Preparation process of medicine-assisted isopropanol

Abstract

The invention provides a preparation process of medicine-assisted isopropanol, and relates to the technical field of isopropanol purification. Comprising the following steps: by taking analytically pure isopropanol as a raw material, adding potassium borohydride and hydroxide according to a solid-to-liquid ratio of (6-8): 1000, and uniformly mixing; carrying out reflux reaction on the mixture at 80-85 DEG C for 3-5 hours; carrying out atmospheric distillation, controlling the top temperature to be 82.3-82.7 DEG C, and collecting a middle fraction; detecting the middle fraction, and obtaining the medicine-assisted grade isopropanol when the middle fraction reaches the standard; in the step S100, hydroxide is added in stages, potassium borohydride and 45%-55% of hydroxide are added into isopropanol at the same time, a reflux reaction is conducted, and the reaction lasts for 1.0-1.2 h; and slowly adding the residual hydroxide in the form of solid powder, and controlling the adding rate to be less than or equal to 0.5 g / min. Through the processes of staged alkali addition, synergistic reduction of potassium borohydride and hydroxide, precise distillation control and the like, the impurity removal efficiency is remarkably improved; the content of carbonyl compounds is reduced to 0.5 ppm; the qualified rate of a potassium permanganate oxidation test is increased to 100%; the absorbance at 230 nm is reduced to be less than or equal to 0.08.

Description

Technical Field

[0001] The present invention relates to the technical field of isopropyl alcohol purification, and particularly to a preparation process of pharmaceutical-grade isopropyl alcohol. Background Art

[0002] Isopropyl Alcohol (IPA), as an important organic solvent and pharmaceutical excipient, is widely used in fields such as injections, topical liquid medicines, and disinfection of medical devices. Pharmacopoeia-grade isopropyl alcohol needs to meet strict quality standards. For example, the "Chinese Pharmacopoeia" (2020 Edition) stipulates that the water content ≤ 0.2%, the ultraviolet absorbance (230 nm) ≤ 0.3, and at the same time, it needs to pass the potassium permanganate oxidation test (detection of easily oxidized substances), etc. However, the traditional purification process has the following technical bottlenecks:

[0003] Limitations of the rectification method: Industrial-grade isopropyl alcohol often uses multi-stage rectification to remove light components (methanol, acetone) and heavy components (higher alcohols), but carbonyl compounds (such as residual acetone) are difficult to be completely separated because their boiling points are close to that of isopropyl alcohol (acetone 56.5°C vs. isopropyl alcohol 82.5°C), and additional adsorption treatment is required.

[0004] Defects of the adsorption method: Activated carbon or ion exchange resin is used to adsorb impurities, but there are two major problems:

[0005] Poor selectivity: The adsorption rate of activated carbon for benzene series compounds (such as toluene) > 90%, but the adsorption rate for small molecule carbonyl compounds (such as formaldehyde) < 50%; Risk of secondary pollution: Resin fragmentation or activated carbon micropowder may introduce non-volatile substances (exceeding the standard to 0.003%), and additional filtration steps are required, resulting in process complexity.

[0006] Challenges of the oxidation-reduction method: Some processes attempt to degrade impurities through oxidation (such as ozone treatment) or reduction (such as NaBH4), but there are reaction control problems: The NaBH4 system needs to strictly control the pH (8 - 9) to prevent the reduction of isopropyl alcohol itself, and the residual borate (≤ 0.001%) is difficult to be completely removed; Although the ozone oxidation method can decompose benzene series compounds, it will generate aldehyde by-products (such as formaldehyde), instead resulting in an increase in the content of carbonyl compounds (0.007% - 0.01%).

[0007] Difficulties in controlling ultraviolet absorbance: Pharmacopoeia-grade isopropyl alcohol requires an absorbance at 230 nm ≤ 0.3, while trace conjugated olefins (such as oxidation products of isopropyl ether) or aromatic impurities (such as benzene series compounds) will cause the absorbance to exceed the standard. The existing technology uses photocatalytic degradation, but the equipment investment is high (requiring an ultraviolet reaction kettle), and it may cause the photolysis of isopropyl alcohol (generating acetone, increasing the carbonyl content in the reverse direction).

[0008] The existing processes either rely on high - energy - consuming rectification or face the risks of incomplete impurity removal and secondary pollution, and it is difficult to meet the requirements of "low impurities, low absorbance, and high stability" for pharmaceutical - grade isopropanol. Summary of the Invention

[0009] The present invention provides a preparation process for pharmaceutical - grade isopropanol. Analytical - grade isopropanol is reduced using borohydride and hydroxide, and then the isopropanol is distilled and purified by atmospheric distillation to obtain pharmaceutical - grade isopropanol with low impurities, low absorbance, and high stability.

[0010] A preparation process for pharmaceutical - grade isopropanol includes the following steps:

[0011] S100: Using analytical - grade isopropanol as the raw material, adding potassium borohydride and hydroxide according to a solid - liquid ratio of 6 - 8:1000, and mixing evenly;

[0012] S200: Reacting the mixture under reflux at 83 - 85 °C for 3 - 5 hours;

[0013] S300: Performing atmospheric distillation, controlling the top temperature at 82.3 - 82.7 °C, discarding the fore - fraction, and collecting the middle - fraction; S400: Detecting the middle - fraction, and obtaining pharmaceutical - grade isopropanol after it meets the standards;

[0014] Among them, in step S100, the hydroxide is added in stages, including: The first stage: adding 45% - 55% mass - fraction hydroxide and potassium borohydride into isopropanol simultaneously, starting the reflux reaction, and reacting for 1.0 - 1.2 hours; The second stage: slowly adding the remaining hydroxide in the form of solid powder, controlling the addition rate ≤0.5 g / min; The hydroxide includes sodium hydroxide.

[0015] By adding hydroxide in stages (synergistic effect with potassium borohydride (KBH4)), the carbonyl compound content is reduced to ≤0.002%. The first stage (45% - 55% mass - fraction hydroxide): The initial alkaline environment activates the reduction activity of KBH4, selectively reducing carbonyl impurities in the raw material (such as acetone → isopropanol); The second stage (the remaining hydroxide): Supplementing alkalinity to maintain pH≥12, decomposing residual easily - oxidizable substances (such as peroxides), ensuring 100% qualified potassium permanganate test. Ultraviolet absorbance control: The absorbance at 230 nm is reduced from 0.3 - 0.5 of the raw material to ≤0.08, and the absorbance at 250 - 310 nm is significantly reduced, indicating that conjugated olefins and aromatic impurities are efficiently removed. Adding in stages avoids local strong alkalinity: reducing the dehydration of isopropanol to form acetone (the side - reaction inhibition rate ≥80%); Precise distillation top temperature (82.3 - 82.7 °C): effectively separating light components (methanol, water) and heavy components (polymers, metal complexes).

[0016] The traditional process uses a one-time feeding, which easily leads to side reactions of isopropanol dehydration caused by local strong alkali, generating acetone. In the present invention, hydroxides are added in stages: 45% - 55% is added in the first stage, and the remaining amount is supplemented in the second stage, controlling the pH fluctuation of the system within ±0.5, and reducing the by-product generation amount by 80%. After the feeding in the first stage, the reaction is carried out for 1.0 - 1.2 hours: the initial alkaline environment activates the reduction activity of KBH4, preferentially degrading easily oxidizable substances; in the second stage, the solid powder is added at a low speed: to avoid violent heat release and maintain the stability of the system (temperature fluctuation ≤ ±1°C). The traditional process relies on a single reducing agent (such as NaBH4) and requires additional addition of a stabilizer (such as ethylenediamine) to prevent self-decomposition. The present invention innovatively uses the KBH4 / NaOH combination, and uses K⁺ ions to improve the solubility of BH4⁻, achieving a 25% increase in reduction efficiency without auxiliary reagents. The staged alkali addition in the present invention maintains pH ≥ 12, increasing the pass rate of the potassium permanganate oxidation test from 70% to 100%, and the reduction system directionally degrades conjugated impurities, and the absorbance at 230 nm drops from 0.489 to 0.08; combining inorganic reduction chemistry (KBH4) with precision distillation, breaking through the single-dimensional limitation of traditional purification processes (adsorption, rectification), achieving the dual goals of impurity removal and product stability, as well as the efficient and low-cost preparation of pharmaceutical-grade isopropanol.

[0017] The hydroxide is preferably sodium hydroxide. NaOH has strong alkalinity, which is more conducive to maintaining the pH ≥ 12 of the reaction system, ensuring the continuous release of BH4⁻; the price of NaOH is significantly lower than that of KOH, reducing the process cost; the solubility of NaOH in isopropanol is moderate (about 5 g / 100 mL), which can avoid crystallization or caking caused by local supersaturation.

[0018] Further, in step S100, the mass ratio of potassium borohydride to hydroxide is 1:0.8 - 1.1.

[0019] KBH4 decomposes under alkaline conditions to generate active BH4⁻ ions, selectively reducing carbonyl compounds (such as acetone) in isopropanol to alcohols (isopropanol); the hydroxide provides an alkaline environment (pH ≥ 12), promoting the release of BH4⁻; neutralizing acidic by-products (such as B(OH)3) generated by the reaction to prevent the reduction efficiency from decreasing due to system acidification.

[0020] The mass ratio of potassium borohydride to hydroxide is 1:0.8 - 1.1, avoiding side reactions caused by excessive alkali: excessive NaOH may catalyze the dehydration of isopropanol. When the mass ratio > 1:1.1, the acetone content in the system increases significantly; at the same time, excessive NaOH accelerates the hydrolysis of KBH4 (2KBH4 + 2H2O → 2KOH + B2H6↑ + 2H2↑), reducing the reduction efficiency.

[0021] Further, in the first stage, the temperature is 80 - 85°C. Sodium hydroxide and potassium borohydride are dry - mixed and then added to isopropanol. The particle size of sodium hydroxide is 100 - 200 mesh.

[0022] The decomposition rate of KBH4 increases significantly at 80 - 85°C, releasing active BH4⁻ ions and rapidly reducing carbonyl compounds (such as acetone → isopropanol). Dry - mixing can reduce the introduction of moisture, avoiding the premature reaction of KBH4 with water: 2KBH4 + 2H2O → 2KOH + B2H6↑ + 2H2↑, reducing the amount of hydrogen generated and lowering the risk of violent boiling. The mixing of solid powders ensures the uniform distribution of NaOH and KBH4 in isopropanol, avoiding local high pH that may cause the dehydration of isopropanol (generating acetone).

[0023] Further, when adding sodium hydroxide in the second stage, the reaction temperature is reduced to 70 - 75°C. After the addition is completed, the temperature is raised to 80 - 83°C at a rate of 0.5 - 1.0°C / min and the reaction continues.

[0024] The purpose of reducing the temperature to add NaOH: inhibiting intense heat release. The dissolution of NaOH and its reaction with KBH4 release heat. Reducing the temperature to 70 - 75°C can slow down the reaction rate and prevent a sudden rise in temperature (ΔT > 5°C) that may cause the dehydration of isopropanol or the excessive decomposition of KBH4. Precise control of the pH gradient: supplementing NaOH in stages to maintain the system pH ≥ 12, avoiding a local strong - base environment (pH > 13) caused by one - time feeding and reducing the generation of by - products.

[0025] The function of slow heating (0.5 - 1.0°C / min): After heating to 80 - 83°C, the remaining carbonyl compounds are further reduced, and the reaction activation energy is lowered. It effectively inhibits side reactions and avoids the dehydration of isopropanol caused by sudden temperature changes.

[0026] Further, in step S100, the hydroxide also includes potassium hydroxide, and the molar ratio of potassium hydroxide to sodium hydroxide is 1:3 - 5.

[0027] The synergistic mechanism of potassium hydroxide and sodium hydroxide:

[0028] The function of KOH: promoting the ionization of BH4⁻. K⁺ ions form a more stable ion pair (K⁺···BH4⁻) with BH4⁻, improving the solubility and reaction activity of potassium borohydride in isopropanol and accelerating the reduction of carbonyl compounds. Inhibiting the self - decomposition of KBH4: K⁺ can partially replace Na⁺ to combine with BH4⁻, slowing down the hydrolysis rate of KBH4 under alkaline conditions (compared with the pure NaOH system, the residual amount of KBH4 is reduced by 50%).

[0029] The leading role of NaOH: Maintaining a high pH environment (pH ≥ 12): NaOH is more alkaline, ensuring the continuous release of BH4⁻; Neutralizing by-products: The boric acid (B(OH)3) generated by the reaction is neutralized by NaOH to prevent the system from acidifying. The reaction equation is: B(OH)3 + NaOH → NaBO2 + 2H2O.

[0030] When the molar ratio of potassium hydroxide to sodium hydroxide is greater than 1:3, excessive NaOH may cause the dehydration of isopropanol (the amount of acetone generated increases to 0.003%); when the molar ratio is less than 1:5, there is insufficient KOH, the ionization of BH4⁻ is insufficient, and the reduction efficiency decreases.

[0031] K⁺ ions can increase the solubility and reactivity of BH4⁻, raising the removal rate of carbonyl compounds to 99%; the residual mixed alkali ≤ 10 ppm can inhibit the growth of microorganisms during the storage of pharmaceutical excipient products.

[0032] Furthermore, the particle size of the potassium hydroxide is ≤ 200 mesh, and the addition time is 5 - 10 minutes before the addition of potassium borohydride.

[0033] Adding KOH 5 - 10 minutes before potassium borohydride can pre-neutralize trace acidic impurities (such as acetic acid) in the raw material isopropanol, avoiding the consumption of KBH4 added subsequently.

[0034] Furthermore, in step S200, the reflux reaction temperature is 81 - 83 °C, the reaction time is 3.8 - 4.2 hours, and the pH of the reaction system is ≥ 12.

[0035] Furthermore, in step S300, the discarded amount of the fore fraction is 5% - 8% of the volume of the raw material; the collected volume of the middle fraction is 85% - 90% of the volume of the raw material; the proportion of the residue in the kettle is ≤ 10%, and the temperature of the kettle is 95 - 105 °C.

[0036] Using a thimble fractionating column (the number of theoretical plates ≥ 10) can enhance the separation effect and reduce the entrainment of light and heavy components; the temperature difference (12.5 - 22.5 °C) between the top temperature (82.5 °C) and the kettle temperature (95 - 105 °C) realizes the gas-liquid equilibrium through the fractionating column to ensure efficient separation.

[0037] Furthermore, the detection includes ultraviolet absorbance detection and potassium permanganate oxidation detection.

[0038] Furthermore, the wavelength range of ultraviolet light is 230 - 310 nm.

[0039] 230 nm: Detecting conjugated double bonds, such as the olefins generated by the oxidation of isopropanol; 250 - 310 nm: Monitoring aromatic impurities, such as benzene series compounds.

[0040] Advantages of the invention

[0041] Through staged alkali addition, synergistic reduction of potassium borohydride (KBH4) and hydroxide (NaOH / KOH), and precise distillation control, the present invention significantly improves the impurity removal efficiency: the content of carbonyl compounds (such as acetone) decreases from 0.0027% of the raw material to 0.5 ppm; the pass rate of the potassium permanganate oxidation test for easily oxidizable substances (reductive impurities) increases from 70% to 100%; ultraviolet absorbance: the absorbance at 230 nm decreases from 0.3 - 0.5 to ≤0.08, and the conjugated impurities are reduced by 90%; through precise distillation, the top temperature is 82.3 - 82.7 °C, reducing the fore-fraction and bottom residue, and the recovery rate of isopropanol increases by 8% - 10%. The preparation process of the present invention does not require additional dehydration or adsorption steps, no organic solvents are introduced, and boron elements (such as borax) can be recovered from the bottom residue, effectively reducing hazardous waste emissions.

[0042] Ultraviolet absorbance detection quantitatively evaluates the content of conjugated olefins, aromatic compounds (such as benzene series) and other ultraviolet-active impurities in isopropanol by measuring the light absorption intensity of isopropanol at specific wavelengths (230 - 310 nm). The absorbance value directly reflects the impurity concentration and is one of the key indicators in the pharmacopoeia. Specific Embodiments

[0043] Example 1

[0044] A preparation process of pharmaceutical-grade isopropanol includes the following steps:

[0045] S100: Using 1000 ml of analytical pure isopropanol as the raw material, in the first stage: at a temperature of 82.5 °C, add 0.9 g of potassium hydroxide powder with a particle size of 100 mesh. After 8 minutes, dry-mix 3.5 g of potassium borohydride and 1.3 g of sodium hydroxide with a particle size of 150 mesh and add them to the isopropanol, then start the reflux reaction for 1.0 hour; in the second stage: lower the reaction temperature to 73 °C, slowly add the remaining 1.3 g of sodium hydroxide in the form of solid powder, control the addition rate at 0.4 g / min, mix evenly, and then raise the temperature to continue the reaction at 82 °C at a rate of 0.8 °C / min.

[0046] The mass ratio of potassium borohydride to hydroxide is 1:1; the molar ratio of potassium hydroxide to sodium hydroxide is 1:4.

[0047] S200: Reflux the mixture at 84 °C for 4 hours.

[0048] S300: Distill at atmospheric pressure, control the top temperature at 82.5 °C, discard the fore-fraction, and collect the middle fraction; the discarded amount of the fore-fraction is 7% of the raw material volume; the collected volume of the middle fraction is 88% of the raw material volume; the bottom residue accounts for 5%, and the bottom temperature is controlled at 100 °C. S400: Conduct ultraviolet absorbance detection and potassium permanganate oxidation detection on the middle fraction, and obtain pharmaceutical-grade isopropanol after passing the standards.

[0049] Example 2

[0050] A preparation process of pharmaceutical-grade isopropanol, comprising the following steps:

[0051] S100: Using 1000 ml of analytically pure isopropanol as raw material. In the first stage: at a temperature of 85°C, add 0.86 g of potassium hydroxide powder with a particle size of 200 mesh. After 5 minutes, dry-mix 3.33 g of potassium borohydride with 0.86 g of sodium hydroxide with a particle size of 200 mesh and add them to the isopropanol, then start the reflux reaction for 1.0 hour. In the second stage: lower the reaction temperature to 70°C, slowly add the remaining 1.05 g of sodium hydroxide in the form of solid powder, control the addition rate at 0.5 g / min, mix evenly, and continue the reaction by heating to 80°C at a rate of 0.5°C / min.

[0052] The mass ratio of potassium borohydride to hydroxide is 1:0.8; the molar ratio of potassium hydroxide to sodium hydroxide is 1:3.

[0053] S200: Reflux the mixture at 85°C for 3 hours.

[0054] S300: Distill at atmospheric pressure, control the top temperature at 82.3°C, discard the fore-fraction, and collect the middle fraction; the amount of discarded fore-fraction is 5% of the raw material volume; the collected volume of the middle fraction is 85% of the raw material volume; the residue in the kettle accounts for 10%, and the kettle temperature is controlled at 95°C. S400: Conduct ultraviolet absorbance detection and potassium permanganate oxidation detection on the middle fraction, and obtain pharmaceutical-grade isopropanol after passing the standards.

[0055] Example 3

[0056] A preparation process of pharmaceutical-grade isopropanol, comprising the following steps:

[0057] S100: Using 1000 ml of analytically pure isopropanol as raw material. In the first stage: at a temperature of 80°C, add 0.91 g of potassium hydroxide powder with a particle size of 150 mesh. After 10 minutes, dry-mix 3.81 g of potassium borohydride with 1.8 g of sodium hydroxide with a particle size of 100 mesh and add them to the isopropanol, then start the reflux reaction for 1.2 hours. In the second stage: lower the reaction temperature to 75°C, slowly add the remaining 1.48 g of sodium hydroxide in the form of solid powder, control the addition rate at 0.3 g / min, mix evenly, and continue the reaction by heating to 83°C at a rate of 1.0°C / min.

[0058] The mass ratio of potassium borohydride to hydroxide is 1:1.1; the molar ratio of potassium hydroxide to sodium hydroxide is 1:5.

[0059] S200: Reflux the mixture at 83°C for 5 hours.

[0060] S300, Atmospheric distillation, control the top temperature at 82.7 °C, discard the fore fraction, and collect the middle fraction; the amount of discarded fore fraction is 8% of the volume of the raw material; the collected volume of the middle fraction is 90% of the volume of the raw material; the residue in the kettle accounts for 2%, and the temperature of the kettle is controlled at 105 °C. S400, Conduct ultraviolet absorbance detection and potassium permanganate oxidation detection on the middle fraction, and obtain pharmaceutical auxiliary grade isopropanol after passing the standards.

[0061] Comparative Example 1

[0062] The molar ratio of KOH to NaOH in the hydroxide is 1:1, and other parameters are the same as those in Example 1.

[0063] Comparative Example 2

[0064] The molar ratio of KOH to NaOH in the hydroxide is 1:7, and other parameters are the same as those in Example 1.

[0065] Comparative Example 3

[0066] The hydroxide only includes sodium hydroxide and no potassium hydroxide; other parameters are the same as those in Example 1.

[0067] Comparative Example 4

[0068] After dry mixing potassium hydroxide, sodium hydroxide and potassium borohydride, add them to analytical grade isopropanol at one time, and other parameters are the same as those in Example 1.

[0069] The specific methods for detecting the above examples and comparative examples are as follows:

[0070] Method for ultraviolet absorbance detection:

[0071] Detection equipment and reagents: UV-visible spectrophotometer UV-2600, 1 cm quartz cuvette; the reference solution is air;

[0072] Sample treatment: The middle fraction of isopropanol is directly detected without dilution.

[0073] Operation steps: Instrument preheating and calibration: Turn on the machine and preheat for 30 minutes, set the wavelength range from 230 to 310 nm; wash the cuvette with high-purity water and zero with air as the blank.

[0074] Sample determination: Inject the isopropanol sample to be tested into the quartz cuvette, and the liquid level height ≥ 80%; scan the absorbance (A) at 230 nm, 250 nm, 270 nm, 290 nm, and 310 nm in sequence, and record the maximum value.

[0075] Method for detecting potassium permanganate oxidation: 0.5 ml of 0.02 mol / L potassium permanganate solution was added dropwise to 10 ml of the purified isopropanol sample and allowed to stand for 15 min. If the red color did not completely fade, it was considered qualified. It is used to detect the content of easily oxidizable substances in purified isopropanol.

[0076] The measured impurity contents of analytical pure isopropanol meeting the HG / T 2892—2020 standard are shown in Table 1.

[0077] Table 1 Measured impurity contents of analytical pure isopropanol

[0078]

[0079] As can be seen from Table 1, the following items of analytical pure isopropanol exceed the standard compared with pharmaceutical auxiliary grade isopropanol: the content of easily oxidizable substances and benzene series compounds exceeds the standard, the ultraviolet absorbance value at 230 nm is relatively large, and the measured values of other items are also close to the standard critical values.

[0080] The impurity contents in the isopropanol purified by the preparation processes of Application Examples 1 - 3 and Comparative Example 4 are shown in Table 2.

[0081] Table 2 Impurity contents in the isopropanol purified by the preparation processes of Application Examples 1 - 3 and Comparative Example 4

[0082]

[0083] As can be seen from Table 2, in Examples 1 - 3 of the present invention, the easily oxidizable substances passed the potassium permanganate detection and all met the standards; the content of carbonyl compounds decreased to 0.001% - 0.004%, showing a significant reduction; the content of benzene series compounds decreased from the original 0.0027% to 0.2 ppm, the absorbance value at 230 nm decreased from the original 0.489 to 0.08 - 0.102, and the absorbance values at wavelengths of 250 - 310 nm all decreased significantly; the contents of other impurities also decreased significantly. In Comparative Example 4, after mixing the compounds in the reduction system evenly and adding them to the analytical pure isopropanol at one time, the content of carbonyl compounds was significantly higher than that in Examples 1 - 3, the absorbance value at 230 nm was 0.35, exceeding the standard value, and in the potassium permanganate detection, the red color completely disappeared, which was unqualified. In summary, the preparation process of the present invention can effectively improve the purity of analytical pure isopropanol to the purity of pharmaceutical auxiliary grade isopropanol through staged alkali addition, synergistic reduction of KBH4 / NaOH, and precise top - temperature distillation.

[0084] The effects of changing the molar ratio of KOH and NaOH on the reaction and product performance in Examples 1 - 3 and Comparative Examples 1 - 3 are shown in Table 3.

[0085] Table 3 Effects of changing the molar ratio of KOH and NaOH on the reaction and product performance

[0086]

[0087] As can be seen from Table 3, in Examples 1-3, the molar ratio of KOH to NaOH was maintained at 1:3 to 5. The content of carbonyl compounds in the purified isopropanol met the standard range, the utilization rate of KBH4 could reach 95% to 99%, and the water content was much lower than the standard value. In Comparative Example 1, the molar ratio of KOH to NaOH was 1:1. Excessive NaOH might cause dehydration of isopropanol, and the content of carbonyl compounds was 25 times higher than that in Comparative Examples 1-3. In Comparative Example 2, the molar ratio of KOH to NaOH was 1:7. KOH was insufficient, and BH4⁻ ionization was not sufficient. The content of carbonyl compounds was 10 times higher than that in Comparative Examples 1-3, and the utilization rate of KBH4 was only 88%. In Comparative Example 3, only sodium hydroxide was used without potassium hydroxide. The content of carbonyl compounds was close to the critical value, the utilization rate of KBH4 was only 82%, and the water content was close to the standard value. The optimal range of the molar ratio of potassium hydroxide to sodium hydroxide in the present invention is 1:1 to 5, which can effectively balance the reduction efficiency and the inhibition of side reactions.

Claims

1. A preparation process of pharmaceutical-grade isopropanol, characterized in that, It includes the following steps: S100: Using analytical pure isopropanol as the raw material, adding potassium borohydride and hydroxide according to a solid-liquid ratio of 6 - 8:1000, and mixing evenly; S200: Refluxing the mixture at 83 - 85 °C for 3 - 5 hours; S300: Atmospheric distillation, controlling the top temperature at 82.3 - 82.7 °C, discarding the pre-fraction, and collecting the middle fraction; S400: Detecting the middle fraction, and obtaining pharmaceutical auxiliary grade isopropanol if it meets the standards; Among them, in step S100, the addition method of the hydroxide is stagewise addition, including: The first stage: Adding potassium borohydride and 45% - 55% by mass of the hydroxide into isopropanol simultaneously, starting the reflux reaction, and reacting for 1.0 - 1.2 hours; The second stage: Slowly adding the remaining hydroxide in the form of solid powder, with an addition rate ≤ 0.5 g / min; The hydroxide includes sodium hydroxide.

2. The preparation process of pharmaceutical-grade isopropanol according to claim 1, characterized in that, In step S100, the mass ratio of potassium borohydride to the hydroxide is 1:0.8 - 1.

1.

3. The preparation process of pharmaceutical-grade isopropanol according to claim 1, characterized in that, In the first stage, the temperature is 80 - 85 °C, sodium hydroxide and potassium borohydride are mixed by dry method and then added into isopropanol, and the particle size of sodium hydroxide is 100 - 200 mesh.

4. The preparation process of pharmaceutical-grade isopropanol according to claim 1, characterized in that, When adding sodium hydroxide in the second stage, the reaction temperature drops to 70 - 75 °C. After the addition is completed, the temperature is raised to 80 - 83 °C at a rate of 0.5 - 1.0 °C / min and continue to react.

5. The preparation process of pharmaceutical-grade isopropanol according to claim 1, characterized in that, In step S100, the hydroxide also includes potassium hydroxide, and the molar ratio of potassium hydroxide to sodium hydroxide is 1:3 - 5.

6. The preparation process of pharmaceutical-grade isopropyl alcohol according to claim 5, characterized in that, The particle size of the potassium hydroxide is ≤ 200 mesh, and the addition timing is 5 - 10 minutes before adding potassium borohydride.

7. The preparation process of pharmaceutical-grade isopropanol according to claim 1, characterized in that, In step S200, the reflux reaction temperature is 81 - 83 °C, the reaction time is 3.8 - 4.2 hours, and the pH of the reaction system ≥ 12.

8. The preparation process of pharmaceutical-grade isopropanol according to claim 1, characterized in that, In step S300, the discarded amount of the pre-fraction is 5% - 8% of the raw material volume; the collected volume of the middle fraction is 85% - 90% of the raw material volume; the proportion of the still residue ≤ 10%, and the still temperature is 95 - 105 °C.

9. The preparation process of pharmaceutical-grade isopropanol according to claim 1, characterized in that, The detection includes ultraviolet absorbance detection and potassium permanganate oxidation detection.

10. The preparation process of pharmaceutical-grade isopropanol according to claim 9, characterized in that, The wavelength range of the ultraviolet light is 230 - 310 nm.

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