一附属医院 | The method for preparing Cefdinir |
| CN110669061A (en) * | 2019-10-30 | 2020-01-10 | 广州牌牌生物科技有限公司 | Preparation method of cefdinir dimer impurity |
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