Preparation method of ALK kinase inhibitor

Abstract

The invention provides a preparation method of a micromolecular ALK kinase inhibitor (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3, 9-diazaspiro [5.5] undecyl-3-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide (compound I), and the method has the advantages of mild reaction conditions and high yield and purity, and is suitable for industrial production.

Description

[0001] This application claims the priority of the Chinese patent application filed with the China Patent Office on September 1, 2023, with application number 202311126373.9 and invention name “Method for preparing ALK kinase inhibitors”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present application belongs to the field of pharmaceutical chemistry technology, and specifically relates to a method for preparing a small molecule ALK kinase inhibitor (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. Background Art

[0003] Tumor is one of the major diseases that seriously threatens human health and life. Traditional tumor treatment is achieved by discovering and destroying tumors. Now, with the continuous deepening of research on cell signal transduction pathways, people have a deeper understanding of the role of oncogenes and anti-cancer genes in tumor cells. The design of new anti-tumor drugs targeting specific molecular targets of tumors has attracted more and more attention and has become a hot research area. Targeted anti-tumor drugs have also been used in clinical practice as a new treatment method and have made significant progress in just a few years.

[0004] In recent years, anaplastic lymphoma kinase (ALK) has been a hot target for anti-tumor research and development. Both China and abroad are vigorously developing ALK inhibitors for the treatment of non-small cell lung cancer. (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, its structural formula is as follows:

[0005]

[0006] A small molecule ALK inhibitor developed by Qilu Pharmaceutical Co., Ltd., it can inhibit the phosphorylation of ALK and ROS1 kinases and then block the activation of downstream signaling pathway proteins such as ERK, STAT5 and AKT, thereby inducing tumor cell death (apoptosis). The drug was approved for marketing by the National Medical Products Administration in June 2023 for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed after previous treatment with crizotinib or are intolerant to crizotinib.

[0007] Patent CN201410317076.7 discloses the above-mentioned compound I as an ALK inhibitor, and its biological test data show that the compound has the potential to be developed into an anti-tumor drug. The patent also discloses a method for preparing the compound I, which includes adding a formaldehyde aqueous solution to a tetrahydrofuran solution of (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)phenyl)dimethylphosphine oxide, and then adding sodium acetate borohydride for reaction. However, the synthesis method is difficult, has a low yield, and uses formaldehyde that is harmful to the human body, and is not suitable for industrial production.

[0008] Patent CN201611178180.8 discloses another method for preparing the above-mentioned compound I, in which intermediate (e) and intermediate (f) react under MeSO3H conditions to generate compound I. This method also has the problem of low yield and purity.

[0009]

[0010] Since the structure of compound I is relatively complex and the synthesis is difficult, the existing preparation methods all have the problems of low yield and purity and are not suitable for industrial production. Therefore, it is still necessary to improve the preparation process of the compound to seek a process method that is simple to operate, high in yield and purity, and suitable for industrial production. Summary of the invention

[0011] The purpose of the present application is to provide a method for synthesizing (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (Compound I) which is simple to operate, has high yield and purity, and is suitable for industrial production. The method comprises the following steps: using Compound II and Compound III as raw materials to react under acid catalysis to obtain Compound I:

[0012]

[0013] Wherein, the acid is selected from trifluoromethanesulfonic acid.

[0014] In certain embodiments of the present application, the reaction temperature of the above steps is 50-100°C, preferably 70-100°C, and more preferably 85-90°C.

[0015] In certain embodiments of the present application, the mass (g / g) ratio of compound III to compound II in the above step is 1.0-2.0:1, preferably 1.0-1.5:1, and more preferably 1.1-1.3:1.

[0016] In certain embodiments of the present application, the reaction solvent in the above steps is selected from one or a mixture of the following solvents: N-methylpyrrolidone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, preferably N-methylpyrrolidone.

[0017] In certain embodiments of the present application, the mass volume (g / ml) ratio of compound II in the above step to the reaction solvent is 1:3.0-6.0, preferably 1:3.0-5.0, and more preferably 1:4.0-5.0.

[0018] In certain embodiments of the present application, the molar ratio (mol:mol) of the acid in the above step to compound II is 2.0 to 6.0:1, preferably 3.0 to 5.0:1, and more preferably 4.0 to 5.0:1.

[0019] A preferred solution of the present application is as follows: Compound II and Compound III are added to N-methylpyrrolidone, and trifluoromethanesulfonic acid is added dropwise at 20-40°C. The reaction temperature is raised to 85-90°C, and the reaction is carried out at 85-90°C for 12 hours. After cooling to room temperature, NaOH solution is added to the reaction solution to adjust the pH to 13, a white solid is precipitated, the solid is filtered, and dried to obtain Compound I.

[0020] In certain embodiments of the present application, the mass (g / g) ratio of compound III to compound II in the above preferred embodiment is 1.0-2.0:1, preferably 1.0-1.5:1, and more preferably 1.1-1.3:1.

[0021] In certain embodiments of the present application, the mass volume (g / ml) ratio of compound II to the reaction solvent in the above preferred embodiment is 1:3.0-6.0, preferably 1:3.0-5.0, and more preferably 1:4.0-5.0.

[0022] In certain embodiments of the present application, the molar ratio (mol:mol) of trifluoromethanesulfonic acid to compound II in the above preferred embodiment is 2.0 to 6.0:1, preferably 3.0 to 5.0:1, and more preferably 4.0 to 5.0:1.

[0023] The second aspect of the present application is to provide a method for preparing an intermediate compound represented by formula II, the method comprising:

[0024] [Step 1]: The compound represented by formula r

[0025]

[0026] Reaction with the compound shown in formula b

[0027]

[0028] To obtain a compound of formula s;

[0029]

[0030] [Step 2]: subjecting the compound represented by formula S to a reduction reaction to obtain a compound represented by formula II.

[0031]

[0032] In certain embodiments of the present application, the molar ratio (mol:mol) of compound r to compound b in [step 1] is 1:1.0 to 2.0, preferably 1:1.55.

[0033] In certain embodiments of the present application, the above [Step 2] undergoes a reduction reaction in the presence of ammonium chloride and zinc powder.

[0034] The third aspect of the present application is to provide a method for preparing an intermediate compound shown in formula III, the method comprising:

[0035]

[0036] Reaction with the intermediate compound 2,4,5-trichloropyrimidine

[0037]

[0038] The compound of formula III is obtained.

[0039]

[0040] In certain embodiments of the present application, the compound 1k in the above step is reacted with 2,4,5-trichloropyrimidine in the presence of DIPEA (N,N-diisopropylethylamine).

[0041] The fourth aspect of the present invention is to provide a compound of formula I prepared by the above method, which is used for treating non-small cell lung cancer (NSCLC).

[0042] In certain embodiments of the present application, the compound of formula I prepared by the above method is used to treat patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed after previous treatment with crizotinib or are intolerant to crizotinib.

[0043] In certain embodiments of the present application, the compound of formula I prepared by the above method is used to treat ALK-positive advanced non-small cell lung cancer (NSCLC) patients who have not received ALK TKI treatment before.

[0044] Those skilled in the art should understand that the compound shown in Formula I, the compound of Formula I and Compound I in the present application have the same meaning, all referring to (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, having the compound structure shown in Formula I.

[0045]

[0046] In this application, unless otherwise specified, the amount of the reaction solvent and related reagents is the conventional amount of the reaction, which can be determined by a person skilled in the art based on the prior art. The reagents used in this application are all conventional reagents, which can be purchased from the market, and the starting materials and reactants used can be prepared from the prior art or the disclosed existing literature.

[0047] Compounds are manually or Software naming, commercially available compounds use supplier catalog names. This application uses the following abbreviations: DCM stands for dichloromethane; DMF stands for N,N-dimethylformamide; EtOH stands for ethanol; EtOAc stands for ethyl acetate; NMP stands for N-methylpyrrolidone; MeOH stands for methanol; Boc stands for tert-butylcarbonyl, which is an amine protecting group; HOAc stands for acetic acid; THF stands for tetrahydrofuran; DIPEA stands for N,N-diisopropylethylamine; AcOH stands for acetic acid.

[0048] Technical Effects

[0049] The preparation method of compound I provided in the present application uses raw materials and reagents different from those in the prior art, achieving a double improvement in yield and purity, laying a good foundation for the large-scale production of the preparation process, and achieving significant technical progress, mainly in the following aspects:

[0050] (1) The yield of the preparation method of the present application is above 75%, and the optimal yield can reach above 85%, which is nearly 2 times higher than that of the prior art, greatly reducing the production cost, having a high atomic utilization rate, and conforming to the concept of economy and green chemistry.

[0051] (2) The preparation method of the present application overcomes the technical defects of the prior art that require liquid phase separation and purification, avoids the use of reagents that are toxic to the human body, can be better applied to large-scale production, and is conducive to the industrialization of the process.

[0052] (3) The product obtained by the preparation method of the present application has good purity, with HPLC purity above 96% and the best reaching above 98%, which is much higher than the existing technical methods. DETAILED DESCRIPTION

[0053] The present application is described in detail below by way of examples, but this does not mean any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0054] Experimental equipment summary:

[0055] The structure of the compound of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS), or ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shift (δ) is given in parts per million (ppm). NMR is measured using a Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic instrument, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), heavy water (D2O), and the internal standard is tetramethylsilane (TMS).

[0056] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260-6125B single quadrupole massspectrometer with a Welch Biomate column (C18, 2.7 μm, 4.6 × 50 mm) or a Waters H-Class SQD2 with a Welch Ultimate column (XB-C18, 1.8 μm, 2.1 × 50 mm) mass spectrometer (the ion source was electrospray ionization).

[0057] Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using a Waters UPLC H-class SQD mass spectrometer (with electrospray ionization as the ion source).

[0058] HPLC determination was performed using Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

[0059] The thin layer chromatography silica gel plate uses GF254 silica gel plate from Yantai Jiangyou Silica Gel Development Co., Ltd. or GF254 silica gel plate from Rushan Shangbang New Materials Co., Ltd. The specification used by TLC is 0.15mm~0.20mm, and the preparation type is 20×20cm. Column chromatography generally uses 200~300 mesh silica gel from Chenghua as the carrier.

[0060] The starting materials in the examples of the present application are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0061] Unless otherwise specified, all reactions in the present application are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius or ° C. Unless otherwise specified, room temperature refers to 25±5° C.

[0062] Preparation of intermediate compound II

[0063]

[0064] Step 1: Preparation of compound(s)

[0065] 3-(3-Methoxy-4-nitrophenyl)-9-methyl-3,9-diazaspiro[5.5]undecane

[0066] Potassium carbonate (30 g, 10.26 equivalents) was added to a solution of compound r (4.83 g, 1 equivalent) and 4-fluoro-2-methoxy-1-nitrobenzene (5.6 g, 1.55 equivalents) in acetonitrile (100 mL), and then the reaction solution was heated to 80°C and stirred for 16 hours. After the reaction was completed by TLC detection, the reaction solution was filtered, and the filtrate was concentrated and purified by column (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain the title compound.

[0067] MS (ESI) M / Z: 320.2 [M+H] + .

[0068] 1 H NMR (400MHz, CD3OD): δ7.95 (d, J=9.6Hz, 1H), 6.56 (dd, J=9.2, 2.4Hz, 1H), 6.49 (d, J=2.4Hz, 1H), 3. 95(s,3H),3.52-3.48(m,4H),3.09-2.91(m,4H),2.68(s,3H),1.78-1.72(m,4H),1.71-1.69(m,4H).

[0069] Step 2: Preparation of Compound II

[0070] 2-Methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)aniline

[0071] Zinc powder (18.43 g, 281.80 mmol, 10 equivalents) was added to a solution of compound s (9.00 g, 1 equivalent) and ammonium chloride (15.07 g, 10 equivalents) in methanol (100 mL) at 10-30°C. After the addition was completed, the mixture was reacted at 30°C for 30 minutes. The reaction was completed by TLC detection. The reaction solution was filtered, and the filtrate was concentrated and then added with saturated sodium carbonate solution (100 mL) and water (50 mL). The mixture was extracted three times with dichloromethane (80 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound in a yield of 86%.

[0072] 1 H NMR (400 MHz, CD3OD): δ 6.72 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H), 3.08-2.96 (m, 4H), 2.58-2.45 (m, 4H), 2.32 (s, 3H), 1.75-1.52 (m, 8H). Preparation of intermediate compound III (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0073]

[0074] At 16 ° C, to a mixture of compound 1K (2.50 g, 14.8 mmol) and 2,4,5-trichloropyrimidine (2.85 g, 15.5 mmol) in DMF (20 mL), DIPEA (3.82 g, 29.6 mmol) was added. The reaction mixture was then heated to 70 ° C and stirred for 16 hours. TLC showed that the reaction was complete. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (40 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was recrystallized in ethanol to give compound III (3.20 g) as a white solid.

[0075] MS (ESI) M / Z: 315.9 [M+H] + .

[0076] 1 H NMR (400MHz, CD3OD): δ8.50(dd,J=8.0,4.0Hz,1H),8.35-8.28(m,1H),7.69-7.59(m,2H),7.36-7.28(m,1H),1.91(s,3H),1.88(s,3H).

[0077] Example 1 Preparation of (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (Compound I)

[0078]

[0079] 5 kg of compound II and 6 kg of compound III were added to 23 L of N-methylpyrrolidone, and 11.5 kg of trifluoromethanesulfonic acid was added dropwise at 20-40 ° C. The reaction temperature was raised to 85-90 ° C, and the reaction was carried out at 85-90 ° C for 12 hours. After cooling to room temperature, NaOH solution was added to the reaction solution to adjust the pH to 13, and a white solid was precipitated. The solid was filtered and dried to obtain compound I. The yield was 85.0%, and the HPLC purity was 98.6%.

[0080] 1 H NMR (400MHz, CD3OD): δ8.28(S,1H),8.12(br,s,1H),7.81-7.68(m,3H),7.65(d,J=2.0Hz,1H),7.56-7.49(m,1H),7.37(d,J=8.8Hz,1 H),4.02(s,3H),3.74(br,S,4H),3.47(d,J=12.8Hz,2H),3.24(t,J=12.8Hz,2H),2.93(s,3H),2.42-1.97(m,5H),1.93-1.75(m,9H).

[0081] MS (ESI) M / Z: 569.2 [M+H] + .

[0082] Example 2. Preparation of Compound I

[0083] 500g of compound II and 600g of compound III were added to 2.3L of N,N-dimethylformamide, and 1.15kg of trifluoromethanesulfonic acid was added dropwise at 20-40°C. The reaction temperature was raised to 85-90°C, and the reaction was carried out at 85-90°C for 12h. After cooling to room temperature, NaOH solution was added to the reaction solution to adjust the pH to 13, and a white solid was precipitated. The solid was filtered and dried to obtain compound I. The yield was 75.3%, and the HPLC purity was 96.3%.

[0084] Example 3 Preparation of Compound I

[0085] 500g of compound II and 600g of compound III were added to 2.3L of acetonitrile, and 1.15kg of trifluoromethanesulfonic acid was added dropwise at 20-40°C. The reaction temperature was raised to 85-90°C, and the reaction was carried out at 85-90°C for 12h. After cooling to room temperature, NaOH solution was added to the reaction solution to adjust the pH to 13, and a white solid was precipitated. The solid was filtered and dried to obtain compound I. The yield was 78.5%, and the HPLC purity was 96.3%.

[0086] Example 4 Preparation of Compound I

[0087] 500g of compound II and 600g of compound III were added to 2.3L of dimethyl sulfoxide, and 1.15kg of trifluoromethanesulfonic acid was added dropwise at 20-40°C. The reaction temperature was raised to 85-90°C, and the reaction was carried out at 85-90°C for 12h. After cooling to room temperature, NaOH solution was added to the reaction solution to adjust the pH to 12-13, and a white solid was precipitated. The solid was filtered and dried to obtain compound I. The yield was 76.0%, and the HPLC purity was 96.4%.

[0088] Comparative Example 1 Preparation of Compound I

[0089] 500g of compound II and 600g of compound III were added to 2.3L of N-methylpyrrolidone, and 0.736kg of methanesulfonic acid was added dropwise at 20-40°C. The reaction temperature was raised to 85-90°C, and the reaction was carried out at 85-90°C for 12h. After cooling to room temperature, NaOH solution was added to the reaction solution to adjust the pH to 13, and a white solid was precipitated. The solid was filtered and dried to obtain compound I. The yield was 67.2%, and the HPLC purity was 95.4%.

[0090] Comparative Example 2 Preparation of Compound I

[0091] 500g of compound II and 600g of compound III were added to 2.3L of N,N-dimethylformamide, and 1.319kg of p-toluenesulfonic acid was added dropwise at 20-40°C. The reaction temperature was raised to 85-90°C, and the reaction was carried out at 85-90°C for 12h. After cooling to room temperature, NaOH solution was added to the reaction solution to adjust the pH to 13, and a white solid was precipitated. The solid was filtered and dried to obtain compound I. The yield was 69.8%, and the HPLC purity was 96.3%.

[0092] Comparative Example 3 Preparation of Compound I

[0093] 500g of compound II and 600g of compound III were added to 2.3L of N-methylpyrrolidone, and 0.874kg of trifluoroacetic acid was added dropwise at 20-40°C. The reaction temperature was raised to 85-90°C, and the reaction was carried out at 85-90°C for 12h. After cooling to room temperature, NaOH solution was added to the reaction solution to adjust the pH to 13, and a white solid was precipitated. The solid was filtered and dried to obtain compound I. The yield was 53.1%, and the HPLC purity was 96.7%.

[0094] Comparative Example 4 Preparation of Compound I

[0095] 500g of compound II and 600g of compound III were added to 2.3L of N,N-dimethylformamide, and 7.66mol of hydrochloric acid was added dropwise at 20-40°C. The reaction temperature was raised to 85-90°C and the reaction was carried out at 85-90°C for 12h. TLC showed that a large amount of compound II remained and the product was small, so no further treatment was performed.

[0096] The yield and purity of Examples 1 to 4 of the present application were compared with those of Comparative Examples 1 to 4, and the results are summarized in Table 1 below.

[0097] Table 1 Comparison of yield and purity using different acids

[0098]

[0099] The above results show that the trifluoromethanesulfonic acid used in the present application has achieved unexpected results in terms of yield and purity compared with similar organic acids such as methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, and conventional inorganic acids such as hydrochloric acid.

[0100] Comparative test example 1

[0101]

[0102] Refer to the method of Example 7 of patent CN201410317076.7. A solution of (2-((5-chloro-2-((2-methoxy-4-(3,9-diazaspiro[5.5]undecane-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (compound h, 0.039mmol) in tetrahydrofuran (5mL) was added with formaldehyde aqueous solution (9.5mg, 37%, 0.117mmol), the reaction mixture was stirred at 16°C for 30 minutes, sodium acetate borohydride (25mg, 0.117mmol) was added, and stirred at 16°C for 12 hours. LCMS showed that the reaction was complete, filtered, and prepared HPLC purification was provided to obtain solid compound I with a yield of 43.0% and a HPLC purity of 90.1%.

[0103] Comparative Test Example 2

[0104]

[0105] Refer to the method of Example 11 of patent CN201611178180.8. NMP (102.6g) was added to the reaction bottle, 20g of compound II was added to the reaction bottle under stirring at room temperature, 21.85g of compound III was added to the reaction bottle, and 19.93g (3eq) of methanesulfonic acid was added dropwise to the reaction bottle (control temperature <40°C) N2 bubbled for 15-20min. The reaction was heated to 85-90°C, and after 12h of reaction at 85-90°C, the central control sampling test (HPLC) was performed, and the sampling test (test method: 0.1ml of the reaction solution was dissolved in 2ml of methanol). When compound III <2.5%, the reaction was stopped. NaOH solution (1M, 287g) was added to the reaction solution to adjust the pH to 13, and a large amount of solid precipitated and continued stirring for 2h. The solid was filtered and the filter cake was washed with water until the filtrate was colorless. Collect the filter cake, filter and dry (55-60°C) to obtain an off-white crude product, add methanol (268g) to the reaction bottle, then add the obtained solid, heat to 60°C to dissolve, add activated carbon (5.2g) to the reaction bottle, then stir at 60°C for 2.5h, cool to 30°C, filter, and concentrate the mother liquor under reduced pressure to obtain a gray-green solid. Add methanol (155.5g) to the reaction bottle, then add the above-obtained solid, and heat to reflux until clear. Add purified water (388g) to the reaction bottle, cool naturally to 15-20°C, and a white solid precipitates. Filter, wash the filtered solid once with purified water (194g), collect the filter cake and dry to obtain compound I. Yield 70%, HPLC purity 89.0%.

[0106] The preparation methods of Examples 1 to 4 of the present application were compared with the preparation methods of Comparative Test Examples 1 to 2 of the prior art in terms of yield and purity. The results are shown in Table 2 below.

[0107] Table 2 Comparison of yield and purity of different preparation methods

[0108] Preparation method Yield (%) purity(%) Example 1 85.0 98.6 Example 2 75.3 96.3 Example 3 78.5 96.3 Example 4 76.0 96.4 Comparative test example 1 46.0 90.1 Comparative Test Example 2 70.0 89.0

[0109] The above results show that the preparation method of compound I adopted in the present application has achieved unexpected results in terms of yield and purity compared with the preparation methods of the prior art as a whole.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: using compound II and compound III as raw materials to obtain compound I through an acid-catalyzed reaction: in, The acid is selected from trifluoromethanesulfonic acid.

2. The preparation method according to claim 1, characterized in that: The reaction temperature is 50 to 100°C, preferably 70 to 100°C, more preferably 85 to 90°C.

3. The preparation method according to claim 1 or 2, characterized in that: The mass (g / g) ratio of compound III to compound II is 1.0 to 2.0:1, preferably 1.0 to 1.5:1, and more preferably 1.1 to 1.3:

1.

4. The preparation method according to any one of claims 1 to 3, characterized in that The reaction solvent is selected from one or a mixture of the following solvents: N-methylpyrrolidone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, preferably N-methylpyrrolidone.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The mass volume ratio (g / ml) of compound II to the reaction solvent is 1:3.0-6.0, preferably 1:3.0-5.0, and more preferably 1:4.0-5.

0.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The molar ratio (mol:mol) of trifluoromethanesulfonic acid to compound II is 2.0 to 6.0:1, preferably 3.0 to 5.0:1, and more preferably 4.0 to 5.0:

1.

7. The preparation method according to claim 1, comprising the following steps: Compound II and compound III are added to N-methylpyrrolidone, trifluoromethanesulfonic acid is added dropwise at 20-40°C, the reaction temperature is raised to 85-90°C, and the reaction is carried out at 85-90°C for 12 hours. After cooling to room temperature, NaOH solution is added to the reaction solution to adjust the pH to 13, a white solid is precipitated, the solid is filtered and dried to obtain compound I.

8. The preparation method according to claim 7, characterized in that: The mass (g / g) ratio of compound III to compound II is 1.0 to 2.0:1, preferably 1.0 to 1.5:1, and more preferably 1.1 to 1.3:

1.

9. The preparation method according to claim 7, characterized in that: The mass volume ratio (g / ml) of compound II to N-methylpyrrolidone is 1:3.0-6.0, preferably 1:3.0-5.0, and more preferably 1:4.0-5.

0.

10. The preparation method according to claim 7, characterized in that: The molar ratio (mol:mol) of trifluoromethanesulfonic acid to compound II is 2.0 to 6.0:1, preferably 3.0 to 5.0:1, and more preferably 4.0 to 5.0:

1.

11. The preparation method according to any one of claims 1 to 10, characterized in that: The method further comprises: [Step 1]: The compound represented by formula r Reaction with the compound shown in formula b The compound shown in formula S is obtained [Step 2]: The compound represented by formula S is subjected to reduction reaction to obtain compound II.

12. The method according to claim 11, [Step 1] The molar ratio (mol:mol) of compound r to compound b is 1:1.0 to 2.0, preferably 1:1.

55.

13. The method according to claim 11, wherein [step 2] the reduction reaction is carried out in the presence of ammonium chloride and zinc powder.

14. The preparation method according to any one of claims 1 to 10, characterized in that: The method further comprises the step of: Reaction with the intermediate 2,4,5-trichloropyrimidine The compound of formula III is obtained.

15. The method according to claim 14, wherein: The compound 1k is reacted with 2,4,5-trichloropyrimidine in the presence of N,N-diisopropylethylamine.

16. The compound of formula I prepared according to the method of claims 1-15, for use in treating non-small cell lung cancer (NSCLC).

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