CN110878060A - Florfenicol intermediate compound and method for preparing florfenicol intermediate - Google Patents
Florfenicol intermediate compound and method for preparing florfenicol intermediate Download PDFInfo
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- CN110878060A CN110878060A CN201911166590.4A CN201911166590A CN110878060A CN 110878060 A CN110878060 A CN 110878060A CN 201911166590 A CN201911166590 A CN 201911166590A CN 110878060 A CN110878060 A CN 110878060A
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- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 title claims abstract description 52
- 229960003760 florfenicol Drugs 0.000 title claims abstract description 52
- 150000001875 compounds Chemical class 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- BNTFCVMJHBNJAR-UHFFFAOYSA-N n,n-diethyl-1,1,2,3,3,3-hexafluoropropan-1-amine Chemical compound CCN(CC)C(F)(F)C(F)C(F)(F)F BNTFCVMJHBNJAR-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 7
- HCDGVLDPFQMKDK-UHFFFAOYSA-N hexafluoropropylene Chemical group FC(F)=C(F)C(F)(F)F HCDGVLDPFQMKDK-UHFFFAOYSA-N 0.000 claims description 6
- 238000003682 fluorination reaction Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 7
- 238000003756 stirring Methods 0.000 abstract description 10
- 239000003270 steroid hormone Substances 0.000 abstract description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 239000012295 chemical reaction liquid Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 238000005070 sampling Methods 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000005086 pumping Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
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- 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
- C07D263/14—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 with radicals substituted by oxygen atoms
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of steroid hormone preparation, and particularly relates to a florfenicol intermediate compound and a method for preparing a florfenicol intermediate, wherein the method for preparing the florfenicol intermediate comprises the steps of adding (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline into a prepared ishikawa reagent, uniformly stirring, and obtaining the florfenicol intermediate compound after the reaction is finished; the florfenicol intermediate compound is subjected to fluoro-reaction in a microchannel reaction system under the conditions that the temperature is controlled to be 130-160 ℃ and the pressure is 1.6-2.0 Mpa to obtain a florfenicol intermediate.
Description
Technical Field
The invention belongs to the field of preparation of steroid hormones, and particularly relates to a florfenicol intermediate compound and a method for preparing the florfenicol intermediate.
Background
The current process for producing florfenicol is disclosed in US5382673 by Clark in 1995, and a one-step primary hydroxyl fluorination process is realized by using (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline and ishikawa reagent, wherein dichloromethane is used as a solvent in the reaction step, the reaction is carried out at high temperature and high pressure for 2-3 hours to obtain a florfenicol key intermediate, namely (4S, 5R) -2-dichloromethyl-4-fluoromethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline, and the florfenicol is obtained by catalyzing and hydrolyzing with potassium acetate. The reaction formula is as follows:
according to statistics, the global use amount of florfenicol is about 7000 tons every year, the existing process needs to use a 3000-5000L autoclave for the reaction, dichloromethane is used as a solvent in the method, the boiling point of dichloromethane is 39.75 ℃ under normal pressure, the temperature is raised to about 100 ℃ during the reaction, the pressure of the autoclave is raised to 6 atmospheric pressures, and great potential safety hazards exist. Once leakage occurs, a large amount of high-temperature dichloromethane is inevitably discharged, operating personnel and nearby environment are seriously harmed, and meanwhile, the potential safety hazard of reaction kettle explosion also exists in the reaction under high pressure.
Disclosure of Invention
The florfenicol intermediate compound is a soluble substance, and when the florfenicol intermediate is prepared by using a microchannel reactor, a reaction container cannot be blocked, so that the florfenicol intermediate compound is safe and reliable.
The content of the invention comprises a florfenicol intermediate compound with a structural formula shown as the specification,
a method for preparing a florfenicol intermediate comprises the steps of adding (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline into an ishikawa reagent, uniformly stirring, and obtaining a florfenicol intermediate compound after the reaction is finished;
carrying out a fluoro reaction on the florfenicol intermediate compound in a microchannel reaction system under the conditions that the temperature is controlled to be 130-160 ℃ and the pressure is 1.6-2.0 Mpa to obtain a florfenicol intermediate;
the reaction formula is as follows:
the ishikawa reagent is prepared by introducing hexafluoropropylene into a diethylamine solution. The solvent used for the diethylamine solution was dichloromethane. The weight ratio of the florfenicol intermediate compound to dichloromethane is preferably 1: 3.
The molar ratio of the (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline to the ishikawa reagent is 1: 1-1: 2.
Preferably, the temperature range of the fluorination reaction is 140-150 ℃, the pressure is 1.5-1.7 MPa, and the time is 10-40 seconds.
The microchannel reaction system comprises a batching kettle, a constant flow pump, a microchannel reactor and a receiving kettle which are connected in sequence. The microchannel reaction system of the present invention is a prior art G4 reactor from corning incorporated, usa.
The invention has the beneficial effects that the solubility of the raw materials in the solution is not good, and the existing method is to directly mix the raw materials: the (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline and the ishikawa reagent react at high temperature and high pressure to generate the florfenicol intermediate, and the solubility of raw materials has no influence on the reaction. The inventor finds that when the reaction is carried out by using the microchannel reaction system, the raw materials are not completely dissolved and are granular, the reaction time of the microchannel reaction system is short, the temperature rise and the pressure rise are high, the raw materials are difficult to completely dissolve in the reaction system, the microchannel is often blocked, the reaction cannot be normally carried out, and serious safety accidents can be caused when the reaction is serious.
The present inventors have found that the starting material can be completely converted to a florfenicol intermediate compound by mixing the starting material with ishikawa reagent at room temperature, while the inventors have found that the florfenicol intermediate compound can be dissolved in 3 times the weight of dichloromethane. Therefore, after the florfenicol intermediate compound after complete reaction, but not raw materials, is added into the microchannel reaction system for reaction, the problem of blocking the microchannel reaction system is completely avoided, a solid foundation is laid for smooth reaction in the microchannel reaction system, and the productivity of the process is obviously improved.
The florfenicol intermediate compound is unstable after separation, and can be better analyzed only in normal phase chromatography through condition screening. The chromatographic conditions were as follows: a chromatographic column: lichrospher Si60, 250 × 4mm 5 μm; mobile phase: isopropanol-n-hexane (60: 40); wavelength: 225 nm; column temperature: at 30 ℃.
Drawings
FIG. 1 is an HPLC chromatogram of (4S, 5R) -2-dichloromethyl-4-fluoromethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline having a peak time of 7.546 min.
Fig. 2 is a table of peak analysis of fig. 1.
FIG. 3 is an HPLC profile of a florfenicol intermediate compound with a peak time of 4.986 min.
Fig. 4 is a table of peak analysis of fig. 3.
FIG. 5 is an HPLC chromatogram of (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline with an appearance time of 11.088 min.
Fig. 6 is a table of peak analysis of fig. 5.
FIG. 7 is a schematic structural diagram of the present invention, in FIG. 4, 1 a batching kettle, 2 a constant flow pump, 3 a microchannel reactor, 4 a backpressure valve, 5 a receiving kettle.
Detailed Description
Example 1
As shown in fig. 4, the microchannel reaction system includes a batching kettle 1, a constant flow pump 2, a microchannel reactor 3, a backpressure valve 4 and a receiving kettle 5 which are connected in sequence.
30kg of dichloromethane and 3.1kg of diethylamine are pumped into the batching kettle 1, and 7kg of hexafluoropropylene is pumped after the temperature is reduced to-30 ℃. Stirring for 30 minutes, adding 10kg of (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline), and stirring for 1 hour at room temperature to obtain a clear solution, wherein the clear solution contains a florfenicol intermediate compound.
FIGS. 5-6 are HPLC profiles and peak analysis tables for the starting material, i.e., (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline.
FIGS. 3-4 are HPLC profiles and peak analysis tables for florfenicol intermediate compounds.
In the above solution, the purity of the florfenicol intermediate compound was 83.0%, and the conversion of the raw material (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline was 94.3%.
Adjusting the pressure of a back pressure valve 4 to 1.6MPa, increasing the external bath temperature to 130 ℃, starting a constant flow pump 2 after the temperature is constant, pumping the mixture in the batching kettle 1 into a microchannel reactor 3 at the flow rate of 50ml/min, sampling and detecting the effluent liquid, and completely reacting.
FIGS. 1-2 are HPLC spectra and peak analysis tables for the fluoro product, i.e., (4S, 5R) -2-dichloromethyl-4-fluoromethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline.
From HPLC (high performance liquid chromatography) spectrum analysis of substances, the florfenicol intermediate compound and raw materials and products have obvious differences, and the structural formula of the florfenicol intermediate compound is shown as the above through analyzing the structure of the reaction and the reaction flow.
And (3) concentrating the reaction liquid in the receiving kettle 5 under reduced pressure until the reaction liquid is dry, adding 30kg of isopropanol, 40kg of water and 4.5kg of anhydrous sodium acetate, performing reflux reaction for 8 hours, sampling and detecting, distilling under reduced pressure to remove the isopropanol after the reaction liquid is qualified, cooling to 20-25 ℃, centrifuging, and drying to obtain 10.21kg of crude florfenicol product with the purity of 98.5%.
Example 2
30kg of dichloromethane and 3.1kg of diethylamine are pumped into the batching kettle, and 7kg of hexafluoropropylene is pumped into the batching kettle after the temperature is reduced to be below minus 30 ℃. Stirring for 30 minutes, adding 10kg of (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline, and stirring for 1 hour at room temperature.
Adjusting the pressure of a back pressure valve 4 to 1.7MPa, raising the external bath temperature to 140 ℃, starting a constant flow pump 2 after the temperature is constant, pumping the mixture in a batching kettle 1 into a microchannel reactor 3 at a flow rate of 100ml/min, sampling and detecting effluent liquid, completely reacting, concentrating reaction liquid in a receiving kettle 5 under reduced pressure until the reaction liquid is dry, adding 30kg of isopropanol, 40kg of water and 4.5kg of anhydrous sodium acetate, carrying out reflux reaction for 8 hours, sampling and detecting, distilling the isopropanol under reduced pressure after the reaction liquid is qualified, cooling to 20-25 ℃, centrifuging, and drying to obtain 10.19kg of crude florfenicol with the purity of 98.4%.
Example 3
30kg of dichloromethane and 3.1kg of diethylamine are pumped into the batching kettle, and 7kg of hexafluoropropylene is pumped into the batching kettle after the temperature is reduced to be below minus 30 ℃. Stirring for 30 minutes, adding 10kg of (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline, and stirring for 1 hour at room temperature.
Adjusting the pressure of a backpressure valve to 1.8MPa, increasing the temperature of an external bath to 150 ℃, starting a constant flow pump after the temperature is constant, pumping a mixture in a batching kettle into a microchannel reactor at a flow rate of 150ml/min, sampling and detecting effluent liquid, completely reacting, concentrating reaction liquid in a receiving kettle to dryness under reduced pressure, adding 30kg of isopropanol, 40kg of water and 4.5kg of anhydrous sodium acetate, carrying out sampling and detecting after 8-hour reflux reaction, distilling under reduced pressure to remove the isopropanol after the reaction liquid is qualified, cooling to 20-25 ℃, centrifuging, and drying to obtain 10.23kg of crude florfenicol with the purity of 98.6%.
Example 4
30kg of dichloromethane and 3.1kg of diethylamine are pumped into the batching kettle, and 7kg of hexafluoropropylene is pumped into the batching kettle after the temperature is reduced to be below minus 30 ℃. Stirring for 30 minutes, adding 10kg of (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline, and stirring for 1 hour at room temperature.
Adjusting the pressure of a backpressure valve to 2MPa, increasing the temperature of an external bath to 160 ℃, starting a constant flow pump after the temperature is constant, pumping a mixture in a batching kettle into a microchannel reactor at a flow rate of 200ml/min, sampling and detecting effluent liquid, completely reacting, concentrating reaction liquid in a receiving kettle under reduced pressure until the reaction liquid is dry, adding 30kg of isopropanol, 40kg of water and 4.5kg of anhydrous sodium acetate, carrying out reflux reaction for 8 hours, sampling and detecting, distilling under reduced pressure to remove the isopropanol after the reaction liquid is qualified, cooling to 20-25 ℃, centrifuging, and drying to obtain 10.16kg of crude florfenicol with the purity of 98.6%.
Claims (9)
1. A florfenicol intermediate compound is characterized in that the structural formula is shown as follows,
2. a method for preparing a florfenicol intermediate is characterized in that (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline is added into an ishikawa reagent and is stirred uniformly, and after the reaction is finished, a florfenicol intermediate compound is obtained;
carrying out a fluoro reaction on the florfenicol intermediate compound in a microchannel reaction system under the conditions that the temperature is controlled to be 130-160 ℃ and the pressure is 1.6-2.0 Mpa to obtain a florfenicol intermediate;
the reaction formula is as follows:
3. the process for preparing florfenicol intermediate as set forth in claim 2 wherein the ishikawa reagent is prepared by introducing hexafluoropropylene into a solution of diethylamine.
4. The process for preparing florfenicol intermediate as set forth in claim 3, wherein the solvent used in the preparation of the ishikawa reagent is dichloromethane.
5. The process for preparing a florfenicol intermediate as set forth in any of claims 2-4, wherein the molar ratio of (4R, 5R) -2-dichloromethyl-4-hydroxymethyl-4, 5-dihydro-5- (4- (methylsulfonyl) phenyl) oxazoline and ishikawa reagent is 1:1 to 1: 2.
6. The process for preparing a florfenicol intermediate as claimed in any one of claims 2-4, wherein the temperature is in the range of 140 to 150 ℃.
7. The process for preparing florfenicol intermediate as set forth in any of claims 2-4, characterized in that the pressure of the fluorination reaction is 1.5-1.7 MPa.
8. The process for preparing a florfenicol intermediate as set forth in any of claims 2-4, characterized in that the time of the fluorination reaction is 10 seconds to 40 seconds.
9. The process for preparing a florfenicol intermediate as set forth in any of claims 2-4, wherein the microchannel reaction system comprises a batching kettle, a constant flow pump, a microchannel reactor and a receiving kettle which are connected in sequence.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113149876A (en) * | 2021-04-26 | 2021-07-23 | 四川大学 | Method for continuously preparing florfenicol based on micro-reaction system |
| CN113264892A (en) * | 2021-04-05 | 2021-08-17 | 复旦大学 | Method for continuously preparing florfenicol key intermediate by using micro-reaction system |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109776365A (en) * | 2017-11-14 | 2019-05-21 | 江苏恒盛药业有限公司 | A method of fluorination reagent and fluoride are prepared using micro passage reaction serialization |
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- 2019-11-25 CN CN201911166590.4A patent/CN110878060A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109776365A (en) * | 2017-11-14 | 2019-05-21 | 江苏恒盛药业有限公司 | A method of fluorination reagent and fluoride are prepared using micro passage reaction serialization |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113264892A (en) * | 2021-04-05 | 2021-08-17 | 复旦大学 | Method for continuously preparing florfenicol key intermediate by using micro-reaction system |
| CN113149876A (en) * | 2021-04-26 | 2021-07-23 | 四川大学 | Method for continuously preparing florfenicol based on micro-reaction system |
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Application publication date: 20200313 |