Synthesis method of dotenorad

Abstract

The invention belongs to the technical field of drug synthesis, and relates to a dotenorad synthesis method, which comprises: weighing 100 g of a compound 1 as a raw material, and carrying out a substitution reaction with dimethyl sulfate to obtain a compound 2; taking the compound 2 as a raw material, and carrying out esterification reaction with methanol under an acidic condition; taking the compound 3 as a raw material, and obtaining a compound 4 after chlorination; hydrolyzing the compound 4 serving as a raw material to obtain a compound A; reacting the compound 5 serving as a raw material with a formaldehyde aqueous solution to obtain a compound 6; taking the compound 6 as a raw material, and performing thioether oxidation to obtain a compound B; taking a compound A as a raw material, and carrying out amide condensation reaction with a compound B to obtain a compound C; and 6, demethylating the compound C serving as a raw material under the action of lithium chloride to obtain a compound D, namely the final product dotenorad. According to the synthesis method of dotenorad, oxidation after condensation is not needed, generation of by-products is avoided, raw materials are low in cost and easy to obtain, and the synthesis method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing polytinorel. Background Art

[0002] Dotinurad is a selective uric acid reabsorption inhibitor used to treat gout and hyperuricemia. The chemical name of Dotinurad is: (3,5-dichloro-4-hydroxyphenyl)

[0003] )(1,1-dioxide-3(2H)-benzothiazolyl)methanone. The currently disclosed method for preparing polytinorel is as follows:

[0004] Method 1: The preparation method of polytinorel disclosed in invention patent WO2011 / 040449 (original research route) uses high-temperature heating in the demethylation reaction, which results in incomplete reaction. The prolonged heating causes the product to appear yellow or even brown, making it difficult to decolorize. The entire process route has a long reaction time, is difficult to purify the product, and has high production costs.

[0005]

[0006] Method 2: Invention patent CN202010693795.4 and patent CN20201069241.6 use different raw materials, but also require the use of expensive condensation reagents, which are costly and not suitable for industrial production.

[0007] Method 3: In the preparation process of dotinorel disclosed in invention patent application 202510146574.8, 3,5-dichloro-4-methoxybenzoyl chloride is first condensed with 2-aminobenzenethiol, and then acylated to obtain the next product. The intermediate is deprotected and then oxidized. The raw materials are adjusted in the order of reaction compared with the original research route. The multi-step reaction in this process is a "one-pot" operation, and the purity of the raw materials is low, which is difficult for the applicant to achieve based on the application documents.

[0008] Therefore, developing a process route with simple operation and cheap and readily available raw materials for the industrial production of polytinorel is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0009] The technical problem to be solved by the present invention is: in view of the above-mentioned defects, the present invention provides a method for synthesizing polytinorel, which does not require oxidation after condensation, avoids the generation of by-products, and has cheap and readily available raw materials, making it suitable for industrial production.

[0010] The present invention solves the technical problem by adopting the following technical solution: a method for synthesizing polytinorel, comprising the following steps:

[0011] Step 1: Compound 1 is used as a raw material to undergo a substitution reaction with dimethyl sulfate to obtain compound 2;

[0012] Step 2: Using compound 2 as raw material, an esterification reaction is carried out with methanol under acidic conditions;

[0013] Step 3, using compound 3 as raw material, chlorination is performed to obtain compound 4;

[0014] Step 4: Compound 4 is used as a raw material and hydrolyzed to obtain compound A;

[0015] Step 5: Compound A is used as a raw material to undergo an amide condensation reaction with compound B to obtain compound C;

[0016] Step 6: Using compound C as a raw material, demethylating the compound under the action of lithium chloride to obtain compound D, i.e., the final product, polytinorel;

[0017]

[0018] The invention provides a synthesis method of polytinol. The method adopts p-hydroxybenzoic acid as a raw material and obtains polytinol through methylation, esterification, chlorination, hydrolysis, amide condensation and demethylation. The raw material is cheap and easily available, the reaction conditions are mild, the operation is simple and suitable for industrial production. In step 1, dimethyl sulfate is used as a methyl donor, which has low cost and high reaction activity. In step 2, esterification is carried out under acidic conditions, and the conditions are mild and controllable. In step 3, chlorine gas is used for chlorination, and combined with the structural characteristics of anisole, two-point substitution of the methoxy group ortho-position on the benzene ring can be accurately positioned, thereby realizing precise positioning of the chlorine atom. In step 4, the hydrolysis conditions can be flexibly selected, and the conditions are mild and reliable. In step 5, an intermediate compound A is directly condensed with a compound B, thereby avoiding the byproducts that may be generated when condensation is first performed and then oxidized in the prior art. In step 6, lithium chloride is used to catalyze the demethylation, and the reaction conditions are mild. The production process of polytinol in this application can significantly improve the safety and selectivity of the reaction, and has good economy and environmental protection. This process solves the safety defects of existing uric acid-lowering drugs while ensuring high yield and purity through mild demethylation technology and low-risk reagent selection, providing a reliable path for the industrial production of polytinol.

[0019] Furthermore, the synthesis method of compound B is as follows:

[0020] Step A, using compound 5 as a raw material, reacting with formaldehyde aqueous solution to obtain compound 6;

[0021] Step B, using compound 6 as a raw material, and subjecting it to thioether oxidation to obtain compound B;

[0022]

[0023] Formaldehyde aqueous solution is used as a cyclizing agent, without the need for additional catalysts and solvents, and the reaction conditions are mild and efficient. After the cyclization, the sulfide is oxidized to sulfone by an oxidant, which can effectively avoid excessive oxidation. The two-step one-pot process reduces the separation and purification steps, improves the overall yield, has high atom utilization, and reduces the pollution of three wastes.

[0024] Furthermore, in the step 1, the molar ratio of compound 1 to dimethyl sulfate is 2:(1.02-1.04), the solvent is methanol, and the reaction pH is between 9-10.

[0025] Furthermore, in step 2, the molar ratio of compound 2 to methanol is 1:(1.3-2), and the reaction temperature is 62°C-70°C.

[0026] Furthermore, in step 3, the chlorine source for the chlorination reaction is chlorine gas, and the molar ratio of compound 3 to chlorine gas is 1:(1.8-2.2). Concentrated sulfuric acid is used as the catalyst, and the catalyst dosage is 0.01-0.05 of compound 3. The reaction temperature is 40°C-60°C, and the solvent used is a mixed solvent of dimethyl sulfoxide and chloroform. Existing technologies use metal catalysts, which can cause certain metal contamination. Using concentrated sulfuric acid as the catalyst offers mild reaction conditions, simple post-processing, and is suitable for industrial production.

[0027] Furthermore, in the step 4, when the hydrolysis reaction is carried out with aqueous ammonia, the molar ratio of compound 4 to aqueous ammonia is 1:(1.2-1.5), the reaction temperature is 60-80°C, and after the reaction is complete, an acid is used to adjust the pH to ≤4;

[0028] In the step 4, when acetic acid is used for the hydrolysis reaction, ethanol is used as the solvent, the amount of acetic acid used is 0.05-0.1 of compound 4, the reaction temperature is 60° C.-80° C., and the product is purified by recrystallization.

[0029] Furthermore, in the step 5, the molar ratio of compound A to compound B is 1:(1.2-1.5), the catalyst is N-chlorosuccinimide and triphenylphosphine, the amount of N-chlorosuccinimide is 0.1-0.3 of compound A, the molar ratio of N-chlorosuccinimide to triphenylphosphine is 1:(3-5), and the reaction temperature is 10°C-40°C.

[0030] Furthermore, in step six, the molar ratio of compound C to lithium chloride is 1:(1.5-2), the solvent is N,N-dimethylformamide, and the reaction temperature is 100°C-120°C.

[0031] Furthermore, in step A, the molar ratio of compound 5 to formalin is 1:(1.5-3), the reaction temperature is room temperature, and the formaldehyde concentration in the formalin is 35%-40%.

[0032] Furthermore, in the step B, the thioether oxidation reagent is m-chloroperbenzoic acid, the solvent is dichloromethane, the molar ratio of the compound 6 to m-chloroperbenzoic acid is 1:(1.05-1.5), and the reaction temperature is room temperature.

[0033] The beneficial effects of the present invention are as follows: adopting the above scheme, the present invention provides a synthesis method of polytinol, using p-hydroxybenzoic acid as a raw material, and obtaining polytinol through methylation, esterification, chlorination, hydrolysis, amide condensation, and demethylation. The raw materials are cheap and easily available, the reaction conditions are mild, the operation is simple, and the method is suitable for industrial production; in step one, dimethyl sulfate is used as a methyl donor, which has low cost and high reaction activity; in step two, esterification is carried out under acidic conditions, and the conditions are mild and controllable; in step three, chlorine gas is used for chlorination, and combined with the structural characteristics of anisole, two-point substitution of the methoxy group ortho-position on the benzene ring can be accurately positioned, thereby realizing precise positioning of the chlorine atom; in step four, the hydrolysis conditions can be flexibly selected, and the conditions are mild and reliable; in step five, the intermediate compound A and the compound B are directly condensed, thereby avoiding the by-products that may be generated when the condensation is first carried out and then oxidized in the prior art; and in step six, lithium chloride is used to catalyze the demethylation, and the reaction conditions are mild. The production process of polytinol in this application can significantly improve the safety and selectivity of the reaction, and has good economy and environmental protection. This process solves the safety defects of existing uric acid-lowering drugs while ensuring high yield and purity through mild demethylation technology and low-risk reagent selection, providing a reliable path for the industrial production of polytinol. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The foregoing and other objects, features and advantages of the present invention will become more apparent from the following detailed description taken in conjunction with the accompanying drawings.

[0035] Figure 1 is the H NMR spectrum of compound D;

[0036] Figure 2 is the carbon NMR spectrum of compound D;

[0037] Figure 3 is the mass spectrum of compound D. DETAILED DESCRIPTION

[0038] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the accompanying drawings and examples. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0039] A method for synthesizing polytinol, the chemical reaction pathway of which is as follows:

[0040]

[0041] Example 1

[0042] A method for synthesizing polytinol, according to the above reaction route, comprises the following steps:

[0043] Step 1: Weigh 100g of compound 1 as raw material, dissolve it in 250mL of methanol solution, add 46.57g of dimethyl sulfate to the mixed solution, adjust the reaction pH between 9-10, and the reaction temperature is room temperature. After the reaction stabilizes, add sodium carbonate and maintain the pH at 7.5 until the reaction is complete. Add concentrated hydrochloric acid to the system to adjust the solution to neutrality. After extraction, washing, concentration, and recrystallization, 106.85g of compound 2 is obtained with a purity of 99.5%;

[0044] Step 2: 106.85 g of compound 2 obtained in step 1 was added to a reactor, 29.25 g of methanol solution was added to the reactor, 3.44 g of concentrated sulfuric acid was added, and the reaction temperature was 62°C-70°C, that is, the reaction was controlled under formaldehyde reflux conditions. After the reaction was complete, the reaction solution was transferred to a separatory funnel to separate the organic layer; washing, washing the organic layer with saturated sodium carbonate solution, neutralizing the residual sulfuric acid and unreacted benzoic acid, drying and distilling: the organic phase was dried with anhydrous sodium sulfate to obtain 114.37 g of compound 3 with a purity of 99.6%;

[0045] Step 3: Using 114.37 g of compound 3 obtained in step 2 as a raw material, compound 3 was added into a mixed solvent of 100 mL of dimethyl sulfoxide and 100 mL of chloroform, with chlorine gas as the chlorine source and a chlorine volume of 66.8 cm 3 , using concentrated sulfuric acid as a catalyst, the amount of concentrated sulfuric acid used was 0.7g; the reaction temperature was controlled at 40°C-60°C; after the reaction was complete, it was washed with sodium bicarbonate, the reaction solution was cooled and filtered, and the filter cake was washed with hot water (60-80°C) to dissolve the by-products. The organic phase was concentrated and purified to obtain 158.54g of compound 4 with a purity of 99.0%;

[0046] Step 4: Using compound 4 obtained in step 3 as a raw material, 158.54 g of compound 4 was added with ammonia water for hydrolysis. The amount of ammonia water was 28.4 g, and the reaction temperature was 60–80°C. After the reaction was complete, hydrochloric acid was used to adjust the pH to ≤ 4. The precipitated solid was filtered and washed with cold water to remove residual sodium salt to obtain 141.6 g of compound A with a purity of 99.5%;

[0047] Step A: 120 g of compound 5 was used as a raw material, compound 5 was dissolved in 500 mL of ether, 130 g of 35% formalin was added, and the mixture was reacted at room temperature. After the reaction was complete, the mixture was separated, washed, and dried. After the solvent was evaporated, the next step of the reaction was directly carried out;

[0048] Step B: Using the crude compound 6 obtained in step A as a raw material, 250 mL of dichloromethane solution was added, and 150 g of m-chloroperbenzoic acid was added under ice bath. The reaction was carried out at room temperature until the reaction was complete. After spin drying and solvent drying, 149.3 g of compound B was obtained;

[0049] Step 5: Using 141.6 g of compound A as a raw material, compound A was dissolved in tetrahydrofuran solution, 50.42 g of triphenylphosphine was added to the system, and then 130 g of compound B was added. After mixing evenly, 8.56 g of N-chlorosuccinimide was slowly added to the system. The reaction temperature was controlled at 10°C-40°C. After the reaction was completed, the mixture was filtered, washed with water, and the filtrate was dried. The filtrate was added with ethanol and precipitated, and filtered to obtain 214.65 g of compound C with a purity of 99.0%.

[0050] Step 6: Using 214.65 g of compound C as raw material, compound C was added to 400 mL of N,N-dimethylformamide, and 36.67 g of lithium chloride was added. The reaction temperature was controlled at 100°C-120°C. After the reaction was complete, water was added to quench the reaction. Concentrated hydrochloric acid was then added to the system to adjust the pH to a weak acidic state. After extraction, drying, and drying the solvent, 185.9 g of compound D was obtained, which was the final product, polytinore.

[0051] Example 2

[0052] A method for synthesizing polytinol, according to the above reaction route, comprises the following steps:

[0053] Step 1: Weigh 100g of compound 1 as raw material, dissolve it in 250mL of methanol solution, add 47.5g of dimethyl sulfate to the mixed solution, adjust the reaction pH between 9-10, and the reaction temperature is room temperature. After the reaction stabilizes, add sodium carbonate and maintain the pH at 7.5 until the reaction is complete. Add concentrated hydrochloric acid to the system to adjust the solution to neutrality. After extraction, washing, concentration, and recrystallization, 108.35g of compound 2 is obtained with a purity of 99.5%;

[0054] Step 2: 108.35 g of compound 2 obtained in step 1 was added to a reactor, 45.6 g of methanol solution was added to the reactor, 1.5 g of concentrated sulfuric acid was added, and the reaction temperature was 62°C-70°C, that is, the reaction was controlled under formaldehyde reflux conditions. After the reaction was complete, the reaction solution was transferred to a separatory funnel to separate the organic layer; washing, washing the organic layer with saturated sodium carbonate solution, neutralizing the residual sulfuric acid and unreacted benzoic acid, drying and distilling: the organic phase was dried with anhydrous sodium sulfate to obtain 117.16 g of compound 3 with a purity of 99.5%;

[0055] Step 3: Using 117.16 g of compound 3 obtained in step 2 as a raw material, compound 3 was added into a mixed solvent of 150 mL of dimethyl sulfoxide and 150 mL of chloroform, with chlorine gas as the chlorine source and a chlorine volume of 80 cm3 , using concentrated sulfuric acid as a catalyst, the amount of concentrated sulfuric acid used was 3.0 g; the reaction temperature was controlled at 40°C-60°C; after the reaction was complete, it was washed with sodium bicarbonate, the reaction solution was cooled and filtered, and the filter cake was washed with hot water (60-80°C) to dissolve the by-products. The organic phase was concentrated and purified to obtain 160.7 g of compound 4 with a purity of 99.0%;

[0056] Step 4: Using compound 4 obtained in step 3 as a raw material, 160.7 g of compound 4 was hydrolyzed by adding ammonia water, the amount of ammonia water was 35 g, the reaction temperature was 60–80°C, and after the reaction was complete, the pH was adjusted to ≤ 4 with hydrochloric acid. The precipitated solid was filtered and washed with cold water to remove residual sodium salt to obtain 147.4 g of compound A with a purity of 99.5%;

[0057] Step A: 120 g of compound 5 was used as a raw material, compound 5 was dissolved in 500 mL of ether, 130 g of 35% formalin was added, and the mixture was reacted at room temperature. After the reaction was complete, the mixture was separated, washed, and dried. After the solvent was evaporated, the next step of the reaction was directly carried out;

[0058] Step B: Using the crude compound 6 obtained in step A as a raw material, 250 mL of dichloromethane solution was added, and 150 g of m-chloroperbenzoic acid was added under ice bath. The reaction was carried out at room temperature until the reaction was complete. After spin drying and solvent drying, 149.3 g of compound B was obtained;

[0059] Step 5, using 147.4g of compound A as raw material, compound A was dissolved in 500mL of tetrahydrofuran solution, 170g of triphenylphosphine was added to the system, and then 168g of compound B was added. After mixing evenly, 22.2g of N-chlorosuccinimide was slowly added to the system. The reaction temperature was controlled at 10°C-40°C. After the reaction was completed, the filtrate was filtered, washed with water, and the filtrate was dried. The filtrate was added with ethanol and precipitated, and filtered to obtain 235.8g of compound C with a purity of 99.0%;

[0060] Step 6: Using 235.8 g of compound C as raw material, compound C was added to 400 mL of N,N-dimethylformamide, and 48 g of lithium chloride was added. The reaction temperature was controlled at 100°C-120°C. After the reaction was complete, water was added to quench the reaction. Concentrated hydrochloric acid was then added to the system to adjust the pH to a weak acidic state. After extraction, drying, and drying the solvent, 213.3 g of compound D was obtained, which was the final product, polytinore.

[0061] Example 3

[0062] The difference between Example 3 and Example 2 is that the hydrolysis in step 4 adopts acidic hydrolysis. 100 g of compound 4 is used as raw material, added to 250 mL of ethanol solution, 2 g of acetic acid is added as a hydrolysis catalyst, the reaction temperature is 60–80 ° C, and recrystallization is performed after the reaction is complete to obtain 135.8 g of compound A with a purity of 99.5%.

[0063] The compound D obtained in Example 1 was subjected to nuclear magnetic resonance and mass spectrometry detection, and after analysis, it was found to be dotinorel.

[0064] With the above-mentioned ideal embodiment of the present invention as inspiration, and through the above description, relevant personnel can make various changes and modifications without departing from the scope of the technical concept of this invention patent. The technical scope of this invention patent is not limited to the content of the specification, but must be determined according to the scope of the claims.

Claims

1. A method for synthesizing polytinol, characterized in that: The following steps are involved: Step 1: Compound 1 is used as a raw material to undergo a substitution reaction with dimethyl sulfate to obtain compound 2; Step 2: Using compound 2 as raw material, an esterification reaction is carried out with methanol under acidic conditions; Step 3, using compound 3 as raw material, chlorination is performed to obtain compound 4; Step 4: Compound 4 is used as a raw material and hydrolyzed to obtain compound A; Step 5: Compound A is used as a raw material to undergo an amide condensation reaction with compound B to obtain compound C; Step 6: Using compound C as a raw material, demethylating the compound under the action of lithium chloride to obtain compound D, i.e., the final product, polytinorel; 2. The method for synthesizing polytinol according to claim 1, wherein: The synthesis method of compound B is as follows: Step A, using compound 5 as a raw material, reacting with formaldehyde aqueous solution to obtain compound 6; Step B, using compound 6 as a raw material, and subjecting it to thioether oxidation to obtain compound B; 3. The method for synthesizing polytinol according to claim 1, wherein: In the step 1, the molar ratio of compound 1 to dimethyl sulfate is 2:(1.02-1.04), the solvent is methanol, and the reaction pH is between 9-10.

4. The method for synthesizing polytinol according to claim 1, wherein: In the step 2, the molar ratio of compound 2 to methanol is 1:(1.3-2), and the reaction temperature is 62°C-70°C.

5. The method for synthesizing polytinoride according to claim 1, wherein: In step 3, the chlorine source for the chlorination reaction is chlorine gas, the molar ratio of compound 3 to chlorine gas is 1:(1.8-2.2), concentrated sulfuric acid is used as a catalyst, and the amount of the catalyst is 0.01-0.05 of compound 3; the reaction temperature is 40°C-60°C; and the solvent used is a mixed solvent of dimethyl sulfoxide and chloroform.

6. The method for synthesizing polytinoride according to claim 1, wherein: In the step 4, when the hydrolysis reaction is carried out with aqueous ammonia, the molar ratio of compound 4 to aqueous ammonia is 1:(1.2-1.5), the reaction temperature is 60-80°C, and after the reaction is complete, the pH is adjusted to ≤4 with acid; In the step 4, when acetic acid is used for the hydrolysis reaction, ethanol is used as the solvent, the amount of acetic acid used is 0.05-0.1 of compound 4, the reaction temperature is 60° C.-80° C., and the product is purified by recrystallization.

7. The method for synthesizing polytinoride according to claim 1, wherein: In the step 5, the molar ratio of compound A to compound B is 1: (1.2-1.5), the catalyst is N-chlorosuccinimide and triphenylphosphine, the amount of N-chlorosuccinimide is 0.1-0.3 of compound A, the molar ratio of N-chlorosuccinimide to triphenylphosphine is 1: (3-5), and the reaction temperature is 10°C-40°C.

8. The method for synthesizing polytinoride according to claim 1, wherein: In the step six, the molar ratio of compound C to lithium chloride is 1:(1.5-2), the solvent is N,N-dimethylformamide, and the reaction temperature is 100°C-120°C.

9. The method for synthesizing polytinoride according to claim 2, wherein: In the step A, the molar ratio of the compound 5 to formalin is 1:(1.5-3), the reaction temperature is room temperature, and the formaldehyde concentration in the formalin is 35%-40%.

10. The method for synthesizing polytinoride according to claim 2, wherein: In the step B, the thioether oxidation reagent is m-chloroperbenzoic acid, the solvent is dichloromethane, the molar ratio of the compound 6 to m-chloroperbenzoic acid is 1:(1.05-1.5), and the reaction temperature is room temperature.

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