Industrial preparation method of rosemeltirol intermediate

Abstract

The invention discloses an industrial preparation method of a rosmeltirol intermediate, and belongs to the field of medicine synthesis. In the prior art, an acetic acid / sodium acetate system is adopted to react a compound I with acetic acid at a high temperature to generate an intermediate state, an intermediate product is obtained through operations such as concentration, extraction and pH adjustment, and then a next hydrolysis reaction is performed, so that the reaction time is long, the post-treatment operation is tedious, and the yield is low. Compared with the prior art, the method disclosed by the invention has the advantages that the formic acid is used for replacing acetic acid / sodium acetate system, the generated compound II is relatively high in purity, and the compound III can be prepared by directly and continuously adding to the next hydrolysis reaction after most formic acid is removed, so that the technological process is greatly simplified, the reaction time is shortened, and the product conversion rate is increased. Through the synergistic effect of the post-treatment process in the step (1) and the solvent in the step (2), the purity and yield of the product are greatly improved, the purity of the product can be greater than 99%, the yield of the product can be greater than 85% without refining, and meanwhile, the process is also suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis, specifically relating to an industrial preparation method for a resmetiro intermediate. Background Technology

[0002] Resmetiro is an orally selective thyroid hormone receptor (THR)-β agonist used to treat non-alcoholic steatohepatitis (NASH) with liver fibrosis. It is the world's first drug for the treatment of NASH, exhibiting high selectivity. It plays a central role in the liver by activating β receptors in hepatocytes, regulating lipid metabolism and reducing LDL-C, triglycerides, and atherogenic lipoproteins. It is inactive on THR-α receptors, thus not affecting bone or cardiac parameters, and does not affect other hormones in the thyroid hormone pathway.

[0003] The main synthetic methods for resimetidine reported in the literature are as follows:

[0004] 1. Synthetic route one (refer to PCT patent WO2014043706A1 and US patent US10894050B2). This route has 7 steps, is relatively long and complicated to operate. The preparation of compound 5 requires harsh reaction conditions, making commercial production difficult.

[0005]

[0006] 2. Synthetic route two (refer to the synthetic route disclosed in PCT patent WO2020227549A1). This process route consists of 4 steps, but when preparing compound 6 and compound 7, it is easy to generate impurities with similar structures to the parent ring, making purification difficult. The process is cumbersome, the yield is low, and it is not conducive to commercial production.

[0007]

[0008] Synthetic route three (referencing the synthetic route disclosed in Chinese patent CN101228135B) simplifies the process steps compared to the previous two routes, relatively reducing the complexity of the process and production costs. However, in the process of preparing compound 4 from compound 3, the method reported in this literature has a long reaction cycle, low reaction conversion rate, and requires multiple concentration, pH adjustment, extraction and washing operations in the post-processing. Finally, the target compound is obtained by column chromatography. The process is cumbersome, has a long processing cycle, and the yield is low.

[0009]

[0010] Therefore, given the problems with route three, there is still a need to develop a simpler and more economical method for preparing resimetidine intermediates. Summary of the Invention

[0011] To address the technical problems of long single-step reaction cycles and cumbersome post-processing operations in the industrial preparation of resimetiro intermediates, this invention provides an industrial preparation method for resimetiro intermediates. This method has a high reaction conversion rate, simple post-processing operations, and is suitable for industrial production.

[0012] To achieve the above objectives, the technical solution provided by the present invention is as follows:

[0013] An industrial method for preparing a resimetrol intermediate, the resimetrol intermediate being as shown in compound III:

[0014]

[0015] The preparation method includes the following steps:

[0016] (1) Compound I undergoes acylation and hydrolysis with formic acid to generate compound II;

[0017]

[0018] (2) Compound II was hydrolyzed in a solvent under alkaline conditions to prepare compound III;

[0019]

[0020] Furthermore, the reaction in step (1) occurs at a temperature of 80–100°C.

[0021] Furthermore, the reaction occurs at a temperature of 60–80°C in step (2).

[0022] Furthermore, the alkali used in step (2) is one of sodium hydroxide, potassium hydroxide, and potassium carbonate.

[0023] Furthermore, the solvent used in step (2) is an aqueous solution of methanol or ethanol, with a mass ratio of alcohol to water of 1:2 to 1:5.

[0024] Furthermore, in step (2), the molar ratio of compound II to the base is 1:7 to 1:10.

[0025] In step (1), the compound II generated from formic acid and compound I has a high purity and does not need to be obtained separately. After removing most of the formic acid, it can be directly added to the next hydrolysis reaction. However, in industrial production, the system has poor dispersibility after the formic acid is concentrated to a certain extent, resulting in incomplete concentration of formic acid. When the formic acid residue exceeds a certain limit, it will inhibit the next hydrolysis reaction, resulting in incomplete hydrolysis of compound II, and it is difficult to remove it in the post-processing.

[0026] To address the aforementioned technical problems, in some examples, step (1) further includes the following post-processing: the reaction product is concentrated to a viscous state, then 2-3 times its mass of water is added for dispersion and entrainment, and the concentration is continued until a viscous state is reached. This operation is repeated 1-2 times. This step can remove most of the formic acid in the system. Combined with the addition of a small amount of alcohol in step (2) during the hydrolysis reaction, the alcohol can consume the formic acid in the system, thereby promoting the hydrolysis of compound II. Furthermore, when the alcohol and water in the system exist in a certain proportion, most impurities in the system can be removed by filtration after the reaction without affecting the yield.

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

[0028] (1) In the prior art, compound I is reacted with acetic acid in an acetic acid / sodium acetate system at high temperature to generate an intermediate state. The intermediate product is then obtained through concentration, extraction, pH adjustment, and other operations before proceeding to the next hydrolysis reaction. This process is time-consuming, involves cumbersome post-processing, and results in low yields at each step. In contrast, this invention replaces the acetic acid / sodium acetate system with formic acid, resulting in compound II with higher purity. After removing most of the formic acid, it can be directly added to the next hydrolysis reaction to obtain compound III. This invention greatly simplifies the process, shortens the reaction time, and improves the product conversion rate.

[0029] (2) The present invention greatly improves the purity and yield of the product by combining the post-processing process in step (1) with the solvent in step (2). The product can achieve a purity of >99% and a yield of >85% without purification. At the same time, the process is also suitable for industrial production. Attached Figure Description

[0030] Figure 1 The hydrogen spectrum of compound III prepared in Example 7 is shown. Detailed Implementation

[0031] To better understand the present invention, the following embodiments further illustrate the invention, but the scope of the invention is not limited to the embodiments described below. All equivalent changes or modifications made based on the core method of the present invention should be covered within the protection scope of the present invention. Furthermore, while adhering to the process parameter ranges described in the present invention application, process parameters can be adjusted according to various embodiments and other suitable processes.

[0032] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0033] Example 1

[0034] At room temperature, 10g of compound I and 50g of formic acid were added to a reaction flask. The mixture was stirred and heated to 80-90℃, and reacted for 20h. After the reaction was completed, the reaction solution was cooled to 65-75℃ and concentrated under reduced pressure to remove most of the formic acid. After concentrating to a viscous state, 20ml of water was added to disperse the formic acid twice, and the mixture was further concentrated to a viscous state. 4.0g of ethanol was added at 70-80℃, and 9.6g of sodium hydroxide dissolved in 20g of water was added dropwise to the reaction system. After the addition was complete, the reaction was kept at this temperature for 2h. After the reaction was completed, the reaction solution was cooled to 20-30℃ and stirred for 1h. The pH was adjusted to 5-6 using 2N hydrochloric acid. The mixture was filtered, and the filter cake was rinsed with 20ml of water, dried under vacuum, and dried at 60℃ to obtain 8.5g of compound III with a purity of 99.1% and a yield of 90.0%.

[0035] Example 2

[0036] At room temperature, 10g of compound I and 50g of formic acid were added to a reaction flask. The mixture was stirred and heated to 90-100℃, and reacted for 15 hours. After the reaction was completed, the reaction solution was cooled to 65-75℃ and concentrated under reduced pressure to remove most of the formic acid. After concentrating to a viscous state, 20ml of water was added to disperse the formic acid twice, and the mixture was further concentrated to a viscous state. 4.0g of methanol was added at 60-70℃, and 9.6g of sodium hydroxide dissolved in 20g of water was added dropwise to the reaction system. After the addition was complete, the reaction was kept at this temperature for 4 hours. After the reaction was completed, the reaction solution was cooled to 20-30℃ and stirred for 1 hour. The pH was adjusted to 5-6 using 2N hydrochloric acid. The mixture was filtered, and the filter cake was rinsed with 20ml of water, dried under vacuum, and dried at 60℃ to obtain 8.6g of compound III with a purity of 99.2% and a yield of 90.5%.

[0037] Example 3

[0038] At room temperature, 10g of compound I and 50g of formic acid were added to a reaction flask. The mixture was stirred and heated to 90-100℃, and reacted for 15 hours. After the reaction was completed, the reaction solution was cooled to 65-75℃ and concentrated under reduced pressure to remove most of the formic acid. After concentrating to a viscous state, 20ml of water was added to disperse the formic acid twice, and the mixture was further concentrated to a viscous state. 10g of ethanol was added at 70-80℃, and 9.6g of sodium hydroxide dissolved in 20g of water was added dropwise to the reaction system. After the addition was complete, the reaction was kept at this temperature for 2 hours. After the reaction was completed, the reaction solution was cooled to 20-30℃ and stirred for 1 hour. The pH was adjusted to 5-6 using 2N hydrochloric acid. The mixture was filtered, and the filter cake was rinsed with 20ml of water, dried under vacuum, and dried at 60℃ to obtain 8.1g of compound III with a purity of 99.7% and a yield of 85.3%.

[0039] Example 4

[0040] At room temperature, 10g of compound I and 50g of formic acid were added to a reaction flask. The mixture was stirred and heated to 90-100℃, and reacted for 15 hours. After the reaction was completed, the reaction solution was cooled to 65-75℃ and concentrated under reduced pressure to remove most of the formic acid. After concentrating to a viscous state, 20ml of water was added to disperse the formic acid twice, and the mixture was further concentrated to a viscous state. 6.7g of ethanol was added at 70-80℃, and 9.6g of sodium hydroxide dissolved in 20g of water was added dropwise to the reaction system. After the addition was complete, the reaction was kept at this temperature for 2 hours. After the reaction was completed, the reaction solution was cooled to 20-30℃ and stirred for 1 hour. The pH was adjusted to 5-6 using 2N hydrochloric acid. The mixture was filtered, and the filter cake was rinsed with 20ml of water, dried under vacuum, and dried at 60℃ to obtain 8.2g of compound III with a purity of 99.5% and a yield of 86.7%.

[0041] Example 5

[0042] At room temperature, 10g of compound I and 50g of formic acid were added to a reaction flask. The mixture was stirred and heated to 90-100℃, and reacted for 15 hours. After the reaction was completed, the reaction solution was cooled to 65-75℃ and concentrated under reduced pressure to remove most of the formic acid. After concentrating to a viscous state, 20ml of water was added to disperse the formic acid twice, and the mixture was further concentrated to a viscous state. 5.0g of ethanol was added at 70-80℃, and 9.6g of sodium hydroxide dissolved in 20g of water was added dropwise to the reaction system. After the addition was complete, the reaction was kept at this temperature for 2 hours. After the reaction was completed, the reaction solution was cooled to 20-30℃ and stirred for 1 hour. The pH was adjusted to 5-6 using 2N hydrochloric acid. The mixture was filtered, and the filter cake was rinsed with 20ml of water, dried under vacuum, and dried at 60℃ to obtain 8.4g of compound III with a purity of 99.3% and a yield of 88.4%.

[0043] Example 6

[0044] At room temperature, 10g of compound I and 50g of formic acid were added to a reaction flask. The mixture was stirred and heated to 90-100℃, and reacted for 15 hours. After the reaction was completed, the reaction solution was cooled to 65-75℃ and concentrated under reduced pressure to remove most of the formic acid. After concentrating to a viscous state, 20ml of water was added to disperse the formic acid twice, and the mixture was further concentrated to a viscous state. 4.0g of ethanol was added at 70-80℃. 11.4g of sodium hydroxide dissolved in 20g of water was added dropwise to the reaction system. After the addition was complete, the reaction was kept at this temperature for 2 hours. After the reaction was completed, the reaction solution was cooled to 20-30℃ and stirred for 1 hour. The pH was adjusted to 5-6 using 2N hydrochloric acid. The mixture was filtered, and the filter cake was rinsed with 20ml of water, dried under vacuum, and dried at 60℃ to obtain 8.6g of compound III with a purity of 99.3% and a yield of 90.7%.

[0045] Example 7

[0046] At room temperature, 1.00 kg of compound I and 5.00 kg of formic acid were added to a reaction vessel. The mixture was stirred and heated to 90–100 °C, and reacted for 15 h. After the reaction was completed, the reaction solution was cooled to 65–75 °C and concentrated under reduced pressure to remove most of the formic acid. After concentrating to a viscous state, 2.00 kg of water was added to disperse the formic acid twice, and the mixture was further concentrated to a viscous state. 0.40 kg of ethanol was added at 70–80 °C. 0.96 kg of sodium hydroxide dissolved in 2.00 kg of water was added dropwise to the reaction system. After the addition was complete, the reaction was kept at this temperature for 2 h. After the reaction was completed, the reaction solution was cooled to 20–30 °C and stirred for 1 h. The pH was adjusted to 5–6 using 2N hydrochloric acid. The mixture was filtered, and the filter cake was rinsed with 2.00 kg of water, dried under vacuum, and dried at 60 °C to obtain 0.86 kg of compound III with a purity of 99.2% and a yield of 91.1%. A suitable amount of the obtained compound III was analyzed for its 1H NMR spectrum. The results were as follows: 1H NMR (DMSO, 400MHz): δppm 1.17–1.19 (d, 6.08H), 3.01–3.05 (t, 1.01H), 5.62 (s, 2.06H), 6.27 (s, 1.99H), 7.27 (s, 1.00H), 12.13 (s, 1.03H), m / z [M+H]+: 316.11. Figure 1 This is the corresponding proton spectrum.

[0047] Comparative Example 1

[0048] At room temperature, 10g of compound I and 50g of acetic acid were added to a reaction flask. The mixture was stirred and heated to 110–120°C, and reacted for 25 hours. After the reaction was completed, the reaction solution was cooled to 75–85°C and concentrated under reduced pressure to remove most of the acetic acid. After concentrating to a viscous state, 20ml of water was added to disperse the acetic acid twice, and the mixture was further concentrated to a viscous state. 4.0g of ethanol was added at 70–80°C. 9.6g of sodium hydroxide dissolved in 20g of water was added dropwise to the reaction system. After the addition was complete, the reaction was kept at this temperature for 12 hours. After the reaction was completed, the reaction solution was cooled to 20–30°C and stirred for 1 hour. The pH was adjusted to 5–6 using 2N hydrochloric acid. The mixture was filtered, and the filter cake was rinsed with 20ml of water, dried under vacuum, and dried at 60°C to obtain 7.86g of compound III with a purity of 85.3% and a yield of 79.1%.

[0049] Comparative Example 2

[0050] The comparative example was prepared using the method disclosed in patent CN101228135B, which was used to prepare the target compound.

[0051] At room temperature, 10g of compound I, 7.8g of sodium acetate, and 300ml of acetic acid were added to a reaction flask. The mixture was stirred and heated to 110-120℃, and reacted for 24 hours. After the reaction was completed, the reaction solution was cooled to 70-80℃ and concentrated under reduced pressure to remove most of the acetic acid. After concentrating to a viscous state, 200ml of water was added and stirred to disperse the solution. The pH was adjusted to approximately 9 using a 1mol / L NaOH aqueous solution. 200ml of ethyl acetate was added and stirred to disperse the solution. The pH of the aqueous phase was adjusted to 5-6 using 36% hydrochloric acid. The mixture was separated, and the organic phase was dried and concentrated to obtain an oily substance. 200ml of methanol and 200ml of 1mol / L sodium acetate were added to the oily substance. The NaOH aqueous solution was heated to 80℃ and reacted for 12 hours. The reaction solution was then cooled to 40-50℃ and concentrated under reduced pressure to remove methanol. 200 ml of ethyl acetate was added and the mixture was stirred and extracted. The pH of the aqueous phase was adjusted to approximately 5 using 36% hydrochloric acid. The mixture was separated, and the organic phase was dried and concentrated. The solution was then loaded onto a column and eluted using PE:EA at a ratio of 5:1 to 3:1 to obtain 5.86 g of product with a purity of 99.1% and a yield of 61.9%.

[0052] Comparative Example 3

[0053] At room temperature, 10g of compound I and 50g of formic acid were added to a reaction flask. The mixture was stirred and heated to 90-100℃, and reacted for 15 hours. After the reaction was completed, the reaction solution was cooled to 65-75℃ and concentrated under reduced pressure to remove most of the formic acid. After concentrating to a viscous state, 20ml of water was added to disperse the formic acid twice, and the mixture was further concentrated to a viscous state. 30g of ethanol was added at 70-80℃. 9.6g of sodium hydroxide dissolved in 20g of water was added dropwise to the reaction system. After the addition was complete, the reaction was kept at this temperature for 2 hours. After the reaction was completed, the reaction solution was cooled to 20-30℃ and stirred for 1 hour. The pH was adjusted to 5-6 using 2N hydrochloric acid. The mixture was filtered, and the filter cake was rinsed with 20ml of water and dried under vacuum to obtain 6.7g of compound III with a purity of 99.5% and a yield of 71.3%.

[0054] Comparative Example 4

[0055] At room temperature, 10g of compound I and 50g of formic acid were added to a reaction flask. The mixture was stirred and heated to 90-100℃, and reacted for 15 hours. After the reaction was completed, the reaction solution was cooled to 65-75℃ and concentrated under reduced pressure to remove most of the formic acid. After concentrating to a viscous state, 20ml of water was added to disperse the formic acid twice, and the mixture was further concentrated to a viscous state. 2g of ethanol was added at 70-80℃. 9.6g of sodium hydroxide dissolved in 20g of water was added dropwise to the reaction system. After the addition was complete, the reaction was kept at this temperature for 2 hours. After the reaction was completed, the reaction solution was cooled to 20-30℃ and stirred for 1 hour. The pH was adjusted to 5-6 using 2N hydrochloric acid. The mixture was filtered, and the filter cake was rinsed with 20ml of water and dried under vacuum to obtain 8.70g of compound III with a purity of 95.5% and a yield of 91.7%.

Claims

1. An industrial method for preparing a resimeltiro intermediate, wherein the resimeltiro intermediate is as shown in compound III: The preparation method includes the following steps: (1) Compound I undergoes acylation and hydrolysis with formic acid to generate compound II; (2) Compound II was hydrolyzed in a solvent under alkaline conditions to prepare compound III; 2. The industrial preparation method according to claim 1, characterized in that, The solvent used in step (2) is an aqueous solution of methanol or ethanol.

3. The industrial preparation method according to claim 2, characterized in that, In the aqueous solution of methanol or ethanol, the mass ratio of alcohol to water is 1:2 to 1:

5.

4. The industrial preparation method according to claim 1, characterized in that, The reaction occurs at a temperature of 80–100°C in step (1).

5. The industrial preparation method according to claim 1, characterized in that, The reaction occurs at a temperature of 60–80°C in step (2).

6. The industrial preparation method according to claim 1, characterized in that, The alkali used in step (2) is one of sodium hydroxide, potassium hydroxide, or potassium carbonate.

7. The industrial preparation method according to claim 1, characterized in that, In step (2), the molar ratio of compound II to the base is 1:7 to 1:

10.

8. The industrial preparation method according to claim 1, characterized in that, Step (1) further includes the following post-processing: after concentrating the reaction product to a viscous state, add water dispersion with a mass of 2 to 3 times the amount of feed, continue to concentrate to a viscous state, and repeat this operation 1 to 2 times.

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