A method for preparing gipotassium methanesulfonate

Abstract

This invention discloses a method for preparing gipotassium methanesulfonate, comprising the following steps: Step a, reacting compound SM1 and compound SM2 to obtain compound 1, then removing the protecting group from compound 1 to obtain compound 2; or, reacting compound SM1 with compound SM5 to obtain compound 2; Step b, subjecting compound 2 and compound SM3 to a substitution reaction to obtain compound 3; Step c, reacting compound 3 with methanesulfonic acid to form a salt, thereby obtaining gipotassium methanesulfonate. The preparation method of this invention features mild reaction conditions, a short reaction route, eliminates the need for highly toxic or hazardous reagents, is simple to operate, suitable for industrial production, uses low-cost materials, and achieves high yield, significantly reducing the production cost of gipotassium methanesulfonate.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis technology, specifically relating to a method for preparing gipotassium methanesulfonate. Background Technology

[0002] Gepotidacin (brand name Blujepa) is a novel oral antibiotic developed by GlaxoSmithKline (GSK) and approved by the U.S. Food and Drug Administration (FDA) on March 25, 2025. This drug is used to treat uncomplicated urinary tract infections (uUTIs) in adult women and pediatric patients caused by specific susceptible microorganisms such as *Escherichia coli*, *Klebsiella pneumoniae*, *Citrobacter freundii* complex, *Staphylococcus saprophyticus*, and *Enterococcus faecalis*. uUTIs are among the most common infections in women, and there is a significant unmet clinical need for novel oral antibiotics, especially those effective against drug-resistant pathogens. As the first oral antibiotic with a novel mechanism of action in nearly thirty years, gepotidacin provides an important treatment option for patients with recurrent infections and those resistant to existing therapies.

[0003] Gepotasin belongs to the novel triazaacenaphthene class of antibiotics. Its mechanism of action involves inhibiting bacterial type II topoisomerases (including bacterial DNA topoisomerase II (gyrase) and topoisomerase IV), thereby inhibiting bacterial DNA replication and producing a bactericidal effect. This unique binding site and mechanism of action make it active against most target pathogens, such as *Escherichia coli* and *Staphylococcus saprophyticus*, including strains resistant to existing antibiotics. Time-effect studies have confirmed the bactericidal activity of gepotasin against pathogens.

[0004] The main routes for synthesizing Gipoda Star are as follows:

[0005]

[0006] For example, the preparation method disclosed in Chinese patent CN101687887A uses chiral compound A as a raw material. It reacts with methanesulfonic anhydride to generate compound 4, then reacts with SM4 to obtain compound 5. After deprotection, compound 5 is obtained. Compound 6 is then separated by chiral preparation to obtain a single isomer, 6A. Finally, compound 6A reacts with SM1 to obtain gipotassium. This method has a low yield of only 52% in the first step, and the multi-step purification process requires column chromatography. In particular, compound 6A requires chiral preparation, with a chiral yield as low as 32%, making it difficult to scale up for industrial production.

[0007] In summary, existing methods for synthesizing gipotassium generally suffer from problems such as lengthy steps, low yields, complex purification procedures (especially relying on chiral separation), and the use of highly toxic or hazardous reagents, making them unsuitable for industrial-scale production. Therefore, developing a process for preparing gipotassium methanesulfonate with mild reaction conditions, a short route, low cost, safe and simple operation, and suitability for large-scale production has significant practical application value. Summary of the Invention

[0008] The purpose of this invention is to provide a method for preparing gipotassium methanesulfonate, so as to solve the problem that existing preparation methods are not suitable for industrial production.

[0009] To achieve the above objectives, the present invention adopts the following technical solution:

[0010] A method for preparing gipotassium methanesulfonate includes the following steps:

[0011] Step a: Compound SM1 and compound SM2 are reacted to obtain compound 1. Then, compound 1 is deprotected to obtain compound 2. The reaction formula is as follows:

[0012]

[0013] Alternatively, reacting compound SM1 with compound SM5 yields compound 2, as shown in the following reaction formula:

[0014]

[0015] Step b involves a substitution reaction between compound 2 and compound SM3 to yield compound 3; the reaction equation is as follows:

[0016]

[0017] In compound SM3, R is one of chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate, and phenylsulfonate; the benzene ring on the phenylsulfonate group is optionally monosubstituted at any position by a C1-C4 alkyl group, nitro group, halogen, or methoxy group.

[0018] Step c, compound 3 is reacted with methanesulfonic acid to form a salt, yielding gipotassium methanesulfonate, as shown in the following reaction formula:

[0019] .

[0020] Preferably, the phenyl sulfonate group is one of benzene sulfonate group, p-toluene sulfonate group, p-nitrobenzene sulfonate group, p-methoxybenzene sulfonate group, and p-chlorobenzene sulfonate group.

[0021] Preferably, in step a, compound SM1 and compound SM2 react in a reaction solvent under reducing conditions or with a palladium-on-carbon catalyst under hydrogen source conditions to obtain compound 1. The reaction solvent is one or two of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, toluene, and water; more preferably, one or a mixture of any two of methanol, ethanol, dichloromethane, and chloroform. The reducing conditions involve adding a reducing agent such as sodium borohydride, sodium triacetylborohydride, sodium cyanoborohydride, lithium borohydride, or potassium borohydride to the reaction solvent; the reducing agent is more preferably sodium triacetylborohydride or sodium cyanoborohydride. The equivalent ratio of the reducing agent, compound SM1, and compound SM2 is 1~5:1~2:1~2; more preferably 1~2:1:1~1.5. The hydrogen source is one or more of hydrogen, formic acid, ammonium formate, and cyclohexene. The reaction temperature is 0-50°C, more preferably 10-40°C.

[0022] Preferably, in step a, compound 1 is reacted with a deprotecting agent in a reaction solvent to obtain compound 2. The reaction solvent is one or two of methanol, ethanol, isopropanol, tetrahydrofuran, methyl tert-butyl ether, toluene, acetonitrile, dichloromethane, and ethyl acetate; more preferably, it is one of acetonitrile, methanol, ethanol, dichloromethane, and ethyl acetate. The deprotecting agent is one of hydrogen chloride, hydrogen bromide, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, and oxalic acid; more preferably, it is one of hydrogen chloride, hydrogen bromide, p-toluenesulfonic acid, and methanesulfonic acid. The reaction temperature is 20-70°C, more preferably 20-50°C.

[0023] Preferably, in step a, compound SM1 and compound SM5 react in a reaction solvent under reducing conditions or with a palladium-on-carbon catalyst under hydrogen source conditions to obtain compound 2. The reaction solvent is one or two of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, toluene, and water; more preferably, it is one or a mixture of any two of methanol, ethanol, dichloromethane, and chloroform. The reducing conditions involve adding a reducing agent such as sodium borohydride, sodium triacetylborohydride, sodium cyanoborohydride, lithium borohydride, or potassium borohydride to the reaction solvent; the reducing agent is more preferably sodium triacetylborohydride or sodium cyanoborohydride. The hydrogen source is one or more of hydrogen, formic acid, ammonium formate, and cyclohexene. The reaction temperature is 0-50°C, more preferably 20-40°C.

[0024] Preferably, in step b, compound 2 participates in the reaction in its free base form or in the form of a pharmaceutically acceptable salt. The salt includes one or more of the following: hydrochloride, hydrobromide, sulfate, phosphate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, oxalate, fumarate, and maleate.

[0025] Preferably, in step b, compound 2 reacts with compound SM3 in the presence of an aprotic solvent and a base to obtain compound 3. The aprotic solvent is one or two of N,N-dimethylformamide, N-methylpyrrolidone, dichloromethane, tetrahydrofuran, chloroform, acetonitrile, acetone, toluene, and ethyl acetate; more preferably, it is N,N-dimethylformamide, tetrahydrofuran, acetonitrile, or acetone. The base is one of potassium carbonate, sodium carbonate, potassium phosphate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, lithium hydroxide, lithium carbonate, triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine; more preferably, it is one of potassium carbonate, triethylamine, and N-methylmorpholine. The reaction temperature is 30-80°C, more preferably 45-75°C.

[0026] Preferably, in step c, the salt formation reaction is carried out in methanol, ethanol, isopropanol, acetone or acetonitrile solvent, and the amount of methanesulfonic acid used is 1 to 1.5 equivalents.

[0027] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0028] On the one hand, this invention avoids the inefficient and costly chiral preparation and separation steps. By using compound SM3 to replace compound 4 in existing technologies (such as Chinese patent CN101687887A) for the reaction, the reaction yield is significantly improved, and cumbersome chromatographic purification operations are avoided, thus making it more conducive to industrial production.

[0029] On the other hand, this invention significantly reduces raw material costs by optimizing the reaction sequence. Specifically, by scheduling the expensive raw material SM3 for a later step, while using the relatively inexpensive raw material SM1 in the first step, this strategy effectively controls overall material costs.

[0030] In summary, the preparation method provided by this invention has several advantages: the reaction conditions are mild, no highly toxic or dangerous reagents are required, the operation is simple, and it is suitable for industrial production; at the same time, the material cost is low and the reaction yield is high, thereby greatly reducing the production cost of gipotassium methanesulfonate. Attached Figure Description

[0031] Figure 1 This is the liquid chromatography chromatogram of compound 1 in Example 1;

[0032] Figure 2 The MS+ spectrum of compound 1 in Example 1 is shown below.

[0033] Figure 3 This is the liquid chromatography chromatogram of compound 2 in Example 1;

[0034] Figure 4 The MS+ spectrum of compound 2 in Example 1;

[0035] Figure 5 The liquid chromatography chromatogram of giberdalin in Example 1;

[0036] Figure 6 The MS+ spectrum of Gibbada star in Example 1;

[0037] Figure 7 The NMR spectrum of Gibbada star in Example 1 1 HNMR;

[0038] Figure 8 The image shows the liquid chromatography chromatogram of giberberine methanesulfonic acid dihydrate in Example 1.

[0039] Figure 9 The NMR spectrum for detecting gipotassium methanesulfonic acid dihydrate in Example 1. 1 HNMR. Detailed Implementation

[0040] The present invention will be further described below with reference to the embodiments.

[0041] Example 1

[0042] Step 1, the reaction formula is:

[0043]

[0044] The steps were as follows: 5.0 g of compound SM1 was weighed and added to a mixed solvent of 60 mL dichloromethane and 10 mL methanol, followed by 6.8 g of compound SM2. 3.5 g of sodium borohydride was added in portions at 20-30 °C, and the reaction was monitored until complete. Then, 50 mL of saturated sodium bicarbonate aqueous solution was added dropwise. The mixture was separated, and the aqueous phase was extracted again with 20 mL of dichloromethane. The organic phases were separated, combined, washed with 20 mL of saturated sodium chloride aqueous solution, separated, and concentrated in a water bath at 40 °C to obtain 9.7 g of oil, namely compound 1, with a purity of 96.5%, a yield of 91.0%, and MS+: 348.2.

[0045] Step 2, the reaction formula is:

[0046]

[0047] The steps are as follows: Weigh 1.0g of compound 1 and add it to 10mL of 4M hydrogen chloride methanol solution. Stir at room temperature. After the reaction is complete, concentrate the methanol to obtain 0.80g of oily substance, namely compound 2, with a purity of 99.6% and a yield of 98.1%, and MS+: 248.2.

[0048] Step 3, the reaction formula is:

[0049]

[0050] The steps are as follows: Weigh 2.0g of compound 2 and add 20mL of acetonitrile, then add 1.1g of compound SM3-A, and finally add 1.7g of N,N-diisopropylethylamine. Heat to reflux and monitor until the reaction is complete. Then cool to 0~10℃, and a large amount of solid precipitates. Filter, and dry the filter cake under vacuum at 45℃ to obtain 1.1g of pale yellow solid, namely gipotassium, with a purity of 98.5%, a yield of 92.3%, and MS+: 449.2.

[0051] Step 4, the reaction formula is:

[0052]

[0053] The steps are as follows: Weigh 0.35g of gipotassium and add it to 3.5mL of isopropanol. Dissolve 0.09g of methanesulfonic acid in 0.18g of water. Add this solution to the above system, heat to 85℃, dissolve until clear, allow to cool naturally to crystallize, filter, wash with isopropanol, and dry under vacuum at 40℃ to obtain 0.41g of gipotassium methanesulfonic acid dihydrate, purity: 99.7%, yield: 91.1%.

[0054] Example 2

[0055] Step 1, the reaction formula is:

[0056]

[0057] The steps are as follows: Weigh 10.0g of compound SM1 and add it to 120mL of dichloromethane, then add 13.5g of compound SM2. Add 19.5g of sodium borohydride acetate in portions at 20~30℃, and monitor until the reaction is complete. Then add 100mL of saturated sodium bicarbonate aqueous solution dropwise, separate the layers, extract the aqueous phase with 50mL of dichloromethane, separate the layers again, combine the organic phases, wash with 50mL of saturated sodium chloride aqueous solution, separate the layers, and concentrate the organic phase in a water bath at 40℃ to obtain 19.4g of oily substance, namely compound 1, with a purity of 97.2% and a yield of 91.0%.

[0058] Step 2, the reaction formula is:

[0059]

[0060] The steps are as follows: Weigh 18.0g of compound 1, add 360mL of ethanol, then add 35.7g of p-toluenesulfonic acid, heat to reflux and monitor until the reaction is complete, then cool to 0~10℃, a large amount of solid precipitates, filter, dry under vacuum at 45℃, to obtain 29.12g of white solid, namely compound 2, with a yield of 73.5% and a purity of 99.0%.

[0061] Step 3, the reaction formula is:

[0062]

[0063] The steps are as follows: Weigh 0.5g of compound 2 and add 20mL of N,N-dimethylformamide, then add 0.7g of compound SM3-B, and finally add 0.3g of potassium carbonate. Heat to 45℃ and continue the reaction at this temperature until the reaction is complete. Then cool to room temperature, add 50mL of water, and extract three times with dichloromethane (20mL each time). Combine the organic phases, wash with 20mL of saturated sodium chloride aqueous solution, separate the layers, dry with anhydrous sodium sulfate, and concentrate under vacuum at 45℃ to obtain 0.6g of solid, namely gipotassium, with a purity of 97.7% and a yield of 64.4%.

[0064] Step 4, the reaction formula is:

[0065]

[0066] The steps are as follows: Weigh 2.0g of gipotassium and add it to 20mL of isopropanol. Dissolve 0.43g of methanesulfonic acid in 0.87g of water. Add this solution to the above system, heat to 85℃, dissolve until clear, allow to cool naturally to crystallize, filter, wash with isopropanol, and dry under vacuum at 40℃ to obtain 2.4g of gipotassium methanesulfonic acid dihydrate, with a purity of 98.5% and a yield of 92.7%.

[0067] Example 3

[0068] Step 1, the reaction formula is:

[0069]

[0070] The steps are as follows: Weigh 3.0 g of compound SM1 and add it to a mixed solvent of 12 mL dichloromethane and 2 mL methanol, then add 0.6 g of compound SM5. Add 3.5 g of sodium cyanoborohydride in portions at 20-30 °C, and monitor until the reaction is complete. Then add 10 mL of saturated sodium bicarbonate aqueous solution dropwise, separate the layers, extract the aqueous phase with 5 mL of dichloromethane, separate the layers again, combine the organic phases, wash with 5 mL of saturated sodium chloride aqueous solution, separate the layers, and concentrate the organic phase in a water bath at 40 °C to obtain 5.0 g of oily substance, namely compound 2, with a purity of 90.9% and a yield of 78.1%.

[0071] Step 2, the reaction formula is:

[0072]

[0073] The steps are as follows: Weigh 1.0g of compound 2 and add 20mL of acetonitrile, then add 1.5g of compound SM3-C, and finally add 0.9g of potassium carbonate. Heat under reflux and monitor until the reaction is complete. Then concentrate the acetonitrile. After concentration, add 20mL of water to dissolve the solid. Extract three times with dichloromethane (20mL each time). Combine the organic phases, wash with 20mL of saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, and concentrate under vacuum at 45℃. After concentration, 1.5g of pale yellow solid, namely giberdazine, is obtained with a purity of 98.0% and a yield of 83.3%.

[0074] Step 3, the reaction formula is:

[0075]

[0076] The steps are as follows: Weigh 2.4g of gipodacin and add it to 48mL of acetone. Dissolve 0.5g of methanesulfonic acid in 1.7g of water and add it to the above reaction solution. After the solution is clear, continue stirring to precipitate a large amount of solid. Heat to 50℃ and beat for 2 hours, cool to 20℃ and beat for 1.5 hours, cool to 5℃ and beat for 2 hours. Filter, wash with acetone, and dry under vacuum at 40℃ to obtain 2.2g of gipodacin methanesulfonic acid dihydrate with a purity of 97.8% and a yield of 71.0%.

[0077] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing gipotassium methanesulfonate, characterized in that: Includes the following steps: Step a: Compound SM1 and compound SM2 are reacted to obtain compound 1. Then, compound 1 is deprotected to obtain compound 2. The reaction formula is as follows: Alternatively, reacting compound SM1 with compound SM5 yields compound 2, as shown in the following reaction formula: Step b involves a substitution reaction between compound 2 and compound SM3 to yield compound 3; the reaction equation is as follows: In compound SM3, R is one of chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate, and phenylsulfonate; the benzene ring on the phenylsulfonate group is optionally monosubstituted at any position by a C1-C4 alkyl group, nitro group, halogen, or methoxy group. Step c, compound 3 is reacted with methanesulfonic acid to form a salt, yielding gipotassium methanesulfonate, as shown in the following reaction formula: 。 2. The preparation method according to claim 1, characterized in that: The phenyl sulfonate group is one of benzene sulfonate group, p-toluene sulfonate group, p-nitrobenzene sulfonate group, p-methoxybenzene sulfonate group, and p-chlorobenzene sulfonate group.

3. The preparation method according to claim 1, characterized in that: In step a, compound SM1 and compound SM2 react in a reaction solvent under reducing conditions or with a palladium on carbon catalyst under hydrogen source conditions to obtain compound 1; The reaction solvent is one or two of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, toluene, and water; The reducing conditions are achieved by adding one of sodium borohydride, sodium triacetylborohydride, sodium cyanoborohydride, or potassium borohydride to the reaction solvent; The hydrogen source is one or more of hydrogen, formic acid, ammonium formate, and cyclohexene; The reaction was carried out at 0-50°C.

4. The preparation method according to claim 1 or 3, characterized in that: In step a, compound 1 is deprotected by adding a deprotecting agent to the reaction solvent to obtain compound 2; The reaction solvent is one or two of methanol, ethanol, isopropanol, tetrahydrofuran, methyl tert-butyl ether, toluene, acetonitrile, dichloromethane, and ethyl acetate. The deprotecting agent is one of hydrogen chloride, hydrogen bromide, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, or oxalic acid. The reaction was carried out at 20-70°C.

5. The preparation method according to claim 1, characterized in that: In step a, the compounds SM1 and SM5 react in a reaction solvent under reducing conditions or with a palladium-on-carbon catalyst under hydrogen source conditions to obtain compound 2; The reaction solvent is one or two of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, toluene, and water; The reducing conditions are achieved by adding one of sodium borohydride, sodium triacetylborohydride, sodium cyanoborohydride, or potassium borohydride to the reaction solvent; The hydrogen source is one or more of hydrogen, formic acid, ammonium formate, and cyclohexene; The reaction was carried out at 0-50°C.

6. The preparation method according to claim 1, characterized in that: In step b, compound 2 participates in the reaction in its free base form or in the form of a pharmaceutically acceptable salt; The salts include one or more of the following: hydrochloride, hydrobromide, sulfate, phosphate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, oxalate, fumarate, and maleate.

7. The preparation method according to claim 1 or 6, characterized in that: In step b, compound 2 reacts with compound SM3 in the presence of an aprotic solvent and a base to obtain compound 3; The aprotic solvent is one or two of N,N-dimethylformamide, N-methylpyrrolidone, dichloromethane, tetrahydrofuran, chloroform, acetonitrile, acetone, toluene, and ethyl acetate. The alkali is one of potassium carbonate, sodium carbonate, potassium phosphate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, lithium hydroxide, lithium carbonate, triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine. The reaction was carried out at 30-80°C.

8. The preparation method according to claim 1, characterized in that: In step c, the salt formation reaction is carried out in methanol, ethanol, isopropanol, acetone or acetonitrile solvent, and the amount of methanesulfonic acid used is 1 to 1.5 equivalents.

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