CN115925647A - Production method of linezolid - Google Patents
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Abstract
The invention belongs to the technical field of medicine production, and particularly relates to a method for producing linezolid, which comprises the steps of preparing 3-fluoro-4-morpholinylaniline and benzyl (3-fluoro-4-morpholinylphenyl) carbamate by using 3,4-difluoronitrobenzene, and obtaining a finished product through ring closing reaction and refining. The method reduces the process steps, reduces the use of solvents, is convenient to recycle and reuse, improves the purity and content of the linezolid product, reduces the impurity types and content, ensures that the prepared linezolid reaches the injection grade quality standard, and has the effects of high quality, low cost and high yield.
Description
Technical Field
The invention belongs to the technical field of drug production, and particularly relates to a production method of linezolid.
Background
The present stage linezolid production process starts from a commercially available intermediate 3,4-difluoronitrobenzene, comprises the first step of carrying out post-treatment procedures of uniformly mixing and reacting ethyl acetate, acid-binding agents such as diisopropylethylamine and morpholine, concentrating and crystallizing, filtering and drying to obtain an intermediate 3-fluoro-4-morpholinyl nitrobenzene, carrying out the next step, and carrying out a nitro reduction reaction in an ethanol solvent system in a hydrogenation reaction kettle under the action of a catalyst palladium carbon by introducing hydrogen, filtering to remove the palladium carbon, concentrating the filtrate, crystallizing, filtering, drying and the like to obtain the intermediate 3-fluoro-4-morpholinyl aniline, and carrying out the next step. The two steps are required to be separately carried out in the production process at the present stage, so that the process is long, the solvents are used in various types, the dosage is large, the conversion rate of the ring closing reaction of the steps is not high, the purity of a crude product is not high, the refining difficulty is increased, and the quality of the obtained product cannot reach the injection level easily
The existing problems restrict the industrial production, so that the production cost of the raw material medicine is high, the profit margin of the preparation is compressed, and the medication cost of patients is increased.
Disclosure of Invention
The method aims to reduce the process steps, reduce the use of solvents, facilitate the recovery and the application, improve the purity and the content of the linezolid product, reduce the types and the content of impurities, and ensure that the prepared linezolid reaches the injection grade quality standard. The technical scheme is that the production method of linezolid comprises the following steps:
and 4, step 4: refining to obtain a finished product: adding the crude linezolid and a solvent into a hot-melting kettle, heating for dissolving, decoloring and impurity removing through a decoloring agent layer while the solution is hot to obtain a filtrate, cooling for crystallization, filtering, and drying to obtain a finished linezolid product.
And the heating reflux in the step 1 refers to heating to 75-85 ℃ for reflux reaction for 3-5 h.
And the weight ratio of the materials used in the reaction in the step 1 is 3,4-difluoronitrobenzene: and (3) morpholine: diisopropylethylamine: ethyl acetate: palladium on carbon =1 (0.65-1): (0.4-0.8): (2-3): (0.8-1).
In step 2, the solvent is one of tetrahydrofuran, dichloromethane, acetone or dioxane, and the weight ratio of materials used in the reaction is that the intermediate 3-fluoro-4-morpholinylaniline: sodium bicarbonate: benzyl chloroformate: solvent =1: (0.6-1): (1.5-2.5): (4-5) the reaction temperature is-2-10 ℃.
And in the step 2, a certain amount of benzyl chloroformate is added into a high-level metering tank, then the benzyl chloroformate is dropwise added into the reaction system and reacts for 2 to 4 hours at the temperature of between-5 and 10 ℃, and the end point of the reaction is detected by TLC.
And in the step 2, the reaction solution is quenched by water to obtain redundant benzyl chloroformate, ethyl acetate is used as an extracting agent for extraction, extraction and liquid separation are carried out to obtain an organic phase, the organic phase is concentrated, and n-heptane is pulped and filtered to obtain an intermediate (3-fluoro-4-morpholinylphenyl) benzyl carbamate.
In step 3, the molar ratio of the side chain (S) -N- [2- (acetoxy-3-chloropropane) ] acetamide is 1.0-2.5, the molar ratio of the tert-butoxide lithium is 2.0-3.0, and the molar ratio of the methanol is 1.0-2.5 based on the intermediate (3-fluoro-4-morpholinylphenyl) benzyl carbamate.
And in the step 3, lithium tert-butoxide is added for three times under the conditions of nitrogen protection and cooling to 0-10 ℃, the mixture is stirred for 0.5-1 h at 0-20 ℃ after the addition, then the side chain (S) -N- [2- (acetoxyl-3-chloropropane) ] acetamide is added, the mixture is slowly heated to 25-35 ℃ after being stirred for 0.5-1 h, and the reaction is carried out for 18-48 h, wherein the reaction end point standard is that the area of a main peak, namely linezolid, is monitored by HPLC and is not less than 75%.
And after finishing the reaction in the step 3, cooling to 0-15 ℃, transferring the reaction liquid to an extraction kettle, slowly adding an ammonium chloride aqueous solution, purified water and dichloromethane, stirring and separating at normal temperature, collecting an organic layer, transferring to a distillation kettle, distilling under reduced pressure until no fraction is produced, adding ethyl acetate as an extracting agent, heating to 70-80 ℃, refluxing, dropwise adding n-heptane, keeping reflux stirring, slowly cooling, stirring at normal temperature overnight, filtering, and adding n-heptane in a weight ratio: ethyl acetate =2:1, pulping the materials, filtering, and drying the filter cake under reduced pressure to obtain a crude product of linezolid.
In addition, in the step 4, the solvent is one of ethanol, methanol, ethyl acetate and n-butanol, and the decolorizing agent is one of neutral alumina and activated carbon.
Compared with the prior art, the technical scheme has the beneficial effects that: 1. the reaction process of preparing 3-fluoro-4-morpholinyl aniline from 3,4-difluoronitrobenzene is simplified to one step, the intermediate 3-fluoro-4-morpholinyl nitrobenzene does not need to be purified and separated, the process steps are obviously reduced, the use of solvent types is reduced, the production cost is reduced, the equipment investment is reduced, and the production period is shortened; 2. the preparation process of (3-fluoro-4-morpholinyl phenyl) benzyl carbamate and the preparation process of ring closure reaction are optimized, so that the prepared linezolid has high quality and high yield and reaches the injection grade quality standard.
Drawings
Fig. 1 to 6 are substance detection spectra of linezolid finished products produced by the method.
Detailed Description
The reaction principle and the materials, the proportion, the reaction conditions, the operation mode and the like which are preferably selected in the actual production process are as follows.
A method for applying an optimized linezolid process to commercial production comprises the following steps:
step 1: the preparation of the intermediate 3-fluoro-4-morpholinyl aniline is obtained by the two-step chemical reaction of a starting material 3,4-difluoronitrobenzene: the method comprises the steps of obtaining a target product by directly boiling in a reaction kettle without intermediate purification and separation, putting a starting material 3,4-difluoronitrobenzene, morpholine, a solvent ethyl acetate, an acid-binding agent diisopropylethylamine and other material systems into the pressure reaction kettle, stirring, heating and refluxing, carrying out substitution reaction to generate an intermediate 3-fluoro-4-morpholinyl nitrobenzene, carrying out hydrogenation reaction without separating direct reaction materials, adding palladium carbon, introducing hydrogen to keep the pressure in the kettle at 0.2-5 MPa, carrying out reduction reaction to generate an intermediate 3-fluoro-4-morpholinyl aniline, filtering the palladium carbon (circularly applying in the next batch) to obtain clear filtrate, concentrating, cooling, crystallizing and filtering to obtain an intermediate 3-fluoro-4-morpholinyl aniline, and drying under reduced pressure for later use.
Step 2: amino protection reaction: adding the intermediate 3-fluoro-4-morpholinyl aniline, tetrahydrofuran, sodium bicarbonate, water and other materials into a reaction kettle together, uniformly stirring, adding a certain amount of benzyl chloroformate into a high-level metering tank, dropwise adding the benzyl chloroformate into the reaction system for reaction, and determining the end point by a TLC point plate. And extracting, separating, concentrating, filtering and drying the reaction solution to obtain an intermediate (3-fluoro-4-morpholinylphenyl) benzyl carbamate.
And step 3: ring closing reaction: adding the intermediate (3-fluoro-4-morpholinylphenyl) benzyl carbamate and a mixed solvent (DMF, methanol and tetrahydrofuran) into a reaction kettle, introducing nitrogen to keep a slight positive pressure, adding lithium tert-butoxide in batches, controlling the temperature of a reaction system to be normal temperature for reaction, removing a reaction sample, and detecting by HPLC (high performance liquid chromatography), wherein the reaction is finished when the end point standard is reached. And quenching, extracting, separating, concentrating, recrystallizing, filtering and drying the reaction solution under reduced pressure to obtain a crude product.
And 4, step 4: refining: adding the crude product and ethyl acetate into a hot melting kettle, heating for dissolving, passing through a neutral alumina layer for decolorization and impurity removal while the crude product and the ethyl acetate are hot to obtain filtrate, cooling for crystallization, filtering, drying to obtain a finished product, sampling, detecting to be qualified, and packaging.
In the step 1, substitution reaction is carried out in a system taking ethyl acetate as a solvent, the reflux reaction is carried out for 3-5h at the heating temperature of 75-85 ℃, TLC monitoring is carried out, and the disappearance of raw material spots is regarded as the completion of the substitution reaction. Cooling to 40-45 ℃, adding palladium carbon, sealing the reaction kettle, discharging air in the kettle by using nitrogen, vacuumizing to the vacuum degree of more than 0.09NPa, introducing hydrogen to keep the pressure of the kettle at 0.2-05 MPa for reduction reaction until the pressure of the kettle is still stable without introducing hydrogen. Filtering out palladium-carbon at 50 ℃ while the solution is hot to obtain clear filtrate, concentrating, cooling, crystallizing, filtering, and drying under reduced pressure (-0.08 MPa) for 8-12 h to obtain the intermediate 3-fluoro-4-morpholinylaniline. The weight ratio of the materials used in the two steps is as follows: 3,4-difluoronitrobenzene: and (3) morpholine: diisopropylethylamine: ethyl acetate: palladium on carbon =1 (0.65-1): (0.4-0.8): (2-3): (0.8-1) the substitution reaction temperature is the boiling point of ethyl acetate, the temperature is 75-85 ℃, reflux is generated, hydrogenation reaction is carried out after the substitution reaction is completely ensured, the temperature is 35-50 ℃, and hydrogen is intermittently introduced to keep the pressure in the range of 0.2-05 MPa. The reaction was terminated while the pressure in the hydrogen-free tank was maintained. Exhausting hydrogen and filling nitrogen to protect and prevent spontaneous combustion. The material temperature is kept at about 50 ℃, so that the phenomenon that the palladium-carbon filtration is influenced by the precipitation of products due to too low temperature is avoided.
In the step 2, an amino reaction is mainly protected, the stability of an intermediate and the reaction selectivity of the next procedure are improved, the solvent is one of tetrahydrofuran, dichloromethane, acetone or dioxane, 3-fluoro-4-morpholinylaniline is dissolved and dispersed, sodium bicarbonate is dissolved by water to be used as an acid-binding agent, benzyl chloroformate is dropwise added, the reaction is carried out for 2 to 4 hours at the temperature of between 5 ℃ below zero and 10 ℃, and the reaction endpoint is detected by TLC. And in the post-treatment, water is adopted to quench redundant benzyl chloroformate, ethyl acetate with better solubility is adopted as an extractant, the organic phase obtained by extraction and liquid separation is concentrated, and n-heptane is pulped and filtered to obtain the intermediate (3-fluoro-4-morpholinylphenyl) benzyl carbamate. The weight ratio of the materials used in the step is as follows: intermediate 3-fluoro-4-morpholinylaniline: sodium bicarbonate: benzyl chloroformate: tetrahydrofuran (or dioxane) =1: (0.6-1): (1.5-2.5): (4-5), wherein the reaction temperature is-2-10 ℃. In the process, the dripping weight ratio of the benzyl chloroformate is 1.5-2.5, the dripping amount of the benzyl chloroformate is reasonably controlled, the post-treatment is simplified, the purity of a target product intermediate is improved, and the conversion rate of the next procedure is greatly improved.
In the step 3, the most critical reaction is realized, the reaction mechanism is complex, the solvent adopted in the process is one or two mixed solvents of DMF, THF and DCM, the reaction solvent is optimized and the THF/DMF mixed solvent is selected, the reaction conversion rate is good, and the post-treatment is simple and convenient; in the process, the equivalent weight of an important initial material (S) -N- [2- (acetoxyl-3-chloropropane) ] acetamide is 1.0-2.5, the equivalent weight of lithium tert-butoxide is 2.0-3.0, and the equivalent weight of methanol is 1.0-2.5; through pilot scale-up, the equivalent weight of (S) -N- [2- (acetoxyl-3-chloropropane) ] acetamide and lithium tert-butoxide is further increased, the conversion rate is basically unchanged, and the intermediate amount in the range can be taken from the comprehensive consideration of cost and product quality. The reaction end point is determined by detecting the reaction conversion rate through HPLC, the conversion rate is found to reach more than 65% after 18 hours, the conversion rate is not obviously improved after the time is prolonged to 48 hours, and the reaction time is determined to be 18-48 hours from the viewpoint of production efficiency. By controlling the ring-closing reaction conditions within the required range and analyzing a plurality of batches of process verification data, the reaction conversion rate is 65-75%, the purity of the crude linezolid is stabilized above 95%, and the ring-closing reaction process is stable and feasible.
In the step 4, the adopted solvent is a common III-class solvent which is low in toxicity, low in price and easy to obtain, and has a certain solubility on linezolid. The solvent is one of ethanol, methanol, ethyl acetate and n-butanol. The decolorizing agent is one of neutral alumina and active carbon. The linezolid has good thermal stability, so the hot-melting temperature is the boiling point temperature of the solvent, the linezolid can be fully dissolved and then decolorized, a decolorizer filter layer is used for decolorizing, the adsorption loss of the product can be reduced, the decolorizing effect is good, a colorless and transparent solution is obtained by filtering while the solution is hot, natural cold crystallization is carried out under stirring, a large amount of white crystals are separated out, filtration is carried out, reduced pressure drying is carried out for 10-24 h, the solvent residue is fully removed, and a finished product is obtained by packaging and sampling detection. The product quality meets the requirement of injection-grade linezolid raw material medicine.
The present invention will be described in detail with reference to examples, but the present invention is not limited to the following examples.
Example 1:
(1) Preparation of intermediate 3-fluoro-4-morpholinylaniline
Adding 16kg of ethyl acetate, 5.5kg of morpholine and 3.7kg of diisopropylethylamine into a 100L hydrogenation reaction kettle, dropwise adding 6kg of 3,4-difluoronitrobenzene, and heating to 75-85 ℃ for reflux reaction for 3-5 h. TLC monitoring, the spot of the raw material disappears, and the temperature is reduced to 50 ℃. 0.6kg of 5% palladium on carbon was added to the reaction kettle, and the airtightness of the kettle was checked. Replacing air with nitrogen for three times; the reaction kettle is vacuumized until the vacuum degree is more than or equal to 0.09MPa. The hydrogen is pressurized to about 0.2 to 0.5MPa, and the pressure is maintained by switching off the hydrogen in the middle of the process. Reacting for 20-25 h at 40-50 ℃. When the hydrogen pressure in the reaction kettle is stable and does not decrease, the TLC detection reaction is carried out, the raw material spots basically disappear, and the reaction is finished. Controlling the temperature of the material below 50 ℃, adding nitrogen and exhausting hydrogen under the pressure of 0.3 MPa. Heating to 70 deg.C, filtering off palladium-carbon, concentrating the filtrate under reduced pressure, and recovering ethyl acetate. Concentrating, pulping with n-heptane, filtering, and draining. The filter cake is dried for 8 to 12 hours under reduced pressure, the vacuum degree is more than or equal to 0.08MPa, the temperature is 40 to 45 ℃, and the intermediate 3-fluoro-4-morpholinylaniline is obtained (the yield range is 85 to 95 percent).
The quality standard is as follows: the HPLC purity is more than or equal to 95.0 percent, and the appearance is red to brown solid;
(2) Preparation of intermediate benzyl (3-fluoro-4-morpholinylphenyl) carbamate
Adding 7kg of intermediate 3-fluoro-4-morpholinylaniline, 6kg of sodium bicarbonate, 34kg of acetone and 34kg of water into a 100L glass reaction kettle, stirring and cooling to-5-10 ℃, and slowly dropwise adding 11.5kg of benzyl chloroformate. Stirring and reacting for 2-4 h at-5-10 ℃. The reaction was checked by TLC. After the reaction, 52kg of ethyl acetate and 5kg of water were added, and the mixture was stirred at room temperature for liquid separation to collect an organic phase. And adding the organic phase into a rotary evaporator, concentrating under reduced pressure to be viscous, adding n-heptane after concentrating and loosening, and fully pulping the materials. Suction filtration is carried out under the protection of nitrogen, and the materials are leached by n-heptane and are dried by suction. Vacuum drying at 40-45 deg.c for about 18 hr to obtain intermediate benzyl (3-fluoro-4-morpholinylphenyl) carbamate (yield range 75-90%).
(3) Preparation of crude product
10.5kg of benzyl intermediate (3-fluoro-4-morpholinophenyl) carbamate, 22kg of DMF, 2.1kg of methanol and 37kg of tetrahydrofuran were charged in a dry 100L glass reactor, and the atmosphere was replaced with nitrogen. Under the protection of nitrogen, the temperature is reduced to 0-10 ℃, and 7.59kg of tert-butyl lithium alkoxide is added in three times. After the feeding is finished, stirring for 0.5-1 h at 0-20 ℃, quickly adding 12.3kg of starting material side chain (S) -N- [2- (acetoxyl-3-chloropropane) ] acetamide, stirring for 0.5-1 h, slowly raising the temperature to 25-35 ℃, and sampling and controlling during reaction for 25h (HPLC: 75% of main peak area (linezolid), which is regarded as the end of the reaction). The temperature is reduced to 0 to 15 ℃, the reaction solution is transferred to a 500L extraction kettle, and 40kg of 23 percent ammonium chloride aqueous solution is slowly added. 40kg of purified water and 65kg of methylene chloride were added thereto, and the mixture was stirred at room temperature for liquid separation to collect an organic layer. Transferring to a distillation kettle for vacuum distillation until no fraction is obtained. Adding ethyl acetate, heating to 70-80 ℃, refluxing and then dropwise adding n-heptane. After the addition is finished, the reflux stirring is kept for 0.5 to 1 hour. Slowly cooling and stirring at normal temperature overnight. Filtration, with n-heptane: ethyl acetate =2: pulping the materials by using the solution with the weight ratio of 1, and filtering to dry. And drying the filter cake for 8-12 h under reduced pressure, wherein the vacuum degree is more than or equal to 0.08MPa, and the temperature is 40-45 ℃, so that a crude product of the linezolid (the yield range is 55-75%) is obtained, and the purity is more than or equal to 95%.
(4) Refining step
6kg of crude linezolid and 130kg of ethyl acetate are added into a 200L hot melting kettle, heated to 70-85 ℃, stirred and dissolved clearly. The hot solution is filtered by a filter device (an alumina filter bed) and the filtrate is pumped into another 200L crystallization kettle. The remaining 1/4 times of the volume was distilled under reduced pressure. Slowly cooling to 0-35 ℃, stirring for more than 3h and crystallizing. And (4) filtering by throwing, pulping the materials by using ethyl acetate, drying by drying, leaching the filter cake by using ethyl acetate, and drying by drying.
Drying under reduced pressure for 10-24 h, wherein the vacuum degree is more than or equal to 0.08MPa, and the temperature is 40-45 ℃ to obtain a fine linezolid product (the mass yield range is 60-85%). And (4) sieving the dried product with a 100-mesh sieve by using a pulverizer, packaging, sampling and fully inspecting.
The quality of the finished product reaches the injection grade standard of linezolid raw material medicaments.
Example 2:
(1) Preparation of intermediate 3-fluoro-4-morpholinylaniline
Adding 60kg of ethyl acetate, 20.6kg of morpholine and 14.2kg of diisopropylethylamine into a 500L enamel reaction kettle, dropwise adding 24kg of 3,4-difluoronitrobenzene, and heating to 75-85 ℃ for reflux reaction for 3-5 h. TLC monitoring, the spot of the raw material disappears, and the temperature is reduced to 40 ℃. Adding 5% palladium carbon into a reaction kettle, and replacing air with nitrogen for three times; the reaction kettle is vacuumized until the vacuum degree is more than or equal to 0.09MPa. The hydrogen is pressurized to about 0.2 to 0.5MPa, and the pressure is maintained by switching off the hydrogen in the middle of the process. Reacting for 15-25 h at 40-50 ℃. When the hydrogen pressure in the reaction kettle is stable and does not decrease, the TLC detection reaction is carried out, the raw material spots basically disappear, and the reaction is finished. Keeping the temperature of the material at 50 ℃, adding nitrogen and discharging hydrogen under the pressure of 0.2-0.3 MPa. Heating to 70 deg.C, filtering off palladium-carbon, concentrating the filtrate under reduced pressure, and recovering ethyl acetate. Concentrating, pulping with n-heptane, filtering, and draining. The filter cake is dried for 8 to 12 hours under reduced pressure, the vacuum degree is more than or equal to 0.08MPa, the temperature is 40 to 45 ℃, and the intermediate 3-fluoro-4-morpholinyl aniline (the yield range is 80 to 95 percent) is obtained.
Quality standard: the HPLC purity is more than or equal to 95.0 percent, and the appearance is red to brown solid;
(2) Preparation of intermediate benzyl (3-fluoro-4-morpholinylphenyl) carbamate
28kg of intermediate 3-fluoro-4-morpholinylaniline, 24kg of sodium bicarbonate, 135kg of tetrahydrofuran and 135kg of water are added into a 500L enamel reaction kettle, stirred and cooled to-5 ℃, and 41kg of benzyl chloroformate is slowly dripped. Stirring and reacting for 2-4 h at-5-10 ℃. The reaction was checked by TLC. After the reaction, 200kg of ethyl acetate and 16kg of water were added, and the mixture was stirred at room temperature for liquid separation, and the organic phase was collected. And adding the organic phase into a distillation retort, concentrating under reduced pressure to be viscous, adding n-heptane after concentrating and loosening, and fully pulping the materials. And (4) carrying out spin filtration under the protection of nitrogen, leaching the materials with n-heptane, and draining. Vacuum drying at 40-45 deg.c for about 18 hr to obtain intermediate benzyl (3-fluoro-4-morpholinylphenyl) carbamate (yield range 80-90%).
(3) Preparation of crude product
40kg of benzyl intermediate (3-fluoro-4-morpholinylphenyl) carbamate, 80kg of DMF, 8.5kg of methanol and 140kg of tetrahydrofuran were placed in a dry 500L enamel reactor, and air was replaced with nitrogen. Under the protection of nitrogen, the temperature is reduced to 0-10 ℃, and 30kg of lithium tert-butoxide is added in three times. After the charging is finished and the stirring is carried out for 0.5 to 1 hour at the temperature of between 0 and 20 ℃, 49kg of side chain (S) -N- [2- (acetoxyl group-3-chloropropane) ] acetamide of the initial material is rapidly added, and after the stirring is carried out for 0.5 to 1 hour, the temperature is slowly increased to between 25 and 35 ℃ for reaction for 18 to 48 hours. Sampling control (HPLC: main peak area (linezolid) ≥ 75%, regarded as reaction end). The temperature is reduced to 0 to 15 ℃, the reaction solution is transferred to a 1.5T extraction kettle, and 160kg of 23 percent ammonium chloride aqueous solution is slowly added. 160kg of purified water and 250kg of dichloromethane were added thereto, and the mixture was stirred at room temperature for liquid separation to collect an organic layer. Transferring to a distillation kettle for vacuum distillation until no fraction is obtained. Adding ethyl acetate, heating to 70-80 ℃, refluxing and then dropwise adding n-heptane. After the addition, the reflux stirring is kept for 0.5 to 1 hour. Slowly cooling and stirring at normal temperature overnight. Filtration, with n-heptane: ethyl acetate =2: pulping the materials by using the solution with the weight ratio of 1, and filtering to dry. And drying the filter cake for 8-12 h under reduced pressure, wherein the vacuum degree is more than or equal to 0.08MPa, and the temperature is 40-45 ℃ to obtain a crude product of linezolid (the yield range is 55-75%).
(4) Refining step
Adding 25kg of crude linezolid and 500kg of ethyl acetate into a 1 ton stainless steel thermosol kettle, heating to 70-85 ℃, and stirring to dissolve the linezolid. The hot solution is filtered by a filter device (an alumina filter bed) and the filtrate is pumped into another 1 ton crystallization kettle. The remaining 1/3 volume was distilled under reduced pressure. Slowly cooling to 0-35 ℃, stirring for more than 3 hours and crystallizing. And (4) filtering by throwing, pulping the materials by using ethyl acetate, drying by drying, leaching the filter cake by using ethyl acetate, and drying by drying.
Drying under reduced pressure for 10-24 h, wherein the vacuum degree is more than or equal to 0.08MPa, and the temperature is 40-45 ℃ to obtain a fine linezolid product (the mass yield range is 65-85%). And (4) sieving the dried product with a 100-mesh sieve by using a pulverizer, packaging, and sampling for full detection.
The quality of the finished product reaches the injection grade standard of linezolid raw material medicaments.
The substance detection spectra of the finished linezolid prepared by the method are shown in figures 1-6.
Claims (10)
1. The production method of linezolid is characterized by comprising the following steps of:
step 1, preparing 3-fluoro-4-morpholinylaniline from 3,4-difluoronitrobenzene: adding 3,4-difluoronitrobenzene, morpholine, ethyl acetate serving as a solvent and diisopropylethylamine serving as an acid binding agent into a reaction kettle, stirring, heating and refluxing to perform substitution reaction to generate an intermediate 3-fluoro-4-morpholinyl nitrobenzene, directly performing hydrogenation reaction under the condition that 3-fluoro-4-morpholinyl nitrobenzene is not separated after monitoring that spots of the starting material disappear, specifically, cooling to 40-45 ℃, adding palladium carbon, sealing the reaction kettle, discharging air in the kettle by using nitrogen, vacuumizing to the vacuum degree of more than 0.09nPa, introducing hydrogen to keep the pressure of the kettle at 0.2-0.5 MPa for reduction reaction until the pressure of the hydrogen tank is not changed, namely the reduction reaction is finished to generate the intermediate 3-fluoro-4-morpholinyl aniline, filtering out palladium carbon to obtain a clear filtrate, concentrating, cooling, crystallizing, filtering, and drying under reduced pressure to obtain the intermediate 3-fluoro-4-morpholinyl aniline;
step 2 preparation of benzyl (3-fluoro-4-morpholinylphenyl) carbamate: adding the 3-fluoro-4-morpholinyl aniline obtained in the step 1, a solvent, an acid-binding agent sodium bicarbonate and water into a reaction kettle, stirring, dropwise adding quantitative benzyl chloroformate into a reaction system, monitoring a reaction end point, and extracting, separating, concentrating, filtering and drying a reaction solution to obtain an intermediate (3-fluoro-4-morpholinyl phenyl) benzyl carbamate;
step 3, ring closing reaction: adding the benzyl (3-fluoro-4-morpholinylphenyl) carbamate obtained in the step 2 and a solvent into a reaction kettle, wherein the solvent is one or two of DMF, THF and DCM, adding tert-butyl lithium alcohol in batches under the protection of nitrogen, adding side chain (S) -N- [2- (acetoxyl-3-chloropropane) ] acetamide, stirring, slowly heating to 25-35 ℃, reacting for 18-48 h, finishing the reaction when a reaction end point standard is reached, quenching the reaction liquid, extracting, separating, concentrating, recrystallizing, filtering, and drying under reduced pressure to obtain a crude linezolid product;
and 4, step 4: refining to obtain a finished product: adding the crude linezolid and a solvent into a hot-melting kettle, heating for dissolving, decoloring and impurity removing through a decoloring agent layer while the solution is hot to obtain a filtrate, cooling for crystallization, filtering, and drying to obtain a finished linezolid product.
2. The method for producing linezolid according to claim 1, characterized in that: the heating reflux in the step 1 refers to heating to 75-85 ℃ for reflux reaction for 3-5 h.
3. The method for producing linezolid according to claim 1, characterized in that: the weight ratio of the materials used in the reaction in the step 1 is 3,4-difluoronitrobenzene: and (2) morpholine: diisopropylethylamine: ethyl acetate: palladium on carbon =1 (0.65-1): (0.4-0.8): (2-3): (0.8-1).
4. The method for producing linezolid according to claim 1, characterized in that: in the step 2, the solvent is one of tetrahydrofuran, dichloromethane, acetone or dioxane, and the weight ratio of materials used in the reaction is intermediate 3-fluoro-4-morpholinylaniline: sodium bicarbonate: benzyl chloroformate: solvent =1: (0.6-1): (1.5-2.5): (4-5) the reaction temperature is-2-10 ℃.
5. The method for producing linezolid according to claim 4, characterized in that: and 2, adding a certain amount of benzyl chloroformate into the high-order metering tank, dropwise adding the benzyl chloroformate into the reaction system, reacting for 2-4 hours at the temperature of-5-10 ℃, and detecting the reaction end point by TLC.
6. The method for producing linezolid according to claim 1, characterized in that: and (3) quenching the reaction solution in the step (2) by using water to quench redundant benzyl chloroformate, extracting by using ethyl acetate as an extracting agent, separating by extraction to obtain an organic phase, concentrating, pulping n-heptane, and filtering to obtain an intermediate (3-fluoro-4-morpholinylphenyl) benzyl carbamate.
7. The method for producing linezolid according to claim 1, characterized in that: in the step 3, the intermediate (3-fluoro-4-morpholinylphenyl) benzyl carbamate is taken as a reference, the molar ratio of the side chain (S) -N- [2- (acetoxyl-3-chloropropane) ] acetamide is 1.0-2.5, the molar ratio of the tert-butyl lithium alkoxide is 2.0-3.0, and the molar ratio of the methanol is 1.0-2.5.
8. The method for producing linezolid according to claim 1, characterized in that: in the step 3, lithium tert-butoxide is added in three times under the protection of nitrogen and the condition of cooling to 0-10 ℃, after the addition is finished, the mixture is stirred for 0.5-1 h at 0-20 ℃, then the side chain (S) -N- [2- (acetoxyl-3-chloropropane) ] acetamide is added, the mixture is slowly raised to 25-35 ℃ after being stirred for 0.5-1 h and reacts for 18-48 h, and the reaction end point standard is that the HPLC monitors the area of a main peak, namely the linezolid is more than or equal to 75 percent.
9. The method for producing linezolid according to claim 1, characterized in that: after finishing the reaction in the step 3, cooling to 0-15 ℃, transferring the reaction solution to an extraction kettle, slowly adding an ammonium chloride aqueous solution, purified water and dichloromethane, stirring and separating at normal temperature, collecting an organic layer, transferring to a distillation kettle, distilling under reduced pressure until no fraction is produced, adding ethyl acetate as an extractant, heating to 70-80 ℃, refluxing, dropwise adding n-heptane, keeping reflux stirring, slowly cooling, stirring at normal temperature overnight, filtering, and adding n-heptane in a weight ratio: ethyl acetate =2:1, pulping the materials, filtering, drying the filter cake under reduced pressure to obtain a crude product of linezolid.
10. The method for producing linezolid according to claim 1, characterized in that: in the step 4, the solvent is one of ethanol, methanol, ethyl acetate and n-butanol, and the decolorizing agent is one of neutral alumina and activated carbon.
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