Process and apparatus for cis-trans isomerization of 4-halo-2-methoxyiminoacetoacetate esters

Abstract

The present application relates to the technical field of organic chemical intermediates purification, in particular to a method and device for cis-trans isomerization conversion of 4-halo-2-methoxy imino acetoacetic acid ethyl ester. After cooling, 4-halo-2-methoxy imino acetoacetic acid ethyl ester is mixed with sodium chloride brine to form crystal slurry; then the crystal slurry is discharged into a crystal conversion kettle for aging; after aging, the crystal slurry is heated, extracted and centrifuged, and the organic phase is collected to obtain 4-halo-2-methoxy imino acetoacetic acid ethyl ester. Through the continuous process of "low-temperature brine crystallization enrichment-crystal conversion aging directional conversion-microwave rapid heating to prevent reverse conversion-two-stage extraction centrifugation purification-brine circulation to reduce cost", the content of cis-4-halo-2-methoxy imino acetoacetic acid ethyl ester is stably increased to 92-95%, and the production cost and environmental risk are reduced.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of purification of organic chemical intermediates, and particularly relates to a method and device for converting 4-halo-2-methoxyimino ethyl acetoacetate into a cis-trans isomer. BACKGROUND

[0002] 4-halo-2-methoxyimino ethyl acetoacetate is a core intermediate for synthesizing the third-generation cephalosporin, the cis (Z type) isomer in the molecular structure of the 4-halo-2-methoxyimino ethyl acetoacetate is an effective configuration for participating in subsequent antibiotic synthesis, the trans (E type) isomer has no biological activity and is easy to generate impurities, therefore, the content of the trans isomer needs to be strictly controlled to be less than or equal to 5% in industrial production.

[0003] At present, the crystal transformation methods of organic substances mainly include the following methods: solvent crystal transformation method, the crystal transformation is induced by changing a solvent system or adjusting a temperature, the solvent crystal transformation method has a large solvent usage, and further increases the energy consumption of subsequent separation; nitric acid crystal transformation method, nitric acid is used as a crystal transformation medium to induce the crystal structure transformation, the method produces a large amount of waste acid; waste acid crystal transformation method, waste acid (such as industrial waste acid) is used as a crystal transformation medium, the crystal structure is induced to change through an acid-base reaction or a solvent effect, the method is easy to introduce new impurities into the system; cooling crystallization method, the crystal transformation is induced by controlling the cooling rate and using the characteristic that the solubility changes with the temperature, the freezing crystallization system of the cooling crystallization method is easy to freeze in a large scale, and the industrialized production has difficulties; anti-solvent method, two mutually soluble solvents (good solvent and anti-solvent) are selected, and the crystal transformation is induced by using the solubility difference, the anti-solvent method needs to introduce a new solvent, and the system load is increased.

[0004] Chinese patent CN118561788A discloses a method for converting cis-trans isomers of methoxyimino furan acetic acid, a cis-trans isomer mixture obtained after reacting alpha-oxo-2-furan acetic acid and methoxyamine hydrochloride is extracted with an organic solvent, dried, treated with a protonic acid or a Lewis acid, and then subjected to isomerization, and then neutralized by using an organic base or an inorganic base, and high-purity Z-methoxyimino furan acetic acid is obtained after extraction. The patent uses a protonic acid or a Lewis acid for treatment, and then uses an organic base or an inorganic base for neutralization treatment, the amount of the organic solvent used is large, the three-waste problem is serious, the treatment is difficult and the cost is high.

[0005] Chinese patent CN118084812A discloses a continuous crystallization method for preparing β-HMX. The method involves: S1. Adding β-HMX seed crystals and nitric acid as the base material to a crystallization reactor; S2. Continuously adding α-HMX and 98% nitric acid to a mixing reactor, and under stirring, continuously overflowing the HMX-nitric acid suspension into a dissolving reactor to completely dissolve and form an HMX-nitric acid solution; S3. Adding softened water and the overflowing HMX-nitric acid solution from the dissolving reactor into the crystallization reactor for crystallization; S4. Continuously overflowing the material from the crystallization reactor into a crystallization maturation reactor for complete crystallization; S5. The material from the crystallization maturation reactor successively enters a first filter, a water washing reactor, and a second filter, and then enters a dryer to obtain β-HMX. This patented method is not suitable for the transformation of halides, as concentrated nitric acid reacts with halides, damaging the structure of the raw materials and products, resulting in a decline in product quality. The concentrated nitric acid used is a strong oxidizing and corrosive agent, making the production process extremely dangerous. At the same time, the water washing step uses a large amount of water and also generates a large amount of acidic wastewater. The three waste problems are serious, difficult to treat, costly, and put enormous pressure on the environment, which is not in line with the trend of green chemical development.

[0006] Therefore, there is an urgent need to develop a halide cis-trans conversion technology that is easy to operate, has low energy consumption, is environmentally friendly, has high cis content and a recyclable medium, and is suitable for industrial production. Summary of the Invention

[0007] The purpose of this invention is to overcome the shortcomings of the existing technology and provide a method for the cis-trans isomerization of ethyl 4-halo-2-methoxyiminoacetoacetate. Through a continuous process of "low-temperature brine crystallization enrichment - crystallization aging directional conversion - microwave rapid heating to prevent reverse conversion - two-stage extraction centrifugation purification - brine circulation to reduce costs", the cis content of ethyl 4-halo-2-methoxyiminoacetoacetate is stably increased to 92-95%, while reducing production costs and environmental risks.

[0008] The technical solution adopted by this invention to solve its technical problem is:

[0009] A method for the cis-trans isomerization of ethyl 4-halo-2-methoxyiminoacetoacetate, comprising the following steps:

[0010] S1. Preparation of crystal slurry: Add sodium chloride brine to the settling crystallizer, cool the sodium chloride brine and stir it; add the halide raw material to the settling crystallizer through a dispersing feeder, mix it with sodium chloride brine to form crystal slurry (solid-liquid mixture).

[0011] S2, Crystal slurry aging: The crystal slurry in the settling crystallizer is discharged into the crystal transfer vessel for aging;

[0012] S3. Microwave heating: The aged crystal slurry is fed into a microwave-heated pipeline reactor for heating.

[0013] S4. Extraction and separation: The heated material is extracted and centrifuged, separated, and the organic phase is collected to obtain ethyl 4-halo-2-methoxyiminoacetoacetate; the aqueous phase is cooled and returned to the settling crystallizer for recycling.

[0014] Furthermore, in step S1, the halide raw material contains 86-90 wt% cis-4-halo-2-methoxyimino acetoacetate, 7-8 wt% trans-4-halo-2-methoxyimino acetoacetate, and the remainder is impurities; the 4-halo-2-methoxyimino acetoacetate is 4-chloro-2-methoxyimino acetoacetate or 4-bromo-2-methoxyimino acetoacetate.

[0015] Furthermore, the sodium chloride brine is a saturated sodium chloride brine, which is an inert crystallization medium. At -20 to -5°C, the solubility of halides is ≤0.2 g / L, which can promote rapid crystallization of halides; Cl - It can inhibit the hydrolysis of ester groups in halide molecules, and the hydrolysis impurities are controlled to ≤0.4%; it can be recycled ≥8 times. The volume ratio of sodium chloride brine to halide raw material is 2.3~2.8:1.

[0016] Furthermore, in step S1, the feed rate of the halide raw material is 30~100L / min, preferably 50L / min; the concentration of the sodium chloride brine is 26.0~26.5wt%.

[0017] Further, in step S1, the sodium chloride brine is cooled to -20 to -5°C; the stirring speed is 10 to 20 r / min, preferably 10 r / min; and the orifice diameter of the dispersant feeder is 0.5 to 1.0 mm. The dispersant feeder breaks the halide into tiny droplets (particle size ≤ 0.1 mm), which, after being thoroughly mixed with the low-temperature saturated sodium chloride brine, rapidly crystallize and precipitate, forming a uniform slurry with a solid content of 15 to 20% (crystallized particles with a diameter D). 50 =100~400μm). Dispersed feeding avoids crystal agglomeration caused by localized accumulation of halides, laying the foundation for subsequent crystallization aging and separation.

[0018] Furthermore, in step S2, the aging temperature is -20 to -5°C, and the aging time is 10 to 20 hours, preferably 15 hours. At -20 to -5°C, the thermodynamic stability of the halide trans isomer decreases, and the trans isomer in the slurry is oriented to transform into the cis isomer through crystal lattice rearrangement. The transformation rate is 0.15 to 0.5% / hour. After 10 to 20 hours, the cis content increases from 86 to 90% to 92 to 95%, while the trans content decreases to 2 to 4%.

[0019] Furthermore, in step S3, the temperature is raised to 10~30℃; the microwave power of the microwave-heated pipeline reactor is 6~10kW, preferably 8kW; the heating time is 10~50s, and the heating rate is ≥1.0℃ / s.

[0020] Microwave heating can achieve "synchronous heating inside and outside" of materials, avoiding local overheating of traditional jacket heating (the local temperature difference of traditional heating is ≥5℃, which can easily lead to cis-to-trans reversal); rapid heating can shorten the residence time of materials in the intermediate temperature range (-10~0℃), and the cis content retention rate is ≥99.5%.

[0021] Further, in step S4, the heated material is first subjected to primary extraction centrifugation to separate the liquid into a primary organic phase and a primary aqueous phase (containing a small amount of residual halides). An organic solvent is added to the primary aqueous phase, and then it is subjected to secondary extraction centrifugation to separate the liquid into a secondary organic phase and a secondary aqueous phase. The primary and secondary organic phases are combined to obtain ethyl 4-halo-2-methoxyiminoacetoacetate. The secondary aqueous phase is cooled to -20~-5℃ and then returned to the sedimentation crystallizer for recycling. The organic solvent is ethyl acetate, methyl tert-butyl ether, dichloromethane, trichloromethane, or tetrachloromethane, and the amount of organic solvent used is 0.02~0.03 times the volume of the primary aqueous phase.

[0022] Another object of the present invention is to provide an apparatus for the cis-trans isomerization of ethyl 4-halo-2-methoxyiminoacetoacetate, comprising a sedimentation crystallizer, a crystallization kettle, a microwave-heated pipeline reactor, and an extraction centrifuge connected in sequence. A dispersing feeder is provided at the top inside the sedimentation crystallizer, and the dispersing feeder is connected to a halide raw material tank through a pipeline. An anchor-type agitator is also provided at the top of the sedimentation crystallizer, and a jacketed cooling layer is provided on the outer wall of the sedimentation crystallizer.

[0023] The extraction centrifuge includes a primary horizontal extraction centrifuge and a secondary horizontal extraction centrifuge. The lower part of the primary horizontal extraction centrifuge is connected to the bottom of the microwave-heated pipeline reactor via a pipeline. The upper part of the primary horizontal extraction centrifuge is connected to the lower part of the secondary horizontal extraction centrifuge via a pipeline. The upper part of the secondary horizontal extraction centrifuge is connected to a brine transfer tank via a pipeline. The brine transfer tank is connected to a cooling heat exchanger and a sodium chloride brine tank via pipelines. The cooling heat exchanger is connected to the top of a settling crystallizer via a pipeline.

[0024] Both the primary and secondary horizontal extraction centrifuges are connected to an organic phase storage tank via pipelines at the top, while the secondary horizontal extraction centrifuge is also connected to an organic solvent storage tank via pipelines at the bottom.

[0025] Furthermore, the crystallization reactor includes a first crystallization reactor, a second crystallization reactor, and a third crystallization reactor. The top of the first crystallization reactor, the second crystallization reactor, and the third crystallization reactor are all connected to the bottom of the settling crystallizer via pipelines. A timed discharge valve is installed on the pipeline between the first crystallization reactor, the second crystallization reactor, and the third crystallization reactor and the settling crystallizer. The bottom of the first crystallization reactor, the second crystallization reactor, and the third crystallization reactor are all connected to the top of the microwave-heated pipeline reactor via pipelines.

[0026] Furthermore, the microwave-heated pipeline reactor is equipped with a quartz pipe (inner diameter 100~120mm, length 2.5~3m), with 4 temperature monitors (0.75m apart) in the middle of the quartz pipe, and 6~8 microwave generators (total power 6~10kW, frequency 2450MHz) arranged on the outside of the quartz pipe; a temperature interlock device (over-temperature and over-pressure alarm) is installed at the outlet of the microwave-heated pipeline reactor, which automatically reduces the microwave power when the material temperature exceeds 22℃.

[0027] A constant flow pump with a flow rate accuracy of ±1 L / min is installed on the pipeline between the disperser and the halide raw material tank. A centrifugal pump is installed on the pipeline between the brine transfer tank and the cooling heat exchanger.

[0028] The effective volume of the sedimentation crystallizer is 15~20m³, and the material is 316L stainless steel. The jacketed cooling layer of the sedimentation crystallizer is filled with ethylene glycol refrigerant at -25~-20℃, and its heat exchange area is 20~25m². The sedimentation crystallizer is used for low-temperature brine storage, chloride dispersion crystallization, and timed discharge of crystal slurry.

[0029] The timed discharge valve has a discharge frequency of 10~30 minutes / time.

[0030] The outer walls of the first, second, and third crystallization reactors are all equipped with a polyurethane insulation layer with a thickness of 120-150 mm to ensure temperature fluctuations ≤ ±0.5℃ / h and prevent a decrease in conversion efficiency. Each reactor is also equipped with a level sensor (range 0-8 m³, accuracy ±0.01 m³) and a temperature sensor (temperature accuracy ±0.1℃). The effective volume of each reactor is 5-10 m³, and they are made of 316L stainless steel.

[0031] Both the primary horizontal extraction centrifuge (30-50 Hz) and the secondary horizontal extraction centrifuge (30-50 Hz) are equipped with density sensors (detection accuracy ±0.001 g / cm³). These density sensors are used to automatically identify the organic-aqueous phase interface. By automatically identifying the interface (halide density 1.12-1.15 g / cm³, brine density 1.20-1.22 g / cm³), the separation error is ≤0.1%, avoiding organic phase loss.

[0032] The brine transfer tank has a volume of 12-15 m³, the centrifugal pump has a flow rate of 50-80 m³ / h, and is made of 316L stainless steel; the cooling heat exchanger has a heat exchange area of ​​18-22 m² and a cooling capacity of 50-70 kW.

[0033] The pipes connecting the devices in this invention are all made of 316L stainless steel, and the pipe diameter matches the device interface.

[0034] This invention establishes a circulation loop between the settling crystallizer, the crystallization vessel, the microwave-heated pipeline reactor, the extraction centrifuge, the brine transfer tank, and the cooling heat exchanger, enabling dynamic balance of the liquid level within the settling crystallizer. When the crystal slurry in the settling crystallizer is transferred to the crystallization vessel, the liquid level in the settling crystallizer drops. The aqueous phase (sodium chloride brine) in the brine transfer tank is then pumped into the cooling heat exchanger, cooled to -20 to -5°C, before entering the settling crystallizer, thus raising the liquid level in the settling crystallizer to the designated level. When the aqueous phase (sodium chloride brine) in the brine transfer tank is insufficient, it is promptly replenished by the sodium chloride brine tank.

[0035] This invention first adds sodium chloride brine to a settling crystallizer, controlling the temperature of the brine at -20 to -5°C. Then, a halide feedstock containing 86-90 wt% ethyl cis-4-halo-2-methoxyiminoacetoacetate and 7-8 wt% trans-4-halo-2-methoxyiminoacetoacetate is added to the settling crystallizer via a dispersing feeder. The dispersing feeder breaks the halide into tiny droplets (≤0.1 mm in diameter), which, after thorough mixing with the low-temperature sodium chloride brine, rapidly crystallize out, forming a uniform slurry with a solid content of 15-20% (crystal particle size D). 50 =100~400μm), avoiding the crystal agglomeration caused by localized halide aggregation, laying the foundation for subsequent crystallization aging and separation.

[0036] In this invention, the obtained crystal slurry is then transferred to a crystallization reactor for aging. The temperature inside the reactor is controlled at -20 to -5°C. At this temperature, the thermodynamic stability of the trans isomers in the halides decreases, and the trans isomers in the crystal slurry are oriented to convert to cis isomers through crystal lattice rearrangement. The cis isomer content increases from 86-90 wt% to 92-95 wt%, while the trans isomer content decreases to 2-4 wt%. The aged crystal slurry is then fed into a microwave-heated pipe reactor. Microwaves penetrate the quartz pipe and directly act on the polar molecules inside the material (such as the C=O and NO polar bonds in halides, and Na+ in brine). + Cl -In microwave electric fields, polar molecules undergo high-frequency reversal in the direction of the electric field, generating heat through intense friction and collisions between molecules. This achieves "synchronous heating inside and outside the material," eliminating the need for heat conduction and fundamentally removing temperature gradients. The heat generation efficiency is far higher than traditional heating methods. Simultaneously, the heating rate is controlled at ≥1.0℃ / s, raising the temperature of the crystal slurry to 10~30℃, completely dissolving the crystals and separating the system into an organic phase (halides) and an aqueous phase (sodium chloride brine). This invention utilizes microwave heating to achieve "synchronous heating inside and outside the material," avoiding localized overheating in traditional jacketed heating (where localized temperature differences ≥5℃ can easily lead to cis-to-trans reversal). Rapid heating shortens the residence time of the material in the intermediate temperature range (-10~0℃), resulting in a cis-halide content retention rate of ≥99.5%.

[0037] In this invention, the heated material is extracted, centrifuged, and separated. The organic phase is collected to obtain ethyl 4-halo-2-methoxyiminoacetoacetate. The aqueous phase (sodium chloride brine) is cooled and returned to the settling crystallizer for recycling. This invention achieves a sodium chloride brine recycling rate of ≥98%, reducing raw material costs.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] (1) The content of cis isomers is steadily increased: through the synergistic effect of crystal aging and microwave heating, the content of cis isomers of halides is increased from 86~90wt% to 92~95wt%, and the content of trans isomers is reduced to 2~4wt%, which meets the quality standard of aminothiazolic acid intermediate (trans isomers ≤5%).

[0040] (2) High continuous efficiency: The continuous process of “low temperature brine crystallization enrichment - crystallization aging directional conversion - microwave rapid heating to prevent reversal - two-stage extraction centrifugation purification - brine circulation” shortens the production cycle and can process up to 4000L of halides per batch, greatly increasing the annual production capacity.

[0041] (3) Significant cost and environmental advantages: The recycling of saturated sodium chloride brine reduces raw material costs; VOC emissions and wastewater emissions are significantly reduced, meeting the requirements of green chemical industry.

[0042] (4) Excellent product yield and quality: Two-stage extraction and centrifugation reduces organic phase loss, and the product yield is ≥98%; microwave rapid heating inhibits product hydrolysis, and hydrolysis impurities are ≤0.4%, eliminating the need for subsequent recrystallization and further reducing production costs.

[0043] (5) Operation is safe and controllable: The whole set of equipment is a closed system, which avoids the leakage of organic vapors; the microwave heating pipeline reactor and the extraction centrifuge are equipped with interlock protection (over-temperature and over-pressure alarms), which significantly improves production safety.

[0044] This invention uses recyclable low-temperature saturated sodium chloride brine as the crystallization medium, combined with continuous equipment and parameter optimization, and has the advantages of simple operation, low energy consumption, good environmental protection, and high product yield (≥98%). It can significantly reduce the industrial production cost of halides and is suitable for the large-scale production of aminothiazide acid intermediates. Attached Figure Description

[0045] Figure 1 This is a schematic diagram of the production apparatus of the present invention;

[0046] Figure 2 This is the liquid phase spectrum of the ethyl 4-chloro-2-methoxyiminoacetoacetate product in Example 1 of the present invention;

[0047] Figure 3 This is the liquid phase spectrum of the ethyl 4-bromo-2-methoxyiminoacetoacetate product in Example 2 of the present invention;

[0048] Figure 4 This is the liquid phase spectrum of the ethyl 4-chloro-2-methoxyiminoacetoacetate product in Example 3 of the present invention;

[0049] Figure 5 The image shows the XRD pattern of the ethyl 4-chloro-2-methoxyiminoacetoacetate product in Example 1 of this invention.

[0050] In the diagram: 1. Halogenated raw material tank; 2. Constant flow pump; 3. Anchor agitator; 4. Dispersing feeder; 5. Sedimentation crystallizer; 6. Jacketed cooling layer; 7. Timed discharge valve; 8. First crystallizer; 9. Second crystallizer; 10. Third crystallizer; 11. Microwave-heated pipeline reactor; 12. Quartz pipe; 13. Microwave generator; 14. Temperature monitor; 15. Organic phase storage tank; 16. First-stage horizontal extraction centrifuge; 17. Second-stage horizontal extraction centrifuge; 18. Organic solvent storage tank; 19. Sodium chloride brine tank; 20. Brine transfer tank; 21. Centrifugal pump; 22. Cooling heat exchanger. Detailed Implementation

[0051] The present invention will be further described below with reference to the embodiments.

[0052] Example 1

[0053] S1. Preparation of crystal slurry: Add 10000L of saturated sodium chloride brine (26.5wt%) to a 15m³ settling crystallizer 5. Introduce -25℃ ethylene glycol cryosol into the jacketed cooling layer 6 to lower the temperature of the saturated sodium chloride brine to -15℃. Turn on the anchor stirrer 3 and adjust the speed to 10r / min. Control the temperature difference inside the settling crystallizer 5 within ±0.8℃.

[0054] 4000L of chloride feedstock (ethyl 4-chloro-2-methoxyiminoacetoacetate, cis content 89.2wt%, trans content 7.3wt%) was fed into the disperser feeder 4 (orifice diameter 0.8mm) inside the settling crystallizer 5 via constant flow pump 2. The feed rate was adjusted to 50L / min. After being dispersed by the disperser feeder 4, the chloride feedstock was mixed with low-temperature saturated sodium chloride brine. After 1.5h, a crystal slurry with a solid content of 18% (crystal particle size D) was formed. 50 =335μm).

[0055] S2. Crystallizer aging: Open the timed discharge valve 7 at the bottom of the settling crystallizer 5 every 27 minutes to discharge the crystallizer slurry containing about 1300L of chloride into the 10m³ crystallizer reactor. Collect a total of 3 batches (about 3900L of chloride, partially dissolved in saturated sodium chloride brine) and then close the timed discharge valve 7. Maintain the temperature of the crystallizer reactor at -15℃ and age for 15 hours. Take a sample and test the cis content to be 94.4wt% and the trans content to be 3.0wt%.

[0056] S3. Microwave heating: The aged crystal slurry is pumped into the microwave heating pipeline reactor 11. The microwave power is adjusted to 8kW. After 30s, the material temperature rises to 20℃. The cis content is maintained at 94.4wt% (no reversible oxidation) when sampled and tested.

[0057] S4. Extraction and Separation: The heated material is fed into a primary horizontal extraction centrifuge 16 at a controlled speed of 40 Hz for extraction centrifugation and separation, yielding 3880 L of primary organic phase (cis 94.4 wt%), which is then fed into organic phase storage tank 15. 10020 L of primary aqueous phase is fed into a secondary horizontal extraction centrifuge 17. 200 L of ethyl acetate is added to the secondary horizontal extraction centrifuge 17, and the mixture is further extracted, centrifuged, and separated at a controlled speed of 40 Hz, yielding 260 L of secondary organic phase (cis 94.4 wt%), which is fed into organic phase storage tank 15. After merging with the primary organic phase, a total organic phase of 4140 L (including 200 L of ethyl acetate) is obtained, yielding ethyl 4-chloro-2-methoxyiminoacetoacetate (yield 98.5%, calculated based on 4000 L of chloride feedstock).

[0058] The secondary aqueous phase (saturated sodium chloride brine) is obtained and enters the brine transfer tank 20. Then, it is pumped by centrifugal pump 21 to the cooling heat exchanger 22, where it is cooled from 20°C to -15°C. After filtration, it is returned to the settling crystallizer 5.

[0059] Final product testing: Ethyl 4-chloro-2-methoxyiminoacetoacetate in organic phase storage tank 15 was tested. The cis content was 94.4 wt%, the trans content was 3.0 wt%, and the hydrolysis impurities were 0.38 wt%, meeting the quality standards for aminothiazide acid intermediates. The yield was 98.5%. Its liquid chromatography spectrum is shown below. Figure 2As shown, the corresponding peak analysis is shown in Table 1. The XRD diffraction pattern of ethyl 4-chloro-2-methoxyiminoacetoacetate is shown in... Figure 5 As shown, from Figure 5 As can be seen, the positions (2θ values) and relative intensities of the characteristic diffraction peaks are in perfect agreement with the theoretical spectrum simulated based on its single-crystal structure, and no impurity peaks appear. This indicates that the prepared sample is the target compound with high crystal purity and a single crystal form, and its crystal structure has been experimentally verified.

[0060] Table 1. Peak analysis of the liquid chromatography spectrum of the final product prepared in Example 1.

[0061] Peak No. Retention Time Area Height Area % Height % 1 2.920 11576 1077 0.033 0.065 2 4.817 133323 2121 0.379 0.129 3 5.112 49810 2659 0.142 0.161 4 7.175 707533 13718 2.011 0.833 5 8.710 1051503 18589 2.989 1.129 6 10.748 33223216 1607974 94.432 97.665 7 12.615 5141 280 0.015 0.017 Total 35182102 1646418 100.000 100.000

[0062] like Figure 1 As shown, the apparatus for realizing the cis-trans isomerization of ethyl 4-chloro-2-methoxyiminoacetoacetate by the method includes a sedimentation crystallizer 5, a crystallization kettle, a microwave-heated pipeline reactor 11, and an extraction centrifuge connected in sequence. A dispersing feeder 4 is provided inside the sedimentation crystallizer 5 at the top, and the dispersing feeder 4 is connected to the halide raw material tank 1 through a pipeline. An anchor agitator 3 is also provided on the top of the sedimentation crystallizer 5, and a jacketed cooling layer 6 is provided on the outer wall of the sedimentation crystallizer 5.

[0063] The extraction centrifuge includes a primary horizontal extraction centrifuge 16 and a secondary horizontal extraction centrifuge 17. The lower part of the primary horizontal extraction centrifuge 16 is connected to the bottom of the microwave-heated pipeline reactor 11 via a pipeline. The upper part of the primary horizontal extraction centrifuge 16 is connected to the lower part of the secondary horizontal extraction centrifuge 17 via a pipeline. The upper part of the secondary horizontal extraction centrifuge 17 is connected to the brine transfer tank 20 via a pipeline. The brine transfer tank 20 is connected to the cooling heat exchanger 22 and the sodium chloride brine tank 19 via pipelines. The cooling heat exchanger 22 is connected to the top of the settling crystallizer 5 via a pipeline.

[0064] Both the primary horizontal extraction centrifuge 16 and the secondary horizontal extraction centrifuge 17 are connected to the organic phase storage tank 15 via pipelines at the top, and the secondary horizontal extraction centrifuge 17 is also connected to the organic solvent storage tank 18 via pipelines at the bottom.

[0065] The crystallization reactor includes a first crystallization reactor 8, a second crystallization reactor 9, and a third crystallization reactor 10. The top of the first crystallization reactor 8, the second crystallization reactor 9, and the third crystallization reactor 10 are all connected to the bottom of the settling crystallizer 5 through pipelines. A timed discharge valve 7 is installed on the pipeline between the first crystallization reactor 8, the second crystallization reactor 9, and the third crystallization reactor 10 and the settling crystallizer 5. The bottom of the first crystallization reactor 8, the second crystallization reactor 9, and the third crystallization reactor 10 are all connected to the top of the microwave-heated pipeline reactor 11 through pipelines.

[0066] The microwave-heated pipeline reactor 11 is equipped with a quartz pipe 12 inside, a temperature monitor 14 is installed in the middle of the quartz pipe 12, and a microwave generator 13 is arranged on the outside of the quartz pipe 12; a constant flow pump 2 is installed on the pipeline between the disperser 4 and the halide raw material tank 1, and a centrifugal pump 21 is installed on the pipeline between the brine transfer tank 20 and the cooling heat exchanger 22.

[0067] The microwave-heated pipeline reactor 11 is equipped with a quartz pipe 12 (inner diameter 110mm, length 3m) inside. Four temperature monitors 14 (spaced 0.75m apart) are installed in the middle of the quartz pipe 12. Six microwave generators 13 (total power 6~10kW, frequency 2450MHz) are arranged on the outside of the quartz pipe 12. A temperature interlock device (over-temperature and over-pressure alarm) is installed at the outlet of the microwave-heated pipeline reactor 11. When the material temperature exceeds 22℃, the microwave power is automatically reduced.

[0068] The settling crystallizer 5 has an effective volume of 15 m³ and is made of 316L stainless steel. The jacketed cooling layer 6 of the settling crystallizer 5 is filled with -25℃ ethylene glycol refrigerant, and its heat exchange area is 20 m².

[0069] The outer walls of the first crystallizer 8, the second crystallizer 9, and the third crystallizer 10 are all equipped with a polyurethane insulation layer with a thickness of 130mm to ensure temperature fluctuations ≤ ±0.5℃ / h and prevent a decrease in conversion efficiency. Each of the three crystallizers is equipped with a liquid level sensor (range 0~8m³, accuracy ±0.01m³) and a temperature sensor (temperature measurement accuracy ±0.1℃). The effective volume of each crystallizer is 10m³, and they are made of 316L stainless steel.

[0070] Both the primary horizontal extraction centrifuge 16 (40 Hz) and the secondary horizontal extraction centrifuge 17 (40 Hz) are equipped with density sensors (detection accuracy ±0.001 g / cm³). The density sensors are used to automatically identify the organic phase-aqueous phase interface.

[0071] The brine transfer tank 20 has a volume of 15 m³, the centrifugal pump 21 has a flow rate of 60 m³ / h and is made of 316L stainless steel; the cooling heat exchanger 22 has a heat exchange area of ​​20 m² and a cooling capacity of 60 kW.

[0072] Example 2

[0073] S1. Preparation of crystal slurry: Add 11000L of saturated sodium chloride brine (26.0wt%) to a 20m³ settling crystallizer 5. Introduce -20℃ ethylene glycol cryosol into the jacketed cooling layer 6 to lower the temperature of the saturated sodium chloride brine to -20℃. Turn on the anchor stirrer 3 and adjust the speed to 15r / min. Control the temperature difference inside the settling crystallizer 5 within ±0.8℃.

[0074] 4500L of bromide feedstock (ethyl 4-bromo-2-methoxyiminoacetoacetate, cis content 88.5wt%, trans content 7.8wt%) was fed into the disperser feeder 4 (orifice diameter 1.0mm) inside the settling crystallizer 5 via constant flow pump 2. The feed rate was adjusted to 80L / min. After being dispersed by the disperser feeder 4, the chloride feedstock was mixed with low-temperature saturated sodium chloride brine. After 2.0h, a crystal slurry with a solid content of 18.5% (crystal particle size D) was formed. 50 =365μm).

[0075] S2. Crystallizer aging: Open the timed discharge valve 7 at the bottom of the settling crystallizer 5 every 18.7 minutes to discharge the crystallizer slurry containing about 1450L of chloride into the 10m³ crystallizer reactor. Collect a total of 3 batches (about 4360L of bromide, partially dissolved in saturated sodium chloride brine) and then close the timed discharge valve 7. Maintain the temperature of the crystallizer reactor at -20℃ and age for 10 hours. Take a sample to test the cis content of 92.7wt% and the trans content of 3.9wt%.

[0076] S3. Microwave heating: The aged crystal slurry is pumped into the microwave heating pipeline reactor 11. The microwave power is adjusted to 10kW. After 15s, the material temperature rises to 10℃. The cis content is sampled and tested to ensure it remains at 92.7wt% (no reversible oxidation).

[0077] S4. Extraction and Separation: The heated material is fed into a primary horizontal extraction centrifuge 16 at a controlled speed of 50 Hz for extraction centrifugation and separation, yielding 4360 L of primary organic phase (cis 92.7 wt%), which is then fed into organic phase storage tank 15. The primary aqueous phase, 11060 L, is fed into a secondary horizontal extraction centrifuge 17. 300 L of methyl tert-butyl ether is added to the secondary horizontal extraction centrifuge 17, and the extraction centrifugation is performed again at a controlled speed of 50 Hz, yielding 385 L of secondary organic phase (cis 92.7 wt%), which is then fed into organic phase storage tank 15. The total organic phase, after merging with the primary organic phase, is 4745 L (including 300 L of methyl tert-butyl ether), yielding ethyl 4-bromo-2-methoxyiminoacetoacetate (yield 98.8%, calculated based on 4500 L of bromide feedstock).

[0078] The secondary aqueous phase (saturated sodium chloride brine) is obtained and enters the brine transfer tank 20. Then, it is transported to the cooling heat exchanger 22 by the centrifugal pump 21 (60 m³ / h) to cool down from 10°C to -20°C. After filtration, it is returned to the settling crystallizer 5.

[0079] Final product testing: Ethyl 4-chloro-2-methoxyiminoacetoacetate in organic phase storage tank 15 was tested. The cis content was 92.7 wt%, the trans content was 3.9 wt%, and the hydrolysis impurities were 0.26 wt%, meeting the quality standards for aminothiazide acid intermediates. The yield was 98.8%, and its liquid chromatography spectrum is shown below. Figure 3 As shown in the figure, the corresponding peak analysis is shown in Table 2.

[0080] The apparatus for achieving the cis-trans isomerization of ethyl 4-bromo-2-methoxyiminoacetoacetate by the method is the same as in Example 1.

[0081] Table 2. Peak analysis of the final liquid phase spectrum of the product prepared in Example 2.

[0082] Peak No. Retention Time Area Height Area % Height % 1 1.069 16691 1740 0.046 0.100 2 1.761 1397 158 0.004 0.009 3 1.993 1009 97 0.003 0.006 4 2.437 1387 100 0.004 0.006 5 2.923 14243 1062 0.039 0.061 6 3.388 16933 915 0.046 0.053 7 3.650 7156 816 0.020 0.047 8 3.841 21351 1430 0.059 0.082 9 4.770 93474 3340 0.256 0.192 10 4.984 25839 2411 0.071 0.138 11 5.518 98302 3797 0.270 0.218 12 5.922 103197 4253 0.283 0.244 13 7.150 832582 39118 2.283 2.244 14 8.662 1416950 42203 3.886 2.421 15 10.687 33810615 1641309 92.718 94.164 16 12.523 5059 289 0.014 0.017 Total 36466183 1743037 100.000 100.000

[0083] Example 3

[0084] S1. Preparation of crystal slurry: Add 10000L of saturated sodium chloride brine (26.3wt%) to a 15m³ settling crystallizer 5. Introduce -25℃ ethylene glycol cryosol into the jacketed cooling layer 6 to lower the temperature of the saturated sodium chloride brine to -5℃. Turn on the anchor stirrer 3 and adjust the speed to 20r / min. Control the temperature difference inside the settling crystallizer 5 within ±0.8℃.

[0085] 4000L of chloride feedstock (ethyl 4-chloro-2-methoxyiminoacetoacetate, cis content 88.6wt%, trans content 8.0wt%) was fed into the disperser feeder 4 (orifice diameter 0.5mm) inside the settling crystallizer 5 via constant flow pump 2. The feed rate was adjusted to 100L / min. After being dispersed by the disperser feeder 4, the chloride feedstock was mixed with low-temperature saturated sodium chloride brine. After 1.8h, a crystal slurry with a solid content of 19% (crystal particle size D) was formed. 50 =297μm).

[0086] S2. Crystallizer aging: Open the timed discharge valve 7 at the bottom of the settling crystallizer 5 every 13.3 minutes to discharge the crystallizer slurry containing about 1300L of chloride into the 10m³ crystallizer reactor. Collect a total of 3 batches (about 3900L of chloride, partially dissolved in saturated sodium chloride brine) and then close the timed discharge valve 7. Maintain the temperature of the crystallizer reactor at -5℃ and age for 20 hours. Take a sample and test the cis content to be 92.4wt% and the trans content to be 3.86wt%.

[0087] S3. Microwave heating: The aged crystal slurry is pumped into the microwave heating pipeline reactor 11. The microwave power is adjusted to 6kW. After 20s, the material temperature rises to 30℃. The cis content is sampled and tested to be 92.4wt% (no reversible oxidation).

[0088] S4. Extraction and Separation: The heated material is fed into a primary horizontal extraction centrifuge 16 at a controlled speed of 45 Hz for extraction centrifugation and separation, yielding 3875 L of primary organic phase (cis 92.4 wt%), which is then fed into organic phase storage tank 15. 10050 L of primary aqueous phase is fed into a secondary horizontal extraction centrifuge 17. 200 L of dichloromethane is added to the secondary horizontal extraction centrifuge 17, and the speed is controlled at 45 Hz for further extraction centrifugation and separation, yielding 270 L of secondary organic phase (cis 92.4 wt%), which is fed into organic phase storage tank 15. The total organic phase after merging with the primary organic phase is 4145 L (including 200 L of dichloromethane), yielding ethyl 4-chloro-2-methoxyiminoacetoacetate (yield 98.6%, calculated based on 4000 L of chloride feedstock).

[0089] The secondary aqueous phase (saturated sodium chloride brine) is obtained and enters the brine transfer tank 20. Then, it is transported to the cooling heat exchanger 22 by the centrifugal pump 21 (60 m³ / h) to cool down from 30°C to -5°C. After filtration, it is returned to the settling crystallizer 5.

[0090] Final product testing: Ethyl 4-chloro-2-methoxyiminoacetoacetate in organic phase storage tank 15 was tested. The cis content was 92.4 wt%, the trans content was 3.86 wt%, and the hydrolysis impurities were 0.31 wt%, meeting the quality standards for aminothiazide acid intermediates. The yield was 98.6%. Its liquid chromatography spectrum is shown below. Figure 4 As shown, the corresponding peak analysis is shown in Table 3.

[0091] The apparatus for achieving the cis-trans isomerization of ethyl 4-chloro-2-methoxyiminoacetoacetate by the method is the same as in Example 1.

[0092] Table 3. Peak analysis of the final liquid phase spectrum of the product prepared in Example 3.

[0093] Peak No. Retention Time Area Height Area % Height % 1 1.074 10873 1644 0.029 0.093 2 2.008 6670 282 0.018 0.016 3 2.448 3770 221 0.010 0.013 4 2.920 14504 1245 0.038 0.071 5 3.385 22342 1127 0.059 0.064 6 3.834 37522 1848 0.099 0.105 7 4.752 115025 4061 0.305 0.231 8 4.976 31723 2840 0.084 0.161 9 5.507 110075 4120 0.292 0.234 10 5.929 94565 4687 0.251 0.266 11 7.140 944458 42986 2.503 2.443 12 8.650 1454756 40781 3.856 2.317 13 10.670 34879723 1653684 92.442 93.969 14 12.513 5333 300 0.014 0.017 Total 37731338 1759826 100.000 100.000

[0094] Comparative Example 1

[0095] S1. Preparation of crystal slurry: Same as in Example 1.

[0096] S2, Crystal slurry aging: Change "maintain the temperature of the crystal transfer vessel at -15°C" in step S2 of Example 1 to "maintain the temperature of the crystal transfer vessel at -4°C", and the rest of the steps are the same as in Example 1.

[0097] During the aging process, it was found that the crystals in the crystal slurry melted in the crystal transfer vessel, making further steps pointless, so this approach was abandoned.

[0098] Comparative Example 2

[0099] S1. Preparation of crystal slurry: Same as in Example 1.

[0100] S2, Crystal slurry aging: Change "maintain the temperature of the crystal transfer vessel at -15°C" in step S2 of Example 1 to "maintain the temperature of the crystal transfer vessel at -21°C", and the rest of the steps are the same as in Example 1.

[0101] During the aging process, it was discovered that the saturated brine in the crystallization reactor was frozen, making it impossible to continue with subsequent steps. Therefore, this approach was abandoned.

[0102] Comparative Example 3

[0103] In step S3 of Example 1, "the material temperature rises to 20°C after 30 seconds" is changed to "the material temperature rises to 20°C after 40 seconds," and the heating rate of the microwave-heated pipeline reactor 11 is controlled to be <1.0°C / s. The remaining steps are the same as in Example 1. A total organic phase of 3925 L (containing 200 L of ethyl acetate) is obtained.

[0104] Final product testing: Ethyl 4-chloro-2-methoxyiminoacetoacetate in organic phase storage tank 15 was tested. The cis content was 90.3 wt% (reversal occurred), the trans content was 6.8 wt%, and the hydrolysis impurities were 0.88 wt%. It did not meet the quality standard for aminothiazide acid intermediates. The yield was 93.1% (calculated based on 4000L of chloride feedstock).

[0105] Comparative Examples 1 and 1-2 show that this invention strictly controls the temperature of the crystallization reactor at -20 to -5°C, achieving low-temperature crystallization aging of ethyl 4-halo-2-methoxyiminoacetoacetate. Comparative Examples 1 and 3 show that this invention strictly controls the heating rate of the microwave-heated pipeline reactor to ≥1.0°C / s, shortening the residence time of the material in the intermediate temperature range (-10 to 0°C) through rapid heating, thus avoiding the conversion of cis-products to trans-products. Through the synergistic effect of low-temperature crystallization aging and microwave heating, this invention increases the cis-halide content from 86-90 wt% to 92-95 wt%, and reduces the trans-halide content to 2-4 wt%, meeting the quality standards for aminothiazolium acid intermediates (trans ≤5%).

Claims

A method for the cis-trans isomerization of ethyl 1,4-halo-2-methoxyiminoacetoacetate, characterized in that, Includes the following steps: S1. Preparation of crystal slurry: Add sodium chloride brine to the settling crystallizer (5), cool the sodium chloride brine and stir it; add the halide raw material to the settling crystallizer (5) through the dispersing feeder (4), mix it with sodium chloride brine to form crystal slurry; the halide raw material contains 86~90wt% cis-4-halo-2-methoxyimino acetoacetate, 7~8wt% trans-4-halo-2-methoxyimino acetoacetate, and the rest are impurities; S2, Crystal slurry aging: The crystal slurry in the settling crystallizer (5) is discharged into the crystal transfer vessel for aging; the aging temperature is -20~-5℃ and the aging time is 10~20h; S3. Microwave heating: The aged crystal slurry is fed into the microwave heating pipeline reactor (11) for heating; the temperature is raised to 10~30℃, the microwave power of the microwave heating pipeline reactor (11) is 6~10kW, the heating time is 10~50s, and the heating rate is ≥1.0℃ / s. S4. Extraction and separation: The heated material is extracted and centrifuged, separated, and the organic phase is collected to obtain ethyl 4-halo-2-methoxyiminoacetoacetate; the aqueous phase is cooled and returned to the sedimentation crystallizer (5) for recycling.

2. The method for the cis-trans isomerization of ethyl 4-halo-2-methoxyiminoacetoacetate according to claim 1, characterized in that, In step S1, the ethyl 4-halo-2-methoxyiminoacetoacetate is ethyl 4-chloro-2-methoxyiminoacetoacetate or ethyl 4-bromo-2-methoxyiminoacetoacetate.

3. The method for the cis-trans isomerization of ethyl 4-halo-2-methoxyiminoacetoacetate according to claim 1, characterized in that, In step S1, the feed rate of the halide raw material is 30~100L / min, and the concentration of the sodium chloride brine is 26.0~26.5wt%.

4. The method for the cis-trans isomerization of ethyl 4-halo-2-methoxyiminoacetoacetate according to claim 1, characterized in that, In step S1, the sodium chloride brine is cooled to -20~-5℃, the stirring speed is 10~20r / min, and the orifice diameter of the dispersing feeder (4) is 0.5~1.0mm.

5. The method for the cis-trans isomerization of ethyl 4-halo-2-methoxyiminoacetoacetate according to claim 1, characterized in that, In step S4, the heated material is first subjected to primary extraction centrifugation to separate the liquid into a primary organic phase and a primary aqueous phase. An organic solvent is added to the primary aqueous phase, and then it is subjected to secondary extraction centrifugation to separate the liquid into a secondary organic phase and a secondary aqueous phase. The primary organic phase and the secondary organic phase are combined to obtain ethyl 4-halo-2-methoxyiminoacetoacetate. The secondary aqueous phase is cooled to -20~-5℃ and then returned to the sedimentation crystallizer (5) for recycling. The organic solvent is ethyl acetate, methyl tert-butyl ether, dichloromethane, trichloromethane or tetrachloromethane.

6. The method for cis-trans isomerization of ethyl 4-halo-2-methoxyiminoacetoacetate according to any one of claims 1 to 5, characterized in that, The apparatus includes a sedimentation crystallizer (5), a crystallization kettle, a microwave-heated pipeline reactor (11), and an extraction centrifuge connected in sequence. A dispersion feeder (4) is installed at the top inside the sedimentation crystallizer (5), and the dispersion feeder (4) is connected to the halide raw material tank (1) through a pipeline. An anchor agitator (3) is also installed at the top of the sedimentation crystallizer (5), and a jacketed cooling layer (6) is installed on the outer wall of the sedimentation crystallizer (5). The extraction centrifuge includes a primary horizontal extraction centrifuge (16) and a secondary horizontal extraction centrifuge (17). The lower part of the primary horizontal extraction centrifuge (16) is connected to the bottom of the microwave-heated pipeline reactor (11) through a pipeline. The upper part of the primary horizontal extraction centrifuge (16) is connected to 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 to the brine transfer tank (20) through a pipeline. The brine transfer tank (20) is connected to the cooling heat exchanger (22) and the sodium chloride brine tank (19) through pipelines. The cooling heat exchanger (22) is connected to the top of the sedimentation crystallizer (5) through a pipeline. Both the first-stage horizontal extraction centrifuge (16) and the second-stage horizontal extraction centrifuge (17) are connected to the organic phase storage tank (15) via pipelines, and the second-stage horizontal extraction centrifuge (17) is also connected to the organic solvent storage tank (18) via pipelines.

7. The method for the cis-trans isomerization of ethyl 4-halo-2-methoxyiminoacetoacetate according to claim 6, characterized in that, The crystallizer includes a first crystallizer (8), a second crystallizer (9), and a third crystallizer (10). The top of the first crystallizer (8), the second crystallizer (9), and the third crystallizer (10) are all connected to the bottom of the settling crystallizer (5) through pipelines. A timed discharge valve (7) is installed on the pipeline between the first crystallizer (8), the second crystallizer (9), and the third crystallizer (10) and the settling crystallizer (5). The bottom of the first crystallizer (8), the second crystallizer (9), and the third crystallizer (10) are all connected to the top of the microwave-heated pipeline reactor (11) through pipelines.

8. The method for the cis-trans isomerization of ethyl 4-halo-2-methoxyiminoacetoacetate according to claim 6, characterized in that, A quartz pipe (12) is installed inside the microwave-heated pipeline reactor (11). A temperature monitor (14) is installed in the middle of the quartz pipe (12), and a microwave generator (13) is arranged on the outside of the quartz pipe (12). A constant flow pump (2) is installed on the pipeline between the disperser (4) and the halide raw material tank (1), and a centrifugal pump (21) is installed on the pipeline between the brine transfer tank (20) and the cooling heat exchanger (22).

Images