Preparation method of dotenorad

Abstract

The invention relates to the technical field of raw material medicine synthesis, and provides a preparation method of dotenorad. The method comprises the following steps: mixing a compound 2, an organic sulfonic acid catalyst, lithium chloride and an organic solvent, and carrying out demethylation reaction to obtain dotenorad. The organic sulfonic acid is used as the catalyst to catalyze the demethylation reaction, the reaction condition is mild, byproducts are few, and the obtained product is high in purity, high in yield, white in appearance, low in preparation cost and suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of raw material drug synthesis, and in particular to a method for preparing polytinorel. Background Art

[0002] Dotinurad is a novel, selective urate transporter inhibitor used to treat some hyperuricemia and gout. It is a urate reabsorption inhibitor that targets and inhibits the activity of urate reabsorption transporters. By selectively inhibiting the urate reabsorption transporter in the kidney, it inhibits uric acid reabsorption and reduces uric acid levels in the blood.

[0003] Currently, the commonly used synthesis route for dotinorel is shown below. The key step is the demethylation of compound 2 (3-(3,5-dichloro-4-methoxybenzoyl-1,1-dioxo-2,3-dihydro-1,3-benzothiazole)) to prepare dotinorel. This step is carried out under lithium chloride conditions and requires high heating temperatures of 130°C. This reaction is difficult to complete, resulting in a high residue of compound 2 in the product, resulting in poor product quality and low yield, making it unsuitable for industrial production.

[0004] Summary of the Invention

[0005] In view of this, the present invention provides a preparation method of polytinorel. The preparation method provided by the present invention has mild reaction conditions, high product quality and high yield.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] A method for preparing polytinorel comprises the following steps:

[0008] A compound of formula 2, an organic sulfonic acid catalyst, lithium chloride and an organic solvent are mixed to perform a demethylation reaction to obtain polytinoride; the demethylation reaction temperature is less than or equal to 95° C.;

[0009]

[0010] Preferably, the organic sulfonic acid catalyst includes one or more of methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

[0011] Preferably, the molar amount of the organic sulfonic acid catalyst is 10% to 20% of the molar amount of the compound of the structure shown in Formula 2.

[0012] Preferably, the molar ratio of the lithium chloride to the compound having the structure shown in Formula 2 is 2 to 2.5:1.

[0013] Preferably, the organic solvent is a polar aprotic organic solvent.

[0014] Preferably, the polar aprotic organic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

[0015] Preferably, the temperature of the demethylation reaction is 90-95°C.

[0016] Preferably, the demethylation reaction time is 2 to 4 hours.

[0017] Preferably, after the demethylation reaction is completed, the method further comprises: cooling the obtained reaction liquid and mixing it with water, performing solid-liquid separation on the obtained mixed liquid to obtain a crude product; refining the crude product with ethanol, then performing solid-liquid separation, washing the obtained solid product with ethanol and then drying to obtain polytinorel.

[0018] Preferably, the ethanol refining comprises: heating and mixing the crude product and ethanol and then cooling.

[0019] The present invention provides a method for preparing polytinol, comprising the following steps: mixing a compound having a structure represented by Formula 2 (denoted as Compound 2), an organic sulfonic acid catalyst, lithium chloride, and an organic solvent to carry out a demethylation reaction to obtain polytinol; wherein the demethylation reaction temperature is less than or equal to 95°C. The present invention uses an organic sulfonic acid as a catalyst to catalyze the demethylation reaction, resulting in mild reaction conditions, few by-products, and low residual Compound 2 in the obtained product. The product has high product quality, high yield, and low preparation cost, making it suitable for industrial production.

[0020] Furthermore, the conventional method requires a long reaction time at high temperature during the demethylation reaction and requires the use of a large amount of lithium chloride (molar equivalent is about 5 to 6 times that of compound 2). The high reaction temperature and the use of a large amount of lithium chloride easily lead to product degradation, resulting in a brown appearance of the product, which is difficult to decolorize. In addition, the crude product obtained after the demethylation reaction has poor purity and is difficult to purify. The present invention, however, uses an organic sulfonic acid catalyst to catalyze the demethylation reaction, which not only reduces the reaction temperature but also greatly reduces the amount of lithium chloride used. Since the reaction temperature and the amount of lithium chloride used are greatly reduced, product degradation is reduced, side reactions are reduced, the difficulty of purifying the crude product is greatly reduced, and the appearance of the product is significantly improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The NMR spectrum of Dotinorel prepared in Example 1;

[0022] Figure 2 This is the mass spectrum of polytinoride prepared in Example 1. DETAILED DESCRIPTION

[0023] The present invention provides a method for preparing polytinoride, comprising the following steps:

[0024] A compound of formula 2, an organic sulfonic acid catalyst, lithium chloride and an organic solvent are mixed to perform a demethylation reaction to obtain polytinol; the demethylation reaction temperature is less than or equal to 95° C.;

[0025]

[0026] In the present invention, the chemical name of the compound represented by Formula 2 is: 3-(3,5-dichloro-4-methoxybenzoyl-1,1-dioxo-2,3-dihydro-1,3-benzothiazole); the present invention has no special requirements on the source of the compound represented by Formula 2, and it can be prepared by methods well known to those skilled in the art. In a specific embodiment of the present invention, it is preferably prepared according to the method disclosed in Chinese Patent CN102639518B.

[0027] In the present invention, the organic sulfonic acid catalyst preferably includes one or more of methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; the benzenesulfonic acid is specifically benzenesulfonic acid monohydrate, and the p-toluenesulfonic acid is specifically p-toluenesulfonic acid monohydrate; the molar amount of the organic sulfonic acid catalyst is preferably 10% to 20% of the molar amount of the compound of the structure shown in Formula 2, and can specifically be 10%, 15%, 18%, 19% or 20%.

[0028] In the present invention, the molar ratio of the lithium chloride to the compound having the structure represented by Formula 2 is preferably 2 to 2.5:1, more preferably 2 to 2.2:1.

[0029] In the present invention, the organic solvent is preferably a polar aprotic organic solvent; the polar aprotic organic solvent preferably includes one or more of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) and N-methylpyrrolidone (NMP); the present invention has no special requirements for the amount of the organic solvent, as long as it can allow the demethylation reaction to proceed smoothly; in a specific embodiment of the present invention, the amount ratio of the compound of the structure represented by Formula 2 to the organic solvent is 30g:180mL.

[0030] In a specific embodiment of the present invention, it is preferred to first dissolve the compound represented by Formula 2 in an organic solvent, then add lithium chloride and an organic sulfonic acid catalyst, and then heat to perform a demethylation reaction.

[0031] In the present invention, the temperature of the demethylation reaction is preferably 90-95°C, specifically 90°C, 92°C or 95°C, and the demethylation reaction time is 2-4 hours, specifically 2 hours. In the present invention, the reaction formula of the demethylation reaction is shown in Formula A, wherein Compound 1 is polytinorel.

[0032]

[0033] In the present invention, after the demethylation reaction is completed, it is preferred that the following steps are further performed: cooling the reaction solution and mixing it with water, subjecting the resulting mixture to solid-liquid separation (referred to as the first solid-liquid separation) to obtain a crude product; subjecting the crude product to ethanol purification, followed by solid-liquid separation (referred to as the second solid-liquid separation), washing the resulting solid product with ethanol and drying it to obtain polytinore. The time for mixing with water is preferably 2 hours, and the mixing with water is preferably carried out under stirring conditions, with a large amount of solid precipitated during the stirring process; the first solid-liquid separation and the second solid-liquid separation are preferably carried out by filtration, and the filter cake obtained after the first solid-liquid separation is the crude product. After the first solid-liquid separation, the filter cake is preferably washed with water; the ethanol purification preferably comprises: heating and mixing the crude product and ethanol and then cooling, the heating and mixing temperature is preferably 75°C, the time is preferably 1 hour, the cooling is specifically cooling to room temperature, and stirring is preferably continued for 1 hour after cooling; the drying temperature is preferably 60°C.

[0034] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0035] Example 1

[0036] In a 500mL three-necked flask, compound 2 (30g, 80.6mmol) and DMF (180mL) were added and stirred to dissolve. Lithium chloride (6.8g, 0.161mol) and p-toluenesulfonic acid monohydrate (3.06g, 16.1mmol) were added. The mixture was heated to 90°C and reacted for 2h. After cooling to room temperature, water (540mL) was added and stirred for 2h. A large amount of solid precipitated. The mixture was filtered and the filter cake was rinsed with water (20mL). The wet filter cake was directly placed in a 1L three-necked flask, ethanol (300mL) was added, and the mixture was heated to 75°C and stirred for 1h. After cooling to room temperature, stirring was continued for 1h. The mixture was filtered and the filter cake was rinsed with ethanol (20mL). The filter cake was dried at 60°C to constant weight to obtain 24.5g of white crystalline solid with a yield of 85% and a purity of 99.9%.

[0037] Figure 1 The NMR spectrum of the polytinol prepared in Example 1 is Figure 2 This is the mass spectrum of polytinorel prepared in Example 1. The specific structural confirmation data are as follows:

[0038] 1H NMR (400MHz, DMSO-d6) δ11.0695(s,1H),8.0403(d,1H),7.9101(d,1H),7.7650(t,3H),7.4422(t,1H),5.3600(s,2H).

[0039] MS-ESI(m / z):356.0[MH] +

[0040] Example 2

[0041] In a 500mL three-necked flask, compound 2 (30g, 80.6mmol) and NMP (180mL) were added and stirred to dissolve. Lithium chloride (6.8g, 0.161mol) and benzenesulfonic acid monohydrate (2.84g, 16.1mmol) were added. The mixture was heated to 90°C and reacted for 2h. After cooling to room temperature, water (540mL) was added and stirred for 2h to precipitate a large amount of solid. Filtered and the filter cake was rinsed with water (20mL). The wet filter cake was directly placed in a 1L three-necked flask, ethanol (300mL) was added, heated to 78°C, stirred for 1h, cooled to room temperature, and continued to stir for 1h. Filtered and the filter cake was rinsed with ethanol (20mL). The filter cake was dried at 60°C to constant weight to obtain 24.8g of white crystalline solid with a yield of 86% and a purity of 99.9%.

[0042] Example 3

[0043] In a 500mL three-necked flask, compound 2 (30g, 80.6mmol) and DMA (180mL) were added and stirred to dissolve. Lithium chloride (6.8g, 0.161mol) and methanesulfonic acid (1.55g, 16.1mmol) were then added. The mixture was heated to 90°C and allowed to react for 2h. After cooling to room temperature, water (540mL) was added and stirred for 2h, resulting in the precipitation of a large amount of solid. The mixture was filtered and the filter cake was rinsed with water (20mL). The wet filter cake was directly placed in a 1L three-necked flask, ethanol (300mL) was added, and the mixture was heated to 78°C and stirred for 1h. The mixture was cooled to room temperature and stirred for another 1h. The mixture was filtered and the filter cake was rinsed with ethanol (20mL). The filter cake was dried at 60°C to constant weight to obtain 25.9g of a white crystalline solid with a yield of 90% and a purity of 99.9%.

[0044] Example 4

[0045] In a 500mL three-necked flask, compound 2 (30g, 80.6mmol) and DMF (180mL) were added and stirred to dissolve. Lithium chloride (6.8g, 0.161mol) and methanesulfonic acid (0.8g, 8.3mmol) were added. The mixture was heated to 95°C and reacted for 2h. After cooling to room temperature, water (540mL) was added and stirred for 2h to precipitate a large amount of solid. Filtered and the filter cake was rinsed with water (20mL). The wet filter cake was directly placed in a 1L three-necked flask, ethanol (300mL) was added, heated to 78°C, stirred for 1h, cooled to room temperature, and continued to stir for 1h. Filtered and the filter cake was rinsed with ethanol (20mL). The filter cake was dried at 60°C to constant weight to obtain 25.3g of white crystalline solid with a yield of 88% and a purity of 99.8%.

[0046] Example 5

[0047] In a 500mL three-necked flask, compound 2 (30g, 80.6mmol) and DMF (180mL) were added and stirred to dissolve. Lithium chloride (8.5g, 0.201mol) and methanesulfonic acid (0.8g, 8.3mmol) were added. The mixture was heated to 95°C and reacted for 2h. After cooling to room temperature, water (540mL) was added and stirred for 2h to precipitate a large amount of solid. Filtered and the filter cake was rinsed with water (20mL). The wet filter cake was directly placed in a 1L three-necked flask, ethanol (300mL) was added, heated to 75°C, stirred for 1h, cooled to room temperature, and continued to stir for 1h. Filtered and the filter cake was rinsed with ethanol (20mL). The filter cake was dried at 60°C to constant weight to obtain 25.8g of white crystalline solid with a yield of 90% and a purity of 99.8%.

[0048] Comparative Example 1

[0049] In a 500mL three-necked flask, compound 2 (30g, 80.6mmol) and DMF (150mL) were added and stirred to dissolve. Lithium chloride (17g, 0.401mol) was added. The mixture was heated to 130°C and reacted for 2h. After cooling to room temperature, 1mol / L aqueous hydrochloric acid solution (400mL) was added and stirred to dissolve. The mixture was extracted with 450mL of ethyl acetate. The organic layer was then washed with 1mol / L aqueous hydrochloric acid solution (100mL) and saturated brine (100mL). The washed organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was added to ethanol (300mL) and heated to 75°C. Stir for 1h, cool to room temperature, and continue stirring for 1h. Filter and rinse the filter cake with ethanol (20mL). The filter cake was dried at 60°C to constant weight to obtain 22.3g of a light yellow crystalline solid with a yield of 78% and a purity of 96.8%.

[0050] Test results

[0051] The content of compound 2 in the products obtained in Examples 1 to 5 and Comparative Example 1 was tested, and the experimental data were summarized. The results are shown in Table 1.

[0052] Table 1 Summary of experimental results

[0053] Experimental example Lithium chloride dosage Reaction temperature Product purity Product Appearance Mass percentage of compound 2 Product yield Example 1 2.0 equivalent 90℃ 99.9％ White 0.05％ 85％ Example 2 2.0 equivalent 90℃ 99.9％ White 0.05％ 86％ Example 3 2.0 equivalent 90℃ 99.9％ White 0.06％ 90％ Example 4 2.0 equivalent 95℃ 99.8％ White 0.06％ 88％ Example 5 2.5 equivalents 95℃ 99.8％ White 0.07％ 90％ Comparative Example 1 5.0 equivalent 130℃ 96.8％ light yellow 1.5％ 78％

[0054] As shown in Table 1, the conventional method (Comparative Example 1) for preparing polytinol is associated with a significant residual amount of Compound 2. Even after ethanol refining, the residual amount is as high as 1.5%, far exceeding the pharmaceutical limit of 0.15%. However, using the preparation method of the present invention, the residual amount of Compound 2 is below 0.07%, meeting pharmaceutical quality requirements. Furthermore, the conventional method (Comparative Example 1) for preparing polytinol is pale yellow and has a poor appearance. However, the preparation method provided by the present invention significantly reduces reaction temperature and lithium chloride dosage, reduces product degradation, significantly improves product appearance, and significantly increases yield.

[0055] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing polytinoride, characterized in that: The following steps are involved: A compound of formula 2, an organic sulfonic acid catalyst, lithium chloride and an organic solvent are mixed to perform a demethylation reaction to obtain polytinoride; the demethylation reaction temperature is less than or equal to 95° C.; 2. The preparation method according to claim 1, characterized in that The organic sulfonic acid catalyst includes one or more of methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

3. The preparation method according to claim 1, characterized in that The molar amount of the organic sulfonic acid catalyst is 10% to 20% of the molar amount of the compound of the structure shown in Formula 2.

4. The preparation method according to claim 1, characterized in that The molar ratio of the lithium chloride to the compound represented by formula 2 is 2 to 2.5:

1.

5. The preparation method according to claim 1, characterized in that The organic solvent is a polar aprotic organic solvent.

6. The preparation method according to claim 5, characterized in that The polar aprotic organic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

7. The preparation method according to claim 1, characterized in that The temperature of the demethylation reaction is 90-95°C.

8. The preparation method according to claim 1 or 7, characterized in that The demethylation reaction time is 2 to 4 hours.

9. The preparation method according to claim 1, characterized in that After the demethylation reaction is completed, the following steps are further included: cooling the obtained reaction solution and mixing it with water, performing solid-liquid separation on the obtained mixed liquid to obtain a crude product; refining the crude product with ethanol, then performing solid-liquid separation, washing the obtained solid product with ethanol and then drying to obtain polytinorel.

10. The preparation method according to claim 9, characterized in that The ethanol refining comprises: heating and mixing the crude product and ethanol and then cooling.

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