Method for preparing EGFR (epidermal growth factor receptor) inhibitor under catalysis of lewis acid

Abstract

The invention discloses a method for preparing an EGFR inhibitor through catalysis of lewis acid. The invention provides a novel preparation method of the compound as shown in the formula (I), and the method is high in yield, high in purity of the obtained product, stable in reaction on a large scale and more suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and specifically discloses a method for preparing an EGFR inhibitor catalyzed by a Lewis acid. Background Art

[0002] WO2021208918A1 discloses a small molecule EGFR inhibitor against the C797S mutation, the structure of which is shown in formula (I), and the chemical name is N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide. This small molecule inhibitor has good kinase inhibitory activity and cell anti-proliferation activity. At the same time, this molecule shows good anti-tumor activity and tolerance in a mouse model and is expected to be developed into a clinical drug.

[0003]

[0004] CN202310709282.1 discloses a preparation method of the compound shown in the above formula (I), which is characterized in that the compound of formula (VIII) is used as a raw material and is prepared by the following method:

[0005]

[0006]

[0007] Compared with the previously disclosed technologies, the synthetic route disclosed in the above invention reduces the usage amount of the expensive raw material, the compound of formula (III). To produce the compound of formula (I) of the same quality, the usage amount of the raw material, the compound of formula (III), can be reduced by half, greatly improving the atom economy of the whole route and effectively reducing the production cost. At the same time, this route also effectively reduces the generation amount of related debromination impurities, greatly reducing the purification difficulty of the final product and improving the purity of the final product, the compound of formula (I).

[0008] In the above route, a protonic acid catalyst such as methylbenzenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc. is used in the reaction process of the compound of formula (II) and the compound of formula (II-A). We found that in the industrial scale-up process of this step reaction, as the scale increases, the reaction solution becomes viscous and pitchy, and almost no target product can be obtained, increasing the probability of failure. Analyzing the reason may be that a large amount of acid catalyst releases protons during the feeding process, resulting in too high a local concentration, thereby causing a series of polymerization reactions to occur, leading to the failure of the reaction. Therefore, it is particularly important to explore a new, scalable and more suitable industrial production method for the preparation of the compound of formula (I). Summary of the Invention

[0009] The present invention aims to provide a new method for preparing a compound of formula (I) by Lewis acid catalysis, which method has a high yield, high purity of the obtained product, and is more suitable for industrial scale-up, specifically as follows:

[0010] The present invention provides a method for preparing a compound of formula (I), which is characterized in that it is prepared from a compound of formula (II) and a compound of formula (II-A) in the presence of a Lewis acid catalyst and a reaction solvent:

[0011]

[0012] Wherein, R1 is selected from trifluoromethanesulfonyl, methanesulfonyl, p-toluenesulfonyl, phenylsulfinyl, p-toluenesulfinyl, methylsulfinyl, ethylsulfinyl, tert-butylsulfinyl or halogen; preferably, R1 is selected from halogen, and more preferably, R1 is selected from chlorine.

[0013] In some embodiments of the present invention, during the reaction of the compound of formula (II) and the compound of formula (II-A), the Lewis acid is selected from one or more of aluminum trichloride, boron trifluoride, sulfur trioxide, niobium pentachloride, antimony pentafluoride, iron(III) chloride, copper(II) chloride, zinc chloride, copper(II) bromide, copper(II) sulfate, iron(III) bromide; preferably, the Lewis acid is selected from zinc chloride.

[0014] In some embodiments of the present invention, during the reaction of the compound of formula (II) and the compound of formula (II-A), the reaction solvent is selected from one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyl isobutyl ketone, dioxane, sulfolane; preferably, the reaction solvent is selected from N-methylpyrrolidone.

[0015] In some embodiments of the present invention, during the reaction of the compound of formula (II) and the compound of formula (II-A), the molar ratio of the compound of formula (II) to the Lewis acid is 1:1.0 - 1:5.0, preferably, the molar ratio of the compound of formula (II) to the Lewis acid is 1:2.5.

[0016] In some embodiments of the present invention, during the reaction of the compound of formula (II) and the compound of formula (II-A), the molar ratio of the compound of formula (II) to the compound of formula (II-A) is 1:1.0 - 1.5:1.0, preferably, the molar ratio of the compound of formula (II) to the compound of formula (II-A) is 1.2:1.0.

[0017] In some embodiments of the present invention, during the reaction of the compound of formula (II) with the compound of formula (II-A), the weight-to-volume ratio of the compound of formula (II-A) to the selected solvent is 1:5.0 g / mL - 1:20.0 g / mL. Preferably, the weight-to-volume ratio of the compound of formula (II-A) to the selected solvent is 1:10.0 g / mL.

[0018] In some embodiments of the present invention, the compound of formula (II) reacts with the compound of formula (II-A) at 80 - 120 °C. Preferably, the reaction occurs at 100 ± 5 °C.

[0019] The compound of formula (I) is prepared from the compound of formula (II) and the compound of formula (II-A) in the presence of a Lewis acid and a reaction solvent, wherein the Lewis acid is selected from zinc chloride; the reaction solvent is selected from N-methylpyrrolidone; preferably, the molar ratio of the compound of formula (II) to zinc chloride is 1:2.5; the molar ratio of the compound of formula (II) to the compound of formula (II-A) is 1.2:1.0; the weight-to-volume ratio of the compound of formula (II-A) to the selected solvent is 1:10.0 g / mL; the reaction temperature is 100 ± 5 °C.

[0020] Technical effects

[0021] The method for preparing the compound of formula (I) catalyzed by the Lewis acid provided by the present invention, compared with the prior art, does not produce protonic acid during the catalysis process, the reaction conditions are milder, the reaction process is more controllable, the risk of scale-up production is lower, and it is more suitable for industrial production. At the same time, compared with the original technology, the yield of this method is increased by about 10%, the generation of related debromination impurities is effectively reduced, no isomeric impurities are generated, the purity of the final product, the compound of formula (I), is improved, and the purification difficulty of the final product is greatly reduced.

[0022] Definitions and explanations

[0023] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indefinite or unclear without a special definition, but should be understood according to its ordinary meaning.

[0024] The term "halogen" means a fluorine, chlorine, bromine or iodine atom.

[0025] The term "weakly basic pH" means that the pH is adjusted to about 7 - 9.

[0026] The "treatment" in the term "treating a solid" refers to simple post-treatment of the obtained solid product, including but not limited to further rinsing, slurrying, drying, etc. of the solid.

[0027] The term "end of the reaction" means that the reaction is judged to be complete by means of monitoring such as liquid phase, TLC plate or gas phase.

[0028] The term "weight - volume ratio" refers to the ratio between the weight of a certain substance and the volume of another substance. For example, the weight - volume ratio of formula (II - A) to N - methylpyrrolidone is 1:10.0 g / mL, which means that for every 1 g weight of the compound of formula (II - A), 10 mL volume of N - methylpyrrolidone is added.

[0029] The zinc chloride in the present invention includes zinc chloride solid and zinc chloride solutions of various concentrations. This is because zinc chloride solid is relatively hygroscopic, and some commercially available zinc chloride is stored in the form of solutions, such as 0.5 M or 1.0 M zinc chloride tetrahydrofuran solution.

[0030] The preparation method of compound (I) in the present invention refers to the preparation methods of the foregoing similar compounds. Those skilled in the art should know that when using or referring to the cited preparation methods, the feeding ratio of reactants, reaction solvents, reaction temperatures, etc. can be appropriately adjusted according to the differences of reactants.

[0031] The compounds of the present invention can be prepared by a variety of synthetic methods well - known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent replacement methods well - known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0032] Instruments and analysis methods:

[0033] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography - mass spectrometry (LC - MS), or ultra - performance liquid chromatography - mass spectrometry (UPLC - MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is carried out using an AVANCE III HD 300 MHz, AVANCE III HD 400 MHz or AVANCE NEO 400 MHz nuclear magnetic instrument. The solvents for measurement are deuterated dimethyl sulfoxide (DMSO - d6), deuterated acetonitrile (CD3CN), deuterated chloroform (CDCl3), and heavy water (D2O). The internal standard is 3,4,5 - trichloropyridine.

[0034] The liquid chromatography - mass spectrometry LC - MS measurement is carried out using an Agilent 1260 - G6135B single quadrupole mass spectrometer (the ion source is electrospray ionization), and the column is Agilent XDB - C18 1.8 μm 4.6 * 50 mm.

[0035] Determination by ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using a Waters UPLC H-class and a Waters Acquity Xevo G2-XS Q-tof mass spectrometer (with an electrospray ionization ion source). The chromatographic column was an Acquity UPLC BEH C18 1.7 μm, 2.1 * 50 mm.

[0036] For HPLC determination, a Waters ARC and an Agilent 1260 high performance liquid chromatograph were used. The chromatographic columns used were YMC Triart C18 150×4.6 mm, 3 μm or YMC Triart C18 EXRS 4.6×150 mm, 3 μm.

[0037] For thin layer chromatography silica gel plates, silica gel plates GF254 from Yantai Jiangyou Silica Gel Development Co., Ltd. or from Rushan Shangbang New Materials Co., Ltd. were used. The TLC specification was 0.15 mm - 0.20 mm, and the preparative specification was 20×20 cm. For column chromatography, silica gel with 200 - 300 mesh from Chenghua Chemical was generally used as the carrier.

[0038] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by methods known in the art or according to such methods. Detailed implementation mode

[0039] The present invention will be described in detail below through examples, but this does not mean any adverse limitation to the present invention. The compounds of the present invention can be prepared by various synthesis methods well-known to those skilled in the art, including the specific implementation modes listed below, the implementation modes formed by their combination with other chemical synthesis methods, and equivalent replacement methods well-known to those skilled in the art. Preferred implementation modes include but are not limited to the examples of the present invention. It will be obvious to those skilled in the art to make various changes and improvements to the specific implementation modes of the present invention without departing from the spirit and scope of the present invention.

[0040] Example 1: Preparation of the compound of formula (I):

[0041]

[0042] Compound II (9.00 kg, 20.95 mol), Compound II-A (5.00 kg, 17.46 mol), and zinc chloride in tetrahydrofuran solution (1.0 M) (52.38 L, 52.38 mol) were added with N-methylpyrrolidone (50.0 L). The temperature was raised to 100 ± 5 °C. After the reaction was completed, sodium hydroxide was used to adjust the pH to 7 - 8. Filtration was carried out. The filter cake was stirred with pyridine (25.0 L) and dichloromethane (75.0 L), followed by filtration. The filter cake was dried in vacuo to a constant weight to obtain 9.61 kg of Compound I, with a yield of 81.0%.

[0043] MS (ESI, m / z): 679.1 [M+H] + .

[0044] 1 1H NMR (300 MHz, DMSO-d6), δ (ppm): 9.89 (s, 1H), 8.95 (d, J = 1.8 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.77 (s, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.75 (s, 1H), 7.51 (s, 1H), 7.42 - 7.31 (m, 1H), 6.58 (s, 1H), 3.95 (p, J = 6.5 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.21 (t, J = 5.4 Hz, 2H), 3.01 (s, 3H), 2.98 - 2.87 (m, 2H), 1.29 (d, J = 6.3 Hz, 6H).

[0045] Example 2: Preparation of the compound of formula (I):

[0046]

[0047] Compound II (9.00 kg, 20.95 mol), Compound II-A (5.00 kg, 17.46 mol), and ferric chloride (8.50 Kg, 52.38 mol) were added with N-methylpyrrolidone (50.0 L). The temperature was raised to 100 ± 5 °C. After the reaction was completed, sodium hydroxide was used to adjust the pH to 7 - 8. Filtration was carried out. The filter cake was stirred with pyridine (25.0 L) and dichloromethane (75.0 L), followed by filtration. The filter cake was dried in vacuo to a constant weight to obtain 9.49 kg of Compound I, with a yield of 80.0%.

[0048] MS (ESI, m / z): 679.1 [M+H] + .

[0049] 11H NMR (300 MHz, DMSO-d6), δ (ppm): 9.89 (s, 1H), 8.95 (d, J = 1.8 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.77 (s, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.75 (s, 1H), 7.51 (s, 1H), 7.42 - 7.31 (m, 1H), 6.58 (s, 1H), 3.95 (p, J = 6.5 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.21 (t, J = 5.4 Hz, 2H), 3.01 (s, 3H), 2.98 - 2.87 (m, 2H), 1.29 (d, J = 6.3 Hz, 6H).

[0050] Example 3: Preparation of the compound of formula (I):

[0051]

[0052] To 9.00 kg (20.95 mol) of Compound II, 5.00 kg (17.46 mol) of Compound II-A, and 7.04 Kg (52.38 mol) of copper chloride was added N-methylpyrrolidone (50.0 L). The temperature was raised to 100 ± 5 °C. After the reaction was completed, the pH was adjusted to 7 - 8 with sodium hydroxide. The mixture was filtered, and the filter cake was stirred with pyridine (25.0 L) and dichloromethane (75.0 L), then filtered again. The filter cake was dried under vacuum to a constant weight to obtain 9.51 kg of Compound I, with a yield of 80.1%.

[0053] MS (ESI, m / z): 679.1 [M + H] + .

[0054] 1 1H NMR (300 MHz, DMSO-d6), δ (ppm): 9.89 (s, 1H), 8.95 (d, J = 1.8 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.77 (s, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.75 (s, 1H), 7.51 (s, 1H), 7.42 - 7.31 (m, 1H), 6.58 (s, 1H), 3.95 (p, J = 6.5 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.21 (t, J = 5.4 Hz, 2H), 3.01 (s, 3H), 2.98 - 2.87 (m, 2H), 1.29 (d, J = 6.3 Hz, 6H).

[0055] Example 4: Comparison of the quality of Compound (I)

[0056] Refer to the preparation method of Example 1 of CN202310709282.1 to obtain compound (I), denoted as I-A, I-B, and I-C. The compound (I) prepared according to the method of Example 1 of the present invention is denoted as I-D and I-E.

[0057]

[0058]

[0059] As can be seen from the above table, compared with the preparation process of the compound of formula (I) in CN202310709282.1, the compound of formula (I) obtained by the preparation method of the present invention has a lower content of debromination impurities, and no isomeric impurities are generated. The product is easier to purify, and the purity of the obtained compound of formula (I) is higher. At the same time, as can be seen from the above table, the preparation method of the compound of formula (I) of the present invention has a certain increase in the yield compared with the preparation method of the compound of formula (I) in CN202310709282.1, reduces the production cost, and has better stability in scale-up, making it more suitable for industrial production.

Claims

1. A method for preparing a compound represented by formula (I), characterized in that, It is prepared from the compound of formula (II) and the compound of formula (II-A) in the presence of a Lewis acid and a reaction solvent: Wherein, R1 is selected from halogen.

2. The preparation method according to claim 1, characterized in that, R1 is selected from chlorine.

3. The preparation method according to any one of claims 1-2, characterized in that The acid is selected from Lewis acids such as aluminum trichloride, boron trifluoride, sulfur trioxide, niobium pentachloride, antimony pentafluoride, iron chloride, copper chloride, zinc chloride, copper bromide, copper sulfate, iron bromide, or any combination thereof.

4. The preparation method according to any one of claims 1-3, characterized in that, The reaction solvent is selected from N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyl isobutyl ketone, dioxane, sulfolane, or any combination thereof.

5. The preparation method according to any one of claims 1-4, characterized in that, During the reaction of the compound of formula (II) and the compound of formula (II-A), the molar ratio of formula (II) to the Lewis acid is 1:1.0 - 1:5.

0.

6. The preparation method according to any one of claims 1-5, characterized in that, During the reaction of the compound of formula (II) and the compound of formula (II-A), the molar ratio of formula (II) to the compound of formula (II-A) is 1:1.0 - 1.5:1.

0.

7. The preparation method according to any one of claims 1-6, characterized in that, During the reaction of the compound of formula (II) and the compound of formula (II-A), the weight-to-volume ratio of formula (II-A) to the selected solvent is 1:5.0 g / mL - 1:20.0 g / mL.

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