A Resmetirom intermediate and its preparation method and preparation method of intermediate III

Abstract

The present 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 an intermediate III. The present invention adopts an intermediate of the structure shown in Formula VI, and prepares Resmetirom intermediate III through an addition-elimination-double bond shift reaction, a substitution reaction, and a deprotection reaction. In the preparation method provided by the present invention, all intermediate products are solid, which is easy to purify, does not require the use of expensive silver nitrate, has low cost, and has a high yield in each step and a short reaction time. 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

Technical Field

[0001] 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 an intermediate III. Background Art

[0002] Resmetirom (Chinese name Ruisi Meitiluo, 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 signal of physical abnormalities in physical examinations, and uncontrolled fatty liver may develop into NASH (non-alcoholic steatohepatitis), liver fibrosis, cirrhosis and even liver cancer. NASH has faced the dilemma of no cure for the past few decades. In December 2022, the original research company Madrigal announced the success of its Phase 3 trial of THR-β agonist MGL-3196 for the treatment of NASH. The company's Phase 3 clinical data showed that using gold standard liver puncture verification, after 52 weeks of administration, Resmetirom achieved the dual endpoints of NASH remission and fibrosis improvement.

[0003] The molecular structure of Resmetirom is shown in Formula I:

[0004]

[0005] Patents WO2007009913 and CN112707892 disclose the following preparation method: Compound D reacts with isobutyric acid in the presence of silver nitrate and ammonium persulfate to produce Compound C with a yield of 67%, over a reaction time of more than 24 hours. Compound C then undergoes a substitution reaction over 24 hours to produce Compound B with a yield of 53%. Compound B is hydrolyzed to produce Compound III with a yield of 50%, over a reaction time of more than 96 hours. Compound III then undergoes a diazotization reaction with Compound A, undergoing double bond shifting, to produce Compound II with a yield of 56%. Finally, Compound II undergoes a ring closure under alkaline conditions to produce Compound I, MGL-3196, with a yield of 50%. The specific synthetic route is as follows:

[0006]

[0007] This synthetic route consists of five steps, each of which has a low yield and high cost. In addition, the first step uses silver nitrate, which is expensive. Furthermore, compound C is an oily substance and difficult to purify. These shortcomings limit the industrial production of this route.

[0008] From the above route, it can be found that compound III is a key intermediate in the synthesis of MGL-3196. However, when synthesizing compound III through this route, there are disadvantages such as difficult purification, low yield and high cost. Therefore, it is urgent to develop a method for preparing MGL-3196 intermediate III that is easy to purify, has high yield and low cost. Summary of the Invention

[0009] 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 present invention provides a resmetirom intermediate having a structure represented by formula VI, and the resmetirom intermediate III is prepared using the resmetirom intermediate represented by formula VI. The product is easy to purify, has a high yield, and is low in cost.

[0010] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0011] A resmetirom intermediate having the structure shown in Formula VI:

[0012]

[0013] The present invention also provides a method for preparing the Resmetirom intermediate described in the above scheme, comprising the following steps:

[0014] Mixing a compound of formula D, sodium benzenesulfinate, and an organic solvent to carry out a substitution-hydrolysis reaction to obtain a compound of formula VII;

[0015]

[0016] The compound represented by the structure of formula VII, 3,4-dihydro-2H-pyran, p-toluenesulfonic acid and an organic solvent are mixed to carry out an amide protection reaction to obtain the Resmetirom intermediate represented by the structure of formula VI.

[0017] Preferably, the molar ratio of the compound represented by the structure of formula D to sodium benzenesulfinate is 1:(1-3);

[0018] The temperature of the substitution-hydrolysis reaction is 50-150° C. and the time is 1-20 hours;

[0019] The organic solvent used in the substitution-hydrolysis reaction is one or more of N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone and acetonitrile.

[0020] Preferably, the molar ratio of the compound of formula VII to 3,4-dihydro-2H-pyran is 1:(1-4); the molar ratio of the compound of formula VII to p-toluenesulfonic acid is 1:(0.05-0.5);

[0021] The amide protection reaction temperature is 30 to 80°C and the time is 1 to 20 hours;

[0022] The organic solvent used in the amide protection reaction is one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone and 1,4-dioxane.

[0023] The present invention also provides a method for preparing Resmetirom intermediate III, comprising the following steps:

[0024] Mixing a compound of formula VI, 2-nitropropane, a first basic compound, and an organic solvent to perform an addition-elimination-double bond shift reaction to obtain a compound of formula V;

[0025] Mixing the compound of the structure shown in Formula V, 2,6-dichloro-4-aminophenol, a second basic compound and an organic solvent to carry out a substitution reaction to obtain a compound of the structure shown in Formula IV;

[0026] The compound represented by the structure of Formula IV is mixed with hydrochloric acid to carry out a deprotection reaction to obtain Resmetirom intermediate III, the structural formula of which is shown in Formula III;

[0027]

[0028] Preferably, the molar ratio of the compound of the structure represented by Formula VI to 2-nitropropane is 1:(1-3);

[0029] The first basic compound is one or more of DBU, triethylamine, potassium carbonate, sodium carbonate, KOH and NaOH; the molar ratio of the compound represented by the structure of formula VI to the first basic compound is 1:(0.2-3);

[0030] The organic solvent used in the addition-elimination-double bond shift reaction is one or more of N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 1,4-dioxane.

[0031] Preferably, the temperature of the addition-elimination-double bond shift reaction is 0-100° C., and the time is 0.5-10 h.

[0032] Preferably, the molar ratio of the compound of the structure represented by Formula V to 2,6-dichloro-4-aminophenol is 1:(1-2);

[0033] The second alkaline 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 molar ratio of the compound represented by the structure of formula V to the second alkaline compound is 1:(1-3);

[0034] The organic solvent used in the substitution reaction is one or more of N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, acetonitrile, and 1,4-dioxane.

[0035] Preferably, the temperature of the substitution reaction is 40-120° C., and the time is 2-20 h.

[0036] Preferably, the mass fraction of the hydrochloric acid is 36-38%, and the ratio of the volume of the hydrochloric acid to the mass of the compound represented by the structure of Formula IV is 1-100 mL:1 g; the temperature of the deprotection reaction is 10-100° C., and the time is 1-10 h.

[0037] The present invention provides a resmetirom intermediate having a structure shown in formula VI. The intermediate having the structure shown in formula VI is used to prepare a resmetirom intermediate III, and the product is easy to purify, has a high yield, and is low in cost.

[0038] The present invention also provides a method for preparing Resmetirom intermediate III, comprising the following steps: mixing a compound represented by Formula VI, 2-nitropropane, a first basic compound, and an organic solvent to conduct an addition-elimination-double bond shift reaction to obtain a compound represented by Formula V; mixing the compound represented by Formula V, 2,6-dichloro-4-aminophenol, a second basic compound, and an organic solvent to conduct a substitution reaction to obtain a compound represented by Formula IV; and mixing the compound represented by Formula IV with hydrochloric acid to conduct a deprotection reaction to obtain Resmetirom intermediate III. The present invention utilizes the intermediate represented by Formula VI to prepare Resmetirom intermediate III. In the synthetic route of the present invention, all intermediate products are solid, facilitating purification. The preparation method of the present invention eliminates the need for expensive silver nitrate, resulting in low cost and high yields in each step. Furthermore, the intermediate represented by Formula VI contains a phenylsulfone group, a strong electron-withdrawing group that greatly enhances the addition reaction activity of Compound VI to Compound V and significantly reduces reaction time. Furthermore, the phenylsulfone group is also a good leaving group, reducing the substitution reaction time of Compound V to 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the H NMR spectrum of Resmetirom intermediate VI prepared in Example 2 of the present invention;

[0040] Figure 2 This is the H NMR spectrum of Resmetirom intermediate III prepared in Example 4 of the present invention. DETAILED DESCRIPTION

[0041] The present invention provides a resmetirom intermediate having a structure shown in Formula VI:

[0042]

[0043] The present invention also provides a method for preparing the Resmetirom intermediate described in the above scheme, comprising the following steps:

[0044] Mixing a compound of formula D, sodium benzenesulfinate, and an organic solvent to carry out a substitution-hydrolysis reaction to obtain a compound of formula VII;

[0045]

[0046] The compound represented by the structure of formula VII, 3,4-dihydro-2H-pyran, p-toluenesulfonic acid and an organic solvent are mixed to carry out an amide protection reaction to obtain a Resmetirom intermediate represented by the structure of formula VI.

[0047] In the present invention, the synthetic route of the Resmetirom intermediate of the structure shown in Formula VI is as follows:

[0048]

[0049] The following is a detailed description of the preparation method of the Resmetirom intermediate having the structure shown in Formula VI.

[0050] The present invention comprises mixing a compound represented by Formula D, sodium benzenesulfinate, and an organic solvent to carry out a substitution-hydrolysis reaction to obtain a compound represented by Formula VII. In the present invention, the molar ratio of the compound represented by Formula D to sodium benzenesulfinate is preferably 1:(1-3), more preferably 1:(1.1-2); the organic solvent used in the substitution-hydrolysis reaction is preferably one or more of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), N-methylpyrrolidone, and acetonitrile, more preferably DMF.

[0051] 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 1-20 h, more preferably 1.5-10 h; the substitution-hydrolysis reaction is preferably carried out under nitrogen protection.

[0052] After the substitution-hydrolysis reaction is completed, the present invention preferably performs post-treatment on the obtained substitution-hydrolysis reaction liquid. The post-treatment method preferably comprises: cooling the obtained substitution-hydrolysis reaction liquid to 50-100° C. (preferably 60° C.) and mixing it with water, then cooling it to room temperature, pouring the obtained coolant into water, stirring at room temperature and filtering, and washing the obtained solid product with water to obtain a compound having the structure shown in Formula VII; the stirring time at room temperature is preferably 5 minutes.

[0053] After obtaining the compound of formula VII, the present invention mixes the compound of formula VII, 3,4-dihydro-2H-pyran, p-toluenesulfonic acid, and an organic solvent to perform an amide protection reaction to obtain a resmetirom intermediate of formula VI. In the present invention, the molar ratio of the compound of formula VII to 3,4-dihydro-2H-pyran is preferably 1:(1-4), more preferably 1:(1.1-2); the molar ratio of the compound of formula VII to p-toluenesulfonic acid is preferably 1:(0.05-0.5), more preferably 1:(0.05-0.3); and the organic solvent used in the amide protection reaction is preferably one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone, and 1,4-dioxane, more preferably tetrahydrofuran.

[0054] In the present invention, the temperature of the amide protection reaction is preferably 30 to 80° C., more preferably 40 to 70° C., and the time of the amide protection reaction is preferably 1 to 20 h, more preferably 1.5 to 8 h.

[0055] After the amide protection reaction is completed, the present invention preferably performs post-treatment on the obtained amide protection reaction liquid. The post-treatment method preferably comprises: cooling the obtained amide protection reaction liquid to room temperature and mixing it with water, adjusting the pH value of the mixed liquid to 8-10, preferably 9, stirring at room temperature and removing the organic solvent by rotary evaporation, filtering the remaining liquid, washing the obtained solid product and drying it to obtain a Resmetirom intermediate having a structure represented by Formula VI; the reagent used to adjust the pH value of the mixed liquid is preferably potassium carbonate; the stirring time at room temperature is preferably 5 minutes; the detergent used to wash the solid product is preferably a mixed solvent of ethyl acetate and heptane, and the volume ratio of ethyl acetate to heptane in the mixed solvent is preferably 1:(1-10), more preferably 1:2.

[0056] The present invention also provides a method for preparing Resmetirom intermediate III, comprising the following steps:

[0057] Mixing a compound of formula VI, 2-nitropropane, a first basic compound, and an organic solvent to perform an addition-elimination-double bond shift reaction to obtain a compound of formula V;

[0058] Mixing the compound of the structure shown in Formula V, 2,6-dichloro-4-aminophenol, a second basic compound and an organic solvent to carry out a substitution reaction to obtain a compound of the structure shown in Formula IV;

[0059] The compound represented by the structure of Formula IV is mixed with hydrochloric acid to carry out a deprotection reaction to obtain Resmetirom intermediate III, the structural formula of which is shown in Formula III;

[0060]

[0061] In the present invention, the synthetic route of the Resmetirom intermediate III is as follows:

[0062]

[0063] The synthesis method of Resmetirom intermediate III is described in detail below.

[0064] The present invention mixes a compound of the structure represented by Formula VI, 2-nitropropane, a first basic compound, and an organic solvent to carry out an addition-elimination-double bond shift reaction to obtain a compound of the structure represented by Formula V. In the present invention, the compound of the structure represented by Formula VI is prepared according to the above method, which will not be repeated here; the molar ratio of the compound of the structure represented by Formula VI to 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 of the structure represented by Formula IV to the first basic compound is preferably 1:(0.2-3), more preferably 1:(0.3-2); the organic solvent used in the addition-elimination-double bond shift reaction is preferably one or more of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), tetrahydrofuran, and 1,4-dioxane, more preferably DMSO.

[0065] 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 a specific embodiment of the present invention, the addition-elimination-double bond shift reaction is preferably carried out 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.

[0066] After the addition-elimination-double bond shift reaction is completed, the present invention preferably performs post-treatment on the obtained addition-elimination-double bond shift reaction liquid, and the post-treatment method preferably comprises: mixing the obtained addition-elimination-double bond shift reaction liquid with water, adjusting the pH value of the obtained mixed liquid to 3 to 7, preferably 5, stirring at room temperature and then filtering, washing the obtained solid product and then drying to obtain a compound having a structure represented by Formula V; the reagent used to adjust the pH value of the obtained mixed liquid is preferably hydrochloric acid; the stirring time at room temperature is preferably 5 minutes; the washing preferably comprises 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 to heptane is preferably 1:2.

[0067] After obtaining the compound of formula V, the present invention mixes the compound of formula V, 2,6-dichloro-4-aminophenol, a second alkaline compound, and an organic solvent to perform a substitution reaction to obtain a compound of formula IV. In the present invention, the molar ratio of the compound of formula V to 2,6-dichloro-4-aminophenol is preferably 1:(1-2), more preferably 1:(1-1.3); the second alkaline 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, more preferably potassium carbonate; the molar ratio of the compound of formula V to the second alkaline compound is preferably 1:(1-3), more preferably 1:(1-2); the organic solvent used in the substitution reaction is preferably one or more of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), acetonitrile, and 1,4-dioxane, more preferably DMF.

[0068] 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.

[0069] After the substitution reaction is completed, the reaction solution does not need to be treated in any way and can be directly processed into the next step.

[0070] After obtaining the compound of formula IV, the present invention mixes the compound of formula IV with 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 36-38%, more preferably 37%, and the ratio of the volume of the hydrochloric acid to the mass of the compound of formula IV is preferably 1-100 mL:1 g; the temperature of the deprotection reaction is preferably 10-100° C., more preferably 30-70° C., and the time of the deprotection reaction is 1-10 hours, more preferably 1.5-5 hours. In the present invention, after the substitution reaction is completed, the temperature of the obtained substitution reaction solution is preferably adjusted to the deprotection reaction temperature, and then hydrochloric acid is directly added thereto.

[0071] After the deprotection reaction is completed, the present invention preferably performs post-treatment on the obtained reaction solution. The post-treatment method preferably comprises: mixing the obtained deprotection reaction solution with water, adjusting the pH value of the obtained mixture to 6 to 8, preferably 7, stirring at room temperature and filtering, washing the obtained solid product and drying it to obtain Resmetirom intermediate III; the reagent used to adjust the pH value of the obtained mixture is preferably liquid alkali; the stirring time at room temperature is preferably 5 minutes; the washing preferably comprises 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 to heptane is preferably 1:2.

[0072] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0073] The methods in the following examples, unless otherwise specified, are conventional methods. The raw materials, reagents, etc. used in the following examples, unless otherwise specified, are all commercially available products. In the following examples: the compound represented by the structure of Formula D, the compound represented by the structure of Formula VII, the compound represented by the structure of Formula VI, the compound represented by the structure of Formula V, the compound represented by the structure of Formula IV, and the compound represented by the structure of Formula III are referred to as Compound D, Compound VII, Compound V, Compound IV, and Compound III, respectively.

[0074] Example 1 Preparation of Compound VII

[0075]

[0076] Method 1: Add 14.9 g of compound D (100 mmol), 19.7 g (120 mmol) of sodium benzenesulfinate and 150 mL of DMF to a reaction flask, protect with nitrogen, and heat to 100°C for 3 h; cool to 60°C, add 10 mL of water, and naturally cool to room temperature with stirring; pour into 600 mL of water and stir at room temperature for 5 min; filter and wash with 50 mL of water to obtain 22.4 g of yellow solid compound VII, with a yield of 95%.

[0077] Method 2: 14.9 g of compound D (100 mmol), 24.6 g (150 mmol) of sodium benzenesulfinate, and 150 mL of DMAc were added to a reaction flask under nitrogen protection. The temperature was raised to 90°C for reaction for 5 h. After cooling to 60°C, 10 mL of water was added and the mixture was naturally cooled to room temperature under stirring. The mixture was poured into 600 mL of water and stirred at room temperature for 5 min. The mixture was filtered and washed with 50 mL of water to obtain 21.7 g of yellow solid compound VII with a yield of 92%.

[0078] The NMR data of compound VII obtained by method 1 are as follows: 1 H-NMR (400M, CDCl3): 8.02 (2H, d), 7.90 (1H, m), 7.71-7.60 (4H, m), 7.07 (1H, d).

[0079] Example 2 Preparation of Compound VI

[0080]

[0081] Method 1: 7.09 g (30 mmol) of compound VII, 3.78 g (45 mmol) of 3,4-dihydro-2H-pyran, 0.52 g (3.0 mmol) of p-toluenesulfonic acid and 50 mL of tetrahydrofuran were added to a reaction flask, and the temperature was raised to 60°C for reaction for 5 h; cooled to room temperature, 100 mL of water was added, and the pH was adjusted to 9 with potassium carbonate, and stirred at room temperature for 5 min; the tetrahydrofuran was spun off to precipitate a large amount of solid, which was filtered and washed with 30 mL of ethyl acetate-heptane mixed solvent (the volume ratio of ethyl acetate and heptane was 1:2), and dried to obtain 9.42 g of light yellow solid compound VI with a yield of 98%.

[0082] Method 2: 7.09 g (30 mmol) of compound VII, 5.04 g (60 mmol) of 3,4-dihydro-2H-pyran, 1.04 g (6.0 mmol) of p-toluenesulfonic acid and 50 mL of acetonitrile were added to the reaction flask, and the temperature was raised to 70 ° C for 6 h; cooled to room temperature, 100 mL of water was added, and the pH was adjusted to 9 with potassium carbonate, and stirred at room temperature for 5 min; the acetonitrile was spun off to precipitate a large amount of solid, which was filtered and washed with 30 mL of ethyl acetate-heptane mixed solvent (the volume ratio of ethyl acetate and heptane was 1:2), and dried to obtain 9.13 g of light yellow solid compound VI with a yield of 95%.

[0083] The nuclear magnetic data of compound VI obtained by method 1 are as follows: 1H-NMR (400M, CDCl3): 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 H NMR spectrum of compound VI.

[0084] Example 3 Preparation of Compound V

[0085]

[0086] Method 1: Add 6.40 g of compound VI (20 mmol), 2.68 g of 2-nitropropane (30 mmol), 4.56 g of DBU (30 mmol) and 80 mL of DMSO to a reaction flask, stir and react at room temperature for 1 h; pour into 240 mL of water, adjust the pH to 5 with hydrochloric acid, stir at room temperature for 5 min, 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 and heptane is 1:2), and dry to obtain 7.16 g of light yellow solid compound V with a yield of 99%.

[0087] Method 2: Add 6.40 g of compound VI (20 mmol), 3.58 g of 2-nitropropane (40 mmol), 5.5 g of potassium carbonate (40 mmol) and 80 mL of DMF to a reaction flask, heat to 40 ° C and react for 1 h; pour into 240 mL of water, stir at room temperature for 5 min, 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 and heptane is 1:2), and dry to obtain 6.88 g of light yellow solid V, with a yield of 95%.

[0088] The NMR data of compound V obtained by method 1 are as follows: 1H-NMR (400M, DMSO-d6): 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).

[0089] Example 4 Preparation of Compound III

[0090]

[0091] Method 1: 3.62 g (10 mmol) of compound V, 2.14 g of 2,6-dichloro-4-aminophenol (12 mmol), 2.07 g of potassium carbonate powder (14 mmol) and 40 mL of DMF were added to a reaction flask, heated to 70 ° C and stirred for 5 h; cooled to room temperature, 10 mL of hydrochloric acid (about 37% mass fraction) was added, and the temperature was raised to 50 ° C and reacted for 2 h; poured into 200 mL of water, and the pH was adjusted to 7 with liquid alkali. The mixture was stirred at room temperature for 5 min, filtered, washed once with 20 mL of water, and then washed with 20 mL of ethyl acetate-heptane mixed solvent (the volume ratio of ethyl acetate and heptane is 1:2), and dried to obtain 2.98 g of off-white compound III with a yield of 95%.

[0092] Method 2: 3.62 g (10 mmol) of compound V, 1.96 g of 2,6-dichloro-4-aminophenol (11 mmol), 2.12 g of sodium carbonate powder (20 mmol) and 40 mL of DMSO were added to the reaction flask, the temperature was raised to 80 ° C and stirred for 4 h; cooled to room temperature, 10 mL of hydrochloric acid (about 37% mass fraction) was added, and the temperature was raised to 50 ° C and reacted for 2 h; poured into 200 mL of water, the pH was adjusted to 7 with liquid alkali, stirred at room temperature for 5 min, filtered, washed once with 20 mL of water, and then washed with 20 mL of ethyl acetate-heptane mixed solvent (the volume ratio of ethyl acetate and heptane is 1:2), and dried to obtain 2.95 g of off-white compound III with a yield of 94%.

[0093] The NMR data of compound III obtained by method 1 are as follows: 1 H-NMR (400M, DMSO-d6): 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 This is the H NMR spectrum of compound III.

[0094] Example 5 Preparation of Compound I (Resmetirom)

[0095]

[0096] Preparation of compound II: 3.14 g of compound III (10.0 mmol), 1.72 g of compound A (11.0 mmol) and 60 mL of water were added to the reaction flask, the ice water was cooled to 0-10 ° C, and 30 mL of hydrochloric acid (37% mass fraction) was added in batches; maintaining 5-10 ° C, 6.9 g of sodium nitrite (100 mmol) and 20 mL of water were added dropwise within 30 min, and then 23.0 g of sodium acetate (280 mmol) and 90 mL of water were added dropwise within 50 min; the ice-water bath was removed, the reaction was stirred at room temperature for 2 h, filtered, washed with 30 mL of water, then washed with 20 mL of isopropyl ether, and dried to obtain 4.23 g of yellow-brown solid compound II with a yield of 88%. 1 H-NMR (400M, DMSO-d6): δ 12.26 (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).

[0097] Preparation of compound II: 2.41 g of compound II (5.0 mmol), 0.54 g of potassium acetate (5.5 mmol) and 20 mL of DMF were added to the reaction flask, heated to 110 ° C for 3 h; cooled to 80 ° C, 1.0 mL of glacial acetic acid was added and the reaction was continued for 2 h; cooled to room temperature, 100 mL of water was added, and the pH was adjusted to 7 with potassium carbonate. The mixture was stirred for 5 min, filtered, washed with 20 mL of acetonitrile: water = 1:2 solvent, and dried to obtain 1.96 g of yellow-brown solid compound I with a yield of 90%. 1 H-NMR (400M, DMSO-d6): 13.21 (1H, brs), 12.261H, brs), 7.81 (2H, s), 7.46 (1H, s), 3.06 (1H, m), 1.18 (6H, d).

[0098] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A Resmetirom intermediate, characterized in that It has the structure shown in formula VI:

2. The method for preparing the Resmetirom intermediate according to claim 1, characterized in that: The following steps are involved: Mixing a compound of formula D, sodium benzenesulfinate, and an organic solvent to carry out a substitution-hydrolysis reaction to obtain a compound of formula VII; The compound represented by the structure of formula VII, 3,4-dihydro-2H-pyran, p-toluenesulfonic acid and an organic solvent are mixed to carry out an amide protection reaction to obtain the Resmetirom intermediate represented by the structure of formula VI.

3. The preparation method according to claim 2, characterized in that The molar ratio of the compound represented by the formula D to sodium benzenesulfinate is 1:(1-3); The temperature of the substitution-hydrolysis reaction is 50-150° C. and the time is 1-20 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 formula VII to 3,4-dihydro-2H-pyran is 1:(1-4); the molar ratio of the compound of formula VII to p-toluenesulfonic acid is 1:(0.05-0.5); The amide protection reaction temperature is 30 to 80°C and the time is 1 to 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, characterized in that: The following steps are involved: Mixing a compound of formula VI, 2-nitropropane, a first basic compound, and an organic solvent to perform an addition-elimination-double bond shift reaction to obtain a compound of formula V; Mixing the compound of the structure shown in Formula V, 2,6-dichloro-4-aminophenol, a second basic compound and an organic solvent to carry out a substitution reaction to obtain a compound of the structure shown in Formula IV; The compound represented by the structure of Formula IV is mixed with hydrochloric acid to carry out a deprotection reaction to obtain Resmetirom intermediate III, the structural formula of which is shown in Formula III; 6. The preparation method according to claim 5, characterized in that The molar ratio of the compound of the structure represented by formula VI to 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 represented by the structure of formula VI to the first basic compound is 1:(0.2-3); The organic solvent used in the addition-elimination-double bond shift reaction is one or more of N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 1,4-dioxane.

7. The preparation method according to claim 5, characterized in that The temperature of the addition-elimination-double bond shift reaction is 0-100° C., and the time is 0.5-10 h.

8. The preparation method according to claim 5, characterized in that The molar ratio of the compound of the structure represented by formula V to 2,6-dichloro-4-aminophenol is 1:(1-2); The second alkaline 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 molar ratio of the compound represented by the structure of formula V to the second alkaline compound is 1:(1-3); The organic solvent used in the substitution reaction is one or more of N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, acetonitrile, and 1,4-dioxane.

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 hours.

10. The preparation method according to claim 5, characterized in that The mass fraction of the hydrochloric acid is 36-38%, and the volume ratio of the hydrochloric acid to the mass of the compound represented by formula IV is 1-100 mL:1 g; the temperature of the deprotection reaction is 10-100° C., and the time is 1-10 h.

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