A preparation method of an iguratimod intermediate

Abstract

The present invention discloses a preparation method of an iguratimod intermediate, belonging to the field of pharmaceutical synthesis. The preparation method comprises the following steps: adding a catalyst to acetone first, and then adding an acylating agent for activation; adding formic acid and an acid-binding agent for heat preservation, and finally adding compound I, and obtaining the iguratimod intermediate through post-treatment. The preparation process of the present invention adopts a homogeneous system, with mild catalytic reaction conditions, high conversion rate, good quality, high yield, low cost, and is suitable for large-scale production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical synthesis, and relates to a preparation method of a compound, in particular to a preparation method of an iguratimod intermediate. Background Art

[0002] Iguratimod, chemically named N-[3-(formamido)-4-oxo-6-phenoxy-4H-1-benzofuran-7-yl]-methanesulfonamide, is a non-steroidal anti-inflammatory drug (NSAIDs) used for the treatment of osteoarthritis and rheumatoid arthritis. It can selectively inhibit cyclooxygenase COX-II and regulate T-cells, with an auto-immune regulatory effect, rapid onset, and few side effects. Non-clinical studies of iguratimod have shown that its improvement effect on various arthritis models in animals is mainly to inhibit the production of immunoglobulins and various inflammatory factors, and have an anabolic effect on bone metabolism.

[0003] In the prior art, formamidomethyl-2-methoxy-4-methanesulfonamido-5-phenoxyphenyl ketone is a key intermediate for the synthesis of iguratimod, which can be prepared from compound I (2-amino-1-(2-methoxy-4-methanesulfonamido-5-phenoxyphenyl)ethanone hydrochloride). The structural formulas of compound I and the iguratimod intermediate are as follows:

[0004]

[0005] In the reported synthesis processes in the prior art, during the preparation of the above intermediate, the reaction rate is slow, the yield is low, the impurities are large, and the product appearance is red.

[0006] The existing synthesis routes of the iguratimod intermediate are mainly as follows:

[0007] Route 1: Takihiro Inaba reported in the literature Chem.Pharm.bull.48(1)131 - 139(2000) that pivaloyl chloride reacts with sodium formate to obtain an acid anhydride, which then reacts with 2-amino-1-(2-methoxy-4-methanesulfonamido-5-phenoxyphenyl)ethanone hydrochloride (compound I) to obtain formamidomethyl-2-methoxy-4-methanesulfonamido-5-phenoxyphenyl ketone (iguratimod intermediate). Since sodium formate is insoluble in the reaction system, the solid-liquid reaction between sodium formate and pivaloyl chloride has a low reaction rate, and the generated sodium chloride is easily wrapped on the surface of sodium formate, reducing the reaction rate between sodium formate and pivaloyl chloride, further resulting in the formation of amide by-products from the unreacted pivaloyl chloride, reducing the yield and increasing the impurities.

[0008]

[0009] The structure of the amide by-products is as follows:

[0010]

[0011] Route 2: Chinese Patent CN108727232A improved the synthesis of the iguratimod intermediate. Formic acid, sodium formate and pivaloyl chloride were used to react to prepare a mixed anhydride, which was then reacted with 2-amino-1-(2-methoxy-4-methylsulfonamido-5-phenoxyphenyl)ethanone hydrochloride (Compound I) to obtain formamidomethyl-2-methoxy-4-methylsulfonamido-5-phenoxyphenyl ketone (iguratimod intermediate). Although this route improved the reaction rate, the sodium formate added was still insoluble in the reaction system and would still undergo a solid-liquid reaction with pivaloyl chloride, which was likely to cause pivaloyl chloride to continue to react with 2-amino-1-(2-methoxy-4-methylsulfonamido-5-phenoxyphenyl)ethanone hydrochloride (Compound I) to form amide by-products, thus affecting the quality of the iguratimod intermediate. On the other hand, this method still used a strong halogen reagent. Pivaloyl chloride is highly corrosive, prone to generating fumes and having a special odor, which is not friendly to equipment and the environment and also poses certain safety risks.

[0012]

[0013] Route 3: Chinese Patent CN112209859A reported that formic acid was used as a raw material, activated with N,N'-carbonyldiimidazole, and then reacted with 2-amino-1-(2-methoxy-4-methylsulfonamido-5-phenoxyphenyl)ethanone hydrochloride (Compound I) to obtain formamidomethyl-2-methoxy-4-methylsulfonamido-5-phenoxyphenyl ketone (iguratimod intermediate). This route was prone to incomplete reaction of the starting materials, and introducing N,N'-carbonyldiimidazole was extremely likely to generate by-products that were not easily removed.

[0014]

[0015] Therefore, it is necessary to develop a preparation method for the iguratimod intermediate with simple process operation, few side reactions, low impurity content, good quality, high yield and suitable for large-scale production. Summary of the Invention

[0016] The object of the present invention is to solve the problems existing in the above routes and provide a preparation method for the iguratimod intermediate that is safer, more environmentally friendly, has a high yield, good quality and is suitable for industrial production.

[0017] In the present invention, Compound I can be prepared by using the prior art or directly using commercially available Compound I produced industrially, and its content meets the requirements of chemically pure (CP) (content ≥ 99.5%).

[0018] Starting from the defects in the prior art, the inventors of the present invention proposed multiple technical route conjectures to solve the problems, carried out a large number of tests on different conditions such as reagent screening, feeding sequence, material ratio, reaction temperature, etc., and verified and optimized them. Finally, the route and method of the present invention were obtained.

[0019] In the prior art, there are various methods for testing impurity content or purity by high performance liquid chromatography, which can be directly or after appropriate optimization, applied to test the content of the products or impurities in the examples of the present invention.

[0020] A method for preparing an ilaprazole intermediate, comprising the following steps:

[0021] (1) Add a catalyst to acetone, and then add an acylating agent for activation to obtain an activated solution;

[0022] (2) Add formic acid and an acid-binding agent to the activated solution, and keep the temperature for reaction to obtain a mixed anhydride solution;

[0023] (3) Add Compound I to the mixed anhydride solution, keep the temperature for reaction, add water for crystallization, filter, and dry to obtain the ilaprazole intermediate;

[0024] The structural formulas of Compound I and the ilaprazole intermediate are respectively:

[0025]

[0026] Further, in the step (1), the catalyst is selected from one or more of sodium iodide, potassium iodide, sodium bromide, and potassium bromide; the acylating agent is selected from one or more of isobutyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate, and benzyl chloroformate.

[0027] Further, in the step (1), the activation condition is stirring at 0 - 30 °C for 1 h.

[0028] Further, the molar ratio of the catalyst: the acylating agent: Compound I is (0.05 - 0.3):(1.5 - 2.5):1, and the preferred molar ratio is (0.05 - 0.2):(1.5 - 2):1.

[0029] Further, in the step (2), the acid-binding agent is selected from one or more of N,N-diisopropylethylamine, triethylamine, diethylamine, and pyridine.

[0030] Further, the molar ratio of formic acid: the acid-binding agent: Compound I is (1 - 2):(2.5 - 4):1, and the preferred molar ratio is (1 - 1.5):(2.5 - 3):1.

[0031] Further, in the step (2), the reaction temperature is 0 - 30 °C, and the reaction time is 0.5 - 4 h; preferably, the reaction temperature is 0 - 15 °C, and the reaction time is 0.5 - 2 h.

[0032] Further, in the step (3), the reaction temperature is 0 - 30 °C, and the reaction time is 2 - 6 h; preferably, the reaction temperature is 0 - 15 °C, and the reaction time is 2 - 4 h.

[0033] Further, the preparation method of the iguratimod intermediate further includes purification; the purification includes pulping or recrystallization.

[0034] Furthermore, the purification method of the recrystallization is as follows: the iguratimod intermediate is dissolved by heating with 10 times the volume (v / m) of acetonitrile, cooled for crystallization, filtered, and the solid is dried.

[0035] The present invention provides a preparation method of iguratimod. Compared with the existing process, the process operation is simple, environmentally friendly, with good quality and high yield, and is suitable for large-scale production.

[0036] Specifically, the present invention has the following advantages:

[0037] (1) The reaction reagents are easily available, strong halogen reagents are not used, it is friendly to equipment and environment, and the production cost is relatively low.

[0038] (2) The reaction is a homogeneous reaction, it is not easy to produce product encapsulation, the reaction is more complete, it can effectively avoid the large by-products caused by heterogeneous reactions, and is conducive to quality control and production scale-up.

[0039] (3) The reaction conditions are mild, the operation is simple, easy to control, with high safety, and the power cost is greatly reduced. And the reaction system is acidic, which greatly inhibits the generation of by-products.

[0040] (4) The product does not need additional purification operations such as pulping and recrystallization, avoiding the loss of yield, with higher yield and further reduced unit production cost.

[0041] (5) The prepared iguratimod intermediate product has good quality, is a light white solid, and the purity without purification reaches more than 99.6%, which can be further applied to improve the yield and quality of iguratimod API. Description of the Drawings

[0042] Figure 1 : MS diagram of the iguratimod intermediate in Example 1;

[0043] Figure 2 : of the iguratimod intermediate in Example 1 1 1H-NMR diagram. Detailed Embodiments

[0044] The present invention will be further described in detail below through specific embodiments. It should be understood that the embodiments are for purposes of explanation only and do not limit the scope of protection of the present invention.

[0045] For the experimental methods without specific conditions noted in the following embodiments, conventional experimental instruments are usually used and reactions or operations are carried out under conventional conditions, or the conditions recommended by the manufacturer are adopted.

[0046] In the following embodiments, Compound I can be prepared by existing technologies, or directly use commercially available industrially produced Compound I with a content meeting the requirements of chemically pure (CP) (content ≥ 99.5%). The structure of Compound I is shown as follows:

[0047]

[0048] Example 1:

[0049] 0.387 g of sodium iodide was added to 160 ml of acetone, and then 10.59 g of isobutyl chloroformate was added. Stir at 20 - 30 °C for 1 h for activation, and then cool down to 0 - 5 °C.

[0050] 2.37 g of formic acid and 16.70 g of N,N - diisopropylethylamine were further added to the above activation solution, and stirred at 0 - 5 °C for 0.5 h to obtain a mixed anhydride solution.

[0051] 20.0 g of Compound I was added to the obtained mixed anhydride solution, and reacted at 0 - 5 °C for 2 h. 200 ml of water was added, and crystallization was carried out at 0 - 15 °C for 2 h. Filtered and dried by blowing air to obtain 18.60 g of a white solid (purity 99.65%, calculated based on 19.56 g in theory).

[0052] The MS and 1 1H - NMR of the intermediate of iguratimod prepared in this example are shown in detail in Figure 1 and Figure 2 .

[0053] 1 1H - NMR (400 MHz, DMSO - d6) δ (ppm): 3.14 (s, 3H), 3.95 (s, 3H), 4.47 - 4.48 (d, 2H), 6.98 - 7.00 (m, 2H), 7.11 - 7.15 (m, 1H), 7.29 - 7.32 (d, 2H), 7.37 - 7.41 (m, 2H), 8.11 - 8.12 (d, 1H), 8.25 - 8.28 (t, 1H), 9.87 (s, 1H);

[0054] m / z: 379.2 [M + H] + .

[0055] Example 2:

[0056] 2.575 g of potassium iodide was added to 160 ml of acetone, and then 15.84 g of isopropyl chloroformate was added. Stir at 20 - 30 °C for 1 h for activation, and then cool down to 10 - 15 °C.

[0057] 4.76 g of formic acid and 20.93 g of triethylamine were further added to the above activation solution, and stirred at 10 - 15 °C for 2 h to obtain a mixed anhydride solution.

[0058] 20.0 g of Compound I was added to the obtained mixed anhydride solution, and reacted at 10 - 15 °C for 6 h. 200 ml of water was added, and crystallization was carried out at 0 - 15 °C for 2 h. Filtered and dried by blowing air to obtain 18.45 g of a pale white solid (purity 99.72%, calculated based on the theory of 19.56 g).

[0059] Example 3:

[0060] 1.064 g of sodium bromide was added to 160 ml of acetone, and then 14.12 g of tert-butyl chloroformate was added. Stir at 10 - 20 °C for 1 h for activation, and then cool down to 5 - 10 °C.

[0061] 3.57 g of formic acid and 11.34 g of diethylamine were further added to the above activation solution, and stirred at 5 - 10 °C for 2 h to obtain a mixed anhydride solution.

[0062] 20.0 g of Compound I was added to the obtained mixed anhydride solution, and reacted at 5 - 10 °C for 4 h. 200 ml of water was added, and crystallization was carried out at 0 - 15 °C for 2 h. Filtered and dried by blowing air to obtain 18.74 g of a pale white solid (purity 99.69%, calculated based on the theory of 19.56 g).

[0063] Example 4:

[0064] 1.230 g of potassium bromide was added to 160 ml of acetone, and then 17.64 g of benzyl chloroformate was added. Stir at 15 - 25 °C for 1 h for activation, and then cool down to 5 - 10 °C.

[0065] 3.57 g of formic acid and 12.27 g of pyridine were further added to the above activation solution, and stirred at 5 - 10 °C for 2 h to obtain a mixed anhydride solution.

[0066] 20.0 g of Compound I was added to the obtained mixed anhydride solution, and reacted at 5 - 10 °C for 4 h. 200 ml of water was added, and crystallization was carried out at 0 - 15 °C for 2 h. Filtered and dried by blowing air to obtain 18.56 g of a pale white solid (purity 99.70%, calculated based on the theory of 19.56 g).

[0067] Example 5:

[0068] 1.22 g of potassium bromide was added to 160 ml of acetone, and then 17.59 g of benzyl chloroformate was added. Stir at 0 - 10 °C for 1 h for activation.

[0069] 3.52 g of formic acid and 12.22 g of pyridine were further added to the above activation solution, and the mixture was stirred at 25 - 30 °C for 4 h to obtain a mixed anhydride solution.

[0070] The obtained mixed anhydride solution was slowly added to 20.0 g of Compound I, and the reaction was carried out at 25 - 30 °C for 6 h. 200 ml of water was added, and crystallization was carried out at 0 - 15 °C for 2 h. After filtration, the product was dried by blowing air to obtain 18.48 g of a white solid (purity 99.62%, calculated based on the theory of 19.56 g).

[0071] Example 6:

[0072] 15 g of the white solid obtained in Example 1 was added to 150 ml of acetonitrile, and the mixture was heated to reflux for 10 min. After cooling to 10 - 20 °C for crystallization, the solid was filtered and collected, and then dried by blowing air to obtain 14.25 g of a white solid with a purity of 99.93% and a yield of 95.0%.

[0073] Comparative Example 1:

[0074] The operation was carried out with reference to the preparation of Compound 24 in the literature Chem. Pharm. Bull. 48(1) 131 - 139(2000) mentioned in Route 1 of the background technology.

[0075] 41.20 g of sodium formate was added to a mixture of 36.60 g of pivaloyl chloride and 300 ml of acetone, and the mixture was stirred at room temperature for 5 h. Then 100.00 g of 2 - amino - 1-(2 - methoxy - 4 - methylsulfonamido - 5 - phenoxyphenyl)ethanone hydrochloride was added, and the reaction was carried out at a constant temperature for 3 h. 900 ml of water was added for crystallization for 2 h, and after filtration, the product was washed with isopropanol and dried to obtain 80.25 g of a solid (yield 82.0%, purity 95.22%).

[0076] Comparative Example 2:

[0077] The operation was carried out with reference to Example 1 of CN108727232A mentioned in Route 2 of the background technology.

[0078] 14.30 g of formic acid and 26.40 g of sodium formate were added to 3000 ml of acetone, and the mixture was stirred at 18 - 20 °C. Then 37.40 g of pivaloyl chloride was added and stirred for 1 h to obtain a mixed anhydride system. 120.20 g of 2 - amino - 1-(2 - methoxy - 4 - methylsulfonamido - 5 - phenoxyphenyl)ethanone hydrochloride and 26.40 g of sodium formate were added to the mixed anhydride system, and the reaction was stirred at 10 - 20 °C for 3 h. The temperature was lowered to 10 ± 5 °C, and 1000 ml of water was added while controlling the temperature below 15 ± 5 °C, and the mixture was stirred for 1 h. After filtration, the filter cake was recrystallized with 2000 ml of acetonitrile, and crystallization was carried out by cooling to 10 - 25 °C. After filtration, the product was dried to obtain 102.51 g of a white solid (yield 87.2%, purity 97.67%).

[0079] Comparative Example 3:

[0080] Operate with reference to Example 1 of CN112209859A mentioned in Background Art Route 3.

[0081] 10.20 g of formic acid was dissolved in 500 ml of dichloromethane, stirred while controlling the temperature at 15 - 25°C, and 52.80 g of N,N'-carbonyldiimidazole was added in batches. After addition, stir for 1 h. Keep the temperature and add 84.00 g of 2-amino-1-(2-methoxy-4-methylsulfonamido-5-phenoxyphenyl)ethanone hydrochloride in batches and react for 2 h. Then add 500 ml of water and 500 ml of dichloromethane and stir for 0.5 h. Separate the layers, concentrate the organic phase to dryness, add 500 ml of isopropanol and slurry for 0.5 h, filter by suction, and dry to obtain 67.05 g of solid (yield 81.6%, purity 88.41%).

[0082] The experimental results of Examples 1 - 5 and Comparative Examples 1 - 3 are shown in the following table:

[0083] Category Yield (%) Purity (%) Amide by-products (%) Example 1 95.1 99.65 Not detected Example 2 94.3 99.72 Not detected Example 3 95.8 99.69 Not detected Example 4 94.9 99.70 Not detected Example 5 94.5 99.62 Not detected Comparative Example 1 82.0 95.22 1.12 Comparative Example 2 87.2 97.67 0.89 Comparative Example 3 81.6 88.41 Not detected

[0084] The above examples are only for the purpose of explanation and illustration, so as to better understand the content of the present invention. Although the above examples have described the present invention in detail, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing examples, or perform equivalent substitution on some or all of the technical features; and these modifications or substitutions do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the examples of the present invention.

Claims

1. A preparation method of an iguratimod intermediate, characterized in that, The method comprises the following steps: (1) Adding a catalyst to acetone, and then adding an acylating agent for activation to obtain an activation solution; the catalyst is selected from one or more of sodium iodide, potassium iodide, sodium bromide, and potassium bromide; the acylating agent is selected from one or more of isobutyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate, and benzyl chloroformate; (2) Adding formic acid and an acid-binding agent to the activation solution, and carrying out a heat-insulated reaction to obtain a mixed anhydride solution; the acid-binding agent is selected from one or more of N,N-diisopropylethylamine, triethylamine, diethylamine, and pyridine; (3) Adding Compound I to the mixed anhydride solution, carrying out a heat-insulated reaction, adding water for crystallization, filtering, and drying to obtain the intermediate of iguratimod; The structural formulas of Compound I and the intermediate of iguratimod are respectively: 。 2. The preparation method of the iguratimod intermediate according to claim 1, characterized in that, In the step (1), the activation condition is stirring at 0 - 30°C for 1 h.

3. The preparation method of the iguratimod intermediate according to claim 1, characterized in that, The molar ratio of the catalyst: the acylating agent: Compound I is (0.05 - 0.3):(1.5 - 2.5):

1.

4. The preparation method of the iguratimod intermediate according to claim 1, wherein The molar ratio of formic acid: the acid-binding agent: Compound I is (1 - 2):(2.5 - 4):

1.

5. The preparation method of the iguratimod intermediate according to claim 1, characterized in that, In the step (2), the reaction temperature is 0 - 30°C, and the reaction time is 0.5 - 4 h.

6. The preparation method of the iguratimod intermediate according to claim 1, wherein, In the step (3), the reaction temperature is 0 - 30°C, and the reaction time is 2 - 6 h.

7. The preparation method of the iguratimod intermediate according to claim 1, characterized in that, The preparation method of the intermediate of iguratimod further includes purification; the purification includes pulping or recrystallization.

8. The preparation method of the iguratimod intermediate according to claim 7, characterized in that, The purification method of recrystallization is: dissolving the intermediate of iguratimod by heating with 10 times the volume (v / m) of acetonitrile, cooling for crystallization, filtering, and drying the solid.

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