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CN-121494740-B - Method and device for cis-trans isomerism conversion of 4-halogen-2-methoxyimino acetoacetic acid ethyl ester

CN121494740BCN 121494740 BCN121494740 BCN 121494740BCN-121494740-B

Abstract

The invention relates to the technical field of purification of organic chemical intermediates, in particular to a method and a device for cis-trans isomerism conversion of 4-halogen-2-methoxyiminoacetoacetic acid ethyl ester. Cooling 4-halogen-2-methoxyiminoacetoacetic acid ethyl ester, mixing with sodium chloride salt water to form crystal slurry, discharging the crystal slurry into a crystal transfer kettle for aging, heating, extracting and centrifuging the aged crystal slurry, and collecting an organic phase to obtain the 4-halogen-2-methoxyiminoacetoacetic acid ethyl ester. According to the invention, through the continuous process of low-temperature brine crystallization enrichment, crystal transformation aging directional conversion, microwave rapid temperature rise anti-reversion conversion, two-stage extraction centrifugal purification and brine circulation cost reduction, the cis-content of the 4-halogen-2-methoxyiminoacetoacetic acid ethyl ester is stably increased to 92-95%, and meanwhile, the production cost and the environmental protection risk are reduced.

Inventors

  • MENG XIANQIANG
  • WU ZE
  • WANG ZIYI
  • GUO FAN
  • LI QIAN
  • YANG JING
  • MU HAIBO
  • WANG JINGTAO
  • AN YUKUN
  • XU HE
  • ZHAO QI
  • ZHAO WENYONG

Assignees

  • 山东金城医药化工有限公司

Dates

Publication Date
20260512
Application Date
20260114

Claims (8)

  1. The cis-trans isomerism conversion method of the 4-halogen-2-methoxyiminoacetoacetic acid ethyl ester is characterized by comprising the following steps: S1, preparing crystal slurry, namely adding sodium chloride brine into a sedimentation type crystallizer (5), cooling the sodium chloride brine, stirring, adding a halide raw material into the sedimentation type crystallizer (5) through a dispersion feeder (4), and mixing with sodium chloride water to form crystal slurry, wherein the halide raw material contains 86-90 wt% of cis-4-halo-2-methoxyiminoacetoacetate, 7-8 wt% of trans-4-halo-2-methoxyiminoacetoacetate and the balance of impurities; s2, crystal slurry aging, namely discharging the crystal slurry in the sedimentation type crystallizer (5) into a crystal transferring kettle for aging, wherein the aging temperature is-20 to-5 ℃, and the aging time is 10-20 hours; S3, heating by microwaves, namely sending the aged crystal slurry into a microwave heating pipeline reactor (11) to heat, wherein the temperature is raised to 10-30 ℃, the microwave power of the microwave heating pipeline reactor (11) is 6-10 kW, the heating time is 10-50S, and the heating rate is more than or equal to 1.0 ℃ per second; S4, extracting and separating, namely extracting and centrifuging the heated material, separating liquid, collecting an organic phase to obtain 4-halogen-2-methoxyiminoacetoacetic acid ethyl ester, cooling a water phase, and returning the cooled water phase to the sedimentation crystallizer (5) for recycling.
  2. 2. The method for cis-trans isomerism conversion of 4-halo-2-methoxyiminoacetoacetate according to claim 1, wherein in step S1, the 4-halo-2-methoxyiminoacetoacetate is 4-chloro-2-methoxyiminoacetoacetate or 4-bromo-2-methoxyiminoacetoacetate.
  3. 3. The method for cis-trans isomerism conversion of 4-halogen-2-methoxyiminoacetoacetate according to claim 1, wherein in the step S1, the feeding speed of the halide raw material is 30-100L/min, and the concentration of sodium chloride brine is 26.0-26.5wt%.
  4. 4. The method for cis-trans isomerism conversion of 4-halogen-2-methoxyiminoacetoacetate according to claim 1, wherein in the step S1, sodium chloride brine is cooled to-20 to-5 ℃, the stirring speed is 10-20 r/min, and the aperture of a dispersion feeder (4) is 0.5-1.0 mm.
  5. 5. The method for cis-trans isomerism conversion of 4-halogen-2-methoxyiminoacetoacetate according to claim 1, wherein in the step S4, the heated material is subjected to primary extraction and centrifugation, a primary organic phase and a primary water phase are obtained through liquid separation, an organic solvent is added into the primary water phase, then the secondary extraction and centrifugation are carried out, a secondary organic phase and a secondary water phase are obtained through liquid separation, the primary organic phase and the secondary organic phase are combined to obtain the 4-halogen-2-methoxyiminoacetoacetate, the secondary water phase is cooled to-20 to-5 ℃, and then the secondary water phase is returned to a sedimentation crystallizer (5) for recycling, wherein the organic solvent is ethyl acetate, methyl tertiary butyl ether, dichloromethane, trichloromethane or tetrachloromethane.
  6. 6. The method for cis-trans isomerism conversion of 4-halogen-2-methoxyiminoacetoacetate according to any one of claims 1-5, which is characterized in that the adopted device comprises a sedimentation crystallizer (5), a crystal transformation kettle, a microwave heating pipeline reactor (11) and an extraction centrifuge which are connected in sequence, wherein a dispersion feeder (4) is arranged above the interior of the sedimentation crystallizer (5), the dispersion feeder (4) is connected with a halide raw material tank (1) through a pipeline, an anchor stirrer (3) is further arranged at the top of the sedimentation crystallizer (5), and a jacket cooling layer (6) is arranged on the outer wall of the sedimentation crystallizer (5); the extraction centrifuge comprises a primary horizontal extraction centrifuge (16) and a secondary horizontal extraction centrifuge (17), wherein the lower part of the primary horizontal extraction centrifuge (16) is connected with the bottom of a microwave heating pipeline reactor (11) through a pipeline, the upper part of the primary horizontal extraction centrifuge (16) is connected with the lower part of the secondary horizontal extraction centrifuge (17) through a pipeline, the upper part of the secondary horizontal extraction centrifuge (17) is connected with a brine transfer tank (20) through a pipeline, the brine transfer tank (20) is respectively connected with a cooling heat exchanger (22) and a sodium chloride salt water tank (19) through pipelines, and the cooling heat exchanger (22) is connected with the top of a sedimentation crystallizer (5) through a pipeline; The upper parts of the primary horizontal extraction centrifugal machine (16) and the secondary horizontal extraction centrifugal machine (17) are connected with an organic phase storage tank (15) through pipelines, and the lower part of the secondary horizontal extraction centrifugal machine (17) is also connected with an organic solvent storage tank (18) through a pipeline.
  7. 7. The method for cis-trans isomerism conversion of 4-halogen-2-methoxyiminoacetoacetate according to claim 6, wherein the crystal transformation kettles comprise a first crystal transformation kettle (8), a second crystal transformation kettle (9) and a third crystal transformation kettle (10), the upper parts of the first crystal transformation kettle (8), the second crystal transformation kettle (9) and the third crystal transformation kettle (10) are connected with the bottom of a sedimentation type crystallizer (5) through pipelines, a timing discharge valve (7) is arranged on the pipeline between the first crystal transformation kettle (8), the second crystal transformation kettle (9) and the third crystal transformation kettle (10) and the sedimentation type crystallizer (5), and the lower parts of the first crystal transformation kettle (8), the second crystal transformation kettle (9) and the third crystal transformation kettle (10) are connected with the top of a microwave heating pipeline reactor (11) through pipelines.
  8. 8. The method for cis-trans isomerism conversion of 4-halogen-2-methoxyiminoacetoacetate is characterized in that a quartz pipeline (12) is arranged in a microwave heating pipeline reactor (11), a temperature monitor (14) is arranged in the middle of the quartz pipeline (12), a microwave generator (13) is arranged outside the quartz pipeline (12), a constant flow pump (2) is arranged on a pipeline between a dispersion feeder (4) and a halide raw material tank (1), and a centrifugal pump (21) is arranged on a pipeline between a brine transfer tank (20) and a cooling heat exchanger (22).

Description

Method and device for cis-trans isomerism conversion of 4-halogen-2-methoxyimino acetoacetic acid ethyl ester Technical Field The invention relates to the technical field of purification of organic chemical intermediates, in particular to a method and a device for cis-trans isomerism conversion of 4-halogen-2-methoxyiminoacetoacetic acid ethyl ester. Background The 4-halogen-2-methoxyiminoacetoacetic acid ethyl ester is a core intermediate for synthesizing third-generation cephalosporin, and cis (Z type) isomer in the molecular structure is an effective configuration participating in the synthesis of subsequent antibiotics, and trans (E type) isomer is not bioactive and easy to generate impurities, so that the trans content is required to be strictly controlled to be less than or equal to 5% in industrial production. At present, the organic matter crystal transformation method mainly comprises the following steps of a solvent crystal transformation method, namely, a solvent system is changed or the temperature is regulated to enable crystals to be transformed in different solvents, the method is large in solvent usage amount, further the subsequent separation energy consumption is increased, nitric acid is used as a crystal transformation medium to enable the crystal structure to be transformed, a large amount of waste acid is produced by the method, waste acid is used as the crystal transformation medium, the waste acid (such as industrial waste acid) is used as the crystal transformation method, the crystal structure is induced to change through acid-base reaction or solvent effect, new impurities are easily introduced into the system by the method, the cooling crystallization method is used for inducing the crystal transformation by utilizing the characteristic that the solubility changes along with the temperature by controlling the cooling rate, the freezing crystallization system of the method is easy to freeze in a large scale, the method is difficult in industrialized amplification production, two mutually-soluble solvents (good solvents and anti-solvents) are selected, the crystal transformation is promoted by utilizing the solubility difference, and the new solvents are required to be introduced, and the system load is increased. Chinese patent CN118561788a discloses a method for cis-trans isomerism conversion of methoxyimino furan acetic acid, which comprises extracting a cis-trans isomerism mixture obtained by reacting alpha-oxo-2-furan acetic acid with methoxyamine hydrochloride, drying the reaction solution, treating with protonic acid or lewis acid, performing inversion, neutralizing with organic base or inorganic base, and extracting to obtain high purity Z-methoxyimino furan acetic acid. The patent uses precursor acid or Lewis acid for treatment and then carries out transformation, and uses organic alkali or inorganic alkali for neutralization treatment, so that the use amount of organic solvents is large, the three wastes are serious, and the treatment difficulty and the cost are high. Chinese patent CN118084812A discloses a method for preparing beta-HMX by continuous crystal transformation, wherein, S1, beta-HMX seed crystal and nitric acid are added into a crystal transformation kettle as crystal transformation base materials, S2, alpha-HMX and 98 percent nitric acid are continuously added into a proportioning kettle, HMX-nitric acid suspension is continuously overflowed to a dissolution kettle under stirring to be completely dissolved to form HMX-nitric acid solution, S3, softened water and HMX-nitric acid solution overflowed from the dissolution kettle are added into the crystal transformation kettle for crystal transformation, S4, materials in the crystal transformation kettle are continuously overflowed into a crystal transformation maturation kettle to fully transform crystals, S5, materials in the crystal transformation maturation kettle are sequentially fed into a first filter, a water washing kettle and a second filter, and then are fed into a dryer to be dried to obtain beta-HMX. The method is not suitable for converting halide, and concentrated nitric acid can react with halide to damage the structures of raw materials and products, so that the quality of the products is reduced. The used concentrated nitric acid belongs to a strong oxidant and a corrosive agent, the production process has extremely high risk, meanwhile, a large amount of acid wastewater can be generated in the water washing step, the three wastes are serious, the treatment difficulty is high, the cost is high, the environmental protection pressure is huge, and the environment-friendly chemical development trend is not met. Therefore, there is a need to develop a halide cis-inversion technology which is simple to operate, low in energy consumption, good in environmental protection, high in cis-content and recyclable in medium, and which can be suitable for industrial production. Disclosure of Invention The inve