Method for preparing high-purity sildenafil intermediate

Abstract

The invention relates to a preparation method of a sildenafil intermediate, and belongs to the field of pharmaceutical chemicals. A compound 4 is obtained through a nucleophilic substitution reaction of a compound 3 and a chlorosulfonation reagent, and generation of a regional impurity M4-01 is fundamentally avoided by adopting a strategy that the position of an ethyoxyl para-position of the compound 3 is occupied in advance. According to the preparation method, the intermediate is stable, the reaction condition avoids ultralow temperature, and the energy consumption is reduced; use of chlorosulfonic acid is avoided, and the process is green and environment-friendly; the post-treatment quenching operation is simple and convenient; the total yield can reach 90% or above, and the method is more suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical industry and relates to a method for preparing an intermediate of sildenafil citrate, a drug for treating erectile dysfunction. Background Technology

[0002] Sildenafil, also known as Sildenafil, was initially used to treat cardiovascular diseases. Through long-term clinical research, it was unexpectedly discovered that sildenafil could significantly improve patients' quality of life regarding sexual function. Pfizer, relying on clinical trials, ultimately confirmed the significant efficacy of sildenafil in treating erectile dysfunction (ED). Pfizer first launched sildenafil on the market in April 1998 under the brand name Viagra. Since its launch, sildenafil has quickly become one of the best-selling drugs in the United States, with its efficacy and safety recognized by the market. In October 2014, Guangzhou Baiyunshan's Jinge brand was successfully launched, further expanding the market size for sildenafil raw materials. To meet the market demand for sildenafil raw materials, process research on sildenafil to produce high-purity sildenafil raw materials has significant socio-economic value and great market potential.

[0003] Sildenafil's chemical name is 1-{4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1-hydro-pyrazolo[4,3d]pyrimidin-5-yl)benzenesulfonyl}-4-methylpiperazine, with the structural formula [insert structural formula here].

[0004] The earliest reported method for synthesizing sildenafil was in US patent 5250534A by Pfizer Inc., which involved a condensation reaction of 1-methyl-3-propyl-4-aminopyrazole-5-carboxamide with 2-ethoxybenzoyl chloride, followed by cyclization and chlorosulfonation, and then reacting with N-methylpiperazine to generate sildenafil.

[0005]

[0006] 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (CAS: 139756-22-2) is a key intermediate in the production of sildenafil.

[0007]

[0008] In the preparation of intermediate 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (CAS: 139756-22-2) under US5250534A, it was found that the amount of chlorosulfonic acid used was as high as 10 equivalents, resulting in a large amount of hydrogen chloride gas generated during production, making production difficult and easily generating impurity M4-01 (retention time approximately 22 min). The content of impurity M4-01 exceeded 2%, and in conventional processes, M4-01 can reach 2-3%, with some batches even reaching around 5%, posing difficulties for subsequent impurity removal and creating significant environmental pressure, directly affecting the quality and yield of sildenafil citrate API production. The removal effect during the subsequent reaction with N-methylpiperazine was poor, requiring multiple purification processes to meet quality requirements. The number and content of other impurities were also high. However, the impurity limits specified in the pharmacopoeia are all no higher than 0.1%. Furthermore, this step involves a reaction time of over 24 hours, generating a large amount of hydrogen chloride waste gas during quenching, resulting in low production efficiency, extremely low economic viability, and a highly unfriendly environment. The process for introducing impurity M4-01 is as follows:

[0009] The paper "Synthesis of Sildenafil Citrate, Gong et al., Journal of Shenyang Pharmaceutical University, Vol. 19, No. 3, pp. 173-175, 191" discloses a sulfonation method involving the addition of approximately 10 equivalents of chlorosulfonic acid without the addition of thionyl chloride. Patent CN11111591A discloses a method for preparing sildenafil, which reduces the formation of M4-01 during sulfonation by not adding thionyl chloride. However, this method requires the addition of an excess of 10 equivalents or more of chlorosulfonic acid to complete the reaction, resulting in the generation of large amounts of hydrogen chloride gas, making production difficult and causing severe damage to machinery. When the amount added is less than 6 equivalents, the product yield is only 39.97%. Summary of the Invention

[0010] Purpose of the invention: To solve the above-mentioned technical problems, the present invention provides a preparation method for producing high-purity sildenafil that is convenient to operate, highly efficient, has controllable impurities, and a high yield.

[0011] Invention process: In order to avoid the formation of process impurity M4-01, the problem of impurity M4-01 in the preparation of sildenafil is solved by adopting the strategy of "occupying" the para position of compound 3 ethoxy beforehand, and a high-purity sildenafil intermediate is obtained. In one aspect, the present invention provides a method for preparing sildenafil citrate intermediate, in which the compound and nitrous acid reagent are reacted under acidic conditions to generate a diazonium salt, and the diazonium salt is then chlorosulfonated to obtain compound 4.

[0012]

[0013] Furthermore, the chlorosulfonating agents in the chlorosulfonation process are thionyl chloride and sodium sulfite; Furthermore, the acidic reagent can be hydrochloric acid or 1,5-naphthalenedisulfonic acid; Furthermore, the reaction temperature for the chlorosulfonation process is 20-60℃; Furthermore, the feed ratio of compound 3 to the chlorosulfonating agent is 1.0-1.5; Furthermore, to promote the reaction, a copper salt reagent can be added to catalyze the reaction. The copper salt reagent can be cuprous chloride, cupric chloride, or copper sulfate.

[0014]

[0015] One aspect of the present invention provides a method for preparing compound 3, the specific scheme of which is as follows: Step 1: 2-Ethoxy-5-nitrobenzoic acid reacts with thionyl chloride to give 2-ethoxy-5-nitrobenzoyl chloride; Step 2: 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide reacts with 2-ethoxy-5-nitrobenzoyl chloride under the action of triethylamine to generate compound 1; Step 3: Compound 1 undergoes cyclization with sodium hydroxide to obtain compound 2; Step 4: Compound 2 is reduced by platinum carbon / H2 to obtain compound 3.

[0016]

[0017] One aspect of the present invention provides a method for preparing sildenafil, the specific scheme of which is as follows:

[0018] Beneficial effects: This invention provides a method for preparing high-purity sildenafil intermediates, which has the following advantages compared with the prior art: the change in the introduction of sulfonyl chloride groups fundamentally avoids the formation of regional impurity M4-01; the intermediates prepared by this method are stable, the reaction conditions avoid ultra-low temperatures, and energy consumption is reduced; the use of chlorosulfonic acid is avoided, making the process green and environmentally friendly; the post-treatment quenching operation is simple; the overall yield can reach more than 90%, making it more suitable for large-scale industrial production. Attached Figure Description

[0019] Figure 1 US5250534A Method for the Controlled Detection of Sildenafil Intermediates Figure 2 US5250534A Method for Sildenafil Detection Figure 3 Method A of the present invention for the detection of sildenafil intermediate reaction solution Figure 4Detection of Sildenafil Intermediate Reaction Solution by Method B of the Present Invention Figure 5 Detection of Sildenafil Intermediate Reaction Solution by Method C of the Present Invention Figure 6 Method A of the present invention for sildenafil quality control Figure 7 Method B of this invention for sildenafil quality control Figure 8 The present invention, method C, for sildenafil quality control Detailed Implementation

[0020] The principles and features of the present invention are described below. The embodiments given are used to further explain the present invention, but do not limit the scope of the present invention. Example 1

[0021] Synthesis of 2-ethoxy-5-nitro-benzoyl chloride Feeding: Add 316.75g of dichloromethane to a 500ml three-necked reaction flask and start stirring. Control the temperature at 20-30℃, add 105.58g of 2-ethoxy-5-nitro-benzoic acid and 1.06g of DMF, start stirring, and add 71.38g of thionyl chloride in a continuous flow, with the temperature not exceeding 35℃.

[0022] Reaction: After feeding, control the temperature at 35-40℃ and react for 1-3 hours.

[0023] Distillation: After the reaction is complete, distill at atmospheric pressure: 40-60℃, until no obvious fraction remains; distill under reduced pressure: 40-60℃, -0.07~-0.1MPa, approximately 0.1-0.5h, yield 100.0%. Use directly for the next step. Example 2 Synthesis of Compound 1

[0024] Feeding: Add 1640.07g of dichloromethane to a 3L three-necked reaction flask and start stirring. Add 91.11g of 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide at 20-30℃, followed by 52.20g of triethylamine. At 20-30℃, add 2-ethoxy-5-nitro-benzoyl chloride as a feedstock.

[0025] Reaction: After feeding, maintain the temperature at 20-30℃ for 4-6 hours.

[0026] Washing: After the reaction is complete, maintain the temperature at 20-30℃ and wash the dichloromethane phase with 637.77g of drinking water.

[0027] Distillation: Distill dichloromethane at atmospheric pressure, 40-80℃, until no obvious fraction remains; Distill under reduced pressure: 40-60℃, -0.07~-0.1MPa, about 0.5h, until no obvious fraction remains.

[0028] Refining: Add 455.55g of isopropanol and 1366.65g of drinking water, stir at 80-90℃ until dissolved, cool to 0-10℃ (about 3-5h), and stir at 0-10℃ for 1h. Filter.

[0029] Drying: Dry at 60-70℃ with forced air for 8 hours.

[0030] Received: 184.24 g, yield 98%, HPLC: 99.5%.

[0031] HPLC: Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0032] For the test solution, take an appropriate amount of this product, accurately weigh it, dissolve and dilute it with solvent to prepare a solution containing approximately 0.5 mg per ml.

[0033] Chromatographic conditions: Octadecyl-bonded silica gel was used as the stationary phase (e.g., Thermo GOLD C18, 4.6 mm × 250 mm, 5 µm). Phosphoric acid solution (appropriate amount of water, pH adjusted to 3.5 with phosphoric acid) was used as mobile phase A, and acetonitrile was used as mobile phase B. Gradient elution was performed according to the table below. The detection wavelength was 233 nm. The flow rate was 1.0 mL per minute. The column temperature was 25 °C. The injection volume was 10 μL.

[0034]

[0035] Example 3 Synthesis of Compound 2 Feeding: Add 1200.00g of isopropanol to a 5L three-necked reaction flask and start stirring. At 20-30℃, add 1150.00g of the compound. If the solid is not completely dissolved, add 79.78g of 30% liquid alkali dropwise at 20-40℃.

[0036] Reaction: After the initial addition is complete, maintain the temperature at 80-82.5℃ for 4-6 hours. Once the reaction is complete, add 2500.00g of drinking water.

[0037] Crystallization: Control the temperature at 60-70℃ and add concentrated sulfuric acid (31.15g, pH 5-7). After adding, cool down and stir at 20-30℃ for 1 hour.

[0038] Centrifugation: Centrifuge and rinse the filter cake with 300.00g of drinking water.

[0039] Drying: Dry with forced air at 70-80℃ for 8 hours.

[0040] Collection: 139.96 g of compound 2 was obtained, with a yield of 98% (HPLC: 99.7%).

[0041] HPLC was performed according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2015 edition, Part IV, General Chapter 0512).

[0042] For the test solution, accurately weigh about 5 mg of this product, place it in a 25 ml volumetric flask, add 10 ml of acetonitrile, sonicate to dissolve, then dilute with water to the mark and shake well.

[0043] Chromatographic conditions: Use octadecyl bonded silica gel as the stationary phase (e.g., Thermo GOLD C18, 4.6 mm × 250 mm, 5 µm or equivalent column); use phosphoric acid solution (adjust pH to 3.5 with appropriate amount of water) as mobile phase A and acetonitrile as mobile phase B, and perform gradient elution according to the table below; flow rate is 1.0 mL / min; column temperature is 30 °C; detection wavelength is 233 nm; injection volume is 20 μL.

[0044]

[0045] Example 4 Synthesis of Compound 3 Feeding: Add 600.00g of isopropanol, 120g of compound 2, and 2.40g of platinum carbon (36% dry basis, 1% metal content) to a 2L high-pressure reactor.

[0046] Reaction: Start stirring, introduce hydrogen gas, and bring the pressure to 1.0 MPa. Control the temperature at 30-40℃ and maintain the pressure at 0.5-1.0 MPa for 1-2 hours, until the pressure no longer drops significantly.

[0047] Filtration: After the reaction is complete, filter out the platinum carbon.

[0048] Crystallization: Add the filtrate to a 3L reaction flask and add 1440.00g of drinking water. Maintain the temperature at 60-70℃ and add 20.46g of concentrated sulfuric acid (pH 5-7). After the addition is complete, cool the mixture and stir at 20-30℃ for 1 hour.

[0049] Centrifugation: Centrifuge and rinse the filter cake with 300.00g of drinking water.

[0050] Drying: Dry with forced air at 70-80℃ for 8 hours.

[0051] Collection: Compound 3, 107.74 g, was obtained, yield 98%, HPLC: 99.8%. HPLC: Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0052] For the test solution, take an appropriate amount of this product, accurately weigh it, dissolve and dilute it with solvent to prepare a solution containing approximately 0.5 mg per ml.

[0053] Chromatographic conditions: Octadecyl-bonded silica gel was used as the stationary phase (e.g., Thermo GOLD C18, 4.6 mm × 250 mm, 5 µm). Phosphoric acid solution (appropriate amount of water, pH adjusted to 3.5 with phosphoric acid) was used as mobile phase A, and acetonitrile was used as mobile phase B. Gradient elution was performed according to the table below. The detection wavelength was 233 nm. The flow rate was 1.0 mL per minute. The column temperature was 25 °C. The injection volume was 10 μL.

[0054]

[0055] Example 5 Synthesis of Compound 4 (1) A process synthesis method Add 85.02 g (2.332 mol, 17 eq) of concentrated hydrochloric acid to a 2 L reaction flask, add 45 g (0.1375 mol, 1 eq) of compound 3, cool to 0 °C, and add dropwise sodium nitrite aqueous solution (containing 28.36 g (0.411 mol, 3 eq) of sodium nitrite and 90 g of water). Control the temperature at 0 °C during the dropwise addition process. After the dropwise addition is completed, control the temperature at 0 °C and set aside for later use. Feeding 2: In another 2L reaction flask, add 450g of drinking water, cool to 5℃, and add 48.50g of thionyl chloride (0.408mol, 2.97eq) dropwise. After the addition is complete, stir and add 0.45g of cuprous chloride (0.00335mol, 0.0244eq), stir for 0.5h, and set aside. Reaction: The solution obtained from feed 1 is added dropwise to the reaction flask containing feed 2. The temperature is controlled at 0-10℃ during the dropwise addition process. After the dropwise addition is completed, the mixture is stirred at 0-10℃ for 1 hour.

[0056] Extraction: After the reaction was complete, 900 g of dichloromethane was added to the reaction solution, stirred, and allowed to stand for separation. The organic phase was washed with 300 g of saturated sodium bicarbonate aqueous solution. The obtained organic phase was used directly in the next step. Quality testing is detailed below. Figure 3 .

[0057] (2) Synthesis method of process B Feeding 1: In another 2L reaction flask, add 43.47g (0.151mol) of 1,5-naphthalenedisulfonic acid, 345g (0.1375mol, 1eq) of the compound, and 16.06g (0.1375mol) of isoamyl nitrite. Stir and cool to -10-0℃ for later use. Feeding 2: In a 2L reaction flask, add 200g of drinking water and 0.54g (0.004mol) of cuprous chloride. Control the temperature at -10 to 0℃, then add 16.31g (0.1375mol) of thionyl chloride. Set aside for later use. Reaction: The solution obtained from feed 1 is added dropwise to the reaction flask containing feed 2. The temperature is controlled at -10 to 0℃ during the dropwise addition process. After the dropwise addition is completed, the mixture is stirred at -10 to 0℃ for 4 hours.

[0058] Extraction: After the reaction was complete, 900 g of dichloromethane was added to the reaction solution, stirred, and allowed to stand for separation. The organic phase was washed with 300 g of saturated sodium bicarbonate aqueous solution. The obtained organic phase was used directly in the next step. Quality testing is detailed below. Figure 4 .

[0059] (3) C process synthesis method Feeding 1: Add 90g of concentrated hydrochloric acid (2.47mol 18.28eq) to a 1L reaction flask, keep the temperature below 20℃, add 45g of compound 3, and slowly add an aqueous solution of sodium nitrite (28.362g of sodium nitrite (0.411mol 3.0eq) + 90g of drinking water) dropwise while keeping the temperature between -10℃ and 0℃. Stir for 0.5h to obtain a diazonium salt solution for later use. Feeding 2: Add 900g of dichloromethane to a 2L reaction flask, and add 43.97g (0.423mol 3.08eq) of sodium bisulfite and 0.50g (0.0037mol 0.027eq) of copper dichloride while stirring.

[0060] Reaction: The diazonium salt solution of feed 1 was added dropwise to the reaction flask of feed 2 at a controlled temperature of -10~-0℃. After the addition was completed, the mixture was kept warm and stirred for 0.5h.

[0061] Extraction: After the reaction was complete, allow the mixture to stand and separate. Wash the organic phase with 300 g (3.571 mol) of saturated sodium bicarbonate aqueous solution. The obtained organic phase was used directly in the next step. For quality testing, see [link to quality control procedures]. Figure 5 .

[0062] (4) A process synthesis method Feeding 1: Add 63.75g (1.75mol 12.72eq) of concentrated hydrochloric acid to another 2L reaction flask, add 345g of the compound, cool to 0℃, and add sodium nitrite aqueous solution (containing 18.91g (0.274mol 2.0eq) sodium nitrite and 90g water) dropwise. Control the temperature at 0℃ during the dropwise addition process. After the dropwise addition is completed, control the temperature at 0℃ and set aside for later use. Feeding 2: In a 2L reaction flask, add 300g of drinking water, cool to 5℃, and add 85.34g of thionyl chloride (0.717mol 5.22eq) dropwise. After the addition is complete, stir and add 0.90g of cuprous chloride. Stir for 1 hour and set aside. Reaction: The solution obtained from feed 1 is added dropwise to the reaction flask containing feed 2. The temperature is controlled at 10-20℃ during the dropwise addition process. After the dropwise addition is completed, the mixture is stirred at 10-20℃ for 2 hours.

[0063] Extraction: After the reaction was complete, 675 g of dichloromethane was added to the reaction solution, stirred, and allowed to stand for separation. The organic phase was washed with 225 g of saturated sodium bicarbonate aqueous solution. The obtained organic phase was used directly in the next step.

[0064] (5) B process synthesis method Feeding 1: In another 2L reaction flask, add 65.21g of 1,5-naphthalenedisulfonic acid, 45g of compound 3, and 29.44g of isoamyl nitrite. Cool to 0℃ and set aside for later use. Feeding 2: In a 2L reaction flask, add 150g of drinking water and 0.54g of cuprous chloride, control the temperature at 0-10℃, and add 22.25g of thionyl chloride. Set aside for later use. Reaction: The solution obtained from feed 1 is added dropwise to the reaction flask containing feed 2. The temperature is controlled at 0-10℃ during the dropwise addition process. After the dropwise addition is completed, the mixture is stirred at 0-10℃ for 2 hours.

[0065] Extraction: After the reaction was complete, 900 g of dichloromethane was added to the reaction solution, stirred, and allowed to stand for separation. The organic phase was washed with 225 g of saturated sodium bicarbonate aqueous solution. The obtained organic phase was used directly in the next step.

[0066] (6) C process synthesis method Feeding 1: Add 72g (14.36 eq) of concentrated hydrochloric acid to a 1L reaction flask, keep the temperature below 20℃, add 345g of the compound, and slowly add an aqueous solution of sodium nitrite (18.91g (2 eq) of sodium nitrite + 90g of drinking water) dropwise while keeping the temperature between -15℃ and -5℃. Stir for 0.5h to obtain a diazonium salt solution for later use.

[0067] Feeding 2: Add 650g of dichloromethane to a 2L reaction flask, and add 65.96g (4.61eq) of sodium bisulfite and 1g (0.054eq) of copper dichloride while stirring.

[0068] Reaction: Control the temperature to -10~0℃ and add the diazonium salt solution of feed 1 dropwise to the reaction flask of feed 2. After the addition is complete, keep the temperature warm and stir for 2 hours.

[0069] Extraction: After the reaction was complete, the mixture was allowed to stand and separated. The organic phase was washed with 225 g of saturated sodium bicarbonate aqueous solution. The resulting organic phase was used directly in the next step.

[0070] Example 6: Synthesis of Sildenafil (1) Preparation of sildenafil from process intermediate A Feeding: Add dichloromethane phase to a 2L three-necked reaction flask and start stirring. At 20-30℃, add 11.08g of N-methylpiperazine and 11.11g of triethylamine dropwise.

[0071] Reaction: After the addition was complete, the reaction was carried out at a controlled temperature for 1 hour.

[0072] Washing with water: After the reaction is complete, the DCM phase is washed with 300g of drinking water.

[0073] Distillation: Separate the dichloromethane phase and add it to a 2L reaction flask. Distill the dichloromethane at atmospheric pressure, 40-60℃, until no obvious fraction remains; distill under reduced pressure: 40-60℃, -0.07~-0.1MPa, about 0.5h, until no obvious fraction remains.

[0074] Crystallization: Add 315g of isopropanol and 450g of drinking water, then add 14.63g of 30% alkali solution. Maintain the temperature at 75℃ to reflux, stirring until dissolved. Cool to 60-70℃, add 5.37g of concentrated sulfuric acid dropwise, adjust the pH to 6.5-7.5, and after solid precipitation, cool to 0-10℃ and stir to crystallize for 2 hours. Filter.

[0075] Drying: Dry at 70-80℃ for 8 hours.

[0076] Collection: 63.24 g of solid was obtained, yield 97%, HPLC: 99.9%. See below for detailed test results. Figure 6 .

[0077] (2) Preparation of Sildenafil from Process Intermediate B Feeding: Add dichloromethane phase to a 2L three-necked reaction flask and start stirring. At 20-30℃, add 11.08g of N-methylpiperazine and 11.11g of triethylamine dropwise.

[0078] Reaction: After the addition was complete, the reaction was carried out at a controlled temperature for 1 hour.

[0079] Washing with water: After the reaction is complete, the DCM phase is washed with 300g of drinking water.

[0080] Distillation: Separate the dichloromethane phase and add it to a 2L reaction flask. Distill the dichloromethane at atmospheric pressure, 40-60℃, until no obvious fraction remains; distill under reduced pressure: 40-60℃, -0.07~-0.1MPa, about 0.5h, until no obvious fraction remains.

[0081] Crystallization: Add 315g of isopropanol and 450g of drinking water, then add 14.63g of 30% alkali solution. Maintain the temperature at 75℃ to reflux, stirring until dissolved. Cool to 60-70℃, add 5.37g of concentrated sulfuric acid dropwise, adjust the pH to 6.5-7.5, and after solid precipitation, cool to 0-10℃ and stir to crystallize for 2 hours. Filter.

[0082] Drying: Dry at 70-80℃ for 8 hours.

[0083] Collection: 63.56 g of solid was obtained, yield 97.5%, HPLC: 99.9%. See below for detailed test results. Figure 7 .

[0084] (3) Preparation of Sildenafil from process intermediate C Feeding: Add dichloromethane phase to a 2L three-necked reaction flask and start stirring. At 20-30℃, add 11.08g of N-methylpiperazine and 11.11g of triethylamine dropwise.

[0085] Reaction: After the addition was complete, the reaction was carried out at a controlled temperature for 1 hour.

[0086] Washing: After the reaction is complete, the DCM phase is washed with 300 ml of drinking water.

[0087] Distillation: Separate the dichloromethane phase and add it to a 2L reaction flask. Distill the dichloromethane at atmospheric pressure, 40-60℃, until no obvious fraction remains; distill under reduced pressure: 40-60℃, -0.07~-0.1MPa, about 0.5h, until no obvious fraction remains.

[0088] Crystallization: Add 315g of isopropanol and 450g of drinking water, then add 14.63g of 30% alkali solution. Maintain the temperature at 75℃ to reflux, stirring until dissolved. Cool to 60-70℃, add 5.37g of concentrated sulfuric acid dropwise, adjust the pH to 6.5-7.5, and after solid precipitation, cool to 0-10℃ and stir to crystallize for 2 hours. Filter.

[0089] Drying: Dry at 70-80℃ for 8 hours.

[0090] Collection: 62.26 g of solid was obtained, yield 95.5%, HPLC: 99.9%. See below for detailed test results. Figure 8 .

[0091] HPLC: Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0092] For the test solution, accurately weigh approximately 12.5 mg of this product, place it in a 25 ml volumetric flask, add 5 ml acetonitrile and 2.5 ml methanol to dissolve it, dilute with water to the mark, and shake well.

[0093] Chromatographic conditions: Octadecyl-bonded silica gel was used as the stationary phase (e.g., Agilent Poroshell 120 EC-C18 4.6mm × 150mm, 4.0µm or equivalent column); acetonitrile-0.025mol / L ammonium acetate solution (adjusted to pH 7.0 with ammonia) (10:90) was used as mobile phase A, and acetonitrile was used as mobile phase B, with gradient elution according to the table below; column temperature was 30℃; detection wavelength was 290 nm; injection volume was 20μl.

[0094] .

Claims

1. A method for preparing a sildenafil intermediate, characterized in that... Compound 3 was subjected to a chlorosulfonation process to obtain intermediate compound 4, the specific steps of which are as follows: Step 1: Compound 3 is subjected to a diazotization reaction under acidic conditions; Step 2: Under the condition of copper salt catalyst, the diazotization solution from the previous step is added dropwise to the chlorosulfonation reagent; Step 3: Extract the above reaction solution; 。 2. The preparation method according to claim 1, characterized in that... The first step of the diazotization reaction involves adding acidic reagents and nitrous acid reagents dropwise to the compound 3 solution at a controlled low temperature.

3. The preparation method according to claim 2, characterized in that... The nitrite reagent is sodium nitrite or isoamyl nitrite.

4. The preparation method according to claim 2, characterized in that... The acidic reagents mentioned are hydrochloric acid and 1,5-naphthalenedisulfonic acid.

5. The preparation method according to claim 1, characterized in that... The chlorosulfonation reagent in the second step can be thionyl chloride or sodium bisulfite.

6. The preparation method according to claim 1, characterized in that... The second step of the reaction is carried out at a temperature below 0°C.

7. The preparation method according to claim 1, characterized in that... The ratio of compound 3 to chlorosulfonating agent is 1-1.

5.

8. The preparation method according to claim 1, characterized in that... Compound 3 was prepared via the following steps. ； Step 1: 2-Ethoxy-5-nitrobenzoic acid reacts with thionyl chloride to give 2-ethoxy-5-nitrobenzoyl chloride; Step 2: 4-Amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide reacts with 2-ethoxy-5-nitrobenzoyl chloride under the action of triethylamine to generate compound 1; Step 3: Compound 1 undergoes cyclization with sodium hydroxide to obtain compound 2; Step 4: Compound 2 is reduced by platinum carbon / H2 to obtain compound 3.

9. The preparation method according to claim 1, characterized in that... The intermediate compound 4 can be used to prepare sildenafil. 。

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