Preparation method of besudil

Abstract

The invention relates to a preparation method of besudil, and belongs to the technical field of organic chemistry. The preparation method of besudil comprises the following steps: (1) preparing an intermediate III under the catalysis of copper chloride by taking m-hydroxybenzaldehyde and 2-aminobenzamide as raw materials; (2) preparing an intermediate II from the intermediate III and 2-hydroxy-N-isopropylacetamide under the catalysis of DIAD and triphenylphosphine; (3) reacting the intermediate II with thionyl chloride to obtain an intermediate I; and (4) reacting the intermediate I with 5-amino indazole to obtain besudil. According to the preparation method, cheap m-hydroxybenzaldehyde and 2-aminobenzamide are adopted as starting materials, and construction of a molecular skeleton can be completed through four-step reaction. The whole route has few side reactions, the intermediate can be separated out in water and alcohol, the solvent cost is greatly reduced, and industrialized large-scale production is facilitated.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemistry, and specifically relates to a preparation method of besuldiol. Background Art

[0002] Besuldiol, with the chemical name of 2-[3-[4-[(1H-indazol-5-yl)amino]quinazolin-2-yl]phenoxy]-N-isopropylethanamide, is an organic compound with the chemical formula C 26 H 24 N6O2, is a white crystalline powder and can be made into an oral drug for the treatment of chronic graft-versus-host disease (cGVHD). cGVHD is a severe and life-threatening complication that may occur in patients who have received stem cell transplantation. Besuldiol is a tyrosine kinase inhibitor that works by blocking the activity of certain enzymes involved in regulating the immune response. In cGVHD, this immune response attacks the patient's own body, causing organ damage. By blocking these enzymes, besuldiol can help inhibit the immune response and relieve the symptoms of cGVHD. After treatment, the condition improves significantly, and it is generally safe and well-tolerated.

[0003] Regarding the synthesis of besuldiol, there are the following several synthesis routes:

[0004] (1) The routes disclosed in patents WO2014055996 and WO2015157556:

[0005]

[0006] (2) The routes disclosed in patents WO2006105081, WO2008054599, WO2010104851, and WO200854599:

[0007]

[0008] (3) The routes disclosed in patents CN106916145A and WO2023187697:

[0009]

[0010] (4) The route disclosed in patent CN118791471A:

[0011]

[0012] The above routes are several existing methods for synthesizing besuldiol. Among them, routes (1) to (4) all use haloacetylated compounds or haloacetamidated compounds (such as bromoacetyl bromide, 2-bromo-N-isopropylethanamide, tert-butyl bromoacetate, methyl chloroacetate, methyl chloroacetate, etc.). Such compounds are extremely irritating, have extremely strong tear-inducing properties, and cause red rashes even with slight skin contact, posing a great threat to the safety of operators in actual production. Moreover, routes (1) and (2) are relatively long, with cumbersome operations, and some of the materials are not easily obtainable, resulting in a low overall yield. Route (3) involves ring-closing to synthesize quinazolinone amide compounds in the latter half of the process route, while the purification of the intermediate in the first half is rather cumbersome, time-consuming, laborious, and solvent-consuming. Additionally, potential impurities will generate many impurities along with the route, increasing the difficulty of controlling the quality of the finished product. Although route (4) shortens the reaction route, strongly irritating haloacetamidated compounds are still used in the reactants. Summary of the Invention

[0013] Aiming at the technical problems of the existing synthesis of besuldiol, such as long synthesis routes and the use of raw materials with strong irritation, the present invention provides a preparation method of besuldiol to solve the above problems. The present invention uses inexpensive m-hydroxybenzaldehyde and 2-aminobenzamide as starting materials to prepare the core of quinazolinone amide, and then introduces two side chains through Mitsnobu etherification reaction and the reaction of aryl halide being substituted by ammonia. The construction of the molecular skeleton can be completed in a total of four steps. At the same time, strongly irritating raw materials are no longer used in the reaction. There are few side reactions in the whole route. The intermediate can precipitate in both water and alcohol, greatly reducing the solvent cost. Moreover, there is no need for excessive concentration and extraction operations, and it is easy to purify. The quality of the intermediate and besuldiol is easy to control, reducing the production risk.

[0014] The technical solution of the present invention is as follows:

[0015] A preparation method of besuldiol, the reaction formula is as follows:

[0016]

[0017] It includes the following steps:

[0018] (1) Using m-hydroxybenzaldehyde and 2-aminobenzamide as raw materials, prepare intermediate III under the catalysis of copper chloride.

[0019] (2) Intermediate III reacts with 2-hydroxy-N-isopropylethanamide under the catalysis of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine to prepare intermediate II.

[0020] (3) Intermediate II reacts with thionyl chloride to obtain intermediate I.

[0021] (4) Intermediate I reacts with 5-aminoindazole to obtain besuldiol.

[0022] Further, step (1) is as follows: Add m-hydroxybenzaldehyde, 2-aminobenzamide, ethanol and copper chloride into a reactor, stir evenly and then reflux for reaction; After detecting that m-hydroxybenzaldehyde has completely reacted by TLC, cool down to 0-5°C; Perform solid-liquid separation, wash the solid with water and dry it to obtain intermediate III.

[0023] Further, the molar ratio of m-hydroxybenzaldehyde, 2-aminobenzamide and copper chloride is 1:(1.1-1.2):(0.1-0.2).

[0024] Further, step (2) is as follows: Add intermediate III, 2-hydroxy-N-isopropylacetamide, triphenylphosphine and tetrahydrofuran into a reactor, protect with nitrogen, and cool the reaction system below 0°C; Dropwise add DIAD; After the dropwise addition, react, and after detecting that intermediate III has completely reacted by TLC, concentrate the reaction system; Then add the concentrated solution into water, perform solid-liquid separation, wash the solid with water and then slurry it with ethanol, and dry it to obtain intermediate II.

[0025] Further, the molar ratio of intermediate III, 2-hydroxy-N-isopropylacetamide, triphenylphosphine and DIAD is 1:(1.05-1.1):(1.2-1.3):(1.2-1.3).

[0026] Further, step (3) is as follows: Add intermediate II, thionyl chloride, dichloromethane and DMF into a reactor, heat and reflux for reaction, and monitor the complete reaction of intermediate II by TLC; Concentrate the reaction solution to obtain intermediate I.

[0027] Further, the molar ratio of intermediate II to thionyl chloride is 1:1.1-1.2.

[0028] Further, step (4) is as follows: Add intermediate I, DMF and sodium bicarbonate into a reactor, stir evenly and then add 5-aminoindazole, heat to 75-80°C for reaction, cool down after detecting the complete reaction of intermediate I by TLC, and then add the reaction system into water, perform solid-liquid separation to obtain besuldiol.

[0029] Further, step (4) also includes adding absolute ethanol for recrystallization to the solid after solid-liquid separation to obtain besuldiol.

[0030] Further, the molar ratio of 5-aminoindazole to intermediate II is 0.95-1:1.

[0031] The beneficial effects of the present invention are as follows:

[0032] The preparation method of the present invention uses inexpensive m-hydroxybenzaldehyde and 2-aminobenzamide as starting materials to prepare the quinazoline lactam nucleus, and then introduces two branched chains through Mitsnobu etherification reaction and amination reaction of aryl halides. The construction of the molecular skeleton can be completed in a total of four steps. There are few side reactions in the whole route, and the intermediates can precipitate out in both water and alcohol, greatly reducing the solvent cost. Moreover, there is no need for excessive concentration and extraction operations, and it is easier to purify. The quality of the intermediates and besuldiol is easy to control, reducing the production risk. At the same time, the conversion rate of each step of the reaction is high, the reaction time is short, the post-treatment of the production process is simple, it is easy to recycle the solvent and treat the wastewater, reducing the solvent consumption and energy consumption cost, and is more conducive to large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, for those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0034] Figure 1 It is the HNMR spectrum of Intermediate III in Example 1 of the present invention.

[0035] Figure 2 It is the HNMR spectrum of Intermediate II in Example 2 of the present invention.

[0036] Figure 3 It is the UPLC spectrum of besuldiol in Example 4 of the present invention.

[0037] Figure 4 It is the HNMR spectrum of besuldiol in Example 4 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0038] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0039] Example 1

[0040] Preparation of Intermediate III (2-(3-hydroxyphenyl)quinazolin-4(3H)-one)

[0041]

[0042] Into a 50 L reactor, 12.2 kg of absolute ethanol was added, followed by 1.22 kg (10 mol) of m-hydroxybenzaldehyde, 1.50 kg (11 mol) of 2-aminobenzamide, and 0.15 kg (1 mol) of CuCl₂·2H₂O. After mixing evenly, the mixture was refluxed for 24 hours. The color of the reaction system changed from blue to white turbidity first, and then to dark green with solid precipitation. TLC monitoring showed that the m-hydroxybenzaldehyde reaction was complete. The reaction system was cooled to 0 - 5 °C and crystallized for 2 h. After filtration, the filter cake was washed with water and dried by blowing air to obtain 2.12 kg of off-white solid intermediate III, with a yield of 89.1%. Melting point: 254.3 - 255.1 °C, and the nuclear magnetic purity > 97%.

[0043] 1 H NMR: (400 MHz, DMSO-d6): δH 12.45 (s, 1H), 9.77 (s, 1H), 8.15 (d, 1H), 7.84 (m, 1H), 7.72 (d, 1H), 7.62 (t, 1H), 7.52 (t, 2H), 7.34 (t, 1H), 6.98 (t, 1H).

[0044] Example 2

[0045] Preparation of Intermediate II (N-isopropyl-2-(3-(4-quinazolin-2-yl)phenoxy)acetamide)

[0046]

[0047] Into a 100 L reactor, 21.00 kg of dried tetrahydrofuran was added. Under nitrogen exchange, 1.00 kg (8.54 mmol) of 2-hydroxy-N-isopropylacetamide, 2.10 kg (8.15 mol) of Intermediate II, and 2.56 kg (9.78 mmol) of triphenylphosphine were added to the reactor. The reaction system was cooled to below 0 °C. Then, 1.98 kg (9.78 mol) of DIAD was added dropwise. After the addition was complete, the reaction was carried out for 1 h. After TLC (petroleum ether:ethyl acetate / 1:1) monitoring showed that the reaction of Intermediate II was complete, most of the tetrahydrofuran was removed by distillation under reduced pressure. Then, the concentrated solution was added to 50 L of water in batches, and solid precipitated. After centrifugation, the filter cake was washed with water. Then, the solid was added to 10 kg of absolute ethanol, stirred for 1 h, centrifuged, washed with 1 kg of absolute ethanol, and dried in vacuo at 40 °C for 6 h to obtain 2.37 kg of off-white solid Intermediate II, with a yield of 79.8%, and the nuclear magnetic purity > 97%.

[0048] 11H NMR: (400 MHz, CDCl3): δH 11.67 (s, 1H), 8.35 (s, 1H), 7.84 - 7.93 (m, 4H), 7.56 (m, 2H), 6.47 (d, 1H), 4.66 (s, 2H), 4.25 (m, 1H), 1.25 (d, 6H).

[0049] Example 3

[0050] Preparation of Intermediate I (2-(3-(4-chloroquinazolin-2-yl)phenoxy)-N-isopropylethanamide)

[0051]

[0052] Add 30 kg of dichloromethane to a 50 L reactor, then add 2.04 kg (6.05 mol) of Intermediate II, 792 g (6.65 mol) of thionyl chloride and 50 g of DMF, and reflux the reaction until it becomes clear. Monitor the reaction of Intermediate II by TLC (petroleum ether: ethyl acetate / 1:1) until it is completely reacted; Concentrate the reaction system under reduced pressure to dryness, then add 5 kg of dichloromethane and concentrate until there are no obvious droplets to obtain a pale yellow solid Intermediate I, which is directly used in the next step.

[0053] Example 4

[0054] Preparation of besudil

[0055]

[0056] To the Intermediate I prepared in Example 3, add 10 kg of DMF and 0.51 kg (6.07 mol) of sodium bicarbonate, stir evenly, then add 0.77 kg (5.75 mol) of 5-aminoindazole, and react at 75 - 80 °C; Monitor the reaction of Intermediate I by TLC (petroleum ether: ethyl acetate / 1:1) until it is completely reacted; Cool the reaction system to room temperature; Then add the reaction solution to a 100 L reactor containing 50 kg of water, stir rapidly for 1 h and then centrifuge. The filter cake is added with 6 kg of absolute ethanol, refluxed until clear and then filtered while hot. Cool to -5 - 0 °C and crystallize for 2 h, then centrifuge. The filter cake is dried under vacuum at 40 °C for 6 h to obtain 2.01 kg of off-white solid besudil. The two-step yield is 73.4%, and the total yield is 52.2%. The purity detected by UPLC is 100%.

[0057] 11H NMR (400 MHz, DMSO): 13.10 (br, 1H), 9.96 (br, 1H), 8.59 (d, 1H), 8.32 (s, 1H), 8.16 (s, 1H), 8.06 - 8.04 (m, 2H), 7.97 - 7.96 (m, 1H), 7.87 - 7.84 (m, 1H), 7.66 - 7.61 (m, 2H), 7.44 - 7.40 (m, 1H), 7.09 - 7.07 (m, 1H), 4.52 (s, 2H), 4.03 - 3.94 (m, 1H), 1.11 (d, 6H).

[0058] Although the present invention has been described in detail by referring to the accompanying drawings and in conjunction with the preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, those of ordinary skill in the art can make various equivalent modifications or substitutions to the embodiments of the present invention, and all such modifications or substitutions should fall within the scope of the present invention. / Any person skilled in the art within the technical scope disclosed by the present invention can easily conceive of changes or substitutions, which should all be covered within the protection scope of the present invention.

Claims

1. A preparation method of besuldiol, characterized in that, The reaction formula is as follows: It includes the following steps: (1) Using m-hydroxybenzaldehyde and 2-aminobenzamide as raw materials, prepare intermediate III under the catalysis of copper chloride; (2) React intermediate III with 2-hydroxy-N-isopropylacetamide under the catalysis of DIAD and triphenylphosphine to prepare intermediate II; (3) React intermediate II with thionyl chloride to obtain intermediate I; (4) React intermediate I with 5-aminoindazole to obtain besudil.

2. The preparation method of besudil according to claim 1, wherein, Step (1) is: Add m-hydroxybenzaldehyde, 2-aminobenzamide, ethanol and copper chloride into the reactor, stir evenly and then reflux for reaction; After detecting that m-hydroxybenzaldehyde has completely reacted by TLC, cool down to 0-5 °C; Perform solid-liquid separation, wash the solid with water and dry it to obtain intermediate III.

3. The preparation method of besudil according to claim 2, wherein, The molar ratio of m-hydroxybenzaldehyde, 2-aminobenzamide and copper chloride is 1:(1.1-1.2):(0.1-0.2).

4. The preparation method of besudil according to claim 1, characterized in that, Step (2) is: Add intermediate III, 2-hydroxy-N-isopropylacetamide, triphenylphosphine and tetrahydrofuran into the reactor, protect with nitrogen, and cool the reaction system below 0 °C; Dropwise add DIAD; After the dropwise addition, react. After detecting that intermediate III has completely reacted by TLC, concentrate the reaction system; Then add the concentrated solution into water, perform solid-liquid separation, wash the solid with water, slurry it with ethanol, and dry it to obtain intermediate II.

5. The preparation method of besudil according to claim 4, characterized in that, The molar ratio of intermediate III, 2-hydroxy-N-isopropylacetamide, triphenylphosphine and DIAD is 1:(1.05-1.1):(1.2-1.3):(1.2-1.3).

6. The preparation method of besudil as described in claim 1, characterized in that, Step (3) is: Add intermediate II, thionyl chloride, dichloromethane and DMF into the reactor, heat and reflux for reaction, and detect that intermediate II has completely reacted by TLC; Concentrate the reaction solution to obtain intermediate I.

7. The preparation method of besudil according to claim 6, characterized in that, The molar ratio of intermediate II to thionyl chloride is 1:1.1-1.

2.

8. The preparation method of besudil as claimed in claim 1, characterized in that, Step (4) is: Add intermediate I, DMF and sodium bicarbonate into the reactor, stir evenly, then add 5-aminoindazole, heat to 75-80 °C for reaction, cool down after detecting that intermediate I has completely reacted by TLC, and then add the reaction system into water, perform solid-liquid separation to obtain besudil.

9. The preparation method of besudil according to claim 8, characterized in that, Step (4) also includes the step of adding anhydrous ethanol for recrystallization to the solid after solid-liquid separation.

10. The preparation method of besudil according to claim 8, characterized in that, The molar ratio of 5-aminoindazole to intermediate II is 0.95-1:1.

Images