Preparation method of rosemeltirol

Abstract

The invention discloses a preparation method of rosmeltirome, and relates to the technical field of drug synthesis, the preparation method comprises the following steps: in the presence of alkali and a first additive, heating a compound III in a solvent for hydrolysis and ring closing to directly obtain the rosmeltirome, the first additive comprises an anhydride compound. The invention provides a preparation method of rosmeltirol, which has the characteristics of short synthetic route, simple operation, high yield and the like, is suitable for industrial production, and makes up for the defects of the prior art.

Description

Technical Field

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

[0002] Resmetirom, an oral small molecule agonist targeting the THR-β receptor developed by Madrigal Pharmaceuticals Inc., received marketing authorization from the U.S. FDA on March 14, 2024, for the treatment of adult patients with nonalcoholic steatohepatitis (NASH) associated with liver fibrosis. As the world's first marketed drug for the treatment of NASH, it holds a promising market prospect.

[0003] The molecular structure of resmetirole is as follows:

[0004]

[0005] Regarding the preparation of resmetirole, the original research company reported two synthetic routes. Among them, international patent WO2007009913 discloses a synthetic method, and its synthetic route is as follows:

[0006]

[0007] This route uses silver nitrate, which is expensive and has low multi-step yields. For example, the process of hydrolyzing intermediate 4 to prepare intermediate 5 is actually a two-step process, which takes a long time and has high industrialization costs.

[0008] International patent WO2014043706 discloses another synthetic route, as follows:

[0009]

[0010] While this route improves yields in some steps, the reaction process is long, resulting in higher production costs. Furthermore, the use of isopropyl magnesium chloride, which requires anhydrous and oxygen-free conditions, creates harsh reaction conditions and poses a high safety risk.

[0011] Therefore, there is still a need to develop a method that is simple, has higher economic benefits and is suitable for industrial production. Summary of the Invention

[0012] In order to solve the above problems, the present invention provides a preparation method of resmetirole.

[0013] The present invention provides a preparation method of resmetirole, which comprises the following steps:

[0014]

[0015] In the presence of a base and a first additive, compound III is heated in a solvent to hydrolyze and cyclize to directly obtain resmetirole;

[0016] The first additive includes an acid anhydride compound.

[0017] Furthermore, the base is selected from one or more of sodium carbonate, potassium carbonate, sodium acetate and potassium acetate.

[0018] Furthermore, the solvent is selected from one or more of formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and toluene; preferably, the solvent is selected from one or more of formic acid, acetic acid, and propionic acid, or a mixed solvent system of the above solvents and one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and toluene.

[0019] Furthermore, the first additive is acetic anhydride.

[0020] Furthermore, the molar ratio of the compound III to the base is 1:1.0 to 5.0.

[0021] Furthermore, the molar ratio of the compound III to the additive is 1:0 to 10.0.

[0022] Furthermore, the molar ratio of the compound III to the base is 1:1.5 to 3.0.

[0023] Furthermore, the molar ratio of the compound III to the additive is 1:3.0-5.0.

[0024] Furthermore, the reaction temperature is 60°C to 120°C.

[0025] Furthermore, the reaction temperature is 100-120°C.

[0026] Furthermore, the preparation method further comprises:

[0027]

[0028] After the compound I is diazotized by a nitrosating agent, it is condensed with the compound II in the presence of a second additive to obtain the intermediate compound III.

[0029] Furthermore, the acid added to the diazotization reaction is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid; the nitrosating agent is selected from sodium nitrite, isoamyl nitrite, or tert-butyl nitrite; the second additive is selected from at least one of pyridine, sodium acetate, and potassium acetate; and the reaction solvent is selected from ethanol, formic acid, acetic acid, or water.

[0030] The above technical solution provided by the embodiment of the present invention has at least the following advantages compared with the prior art:

[0031] The present invention provides a method for preparing resmetirole, which has the advantages of a short synthetic route, simple operation, high yield, etc., is suitable for industrial production, and makes up for the shortcomings of the existing technology. Specifically:

[0032] (1) The conventional preparation method avoids the need to first hydrolyze 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (Compound I) and then diazotize and ring-close to obtain resmetirole. This process takes a long time to react, is cumbersome to handle, has poor quality, and has a low yield.

[0033] (2) Compound I is directly diazotized and condensed to obtain intermediate III with high yield and purity;

[0034] (3) Intermediate III is directly cyclized and hydrolyzed in one step to obtain crude resmetirol, which is then purified to obtain the target product with high purity. The yield is high, the working time is short, the efficiency is higher, the cost is lower, and it is more conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention.

[0036] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative labor.

[0037] Figure 1 HPLC spectrum of intermediate III prepared in Example 1 of the present invention;

[0038] Figure 2 The mass spectrum of intermediate III prepared in Example 1 of the present invention;

[0039] Figure 3 HPLC spectrum of resmetirole prepared in Example 6 of the present invention;

[0040] Figure 4 This is the mass spectrum of resmetirole prepared in Example 6 of the present invention;

[0041] Figure 5 This is the H NMR spectrum of resmetirole prepared in Example 6 of the present invention. DETAILED DESCRIPTION

[0042] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.

[0043] It should be noted that the components and raw materials involved in the preparation method of resmetirole provided in the embodiment of the present invention, unless otherwise specified or specifically explained, can be directly commercially available products or homemade using existing disclosed preparation methods; at the same time, the steps and parameters involved, unless otherwise specified or specifically explained, can be carried out in accordance with the preparation process disclosed in the prior art or directly using existing equipment with reference to the instructions for use, and the present invention document will not elaborate on them one by one.

[0044] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples where specific conditions are not specified are generally measured in accordance with national standards. If there are no corresponding national standards, then the methods are carried out in accordance with general international standards, conventional conditions, or the conditions recommended by the manufacturer.

[0045] In the following examples, 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (Compound I) was synthesized with reference to WO2007009913.

[0046] Example 1: Preparation of Intermediate III

[0047] In a 500mL three-necked flask, add 15g of compound I, 120mL of glacial acetic acid, 30mL of water, and 22.86g of concentrated hydrochloric acid, and stir to dissolve. Control the temperature at 0-10℃, and dropwise add sodium nitrite aqueous solution (NaNO2: 3.42g, water: 7.5ml). Keep warm and stir for 30min, and the reaction of compound I is complete. Add 17.8g of pyridine at 0-10℃, add 8.45g of compound II, keep warm and stir for 30min, return to room temperature and stir for 2h, filter and dry to obtain 19.6g of light yellow powder solid intermediate III, with a yield of 87.1% and a HPLC purity of 95.1%. See attached. Figure 1 .

[0048] MS (ESI) m / z = 499.1 [M+H] + , see attached Figure 2 .

[0049] Example 2: Preparation of Intermediate III

[0050] To a 500mL three-necked flask, add 15g of compound I, 120mL of glacial acetic acid, 30mL of water, and 22.86g of concentrated hydrochloric acid, and stir to dissolve. Control the temperature at 0-10°C and dropwise add an aqueous sodium nitrite solution (3.42g of NaNO2, 7.5ml of water). Maintain the temperature and stir for 30 minutes, and the reaction of compound I is complete. Add an aqueous sodium acetate solution (14.79g of NaOAc, 45mL of water) at 0-10°C, then add 8.45g of compound II, maintain the temperature and stir for 30 minutes, return to room temperature and stir for 2 hours, filter and dry to obtain 21.6g of intermediate III as a light yellow powder, with a yield of 95.8% and an HPLC purity of 98.69%.

[0051] Example 3: Preparation of Resmetirol

[0052] To a 500mL three-necked flask, 10g of Intermediate III, 4.92g of sodium acetate, and 200mL of glacial acetic acid were added. The mixture was refluxed at 120°C for 8 hours until the reaction was complete. After cooling to room temperature, 400mL of purified water was added and stirred for 1 hour. The mixture was filtered and the crude product was recrystallized from isopropanol and water to obtain 4.7g of resmetirol, with a yield of 53.9% and an HPLC purity of 94.5%.

[0053] Example 4: Preparation of Resmetirole

[0054] To a 500mL three-necked flask, add 10g of Intermediate III, 4.92g of sodium acetate, 200mL of glacial acetic acid, and 6.14g of acetic anhydride. Reflux at 120°C for 8 hours until the reaction is complete. Cool to room temperature, add 400mL of purified water, stir for 1 hour, filter, and recrystallize the crude product from isopropanol and water to obtain 6.6g of resmetirol, with a yield of 75.6% and an HPLC purity of 98.6%.

[0055] Example 5: Preparation of Resmetirol

[0056] To a 500mL three-necked flask, add 10g of Intermediate III, 2.46g of sodium acetate, and 50mL of N,N-dimethylacetamide. Stir at 110°C for 2h. Then add 100mL of glacial acetic acid and continue the reaction at 120°C for 8h. Cool to room temperature, add 300mL of purified water, stir for 1h, filter, and recrystallize the crude product from isopropanol and water to obtain 5.8g of resmetirol (yield 66.5%) with an HPLC purity of 95.2%.

[0057] Example 6: Preparation of Resmetirole

[0058] To a 500mL three-necked flask, 10g of intermediate III, 2.46g of sodium acetate, and 50mL of N,N-dimethylacetamide were added and stirred at 110°C for 2h. 100mL of glacial acetic acid and 6.14g of acetic anhydride were added and the reaction was continued at 120°C for 8h. Cooled to room temperature, 300mL of purified water was added, stirred for 1h, filtered, and the crude product was recrystallized from isopropanol and water to obtain 7.4g of resmetirox, with a yield of 84.8% and an HPLC purity of 99.7%. See attached. Figure 3 .

[0059] MS (ESI) m / z = 435.1 [M+H] + , see attached Figure 4 .

[0060] 1 H-NMR (DMSO-d6): δ1.186~1.203ppm (6H,d), δ3.015~3.083ppm (1H,m), δ7.442~ 7.444ppm(1H,d), δ7.786ppm(2H,s), δ12.249ppm(1H,s), δ13.292ppm(1H,s), see attachment Figure 5 .

[0061] Example 7: Preparation of Resmetirole

[0062]

[0063] In this example, a condition screening experiment was conducted in the method for preparing resmetirol. The reaction mainly involved the resmetirol cyanide hydrolysis impurity shown below.

[0064]

[0065] 1. Alkali type screening experiment

[0066] Referring to the preparation method of Example 6, the only difference is the type of base. The other conditions, amounts and steps are the same. The impurity content in the reaction solution and the post-treatment are respectively detected and the sample yield is shown in Table 1 below (Note: eq represents molar equivalent, which represents the molar equivalent ratio to intermediate III, and the same expression is used below).

[0067] Table 1

[0068] serial number Types of alkali Impurity A Main Peak Sample yield 1 sodium carbonate 2.5％ 83％ 76.2％ 2 potassium carbonate 3.6％ 81％ 73.8％ 3 Sodium acetate 1.5％ 89％ 84.8％ 4 Potassium acetate 1.9％ 87％ 82.1％

[0069] As can be seen from the above table, when the other conditions are the same as those in Example 6, when sodium acetate and potassium acetate are used, the reaction effect and sample yield are relatively better, and sodium acetate is relatively the best.

[0070] 2. Sodium acetate usage screening experiment

[0071] The preparation method of Example 6 was followed, with the only difference being the amount of sodium acetate used. Other conditions and steps were the same. The impurity content in the reaction solution was detected and the samples obtained by post-treatment were shown in Table 2 below.

[0072] Table 2

[0073] serial number Sodium acetate equivalent Impurity A Main Peak Sample yield 1 1.0eq 0.5％ 60％ 50.6％ 2 1.5eq 1.5％ 89％ 84.8％ 3 3.0eq 1.6％ 88％ 83.2％ 4 5.0eq 3.2％ 85％ 79.5％

[0074] As can be seen from the above table, when the other conditions are the same as those in Example 6, the amount of sodium acetate used is 1 eq, and the reaction is not completely converted. When the amount of sodium acetate used is 1.5-3.0 eq, the reaction effect is better and the post-treatment yield is higher.

[0075] 3. Screening experiment of acetic anhydride usage

[0076] The preparation method of Example 6 was followed, with the only difference being the amount of acetic anhydride used. Other conditions and steps were the same. The impurity content in the reaction solution was detected and the samples obtained by post-treatment were shown in Table 3 below.

[0077] Table 3

[0078]

[0079]

[0080] As can be seen from the above table, the addition of acetic anhydride can significantly inhibit the generation of impurity A during the reaction process. When the amount of acetic anhydride is 3.0-5.0eq, the hydrolyzed impurity A is relatively small and the main peak purity is high.

[0081] 4. Reaction solvent type screening experiment

[0082] Referring to the preparation methods of Example 4 and Example 6, the only difference is the type of solvent. Other conditions and steps are the same. The impurity content in the reaction solution is detected and the samples obtained by post-treatment are shown in Table 4 below.

[0083] Table 4

[0084] serial number solvent Impurity A Main Peak Sample yield 1 Formic acid 16.7％ 59.1％ 52.6％ 2 Acetic acid 15.6％ 60.2％ 53.9％ 3 Propionic acid 14.6％ 62.3％ 54.5％ 4 Acetic acid + propionic acid 14.9％ 63.3％ 55.6％ 5 DMF 0％ 0％ 0％ 6 DMAC 0％ 0％ 0％ 7 DMAC+acetic acid 1.5％ 89％ 84.8％ 8 DMAC+Propionic Acid 1.5％ 86％ 82.7％

[0085] As can be seen from the table above, single solvent systems such as formic acid, acetic acid, and propionic acid, or their mixtures, can effectively obtain the target product. Single solvent systems such as DMF and DMAC only produce cyclization intermediates and fail to effectively obtain the target product. However, referring to the method of Example 6, when mixed with one or more of formic acid, acetic acid, and propionic acid, the target product can be effectively obtained, and the performance is better than that of the single solvents.

[0086] Various embodiments of the present invention may be presented in the form of a range; it should be understood that the description in a range format is only for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention; therefore, the range description should be considered to have specifically disclosed all possible subranges and single numerical values within the range. For example, the description of a range from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as single numbers within the range, such as 1, 2, 3, 4, 5, and 6, regardless of the range. In addition, whenever a numerical range is indicated herein, it is intended to include any cited numeral (fractional or integer) within the indicated range.

[0087] The foregoing description is intended only to provide specific embodiments of the present invention, which will enable those skilled in the art to understand and implement the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not intended to be limited to the embodiments shown herein, but is intended to be accorded the widest scope consistent with the principles and novel features claimed herein.

Claims

1. A method for preparing resmetirole, characterized in that: The preparation method comprises the following steps: In the presence of a base and a first additive, compound III is heated in a solvent to hydrolyze and cyclize to directly obtain resmetirole; The first additive includes an acid anhydride compound.

2. The method for preparing resmetirole according to claim 1, wherein The base is selected from one or more of sodium carbonate, potassium carbonate, sodium acetate and potassium acetate.

3. The method for preparing resmetirole according to claim 1, wherein The solvent is selected from one or more of formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and toluene.

4. The method for preparing resmetirole according to claim 1, wherein The first additive is acetic anhydride.

5. The method for preparing resmetirole according to claim 1, wherein The molar ratio of the compound III to the base is 1:1.0-5.

0.

6. The method for preparing resmetirole according to claim 1, wherein The molar ratio of the compound III to the additive is 1:0 to 10.

0.

7. The method for preparing resmetirole according to claim 1, wherein: The reaction temperature is 60°C to 120°C.

8. The method for preparing resmetirole according to claim 1, wherein The reaction temperature is 100-120° C., the molar ratio of the compound III to the base is 1:1.5-3.0, and the molar ratio of the compound III to the additive is 1:3.0-5.

0.

9. The method for preparing resmetirole according to any one of claims 1 to 8, characterized in that: The preparation method further comprises: After the compound I is diazotized by a nitrosating agent, it is condensed with the compound II in the presence of a second additive to obtain the intermediate compound III.

10. The method for preparing resmetirole according to claim 9, characterized in that: The acid added to the diazotization reaction is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid; the nitrosating agent is selected from sodium nitrite, isoamyl nitrite, or tert-butyl nitrite; the second additive is selected from at least one of pyridine, sodium acetate, and potassium acetate; and the reaction solvent is selected from ethanol, formic acid, acetic acid, or water.

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