CN117164568A - Resmetirom intermediate and preparation method thereof as well as preparation method of intermediate III - Google Patents

Abstract

The invention relates to the technical field of pharmaceutical intermediates and provides a Resmetirom intermediate and a preparation method thereof as well as a preparation method of Intermediate III. The present invention adopts the intermediate with the structure shown in Formula VI to prepare Resmetirom intermediate III through addition-elimination-double bond shift reaction, substitution reaction and deprotection reaction. All intermediate products of the preparation method provided by the invention are solid, which is easy to purify, without the need to use expensive silver nitrate, has low cost, and the yield of each step is high and the reaction time is short. In summary, the preparation method provided by the present invention significantly reduces the production difficulty, production cost and production cycle of Resmetirom intermediate III, and is more conducive to industrial production.

Description

A kind of Resmetirom intermediate and preparation method thereof and preparation of intermediate III method

Technical field

The present invention relates to the technical field of pharmaceutical intermediates, and in particular to a Resmetirom intermediate and a preparation method thereof as well as a preparation method of Intermediate III.

Background technique

Resmetirom (Chinese name: Resmetirom, CAS number: 920509-32-6) is a drug for the treatment of cirrhosis and fatty liver. It reduces liver fat by targeting the thyroid hormone pathway and is currently in Phase III clinical research. Fatty liver has become the most common sign of physical abnormality in physical examination. If fatty liver is not controlled, it may develop into NASH (non-alcoholic steatohepatitis), liver fibrosis, cirrhosis and even liver cancer. NASH has faced the dilemma of having no cure for the past few decades. In December 2022, the original research company Madrigal announced that the Phase 3 trial of its THR-β agonist MGL-3196 in the treatment of NASH was successful. The company's Phase 3 clinical data showed that Resmetirom achieved remission of NASH using gold standard liver puncture verification and 52 weeks of administration. and fibrosis improvement dual endpoint.

The molecular structure of Resmetirom is shown in Formula I:

Patents WO2007009913 and CN112707892 disclose the following preparation method: Compound D and isobutyric acid, under the action of silver nitrate and ammonium persulfate, generate Compound C with a yield of 67%, and the reaction time is greater than 24h; Compound C is prepared through a 24h substitution reaction Compound B is produced with a yield of 53%; Compound B is hydrolyzed to obtain Compound III with a yield of 50% and a reaction time of more than 96 hours; Compound III is added to Compound A after diazo reaction and the double bond is shifted to generate Compound II, yielding The yield is 56%; finally, compound II is ring-closed under basic conditions to obtain compound I, namely MGL-3196, with a yield of 50%. The specific synthesis route is as follows:

This synthetic route has a total of 5 steps, and the yield of each step is low and the cost is high; in addition, the first step uses silver nitrate, which is more expensive; furthermore, compound C is an oily substance and is difficult to purify; the above shortcomings limit the route of industrialized production.

From the above route, it can be found that compound III is a key intermediate for the synthesis of MGL-3196. However, when compound III is synthesized by this route, it has the disadvantages of difficulty in purification, low yield, and high cost; therefore, it is urgent to develop a method that is easy to purify and recover. A method for preparing MGL-3196 intermediate III with high efficiency and low cost.

Contents of the invention

In view of this, the present invention provides a Resmetirom intermediate and a preparation method thereof as well as a preparation method of Intermediate III. The invention provides a Resmetirom intermediate with a structure shown in formula VI. The Resmetirom intermediate III with a structure shown in formula VI is used to prepare Resmetirom intermediate III. The product is easy to purify, has high yield and low cost.

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

A Resmetirom intermediate having the structure shown in Formula VI:

The present invention also provides a preparation method for the Resmetirom intermediate described in the above scheme, which includes the following steps:

Mix the compound with the structure shown in Formula D, sodium benzene sulfinate and an organic solvent to perform a substitution-hydrolysis reaction to obtain the compound with the structure shown in Formula VII;

The compound with the structure represented by Formula VII, 3,4-dihydro-2H-pyran, p-toluenesulfonic acid and an organic solvent are mixed to perform an amide protection reaction to obtain the Resmetirom intermediate with the structure represented by Formula VI.

Preferably, the molar ratio of the compound having the structure represented by formula D and sodium benzene sulfinate is 1: (1-3);

The temperature of the substitution-hydrolysis reaction is 50 to 150°C, and the time is 1 to 20 hours;

The organic solvent used in the substitution-hydrolysis reaction is one or more of N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone and acetonitrile.

Preferably, the molar ratio of the compound with the structure shown in Formula VII and 3,4-dihydro-2H-pyran is 1:(1-4); the compound with the structure shown in Formula VII and p-toluenesulfonic acid The molar ratio is 1:(0.05～0.5);

The temperature of the amide protection reaction is 30-80°C, and the time is 1-20 hours;

The organic solvent used in the amide protection reaction is one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone and 1,4-dioxane.

The invention also provides a preparation method of Resmetirom intermediate III, which includes the following steps:

Mix the compound with the structure shown in Formula VI, 2-nitropropane, the first basic compound and an organic solvent to perform an addition-elimination-double bond shift reaction to obtain the compound with the structure shown in Formula V;

Mix the compound with the structure shown in Formula V, 2,6-dichloro-4-aminophenol, a second basic compound and an organic solvent to perform a substitution reaction to obtain the compound with the structure shown in Formula IV;

Mix the compound with the structure shown in formula IV and hydrochloric acid to perform a deprotection reaction to obtain Resmetirom intermediate III, with the structural formula shown in formula III;

Preferably, the molar ratio of the compound having the structure shown in Formula VI and 2-nitropropane is 1:(1-3);

The first basic compound is one or more of DBU, triethylamine, potassium carbonate, sodium carbonate, KOH and NaOH; the molar ratio of the compound with the structure shown in Formula VI and the first basic compound is 1:(0.2～3);

The organic solvents used in the addition-elimination-double bond shift reaction are N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 1,4 - One or more dioxanes.

Preferably, the temperature of the addition-elimination-double bond shift reaction is 0-100°C and the time is 0.5-10 h.

Preferably, the molar ratio of the compound having the structure shown in Formula V and 2,6-dichloro-4-aminophenol is 1:(1-2);

The second basic compound is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide; the structure shown in the formula V The molar ratio of the compound and the second basic compound is 1: (1 ~ 3);

The organic solvent used in the substitution reaction is one of N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, acetonitrile, and 1,4-dioxane. Kind or variety.

Preferably, the temperature of the substitution reaction is 40-120°C and the time is 2-20 hours.

Preferably, the mass fraction of the hydrochloric acid is 36-38%, the ratio of the volume of the hydrochloric acid to the mass of the compound having the structure shown in Formula IV is 1-100 mL:1g; the temperature of the deprotection reaction is 10-100 ℃, time is 1~10h.

The invention provides a Resmetirom intermediate having a structure shown in formula VI. Resmetirom intermediate III is prepared using the intermediate having the structure shown in Formula VI. The product is easy to purify, has high yield and low cost.

The invention also provides a method for preparing Resmetirom intermediate III, which includes the following steps: mixing the compound with the structure shown in formula VI, 2-nitropropane, the first basic compound and an organic solvent to perform addition-elimination-double bond transfer. reaction to obtain a compound with a structure represented by formula V; mix the compound with a structure represented by formula V, 2,6-dichloro-4-aminophenol, a second basic compound and an organic solvent to perform a substitution reaction, obtaining formula A compound with a structure represented by formula IV; the compound with a structure represented by formula IV is mixed with hydrochloric acid to perform a deprotection reaction to obtain Resmetirom intermediate III. The present invention uses the intermediate represented by formula VI to prepare Resmetirom intermediate III. In the synthesis route of the present invention, all intermediate products are solid, which is easy to purify; the preparation method of the present invention does not require the use of expensive silver nitrate, has low cost, and The yield at each step is higher. Moreover, the intermediate of the structure shown in formula VI contains a phenyl sulfone group, which is a strong electron-withdrawing group, which greatly enhances the addition reaction activity of compound VI to prepare compound V and significantly reduces the reaction time. At the same time, the phenyl sulfone group It is also a good leaving group and reduces the substitution reaction time of compound V to prepare compound IV. In summary, the preparation method provided by the present invention significantly reduces the production difficulty, production cost and production cycle of Resmetirom intermediate III, and is more conducive to industrial production.

Description of drawings

Figure 1 is a hydrogen nuclear magnetic spectrum of Resmetirom intermediate VI prepared in Example 2 of the present invention;

Figure 2 is a hydrogen nuclear magnetic spectrum of Resmetirom intermediate III prepared in Example 4 of the present invention.

Detailed ways

The invention provides a Resmetirom intermediate having the structure shown in formula VI:

The present invention also provides a preparation method for the Resmetirom intermediate described in the above scheme, which includes the following steps:

Mix the compound with the structure shown in Formula D, sodium benzene sulfinate and an organic solvent to perform a substitution-hydrolysis reaction to obtain the compound with the structure shown in Formula VII;

The compound with the structure shown in Formula VII, 3,4-dihydro-2H-pyran, p-toluenesulfonic acid and an organic solvent are mixed to perform an amide protection reaction to obtain the Resmetirom intermediate with the structure shown in Formula VI.

In the present invention, the synthetic route of the Resmetirom intermediate with the structure shown in Formula VI is as follows:

The preparation method of the Resmetirom intermediate having the structure represented by Formula VI is described in detail below.

In the present invention, a compound with a structure represented by formula D, sodium benzene sulfinate and an organic solvent are mixed to perform a substitution-hydrolysis reaction to obtain a compound with a structure represented by formula VII. In the present invention, the molar ratio of the compound having the structure represented by formula D and sodium benzene sulfinate is preferably 1: (1-3), more preferably 1: (1.1-2); the substitution-hydrolysis reaction The organic solvent used is preferably one or more of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), N-methylpyrrolidone and acetonitrile. species, more preferably DMF.

In the present invention, the temperature of the substitution-hydrolysis reaction is preferably 50-150°C, more preferably 80-120°C, and the time of the substitution-hydrolysis reaction is preferably 1-20h, more preferably 1.5-10h; so The substitution-hydrolysis reaction is preferably carried out under nitrogen protection.

After the substitution-hydrolysis reaction is completed, the present invention preferably performs post-processing on the obtained substitution-hydrolysis reaction liquid. The post-processing method preferably includes: cooling the obtained substitution-hydrolysis reaction liquid to 50-100°C (preferably 60°C ) and mix with water, then cool to room temperature, pour the obtained cooling liquid into water, stir at room temperature and then filter, wash the obtained solid product with water to obtain a compound with the structure shown in formula VII; the stirring time at room temperature is preferably 5 minutes .

After obtaining the compound with the structure shown in formula VII, the present invention mixes the compound with the structure shown in formula VII, 3,4-dihydro-2H-pyran, p-toluenesulfonic acid and an organic solvent to perform an amide protection reaction to obtain the compound of formula VI. The structure of Resmetirom intermediate is shown. In the present invention, the molar ratio of the compound having the structure shown in Formula VII and 3,4-dihydro-2H-pyran is preferably 1:(1-4), more preferably 1:(1.1-2); The molar ratio of the compound having the structure shown in Formula VII to p-toluenesulfonic acid is preferably 1:(0.05~0.5), more preferably 1:(0.05~0.3); the organic solvent used in the amide protection reaction is preferably tetrahydrofuran , ethyl acetate, dichloromethane, acetonitrile, acetone and one or more of 1,4-dioxane, more preferably tetrahydrofuran.

In the present invention, the temperature of the amide protection reaction is preferably 30-80°C, more preferably 40-70°C, and the time of the amide protection reaction is preferably 1-20h, more preferably 1.5-8h.

After the amide protection reaction is completed, the present invention preferably performs post-processing on the obtained amide protection reaction solution. The post-processing method preferably includes: cooling the obtained amide protection reaction solution to room temperature and then mixing it with water to adjust the pH value of the mixed solution. to 8 to 10, preferably 9, stir at room temperature and then spin evaporate to remove the organic solvent, filter the remaining liquid, and wash and dry the solid product to obtain the Resmetirom intermediate with the structure shown in Formula VI; adjust the pH value of the mixed solution using The reagent is preferably potassium carbonate; the room temperature stirring time is preferably 5 min; the detergent for washing the solid product is preferably a mixed solvent of ethyl acetate and heptane, and the volume ratio of ethyl acetate and heptane in the mixed solvent is preferably It is 1: (1-10), and it is more preferable that it is 1:2.

The invention also provides a preparation method of Resmetirom intermediate III, which includes the following steps:

Mix the compound with the structure shown in Formula VI, 2-nitropropane, the first basic compound and an organic solvent to perform an addition-elimination-double bond shift reaction to obtain the compound with the structure shown in Formula V;

Mix the compound with the structure shown in Formula V, 2,6-dichloro-4-aminophenol, a second basic compound and an organic solvent to perform a substitution reaction to obtain the compound with the structure shown in Formula IV;

Mix the compound with the structure shown in formula IV and hydrochloric acid to perform a deprotection reaction to obtain Resmetirom intermediate III, with the structural formula shown in formula III;

In the present invention, the synthetic route of the Resmetirom intermediate III is as follows:

The synthesis method of Resmetirom intermediate III is described in detail below.

In the present invention, a compound with a structure represented by Formula VI, 2-nitropropane, a first basic compound and an organic solvent are mixed to perform an addition-elimination-double bond shift reaction to obtain a compound with a structure represented by Formula V. In the present invention, the compound with the structure represented by Formula VI is prepared according to the above method, which will not be described again; the molar ratio of the compound with the structure represented by Formula VI and 2-nitropropane is preferably 1:(1~ 3), more preferably 1: (1.1～2); the first basic compound is preferably one or more of DBU, triethylamine, potassium carbonate, sodium carbonate, KOH and NaOH, more preferably DBU ; The molar ratio of the compound having the structure shown in formula IV and the first basic compound is preferably 1: (0.2～3), more preferably 1: (0.3～2); the addition-elimination-double bond transfer The organic solvent used in the reaction is preferably N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), tetrahydrofuran and One or more types of 1,4-dioxane, more preferably DMSO.

In the present invention, the temperature of the addition-elimination-double bond shift reaction is preferably 0 to 100°C, more preferably 5 to 50°C. In specific embodiments of the invention, the addition-elimination-double bond shift reaction is The double bond shift reaction is preferably performed at room temperature; the time of the addition-elimination-double bond shift reaction is preferably 0.5 to 10 h, more preferably 0.5 to 5 h.

After the addition-elimination-double bond shift reaction is completed, the present invention preferably performs post-processing on the resulting addition-elimination-double bond shift reaction solution. The post-processing method preferably includes: performing the addition-elimination reaction solution. - Mix the double bond displacement reaction liquid and water, adjust the pH value of the resulting mixed liquid to 3 to 7, preferably 5, stir at room temperature and then filter, wash and dry the obtained solid product to obtain a compound with the structure represented by Formula V ; The reagent used to adjust the pH value of the resulting mixed solution is preferably hydrochloric acid; the stirring time at room temperature is preferably 5 minutes; the washing preferably includes water washing and mixed solvent washing in sequence; the mixed solvent is preferably ethyl acetate and heptane. Mixing solvents, the volume ratio of ethyl acetate and heptane is preferably 1:2.

After obtaining the compound with the structure represented by formula V, the present invention mixes the compound with the structure represented by formula V, 2,6-dichloro-4-aminophenol, the second basic compound and an organic solvent to perform a substitution reaction to obtain the formula Compounds with the structure shown in IV. In the present invention, the molar ratio of the compound having the structure represented by formula V and 2,6-dichloro-4-aminophenol is preferably 1:(1~2), more preferably 1:(1~1.3); The second basic compound is preferably one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide, and is more preferably potassium carbonate; The molar ratio of the compound with the structure shown in Formula V and the second basic compound is preferably 1:(1~3), more preferably 1:(1~2); the organic solvent used in the substitution reaction is preferably It is N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), acetonitrile, 1,4-dioxane One or more rings, more preferably DMF.

In the present invention, the temperature of the substitution reaction is preferably 40 to 120°C, more preferably 50 to 100°C, and the time of the substitution reaction is preferably 2 to 20 h, more preferably 2 to 10 h.

After the substitution reaction is completed, there is no need to perform any treatment on the reaction solution, and the next step of reaction can be carried out directly.

After obtaining the compound with the structure represented by Formula IV, the present invention mixes the compound with the structure represented by Formula IV and hydrochloric acid to perform a deprotection reaction to obtain Resmetirom intermediate III. In the present invention, the mass fraction of the hydrochloric acid is preferably 36 to 38%, more preferably 37%, and the ratio of the volume of the hydrochloric acid to the mass of the compound with the structure represented by formula IV is preferably 1 to 100 mL:1g; so The temperature of the deprotection reaction is preferably 10 to 100°C, more preferably 30 to 70°C, and the time of the deprotection reaction is 1 to 10 hours, more preferably 1.5 to 5 hours. In the present invention, it is preferred that after the substitution reaction is completed, the temperature of the obtained substitution reaction liquid is adjusted to the temperature of the deprotection reaction, and then hydrochloric acid is directly added thereto.

After the deprotection reaction is completed, the present invention preferably performs post-processing on the obtained reaction liquid. The post-processing method preferably includes: mixing the obtained deprotection reaction liquid and water, and adjusting the pH value of the obtained mixed liquid to 6 to 8. , preferably 7, stir at room temperature and then filter, wash and dry the obtained solid product to obtain Resmetirom intermediate III; the reagent used to adjust the pH value of the obtained mixture is preferably liquid caustic soda; the room temperature stirring time is preferably 5 min; The washing preferably includes water washing and mixed solvent washing in sequence; the mixed solvent is preferably a mixed solvent of ethyl acetate and heptane, and the volume ratio of ethyl acetate and heptane is preferably 1:2.

The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention.

The methods in the following examples are all conventional methods unless otherwise specified. The raw materials, reagent materials, etc. used in the following examples are all commercially available products unless otherwise specified. In the following examples: compounds with the structure shown in Formula D, compounds with the structure shown in Formula VII, compounds with the structure shown in Formula VI, compounds with the structure shown in Formula V, compounds with the structure shown in Formula IV and compounds with the structure shown in Formula III. The compounds of the structures are respectively called compound D, compound VII, compound V, compound IV and compound III.

Example 1 Preparation of Compound VII

Method 1: Add 14.9g of compound D (100mmol), 19.7g (120mmol) of sodium benzene sulfinate and 150mL of DMF into the reaction flask, under nitrogen protection, raise the temperature to 100°C and react for 3 hours; after cooling to 60°C, add 10mL of water. Cool to room temperature naturally while stirring; pour 600 mL of water and stir for 5 minutes at room temperature; filter and wash with 50 mL of water to obtain 22.4 g of yellow solid compound VII with a yield of 95%.

Method 2: Add 14.9g compound D (100mmol), 24.6g (150mmol) sodium benzene sulfinate and 150mL DMAc into the reaction bottle, under nitrogen protection, raise the temperature to 90°C and react for 5 hours; after cooling to 60°C, add 10mL water. Cool to room temperature naturally while stirring; pour into 600 mL of water, stir at room temperature for 5 min; filter, and wash with 50 mL of water to obtain 21.7 g of yellow solid compound VII with a yield of 92%.

The NMR data of compound VII obtained by method 1 are as follows: ¹ H-NMR (400M, CDCl ₃ ): 8.02 (2H, d), 7.90 (1H, m), 7.71-7.60 (4H, m), 7.07 (1H, d) .

Example 2 Preparation of Compound VI

Method 1: Add 7.09g (30mmol) compound VII, 3.78g (45mmol) 3,4-dihydro-2H-pyran, 0.52g (3.0mmol) p-toluenesulfonic acid and 50mL tetrahydrofuran into the reaction bottle, and heat to 60 React at ℃ for 5 hours; cool to room temperature, add 100 mL of water, adjust the pH to 9 with potassium carbonate, and stir at room temperature for 5 minutes; spin off the tetrahydrofuran, a large amount of solid will precipitate, filter, and use 30 mL of ethyl acetate-heptane mixed solvent (ethyl acetate and heptane) The volume ratio is 1:2), washed and dried to obtain 9.42g of light yellow solid compound VI, with a yield of 98%.

Method 2: Add 7.09g (30mmol) compound VII, 5.04g (60mmol) 3,4-dihydro-2H-pyran, 1.04g (6.0mmol) p-toluenesulfonic acid and 50mL acetonitrile into the reaction bottle, and heat to 70 React at ℃ for 6 hours; cool to room temperature, add 100 mL of water, adjust the pH to 9 with potassium carbonate, and stir at room temperature for 5 minutes; spin off the acetonitrile, a large amount of solid will precipitate, filter, and add 30 mL of ethyl acetate-heptane mixed solvent (a mixture of ethyl acetate and heptane) The volume ratio is 1:2), washed and dried to obtain 9.13g of light yellow solid compound VI, with a yield of 95%.

The NMR data of compound VI obtained by method 1 are as follows: 1H-NMR (400M, CDCl ₃ ): 8.01 (2H, d), 7.77 (1H, d), 7.69 (1H, t), 7.59 (2H, t), 7.00 ( 1H, d), 5.93 (1H, d), 3.99 (1H, d), 3.69 (1H, t), 1.98 (2H, br), 1.62 (4H, br). Figure 1 is the hydrogen nuclear magnetic spectrum of compound VI.

Example 3 Preparation of Compound V

Method 1: Add 6.40g compound VI (20mmol), 2.68g 2-nitropropane (30mmol), 4.56g DBU (30mmol) and 80mL DMSO into the reaction bottle, stir and react at room temperature for 1 hour; pour into 240mL water. Adjust pH to 5 with hydrochloric acid, stir at room temperature for 5 minutes, filter, wash once with 40 mL of water, then wash with 40 mL of ethyl acetate-heptane mixed solvent (the volume ratio of ethyl acetate to heptane is 1:2), and dry. 7.16 g of light yellow solid compound V was obtained, with a yield of 99%.

Method 2: Add 6.40g compound VI (20mmol), 3.58g 2-nitropropane (40mmol), 5.5g potassium carbonate (40mmol) and 80mL DMF into the reaction bottle, raise the temperature to 40°C and react for 1 hour; pour into 240mL water , stir at room temperature for 5 minutes, filter, wash once with 40mL of water, then wash with 40mL of ethyl acetate-heptane mixed solvent (the volume ratio of ethyl acetate and heptane is 1:2), and dry to obtain 6.88g of light yellow Solid V, yield 95%.

The NMR data of compound V obtained by method 1 are as follows: ¹ H-NMR (400M, DMSO-d ₆ ): 7.97 (2H, d), 7.86 (1H, m), 7.70-7.55 (3H, m), 5.64 (1H, dd), 3.81 (1H, m), 3.51 (1H, m), 3.08 (1H, m), 1.62-1.43 (6H, m), 1.18 (6H, d).

Example 4 Preparation of Compound III

Method 1: Add 3.62g (10mmol) of compound V, 2.14g of 2,6-dichloro-4-aminophenol (12mmol), 2.07g of potassium carbonate powder (14mmol) and 40mL of DMF into the reaction bottle, and heat to 70 Stir and react for 5 hours at ℃; cool to room temperature, add 10 mL hydrochloric acid (about 37% mass fraction), raise the temperature to 50 ℃ and react for 2 hours; pour into 200 mL of water, adjust the pH to 7 with liquid caustic soda, stir at room temperature for 5 minutes, filter, and wash with 20 mL of water first Once, it was washed with 20 mL of ethyl acetate-heptane mixed solvent (the volume ratio of ethyl acetate and heptane was 1:2), and dried to obtain 2.98 g of off-white compound III with a yield of 95%.

Method 2: Add 3.62g (10mmol) compound V, 1.96g 2,6-dichloro-4-aminophenol (11mmol), 2.12g sodium carbonate powder (20mmol) and 40mL DMSO into the reaction bottle, and heat it to 80°C Stir and react for 4 hours; cool to room temperature, add 10 mL hydrochloric acid (about 37% mass fraction), raise the temperature to 50°C and react for 2 hours; pour into 200 mL of water, adjust the pH to 7 with liquid caustic soda, stir at room temperature for 5 minutes, filter, and wash once with 20 mL of water. , then washed with 20 mL of ethyl acetate-heptane mixed solvent (the volume ratio of ethyl acetate to heptane is 1:2), and dried to obtain 2.95 g of off-white compound III with a yield of 94%.

The NMR data of compound III obtained by method 1 are as follows: ¹ H-NMR (400M, DMSO-d ₆ ): 12.12 (1H, s), 7.27 (1H, s), 6.67 (2H, s), 5.61 (2H, brs) , 3.03 (1H, m), 1.17 (6H, d); Figure 2 is the hydrogen nuclear magnetic spectrum of compound III.

Example 5 Preparation of Compound I (Resmetirom)

Preparation of compound II: Add 3.14g compound III (10.0mmol), 1.72g compound A (11.0mmol) and 60mL water into the reaction bottle. Cool the ice water to 0~10°C and add 30mL hydrochloric acid (37% mass) in batches. fraction); keep at 5 to 10°C, add dropwise a solution of 6.9g sodium nitrite (100mmol) and 20mL water within 30 minutes, and then add dropwise a solution of 23.0g sodium acetate (280mmol) and 90mL water within 50 minutes; Remove the ice water bath, stir the reaction at room temperature for 2 hours, filter, first wash with 30 mL of water, then 20 mL of isopropyl ether, and dry to obtain 4.23 g of yellow-brown solid Compound II with a yield of 88%. ¹ H-NMR (400M, DMSO-d ₆ ): δ12.26 (2H, brs), 10.90 (1H, s), 8.00 (2H, s), 7.36 (1H, s), 4.23 (2H, q), 3.07 (1H, m), 1.28-1.20 (9H, m).

Preparation of compound II: Add 2.41g of compound II (5.0mmol), 0.54g of potassium acetate (5.5mmol) and 20mL of DMF into the reaction bottle, raise the temperature to 110°C and react for 3 hours; cool to 80°C, add 1.0mL of glacial acetic acid and continue. React for 2 hours; cool to room temperature, add 100 mL of water, adjust the pH to 7 with potassium carbonate, stir for 5 minutes, filter, wash with 20 mL of acetonitrile: water = 1:2 solvent, and dry to obtain 1.96 g of yellow-brown solid compound I, yield 90 %. ¹ H-NMR (400M, DMSO-d ₆ ): 13.21 (1H, brs), 12.261H, brs), 7.81 (2H, s), 7.46 (1H, s), 3.06 (1H, m), 1.18 (6H ,d).

The above are only preferred embodiments of the present invention. It should be noted that those skilled in the art can make several improvements and modifications without departing from the principles of the present invention. These improvements and modifications can also be made. should be regarded as the protection scope of the present invention.

Claims (10)

1. A Resmetirom intermediate, characterized in that it has the structure shown in Formula VI: 2. The preparation method of Resmetirom intermediate according to claim 1, characterized in that it includes the following steps: Mix the compound with the structure shown in Formula D, sodium benzene sulfinate and an organic solvent to perform a substitution-hydrolysis reaction to obtain the compound with the structure shown in Formula VII; The compound with the structure represented by Formula VII, 3,4-dihydro-2H-pyran, p-toluenesulfonic acid and an organic solvent are mixed to perform an amide protection reaction to obtain the Resmetirom intermediate with the structure represented by Formula VI. 3. The preparation method according to claim 2, characterized in that the molar ratio of the compound of the structure shown in formula D and sodium benzene sulfinate is 1: (1 ~ 3); The temperature of the substitution-hydrolysis reaction is 50 to 150°C, and the time is 1 to 20 hours; The organic solvent used in the substitution-hydrolysis reaction is one or more of N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone and acetonitrile. 4. The preparation method according to claim 2, characterized in that the molar ratio of the compound of the structure shown in formula VII and 3,4-dihydro-2H-pyran is 1:(1～4); The molar ratio of the compound having the structure shown in Formula VII and p-toluenesulfonic acid is 1: (0.05～0.5); The temperature of the amide protection reaction is 30-80°C, and the time is 1-20 hours; The organic solvent used in the amide protection reaction is one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone and 1,4-dioxane. 5. A method for preparing Resmetirom intermediate III, which is characterized by comprising the following steps: Mix the compound with the structure shown in Formula VI, 2-nitropropane, the first basic compound and an organic solvent to perform an addition-elimination-double bond shift reaction to obtain the compound with the structure shown in Formula V; Mix the compound with the structure shown in Formula V, 2,6-dichloro-4-aminophenol, a second basic compound and an organic solvent to perform a substitution reaction to obtain the compound with the structure shown in Formula IV; Mix the compound with the structure shown in formula IV and hydrochloric acid to perform a deprotection reaction to obtain Resmetirom intermediate III, with the structural formula shown in formula III; 6. The preparation method according to claim 5, characterized in that the molar ratio of the compound of the structure shown in Formula VI and 2-nitropropane is 1: (1-3); The first basic compound is one or more of DBU, triethylamine, potassium carbonate, sodium carbonate, KOH and NaOH; the molar ratio of the compound with the structure shown in Formula VI and the first basic compound is 1:(0.2～3); The organic solvents used in the addition-elimination-double bond shift reaction are N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 1,4 - One or more dioxanes. 7. The preparation method according to claim 5, characterized in that the addition-elimination-double bond shift reaction occurs at a temperature of 0 to 100°C and a time of 0.5 to 10 hours. 8. The preparation method according to claim 5, characterized in that the molar ratio of the compound of the structure shown in formula V and 2,6-dichloro-4-aminophenol is 1: (1-2); The second basic compound is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide; the structure shown in the formula V The molar ratio of the compound and the second basic compound is 1: (1 ~ 3); The organic solvent used in the substitution reaction is one of N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, acetonitrile, and 1,4-dioxane. Kind or variety. 9. The preparation method according to claim 5, characterized in that the temperature of the substitution reaction is 40-120°C and the time is 2-20 h. 10. The preparation method according to claim 5, characterized in that the mass fraction of the hydrochloric acid is 36 to 38%, and the ratio of the volume of the hydrochloric acid to the mass of the compound having the structure shown in Formula IV is 1 to 100 mL: 1g; the temperature of the deprotection reaction is 10-100°C, and the time is 1-10h.