A process for the preparation of resmetiromide and intermediates thereof

Abstract

The present application provides a preparation method of resmetirom and its intermediate, compound II. The preparation method of compound II comprises the following steps: performing a nucleophilic substitution reaction on compound I with a silanolate to obtain an intermediate, and performing hydrolysis on the obtained intermediate to generate compound II, and the reaction formula is as follows. The preparation method of the present application has the advantages of mild reaction condition, fast reaction speed, simple post-treatment, and less impurities in the obtained product. In the formula, R4 is selected from H or an amino protecting group, and R5 is selected from H or an isopropyl group.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and more specifically, to a method for preparing resmetiro and its intermediate, (6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one) or its derivatives. Background Technology

[0002] Resmetirom is a thyroid hormone receptor-β selective agonist used to treat non-alcoholic steatohepatitis (NASH) and has the potential to regulate multiple liver metabolic pathways to treat NASH.

[0003] Existing technology WO2007009913A1 discloses a method for preparing resimeltiro, as shown in route 1 below:

[0004]

[0005] Route 1

[0006] Route 1 uses 4-amino-2,6-dichlorophenol as a starting material, which is condensed with compound 7 to prepare compound 24. Compound 24 is converted into pyridazinone (compound 25), which then reacts with nitrite to generate a diazo compound, followed by a coupling reaction with cyanoacetylcarbamate to generate compound 30. Compound 30 undergoes a cyclization reaction to generate resmetiro. In this route, the preparation of (6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one) (compound 25) from 3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-aniline (compound 24) is a key transformation step in constructing the core molecular skeleton. The process of preparing compound 25 from compound 24 in Route 1 employs a two-step high-temperature reaction. Step 1: Compound 24 reacts in a glacial acetic acid / sodium acetate system at 100°C for 24 hours to generate an acetate intermediate; Step 2: A methanol solution of sodium hydroxide is added, and the reaction continues at 100°C for 24 hours to generate compound 25. The total reaction time for these two steps is extremely long, the overall molar yield is only about 57%, and the operation is cumbersome.

[0007] The existing technology CN119504714A improves the method for preparing compound 25 from compound 24 in route 1, proposing a process for preparing (6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one) from 3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazine-3-yloxy)-aniline: the raw materials are first reacted in acetic acid containing sodium acetate at 100°C for 15 hours, and then subjected to a second hydrolysis (2 hours) in an aqueous sodium hydroxide solution at 100°C. Although this improved process increases the yield and shortens the reaction time of the second step in a small-scale laboratory setting, its inherent nature still fails to overcome the defect of "high-temperature stepwise reaction". The first step reaction still requires a high-temperature reaction at 100°C for 15 hours in an acetic acid / sodium acetate solution, and the second step hydrolysis reaction under alkaline conditions still requires a temperature as high as 100°C.

[0008] Existing technology WO2014043706A also discloses a method for preparing resimeltiro, as shown in route 2 below:

[0009]

[0010] Route 2

[0011] Route 2 also uses 4-amino-2,6-dichlorophenol as a starting material, which is sequentially coupled with 3,6-dichloropyridazine (compound III-1). The coupling product (compound B2) undergoes amino protection, and the chlorine on the pyridazine ring of the amino-protected product (compound B3) is carbonylated to generate compound B4. Compound B4 then reacts with a Grignard reagent, and the resulting product (compound B5) is converted to compound B6. After removing the amino protecting group, compound B6 reacts with nitrite under acidic conditions to generate a diazo compound, which then undergoes a coupling reaction with N-cyanoacetylurane to generate compound A4. Compound A4 undergoes a cyclization reaction to generate resmetiro. In this route, the process of preparing compound B4 from compound B3 is as follows: compound B3 is reacted in an acetic acid and sodium acetate system at 110°C for 18.5 hours, followed by hydrolysis with water slowly added at 74.7°C (2 hours). It can be seen that the process of preparing compound B4 from compound B3 is similar to the process of preparing compound 25 from compound 24 in route 1. It is also a stepwise reaction at high temperature and uses an acetic acid and sodium acetate system.

[0012] Through in-depth research, the inventors of this application have discovered that the methods disclosed in the prior art for preparing (6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one) (compound 25) from 3,5-dichloro-4-(6-chloro-5-isopropylpyridazine-3-yloxy)-aniline (compound 24) share a common drawback: both the raw materials and the product contain a diphenyl ether bond (-O-) at their core, which is extremely sensitive to heat, acid, and alkali. In large-scale industrial production, due to the inherent limitations of mass and heat transfer in large reactors and local overheating, the diphenyl ether bond in both the raw materials and the product is prone to chemical cleavage during prolonged reactions in a high-temperature aqueous phase (strong acid or strong alkali) system at 100℃~120℃. This cleavage side reaction produces two extremely persistent specific impurities: 4-amino-2,6-dichlorophenol (impurity A) and 6-chloro-5-isopropylpyridazine-3-ol (impurity B), with the structures shown in the following structural formula. These two impurities have polarities similar to the main component, which not only leads to a severe reduction in the yield of the target product, but also significantly increases the difficulty of final purification.

[0013]

[0014] The reaction process for preparing 6-(4-benzoylamino-2,6-dichlorophenoxy)pyridazine-3(2H)-one (compound B4) from N-(3,5-dichloro-4-((6-chloropyridazine-3-yl)oxy)phenyl)benzamide (compound B3) should also involve similar impurities formed by the cleavage of diphenyl ether bonds.

[0015] Therefore, there is an urgent need in the field for a method that can prepare 6-(4-benzoylamino-2,6-dichlorophenoxy)pyridazine-3(2H)-one (compound B4) or its derivative (compound 25) from N-(3,5-dichloro-4-((6-chloropyridazine-3-yl)oxy)phenyl)benzamide (compound B3) or its derivative (compound 24) under mild conditions. This preparation method has high conversion efficiency of raw materials and can avoid the generation of diphenyl ether bond cleavage products from the chemical mechanism source. Summary of the Invention

[0016] In view of the shortcomings of existing methods for preparing compound II from compound I, such as cumbersome operation, high temperature, easy breakage of diphenyl ether bonds leading to many impurities, use of strong acids and strong bases, and large environmental pollution, this invention provides a new method for preparing compound II. The reaction conditions of this method are mild, the reaction rate is fast, the post-processing is simple, and the product obtained has few impurities.

[0017] This invention discloses a method for preparing a key intermediate of resmemetiro, compound II, comprising the steps of: compound I undergoing a nucleophilic substitution reaction with a silanolate, the resulting intermediate compound I-1 being hydrolyzed to generate compound II, as shown in the following reaction formula:

[0018] ,

[0019] R1, R2, and R3 are each independently selected from methyl, ethyl, propyl, isopropyl, phenyl, allyl, thiophene, or furanyl, and X represents... or R4 is selected from H or an amino protecting group, and R5 is selected from H or an isopropyl group.

[0020] In another preferred embodiment, the amino protecting group is selected from benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (TFA), p-toluenesulfonyl (Ts) or acetyl (Ac).

[0021] In another preferred embodiment, the silanolate is selected from sodium trimethylsilanolate, potassium trimethylsilanolate, sodium triethylsilanolate, potassium triethylsilanolate, sodium phenyl(dimethyl)silanolate, potassium phenyl(dimethyl)silanolate, sodium allyl dimethylsilanolate, sodium allyl dimethylsilanolate, sodium (2-thiophene)dimethylsilanolate, potassium (2-thiophene)dimethylsilanolate, sodium 2-furanyldimethylsilanolate, or combinations thereof.

[0022] In another preferred embodiment, R4 is an amino protecting group and R5 is H, or R4 is H and R5 is isopropyl.

[0023] In another preferred embodiment, R4 is H and R5 is isopropyl.

[0024] In another preferred embodiment, the molar ratio of compound I to the silanolate is 1.0:2.0 to 1.0:6.0, more preferably 1.0:2.5 to 1.0:4.5.

[0025] In another preferred embodiment, the solvent used for the reaction of compound I with the silanolate is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methylpyrrolidone; more preferably, it is selected from toluene, tetrahydrofuran, or 2-methyltetrahydrofuran.

[0026] In another preferred embodiment, the reaction temperature for the reaction of compound I with the silanolate is 40-90°C, more preferably 50-80°C.

[0027] In another preferred embodiment, the temperature at which compound I-1 is hydrolyzed is 0~40°C, more preferably 5~35°C.

[0028] In another preferred embodiment, the reaction time of compound I with the silanol salt is 1 to 5 hours, more preferably 2 to 3.5 hours.

[0029] In another preferred embodiment, the hydrolysis time of compound I-1 is 5 to 60 minutes, more preferably 10 to 40 minutes.

[0030] In another preferred embodiment, the preparation method further includes: adjusting the pH of the hydrolyzed reaction solution to 4.0~8.0 with acid, then cooling it to -5℃~25℃ for crystallization, filtering, and drying the obtained solid to obtain compound II.

[0031] In another preferred embodiment, the acid used to adjust the pH value is selected from hydrochloric acid, aqueous sulfuric acid solution, aqueous phosphoric acid solution, formic acid or aqueous solution thereof, acetic acid or aqueous solution thereof, citric acid or aqueous solution thereof, or combinations thereof.

[0032] In another preferred embodiment, the pH of the reaction solution is 4.0 to 6.5.

[0033] In another preferred embodiment, the preparation method of the resmetiro intermediate, compound II, of the present invention includes the following steps:

[0034] (1) Compound I reacts with silanol salt in an aprotic organic solvent in a nucleophilic substitution reaction to generate compound I-1;

[0035] (2) Add water to the reaction solution from step (1) to hydrolyze compound I-1, generating compound II.

[0036] (3) Adjust the pH of the reaction solution in step (2) to 4.0~8.0, and crystallize at -5~25℃. Filter and dry the obtained solid.

[0037] In another preferred embodiment, the volume of water added in step (2) is 0.2 to 3 times the volume of the aprotic organic solvent in step (1).

[0038] This invention also provides a method for preparing resmetidine, which includes the following steps:

[0039] (1) Compound II-a was prepared using the method described above for preparing compound II.

[0040] (2) Compound II-a reacts with nitrite under acidic conditions to form a diazonium salt, which then undergoes a coupling reaction with compound III to form compound IV.

[0041] (3) Compound IV undergoes a cyclization reaction to generate resmetiro.

[0042] The reaction formula is as follows:

[0043] .

[0044] This invention also provides a method for preparing resmetidine, which includes the following steps:

[0045] (1) Compound II-b was prepared using the method described above for preparing compound II.

[0046] (2) Compound II-b reacts with isopropenyl Grignard reagent to form compound B5.

[0047] (3) Compound B5 is converted into compound B6.

[0048] (4) Compound B6 loses its amino protecting group to form compound II-a.

[0049] (5) Compound II-a reacts with nitrite under acidic conditions to form a diazo compound, which then undergoes a coupling reaction with compound III to form compound IV.

[0050] (6) Compound IV undergoes a cyclization reaction to generate resmetiro.

[0051] The reaction formula is as follows:

[0052] . Attached Figure Description

[0053] Figure 1 The HPLC chromatogram of the crude product obtained in Comparative Example 1 (referencing the high-temperature stepwise hydrolysis process disclosed in the original patent application WO2007009913A);

[0054] Figure 2 The 1H NMR spectrum of a specific impurity, 4-amino-2,6-dichlorophenol (impurity A). 1 H NMR spectrum;

[0055] Figure 3 The 1H NMR spectrum of the specific impurity 6-chloro-5-isopropylpyridazine-3-ol (impurity B) 1 H NMR spectrum;

[0056] Figure 4 This is the HPLC chromatogram of compound II-a obtained in Example 1 of this invention;

[0057] Figure 5 This is the HPLC chromatogram of compound II-a obtained in Example 2 of this invention;

[0058] Figure 6 This is the HPLC chromatogram of compound II-a obtained in Example 3 of the present invention;

[0059] Figure 7 This is the HPLC chromatogram of compound II-a obtained in Example 4 of this invention;

[0060] Figure 8 This is the HPLC chromatogram of compound II-a obtained in Example 5 of this invention;

[0061] Figure 9 The proton nuclear magnetic resonance spectrum of compound II-a obtained in Example 1 of this invention (… 1 H NMR spectrum;

[0062] Figure 10 This is the HPLC chromatogram of compound IV, a diazotization intermediate prepared in Example 7 of this invention;

[0063] Figure 11 This is the diazotization intermediate prepared in Example 7 of this invention. The nuclear magnetic resonance (NMR) spectrum of compound IV (H1N) is shown. 1 H NMR spectrum;

[0064] Figure 12 This is the HPLC chromatogram of resmetiro, the final product prepared in Example 8 of this invention;

[0065] Figure 13 The proton nuclear magnetic resonance spectrum of resimetidine, the final product prepared in Example 8 of this invention ( 1 H NMR spectrum; Detailed Implementation

[0066] To address the shortcomings of existing methods for preparing compound II from compound I, such as high reaction temperature, long reaction time, low yield, high product impurity content, use of strong acids and bases leading to significant environmental pollution, and cumbersome reaction steps, the inventors of this application have conducted in-depth research on the preparation method of compound II. They discovered that by using compound I as a raw material, it first undergoes a nucleophilic substitution reaction with a silanolate. The resulting intermediate is then directly hydrolyzed in the original reaction solution with added water to generate compound II. After adjusting the pH of the hydrolyzed reaction solution, crystallization occurs at -5℃ to 25℃, followed by filtration, resulting in a high-yield, high-purity target compound. Based on this, the present invention was completed.

[0067] Preparation of Compound II

[0068] In one specific embodiment of the present invention, the preparation method of compound II includes the following steps:

[0069] (1) Compound I is reacted with a silanolate in an aprotic organic solvent to undergo a nucleophilic substitution reaction to generate compound I-1;

[0070] (2) Add water to the reaction solution from step (1) to hydrolyze compound I-1, generating compound II.

[0071] (3) Adjust the pH of the reaction solution in step (2) to 4.0~8.0, and crystallize at -5~25℃. Filter the solution and dry the resulting solid.

[0072] The reaction formula is as follows:

[0073] ,

[0074] R1, R2, and R3 are each independently selected from methyl, ethyl, propyl, isopropyl, phenyl, allyl, thiophene, or furanyl, and X represents... or R4 is selected from H or an amino protecting group, and R5 is selected from H or an isopropyl group.

[0075] The silanolates used in step (1) include, but are not limited to, sodium trimethylsilanolate, potassium trimethylsilanolate, sodium triethylsilanolate, potassium triethylsilanolate, sodium phenyl(dimethyl)silanolate, potassium phenyl(dimethyl)silanolate, sodium allyl dimethylsilanolate, potassium allyl dimethylsilanolate, sodium (2-thiophene)dimethylsilanolate, potassium (2-thiophene)dimethylsilanolate, sodium 2-furanyldimethylsilanolate, and potassium 2-furanyldimethylsilanolate. Any silanolate that can undergo a nucleophilic substitution reaction with compound I to generate a silanolate similar to the active intermediate compound I-1 can be used in this invention. The aprotic organic solvent includes, but is not limited to, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methylpyrrolidone. In some specific embodiments of the present invention, in step (1), compound I reacts with sodium / potassium trimethylsilanolate or sodium / potassium triethylsilanolate in an aprotic organic solvent at 50°C to 80°C with a nucleophilic substitution reaction to generate the active intermediate compound I-1. The resulting reaction solution does not require any further treatment and can be directly used for the next reaction.

[0076] In some specific embodiments of the present invention, in step (2), water is directly added to the reaction solution obtained in step (1), and the mixture is stirred at 5°C to 20°C for 10 to 40 minutes to hydrolyze intermediate compound I-1 and generate compound II. Adding water, on the one hand, hydrolyzes the active intermediate, compound I-1, to generate compound II; on the other hand, the addition of water reduces the solubility of compound II in aprotic organic solvents, facilitating its subsequent precipitation. There is no strict limit to the amount of water added; the higher the solubility of compound II in the organic solvent, the more water needs to be added, and vice versa.

[0077] In some specific embodiments of the present invention, in step (3), the pH value of the hydrolyzed reaction solution is adjusted to 4.0~8.0 with an acidic reagent, and compound II can precipitate from the reaction solution. The solid is obtained by filtration and drying to obtain the target compound. The pH value of the aqueous system affects the yield of compound II precipitation. Since the pyridazinone structure of compound II is weakly acidic, if the pH value of the system is adjusted too high (becoming strongly alkaline), compound II will partially form salt and increase its solubility in the aqueous phase, resulting in product loss and a decrease in yield.

[0078] Preparation method of resimetidine

[0079] In some specific embodiments of the present invention, compound II-a is prepared from compound Ia using the preparation method of compound II of the present invention, as shown in the following reaction formula.

[0080] .

[0081] Compound Ia can be prepared according to the method disclosed in prior art WO2007009913A1, and the prepared compound II-a can be used to prepare resmetiro according to the method disclosed in the prior art.

[0082] In some specific embodiments of the present invention, compound II-b is prepared from compound Ib using the preparation method of compound II of the present invention, as shown in the following reaction formula.

[0083] , where R4 is an amino protecting group.

[0084] Compound Ib can be prepared according to the method disclosed in prior art WO2014043706A1, and the resulting compound II-b can be prepared as resmetiro according to the method disclosed in the prior art.

[0085] Because the preparation method of compound II of the present invention is mild, it is not only compatible with the above-mentioned amino-protected substrates, but its more prominent advantage is that it can be directly applied to amino-free protected substrates.

[0086] Compared with the prior art, the preparation method of compound II of the present invention has the following beneficial effects:

[0087] (1) Breakthrough in chemical reaction mechanism and effective protection of diphenyl ether bond: This invention utilizes the excellent nucleophilicity and steric hindrance effect of silanol salt in aprotic organic phase to specifically target and attack the carbon-chlorine bond on the pyridazine ring, generating a stable silanol intermediate, thus avoiding the indiscriminate destruction of diphenyl ether bond by strong acid and strong base aqueous phase system at high temperature.

[0088] (2) Significantly shortened single-step conversion and process cycle: The present invention reduces the temperature of the preparation method disclosed in the prior art from 100~120℃ to 45~80℃, reduces the two-step reaction of the prior art which takes 15~48 hours to a "one-pot" conversion of 2~4 hours, and allows the product to be directly precipitated from a slightly acidic aqueous environment in the post-processing stage. After filtration, the target product is obtained, which significantly reduces equipment energy consumption and operation complexity.

[0089] (3) Thorough removal of specific impurities and improved industrial yield: The preparation method of compound II of the present invention effectively avoids the formation of specific ether bond cleavage impurities (such as 4-amino-2,6-dichlorophenol) in a high-temperature aqueous environment, or the impurity is strictly suppressed to below 0.05%, and the purity of the target product reaches above 99.5%. The molar yield has steadily increased from the low yield of conventional processes to above 98.0%, which has extremely high economic value for industrial mass production.

[0090] (4) Environmentally friendly. The preparation method of compound II of the present invention does not use a large amount of acidic solvent acetic acid and alkaline solvent sodium hydroxide solution. The post-processing is simple and the environmental pollution is minimal.

[0091] Comparative Example 1: Refer to the high-temperature stepwise hydrolysis process disclosed in the original patent WO2007009913A1.

[0092]

[0093] A mixture of compound Ia (1.00 g, 3.00 mmol, 1.00 equivalent), glacial acetic acid (30 mL), and anhydrous sodium acetate (860 mg, 10.48 mmol, 3.49 equivalent) was heated to 100 °C and reacted for 24 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (200 mL), alkalized to pH 9 with 1 N sodium hydroxide aqueous solution, and the suspension was extracted with ethyl acetate. Subsequently, concentrated hydrochloric acid was added to acidify the aqueous layer to pH 5, and the mixture was extracted again with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated.

[0094] The resulting oily substance was diluted with methanol (20 mL) and 1N sodium hydroxide aqueous solution (20 mL, 20 mmol) was added. The reaction mixture was heated to 120 °C and reacted for 24 hours. After cooling to room temperature, the solvent was removed by concentration, and the residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid to pH=5, then washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography, the desired fraction was collected and concentrated under vacuum, and finally stirred in diethyl ether (10 mL) and petroleum ether (10 mL) for 20 minutes, filtered, washed with petroleum ether, and dried to give compound II-a 535 mg, in a yield of 56.6%.

[0095] Detection results: HPLC analysis of the reaction solution, which reacted in methanol and 1N sodium hydroxide aqueous solution at 120℃ for 24 hours, showed that specific bond-broken impurities accumulated significantly after this extended reaction process and high temperature. For example... Figure 1 As shown, there is a distinct impurity peak near the product peak (relative retention time RRT=1.00) (already seen in...). Figure 1 (Selected by the bidder). The chromatographic peak with a relative retention time (RRT) of approximately 0.19 is impurity A, with a relative peak area content of 5.220%; the chromatographic peak with a relative retention time (RRT) of approximately 0.52 is impurity B, with a relative peak area content of 7.170%.

[0096] Impurity A and impurity B were obtained by separating the crude product of Comparative Example 1 by column chromatography.

[0097] The spectral data of impurity A are as follows: (See the 1H NMR spectrum). Figure 2 .

[0098] 1 1H NMR data: δ 8.80 (1H), 6.56 (2H), 5.01 (2H).

[0099] MS data: m / z = 177.98 [M+H] + .

[0100] The spectral data of impurity B are as follows: (See the 1H NMR spectrum). Figure 3 .

[0101] 1 1H NMR data: δ 13.10 (1H), 6.82 (1H), 2.87 (1H), 1.16 (6H).

[0102] MS data: m / z = 173.00 [M+H] + .

[0103] Example 1

[0104]

[0105] 250 mL of toluene and compound Ia (50.0 g, 150.3 mmol, 1.00 equivalent) were added to a reaction flask, and stirring was started. Under nitrogen protection, sodium trimethylsilanolate (NaOTMS, 50.6 g, 451.0 mmol, 3.00 equivalent) was added. The reaction mixture was slowly heated to 50 °C and stirred for 3.5 hours. TLC analysis of the reactants showed that compound Ia had essentially completed the reaction, and the reaction was stopped. The reaction system was cooled to 20 °C, and 100 mL of water was slowly added dropwise. After the addition was complete, stirring was continued at 25 °C for 30 minutes. TLC analysis showed that the trimethylsilanolate product formed in the reaction was essentially completely hydrolyzed. A 2 mol / L hydrochloric acid aqueous solution was added dropwise to the hydrolyzed reaction solution to adjust the pH to 5.5, and the mixture was cooled to 15 °C. After crystallization at this temperature for 1 hour, the mixture was filtered, the obtained solid was washed with water, and dried at 60 °C to obtain compound II-a.

[0106] Test results: Detected by HPLC (see...) Figure 4 The product purity reached 99.838%, and specific bond-breaking impurities A and B were not detected (0.00%). 46.5 g of pure white, dried product was obtained, with a molar yield of 98.5%.

[0107] The 1H NMR spectrum of the product is shown below. Figure 9 .

[0108] 1 1H NMR data: δ 12.14 (1H), 7.28 (1H), 6.67 (2H), 5.63 (2H), 3.01 (1H), 1.19 (6H).

[0109] MS data: m / z = 314.05 [M+H] + .

[0110] Example 2

[0111]

[0112] Add 300 mL of tetrahydrofuran, compound Ia (50.0 g, 150.3 mmol, 1.00 equivalent), and potassium trimethylsilanolate (KOTMS, 48.2 g, 375.8 mmol, 2.50 equivalent) to a reaction vessel. Heat the mixture to 60 °C and reflux for 2.5 hours. TLC analysis of the starting materials showed that compound Ia had essentially completed the reaction, and the reaction was stopped. Cool the reaction solution to 15 °C, add 80 mL of water, and continue stirring at 25 °C for 40 minutes. TLC analysis showed that the trimethylsilanolate product formed was essentially completely hydrolyzed. Concentrate to remove most of the tetrahydrofuran (approximately 2 / 3). Adjust the pH of the residue to 4.0 using an aqueous acetic acid solution and cool to 15 °C. Stir and crystallize at this temperature for 0.5 hours, filter, wash the resulting solid with water, and dry to obtain the target product, compound II-a.

[0113] Product detection results: HPLC analysis (see...) Figure 5 The product purity was 99.810%, and impurities A and B were not detected. 46.7 g of product was obtained, with a molar yield of 98.9%.

[0114] Example 3

[0115] 250 mL of 2-methyltetrahydrofuran, compound Ia (100.0 g, 300.7 mmol, 1.00 equivalent), and sodium trimethylsilanolate (NaOTMS, 101.2 g, 902.1 mmol, 3.00 equivalent) were added to a reaction vessel. The mixture was heated to 65 °C and reacted for 3.0 h. TLC analysis of the starting materials showed that compound I was essentially completely reacted, and the reaction was stopped. The reaction solution was cooled to 25 °C, and 200 mL of purified water was added. The mixture was stirred at 20 °C for 40 min. TLC analysis showed that the trimethylsilanolate product was essentially completely hydrolyzed. A 30% sulfuric acid aqueous solution was added dropwise to the hydrolyzed reaction solution to adjust the pH to 5.0, and the mixture was cooled to 15 °C. The mixture was stirred and crystallized at this temperature for 1.5 h. The product was filtered, washed with water, and dried to obtain the target product II-a.

[0116] Test results: Detected by HPLC (see...) Figure 6 The product purity was 99.858%, and impurities A and B were not detected. 93.6 g of product was obtained, with a molar yield of 99.1%.

[0117] Example 4

[0118] 200 mL of dimethyl sulfoxide, compound Ia (50.0 g, 150.3 mmol, 1.00 equivalent), and sodium trimethylsilanolate (NaOTMS, 67.5 g, 601.2 mmol, 4.00 equivalent) were added to a reaction vessel. The mixture was reacted at 75 °C for 2.0 h. TLC analysis of the starting materials showed that compound Ia had essentially completed the reaction, and the reaction was stopped. The reaction solution was cooled to 25 °C, and 500 mL of water was added. The mixture was stirred at 20 °C for 40 min. TLC analysis showed that the trimethylsilanolate product was essentially completely hydrolyzed. 25% phosphoric acid was added dropwise to the hydrolyzed reaction solution to adjust the pH to 6.5, and the mixture was cooled to 10 °C. The mixture was stirred at this temperature for 1.5 h, and a solid precipitated. The solid was filtered, washed with water, and dried to obtain the target product, compound II-a.

[0119] Test results: Detected by HPLC (see...) Figure 7 The product purity was 99.896%, and impurities A and B were not detected. 46.4 g of product was obtained, with a molar yield of 98.3%.

[0120] Example 5

[0121]

[0122] 250 mL of xylene, compound Ia (50.0 g, 150.3 mmol, 1.00 equivalent), and sodium triethylsilanolate (NaOTES, 69.6 g, 451.0 mmol, 3.00 equivalent) were added to a reaction vessel. The mixture was reacted at 80 °C for 2.5 h. TLC analysis of the starting materials showed that compound Ia had essentially completed the reaction, and the reaction was stopped. The reaction solution was cooled to 20 °C, and 100 mL of water was slowly added. The mixture was stirred at 20 °C for 35 min. TLC analysis showed that the trimethylsilanolate product generated in the reaction was essentially completely hydrolyzed. The pH of the hydrolyzed reaction solution was adjusted to 6.8 by adding 2 mol / L hydrochloric acid solution dropwise, and the solution was cooled to 10 °C. The mixture was stirred at this temperature for 1.5 h, and a solid precipitated. The solid was filtered, washed with water, and dried to obtain the target product, compound II-a.

[0123] Test results: Detected by HPLC (see...) Figure 8 The product purity was 99.887%, and impurities A and B were not detected. 46.3 g of product was obtained, with a molar yield of 98.1%.

[0124] Example 6

[0125] The raw materials and their amounts, as well as the reaction conditions, are the same in this embodiment as in Example 5. The only difference is in the post-processing. The post-processing of this invention includes the following steps:

[0126] The pH of the hydrolyzed reaction solution was adjusted to 8.0 by adding 2 mol / L hydrochloric acid solution dropwise, and then cooled to 15°C. The mixture was stirred at this temperature for 1.5 h, resulting in the precipitation of a solid. The solid was filtered, washed with water, and dried to obtain the target product compound II-a. 43.4 g of the product was obtained, with a molar yield of 92.0%.

[0127] The results showed that in a slightly alkaline environment (pH=8.0), the solubility of compound II-a in the aqueous phase may increase slightly due to partial salt formation, and the yield decreases slightly compared to slightly acidic conditions, but still remains at a high industrial yield level of over 90%.

[0128] As can be seen from the above embodiments, in this invention, compound I first undergoes a nucleophilic substitution reaction with a silanol in an aprotic organic phase to generate an active intermediate 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3-yltrialkylsilyl ether in situ. This intermediate does not require separation; it can be hydrolyzed by directly adding water to the reaction solution. Furthermore, by adjusting the system to near acidity or neutrality, compound II-a can be directly precipitated from the system. After filtration and drying, the target compound can be obtained.

[0129] Example 7

[0130]

[0131] Add 150 mL of water and 30 mL of concentrated hydrochloric acid to the reaction vessel, start stirring, and add in batches the high-purity compound II-a (15.7 g, 50.0 mmol, 1.00 equivalent) prepared in Example 1. Cool the system to 0–5 °C. Within this temperature range, slowly add 20 mL of an aqueous solution of sodium nitrite (3.62 g, 52.5 mmol, 1.05 equivalent). After the addition is complete, continue stirring at this temperature for 1 hour to obtain a diazo compound solution.

[0132] In another mixing vessel, 200 mL of water, 50 mL of ethanol, anhydrous sodium acetate (18.5 g, 225.0 mmol, 4.50 equivalents), and N-(cyanoacetyl)carbamate (7.96 g, 51.0 mmol, 1.02 equivalents) were added and stirred until dissolved, then cooled to 0–5 °C. The above diazo compound solution was added to the mixture, and a large amount of yellow solid rapidly precipitated. After the addition was complete, the reaction solution was naturally heated to 20–25 °C and stirred for 2.0 hours. The mixture was filtered, the filter cake was thoroughly washed with water, and dried under vacuum at 55 °C to constant weight to obtain the diazotized intermediate, compound IV, in a yield of 20.45 g, with a molar yield of 85.0%.

[0133] Test results: Detected by HPLC (see...) Figure 10 The purity of compound IV was 98.435%.

[0134] Product structure confirmation data: its 1H NMR spectrum is shown below. Figure 11 .

[0135] 1 1H NMR data: δ 12.21 (1H), 12.12 (1H), 10.90 (1H), 7.99 (2H), 7.37 (1H), 4.22 (2H), 3.08 (1H), 1.27 (3H), 1.19 (6H).

[0136] MS data: m / z = 481.08 [M+H] + .

[0137] Example 8: Preparation of Resmetiro

[0138]

[0139] 150 mL of N,N-dimethylacetamide (DMAc) was added to a reaction vessel, followed by compound IV (14.44 g, 30.0 mmol, 1.00 equivalent) prepared in Example 7 and anhydrous potassium acetate (8.83 g, 90.0 mmol, 3.00 equivalent). Under nitrogen protection, the reaction system was slowly heated to 115 °C and stirred for 3.0 h. After the reaction was complete as monitored by TLC, the system was cooled to 25 °C. 250 mL of purified water was slowly added dropwise to the reaction solution, followed by the addition of 2 mol / L hydrochloric acid aqueous solution to adjust the pH to 2.0. A large amount of pale yellow to off-white solid precipitated in the system. The mixture was stirred at 10 °C for another 1.5 h to allow crystallization. The solid was filtered, washed with water, and then purified by heating and beating with ethanol. The purified solid was filtered and dried under vacuum at 60 °C to obtain 10.71 g of the target active pharmaceutical ingredient, resmetiro, in solid form, with a molar yield of 82.0%.

[0140] Test results: Detected by HPLC (see...) Figure 12 The final product has a main peak purity of 99.701%.

[0141] Product structure confirmation data: its 1H NMR spectrum is shown below. Figure 13 .

[0142] 1 1H NMR data: δ 13.29 (1H), 12.24 (1H), 7.79 (2H), 7.44 (1H), 3.06 (1H), 1.19 (6H).

[0143] MS data: m / z = 435.04 [M+H] + .

[0144] Example 9

[0145]

[0146] Add 250 mL of toluene and compound Ib (50.0 g, 128.0 mmol, 1.00 equivalent) to a reaction flask and start stirring. Under nitrogen protection, add sodium trimethylsilanolate (NaOTMS, 50.3 g, 448.0 mmol, 3.5 equivalent). Slowly heat the reaction solution to 65 °C and stir for 3.0 hours. TLC analysis of the starting materials showed that compound Ib had reacted substantially completely, so the reaction was stopped. Cool the reaction system to 20 °C and slowly add 100 mL of water dropwise. After the addition was complete, continue stirring at 25 °C for 30 minutes. TLC analysis showed that the trimethylsilanolate product formed in the reaction was substantially hydrolyzed. Add 2 mol / L hydrochloric acid aqueous solution to the hydrolyzed reaction solution to adjust its pH to 5.5, and cool to 15 °C. After stirring and crystallizing at this temperature for 1 hour, filter, wash the obtained solid with water, and dry at 60 °C to obtain compound II-b (43.2 g of product, molar yield 90.7%).

[0147] MS data: m / z = 372.05 [M+H] + .

[0148] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A process for the preparation of a compound II, characterized in that, The preparation method includes the following steps: Compound I undergoes a nucleophilic substitution reaction with a silanolate, and the resulting compound I-1 is hydrolyzed to generate compound II, as shown in the following reaction formula: ， R1, R2, and R3 are each independently selected from methyl, ethyl, propyl, or isopropyl, X represents Na or K, R4 is selected from H or an amino protecting group, and R5 is selected from H or isopropyl.

2. The method for preparing compound II according to claim 1, characterized in that, The amino protecting group is selected from benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, trifluoroacetyl, p-toluenesulfonyl, or acetyl. The silanol salt is selected from sodium trimethylsilanolate, potassium trimethylsilanolate, sodium triethylsilanolate, potassium triethylsilanolate, or a combination thereof.

3. Process for the preparation of compounds II according to claim 1, characterized in that, R4 is an amino protecting group and R5 is H, or R4 is H and R5 is isopropyl.

4. Process for the preparation of compounds II according to claim 1, characterized in that, The molar ratio of compound I to the silanolate is 1.0:2.0 to 1.0:6.

0.

5. The process for the preparation of compounds II according to claim 1, characterized in that, The solvent used for the reaction of compound I with the silanolate is an aprotic organic solvent. The aprotic organic solvent is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methylpyrrolidone.

6. Process for the preparation of compounds II according to claim 1, characterized in that, The preparation method satisfies one or more of the following conditions: i) The reaction temperature for the reaction of compound I with the silanolate is 40~90℃. ii) The reaction time of compound I with the silanolate is 1-5 hours. iii) Compound I-1 undergoes hydrolysis at temperatures ranging from 0 to 40°C. iv) The hydrolysis time of compound I-1 is 5 to 60 minutes.

7. Process for the preparation of compounds II according to claim 1, characterized in that, The preparation method further includes: adjusting the pH of the hydrolyzed reaction solution to 4.0~8.0 with acid, then cooling to -5℃~25℃ for crystallization, filtering, and drying the obtained solid. The acid used to adjust the pH of the reaction solution is selected from hydrochloric acid, sulfuric acid aqueous solution, phosphoric acid aqueous solution, formic acid or aqueous solution thereof, acetic acid or aqueous solution thereof, citric acid or aqueous solution thereof, or combinations thereof.

8. Process for the preparation of compounds II according to claim 1, characterized in that, The preparation method includes the following steps: (1) Compound I reacts with a silanolate in an aprotic organic solvent in a nucleophilic substitution reaction to form compound I-1. (2) Add water to the reaction solution from step (1) to hydrolyze compound I-1, generating compound II. (3) Adjust the pH of the reaction solution in step (2) to 4.0~8.0, and crystallize at -5~25℃. Filter and dry the obtained solid.

9. The method for preparing compound II according to claim 8, characterized in that, In step (2), the volume of water added is 0.2 to 3 times the volume of the aprotic organic solvent.

10. A method for preparing resmetidine, characterized in that, The preparation method includes the following steps: (1) Compound II-a is prepared by the preparation method according to any one of claims 1 to 9. (2) The compound II-a obtained in step (1) reacts with nitrite under acidic conditions to form a diazo compound, which then undergoes a coupling reaction with compound III to form compound IV. (3) Compound IV undergoes a cyclization reaction to generate resmetiro. The reaction formula is as follows: 。 11. A method for preparing resmetidine, characterized in that, The preparation method includes the following steps: (1) Compound II-b was prepared by the preparation method according to any one of claims 1 to 9. (2) Compound II-b reacts with isopropenyl Grignard reagent to form compound B5. (3) Compound B5 is converted into compound B6. (4) Compound B6 loses its amino protecting group to form compound II-a. (5) Compound II-a reacts with nitrite under acidic conditions to form a diazo compound, which then undergoes a coupling reaction with compound III to form compound IV. (6) Compound IV undergoes a cyclization reaction to generate resmetiro. The reaction formula is as follows: 。

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