CN101429208A - Synthesis method for 7-neophedan-3-chloromethyl cephalosporanic p-methoxy benzyl ester - Google Patents
Synthesis method for 7-neophedan-3-chloromethyl cephalosporanic p-methoxy benzyl ester Download PDFInfo
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Abstract
The invention provides a method for synthesizing 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (GCLE). The method produces the GCLE by taking methoxybenzyl alcohol as a raw material through steps such as esterification and oxidation, ring opening and exchange, chlorization and ring closure and so on. The method has the advantages that the method has a simplified solvent and easy recovery, obviously improves the quality, ensures that the content is more than or equal to 95 percent, reduces the cost, has convenient operation, and is easy for industrialized production.
Description
Technical field:
It is synthetic to the present invention relates to medicine, is specifically related to 7-phenylacetamide-3-chloromethyl cephalosporanic to the methoxy benzyl ester synthetic method of (being called for short GCLE).
Background technology:
7-phenylacetamide-3-chloromethyl cephalosporanic is important microbiotic raw material to methoxy benzyl ester (being called for short GCLE), it is one of important semisynthetic antibiotics parent nucleus, another new parent nucleus after 7ACA, 7ADCA, as lead compound, can make the C3 position and contain cephalo medicines of new generation such as two keys, thiomethyl, quaternary ammonium salt.As Cefixime Micronized, Prozef, ceftazime.Because its 3 are-CH
2The Cl base, and have more activity, easier synthetic new cynnematin.
Relevant 7-phenylacetamide-3-chloromethyl cephalosporanic mainly contains the production method of methoxy benzyl ester (GCLE):
One, synthetic about penicillin sulfoxide ester
(1) adopting potassium penicillin G is starting raw material, earlier with to the esterification of methoxybenzyl chlorine (or use earlier Peracetic Acid oxidation), again through the Peracetic Acid oxidation, the generation penicillin sulfoxide ester.
(2) methoxybenzyl chlorine is got with p-methoxybenzyl alcohol (1) chloro.
(3) when the synthetic phase-transfer catalysis to carboxylate of chloro thing, all adopt methylene dichloride to make solvent (containing buck, saturated brackish water) in order to remove quaternary amine.
(4) in the aftertreatment of peroxide oxidation of ethanol, with the sodium thiosulfate solution washing, methylene dichloride is removed in soda lye wash, saturated brine washing, uses alcohol crystal again.
Yield 90%, content 94%.
Two, synthetic about quid pro quo (azepine butanone-sulfinic acid intermediate :)
1. open loop (penicillin-sulfinic acid mercaptobenzothiazole ester 7)
Adopt dioxane or toluene to make solvent, carry out at 100～110 ℃, because the 2-mercaptobenzothiazole conversion rate of oxidation is 90～95%, leather desolvates, and what have dissolves with methylene dichloride, and what have dissolves with ethanol or Virahol.
2. exchange (azepine butanone-sulfinic acid intermediate 9)
Adopt methylene dichloride, Virahol to make solvent, but all adopt first example hydrochloric acid, add benzene sulfinic acid sodium salt again and exchange the formation reversible reaction.Remove methylene dichloride, crystallization in Virahol or in the ethanol.Yield 60～63%, content 94% (having insolubles to produce).
Three, synthetic about GCLE
1. chlorination
General dioxane or the toluene of adopting is made solvent, uses ClO
2, the clorox chlorination, Japan adopts electrolytic chlorination, transformation efficiency is removed solvent generally 90%, dissolves with DMF.
2. closed loop
In DMF solution, useful ammoniacal liquor or liquefied ammonia closed loop (after adding hydrochloric acid) are removed DMF, the dissolving that adds methylene chloride, and methylene dichloride is removed in washing again, uses alcohol crystal, content 92～94%, yield is low.
But above-mentioned each method all fails to solve the difficult problem that the GCLE yield is low, the industrialization cost is high, and main deficiency is:
1, adopt methylene dichloride to make solvent, because feed liquid is heavy, again in order to remove quaternary ammonium salt, used the stratified troublesome operation of washing, the quaternary ammonium salt residual volume makes subsequent reactions be difficult to high-level efficiency and carries out at 60ppm.Investment simultaneously increases, and equipment increases, complicated operation, and again owing to methylene dichloride solubleness (2%) in water, yield reduces.
2, " open loop " in the existing method generally carried out open loop with dioxane or toluene as solvent, but because atmospheric oxidation, 2-mercaptobenzothiazole has been easy to oxidation and has formed DM (dibenzothiazyl disulfide), not only do not participate in reaction, easily form insolubles on the contrary, the open loop transformation efficiency is 80～90%
3, electrolytic chlorination, the equipment complexity, and adopt methylene dichloride, other chlorizating agents of clorox, it is too much to form the dichloro trichloro-compound.
4, be difficult to after the closed loop handle, dimethyl formamide, methylene dichloride, a large amount of multiple solvents of ethanol adopt, and are difficult to realize industrialization.
Summary of the invention:
The technical problem to be solved in the present invention is to overcome above-mentioned weak point, and the research and design production cost is low, yield is high, and is simple to operate, is suitable for the GCLE synthetic method of suitability for industrialized production.
The invention provides the synthetic method of a kind of 7-phenylacetamide-3-chloromethyl cephalosporanic to methoxy benzyl ester (GCLE).The inventive method comprises the following steps:
1. esterification, oxidation
1) synthetic to methoxybenzyl chlorine:
[in the formula 1: p-methoxybenzyl alcohol 2 :] to methoxybenzyl chlorine
In toluene solution, add p-methoxybenzyl alcohol, under Tetrabutyl amonium bromide and zinc chloride catalysis ,-10～0 ℃ drips 30～36% hydrochloric acid down, forms methoxybenzyl chlorine, divides the acid layer that desalts, and is methoxybenzyl toluene(mono)chloride solution.Mol ratio is a p-methoxybenzyl alcohol: Tetrabutyl amonium bromide: zinc chloride: hydrochloric acid=1:0.020:0.016:3.358
2) esterification oxidation:
[in the formula 3: potassium penicillin G 4: penicillin is to methoxy benzyl ester 5: penicillin sulfoxide is to methoxy benzyl ester]
Above-mentioned to methoxybenzyl toluene(mono)chloride solution in, add a small amount of DMF (N, dinethylformamide), add potassium penicillin G in batches, 30～32 ℃ of reactions promptly generate penicillin to the methoxy benzyl ester toluene solution, add water, branch vibration layer (containing DMF)
Mol ratio is a potassium penicillin G: to methoxybenzyl chlorine: Tetrabutyl amonium bromide=1:1.08:0.115
Above-mentioned penicillin is in the methoxy benzyl ester toluene solution, at low temperatures-20～+ 5 ℃, drips Peracetic Acid, promptly is oxidized to penicillin sulfoxide to the methoxy benzyl ester crystallisate.Filter, water washing promptly gets penicillin sulfoxide to methoxy benzyl ester crystallisate solid.
Mol ratio is carboxylate: Peracetic Acid=1:1.08
2. open loop, exchange:
[in the formula 5: penicillin sulfoxide is to methoxy benzyl ester 6:2-mercaptobenzothiazole 7: penicillin-sulfinic acid mercaptobenzothiazole ester 8: benzene sulfinic acid sodium salt 9: azepine butanone-sulfinic acid intermediate: 2-phenylacetyl amido, 1-benzene sulfinic acid thioesters, N-acetate is to methoxy benzyl ester (1-propenyl)]
In dioxane or toluene or mixed solvent, add penicillin sulfoxide to the methoxy benzyl ester solid, add 2-mercaptobenzothiazole, 90～110 ℃ of following open loops, form penicillin-sulfinic acid intermediate earlier, in the presence of the trapping agent 2-mercaptobenzothiazole, form penicillin-sulfinic acid mercaptobenzothiazole ester.The decompression leather desolvates, and with the Virahol dissolving, carries out permutoid reaction with benzene sulfinic acid sodium salt, forms azepine butanone-sulfinic acid intermediate.
Mol ratio is a penicillin sulfoxide to methoxy benzyl ester: 2-mercaptobenzothiazole: benzene sulfinic acid sodium salt=1:1:1.1
3. chlorination, closed loop:
[in the formula 10: chlorine 11: azepine butanone-sulfinic acid allyl chloride 12:GCLE]
Azepine butanone-sulfinic acid intermediate in its allylic base chlorination, forms azepine butanone-sulfinic acid allyl chloride with chlorine in dioxane or toluene or their mixed solvent, remove and desolvate, and then uses the liquefied ammonia closed loop at-60～-40 ℃, and forms GCLE.
Mol ratio is an azepine butanone-sulfinic acid intermediate: chlorine: propylene oxide: liquefied ammonia=1:3:5.2:3.8
Through comparison, GCLE infared spectrum and hydrogen spectrum that the inventive method makes product are consistent with standard substance (Japan).
Analytical procedure: per step intermediate content all with reference substance with external standard method (HPLC), GCLE and Japan and stdn reference substance external standard method HPLC measure.
Quality standard:
Outward appearance: off-white color crystalline powder
Content: 〉=95.0%
Fusing point: 〉=153 ℃
Moisture :≤0.5%
Characteristics of the present invention:
1. phase-transfer-catalyzed reactions technology
It is the best solvent of phase transition that the present invention adopts lower boiling hydrochloric ether (methylene dichloride, trichloromethane), because hydrogen bond is enough strong between hydrochloric ether and the hydrogenchloride, makes QUATERNARY AMMONIUM SALT in halohydrocarbon, and reaction is carried out smoothly.
The present invention adopts aromatic hydrocarbon (as toluene, ethylbenzene), because lighter than water, operation of equipment is simple, and the number of times of layering simultaneously is kept to 4～5 times by 11～18 times of former method.Because no hydrogen bond influence, quaternary ammonium salt also is easy to remove.Under similarity condition (yield, quality), the quaternary ammonium salt residual volume is reduced to 0～5ppm, helps the next step, and aromatic hydrocarbon is easy to absorb simultaneously, is beneficial to reduce cost.
Chloro, esterification, oxidization-hydrogenation ratio (weight) 1.16 (in penicilline g potassium).
2. ring-opening reaction
Making reductive agent with oxalic acid, is catalyzer (being trace) with the Virahol, and transformation efficiency is brought up to more than 99% by general 80%～90%, and it only is 1%～2% that reactant (6) transfers DM to.
3. permutoid reaction
The present invention makes the hydrochloric acid reinforcer with sulfuric acid, form whole benzene sulfinic acid alcoholic solutions and exchange, but present method advantage is dropwise reaction, makes reaction PH stable, and inclusion-free (or claiming insolubles) produces.
Weight yield 1:1 (in the chloro thing), content 〉=97～98%, yield improves 10%.
4. chlorination reaction
Make acid binding agent with a kind of oxide compound (propylene oxide, oxyethane), at N
2Dilution is used the chlorine direct chlorination down, and transformation efficiency 〉=98% has replaced electrolytic chlorination.
5. closed loop
The present invention makes catalyzer with the liquefied ammonia closed loop with subacidity ammonia salt, after the closed loop, with certain aromatic hydrocarbon, portion water is existed down, utilizes the sub-saturated state, and direct layering is handled, and removes the closed loop solvent, adds water crystallization again.Impurity is in aromatic hydrocarbon, and GCLE forms crystallization and separates out, and quality significantly improves, simplified control.
Yield 1:0.6～0.55 (in quid pro quo).
The inventive method solvent is simplified easily recovery, and quality product obviously improves, content 〉=95%, and investment significantly reduces, and is easy to operate, is suitable for suitability for industrialized production.
Embodiment:
Following example helps to understand the present invention, but is not limited to content of the present invention.
Example 1 chloro
60g p-methoxybenzyl alcohol (0.43mmol), add toluene 300ml, be cooled to-10 ℃, add 3g Tetrabutyl amonium bromide (0.009mmol), 1g zinc chloride (0.007mmol), under-10～0 ℃, drip 30% hydrochloric acid (1.444mmol) of 150ml, about 0.5h keeps reaction 1h simultaneously, divide the acid layer that desalts, to methoxybenzyl toluene(mono)chloride solution for standby.
1. esterification
Above-mentioned in the methoxybenzyl toluene(mono)chloride solution, add penicilline g potassium 150g (0.40mmol), Tetrabutyl amonium bromide 15g (0.046mmol), DMF72ml, at 30～32 ℃, insulated and stirred, 10～12h, add water 300ml standing demix, remove water layer (containing DMF), remaining penicillin is standby to the methoxy benzyl ester toluene solution.
2. oxidation
Above-mentioned penicillin is cooled to-10～-5 ℃ to the methoxy benzyl ester toluene solution, drips 22 ± 2% Peracetic Acid 150ml (0.43mmol), and about 3h of dropping time is incubated 30min after the titration, filters, and gets the about 210g of crude product.
After the washing, drying gets dry product 174g penicillin sulfoxide to methoxy benzyl ester.
Content 97～98%, yield 95%.
3. open loop, exchange
The 100ml dioxane adds 100ml toluene, 5ml Virahol, 7g2-mercaptobenzothiazole (0.042mmol), 20g penicillin sulfoxide to methoxy benzyl ester (0.042mmol), 0.12g oxalic acid, 100～101 ℃ of reactions, steam the 40ml solvent, about 2.5～4h, reaction finishes, dioxane and toluene are removed in decompression, add the Virahol dissolving.Drip the good benzene sulfinic acid alcoholic solution (containing 9.3g benzene sulfinic acid sodium salt two water things) of configured in advance at 30～35 ℃ and (0.046mmol), drip about 1.5～2h, be cooled to 0 ℃, insulation 2h filters, and uses washed with isopropyl alcohol, drying gets quid pro quo azepine butanone-sulfinic acid intermediate 20g.Content 97～98%, yield 79.13, moisture≤0.2%.
4. chlorination, closed loop
The 200ml dioxane adds 100ml toluene, 18ml chloropropane (0.26mmol), 30g azepine butanone-sulfinic acid intermediate (0.05mmol), 0～-2 ℃ of stirring, slowly sends into chlorine, about 6h, and HPLC analyzes, and transformation efficiency is more than 99%, and main content is more than 85%.
Decompression absorbs dioxane and toluene, dissolves with 225mlDMF.
Be cooled to-45～-40 ℃, add liquefied ammonia 5ml (0.19mmol), closed loop 30min adds hydrochloric acid 17ml (0.17mmol), toluene 200ml, drips water 50ml, clarifies to solution.Standing demix, branch vibration layer.
The GCLE toluene layer drips water 250ml again, is cooled to about 0 ℃, stirs 4h, filters, and uses washing with alcohol.Dry GCLE17～the 18g that gets.Yield 70～73.5%, content 〉=95%.
Example 2
1. chloro
60g p-methoxybenzyl alcohol (0.43mmol), add toluene 300ml, be cooled to 0 ℃, add 3g Tetrabutyl amonium bromide (0.009mmol), 1g zinc chloride (0.007mmol), under 0～10 ℃, drip 30% hydrochloric acid (1.444mmol) of 150ml, about 0.5h keeps reaction 1h simultaneously, divide the acid layer that desalts, standby to methoxybenzyl toluene(mono)chloride layer.
2. esterification
Add penicilline g potassium 150g (0.40mmol) in the above-mentioned toluene layer, Tetrabutyl amonium bromide 15g (0.046mmol), DMF72ml, at 25～30 ℃, insulated and stirred, 10～12h, add water 300ml standing demix, water layer (containing DMF), surplus penicillin is standby to the methoxy benzyl ester toluene layer.
3. oxidation
Above-mentioned penicillin is cooled to-20～-10 ℃ to the methoxy benzyl ester toluene solution, drips 22 ± 2% Peracetic Acid 150ml (0.43mmol), and about 3h of dropping time is incubated 30min after the titration, filters, and gets the about 210g of crude product.
After the washing, drying gets dry product 174g oxide compound penicillin sulfoxide to methoxy benzyl ester.
Content 97～98%, yield 95%.
4. open loop, exchange
The 100ml dioxane adds 100ml toluene, 5ml Virahol, 7g2-mercaptobenzothiazole (0.042mmol), 20g penicillin sulfoxide to methoxy benzyl ester (0.042mmol), 0.12g oxalic acid, 100～101 ℃ of reactions, steam the 40ml solvent, about 2.5～4h, reaction finishes, dioxane and toluene are removed in decompression, add the Virahol dissolving.Drip the good benzene sulfinic acid alcoholic solution (containing 9.3g benzene sulfinic acid sodium salt two water things) of configured in advance at 30～35 ℃ and (0.046mmol), drip about 1.5～2h, be cooled to 0 ℃, insulation 2h filters, and uses washed with isopropyl alcohol, drying gets quid pro quo azepine butanone-sulfinic acid intermediate 20g.Content 97～98%, yield 79.13, moisture≤0.2%.
5. chlorination, closed loop
The 200ml dioxane adds 100ml toluene, 18ml chloropropane (0.26mmol), 30g azepine butanone-sulfinic acid intermediate (0.05mmol), 0～+ 2 ℃ of stirring, slowly sends into chlorine, about 6h, and HPLC analyzes, and transformation efficiency is more than 99%, and main content is more than 85%.
Decompression absorbs dioxane and toluene, dissolves with 225mlDMF.
Be cooled to-40～-60 ℃, add liquefied ammonia 5ml (0.19mmol), closed loop 30min adds hydrochloric acid 17ml (0.17mmol), toluene 200ml, drips water 50ml, clarifies to solution.Standing demix divides to walk water layer.
The GCLE toluene layer drips water 250ml again, is cooled to about 0 ℃, stirs 4h, filters, and uses washing with alcohol, the dry GCLE17～18g that gets.Yield 70～73.5%, content 〉=95%.
Claims (5)
1, a kind of 7-phenylacetamide-3-chloromethyl cephalosporanic is characterized in that the synthetic method of methoxy benzyl ester
This method comprises the following steps:
(1):
(1)：
In the formula 1: p-methoxybenzyl alcohol, 2: to methoxybenzyl chlorine;
(2)：
In the formula 3: potassium penicillin G formula 4: penicillin is to methoxy benzyl ester 5: penicillin sulfoxide is to methoxy benzyl ester;
(2):
6:2-mercaptobenzothiazole 7 in the formula: penicillin-sulfinic acid mercaptobenzothiazole ester 8: benzene sulfinic acid sodium salt 9: azepine butanone-sulfinic acid intermediate;
(3) chlorination, closed loop:
In the formula 10: chlorine 11: azepine butanone-sulfinic acid allyl chloride 12:GCLE;
(1) esterification, oxidation
(1) synthetic to methoxybenzyl chlorine: as in toluene solution, to add p-methoxybenzyl alcohol, under Tetrabutyl amonium bromide and zinc chloride catalysis,-10～0 ℃ drips 30～36% hydrochloric acid down, formation divides the acid layer that desalts to methoxybenzyl chlorine, must be to methoxybenzyl toluene(mono)chloride solution;
(2) esterification, oxidation: above-mentioned to methoxybenzyl toluene(mono)chloride solution in, add N, dinethylformamide adds potassium penicillin G in batches, 30～32 ℃ of reactions generate penicillin to the methoxy benzyl ester toluene solution, add water in this solution, branch vibration layer; In low temperature-20～+ 5 ℃, drip Peracetic Acid to penicillin in to the methoxy benzyl ester toluene solution, promptly be oxidized to penicillin sulfoxide to the methoxy benzyl ester crystallisate, to filter, water washing promptly gets penicillin sulfoxide to the methoxy benzyl ester solid;
(2) open loop, exchange:
In dioxane or toluene or their mixed solvent, add penicillin sulfoxide to the methoxy benzyl ester solid, add 2-mercaptobenzothiazole again,, form penicillin-sulfinic acid intermediate earlier 90～110 ℃ of following open loops, then in the presence of the trapping agent 2-mercaptobenzothiazole, form penicillin-sulfinic acid mercaptobenzothiazole ester, removal of solvent under reduced pressure is dissolved with isopropanol solvent, carry out permutoid reaction with benzene sulfinic acid sodium salt, form azepine butanone-sulfinic acid intermediate;
(3) chlorination, closed loop:
Azepine butanone-sulfinic acid intermediate in its allylic base chlorination, forms azepine butanone-sulfinic acid allyl chloride with chlorine in dioxane or toluene or mixed solvent, remove and desolvate, and then uses the liquefied ammonia closed loop at-60～-40 ℃, obtains GCLE;
2, a kind of 7-phenylacetamide according to claim 1-3-chloromethyl cephalosporanic is to the synthetic method of methoxy benzyl ester, in it is characterized in that step () is synthesized methoxybenzyl chlorine, p-methoxybenzyl alcohol: Tetrabutyl amonium bromide: zinc chloride: the mol ratio of hydrochloric acid is 1:0.020:0.016:3.358.
3, a kind of 7-phenylacetamide according to claim 1-3-chloromethyl cephalosporanic is to the synthetic method of methoxy benzyl ester, it is characterized in that in step () esterification potassium penicillin G: to methoxybenzyl chlorine: the mol ratio of Tetrabutyl amonium bromide is 1:1.08:0.115; Carboxylate in the oxidation: the mol ratio of Peracetic Acid is 1:1.08.
4, a kind of 7-phenylacetamide according to claim 1-3-chloromethyl cephalosporanic is to the synthetic method of methoxy benzyl ester, it is characterized in that penicillin sulfoxide is to methoxy benzyl ester: 2-mercaptobenzothiazole: the mol ratio of benzene sulfinic acid sodium salt is 1:1:1.1 in step (two) open loop, the exchange.
5, a kind of 7-phenylacetamide according to claim 1-3-chloromethyl cephalosporanic is to the synthetic method of methoxy benzyl ester, it is characterized in that in step (three) chlorination, the closed loop that mol ratio is an azepine butanone-sulfinic acid intermediate: chlorine: propylene oxide: the mol ratio of liquefied ammonia is 1:3:5.2:3.8.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102285997A (en) * | 2011-07-05 | 2011-12-21 | 山东睿鹰先锋制药有限公司 | Method for preparing chloroallyl beta-lactam antibiotic intermediate |
| CN102344459A (en) * | 2011-07-27 | 2012-02-08 | 山西新天源医药化工有限公司 | Preparation method of cephalosporin intermediate GCLE |
| CN102643294A (en) * | 2012-04-18 | 2012-08-22 | 山东普洛得邦医药有限公司 | Preparation method of cephalosporin nucleus intermediate |
| CN102690243A (en) * | 2012-05-25 | 2012-09-26 | 伊犁川宁生物技术有限公司 | Method for recovering raw materials in preparation process of 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl |
| CN107033162A (en) * | 2016-02-03 | 2017-08-11 | 湖北凌晟药业有限公司 | The preparation of GCLE |
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2007
- 2007-11-07 CN CNA2007100478969A patent/CN101429208A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102285997A (en) * | 2011-07-05 | 2011-12-21 | 山东睿鹰先锋制药有限公司 | Method for preparing chloroallyl beta-lactam antibiotic intermediate |
| CN102285997B (en) * | 2011-07-05 | 2013-04-03 | 山东睿鹰先锋制药有限公司 | Method for preparing chloroallyl beta-lactam antibiotic intermediate |
| CN102344459A (en) * | 2011-07-27 | 2012-02-08 | 山西新天源医药化工有限公司 | Preparation method of cephalosporin intermediate GCLE |
| CN102344459B (en) * | 2011-07-27 | 2014-08-06 | 山西新天源医药化工有限公司 | Preparation method of cephalosporin intermediate GCLE |
| CN102643294A (en) * | 2012-04-18 | 2012-08-22 | 山东普洛得邦医药有限公司 | Preparation method of cephalosporin nucleus intermediate |
| CN102643294B (en) * | 2012-04-18 | 2014-11-26 | 山东普洛得邦医药有限公司 | Preparation method of cephalosporin nucleus intermediate |
| CN102690243A (en) * | 2012-05-25 | 2012-09-26 | 伊犁川宁生物技术有限公司 | Method for recovering raw materials in preparation process of 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl |
| CN102690243B (en) * | 2012-05-25 | 2014-07-16 | 伊犁川宁生物技术有限公司 | Method for recovering raw materials in preparation process of 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl |
| CN107033162A (en) * | 2016-02-03 | 2017-08-11 | 湖北凌晟药业有限公司 | The preparation of GCLE |
| CN107033162B (en) * | 2016-02-03 | 2020-05-01 | 湖北凌晟药业有限公司 | Preparation of 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester |
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