CN101265220A - Method for synthesizing florfenicol - Google Patents
Method for synthesizing florfenicol Download PDFInfo
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- CN101265220A CN101265220A CNA200810036942XA CN200810036942A CN101265220A CN 101265220 A CN101265220 A CN 101265220A CN A200810036942X A CNA200810036942X A CN A200810036942XA CN 200810036942 A CN200810036942 A CN 200810036942A CN 101265220 A CN101265220 A CN 101265220A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a synthesis method of synthesizing florfenicol. The synthesis method comprises the following steps: L-threo-(p-(methylsylfonyl) phenyl) serine ethyl ester which is used as raw material is processed by the protection by a protecting group, configurational transition, hydrolyzation, acetylation, re-protection, deoxidation, fluorination, and pre-hydrolyzation, so that the florfenicol is obtained, wherein, the protecting group R is one of benzoyl chloride, phthalic anhydride, cyanophenyl, and allyl compounds; the configurational transition is performed when sodium alcoholate or sodium methoxide exists. The raw material which is used in the method is a byproduct which is generated during the process of preparing thiamphenicol, is easy to get in the market, and is inexpensive; the technological operation is simple, the cost is low, the yield rate is high, and the synthesis method has industrialized value.
Description
Technical field
The present invention relates to a kind of synthetic method of florfenicol.
Background technology
Florfenicol is a kind of chloromycetin broad-spectrum antibiotics.Florfenicol (Florfenicol) claim Florfenicol again, and chlorine sulfone Buddhist nun can.Florfenicol 1996 is registered by U.S. FDA, be the novel anti gram-positive microorganism that special exploitation is used for animal health market, be the animal specific broad spectrum antibiotic, its similar is in thiamphenicol, but its antibacterial ability can reach 10 times more than of thiamphenicol, so it is widely used.
Florfenicol generally from intermediate D-(-)-2-amino-1-[(of thiamphenicol right-methylsulfonyl) phenyl]-1, ammediol is synthesized into (US4235892, US4311897, Tetrahedron Lett, 1988.29 reaction scheme is as follows (43) .5561-5564):
Above-mentioned route be because the asymmetry of chirality functional group on its structure need be carried out chiral separation, causes in the building-up process by product many, and transformation efficiency is low, thereby has caused the rising of synthetic cost.
Thiamphenicol intermediate D-(-)-Su Shi-[right-(methylsulfonyl) phenyl] serine ethyl ester of U.S. Schering-Plough company employing subsequently is that synthetic florfenicol (J.Org.Chem.1990.55 (18) the .5291-5294) reaction scheme of raw material is as follows:
People such as Clark has proposed novel synthesis technique afterwards, no longer need to split, but by aqueous isopropanol with saturated ammonia, pyroreaction is carried out an isomerization and is transformed, Giordano has developed the technology that the enantiomorph of directly changing to be configured as it synthesizes florfenicol, to have proposed with the methylsulfonyl phenyl aldehyde be raw material to Wu of the Schering-Plough of the U.S. etc. afterwards, technological process (the WO9207824.1992 of asymmetric synthesis florfenicol, EP423705.1991, WO9414764.1994).
Nineteen ninety-five, Clark has applied for synthetic florfenicol patent, and its building-up process is as follows:
Chinese patent notification number CN1743308 discloses the synthetic method of a kind of thiamphenicol and florfenicol compounds, through hydrolysis degreasing protection, through Pd/C hydrogenation deaminize protecting group, makes through acetylize again, and its building-up process is as follows:
The present invention aims to provide the different protecting groups of a kind of employing and protects, and the process with a configuration conversion, improves reaction conversion ratio and yield, the simple more synthetic method of operation.
Summary of the invention
Technical problem to be solved by this invention is to provide the synthetic method of the florfenicol that a kind of method is easy, cost is low, yield is high.
A kind of novel synthesis of florfenicol; be to be raw material with compound 1:L-Su Shi-[right-(methylsulfonyl) phenyl] serine ethyl ester (thiamphenicol by product); protect through protecting group; the configuration conversion; hydrolysis, acetylize, protect again, reduce, fluoridize, the process of hydrolysis again obtains florfenicol, be expressed as follows with reaction formula:
R, R ' they are protecting group, wherein,
Protecting group R is a kind of in Benzoyl chloride, phthalic anhydride, benzene nitrile, the allylic compound;
Protecting group R ' is a kind of in phthalic anhydride, benzene nitrile, the allylic compound.
Compound 1 is a kind of by product in preparation thiamphenicol process, is easy to get very much on the market, and cheap.
Compound 2; chemical name L-Su Shi-5-[is right-(methylsulfonyl) phenyl]-2-R-4; 5-dihydro-4-oxazole carboxylic acid, ethyl ester; obtain compound 2 by compound 1 through protecting group R protection; wherein; protecting group R is a kind of in Benzoyl chloride, phthalic anhydride, benzene nitrile, the allyl compounds (as 2-methoxyl group propylene), preferably uses Benzoyl chloride.
On the basis of such scheme, described compound 1 is 1: 1～3 with the reaction mol ratio of protecting group R, reacts 1～10 hour down at 20～80 ℃, and used organic solvent is a kind of or its combination in methyl alcohol, ethanol, methylene dichloride, the ethylene dichloride.
Compound 1 can be 1: 1 with the reaction mol ratio of protecting group R, 1.2,1.5,1.8,2,2.2,2.5,2.8,3, preferably use 1: 1.5～2.
Compound 3, chemical name D-Su Shi-5-[is right-(methylsulfonyl) phenyl]-2-R-4,5-dihydro-4-oxazole carboxylic acid, ethyl ester, the preparation of compound 3 is processes of a configuration conversion, compound 2 at room temperature carries out configuration conversion and obtains compound 3 in the presence of sodium ethylate or sodium methylate.The preferred sodium ethylate that uses is made solvent with methyl alcohol, at room temperature carries out configuration conversion.
Compound 4, chemical name D-Su Shi-[right-(methylsulfonyl) phenyl] serine ethyl ester, compound 3 obtains compound 4 through the open loop that is hydrolyzed of hydrochloric acid or sulfuric acid.
Wherein, adopt the hydrochloric acid hydrolysis open loop, the volumetric molar concentration of hydrochloric acid is 1～10mol/L, and the concentration of hydrochloric acid is specifically as follows 1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10mol/L.
Or adopt the sulphuric acid hydrolysis open loop, and the vitriolic volumetric molar concentration is 0.5～6mol/L, the vitriolic volumetric molar concentration is specifically as follows 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6mol/L;
The preferred intermediate concentration of using, volumetric molar concentration is the acid of 2～6mol/L.
Compound 3 is 1: 3～8 with hydrochloric acid or vitriolic reaction mol ratio, reacts 2～10 hours down at 20～80 ℃.
Compound 3 is specifically as follows 1: 3,3.2,3.5,3.8,4,4.2,4.5,4.8,5,5.2,5.5,5.8,6,6.2,6.5,6.8,7,7.2,7.5,7.8,8 with hydrochloric acid or vitriolic reaction mol ratio.
Also can adopt mineral alkali, comprise the open loops that are hydrolyzed such as sodium hydroxide, sodium hydroxide, yellow soda ash, but product purity that the mineral alkali hydrolysis makes and yield all are lower than the product that adopts acid to be hydrolyzed and to make, concrete purity, yield are shown in Table 1:
Table 1
| Compound 3 (g) | Hydrolyzate | Compound 4 (g) | Purity (%) | Yield (%) |
| 10 | 3mol/L sulfuric acid | 7 | 98 | 70 |
| 10 | 6mol/L hydrochloric acid | 7.5 | 98 | 75 |
| 10 | Sodium bicarbonate | 6 | 95 | 60 |
| 10 | Potassium hydroxide | 5 | 96 | 50 |
| 10 | Yellow soda ash | 5 | 96 | 50 |
Described compound 4 crude products can be through recrystallization purifying, and wherein, recrystallization solvent is a kind of in Virahol, ethanol, the sherwood oil.
Compound 5, chemical name D-Su-Type-2--(2, the 2-dichloro) acetylaminohydroxyphenylarsonic acid 3-hydroxyl-3-is right-(methylsulfonyl) phenyl]-ethyl propionate.Described compound 4 can obtain 5 through acetylization reaction, and reaction conditions is seen document US 4235892, J.Org.Chem.1990.55 (18) .5291-5294.
Compound 6, chemical name D-Su Shi-5-[is right-(methylsulfonyl) phenyl]-2-R '-3-dichloro-acetyl-4,5-dihydro-4-oxazole carboxylic acid, ethyl ester.The preparation of compound 6 also is the reaction of a protecting group protection, and step is synthetic consistent with compound 2, but the range of choice of protecting group R ' is less than the first step reaction, should select the little protecting group of some resistances.
Described compound 5 is protected through protecting group R ' again and is obtained compound 6, and wherein, protecting group R ' is a kind of in phthalic anhydride, benzene nitrile, the allylic compound (as 2-methoxyl group propylene), preferably uses 2-methoxyl group propylene.
On the basis of such scheme, described compound 5 is 1: 1～3 with the reaction mol ratio of protecting group R ', and 20～80 ℃ of reactions 1～10 hour down, used organic solvent is a kind of in methyl alcohol, ethanol, methylene dichloride, the ethylene dichloride.
Compound 5 can be 1: 1 with the reaction mol ratio of protecting group R ', 1.2,1.5,1.8,2,2.2,2.5,2.8,3, preferably used 1: 1.5.
To compound 1 protection, to the protection again of compound 5, both described protecting group R, R ' can be same kind of protecting group, also can plant protecting group for difference.
Compound 7, chemical name D-Su Shi-5-[is right-(methylsulfonyl) phenyl]-2-R '-3-dichloro-acetyl-4,5-dihydro-4-oxazole methyl alcohol.Described compound 6 obtains compound 7 through reduction, and wherein, reductive agent is POTASSIUM BOROHYDRIDE or sodium borohydride, and compound 6 is 1: 1～5 with the reaction mol ratio of reductive agent, reacts 3～8 hours down at 20～60 ℃.
Compound 6 is specifically as follows 1: 1,1.2,1.5,1.8,2,2.2,2.5,2.8,3,3.2,3.5,3.8,4,4.2,4.5,4.8,5 with the reaction mol ratio of reductive agent.
It is good that preferred recommendation is reacted 5 hours down for 30 ℃.
Compound 7 crude products can be through recrystallization purifying, and wherein, recrystallization solvent is a kind of in Virahol, ethanol, the sherwood oil.
Compound 8, chemical name D-Su Shi-5-[is right-(methylsulfonyl) phenyl]-2-R '-3-dichloro-acetyl-4,5-dihydro-4-oxazole methyl alcohol.Compound 7 is fluoridized through Ishikawa reagent can obtain compound 8, and reaction conditions is seen document US 4235892, J.Org.Chem.1990.55 (18) .5291-5294 in detail.
Florfenicol, chemical name D-Su Shi-2,2-two chloro-N-[1-methyl fluoride-2-hydroxyl-2-(to the methylsulfonyl phenyl) ethyls] ethanamide, florfenicol is hydrolysis and getting again on the basis of compound 8, method for hydrolysis is same as the preparation of compound 4.Compound 8 obtains florfenicol through hydrolysis again, and florfenicol herein is a crude product, and wherein, the open loop that is hydrolyzed of hydrochloric acid or sulfuric acid is adopted in described hydrolysis again.
Wherein, adopt the hydrochloric acid hydrolysis open loop, the volumetric molar concentration of hydrochloric acid is 1～10mol/L, and the volumetric molar concentration of hydrochloric acid is specifically as follows 1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10mol/L.
Or adopt the sulphuric acid hydrolysis open loop, and the vitriolic volumetric molar concentration is 0.5～6mol/L, vitriolic concentration is specifically as follows 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6mol/L..5
The preferred intermediate concentration of using, volumetric molar concentration is the acid of 2～6mol/L.
Compound 8 is 1: 3～8 with hydrochloric acid or vitriolic reaction mol ratio, reacts 2～10 hours down at 20～80 ℃.
Compound 8 is specifically as follows 1: 3,3.2,3.5,3.8,4,4.2,4.5,4.8,5,5.2,5.5,5.8,6,6.2,6.5,6.8,7,7.2,7.5,7.8,8 with hydrochloric acid or vitriolic reaction mol ratio.
The florfenicol crude product that makes can be through recrystallization purifying, and wherein, recrystallization solvent is a kind of in Virahol, ethanol, the sherwood oil, and concrete recrystallization data are as shown in table 2:
Table 2
| Florfenicol crude product/g (crude product purity) | Solvent/consumption (ml) | Pure product (g) | Purity (%) | Yield (%) |
| 5(97％) | Sherwood oil/20 | 3.3 | 98.2 | 66 |
| 5(97％) | Virahol/20 | 3.6 | 98.6 | 72 |
| 5(97％) | Virahol/15 | 3.8 | 98.4 | 76 |
| 5(97％) | Ethanol/20 | 4.6 | 99.4 | 92 |
| 5(97％) | Ethanol/15 | 4.7 | 98.6 | 94 |
Product the best that the purifying of florfenicol crude product makes as recrystallization solvent with ethanol especially.
Excellent effect of the present invention is:
The L-Su Shi that the synthetic method utilization of florfenicol of the present invention cheaply is easy to get-[right-(methylsulfonyl) phenyl] serine ethyl ester is a raw material; through the protecting group protection; configuration conversion, hydrolysis, acetylize; protection again; dehydroxylation is fluoridized, the florfenicol that obtains of hydrolysis again, and raw materials used is a kind of by product in preparation thiamphenicol process; be easy to get very much on the market, inexpensive, and technological operation simply, does not have danger, cost is low, yield is high, have industrial value.
Embodiment
Further specify the present invention below in conjunction with specific embodiment and how to realize that following examples help to understand the present invention, but be not limited to content of the present invention.
(A) compound 1 is through protecting group protection preparation compound 2
5g L-Su Shi-[right-(methylsulfonyl) phenyl] serine ethyl ester is dissolved in the methylene dichloride of 10ml methyl alcohol and 30ml, and ice bath is cooled to 10 ℃.Benzoyl chloride mixed with the 2.2ml methylene dichloride drop to then in the reaction flask, controlled temperature is not higher than 20 ℃, stirring at room 2 hours, add the 2.7g sulfur oxychloride, compound 1 and Benzoyl chloride are reacted with the reaction mol ratio at 1: 1.5, reaction system is heated to 50 ℃ and kept 2 hours under this temperature, naturally reduce to room temperature, add the 30g frozen water, stirred standing demix 30 minutes.Organic phase 30ml water, the 30ml saturated sodium carbonate solution, the 30ml water washing, anhydrous sodium sulfate drying, concentrate compound 2, reactions steps is as follows:
(B) compound 2 converts compound 3 to through configuration, makes compound 4 through hydrolysis again
The compound 2 that the last step was obtained is dissolved in the 50ml methyl alcohol, adds self-control sodium ethylate (0.2g sodium is added in the 10ml ethanol), stirs 2 hours under the room temperature, adds the 1ml Glacial acetic acid.Concentrate and reclaim solvent, the hydrochloric acid that adds 20ml volumetric molar concentration 6mol/L, be heated to backflow, keep refluxing 3 hours, naturally cool to room temperature, the sodium hydroxide solution that adds 2mol/L is regulated the pH value 10～11, after organic phase extracts with methylene dichloride (40ml * 2), anhydrous sodium sulfate drying concentrates the crude product that obtains compound 4, and reactions steps is as follows:
Compound 4 crude products finally obtain the compound 4 of 3.5g (purity 98%) through the Virahol recrystallization purifying.
(C) compound 4 gets compound 5 through acetylize, protects through protecting group to make compound 6 again again
Add 55ml methyl alcohol, 5.5g compound 4,3.0ml triethylamine and 11ml methyl dichloroacetate in the 250ml there-necked flask successively, 35 ℃ were reacted 20 hours, and concentrating under reduced pressure reclaims methyl alcohol then, add 50ml toluene in concentrated solution, 50ml water stirred 30 minutes, filter, make compound 5.
Compound 5 is dissolved in the 60ml methylene dichloride, the tosic acid that adds 2-methoxyl group propylene and catalytic amount, compound 5 reacts with the reaction mol ratio with 2-methoxyl group propylene at 1: 1.5, and 40 ℃ were stirred 3 hours down, add the 50ml saturated solution of sodium bicarbonate under the room temperature, stirred separatory, water dichloromethane extraction 30 minutes, merge organic phase, anhydrous sodium sulfate drying, concentrate 7g compound 6, reactions steps is as follows:
(D) compound 6 makes compound 7 through reduction
Compound 6 is dissolved in the 20ml methyl alcohol, 2.5g KBH4 is dissolved in the 10ml water, then the KBH4 drips of solution is added in the reaction system, the control rate of addition maintains the temperature at below 50 ℃, dropwises under the room temperature of back to stir 5 hours, filter compound 7 crude products, crude product can be used the Virahol recrystallization purifying, obtains 3.2g compound 7 at last, and reactions steps is as follows:
(E) compound 7 makes compound 8 through fluoridizing, and makes the compound florfenicol through hydrolysis again
3.0g compound 7 is mixed with the 30ml methylene dichloride, stir nitrogen protection; add 2.1ml Ishikawa reagent (Ishikawa reagent) under the room temperature, then, change system over to autoclave; 100 ℃ were reacted 2 hours down, naturally cooled to room temperature, reaction system is changed over to carry out hydrolysis again in the 250ml there-necked flask.Hydrolytic process is: adding 20ml concentration is the hydrochloric acid of 6mol/L, be heated to backflow, keep refluxing 4 hours, naturally cool to room temperature, the sodium hydroxide solution adjust pH that adds 30ml concentration 2mol/L, with methylene dichloride (40ml * 3) extracted organic phase, merge organic phase, anhydrous sodium sulfate drying, concentrate the florfenicol crude product, crude product gets 0.8g with ethyl alcohol recrystallization, the white solid florfenicol of purity 99%, and reactions steps is as follows:
Claims (9)
1, a kind of synthetic method of florfenicol is characterized in that: with compound 1 is raw material, through protecting group protection, configuration conversion, hydrolysis, acetylize, protect again, reduce, fluoridize, the process of hydrolysis again obtains florfenicol, be expressed as follows with reaction formula:
R, R ' they are protecting group, wherein,
Protecting group R is a kind of in Benzoyl chloride, phthalic anhydride, benzene nitrile, the allylic compound;
Protecting group R ' is a kind of in phthalic anhydride, benzene nitrile, the allylic compound.
2, the synthetic method of a kind of florfenicol according to claim 1 is characterized in that: described protecting group R and R ' are identical or different.
3, the synthetic method of a kind of florfenicol according to claim 1 and 2 is characterized in that: described compound 1 obtains compound 2 through the protecting group protection, and wherein, protecting group is R;
Described compound 5 is protected through protecting group again and is obtained compound 6, and wherein, protecting group is R '.
4, the synthetic method of a kind of florfenicol according to claim 3; it is characterized in that: described compound 1 is 1: 1 with protecting group R, compound 5 with the mol ratio of protecting group R '～and 3; reacted 1～10 hour down at 20～80 ℃, used organic solvent is a kind of or its combination in methyl alcohol, ethanol, methylene dichloride, the ethylene dichloride.
5, the synthetic method of a kind of florfenicol according to claim 1 is characterized in that: described configuration is converted to compound 2 in the presence of sodium ethylate or sodium methylate, at room temperature carries out configuration conversion and obtains compound 3.
6, the synthetic method of a kind of florfenicol according to claim 1, it is characterized in that: described compound 3 obtains compound 4 through hydrolysis, wherein, use the hydrochloric acid hydrolysis open loop, the volumetric molar concentration of hydrochloric acid is 1～10mol/L, or uses the sulphuric acid hydrolysis open loop, and the vitriolic volumetric molar concentration is 0.5～6mol/L, compound 3 is 1: 3～8 with hydrochloric acid or vitriolic mol ratio, reacts 2～10 hours down at 20～80 ℃.
7, the synthetic method of a kind of florfenicol according to claim 1, it is characterized in that: described compound 6 obtains compound 7 through reduction, and wherein, reductive agent is POTASSIUM BOROHYDRIDE or sodium borohydride, compound 6 is 1: 1～5 with the mol ratio of reductive agent, reacts 3～8 hours down at 20～60 ℃.
8, the synthetic method of a kind of florfenicol according to claim 1, it is characterized in that: described compound 8 obtains florfenicol through hydrolysis again, wherein, use the hydrochloric acid hydrolysis open loop, the volumetric molar concentration of hydrochloric acid is 1～10mol/L, or uses the sulphuric acid hydrolysis open loop, and the vitriolic volumetric molar concentration is 0.5～6mol/L, compound 8 is 1: 3～8 with hydrochloric acid or vitriolic mol ratio, reacts 2～10 hours down at 20～80 ℃.
9, the synthetic method of a kind of florfenicol according to claim 1 is characterized in that: described compound 4, compound 7 and florfenicol crude product need carry out recrystallization purifying, a kind of as in Virahol, ethanol, the sherwood oil of the recrystallization solvent that uses.
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| CN102417472A (en) * | 2011-12-12 | 2012-04-18 | 齐鲁动物保健品有限公司 | Preparation method of florfenicol |
| CN103936638A (en) * | 2014-04-16 | 2014-07-23 | 湖北美天生物科技有限公司 | Synthetic method of florfenicol |
| CN103980166A (en) * | 2014-04-17 | 2014-08-13 | 天津大学 | New florfenicol crystal form and preparation method thereof |
| CN103980167A (en) * | 2014-04-17 | 2014-08-13 | 天津大学 | Amorphous florfenicol and preparation method thereof |
| CN104370782A (en) * | 2014-11-29 | 2015-02-25 | 郑州后羿制药有限公司 | Florfenicol refining method |
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| CN103936638A (en) * | 2014-04-16 | 2014-07-23 | 湖北美天生物科技有限公司 | Synthetic method of florfenicol |
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| CN103980167A (en) * | 2014-04-17 | 2014-08-13 | 天津大学 | Amorphous florfenicol and preparation method thereof |
| CN103980166B (en) * | 2014-04-17 | 2016-06-22 | 天津大学 | A kind of novel crystal forms of florfenicol and preparation method thereof |
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| CN106278964B (en) * | 2016-07-31 | 2018-01-16 | 浙江润康药业有限公司 | The preparation method of Florfenicol |
| CN106278964A (en) * | 2016-07-31 | 2017-01-04 | 浙江润康药业有限公司 | The preparation method of florfenicol |
| CN106316898A (en) * | 2016-08-04 | 2017-01-11 | 湖北美天生物科技股份有限公司 | Method for synthesis of florfenicol |
| CN106316898B (en) * | 2016-08-04 | 2018-06-01 | 湖北美天生物科技股份有限公司 | The synthetic method of Florfenicol |
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| CN111153838A (en) * | 2020-01-19 | 2020-05-15 | 浙江大学宁波理工学院 | Synthetic method of florfenicol |
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| CN114656388A (en) * | 2020-12-23 | 2022-06-24 | 苏州引航生物科技有限公司 | Method for preparing florfenicol intermediate |
| CN114656388B (en) * | 2020-12-23 | 2024-01-30 | 苏州引航生物科技有限公司 | Method for preparing florfenicol intermediate |
| CN112321467A (en) * | 2020-12-30 | 2021-02-05 | 苏州开元民生科技股份有限公司 | Preparation method of (2S,3R) -p-methylsulfonylphenylserine ethyl ester |
| WO2022166848A1 (en) * | 2021-02-05 | 2022-08-11 | 浙江普洛康裕制药有限公司 | Method for synthesizing (1r,2r)-ampp by using enzyme cascade reaction |
| CN117466787A (en) * | 2023-12-28 | 2024-01-30 | 山东国邦药业有限公司 | Preparation method of florfenicol intermediate |
| CN117466787B (en) * | 2023-12-28 | 2024-03-22 | 山东国邦药业有限公司 | Preparation method of florfenicol intermediate |
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