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Florfenicol intermediate state compound, and method for preparing florfenicol intermediate

A technology of florfenicol and intermediates, which is applied in the field of steroid hormone preparation and can solve problems such as hidden dangers of safety, release of dichloromethane, and harm to the environment of operators.

Pending Publication Date: 2020-03-13
HUNAN NORCHEM PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] According to statistics, the global consumption of Florfenicol is about 7,000 tons per year. The current process requires the use of a 3,000-5,000L autoclave for this step. This method requires the use of dichloromethane as a solvent, and its boiling point is 39.75°C under normal pressure. , when the temperature is raised to about 100°C during the reaction, the pressure of the autoclave will rise to 6 atmospheres, which poses a great safety hazard
Once a leak occurs, it will inevitably cause a large amount of high-temperature dichloromethane to be released, which will seriously endanger the operator and the surrounding environment. At the same time, the reaction under high pressure also has a safety hazard of reactor explosion.

Method used

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  • Florfenicol intermediate state compound, and method for preparing florfenicol intermediate
  • Florfenicol intermediate state compound, and method for preparing florfenicol intermediate
  • Florfenicol intermediate state compound, and method for preparing florfenicol intermediate

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Embodiment 1

[0027] Such as Figure 4 Said microchannel reaction system includes a batching tank 1, a constant flow pump 2, a microchannel reactor 3, a back pressure valve 4 and a receiving tank 5 connected in sequence.

[0028] 30kg of dichloromethane and 3.1kg of diethylamine are pumped into batching kettle 1, and 7kg of hexafluoropropylene is passed through after cooling down to below -30°C. Stir for 30 minutes, add (4R, 5R)-2-dichloromethyl-4-hydroxymethyl-4,5-dihydro-5-(4-(methylsulfonyl)phenyl)oxazoline 10kg, Stir at room temperature for 1 hour to dissolve and obtain a solution, which contains the intermediate compound of Florfenicol.

[0029] Figure 5-6 As the raw material, the HPLC spectrum of (4R, 5R)-2-dichloromethyl-4-hydroxymethyl-4,5-dihydro-5-(4-(methylsulfonyl)phenyl)oxazoline and peak analysis tables.

[0030] Figure 3-4 It is the HPLC spectrum and peak analysis table of the intermediate state compound of Florfenicol.

[0031] In the above solution, the purity of th...

Embodiment 2

[0037] 30kg of dichloromethane and 3.1kg of diethylamine were pumped into the batching kettle, and 7kg of hexafluoropropylene was passed through after cooling down to below -30°C. Stir for 30 minutes, add (4R, 5R)-2-dichloromethyl-4-hydroxymethyl-4,5-dihydro-5-(4-(methylsulfonyl)phenyl)oxazoline 10kg, Stir at room temperature for 1 hour.

[0038] Adjust the pressure of the back pressure valve 4 to 1.7MPa, and the temperature of the external bath rises to 140°C. After the temperature is constant, start the constant flow pump 2, and pump the mixture in the batching kettle 1 into the microchannel reactor 3 at a flow rate of 100ml / min. Sampling and testing, the reaction is complete, the reaction solution in the receiving kettle 5 is concentrated to dryness under reduced pressure, 30 kg of isopropanol, 40 kg of water, and 4.5 kg of anhydrous sodium acetate are added, and the sample is tested after reflux reaction for 8 hours. Isopropanol, cooled to 20-25° C., centrifuged, and drie...

Embodiment 3

[0040] 30kg of dichloromethane and 3.1kg of diethylamine were pumped into the batching kettle, and 7kg of hexafluoropropylene was passed through after cooling down to below -30°C. Stir for 30 minutes, add (4R, 5R)-2-dichloromethyl-4-hydroxymethyl-4,5-dihydro-5-(4-(methylsulfonyl)phenyl)oxazoline 10kg, Stir at room temperature for 1 hour.

[0041] Adjust the pressure of the back pressure valve to 1.8MPa, and the temperature of the external bath rises to 150°C. After the temperature is constant, start the constant flow pump, pump the mixture in the batching kettle into the microchannel reactor at a flow rate of 150ml / min, and take samples from the effluent for detection. After the reaction is complete, concentrate the reaction solution in the receiving kettle to dryness under reduced pressure, add 30kg of isopropanol, 40kg of water, and 4.5kg of anhydrous sodium acetate, and take a sample for 8 hours of reflux reaction. to 20–25°C, centrifuge, and dry to obtain 10.23kg of florf...

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Abstract

The invention belongs to the field of steroid hormone preparation, and in particular relates to a florfenicol intermediate state compound and a method for preparing the florfenicol intermediate. The method comprises the following steps: adding (4R, 5R)-2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5-(4-(methylsulfonyl) phenyl) oxazoline into a prepared ishikawa reagent, uniformly stirring, and reacting to obtain a florfenicol intermediate compound; carrying out fluorination reaction of the florfenicol intermediate compound in a micro-channel reaction system at a temperature controlled to be 130 to 160 DEG C and pressure controlled to be 1.6 to 2.0Mpa to obtain the florfenicol intermediate. The florfenicol intermediate disclosed by the invention is a soluble substance, the reaction container is not blocked when the florfenicol intermediate is prepared by using the micro-channel reactor, and the method is safe and reliable.

Description

technical field [0001] The invention belongs to the field of steroid hormone preparation, and in particular relates to a florfenicol intermediate compound and a method for preparing the florfenicol intermediate. Background technique [0002] The current technology of producing Florfenicol all refers to the method disclosed by Clark in US5382673 in 1995, and (4R, 5R)-2-dichloromethyl-4-hydroxymethyl-4,5-dihydro- 5-(4-(thymphenyl) phenyl) oxazoline utilizes ishikawa reagent to realize the process of one-step primary hydroxyl fluorination, and this step reaction uses dichloromethane as solvent, reacts 2-3 hour under high temperature and high pressure, obtains The key intermediate of Florfenicol, namely (4S,5R)-2-dichloromethyl-4-fluoromethyl-4,5-dihydro-5-(4-(thymphenyl)phenyl) Oxazoline, and then catalyzed hydrolysis with potassium acetate to obtain Florfenicol. The reaction formula is as follows: [0003] [0004] According to statistics, the global consumption of Florf...

Claims

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Application Information

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IPC IPC(8): C07D263/14C07D263/10
CPCC07D263/14C07D263/10
Inventor 靳志忠刘喜荣曾春玲杨文杰
Owner HUNAN NORCHEM PHARMACEUTICAL CO LTD
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