Synthesis method of rosmeltirome intermediate

Abstract

The invention discloses a method for synthesizing a rosmeltirol intermediate, which comprises the following steps: a compound in a formula a is subjected to a double-bond shift reaction under an acidic condition to generate a compound in a formula b, and R1 and R2 are H or amino protecting groups. The method solves the problem of isomer residue, has mild reaction conditions and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and specifically relates to a method for synthesizing an intermediate of resmetirom. Background Art

[0002] Resmetirom (MGL-3196) is a thyroid hormone receptor β (THR-β) agonist developed by the US biotech company Madrigal. It was approved for marketing by the US FDA on March 14, 2024, for the treatment of adult non-alcoholic steatohepatitis (NASH).

[0003] Hoffmann-La Roche Ltd. disclosed a synthesis method in the resmetirom compound patent CN101228135B. The synthesis of its key intermediate includes the following steps:

[0004] This route uses the Minisci reaction catalyzed by silver nitrate to isopropylate compound 1 to obtain 2. Subsequently, compound 2 is directly coupled with compound 3 to obtain 4, and finally, hydrolysis gives intermediate 5. In this route, the equivalent amount of silver nitrate used is large, and the cost proportion is high. At the same time, silver nitrate has a high EHS risk. On the other hand, during the coupling process, the amino group of compound 3 will also participate in the coupling reaction, resulting in low purity of compound 4 and difficulty in purification. These problems limit the industrial application of this route.

[0005] The patent CN105008335B of Madrigal Pharmaceuticals reported another synthesis method. Using isopropenylmagnesium bromide as the isopropylating reagent, the reaction selectivity is better and it is easy to purify. However, the isomerization process under high-temperature reflux conditions using a strong base may cause hydrolysis of some substrates; in addition, the unprotected amino group may also lead to the generation of isomeric impurities.

[0006]

[0007] In summary, the above several methods still have problems such as difficult purification, poor reaction selectivity, and severe reaction conditions, which are not suitable for industrial production. The purpose of the present invention is to provide a new, more efficient, higher product purity, milder conditions, and more suitable for industrial production synthesis route for resmetirom intermediate. Summary of the Invention

[0008] The purpose of the present invention is to provide a method for synthesizing an intermediate of resmetirom. This method is efficient, has mild conditions, high product purity, and is more suitable for industrial production.

[0009] To achieve the above purpose, the present invention adopts the following technical solutions: The present invention provides a method for preparing a key intermediate of resmetirom, which includes the following content: In one embodiment, a method for synthesizing an intermediate of resmetirom according to the present invention has the following synthetic route:

[0010] wherein, R1 and R2 are H or an amino protecting group; This method includes subjecting the compound of formula a to a double bond shift reaction under acidic conditions to generate the intermediate compound of formula b.

[0011] Preferably, in the method of the present invention above, the acid is an inorganic acid or an organic acid. The inorganic acid is selected from one or more of HCl, AlCl3, H2SO4, and H3PO4, etc., preferably HCl. The organic acid is selected from CF3CO2H, CF3SO3H, and CH3SO3H, preferably CF3CO2H.

[0012] Preferably, in the method of the present invention above, the amino protecting group is p-toluoyl.

[0013] Furthermore, in the method of the present invention above, the double bond shift reaction is carried out in an aprotic solvent.

[0014] Preferably, in the method of the present invention above, the aprotic solvent is selected from one or more of THF, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, ethyl acetate, and methyl tert-butyl ether. Preferably, the aprotic solvent is THF, 1,4-dioxane, or ethyl acetate.

[0015] Preferably, in the method of the present invention above, the reaction is carried out at a temperature of 40-100 °C, more preferably 50-80 °C.

[0016] In another embodiment, the present invention also provides a compound selected from:

[0017] In another embodiment, the present invention provides a method for preparing the compound of formula VIII of the resmetirom intermediate, including the following steps: 1) Protect the amino group of compound I. In a preferred embodiment, the protecting group is selected as p-methylbenzoyl;

[0018] 2) Couple compound II with compound III under basic conditions to obtain compound IV

[0019] In a preferred embodiment, the base used is potassium carbonate, the solvent is dimethyl sulfoxide, and the additive is copper(I) iodide; 3) Compound IV is hydrolyzed under acidic conditions to obtain Compound V;

[0020] In a preferred embodiment, the acid used is acetic acid; 4) Compound V reacts with isopropenylmagnesium bromide to obtain Compound VI;

[0021] 5) Compound VI is isomerized to Compound VII by a double bond shift reaction under the action of an acid in an aprotic solvent;

[0022] In a preferred embodiment, the reaction temperature is 50 - 80 °C, the acid used is HCl or trifluoroacetic acid, and the preferred aprotic solvents are THF, 1,4 - dioxane or ethyl acetate;

[0023] 6.) Compound VII is deprotected under the action of a base to obtain the key intermediate VIII;

[0024] In a preferred embodiment, the base used is sodium hydroxide.

[0025] The beneficial effects of the present invention are as follows: 1) Protecting the amino group in advance to avoid the formation of isomeric impurities in the amino reaction; 2) Using an acid to activate Compound VI, making the conditions of the isomerization process milder, the reaction time shorter, and the conversion rate higher. Specific Embodiments

[0026] The following examples are used to further illustrate and understand the spiritual essence of the present invention, but do not limit the protection scope of the present invention in any way.

[0027] Example 1

[0028] 100.0 g of Compound I was added to 500 mL of DCM, the temperature was lowered to about 0 °C, and 87.0 g of p - methylbenzoyl chloride was added dropwise. After the addition was complete, the system was stirred at room temperature for 2 h. The liquid was washed with a sodium bicarbonate solution, and then the solvent was concentrated under reduced pressure to obtain 164.1 g of Compound II (yield 98.62%), and the HPLC purity was 98.95%. [M + H] + = 296. The NMR data of Compound II: 1HNMR (600 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.87 (s, 1H), 7.92 – 7.90 (m, 4H), 7.28 (d, J = 7.9 Hz, 2H), 2.34 (s, 3H). 13 C NMR (151 MHz, DMSO) δ 165.7, 145.6, 142.2, 132.8, 132.0, 129.3, 128.1, 122.5, 120.8, 21.4.

[0029] Example 2

[0030] Add 200.0 g of Compound II, 100.0 g of Compound III, 139.0 g of potassium carbonate, and 13.0 g of cuprous iodide to 500 mL of DMSO. Heat the mixture to 100 °C and stir for 16 hours. After the reaction is completed, cool the mixture to room temperature, filter by suction, and collect the filtrate. Add 500 mL of purified water to the filtrate, filter by suction, and dry the obtained solid in a vacuum drying oven at 60 °C under reduced pressure for 8 hours to obtain 260.2 g of the target compound IV (yield 94.86%), with an HPLC purity of 91.37%. [M+H] + = 408. NMR data of Compound IV: 1 H NMR (600 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.05 (s, 2H), 7.96 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 9.1 Hz, 1H), 7.26 (d, J = 7.9 Hz, 2H), 2.30 (s, 3H). 13 C NMR (151 MHz, DMSO) δ 166.1, 163.8, 153.2, 142.6, 140.7, 138.9, 133.8, 131.7, 129.4, 128.2, 128.1, 120.7, 120.5, 21.5.

[0031] Example 3

[0032] 200.0 g of Compound IV was added to 1000 mL of acetic acid, and 44.1 g of sodium acetate was added. The temperature was raised to 105 °C and the reaction was carried out for 20 h. After the reaction was completed, the temperature was lowered to room temperature. 1000 mL of purified water was added to the system, stirred for 1 h, filtered by suction, and the solid was collected. It was dried in a vacuum drying oven at 60 °C for 8 h to obtain 181.4 g of the crude product of the target compound V, with an HPLC purity of 86.53%.

[0033] 150.0 g of the crude product of Compound V was added to 500 mL of acetic acid, heated to 70 °C and stirred for 2 h. After cooling to room temperature, it was filtered by suction, and the solid was collected. After washing with purified water, it was vacuum dried in an oven for 20 h to obtain 132.3 g of the refined product of Compound V (yield 69.30%), with an HPLC purity of 96.58%. [M+H] + = 390. NMR data of Compound V: 1 H NMR (600 MHz, DMSO-d6) δ12.38 (s, 1H), 10.47 (s, 1H), 8.08 (s, 2H), 7.92 (d, J = 7.7 Hz, 2H), 7.62(d, J = 9.5 Hz, 1H), 7.36 (d, J = 7.7 Hz, 2H), 7.13 (d, J = 10.1 Hz, 1H),2.40 (s, 3H). 13 C NMR (151 MHz, DMSO) δ 166.1, 160.2, 151.5, 142.7, 140.7,138.7, 135.0, 131.6, 129.5, 128.2, 126.9, 120.5, 120.2, 21.5.

[0034] Example 4

[0035] 100 g of Compound V and 32.6 g of anhydrous lithium chloride were added to 800 mL of tetrahydrofuran. After the system was replaced with nitrogen and sealed, 890 mL of 1.0 M isopropenylmagnesium bromide solution was added dropwise. After the addition was completed, the mixture was stirred at a constant temperature for 4 h. Dilute hydrochloric acid was added to the system to quench the reaction, and then 2000 mL of purified water was added. The solid was filtered by suction to obtain 115.9 g of the crude product of Compound VI (yield 104.6%). The crude product was directly used for the next reaction without purification. NMR data of Compound VI: 11H NMR (600 MHz, DMSO-d6) δ 10.41 (s, 1H), 10.19 (s, 1H), 8.01 (s, 2H), 7.88 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 4.96 (d, J = 22.5 Hz, 2H), 3.23 (t, J = 7.1 Hz, 1H), 3.12 (dd, J = 17.4, 7.8 Hz, 1H), 2.96 (dd, J = 17.4, 6.4 Hz, 1H), 2.39 (s, 3H), 1.82 (s, 3H). 13 13C NMR (151 MHz, DMSO) δ 166.6, 166.1, 155.4, 142.7, 141.6, 140.7, 138.5, 131.7, 129.5, 128.2, 128.0, 120.4, 113.8, 43.9, 27.1, 21.5, 21.2.

[0036] Example 5

[0037] 100.0 g of the crude compound VI was added to a reaction kettle, 500 mL of hydrogen chloride dioxane solution was added, and the mixture was heated to 50 °C and reacted for 2 hours. The raw materials were completely converted. After cooling to room temperature, 500 mL of purified water was added to the system. After liquid separation, the organic phase was crystallized by adding water, and then filtered by suction to obtain 98.5 g of the crude compound VII (yield 98.50%), and the HPLC purity was 93.25%. [M+H] + = 432. The NMR data of compound VII are as follows: 1 1H NMR (600 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.47 (s, 1H), 8.07 (s, 2H), 7.91 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 7.1 Hz, 3H), 3.08 (hept, J = 7.0 Hz, 1H), 2.40 (s, 3H), 1.21 (d, J = 7.0 Hz, 6H). 1313C NMR (151 MHz, DMSO) δ 166.1, 160.1, 154.0, 151.9, 142.7, 140.7, 138.6, 131.7, 129.5, 128.3, 128.3, 120.5, 119.8, 28.2, 21.5, 20.9.

[0038] Example 6

[0039] 100.0 g of solid compound VI was added to a reaction kettle, 500 mL of ethyl acetate solution of hydrogen chloride was added, and the mixture was heated to 50 °C and reacted for 6 hours. The raw materials were completely converted. After cooling to room temperature, 500 mL of n-heptane was added to the system, and filtration was carried out to obtain 92.1 g of crude product of compound VII (yield 92.10%), and the HPLC purity was 90.43%.

[0040] Example 7

[0041] 100.0 g of crude product of compound VI was added to a reaction kettle, 500 mL of tetrahydrofuran and 50 mL of trifluoroacetic acid were added, and the mixture was heated to 80 °C and reacted for 8 hours. It was monitored that the raw materials were completely converted. After cooling to room temperature, 500 mL of purified water was added to the system, and filtration was carried out to obtain 82.6 g of crude product of compound VII (yield 82.60%), and the HPLC purity was 88.79%.

[0042] Example 8

[0043] 10.0 g of crude product of compound VI was added to a reaction kettle, 50 mL of tetrahydrofuran and 5 mL of trifluoromethanesulfonic acid were added, and the mixture was heated to 80 °C and reacted for 8 hours. It was monitored that the raw materials were basically completely converted. After cooling to room temperature, 500 mL of purified water was added to the system, and filtration was carried out to obtain 6.3 g of crude product of compound VII (yield 63.00%), and the HPLC purity was 89.46%.

[0044] Example 9

[0045] 50.0 g of Compound VII was dispersed in 100 mL of ethanol, 250 mL of aqueous sodium hydroxide solution (10%) was added, the temperature was raised to 85 °C, and the mixture was stirred for 16 h until the raw materials were completely converted. Then the temperature was lowered to 0 °C, stirred for 1 h, filtered by suction, and the solid was collected. The solid was slurried with 250 mL of purified water at room temperature for 1 h, filtered by suction, and the solid was collected. It was placed in an oven and dried under reduced pressure at 60 °C for 8 h to obtain 31.5 g of the target compound VIII (yield 86.78%), and the HPLC purity was 98.75%.

[0046] Comparative Example:

[0047] 10.0 g of Compound V was dispersed in 100 mL of THF, 3.3 g of lithium chloride was added. After purging with nitrogen, 89 mL of isopropenylmagnesium bromide solution was added dropwise. After the addition was complete, the temperature was raised to 35 °C and reacted for 4 h. After adding 50 mL of 3N dilute hydrochloric acid to quench the reaction, the layers were separated and the aqueous phase was removed. The remaining liquid was transferred to a flask and a distillation and water separation device was installed. 60 mL of purified water was added to the flask, and then 6.3 g of KOH was added. The temperature was raised to 85 °C, and while reacting, the distillation was carried out. After most of the THF in the system was distilled off, the reaction was continued under insulation overnight. After cooling, the pH of the solution was adjusted to neutral with 3N dilute hydrochloric acid, and filtered by suction to obtain 8.3 g of the crude product of Compound VIII (yield 103.1%), and the HPLC purity was 62.27%.

Claims

1. A method for synthesizing a resmetirom intermediate, and its synthetic route is as follows, ； Among them, R1 and R2 are H or an amino protecting group; This method includes subjecting the compound of formula a to a double bond migration reaction under acidic conditions to generate the intermediate compound of formula b.

2. According to the synthesis method described in claim 1, the acid is an inorganic acid or an organic acid. The inorganic acid is selected from HCl, AlCl3, H2SO4 and H3PO4, and the organic acid is selected from CF3CO2H, CF3SO3H and CH3SO3H.

3. According to the synthesis method described in claim 2, the acid is HCl or CF3CO2H.

4. According to the synthesis method described in claim 1, the reaction is carried out in an aprotic solvent.

5. According to the synthesis method described in claim 4, the aprotic solvent is selected from one or more of THF, 1,4-dioxane, 2-methyltetrahydrofuran, ether, ethyl acetate, and methyl tert-butyl ether, and preferably THF, 1,4-dioxane or ethyl acetate.

6. According to the synthesis method described in claim 1, the reaction temperature is carried out under the condition of 40-100 °C, preferably 50-80 °C.

7. According to the synthesis method described in claim 1, the amino protecting group is p-toluoyl.

8. A method for preparing the resmetirom intermediate compound of formula VIII, including the following steps: 1) Protect the amino group of compound I, and the protecting group is p-methylbenzoyl; ； 2) Couple compound II and compound III under basic conditions to obtain compound IV; ； 3) Hydrolyze compound IV under acidic conditions to obtain compound V; ； 4) React compound V with isopropylmagnesium bromide to obtain compound VI, ； 5) Carry out a double bond migration reaction on compound VI under acidic conditions in an aprotic solvent to generate compound VII, The reaction temperature is 50 to 80 °C; 6) Deprotect compound VII under the action of a base to obtain the intermediate compound of formula VIII, 。 9. According to the method described in claim 8, the acid in step 5) is HCl or CF3CO2H, and the aprotic solvent is THF, 1,4-dioxane or ethyl acetate.

10. A compound, which is selected from: 。

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