CN104045655A - Synthesis method of antibiotic cephalosporin mother nucleus - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
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Abstract
The invention belongs to the technical field of synthesis of cephalosporin intermediates and in particular relates to a synthesis method of antibiotic cephalosporin mother nucleus. The synthesis method of the antibiotic cephalosporin mother nucleus comprises the following steps: (1) preparing a reaction liquid I; (2) preparing a reaction liquid II; (3) preparing a compound GVNA; and (4) preparing AVNA. The synthesis method of the antibiotic cephalosporin mother nucleus has the advantages that production cost is low, reaction time is short, recovery rate of the organic solvent is high, secondary utilization is facilitated, and product yield is high.
Description
Technical field
The invention belongs to cephalosporin intermediate synthesis technical field, relate in particular to a kind of synthetic method of antibiotic cephalosporin nucleus.
Background technology
Cefdinir and Cefixime Micronized are third generation cephalosporin, the clinical treatment that is mainly applicable to acute episode of chronic bronchitis, bacterial pneumonia, upper respiratory tract infection, skin and soft tissue infection etc. of Cefdinir.Cefixime Micronized is also had an anti-microbial activity to streptococcus pneumoniae, para-influenza Bacillus, proteus vulgaris, Klebsiella Pneumoniae, Pasteurella multocida, Providian bacterium, Salmonella, Shigella, serratia marcesens, special-shaped citric acid bacteria, malonate citric acid bacteria in vitro, and it has the features such as wide spectrum, efficient, resistance to enzyme, low toxicity.
Cefdinir and Cefixime Micronized are all widely used anti-infective oral pharmaceutical clinically, and its synthetic crucial parent nucleus be (6R, 7R)-7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, abbreviation AVNA.Its structural formula is:
AVNA is the important starting raw material of synthetic third generation cephalosporin Cefdinir and Cefixime Micronized, but because the preparation technology of antibiotic cephalosporin nucleus AVNA is still perfect not, make the popularization of third generation cephalosporin be subject to very big restriction, therefore, the synthesis technique of exploitation AVNA, and realize its suitability for industrialized production tool and be of great significance.Based on this, to its synthetic conducting extensive research, specific as follows both at home and abroad:
CN102212072 discloses that " adopting sodium iodide, GCLE (7 one phenylacetylaminos-3-chloromethyl, 4 one Cephalosporanic acids are to methoxy benzyl ester) is raw material; obtain GNVE (7-phenylacetyl amido-3-vinyl base-4-Cephalosporanic acid is to methoxy-benzyl ester), GVNE sloughs parent nucleus 4-position carboxy protective agent group in the system of phenol, acetic acid and obtains GVNA (7-phenylacetyl amido-3-vinyl base-4-Cephalosporanic acid).”
Dandala; Ramesh etc. are open in Indian 2009MU01710; take GVNE as raw material; by the phenol solution cracking of phenol or acetone, slough the GVNA of parent nucleus 4-position carboxy protective agent group; adopt fixedly acylase at sodium bicarbonate/aqueous solution; PH is controlled at 7.8-8.2 and sloughs toluylic acid, with obtaining AVNA after hydrochloric acid acid adjustment PH=3.8-4.
Oh, Chang Hyeon and Cho, Jeong Hyeok is open in Korean 2011070523; with GVNA 35-40 ℃ of one night of reaction in cresol liquor, be extracted with ethyl acetate, with sodium bicarbonate; fixedly acylase is at 25-30 ℃, and PH7.5-8.0 reacts 3 hours, and acid adjustment obtains AVNA.
Bai; Guo-yi etc. are at the journal > > of < < University Of Hebei natural science edition 30 (4); 375-380; 2010; disclose with GCLE, triphenylphosphine, sodium iodide; sheet alkali, formaldehyde are raw material; at methylene dichloride, acetone solvent, obtain GVNE; GVNE sloughs parent nucleus 4-position carboxy protective agent group in phenol; by reclaiming phenol at sodium bicarbonate, ethyl acetate extraction, obtain GNVA, GVNA obtains AVNA by fixedly acylase reaction, ammoniacal liquor reaction.
Teng, Jiangbo etc. are at the journal > > of < < University Of Ji'nan natural science edition 24 (2), 156-158, 2010, disclose with GCLE, sodium iodide and Sodium Bromide, triphenylphosphine, salt of wormwood, formaldehyde is raw material, at acetone, dichloromethane solvent reaction obtains GVNE, GVNE is 45-50 ℃ in phenol, PH6.7-7.1 sloughs parent nucleus 4-position carboxy protective agent group, by at sodium bicarbonate, ethyl acetate extraction reclaims phenol and obtains GNVA, GVNA passes through fixedly acylase, control PH7.5-7.9, 30 ℃ are reacted 2 hours, sulfuric acid acid adjustment PH=6 reaction obtains AVNA.
Bai; jin-long etc. are at < < synthetic chemistry > >; 18 (1); 134-136; 2010; disclose with GCLE, sodium iodide; triphenylphosphine, sheet alkali, formaldehyde are raw material, in dichloromethane solvent reaction, obtain GVNE; GVNE is 45-50 ℃ in phenol and phosphoric acid; react and within 1 hour, slough parent nucleus 4-position carboxy protective agent group and obtain GVNA, GVNA is by sodium bicarbonate, fixing acylase, control PH7.5-8.0; 30 ℃ of-32 ℃ of reactions, sulfuric acid acid adjustment PH=4 reaction obtains AVNA.
Chao, Mingyong and Hao, Aiyou is at < < Organic Process Research & Development > >, 13 (5), 924-927, 2009, disclose with GCLE, sodium iodide, triphenylphosphine, at dichloromethane solvent, hydrochloric acid is controlled PH=3, 36 ℃ are carried out quaternary alkylphosphonium salt reaction, adding sheet alkali, formaldehyde, DMF is that raw material reaction obtains GVNE, GVNE is 45-50 ℃ in phenol, react and within 12-18 hour, slough parent nucleus 4-position carboxy protective agent group, with sodium bicarbonate, after N-BUTYL ACETATE extracting phenols, obtain GVNA, GVNA passes through at sodium bicarbonate, fixing acylase, control PH8.0, 29 ℃ of-33 ℃ of reactions, sulfuric acid acid adjustment is to PH=4, filter and obtain AVNA with methanol wash filter cake.
Wang; Qiufen etc. are open in CN101182326; with GCLE, sodium iodide; triethyl-phosphite, at THF solvent, formaldehyde temperature control carries out at 10 ℃, by little Su, to washing, obtains GVNE; GVNE is methylene dichloride, pyridine-25 ℃-30 ℃; react and after 2 hours, count cresols and continue reaction and within 4 hours, slough parent nucleus protective material group, with alkali lye, be transferred to PH=3, obtain AVNA.
Du, Bingsong etc. are at < < China medicine magazine > >, 16 (2), 85-87, 2006, disclose with GCLE, sodium iodide, triphenylphosphine, 15 ℃-20 ℃ of THF solvents, carry out adding sodium bicarbonate after wittig reaction, formaldehyde temperature control is at 15-20 ℃, PH9.7-8.9 reaction obtains GVNE, GVNE in trifluoroacetic acid 5 ℃, react and within 4 hours, slough parent nucleus 4-position carboxy protective agent group and obtain GVNA, GVNA passes through at ammoniacal liquor, fixing acylase, boric acid is controlled PH7.8-8.2, 30 ℃ of-32 ℃ of reactions, sulfuric acid acid adjustment obtains AVNA.
Dutterly; Tyagi Om etc. are open in Indian 2004MU00961; take GCLE, Sodium Bromide, DMF, methylene dichloride, Hydrogen bromide, triphenylphosphine, formaldehyde sheet alkali obtains GVNE as raw material, GVNE by phenol and fixedly acylase cracking slough protective material and obtain AVNA.
Prasad; Ashok and Prasad; Mohan is open in PCT2007013043; take GCLE, sodium iodide, triphenylphosphine, acetone carries out after wittig reaction, adds methylene dichloride, formaldehyde, sheet alkali to obtain GVNE as raw material, and GVNE, by phenol, cracking, adds N-BUTYL ACETATE and sodium bicarbonate; obtain GVNA; GVNA is by fixedly acylase and sodium carbonate are at 20-25 ℃, and protective material is sloughed in PH7.5-7.9 cracking, with filtering to obtain AVNA after hydrochloric acid adjusting PH=2.4-2.5.
Kameyamaukae; Yutaka and Fuke Kazuhiro etc. are open in Korean2002316991; with GVNA, pass through fixedly acylase, in 5% sodium carbonate and 5% sodium bicarbonate aqueous solution, protective material is sloughed in cracking, with filtering to obtain AVNA after hydrochloric acid adjusting PH-2.7.
Xu, shu-wen etc. are open in < < Chinese Journal of Pharmaceuticals > >, with GVNA, in water, by fixing acylase, slough toluylic acid protecting group, obtain AVNA.
Kameyama, Yutaka etc. are open in PCT 2000001703, and GVNE, in methylene dichloride, adds phosphorus pentachloride under low temperature, pyridine, adds meta-cresol and obtains AVNA.
DeVroom, Erik and van der Mey, Margaretha is open in EP638649, with GVNA, in water, by fixing acylase, sloughs toluylic acid protecting group, obtains AVNA.
Hu, Shuchen etc. are at the journal > > of < < China Medicine University, 24 (4), 246-7, 1993, disclose that to take 7-phenylacetyl amido-3-hydroxymethyl-4-Cephalosporanic acid benzhydryl ester be raw material, by 3 side chains of PBr3 bromination parent nucleus, add again triphenylphosphine wittig reacting generating compound (1), add again formaldehyde, sheet alkali obtains compound 2, compound 2 is used phosphorus trichloride after taking off diphenyl-methyl by trifluoroacetic acid again, methyl alcohol is sloughed toluylic acid protecting group in methylene dichloride, obtain AVNA.
Synthetic many employing GCLE of existing AVNA are raw material, under sodium iodide exists, react with triphenylphosphine and generate season phosphonium salt, through Wittig reaction, at 3, introduce vinyl, generate 7-phenylacetyl-3-ethene-4-methyl Cephalosporanic acid to methoxy benzyl ester (DPVC); Then under phenol effect, slough C-4 position methoxy-benzyl; Under the enzymolysis of PGA-450 acylase, slough C-7 position phenylacetyl ester again; Finally make AVNA.Or adopting GVNE is raw material, first synthetic GVNA, and then through enzymolysis, slough C-7 position phenylacetyl ester and make AVNA.Also having directly employing GVNA is that raw material passes through fixedly acylase, and in 5% sodium carbonate and 5% sodium bicarbonate aqueous solution, protective material is sloughed in cracking, with filtering to obtain AVNA after hydrochloric acid adjusting PH=2.7.
The synthesis technique of existing AVNA exists material cost high, the shortcoming that yield is low, and along with the continuous variation in market, existing process costs can not meet the demand in market.
Summary of the invention
Technical problem to be solved by this invention is: the deficiency existing for prior art, a kind of material cost that reduces is provided, and improve the synthetic method of the antibiotic cephalosporin nucleus of product yield.
For solving the problems of the technologies described above, technical scheme of the present invention is:
A synthetic method for antibiotic cephalosporin nucleus, described synthetic method comprises the following steps:
(1) 7-phenylacetyl amido-3-chloromethyl-4-Cephalosporanic acid benzhydryl ester (GCLH), Sodium Bromide, triphenylphosphine are dissolved in organic solvent, in described organic solvent, add mineral acid to carry out catalysis again, be warming up to 35～40 ℃, insulation reaction 2～3 hours, obtain reaction solution I, in reaction solution I, contain compound 1; Its reaction equation is:
(2) described reaction solution I is cooled to sub-zero zero, adding formaldehyde solution, then to the mixed aqueous solution that adds salt of wormwood and sodium hydroxide in described reaction solution I, is to react 2～3 hours under the condition of 5～10 ℃ in temperature, obtain reaction solution II, in reaction solution II, contain compound 2; Its reaction equation is:
(3) by described reaction solution II, in temperature, be underpressure distillation under the condition of 45～50 ℃, reclaim described organic solvent, separate out solid, filter, obtain filter cake, described filter cake is dropped in methyl alcohol to reflux 1～1.5 hour, be cooled to sub-zero zero, filter, obtain whitening compound 3, whitening compound 3 is GVNA; Its reaction equation is:
(4) by described whitening compound 3 and phenol, organic acid is to react 4～6 hours under the condition of 35～50 ℃ in temperature, obtain reaction solution IV, described reaction solution IV is added to sodium bicarbonate, in the mixing solutions of purified water and N-BUTYL ACETATE, control 20～25 ℃ of temperature, stir 1～2 hour, stratification, collect water layer, described water layer adds N-BUTYL ACETATE extracting phenols twice, again collect water layer, in described water layer, add fixedly acylase PGA-450 again, add again aqueous sodium carbonate, filtered and recycled enzyme, collect filtrate, filtrate regulates PH≤3.4 with hydrochloric acid soln, obtain solidliquid mixture, filter, by described filtration cakes torrefaction, obtain products A VNA, its reaction equation is:
Preferably, organic solvent described in step (1) is a kind of in acetonitrile or acetone.
As a kind of improvement, the weight ratio of mineral acid described in step (1) and described 7-phenylacetyl amido-3-chloromethyl-4-Cephalosporanic acid benzhydryl ester is 1:45～50.
Preferably, mineral acid described in step (1) is a kind of in hydrochloric acid or Hydrogen bromide.
As a kind of improvement, described in step (2), the mass concentration of formaldehyde solution is 35～40%.
As improving further, described in step (2), in the mixed aqueous solution of salt of wormwood and sodium hydroxide, the quality mol ratio of salt of wormwood and sodium hydroxide is 3:8.
Preferably, organic acid described in step (4) is a kind of in formic acid or trichoroacetic acid(TCA).
Preferably, described in step (4), the concentration of aqueous sodium carbonate is 10～15%, and the mass concentration of described hydrochloric acid soln is 10～15%.
As a kind of improvement, step adds after aqueous sodium carbonate in (4), controls PH=8.0～8.2 of solution.
As improving further, in step (4), filter cake is with being dried after acetone drip washing again.
Owing to having adopted technique scheme, the invention has the beneficial effects as follows:
The invention provides a kind of synthetic method of antibiotic cephalosporin nucleus, it is raw material that this synthetic method mainly adopts cheap GCLH, and its cost is starkly lower than the price of GCLE, GVNE and GVNA, greatly reduces raw materials cost; In this synthetic method, adopt acetonitrile or acetone and other organic solvent, first, can greatly improve the solubleness of Sodium Bromide, thereby the concentration of Sodium Bromide in can augmenting response liquid, make reaction be easier to carry out to forward, thereby further improve speed of response and synthesis yield, secondly, acetonitrile or acetone and other organic solvent are easy to reclaim, thereby can reduce production costs and labour intensity; The pH that controls reaction solution in step (4) is at 8.0～8.2 yields that are more conducive to improve product, and lower than 8.0 or higher than 8.2 o'clock, enzymic activity was lower, complete reaction required time is longer, thereby can cause resultant velocity and yield to decline; The advantage of this synthetic method is that production cost is low, and the reaction times is short, and the organic solvent rate of recovery used is high, be beneficial to second stage employ, and product yield is high.
Embodiment
In order to make object of the present invention, technical scheme and advantage clearer, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein, only in order to explain the present invention, is not intended to limit the present invention.
Embodiment mono-
(1) preparation of reaction solution I: the there-necked flask (band thermometer, mechanical stirring) at 500ml takes 53.4gGCLH, add 200ml acetonitrile, add 28.8g triphenylphosphine, 11.3g Sodium Bromide again, then add 30% hydrochloric acid 1.1g, be warming up to 35 ℃, insulation reaction 2 hours, HPLC controls GCLH < 1% in reaction solution, obtain reaction solution I, in reaction solution I, contain compound 1;
(2) preparation of reaction solution II: reaction solution I is cooled to zero degree, add 40% formaldehyde, the mixing solutions that adds again (0.03mol) salt of wormwood/sodium hydroxide (0.08mol), temperature control was 5 ℃ of reactions 3 hours, HPLC controls compound 1 < 0.5%, obtain reaction solution II, in reaction solution II, contain compound 2;
(3) preparation of compound GVNA: by the underpressure distillation of reaction solution II, control temperature 45 C, reclaim after acetonitrile, separate out white solid, filter, gained filter cake drops in 300ml methyl alcohol and refluxes 1.5 hours, cools to zero degree.Filter, obtain 484.6g whitening compound GVNA (yield of GVNA is 95%, calculates with GCLH);
(4) preparation of AVNA: there-necked flask (the band thermometer that GVNA25.5g (0.05mol) is dropped into 1000mL, mechanical stirring), add phenol 300g, add formic acid 2g, 40 ℃ of insulation reaction 4 hours, react completely, slowly pour reaction solution into previously prepd sodium bicarbonate (sodium bicarbonate), (sodium bicarbonate 5g wherein in purified water and N-BUTYL ACETATE mixing solutions, purified water 200ml, N-BUTYL ACETATE 200ml), control temperature at 25 ℃, stir 1 hour, standing, layering, collect water layer, water layer extracts phenol secondary again with N-BUTYL ACETATE 50ml, again collect water layer, water layer drops in 500ml reaction flask, in reaction flask, add fixedly acylase PGA-450 of 4g, drip 15% aqueous sodium carbonate, control PH=8.0-8.2, HPLC detects GVNA < 0.5%, filtered and recycled enzyme, collect filtrate, with 15% hydrochloric acid, regulate PH=3.4, filter, 50ml acetone drip washing for filter cake, dry 10.5gAVNA (the yield 92.9% of AVNA that obtains, with GVNA, calculate).
Embodiment bis-
(1) preparation of reaction solution I: the there-necked flask (band thermometer, mechanical stirring) at 500ml takes 50.2gGCLH, add 200ml acetone, add 28.5g triphenylphosphine, 10.9g Sodium Bromide again, then add 40% Hydrogen bromide 1.1g, be warming up to 38 ℃, insulation reaction 2.5 hours, HPLC controls GCLH < 1% in reaction solution, obtain reaction solution I, in reaction solution I, contain compound 1;
(2) reaction solution I is cooled to zero degree, add 40% formaldehyde, the mixing solutions that adds again (0.03mol) salt of wormwood/sodium hydroxide (0.08mol), temperature control was 8 ℃ of reactions 2.5 hours, HPLC controls compound 1 < 0.5%, obtain reaction solution II, in reaction solution II, contain compound 2;
(3) preparation of compound GVNA: by the underpressure distillation of reaction solution II, control 47 ℃ of temperature, reclaim after acetone, separate out white solid, filter, gained filter cake drops in 400ml methyl alcohol and refluxes 1 hour, cools to zero degree.Filter, obtain 456.6g whitening compound GVNA (yield of GVNA is 95.5%, calculates with GCLH);
(4) preparation of AVNA: there-necked flask (the band thermometer that GVNA25.5g (0.05mol) is dropped into 1000mL, mechanical stirring), add phenol 300g, add trichoroacetic acid(TCA) 3.3g, 38 ℃ of insulation reaction 5 hours, react completely, slowly pour reaction solution into previously prepd sodium bicarbonate (sodium bicarbonate), (sodium bicarbonate 5g wherein in purified water and N-BUTYL ACETATE mixing solutions, purified water 200ml, N-BUTYL ACETATE 200ml), control temperature at 23 ℃, stir 1.5 hours, standing, layering, collect water layer, water layer extracts phenol secondary again with N-BUTYL ACETATE 50ml, again collect water layer, water layer drops in 500ml reaction flask, in reaction flask, add fixedly acylase PGA-450 of 4g, drip 10% aqueous sodium carbonate, control PH=8.0-8.2, HPLC detects GVNA < 0.5%, filtered and recycled enzyme, collect filtrate, with 10% hydrochloric acid, regulate PH=3.4, filter, 50ml acetone drip washing for filter cake, dry 10.6gAVNA (the yield 93.5% of AVNA that obtains, with GVNA, calculate).
Embodiment tri-
(1) preparation of reaction solution I: the there-necked flask (band thermometer, mechanical stirring) at 500ml takes 51.2gGCLH, add 200ml acetone, add 28.3g triphenylphosphine, 11.1g Sodium Bromide again, then add 35% nitric acid 1.1g, be warming up to 40 ℃, insulation reaction 3 hours, HPLC controls GCLH < 1% in reaction solution, obtain reaction solution I, in reaction solution I, contain compound 1;
(2) preparation of reaction solution II: reaction solution I is cooled to zero degree, add 40% formaldehyde, the mixing solutions that adds again (0.03mol) salt of wormwood/sodium hydroxide (0.08mol), temperature control was 10 ℃ of reactions 2 hours, HPLC controls compound 1 < 0.5%, obtain reaction solution II, in reaction solution II, contain compound 2;
(3) preparation of compound GVNA: by the underpressure distillation of reaction solution II, control temperature 50 C, reclaim after acetone, separate out white solid, filter, gained filter cake drops in 400ml methyl alcohol and refluxes 1 hour, cools to zero degree.Filter, obtain 469.7g whitening compound GVNA (yield of GVNA is 96%, calculates with GCLH);
(4) preparation of AVNA: there-necked flask (the band thermometer that GVNA25.5g (0.05mol) is dropped into 1000mL, mechanical stirring), add phenol 300g, add acetic acid 2.8g, 35 ℃ of insulation reaction 6 hours, react completely, slowly pour reaction solution into previously prepd sodium bicarbonate (sodium bicarbonate), (sodium bicarbonate 5g wherein in purified water and N-BUTYL ACETATE mixing solutions, purified water 200ml, N-BUTYL ACETATE 200ml), control temperature at 20 ℃, stir 2 hours, standing, layering, collect water layer, water layer extracts phenol secondary again with N-BUTYL ACETATE 50ml, again collect water layer, water layer drops in 500ml reaction flask, in reaction flask, add fixedly acylase PGA-450 of 4g, drip 15% aqueous sodium carbonate, control PH=8.0-8.2, HPLC detects GVNA < 0.5%, filtered and recycled enzyme, collect filtrate, with 10% hydrochloric acid, regulate PH=3.4, filter, 50ml acetone drip washing for filter cake, dry 10.7gAVNA (the yield 93.8% of AVNA that obtains, with GVNA, calculate).
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any modifications of doing within the spirit and principles in the present invention, be equal to and replace and improvement etc., within all should being included in protection scope of the present invention.
Claims (10)
1. a synthetic method for antibiotic cephalosporin nucleus, is characterized in that, described synthetic method comprises the following steps:
(1) 7-phenylacetyl amido-3-chloromethyl-4-Cephalosporanic acid benzhydryl ester, Sodium Bromide, triphenylphosphine are dissolved in organic solvent, in described organic solvent, add mineral acid to carry out catalysis again, be warming up to 35～40 ℃, insulation reaction 2～3 hours, obtains reaction solution I;
(2) described reaction solution I being cooled to sub-zero zero, adding formaldehyde solution, then to the mixed aqueous solution that adds salt of wormwood and sodium hydroxide in described reaction solution I, is to react 2～3 hours under the condition of 5～10 ℃ in temperature, obtains reaction solution II;
(3) by described reaction solution II, in temperature, be underpressure distillation under the condition of 45～50 ℃, reclaim described organic solvent, separate out solid, filter, obtain filter cake, described filter cake is dropped in methyl alcohol to reflux 1～1.5 hour, be cooled to sub-zero zero, filter, obtain whitening compound;
(4) by described whitening compound and phenol, organic acid is to react 4～6 hours under the condition of 35～50 ℃ in temperature, obtain reaction solution IV, described reaction solution IV is added to sodium bicarbonate, in the mixing solutions of purified water and N-BUTYL ACETATE, control 20～25 ℃ of temperature, stir 1～2 hour, stratification, collect water layer, described water layer adds N-BUTYL ACETATE extracting phenols twice, again collect water layer, in the water layer of collecting for the second time, add fixedly acylase PGA-450, add again aqueous sodium carbonate, filtered and recycled enzyme, collect filtrate, filtrate regulates PH≤3.4 with hydrochloric acid soln, obtain solidliquid mixture, filter, by described filtration cakes torrefaction, obtain product.
2. the synthetic method of antibiotic cephalosporin nucleus as claimed in claim 1, is characterized in that: organic solvent described in step (1) is a kind of in acetonitrile or acetone.
3. the synthetic method of antibiotic cephalosporin nucleus as claimed in claim 1, is characterized in that: the weight ratio of mineral acid described in step (1) and described 7-phenylacetyl amido-3-chloromethyl-4-Cephalosporanic acid benzhydryl ester is 1:45～50.
4. the synthetic method of the antibiotic cephalosporin nucleus as described in claim 1 or 3, is characterized in that: mineral acid described in step (1) is a kind of in hydrochloric acid or Hydrogen bromide.
5. the synthetic method of antibiotic cephalosporin nucleus as claimed in claim 1, is characterized in that: described in step (2), the mass concentration of formaldehyde solution is 35～40%.
6. the synthetic method of the antibiotic cephalosporin nucleus as described in claim 1 or 5, is characterized in that: described in step (2), in the mixed aqueous solution of salt of wormwood and sodium hydroxide, the quality mol ratio of salt of wormwood and sodium hydroxide is 3:8.
7. the synthetic method of antibiotic cephalosporin nucleus as claimed in claim 1, is characterized in that: organic acid described in step (4) is a kind of in formic acid or trichoroacetic acid(TCA).
8. the synthetic method of antibiotic cephalosporin nucleus as claimed in claim 1, is characterized in that: described in step (4), the concentration of aqueous sodium carbonate is 10～15%, and the mass concentration of described hydrochloric acid soln is 10～15%.
9. the synthetic method of antibiotic cephalosporin nucleus as claimed in claim 1, is characterized in that: step adds after aqueous sodium carbonate in (4), controls PH=8.0～8.2 of solution.
10. the synthetic method of antibiotic cephalosporin nucleus as claimed in claim 1, is characterized in that: in step (4), filter cake is with being dried after acetone drip washing again.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107586305A (en) * | 2017-06-23 | 2018-01-16 | 浙江惠迪森药业有限公司 | A kind of beta-lactam class compound carboxyl and hydroxyl protecting group removal methods |
| CN109293677A (en) * | 2018-09-12 | 2019-02-01 | 山东普洛得邦医药有限公司 | A kind of continuous production method and device of 7-AVCA |
| CN110878101A (en) * | 2019-12-11 | 2020-03-13 | 华中药业股份有限公司 | Novel method for preparing cefixime mother nucleus 7-AMOCA |
| CN111592557A (en) * | 2020-05-09 | 2020-08-28 | 河北合佳医药科技集团股份有限公司 | One-step environment-friendly preparation method of 7-amino-3-vinyl cephalosporanic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107586305A (en) * | 2017-06-23 | 2018-01-16 | 浙江惠迪森药业有限公司 | A kind of beta-lactam class compound carboxyl and hydroxyl protecting group removal methods |
| CN109293677A (en) * | 2018-09-12 | 2019-02-01 | 山东普洛得邦医药有限公司 | A kind of continuous production method and device of 7-AVCA |
| CN109293677B (en) * | 2018-09-12 | 2021-09-17 | 普洛药业股份有限公司 | Continuous production method and device of 7-amino-3-vinyl cephalosporanic acid |
| CN110878101A (en) * | 2019-12-11 | 2020-03-13 | 华中药业股份有限公司 | Novel method for preparing cefixime mother nucleus 7-AMOCA |
| CN111592557A (en) * | 2020-05-09 | 2020-08-28 | 河北合佳医药科技集团股份有限公司 | One-step environment-friendly preparation method of 7-amino-3-vinyl cephalosporanic acid |
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| CN104045655B (en) | 2016-08-17 |
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