Preparation process of tiopronin with high stability

Abstract

The invention relates to the technical field of medicines, in particular to a high-stability tiopronin preparation process which comprises the following steps: synthesizing alpha-chloropropionyl glycine by using alpha-chloropropionyl chloride, sodium carbonate and glycine to obtain alpha-chloropropionyl glycine; the method comprises the following steps: synthesizing alpha-dithio-bis-propionyl glycine by adopting alpha-chloropropionyl glycine and a sodium disulfide solution, adding zinc powder, extracting, concentrating and crystallizing to obtain a tiopronin crude product; the method comprises the following steps: stirring and heating a tiopronin crude product by using ethyl acetate, adding activated carbon to keep a constant-temperature reaction after the tiopronin crude product is completely dissolved, acquiring a sufficient reaction coefficient at each moment based on hyperspectral data characteristics of a reaction solution at each moment, adjusting the duration of the constant-temperature reaction, and then filtering, cooling and crystallizing; and separating mother liquor from the crystals by a centrifugal machine, and performing vacuum drying to obtain a tiopronin refined product. According to the invention, the accuracy of controlling the constant-temperature reaction time by adding the activated carbon is improved.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a process for preparing tiopronin with high stability. Background Art

[0002] Tiopronin, also known as N-(2-mercaptopropionyl)glycine, is a white crystalline powder with a sulfur odor. It is easily soluble in water or ethanol and very slightly soluble in ether.

[0003] In the preparation process of thiopronin, the reaction time of adding activated carbon in the thiopronin refining stage needs to be strictly controlled. When the reaction time of activated carbon is too long, it may also cause adsorption of thiopronin molecules, resulting in loss of target product and reduced yield. At the same time, under heating conditions, long-term reaction may accelerate the degradation of adsorbed substances on activated carbon and affect product quality. However, when the reaction time of activated carbon is too short, the activated carbon does not have sufficient time to adsorb pigments and other impurities, which may affect the subsequent crystallization effect of the material and affect the purity and stability of the product. Summary of the invention

[0004] In order to solve the above technical problems, the present application provides a highly stable tiopronin preparation process to solve the existing problems.

[0005] A highly stable tiopronin preparation process of the present application adopts the following technical solution:

[0006] One embodiment of the present application provides a process for preparing tiopronin with high stability, the process comprising the following steps:

[0007] α-chloropropionylglycine is synthesized by using α-chloropropionyl chloride, sodium carbonate and glycine to obtain α-chloropropionylglycine;

[0008] α-dithiodipropionylglycine was synthesized by using α-chloropropionylglycine and sodium disulfide solution, and zinc powder was added, and the crude product of tiopronin was obtained after extraction, concentration and crystallization.

[0009] The crude tiopronin was heated and stirred with ethyl acetate, and activated carbon was added to maintain a constant temperature reaction after it was completely dissolved. The duration of the constant temperature reaction was adjusted as follows:

[0010] The hyperspectral data of the reaction solution at each time after adding activated carbon are collected, and the difference in reflectance of different pixels in the local range at each time and each band, as well as the difference in reflectance of each pixel at adjacent times, are analyzed to obtain the reflection characteristic coefficient of each pixel in each band;

[0011] Based on all the reflection characteristic coefficients of all the pixels at each moment, a feature selection algorithm is used to obtain the spectral characteristic band at each moment, the difference in reflectance of each pixel at each moment and the pixel at the same position at the adjacent moment in the spectral characteristic band is calculated, the distribution trend of the reflectance of each pixel in the spectral characteristic band at each moment, and the probability distribution of the difference in reflectance in the spectral characteristic band are analyzed, and the reaction sufficiency coefficient of the reaction solution at each moment is obtained;

[0012] Controlling the duration of the isothermal reaction based on the reaction sufficiency coefficient, and then filtering, cooling, and crystallizing;

[0013] The crystals are separated from the mother liquor by a centrifuge and then vacuum dried to obtain the fine product of tiopronin.

[0014] In one embodiment, the synthesis of α-chloropropionylglycine comprises:

[0015] Add 8 kg of glycine and 40 kg of purified water to the reactor, add 5.8 kg of anhydrous sodium carbonate after stirring, continue stirring to dissolve all the solids, cool to -15 ° C, add sodium carbonate solution and α-chloropropionyl chloride under the condition of a reaction temperature of -10 ° C, keep reacting for 4 hours, adjust the pH to 2 with hydrochloric acid, use ethyl acetate to vacuum extract 3 times, filter, and concentrate the filtrate under reduced pressure below 55 ° C until tiny crystals precipitate. Cool to -10 ° C for more than two hours, combine the ethyl acetate extracts, filter, and vacuum dry to obtain α-chloropropionyl glycine.

[0016] In one embodiment, the preparation of the sodium disulfide solution comprises:

[0017] 14 kg of sodium sulfide nonahydrate and 16.5 kg of purified water were stirred and dissolved, 1.9 kg of sublimed sulfur was added, heated to 50°C, and the reaction was maintained for 1 hour to obtain a sodium disulfide solution.

[0018] In one embodiment, the synthesis of α-dithiodipropionylglycine comprises:

[0019] Add 10.2 kg of α-chloropropionylglycine and 60 kg of purified water into the synthesis extraction tank, slowly add 3.1 kg of anhydrous sodium carbonate under stirring, raise the temperature to 40°C, keep the temperature for reaction for 1 hour, cool to 10°C, add sodium disulfide solution dropwise, raise the temperature to room temperature, and react for 10 hours.

[0020] In one embodiment, the synthesis of the crude tiopronin comprises:

[0021] After the reaction for 10 hours, the temperature is lowered to 5°C, 18 kg of concentrated sulfuric acid is slowly added, the pH is adjusted to 2, the filtrate is filtered, the filtrate is poured into a synthetic extraction tank, the temperature is controlled at 10°C, 8.7 kg of zinc powder is added, and then the reaction is carried out at room temperature for 6 hours, the filtrate is filtered, and the ethyl acetate extracts are combined, dried, filtered, and the filtrate is concentrated until crystals are precipitated, cooled to -10°C, centrifuged, and vacuum dried to obtain a crude product of tiopronin.

[0022] In one embodiment, the mass of the activated carbon is 40 g, the constant temperature is 50° C., and the temperature is lowered to -5° C.

[0023] In one embodiment, the process of determining the reflection characteristic coefficient is:

[0024] Taking each pixel as the center, a pixel window of preset size is constructed, all reflectances of all pixels in each pixel window under each band are combined into a neighborhood reflectance sequence of each pixel window, the difference between any two elements in the neighborhood reflectance sequence is calculated, recorded as the first difference, and the fusion results of all the first differences in the neighborhood reflectance sequence are reversely mapped to obtain the neighborhood spectral consistency of the central pixel of the corresponding pixel window under each band;

[0025] The reflectance of each pixel at each moment in all bands is combined into a reflectance sequence, and the value variance of the reflectance sequence of each pixel at each moment and the pixel at the same position at the adjacent moment is calculated as the reflectance improvement degree of each pixel at each moment;

[0026] The fused normalized value of the neighborhood spectrum consistency and the reflectivity improvement degree is used as the reflection characteristic coefficient.

[0027] In one embodiment, the process of determining the reaction sufficiency coefficient is:

[0028] All reflectances of all pixels at each moment in the spectral characteristic band are combined into a characteristic reflection sequence, a fitting curve of the characteristic reflection sequence is obtained, the difference between each element in the characteristic reflection sequence and the fitting value in the corresponding fitting curve is calculated, recorded as the second difference, and the fusion results of all the second differences of all pixels at each moment are reversely mapped to obtain the smoothness of the spectral curve at each moment;

[0029] Calculate the difference between the elements at the same position in the characteristic reflection sequence of each pixel at each moment and the pixels at the same position at the adjacent moments to form the spectral absorption difference sequence of each pixel at each moment, and take the fusion result of the JS divergence of the spectral absorption difference sequence of all arbitrary two pixels at each moment as the spectral absorption difference degree at each moment;

[0030] Determining the reaction sufficiency coefficient based on the smoothness of the spectral curve and the degree of difference in spectral absorption;

[0031] The reaction sufficiency coefficient is positively correlated with the smoothness of the spectral curve, and negatively correlated with the degree of spectral absorption difference.

[0032] In one embodiment, controlling the duration of the isothermal reaction based on the reaction sufficiency coefficient includes:

[0033] If the reaction sufficiency coefficient is greater than or equal to the preset reaction sufficiency threshold, the constant temperature reaction is stopped; otherwise, the reaction is continued until the reaction sufficiency coefficient is greater than or equal to the preset reaction sufficiency threshold or the preset reaction time is reached.

[0034] In one embodiment, the vacuum drying temperature is below 55° C. and the time is 4 hours.

[0035] This application has at least the following beneficial effects:

[0036] The present application collects high-spectral data of the reaction solution at each moment after adding activated carbon during the preparation stage of the thiopronine fine product, analyzes the difference in reflectance of different pixels in the local range at each moment and each band, as well as the difference in reflectance of each pixel at adjacent moments, and obtains the reflectance characteristic coefficient of each pixel at each band; reflects the significance of the reflectance change of each pixel at each band, and quantifies the distinctive features of the reflectance change of each pixel at different bands; then, based on all the reflection characteristic coefficients of all pixels at each moment, a feature selection algorithm is used to obtain the spectral characteristic band at each moment, thereby improving the accuracy of determining the spectral characteristic band. ; Calculate the difference in reflectance of each pixel at each moment and the pixel at the same position at the adjacent moment in the spectral characteristic band, analyze the distribution trend of the reflectance of each pixel in the spectral characteristic band at each moment, and the probability distribution of the difference in reflectance in the spectral characteristic band, obtain the reaction sufficiency coefficient of the reaction solution at each moment, reflect the adsorption effect of activated carbon on impurities and colored substances in the reaction solution at each moment, evaluate the adsorption sufficiency of activated carbon on impurities and colored substances, and adjust the reaction time after adding activated carbon based on this, improve the rationality and accuracy of reaction time control, and then improve the purity and stability of the prepared tiopronin. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to more clearly illustrate the technical solutions and advantages in the embodiments of the present application or the prior art, the drawings required for use in the embodiments or the prior art descriptions are briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0038] Figure 1 A flow chart of the steps of a preparation process of tiopronin with high stability provided in the present application;

[0039] Figure 2 Schematic diagram of hyperspectral data collection;

[0040] Figure 3 It is a schematic diagram of some fitting curves of characteristic reflection sequence;

[0041] Figure 4 Adjust the flow chart for activated carbon reaction time. DETAILED DESCRIPTION

[0042] In order to further explain the technical means and effects adopted by the present application to achieve the predetermined invention purpose, the following is a detailed description of the high-stability tiopronin preparation process proposed in the present application, its specific implementation method, structure, characteristics and effects, in combination with the accompanying drawings and preferred embodiments. In the following description, different "one embodiment" or "another embodiment" does not necessarily refer to the same embodiment. In addition, specific features, structures or characteristics in one or more embodiments can be combined in any suitable form.

[0043] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0044] The specific scheme of the preparation process of tiopronin with high stability provided by the present application is described in detail below with reference to the accompanying drawings.

[0045] An embodiment of the present application provides a high-stability thiopronine preparation process. Specifically, the following high-stability thiopronine preparation process is provided. Figure 1 , the process comprises the following steps:

[0046] (1) Synthesis of α-chloropropionylglycine

[0047] (1.1) Add 8 kg of glycine and 40 kg of purified water into a glass-lined reactor and stir. Then, add 5.8 kg of anhydrous sodium carbonate into the reactor and stir until all the solids are dissolved.

[0048] (1.2) Pass ice-salt water through the jacket to cool the reaction solution to -15°C.

[0049] (1.3) Dissolve 6.7 kg of anhydrous sodium carbonate in 50 kg of water and add it into the alkali adding tank. Weigh 13.6 kg of α-chloropropionyl chloride and add it into the α-chloropropionyl chloride acid adding tank.

[0050] (1.4) Control the reaction temperature at about -10°C, and simultaneously add α-chloropropionyl chloride and sodium carbonate solution dropwise, always keeping the kettle weakly alkaline. After the addition is completed, continue to keep the temperature constant and react for 4 hours.

[0051] (1.5) Then adjust the pH to 2 with hydrochloric acid, extract with 60L of ethyl acetate for 3 times, open the vacuum valve on the tank, pump ethyl acetate into the extraction tank, and stir for 15 minutes. Let stand for 20 minutes to separate the layers and discharge the materials. Put the water phase into a turnover container and the ethyl acetate into another turnover container. Pump the water phase in the turnover container into the extraction tank and extract for 3 times, then discard the water phase. Combine the ethyl acetate extracts, add 1kg of anhydrous sodium sulfate to the turnover container, dry for 1 hour, and filter to obtain a filtrate.

[0052] (1.6) The filtrate was concentrated under reduced pressure at a temperature below 55°C until tiny crystals precipitated. The concentration was stopped and the filtrate was cooled to -10°C and kept for more than 2 h. In this embodiment, the temperature was kept for 2.5 h. The filtrate was filtered and the filter cake was washed once with ethyl acetate.

[0053] (1.7) Dry the wet α-chloropropionylglycine under vacuum conditions less than 55°C, 50°C in this embodiment, to obtain about 10.5 kg of dry α-chloropropionylglycine, with a melting point of 102-103°C. After passing the test, proceed with subsequent operations.

[0054] (2) Sodium disulfide preparation process

[0055] Add 14 kg of sodium sulfide nonahydrate and 16.5 kg of purified water into a sodium disulfide drop reaction tank, stir until the solid dissolves, slowly add 1.9 kg of sublimated sulfur, heat to 50°C until all the solid dissolves, maintain 50°C for 1 hour to obtain a sodium disulfide solution.

[0056] (3) Synthesis of α-dithiodipropionylglycine

[0057] (3.1) Add 10.2 kg of α-chloropropionylglycine and 60 kg of purified water into a synthetic extraction tank, slowly add 3.1 kg of anhydrous sodium carbonate while stirring, raise the temperature to 40°C, and keep the temperature to react for 1 hour.

[0058] (3.2) The reaction solution was cooled to 10°C and sodium disulfide solution was added dropwise.

[0059] (3.3) After the addition was complete, the temperature was raised to room temperature and the reaction was continued for 10 hours.

[0060] (4) Synthesis of crude tiopronin

[0061] (4.1) After step (3), the temperature was lowered to 5°C, and 18 kg of concentrated sulfuric acid was slowly added to adjust the pH to 2. After the addition, the mixture was reacted for half an hour, and then filtered with suction. The filtrate was poured into a synthetic extraction tank, and the temperature was controlled at 10°C. A total of 8.7 kg of zinc powder was added in portions, and the addition was completed within 2 hours. After the addition, the mixture was reacted at room temperature for 6 hours.

[0062] (4.2) Filter with suction, extract three times with 70 L of ethyl acetate, combine the ethyl acetate extracts, dry the organic phase with 1 kg of anhydrous sodium sulfate, filter, concentrate the filtrate until crystals precipitate, stop concentrating, and cool to -10°C.

[0063] (4.3) The material is crystallized and filtered by centrifugation.

[0064] (4.4) Dry under vacuum at 55°C to obtain crude thiopronine. The melting point of the crude product is 96-99°C. After the product is qualified, the subsequent operation can be carried out.

[0065] (5) Refining of Tiopronin

[0066] Add 2 batches of crude thiopronin to the refining tank, add 100L of ethyl acetate, heat to 50°C with stirring, and after all the solids are dissolved, add 40g of activated carbon, keep the temperature at 50°C for 20-60min, filter, add the filtrate to the crystallization kettle, cool to -5°C, and allow the material to crystallize. Adjust the time for keeping the temperature at 50°C for reaction after adding activated carbon, specifically:

[0067] Step S001, collecting hyperspectral data of the reaction solution at each time after adding activated carbon, and performing preprocessing.

[0068] The reaction solution after adding activated carbon to the refining tank during the refining stage of thiopronin was sampled and collected. The sampling was carried out 20 minutes after the start of the reaction. The amount of reaction solution collected each time accounted for 10% of the total reaction solution. The sampling interval is 1 minute, and a hyperspectral imager is used to collect hyperspectral data of the sampled reaction solution at a top-down angle. The amount of reaction solution sampled and the time interval for collection can be set by the implementer according to actual conditions, and this application will not go into detail. In order to prevent the hyperspectral data from being seriously interfered with by external environmental noise and affecting subsequent analysis, in one embodiment of the present application, a Wiener filtering algorithm is used to denoise the sampled hyperspectral data of the reaction solution. Since the Wiener filtering algorithm is a well-known technology, the specific acquisition process will not be described in detail. The schematic diagram of hyperspectral data collection is shown in the figure. Figure 2 As shown, 1, 2, and 3 represent a refining tank, a sampling reaction solution after adding activated carbon, and a hyperspectral imager, respectively.

[0069] To facilitate subsequent analysis and calculation, the hyperspectral data collected at each time is normalized by Z-Score standardization. Z-Score standardization is an existing well-known technology and will not be described in detail in this application.

[0070] It should be noted that the implementer may select other existing feasible denoising algorithms and normalization algorithms according to actual conditions to pre-process the collected hyperspectral data, and this application does not impose any restrictions on this.

[0071] Step S002, analyzing the difference in reflectance of different pixels in a local range at each time and each band, as well as the difference in reflectance of each pixel at adjacent times, to obtain the reflection characteristic coefficient of each pixel at each band.

[0072] During the refining stage of thiopronine, with the adsorption of impurities and colored substances by activated carbon after addition, the reflectivity of the reaction solution in different bands will also change significantly. As the activated carbon adsorbs impurities and colored substances, the reflectivity of the reaction solution at a specific wavelength increases more significantly; at the same time, the spectral characteristics of the reaction solution in a local range are more consistent; secondly, with the effective removal of impurities, the characteristic absorption peaks of the impurities will decrease or narrow, making the smoothness of the spectral curve of the reaction solution more obvious.

[0073] Now, the hyperspectral data of the sampled reaction solution at the tth moment is taken as an example for analysis, and the sequence of the reflectance of each pixel in all bands in ascending order of wavelength is used as the reflectance sequence of each pixel; with each pixel as the center, a 5×5 pixel window is constructed, and the sequence of the reflectance of all pixels in each pixel window in each band in ascending order is used as the neighborhood reflectance sequence of each pixel window in each band. Among them, the size of the pixel window can be set by the implementer according to the actual situation, and this application does not limit it.

[0074] The difference between any two elements in the neighborhood reflectance sequence is calculated and recorded as the first difference. The fusion results of all the first differences in the neighborhood reflectance sequence are reversely mapped to obtain the neighborhood spectral consistency of the central pixel of the corresponding pixel window in each band.

[0075] It should be understood that the difference indicates the degree of difference between two data, which can be calculated by difference, absolute value of difference, ratio, etc.; fusion means combining multiple variables in a way to enhance the overall effect, which can be specifically addition, multiplication, etc.; reverse mapping means that the dependent variable will decrease as the independent variable increases, and the dependent variable will increase as the independent variable decreases.

[0076] In one embodiment of the present application, for the neighborhood reflectance sequence of each pixel window under each band, the absolute value of the difference between any two elements in the neighborhood reflectance sequence is calculated, recorded as the first difference, and the inverse of the accumulated result of all the first differences in the neighborhood reflectance sequence is taken as the neighborhood spectral consistency of the central pixel in each pixel window under each band.

[0077] When the reflectivity change characteristics presented by the adsorption of activated carbon on impurities and colored substances in a certain band are more significant, the reflectivity consistency of all pixels in the neighborhood range is stronger, and the difference between all elements in the neighborhood reflectivity sequence of the pixel window in the corresponding band is smaller, that is, the smaller the cumulative result of the absolute value of the difference between all elements in the neighborhood reflectivity sequence is, the greater the consistency of the neighborhood spectrum is.

[0078] The variance of the reflectivity sequence of each pixel at each moment and the pixel at the same position at the adjacent moments is calculated as the degree of improvement of the reflectivity of each pixel at each moment.

[0079] In one embodiment of the present application, the value variance of the reflectivity sequence of each pixel at each moment and the reflectivity sequence of the pixel at the same position at the previous moment is calculated as the reflectivity improvement degree of each pixel at each moment.

[0080] The calculation of the variance of the values ​​is a known technique and will not be described in detail in this application.

[0081] When the adsorption of impurities and colored substances by activated carbon makes the reflectivity increase more obvious in the corresponding band, the greater the degree of reflectivity improvement, the greater the difference in reflectivity between the reflectivity sequence corresponding to the current moment of the pixel and the reflectivity sequence corresponding to the previous moment at the same position order, that is, the greater the value variance result.

[0082] The reflectivity enhancement degree and the neighborhood spectrum consistency are combined to determine the reflectivity characteristic coefficient of each pixel in each band at each moment. Specifically, the fusion value of the neighborhood spectrum consistency and the reflectivity enhancement degree is used as the reflectivity characteristic coefficient.

[0083] In one embodiment of the present application, the product of the neighborhood spectral consistency of each pixel at each moment in each band and the reflectivity improvement degree of the corresponding pixel at the corresponding moment is calculated, and the normalized result of the product is used as the reflection characteristic coefficient of each pixel at each moment in each band.

[0084] When the adsorption of impurities and colored substances by activated carbon makes the reflectivity characteristics in a specific band more significant, the phenomenon of increased reflectivity in a specific band and the spectral consistency within the neighborhood of the reaction solution are more significant, the stronger the neighborhood spectral consistency, the greater the degree of reflectivity improvement, and the greater the reflection characteristic coefficient.

[0085] Step S003, based on all the reflection characteristic coefficients of all the pixels at each moment, a feature selection algorithm is used to obtain the spectral characteristic band at each moment, the difference in reflectance of each pixel at each moment and the pixel at the same position at the adjacent moment in the spectral characteristic band is calculated, the distribution trend of the reflectance of each pixel at each moment in the spectral characteristic band, and the probability distribution of the difference in reflectance in the spectral characteristic band are analyzed, and the reaction sufficiency coefficient of the reaction solution at each moment is obtained.

[0086] The sequence of reflection characteristic coefficients of each pixel in all bands at each moment in ascending order of wavelength is taken as the band characteristic sequence of each pixel at each moment, the band characteristic sequences of all pixels at each moment are taken as a row of the matrix, and the matrix composed of the ascending order of the horizontal coordinates and the vertical coordinates of the pixels is taken as the spectral characteristic matrix at each moment.

[0087] In one embodiment of the present application, the spectral feature matrix at each moment is used as input, and the SPCAFS based on sparse principal component analysis feature selection algorithm (Sparse Principal Component Analysis for Feature Selection) is used to output the spectral feature bands at each moment. The SPCAFS based on sparse principal component analysis feature selection algorithm is an existing well-known technology, which is not described in detail in this application, and the implementer can select other existing feasible feature selection algorithms according to actual conditions, which is not described in detail in this application.

[0088] The beneficial effect of obtaining spectral characteristic bands is that the effective hyperspectral data of the reaction solution can be more accurately obtained based on the reflectivity change characteristics produced by the activated carbon adsorption effect, which facilitates a more accurate evaluation of the sufficiency of the activated carbon reaction time in the subsequent period while reducing the amount of calculation.

[0089] Taking the tth moment as an example, in one embodiment of the present application, a sequence composed of all reflectivities of each pixel in the spectral characteristic band at the tth moment in ascending order of the wavelength of the spectral characteristic band is used as the characteristic reflection sequence of each pixel at the tth moment; a sequence composed of data differences of the same order as the characteristic reflection sequence of each pixel at the tth moment and the t-1th moment is used as the spectral absorption difference sequence of each pixel at the tth moment.

[0090] The beneficial effect of constructing characteristic reflection sequences and spectral absorption difference sequences is that, based on screening out spectral characteristic bands with increased reflectivity and more significant neighborhood spectral consistency, the spectral curve characteristics and spectral absorption change characteristics of the activated carbon reaction solution hyperspectral data can be more accurately quantitatively evaluated.

[0091] At the tth moment, the JS divergence of the spectral absorption difference sequence of any two pixels is calculated, and the fusion result of all the JS divergences is taken as the spectral absorption difference degree at the tth moment.

[0092] In one embodiment of the present application, the cumulative result of all the JS divergences at the tth moment is taken as the spectral absorption difference degree at the tth moment.

[0093] When the adsorption effect of activated carbon on impurities and colored substances in the reaction solution is more sufficient, the spectral absorption similarity of all pixels in the spectral characteristic band is stronger, the spectral absorption difference is smaller, and the JS divergence accumulation result between the spectral absorption difference sequences between all pixels is smaller.

[0094] At the tth moment, the least square method is used to obtain the fitting curve of the characteristic reflection sequence of each pixel, and the difference between each element in the characteristic reflection sequence and the fitting value in the corresponding fitting curve is calculated, which is recorded as the second difference. The fusion results of all the second differences of all pixels at the tth moment are reversely mapped to obtain the smoothness of the spectral curve at each moment. Among them, the least square method is an existing well-known technology, which will not be described in detail in this application, and the implementer can choose other existing feasible fitting algorithms according to actual conditions, which will not be limited in this application. The schematic diagram of a partial fitting curve of the characteristic reflection sequence is shown in FIG. Figure 3 shown.

[0095] In one embodiment of the present application, at the tth moment, the absolute value of the difference between each element in the characteristic reflection sequence and the fitting value in the corresponding fitting curve is calculated, which is recorded as the second difference. The smoothness of the spectral curve at the tth moment c is t It can be expressed as:

[0096] Among them, RMse t,i,j represents the i-th second difference of the j-th pixel at the t-th moment, I represents the number of elements in the characteristic reflection sequence, J represents the number of pixels at the t-th moment, ∈ represents an adjustment factor preset to be greater than 0 to avoid the denominator being 0. In this embodiment, ∈=1, and the implementer can set it according to the actual situation, and this application does not impose any restrictions on this.

[0097] When the adsorption effect of activated carbon on impurities and colored substances in the reaction solution is more sufficient, the reflectivity change of all pixels in the spectral characteristic band is more uniform, the smoothness of the spectral curve in the spectral characteristic band is higher, and the second difference accumulation result corresponding to each pixel in the reaction solution hyperspectral data is smaller.

[0098] The reaction sufficiency coefficient at the tth moment is determined based on the smoothness of the spectral curve and the degree of spectral absorption difference at the tth moment, and the reaction sufficiency coefficient is positively correlated with the smoothness of the spectral curve and negatively correlated with the degree of spectral absorption difference. A positive correlation means that the dependent variable will increase as the independent variable increases, and the dependent variable will decrease as the independent variable decreases, and a negative correlation means that the dependent variable will decrease as the independent variable increases, and the dependent variable will increase as the independent variable decreases.

[0099] The response sufficiency coefficient B at the specific time t t It can be expressed as:

[0100] Among them, c t is the smoothness of the spectral curve at the tth moment; b t is the degree of spectral absorption difference at the tth moment; ε is a preset adjustment parameter, which is taken as 1 in this embodiment to prevent the denominator from being 0 and causing calculation failure. The implementer can set it according to the actual situation, and this application does not impose any restrictions on this.

[0101] When there is no need to extend the activated carbon reaction time, the adsorption effect of the activated carbon in the reaction solution on impurities and colored substances is more sufficient, the smoothness of the spectral curve under the spectral characteristic band is more significant, the spectral absorption characteristics are more similar, and the reaction sufficiency coefficient is greater.

[0102] The reaction sufficiency coefficient of the reaction solution at each time can be calculated by using the same calculation method as that of the reaction sufficiency coefficient of the reaction solution at time t.

[0103] Step S004, adjusting the reaction time of the activated carbon based on the reaction sufficiency coefficient of the reaction solution at each moment.

[0104] Compare the reaction sufficiency coefficient obtained in real time with the set reaction sufficiency threshold. When the reaction sufficiency coefficient is greater than or equal to the reaction sufficiency threshold, it is determined that the current activated carbon reaction time has reached a sufficient level, and the activated carbon reaction process should be stopped in time for subsequent process treatment; when the reaction sufficiency coefficient is less than the reaction sufficiency threshold, it is determined that the current activated carbon reaction time has not reached a sufficient level, and the reaction needs to continue until the reaction sufficiency coefficient is greater than or equal to the reaction sufficiency threshold, or the preset reaction time is reached. In this embodiment, the reaction sufficiency threshold is set to 0.6, and the preset reaction time is 1h. The implementer can adjust it according to the actual situation, and this application does not impose any restrictions on this. The activated carbon reaction time adjustment flow chart is as follows: Figure 4 shown.

[0105] (6) The crystals from step (5) are placed in a centrifuge to separate the mother liquor, and the mother liquor is collected.

[0106] (7) The filter cake was dried under vacuum at 55° C. or below for 4 h to obtain the thiopronine concentrate. In this embodiment, the filter cake was dried under vacuum at 50° C. for 4 h to obtain the thiopronine concentrate.

[0107] (8) The dried thiopronine fine product is crushed into a size larger than 120 meshes by a crusher; and then passed through a 120-mesh sieve by a vibrating sieve machine.

[0108] (9) The sieved tiopronin is mixed and packaged.

[0109] In summary, the present application collects high-spectral data of the reaction solution at each moment after adding activated carbon during the preparation stage of the thiopronine fine product, analyzes the difference in reflectance of different pixels in the local range at each moment and each band, as well as the difference in reflectance of each pixel at adjacent moments, and obtains the reflection characteristic coefficient of each pixel at each band; reflects the significance of the change in reflectance of each pixel at each band, and quantifies the distinctive features of the change in reflectance of each pixel at different bands; then, based on all the reflection characteristic coefficients of all pixels at each moment, a feature selection algorithm is used to obtain the spectral characteristic band at each moment, thereby improving the determination of the spectral characteristic band. The accuracy of the method is improved; the difference in reflectance of each pixel at each moment and the pixel at the same position at the adjacent moment in the spectral characteristic band is calculated, the distribution trend of the reflectance of each pixel at each moment in the spectral characteristic band, and the probability distribution of the difference in reflectance in the spectral characteristic band are analyzed, and the reaction sufficiency coefficient of the reaction solution at each moment is obtained, which reflects the adsorption effect of the activated carbon in the reaction solution at each moment on impurities and colored substances, evaluates the adsorption sufficiency of the activated carbon on impurities and colored substances, and adjusts the reaction time after adding the activated carbon, thereby improving the rationality and accuracy of the reaction time control, and thus improving the purity of the prepared tiopronin.

[0110] It should be noted that the above sequence of the embodiments of the present application is for description only and does not represent the advantages and disadvantages of the embodiments. The above is a description of a specific embodiment of this specification. In addition, the processes depicted in the accompanying drawings do not necessarily require the specific order or continuous order shown to achieve the desired results. In some embodiments, multitasking and parallel processing are also possible or may be advantageous.

[0111] The various embodiments in this specification are described in a progressive manner, and the same or similar parts between the various embodiments can be referenced to each other, and each embodiment focuses on the differences from other embodiments.

[0112] The embodiments described above are only used to illustrate the technical solutions of the present application, rather than to limit them. Modifications to the technical solutions recorded in the aforementioned embodiments, or equivalent replacement of some of the technical features therein, do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application, and should all be included in the protection scope of the present application.

Claims

1. A highly stable preparation process of tiopronin, It is characterized in that The process includes the following steps: α-chloropropionylglycine is synthesized by using α-chloropropionyl chloride, sodium carbonate and glycine to obtain α-chloropropionylglycine; α-dithiodipropionylglycine was synthesized by using α-chloropropionylglycine and sodium disulfide solution, and zinc powder was added, and the crude product of tiopronin was obtained after extraction, concentration and crystallization. The crude tiopronin was heated and stirred with ethyl acetate, and activated carbon was added to maintain a constant temperature reaction after it was completely dissolved. The duration of the constant temperature reaction was adjusted as follows: The hyperspectral data of the reaction solution at each time after the addition of activated carbon are collected, and the difference in reflectance of different pixels in the local range at each time and each band, as well as the difference in reflectance of each pixel at adjacent times, are analyzed to obtain the reflection characteristic coefficient of each pixel in each band; Based on all the reflection characteristic coefficients of all the pixels at each moment, a feature selection algorithm is used to obtain the spectral characteristic band at each moment, the difference in reflectance of each pixel at each moment and the pixel at the same position at the adjacent moment in the spectral characteristic band is calculated, the distribution trend of the reflectance of each pixel in the spectral characteristic band at each moment, and the probability distribution of the difference in reflectance in the spectral characteristic band are analyzed, and the reaction sufficiency coefficient of the reaction solution at each moment is obtained; Controlling the duration of the isothermal reaction based on the reaction sufficiency coefficient, and then filtering, cooling, and crystallizing; The crystals are separated from the mother liquor by a centrifuge and then vacuum dried to obtain the fine product of tiopronin.

2. A process for preparing tiopronin with high stability as claimed in claim 1, It is characterized in that The synthesis of α-chloropropionylglycine comprises: Add 8 kg of glycine and 40 kg of purified water to the reactor, add 5.8 kg of anhydrous sodium carbonate after stirring, continue stirring to dissolve all the solids, cool to -15 ° C, add sodium carbonate solution and α-chloropropionyl chloride under the condition of a reaction temperature of -10 ° C, keep reacting for 4 hours, adjust the pH to 2 with hydrochloric acid, use ethyl acetate to vacuum extract 3 times, filter, and concentrate the filtrate under reduced pressure below 55 ° C until tiny crystals precipitate. Cool to -10 ° C for more than two hours, combine the ethyl acetate extracts, filter, and vacuum dry to obtain α-chloropropionyl glycine.

3. A process for preparing tiopronin with high stability as claimed in claim 1, It is characterized in that The preparation of the sodium disulfide solution comprises: 14 kg of sodium sulfide nonahydrate and 16.5 kg of purified water were stirred and dissolved, 1.9 kg of sublimed sulfur was added, heated to 50°C, and the reaction was maintained for 1 hour to obtain a sodium disulfide solution.

4. A process for preparing tiopronin with high stability as claimed in claim 1, It is characterized in that The synthesis of α-dithiodipropionylglycine comprises: Add 10.2 kg of α-chloropropionylglycine and 60 kg of purified water into the synthesis extraction tank, slowly add 3.1 kg of anhydrous sodium carbonate under stirring, raise the temperature to 40°C, keep the temperature for reaction for 1 hour, cool to 10°C, add sodium disulfide solution dropwise, raise the temperature to room temperature, and react for 10 hours.

5. A process for preparing tiopronin with high stability as claimed in claim 4, It is characterized in that The synthesis of the crude tiopronin product comprises: After the reaction for 10 hours, the temperature is lowered to 5°C, 18 kg of concentrated sulfuric acid is slowly added, the pH is adjusted to 2, the filtrate is filtered, the filtrate is poured into a synthetic extraction tank, the temperature is controlled at 10°C, 8.7 kg of zinc powder is added, and then the reaction is carried out at room temperature for 6 hours, the filtrate is filtered, and the ethyl acetate extracts are combined, dried, filtered, and the filtrate is concentrated until crystals are precipitated, cooled to -10°C, centrifuged, and vacuum dried to obtain a crude product of tiopronin.

6. A process for preparing tiopronin with high stability as claimed in claim 1, It is characterized in that The mass of the activated carbon is 40 g, the constant temperature is 50° C., and the temperature is lowered to -5° C.

7. A process for preparing tiopronin with high stability as claimed in claim 1, It is characterized in that The determination process of the reflection characteristic coefficient is: Taking each pixel as the center, a pixel window of preset size is constructed, all reflectances of all pixels in each pixel window under each band are combined into a neighborhood reflectance sequence of each pixel window, the difference between any two elements in the neighborhood reflectance sequence is calculated, recorded as the first difference, and the fusion results of all the first differences in the neighborhood reflectance sequence are reversely mapped to obtain the neighborhood spectral consistency of the central pixel of the corresponding pixel window under each band; The reflectance of each pixel at each moment in all bands is combined into a reflectance sequence, and the value variance of the reflectance sequence of each pixel at each moment and the pixel at the same position at the adjacent moment is calculated as the reflectance improvement degree of each pixel at each moment; The fused normalized value of the neighborhood spectrum consistency and the reflectivity improvement degree is used as the reflection characteristic coefficient.

8. A process for preparing tiopronin with high stability as claimed in claim 1, It is characterized in that The determination process of the reaction sufficiency coefficient is: All reflectances of all pixels at each moment in the spectral characteristic band are combined into a characteristic reflection sequence, a fitting curve of the characteristic reflection sequence is obtained, the difference between each element in the characteristic reflection sequence and the fitting value in the corresponding fitting curve is calculated, recorded as the second difference, and the fusion results of all the second differences of all pixels at each moment are reversely mapped to obtain the smoothness of the spectral curve at each moment; Calculate the difference between the elements at the same position in the characteristic reflection sequence of each pixel at each moment and the pixels at the same position at the adjacent moments to form the spectral absorption difference sequence of each pixel at each moment, and take the fusion result of the JS divergence of the spectral absorption difference sequence of all arbitrary two pixels at each moment as the spectral absorption difference degree at each moment; Determining the reaction sufficiency coefficient based on the smoothness of the spectral curve and the degree of difference in spectral absorption; The reaction sufficiency coefficient is positively correlated with the smoothness of the spectral curve, and negatively correlated with the degree of spectral absorption difference.

9. A process for preparing tiopronin with high stability as claimed in claim 1, It is characterized in that The controlling the duration of the isothermal reaction based on the reaction sufficiency coefficient comprises: If the reaction sufficiency coefficient is greater than or equal to the preset reaction sufficiency threshold, the constant temperature reaction is stopped; otherwise, the reaction is continued until the reaction sufficiency coefficient is greater than or equal to the preset reaction sufficiency threshold or the preset reaction time is reached.

10. A process for preparing tiopronin with high stability as claimed in claim 1, It is characterized in that The vacuum drying is carried out at a temperature below 55° C. and for a period of 4 hours.

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