A process for the synthesis of 4-fluoro-isoquinoline-5-sulfonyl chloride

Abstract

The application discloses a synthesis process of 4-fluoro-isoquinoline-5-sulfonyl chloride. 5-nitroisoquinoline is used as raw material, and 4-fluoro-isoquinoline-5-sulfonyl chloride is synthesized through directional fluorination, reduction and sulfonylation. The process has the advantages of easy and cheap raw material, mild reaction condition, high total yield of product, avoidance of involving isoquinoline nitrogen oxide intermediate, essential safety and the like, and realizes efficient preparation of 4-fluoro-isoquinoline-5-sulfonyl chloride.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a synthesis process for 4-fluoro-isoquinoline-5-sulfonyl chloride. Background Technology

[0002] Rosudil (K-115) is a small-molecule isoquinoline Rho-associated kinase (ROCK) inhibitor used to treat glaucoma and intraocular hypertension. Glaucoma is a leading chronic eye disease causing irreversible blindness, and lowering intraocular pressure is a core treatment strategy. Rosudil, as a novel Rho kinase (ROCK) inhibitor, lowers intraocular pressure by promoting aqueous humor outflow and has potential neuroprotective effects.

[0003]

[0004] The synthesis of rosudil is based on the construction process of the diazonium ring structure in its structure, and there are two main synthetic routes.

[0005] The first method uses 4-fluoro-isoquinoline-5-sulfonyl chloride as a starting material to synthesize a chain sulfonamide, which is then cyclized to obtain rosudil; this is the so-called tandem synthesis method. The reaction route is shown below:

[0006]

[0007] Another synthetic method is the aggregation method. This involves first synthesizing the intermediate (S)-3-methyl-1-tert-butoxycarboxylo-1,4-diazacycloheptane, and then reacting it with 4-fluoro-isoquinoline 5-sulfonyl chloride to synthesize rosudil. The reaction route is shown below:

[0008]

[0009] Both the aggregation method and the tandem method use 4-fluoro-isoquinoline-5-sulfonyl chloride as the starting material, so the synthesis of this intermediate has a decisive influence on the preparation of rosudil.

[0010] In 2011, Japanese researchers Gomi, Noriaki, et al. reported a method for synthesizing 4-fluoroisoquinoline-5-sulfonyl chloride. This route uses 4-fluoroisoquinoline as a starting material, undergoing sulfonation in a mixture of concentrated sulfuric acid and sulfur trioxide, followed by chlorination with thionyl chloride (SOCl2) in the same reactor. The final product, 4-fluoroisoquinoline-5-sulfonyl chloride, is obtained by recrystallization. Although this method is a major method for synthesizing 4-fluoroisoquinoline-5-sulfonyl chloride, it suffers from poor reaction selectivity, is prone to producing byproducts, resulting in low main yields and low raw material utilization, which complicates subsequent separation and purification. The mixture of concentrated sulfuric acid and sulfur trioxide used in the synthesis is highly corrosive and oxidizing, the reaction is exothermic, and it may release toxic gases, posing safety risks. Furthermore, the use of highly toxic organic solvents such as thionyl chloride in this process route leads to complex residue control in the final drug. In summary, although this route can achieve the synthesis of the target product 4-fluoroisoquinoline-5-sulfonyl chloride, it has significant limitations in terms of reaction efficiency, process safety, and environmental friendliness, providing a clear direction for subsequent process optimization and greening improvements.

[0011]

[0012] 4-Fluoroisoquinoline is used as the starting material for the synthesis of 4-fluoroisoquinoline-5-sulfonyl chloride, and there are two main synthetic methods. Among them, Zhao Xiaoying et al. disclosed a synthetic method (Scheme 1) in 2018, the specific synthetic route of which is as follows:

[0013]

[0014] This method uses 1-hydroxyisoquinoline as a starting material, introduces 4-fluorine through Selectfluor electrophilic fluorination, optimizes the hydroxyl activity using a protection-deprotection strategy, and then removes the 1-hydroxyl group through chlorination and catalytic hydrogenation to obtain 4-fluoroisoquinoline. However, this synthetic method suffers from problems such as expensive starting materials, cumbersome steps, and low yield, making it unsuitable for industrial production.

[0015] Another method for synthesizing 4-fluoroisoquinoline, published by Dou Yandong et al. in 2024, is as follows (Scheme 2).

[0016]

[0017] This method uses isoquinoline as the starting material and proceeds through a multi-step reaction involving oxidation, substitution, fluorination, chlorination, and dechlorination to finally obtain 4-fluoroisoquinoline. Isoquinoline, as the starting material, is oxidized to generate isoquinoline nitrides; however, isoquinoline nitrides are unstable and pose an explosion risk, which is one of the most significant drawbacks of this method. Furthermore, in the fluorination process, an indirect strategy of "fluorination-chlorination-dehalogenation" is employed to introduce a single fluorine atom at a specific position, adding at least two unnecessary transformations, significantly increasing operational complexity and leading to a decrease in overall yield. Summary of the Invention

[0018] This invention addresses the shortcomings of existing technologies by providing a synthetic process for 4-fluoro-isoquinoline-5-sulfonyl chloride, a key intermediate in rosudil. The process utilizes readily available and inexpensive raw materials, employs mild reaction conditions, eliminates the need for intermediate separation, achieves a high overall product yield, avoids the involvement of isoquinoline nitride intermediates, and possesses inherent safety advantages, thus realizing the efficient preparation of 4-fluoro-isoquinoline-5-sulfonyl chloride.

[0019] The present invention provides a synthesis process for 4-fluoro-isoquinoline-5-sulfonyl chloride, which uses inexpensive and readily available 5-nitroisoquinoline as a raw material and efficiently synthesizes 4-fluoro-isoquinoline-5-sulfonyl chloride through directed fluorination, reduction, and sulfonation reactions. Rosudil can then be further synthesized via a polymerization or tandem method.

[0020] Specifically, the steps include the following:

[0021] Step 1: Add 5-nitroisoquinoline, methyl pyruvate, and an organic solvent sequentially to a reaction flask equipped with a stirrer, thermometer, and dropping funnel. Start the stirrer and add dimethyl butynedioate dropwise to the reaction solution at room temperature. After the addition is complete, allow the reaction to proceed at room temperature, monitoring for complete reaction of the starting material, nitroisoquinoline. Concentrate the reaction solution under vacuum to remove the solvent. Add ethanol to the remaining concentrate and stir. A yellow solid precipitate gradually forms in the reaction solution. Filter and wash with ethanol to obtain a yellow solid, 2H-11bH-[1,3]oxazin[2,3-a]isoquinoline-2,3,4-tricarboxylic acid 2-methyl-8-nitro-2,3,4-trimethyl ester, which is intermediate I. Intermediate I is directly used in the subsequent fluorination reaction.

[0022] Step 2: Add intermediate I to the reactor, followed by the selective fluorine reagent, catalyst, nucleophilic fluorine source reagent, and organic solvent in sequence. Heat to 40-50 °C with stirring to carry out the reaction. Monitor intermediate I during the reaction until the reaction is complete. Add an equal amount of 6 mol / L hydrochloric acid to the reaction mixture to raise the temperature of the reaction mixture to 65 °C. Continue the reaction for a period of time and then stop the reaction. Cool the reaction mixture and add saturated sodium hydroxide solution to adjust the pH to ≥12. Extract the reaction mixture multiple times with ethyl acetate. After mixing the extracts, remove the solvent ethyl acetate under vacuum. Add a certain amount of ethanol to the remaining concentrate, stir, and solid crystals will precipitate. Filter and collect the solid, wash with ethanol, and dry to obtain 4-fluoro-5-nitroisoquinoline, which can be directly used in the next step of nitro reduction reaction.

[0023] Step 3: Reduce 4-fluoro-5-nitroisoquinoline to 4-fluoro-5-aminoisoquinoline using conventional methods. For example, using stannous chloride as the reducing agent: Take a certain amount of 4-fluoro-5-nitroisoquinoline, dissolve it in 37% hydrochloric acid (1.0 M), add stannous chloride dihydrate while stirring, and react at 50 °C until 4-fluoro-5-nitroisoquinoline is completely reacted; add sodium hydroxide solution to the reaction mixture to adjust its pH to ≥12, extract the reaction mixture with ethyl acetate, combine the extracted organic phases, remove most of the ethyl acetate solvent under reduced pressure, cool the residue to crystallize, filter and wash to obtain 4-fluoro-5-aminoisoquinoline, which can be directly used in the next step of sulfonation reaction.

[0024] Step 4: Under nitrogen protection, 4-fluoro-5-aminoisoquinoline, 1,4-diazacyclic [2,2,2]octane-1,4-diconium-1,4-disulfinic acid (DABSO), cuprous halide catalyst, and solvent were sequentially added to a reaction flask. After cooling the reaction mixture, 37% hydrochloric acid solution was added dropwise, controlling the temperature of the reaction mixture to 18°C. Then, tert-butyl nitrite was added dropwise, and the reaction mixture was thoroughly cooled, controlling the reaction temperature not to exceed 0°C. After the addition of tert-butyl nitrite was completed, the reaction was stirred for a period of time. The cold bath was removed, and the reaction mixture was stirred for a period of time at room temperature to obtain a solution containing 4-fluoro-isoquinoline 5-sulfonyl chloride. This solution can be directly used for the synthesis of rosudil.

[0025] The synthesis route is shown below:

[0026] .

[0027] In the above synthesis process:

[0028] In step 1:

[0029] The molar ratio of the raw materials 5-nitroisoquinoline, methyl pyruvate and dimethyl butynedioate is 1:1.0~5.0:1.0~5.0, preferably 1.0:1.0~2.0:1.0~2.0.

[0030] The organic solvent is an aprotic polar solvent, such as aliphatic ethers, aliphatic nitriles, halogenated hydrocarbons, DMF or DMSO, etc., preferably acetonitrile, THF or MTBE, etc.

[0031] The reaction in step 1 is carried out at room temperature for 2 to 40 hours, preferably 15 to 20 hours.

[0032] In step 2:

[0033] The selective fluorine reagent is 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate), N-fluorobisbenzenesulfonamide (NFSI), N-fluoropyridine salt or lashikawa reagent, preferably 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) or N-fluoropyridine salt.

[0034] The catalyst is 15-crown ether-5, 18-crown ether-6, or β-cyclodextrin.

[0035] The nucleophilic fluorine source reagent is potassium fluoride, cesium fluoride, tetrabutylammonium fluoride or diethylaminosulfur trifluoride, preferably potassium fluoride or cesium fluoride.

[0036] The molar ratio of intermediate I to the selective fluorine reagent, catalyst, and nucleophilic fluorine source reagent is 1.0:1.0~5.0:1.0~5.0:1.0~5.0, preferably 1.0:1.0~3.0:1.0~3.0:1.0~3.0.

[0037] The reaction temperature in step 2 is 30~80℃, preferably 40~70℃; the reaction time is 24~48 h, preferably 24~36 h.

[0038] In step 3:

[0039] The reduction of 4-fluoro-5-nitroisoquinoline to 4-fluoro-5-aminoisoquinoline can be achieved using conventional methods such as catalytic hydrogenation reduction, acid-metal reduction, inorganic sulfide reduction, or stannous chloride reduction. Zinc powder / methanol reduction and stannous chloride / hydrochloric acid reduction are preferred. The reaction temperature is 40–65°C, preferably 40–50°C.

[0040] In step 4:

[0041] The cuprous halide catalyst is cuprous iodide, cuprous chloride, or cuprous bromide, preferably cuprous chloride.

[0042] The molar ratio of 4-fluoro-5-aminoisoquinoline, cuprous halide catalyst, DABSO, tert-butyl nitrite, and 37% hydrogen chloride solution is 1.0:0.1~1.0:0.1~1.0:1.0~3.0:1.0~3.0, preferably 1.0:0.1~0.5:0.5~1.0:1.0~2.0:2.0~3.0.

[0043] The reaction time for step 4 is 12h~48h, preferably 20~24h.

[0044] The subsequent synthesis steps of rosuddhiazine employ conventional tandem or convergent synthesis methods. For example, the convergent synthesis process:

[0045] .

[0046] The process of synthesizing rosudil using 4-fluoro-isoquinoline-5-sulfonyl chloride as a starting material is illustrated below:

[0047] The 4-fluoro-isoquinoline-5-sulfonyl chloride mixture obtained in this invention was cooled to 0°C, and (S)-1-BOC-2-methyl-[1,4]diazacycloheptane was added dropwise. After the addition was complete, the cold water bath was removed, the reaction mixture was raised to room temperature and stirred for 30 minutes, and then a saturated ammonium chloride aqueous solution was added to terminate the reaction. Subsequently, the mixture was extracted, dried, filtered, concentrated and purified to obtain rosudil intermediate. The rosudil intermediate was deprotected with the Boc protecting group under acidic conditions to obtain rosudil.

[0048] In the synthesis of rosudil, the molar ratio of the reactants 4-fluoro-isoquinoline-5-sulfonyl chloride and (S)-1-BOC-2-methyl-[1,4]diazacycloheptane is 1:5.0; preferably 1:3.0.

[0049] When removing the Boc protecting group under acidic conditions, a trifluoroacetic acid / dichloromethane (acid / solvent) system, an HCl / dioxane (acid / solvent) system, or an HCl / ethyl acetate (acid / solvent) system can be used, with the trifluoroacetic acid / dichloromethane system being preferred.

[0050] The advantages of this invention compared to the prior art are as follows:

[0051] This invention uses safe and readily available 5-nitroisoquinoline as a starting material to efficiently construct the target molecule through a continuous fluorination-sulfonation reaction. The overall process conditions are mild and the operation is simple, exhibiting significant advantages in terms of safety, selectivity, and economy, as specifically demonstrated below:

[0052] 1. The raw material 5-nitroisoquinoline is inexpensive and readily available, reducing the production cost of 4-fluoroisoquinoline-5-sulfonyl chloride.

[0053] 2. No protecting or directing groups need to be introduced in the fluorination step; the product is directly and precisely positioned at isoquinoline 4-, resulting in a high yield of fluorinated products.

[0054] 3. Avoid using fuming sulfuric acid, SO3, or isoquinoline nitrogen oxides in the synthesis of the key intermediate 4-fluoro-isoquinoline-5-sulfonyl chloride. This significantly reduces corrosion and safety risks. The use of stable and safe solid fluorinating reagents eliminates the need for high-pressure hydrogenation or extreme conditions, resulting in lower equipment requirements and suitability for large-scale production.

[0055] 4. Although 4-fluoroisoquinoline-5-sulfonyl chloride is synthesized through a four-step reaction, the intermediates in each step do not require crystallization and purification before proceeding to subsequent reactions. The reaction conditions in each step are mild, the process is simple, and the overall product yield is high.

[0056] 5. The new method for synthesizing 4-fluoroisoquinoline-5-sulfonyl chloride has both atom economy and step economy in its overall process, reduces the emission of waste gas, wastewater, and solid waste, and is easy to implement on an industrial scale. Attached Figure Description

[0057] Figure 1 The liquid chromatography-mass spectrum of 4-fluoro-5-aminoisoquinoline is shown.

[0058] Figure 2 This is a liquid chromatography-mass spectrum of a solution containing benzenesulfonyl chloride.

[0059] Figure 3 This is the liquid chromatography-mass spectrum of rosudil. Detailed Implementation

[0060] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0061] Example 1:

[0062] This embodiment prepares 4-fluoro-isoquinoline-5-sulfonyl chloride via the following steps, and then uses it as a raw material to further prepare rosudil:

[0063] 1. Add 5-nitroisoquinoline (1.05 g, 6.0 mmol), methyl pyruvate (1.23 g, 12.0 mmol), and acetonitrile (20 ml) sequentially to a 250 ml Erlenmeyer flask. Add dimethyl butynedioate (1.71 g, 12.0 mmol) dropwise at a uniform rate at room temperature. After the addition is complete, continue the reaction at room temperature for 24 h. Then, concentrate the reaction solution under vacuum to remove the acetonitrile solvent. Add ethanol (10 ml) to the remaining concentrate and stir for 30 min to form a yellow suspension. Filter the suspension and wash the filter cake several times with ethanol to obtain a yellow solid intermediate I, weighing 2.50 g, with a yield of 99%. Used directly in the next synthesis.

[0064] 2. Add the previously synthesized yellow intermediate I (2.50 g, 6.0 mmol), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (2.34 g, 6.6 mmol), 18-crown ether-6 (1.58 g, 6.0 mmol), potassium fluoride (0.52 g, 9.0 mmol), and acetonitrile (30 ml) to a 500 ml three-necked flask, and purge with nitrogen for protection. After reflux at 45 °C for 3 h, add 6 mol / L hydrochloric acid (30 ml) dropwise at a uniform rate, and continue the reaction at 65 °C for 24 h. After adjusting the pH of the reaction mixture to greater than 12 with saturated sodium hydroxide solution, the reaction solution was extracted multiple times with ethyl acetate. The extract was collected and concentrated under vacuum to remove the ethyl acetate. A certain amount of ethanol was added to the concentrate, and the mixture was stirred for 2 hours to precipitate a solid. The solid was filtered, washed with ethanol, and dried to obtain 0.92 g of 4-fluoro-5-nitroisoquinoline, with a yield of 80%. This solid was used directly in the next synthesis. The 4-fluoro-5-nitroisoquinoline, purified by recrystallization, can be directly used for subsequent liquid chromatography-mass spectrometry measurements.

[0065] 3. Add 0.92 g (5.8 mmol) of 4-fluoro-5-nitroisoquinoline to a flask and dissolve it in 10 ml of 37% hydrochloric acid (1.0 M). Then add stannous dichloride (3.32 g, 14.3 mmol), stir, and heat at 50°C for 12 h. Adjust the pH to greater than 12 by adding saturated sodium hydroxide solution to the flask, extract with ethyl acetate, and combine the organic phases to obtain 0.65 g of 4-fluoro-5-aminoisoquinoline, with a yield of 80%. Use this directly in the next synthesis reaction.

[0066] 4. In a round-bottom flask, add 0.65 g (4.0 mmol) of 4-fluoro-5-aminoisoquinoline, 0.58 g (2.4 mmol) of DABSO, and 0.05 g (0.4 mmol) of CuCl2 catalyst. Seal the flask and add 0.2 M acetonitrile under a nitrogen atmosphere. Place the resulting solution in a cold water bath (0°C) and add dropwise 37% hydrogen chloride solution (0.29 g, 8.0 mmol). After stirring and mixing thoroughly, add 0.45 g (4.4 mmol) of tert-butyl nitrite. Cool the reaction mixture thoroughly, controlling the reaction temperature not to exceed 0°C. After the addition is complete, remove the cold water bath and stir the reaction mixture overnight at room temperature. A mixture containing 4-fluoroisoquinoline-5-sulfonyl chloride is obtained, which can be directly used in the next step of rosudil synthesis.

[0067] 5. The reaction mixture of 4-fluoroisoquinoline-5-sulfonyl chloride was cooled to 0°C, and (S)-1-BOC-2-methyl-[1,4]diazacycloheptane (1.11 g, 5.2 mmol) was added dropwise. After the addition was complete, the water bath was removed, the reaction mixture was brought to room temperature, and stirred for 30 minutes. The reaction was then terminated by adding 6.0 mL of saturated ammonium chloride aqueous solution. The resulting mixture was adjusted to pH greater than 12 with sodium hydroxide and extracted with ethyl acetate. The collected organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized to give rosudil intermediate II, with a weight of 0.77 g and a yield of 70%.

[0068] 6. Rosudil intermediate II (0.77 g, 1.8 mmol), trifluoroacetic acid (0.21 g, 1.8 mmol), and tetrahydrofuran (1.5 V) were stirred at room temperature for 4 h. The resulting mixture was adjusted to pH greater than 12 with sodium hydroxide, extracted with ethyl acetate, and the collected organic phase was dried on anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and recrystallized to obtain rosudil with a weight of 0.41 g, yielding 70%.

[0069] Example 2:

[0070] This embodiment prepares 4-fluoro-isoquinoline-5-sulfonyl chloride via the following steps, and then uses it as a raw material to further prepare rosudil:

[0071] 1. Nitroisoquinoline (1.05 g, 6.0 mmol), methyl pyruvate (1.23 g, 12.0 mmol), and acetonitrile (20 ml) were added sequentially to a 250 ml Erlenmeyer flask. Dimethyl butynedioate (1.71 g, 12.0 mmol) was added dropwise at a uniform rate at room temperature. After the addition was complete, the reaction was continued at room temperature for 24 h. The reaction solution was then concentrated under vacuum to remove the acetonitrile solvent. Ethanol (10 ml) was added to the remaining concentrate and stirred for 30 min to form a yellow suspension. The suspension was then filtered, and the filter cake was washed several times with ethanol to obtain a yellow solid intermediate I, weighing 2.50 g, with a yield of 99%. This was used directly in the next synthesis.

[0072] 2. Add the previously synthesized yellow intermediate I (2.50 g, 6.0 mmol), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (2.34 g, 6.6 mmol), 18-crown ether-6 (3.17 g, 12.0 mmol), potassium fluoride (0.52 g, 9.0 mmol), and acetonitrile (30 ml) to a 500 ml three-necked flask, and purge with nitrogen for protection. After reflux at 45 °C for 3 h, add 6 mol / L hydrochloric acid (30 ml) dropwise at a uniform rate, and continue the reaction at 65 °C for 24 h. After adjusting the pH of the reaction mixture to greater than 12 with saturated sodium hydroxide solution, the reaction solution was extracted multiple times with ethyl acetate. The extract was collected and concentrated under vacuum to remove the ethyl acetate. A certain amount of ethanol was added to the concentrate, and the mixture was stirred for 2 hours to precipitate a solid. The solid was filtered, washed with ethanol, and dried to obtain 0.70 g of 4-fluoro-5-nitroisoquinoline, with a yield of 60%. This solid was used directly in the next synthesis. The 4-fluoro-5-nitroisoquinoline, purified by recrystallization, can be directly used for subsequent liquid chromatography-mass spectrometry measurements.

[0073] 3. Add 0.70 g (3.6 mmol) of 4-fluoro-5-nitroisoquinoline to a flask and dissolve it in 10 ml of 37% hydrochloric acid (1.0 M). Then add stannous dichloride (2.44 g, 10.8 mmol), stir, and heat at 50°C for 12 h. Adjust the pH to greater than 12 by adding saturated sodium hydroxide solution to the flask, extract with ethyl acetate, and combine the organic phases to obtain 0.49 g of 4-fluoro-5-aminoisoquinoline in 80% yield, which can be used directly in the next synthesis reaction.

[0074] 4. In a round-bottom flask, add 0.49 g (3.0 mmol) of 4-fluoro-5-aminoisoquinoline, 0.43 g (1.8 mmol) of DABSO, and 0.04 g (0.3 mmol) of CuCl2 catalyst. Seal the flask and add 0.2 M acetonitrile under a nitrogen atmosphere. Place the resulting solution in a cold water bath (18°C) and add dropwise 37% hydrogen chloride solution (0.27 g, 7.4 mmol). After stirring and mixing thoroughly, add 0.22 g (3.3 mmol) of tert-butyl nitrite. After the addition is complete, remove the flask from the cold water bath and stir the reaction mixture overnight at room temperature. A mixture containing 4-fluoroisoquinoline-5-sulfonyl chloride is obtained, which can be directly used in the next step of rosudil synthesis.

[0075] 5. Cool the 4-fluoroisoquinoline-5-sulfonyl chloride reaction mixture to 0°C and add (S)-1-BOC-2-methyl-[1,4]diazacycloheptane (0.85 g, 4.0 mmol) dropwise. After the addition is complete, remove the water bath and allow the reaction mixture to reach room temperature. Stir for 30 minutes, then add 6.0 mL of saturated ammonium chloride aqueous solution to terminate the reaction. Adjust the pH of the resulting mixture to greater than 12 with sodium hydroxide and extract with ethyl acetate. Dry the collected organic phase on anhydrous sodium sulfate, filter, concentrate under reduced pressure, and recrystallize to give rosudil intermediate II, weighing 0.59 g, in 70% yield.

[0076] 6. Rosudil intermediate II (0.59 g, 1.4 mmol), trifluoroacetic acid (0.16 g, 1.4 mmol), and tetrahydrofuran (1.5 V) were stirred at room temperature for 4 h. The resulting mixture was adjusted to pH greater than 12 with sodium hydroxide, extracted with ethyl acetate, and the collected organic phase was dried on anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and recrystallized to obtain rosudil with a weight of 0.32 g, yielding 70%.

Claims

1. A process for synthesizing 4-fluoro-isoquinoline-5-sulfonyl chloride, characterized in that: 4-Fluoro-isoquinoline-5-sulfonyl chloride was synthesized from 5-nitroisoquinoline via directed fluorination, reduction, and sulfonation reactions, including the following steps: Step 1: Add 5-nitroisoquinoline, methyl pyruvate and organic solvent to the reactor in sequence, then add dimethyl butynedioate dropwise to the reaction solution. After the addition is complete, react at room temperature. After the reaction is complete, concentrate the reaction solution under vacuum to remove the solvent, add ethanol to the remaining concentrate and stir. The reaction solution gradually forms a yellow solid precipitate, which is filtered and washed with ethanol to obtain intermediate I. Step 2: Add intermediate I to the reactor, followed by selective fluorine reagent, catalyst, nucleophilic fluorine source reagent and organic solvent in sequence. Heat to 40-50 °C with stirring to carry out the reaction. Monitor intermediate I during the reaction until the reaction is complete. Add hydrochloric acid dropwise to the reaction mixture to raise the temperature of the reaction mixture to 60-70 °C and continue the reaction. After the reaction is completed, 4-fluoro-5-nitroisoquinoline is obtained by separation. Step 3: 4-Fluoro-5-nitroisoquinoline was reduced to prepare 4-fluoro-5-aminoisoquinoline; Step 4: Under nitrogen protection, 4-fluoro-5-aminoisoquinoline, 1,4-diazacyclic [2,2,2]octane-1,4-diaonium-1,4-disulfinic acid, cuprous halide catalyst and solvent were added to the reactor in sequence. After cooling the reaction mixture, hydrochloric acid solution was added dropwise to control the temperature of the reaction mixture to 18°C. Then tert-butyl nitrite was added dropwise. The reaction mixture was cooled completely and the reaction temperature was controlled not to exceed 0°C. The reaction was stirred and then the cold bath was removed. The reaction mixture was stirred and stirred at room temperature to obtain a solution containing 4-fluoro-isoquinoline 5-sulfonyl chloride. The synthesis route is shown below: 。 2. The synthesis process according to claim 1, characterized in that: In step 1, the molar ratio of the raw materials 5-nitroisoquinoline, methyl pyruvate and dimethyl butynedioate is 1:1.0~5.0:1.0~5.

0.

3. The synthesis process according to claim 1, characterized in that: In step 2, the selective fluorine reagent is 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt, N-fluorobisbenzenesulfonylimide, N-fluoropyridine salt, or lashikawa reagent.

4. The synthesis process according to claim 1, characterized in that: In step 2, the catalyst is 15-crown ether-5, 18-crown ether-6, or β-cyclodextrin.

5. The synthesis process according to claim 1, characterized in that: In step 2, the nucleophilic fluorine source reagent is potassium fluoride, cesium fluoride, tetrabutylammonium fluoride, or diethylaminosulfur trifluoride.

6. The synthesis process according to claim 1, characterized in that: In step 3, the reduction of 4-fluoro-5-nitroisoquinoline to 4-fluoro-5-aminoisoquinoline is achieved by conventional catalytic hydrogenation reduction, acid-metal element reduction, inorganic sulfide reduction, or stannous chloride reduction.

7. The synthesis process according to claim 1, characterized in that: In step 4, the cuprous halide catalyst is cuprous iodide, cuprous chloride, or cuprous bromide.

8. The synthesis process according to claim 1, characterized in that: The solution containing 4-fluoro-isoquinoline 5-sulfonyl chloride is used to synthesize rosudil via a tandem or aggregation method.

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