CN118791471A - A preparation method of Besudil - Google Patents

Abstract

The invention relates to Bei Shude mol, in particular to a preparation method of besudil. The method takes 2-hydroxybenzaldehyde and methyl chloroacetate as raw materials and synthesizes the materials through 5 steps of reactions. The invention provides a brand-new preparation method of the besudil, which has the advantages of short route, low-cost and easily-obtained raw materials, mild conditions, high reaction yield, environment friendliness, easy industrial production and capability of avoiding the use of dangerous drastic drugs and greatly reducing the production cost of Bei Shude mol.

Description

A preparation method of Besudil

Technical Field

The invention relates to besudil, and in particular to a preparation method of besudil.

Background Art

Belumosudil is a selective Rho-associated coiled-coil protein kinase 2 (ROCK2) inhibitor. Clinical studies have confirmed that it has good efficacy and safety in treating cGVHD patients. It was approved for marketing in the United States in 2021 for the treatment of cGVHD. It has been approved for marketing in Canada, Australia, the United Kingdom and other countries for the treatment of cGVHD. Its chemical name is 2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide, CAS registration number: 911417-87-3, and the structural formula is as follows:

After searching with literature search tools such as Reaxys and Scifinder, there are mainly 5 routes. The main strategy is that the raw materials and key intermediates are different, and the length of the routes varies.

WO2014055996 and WO2015157556 disclose that bromoacetyl bromide and propylamine are used as raw materials, and the desired product is obtained by nucleophilic substitution with phenol boron ester, and quinazoline undergoes Lingmu reaction and deprotection, with a total of 5 steps. However, this route uses environmentally unfriendly coupling catalysts, toxic boric esters and expensive 2,4-dihydroquinazoline, and has a high overall cost, which is not suitable for industrial production.

WO2006105081, WO2008054599, WO2010104851 and WO201201040499 disclose another modified route, the steps are consistent with the first 7 steps of WO2014055996, in which tert-butyl bromopropionate is used to introduce an acetic acid group in the 8th step, and the target product is obtained by deprotection and condensation. The economic efficiency of the whole route is worse than that of the first 7 steps of WO2014055996.

WO200854599 uses acyl chloride as a raw material and obtains besudil through as many as 10 steps of reaction. Too many commonly used reagents are used, and the overall yield is low, resulting in excessively high industrial production costs.

Nature, 2023 vol. 623, #7985, p. 77-82 revealed a novel route to obtain besudil in three steps: oxidation, pyrimidation, and condensation. This route has harsh conditions and high raw material costs. The complex processes such as low temperature and oxidation are not conducive to industrial production.

CN106916145 and WO2023/187697 use bromoacetyl bromide and propylamine to obtain besudil through 7 steps. Although the conditions of this route are not harsh and the raw materials are easily available, the reaction steps are long and too much low-boiling dichloromethane solvent is used. The process of preparing acyl chloride by the whole route is not desirable in industrial scale-up.

The technical paths of the above patents have obvious defects: the synthesis route is too long, the raw materials are not easy to obtain, toxic or harsh conditions are used, the atom economy is poor, and it is very unfriendly to the environment.

Summary of the invention

In order to overcome the defects of the existing technical route, the present invention provides a new method for preparing besudil. The specific technical scheme is as follows:

The steps include:

S1: Synthesis of Compound B

Dissolve compound A in an organic solvent, add methyl chloroacetate and a base, and heat to react to obtain compound B;

S2: Synthesis of Compound C

Compound B is added to an organic solvent, sodium sulfite and p-toluenesulfonic acid are added, and heated to react to obtain compound C;

S3: Synthesis of Compound D

Compound C is dissolved in N,N-dimethylformamide, and dichlorothionyl is added at 0-5°C to react to obtain compound D;

S4: Synthesis of Compound E

Compound D and 5-aminoindazole are dissolved in N, N-dimethylformamide, N, N-diisopropylethylamine is added, and heated to react to obtain compound E.

S5: Synthesis of Compound F

Compound E is dissolved in an organic solvent, isopropylamine is added, and the mixture is heated for reaction to obtain compound F, namely besudil.

More specifically:

The solvent used in the synthesis of step S1 is one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, butanone, acetone, tetrahydrofuran, etc., the base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N,N-isopropylethylamine, etc., the molar ratio of compound A: methyl chloroformate: base is 1: 1.05-2.5: 1.5-3; the reaction temperature is 40-90°C.

The method is characterized in that

The solvent used in the synthesis of step S2 is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; the ratio of compound B: sodium sulfite: p-toluenesulfonic acid is 1:1-1.5:0.05-0.25; and the reaction temperature is 100-150°C.

The method is characterized in that

In the synthesis of step S3, the molar ratio of compound C to thionyl chloride is 1:1.2-5.

The method is characterized in that

In the synthesis of step S4, the molar ratio of compound D: 5-aminoindazole: N, N-diisopropylethylamine is 1: 1.05-1.3: 1.5-5. The method is characterized in that:

The organic solvent used in the synthesis of step S5 is one or more of isopropanol, ethanol, butanol, dioxane, dimethyltetrahydrofuran, etc.; the molar ratio of compound E to isopropylamine is 1:3-20; and the reaction temperature is 60-120°C.

Beneficial effects:

1. The total synthesis steps are 5 steps, which is significantly better than the route reported in the literature, and the total synthesis yield is 60% (based on 2-aminoacetaldehyde);

2. The raw materials are cheap, widely available, simple to operate, and have mild reaction conditions. The reagents used are commonly used reagents, and all the reagents are environmentally friendly, which greatly reduces the harm to the human body and the environment.

3. The raw materials are well selected, the groups run through the entire reaction, the cost is reduced, the epoxidation process of compounds B and C is special, and the ultra-high temperature reaction conditions are overcome.

4. This process route has good atom economy and is particularly suitable for industrial production, and can produce besudil in large quantities in a short time.

DETAILED DESCRIPTION

In order to make the purpose, technical scheme and advantages of the present invention clearer, the following specific examples further describe the present invention in detail. The experimental methods in the present invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance of the starting material is generally regarded as the reaction endpoint.

Example 1: A method for preparing compound B is provided, and its synthetic route is as follows:

The specific preparation method is as follows:

In a nitrogen atmosphere, compound A (50 g, 409 mmol) was dissolved in acetonitrile (0.5 L), potassium carbonate (113 g, 819 mmol) was added, and methyl chloroacetate (53.3 g, 491 mmol) was stirred for 30 min. The mixture was heated to 80 ° C and refluxed for 6 h. The raw material was monitored by TLC until it disappeared, filtered, concentrated, and the solvent was recovered to obtain the product. The method was used to prepare a colorless oil, 72 g, with a yield of 92% and a purity of 96.3%.

The intermediate II obtained in this example was identified to obtain the following results:

ESI-MS (m/z): 194.19;

1H NMR (400MHz, CDCl3) δppm 10.02 (s, 1H), 7.53 (m, 1H) 7.49 (t, J=7.8Hz, 1H), 7.37 (dd, J=2.8, 1.6Hz, 1H) 7.24 (ddd, J=8.8, 2.8, 1.6Hz, 1H), 4.74 (s, 2H), 3.85 (s, 3H).

Example 2: A method for preparing compound C is provided, and its synthetic route is as follows:

The specific preparation method is as follows: Compound B: sodium sulfite: p-toluenesulfonic acid in a ratio of 1:1:1

Compound B (150 g, 772 mmol) and aminobenzamide (105 g, 772 mmol) were dissolved in N, N-dimethylacetamide (1.25 L), and sodium sulfite (80.4 g, 772 mmol) and p-toluenesulfonic acid (10 g, 58 mmol) were added. The mixture was heated to 120 °C for 16 h. After HPLC monitoring until the raw material and the intermediate disappeared, the mixture was cooled to room temperature and introduced into 7 L of water. After sufficient stirring, the mixture was filtered. After the filter cake was dried, it was slurried with ethyl acetate/petroleum ether (200 ml/400 ml) to obtain compound C.

The method was used to prepare 184 g of a white solid with a yield of 77% and a purity of 95.2%.

ESI-MS (m/z): 310.10;

¹ H NMR (400MHz, DMSO), 12.52 (s, 1H), 8.16 (d, J=8.0, 1H), 7.90-7.80 (m, 2H), 7.80-7.70 (m, 2H), 7.54 (t, 1H ), 7.48 (t, 1H), 7.18 (dd, J=8.0, J=4.0, 1H), 4.95 (s, 2H), 3.75 (s, 3H).

Example 3: A method for preparing compound D is provided:

Compound C (31.0 g, 0.1 mol) was dissolved in N, N-dimethylformamide (150 ml), and thionyl chloride (35.7 g, 0.3 mol) was added dropwise at 0-5°C. After the addition, the temperature was gradually raised to room temperature for 2 hours. After TLC monitoring, the reaction of the raw material was completed and then introduced into ice water for quenching. After sufficient stirring, the compound D was obtained after filtration.

The method was used to prepare 33 g of a white solid with a yield of 100% and a purity of 95.4%.

ESI-MS(m/z):328.75

¹ H NMR (400MHz, DMSO), 8.18 (d, J=8.0, 1H), 7.90 (dt, 1H), 7.85-7.80 (m, 2H), 7.78-7.72 (m, 2H), 7.57 (t, 1H ), 7.50 (t, 1H), 7.20 (dd, J=8.0, J=4.0, 1H), 4.95 (s, 2H), 3.75 (s, 3H).

Example 4: A method for preparing compound E is provided:

Compound D (33.0 g, 0.100 mol), 5-aminoindazole (14.0 g, 0.105 mmol), and N,N-diisopropylethylamine (38.9 g, 0.301 mol) were dissolved in N,N-dimethylformamide (0.5 L) and heated to 120 °C in a nitrogen atmosphere for 8 h. After TLC monitoring until the reaction of the raw materials was completed, the mixture was poured into water for quenching and slurried with dichloromethane (100 ml) to obtain compound E.

The method was used to prepare 38 g of a white solid with a yield of 89% and a purity of 96.1%.

ESI-MS (m/z): 425.15;

¹ H NMR (400MHz, DMSO) δ13.11 (s, 1H), 9.98 (s, 1H), 8.59 (d, J=8.0, 1H), 8.26 (s,

1H), 8.14 (s, 1H), 8.06 (dd, J=8.0, 1H), 8.00-7.92 (m, 1H), 7.90-7.80 (m, 3H), 7.70-7.55 (m,

2H), 7.40(t, 1H), 7.06(t, 1H), 4.88(s, 2H), 3.65(s, 3H).

Example 5: A method for preparing compound F (besudildil) is provided:

Compound E (17.0 g, 44.0 mmol) was dissolved in isopropanol (170 ml), and isopropylamine (23.6 g, 0.400 mol) was added and heated to 75°C and sealed for reaction for 3 h. After TLC monitoring, the raw material reaction was completed and cooled to room temperature, and then the solvent was removed by concentration. Ethyl acetate (100 ml) was slurried to obtain compound F.

The method was used to prepare 17 g of a light yellow solid with a yield of 94% and a purity of 99.2%.

ESI-MS (m/z): 452.52;

¹ H NMR (400MHz, DMSO) δ13.02 (s, 1H), 8.52 (dd, J=4.0, 1H), 8.25 (s, 1H),

8.09 (s, 1H), 7.99 (s, 1H), 7.96 (dd, J=4.0, 1H), 7.85 (dd, J=4.0, 1H), 7.82-7.74 (m,

3H), 7.65-7.45(m, 2H), 7.35(t, 1H), 7.02(d, J=4.0, 1H), 4.45(s, 3H), 4.00-3.84(m,

1H), 1.04 (d, J=4.0, 6H).

Example 6 provides a method for preparing compound B, and its synthetic route is as follows:

The specific preparation method is as follows:

In a nitrogen atmosphere, compound A (50 g, 409 mmol) was dissolved in N, N-dimethylformamide (0.5 L), potassium carbonate (113 g, 819 mmol) was added, and methyl chloroacetate (53.3 g, 491 mmol) was stirred for 30 min. The mixture was heated to 70 ° C and refluxed for 8 h. The raw material was monitored by TLC until it disappeared and filtered. The solvent was concentrated and recovered to obtain the product. The method was used to prepare a colorless oil, 72 g, with a yield of 87% and a purity of 95.1%.

Example 7: A method for preparing compound C is provided, and its synthetic route is as follows:

The specific preparation method is as follows:

Compound I (150 g, 772 mmol) and aminobenzamide (105 g, 772 mmol) were dissolved in N, N-dimethylacetamide (1.25 L), and sodium sulfite (121 g, 1.16 mol) and p-toluenesulfonic acid (20 g, 116 mmol) were added. The mixture was heated to 120 °C and reacted for 8 h. After HPLC monitoring until the raw material and the intermediate disappeared, the mixture was cooled to room temperature and introduced into 7 L of water. After sufficient stirring, the mixture was filtered. After the filter cake was dried, it was slurried with ethyl acetate/petroleum ether (200 ml/400 ml) to obtain compound C.

The method was used to prepare 123 g of a white solid with a yield of 51% and a purity of 96.7%.

Example 8: A method for preparing compound D is provided:

Compound C (31.0 g, 0.099 mol) was dissolved in N, N-dimethylformamide (150 ml), and thionyl chloride (11.9 g, 0.198 mol) was added dropwise at 0-5°. After the addition, the temperature was gradually raised to room temperature and reacted for 2 h. After TLC monitoring until the raw material stopped, it was poured into ice water for quenching, stirred thoroughly, filtered, and slurried with tert-methyl ether (100 ml) to obtain compound D.

The method was used to prepare 28 g of a white solid with a yield of 85% and a purity of 97.8%.

Example 9: A method for preparing compound E is provided:

Compound D (33.0 g, 0.100 mol), 5-aminoindazole (14.0 g, 0.105 mmol), and N,N-diisopropylethylamine (25.9 g, 0.200 mol) were dissolved in N,N-dimethylformamide (0.5 L) and heated to 120 °C in a nitrogen atmosphere for 8 h. After TLC monitoring until the reaction of the raw materials was completed, the mixture was poured into water for quenching and slurried with dichloromethane (100 ml) to obtain compound E.

The method was used to prepare 33 g of a white solid with a yield of 87% and a purity of 96.3%.

Example 10: A method for preparing compound F (besudildil) is provided:

Compound E (17.0 g, 44.0 mmol) was dissolved in 2-dioxane (170 ml), and isopropylamine (23.6 g, 0.400 mol) was added and heated to 90°C in a sealed container for 2 h. After TLC monitoring, the raw material reaction was completed and the temperature dropped to room temperature, and then the solvent was removed by concentration. Ethyl acetate (100 ml) was used for slurrying to obtain compound F.

The method was used to prepare 16 g of a light yellow solid with a yield of 88% and a purity of 98.5%.

Claims (6)

1. A method for preparing Besudil, characterized in that the method is implemented by the following steps: The steps include: S1: Synthesis of Compound B Dissolve compound A in an organic solvent, add methyl chloroacetate and a base, and heat to react to obtain compound B; S2: Synthesis of Compound C Compound B is added to an organic solvent, sodium sulfite and p-toluenesulfonic acid are added, and heated to react to obtain compound C; S3: Synthesis of Compound D Compound C is dissolved in N,N-dimethylformamide, and dichlorothionyl is added at 0-5°C to react to obtain compound D; S4: Synthesis of Compound E Compound D and 5-aminoindazole are dissolved in N, N-dimethylformamide, N, N-diisopropylethylamine is added, and heated to react to obtain compound E. S5: Synthesis of Compound F Compound E is dissolved in an organic solvent, isopropylamine is added, and the mixture is heated for reaction to obtain compound F, namely besudil. 2. The method according to claim 1, characterized in that The solvent used in the synthesis of step S1 is one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, butanone, acetone, tetrahydrofuran, etc., the base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N,N-isopropylethylamine, etc., the molar ratio of compound A: methyl chloroformate: base is 1: 1.05-2.5: 1.5-3; the reaction temperature is 40-90°C. 3. The method according to claim 1, characterized in that The solvent used in the synthesis of step S2 is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; the ratio of compound B: sodium sulfite: p-toluenesulfonic acid is 1:1-1.5:0.05-0.25; and the reaction temperature is 100-150°C. 4. The method according to claim 1, characterized in that: In the synthesis of step S3, the molar ratio of compound C to thionyl chloride is 1:1.2-5. 5. The method according to claim 1, characterized in that In the synthesis of step S4, the molar ratio of compound D: 5-aminoindazole: N,N-diisopropylethylamine is 1:1.05-1.3:1.5-5. 6. The method according to claim 1, characterized in that The organic solvent used in the synthesis of step S5 is one or more of isopropanol, ethanol, butanol, dioxane, dimethyltetrahydrofuran, etc.; the molar ratio of compound E to isopropylamine is 1:3-20; and the reaction temperature is 60-120°C.