Synthesis method of lesinurad

Abstract

The invention relates to a method for synthesizing lesinurad, which comprises the following steps of: sequentially performing aldehyde-thiosemicarbazide condensation, cyclization, bromination and hydrolysis reaction on a compound 4-cyclopropyl naphthalene-1-formaldehyde as shown in a formula I serving as a raw material to obtain a compound lesinurad as shown in a formula V; according to the invention, a 1, 2, 4-triazole ring is constructed by an innovative strategy of aldehyde-thiosemicarbazide condensation-cyclization, so that tedious steps of a traditional step-by-step process are omitted, and the cyclization yield is increased from 85% to 92%; the method is mild in overall reaction condition, low in equipment damage, simple in process, green and environment-friendly, capable of ensuring continuous production of high-quality products and high in application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical synthesis technology, and in particular to a continuous flow synthesis method for Recinard active pharmaceutical ingredient. Background Technology

[0002] Gout is a metabolic disease caused by high levels of uric acid in the body, leading to the deposition of urate crystals in joints and other areas, causing severe pain and inflammation. Impaired renal excretion of uric acid is the main cause of hyperuricemia. Recinard has a very specific target: it selectively inhibits urate transporter 1 (URAT1), expressed on the epithelial cells of the proximal convoluted tubules of the kidney. URAT1 is responsible for the reabsorption of approximately 90% of uric acid in the glomerular filtrate. By inhibiting URAT1, Recinard can effectively block the reabsorption of uric acid, thereby significantly increasing the amount of uric acid excreted in the urine and lowering serum uric acid levels. Compared to the established uricosuric drug benzbromarone, Recinard does not inhibit or only slightly inhibits glucuronyl transferase, thus posing a lower potential risk of drug interactions and relatively less impact on liver function. Compared to xanthine oxidase inhibitors (such as allopurinol and febuxostat), which inhibit uric acid production, Recinard offers a novel therapeutic pathway with a complementary mechanism of action. For patients who cannot achieve target levels or have contraindications to xanthine oxidase inhibitors alone, retinal combined with them has shown a significant synergistic effect in lowering uric acid, providing a crucial treatment option for patients with refractory gout.

[0003] Currently, most publicly disclosed synthetic routes for Resinard are traditional batch-process reactors, mainly of two types. One is reported in patent WO2009070740, which has the following limitations: the overall process is lengthy, with a total yield of only 9.5%; the initial cyclopropylation reaction requires a strictly anhydrous and oxygen-free environment, with stringent operating conditions; the catalysts used, such as 1,3-bis(diphenylphosphine)propane nickel chloride (NiCl2(dppp)) and cyclopropylmagnesium bromide, are expensive, increasing the cost burden; furthermore, the sulfur phosgene involved in the reaction has a low boiling point, high volatility, pungent odor, and strong toxicity, requiring production in a fully enclosed system. To meet environmental protection requirements, the subsequent treatment of related toxic products also requires significant investment.

[0004] Summary of the Invention

[0005] To address the aforementioned problems, the present invention aims to provide a continuous flow synthesis method for Resinard active pharmaceutical ingredient that produces products with stable quality, mild reaction conditions, and minimal damage to equipment.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: a method for synthesizing Recinard, using the compound of formula I: 4-cyclopropylnaphthalene-1-carboxaldehyde as raw material, and successively undergoing aldehyde-thioaminourea condensation → cyclization → bromination → hydrolysis reaction to obtain the compound of formula V: Recinard.

[0007] .

[0008] The specific steps are as follows:

[0009] 1) Thioaminourea (or its salt) is dissolved or suspended in a suitable solvent to form fluid A; 4-cyclopropylnaphthalene-1-carboxaldehyde is prepared into fluid B; a catalyst (such as acetic acid or citric acid) is prepared into fluid C; and an alkaline solution is prepared into fluid D. Fluids A, B and C are delivered to a micro mixer via a precision metering pump to achieve instantaneous and uniform mixing, and then enter a microchannel reactor for condensation reaction.

[0010] 2) The reaction temperature is precisely controlled at 62℃~65℃ by the temperature control system, the system pressure is precisely controlled at 0.3~0.32MPa by the back pressure regulating valve, and the residence time of the material in the reactor is precisely controlled at 3min by adjusting the total flow rate. After the reaction liquid flows out, it immediately enters the online quenching module and is mixed online with fluid D. Then it is continuously concentrated and crystallized to obtain compound of formula II: 4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-thiol.

[0011] 3) Dissolve Formula II and tert-butyl bromoacetate in an organic solvent, add an acid-binding agent, and stir at room temperature for 4 to 12 hours to obtain the compound of Formula III: 2-{[4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-yl]thio}tert-butyl bromoacetate.

[0012] 4) Dissolve Formula III in an organic solvent, add N-bromosuccinimide (NBS) and a catalytic amount of silver trifluoromethanesulfonate at 0℃~25℃, stir for 1.5~6 hours to obtain the compound of Formula IV: 2-{[5-bromo-4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-yl]thio}tert-butyl acetate.

[0013] 5) Dissolve Formula IV in the deprotection system and react at room temperature for 2 to 6 hours; after rotary evaporation and concentration, add ethyl acetate / water to adjust the pH to alkaline, separate the liquid and concentrate the organic phase, and recrystallize from n-heptane to obtain the compound of Formula V.

[0014] In step 1) of the present invention, the molar ratio of formula I to thioaminourea is 1:1.0~3.0; the preferred molar ratio is 1:1.05~1.1; the preferred reaction temperature in step 2) is 65°C.

[0015] In step 1) of the present invention, fluids A, B, and C are in a pump speed ratio of 5:1:0.2.

[0016] In step 3) of the present invention, the molar ratio of formula II to tert-butyl bromoacetate is 1:1.05~1.5; the acid-binding agent is selected from one or two of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, diethylamine or triethylamine; and the solvent is selected from one or two of N,N-dimethylformamide, 1,4-dioxane and tetrahydrofuran.

[0017] In step 4) of this invention, the molar ratio of formula III to NBS is 1:1.05~1.2, the molar ratio of silver trifluoromethanesulfonate catalyst is 1:0.02~0.05, and the solvent is selected from one or two of dichloromethane, trichloromethane, dichloroethane, tetrahydrofuran, acetone and toluene.

[0018] In step 5) of this invention, the deprotection system is selected from one of dichloromethane / trifluoroacetic acid, ethyl acetate / hydrogen chloride, or 1,4-dioxane / hydrogen chloride; the volume ratio of ethyl acetate to water is 2:1; and NaOH is used to adjust the pH to 7.

[0019] The advantages of this invention are: 1. The innovative strategy of “aldehyde-thioaminourea condensation-cyclization” is used to construct 1,2,4-triazole ring, which not only eliminates the cumbersome steps of the traditional step process, but also increases the cyclization yield from 85% to 92%.

[0020] 2. By eliminating transition metal catalysts in the S-alkylation process, the costs and residual risks of precious metals are avoided, the separation process is simplified, and the industrialization cost is reduced by about 25%.

[0021] 3. By controlling the regioselectivity of bromination with silver trifluoromethanesulfonate, the proportion of monobrominated products exceeds 99%, completely solving the purification problem of polybrominated impurities and reducing post-processing costs by 40%.

[0022] 4. Using tert-butyl ester as a protecting group and trifluoroacetic acid for gentle deprotection avoids the side reaction of strong alkaline hydrolysis. The final product has a purity of over 99.95% and a single impurity of less than 0.03%, which is far superior to the pharmacopoeia standard. This approach balances process economy with high product quality.

[0023] The process route of this invention produces products with stable quality, mild reaction conditions, low damage to equipment, simple process, environmental friendliness and low cost, and can ensure continuous production of high-quality products, thus having high application value. Detailed Implementation

[0024] The present invention will now be described in further detail with reference to specific embodiments.

[0025] Example 1:

[0026] Thioaminourea (5.01 g) and tetrahydrofuran (150 mL) were added to a 500 mL three-necked glass bottle and stirred for 20 minutes until completely dissolved to obtain fluid A. 4-Cyclopropylnaphthalene-1-carboxaldehyde (10.0 g, Formula I) and tetrahydrofuran (30 mL) were added to a 250 mL single-necked flask and ultrasonically dispersed for 10 minutes to obtain a uniformly suspended fluid B. Acetic acid (2 g) and deionized water (18 g) were added to a 100 mL beaker and stirred until homogeneous to obtain a 10% (w / w) aqueous solution of acetic acid (fluid C). Sodium hydroxide (2 g) and deionized water (18 mL) were added to a 100 mL beaker and stirred until dissolved to obtain a 10% sodium hydroxide aqueous solution (fluid D).

[0027] Fluids A, B, and C are delivered to a micro-mixer at a pump speed ratio of 5:1:0.2 using a precision metering pump, achieving instantaneous and uniform mixing. The mixture then enters a microchannel reactor. The reactor temperature is controlled at 65°C, and the system pressure is maintained at 0.3~0.32MPa using a back pressure regulating valve. The total flow rate is adjusted to ensure a residence time of 3 minutes for the materials within the reactor. The reaction solution immediately flows out and enters an online quenching module, where it is mixed online with fluid D at a molar ratio of 1:1 to complete the quenching reaction.

[0028] After quenching, the material was transferred to a 500mL rotary evaporator and concentrated under reduced pressure at 60℃ in a water bath and a vacuum degree ≤-0.09MPa to 1 / 3 of the original volume (approximately 60mL). The concentrate was then transferred to a 250mL three-necked flask and cooled to 10℃ for crystallization for 30min. After crystallization, the mixture was filtered, and the filter cake was washed twice with 10mL of tetrahydrofuran at 5℃. The filter cake was then placed in a vacuum drying oven and dried under vacuum at 45℃ for 4 hours to obtain 13.2g of Resinard intermediate (Formula II), with an HPLC purity of 99.5% and a yield of 92.80%, which was directly used in the next production step.

[0029] Add Resinard intermediate (Formula II) (10 g), tert-butyl bromoacetate (7.82 g), and N,N-dimethylformamide (50 mL) to a 250 mL three-necked glass flask and stir to dissolve. Add triethylamine (5.49 g) to the reaction system, maintain the reaction temperature at 25 °C, and stir for 8 hours. The reaction is complete when the starting material spot disappears as monitored by thin-layer chromatography (TLC).

[0030] Slowly add 200 mL of deionized water to the reaction solution, stir for 10 minutes, and extract three times with ethyl acetate (100 mL each time). Combine the organic phases. Wash the organic phase twice with saturated brine (50 mL each time), and dry with anhydrous sodium sulfate (10 g) for 2 hours. Filter to remove the drying agent, transfer the filtrate to a rotary evaporator, and concentrate under reduced pressure at 50 °C in a water bath and a vacuum degree ≤ -0.09 MPa to remove the solvent, yielding 14.1 g of crude tert-butyl 2-((4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (Formula III), which can be directly used in the next production step.

[0031] Crude product of Formula III (14.1 g) and dichloromethane (80 mL) were added to a 250 mL three-necked glass flask and stirred to dissolve. The reaction solution was cooled to 10 °C, and N-bromosuccinimide (7.0 g) and silver trifluoromethanesulfonate (0.32 g) were added in portions. After the addition was complete, the temperature was raised to 20 °C and the reaction was stirred for 3 hours. The reaction was monitored by TLC until complete. 50 mL of saturated sodium thiosulfate aqueous solution was added to the reaction solution, and the mixture was stirred for 10 minutes to quench unreacted N-bromosuccinimide. The mixture was extracted and separated, and the organic phase was collected. It was washed once with saturated brine (30 mL) and dried with anhydrous sodium sulfate (8 g) for 1 hour. The desiccant was removed by filtration, and the filtrate was transferred to a rotary evaporator flask. The solvent was removed by vacuum concentration under reduced pressure at 45°C and a vacuum degree of ≤-0.09MPa to obtain 16.8g of crude tert-butyl 2-((5-bromo-4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (Formula IV), which was directly used in the next production step.

[0032] 16.8 g of crude product of formula IV and 30 mL of dichloromethane were added to a 250 mL three-necked glass flask and stirred to dissolve. Then, 30 mL of trifluoroacetic acid was added, and the reaction mixture was stirred for 4 hours while maintaining the temperature at 25 °C (room temperature). The deprotection reaction was monitored by TLC until it was complete. The reaction mixture was then transferred to a rotary evaporator and the solvent was removed by rotary evaporation under reduced pressure at 50 °C in a water bath and a vacuum of ≤-0.09 MPa.

[0033] Add an ethyl acetate / water mixture (2:1 volume ratio, total volume 120 mL, including 80 mL ethyl acetate and 40 mL water) to the residue and stir to dissolve. Adjust the pH of the reaction solution to 7 with 10% sodium hydroxide aqueous solution, stir for 10 minutes, then separate the liquids. Transfer the organic phase to a rotary evaporator flask and concentrate to dryness under reduced pressure at 50°C and a vacuum of ≤-0.09 MPa. Add 30 mL of n-heptane to the concentrated residue, heat to 60°C and stir to dissolve, then slowly cool to 5°C and maintain the temperature for crystallization for 2 hours.

[0034] After crystallization, the mixture was filtered, and the filter cake was washed once with 5 mL of cold n-heptane. The filter cake was then placed in a vacuum drying oven and dried under vacuum at 40°C for 6 hours to obtain 10.8 g of Resinard (Formula V) product. The HPLC purity was 99.86%, the total impurity content was 0.21%, and the total molar yield based on Formula I was 68.31%.

[0035] Example 2:

[0036] Thioaminourea (5.01 g) and acetone (150 mL) were added to a 500 mL three-necked glass bottle and stirred for 20 minutes until completely dissolved to obtain fluid A. 4-Cyclopropylnaphthalene-1-carboxaldehyde (10 g, Formula I) and acetone (30 mL) were added to a 250 mL single-necked flask and ultrasonically dispersed for 10 minutes to obtain a uniformly suspended fluid B. Acetic acid (2 g) and deionized water (18 g) were added to a 100 mL beaker and stirred until homogeneous to obtain a 10% (w / w) aqueous solution of acetic acid (fluid C). Sodium hydroxide (2 g) and deionized water (18 mL) were added to a 100 mL beaker and stirred until dissolved to obtain a 10% sodium hydroxide aqueous solution (fluid D).

[0037] Fluids A, B, and C are delivered to a micro-mixer at a pump speed ratio of 5:1:0.2 using a precision metering pump, achieving instantaneous and uniform mixing. The mixture then enters a microchannel reactor. The reactor temperature is controlled at 65°C, and the system pressure is maintained at 0.3~0.32MPa using a back pressure regulating valve. The total flow rate is adjusted to ensure a residence time of 3 minutes for the materials within the reactor. The reaction solution immediately flows out and enters an online quenching module, where it is mixed online with fluid D at a molar ratio of 1:1 to complete the quenching reaction.

[0038] After quenching, the material was transferred to a 500mL rotary evaporator and concentrated under reduced pressure at 60℃ in a water bath and a vacuum degree ≤-0.09MPa to 1 / 3 of the original volume (approximately 60mL). The concentrate was then transferred to a 250mL three-necked flask and cooled to 10℃ for crystallization for 30min. After crystallization, the mixture was filtered, and the filter cake was washed twice with 10mL of acetone at 5℃. The filter cake was then placed in a vacuum drying oven and dried under vacuum at 45℃ for 4 hours to obtain 10.9g of Resinard intermediate (Formula II), with an HPLC purity of 94.2% and a yield of 76.63%, which was directly used in the next production step.

[0039] Add Resinard intermediate (Formula II) (10 g), tert-butyl bromoacetate (7.82 g), and N,N-dimethylformamide (50 mL) to a 250 mL three-necked glass flask and stir to dissolve. Add triethylamine (5.49 g) to the reaction system, maintain the reaction temperature at 25 °C, and stir for 8 hours. The reaction is complete when the starting material spot disappears as monitored by thin-layer chromatography (TLC).

[0040] Slowly add 200 mL of deionized water to the reaction solution, stir for 10 minutes, and extract three times with ethyl acetate (100 mL each time). Combine the organic phases. Wash the organic phase twice with saturated brine (50 mL each time), and dry with anhydrous sodium sulfate (10 g) for 2 hours. Filter to remove the drying agent, transfer the filtrate to a rotary evaporator, and concentrate under reduced pressure at 50 °C in a water bath and a vacuum degree ≤ -0.09 MPa to remove the solvent, yielding 13.9 g of crude tert-butyl 2-((4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (Formula III), which can be directly used in the next production step.

[0041] Crude product of Formula III (13.9 g) and dichloromethane (80 mL) were added to a 250 mL three-necked glass flask and stirred to dissolve. The reaction solution was cooled to 10 °C, and N-bromosuccinimide (7.0 g) and silver trifluoromethanesulfonate (0.32 g) were added in portions. After the addition was complete, the temperature was raised to 20 °C and the reaction was stirred for 3 hours. The reaction was monitored by TLC until complete. 50 mL of saturated sodium thiosulfate aqueous solution was added to the reaction solution, and the mixture was stirred for 10 minutes to quench any unreacted N-bromosuccinimide. The mixture was extracted and separated, and the organic phase was collected, washed once with saturated brine (30 mL), and dried for 1 hour with anhydrous sodium sulfate (8 g). The desiccant was removed by filtration, and the filtrate was transferred to a rotary evaporator flask. The solvent was removed by vacuum concentration under reduced pressure at 45°C and a vacuum degree of ≤-0.09MPa to obtain 16.7g of crude tert-butyl 2-((5-bromo-4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (Formula IV), which was directly used in the next production step.

[0042] 16.7 g of crude product of formula IV and 30 mL of dichloromethane were added to a 250 mL three-necked glass flask and stirred to dissolve. Then, 30 mL of trifluoroacetic acid was added, and the reaction mixture was stirred for 4 hours while maintaining the temperature at 25 °C (room temperature). The deprotection reaction was monitored by TLC until it was complete. The reaction mixture was then transferred to a rotary evaporator and the solvent was removed by rotary evaporation under reduced pressure at 50 °C in a water bath and a vacuum of ≤-0.09 MPa.

[0043] Add an ethyl acetate / water mixture (2:1 volume ratio, total volume 120 mL, including 80 mL ethyl acetate and 40 mL water) to the residue and stir to dissolve. Adjust the pH of the reaction solution to 7 with 10% sodium hydroxide aqueous solution, stir for 10 minutes, then separate the liquids. Transfer the organic phase to a rotary evaporator flask and concentrate to dryness under reduced pressure at 50°C and a vacuum of ≤-0.09 MPa. Add 30 mL of n-heptane to the concentrated residue, heat to 60°C and stir to dissolve, then slowly cool to 5°C and maintain the temperature for crystallization for 2 hours.

[0044] After crystallization, the mixture was filtered, and the filter cake was washed once with 5 mL of cold n-heptane. The filter cake was then placed in a vacuum drying oven and dried under vacuum at 40°C for 6 hours to obtain 10.1 g of Resinard (Formula V) product with an HPLC purity of 99.78% and a total impurity content of 0.23%. The total molar yield based on Formula I was 63.87%.

[0045] Example 3:

[0046] Thioaminourea (5.01 g) and methanol (150 mL) were added to a 500 mL three-necked glass bottle and stirred for 20 minutes until completely dissolved to obtain fluid A. 4-Cyclopropylnaphthalene-1-carboxaldehyde (10 g, Formula I) and methanol (30 mL) were added to a 250 mL single-necked flask and ultrasonically dispersed for 10 minutes to obtain a uniformly suspended fluid B. Acetic acid (2 g) and deionized water (18 g) were added to a 100 mL beaker and stirred until homogeneous to obtain a 10% (w / w) aqueous solution of acetic acid (fluid C). Sodium hydroxide (2 g) and deionized water (18 mL) were added to a 100 mL beaker and stirred until dissolved to obtain a 10% sodium hydroxide aqueous solution (fluid D).

[0047] Fluids A, B, and C are delivered to a micro-mixer at a pump speed ratio of 5:1:0.2 using a precision metering pump, achieving instantaneous and uniform mixing. The mixture then enters a microchannel reactor. The reactor temperature is controlled at 65°C, and the system pressure is maintained at 0.3~0.32MPa using a back pressure regulating valve. The total flow rate is adjusted to ensure a residence time of 3 minutes for the materials within the reactor. The reaction solution immediately flows out and enters an online quenching module, where it is mixed online with fluid D at a molar ratio of 1:1 to complete the quenching reaction.

[0048] After quenching, the material was transferred to a 500mL rotary evaporator and concentrated under reduced pressure at 60℃ in a water bath and a vacuum degree ≤-0.09MPa to 1 / 3 of the original volume (approximately 60mL). The concentrate was then transferred to a 250mL three-necked flask and cooled to 10℃ for crystallization for 30min. After crystallization, the mixture was filtered, and the filter cake was washed twice with 10mL of 5℃ methanol. The filter cake was then placed in a vacuum drying oven and dried under vacuum at 45℃ for 4 hours to obtain 10.2g of Resinard intermediate (Formula II), with an HPLC purity of 96.7% and a yield of 71.71%, which was directly used in the next production step.

[0049] Add Resinard intermediate (Formula II) (10 g), tert-butyl bromoacetate (7.82 g), and N,N-dimethylformamide (50 mL) to a 250 mL three-necked glass flask and stir to dissolve. Add triethylamine (5.49 g) to the reaction system, maintain the reaction temperature at 25 °C, and stir for 8 hours. The reaction is complete when the starting material spot disappears as monitored by thin-layer chromatography (TLC).

[0050] Slowly add 200 mL of deionized water to the reaction solution, stir for 10 minutes, and extract three times with ethyl acetate (100 mL each time). Combine the organic phases. Wash the organic phase twice with saturated brine (50 mL each time), and dry with anhydrous sodium sulfate (10 g) for 2 hours. Filter to remove the drying agent, transfer the filtrate to a rotary evaporator, and concentrate under reduced pressure at 50 °C in a water bath and a vacuum degree ≤ -0.09 MPa to remove the solvent, yielding 12.4 g of crude tert-butyl 2-((4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (Formula III), which can be directly used in the next production step.

[0051] 12.4 g of crude product of formula III and 80 mL of dichloromethane were added to a 250 mL three-necked glass flask and stirred to dissolve. The reaction solution was cooled to 10 °C, and N-bromosuccinimide (7.0 g) and silver trifluoromethanesulfonate (0.32 g) were added in portions. After the addition was complete, the temperature was raised to 20 °C and the reaction was stirred for 3 hours. The reaction was monitored by TLC until complete. 50 mL of saturated sodium thiosulfate aqueous solution was added to the reaction solution, and the mixture was stirred for 10 minutes to quench any unreacted N-bromosuccinimide. The mixture was extracted and separated, and the organic phase was collected, washed once with saturated brine (30 mL), and dried for 1 hour with anhydrous sodium sulfate (8 g). The desiccant was removed by filtration, and the filtrate was transferred to a rotary evaporator flask. The solvent was removed by vacuum concentration under reduced pressure at 45°C and a vacuum degree of ≤-0.09MPa to obtain 15.6g of crude tert-butyl 2-((5-bromo-4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (Formula IV), which was directly used in the next production step.

[0052] 15.6 g of crude product of formula IV and 30 mL of dichloromethane were added to a 250 mL three-necked glass flask and stirred to dissolve. Then, 30 mL of trifluoroacetic acid was added, and the reaction mixture was stirred for 4 hours while maintaining the temperature at 25 °C (room temperature). The deprotection reaction was monitored by TLC until it was complete. The reaction mixture was then transferred to a rotary evaporator and the solvent was removed by rotary evaporation under reduced pressure at 50 °C in a water bath and a vacuum of ≤-0.09 MPa.

[0053] Add an ethyl acetate / water mixture (2:1 volume ratio, total volume 120 mL, including 80 mL ethyl acetate and 40 mL water) to the residue and stir to dissolve. Adjust the pH of the reaction solution to 7 with 10% sodium hydroxide aqueous solution, stir for 10 minutes, then separate the liquids. Transfer the organic phase to a rotary evaporator flask and concentrate to dryness under reduced pressure at 50°C and a vacuum of ≤-0.09 MPa. Add 30 mL of n-heptane to the concentrated residue, heat to 60°C and stir to dissolve, then slowly cool to 5°C and maintain the temperature for crystallization for 2 hours.

[0054] After crystallization, the mixture was filtered, and the filter cake was washed once with 5 mL of cold n-heptane. The filter cake was then placed in a vacuum drying oven and dried under vacuum at 40°C for 6 hours to obtain 9.7 g of Resinard (Formula V) product with an HPLC purity of 99.79% and a total impurity content of 0.20%. The total molar yield based on Formula I was 61.47%.

[0055] Comparative Example 1: Traditional Synthesis Process

[0056] Thioaminourea (5.01 g) and tetrahydrofuran (150 mL) were added to a 500 mL three-necked glass flask and stirred for 20 minutes until completely dissolved. 4-Cyclopropylnaphthalene-1-carboxaldehyde (10.0 g) was added to the reaction solution. Then, an aqueous acetic acid solution (2 g acetic acid + 18 g water) was added to the reaction solution. After the addition was complete, the three-necked flask was placed in an oil bath and heated to 65°C. The reaction was maintained at this temperature for 10 hours. TLC was used to confirm complete reaction of the reactants. The reaction solution was then cooled to 0-10°C, and an aqueous sodium hydroxide solution (2.5 g sodium hydroxide + 20 g water) was slowly added dropwise to control the temperature of the reaction solution at 0-10°C. After the addition was complete, stirring was continued for 35 minutes to complete the quenching reaction.

[0057] After quenching, the material was transferred to a 500mL rotary evaporator flask. The solution was concentrated under reduced pressure (approximately 60mL) at a water bath temperature of 60℃ and a vacuum degree ≤-0.09MPa to obtain about 60mL of tetrahydrofuran solution. The concentrated solution was transferred to a 500mL three-necked flask, and the reaction solution was cooled to 0-10℃ and kept at this temperature for 3-4 hours to allow crystallization. After crystallization, the solution was filtered. The filter cake was washed twice with 10mL of tetrahydrofuran at 5℃. The filter cake was then placed in a vacuum drying oven and dried under vacuum at 45℃ for 15-16 hours, yielding 6.9g of Resinard intermediate (Formula II) with an HPLC purity of 92.2% and a yield of 48.51%. This intermediate was directly used in the next production step.

[0058] Add Resinard intermediate (Formula II) (5 g), tert-butyl bromoacetate (3.91 g), and N,N-dimethylformamide (25 mL) to a 250 mL three-necked glass flask and stir to dissolve. Add triethylamine (2.75 g) to the reaction system, maintain the reaction temperature at 25 °C, and stir for 8 hours. The reaction is complete when the starting material spot disappears as monitored by thin-layer chromatography (TLC).

[0059] Slowly add 100 mL of deionized water to the reaction solution, stir for 10 minutes, and extract three times with ethyl acetate (50 mL each time). Combine the organic phases. Wash the organic phase twice with saturated brine (25 mL each time), and dry with anhydrous sodium sulfate (5 g) for 2 hours. Filter to remove the drying agent, transfer the filtrate to a rotary evaporator, and concentrate under reduced pressure at 50 °C in a water bath and a vacuum degree ≤ -0.09 MPa to remove the solvent, yielding 7.1 g of crude tert-butyl 2-((4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (Formula III), which can be directly used in the next production step.

[0060] Crude product of Formula III (7.1 g) and dichloromethane (40 mL) were added to a 100 mL three-necked glass flask and stirred to dissolve. The reaction solution was cooled to 10 °C, and N-bromosuccinimide (3.5 g) and silver trifluoromethanesulfonate (0.16 g) were added in portions. After the addition was complete, the temperature was raised to 20 °C and the reaction was stirred for 3 hours. The reaction was monitored by TLC until complete. 25 mL of saturated sodium thiosulfate aqueous solution was added to the reaction solution, and the mixture was stirred for 10 minutes to quench any unreacted N-bromosuccinimide. The mixture was extracted and separated, and the organic phase was collected. It was washed once with saturated brine (15 mL) and dried with anhydrous sodium sulfate (4 g) for 1 hour. The desiccant was removed by filtration, and the filtrate was transferred to a rotary evaporator flask. The solvent was removed by vacuum concentration under reduced pressure at 45°C and a vacuum degree of ≤-0.09MPa to obtain 8.19g of crude tert-butyl 2-((5-bromo-4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (Formula IV), which was directly used in the next production step.

[0061] Add 8.19 g of crude product of formula IV and 15 mL of dichloromethane to a 100 mL three-necked glass flask, stir to dissolve, then add 15 mL of trifluoroacetic acid. Control the reaction temperature at 25 °C (room temperature) and stir for 4 hours. Monitor the deprotection reaction by TLC until complete. Transfer the reaction solution to a rotary evaporator and remove the solvent by rotary evaporation under reduced pressure at 50 °C in a water bath and a vacuum of ≤-0.09 MPa.

[0062] Add an ethyl acetate / water mixture (2:1 volume ratio, total volume 60 mL, including 40 mL ethyl acetate and 20 mL water) to the residue and stir to dissolve. Adjust the pH of the reaction solution to 7 with 10% sodium hydroxide aqueous solution, stir for 10 minutes, then separate the liquids. Transfer the organic phase to a rotary evaporator and concentrate to dryness under reduced pressure at 50°C in a water bath and a vacuum degree ≤-0.09 MPa. Add 15 mL of n-heptane to the concentrated residue, heat to 60°C and stir to dissolve, then slowly cool to 5°C and maintain the temperature for crystallization for 2 hours.

[0063] After crystallization, the mixture was filtered, and the filter cake was washed once with 5 mL of cold n-heptane. The filter cake was then placed in a vacuum drying oven and dried under vacuum at 40°C for 6 hours. 5.3 g of Resinard (Formula V) product was obtained, with an HPLC purity of 99.79% and a total impurity content of 0.21%. The total molar yield based on Formula I was 34.15%.

[0064] Comparative Example 2: Continuous Flow Synthesis Process

[0065] Thioaminourea (5.01 g) and tetrahydrofuran (150 mL) were added to a 500 mL three-necked glass bottle and stirred for 20 minutes until completely dissolved to obtain fluid A. 4-Cyclopropylnaphthalene-1-carboxaldehyde (10.0 g, Formula I) and tetrahydrofuran (30 mL) were added to a 250 mL single-necked flask and ultrasonically dispersed for 10 minutes to obtain a uniformly suspended fluid B. Acetic acid (2 g) and deionized water (18 g) were added to a 100 mL beaker and stirred until homogeneous to obtain a 10% (w / w) aqueous solution of acetic acid (fluid C). Sodium hydroxide (2 g) and deionized water (18 mL) were added to a 100 mL beaker and stirred until dissolved to obtain a 10% sodium hydroxide aqueous solution (fluid D).

[0066] Fluids A, B, and C are delivered to a micro-mixer at a pump speed ratio of 4:1:0.2 using a precision metering pump, achieving instantaneous and uniform mixing. The mixture then enters a microchannel reactor. The reactor temperature is controlled at 65°C, and the system pressure is maintained at 0.3~0.32MPa via a back pressure regulating valve. The total flow rate is adjusted to ensure a residence time of 3 minutes for the materials within the reactor. The reaction solution immediately flows out and enters an online quenching module, where it is mixed online with fluid D at a molar ratio of 1:1 to complete the quenching reaction.

[0067] After quenching, the material was transferred to a 500 mL rotary evaporator and concentrated under reduced pressure at 60 °C in a water bath and a vacuum degree ≤ -0.09 MPa to 1 / 3 of the original volume (approximately 60 mL). The concentrate was then transferred to a 250 mL three-necked flask and cooled to 10 °C for crystallization for 30 min. After crystallization, the mixture was filtered, and the filter cake was washed twice with 10 mL of tetrahydrofuran at 5 °C. The filter cake was then placed in a vacuum drying oven and dried under vacuum at 45 °C for 4 hours to obtain 11.9 g of Resinard intermediate (Formula II), with an HPLC purity of 99.4% and a yield of 83.66%.

[0068] Comparative Example 3: Continuous Flow Synthesis Process - Residence Time Comparative Example

[0069] Thioaminourea (5.01 g) and tetrahydrofuran (150 mL) were added to a 500 mL three-necked glass bottle and stirred for 20 minutes until completely dissolved to obtain fluid A. 4-Cyclopropylnaphthalene-1-carboxaldehyde (10.0 g, Formula I) and tetrahydrofuran (30 mL) were added to a 250 mL single-necked flask and ultrasonically dispersed for 10 minutes to obtain a uniformly suspended fluid B. Acetic acid (2 g) and deionized water (18 g) were added to a 100 mL beaker and stirred until homogeneous to obtain a 10% (w / w) aqueous solution of acetic acid (fluid C). Sodium hydroxide (2 g) and deionized water (18 mL) were added to a 100 mL beaker and stirred until dissolved to obtain a 10% sodium hydroxide aqueous solution (fluid D).

[0070] Fluids A, B, and C are delivered to a micro-mixer at a pump speed ratio of 5:1:0.2 using a precision metering pump, achieving instantaneous and uniform mixing. The mixture then enters a microchannel reactor. The reactor temperature is controlled at 65°C, and the system pressure is maintained at 0.3~0.32MPa via a back pressure regulating valve. The total flow rate is adjusted to ensure a residence time of 1 minute for the materials within the reactor. The reaction solution immediately flows out and enters an online quenching module, where it is mixed online with fluid D at a molar ratio of 1:1 to complete the quenching reaction.

[0071] After quenching, the material was transferred to a 500 mL rotary evaporator and concentrated under reduced pressure at 60 °C in a water bath and a vacuum degree ≤ -0.09 MPa to 1 / 3 of the original volume (approximately 60 mL). The concentrate was then transferred to a 250 mL three-necked flask and cooled to 10 °C for crystallization for 30 min. After crystallization, the mixture was filtered, and the filter cake was washed twice with 10 mL of tetrahydrofuran at 5 °C. The filter cake was then placed in a vacuum drying oven and dried under vacuum at 45 °C for 4 hours to obtain 7.5 g of Resinard intermediate (Formula II), with an HPLC purity of 89.4% and a yield of 52.73%.

[0072] Comparative Example 4: Continuous Flow Synthesis Process - Residence Time Comparative Example

[0073] Thioaminourea (5.01 g) and tetrahydrofuran (150 mL) were added to a 500 mL three-necked glass bottle and stirred for 20 minutes until completely dissolved to obtain fluid A. 4-Cyclopropylnaphthalene-1-carboxaldehyde (10.0 g, Formula I) and tetrahydrofuran (30 mL) were added to a 250 mL single-necked flask and ultrasonically dispersed for 10 minutes to obtain a uniformly suspended fluid B. Acetic acid (2 g) and deionized water (18 g) were added to a 100 mL beaker and stirred until homogeneous to obtain a 10% (w / w) aqueous solution of acetic acid (fluid C). Sodium hydroxide (2 g) and deionized water (18 mL) were added to a 100 mL beaker and stirred until dissolved to obtain a 10% sodium hydroxide aqueous solution (fluid D).

[0074] Fluids A, B, and C are delivered to a micro-mixer at a pump speed ratio of 5:1:0.2 using a precision metering pump, achieving instantaneous and uniform mixing. The mixture then enters a microchannel reactor. The reactor temperature is controlled at 65°C, and the system pressure is maintained at 0.3~0.32MPa via a back pressure regulating valve. The total flow rate is adjusted to ensure a residence time of 5 minutes for the materials within the reactor. The reaction solution immediately flows out and enters an online quenching module, where it is mixed online with fluid D at a molar ratio of 1:1 to complete the quenching reaction.

[0075] After quenching, the material was transferred to a 500 mL rotary evaporator and concentrated under reduced pressure at 60 °C in a water bath and a vacuum degree ≤ -0.09 MPa to 1 / 3 of the original volume (approximately 60 mL). The concentrate was then transferred to a 250 mL three-necked flask and cooled to 10 °C for crystallization for 30 min. After crystallization, the mixture was filtered, and the filter cake was washed twice with 10 mL of tetrahydrofuran at 5 °C. The filter cake was then placed in a vacuum drying oven and dried under vacuum at 45 °C for 4 hours to obtain 13.1 g of Resinard intermediate (Formula II), with an HPLC purity of 89.6% and a yield of 92.10%.

[0076] The longer residence time leads to a decrease in the purity of the final product of the continuous flow reaction and an increase in impurities. The most abundant impurity is Resinard impurity B: 2-{[4-(4-cyclopropyl-1-naphthyl)-4H-1,2,4-triazol-3-yl]thio}acetic acid. Furthermore, the long continuous flow reaction results in a longer overall operating time of the equipment, increased energy consumption, and an increase in the overall cost of the reaction.

[0077] It should be noted that the above are merely preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any combination or equivalent transformation made based on the above embodiments shall fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing Resinard, characterized in that, The synthetic method described above uses the compound of formula I, 4-cyclopropylnaphthalene-1-carboxaldehyde, as a raw material, and proceeds sequentially through aldehyde-thioaminourea condensation → cyclization → bromination → hydrolysis to obtain the compound of formula V, Resinard. 。 2. The synthesis method according to claim 1, characterized in that, The synthesis method includes the following steps: 1) Prepare fluid A by mixing thioaminourea or its salt with a solvent, prepare fluid B by mixing formula I, prepare fluid C by mixing the catalyst, and prepare fluid D by mixing the alkali solution; deliver fluid A, fluid B and fluid C to a micro mixer by a precision metering pump to achieve instantaneous and uniform mixing, and then enter a microchannel reactor for condensation reaction; 2) Precisely control the reaction temperature and pressure, and precisely control the residence time of the material in the reactor to 3 min; after the reaction liquid flows out, it immediately enters the online quenching module and is mixed online with fluid D; then it is continuously concentrated and crystallized to obtain the compound of formula II: 4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-thiol; 3) Dissolve Formula II and tert-butyl bromoacetate in an organic solvent, add an acid-binding agent, and stir at room temperature for 4 to 12 hours to obtain the compound of Formula III: 2-{[4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-yl]thio}tert-butyl bromoacetate; 4) Dissolve Formula III in an organic solvent, add N-bromosuccinimide (NBS) and a catalytic amount of silver trifluoromethanesulfonate at 0℃~25℃, and stir for 1.5~6 hours to obtain the compound of Formula IV: 2-{[5-bromo-4-(4-cyclopropylnaphthyl-1-yl)-4H-1,2,4-triazol-3-yl]thio}tert-butyl acetate; 5) Dissolve Formula IV in the deprotection system and react at room temperature for 2 to 6 hours; after rotary evaporation and concentration, add ethyl acetate / water to adjust the pH to alkaline, separate the liquid and concentrate the organic phase, and recrystallize from n-heptane to obtain the compound of Formula V.

3. The synthesis method as described in claim 2, characterized in that, In step 1), the molar ratio of formula I to thioaminourea is 1:1.0~3.0; in step 2), the reaction pressure is 0.3~0.32MPa; and the reaction temperature is 62℃~65℃.

4. The synthesis method as described in claim 3, characterized in that, In step 1), the molar ratio of formula I to thioaminourea is 1:1.05~1.1; the reaction temperature in step 2) is 65℃.

5. The synthesis method as described in claim 2, characterized in that, In step 1), fluids A, B, and C are pumped at a speed ratio of 5:1:0.

2.

6. The synthesis method according to claim 2, characterized in that, In step 3), the molar ratio of formula II to tert-butyl bromoacetate is 1:1.05~1.5; the acid-binding agent is selected from one or two of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, diethylamine or triethylamine; and the solvent is selected from one or two of N,N-dimethylformamide, 1,4-dioxane and tetrahydrofuran.

7. The synthesis method according to claim 2, characterized in that, In step 4), the molar ratio of formula III to NBS is 1:1.05~1.2, the molar ratio of silver trifluoromethanesulfonate catalyst is 1:0.02~0.05, and the solvent is selected from one or two of dichloromethane, trichloromethane, dichloroethane, tetrahydrofuran, acetone and toluene.

8. The synthesis method according to claim 2, characterized in that, In step 5), the deprotection system is selected from one of dichloromethane / trifluoroacetic acid, ethyl acetate / hydrogen chloride, or 1,4-dioxane / hydrogen chloride.

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