A pytotobrutinib intermediate and a method for preparing the same

Abstract

The application discloses a pyrotuberastine intermediate and a preparation method thereof, and belongs to the technical field of BTK inhibitors. The pyrotuberastine intermediate has a structure shown in formula IV, wherein X is selected from Cl, Br or I. The synthesis method for preparing pyrotuberastine by taking the structure shown in formula IV as a key intermediate is simple and mild, has a short synthesis route, and has a high reaction yield, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of BTK inhibitor technology, and in particular to a pyrobrutinib intermediate and its preparation method. Background Technology

[0002] Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that plays a crucial role in signal transduction of the B-cell antigen receptor (BCR) and other cell surface receptors in both normal and malignant B lymphocytes. Over the past decade, BTK inhibitors have increasingly replaced chemotherapy-based treatment regimens, particularly in the treatment of CLL and mantle cell lymphoma (MCL), where they have proven particularly effective. Furthermore, BTK inhibitors have also been approved for diseases such as small lymphocytic lymphoma and marginal zone lymphoma.

[0003] Currently, BTK inhibitors include first-generation, second-generation, and third-generation (non-covalent) BTK inhibitors. First-generation BTK inhibitors have poor selectivity for BTK and exhibit off-target effects. While second-generation BTK inhibitors have improved selectivity and reduced off-target effects, they have not yet completely improved performance in addressing drug resistance mutations in tumor cells. Therefore, researchers have focused their attention on the development of non-covalent BTK inhibitors.

[0004] Pirtobrutinib is a novel third-generation non-covalent (reversible) BTK inhibitor developed by Eli Lilly and Company. It received accelerated approval from the FDA in January 2023, marketed under the brand name Jaypirca. Pirtobrutinib is the first approved non-covalent BTK inhibitor and the first BTK inhibitor approved for the treatment of mantle cell lymphoma patients who have previously received covalent BTK inhibitor therapy. FDA approval was based on subgroup data from the BRUIN Phase I / II trial, in which 120 MCL patients treated with pirtobrutinib showed an objective response rate of 50% and a complete response rate of 13%. Because pirtobrutinib does not covalently bind to C481, resistance is not affected by C481 mutations. Pirtobrutinib holds promise for overcoming resistance to covalent BTK inhibitors and offers a higher safety profile compared to covalent BTK inhibitors.

[0005] Pytobrutinib has the structure shown in Formula I:

[0006]

[0007] The original research company's patent application WO2022056100A1 discloses a method for preparing pirobrutinib, the synthetic route of which includes the following steps:

[0008]

[0009]

[0010] However, the above synthetic route still has drawbacks such as complicated steps and low overall preparation yield.

[0011] Therefore, researching and developing a novel method for preparing pitobrutinib is of great significance for the widespread application of pitobrutinib. Summary of the Invention

[0012] In view of this, the technical problem to be solved by the present invention is to provide a pyrobrutinib intermediate and a method for preparing the same. The method for preparing pyrobrutinib using the aforementioned pyrobrutinib intermediate has the advantages of simple and mild reaction and high yield.

[0013] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0014] This invention provides a pitobrutinib intermediate having the structure shown in Formula IV:

[0015]

[0016] X is selected from Cl, Br, or I.

[0017] This invention also provides a method for preparing a pitobrutinib intermediate, comprising the following steps:

[0018] 1) The compound of formula II and (1S)-2,2,2-trifluoro-1-methylethyl]hydrazine or its salt are reacted in the presence of a condensing agent to obtain the compound of formula III;

[0019] 2) The compound of formula III was mixed with triphenylphosphine and a halogenated reagent and reacted to obtain the pyrobrutinib intermediate shown in formula IV;

[0020] The halogenated reagent is selected from brominated reagents, chlorinated reagents, or iodinated reagents;

[0021]

[0022] The above-mentioned method for preparing the pyrobrutinib intermediate involves reacting compound II, 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzoic acid, as a starting material to prepare compound III.

[0023] The preparation method of the compound of formula II is as follows:

[0024] 1) Mixing compounds of formula VI and formula VII yields an intermediate compound of formula VIII;

[0025] 2) The intermediate compound VIII obtained in step 1) is reacted with 4-(aminomethyl)benzoic acid or its salt to obtain 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzoic acid, which is compound II.

[0026]

[0027] Preferably, the method for preparing the compound of formula II includes the following steps:

[0028] 1) 5-fluoro-2-methoxybenzoic acid (compound of formula VI), N,N-carbonyldiimidazole (compound of formula VII) and an organic solvent are mixed and reacted to obtain a reaction system S1 containing compound of formula VIII;

[0029] 2) React reaction system S1 with 4-(aminomethyl)benzoic acid or its salt, and after the reaction is completed, acidify the reaction mixture to prepare compound II.

[0030] The reaction temperature in step 1) is preferably 15℃~30℃; more preferably 20℃~30℃.

[0031] The organic solvent in step 1) is preferably one or more of tetrahydrofuran, dichloromethane, acetonitrile, and ethyl acetate; more preferably tetrahydrofuran.

[0032] The preferred salt of 4-(aminomethyl)benzoic acid is sodium 4-(aminomethyl)benzoate.

[0033] In some specific embodiments of the present invention, in step 2) above, a sodium hydroxide solution of 4-(aminomethyl)benzoic acid is used for the reaction, that is, sodium 4-(aminomethyl)benzoate is actually involved in the preparation of compound II.

[0034] The preferred pH value for acidification in step 2) is 5 to 6.

[0035] The preferred acidification reagent is 5N HCl.

[0036] After halogenation, the above-mentioned compound III yields formula IV-1 (X selected from Cl), formula IV-2 (X selected from Br), or formula IV-3 (X selected from I).

[0037] Preferably, the condensing agent in step 1) of this invention is selected from one or more of N,N-carbonyldiimidazole, oxalyl chloride, N,N-dicyclohexylcarbodiimide, and N,N-diisopropylcarbodiimide; more preferably, it is N,N-carbonyldiimidazole or oxalyl chloride.

[0038] Preferably, the halogenated reagent in step 2) of this invention is selected from one or more of carbon tetrachloride, carbon tetrabromide, N-chlorosuccinimide, N-bromosuccinimide, and iodine; more preferably, it is N-chlorosuccinimide, N-bromosuccinimide, or iodine.

[0039] Preferably, in step 1), the molar ratio of compound II and (1S)-2,2,2-trifluoro-1-methylethyl]hydrazine or its salt is 1:(1.0 to 2.0); more preferably, it is 1:1.1.

[0040] Preferably, the molar ratio of the compound of formula II and the condensing agent in step 1) is 1:(1.0 to 2.0); more preferably, it is 1:(1.0 to 1.5). In some specific embodiments of the present invention, it is preferably 1:1.3 or 1:1.2.

[0041] Preferably, the reaction temperature in step 1) is 0℃~50℃; more preferably 10℃~30℃; and even more preferably 15℃~30℃.

[0042] Preferably, the molar ratio of compound III and triphenylphosphine in step 2) is 1:(1.0 to 3.5); more preferably 1:(1.0 to 2.0); and even more preferably 1:1.5.

[0043] Preferably, the molar ratio of the compound of formula III and the halogenated reagent in step 2) is 1:(1.0 to 3.5); more preferably 1:(1.2 to 2.5); and even more preferably 1:1.5.

[0044] Preferably, the reaction temperature in step 2) is 10℃~40℃; more preferably, it is 30℃~40℃.

[0045] The present invention also provides a method for preparing a pyrobrutinib intermediate, wherein the pyrobrutinib intermediate shown in Formula V is prepared by reacting a compound of Formula IV with malononitrile and a base.

[0046]

[0047] X is selected from Cl, Br, or I.

[0048] The compounds of formula IV-1, IV-2 or IV-3 above react with malononitrile in the presence of a basic catalyst to obtain the pyrobrutinib intermediate shown in formula V.

[0049] Preferably, the alkali is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, and sodium ethoxide; more preferably, it is selected from one or more of triethylamine, N,N-diisopropylethylamine, and pyridine. In some specific embodiments of the present invention, N,N-diisopropylethylamine is preferred.

[0050] Preferably, the molar ratio of the compound of formula IV to malononitrile is 1:(1.0 to 2.5); more preferably, it is 1:(1.1 to 2). In some specific embodiments of the present invention, it is preferably 1:1.1, 1:1.5, or 1:2.

[0051] Preferably, the molar ratio of the compound of formula IV to the base is 1:(1.0 to 2.5); more preferably, it is 1:(1.2 to 2.5). In some specific embodiments of the present invention, it is preferably 1:1.5, 1:2, or 1:2.5.

[0052] Preferably, the reaction temperature is 15℃~30℃; more preferably, it is 20℃~30℃.

[0053] The present invention also provides a pyrobrutinib prepared by reacting a pyrobrutinib intermediate obtained by the above preparation method with an acid.

[0054] The structure of pitobrutinib is shown in Formula I:

[0055]

[0056] Preferably, the acid is selected from one or more of methanesulfonic acid, sulfuric acid, and p-toluenesulfonic acid.

[0057] Preferably, the reaction temperature for preparing pitobrutinib from the pitobrutinib intermediate and acid is 50°C to 100°C. In some specific embodiments of the present invention, 85°C is preferred.

[0058] The method for preparing pyrobrutinib includes reacting a mixture of compound V, MsOH, and water.

[0059] The above-mentioned method for preparing pyrobrutinib includes post-treatment processes such as quenching, extraction, concentration, and recrystallization after the reaction is completed.

[0060] The present invention does not impose any particular limitation on the solvents used for quenching, extraction, and recrystallization, but uses solvents that are well known to those skilled in the art.

[0061] In this invention, preferably, the quenching solvent is selected from a mixed solution of water and ammonia.

[0062] The volume of water is preferably 100 mL.

[0063] The concentration of the ammonia solution is 28 wt%, and the volume is 200 mL.

[0064] Preferably, the solvent used for extraction is selected from ethyl acetate.

[0065] Preferably, the solvent for recrystallization is selected from a mixture of aqueous ethanol and n-heptane.

[0066] Compared with existing technologies, the pyrobrutinib intermediate provided by this invention has the structure shown in Formula IV, wherein X is selected from Cl, Br, or I. The synthetic method for preparing pyrobrutinib using the structure shown in Formula IV as a key intermediate is simple, mild, has a short synthetic route, and high reaction yield, making it suitable for large-scale industrial production. Attached Figure Description

[0067] Figure 1 The 1H NMR spectrum of the compound of formula IV-1 prepared in Example 3;

[0068] Figure 2 The 1H NMR spectrum of Pirtobrutinib prepared in Example 9. Detailed Implementation

[0069] To further illustrate the present invention, the preparation method of the pyrobrutinib intermediate provided by the present invention will be described in detail below with reference to the embodiments.

[0070] Example 1

[0071] Synthesis of Compounds of Formula III

[0072] 30.3 g (0.1 mol) of 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzoic acid, 21.1 g (0.13 mol) of N,N-carbonyldiimidazole (CDI, 21.1 g, 0.13 mol), and 250 mL of tetrahydrofuran were added to a three-necked flask, and the reaction was carried out at 15–30 °C for 1.5 h. Then, 18.1 g (0.11 mol) of (1S)-2,2,2-trifluoro-1-methylethyl]hydrazine hydrochloride was added, and the reaction continued for another 2 h. After the reaction was complete, 750 mL of water was added, and a large amount of solid precipitated. The solid was filtered, the filter cake was washed with water, and dried to obtain compound III (38.4 g, 93% yield), Msm / z 414.19 (M+1), 827.31 (2M+1).

[0073] Example 2

[0074] Synthesis of Compounds of Formula III

[0075] 30.3 g (0.1 mol) of 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzoic acid and 250 mL of dichloromethane were added to a three-necked flask. The temperature was lowered to 0–10 °C, and oxalyl chloride (15.2 g, 0.12 mL) was added dropwise. After the addition was complete, the reaction was maintained at 10–30 °C for 3 hours. The solvent and excess oxalyl chloride were concentrated under reduced pressure. Then, 100 mL of tetrahydrofuran and (1S)-2,2,2-trifluoro-1-methylethyl]hydrazine hydrochloride (18.1 g, 0.11 mol) were added, and the reaction was continued for 2 hours. 100 mL of water was added dropwise, and the mixture was extracted and separated. The organic phase was concentrated under reduced pressure until no fraction remained. 200 mL of tetrahydrofuran was added to dissolve the solid, and 600 mL of water was added dropwise, resulting in the precipitation of a large amount of solid. The mixture was filtered, the filter cake was washed with water and dried to obtain compound III (35.5 g, yield 86%), Ms m / z 414.19 (M+1), 827.31 (2M+1).

[0076] Example 3

[0077] Synthesis of Compound IV-1

[0078]

[0079] Compound III (20.7 g, 0.05 mol), triphenylphosphine (19.7 g, 0.075 mol), and 200 mL of dichloromethane were added to a three-necked flask. A solution of N-chlorosuccinimide (10.0 g, 0.075 mol) and 20 mL of dichloromethane was added dropwise at 0–10 °C. After the addition was complete, the reaction was carried out at 30–40 °C for 3 hours. After the reaction was complete, the solution was concentrated under reduced pressure until no fraction remained. The resulting product, purified by silica gel column chromatography, was compound IV-1 (19.9 g, 92% yield). Ms m / z 432.14 (M+1), 863.20 (2M+1).

[0080] Example 4

[0081] Synthesis of Compound IV-2

[0082]

[0083] Compound III (20.7 g, 0.05 mol), triphenylphosphine (19.7 g, 0.075 mol), and 200 mL of dichloromethane were added to a three-necked flask. A solution of N-bromosuccinimide (13.3 g, 0.075 mol) and 20 mL of dichloromethane was added dropwise, controlled at 0–10 °C. After the addition was complete, the reaction was carried out at 30–40 °C for 3 hours. After the reaction was complete, the solution was concentrated under reduced pressure until no fraction remained, yielding compound IV-2, which was directly used in the next reaction. Ms m / z 477.26 (M+1), 953.46 (2M+1).

[0084] Example 5

[0085] Synthesis of Compound IV-3

[0086]

[0087] Compound III (20.7 g, 0.05 mol), triphenylphosphine (19.7 g, 0.075 mol), and 200 mL of dichloromethane were added to a three-necked flask. A solution of iodine (19.0 g, 0.075 mol) and 20 mL of dichloromethane was added dropwise at 0–10 °C. After the addition was complete, the reaction was carried out at 30–40 °C for 3 hours. After the reaction was complete, the solution was concentrated under reduced pressure until no fraction remained, yielding compound IV-3, which was directly used in the next reaction. Ms m / z 524.19 (M+1), 1047.38 (2M+1).

[0088] Example 6

[0089] Synthesis of compound V

[0090] Compound IV-1 (21.6 g, 0.05 mol) and malononitrile (3.6 g, 0.055 mol) were added to acetonitrile (200 mL) to give a mixture. This mixture was then added dropwise to acetonitrile (200 mL) and N,N-diisopropylethylamine (9.7 g, 0.075 mol), and stirred at 20–30 °C for 6 hours. The mixture was concentrated under reduced pressure, crystallized from ethanol and water, filtered, and the filter cake was collected and dried under vacuum at 50 °C to give a grayish-white solid (20.2 g, yield 87.5%). Ms m / z 462.19 (M+1), 923.48 (2M+1).

[0091] Example 7

[0092] Synthesis of compound V

[0093] Acetonitrile (200 mL) and malononitrile (4.95 g, 0.075 mol) were added to a 0.05 mol concentrate of compound IV-2 to dissolve the concentrate, yielding a mixture. This mixture was then added dropwise to acetonitrile (200 mL) and N,N-diisopropylethylamine (12.9 g, 0.1 mol), and stirred at 20–30 °C for 6 hours. The mixture was concentrated under reduced pressure, crystallized from ethanol and water, filtered, and the filter cake was collected and dried under vacuum at 50 °C to give a grayish-white solid (20.6 g, yield 89.5%). Ms m / z 462.19 (M+1), 923.48 (2M+1).

[0094] Example 8

[0095] Synthesis of compound V

[0096] Acetonitrile (200 mL) and malononitrile (6.6 g, 0.1 mol) were added to a 0.05 mol concentrate of compound IV-3 to dissolve the concentrate, yielding a mixture. This mixture was then added dropwise to acetonitrile (200 mL) and N,N-diisopropylethylamine (16.2 g, 0.125 mol), and stirred at 20–30 °C for 6 hours. The mixture was concentrated under reduced pressure, crystallized from ethanol and water, filtered, and the filter cake was collected and dried under vacuum at 50 °C to give a grayish-white solid (20.4 g, yield 88.5%). Ms m / z 462.19 (M+1), 923.48 (2M+1).

[0097] Example 9

[0098] Synthesis of 5-amino-3-[4-[[5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyrazole-4-carboxamide (Pirtobrutinib)

[0099] Compound N-[[4-[(1S)-5-amino-4-cyano-1-(2,2,2-trifluoro-1-methyl-ethyl)pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide (20 g, 43.4 mmol), MsOH (80 mL, 1220 mmol), and water (1.5 g, 83.3 mmol) of formula V were added together and stirred. The mixture was then added to 85 °C for 6 hours. The temperature was lowered to 0–10 °C, and a solution of water (100 mL) and ammonia (28 wt%, 200 mL) was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (200 mL × 3), and the organic phase was washed with water (100 mL × 3). The solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from anhydrous ethanol and n-heptane. The solid was filtered and dried to constant weight below 50 °C to give the target compound (17.5 g, yield 84%). Ms m / z 480.2(M+1).

[0100] Example 10

[0101] Preparation of 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzoic acid

[0102] 17.0 g of 5-fluoro-2-methoxybenzoic acid, 16.2 g of N,N-carbonyldiimidazole (CDI), and 100 mL of tetrahydrofuran were added to a three-necked flask and reacted at 20 °C for 1.5 h. 15.1 g of 4-(aminomethyl)benzoic acid was added to 100 mL of 1.0 mol / L sodium hydroxide solution and set aside. The sodium hydroxide solution of 4-(aminomethyl)benzoic acid was added dropwise to the reaction mixture and reacted at 30 °C for 5 h. The pH was adjusted to 5-6 with 5N HCl, filtered, the filter cake was washed with water, and dried to obtain 28.2 g of 4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]benzoic acid compound, with a yield of 93%, a purity of over 98%, and Ms m / z 304.2 (M+1) and 607.3 (2M+1).

[0103] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A pitobrutinib intermediate, characterized in that, It has the structure shown in Equation IV: Formula IV; X is selected from Cl, Br, or I.

2. The method for preparing the pyrobrutinib intermediate according to claim 1, characterized in that, Includes the following steps: 1) The compound of formula II is reacted with (1S)-2,2,2-trifluoro-1-methylethyl]hydrazine or its salt in the presence of a condensing agent to obtain the compound of formula III; 2) The compound of formula III was mixed with triphenylphosphine and a halogenated reagent and reacted to obtain the pyrobrutinib intermediate shown in formula IV; The halogenated reagent is selected from brominated reagents, chlorinated reagents, or iodinated reagents; Formula II Formula III Formula IV.

3. The preparation method according to claim 2, characterized in that, The condensing agent in step 1) is selected from one or more of N,N-carbonyldiimidazole, oxalyl chloride, N,N-dicyclohexylcarbodiimide, and N,N-diisopropylcarbodiimide.

4. The preparation method according to claim 2, characterized in that, The halogenated reagent in step 2) is selected from one or more of carbon tetrachloride, carbon tetrabromide, N-chlorosuccinimide, N-bromosuccinimide, and iodine.

5. The preparation method according to claim 2, characterized in that, The molar ratio of compound II in step 1) to (1S)-2,2,2-trifluoro-1-methylethyl]hydrazine or its salt is 1:(1.0~2.0). The molar ratio of compound II and condensing agent in step 1) is 1:(1.0~2.0). The reaction temperature in step 1) is 0℃~50℃; The molar ratio of compound III and triphenylphosphine in step 2) is 1:(1.0~3.5). The molar ratio of the compound of formula III and the halogenated reagent in step 2) is 1:(1.0~3.5). The reaction temperature in step 2) is 10℃~40℃.

6. A method for preparing a pitobrutinib intermediate, characterized in that, The intermediate of pyrobrutinib shown in formula V was prepared by reacting a compound of formula IV with malononitrile and a base. Formula IV Formula V; X is selected from Cl, Br, or I.

7. The preparation method according to claim 6, characterized in that, The base is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, and sodium ethoxide.

8. The preparation method according to claim 6, characterized in that, The molar ratio of the compound of formula IV to malononitrile is 1:(1.0~2.5). The molar ratio of the compound of formula IV to the base is 1:(1.0~2.5). The reaction temperature is 15℃~30℃.

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