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WO2020238779A1 - Procédé pour la synthèse de florfénicol - Google Patents

Procédé pour la synthèse de florfénicol Download PDF

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Publication number
WO2020238779A1
WO2020238779A1 PCT/CN2020/091701 CN2020091701W WO2020238779A1 WO 2020238779 A1 WO2020238779 A1 WO 2020238779A1 CN 2020091701 W CN2020091701 W CN 2020091701W WO 2020238779 A1 WO2020238779 A1 WO 2020238779A1
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Prior art keywords
florfenicol
waste liquid
another preferred
reaction
compound
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Ceased
Application number
PCT/CN2020/091701
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English (en)
Chinese (zh)
Inventor
朱文峰
郭朋
黄嘉慧
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Shanghai Vastpro Technology Development Co Ltd
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Shanghai Vastpro Technology Development Co Ltd
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Priority to CN202080038005.7A priority Critical patent/CN113874351B/zh
Publication of WO2020238779A1 publication Critical patent/WO2020238779A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F9/00—Multistage treatment of water, waste water or sewage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/40—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F1/00—Treatment of water, waste water, or sewage
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F1/00—Treatment of water, waste water, or sewage
    • C02F1/001—Processes for the treatment of water whereby the filtration technique is of importance
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F1/00—Treatment of water, waste water, or sewage
    • C02F1/02—Treatment of water, waste water, or sewage by heating
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2101/00—Nature of the contaminant
    • C02F2101/10—Inorganic compounds
    • C02F2101/12—Halogens or halogen-containing compounds
    • C02F2101/14—Fluorine or fluorine-containing compounds
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2101/00—Nature of the contaminant
    • C02F2101/30—Organic compounds
    • C02F2101/36—Organic compounds containing halogen
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2103/00—Nature of the water, waste water, sewage or sludge to be treated
    • C02F2103/34—Nature of the water, waste water, sewage or sludge to be treated from industrial activities not provided for in groups C02F2103/12 - C02F2103/32
    • C02F2103/343—Nature of the water, waste water, sewage or sludge to be treated from industrial activities not provided for in groups C02F2103/12 - C02F2103/32 from the pharmaceutical industry, e.g. containing antibiotics
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2103/00—Nature of the water, waste water, sewage or sludge to be treated
    • C02F2103/34—Nature of the water, waste water, sewage or sludge to be treated from industrial activities not provided for in groups C02F2103/12 - C02F2103/32
    • C02F2103/36—Nature of the water, waste water, sewage or sludge to be treated from industrial activities not provided for in groups C02F2103/12 - C02F2103/32 from the manufacture of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a method for synthesizing florfenicol.
  • Florfenicol also known as fluprofen, florfenicol, etc.
  • Fluprofen florfenicol
  • Florfenicol is the 3-position fluorine derivative of thiamphenicol in chloramphenicol broad-spectrum antibacterial drugs. It is mainly used for the prevention and treatment of animal diseases and livestock Treatment of systemic infections in poultry and aquatic animals, etc.
  • the production and export of florfenicol in my country have been increasing, and it has been listed in the list of my country's pharmaceutical raw materials with an annual export value of more than 100 million US dollars, attracting attention.
  • Florfenicol 2,2-Dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(methylsulfonyl)phenyl)propan-2- Yl)acetamide, its chemical structure is shown in the following formula:
  • the fluorination step adopts the Ishikawa reagent fluorination method for fluorination.
  • the fluorinated reagent accounts for about 15% of the total material cost.
  • the actual amount of the process is 1.5 times the theoretical amount of the chemical reaction, and the theoretical utilization rate of the fluorine atom is only one-sixth, causing a large amount of fluorine-containing materials to become waste.
  • Ishikawa reagent N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine
  • N,N-diethyl-2,3,3,3-tetrafluoropropionamide is difficult to recycle, and its fluorine-containing wastewater cannot meet the discharge standard.
  • the poisoning effect of the treatment system is very serious.
  • factory production usually adopts off-the-shelf methods.
  • the production process of this reagent requires ultra-low temperature, high pressure, high temperature and other conditions, which increases energy consumption and safety risks.
  • the purpose of the present invention is to provide a simpler, more environmentally friendly and economical synthesis method of florfenicol suitable for industrialization.
  • the first aspect of the present invention provides a method for preparing florfenicol, the method comprising the steps:
  • the compound I is subjected to a fluorination reaction with a fluorinating reagent to obtain a reaction mixture containing compound II;
  • the fluorinating reagent is sulfuryl fluoride;
  • reaction mixture containing compound II obtained in the foregoing step is subjected to a ring-opening reaction to obtain florfenicol.
  • the inert solvent is selected from the following group: acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran or a combination thereof.
  • the amount ratio of compound I to the inert solvent is 1 kg: 5-15 kg or liter; preferably 1 kg: 7-10 kg or liter.
  • the amount of the fluorinating reagent is 1 to 1.5 times that of compound I.
  • the organic base is selected from the group consisting of triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or a combination thereof.
  • step (1) the amount of the organic base is 1 to 1.5 times that of compound I.
  • step (1) the amount of the organic base is 1.2 to 1.5 times that of compound I.
  • the temperature of the fluorination reaction is -15 to 30 degrees; preferably -15 to 0 degrees.
  • step (1) when the fluorination reaction is carried out, the system pressure is 1 to 3 atmospheres or 1 to 2 atmospheres or 2 to 3 atmospheres.
  • the fluorination reaction time is 1 hour to 24 hours.
  • step (1) after the fluorination reaction is completed, the reaction mixture is concentrated, and the concentrated mixture is a reaction mixture containing compound II, which is directly used in step (2) without separation.
  • the aqueous system is a mixture of C1-6 alkyl alcohol and water.
  • the C1-6 alkyl alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol.
  • the volume dosage (liter) of the aqueous system is 5-10 times the weight dosage (kg) of Compound I; preferably 7-8 times.
  • the water content in the water-containing system is 20%-40%.
  • the water content in the water-containing system is 20%-30%; more preferably, the water content is 25%-30%.
  • step (2) the temperature of the ring-opening reaction is 60-100 degrees.
  • the temperature of the ring-opening reaction is 80-85 degrees.
  • step (2) the time of the ring-opening reaction is 1 hour to 10 hours; preferably 2 to 4 hours.
  • step (2) after the ring-opening reaction is completed, the reaction mixture is filtered to collect the solid as florfenicol.
  • step (2) after the completion of the ring-opening reaction and before the filtration, the method further includes cooling the reaction mixture after the completion of the reaction (for example, cooling to 0-10 degrees).
  • step (2) after step (2), it further includes step (3): recrystallize the florfenicol obtained in step (2) in an aqueous system, filter after crystallization, and collect the solids to obtain purification Florfenicol.
  • the aqueous system is a mixture of C1-6 alkyl alcohol and water.
  • the C1-6 alkyl alcohol is methanol, ethanol, n-propanol, isopropanol or tert-butanol.
  • the water content in the aqueous system is 20%-40%; preferably 25%-30%.
  • the volume dosage (liter) of the aqueous system is 5-10 times the weight dosage (kg) of Compound I; preferably 7-8 times.
  • the recrystallization includes the steps of: first dissolving the florfenicol obtained in step (2), and then cooling and standing for crystallization.
  • the cooling includes: first cooling to 20-25°C; then cooling to 5-10°C.
  • the purified florfenicol obtained in step (3) meets the standards of the Pharmacopoeia sold in the People's Republic of China.
  • the waste liquid treatment step (4) is further included: the waste liquid obtained by the preparation method and the sodium hydroxide aqueous solution are heated and refluxed, and the The fluorine atoms in the waste liquid are converted into fluorine ions.
  • the sodium hydroxide aqueous solution is a 5%-20% sodium hydroxide aqueous solution by weight; preferably 5%-15% sodium hydroxide aqueous solution.
  • the weight of the sodium hydroxide aqueous solution is equivalent to the weight of the waste liquid obtained in the previous step.
  • the heating and refluxing treatment is 1-10 hours; preferably 1-8 hours; more preferably 3-6 hours.
  • step (5) is included after step (4); the waste liquid processed in step (4) is treated with lime water, and after filtration, the filtrate reaches the discharge standard of the industrial park.
  • the weight of the lime water is equivalent to the weight of the waste liquid obtained in the previous step.
  • the said meeting the emission standard of the industrial park means that the content of fluoride ion in the filtrate is ⁇ 10 ppm.
  • the waste liquid obtained by the preparation method in step (4) is the filtrate obtained in step (2) and/or step (3).
  • the second aspect of the present invention provides a method for processing waste liquid, the waste liquid is the waste liquid produced by the preparation method described in the first aspect; the method includes the step of heating the waste liquid and the sodium hydroxide aqueous solution Reflux treatment converts fluorine atoms into fluoride ions; then after lime water treatment, a waste liquid meeting the discharge standards of the industrial park is formed.
  • the sodium hydroxide aqueous solution is a 5%-20% sodium hydroxide aqueous solution by weight; preferably 5%-15% sodium hydroxide aqueous solution.
  • the weight of the sodium hydroxide aqueous solution is equivalent to the weight of the waste liquid obtained in the previous step.
  • the heating and refluxing treatment is 1-10 hours; preferably 1-8 hours; more preferably 3-6 hours.
  • the weight of the lime water is equivalent to the weight of the waste liquid obtained in the previous step.
  • the fluoride ion content in the waste liquid that meets the discharge standard of the industrial park is less than or equal to 10 ppm.
  • the synthesis method of the present invention has the advantages of simple operation, fewer by-products, safety and environmental protection, and low production cost, and is suitable for industrial production.
  • the inventor unexpectedly discovered a production method of florfenicol that is very suitable for industrialization.
  • the method uses sulfuryl fluoride as a fluorination reagent to fluorinate compound I. After the reaction, the fluorine The chemical product can be put into the ring-opening reaction without additional purification and separation, thereby obtaining florfenicol.
  • the post-treatment of the waste liquid generated by the production method is very simple, and only sodium hydroxide and lime water are used successively, and the waste liquid can meet the industrial discharge standard.
  • the fluorinated reagent has a stable source and low cost, which can greatly reduce the cost of the fluorination reaction.
  • the synthesis cost of florfenicol is also greatly reduced, which is very suitable for industrialization.
  • the present invention provides a method for preparing florfenicol, the method comprising the steps:
  • step (a) the amount ratio of compound I to the inert solvent is 1 kg: 5-15 kg or liter; preferably 1 kg: 7-10 kg or liter.
  • the inert solvent is selected from the group consisting of acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran or a combination thereof.
  • the amount of the fluorinating reagent is 1 to 2.0 times that of compound I; preferably 1 to 1.5 times.
  • the organic base is selected from the following group: triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or a combination thereof.
  • step (a) the amount of the organic base is 1 to 1.5 times that of Compound I; preferably 1.2 to 1.5 times.
  • the temperature of the fluorination reaction is -15 to 30 degrees; preferably -15 to 0 degrees.
  • step (a) when the fluorination reaction is carried out, the system pressure is 1 to 3 atmospheres or 1 to 2 atmospheres or 2 to 3 atmospheres.
  • step (a) the fluorination reaction time is 1 hour to 24 hours.
  • the aqueous system is a mixture of C1-6 alkyl alcohol and water.
  • the C1-6 alkyl alcohol is methanol, ethanol, n-propanol, isopropanol or tert-butanol.
  • the water content in the water-containing system is 20%-40%; more preferably, the water content is 25%-30%.
  • the temperature of the ring-opening reaction is 60-100 degrees; preferably 80-85 degrees.
  • the ring-opening reaction time is 1 hour to 10 hours; preferably 2 to 4 hours.
  • step (b) after the ring-opening reaction is completed, the reaction mixture is filtered to collect the solid as florfenicol.
  • step (b) after the completion of the ring-opening reaction and before the filtration, it further includes cooling the reaction mixture after the completion of the reaction (for example, cooling to 0-10 degrees).
  • step (b) after step (b), it further includes step (c): recrystallize the florfenicol obtained in step (b) in an aqueous system, filter after crystallization, and collect the solid to obtain a purified Florfenicol.
  • the aqueous system is a mixture of C1-6 alkyl alcohol and water.
  • the C1-6 alkyl alcohol is methanol, ethanol, n-propanol, isopropanol or tert-butanol.
  • the water content in the aqueous system is 20%-40%; preferably 25%-30%.
  • the recrystallization includes the steps of: first dissolving the florfenicol obtained in step (2), and then cooling and standing for crystallization.
  • the cooling includes: first cooling to 20-25°C; then cooling to 5-10°C.
  • the purified florfenicol obtained in step (c) meets the standards of the Pharmacopoeia of the People's Republic of China.
  • the invention also provides a waste liquid treatment method.
  • the treatment method of the waste liquid includes a sodium hydroxide treatment step: the waste liquid and the sodium hydroxide aqueous solution are heated and refluxed, so that all the fluorine atoms in the waste liquid are converted into fluorine ions.
  • the waste liquid treatment method further includes a lime water treatment step: the sodium hydroxide treated waste liquid obtained in the above steps is treated with lime water and filtered to form a waste liquid meeting the discharge standard of the industrial park.
  • the fluoride ion content in the waste liquid that meets the discharge standard of the industrial park is less than or equal to 10 ppm.
  • the waste liquid may be the filtrate obtained in step (b) and/or step (c).
  • the waste liquid of the present invention contains the compound salt of fluorosulfonic acid and organic base and excess sulfuryl fluoride.
  • sulfuryl fluoride is used as a fluorination reagent, no additional fluorine source is needed, and the utilization rate of fluorine atoms is high, and the utilization rate can reach 50%.
  • the fluorinated reagent is a widely used fumigant sulfuryl fluoride, with stable source and low cost, and the amount of the fluorinated reagent is small, so the cost of the fluorinated reagent is reduced by more than 50%.
  • the reaction of each step does not require harsh operations such as ultra-low temperature, high temperature, high pressure, etc., and no complicated post-treatment between steps. This method is safer, more economical and simpler.
  • the reaction yield of the preparation method of the invention is high and the product quality meets the standard.
  • the by-product is single, and all the fluorine atoms in the waste liquid can be converted into recoverable fluoride ions after simple treatment. Moreover, the waste liquid can meet the discharge standards of the industrial park after simple treatment. Therefore, this method is more environmentally friendly.
  • the method of the present invention is very suitable as an industrial production method for florfenicol.
  • the equivalent used in the present invention refers to a molar equivalent.
  • compound I is 1 equivalent and diisopropylethylamine is 1.4 equivalents, which means that the molar ratio of compound I and diisopropylethylamine is 1:1.4. The rest is similar.
  • the “volume” of the solvent or solution used in the present invention refers to the weight-volume ratio of the raw material (such as compound I) or the crude product and the solvent (kg/liter), for example, in Example 1, “add compound I (1 equivalent), Acetonitrile (8 volumes)” means that the weight-volume ratio of compound I to solvent is 1 kg compound I: 8 liters of solvent.
  • “the crude product is recrystallized in 7 volumes of 30% isopropanol aqueous solution” it means that the weight-volume ratio of the crude product to the 30% isopropanol aqueous solution is 1 kg crude product: 7 liters of 30% isopropanol aqueous solution. The rest is similar.
  • the "weight” of the solvent or solution used in the present invention refers to the weight-to-weight ratio of the raw material (such as compound I) and the solvent (kg/kg). For example, if 10 weights of the solvent are used in Example 2, it means the weight of the compound I and the solvent The weight-to-weight ratio is 1 kg of compound I: 10 kg of solvent. The rest is similar.
  • the Pharmacopoeia of the People's Republic of China in the present invention is the first part of the 2010 edition of the Pharmacopoeia of the People's Republic of China.
  • the filter cake is washed with water and drained. It was dried in a vacuum oven at 60-65 degrees Celsius for 16 hours to obtain a white solid, which met the standards of the Pharmacopoeia of the People’s Republic of China, with a yield of 93.0%.
  • Waste liquid treatment method the mother liquor after the crude florfenicol is recrystallized, the isopropanol is separated by concentration first, sodium hydroxide solid of 10% by weight of the remaining liquid is added, and the temperature is cooled after refluxing and stirring for 5 hours.
  • the nuclear magnetic fluorine spectrum test showed that all the acid fluoride in the waste liquid was converted into fluoride ion at this time.
  • sodium fluoride can also be separated from the treated waste liquid and recycled, which greatly improves the utilization rate of fluorine atoms.
  • the production method of florfenicol of the present invention greatly reduces the production cost. Considering the compliance of factory environment and safety management standards, the florfenicol production method of the present invention discards the pollution and dangerous production process, and is more in line with the unprecedented situation of current environmental protection and safety compliance supervision. Important economic and social significance.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hydrology & Water Resources (AREA)
  • Engineering & Computer Science (AREA)
  • Environmental & Geological Engineering (AREA)
  • Water Supply & Treatment (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé pour la synthèse de florfénicol. Le procédé comprend les étapes consistant à : utiliser du fluorure de sulfuryle en tant que réactif de fluoration pour fluorer le composé I pour obtenir un produit, puis effectuer une réaction d'ouverture de cycle dans un système aqueux, de sorte que du florfénicol peut être facilement préparé. Le procédé selon la présente invention est simple à mettre en œuvre, produit peu de sous-produits, est sans danger et respectueux de l'environnement, a un faible coût de production et est approprié pour une utilisation industrielle.
PCT/CN2020/091701 2019-05-24 2020-05-22 Procédé pour la synthèse de florfénicol Ceased WO2020238779A1 (fr)

Priority Applications (1)

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CN202080038005.7A CN113874351B (zh) 2019-05-24 2020-05-22 一种氟苯尼考的合成方法

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CN201910438274.1 2019-05-24
CN201910438274.1A CN111978218A (zh) 2019-05-24 2019-05-24 一种氟苯尼考的合成方法

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Cited By (1)

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CN118084747A (zh) * 2024-04-28 2024-05-28 山东国邦药业有限公司 一种氟苯尼考的制备方法

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CN116789702B (zh) * 2023-06-15 2024-11-26 浙江工业大学 一种膦酸化合物的氟化方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006098444A1 (fr) * 2005-03-18 2006-09-21 Central Glass Company, Limited Procede de production d’un derive fluore
CN101578254A (zh) * 2007-01-23 2009-11-11 中央硝子株式会社 用于生产光学活性α-氟代羧酸酯的方法
US20110166359A1 (en) * 2008-07-30 2011-07-07 Paquette Leo A Process for preparing oxazoline-protected aminodiol compounds useful as intermediates to florfenicol
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