CN102010427B - Method for preparing cefdinir - Google Patents
Method for preparing cefdinir Download PDFInfo
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- CN102010427B CN102010427B CN201010549871A CN201010549871A CN102010427B CN 102010427 B CN102010427 B CN 102010427B CN 201010549871 A CN201010549871 A CN 201010549871A CN 201010549871 A CN201010549871 A CN 201010549871A CN 102010427 B CN102010427 B CN 102010427B
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Abstract
The invention relates to a method for preparing cefdinir, which comprises the following steps of: performing silanization protection of carboxyl on 7-amino-3-vinyl-3-cephem-4-carboxylic acid (7-AVCA), performing acylation reaction on the 7-AVCA and cefdinir active ester (CAEM) to obtain acetyl cefdinir with carboxyl subjected to silanization protection, performing hydrolysis or alcoholysis or simple salifying reaction on the acetyl cefdinir to obtain acetyl cefdinir dicyclohexylamine salt, and hydrolyzing the salt to obtain the cefdinir. Compared with the prior art, the method improves the purity of the finally obtained cefdinir product and improves the yield of the cefdinir product at the same time, and the obtained product can be directly used as a raw material medicament for clinical use; 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 preparation 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 preparation 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 preparation 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:
(1), be raw material with 7-AVCA, at first make itself and silylating reagent in solvent and under 0 ℃～50 ℃ of the temperature, carry out Silanization reaction, obtain the solution of the silica-based ester of 7-AVCA front three;
(2), in the solution of the silica-based ester of step (1) gained 7-AVCA front three, add 2-(thiazolamine-4-yl)-2-(Z)-(acetyl oxygen imido grpup) acetyl benzothiazole thioesters, under 0～50 ℃, carry out acylation reaction, generate the silica-based ester of acetyl cefdinir front three;
(3), make the silica-based ester of acetyl cefdinir front three slough the silica-based protection of front three through hydrolysis or alcoholysis, obtain the acetyl cefdinir, and make the reaction of acetyl cefdinir and dicyclohexyl amine generate acetyl cefdinir dicyclohexyl amine salt;
(4), make acetyl cefdinir dicyclohexyl amine salt hydrolytic reactions deacetylate, generate said cefdinir,
Said preparing method's synthetic route is following:
According to the present invention; Solvent described in the step (1) can be for being selected from THF, N; The mixed solvent of one or more in dinethylformamide (DMF), DMAC N,N (DMAC), methylene dichloride, ethylene dichloride, acetone, acetonitrile, ETHYLE ACETATE, butylacetate and the isopropyl acetate.
According to the present invention; A detailed process of step (3) is: in the reaction solution that contains the silica-based ester of acetyl cefdinir front three of step (2) gained, add the mixed solution of being made up of water or methyl alcohol and organic solvent, dicyclohexyl amine; React, 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 the cefdinir dicyclohexyl amine salt of said ethanoyl protection through washing with at the dry solid that obtains white below 35 ℃.Wherein used organic solvent can be THF, N, the mixed solvent of one or more of dinethylformamide, DMAC, methylene dichloride, ethylene dichloride, acetone, acetonitrile, ETHYLE ACETATE, butylacetate and isopropyl acetate.Preferably use identical solvent with step (1).
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; The said hydrolysis reaction of step (4) carries out under acidic conditions; Detailed process is: step (3) 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 step (4) 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 alkaline solution can be for being 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; The said hydrolysis reaction of step (4) carries out under alkaline condition; Detailed process is: step (3) 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 step (4) 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:
1, the present invention at first utilizes silanizing agent that the carboxyl on the 7-AVCA is protected, and then carries out acylation reaction, has improved the selectivity of acetyl cefdinir;
2, 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-AVCA (chemical name: 7-amino-3-vinyl-3-cephem-4-carboxylic acid) and 2-(thiazolamine-4-yl)-2-(Z)-(acetyl oxygen imido grpup) acetyl benzothiazole thioesters (CAEM) all can be through being purchased acquisition, or through known method preparation.
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
Present embodiment provides a kind of preparation method of cefdinir, and practical implementation is following:
(1), Silanization reaction: 7-AVCA 15g is joined in the 150ml methylene dichloride, drip 16mlBSA, 30～35 ℃ of insulation reaction.Question response liquid dissolves clear, is cooled to 15～20 ℃;
(2), acylation reaction: after step (1) Silanization reaction is accomplished, drop into CAEM 26g, at 20～25 ℃ of stirring reaction 4～5h, to 7-AVCA detection residual concentration＜3mg/ml;
(3), salt-forming reaction: after step (2) acylation reaction is accomplished, add the mixing solutions of being made up of acetone 200ml, methyl alcohol 10ml and dicyclohexyl amine 14.5ml, 20～25 ℃ are stirred 30min; Be cooled to 0 ℃; Stir 1h, filter washing with acetone; 35 ℃ of dryings obtain acetyl cefdinir dicyclohexyl amine salt 37g.Yield 94%.Purity: 99.1%, acetyl cefdinir content: 66.3%, dicyclohexyl amine content: 32.9%;
(4), hydrolysis reaction: get step (3) 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), 135 (NH2).
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 preparation process of acetyl cefdinir dicyclohexyl amine salt, and is specific as follows: 7-AVCA 15g is joined in the 150ml ETHYLE ACETATE, drip 16ml BSA, 30～35 ℃ of insulation reaction.Question response liquid dissolves clear, is cooled to 15～20 ℃, drops into CAEM 26g, and stirring reaction 4～5h is to 7-AVCA detection residual concentration＜3mg/ml.The mixing solutions that adding is made up of ETHYLE ACETATE 100ml, methyl alcohol 10ml and dicyclohexyl amine 14.5ml, 20～25 ℃ are stirred 30min, are cooled to 0 ℃, stir 1h, filter, the ETHYLE ACETATE washing, 35 ℃ of dryings obtain acetyl cefdinir dicyclohexyl amine salt 36.7g.Yield 94%.Purity: 99.3%, cefdinir content: 66.4%, dicyclohexyl amine content: 32.5%.
Embodiment 3
A kind of compound method of cefdinir, detailed process is following: get embodiment 2 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 get cefdinir 10.6g, yield 80.5%, cefdinir weight content 97.2%, purity 99.2%.
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 (9)
1. the preparation method of a cefdinir is characterized in that: comprise the steps:
(1), be raw material with 7-AVCA, at first make itself and silylating reagent in solvent and under 0 ℃～50 ℃ of the temperature, carry out Silanization reaction, obtain the solution of the silica-based ester of 7-AVCA front three;
(2), in the solution of the silica-based ester of step (1) gained 7-AVCA front three, add (Z)-2-(thiazolamine-4-yl)-2-acetyl oxyimino group thioacetic acid (S-2-benzothiazole) ester; Under 0～50 ℃, carry out acylation reaction, generate the silica-based ester of acetyl cefdinir front three;
(3), make the silica-based ester of acetyl cefdinir front three slough the silica-based protection of front three through alcoholysis, obtain the acetyl cefdinir, and make the reaction of acetyl cefdinir and dicyclohexyl amine generate acetyl cefdinir dicyclohexyl amine salt;
(4), make acetyl cefdinir dicyclohexyl amine salt hydrolytic reactions deacetylate, generate said cefdinir,
Said preparing method's synthetic route is following:
2. the preparation method of cefdinir according to claim 1; It is characterized in that: solvent is for being selected from THF, N described in the step (1); The mixed solvent of one or more in dinethylformamide, DMAC N,N, methylene dichloride, ethylene dichloride, acetone, acetonitrile, ETHYLE ACETATE, butylacetate and the isopropyl acetate.
3. the preparation method of cefdinir according to claim 1; It is characterized in that: silanizing agent is for being selected from trimethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, hexamethyldisilazane, hexamethyl two silicon urea and N, the combination of one or more in the two silica-based ethanamides of front three of O-in the step (1).
4. the preparation method of cefdinir according to claim 1; It is characterized in that: the detailed process of step (3) is: in the reaction solution that contains the silica-based ester of acetyl cefdinir front three of step (2) gained, add the mixed solution of being made up of methyl alcohol and organic solvent, dicyclohexyl amine; React; Wherein organic solvent is for being selected from THF, N; One or more of dinethylformamide, DMAC N,N, methylene dichloride, ethylene dichloride, acetone, acetonitrile, ETHYLE ACETATE, butylacetate and isopropyl acetate.
5. according to the preparation method of the described cefdinir of each claim in the claim 1 to 4; It is characterized in that: the said hydrolysis reaction of step (4) carries out under acidic conditions; Detailed process is: step (3) 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.
6. the preparation method of cefdinir according to claim 5 is characterized in that: after step (4) 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.
7. the preparation method of cefdinir according to claim 6 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.
8. according to the preparation method of the described cefdinir of each claim in the claim 1 to 4; It is characterized in that: the said hydrolysis reaction of step (4) carries out under alkaline condition; Detailed process is: step (3) 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.
9. the preparation method of cefdinir according to claim 8 is characterized in that: after step (4) 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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| CN103012433B (en) * | 2012-12-13 | 2015-06-24 | 珠海保税区丽珠合成制药有限公司 | Preparation method of cefdinir crystal form B |
| CN103497204B (en) * | 2013-10-10 | 2016-03-23 | 珠海金鸿药业股份有限公司 | A kind of Cefdinir compound, its dispersible tablet and preparation method |
| CN108546270B (en) * | 2017-05-31 | 2019-11-08 | 郑州大学第一附属医院 | The method for preparing Cefdinir |
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| CN1251590A (en) * | 1997-04-04 | 2000-04-26 | 生物化学有限公司 | Crystalline amine salt of cefdinir |
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