CN102702229A - Preparation of ceftizoxime sodium key intermediate and preparation of high-content ceftizoxime sodium - Google Patents
Preparation of ceftizoxime sodium key intermediate and preparation of high-content ceftizoxime sodium Download PDFInfo
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- CN102702229A CN102702229A CN2011102302021A CN201110230202A CN102702229A CN 102702229 A CN102702229 A CN 102702229A CN 2011102302021 A CN2011102302021 A CN 2011102302021A CN 201110230202 A CN201110230202 A CN 201110230202A CN 102702229 A CN102702229 A CN 102702229A
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Abstract
Cephalosporin C is used as a raw material; an acetoxyl at a 3rd position is hydrolyzed, and is oxidized into aldehyde by organic iodine; decarbonylation reduction is performed in the presence of hydrogen with triphenylphosphine as a cocatalyst and cobalt carbonyl as a catalyst; 7-amino-3-norcephalosporanic acid is prepared by enzyme hydrolysis and acid hydrolysis, and reacts with active ester under the catalysis of organic amine to obtain ceftizoxime acid; and an exchange reaction is performed with a salt forming agent to obtain high-content ceftizoxime sodium.
Description
The technical background ceftizoxime; Ceftizoxime pivoxil and Ceftibuten are important third generation cephalosporin analog antibiotics, and required key intermediate 7 beta-aminos of SKF-88373 (ester) and Ceftibuten-3-does not have-3-cephalo-4-carboxylic acid (7-ANCA), its current technology; Be to be raw material with PNG-k; Synthetic route is long, and some midbodys are unstable in the preparation process, not easy separation and easy purification.Cost is high, makes SKF-88373 be difficult for popularizing.
DeacetylcephalosporinC (DCPC) is the by product that produces in fermentative production of cephalosporin C (CPC) process, accounts for 15～20% of cephalosporin.In the downstream purification operation of cephalosporin, be disposed in the environment with discarded liquid, not only cause environmental pollution, and wasted resource.The structure and the 7-ANCA of deacetylcephalosporinC are similar, contain beta-lactam nucleus.Its methylol in the C-3 position makes it to be advantageously used in the synthetic transformation of some semi-synthetic cynnematin.So, deacetylcephalosporinC by Separation and Recovery in the discarded liquid, is made it to become the key intermediate of some cephalosporin medicament through structure of modification, so not only help environment protection, and reduced the production cost of cynnematin subsequent product.Not having the cephalosporin sodium salt with 3-is substrate, utilizes immobilization D-amino-acid oxidase (DAAO) can it transformed to generate and goes the amino 3-of acetyl glutaryl--7-not have-(G1-7ANCA).Then directly utilize immobilization glutaryl--7-ANCA acylase (GA) that its cracking is generated 7-amino-3-and do not have cephalo olefin(e) acid (7-ANCA).Can be used as the key intermediate of producing SKF-88373 (ester) Ceftibuten.
Original 7-amino-3-do not have-and the preparation of Cephalosporanic acid (7-ANCA) is to be the mode of raw material through ring expansion with penicillin G-Ka, wherein oxidation, esterification, ring expansion, the bromo closed loop, ozone oxidation, specific as follows:
The wild justice preparation of crude salt 7-ANCE route:
Improve through the closed loop route in big afterwards tomb; And recent process modification; Then its main body thinking does not become; Because this route process step is longer, be that the three-step reaction unification is carried out in the closed loop step simultaneously, because reaction is complicated and do not have the intermediate treatment process certainly will the quality of its subsequent product be had a negative impact.
Original route is a raw material with the PNG-K of cheapness, but route is long, reacts loaded down with trivial details, and the midbody quality is wayward, and the production difficulty is high, and final product quality is difficult for guaranteeing.Because synthesis step is long, raw materials cost is high simultaneously.
Summary of the invention operational path of the present invention:
It is raw material that the present invention utilizes the by product deacetylation cephalosporin (DCPC) of producing cynnematin formation, and through making the methylol oxidizing reaction with the organic iodine oxidation behind the carboxy protective of 4-position, reaction is easy to control with this understanding; Post-processing step is simple, and environmental pollution is little, the allyl aldehyde of generation; The latter is under the catalysis of organic rhodium salt; With the triphenylphosphine is part, decarbonylation base under dioxygen oxidation, and in ionic liquid 1-butyl-3-Methylimidazole hexafluorophosphate (bmimPF6), generating 3-does not have the cephalo alkanoic acid ester; It is synthetic to accomplish the 7-ANCA parent nucleus, makes 7-ANCA. through two conventional step enzyme method hydrolysis then
The method of its 3-methylol functional group of selective oxidation; Discovery has the operational condition gentleness through 2-iodoxy phenylformic acid (IBX) oxidation in acetonitrile; Reaction is easy to control, and post-processing step is simple, pollutes few characteristics; We found metachloroperbenzoic acid afterwards, and Peracetic Acid is equally participated in oxidizing reaction.Substrate conversion efficiency reaches 96% under this condition, and the yield of oxidation products 3-formyl radical-7 β-phenylacetamide-3-cephalo-4-carboxylic acid benzhydryl ester is up to more than 90%.
The inventive method need not change the agent structure of title product; Only carry out the transformation of side chain,, simply remove through soda acid phase inversion and dissolution with solvents method easily because product and raw material physico-chemical property differ greatly; Because route is less; Transformation efficiency is high, and quality improves a lot, and reduces greatly than original technology on the cost.Through the 7-ANCA condensation being produced the contrast of ceftizoxime acid and SKF-88373, can find out both difference.
The SKF-88373 salt-forming reaction:
The contrast of ceftizoxime acid mass yield
With the ceftizoxime acid of former 7-ANCA preparation, solution look＜No. 4, the outward appearance band is yellow, and is whiter with the ceftizoxime acid color of the present invention's preparation, solution look＜No. 2
SKF-88373 quality mass yield and accelerated stability contrast
Specify at present; In cynnematin fermented extracted CPC zinc salt, the 3-deacetyl cephalosporin C (DCPC) that about 15-20% is arranged generates D-7ACA with discharging of waste liquid even there is part producer to recycle; But derived product has only cephalofruxin to utilize, so its added value is low.Utilize the special construction of 3-methylol among the DCPC and the hydroxyl activity of vinyl carbinol, under the condition of neutral oxygenant, can smoothly vinyl carbinol be oxidized to allyl aldehyde, in the preparation process; In order to reduce the destruction of oxygenant to main ring; The protection of 4-carboxyl is absolutely necessary, and commonly used benzhydrol and phenylazide methane p-methoxybenzyl alcohol and PNB, BOC etc. all are esterifying agents preferably; Consider carrying out smoothly of back step esterlysis; Be easier to hydrolysis with the benzhydrol ratio, esterification temperature is at 0--60 ℃, and optimum temps is advisable with 15-35 ℃.
The oxidation of 3-methylol vinyl carbinol is carried out than being easier to, and oxygenant is relatively more neutral, like tin anhydride, and activated manganese dioxide; Periodic acid, ortho-vanadic acid is considered environmental influence, carries out homogeneous reaction with organic oxidizing agent, the no initiation time; Reaction temperature with, be easy to control, product is single, aftertreatment is simplified, organic oxidizing agent commonly used is a Peracetic Acid; The peroxide m-chlorobenzoic acid, 2-iodoxy phenylformic acid (IBX) etc., oxidation smoothly, but the security of the big production of consideration yield, metachloroperbenzoic acid; For improving oxidizing temperature, with the THF solvent, temperature of reaction 15-80 ℃, optimum temperuture is 60-65 ℃
For increasing the solvability of raw material, suitably add small amount of methanol, its ratio with THF is 1-5: 9-5, and the best is that reaction oxidation in 1: 9 is the most thorough, and transformation efficiency is that 99.1% unreacted substrate be＜0.5%, and is behind the reaction solution extraction washing and drying, directly concentrated.The decarbonylation of 3-formyl radical is because allyl aldehyde is gripped structure altogether, and carbonyl is easy to take place decarbonylation reaction, and catalyzer is joined with rhodium salt under the effect of cobalt-carbonyl and part organophosphorus, is promotor with the molecular oxygen; React rapider, be quick initiation reaction, add ionic solvent such as tosic acid; The NN-dimethyl aminopyridine, 1-butyl-3-Methylimidazole hexafluorophosphate is good with 1-butyl-3-Methylimidazole hexafluorophosphate; Its reaction temperature with, gas blow-through is slow, easily control.It is necessary when reaction is initial, adding molecular oxygen, with the activation solvent systems, in case there is gas to produce (solution temperature rises and promptly stops ventilation); And maintaining the temperature at 70-75 ℃, after half a hour, temperature is brought up to 75-78 ℃ and is continued to react 15 minutes until there not being gas to produce; Reaction terminating; The decolouring of solvent extraction washing after drying, condensing crystal obtains the white crystalline particulate solid.
4 carboxyester hydrolysis of 7-ANCA parent nucleus are trans by the hydrolysis of routine, and the benzhydrol ester can carry out under trifluoroacetic acid is returned, and accomplish reaction in one hour, and hydrolyzed solution directly carries out enzymolysis by normal 7-ACA after handling.For the solvent triethylamine is that catalyzer compares the acid of checking (little with the THF otherness) ceftizoxime, SKF-88373 changes sodium by conventional yellow soda ash to be handled gained 7-ANCA with the methylene dichloride.Acceleration is investigated with 60 ℃ of 60% humidity.The mass yield stability of carrying out SKF-88373 compares.
Embodiment: content of the present invention is further explained and explained to following method through testing.But the embodiment that is provided should not be understood that protection domain of the present invention is constituted restriction.
Embodiment 1
Two benzene alcohol esters: in the 500ml three-necked flask, add 43gDCPC (content is 96.6%), add among 350ml methyl alcohol-methylene dichloride 50ml, stirring and dissolving adds benzhydrol 20g; Be warmed up to 35-40 ℃, reacted 6 hours, add ETHYLE ACETATE 400ml, respectively with 200ml purified water washing three times; Remove water layer, methacrylate layer adds the 5g gac, and 10g anhydrous magnesium sulfate drying decolouring 30 minutes is filtered; Be evaporated to residual heavy 130-135g below 30 ℃, crystallisation by cooling, filtration washing is dry; Get white powder solid: 54g, yield 93.26%, content 98.53%
Embodiment 2: the allyl aldehyde preparation: two benzene alcohol ester 40g join in the 500ml three-necked bottle, add THF-methyl alcohol (9: 1) 250ml stirring and dissolving, add metachloroperbenzoic acid (40g is dissolved in the 50ml methyl alcohol), are warming up to 60 ℃ of reactions 4 hours; Be cooled to room temperature, add ethyl ester 400ml, with 400ml purified water washing three times, organic layer adds the 5g gac respectively; 10g anhydrous magnesium sulfate drying decolouring 30 minutes is filtered, and is concentrated into residual heavy 155-160g, adds isopropyl ether 30ml; Stir, crystallization is separated out in cooling, filters; An amount of ethyl ester-isopropyl ether (1: 1) washing, 45 ℃ of drying under reduced pressure get white powder 36.8g, yield 92%.Content 97.91%
Embodiment 3: the allyl aldehyde preparation: 40g joins in the 500ml three-necked bottle, adds THF-methyl alcohol (9: 1) 250ml stirring and dissolving, adds IBX (55g is dissolved in the 80ml methyl alcohol), is warming up to 60 ℃ of reactions 4 hours; Be cooled to room temperature, add ethyl ester 400ml, with 400ml purified water washing three times, organic layer adds the 5g gac respectively; 10g anhydrous magnesium sulfate drying decolouring 30 minutes is filtered, and is concentrated into residual heavy 155-160g, adds isopropyl ether 30ml; Stir, crystallization is separated out in cooling, filters; An amount of ethyl ester-isopropyl ether (1: 1) washing, 45 ℃ of drying under reduced pressure get white powder 35.9g, yield 89.75%.Content 97.84%
Embodiment 4:3-does not have the parent nucleus preparation: among the easy 200mlDMF of allyl aldehyde 20g, add 1-butyl-3-Methylimidazole hexafluorophosphate 10g, after the stirring and dissolving, be warming up to 70 ℃, aerating oxygen; Add sad rhodium 20mg, cobalt-carbonyl 100mg is warming up to 75 ℃, and gas flow rate obviously strengthens, and stops logical oxygen; Be incubated 30 minutes, be warming up to 78 ℃ of insulations 15 minutes once more, be cooled to 25 ℃, add the 2g activated carbon, decoloured 30 minutes; Filter, join precooling to 0-5 ℃ 500ml frozen water, stirred 30 minutes, filter, suitably washing with acetone; Drying under reduced pressure gets white powder solid 18.6g, yield 97.74g, content 97.36%
Embodiment 5:3-does not have the parent nucleus preparation: among the easy 200mlDMF of allyl aldehyde 20g, add 1-butyl-3-Methylimidazole hexafluorophosphate 10g, after the stirring and dissolving, be warming up to 70 ℃, aerating oxygen; Add four triphenylphosphine rhodium carbonyl chlorides, 25mg, cobalt-carbonyl 100mg is warming up to 75 ℃, and gas flow rate obviously strengthens; Stop logical oxygen, be incubated 30 minutes, be warming up to 78 ℃ of insulations 15 minutes once more, be cooled to 25 ℃, add the 2g activated carbon; Decoloured 30 minutes, and filtered, join precooling to 0-5 ℃ 500ml frozen water, stirred 30 minutes, filter; Suitable washing with acetone, drying under reduced pressure gets white powder solid 18.2g, yield 95.64g, content 97.25%
Embodiment 6: hydrolyzate: 20g3-does not have parent nucleus and joins in the 100ml trifluoroacetic acid, and reflux 50 minutes is cooled to room temperature; Reaction solution stirs and joins precooling to 0-5 ℃ 1000ml frozen water, separates out solid, static 30 minutes after-filtration; The small amount of acetone washing, drying under reduced pressure gets the white granular pressed powder; 12.1g, yield 90.7%, content: 96.46%.
The preparation of embodiment 7:GL-7ANCA: the 40g hydrolyzate joins in 5% the sodium hydrogencarbonate 400ml aqueous solution, regulates ph to 7-7.5 with sodium hydrogencarbonate, and complete dissolving adds DAAO15g, and bubbling air stirs and is warming up to 30-35 ℃; Keep PH=7-8 with sodium hydrogencarbonate, react and removed by filter DAAO in 2 hours, add GL-7-ANCA acylase 18g, 25-28 ℃ of reaction 2.5 hours removes by filter the curing enzyme; Mother liquor adds gac 4g, vat powder 0.5g, and EDTA0.5g filtered in 30 minutes; Regulate PH to 4-5 with 10% hydrochloric acid, separate out solid, filter, the small amount of acetone washing; Drying under reduced pressure gets 7-ANCA white crystalline powder 16.54g, yield 80%, content 98.89%.
7-ANCA that below makes for the present invention and outsourcing 7-ANCA prepare the contrast of the mass yield of ceftizoxime acid and sodium:
Control Example 8 (outsourcing 7-ANCA)
Ceftizoxime acid: 20g7-ANCA joins in 200ml methylene dichloride and the 20g water, and 5-10 ℃ adds triethylamine 18g down, and complete dissolving adds AE-active ester 38g; 20-2 ℃ 5 reactions 2 hours are used the 200ml purified water extraction respectively 3 times, and combining water layer drips 10% to PH=1.5-1.8 in 20-25 ℃; Separate out solid, filtered in 30 minutes, the small amount of acetone washing; Drying under reduced pressure gets pale yellow powder shape solid 35.2g, solution look＜No. 5, content 94.56%
SKF-88373: the acid of 25g ceftizoxime joins in the 50ml water, adds triethylamine and is adjusted to complete dissolving, and adds carbon 0.5g decolouring 30 minutes, filters, and adds 5.8g aqueous sodium acetate solution 15ml; Add methyl alcohol 10ml, acetone 500ml separates out solid, filters the washing with acetone drying under reduced pressure; White crystalline powder 22.56g, yield 79.85%, solution look＜No. 3 quicken 1; 3,5 days corresponding looks number are 5,7,8
Embodiment 9 (self-produced 7-ANCA)
Ceftizoxime acid: 20g7-ANCA joins in 200ml methylene dichloride and the 20g water, and 5-10 ℃ adds triethylamine 18g down, and complete dissolving adds AE-active ester 38g; 20-2 ℃ 5 reactions 2 hours are used the 200ml purified water extraction respectively 3 times, and combining water layer drips 10% to PH=1.5-1.8 in 20-25 ℃; Separate out solid, filtered in 30 minutes, the small amount of acetone washing; Drying under reduced pressure gets pale yellow powder shape solid 37.3g, solution look＜No. 2, content 96.25%
SKF-88373: the acid of 25g ceftizoxime joins in the 50ml water, adds triethylamine and is adjusted to complete dissolving, and adds carbon 0.5g decolouring 30 minutes, filters, and adds 5.8g aqueous sodium acetate solution 15ml; Add methyl alcohol 10ml, acetone 500ml separates out solid, filters small amount of acetone washing drying under reduced pressure; White crystalline powder 23.75g, yield 84.07%, content 95.78%, solution look＜No. 1 quickens 1; Be respectively in 3,5 days 3,4, No. 5.
Claims (6)
- The preparation of a kind of preparation method of SKF-88373 key intermediate and high-content SKF-88373 is characterized in comprising following several steps:1. being raw material with cephalosporin sub product DCPC, being oxidized to aldehyde through over-churning and 3-position methylol, is under the katalysis of part for the catalyzer triphenyl phosphine at rhodium salt again, is oxygenant with the molecular oxygen, carries out de-carbonyl reaction, and directly making 3-does not have cephalosporin mother nucleus.
- 2. by shown in the claim (1), the 4-carboxylic esterification comprises methoxy-benzyl for esterifying reagent commonly used; Benzhydrol, hexichol triazonmethane, PNB; The protective material that BOC etc. are commonly used is considered the easy property and the arts demand of esterlysis, and most preferred protective material is a benzhydrol.
- 3. by shown in the claim (1), the 3-methylol is oxidized to aldehyde radical, owing to be the vinyl carbinol oxidation, its oxidation is prone to carry out; Tin anhydride commonly used, manganese powder, periodic acid, mineral acids such as ortho-vanadic acid; Peracetic Acid, peroxide m-chlorobenzoic acid, 2-iodoxy phenylformic acid (IBX) etc., preferred peroxide m-chlorobenzoic acid.
- 4. by shown in the claim (1), taking off the used rhodium salt of 3-position carbonyl is three carbonyl rhodium chlorides, the hydrogenchloride rhodium; Sad rhodium, rhodium acetate, cocatalyst is a cobalt-carbonyl; Part is a triphenylphosphine, triphenyl phosphine sodium sulfonate, preferred three carbonyl rhodium chloride cobalt-carbonyls and triphenylphosphine sodium sulfonate compsn; Proportioning is 1: 5: 5, and solvent is an ionic.
- 5. by shown in the claim (1), molecular oxygen is an oxygen, is the quickening velocity of initiation, suitable ozone ability fast reaction speed, and the ozone ratio is that 1-2% is an optimal conditions.
- 6. by shown in the claim (1), make the crucial parent nucleus of 7-ANCA after, 7-position enzymolysis and 2-are that esterlysis prepares the 7-ACA mode by routine, needn't stress separately at this.Prepared key intermediate and the condensation of AE-active ester, obviously content is higher than original for gained azoles oxime acid, the solution look more shallow, prepared ceftizoxime sodium content and quality stability all than original be the good of raw material with PNG-K.
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Cited By (5)
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| CN102977121A (en) * | 2012-12-25 | 2013-03-20 | 菏泽睿智科技开发有限公司 | Synthetic method of ceftizoxime acid |
| CN103755725A (en) * | 2013-12-26 | 2014-04-30 | 浙江工业大学 | Preparation method of 7beta-phenylacetyl amino-3-free-3-cephem-4-carboxylic acid benzyl ester |
| CN105585580A (en) * | 2016-01-19 | 2016-05-18 | 上海理工大学 | Synthesis method of methoxy cephalosporin drug intermediate 7-MAC |
| CN105622634A (en) * | 2016-03-04 | 2016-06-01 | 中山福运生物科技有限公司 | Method for producing ceftizoxime acid |
| CN114315858A (en) * | 2022-01-11 | 2022-04-12 | 深圳市立国药物研究有限公司 | Synthesis method of flomoxef intermediate |
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| CN102977121A (en) * | 2012-12-25 | 2013-03-20 | 菏泽睿智科技开发有限公司 | Synthetic method of ceftizoxime acid |
| CN103755725A (en) * | 2013-12-26 | 2014-04-30 | 浙江工业大学 | Preparation method of 7beta-phenylacetyl amino-3-free-3-cephem-4-carboxylic acid benzyl ester |
| CN103755725B (en) * | 2013-12-26 | 2016-05-18 | 浙江工业大学 | 7 β-phenylacetylamino-3-is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate |
| CN105585580A (en) * | 2016-01-19 | 2016-05-18 | 上海理工大学 | Synthesis method of methoxy cephalosporin drug intermediate 7-MAC |
| CN105622634A (en) * | 2016-03-04 | 2016-06-01 | 中山福运生物科技有限公司 | Method for producing ceftizoxime acid |
| CN114315858A (en) * | 2022-01-11 | 2022-04-12 | 深圳市立国药物研究有限公司 | Synthesis method of flomoxef intermediate |
| CN114315858B (en) * | 2022-01-11 | 2023-05-09 | 深圳市立国药物研究有限公司 | Synthesis method of flomoxef intermediate |
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Application publication date: 20121003 |