CN113264892B - Method for continuously preparing florfenicol key intermediate by using micro-reaction system - Google Patents
Method for continuously preparing florfenicol key intermediate by using micro-reaction system Download PDFInfo
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- 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
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- 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
Abstract
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a method for continuously preparing a florfenicol key intermediate by using a micro-reaction system. The invention uses a micro-reaction system consisting of a micro-mixer, a micro-channel reactor and a back pressure device; in this method, (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol solution and dichloroacetonitrile acid solution are respectively pumped into a microreactor at the same time to carry out cyclization reaction, and the reaction product is concentrated, recrystallized, filtered, washed and dried to obtain (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol product. The method has the advantages of reaction time of only a few minutes, product yield of more than 95 percent, purity of more than 99 percent, convenient operation, continuous controllability, no amplification effect, high process efficiency and good industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a method for continuously preparing a florfenicol key intermediate by using a micro-reaction system.
Background
The compound (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol with the chemical structural formula (I) is a key intermediate for synthesizing the amidol antibiotic florfenicol:
florfenicol is a beta-amidol antibiotic developed by Schering-Plough company in 1979 by replacing C-3 hydroxyl of thiamphenicol with isostere F, has better antibacterial activity, safety, effectiveness and drug resistance, and has no aplastic anemia, teratogenesis, carcinogenesis and mutagenic effects. At present, the compound has been used for preventing and treating bacterial diseases of fishes, pigs, cattle and the like in aquaculture and livestock breeding.
U.S. Pat. Nos. 5382673 and Wu et al (J. Org. Chem. 1997, 62, 2996-2998) report the preparation of (4 R,5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4,5-dihydrooxazol-4-yl) methanol by the reaction of (1R,2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1,3-diol with dichloroacetonitrile under the catalysis of concentrated sulfuric acid. In the method, strong corrosive sulfuric acid is used, so that the method has high requirements on equipment and serious pollution, and does not meet the requirements of green chemistry. Chen Feng et al (Tetrahedron: asymmetry,2011, 22, 1337-1341) based on this, replace concentrated sulfuric acid with concentrated hydrochloric acid, can also achieve the same yield. However, the use of large amounts of concentrated hydrochloric acid in industrial production is still dangerous, requires high equipment and causes large amounts of waste water pollution.
In recent years, since many advantages of the micro-reaction system are receiving increasing attention from scientists and research technicians, the micro-reaction system is widely applied to the fields of organic synthesis and pharmacy. Compared with the traditional kettle type reaction equipment, the continuous flow micro-reaction technology has the following advantages: (1) The reaction equipment has small size, fast material mixing, high mass and heat transfer efficiency and easy realization of process reinforcement; (2) The residence time distribution is narrow, the system response is rapid, the process repeatability is good, and the product quality is stable; (3) The parameters are accurately controlled (including concentration distribution, temperature distribution, pressure distribution and the like), and automatic control is easy to realize; (4) almost no amplification effect exists, and the amplification can be rapidly carried out; (5) The online material quantity is small, the method is suitable for unconventional reaction conditions (such as high temperature and high pressure), and the process is intrinsically safe; (6) continuous operation, high space-time efficiency and labor saving. Therefore, based on the problems of the existing kettle-type reaction for preparing (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol, the development of a continuous preparation method with short reaction time, high yield, low preparation cost, low energy consumption and high process efficiency is a problem which needs to be solved urgently by the technical personnel in the field.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a method for continuously preparing a florfenicol key intermediate by using a micro-reaction system. Compared with the existing preparation method, the method provided by the invention has the advantages that the reaction time is greatly shortened, the automation degree and efficiency of the technological process are obviously improved, the energy consumption is greatly reduced, the safety is greatly improved, and the industrial application is easy.
The invention provides a method for continuously preparing a florfenicol key intermediate by using a micro-reaction system, wherein the micro-reaction system comprises a micro-mixer, a micro-channel reactor and a back pressure device which are sequentially communicated, and the method comprises the following specific steps:
(1) Dissolving (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (II) in an organic solution and simultaneously conveying the organic solution and an acid solution of dichloroacetonitrile into a micro mixer for mixing, and directly feeding a mixed reaction material flowing out of the micro mixer into a microchannel reactor for continuous cyclization reaction;
(2) Collecting reaction mixed liquid flowing out of the micro-reaction system, and separating and purifying to obtain a target product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol (I);
wherein the (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol is a compound represented by the formula (I), and the (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol is a compound represented by the formula (II); the reaction formula is as follows:
preferably, the acid agent may be an inorganic acid or an organic acid;
preferably, the inorganic acid is one of sulfuric acid, hydrochloric acid, boric acid or phosphoric acid;
preferably, the organic acid is one of formic acid, acetic acid, glycolic acid, oxalic acid, citric acid, benzoic acid, methane sulfonic acid, trifluoromethane sulfonic acid, p-toluene sulfonic acid or sulfamic acid.
In the invention, the organic solution is selected from halogenated hydrocarbon solvents, acetate solvents, substituted benzene solvents, alkyl ether solvents and C1-C4 alkanol solvents;
preferably, the halogenated hydrocarbon solvent is at least one of dichloromethane, trichloromethane, carbon tetrachloride and 1, 2-dichloroethane; the acetate solvent is at least one of methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and tert-butyl acetate; the substituted benzene solvent is at least one of toluene and xylene; the alkyl ether solvent is at least one of diethyl ether, propyl ether, methyl tert-butyl ether and n-butyl ether; the alkanol solvent of C1-C4 is at least one of methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 1, 2-propylene glycol, 1, 3-propylene glycol and 1-butanol.
As a preferred technical scheme, the molar ratio of (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol to dichloroacetonitrile to acid agent is 1: (1-3): (0.1 to 1); preferably, the molar ratio of (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol, dichloroacetonitrile to acid agent is 1: (1.1-2.5): (0.1-0.8), the reaction effect is better.
Preferably, the temperature in the micromixer is controlled to be 25-120 ℃. More preferably, the temperature in the micromixer is controlled between 40 and 100 ℃.
Preferably, the temperature in the microchannel reactor is controlled to be 25-120 ℃; more preferably, the temperature in the microchannel reactor is controlled to be 40-100 ℃.
Preferably, the back pressure of the microchannel reactor is 0.1-5 Mpa; more preferably, the back pressure of the microchannel reactor is 0.3-2 Mpa, and the reaction effect is better.
Preferably, the residence time of the mixed reaction mass in the microchannel reactor is between 0.2 and 30 minutes. More preferably, the residence time of the mixed reaction mass in the microchannel reactor is from 1 to 20 minutes.
As a preferable technical solution, the micro mixer is any one of a static mixer, a T-type micro mixer, a Y-type micro mixer, a coaxial flow micro mixer, or a flow-focusing micro mixer.
As a preferred technical scheme, the microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor.
As a preferred technical scheme, the inner diameter of the tubular microchannel reactor is 100 micrometers to 50 millimeters, preferably 120 micrometers to 30 millimeters.
As a preferable technical scheme, the plate-type microchannel reactor comprises a first heat exchange layer, a reaction layer and a second heat exchange layer which are sequentially arranged from top to bottom, wherein the reaction layer is provided with a reaction fluid channel, and the hydraulic diameter of the reaction fluid channel is 100 micrometers-50 millimeters. More preferably, the hydraulic diameter of the reaction fluid channel is 120 micrometers to 30 millimeters.
As a preferable technical scheme, in the step (2), "collecting the reaction mixture flowing out from the micro-reaction system, and separating and purifying to obtain the target product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol" specifically comprises: and collecting the reaction mixed liquid flowing out of the micro-reaction system, and concentrating and drying the reaction mixed liquid under reduced pressure to obtain the target product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol.
The invention has the beneficial effects that: compared with the prior synthesis method adopting a traditional batch reaction kettle, the method for preparing (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol by adopting the continuous cyclization reaction of (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol and dichloroacetonitrile by adopting the micro-reaction system comprising the micro-mixer and the microchannel reactor which are communicated in sequence has the following advantages:
1. the method has the advantages that the continuous synthesis from raw materials to products is realized, the technological process is continuously carried out, the automation degree is high, external intervention is not needed in the middle, the number of operators and the labor intensity are greatly reduced, and the production cost is obviously reduced;
2. the microchannel reactor has excellent mass and heat transfer and material mixing performance, so that the reaction time of the cyclization reaction of (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol and dichloroacetonitrile is greatly shortened, and the reaction time is shortened from several hours of the traditional batch kettle type reaction to several minutes;
3. the multiphase mixing, mass transfer and reaction processes in the reaction process are finished in the reaction fluid channels of the micro mixer and the micro channel reactor, a stirring device is not needed, and the energy consumption in the process is greatly reduced;
4. the cyclization reaction of (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol and dichloroacetonitrile is completed in a microchannel reactor, and the total volume of a reaction fluid channel is small, so that the online liquid holdup is small, and the reaction process is intrinsically safe.
Drawings
FIG. 1 is a schematic view of a micro-reaction system used in an embodiment of the present invention.
Reference numbers in the figures: 1. the device comprises a feeding pump, 2, a constant-temperature oil bath, 3, a micro mixer, 4, a micro-channel reactor, 5, a back pressure valve, 6 and a storage tank.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
This example provides a process for continuously producing (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol using a micro-reaction system, as shown in FIG. 1, comprising a micro-mixer 3, a microchannel reactor 4, which are connected in series, a feed pump 1 for regulating and controlling the flow rate of reaction mixed liquid in the micro-reaction system, a thermostatic oil bath 2 for regulating and controlling the reaction temperature of the microchannel reactor 4, a back pressure valve 5 for regulating and controlling the reaction pressure in the micro-reaction system, and a storage tank 6. The micro mixer 3 is a T-shaped micro mixer. The microchannel reactor 4 is a polytetrafluoroethylene tubular microchannel reactor with an inner diameter of 0.8 mm, and the reaction volume is 1mL. The back pressure valve 5 provides a pressure of 0.5 Mpa. The storage tank 6 is used for collecting reaction liquid. The method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol, 1.23g) was added to 6mL of methanol, and the mixture was dissolved with stirring to give Material 1; dichloroacetonitrile (5.6 mmol,616 mg) and concentrated hydrochloric acid (1.5 mmol, 126 mu L) are added into 1mL of methanol, and the mixture is stirred and dissolved to be used as a material 2;
(2) Controlling the flow rate of the material 1 to be 80.6 mu L/min; controlling the flow rate of the material 2 to be 19.4 mu L/min; the temperature of the micro mixer is 50 ℃; the temperature of the micro-channel is 50 ℃; the residence time of the reaction was 10 minutes;
(3) The reaction mixture discharged from the micro-reaction system was collected, concentrated under reduced pressure, and dried to obtain the desired product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol in a yield of 95%.
1 H NMR (400 MHz, DMSO): δ 7.99 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 5.75 (d, J = 6.4 Hz, 1H), 5.17 (t, J = 5.6 Hz, 1H), 4.08 (dd, J 1 = 10.8 Hz, J 2 = 5.6 Hz, 1H), 3.75-3.70 (m, 1H), 3.60-3.55 (m, 1H), 3.23 (s, 3H) ppm; 13 C NMR (100 MHz, DMSO): δ 161.3, 146.4, 141.0, 128.1, 126.5, 83.3, 76.9, 62.4, 43.9 ppm. ESI HRMS: calcd. for C 12 H 13 Cl 2 NO 4 Theoretical value of S + Na: 359.9840, found: 359.9843.
example 2
The embodiment is the same as embodiment 1, except that in the embodiment, the method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol, 1.23g) was added to 6mL of methanol, and the mixture was dissolved with stirring to give Material 1; dichloroacetonitrile (5.6 mmol, 616mg) and concentrated hydrochloric acid (1.5 mmol, 126 μ L) are added into 1mL of methanol, and stirred to dissolve the mixture to obtain a material 2;
(2) Controlling the flow rate of the material 1 to be 161.2 mu L/min; controlling the flow rate of the material 2 to be 38.8 mu L/min; the temperature of the micro mixer is 50 ℃; the temperature of the micro-channel is 50 ℃; the residence time of the reaction was 5 minutes;
(3) The reaction mixture discharged from the micro-reaction system was collected, concentrated under reduced pressure, and dried to obtain the desired product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol in a yield of 90%.
Example 3
This embodiment is the same as embodiment 2 except that the back pressure valve 5 provides a pressure of 1.0 Mpa. The method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol, 1.23g) was added to 6mL of methanol, and the mixture was dissolved with stirring to give Material 1; dichloroacetonitrile (5.6 mmol,616 mg) and concentrated hydrochloric acid (1.5 mmol, 126 mu L) are added into 1mL of methanol, and the mixture is stirred and dissolved to be used as a material 2;
(2) Controlling the flow rate of the material 1 to be 161.2 mu L/min; controlling the flow rate of the material 2 to be 38.8 mu L/min; the temperature of the micro mixer is 50 ℃; the temperature of the micro-channel is 50 ℃; the residence time of the reaction was 5 minutes;
(3) The reaction mixture discharged from the micro-reaction system was collected, concentrated under reduced pressure, and dried to obtain the desired product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol in a yield of 94%.
Example 4
This example is the same as example 3 except that in this example, the back pressure valve 5 provides a pressure of 2.0 Mpa. The method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol, 1.23g) was added to 6mL of methanol, and dissolved with stirring to give Material 1; dichloroacetonitrile (5.6 mmol,616 mg) and concentrated hydrochloric acid (1.5 mmol, 126 mu L) are added into 1mL of methanol, and the mixture is stirred and dissolved to be used as a material 2;
(2) Controlling the flow rate of the material 1 to be 161.2 mu L/min; controlling the flow rate of the material 2 to be 38.8 mu L/min; the temperature of the micro mixer is 50 ℃; the temperature of the micro-channel is 50 ℃; the residence time of the reaction was 5 minutes;
(3) The reaction mixture discharged from the micro-reaction system was collected, concentrated under reduced pressure, and dried to obtain the desired product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol in a yield of 96%.
Example 5
The embodiment is the same as embodiment 4, except that in the embodiment, the method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol, 1.23g) was added to 6mL of methanol, and the mixture was dissolved with stirring to give Material 1; dichloroacetonitrile (5.6 mmol, 616mg) and concentrated hydrochloric acid (1.5 mmol, 126 μ L) are added into 1mL of methanol, and stirred to dissolve the mixture to obtain a material 2;
(2) Controlling the flow rate of the material 1 to be 161.2 mu L/min; controlling the flow rate of the material 2 to be 38.8 mu L/min; the temperature of the micro mixer is 70 ℃; the temperature of the micro-channel is 70 ℃; the residence time of the reaction was 5 minutes;
(3) The reaction mixture discharged from the micro-reaction system was collected, concentrated under reduced pressure, and dried to obtain the desired product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol in a yield of 99%.
Example 6
The embodiment is the same as embodiment 5, except that in the embodiment, the method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol, 1.23g) was added to 6mL of methanol, and dissolved with stirring to give Material 1; dichloroacetonitrile (5.6 mmol, 616mg) and concentrated hydrochloric acid (1.5 mmol, 126 μ L) are added into 1mL of methanol, and stirred to dissolve the mixture to obtain a material 2;
(2) Controlling the flow rate of the material 1 to be 322.4 mu L/min; controlling the flow rate of the material 2 to be 77.6 mu L/min; the temperature of the micro mixer is 70 ℃; the temperature of the micro-channel is 70 ℃; the residence time of the reaction was 2.5 minutes;
(3) The reaction mixture discharged from the micro-reaction system was collected, concentrated under reduced pressure, and dried to obtain the desired product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol in a yield of 90%.
Example 7
The embodiment is the same as the embodiment 6, except that the method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol, 1.23g) was added to 6mL of methanol, and dissolved with stirring to give Material 1; dichloroacetonitrile (5.6 mmol, 616mg) and concentrated hydrochloric acid (1.5 mmol, 126 μ L) are added into 1mL of methanol, and stirred to dissolve the mixture to obtain a material 2;
(2) Controlling the flow rate of the material 1 to be 322.4 mu L/min; controlling the flow rate of the material 2 to be 77.6 mu L/min; the temperature of the micro mixer is 80 ℃; the temperature of the micro-channel is 100 ℃; the residence time of the reaction was 2.5 minutes;
(3) The reaction mixture discharged from the micro-reaction system was collected, concentrated under reduced pressure, and dried to obtain the desired product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol in a yield of 96%.
Example 8
This example is the same as example 1, except that in this example, a static mixer was used as the micromixer. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol was 95%.
Example 9
This example is the same as example 1, except that in this example, a Y-type micromixer is used as the micromixer. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol was 95%.
Example 10
This example is the same as example 1, except that in this example, a coaxial flow micromixer is used for the micromixer. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol was 95%.
Example 11
This example is the same as example 1, except that in this example, a flow focusing micromixer is used as the micromixer. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol was 95%.
Example 12
This example is the same as example 1, except that in this example, the acid used in the continuous cyclization reaction was concentrated sulfuric acid, which is an inorganic acid. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol was 95%.
Example 13
This example is the same as example 1, except that in this example, the acid used in the continuous cyclization reaction is an inorganic acid phosphoric acid. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol was 94%.
Example 14
This example is the same as example 1, except that in this example, the acid used in the continuous cyclization reaction was the organic acid formic acid. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol was 95%.
Example 15
This example is the same as example 1, except that in this example the acid used in the continuous cyclization is the organic acid trifluoromethanesulfonic acid. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol was 95%.
Example 16
This example is the same as example 1, except that in this example, the acid used in the continuous cyclization reaction was the organic acid p-toluenesulfonic acid. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol was 94%.
Example 17
This example is the same as example 1, except that in this example, the organic solvent used in the continuous cyclization reaction is 2-propanol. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol was 93%.
Example 18
This example is the same as example 1, except that in this example, the organic solvent used in the continuous cyclization reaction is 1-butanol. In this example, the substrate (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was completely converted, and the yield of the product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol was 94%.
Example 19
This example is the same as example 5 except that in this example, the microchannel reactor 4 is a polytetrafluoroethylene tubular microchannel reactor having an inner diameter of 0.8 mm and a reaction volume of 10mL. The back pressure valve 5 provides a pressure of 2.0 Mpa. The method comprises the following steps:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (50 mmol, 12.3g) was added to 60mL of methanol, and dissolved with stirring to give Material 1; dichloroacetonitrile (56 mmol, 6.2g) and concentrated hydrochloric acid (15 mmol, 1.3mL) are added into 10mL of methanol, and the mixture is stirred and dissolved to be used as a material 2;
(2) Controlling the flow rate of the material 1 to be 1.6mL/min; controlling the flow rate of the material 2 to be 0.4ml/min; the temperature of the micro mixer is 70 ℃; the temperature of the micro-channel is 70 ℃; the residence time of the reaction was 5 minutes;
(3) The reaction mixture discharged from the micro-reaction system was collected, concentrated under reduced pressure, and dried to obtain the desired product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol in a yield of 99%.
Example 20
The present embodiment is the same as embodiment 19, except that in the present embodiment, the method includes the steps of:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (50 mmol, 12.3g) was added to 60mL of methanol, and dissolved with stirring to give Material 1; adding dichloroacetonitrile (56 mmol, 6.2g) and concentrated hydrochloric acid (6 mmol, 0.5mL) into 10mL of methanol, and stirring to dissolve the mixture to obtain a material 2;
(2) Controlling the flow rate of the material 1 to be 1.6mL/min; controlling the flow rate of the material 2 to be 0.4ml/min; the temperature of the micro mixer is 70 ℃; the temperature of the micro-channel is 70 ℃; the residence time of the reaction was 5 minutes;
(3) The reaction mixture discharged from the micro-reaction system was collected, concentrated under reduced pressure, and dried to obtain the desired product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol in a yield of 99%.
Example 21
This embodiment is the same as embodiment 20, except that in this embodiment, the method includes the steps of:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (50 mmol, 12.3g) was added to 60mL of methanol, and dissolved with stirring to give Material 1; adding dichloroacetonitrile (56 mmol, 6.2g) and concentrated hydrochloric acid (6 mmol, 0.5mL) into 10mL of methanol, and stirring to dissolve the mixture to obtain a material 2;
(2) Controlling the flow rate of the material 1 to be 3.2mL/min; controlling the flow rate of the material 2 to be 0.8ml/min; the temperature of the micro mixer is 70 ℃; the temperature of the micro-channel is 70 ℃; the residence time of the reaction was 2.5 minutes;
(3) The reaction mixture discharged from the micro-reaction system was collected, concentrated under reduced pressure, and dried to obtain the desired product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol in a yield of 95%.
Example 22
This embodiment is the same as embodiment 21, except that in this embodiment, the method includes the steps of:
(1) (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (50 mmol, 12.3g) was added to 60mL of methanol, and dissolved with stirring to give Material 1; dichloroacetonitrile (70 mmol, 7.8g) and concentrated hydrochloric acid (6 mmol, 0.5mL) were added to 10mL of methanol, and the mixture was dissolved by stirring to obtain a material 2;
(2) Controlling the flow rate of the material 1 to be 3.2mL/min; controlling the flow rate of the material 2 to be 0.8ml/min; the temperature of the micro mixer is 70 ℃; the temperature of the micro-channel is 70 ℃; the residence time of the reaction was 2.5 minutes;
(3) The reaction mixture discharged from the micro-reaction system was collected, concentrated under reduced pressure, and dried to obtain the desired product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol in a yield of 99%.
Comparative example 1
In the comparative example, (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol was prepared using a conventional batch reactor, specifically prepared as follows: to a 50mL round-bottomed flask were added methanol (7 mL), (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (5.0 mmol, 1.23g), dichloroacetonitrile (5.6 mmol, 616mg) and concentrated hydrochloric acid (1.5 mmol, 0.13mL) in that order. Raising the temperature to 70 ℃, adjusting the stirring speed to 600 r/min, stirring for 2 hours, cooling to 50 ℃, and continuing stirring for 16 hours. The reaction time was measured and analyzed, and the conversion of the substrate (1r, 2r) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was about 32% at 2 hours of the reaction, and the conversion of the substrate (1r, 2r) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was about 50% at 6 hours of the reaction, the conversion of the substrate (1r, 2r) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was about 50% at 9 hours of the reaction, the conversion of the substrate (1r, 2r) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was about 87% at 18 hours of the reaction, the conversion of the substrate (1r, 2r) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was about 99% at 87% at 18 hours of the reaction, and the yield of the product (1r, 2r) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol was about 87% at 2-hour of the reaction.
The charge ratio of the comparative example 1 and the example 5 is the same. Through comparison, compared with the traditional batch kettle type synthesis mode, the method disclosed by the invention has the advantages that (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol is continuously prepared by adopting a micro-reaction system, the reaction time is greatly shortened, the product yield is high (more than 95%), no stirring device is needed, the energy consumption is greatly reduced, the process is continuously carried out, the operation is simple and convenient, the automation degree is high, and the efficiency is greatly improved. In addition, the microchannel reactor has excellent mass and heat transfer characteristics, and the dosage of dichloroacetonitrile and acid in the cyclization reaction process can be accurately regulated and controlled.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (7)
1. A method for continuously preparing a florfenicol key intermediate by using a micro-reaction system, which is characterized in that the micro-reaction system is used, the micro-reaction system comprises a micro mixer, a microchannel reactor and a back pressure device, and no stirring device is used, and the method comprises the following specific steps:
(1) Dissolving (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol (II) in an organic solution and simultaneously conveying the organic solution and an acid solution of dichloroacetonitrile into a micro mixer for mixing, and directly feeding a mixed reaction material flowing out of the micro mixer into a microchannel reactor for continuous cyclization reaction;
(2) Collecting reaction mixed liquid flowing out of the micro-reaction system, and separating and purifying to obtain a target product (4R, 5R) -2- (dichloromethyl) -5- (4- (methylsulfonyl) phenyl) -4, 5-dihydrooxazol-4-yl) methanol (I);
the reaction formula is as follows:
2. the process according to claim 1, wherein the molar ratio of (1r, 2r) -2-amino-1- (4- (methylsulfonyl) phenyl) propane-1, 3-diol, dichloroacetonitrile and acid in step (1) is 1: (1-3): (0.1-1).
3. The method according to claim 1, wherein the temperature in the micromixer in the step (1) is 25 to 120 ℃, the reaction temperature in the microchannel reactor is 25 to 120 ℃, the residence time of the mixed reaction material in the microchannel reactor is 0.5 to 30 minutes, and the back pressure of the microchannel reactor is 0.1 to 5Mpa.
4. The method according to claim 1, wherein the organic solvent in step (1) is selected from the group consisting of halogenated hydrocarbon solvents, acetate solvents, substituted benzene solvents, alkyl ether solvents, and C1-C4 alkanols.
5. The method according to claim 1, wherein the acid in step (1) is an inorganic acid or an organic acid;
the inorganic acid is one of sulfuric acid, hydrochloric acid, boric acid or phosphoric acid;
the organic acid is one of formic acid, acetic acid, glycolic acid, oxalic acid, citric acid, benzoic acid, methane sulfonic acid, trifluoromethane sulfonic acid, p-toluene sulfonic acid or sulfamic acid.
6. The method of claim 1, wherein the micromixer is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, or a flow focusing micromixer.
7. The process of claim 1 wherein the microchannel reactor is a tubular microchannel reactor, or a plate microchannel reactor;
the inner diameter of the tubular micro-channel reactor is 100 micrometers-50 millimeters; alternatively, the first and second liquid crystal display panels may be,
the plate-type microchannel reactor comprises a first heat exchange layer, a reaction layer and a second heat exchange layer which are sequentially arranged from top to bottom, wherein the reaction layer is provided with a reaction fluid channel, and the hydraulic diameter of the reaction fluid channel is 100 micrometers-50 millimeters.
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