A method for preparing a rucotril intermediate and a method for preparing rucotril

Abstract

The present application relates to the technical field of organic chemistry, and provides a roxadustat intermediate, a preparation method thereof and a preparation method of roxadustat.The roxadustat intermediate provided by the present application has high activity, can be hydrolyzed at the same time of ring closure, and does not need additional protection and deprotection steps of amino group, thereby shortening the synthesis route.The preparation method of roxadustat provided by the present application has a short synthesis route, and roxadustat can be prepared through 5 reaction steps, so that the production efficiency of roxadustat can be significantly improved;the reagent used in the present application is cheap, and can greatly reduce the production cost and the amount of solid waste and waste water;the obtained roxadustat product is easy to separate and purify, which is beneficial to reduce the refining times, improve the yield and production efficiency.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemistry, and particularly relates to a resmetirom intermediate, a preparation method thereof and a preparation method of resmetirom. BACKGROUND

[0002] Resmetirom (CAS: 920509-32-6) is a once-daily oral thyroid hormone receptor-beta (THR-beta) selective agonist developed by Madrigal Pharmaceuticals for the treatment of metabolic-associated steatohepatitis (MASH) in adult patients with liver fibrosis. Resmetirom has good safety and tolerability, and has a low incidence of adverse reactions. In July 2023, an application for marketing was submitted to the FDA, and on March 15, 2024, it was approved for marketing. Therefore, resmetirom has become the first MASH drug in the world, and has a very broad market prospect. The molecular structure of resmetirom is shown as formula I:

[0003]

[0004] Patents WO2014043706 and CN105008335A disclose a synthetic route of resmetirom. First, compound G and 2,6-dichloro-4-aminophenol are reacted in the presence of cesium carbonate to prepare compound F by aromatic nucleophilic substitution reaction; second, compound F is subjected to amino protection with benzoic anhydride to obtain compound E; third, compound E is subjected to hydrolysis reaction in glacial acetic acid to prepare compound D, and the total yield of the above three steps is 74%; fourth, compound D and 3.5 times of isopropenyl magnesium bromide and 3.0 times of lithium chloride are subjected to addition reaction to generate compound C-b, and then the double bond is shifted in the presence of base hydrolysis to obtain compound C-a, and the total yield of the above two steps is 95% and the purity is 87.6% (containing isomers); compound C-a is difficult to separate from isomers, and is therefore directly used in the next step, i.e., after diazotization, compound B is added and then the double bond is shifted to generate compound A, with a yield of 90% and a purity of 90.4% (containing isomers); then, compound A is subjected to ring closure to obtain resmetirom I, with a yield of 89% and a purity of 93.7% (containing isomers); finally, the crude resmetirom I is refined for three times to obtain the final resmetirom product, with a yield of 68%. The specific synthetic route is as follows:

[0005]

[0006] The route has the following disadvantages: first, the activity of chlorine in the first step of aromatic nucleophilic substitution is not high, so that compound G needs to react with 2,6-dichloro-4-aminophenol in the presence of strong base cesium carbonate at 65 DEG C for 20 h to complete the conversion, and 2,6-dichloro-4-aminophenol is chemically unstable and is easily oxidized, thus resulting in a reduced yield and high cost of cesium carbonate; second, the amino group needs to be protected and deprotected, which increases the reaction steps, the operation difficulty and the production cost; third, expensive isopropenyl magnesium bromide (3.5 times the amount) and lithium chloride (3.0 times the amount) are used in the synthesis of compound C-a, which greatly increases the cost and the amount of solid waste and liquid waste, and is not conducive to environmental protection; fourth, compound C-a and its isomers are difficult to separate, so that the final crude product needs to be refined three times to obtain qualified rucotril, and the yield is obviously reduced.

[0007] Therefore, it is urgent to develop a method for preparing rucotril with a short synthesis route, high yield, environmental protection, easy separation and purification and low production cost. SUMMARY

[0008] Therefore, the present application provides a rucotril intermediate, a preparation method thereof and a preparation method of rucotril. The present application provides a rucotril intermediate with a structure shown in formula III, and the rucotril intermediate is used to prepare rucotril, has a short synthesis route, high yield, less waste liquid, easy separation and purification of the product and low production cost.

[0009] In order to achieve the above-mentioned purposes, the present application provides the following technical solutions:

[0010] A rucotril intermediate has a structure shown in formula III:

[0011]

[0012] The present application also provides a preparation method of the rucotril intermediate described in the above-mentioned scheme, which comprises the following steps:

[0013] (1) mixing a compound shown in formula G, a fluorination reagent, a phase transfer catalyst and an organic solvent to perform an aromatic nucleophilic substitution reaction, so as to obtain a compound shown in formula V;

[0014]

[0015] (2) mixing the compound shown in formula V, 2,6-dichloro-4-aminophenol, an alkaline compound and an organic solvent to perform a substitution reaction, so as to obtain a compound shown in formula IV; the alkaline compound is potassium carbonate and / or sodium carbonate;

[0016]

[0017] (3) mixing a compound of formula IV, a compound of formula B, sodium nitrite, hydrochloric acid and glacial acetic acid to react, to obtain a resocortol intermediate of formula III;

[0018]

[0019] Preferably, in the step (1), the fluorination reagent is potassium fluoride and / or sodium fluoride; the molar ratio of the compound of formula G to the fluorination reagent is 1:2-10;

[0020] The phase transfer catalyst comprises one or more of tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium bromide and triethylbenzylammonium chloride; the molar ratio of the compound of formula G to the phase transfer catalyst is 1:0.1-2;

[0021] The organic solvent in the step (1) comprises one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide and acetonitrile;

[0022] The temperature of the aromatic nucleophilic substitution reaction is 10-160℃, and the reaction time is 1-24h.

[0023] Preferably, in the step (2), the molar ratio of the compound of formula V to the basic compound is 1:1-5;

[0024] The molar ratio of the compound of formula V to 2,6-dichloro-4-aminophenol is 1:1-1.5;

[0025] The organic solvent in the step (2) comprises one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and tetrahydrofuran;

[0026] The temperature of the substitution reaction is 20-100℃, and the reaction time is 1-10h.

[0027] Preferably, in the step (3), the molar ratio of the compound of formula IV to sodium nitrite is 1:1-10; the molar ratio of the compound of formula IV to hydrochloric acid is 1:1-20; and the molar ratio of the compound of formula IV to the compound of formula B is 1:1-2;

[0028] The temperature of the reaction in the step (3) is -10-60℃, and the reaction time is 1-48h.

[0029] The application further provides a preparation method of resocortol, comprising the following steps:

[0030] (A) mixing a ressitrex intermediate of a structure shown in formula III, a basic compound and an organic solvent to perform a hydrolysis-cyclization reaction, to obtain a compound of a structure shown in formula II;

[0031]

[0032] (B) mixing a compound of a structure shown in formula II, 2-nitropropane, a basic compound and an organic solvent to perform an addition-elimination-double bond migration reaction, to obtain ressitrex; the structure of the ressitrex is shown in formula I;

[0033]

[0034] Preferably, in the step (A), the basic compound is potassium acetate and / or sodium acetate; the molar ratio of the ressitrex intermediate of a structure shown in formula III and the basic compound is 1:1-10;

[0035] The organic solvent in the step (A) includes one or more of dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide.

[0036] Preferably, the temperature of the hydrolysis-cyclization reaction is 30-160℃, and the reaction time is 1-24h.

[0037] Preferably, in the step (B), the basic compound is DBU or tetramethyl guanidine; the molar ratio of the compound of a structure shown in formula II and the basic compound is 1:1-5;

[0038] The molar ratio of the compound of a structure shown in formula II and 2-nitropropane is 1:1-3;

[0039] The organic solvent in the step (B) includes one or more of dimethyl sulfoxide, sulfolane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and acetone.

[0040] The temperature of the addition-elimination-double bond migration reaction is 20-120℃, and the reaction time is 1-48h.

[0041] Preferably, after the addition-elimination-double bond migration reaction, the obtained reaction solution is further treated, and the treatment includes mixing the reaction solution with ice water and adjusting the pH value to be acidic, and standing to precipitate the solid product; the solid product is filtered and sequentially washed and recrystallized to obtain the ressitrex.

[0042] The present application provides a roxadustat intermediate, and the structure is shown in formula III. The roxadustat intermediate provided by the present application has high activity, and can be hydrolyzed while ring closing, without the need of additional protection and deprotection steps for amino groups. The roxadustat intermediate provided by the present application can shorten the synthesis route, has high yield, produces less waste liquid, and is easy to separate and purify, thereby reducing the production cost.

[0043] The present application also provides a preparation method of the roxadustat intermediate described in the above scheme. The present application uses a compound with the structure shown in formula G as a starting material, obtains a compound with the structure shown in formula V through an aromatic nucleophilic substitution reaction, then obtains a compound with the structure shown in formula IV through a substitution reaction under alkaline conditions, and finally obtains the roxadustat intermediate with the structure shown in formula III through a diazotization reaction and an addition-double bond shift reaction with a compound shown in formula B. The present application uses a compound with the structure shown in formula V instead of a chloro compound G in the traditional method, which significantly improves the activity of the compound, shortens the reaction time, and does not need to use expensive cesium carbonate with strong alkalinity. The results of the examples show that the time of the substitution reaction is reduced from 20 h in WO2014043706 to 1-3 h, and the production efficiency is greatly improved.

[0044] The present application also provides a preparation method of roxadustat. The roxadustat is obtained through a hydrolysis-ring closing reaction and an addition-elimination-double bond shift reaction using the roxadustat intermediate with the structure shown in formula III. The preparation method provided by the present application has a short synthesis route. Starting from a compound with the structure shown in formula G, roxadustat can be prepared through 5 reaction steps, while 7 reaction steps are needed in WO2014043706. The method of the present application can significantly improve the production efficiency of roxadustat. In addition, 2-nitropropane used in the present application is cheap, and does not need to use isopropyl magnesium bromide and lithium chloride in WO2014043706, which are expensive and in large quantities, thereby greatly reducing the production cost and the amount of solid waste and waste water. The carbonyl and cyano in the amino aromatic heterocycle connected to the benzene ring in the compound with the structure shown in formula II belong to strong electron-withdrawing groups, and have large steric hindrance, which can effectively reduce the generation of roxadustat isomers of the compound I-a (the structure is shown below), so that the product is easy to separate and purify, the number of refining times is reduced, and the yield and production efficiency are improved.

[0045] BRIEF DESCRIPTION OF DRAWINGS

[0046] Figure 1 The nuclear magnetic hydrogen spectrum of the compound III prepared in Example 3;

[0047] Figure 2 The nuclear magnetic hydrogen spectrum of the compound II prepared in Example 5;

[0048] Figure 3 NMR spectrum of the compound, roxadustat, prepared in Example 7. DETAILED DESCRIPTION

[0049] The present application provides a roxadustat intermediate, which has a structure as shown in formula III:

[0050]

[0051] The present application also provides a preparation method of the roxadustat intermediate described in the above scheme, which comprises the following steps:

[0052] (1) mixing a compound having a structure as shown in formula G, a fluorination reagent, a phase transfer catalyst and an organic solvent to perform an aromatic nucleophilic substitution reaction, so as to obtain a compound having a structure as shown in formula V;

[0053]

[0054] (2) mixing a compound having a structure as shown in formula V, 2,6-dichloro-4-aminophenol, an alkaline compound and an organic solvent to perform a substitution reaction, so as to obtain a compound having a structure as shown in formula IV; the alkaline compound is potassium carbonate and / or sodium carbonate;

[0055]

[0056] (3) mixing a compound having a structure as shown in formula IV, a compound having a structure as shown in formula B, sodium nitrite, hydrochloric acid and glacial acetic acid to perform a reaction, so as to obtain a roxadustat intermediate having a structure as shown in formula III;

[0057]

[0058] The compound of formula G, a fluorination reagent, a phase transfer catalyst and an organic solvent are mixed to perform an aromatic nucleophilic substitution reaction to obtain a compound of formula V. In the present application, the fluorination reagent is preferably potassium fluoride and / or sodium fluoride; the molar ratio of the compound of formula G to the fluorination reagent is preferably 1:2-10, more preferably 1:2-5; the phase transfer catalyst preferably comprises one or more of tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium bromide and triethylbenzylammonium chloride, more preferably tetrabutylammonium fluoride; the molar ratio of the compound of formula G to the phase transfer catalyst is preferably 1:0.1-2, more preferably 1:0.15-1.2; the organic solvent in step (1) preferably comprises one or more of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc) and acetonitrile, more preferably DMSO; the present application does not have special requirements for the amount of the organic solvent, which can ensure the smooth progress of the reaction; the temperature of the aromatic nucleophilic substitution reaction is preferably 10-160°C, more preferably 20-120°C, and the time of the aromatic nucleophilic substitution reaction is preferably 1-24h, more preferably 3-20h.

[0059] In specific embodiments of the present application, the compound of formula G, the fluorination reagent, the phase transfer catalyst and the organic solvent are mixed, and then the reaction is performed by warming to the temperature of the aromatic nucleophilic substitution reaction; when the phase transfer catalyst is tetrabutylammonium fluoride, it is preferably added in the form of a tetrabutylammonium fluoride tetrahydrofuran solution, and after mixing the reaction raw materials, tetrahydrofuran is first removed by rotary evaporation at 40°C, and then the reaction is performed by warming. After the completion of the aromatic nucleophilic substitution reaction, no post-treatment is required, and the next step can be directly performed.

[0060] After obtaining the compound of formula V, the compound of formula V, 2,6-dichloro-4-aminophenol, a basic compound and an organic solvent are mixed to perform a substitution reaction to obtain a compound of formula IV. In the present application, the basic compound is preferably potassium carbonate and / or sodium carbonate; the molar ratio of the compound of formula V to the basic compound is preferably 1:1-5, more preferably 1:1-3; the molar ratio of the compound of formula V to 2,6-dichloro-4-aminophenol is preferably 1:1-1.5, more preferably 1:1-1.2; the organic solvent in step (2) preferably comprises one or more of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), acetonitrile and tetrahydrofuran (THF), more preferably DMSO; the temperature of the substitution reaction is preferably 20-100°C, more preferably 30-80°C, the time of the substitution reaction is preferably 1-10h, more preferably 1-3h; and the substitution reaction is preferably performed under nitrogen protection.

[0061] In the specific embodiment of the present application, the reaction solution obtained from the aromatic nucleophilic substitution reaction is preferably cooled to room temperature, and then 2,6-dichloro-4-aminophenol and a basic compound are added, and the reaction is carried out under nitrogen protection by heating to the temperature of the substitution reaction.

[0062] After the completion of the substitution reaction, the reaction solution obtained is preferably added to ice water, stirred uniformly, and then allowed to stand to precipitate solids, and the precipitated solid product is filtered, washed, and dried to obtain the compound of the structure shown in Formula IV; the standing time is preferably 5 min, and the washing is preferably water washing.

[0063] After obtaining the compound of the structure shown in Formula IV, the compound of the structure shown in Formula IV, the compound of the structure shown in Formula B, sodium nitrite, hydrochloric acid, and glacial acetic acid are mixed to react to obtain the Roxadustat intermediate of the structure shown in Formula III. In the present application, the molar ratio of the compound of the structure shown in Formula IV to sodium nitrite is preferably 1:1-10, and more preferably 1:1.1-5; the molar ratio of the compound of the structure shown in Formula IV to hydrochloric acid is preferably 1:1-20, and more preferably 1:2-10; the molar ratio of the compound of the structure shown in Formula IV to the compound of the structure shown in Formula B is preferably 1:1-2, and more preferably 1:1-1.3; the temperature of the reaction in step (3) is preferably -10-60°C, more preferably 0-40°C, and further preferably room temperature, and the reaction time is preferably 1-48 h, and more preferably 5-24 h; in the present application, the reaction occurring in step (3) is specifically as follows: the compound of the structure shown in Formula IV first undergoes diazotization reaction with sodium nitrite and hydrochloric acid, and then addition and double bond migration reaction with compound B to obtain the Roxadustat intermediate of the structure shown in Formula III.

[0064] In the specific embodiment of the present application, the compound of the structure shown in Formula IV, the compound of the structure shown in Formula B, and glacial acetic acid are first mixed, and then cooled to 0-10°C, and then hydrochloric acid is added in batches, and then the temperature is maintained at 5-10°C, and then sodium nitrite aqueous solution is added dropwise to the system, and then the reaction is carried out at room temperature.

[0065] After the completion of the reaction in step (3), the reaction solution obtained is preferably poured into water, stirred uniformly, and then allowed to stand to precipitate solids, and the precipitated solid product is filtered, slurried in potassium carbonate aqueous solution, and then filtered again, and the filter cake obtained is washed and dried to obtain the Roxadustat intermediate of the structure shown in Formula III; the standing time is preferably 10 min, the slurry time is preferably 30 min, and the washing is preferably water washing.

[0066] The present application also provides a preparation method of Roxadustat, comprising the following steps:

[0067] (A) mixing a ressitrex intermediate of formula III, a basic compound and an organic solvent to carry out a hydrolysis-cyclization reaction, to obtain a compound of formula II;

[0068]

[0069] (B) mixing a compound of formula II, 2-nitropropane, a basic compound and an organic solvent to carry out an addition-elimination-double bond migration reaction, to obtain ressitrex; the structure of the ressitrex is shown in formula I;

[0070]

[0071] The present application mixes a ressitrex intermediate of formula III, a basic compound and an organic solvent to carry out a hydrolysis-cyclization reaction, to obtain a compound of formula II. In the present application, the preparation method of the ressitrex intermediate of formula III is the same as the above-mentioned scheme, and will not be repeated here; the basic compound in step (A) is preferably potassium acetate and / or sodium acetate; the molar ratio of the ressitrex intermediate of formula III and the basic compound is preferably 1:1-10, more preferably 1:1.5-5; the organic solvent in step (A) preferably includes one or more of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMAc), more preferably DMF.

[0072] In the present application, the temperature of the hydrolysis-cyclization reaction is preferably 30-160°C, more preferably 50-130°C, and the time of the hydrolysis-cyclization reaction is preferably 1-24h, more preferably 1-10h.

[0073] After the completion of the hydrolysis-cyclization reaction, the present application preferably cools the obtained reaction solution to room temperature, then pours it into water, stirs it uniformly, then stands it, to make the solid product precipitate, filters the precipitated solid product, then washes and dries it, to obtain a compound of formula II; the standing time is preferably 10min, and the washing is preferably water washing.

[0074] After obtaining the compound of structure II, the compound of structure II, 2-nitropropane, a basic compound and an organic solvent are mixed to perform an addition-elimination-double bond shift reaction, thereby obtaining the compound of structure III. In the present application, the basic compound in step (B) is preferably DBU or tetramethylguanidine, more preferably DBBU; the molar ratio of the compound of structure II to the basic compound is preferably 1:1-5, more preferably 1:1.1-3; the molar ratio of the compound of structure II to 2-nitropropane is preferably 1:1-3, more preferably 1:1-2; the organic solvent in step (B) preferably comprises one or more of dimethyl sulfoxide (DMSO), sulfolane, acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc) and acetone, more preferably DMSO; the temperature of the addition-elimination-double bond shift reaction is preferably 20-120°C, more preferably 40-100°C; and the time of the addition-elimination-double bond shift reaction is preferably 1-48 h, more preferably 3-24 h.

[0075] After the addition-elimination-double bond shift reaction is completed, the present application preferably further comprises post-treatment of the obtained reaction solution, which comprises: mixing the reaction solution with ice water and adjusting the pH value to be acidic, and standing to precipitate the solid product; filtering the solid product and sequentially performing washing and recrystallization, thereby obtaining the compound of structure III; in the present application, when the organic solvent used in the addition-elimination-double bond shift reaction is acetonitrile, before mixing with ice water, the present application preferably further comprises removing the organic solvent in the reaction solution by rotary evaporation, and adjusting the pH value to be acidic, specifically adjusting the pH value to be 6; the reagent used for adjusting the pH value is preferably hydrochloric acid; the washing preferably comprises sequentially performing water washing and heptane washing; and the recrystallization solvent is preferably a mixed solvent of isopropanol and water, and the volume ratio of isopropanol to water in the mixed solvent is preferably 4:1.

[0076] The technical solutions in the present application will be described clearly and completely below in combination with the embodiments in the present application. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the protection scope of the present application.

[0077] In the following embodiments, the compound of structure G, the compound of structure V, the compound of structure IV, the compound of structure III, the compound of structure II and the compound of structure B are respectively denoted as compound G, compound V, compound IV, compound III, compound II and compound B.

[0078] Preparation of compound IV in Example 1

[0079]

[0080] In a reaction flask was added 14.9 g (100 mmol) of compound G, 14.5 g (250 mmol) of potassium fluoride, 30 mL of tetrabutylammonium fluoride tetrahydrofuran solution (1 mol / L, 30 mmol), and 150 mL of DMSO; 10 min of rotary evaporation at 40 °C removed the tetrahydrofuran, and then the reaction solution was warmed to 80 °C for 12 h; cooling to room temperature, 18.7 g (105 mmol) of 2,6-dichloro-4-aminophenol and 16.6 g (120 mmol) of potassium carbonate powder were added, and the reaction was warmed to 50 °C for 3 h under nitrogen protection; cooling to room temperature, the reaction mixture was added to 1000 mL of ice water, and after stirring well, it was allowed to stand for 5 min, a large amount of solid was precipitated, which was filtered, the filter cake was washed with 100 mL of water, and dried to obtain 26.0 g of off-white solid compound IV with a yield of 95%.

[0081] 1 H-NMR (400M, DMSO-d6): 7.78 (1H, d), 7.61 (1H, d), 6.66 (2H, s), 5.65 (2H, brs).

[0082] Preparation of compound IV in Example 2

[0083]

[0084] In a reaction flask was added 14.9 g (100 mmol) of compound G, 14.5 g (250 mmol) of potassium fluoride, 30 mL of tetrabutylammonium fluoride tetrahydrofuran solution (1 mol / L, 30 mmol), and 150 mL of DMSO; 10 min of rotary evaporation at 40 °C removed the tetrahydrofuran, and then the reaction solution was warmed to 80 °C for 12 h; cooling to room temperature, 18.7 g (105 mmol) of 2,6-dichloro-4-aminophenol and 16.6 g (120 mmol) of potassium carbonate powder were added, and the reaction was warmed to 50 °C for 3 h under nitrogen protection; cooling to room temperature, the reaction mixture was added to 1000 mL of ice water, and after stirring well, it was allowed to stand for 5 min, a large amount of solid was precipitated, which was filtered, the filter cake was washed with 100 mL of water, and dried to obtain 26.0 g of off-white solid compound IV with a yield of 95%.

[0085] Preparation of compound III in Example 3

[0086]

[0087] In a reaction flask, 11.0 g (40 mmol) of compound IV, 7.5 g of compound B (48 mmol) and 50 mL of glacial acetic acid were added, and the ice water was cooled to 0-10 °C. 15 mL of hydrochloric acid (30% by mass) was added in batches. The temperature was maintained at 5-10 °C, and a solution of 3.3 g of sodium nitrite (48 mmol) in 20 mL of water was added dropwise within 30 min. After the addition was completed, the reaction was stirred at room temperature for 2 h. The reaction solution was poured into 200 mL of water, stirred uniformly, and then allowed to stand for 10 min. A large amount of solid was precipitated, which was filtered. The filter cake was slurried with 50 mL of a potassium carbonate aqueous solution for 30 min. The filter cake was filtered again, washed with 30 mL of water, and dried to obtain 16.8 g of a light yellow solid of compound III with a yield of 95%.

[0088] 1 H-NMR (400M, DMSO-d6): 12.16 (1H, s), 10.63 (1H, s), 8.07 (1H, d), 7.95 (2H, s), 7.85 (1H, d), 4.19 (2H, q), 1.27 (3H, t). The H-NMR spectrum is shown in Figure 1

[0089] Preparation of compound III in Example 4

[0090]

[0091] In a reaction flask, 11.0 g (40 mmol) of compound IV, 7.5 g of compound B (48 mmol) and 50 mL of glacial acetic acid were added, and the ice water was cooled to 0-10 °C. 15 mL of hydrochloric acid (30% by mass) was added in batches. The temperature was maintained at 5-10 °C, and a solution of 3.3 g of sodium nitrite (48 mmol) in 20 mL of water was added dropwise within 30 min. After the addition was completed, the reaction was stirred at room temperature for 2 h. The reaction solution was poured into 200 mL of water, stirred uniformly, and then allowed to stand for 10 min. A large amount of solid was precipitated, which was filtered. The filter cake was slurried with 50 mL of a potassium carbonate aqueous solution for 30 min. The filter cake was filtered again, washed with 30 mL of water, and dried to obtain 16.8 g of a light yellow solid of compound III with a yield of 95%.

[0092] Preparation of compound II in Example 5

[0093]

[0094] In a reaction flask, 11.0 g (40 mmol) of compound IV, 7.5 g of compound B (48 mmol) and 50 mL of glacial acetic acid were added, and the ice water was cooled to 0-10 °C. 15 mL of hydrochloric acid (30% by mass) was added in batches. The temperature was maintained at 5-10 °C, and a solution of 3.3 g of sodium nitrite (48 mmol) in 20 mL of water was added dropwise within 30 min. After the addition was completed, the reaction was stirred at room temperature for 2 h. The reaction solution was poured into 200 mL of water, stirred uniformly, and then allowed to stand for 10 min. A large amount of solid was precipitated, which was filtered. The filter cake was slurried with 50 mL of a potassium carbonate aqueous solution for 30 min. The filter cake was filtered again, washed with 30 mL of water, and dried to obtain 16.8 g of a light yellow solid of compound III with a yield of 95%.​

[0095] 1 H-NMR (400M, DMSO-d6): 13.28 (1H, brs), 12.24 (1H, brs), 7.79 (2H, s), 7.44 (1H, s), 3.05 (1H, m), 1.20 (6H, d). The hydrogen nuclear magnetic resonance spectrum is shown as follows. Figure 2

[0096] Preparation of compound II in Example 6

[0097]

[0098] In a reaction bottle, 8.83 g (20 mmol) of compound III, 4.9 g (50 mmol) of potassium acetate and 50 mL of DMAc were added, and the temperature was raised to 120°C for 2 h; after cooling to room temperature, the reaction solution was poured into 300 mL of water, stirred uniformly, and then left to stand for 10 min, and a large amount of solid was precipitated, which was filtered, the filter cake was washed with 30 mL of water, and then dried to obtain 7.2 g of white solid compound II, with a yield of 92%.

[0099] Preparation of ranibizumab (Formula I) in Example 7

[0100]

[0101] In a reaction bottle, 3.93 g (10 mmol) of compound II, 1.34 g of 2-nitropropane (15 mmol), 3.04 g of DBU (20 mmol) and 20 mL of DMSO were added, and the temperature was raised to 50°C for 24 h, and the liquid phase showed that the ratio of product to isomer was 97:3; the reaction solution was added to 100 mL of ice water, and the pH was adjusted to 6 with hydrochloric acid, and then left to stand for 5 min, and a large amount of solid was precipitated, which was filtered, the filter cake was washed with 20 mL of water, and then washed with 20 mL of heptane; the obtained solid was recrystallized with isopropyl alcohol and water to obtain 3.6 g of white solid compound I, with a yield of 82% and a purity of 99.8%.

[0102] 1 H-NMR (400M, DMSO-d6): 13.28 (1H, brs), 12.24 (1H, brs), 7.79 (2H, s), 7.44 (1H, s), 3.05 (1H, m), 1.20 (6H, d). The hydrogen nuclear magnetic resonance spectrum is shown as follows. Figure 3

[0103] Preparation of ranibizumab (Formula I) in Example 8

[0104]

[0105] ​​In a reaction flask was added 3.93 g (10 mmol) of compound II, 1.78 g of 2-nitropropane (20 mmol), 3.45 g of tetramethylguanidine (30 mmol) and 40 mL of acetonitrile, and the temperature was raised to 80°C for 24 h. Liquid phase showed a product to isomer ratio of 95:5. The acetonitrile was evaporated, 50 mL of ice water was added, and the pH was adjusted to 6 with hydrochloric acid. A large amount of solid was precipitated, which was filtered, and the filter cake was washed with 20 mL of water and then with 20 mL of heptane. The resulting solid was recrystallized from isopropanol and water to obtain 3.4 g of white solid compound I, with a yield of 78% and a purity of 99.5%.

[0106] The above description is only preferred embodiments of the present application, and it should be pointed out that for those skilled in the art, several improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A process for the preparation of resmetiromide, characterized by, The method comprises the following steps: (A) mixing a roscovitine intermediate of formula III, a basic compound and an organic solvent to perform a hydrolysis-cyclization reaction, to obtain a compound of formula II; Formula III; Formula II; (B) mixing the compound of formula II, 2-nitropropane, a basic compound and an organic solvent to perform an addition-elimination-double bond migration reaction, to obtain roscovitine; the structure of the roscovitine is shown in formula I; Formula I; The preparation method of the roscovitine intermediate comprises the following steps: (1) mixing a compound of formula G, a fluorination reagent, a phase transfer catalyst and an organic solvent to perform an aromatic nucleophilic substitution reaction, to obtain a compound of formula V; the phase transfer catalyst comprises one or more of tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium bromide and triethylbenzylammonium chloride; the molar ratio of the compound of formula G to the phase transfer catalyst is 1:0.1-2; Formula G; Formula V; (2) mixing the compound of formula V, 2,6-dichloro-4-aminophenol, a basic compound and an organic solvent to perform a substitution reaction, to obtain a compound of formula IV; the basic compound is potassium carbonate and / or sodium carbonate; Formula IV; (3) mixing the compound of formula IV, a compound of formula B, sodium nitrite, hydrochloric acid and glacial acetic acid to perform a reaction, to obtain the roscovitine intermediate of formula III; Formula B.

2. The production method according to claim 1, characterized by, In the step (1), the fluorination reagent is potassium fluoride and / or sodium fluoride; the molar ratio of the compound of formula G to the fluorination reagent is 1:2-10; The organic solvent in the step (1) comprises one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide and acetonitrile; The temperature of the aromatic nucleophilic substitution reaction is 10-160℃, and the reaction time is 1-24h.

3. The preparation method according to claim 1, characterized in that, In the step (2), the molar ratio of the compound of formula V to the basic compound is 1:1-5; The molar ratio of the compound of formula V to 2,6-dichloro-4-aminophenol is 1:1-1.5; The organic solvent in the step (2) comprises one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and tetrahydrofuran; The temperature of the substitution reaction is 20-100℃, and the reaction time is 1-10h.

4. The production method according to claim 1, characterized by, In the step (3), the molar ratio of the compound of formula IV to sodium nitrite is 1:1-10; the molar ratio of the compound of formula IV to hydrochloric acid is 1:1-20; the molar ratio of the compound of formula IV to the compound of formula B is 1:1-2; The temperature of the reaction in the step (3) is -10-60℃, and the reaction time is 1-48h.

5. The preparation method according to claim 1, characterized in that, In the step (A), the basic compound is potassium acetate and / or sodium acetate; the molar ratio of the roscovitine intermediate of formula III to the basic compound is 1:1-10; The organic solvent in the step (A) comprises one or more of dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide.

6. The production method according to claim 1 or 5, characterized by, The temperature of the hydrolysis-cyclization reaction is 30-160℃, and the reaction time is 1-24h.

7. The preparation method according to claim 1, characterized in that, In the step (B), the basic compound is DBU or tetramethylguanidine; the molar ratio of the compound of the structure shown in formula II to the basic compound is 1:1-5; The molar ratio of the compound of the structure shown in formula II to 2-nitropropane is 1:1-3; The organic solvent in the step (B) includes one or more of dimethyl sulfoxide, sulfolane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide and acetone; The temperature of the addition-elimination-double bond migration reaction is 20-120℃, and the reaction time is 1-48h.

8. The method of claim 1, wherein, After the addition-elimination-double bond migration reaction, the obtained reaction solution is further treated, and the treatment includes: mixing the reaction solution with ice water and adjusting the pH value to be acidic, and standing to precipitate the solid product; filtering the solid product and sequentially washing and recrystallizing to obtain the resmetirom.

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