Preparation method of anhydrous 2-aminothiazole-4-oxime acid

Abstract

The invention discloses a preparation method of anhydrous 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetic acid, and belongs to the technical field of chemical synthesis. Comprising the following steps: introducing water-containing 2-aminothiazole-4-oxime acid into an upper chamber of a vertical fluidized bed drying device, pressing an alcohol reagent into a lower chamber of the vertical fluidized bed drying device through the pressure of a gas source, heating the alcohol reagent into a gas state, and enabling the gas-state alcohol reagent to enter the upper chamber through a sieve plate to generate a dehydration effect with the water-containing 2-aminothiazole-4-oxime acid, the anhydrous 2-aminothiazole-4-oxime acid is obtained. With the adoption of the method, rapid dehydration of the 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetic acid can be realized, and an alcohol solvate is not easy to generate, so that a step of removing an alcohol solvent by adopting vacuum drying is avoided; meanwhile, the alcohol reagent can be recycled. The process method provided by the invention is good in economical efficiency, the yield and the purity can be improved, and the dried anhydrous 2-aminothiazole-4-carboxylic acid product has good flowability.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing anhydrous aminothioxamic acid. Background Art

[0002] Ammonia thiocarbamate is an important pharmaceutical intermediate, mainly used in the synthesis of cephalosporin antibiotic preparations. It is the side chain of ceftriaxone sodium, ceftriaxone, ceftriaxone, etc. This antibiotic preparation is a new type of antibiotic drug with strong antibacterial power developed abroad in the 1970s. At present, the world sales of this type of antibiotics account for about 35% of the total sales of the entire antibiotic drug market. Ammonia thiocarbamate is a raw material for the synthesis of the third-generation cephalosporin, namely cephalosporin. This type of antibiotic called aminothiocarbamate is effective against infections caused by some drug-resistant bacteria and difficult-to-control pathogens, and has low toxicity, broad spectrum and long-term effect. Its efficacy is dozens of times higher than that of penicillin. This type of drug is currently selling well in both the international and domestic markets.

[0003] At present, the process for producing aminothioxamic acid generally adopts ethyl acetoacetate as the starting material, and obtains aminothioxamic acid ethyl ester through oximation, methylation, bromination, distillation, and cyclization reaction, and then obtains aminothioxamic acid through hydrolysis, acid adjustment and crystallization.

[0004] Ammonia thiophene acid has polymorphic forms. The hydrolysis of aminothiophene acid ethyl ester gives aminothiophene acid crystals containing 1.5 crystal waters. The crystal waters must be removed before they can be used in the synthesis of cephalosporin antibiotics or AE-active esters. In current industrial production, the crude aminothiophene acid is usually placed in methanol or ethanol for high-temperature reflux treatment, filtered after a period of time, and vacuum dried to obtain anhydrous aminothiophene acid crystals.

[0005] Patent CN201110204495.6 proposes a synthesis scheme of aminothioxime acid, that is, dissolving aqueous aminothioxime acid in a solvent capable of forming an azeotropic mixture with water, and then removing water through an azeotropic process. The patent adopts acetonitrile as an azeotropic agent, wherein the proportion of acetonitrile in the azeotropic mixture is 85%. However, this method needs to consume a large amount of acetonitrile during the drying and dehydration process, thereby increasing production costs.

[0006] Patent CN201711351682.0 proposes a synthesis scheme of aminothioxime acid, that is, by adding crude aminothioxime acid to an alcohol reagent for reflux refining, thereby obtaining pure aminothioxime acid. The alcohol reagent used in the dehydration process described in the patent is easy to form a solvate with the product, and vacuum drying and high-temperature drying steps must be used to remove the alcohol solvent, which reduces production efficiency.

[0007] Patent CN202110731237.7 discloses a continuous refining method for anhydrous aminothioxime acid, which comprises the following steps: (1) connecting multiple refining kettles in series, adding a solvent to the first refining kettle, adding aqueous aminothioxime acid to be refined and stirring evenly, and heating to the crystallization temperature as a continuous reaction base material; (2) controlling the addition rate of aqueous aminothioxime acid and solvent, and continuously adding aqueous aminothioxime acid and solvent in proportion to the first refining kettle; (3) controlling the temperature and stirring speed of each refining kettle; (4) after the discharging kettle is full, releasing the feed-liquid mixture, and obtaining anhydrous aminothioxime acid after solid-liquid separation, washing, and drying. This method occupies more equipment, is complicated to operate, and is not conducive to industrial production.

[0008] The above-mentioned method for preparing anhydrous aminothioxamic acid is not ideal in terms of economic efficiency. Therefore, how to obtain anhydrous aminothioxamic acid simply and efficiently needs further research. Summary of the invention

[0009] In order to solve the above problems, the present invention provides a method for preparing anhydrous aminothioxamic acid.

[0010] To achieve the above purpose, the technical solution adopted by the present invention is as follows: A method for preparing anhydrous aminothioxamic acid comprises the following steps: Step 1, introducing aqueous aminothioxamic acid into the upper chamber of a vertical fluidized bed drying device; Step 2, heating the alcohol reagent in the alcohol reagent tank; Step 3, turning on the gas source generator, and passing the generated gas source into the alcohol reagent tank; Step 4, pressing the alcohol reagent into the lower chamber of the vertical fluidized bed drying device by the pressure of the gas source; Step 5, the alcohol reagent is heated again into a gaseous state in the lower chamber and enters the upper chamber through the sieve plate; Step 6, the alcohol reagent reacts with the aqueous aminothioxamic acid in the upper chamber to dehydrate; Step 7, drying aqueous aminothioxamic acid: opening the decompression device connected to the vertical fluidized bed drying device, so that the alcohol reagent leaves the upper chamber, enters the condensation collector, and refluxes to the alcohol reagent tank; Step 8, the drying process of steps 3-7 is circulated until the moisture content of the dried aqueous aminothioxamic acid is qualified, the gas source generator is stopped, the drying is completed, and anhydrous aminothioxamic acid is obtained; The upper chamber of the vertical fluidized bed drying device can accommodate aqueous aminothioxamic acid, and the lower chamber of the vertical fluidized bed drying device can accommodate alcohol reagents. A sieve plate is provided between the upper chamber and the lower chamber.

[0011] Furthermore, in step 1, the aqueous aminothioxamic acid is a hydrolysis acidification product of aminothioxamic acid ethyl ester, wherein the mass percentage of water is ≤30%.

[0012] Furthermore, in step 2, a jacket with a heating medium passing therethrough is disposed on the outside of the alcohol reagent tank, and the heating temperature of the jacket is controlled at 30-40°C.

[0013] Furthermore, in step 2, the alcohol reagent is methanol or ethanol, and the mass ratio of the alcohol reagent to the aqueous aminothioxamic acid is 1-3:5.

[0014] Furthermore, in step 3, the air source generator is an air compressor for generating compressed air.

[0015] Furthermore, in step 5, the heating temperature of the lower chamber of the vertical fluidized bed drying device is controlled at 30-40°C.

[0016] Furthermore, in step 5, the sieve plate is covered with filter holes, the pore size of the filter holes is 0.22 μm, the gas in the lower chamber can enter the upper chamber through the filter holes, and the aqueous aminothioxamic acid and the anhydrous aminothioxamic acid in the upper chamber cannot enter the lower chamber.

[0017] Furthermore, in step 7, the pressure reducing device is a vacuum pump, and the vacuum degree of the vacuum pump is -0.9 MPa; the exhaust pipe of the vacuum pump is connected to the exhaust port of the vertical fluidized bed drying device.

[0018] Furthermore, in step 7, the time for drying the aqueous aminothioxamic acid is 3-5 hours.

[0019] Compared with the prior art, the present invention has the following technical advances: The present invention introduces aqueous aminothioxamic acid into the upper chamber of a vertical fluidized bed drying device, and then uses the pressure of the gas source to press the alcohol reagent into the lower chamber of the vertical fluidized bed drying device; the alcohol reagent heated to a gaseous state enters the upper chamber through a sieve plate to dehydrate the aqueous aminothioxamic acid, which can act on the aqueous aminothioxamic acid to obtain anhydrous aminothioxamic acid. The present invention can achieve rapid dehydration of aminothioxamic acid, and is not easy to produce alcohol solvates, thereby avoiding the step of removing alcohol solvents by vacuum drying. The process method provided by the present invention has good economic efficiency, can improve yield and purity, and the dried anhydrous aminothioxamic acid product has good fluidity. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The accompanying drawings are used to provide further understanding of the present invention and constitute a part of the specification. They are used to explain the present invention together with the embodiments of the present invention and do not constitute a limitation of the present invention.

[0021] In the attached picture: Figure 1 is an infrared spectrum of the anhydrous aminothioxamic acid sample prepared in Example 1 of the present invention; Figure 2 The liquid chromatogram of the anhydrous aminothioxamic acid sample prepared in Example 1 of the present invention; Figure 3 This is a microscopic crystal image of the anhydrous aminothioxamic acid sample prepared in Example 1 of the present invention; Figure 4 It is the structural formula of aminothioxamic acid. DETAILED DESCRIPTION

[0022] The following specific embodiments may be combined with each other, and the same or similar concepts or processes may not be described in detail in some embodiments. The embodiments of the present invention will be described below in conjunction with the accompanying drawings.

[0023] The present invention provides a method for preparing anhydrous aminothioxamic acid, comprising the following steps: Step 1, introducing aqueous aminothioxamic acid into the upper chamber of a vertical fluidized bed drying device; The aqueous aminothioxamic acid is a hydrolysis and acidification product of aminothioxamic acid ethyl ester, wherein the mass percentage of water is ≤30%.

[0024] The upper chamber of the vertical fluidized bed drying device can accommodate aqueous aminothioxamic acid, the lower chamber of the vertical fluidized bed drying device can accommodate alcohol reagents, and a sieve plate is provided between the upper chamber and the lower chamber. The vertical fluidized bed drying device used in the present invention is a prior art, and the specific structure and function can refer to the vertical fluidized bed drying device disclosed in patent CN206919530U.

[0025] Step 2, heating the alcohol reagent in the alcohol reagent tank; The alcohol reagent tank is provided with a jacket with a heating medium passing therein, and the heating temperature of the jacket is controlled at 30-40°C.

[0026] The alcohol reagent is methanol or ethanol, and the mass ratio of the alcohol reagent to the aqueous aminothioxamic acid is 1-3:5.

[0027] Step 3, turning on the gas source generator, and passing the generated gas source into the alcohol reagent tank; The air source generator is an air compressor, and the prepared compressed air is passed into the alcohol reagent tank, which can be used as a power source to press the alcohol reagent out of the alcohol reagent tank.

[0028] Step 4: Press the alcohol reagent into the lower chamber of the vertical fluidized bed drying device by the pressure of the gas source.

[0029] Step 5: The alcohol reagent is heated again into a gaseous state in the lower chamber, and the heating temperature is controlled at 30-40° C.; the gaseous alcohol reagent can pass through the sieve plate into the upper chamber.

[0030] The sieve plate is covered with filter holes, the pore size of the filter holes is 0.22 μm, the gas in the lower chamber can enter the upper chamber through the filter holes, and the aqueous aminothioxamic acid and the anhydrous aminothioxamic acid in the upper chamber cannot enter the lower chamber.

[0031] Step 6, the alcohol reagent reacts with the aqueous aminothioxamic acid in the upper chamber to dehydrate; Step 7, drying aqueous aminothioxime acid: opening the decompression device connected to the vertical fluidized bed drying device, allowing the alcohol reagent to leave the upper chamber, enter the condensation collector, and reflux to the alcohol reagent tank; the drying time of aqueous aminothioxime acid is 3-5h.

[0032] The decompression device is a vacuum pump, and the vacuum degree of the vacuum pump is set to -0.9 MPa; the vacuum pipe of the vacuum pump is connected to the exhaust port of the vertical fluidized bed drying device.

[0033] Step 8, the drying process of steps 3-7 is circulated until the moisture content of the dried aqueous aminothioxamic acid is qualified, the gas source generator is stopped, the drying is completed, and anhydrous aminothioxamic acid is obtained.

[0034] The following are three specific embodiments and five comparative examples: Example 1

[0035] Take 10g of aqueous aminothioxamic acid (water content of 23%), add it into a vertical fluidized bed drying device for standby use, take 2g of methanol and put it into a glass bottle, heat it to 30°C, introduce compressed air, introduce the vaporized methanol into the vertical fluidized bed drying device, turn on the pressure reducing device, methanol is drawn out and condensed, and refluxed into the methanol glass bottle (i.e., alcohol reagent tank), circulate and dry for 3h, stop the compressed air, and obtain 7.60g of white solid, water content (≤0.3%) 0.09%, methanol residue (≤0.3%) 0.06%, HPLC purity (≥99.50%): 99.73%, and the crystal form is observed to be flaky crystals, which is anhydrous aminothioxamic acid. Example 2

[0036] Take 10g of aqueous aminothioxamic acid (water content 23%) and add it to a vertical fluidized bed drying device for standby use. Take 6g of methanol and put it into a glass bottle. Heat it to 40°C, introduce compressed air, and introduce the vaporized methanol into the vertical fluidized bed drying device. Turn on the pressure reducing device, and the methanol is drawn out and condensed, and refluxed into the methanol glass bottle. Circulate and dry for 5h, stop the compressed air, and obtain 7.53g of white solid, with water content (≤0.3%) 0.07%, methanol residue (≤0.3%) 0.09%, HPLC purity (≥99.50%): 99.66%, and the crystal form is observed to be flaky crystals, which is anhydrous aminothioxamic acid. Example 3

[0037] Take 10g of aqueous aminothioxamic acid (water content 23%) and add it to a vertical fluidized bed drying device for standby use. Take 4g of methanol and put it into a glass bottle. Heat it to 35°C, introduce compressed air, and introduce the vaporized methanol into the vertical fluidized bed drying device. Turn on the pressure reducing device, and the methanol is drawn out and condensed, and refluxed into the methanol glass bottle. Circulate and dry for 4h, stop the compressed air, and obtain 7.56g of white solid, with water content (≤0.3%) 0.08%, methanol residue (≤0.3%) 0.07%, HPLC purity (≥99.50%): 99.70%, and the crystal form is observed to be flaky crystals, which is anhydrous aminothioxamic acid.

[0038] Comparative Example 1 (No alcohol reagent is used in the vertical fluidized bed drying process, and the remaining steps refer to Example 1) Take 10g of aqueous aminothioxime acid (water content of 23%), add it into a vertical fluidized bed drying device for standby use, introduce compressed air and heat it to 30°C, introduce the airflow into the vertical fluidized bed drying device, open the pressure reducing device, and allow the compressed air to pass through the aqueous aminothioxime acid and be discharged from the top of the vertical fluidized bed drying equipment into the tail gas recovery device. Dry for 3h, stop compressing the air, and obtain 8.16g of white solid with a water content of 8.15%. HPLC purity: 99.73%. It was observed that the crystal form still had some rod-shaped crystals, which was a mixture of anhydrous aminothioxime acid and aqueous aminothioxime acid.

[0039] Comparative Example 2 (Refer to patent CN201110204495.6, acetonitrile is used instead of alcohol reagent, and the remaining steps refer to Example 1) Take 10g of aqueous aminothioxime acid (water content of 23%), add it to a vertical fluidized bed drying device for standby use, take 2g of acetonitrile and put it into a glass bottle, heat it to 30°C, pass compressed air, introduce the airflow into the vertical fluidized bed drying device, turn on the pressure reducing device, and the compressed air passes through the aqueous aminothioxime acid and is discharged from the top of the vertical fluidized bed drying equipment into the tail gas recovery device. Dry for 3h, stop the compressed air, and obtain 8.02g of white solid, with a water content of 4.19%, acetonitrile residue of 2.3%, HPLC purity: 99.73%, and the crystal form still has some rod-shaped crystals, which is a mixture of anhydrous aminothioxime acid and aqueous aminothioxime acid.

[0040] Comparative Example 3 (vertical fluidized bed drying device is not used, and the remaining steps refer to Example 1) Take 10g of aqueous aminothioxime acid (water content of 23%), add it to a three-in-one filtering, washing and drying device for standby use, take 2g of methanol and put it into a glass bottle, heat it to 30°C, introduce nitrogen, introduce the airflow into the three-in-one device, turn on the three-in-one bottom vacuum device, and the airflow passes through the aqueous aminothioxime acid and is discharged from the bottom of the three-in-one equipment into the tail gas recovery device. Dry for 3h, stop nitrogen, observe that the upper layer of the sample is dried into powder, and the bottom is not completely dry, then take 2g of methanol and put it into a glass bottle, continue drying for 3h, and obtain 7.97g of light yellow solid, 4.15% water, 1.8% methanol residue, HPLC purity: 99.73%, and observe that the crystal form still has some rod-shaped crystals, which is a mixture of anhydrous aminothioxime acid and aqueous aminothioxime acid.

[0041] Comparative Example 4 (parameter values ​​different from those in this application, steps refer to Example 1) Take 10g of aqueous aminothioxime acid (water content of 23%), add it to a vertical fluidized bed drying device for standby use, take 10g of methanol and put it into a glass bottle, heat it to 50°C, introduce compressed air, introduce the airflow into the vertical fluidized bed drying device, turn on the pressure reducing device, and allow the compressed air to pass through the aqueous aminothioxime acid and be discharged from the top of the vertical fluidized bed drying equipment into the tail gas recovery device. Dry for 3h, stop compressing the air, and obtain 7.51g of white solid, with a water content of 0.02%, a methanol residue of 0.52%, and a HPLC purity of 99.36%. The crystal form is observed to be flaky crystals, which is anhydrous aminothioxime acid.

[0042] Comparative Example 5 (Steps refer to patent CN201711351682.0, parameter values ​​are the same as Example 1) Take 10g of aqueous aminothioxamic acid (water content of 23%), put it into 30g of methanol and reflux for 1h, cool to 10℃ for crystallization, and dry for 3h to obtain 7.75g of white solid, with 0.04% water content and 3.2% residual methanol. HPLC purity: 99.66%. The crystal form is observed to be flaky crystals, which is anhydrous aminothioxamic acid.

[0043] Compared with the traditional production process, the present invention has the following advantages: 1. The traditional drying process usually uses mechanical stirring to disperse the materials. However, the block materials are not easy to be broken up. Once the surface hardens, the internal solvent is difficult to be blown dry. The present invention uses fluidized bed drying technology to disperse the materials with the help of airflow, which more effectively promotes the full contact between the alcohol reagent and aminothioxamic acid and replaces the bound water.

[0044] 2. The present invention adopts a method of replacing the alcohol reagent with gasification. After the alcohol reagent is replaced with bound water, it is quickly taken away by compressed air, thereby achieving rapid separation from the product. This method effectively prevents the formation of solvates, significantly shortens the drying time, and avoids the product from being damaged by long-term exposure to high temperature environment.

[0045] 3. The traditional methanol reflux recrystallization method will cause part of the product to dissolve in the solvent system, resulting in a loss in yield. However, the present invention collects and recycles alcohol reagents through tail gas condensation, which significantly improves the utilization rate of the reagents. In addition, the loss of product yield is relatively small.

[0046] In summary, the present invention presses the alcohol reagent into the lower chamber of the vertical fluidized bed drying device, and the alcohol reagent heated to a gaseous state enters the upper chamber through the sieve plate to dehydrate the aqueous aminothioxime acid, successfully separating the bound water from the aqueous aminothioxime acid to prepare anhydrous aminothioxime acid; at the same time, the alcohol reagent can be recovered and reused, further reducing the production cost. The present invention can achieve rapid dehydration of aminothioxime acid, and the prepared anhydrous aminothioxime acid product has a high yield and good fluidity, which solves the problems of long dehydration time, easy formation of solvates, and large amount of reagent usage in the prior art; at the same time, it can also improve the yield and purity of the product, and is more economical.

[0047] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein with equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the scope of protection of the claims of the present invention.

Claims

1. A method for preparing anhydrous aminothioxamic acid, characterized in that: The following steps are involved: Step 1, introducing aqueous aminothioxamic acid into the upper chamber of a vertical fluidized bed drying device; Step 2, heating the alcohol reagent in the alcohol reagent tank; Step 3, turning on the gas source generator, and passing the generated gas source into the alcohol reagent tank; Step 4, pressing the alcohol reagent into the lower chamber of the vertical fluidized bed drying device by the pressure of the gas source; Step 5, the alcohol reagent is heated again into a gaseous state in the lower chamber and enters the upper chamber through the sieve plate; Step 6, the alcohol reagent reacts with the aqueous aminothioxamic acid in the upper chamber to dehydrate; Step 7, drying aqueous aminothioxamic acid: opening the decompression device connected to the vertical fluidized bed drying device, so that the alcohol reagent leaves the upper chamber, enters the condensation collector, and refluxes to the alcohol reagent tank; Step 8, the drying process of steps 3-7 is circulated until the moisture content of the dried aqueous aminothioxamic acid is qualified, the gas source generator is stopped, the drying is completed, and anhydrous aminothioxamic acid is obtained; The upper chamber of the vertical fluidized bed drying device can accommodate aqueous aminothioxamic acid, and the lower chamber of the vertical fluidized bed drying device can accommodate alcohol reagents. A sieve plate is provided between the upper chamber and the lower chamber.

2. The method for preparing anhydrous aminothioxamic acid according to claim 1, characterized in that: In step 1, the aqueous aminothioxamic acid is a hydrolysis acidification product of aminothioxamic acid ethyl ester, wherein the mass percentage of water is ≤30%.

3. The method for preparing anhydrous aminothioxamic acid according to claim 1, characterized in that: In step 2, a jacket with a heating medium passing therethrough is disposed outside the alcohol reagent tank, and the heating temperature of the jacket is controlled at 30-40°C.

4. The method for preparing anhydrous aminothioxamic acid according to claim 1, characterized in that: In step 2, the alcohol reagent is methanol or ethanol, and the mass ratio of the alcohol reagent to the aqueous aminothioxamic acid is 1-3:

5.

5. The method for preparing anhydrous aminothioxamic acid according to claim 1, characterized in that: In step 3, the air source generator is an air compressor for generating compressed air.

6. The method for preparing anhydrous aminothioxamic acid according to claim 1, characterized in that: In step 5, the heating temperature of the lower chamber of the vertical fluidized bed drying device is controlled at 30-40°C.

7. The method for preparing anhydrous aminothioxamic acid according to claim 1, characterized in that: In step 5, the sieve plate is covered with filter holes, the pore size of the filter holes is 0.22 μm, the gas in the lower chamber can enter the upper chamber through the filter holes, and the aqueous aminothioxamic acid and the anhydrous aminothioxamic acid in the upper chamber cannot enter the lower chamber.

8. The method for preparing anhydrous aminothioxamic acid according to claim 1, characterized in that: In step 7, the pressure reducing device is a vacuum pump, and the vacuum degree of the vacuum pump is -0.9 MPa; the exhaust pipe of the vacuum pump is connected to the exhaust port of the vertical fluidized bed drying device.

9. The method for preparing anhydrous aminothioxamic acid according to claim 1, characterized in that: In step 7, the drying time of aqueous aminothioxamic acid is 3-5 hours.

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