Preparation method of rosemeltirol

Abstract

The invention relates to the technical field of medicine synthesis, and particularly discloses a preparation method of rosmeltirol. According to the preparation method of the rosmeltirol, provided by the invention, an existing production process of the rosmeltirol is adjusted, so that the total yield of a route is increased from 8.9% to 40% or above, the purity of the prepared rosmeltirol is greater than 99.9%, the content of the maximum single impurity in the product is less than 0.05%, and column chromatography purification is not adopted in the whole production process, so that the yield of the rosmeltirol is greatly improved. The method has the advantages of simple operation, mild production conditions, high safety, environmental protection, facilitation of realization of industrial production of the rosmeltirol, and high practical value, and the production cost and the production period are reduced.

Description

Technical Field

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

[0002] Resmetirom (MGL-3196, trade name Rezdiffra), chemical name 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]-triazine-6-carbonitrile, with the structural formula as follows, is a drug used to treat non-alcoholic steatohepatitis with liver fibrosis (NASH, now known as metabolic dysfunction-associated steatohepatitis (MASH)). It was originally developed by Roche and was approved for accelerated marketing by the FDA on March 14, 2024. This is the first innovative drug approved by the FDA to treat NASH.

[0003]

[0004] MASH is a severe type of metabolic dysfunction-associated steatotic liver disease (MASLD). Research results show that 10% to 30% of ordinary adult MASLD patients worldwide suffer from MASH, and the prevalence of MASLD is increasing year by year. Therefore, the demand for this drug will increase in the future.

[0005] In existing literature reports, the synthetic route for synthesizing resmetiro is shown in Route 1. The defects of this route are: the yield of each step is low, the yield of the raw material 3,6-dichloropyridazine reacting with isobutyric acid to generate compound V is about 67%; the yield of compound V preparing compound IV through Ullmann reaction is about 50%; the yield of compound III after hydrolysis of compound IV is about 57%, and the reaction time is greater than 96h; the yield of compound III after diazotization reaction and reaction with (2-cyanoacetylamino) ethyl carbonate to generate compound II is about 56% to 76%; finally, the yield of compound II to obtain compound I under alkaline conditions is about 50% to 60%. In addition, column chromatography purification is required from the first to the third steps, the post-treatment is cumbersome, and the reaction time is too long, which limits the industrial production of this route. Therefore, in order to improve the yield of resmetiro and reduce production costs, it is necessary to find a simpler and industrializable production process.

[0006] Summary of the invention

[0007] In view of the problems that the process for preparing resmetiro in the prior art has low yield in each step, long reaction time, complicated post-treatment, high preparation cost, etc., the present invention provides a preparation method of resmetiro.

[0008] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0009] A preparation method of resmetiro comprises the steps:

[0010] Step 1: Under the condition of -10°C to 10°C, with water as solvent, in the presence of a catalyst and an initiator, 3,6-dichloropyridazine and isobutyric acid undergo Minisci reaction. After the reaction, the pH of the system is adjusted to weak alkalinity, the solid-liquid separation is performed, the obtained aqueous phase is extracted with n-hexane, the oil phase is washed and dried, and the solvent is removed to obtain 3,6-dichloro-4-isopropylpyridazine (V). The reaction equation is as follows.

[0011]

[0012] Through creative thinking, the inventors found that controlling the temperature of the Minisci reaction of 3,6-dichloropyridazine and isobutyric acid to -10°C to 10°C can effectively reduce the occurrence of side reactions and improve the conversion rate of raw materials, thereby significantly improving the purity and yield of 3,6-dichloro-4-isopropylpyridazine (V). The yield of 3,6-dichloro-4-isopropylpyridazine (V) can reach more than 97%, and the purity can reach more than 95%. In addition, the process conditions are mild and the operation is highly safe, which is beneficial to improving the yield and purity of downstream products and resmetiro products. In addition, the post-processing process is simple, and there is no need for high-cost and low-efficiency column chromatography, which is more conducive to industrial production.

[0013] Preferably, the catalyst is concentrated sulfuric acid and silver nitrate, and the initiator is ammonium persulfate.

[0014] Preferably, the reaction time of the Minisci reaction is 3 h to 4 h.

[0015] Preferably, the reaction temperature of the Minisci reaction is -5°C to 5°C.

[0016] Preferably, the weak alkalinity refers to pH=8-9.

[0017] Preferably, the washing comprises: washing with deionized water and saturated salt water in sequence.

[0018] Furthermore, the preparation method of the preparation method of resmetirol further comprises the following steps:

[0019] Step 2: Under the action of a catalyst and an acid-binding agent, 3,6-dichloro-4-isopropylpyridazine and 2,6-dichloro-4-aminophenol undergo an Ullmann reaction. After the reaction is completed, the pH of the system is adjusted to a weak alkaline state, the solid-liquid separation is performed, an extractant is added to elute the solid, alkaline activated carbon is added to the obtained filtrate for decolorization, the decolorized liquid is allowed to stand for separation, the obtained oil phase is washed, dried, and concentrated to obtain a crude product of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline; the crude product of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline is dissolved in anhydrous ethanol, cooled to -5°C to 5°C, and crystallized by heat preservation to obtain a product of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline (IV), and the reaction equation is as follows.

[0020]

[0021] Compared with the prior art, the present invention avoids the use of column chromatography for purification and uses non-toxic and safe anhydrous ethanol for recrystallization, which significantly reduces the production difficulty, production cost and production cycle while improving the yield and purity, and prepares 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (IV) product with a purity of more than 99.8% and a yield of more than 78.5%, thereby helping to improve the yield and purity of the resmetiro product. Experiments have shown that the use of other organic solvents, such as ethyl acetate, cannot achieve the above effect.

[0022] Preferably, in step 2, the catalyst is cuprous iodide, the acid binding agent is potassium carbonate, and the extractant is ethyl acetate.

[0023] Preferably, the temperature of the Ullmann reaction is 90°C to 100°C.

[0024] Preferably, in step 2, the weak alkalinity refers to pH=8-10.

[0025] Preferably, in step 2, the decolorization time is 30 min to 40 min.

[0026] Preferably, in step 2, the mass volume ratio of the crude 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline to anhydrous ethanol is 1 g:3 mL to 1 g:5 mL.

[0027] Preferably, in step 2, the heat preservation and crystallization time is 4h to 6h.

[0028] Furthermore, the preparation method of resmetirol further comprises:

[0029] Step 3: hydrolyze 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline in acetic acid and sodium acetate solution, add water, separate the solid and liquid, and obtain a wet product;

[0030] A sodium hydroxide solution is added to the wet product to carry out a secondary hydrolysis reaction. After the reaction is completed, water is added to the reaction solution to adjust the pH to neutral or weakly alkaline, and the solid-liquid separation is performed. The obtained solid-liquid is dispersed in water, and the solid-liquid is separated and dried to obtain 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one (III). The reaction equation is as follows.

[0031]

[0032] The inventors have found through research that in the prior art, when methanol and sodium hydroxide aqueous solution are used for hydrolysis, N-methylation side reactions will occur, resulting in a low yield of this step, which is about 57%, and the reaction time is greater than 96 hours. Through creative thinking, the inventors have found that the use of sodium hydroxide aqueous solution as a secondary hydrolysis reagent effectively avoids the occurrence of side reactions during the hydrolysis process, and can effectively reduce the time of the secondary hydrolysis reaction (only 2h to 3h, the original process is more than 24h), therefore, the yield of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one (III) is significantly improved, and the above process is used to prepare 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one (III) with a yield of more than 99.5% and a purity of more than 99.5%.

[0033] Preferably, in step three, the mass volume ratio of the 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline and the sodium hydroxide solution is 1 g:2 mL to 1 g:5 mL, and the concentration of the sodium hydroxide solution is 0.8 mol / L to 1.2 mol / L.

[0034] Preferably, in step three, the temperature of the secondary hydrolysis reaction is 90° C. to 120° C., and the time is 2 h to 3 h.

[0035] Furthermore, the preparation method of resmetirol further comprises:

[0036] Step 4: After diazotizing 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one, add (2-cyanoacetylamino)ethyl carbonate and sodium acetate aqueous solution to the reaction solution for condensation reaction. After the reaction is completed, solid-liquid separation is performed, and the obtained solid is dispersed in water for solid-liquid separation to obtain a crude product of (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate;

[0037] The crude product of (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxygen-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate is added to glacial acetic acid, the temperature is raised to 50°C to 70°C and kept warm, then the temperature is lowered to room temperature, and the solid-liquid is separated to obtain (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxygen-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate (II) product, and the reaction equation is as follows.

[0038]

[0039] Compared with the prior art, the present invention replaces the solvent of the condensation reaction with a sodium acetate aqueous solution, which can effectively improve the yield of the reaction compared with the original use of a pyridine solution as the reaction solvent. In addition, the obtained (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamic acid ethyl ester (II) crude product is purified in glacial acetic acid, which can effectively improve the yield of (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamic acid ethyl ester (II) The purity of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate (II) is improved, thereby preparing ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate (II) with a purity of more than 98.5% and a yield of more than 77.5%. In addition, compared with pyridine, a Class III hazardous chemical, sodium acetate is more conducive to improving the safety of drug intermediates.

[0040] Preferably, in step 4, the temperature of the diazotization reaction is -5°C to 0°C, and the reaction time is 30min to 40min.

[0041] Preferably, in step 4, the molar ratio of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one to sodium acetate is 1:2 to 1:6.

[0042] Preferably, in step 4, the temperature of the condensation reaction is -5°C to 0°C, and the reaction time is 1h to 2h.

[0043] In step 4, the mass volume ratio of the 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one to glacial acetic acid is 1 g:2 mL to 1 g:4 mL.

[0044] Preferably, in step 4, the insulation time at 50°C to 70°C is 1 h to 2 h.

[0045] Furthermore, the preparation method of resmetirol further comprises:

[0046] Step 5, using dimethylacetamide as a solvent, (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate is subjected to a cyclization reaction under alkaline conditions. After the reaction is completed, water is added to the reaction solution, and the solid-liquid separation is performed to obtain a crude product of resmetiro;

[0047] The crude resmetirol product is dissolved in anhydrous ethanol, activated carbon is added for decolorization, and the solid-liquid separation is performed. The obtained filtrate is cooled for crystallization, the solid-liquid separation is performed, and the product resmetirol is obtained. The reaction equation is shown below.

[0048]

[0049] Compared with the prior art, the present invention replaces the solvent of the high-temperature cyclization reaction with dimethylacetamide, which can effectively avoid the formation of cyano hydrolysis products and improve the conversion rate of the reaction. At the same time, anhydrous ethanol is selected as the crystallization solvent of the crude product, which can effectively improve the purity of the product and prepare a resmetiro product with a purity of more than 99.9% and a yield of more than 80.3%.

[0050] Preferably, in step five, the mass volume ratio of the ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate to dimethylacetamide is 1 g:5 mL to 1 g:7 mL.

[0051] Preferably, in step five, the temperature of the cyclization reaction is 110° C. to 130° C., and the reaction time is 2 h to 3 h.

[0052] Preferably, in step 5, the mass volume ratio of the crude resmetirol to anhydrous ethanol is 1 g:3 mL to 1 g:4 mL.

[0053] Preferably, in step five, the temperature of the cooling and crystallization is -5°C to 5°C, and the time of the cooling and crystallization is 4h to 5h.

[0054] The preparation method of resmetiro provided by the present invention increases the total yield of the route from the original 8.9% to more than 40% by adjusting the existing production process of resmetiro, and the purity of the prepared resmetiro is greater than 99.9%, the maximum content of a single impurity in the product is less than 0.05%, and column chromatography purification is not used in the entire production process, thereby reducing the production cost and production cycle, and the method has simple operation, mild production conditions, high safety, and is environmentally friendly, and is conducive to the industrial production of resmetiro, and has high practical value. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 This is the H NMR spectrum of 3,6-dichloro-4-isopropylpyridazine (V) synthesized in Example 1 of the present invention;

[0056] Figure 2 is the carbon NMR spectrum of 3,6-dichloro-4-isopropylpyridazine (V) synthesized in Example 1 of the present invention;

[0057] Figure 3 is the NMR mass spectrum of 3,6-dichloro-4-isopropylpyridazine (V) synthesized in Example 1 of the present invention;

[0058] Figure 4 This is the H NMR spectrum of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (IV) synthesized in Example 2 of the present invention;

[0059] Figure 5 This is the NMR carbon spectrum of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (IV) synthesized in Example 2 of the present invention;

[0060] Figure 6 This is the NMR mass spectrum of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (IV) synthesized in Example 2 of the present invention;

[0061] Figure 7 This is the H NMR spectrum of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (III) synthesized in Example 3 of the present invention;

[0062] Figure 8 This is the carbon NMR spectrum of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (III) synthesized in Example 3 of the present invention;

[0063] Fig. 9 This is the NMR mass spectrum of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (III) synthesized in Example 3 of the present invention;

[0064] Fig.10 It is the H NMR spectrum of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate (II) synthesized in Example 4 of the present invention;

[0065] Fig.11This is the NMR carbon spectrum of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate (II) synthesized in Example 4 of the present invention;

[0066] Fig.12 It is the NMR mass spectrum of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate (II) synthesized in Example 4 of the present invention;

[0067] Fig.13 is the H NMR spectrum of resmetirol (I) synthesized in Example 5 of the present invention;

[0068] Fig.14 is the NMR carbon spectrum of resmetirol (I) synthesized in Example 5 of the present invention;

[0069] Fig.15 is the nuclear magnetic resonance mass spectrum of resmetiro (I) synthesized in Example 5 of the present invention;

[0070] Fig.16 It is a high performance liquid chromatography (HPLC) chart of resmetiro (I) synthesized in Example 5 of the present invention. DETAILED DESCRIPTION

[0071] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0072] The synthetic route for preparing resmetirol in the following examples is as follows:

[0073]

[0074] In order to better illustrate the present invention, further examples are given below.

[0075] Example 1

[0076] The embodiment of the present invention provides a method for synthesizing 3,6-dichloro-4-isopropylpyridazine (V), which specifically comprises the following steps:

[0077] In a 1000 mL three-necked round-bottom flask under ice bath, 3,6-dichloropyridazine (VI) (60 g, 0.403 mol), isobutyric acid (46.13 g, 0.524 mol), water (500 mL) and silver nitrate (20.53 g, 0.3 mol) were added in sequence, and the mechanical stirring device (speed 250 r / min) was turned on. Concentrated sulfuric acid (118.41 g, 1.208 mol) was slowly added dropwise under stirring, and then ammonium persulfate (137.86 g, 0.604 mol) dissolved in 240 mL of water was slowly added dropwise using a constant pressure dropping funnel. The addition process was 3 0min, after the addition is completed, the temperature is maintained at -5 to 5°C, and thin layer chromatography is used for monitoring (petroleum ether / ethyl acetate=17 / 3). After 3h, the reaction is complete, and the reaction is stopped. The pH value is adjusted to 8 to 9 with 10% sodium carbonate aqueous solution, filtered, and the aqueous phase is extracted with n-hexane (200ml×3). The organic phases are combined, and the organic phases are washed with deionized water (400mL) and saturated brine (400mL) in turn, dried over anhydrous sodium sulfate overnight, filtered, and concentrated under reduced pressure at 50°C to remove the solvent to obtain 75.25g of a light yellow oily liquid (V) with a molar yield of 97.8% and a purity of 95.01%.

[0078] HRMS[M+H] + (C7H8Cl2N2): Theoretical calculated value: 191.0065, actual value: 191.0132.

[0079] 1 H NMR (500MHz, DMSO-d6): δ8.00 (s, 1H), 3.17 (pd, J = 6.9, 0.6Hz, 1H), 1.27 (d, J = 6.8Hz, 6H).

[0080] 13 C NMR (126MHz, DMSO-d6): δ156.72, 156.60, 150.60, 128.63, 30.64, 21.26.

[0081] Comparative Example 1

[0082] The embodiment of the present invention provides a method for synthesizing 3,6-dichloro-4-isopropylpyridazine (V), which specifically comprises the following steps:

[0083] 3,6-dichloropyridazine (VI) (2 g, 0.0134 mol), isobutyric acid (1.54 g, 0.0175 mol), water (20 mL) and silver nitrate (0.68 g, 0.01 mol) were added to a 100 mL round-bottom flask in sequence. The stirring device was turned on and concentrated sulfuric acid (4 g, 0.04 mol) was slowly added dropwise. The temperature was raised to 70 °C and ammonium persulfate (4.6 g, 0.02 mol) dissolved in 10 mL of water was slowly added dropwise. The reaction mixture was monitored by TLC. (petroleum ether / ethyl acetate=17 / 3), the reaction was completed in 30 minutes, the reaction was stopped, the pH value was adjusted to 8-9 with 10% sodium carbonate aqueous solution, filtered, extracted with n-hexane (10 mL×3), the organic phases were combined, the organic phases were washed with deionized water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 50°C to remove the solvent to obtain 1.93 g of a yellow oily liquid (V), with a molar yield of 75.8% and a purity of 90.01%.

[0084] Example 2

[0085] The embodiment of the present invention provides a method for synthesizing 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (IV), which specifically comprises the following steps:

[0086] Under nitrogen protection, 3,6-dichloro-4-isopropylpyridazine (V) (20 g, 0.105 mol), 2,6-dichloro-4-aminophenol (18.63 g, 0.105 mol), potassium carbonate (57.87 g, 0.419 mol), cuprous iodide (11.96 g, 0.0628 mol) and anhydrous dimethyl sulfoxide (60 mL) were added to a 250 mL three-necked flask in sequence. The mixture was heated at 90 ° C. The reaction was completed after 3 h of TLC monitoring (petroleum ether / ethyl acetate = 19 / 5). The reaction was stopped and the reaction solution was cooled to room temperature. , pour into 300mL of water, adjust the pH to 8-9 with 1mol / L dilute hydrochloric acid, filter with diatomaceous earth, repeatedly rinse the filter cake with ethyl acetate (500mL), add 2g of alkaline activated carbon to the filtrate, stir and decolorize for 30min, filter with diatomaceous earth, repeat decolorization three times, separate the liquids, extract the aqueous phase with ethyl acetate (200mL×3) until there is no ultraviolet color, combine the organic phases, wash the organic phases with deionized water (500mL) and saturated brine (500mL) in turn, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate in vacuo at 50°C to obtain a pink solid crude product. To the obtained crude product, 100 mL of ethanol was added and refluxed until completely dissolved. After stirring for 30 min, the heating was turned off and the product was allowed to cool to precipitate a white solid. The product was cooled at -5 to 5 °C for 5 h to crystallize. The product was filtered and dried overnight in a vacuum at 45 °C to obtain a white powder, 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (IV) 27.20 g, with a molar yield of 78.5% and a purity of 99.80%.

[0087] HRMS[M+H] + (C 13 H 12 Cl3N3O): calculated value: 332.0046, actual value: 332.0108.

[0088] 1 H NMR (500MHz, DMSO-d6): δ7.68 (s, 1H), 6.73 (s, 2H), 5.70 (s, 2H), 3.17 (p, J = 6.8Hz, 1H), 1.29 (d, J = 6.9Hz, 6H).

[0089] 13 C NMR (126MHz, DMSO-d6): δ164.86, 153.36, 151.79, 148.67, 134.49, 128.21, 116.55, 113.45, 30.62, 21.50.

[0090] Comparative Example 2

[0091] This comparative example provides a method for synthesizing 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (IV), which specifically comprises the following steps:

[0092] Under nitrogen protection, 3,6-dichloro-4-isopropylpyridazine (V) (1 g, 5.23 mmol), 2,6-dichloro-4-aminophenol (0.932 g, 5.23 mmol), potassium carbonate (2.89 g, 0.0209 mol), cuprous iodide (0.598 g, 3.14 mmol) and anhydrous dimethyl sulfoxide (4 mL) were added to a 100 mL three-necked flask in sequence, and the mixture was reacted at 90 ° C for 3 h. The reaction solution was cooled to At room temperature, pour into 25mL water, adjust pH to 8-9 with 1mol / L dilute hydrochloric acid, use diatomaceous earth to assist filtering, rinse filter cake with ethyl acetate (20mL), add 0.1g alkaline activated carbon to the filtrate for decolorization, repeat decolorization three times, extract the aqueous phase with ethyl acetate (10mL×3) until no ultraviolet coloration, combine the organic phases, wash the organic phases with deionized water and saturated brine in turn, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate at 50℃ in vacuum to obtain a brown solid crude product. Add the crude product to 3mL ethyl acetate and heat to dissolve completely, place to cool, and a white solid precipitates, -5-5℃, cool and crystallize for 5h, filter, and vacuum dry at 45℃ overnight to obtain a light pink solid, 0.88g of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (IV), with a molar yield of 50.8% and a purity of 97.32%.

[0093] Example 3

[0094] This embodiment provides a method for synthesizing 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (III), which specifically comprises the following steps:

[0095] Into a 500 mL flask, 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (IV) (20 g, 0.0604 mol), sodium acetate (24.78 g, 0.302 mol) and acetic acid (200 mL) were added in sequence, and the reaction was carried out at 100 °C for 15 h. After TLC monitoring showed that the raw material conversion was complete, the reaction was stopped. After the reaction solution was cooled to room temperature, 100 mL of deionized water was slowly added and stirred for 30 min. A large amount of white solid precipitated, and the solution was filtered under reduced pressure. The solution was slurried with 300 mL of deionized water again, and 24.07 g (wet weight) of white solid was obtained by filtration. 1 mol / L sodium hydroxide solution (100 mL) was added to 24.07 g of the wet product, and the reaction temperature was set to 100° C. and monitored by TLC (petroleum ether / ethyl acetate=8 / 20). The reaction was completed after 2 h, and the reaction was stopped. The reaction solution was cooled to room temperature and slowly poured into 200 mL of deionized water. The mixture was stirred for 30 min and the pH was adjusted to 7-8 with 1 mol / L HCl solution. A large amount of white solid precipitated. The mixture was filtered under reduced pressure, slurried with 200 mL of deionized water for 30 min, filtered, and dried in vacuo at 45° C. for 6 h to obtain 18.06 g of a light pink solid (III) with a molar yield of 95.5% and a purity of 99.59%.

[0096] HRMS[M+H] + (C 13 H 13 Cl2N3O2): calculated value: 314.03848, actual value: 314.0437.

[0097] 1 H NMR (500MHz, DMSO-d6): δ12.15(s,1H),7.29(s,1H),6.68(s,2H),5.63(s,2H),3.07–3.02(m,1H),1.19(d,J=6.9Hz,6H).

[0098] 13 C NMR (126MHz, DMSO-d6): δ160.19, 153.59, 152.36, 148.49, 134.32, 128.38, 120.01, 113.41, 28.10, 21.00.

[0099] Comparative Example 3

[0100] This comparative example provides a method for synthesizing 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one (III), which specifically comprises the following steps:

[0101] 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (IV) (1 g, 3.02 mmol), sodium acetate (0.74 g, 9.06 mol) and glacial acetic acid (10 mL) were added to a 100 mL flask in sequence, and the reaction was carried out at 100 ° C for 21 h. After the conversion of the raw materials was complete, the reaction was stopped. After the reaction solution was cooled to room temperature, 10 mL of water was slowly added and stirred. A large amount of solid precipitated, which was filtered off and slurried twice with 20 mL of deionized water. The white solid was filtered off to obtain a white solid. The white solid was added to a 100 mL round-bottom flask, diluted with 10 mL of methanol, and 1 mol / L sodium hydroxide solution (20 mL) was added. The reaction temperature was set to 100 ° C. TLC monitoring (petroleum ether / ethyl acetate = 8 / 20) was performed. After 13 h, the reaction was complete and the reaction was stopped. The reaction solution was cooled to room temperature, and 20 mL of deionized water was slowly poured into it. Stir for 30 min and the pH was adjusted with 1 mol / L HCl solution. 7-8, a large amount of pink solid precipitated, filtered, slurried with 30 mL of deionized water for 30 min, filtered, and dried in vacuo at 45 °C for 6 h to obtain 0.394 g of white solid (III) with a molar yield of 41.7% and a purity of 96.83%.

[0102] Example 4

[0103] This embodiment provides a method for synthesizing ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate (II), and the specific steps are as follows:

[0104] Concentrated hydrochloric acid (60 mL) was added to a suspension of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (III) (15 g, 0.048 mol) in water (60 mL), and the mixture was cooled to 0-5°C. Then, a solution of sodium nitrite (3.64 g, 0.053 mol) in water (8 mL) was added for 8 min. The resulting mixture was stirred at 0-5°C for 30 min and monitored by TLC (ethyl acetate / methanol = 17 / 3) until it was completely converted to the diazo intermediate. Then, the mixture was added to a mixed system of ethyl (2-cyanoacetylamino) carbonate (8.23 g, 0.053 mol), water (45 ml), and sodium acetate (11.79 g, 0.144 mol) precooled to 0°C, and the obtained suspension was stirred at 0°C to form an orange slurry. The reaction was completed after 1 hour and filtered. The filter cake was slurried twice with deionized water (200 mL) and filtered to obtain a bright orange solid crude product. The crude product was added to glacial acetic acid (45 mL), stirred at 60°C for 1 hour, cooled to room temperature, and filtered to obtain an orange solid. The product was dried in vacuo at 45°C overnight to obtain an orange solid, 18.0 g of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate (II), with a molar yield of 77.9% and a purity of 98.71%.

[0105] HRMS[MH] - (C 19 H 18 Cl2N6O5): calculated value: 479.07157, actual value: 479.0618.

[0106] 1 H NMR (500MHz, DMSO-d6): δ12.23(s,1H),12.14(s,1H),10.89(s,1H),8.00(s,2H),7.39(s,1 H), 4.22 (q, J = 7.1Hz, 2H), 3.09–3.04 (m, 1H), 1.29 (t, J = 7.1Hz, 3H), 1.21 (d, J = 6.9Hz, 6H).

[0107] 13 C NMR (126MHz, DMSO-d6): δ160.21,160.15,154.14,151.91,151.41,141.54,1 41.30,129.15,119.88,117.40,111.21,109.79,61.94,28.19,20.99,14.71.

[0108] Comparative Example 4

[0109] This comparative example provides a method for synthesizing ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate (II), and the specific steps are as follows:

[0110] Concentrated hydrochloric acid (4 mL) was added to a suspension of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (III) (2 g, 6.39 mmol) in water (8 mL), and the mixture was cooled to 0 to -5°C. Then, a solution of sodium nitrite (0.57 g, 8.31 mmol) in water (1 mL) was added dropwise over 2 min, and the resulting mixture was reacted at room temperature for 30 min. Then, it was added to a mixed system of ethyl (2-cyanoacetylamino) carbonate (0.11 g, 7.03 mmol), water (6 mL), and pyridine (4 g) precooled to 0°C. The resulting suspension was stirred at 0°C for 1 h. After the reaction was complete, the system turned into an orange slurry and was filtered. The filter cake was slurried twice with deionized water (25 mL) and the crude product was filtered. The crude product was added to glacial acetic acid (6 mL), stirred at 60°C for 1 h, cooled, and filtered to obtain an orange solid. The solid was dried in vacuo at 45°C overnight to obtain 1.52 g of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate (II) with a molar yield of 49.6% and a purity of 97.05%.

[0111] Example 5

[0112] This embodiment provides a method for synthesizing (3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (resmetirox) (I), comprising the following steps:

[0113] Under nitrogen protection, 50 g (0.104 mol) (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamic acid ethyl ester (II), 300 mL of dimethylacetamide and 25.63 g (0.313 mmol) of sodium acetate were added to a 50 mL flask in sequence, and the mixture was reacted at 120 ° C for 2 h. After TLC detection (ethyl acetate / methanol = 17 / 4), the reaction was complete. The heating was turned off, the mixture was cooled to 0 ° C, and 250 mL of deionized water was slowly added. A large amount of orange solid precipitated. The mixture was stirred for 3 hours. 0min, filter to obtain a dark orange crude product, add the crude product into anhydrous ethanol (250mL), heat to 60℃ and dissolve completely, add 5g of medicinal activated carbon, heat to decolorize for 30min, filter while hot, filter with diatomaceous earth to obtain a light yellow filtrate, add 5g of medicinal activated carbon to decolorize the filtrate again, filter while hot, filter with diatomaceous earth to obtain a colorless and transparent filtrate, concentrate the filtrate to 100mL, cool at -5~5℃ for crystallization for 5h, filter, and dry in vacuo at 45℃ for 10h to obtain a white powder, 36.25g of resmetiro (Ⅰ), with a yield of 80.3%, a purity of 99.91%, and a maximum single impurity of <0.05%.

[0114] HRMS[M+H] + (C 17 H 12 C l2 N6O4): calculated value: 435.02971, actual value: 435.0362.

[0115] 1 H NMR (500MHz, DMSO-d6) δ 13.30 (s, 1H), 12.26 (s, 1H), 7.81 (s, 2H), 7.46 (s, 1H), 3.07 (pd, J = 6.9, 1.0Hz, 1H), 1.22 (d, J = 6.9Hz, 6H).

[0116] 13 C NMR (126MHz, DMSO-d6) δ160.07,155.05,154.48,151.65,147.44,145.81,137.79,128.89,127.18,123.38,119.81,112.61,28.26,20.97.

[0117] Comparative Example 5

[0118] This comparative example provides a method for synthesizing (3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (resmetirox) (I), comprising the following steps:

[0119] In a 50 mL flask, 2 g (4.17 mmol) of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate (II), 10 mL of glacial acetic acid and 1.71 g (20.8 mmol) of sodium acetate were added in sequence. The reaction was carried out at 120 °C. TLC detection (ethyl acetate / methanol = 17 / 4) was performed. The reaction was completed in 3 h. The mixture was cooled to 0 °C and 20 mL of water was slowly added. A bright orange solid was precipitated. The mixture was stirred for 30 min and filtered under reduced pressure. The crude product was obtained as an orange solid. The crude product was added to anhydrous ethanol (20 mL), heated to 60 ° C for complete dissolution, 0.2 g of medicinal activated carbon was added, heated for decolorization for 30 min, filtered while hot, and filtered with diatomaceous earth to obtain a light orange filtrate, 0.2 g of medicinal activated carbon was added to the filtrate for decolorization again, filtered while hot, and filtered with diatomaceous earth to obtain a light yellow filtrate, the filtrate was concentrated to 10 mL, cooled at -5 to 5 ° C for crystallization for 5 h, filtered, and dried in vacuo at 45 ° C for 8 h to obtain a light yellow solid, 0.78 g of resmetiro (Ⅰ), with a yield of 43.1% and a purity of 98.50%.

[0120] The reaction conditions in Examples 1 to 5 can adopt other conditions specified in the present invention to achieve technical effects equivalent to those in Examples 1 to 5.

[0121] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing resmetiro, characterized in that: The steps include: Step 1: Under the condition of -10°C to 10°C, with water as solvent, in the presence of a catalyst and an initiator, 3,6-dichloropyridazine and isobutyric acid undergo Minisci reaction. After the reaction, the pH of the system is adjusted to weak alkalinity, the solid-liquid separation is performed, the obtained aqueous phase is extracted with n-hexane, the oil phase is washed and dried, and the solvent is removed to obtain 3,6-dichloro-4-isopropylpyridazine.

2. The method for preparing resmetirol according to claim 1, characterized in that: The catalyst is concentrated sulfuric acid and silver nitrate, and the initiator is ammonium persulfate; and / or The reaction time of the Minisci reaction is 3h to 4h; and / or The reaction temperature of the Minisci reaction is -5°C to 5°C; and / or The weak alkalinity refers to pH=8-9; and / or The washing comprises: washing with deionized water and saturated salt water in sequence.

3. The method for preparing resmetirol according to claim 1, characterized in that: Also includes: Step 2: Under the action of a catalyst and an acid-binding agent, 3,6-dichloro-4-isopropylpyridazine and 2,6-dichloro-4-aminophenol undergo an Ullmann reaction. After the reaction is completed, the pH of the system is adjusted to a weak alkaline state, the solid-liquid separation is performed, an extractant is added to elute the solid, alkaline activated carbon is added to the obtained filtrate for decolorization, the decolorized liquid is allowed to stand for separation, the obtained oil phase is washed, dried, and concentrated to obtain a crude 3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline product; the crude 3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline product is dissolved in anhydrous ethanol, cooled to -5°C to 5°C, and kept warm for crystallization to obtain a 3,5-dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline product.

4. The method for preparing resmetirol according to claim 3, characterized in that: In step 2, the catalyst is cuprous iodide, the acid binding agent is potassium carbonate, and the extractant is ethyl acetate; and / or In step 2, the weak alkalinity refers to pH=8-10; and / or In step 2, the decolorization time is 30 min to 40 min; and / or In step 2, the mass volume ratio of the crude 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline to anhydrous ethanol is 1 g:3 mL to 1 g:5 mL; and / or In step 2, the heat preservation and crystallization time is 4h to 6h.

5. The method for preparing resmetirol according to claim 3, characterized in that: Also includes: Step 3: hydrolyze 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline in acetic acid and sodium acetate solution, add water, separate the solid and liquid, and obtain a wet product; A sodium hydroxide solution is added to the wet product to carry out a secondary hydrolysis reaction. After the reaction is completed, water is added to the reaction solution to adjust the pH to neutral or weakly alkaline, separate the solid and liquid, disperse the obtained solid and liquid in water, separate the solid and liquid, and dry to obtain 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one.

6. The method for preparing resmetirol according to claim 5, characterized in that: In step 3, the mass volume ratio of the 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline to the sodium hydroxide solution is 1 g:2 mL to 1 g:5 mL, and the concentration of the sodium hydroxide solution is 0.8 mol / L to 1.2 mol / L; and / or In step 3, the temperature of the secondary hydrolysis reaction is 90° C. to 120° C., and the time is 2 h to 3 h.

7. The method for preparing resmetirole according to claim 5, characterized in that: Also includes: Step 4: After diazotizing 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one, add (2-cyanoacetylamino)ethyl carbonate and sodium acetate aqueous solution to the reaction solution for condensation reaction. After the reaction is completed, solid-liquid separation is performed, and the obtained solid is dispersed in water for solid-liquid separation to obtain a crude product of (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate; The crude (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxygen-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate product is added to glacial acetic acid, the temperature is raised to 50° C. to 70° C. and then cooled to room temperature for solid-liquid separation to obtain the (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxygen-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate product.

8. The method for preparing resmetirole according to claim 7, characterized in that: In step 4, the molar ratio of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one to sodium acetate is 1:2 to 1:6; and / or In step 4, the condensation reaction temperature is -5°C to 0°C, and the reaction time is 1h to 2h; and / or In step 4, the mass volume ratio of the 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one to glacial acetic acid is 1 g:2 mL to 1 g:4 mL; and / or In step 4, the insulation time at 50°C to 70°C is 1h to 2h.

9. The method for preparing resmetirole according to claim 7, characterized in that: Also includes: Step 5, using dimethylacetamide as a solvent, (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate is subjected to a cyclization reaction under alkaline conditions. After the reaction is completed, water is added to the reaction solution, and the solid-liquid separation is performed to obtain a crude product of resmetiro; The crude resmetiro product is dissolved in anhydrous ethanol, activated carbon is added for decolorization, the solid-liquid separation is performed, the obtained filtrate is cooled for crystallization, the solid-liquid separation is performed, and the product resmetiro is obtained by drying.

10. The method for preparing resmetirole according to claim 9, characterized in that: In step 5, the mass volume ratio of the ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate to dimethylacetamide is 1 g:5 mL to 1 g:7 mL; and / or In step 5, the mass volume ratio of the crude resmetirol to anhydrous ethanol is 1 g:3 mL to 1 g:4 mL; and / or In step 5, the temperature of the cooling and crystallization is -5°C to 5°C, and the time of the cooling and crystallization is 4h to 5h.

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