73231-34-2

Basic information

• Product Name: Florfenicol
• Synonyms: (r-(r*,s*))-methyleste;2,2-dichloro-n-(1-(fluoromethyl)-2-hydroxy-2-(4-(methylsulfonyl)phenyl)ethyl;4-(2-((dichloroacetyl)amino)-3-fluoro-1-hydroxypropyl)-benzenesulfonicaci;FLORFENICOL;AQUAFEN;2,2-dichloro-n-[(1r,2s)-3-fluoro-1-hydroxy-1-(4-methylsulfonylphenyl)propan-2-yl]acetamide;NUFLOR;[r-(r*, r*)]-n-[1-(fluoromethyl)-2-hydroxy-2-(4-(methylsulforyl)phenyl)-ethyl]-2,2-dichloroacetamide
• CAS NO: 73231-34-2
• Molecular Formula: C₁₂H₁₄Cl₂FNO₄S
• Molecular Weight: 358.21
• EINECS: 1806241-263-5
• Product Categories: FEED ADDITIVES;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;API;Antimicrobials
• Mol File: 73231-34-2.mol

Chemical Properties

• Melting Point: 153 °C
• Boiling Point: 618℃
• Flash Point: >110°(230°F)
• Appearance: /solid
• Density: 1.451 g/cm³
• Vapor Pressure: 4.05E-12mmHg at 25°C
• Refractive Index: 1.575
• Storage Temp.: 0-6°C
• Solubility: Soluble in ethanol to 25mM and in DMSO to 100mM
• PKA: 10.73±0.46(Predicted)
• Merck: 14,4109
• CAS DataBase Reference: Florfenicol(CAS DataBase Reference)
• NIST Chemistry Reference: Florfenicol(73231-34-2)
• EPA Substance Registry System: Florfenicol(73231-34-2)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36
• WGK Germany: 3
• RTECS: DB6034000
• Hazardous Substances Data: 73231-34-2(Hazardous Substances Data)

Usage

Veterinary antibiotics

Florfenicol is currently a commonly used veterinary antibiotic with a broad antibacterial spectrum and a strong antibacterial effect as well as a low the minimum inhibitory concentration (MIC). The antibacterial of florfenicol is about 15-20 times as high as that of chloramphenicol and the thiamphenicol. After administration through feed for 60 minutes, the drug concentration in the tissue can reach peak which can quickly control the disease with having characteristics such as being safe, non-toxic, no residue, and no risk for triggering aplastic anemia. Therefore, it is quite suitable for large-scale farms application. It is mainly used for the treatment of bovine respiratory disease caused by Pasteurella and Haemophilus. It has good efficacy in treating the cattle footrot disease cause by Fusobacterium, and can be also used for treating the infection diseases of pigs and chickens caused by sensitive strains as well as the bacterial disease of fish. It is not easy for bacteria to evolve resistance against florfenicol: Because it has a fluorine atom which replaces the hydroxyl group on the molecular structure of thiamphenicol, thus effectively solving the drug resistant issue of chloramphenicol, and thiamphenicol. Bacteria which are resistant to thiamphenicol, chloramphenicol, amoxicillin, and quinolone remain sensitive to the chemicals. Since chloramphenicol can result in severe adverse reactions such as aplastic anemia and immune suppression, it is banned from being applied in food animal production. Studies have demonstrated that: the major group in the chemical structure of chloramphenicol which causes aplastic anemia is para-nitro in the aromatic ring. Instead, florfenicol has the CH3SO4 which replaces the NO2 groups so that its chemical structure has been changed. In this case, its application to animal will not cause any adverse reactions such as aplastic anemia. Therefore, it is approved for application in more than a dozen of countries such as Japan, Mexico and China. Florfenicol is characterized by: a broad spectrum antibiotic; Salmonella, Escherichia coli, Proteus, Haemophilus, Actinobacillus pleuropneumoniae, Mycoplasma hyopneumoniae, Streptococcus Suis, swine Pasteurella, Bordetclla bronchiseptica, and Staphylococcus aureus are all sensitive to it. The drug is easy for absorbing and is widely distributed in the body and is quick-acting and long-acting formulations with no potential risk of causing aplastic anemia risks and thus having a better security. In addition, it has an affordable price which is cheaper than other drugs for prevention and treatment of respiratory diseases such as tiamulin, tilmicosin, and azithromycin. The cost of medication is easy for users to accept. Because of all these excellent characteristics, domestic florfenicol is widely applied and has currently become the first-choice drug for prevention and treatment of livestock respiratory diseases and gastrointestinal bacterial infection diseases. Florfenicol is not suitable to be applied in combination with quinolones, penicillins, and cephalosporins, and it has no compatibility with ampicillin, sulfonamides, and furans. The above information is edited by the lookchem of Dai Xiongfeng.

Pharmacological effects

Florfenicol binds tightly with the 50S subunit of the bacterial ribosome and block the transpeptidation reaction mediated by peptidyl transferase, and thereby suppressing the elongation process of the peptide chain; meanwhile selectively acts on the bacterial 70S ribosome receptors and changes, interferes with the function of peptidyl transferase enzyme. Therefore, it interferes with the bacterial protein synthesis based on dual mechanism.

Indications

Florfenicol can strongly interfere with the bacterial protein synthesis. It has a rapid absorption rate and is widely distributed in the body; it has long half-life without side effects such as aplastic anemia; not easy for bacteria to evolve drug resistance, and has no cross-resistance. Florfenicol can be used for the treatment of the systemic infection of livestock and aquatic animals, and has significant efficacy on treating respiratory infections and intestinal infections. Poultry: Escherichia coli disease, salmonellosis, infectious rhinitis, chronic respiratory disease, duck plague and other kinds of mixed infections caused by susceptible strains. Animals: Mixed infections such as infectious pleurisy, asthma, streptococcal disease, Escherichia coli disease, salmonellosis, contagious pleuropneumonia, enzootic pneumonia, paratyphoid piglets yellow white diarrhea, edema disease, atrophic rhinitis, lung epidemic, red white diarrhea piglets, and agalactia syndrome occurred in animals such as pigs, cows, and sheep. Crab: appendages ulcer disease, yellow gills, rotten gill, red legs and red fluorescent body inflammatory disease syndrome. Turtle: red neck disease, furunculosis, shot-hole disease, skin fester disease, inflammatory bowel disease, mumps, and bacterial sepsis. Frogs: cataract syndrome, ascites disease, sepsis, enteritis. Fish: enteritis disease, ascites disease, vibriosis, Edward coli disease. Eel: debonding septicemia (unique effect), Edward coli disease, red skin disease, inflammatory bowel disease.

Uses

Different sources of media describe the Uses of 73231-34-2 differently. You can refer to the following data:
1. It is a kind of antibacterial drug. It is used as the veterinary antimicrobial drugs for treating bacterial diseases of pigs, chickens and fish. It has good efficacy in treating the infection disease of pigs, chickens and fish induced by sensitive bacteria, especially for treating respiratory infections and intestinal infections.
2. Florfenicol is a fluorinated derivative of thiamphenicol. It is a protein synthesis inhibitor that inhibits bacterial protein synthesis by binding to ribosome 50S and 70S subunits. Florfenicol is used as an antibacterial.

Chemical Properties

White or off-white crystalline powder, odorless. Easily soluble in dimethylformamide, soluble in methanol, slightly soluble in glacial acetic acid, very slightly soluble in water or chloroform.

Definition

ChEBI: Florfenicol is a carboxamide that is the N-dichloroacetyl derivative of (1R,2S)-2-amino-3-fluoro-1-[4-(methanesulfonyl)phenyl]propan-1-ol. A synthetic veterinary antibiotic that is used for treatment of bovine respiratory disease and foot rot; also used in aquaculture. It has a role as an antimicrobial agent. It is a sulfone, a secondary alcohol, an organofluorine compound, an organochlorine compound and a secondary carboxamide. It is functionally related to a dichloroacetic acid.

Preparation

Florfenicol is synthesised from thiamphenicol by replacing the 3-hydroxy group with fluorine, first synthesised at Schering in 1980. By replacing the hydroxy group, it was rationalised that chloramphenicol resistance via chloramphenicol acetyltransferase could be eliminated. Florfenicol is a broad spectrum antibiotic with good activity against Gram negative and anaerobic bacteria. It acts by binding to the 23S sub-unit of the 50S ribosome, inhibiting protein synthesis. Florfenicol has been extensively studied with over 400 literature citations.

Veterinary Drugs and Treatments

The drug is approved for use in cattle only (in the USA) for the treatment of bovine respiratory disease (BRD) associated with Pasteurella haemolytica, Pasteurella multocida, and Haemophilus somnus. Because florfenicol has activity against a wide range of microorganisms (e.g., Mycoplasma), it may be useful for treating other infections in cattle (or other species) as well, but specific data is limited.

InChI:InChI=1/C12H14Cl2FNO2S/c1-19-8-4-2-7(3-5-8)10(17)9(6-15)16-12(18)11(13)14/h2-5,9-11,17H,6H2,1H3,(H,16,18)

Synthetic route

(4S,5R)-2-dichloromethyl-4-fluoromethyl-4,5-dihydro-5-(4-(methylsulfonyl)phenyl)oxazoline (143026-79-3) → Florfenicol (73231-34-2)

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 70℃; for 5h; pH=6;	99%
With potassium acetate In methanol; water; isopropyl alcohol for 3h; Heating; pH 5; Yield given;
With ammonium hydroxide; water at 25℃;
With sodium acetate In water; isopropyl alcohol for 3h; pH=5; Reflux;	4.15 g
In water; isopropyl alcohol at 80℃; for 1h;	9.2 g

dichloroacetic acid methyl ester (116-54-1) + (1R,2S)-2-amino-3-fluoro-1-<4-(methylsulphonyl)phenyl>-1-propanol (76639-93-5, 105182-37-4, 118015-48-8) → Florfenicol (73231-34-2)

Conditions	Yield
With triethylamine In methanol at 20℃;	96%
With triethylamine In methanol for 18h; Ambient temperature;	84%
With triethylamine for 3.5h; Heating; Yield given;

(1R,2S)-1-(4-methylsulfonylphenyl)-2-benzylamino-3-fluoro-1-propanol (895571-10-5) + ethyl 1,1-dichloroacetate (535-15-9) → Florfenicol (73231-34-2)

Conditions	Yield
Stage #1: (1R,2S)-1-(4-methylsulfonylphenyl)-2-benzylamino-3-fluoro-1-propanol With sulfuric acid; hydrogen; palladium on activated charcoal In ethanol at 20℃; for 2h; Stage #2: ethyl 1,1-dichloroacetate With triethylamine In methanol at 30℃; for 6h; Further stages.;	96%

(1R,2S)-2-amino-3-fluoro-1-(4-methylsulphonylphenyl)-1-propanol hydrochloride + dichloroacetic acid methyl ester (116-54-1) → Florfenicol (73231-34-2)

Conditions	Yield
With triethylamine In methanol Heating;	95%
With sodium hydrogencarbonate In methanol at 50℃; for 16h;	5.6 g
With triethylamine In methanol at 50℃; for 10h;	7.1 g

C12H12Cl2FNO3S → Florfenicol (73231-34-2)

Conditions	Yield
With methanol; sodium acetate at 60℃; for 1h; Reagent/catalyst;	95%

D-threo-2-(dichloromethyl)-5-(4-methanesulfonylphenyl)-4,5-dihydro-1,3-oxazol-4-yl methanol (126813-11-4) → Florfenicol (73231-34-2)

Conditions	Yield
With fluorosulfonyl fluoride; N-ethyl-N,N-diisopropylamine In dichloromethane at 15 - 25℃; under 1520.1 - 2280.15 Torr; for 24h;	93%
Multi-step reaction with 2 steps 1: CF3CHCF2NEt2 / CH2Cl2 / 2 h / 100 °C 2: KOAc / methanol; propan-2-ol; H2O / 3 h / Heating; pH 5 View Scheme
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 25 °C 2: triethylamine tris(hydrogen fluoride) / acetonitrile / 10 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: phosgene / dichloromethane / 16 h / 20 - 25 °C / Cooling with ice 2: sodium fluoride / N,N-dimethyl-formamide / 7 h / 80 °C / Inert atmosphere 3: hydrogenchloride / isopropyl alcohol; water / 5 h / 70 °C / pH 6 View Scheme

dichloroacetic acid methyl ester (116-54-1) + (1R,2S)-3-fluoro-1-(4-(methylsulfonyl)phenyl)-2-nitropropan-1-ol → Florfenicol (73231-34-2)

Conditions	Yield
Stage #1: (1R,2S)-3-fluoro-1-(4-(methylsulfonyl)phenyl)-2-nitropropan-1-ol With palladium 10% on activated carbon; hydrogen In methanol Stage #2: dichloroacetic acid methyl ester With triethylamine In methanol at 20℃; for 18h;	70%

C13H15Cl2NO6S2 (96795-01-6) → Florfenicol (73231-34-2)

Conditions	Yield
With triethylamine tris(hydrogen fluoride) In acetonitrile for 10h; Reflux;	65%

dichloroacetic acid methyl ester (116-54-1) + (4S,5R)-4-fluoromethyl-5-<4-(methylsulphonyl)phenyl>-2-oxazolidinone (108656-28-6) → Florfenicol (73231-34-2)

Conditions	Yield
Stage #1: (4S,5R)-4-fluoromethyl-5-<4-(methylsulphonyl)phenyl>-2-oxazolidinone With sodium hydroxide In ethanol at 80℃; for 3h; Stage #2: With sodium acetate In tetrahydrofuran at 0℃; for 0.166667h; Stage #3: dichloroacetic acid methyl ester In tetrahydrofuran at 25℃; for 5h;	56%

2,2-dichloro-N-{(4R,5R)-4-[4-(methylsulfonyl)phenyl]-2,2-dioxido-1,3,2-dioxathian-5-yl}acetamide → Florfenicol (73231-34-2)

Conditions	Yield
Stage #1: 2,2-dichloro-N-{(4R,5R)-4-[4-(methylsulfonyl)phenyl]-2,2-dioxido-1,3,2-dioxathian-5-yl}acetamide With triethylamine tris(hydrogen fluoride) In 1,2-dichloro-ethane at 70℃; for 8h; Stage #2: With hydrogenchloride In ethyl acetate at 0℃; for 2h;	35%

florfenicol phosphate (857859-74-6) → C12H14Cl2NO7PS + Florfenicol (73231-34-2)

Conditions	Yield
With sodium hydroxide In water pH=4.54 - 5.53; Conversion of starting material;	A 0.17% B 0.93%
With ethanolamine In water pH=4.48 - 5.51; Conversion of starting material;	A 0.18% B 0.7%

dichloroacetic acid methyl ester (116-54-1) + (1R,2S)-2-(2,3-dimethylbenzoyl)amino-3-fluoro-1-<4-(methylsulphonyl)phenyl>-1-propanol (108656-27-5) → thiamphenicol (15318-45-3) + Florfenicol (73231-34-2)

Conditions	Yield
With hydrogenchloride; triethylamine 1.) 120 deg C, 5 h, 2.) 80 deg C, 2 h; Yield given. Multistep reaction. Yields of byproduct given;

(1R,2R)-2-(2,2-dichloro-acetylamino)-1-(4-methylsulfanyl-phenyl)-propane-1,3-diol (4302-89-0) → Florfenicol (73231-34-2)

Conditions	Yield
Multistep reaction;

dichloroacetic acid methyl ester (116-54-1) + (1R,2S)-2-amino-3-fluoro-1-<4-(methylsulphonyl)phenyl>-1-propanol (76639-93-5, 105182-37-4, 118015-48-8) → (1R,2S)-2-Dichloroacetamido-3-Fluoro-1-[4-(Methylsulfonyl)Phenyl]-1-Propanol(Florfenicol) + Florfenicol (73231-34-2)

Conditions	Yield
In methanol; water; toluene

para-methanesulfonylbenzaldehyde (5398-77-6) → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 7 steps 1: 83 percent / piperidine / pyridine / 4 h / 95 - 100 °C 2: 1.) SOCl2, 2.) NaBH4 / 1) reflux, 1 h; 2) CH2Cl2, EtOH, 10 deg C, 1 h 3: 82 percent / 4 Anstroem molecular sieves, diisopropyl L-tartrate, Ti(OPr-i)4, t-BuOOH / CH2Cl2; 2,2,4-trimethyl-pentane / 4 h / -20 °C 4: 1.) NaH, 2.) ZnCl2, 3.) 4 Angstroem molecular sieves / 1) THF, 5 deg C, 30 min; 2) THF, 5 deg C, 30 min; 3) THF, 55 deg C, 16 h 5: 1.) Et3N, MeSO2Cl, 2.) aq. NaOH / 1) pyridine, 5 deg C, 2 h; 2) pyridine, pH 12.5 6: CF3CHCF2NEt2 / CH2Cl2 / 2 h / 100 °C 7: KOAc / methanol; propan-2-ol; H2O / 3 h / Heating; pH 5 View Scheme
Multi-step reaction with 7 steps 1.1: ethanol / 3 h / Inert atmosphere; Reflux 2.1: (2R)-(+)-3,3'-diphenyl-[2,2'-dinaphthalene]-1,1'-diol; triphenylborane / toluene / 0.17 h / 20 °C / Molecular sieve; Inert atmosphere 2.2: 19 h / -10 - 20 °C / Molecular sieve; Inert atmosphere 3.1: lithium borohydride / tetrahydrofuran / 50 °C / Inert atmosphere 3.2: 1 h / 20 °C / Inert atmosphere 4.1: diethylamino-sulfur trifluoride; triethylamine / dichloromethane / 8 h / -40 - 20 °C / Inert atmosphere 5.1: water; toluene-4-sulfonic acid / acetonitrile / 24 h / 40 °C / Inert atmosphere 5.2: Inert atmosphere 6.1: hydrogenchloride; palladium 10% on activated carbon; hydrogen / methanol; water / 6 h / 20 °C / 760.05 Torr 7.1: triethylamine / methanol / 3 h / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide / dichloromethane; ethanol / 0 - 20 °C 1.2: 1 h / 20 °C / Cooling with ice 2.1: thionyl chloride / 8 h / 0 - 60 °C 2.2: 2 h / 20 - 60 °C 3.1: hydrogenchloride / water; methanol / 6 h / Reflux 3.2: 8 h / 0 - 60 °C 3.3: 6 h / 20 °C 4.1: sodium tetrahydroborate; methanol / 5 h / 0 - 20 °C 5.1: triethylamine; thionyl chloride / dichloromethane / 0 °C 5.2: 20 °C 6.1: triethylamine tris(hydrogen fluoride) / 1,2-dichloro-ethane / 8 h / 70 °C 6.2: 2 h / 0 - 20 °C 7.1: triethylamine / methanol / Heating View Scheme

3-(4-methanesulfonyl-phenyl)-acrylic acid (5345-30-2, 88899-85-8) → Florfenicol (73231-34-2)

Conditions

Yield

Multi-step reaction with 6 steps 1: 1.) SOCl2, 2.) NaBH4 / 1) reflux, 1 h; 2) CH2Cl2, EtOH, 10 deg C, 1 h 2: 82 percent / 4 Anstroem molecular sieves, diisopropyl L-tartrate, Ti(OPr-i)4, t-BuOOH / CH2Cl2; 2,2,4-trimethyl-pentane / 4 h / -20 °C 3: 1.) NaH, 2.) ZnCl2, 3.) 4 Angstroem molecular sieves / 1) THF, 5 deg C, 30 min; 2) THF, 5 deg C, 30 min; 3) THF, 55 deg C, 16 h 4: 1.) Et3N, MeSO2Cl, 2.) aq. NaOH / 1) pyridine, 5 deg C, 2 h; 2) pyridine, pH 12.5 5: CF3CHCF2NEt2 / CH2Cl2 / 2 h / 100 °C 6: KOAc / methanol; propan-2-ol; H2O / 3 h / Heating; pH 5 View Scheme

(1R,2R)-2-amino-1-<4-(methylsulphonyl)phenyl>-1,3-propanediol (51458-28-7) → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 88 percent / conc. H2SO4 / propan-2-ol / 1) 70 deg C, 1.5-2 h; 2) 50 deg C, 14 h 2: CF3CHCF2NEt2 / CH2Cl2 / 2 h / 100 °C 3: KOAc / methanol; propan-2-ol; H2O / 3 h / Heating; pH 5 View Scheme
Multi-step reaction with 6 steps 1: K2CO3 / H2O / 1 h / Ambient temperature 2: EtONa / ethanol 3: 40 percent / (2-chloro-1,1,2-trifluoroethyl)diethylamine / acetonitrile / 1.) room temp., 1 h, 2.) reflux, 3 h 4: 1.) BuLi / 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30 min; room temp., 1 h 5: 70 percent / KOH / methanol / 7 h / -30 °C 6: 1.) 6N HCl, 2.) Et3N / 1.) 120 deg C, 5 h, 2.) 80 deg C, 2 h View Scheme
Multi-step reaction with 4 steps 1: 95 percent / K2CO3 / glycerol / 18 h / 115 °C 2: 95 percent Chromat. / (1,1,2,3,3,3-hexafluoropropyl)diethylamine (FPA) / CH2Cl2 / 2 h / 100 °C / 5171.5 Torr 3: 95 percent / 6 N HCl / 12 h / 100 - 105 °C 4: 84 percent / Et3N / methanol / 18 h / Ambient temperature View Scheme

(E)-3-(4-(methylsulfonyl)phenyl)prop-2-en-1-ol (125872-64-2) → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 82 percent / 4 Anstroem molecular sieves, diisopropyl L-tartrate, Ti(OPr-i)4, t-BuOOH / CH2Cl2; 2,2,4-trimethyl-pentane / 4 h / -20 °C 2: 1.) NaH, 2.) ZnCl2, 3.) 4 Angstroem molecular sieves / 1) THF, 5 deg C, 30 min; 2) THF, 5 deg C, 30 min; 3) THF, 55 deg C, 16 h 3: 1.) Et3N, MeSO2Cl, 2.) aq. NaOH / 1) pyridine, 5 deg C, 2 h; 2) pyridine, pH 12.5 4: CF3CHCF2NEt2 / CH2Cl2 / 2 h / 100 °C 5: KOAc / methanol; propan-2-ol; H2O / 3 h / Heating; pH 5 View Scheme
Multi-step reaction with 10 steps 1: tert.-butylhydroperoxide; C3H7O(1-)*C34H32N2O4(2-)*V(3+) / dichloromethane; water / 72 h / 0 °C 2: N,N-dimethyl-formamide / 10 h / 20 °C 3: sodium hydride / N,N-dimethyl-formamide / 1 h / 20 °C 4: triethylamine / dichloromethane / 2 h / 0 - 20 °C 5: 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 8 h / 90 °C 6: potassium hydroxide / methanol; water / 1 h / Reflux; Inert atmosphere 7: palladium 10% on activated carbon; formic acid / methanol / 10 h / 20 °C / Inert atmosphere 8: hydrogenchloride / water; isopropyl alcohol / 16 h / 50 - 70 °C 9: Nonafluorobutanesulfonyl fluoride; triethylamine tris(hydrogen fluoride); triethylamine / tetrahydrofuran / 12 h / 20 °C 10: sodium acetate / water; isopropyl alcohol / 3 h / pH 5 / Reflux View Scheme

(S,S)-3-[4-(methylsulfonyl)phenyl]-2,3-epoxypropyl alcohol → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) NaH, 2.) ZnCl2, 3.) 4 Angstroem molecular sieves / 1) THF, 5 deg C, 30 min; 2) THF, 5 deg C, 30 min; 3) THF, 55 deg C, 16 h 2: 1.) Et3N, MeSO2Cl, 2.) aq. NaOH / 1) pyridine, 5 deg C, 2 h; 2) pyridine, pH 12.5 3: CF3CHCF2NEt2 / CH2Cl2 / 2 h / 100 °C 4: KOAc / methanol; propan-2-ol; H2O / 3 h / Heating; pH 5 View Scheme
Multi-step reaction with 9 steps 1: N,N-dimethyl-formamide / 10 h / 20 °C 2: sodium hydride / N,N-dimethyl-formamide / 1 h / 20 °C 3: triethylamine / dichloromethane / 2 h / 0 - 20 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 8 h / 90 °C 5: potassium hydroxide / methanol; water / 1 h / Reflux; Inert atmosphere 6: palladium 10% on activated carbon; formic acid / methanol / 10 h / 20 °C / Inert atmosphere 7: hydrogenchloride / water; isopropyl alcohol / 16 h / 50 - 70 °C 8: Nonafluorobutanesulfonyl fluoride; triethylamine tris(hydrogen fluoride); triethylamine / tetrahydrofuran / 12 h / 20 °C 9: sodium acetate / water; isopropyl alcohol / 3 h / pH 5 / Reflux View Scheme

(3S,4R)-2-(dichloromethyl)-4,5-dihydro-α-[4-(methylsulfonyl)phenyl]oxazole-4-methanol (157142-64-8) → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) Et3N, MeSO2Cl, 2.) aq. NaOH / 1) pyridine, 5 deg C, 2 h; 2) pyridine, pH 12.5 2: CF3CHCF2NEt2 / CH2Cl2 / 2 h / 100 °C 3: KOAc / methanol; propan-2-ol; H2O / 3 h / Heating; pH 5 View Scheme

(2R,3S,9bRS)-3-(mesyloxymethyl)-2-<4-(methylsulphonyl)phenyl>-2,3-dihydrooxazolo<2,3-a>isoindol-5(9bH)-one → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 27 percent Chromat. / hexadecyltributylphosphonium chloride, potassium fluoride hydrate / toluene; H2O / 7 h / Heating 2: 2N HCl / 6 h / Heating 3: Et3N / 3.5 h / Heating View Scheme

(2R,3R,9bRS)-3-hydroxymethyl-2-<4-(methylsulphonyl)phenyl>-2,3-dihydrooxazolo<2,3-a>isoindol-5(9bH)-one → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92.8 percent / pyridine / 0 °C 2: 27 percent Chromat. / hexadecyltributylphosphonium chloride, potassium fluoride hydrate / toluene; H2O / 7 h / Heating 3: 2N HCl / 6 h / Heating 4: Et3N / 3.5 h / Heating View Scheme

(2R,3S,9bRS)-3-fluoromethyl-2-<4-(methylsulphonyl)phenyl>-2,3-dihydrooxazolo<2,3-a>isoindol-5(9bH)-one → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2N HCl / 6 h / Heating 2: Et3N / 3.5 h / Heating View Scheme

(R*,R*)-(+)-thiomicamine (23150-35-8) → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 7 steps 1: K2CO3 / H2O / 1 h / Ambient temperature 2: t-BuOK / ethanol / 3 h / Heating 3: 81 percent / H2O2 / H2O / 20 h / 45 °C 4: 40 percent / (2-chloro-1,1,2-trifluoroethyl)diethylamine / acetonitrile / 1.) room temp., 1 h, 2.) reflux, 3 h 5: 1.) BuLi / 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30 min; room temp., 1 h 6: 70 percent / KOH / methanol / 7 h / -30 °C 7: 1.) 6N HCl, 2.) Et3N / 1.) 120 deg C, 5 h, 2.) 80 deg C, 2 h View Scheme
Multi-step reaction with 7 steps 1: K2CO3 / H2O / 1 h / Ambient temperature 2: t-BuOK / toluene / 3 h / Heating 3: 81 percent / H2O2 / H2O / 20 h / 45 °C 4: 40 percent / (2-chloro-1,1,2-trifluoroethyl)diethylamine / acetonitrile / 1.) room temp., 1 h, 2.) reflux, 3 h 5: 1.) BuLi / 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30 min; room temp., 1 h 6: 70 percent / KOH / methanol / 7 h / -30 °C 7: 1.) 6N HCl, 2.) Et3N / 1.) 120 deg C, 5 h, 2.) 80 deg C, 2 h View Scheme
Multi-step reaction with 4 steps 1: 1.) K2CO3, 2.) CH3CO3H / 1.) ethylene glycol, glycerol, 105 deg C, 18 h, 2.) AcOH, 20-25 deg C , 1 h 2: 95 percent Chromat. / (1,1,2,3,3,3-hexafluoropropyl)diethylamine (FPA) / CH2Cl2 / 2 h / 100 °C / 5171.5 Torr 3: 95 percent / 6 N HCl / 12 h / 100 - 105 °C 4: 84 percent / Et3N / methanol / 18 h / Ambient temperature View Scheme
Multi-step reaction with 4 steps 1: 1.) K2CO3, 2.) CH3CO3H / 1.) ethylene glycol, glycerol, 105 deg C, 18 h, 2.) AcOH, 20-25 deg C , 1 h 2: (2-chloro-1,1,2-trifluoroethyl)diethylamine (FAR) / CH2Cl2 / 5 h / 100 °C 3: 95 percent / 6 N HCl / 12 h / 100 - 105 °C 4: 84 percent / Et3N / methanol / 18 h / Ambient temperature View Scheme

(4R,5R)-4-hydroxymethyl-5-<4-(methylthio)phenyl>-2-oxazolidinone (96795-21-0) → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 81 percent / H2O2 / H2O / 20 h / 45 °C 2: 40 percent / (2-chloro-1,1,2-trifluoroethyl)diethylamine / acetonitrile / 1.) room temp., 1 h, 2.) reflux, 3 h 3: 1.) BuLi / 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30 min; room temp., 1 h 4: 70 percent / KOH / methanol / 7 h / -30 °C 5: 1.) 6N HCl, 2.) Et3N / 1.) 120 deg C, 5 h, 2.) 80 deg C, 2 h View Scheme

(1R,2R)-2-ethoxycarbonylamino-1-<4-(methylthio)phenyl>-1,3-propanediol (96795-20-9) → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: t-BuOK / ethanol / 3 h / Heating 2: 81 percent / H2O2 / H2O / 20 h / 45 °C 3: 40 percent / (2-chloro-1,1,2-trifluoroethyl)diethylamine / acetonitrile / 1.) room temp., 1 h, 2.) reflux, 3 h 4: 1.) BuLi / 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30 min; room temp., 1 h 5: 70 percent / KOH / methanol / 7 h / -30 °C 6: 1.) 6N HCl, 2.) Et3N / 1.) 120 deg C, 5 h, 2.) 80 deg C, 2 h View Scheme
Multi-step reaction with 6 steps 1: t-BuOK / toluene / 3 h / Heating 2: 81 percent / H2O2 / H2O / 20 h / 45 °C 3: 40 percent / (2-chloro-1,1,2-trifluoroethyl)diethylamine / acetonitrile / 1.) room temp., 1 h, 2.) reflux, 3 h 4: 1.) BuLi / 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30 min; room temp., 1 h 5: 70 percent / KOH / methanol / 7 h / -30 °C 6: 1.) 6N HCl, 2.) Et3N / 1.) 120 deg C, 5 h, 2.) 80 deg C, 2 h View Scheme

(4R,5R)-4-hydroxymethyl-5-<4-(methylsulphonyl)phenyl>-2-oxazolidinone (96795-22-1) → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 40 percent / (2-chloro-1,1,2-trifluoroethyl)diethylamine / acetonitrile / 1.) room temp., 1 h, 2.) reflux, 3 h 2: 1.) BuLi / 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30 min; room temp., 1 h 3: 70 percent / KOH / methanol / 7 h / -30 °C 4: 1.) 6N HCl, 2.) Et3N / 1.) 120 deg C, 5 h, 2.) 80 deg C, 2 h View Scheme
Multi-step reaction with 3 steps 1: hexafluoropropene-diethylamine adduct / dichloromethane / 1 h / 105 - 110 °C / Autoclave 2: hydrogenchloride / 1 h / Reflux 3: triethylamine / methanol / 20 °C View Scheme

(4S,5R)-4-fluoromethyl-5-<4-(methylsulphonyl)phenyl>-2-oxazolidinone (108656-28-6) → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) BuLi / 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30 min; room temp., 1 h 2: 70 percent / KOH / methanol / 7 h / -30 °C 3: 1.) 6N HCl, 2.) Et3N / 1.) 120 deg C, 5 h, 2.) 80 deg C, 2 h View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / 1 h / Reflux 2: triethylamine / methanol / 20 °C View Scheme

(1R,2R)-2-ethoxycarbonylamino-1-<4-(methylsulphonyl)phenyl>-1,3-propanediol (108656-26-4) → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: EtONa / ethanol 2: 40 percent / (2-chloro-1,1,2-trifluoroethyl)diethylamine / acetonitrile / 1.) room temp., 1 h, 2.) reflux, 3 h 3: 1.) BuLi / 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30 min; room temp., 1 h 4: 70 percent / KOH / methanol / 7 h / -30 °C 5: 1.) 6N HCl, 2.) Et3N / 1.) 120 deg C, 5 h, 2.) 80 deg C, 2 h View Scheme

(4S,5R)-N-(2,3-dimethylbenzoyl)-4-fluoromethyl-5-<4-(methylsulphonyl)phenyl>-2-oxazolidinone (108656-29-7) → Florfenicol (73231-34-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 70 percent / KOH / methanol / 7 h / -30 °C 2: 1.) 6N HCl, 2.) Et3N / 1.) 120 deg C, 5 h, 2.) 80 deg C, 2 h View Scheme

succinic acid (110-15-6) + Florfenicol (73231-34-2) → sodium 4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propoxy)-4-oxobutanoate (1073342-32-1)

Conditions	Yield
Stage #1: succinic acid; Florfenicol With triethylamine In ethyl acetate at 20℃; for 1h; Stage #2: With sodium hydrogencarbonate In ethyl acetate at 0 - 5℃; for 2h; Solvent;	97.8%

N-benzyloxycarbonyl-L-alanyl chloride (49760-60-3) + Florfenicol (73231-34-2) → florfenicol-N-Cbz-L-alanine ester

Conditions	Yield
With triethylamine In 1,2-dichloro-ethane at 20 - 90℃; for 10h; Reagent/catalyst; Solvent; Temperature;	94.3%

Florfenicol (73231-34-2) + methyl chloroformate (79-22-1) → (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl methyl carbonate

Conditions	Yield
With dmap; triethylamine In tetrahydrofuran at 0℃;	93%

N-Z-Leucine chloride (87052-59-3) + Florfenicol (73231-34-2) → florfenicol-N-Cbz-L-leucine ester

Conditions	Yield
With pyridine In chloroform at 20℃; for 8h; Reflux;	89.64%

succinic acid anhydride (108-30-5) + Florfenicol (73231-34-2) → 4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propoxy)-4-oxobutanoic acid (1073342-33-2)

Conditions	Yield
With dmap In acetone at 60℃; for 4h;	88.1%
With dmap In acetone at 40 - 70℃;

Z-(L)-Val-Cl (87052-60-6) + Florfenicol (73231-34-2) → florfenicol-N-Cbz-L-valine ester

Conditions	Yield
With pyridine; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 10h; Reflux;	83.29%

Florfenicol (73231-34-2) → bis((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl) hydrogen phosphate (1450713-53-7)

Conditions	Yield
Stage #1: Florfenicol With pyridine; trichlorophosphate In acetonitrile at 0 - 25℃; for 12.5h; Stage #2: With water In acetonitrile at 0 - 25℃; for 8.16667h; Reagent/catalyst; Solvent;	80.72%

(S)-benzyloxycarbonyl-proline acid chloride (61350-60-5, 61350-62-7, 89705-40-8, 106709-50-6) + Florfenicol (73231-34-2) → florfenicol-N-Cbz-L-proline ester

Conditions	Yield
With pyridine In chloroform at 20℃; for 10h; Reflux;	70.39%

ethylenebis(chloroformate) (124-05-0) + Florfenicol (73231-34-2) → bis((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl)ethane-1,2-diyl dicarbonate

Conditions	Yield
With dmap; triethylamine In tetrahydrofuran at 0 - 20℃;	62%

Florfenicol (73231-34-2) + 2-O-benzoyl-3,4,6-tri-O-benzyl-β-D-glucopyranoside (148926-02-7) → 2,2-dichloro-N-[(1R,2S)-3-fluoro-1-(2-O-benzoyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyloxy)-1-(4-methanesulfonylphenyl)propan-2-yl]acetamide

Conditions	Yield
Stage #1: 2-O-benzoyl-3,4,6-tri-O-benzyl-β-D-glucopyranoside With trifluoromethylsulfonic anhydride; beta-pinene In dichloromethane at -50℃; for 0.75h; Stage #2: Florfenicol In dichloromethane at -50 - 20℃; for 18h; stereoselective reaction;	55%

N,O-bis-(trimethylsilyl)-acetamide (10416-59-8) + Florfenicol (73231-34-2) → 2,2-Dichloro-N-[(1S,2R)-1-fluoromethyl-2-(4-methanesulfonyl-phenyl)-2-trimethylsilanyloxy-ethyl]-acetamide

Conditions	Yield
In acetonitrile at 50℃; for 0.166667h;

Upstream product

• 96-34-4 methyl chloroacetate 
• 895571-10-5 (1R,2S)-1-(4-methylsulfonylphenyl)-2-benzylamino-3-fluoro-1-propanol 
• 535-15-9 ethyl 1,1-dichloroacetate 
• 1470142-33-6 (4S,5R)-4-(fluoromethyl)-5-phenyloxazolidin-2-one 
• 1470142-34-7 4-((4S,5R)-4-(fluoromethyl)-2-oxooxazolidin-5-yl)benzene-1-sulfonyl chloride 
• 15318-45-3 thiamphenicol 
• 157142-64-8 (3S,4R)-2-(dichloromethyl)-4,5-dihydro-α-[4-(methylsulfonyl)phenyl]oxazole-4-methanol 
• 126813-11-4 D-threo-2-(dichloromethyl)-5-(4-methanesulfonylphenyl)-4,5-dihydro-1,3-oxazol-4-yl methanol 
• 125872-64-2 (E)-3-[4-(methylsulfonyl)phenyl]prop-2-en-1-ol 
• 51458-28-7 (1R,2R)-2-amino-1-<4-(methylsulphonyl)phenyl>-1,3-propanediol 
• 5345-30-2 3-(4-methanesulfonyl-phenyl)-acrylic acid 
• 5398-77-6 para-methanesulfonylbenzaldehyde 
• 116-54-1 dichloroacetic acid methyl ester 
• 76639-93-5 (1R,2S)-2-amino-3-fluoro-1-<4-(methylsulphonyl)phenyl>-1-propanol 

Downstream Products

• 76639-93-5 (1R,2S)-2-amino-3-fluoro-1-<4-(methylsulphonyl)phenyl>-1-propanol 
• 864529-18-0 C₁₂H₁₃BrCl₂FNO₃S 
• 1073342-32-1 sodium 4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propoxy)-4-oxobutanoate 
• 75-75-2 methanesulfonic acid 
• 5398-77-6 para-methanesulfonylbenzaldehyde 
• 100-52-7 benzaldehyde 
• 65-85-0 benzoic acid 
• 1431545-23-1 C₁₇H₁₈FNO₆S 
• 1450713-53-7 bis((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl) hydrogen phosphate 
• 1073342-33-2 4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propoxy)-4-oxobutanoic acid 

Relevant articles and documents

Synthesis method of florfenicol

The invention discloses a synthesis method of florfenicol, which comprises the following steps: by using (4R,5R)-2-dichloromethyl-4,5-dihydro-5-[4-(methylsulfonyl)phenyl]-4-oxazolemethanol (compound Ifor short) as a reaction raw material, carrying out chlorination, fluorination and hydrolysis to obtain florfenicol. The method has the advantages of cheap and easily available raw materials, simpleprocess operation, environmental protection and no pollution, accords with the industrialization concept of green production, and has extremely high industrialization value.

METHODS FOR PREPARING FLORFENIOL AND INTERMEDIATE THEREOF

The present invention discloses a method for preparing florfenicol and its intermediate (V), comprising an addition reaction, a ring closure reaction, a hydrolysis reaction, a ring opening reaction, a reduction reaction, a ring reaction, a fluorination reaction and a ring opening reaction. In the present method for preparing florfenicol, respective reaction steps can be continuously operated, therefore the methods of the present invention features simplified process and shorter synthetic route, and obtained florfenicol has high chiral purity and is of high yield. The method of the present invention for preparing florfenicol (TM) using the intermediate (V) avoids waste water pollution and reduces the cost for treating wastewater and alleviates environmental pollution. At the same time, the methods of the present invention eliminates a chiral resolution procedure, thus increasing the utilization rate of atoms in the reaction. As a result, cost is reduced and process is simplified.

Method for continuously preparing florfenicol based on micro-reaction system

The invention provides a method for continuously preparing florfenicol based on a micro-reaction system. The preparation method comprises the following steps: respectively pumping an organic solution of a raw material {(4R, 5R)-2-(dichloromethyl)-5-[4-(methylsulfonyl) phenyl]-4, 5-dihydrooxazole-4-yl} methanol and an organic solution of a fluorinating reagent into a micro-mixer for mixing; introducing into a first micro-channel reactor for continuous fluorination reaction, and concentrating; obtaining a crude product; dissolving the crude product in alcohol and water, pumping into a second microchannel reactor, carrying out continuous hydrolysis ring-opening reaction, and separating and purifying a reaction product to obtain a florfenicol product. According to the method provided by the invention, the reaction time is only several minutes, the yield of the product florfenicol is greater than 95%, the operation is convenient, continuous and controllable, the amplification effect is avoided, the efficiency of the technological process is high, and the method has a very good industrial application prospect.

Catalytic Syn-Selective Nitroaldol Approach to Amphenicol Antibiotics: Evolution of a Unified Asymmetric Synthesis of (-)-Chloramphenicol, (-)-Azidamphenicol, (+)-Thiamphenicol, and (+)-Florfenicol

A unified strategy for an efficient and high diastereo- and enantioselective synthesis of (-)-chloramphenicol, (-)-azidamphenicol, (+)-thiamphenicol, and (+)-florfenicol based on a key catalytic syn-selective Henry reaction is reported. The stereochemistry of the ligand-enabled copper(II)-catalyzed aryl aldehyde Henry reaction of nitroethanol was first explored to forge a challenging syn-2-amino-1,3-diol structure unit with vicinal stereocenters with excellent stereocontrol. Multistep continuous flow manipulations were carried out to achieve the efficient asymmetric synthesis of this family of amphenicol antibiotics.

Unified Strategy to Amphenicol Antibiotics: Asymmetric Synthesis of (-)-Chloramphenicol, (-)-Azidamphenicol, and (+)-Thiamphenicol and Its (+)-3-Floride

The asymmetric synthesis of (-)-chloramphenicol, (-)-azidamphenicol, and (+)-thiamphenicol and its (+)-3-floride, (+)-florfenicol, is reported. This approach toward the amphenicol antibiotic family features two key steps: (1) a cinchona alkaloid derived urea-catalyzed aldol reaction allows highly enantioselective access to oxazolidinone gem-diesters and (2) a continuous flow diastereoselective decarboxylation of thermally stable oxazolidinone gem-diesters to form the desired trans-oxazolidinone monoesters with two adjacent stereocenters that provide the desired privileged scaffolds of syn-vicinal amino alcohols in the amphenicol family.

Florfenicol synthesis method

The invention relates to a florfenicol synthesis method. The method comprises the step of carrying out a ring opening reaction on a product obtained by fluorinating a compound I by using sulfuryl fluoride as a fluorination reagent in a water-containing system to easily prepare florfenicol. The method has the advantages of simple operation, few by-products, safety, environmental protection, low production cost and the like, and is very suitable for industrial use.

Synthetic method of florfenicol intermediate

The invention relates to a synthetic method of a florfenicol intermediate. The synthetic method comprises following specific steps: compound II is dissolved in an organic solvent, under alkaline conditions, methyl sulfonyylation is carried out so as to obtain compound III; the compound III is subjected to ring closing reaction under alkaline conditions so as to obtain compound IV; and the compoundIV is subjected to fluorination ring opening reaction so as to obtain the florfenicol intermediate I. The synthetic method is novel in design, mild in conditions, and convenient in operation, and issuitable for industrialized production.

Florfenicol intermediate synthesis method

The invention belongs to the field of synthesis of pharmaceutical raw materials, and specifically discloses a florfenicol intermediate synthesis method, which comprises: (1) carrying out a reaction ona compound (II) and an acylating reagent in an organic solvent to form a compound (III); (2) carrying out a reaction on the compound (III) and an oxidizing agent in an organic solvent in the presenceof a catalyst to form a compound (IV); (3) carrying out a reaction on the compound (IV) and a fluorinating reagent in an organic solvent to form a compound (V); and (4) carrying out acidolysis on thecompound (V) in an organic solvent, and carrying out deprotection to obtain a compound (I), wherein various groups in the formulas are defined in the specification. According to the present invention, the florfenicol intermediate can be used for preparing florfenicol; and the method has characteristics of novel design, mild conditions and simple operation, and is suitable for industrial production.

Method for preparing fluorinating reagent and fluoride continuously by microchannel reactor

The invention discloses a method for preparing a fluorinating reagent and fluoride continuously by a microchannel reactor. The method comprises the following steps: introducing a mixed solution of amine and a solvent as well as fluorine-containing olefin into the microchannel reactor separately, performing reaction at the reaction temperature of subzero 20 to 30 DEG C for 30 to 180 seconds to prepare the fluorinating reagent, introducing the fluorinating reagent and a compound A into the microchannel reactor, performing mixing, heating and reaction to obtain a compound B, and performing hydrolysis reaction on the reaction liquid of the compound B to obtain a compound C. The method is simple to operate and safe to use, the use amount of the materials is greatly reduced, the process is environmentally-friendly and continuous, and the risk of high pressure and high temperature is avoided, so that high-yield continuous production of the fluorinating agent or fluoride is feasible. The comprehensive yield of the fluoride reaches 90 to 95 percent, basic quantitative reaction of the fluorinating reagent is realized and industrialized production is facilitated.

Asymmetric Synthesis of Florfenicol by Dynamic Reductive Kinetic Resolution with Ketoreductases

A chemoenzymatic synthesis of the veterinary antibiotic florfenicol is described. The key step involves the dynamic reductive kinetic resolution (DYRKR) of a keto ester by using a ketoreductase-02 (KRED-02) to afford the two contiguous stereocenters of the (2S,3R)-cis-1,2-amino alcohol intermediate in >99 % ee and a diastereomeric ratio (dr) of 99 %. This green biocatalysis is environmental friendly with high enantioselectivity and product yields. Two methods for the nucleophilic fluorination step involved the use of aziridines and cyclic sulfates to safely prepare fluoroamines with high regioselectivity. Additional studies have indicated that KRED-02 can also be used to afford chiral alcohol (S)-21 in good yields with high enantioselectivity. This study shows that the integration of biocatalysis into organic synthesis can be useful and provide industrial opportunities for applications of florfenicol.