A method for preparing sodium nitroprusside raw material

Abstract

This invention belongs to the field of pharmaceutical synthesis technology and discloses a method for preparing sodium nitroprusside raw material. The method employs weak acid catalysis and significantly reduces the generation of toxic substances such as cyanide and nitrogen dioxide by controlling the material dropping rate and pH. The reaction is mild, the process is safe and controllable, and it facilitates the industrial production of sodium nitroprusside raw material. In some examples of the preparation method, silica gel filtration is used in the post-processing to reduce the residual risk of impurities such as sodium ferrocyanide, ferrous ferrocyanide, and ferric ferric ferrocyanide. The purity of the raw material is ≥99.9%, far exceeding the requirements of pharmacopoeias of various countries.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing sodium nitroprusside raw material. Background Technology

[0002] Sodium nitroprusside (molecular formula Na2[Fe(CN)5NO]·2H2O, molecular weight 297.95, CAS: 13755-38-9), chemically named sodium nitroprusside dihydrate, is a fast-acting and short-duration vasodilator used clinically for hypertensive emergencies and acute heart failure.

[0003] Sodium nitroprusside raw material is currently included in the Chinese Pharmacopoeia (ChP), the European Pharmacopoeia (EP), and the United States Pharmacopoeia (USP).

[0004] Page 1505 of the Annotations to Part II of the Pharmacopoeia of the People's Republic of China (2015 Edition) outlines the preparation method of sodium nitroprusside as follows: iron filings are added to hydrochloric acid to produce ferrous chloride, which is then reacted with cyanide (such as sodium cyanide) and sodium nitrite. This route uses highly toxic cyanide, and the reaction produces toxic nitric oxide gas, making it unsuitable for the safe production of the active pharmaceutical ingredient sodium nitroprusside.

[0005] Currently, the methods for preparing sodium nitroprusside raw materials reported in publicly available domestic and international literature include:

[0006] 1) Potassium nitrate salt transfer method

[0007] Chinese patent application CN201110406273.2 discloses a synthesis process for sodium nitroprusside. The method uses potassium nitroprusside (potassium nitroprusside) as raw material, first converting it to copper nitroprusside (copper nitroprusside) via copper sulfate, and then converting it to sodium nitroprusside (sodium nitroprusside) via sodium bicarbonate. This route is only a salt conversion process and does not involve any substantial chemical reaction. It cannot meet the requirements for quality control of active pharmaceutical ingredients, and the sodium nitroprusside obtained has a content of only about 95%, which is not suitable for the production of active pharmaceutical ingredient sodium nitroprusside.

[0008] Chinese patent application CN202111260924.1 improved the above-mentioned salt conversion process, still using potassium nitroprusside (potassium nitroprusside) as raw material, and directly converting sodium nitroprusside (sodium nitroprusside) to sodium nitroprusside via sodium iodide. The single-step salt conversion process cannot meet the current requirements for the quality control of active pharmaceutical ingredients and is not suitable for the production of sodium nitroprusside.

[0009] 2) Nitrification with concentrated nitric acid

[0010] The Chemical Society of Japan disclosed the synthetic route of sodium nitroprusside (i.e., sodium nitroprusside) in Volume 3, page 204 of the "Handbook of Inorganic Compound Synthesis" published in 1988. The route uses potassium ferrocyanide trihydrate as raw material, reacts it with concentrated nitric acid in water for 1-2 days, then neutralizes it with sodium carbonate, adds ethanol to remove impurities, and then filters, concentrates, and crystallizes to obtain sodium nitroprusside.

[0011] The literature Z. Anorg. Allg. Chem. 2001(627):1663-1668 discloses a method for preparing sodium nitroprusside, which uses potassium ferrocyanide and nitric acid as raw materials to carry out a nitrosation reaction, and then uses sodium carbonate to adjust the alkalinity to obtain sodium nitroprusside.

[0012] Chinese patent application CN201810638263.3 discloses a method for preparing sodium nitroprusside, using potassium ferrocyanide trihydrate as raw material, reacting it with concentrated nitric acid in water to generate hydrogen nitroprusside (H2[Fe(CN)5NO]), followed by filtration, neutralization, concentration, and crystallization to obtain sodium nitroprusside. CN201910585001.X, based on the aforementioned process, first neutralizes hydrogen nitroprusside to copper nitroprusside, then refines it before converting it to sodium nitroprusside, improving impurity removal and obtaining sodium nitroprusside with a purity of over 99%. CN202210009167.9, based on the aforementioned process, adds glacial acetic acid backwashing during crystallization to enhance inorganic salt removal. CN202310340400.6, based on the aforementioned process, adds trisodium citrate and vitamin C for neutralization reaction during post-treatment.

[0013] The inventors reproduced the concentrated nitric acid nitrosation process and found that the reaction between potassium ferrocyanide and concentrated nitric acid in this route is extremely vigorous, with severe secondary exothermic reactions during the temperature rise. The reaction produces a large amount of toxic yellow-brown nitrogen dioxide gas, and high concentrations of cyanide were detected in the mother liquor, making it unsuitable for current safety and environmental protection requirements. The low conversion rate and high impurity content of the crude product from the nitrosation reaction are also detrimental to the industrial production of the active pharmaceutical ingredient, sodium nitroprusside.

[0014] 3) Catalytic nitrification method

[0015] Chinese patent application CN202111324863.0 discloses a method for preparing sodium nitroprusside. Using potassium ferrocyanide trihydrate as a raw material, it reacts with sodium nitrite under the catalysis of ultrafine copper powder to obtain crude sodium nitroprusside. This crude product is then refined by salt conversion to copper nitroprusside, and finally converted to sodium nitroprusside via sodium bicarbonate. This route uses nanoscale ultrafine copper powder (1–100 nm) as a catalyst. However, nanoscale ultrafine copper powder is expensive and commercially unavailable, making it unsuitable for large-scale industrial production.

[0016] Table 1 summarizes and compares the preparation methods of sodium nitroprusside API reported in currently available domestic and international literature:

[0017] Table 1. Summary and Comparison of Existing Methods for Preparing Sodium Nitroprusside API

[0018]

[0019] Currently, the mainstream preparation process for sodium nitroprusside is the nitrosation reaction of potassium ferrocyanide trihydrate. Chemically, the reaction of introducing a nitroso group onto a carbon atom of an aromatic or heterocyclic ring is called nitrosation. Commonly used nitrosation reaction conditions are recorded in representative books in this industry, such as "Fine Organic Synthesis Chemistry and Technology" by Tang Peikun (ISBN: 7-5618-1829-7), which lists common nitrosation reaction conditions as sodium nitrite / dilute sulfuric acid and sodium nitrite / dilute hydrochloric acid; and "Drug Synthesis Reactions" by Xin Bingwei (ISBN: 9787122334022), which lists common nitrosation reaction conditions as sodium nitrite / dilute sulfuric acid, sodium nitrite / dilute hydrochloric acid, or nitrous acid. The reaction is usually carried out at low temperatures because nitrous acid, formed by the reaction of nitrite with acid, is unstable and easily decomposes at high temperatures.

[0020] Currently, the mainstream synthesis process for sodium nitroprusside API is nitrosation with concentrated nitric acid. Nitrification and nitrosation reactions are among the first batch of hazardous chemical processes under key supervision by the State Administration of Work Safety, requiring special attention to their reaction safety risks. Currently published literature processes all involve violent reaction processes, significant secondary exothermic reactions during the temperature rise, and the production of highly toxic byproducts, posing a high risk of explosions, leaks, and poisoning during production, and thus failing to meet current safety and environmental protection requirements. Summary of the Invention

[0021] The purpose of this invention is to overcome at least one deficiency of the prior art and provide a safe and environmentally friendly process for preparing sodium nitroprusside. This process does not employ the commonly reported nitric acid method, or the commonly used sodium nitrite, hydrochloric acid, or sulfuric acid method. This invention uses a weak acid catalyst (such as acetic acid) and controls the material dropping rate and pH to significantly reduce the generation of toxic substances such as cyanide and nitrogen dioxide. Furthermore, the reaction is mild, the process is safe and controllable, and it facilitates the industrial production of sodium nitroprusside raw materials.

[0022] The technical solution adopted in this invention is:

[0023] A method for preparing sodium nitroprusside raw material includes the following steps:

[0024] Dissolve ferrocyanide in water, add a weak acid to pre-adjust the pH to 3.8-4.5 to obtain a ferrocyanide solution;

[0025] A weak acid and sodium nitrite solution were added to a ferrocyanide salt solution, respectively, and the addition rate was controlled to keep the pH of the reaction system between pH 4.0 and 5.0 to carry out the nitrosation reaction.

[0026] After the reaction is complete, the solution is cooled, neutralized, filtered to remove impurities, concentrated, purified, and dried to obtain sodium nitroprusside raw material.

[0027] In some instances, the reaction temperature is 70–100°C.

[0028] In some instances, the reaction temperature is 75–85°C.

[0029] In some instances, the concentration of the ferrocyanide salt solution is 0.5–2.0 mol / L.

[0030] In some instances, the ferrocyanide salt is selected from at least one of sodium ferrocyanide, anhydrous form or hydrate of potassium ferrocyanide.

[0031] In some instances, the concentration of the sodium nitrite solution is 2.0–4.0 mol / L.

[0032] In some instances, the weak acid is selected from acetic acid, formic acid, propionic acid, and trifluoroacetic acid.

[0033] In some instances, the purification method is recrystallization.

[0034] In some instances, the solvent used in the recrystallization method is an aqueous solution of methanol.

[0035] In some instances, post-processing uses silica gel filtration to remove impurities, with the silica gel powder used being 100–300 mesh.

[0036] The above features can be combined arbitrarily as long as they do not conflict with each other.

[0037] The beneficial effects of this invention are:

[0038] The preparation methods of some examples of the present invention, in the nitrosation reaction, use a weak acid to control the pH of the reaction, making the reaction mild and controllable, and can significantly reduce the generation of toxic substances such as hydrogen cyanide and nitrogen dioxide, significantly reducing the safety risks of the reaction, and facilitating the industrial production of sodium nitroprusside raw material.

[0039] The preparation methods of some examples of this invention use silica gel filtration in the post-processing to reduce the residual risk of impurities such as sodium ferricyanide, ferrous ferrocyanide, and ferric ferricyanide, and the purity of the raw material is ≥99.9%, which is far superior to the requirements of pharmacopoeias of various countries. Attached Figure Description

[0040] Figure 1 This is the HPLC chromatogram of related substance A of sodium nitroprusside prepared in Example 1.

[0041] Figure 2 This is the HPLC chromatogram of sodium nitroprusside B prepared in Example 1.

[0042] Figure 3 This is the HPLC chromatogram of sodium nitroprusside A prepared in Example 2.

[0043] Figure 4 The image shows the HPLC chromatogram of sodium nitroprusside B prepared in Example 2.

[0044] Figure 5 The image shows the HPLC chromatogram of related substance A of sodium nitroprusside prepared in Example 3.

[0045] Figure 6 The image shows the HPLC chromatogram of sodium nitroprusside B prepared in Example 3.

[0046] Figure 7 The image shows a comparative HPLC chromatogram of the nitrosation reaction system in Example 7.

[0047] Figure 8 This is an HPLC comparison chromatogram of the pH values ​​for the addition of materials and the reaction in Example 8.

[0048] Figure 9 This is an HPLC comparison chart of the reaction temperatures in Example 9.

[0049] Figure 10 This is a DCS test diagram of the safety risk assessment of the nitrosation reaction in Example 10.

[0050] Figure 11 This is the RC1 test diagram for the safety risk assessment of the nitrosation reaction in Example 10.

[0051] Figure 12 This serves as the assessment criterion for the acceptability of runaway reactions in Example 10. Detailed Implementation

[0052] A method for preparing sodium nitroprusside raw material includes the following steps:

[0053] Dissolve ferrocyanide in water, add a weak acid to pre-adjust the pH to 3.8-4.5 to obtain a ferrocyanide solution;

[0054] A weak acid and sodium nitrite solution were added to a ferrocyanide salt solution, respectively, and the addition rate was controlled to keep the pH of the reaction system between pH 4.0 and 5.0 to carry out the nitrosation reaction.

[0055] After the reaction is complete, the solution is cooled, neutralized, filtered to remove impurities, concentrated, purified, and dried to obtain sodium nitroprusside raw material.

[0056] In some instances, the reaction temperature is 70–100°C. This allows for faster nitrosation and also facilitates the conversion of sodium nitroprusside.

[0057] In some instances, the reaction temperature was 75–85°C. Experimental data showed that within this temperature range, sodium nitroprusside achieved higher conversion rates, lower impurity content, and simpler subsequent purification processes.

[0058] In some instances, the concentration of the ferrocyanide salt solution is 0.5–2.0 mol / L. This is more conducive to the reaction.

[0059] In some instances, the ferrocyanide salt is selected from at least one of sodium ferrocyanide, anhydrous form or hydrate of potassium ferrocyanide.

[0060] In some instances, the concentration of the sodium nitrite solution is 2.0–4.0 mol / L. This is more conducive to the reaction.

[0061] In some instances, the weak acid is selected from acetic acid, formic acid, propionic acid, and trifluoroacetic acid. Acetic acid is a better choice due to its low cost and high safety.

[0062] In some instances, the purification method is recrystallization. Recrystallization is simple to operate and yields good purification results.

[0063] In some instances, the solvent used in the recrystallization method is an aqueous solution of methanol. Preferably, the volume concentration of methanol in the aqueous solution is 60–80%.

[0064] In some instances, post-processing uses silica gel filtration to remove impurities, with the silica gel powder used being 100–300 mesh.

[0065] In some instances, the purification operation specifically includes:

[0066] The concentrated filtrate was cooled to allow crystallization, yielding filtrate 1.

[0067] Filter solid 1 was dissolved in an aqueous methanol solution, heated and stirred until dissolved, filtered through silica gel, the filtrate was concentrated, cooled and crystallized to obtain filter solid 2;

[0068] Filter solid 2 was added to water, and crystallization was performed to obtain crude sodium nitroprusside;

[0069] Sodium nitroprusside crude product is added to water and heated to dissolve. Methanol is added after cooling. The mixture is then filtered, concentrated, cooled to crystallize, and dried to obtain sodium nitroprusside raw material.

[0070] The above features can be combined arbitrarily as long as they do not conflict with each other.

[0071] The technical solution of the present invention will be further illustrated below with examples.

[0072] The purity and related substances of the sodium nitroprusside were determined by high performance liquid chromatography (HPLC), following the methods described in United States Pharmacopeia (USP) 2025, under the following conditions:

[0073] Related substance A (ferrocyanide and other related substances):

[0074] Instrument Model: Shimadzu LC-20AD High Performance Liquid Chromatograph

[0075] Column: Inert sustain swift C18 (250×4.6mm, 5μm)

[0076] Mobile phase: Buffer (dissolve approximately 6.80 g of potassium dihydrogen phosphate in 500 mL of water, then add 1.0 g of tetrabutylammonium hydrogen sulfate to dissolve, dilute with water to 1000 mL, adjust the pH to 7.2 ± 0.1 with 25% tetrabutylammonium hydroxide methanol solution, and shake well) - acetonitrile (70:30)

[0077] Detection wavelength: 220 nm; Flow rate: 0.8 mL / min; Column temperature: 25 °C; Injection volume: 10 μL;

[0078] Quantitative method: External standard method.

[0079] Relevant substance B (ferricyanide):

[0080] Instrument Model: Shimadzu LC-20AD High Performance Liquid Chromatograph

[0081] Column: Waters Xterra Phenyl (250×4.6mm, 3.5μm)

[0082] Mobile phase: Buffer (dissolve approximately 6.80 g of potassium dihydrogen phosphate in 900 mL of water, add 2.0 g of tetrabutylammonium hydrogen sulfate, sonicate to dissolve, adjust the pH to 7.5 with 40% tetrabutylammonium hydroxide solution, dilute with water to 1000 mL, and shake well) - Acetonitrile (73:27)

[0083] Detection wavelength: 210 nm; Flow rate: 1 mL / min; Autosampler temperature: 5 °C; Injection volume: 10 μL;

[0084] Quantitative method: External standard method.

[0085] The cyanide (hydrogen cyanide) was determined by gas chromatography (GC) under the following conditions:

[0086] Instrument Model: Agilent 7890B Gas Chromatograph

[0087] Column: Agilent DB-WAX (30m × 0.52mm, 1μm)

[0088] Detector: Electron Capture Detector (ECD)

[0089] Inlet temperature: 200℃

[0090] Detector temperature: 300℃

[0091] Flow split ratio: 5:1

[0092] Flow rate: 1 mL / min

[0093] Temperature program: Start at 40℃, maintain for 5 minutes, then increase to 200℃ at a rate of 30℃ per minute, and maintain for 4 minutes.

[0094] Headspace equilibrium temperature: 50℃

[0095] Headspace balancing time: 20 minutes

[0096] Metering loop temperature: 90℃

[0097] Transmission line temperature: 100℃

[0098] Quantitative method: External standard method.

[0099] Example 1

[0100] 45 kg of sodium ferrocyanide decahydrate was dissolved in 90 kg of water. The mixture was heated to 80 °C, and sodium nitrite aqueous solution (25.65 kg of sodium nitrite dissolved in 90 kg of water) and acetic acid were added dropwise at the rates shown in Table 2. The pH of the reaction system was controlled to be 4–5.

[0101] Table 2. Material Dropping Details

[0102]

[0103] After the addition was complete, the reaction was continued at 80℃ for 4 hours, and the reaction was monitored by HPLC. The temperature was lowered to room temperature, 9.3 kg of anhydrous sodium carbonate was added for neutralization, the mixture was filtered through silica gel, the filtrate was concentrated to 1 / 3 of its original volume, cooled to 20-30℃ to crystallize, and centrifuged to obtain filtrate 1.

[0104] Filter solid 1 was added to 56 kg of water and 149.8 kg of methanol, kept at 60 °C in the dark and stirred for 1 h, cooled to room temperature, filtered through silica gel, concentrated the filtrate to about 60 kg, cooled to 5 °C to crystallize, and centrifuged to obtain Filter solid 2.

[0105] Filter solid 2 was added to 15 kg of water, stirred at 90 °C in the dark for 1 h, cooled to 5 °C to crystallize, and centrifuged to obtain crude sodium nitroprusside, which was divided into 21 kg after water removal, with a yield of 75%.

[0106] Crude sodium nitroprusside was added to 42 kg of water and heated to 90 °C to dissolve. 50 g of activated carbon was added for decolorization for 1 h. The mixture was cooled to room temperature, and 85 kg of methanol was added. The mixture was filtered into a clean area and concentrated until about 30 kg remained. The mixture was cooled to 5 °C to crystallize, centrifuged, and dried to obtain about 16 kg of reddish-brown crystalline powder (yield about 77%).

[0107] The HPLC chromatogram of related substance A (purity, ferrocyanide) for sodium nitroprusside is shown below. Figure 1 The HPLC chromatogram of related substance B (ferricyanide) of sodium nitroprusside is shown in [reference needed]. Figure 2 As shown in the figure, the purity was calculated using the sodium nitroprusside peak area according to the external standard method: 99.98%, 0.002% ferrocyanide, and 0.0007% ferricyanide.

[0108] Example 2

[0109] 5 kg of sodium ferrocyanide decahydrate is dissolved in 10 kg of water. The mixture is heated to 80°C, and sodium nitrite aqueous solution (2.85 kg of sodium nitrite dissolved in 10 kg of water) and acetic acid are added dropwise at the rates shown in Table 3, controlling the pH of the reaction system to be 4–5.

[0110] Table 3. Material Dropping Details

[0111]

[0112] After the addition was complete, the reaction was continued at 80℃ for 4 hours, and the reaction was monitored by HPLC. The temperature was lowered to room temperature, 1.1 kg of anhydrous sodium carbonate was added for neutralization, the mixture was filtered through silica gel, the filtrate was concentrated to 1 / 3 of its original volume, cooled to 20-30℃ to crystallize, and centrifuged to obtain filtrate 1.

[0113] Filter solid 1 was added to 5.75 kg of water and 16.7 kg of methanol, kept at 60 °C in the dark and stirred for 1 h, cooled to room temperature, filtered through silica gel, concentrated the filtrate to about 5.5 kg, cooled to 5 °C to crystallize, and centrifuged to obtain filter solid 2.

[0114] Filter solid 2 was added to 1.2 kg of water, kept at 90°C in the dark and stirred for 1 hour, then cooled to 5°C to crystallize, and centrifuged to obtain crude sodium nitroprusside, which yielded 1.87 kg after water removal, with a yield of 60.8%.

[0115] Crude sodium nitroprusside was added to 3.4 kg of water and heated to 90 °C to dissolve. 9.4 g of activated carbon was added for decolorization for 1 h. The mixture was cooled to room temperature, and 6.5 kg of methanol was added. The mixture was filtered into a clean area and concentrated until about 2 kg remained. The mixture was cooled to 5 °C to crystallize, centrifuged, and dried to obtain about 1.3 kg of reddish-brown crystalline powder (yield about 69.5%).

[0116] The HPLC chromatogram of related substance A (purity, ferrocyanide) for sodium nitroprusside is shown below. Figure 3 The HPLC chromatogram of related substance B (ferricyanide) of sodium nitroprusside is shown in [reference needed]. Figure 4 As shown in the figure, the purity was calculated using the sodium nitroprusside peak area according to the external standard method: 99.93%, 0.0032% ferrocyanide, and 0.0008% ferricyanide.

[0117] Example 3

[0118] 200g of potassium ferrocyanide trihydrate was dissolved in 400g of water, heated to 85℃, and 4g of acetic acid was added dropwise to adjust the pH to 4.0. 514g of sodium nitrite solution (22.2% by mass) was added dropwise at a uniform rate over 9.5h, while 145g of acetic acid was added dropwise to maintain the pH at 4.0-5.0 throughout the process. After the addition was complete, the reaction was maintained at 85℃ for 4h, and the reaction was monitored by HPLC. The mixture was cooled to room temperature, and 40g of anhydrous sodium carbonate was added for neutralization. The neutralized reaction solution was filtered through silica gel, and the filtrate was concentrated to 1 / 3 of its original volume. The solution was cooled to 20-30℃ to crystallize, and centrifuged to obtain filtrate 1.

[0119] Add 228g of water and 589g of methanol to Filter Solid 1, keep warm at 60℃ in the dark and stir for 1 hour, cool to room temperature, filter with silica gel, concentrate the filtrate to about 220g remaining, cool to 5℃ to crystallize, and centrifuge to obtain Filter Solid 2.

[0120] Add 53g of water to the filtered solid 2, keep it at 90℃ in the dark and stir for 1 hour, cool to 5℃ to precipitate crystals, centrifuge to obtain crude sodium nitroprusside, which has a water content of 72.6g, yield 59.0%;

[0121] Crude sodium nitroprusside was added to 130g of water and heated to 90℃ to dissolve. 0.4g of activated carbon was added for decolorization for 1 hour. The mixture was cooled to room temperature, and 254g of methanol was added. The mixture was filtered into a clean area and concentrated to about 80g. The mixture was cooled to 5℃ to crystallize, centrifuged, and dried to obtain 53.3g of reddish-brown crystalline powder (yield about 73.4%).

[0122] The HPLC chromatogram of related substance A (purity, ferrocyanide) for sodium nitroprusside is shown below. Figure 5 The HPLC chromatogram of related substance B (ferricyanide) of sodium nitroprusside is shown in [reference needed]. Figure 6 As shown in the figure, the purity was calculated using the peak area of ​​sodium nitroprusside by the external standard method: 99.95%, 0.0014% ferrocyanide, and 0.0017% ferricyanide.

[0123] Example 4

[0124] The feeding ratio and post-processing method were the same as in Example 3, except that formic acid was used as a catalyst to obtain sodium nitroprusside with a purity of 99.97%, no ferrocyanide was detected, and ferrocyanide was 0.00005%.

[0125] Example 5

[0126] The feeding ratio and post-processing method of Example 3 are the same, except that propionic acid is used as a catalyst to obtain sodium nitroprusside with a purity of 99.96%, ferrocyanide of 0.003%, and ferricyanide of 0.0008%.

[0127] Example 6

[0128] The feeding ratio and post-processing method in Example 3 are the same, except that trifluoroacetic acid is used as a catalyst to obtain sodium nitroprusside with a purity of 99.96%, ferrocyanide of 0.004%, and ferricyanide of 0.0010%.

[0129] Example 7: Comparison of nitrosation reaction systems

[0130] Nitric acid system: Refer to the conditions of Example 1 in patent CN201810638263.3

[0131] Sodium nitrite / sulfuric acid, sodium nitrite / hydrochloric acid: The conventional nitrosation reaction conditions reported by Xin Bingwei in *Pharmaceutical Synthesis Reactions* were used, with the reaction temperature set at 90℃ according to CN201810638263.3. HPLC comparisons were performed, for example... Figure 7 As shown, Figure 7 From top to bottom, the table shows the preparation process of Example 1 of this invention, the sodium nitrite / hydrochloric acid nitrosation reaction, the conditions of Example 1 under CN201810638263.3, and the HPLC curves of the sodium nitrite / sulfuric acid nitrosation reaction. Comparative results are shown in Table 4.

[0132] Table 4. Comparison of different nitrosation reaction systems

[0133]

[0134] As shown in Table 4, compared with the disclosed nitrosation reaction conditions, the conditions of this invention (Example 1) have a higher raw material conversion rate, a purity of approximately 80% in the reaction solution (excluding sodium nitrite, solvent, and other base materials), and fewer impurities; no brown-red gases such as nitrogen dioxide are generated during the reaction process, and the production of cyanide is significantly reduced. The reaction conditions of this invention significantly improve the safety of the reaction compared with the disclosed literature conditions.

[0135] Example 8: Effect of Feeding and Reaction pH on the Preparation of Sodium Nitroprusside

[0136] This example compares the effects of the feeding process and pH control during the reaction process on the preparation of sodium nitroprusside (other conditions such as feed ratio, reaction temperature, time, etc. are the same as in Example 1). The results, obtained by HPLC, show that... Figure 8 As shown, Figure 8 The HPLC curves from top to bottom are for pH 4–5, pH 5–6, and pH 6–7. The data are shown in Table 5.

[0137] Table 5. Effect of reaction pH on the preparation of sodium nitroprusside

[0138]

[0139] As shown in Table 5, controlling the pH of the reaction system at 4-5 results in the optimal product conversion rate and the lowest impurity content. As the pH increases, the proportion of sodium nitroprusside decreases significantly. Since acetic acid is relatively weak, the feeding and reaction process is relatively mild, and the pH control range of 4-5 is preferred.

[0140] Example 9: Effect of reaction temperature on the preparation of sodium nitroprusside

[0141] This example compares the effect of reaction temperature on the preparation of sodium nitroprusside (other conditions such as feed ratio, feed addition, reaction pH, and time are the same as in Example 1). The results, obtained by HPLC, show that... Figure 9 As shown, Figure 9 The HPLC curves from top to bottom are for 50℃, 60℃, 70℃, and 80℃. The results are shown in Table 6.

[0142] Table 6. Effect of reaction temperature on the preparation of sodium nitroprusside

[0143]

[0144] As shown in Table 6, increasing the reaction temperature is beneficial to the conversion of the reaction. The preferred reaction temperature is 70-100℃. Based on the calorimetric ARC and RC1 tests of the nitrosation reaction, the reaction temperature should not exceed 85℃, and is preferably 80±5℃.

[0145] Example 10: Reaction safety risk test of the nitrosation reaction in the preparation method of the present invention

[0146] The reaction safety risk assessment of the preparation method of this invention includes assessment of the heat of decomposition of substances, severity assessment, probability assessment, and process reaction hazard assessment. The assessment method is based on the industry consensus standard "GB / T 42300-2022 Standard for Reaction Safety Risk Assessment of Fine Chemicals".

[0147] Test 1: Heat of Decomposition of Substances Test

[0148] The heat of decomposition is the energy released when a substance decomposes. The explosiveness of a material is assessed based on the heat of decomposition, and it is divided into four levels, as shown in Table 7.

[0149] Table 7. Explosiveness Classification of Materials

[0150]

[0151] Based on the material stability test results of the nitrosation reaction liquid (see attached) Figure 10In the nitrosation reaction solution prepared by the present invention, two small-scale exothermic processes occurred within the detection range up to 400℃. The first exothermic temperature range was 180.72℃~220.60℃, with a decomposition heat of 67.79J / g; the second exothermic temperature range was 282.90℃~329.06℃, with a decomposition heat of 50.33J / g. The decomposition temperature was higher than the reaction temperature T. p It releases little heat, has a decomposition heat level of 1, and has a low potential explosion risk.

[0152] Test 2: Severity Assessment Test for Out-of-Control Response

[0153] Utilizing adiabatic temperature rise ΔT ad The severity of the out-of-control reaction was assessed and divided into four levels, as shown in Table 8.

[0154] Table 8. Severity Grading Table for Runaway Reactions

[0155]

[0156] Based on the RC1 test results of the nitrosation reaction solution (see attached) Figure 11 The heat released during the reaction is Q. A It is 70.41 kJ, ΔT ad =Q A / (M) r ×C pr =23.50K, ≤50 and no pressure affects the reaction process, the severity level is 1, and the potential risk is low.

[0157] Test 3: Assessment Test of the Probability of Uncontrolled Reactions

[0158] The likelihood of a runaway reaction is assessed based on the time it takes to reach the maximum reaction rate, and is divided into four levels, as shown in Table 9.

[0159] Table 9. Randomization of Reaction

[0160]

[0161] Based on the DSC and RC1 test results of the nitrosation reaction solution (see attached) Figure 10 Appendix Figure 11 The highest temperature reached during the reaction process was MTSR 108.50℃, and the decomposition temperature T of the nitrosation reaction solution was determined by DSC testing. onse =180.72℃, T is calculated theoretically using the Semenov formula. D24 =122.90℃, which is greater than Tp and MTSR; within the highest temperature range of the process temperature and the synthesis system, the possibility of the material initiating a secondary decomposition reaction is low, the possibility of runaway reaction is level 1, and the potential risk is low.

[0162] Test 4: Assessment Test of the Probability of Uncontrolled Reactions

[0163] A matrix is ​​constructed based on the likelihood and severity of runaway reactions to assess the acceptability of runaway reactions, categorized as follows: Figure 12 The four levels are shown.

[0164] According to Test 2: Severity Assessment Test of Runaway Reaction and Test 3: Probability Assessment Test of Runaway Reaction, both are Level I. Therefore, the runaway level of the nitrosation process reaction in this invention is Level I, indicating low potential risk.

[0165] Test 5: Process Hazard Test

[0166] The hazard level of the reaction process is assessed in stages, using the process operating temperature Tp, the maximum technical temperature MTT, and the temperature T corresponding to the time to reach the maximum reaction rate of the runaway system in 24 hours as the time to reach the maximum reaction rate TMRad. D24 The maximum temperature (MTSR) that the runaway system may reach is assessed and divided into 5 levels, as shown in Table 10.

[0167] Table 10. Reaction Process Hazard Grouping Table

[0168]

[0169] When the process hazard level is 4 or 5, the risk is high, and production is generally prohibited under safety and environmental protection policies; when the process hazard level is 3 or below, production is permissible under certain engineering conditions, and the potential process safety risks are controllable. Based on the DCS, ARC, and RC1 test results of the nitrosation reaction liquid ( Figure 10 , Figure 11 The maximum operating temperature Tp of this invention is 85°C, the highest technical temperature MTT is 100°C, and the time to reach the maximum reaction rate of the runaway system (TMRad) is the temperature T corresponding to 24 hours. D24 The highest possible temperature (MTSR) that the runaway system could reach is 108.50℃. p <MTT<MTSR<T D24 The nitrosation reaction process of this invention has a reaction hazard level of 3, and the potential risks are acceptable.

[0170] The above is a further detailed description of the present invention and should not be considered as a limitation on the specific implementation of the present invention. For those skilled in the art, simple deductions or substitutions without departing from the concept of the present invention are all within the protection scope of the present invention.

Claims

1. A process for the preparation of sodium nitroprusside bulk drug substance, characterized in that, The method comprises the following steps: 45 kg of sodium ferrocyanide decahydrate is dissolved in 90 kg of water, and the temperature is raised to 80°C, and 900 g of acetic acid is added to adjust the pH to 3.8-4.5; 25.65 kg of sodium nitrite is dissolved in 90 kg of water to obtain a sodium nitrite solution; The acetic acid and the sodium nitrite solution are added to the ferrocyanide salt solution, wherein the sodium nitrite solution is added at a speed of 11.5-14.5 kg of solution per hour, and the acetic acid is added at a speed of 3.5-4.6 kg of acetic acid per 0.5 hour for 14 kg of acetic acid, and then 2.3-3 kg of acetic acid per hour for 18.4 kg of acetic acid, so that the pH of the reaction system is 4.0-5.0, and the nitrosation reaction is carried out at a temperature of 80°C; After the dropping is completed, the reaction is continued at 80°C for 4 hours, and HPLC is used to monitor the completion of the reaction; After the reaction is completed, the temperature is lowered, neutralization is carried out, impurities are removed by filtration, the filtrate is concentrated, purified, and dried to obtain sodium nitroprusside raw material medicine.

2. The production method according to claim 1, characterized by, The purification method is a recrystallization method.

3. The preparation method according to claim 2, characterized in that, The solvent used in the recrystallization method is a methanol aqueous solution.

4. The production method according to claim 2 or 3, characterized by, Silica gel is used for filtration for impurity removal in the post-treatment, and the silica gel powder used is 100-300 mesh.

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