Synthesis method of aminoquinazoline tyrosine kinase inhibitor compound (A)

Abstract

The present invention discloses a method for synthesizing an aminoquinazoline tyrosine kinase inhibitor compound (A). The synthesis method includes mixing a compound of formula (I), an alcohol solvent, and ammonium sulfide, stirring, and then heating to 65-80 °C for reaction to obtain a compound of formula (II); mixing diethylphosphonoacetic acid, a first solvent, and N,N'-carbonyldiimidazole, stirring, adding the compound of formula (II) for reaction, and obtaining a compound of formula (III) through post-treatment; mixing the compound of formula (III) with a second solvent, cooling, adding anhydrous lithium chloride, a potassium hydroxide solution, and a compound of formula (IV) for reaction to obtain the aminoquinazoline tyrosine kinase inhibitor compound (A). The method greatly improves the yield of the intermediate of the aminoquinazoline tyrosine kinase inhibitor compound, has high purity, high raw material conversion efficiency, and can simultaneously achieve scale-up production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and more specifically, to a method for synthesizing an aminoquinazoline tyrosine kinase inhibitor compound (A). Background Art

[0002] Tyrosine protein kinase can specifically transfer phosphate groups to tyrosine residues of proteins to phosphorylate them. It is a product of many ligand-activated growth factor receptors and some oncogenes, and is highly abundant in tumor tissues. Tyrosine protein kinase inhibitors can act as competitive inhibitors for the binding of ATP to tyrosine protein kinase, or as analogs of tyrosine to block the peptide sites of epidermal growth factor receptors and the coding of tyrosine protein kinase, inhibiting cell proliferation, cell cycle progression, and accelerating apoptosis to play a therapeutic role, and can be used as anti-tumor drugs.

[0003] Research shows that in addition to effectively inhibiting EGFR, the Pan-HER tyrosine kinase irreversible inhibitor also has an inhibitory effect on HER2 / 4. Such drugs that have an irreversible inhibitory effect on the HER / ErbB family not only improve drug activity but also reduce the generation of drug resistance, and have a significant inhibitory effect on the H1975 cell line resistant to Erlotinib.

[0004] Patent CN 104119350A discloses a class of aminoquinazoline tyrosine kinase inhibitors with Pan-HER irreversible inhibitory effects. These compounds are drugs with excellent anti-tumor effects, reduced drug resistance generation, and good tolerance at the same time. Among them, the compound (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(methoxy-d3)quinazolin-6-yl)-4-((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)but-2-enamide in Example 20 (compound (A) described below) has excellent anti-tumor effects, can reduce the generation of drug resistance, and has good tolerance at the same time.

[0005]

[0006] Furthermore, the patent discloses a synthesis method for compound (A), and its synthesis route is as follows:

[0007]

[0008] However, concentrated hydrochloric acid is used in the second step of this synthesis, which requires high equipment and instruments, generates a large amount of solid iron mud waste residue, pollutes the environment, is not suitable for industrial production, and the yield is 60.8%; the yield of the subsequent third-step reaction is 37.9%, and the yield of the fourth-step reaction is 27.3%. It can be seen that the yield of the compound generated by this synthetic route is low and the cost is high; in addition, the raw material E-4-bromobut-2-enoyl chloride used in the third-step reaction is not easy to store and is also highly toxic, making it not suitable for large-scale industrial production.

[0009] The existing synthetic methods severely restrict the preparation and preparation cost of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(methoxy-d3)quinazolin-6-yl)-4-((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)but-2-enamide. Therefore, how to improve and optimize the process methods and processes of this type of compound and increase the yield and purity of this type of compound have become technical problems that need to be solved urgently. Summary of the Invention

[0010] Aiming at the above-mentioned problems in the prior art, the primary object of the present invention is to provide a synthetic method of the aminoquinazoline tyrosine kinase inhibitor compound (A), which greatly improves the yield of the aminoquinazoline tyrosine kinase inhibitor compound (A), has high purity, high raw material conversion efficiency, and can simultaneously achieve scale-up production; in addition, this method is safe, has low requirements for equipment, and is more suitable for industrial production.

[0011] The above object of the present invention is achieved by the following solutions:

[0012] The aminoquinazoline tyrosine kinase inhibitor compound (A) described in the present invention has the Chinese name: (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(methoxy-d3)quinazolin-6-yl)-4-((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)but-2-enamide, which is a known aminoquinazoline tyrosine kinase inhibitor compound.

[0013] On the one hand, the present invention provides a synthetic method of the aminoquinazoline tyrosine kinase inhibitor compound (A), and the method includes the following steps:

[0014] S1. Mix and stir the compound of formula (I), an alcohol solvent, and ammonium sulfide, and then heat to 65-80 °C for reaction to obtain the compound of formula (II);

[0015] S2. Mix and stir diethyl phosphonoacetate, a first solvent, and N,N'-carbonyldiimidazole, add the compound of formula (II) for reaction, and obtain the compound of formula (III) after post-treatment;

[0016] S3. The compound of formula (III) is mixed with a second solvent, the temperature is lowered, and anhydrous lithium chloride, potassium hydroxide solution and the compound of formula (IV) are added for reaction to obtain the aminoquinazoline tyrosine kinase inhibitor compound (A);

[0017] The reaction formula of the synthesis method is as follows:

[0018]

[0019] The synthesis method of the aminoquinazoline tyrosine kinase inhibitor compound (A) provided by the present invention uses ammonium sulfide to carry out a reduction reaction on the compound of formula (I) in an alcohol solvent. Compared with the reduction scheme using Fe + concentrated hydrochloric acid, the reduction method adopted by the present invention is safe, simple, and has low requirements for equipment, making it more suitable for industrial production. The yield of the reduction method adopted in this step S1 can be as high as 85%, and the purity can be as high as 90%. Subsequently, the present invention uses a system of N,N'-carbonyldiimidazole (CDI) and diethylphosphonoacetic acid. By optimizing the selection of solvents and the optimal feeding ratio, the intermediate compound of formula (III) prepared has extremely high yield and purity, and its yield and purity can be as high as 97%. Finally, the intermediate compound of formula (III) is prepared to obtain the aminoquinazoline tyrosine kinase inhibitor compound (A) under the system of anhydrous lithium chloride and potassium hydroxide. The present invention optimizes the process route and process conditions of each step in the compound, ultimately greatly improving the yield of the compound, high purity, and high raw material conversion efficiency, and can simultaneously achieve scale-up production. In addition, the method is safe, simple, has low requirements for equipment, and is more suitable for industrial production compared with the prior art.

[0020] Preferably, in the step S1, the remaining amount of the hydroxylamine intermediate state generated during the reaction of the compound of formula (I) is monitored. When the remaining amount of the hydroxylamine intermediate state of the compound of formula (I) ≤ 2.5%, the reaction is terminated to obtain the compound of formula (II). The inventors found that during the process of synthesizing the compound of formula (II) from the compound of formula (I), the nitro group on the benzene ring to be reduced will appear in an intermediate state of hydroxylamine, and its structural formula is as follows Therefore, it is not that all the compound of formula (I) can be completely converted into the compound of formula (II) at the same time. During the synthesis of the compound of formula (II), it is necessary to carefully observe the conversion of the hydroxylamine intermediate state. Accordingly, the inventors monitored the conversion of the hydroxylamine intermediate state by HPLC. When the remaining amount of the hydroxylamine intermediate state ≤ 2.5%, the reaction ended, and at this time, the compound of formula (II) had a high yield and purity.

[0021] Preferably, in the step S1, the alcohol solvent is n-propanol, isopropanol, n-butanol or sec-butanol. More preferably, the alcohol solvent is sec-butanol. When sec-butanol is selected as the reaction solvent in the step S1, compared with other reaction solvents, the compound of formula (II) can obtain higher yield and purity.

[0022] Preferably, in the step S1, the equivalent ratio of the compound of formula (I) to ammonium sulfide is 1:(5.5 - 10); preferably, the equivalent ratio of the compound of formula (I) to ammonium sulfide is 1:(5.5 - 7); more preferably, the equivalent ratio of the compound of formula (I) to ammonium sulfide is 1:(5.8 - 6.2). The inventors found that when the equivalent ratio of the compound of formula (I) to ammonium sulfide is lower than 1:5.0, the reaction in the step S1 and the synthesis of the compound of formula (II) are affected, the reaction in the step S1 is incomplete, and the purity of the compound of formula (II) is also low.

[0023] Preferably, in the step S1, the equivalent ratio of the compound of formula (I) to ammonium sulfide is 1:(5.8 - 6.2); the alcohol solvent is sec-butanol.

[0024] Preferably, in the step S1, the mass ratio of the compound of formula (I) to the alcohol solvent is 1:(12 - 13).

[0025] Preferably, in the step S1, the ammonium sulfide is an aqueous ammonium sulfide solution with a concentration of 40 - 48%.

[0026] In this step S1, the reduction reaction of the compound of formula (I) with ammonium sulfide in sec-butanol solvent is carried out. Compared with the reduction scheme using Fe + concentrated hydrochloric acid, the reduction method adopted in the present invention is safe, simple, and has low requirements for equipment, and is more suitable for industrial production. Moreover, the yield obtained by the reduction method adopted in this step S1 is as high as 85%, and the purity is as high as 90%.

[0027] Preferably, in the step S2, the equivalent ratio of the compound of formula (II), N,N'-carbonyldiimidazole (CDI) and diethylphosphonoacetic acid is 1:(1.5 - 2.5):(1.5 - 2.0); preferably, the equivalent ratio of the compound of formula (II), N,N'-carbonyldiimidazole and diethylphosphonoacetic acid is 1:1.5:(1.5 - 1.7); further, the equivalent ratio of the compound of formula (II), N,N'-carbonyldiimidazole and diethylphosphonoacetic acid is 1:1.5:1.5.

[0028] Preferably, in the step S2, the first solvent is selected from one or more of N,N-dimethylformamide, tetrahydrofuran or ethylene glycol dimethyl ether; more preferably, the first solvent is selected from N,N-dimethylformamide.

[0029] Preferably, in the step S2, the mass ratio of the compound of formula (II) to the first solvent is 1:(9.0 - 9.2).

[0030] Preferably, in the step S2, the reaction is monitored by HPLC until the content of the compound of formula (II) is ≤ 0.30%, then the reaction ends.

[0031] Preferably, in the step S2, the post-treatment is as follows: after the reaction ends, the reaction solution is poured into ice water to precipitate a solid, filtered, and the filter cake is slurried with EA:Hexane (v:v) = 1:2, filtered, and dried. Further preferably, the solid obtained after drying the slurry is heated under reflux with toluene to remove the residual sulfur, then cooled, and the solid is filtered and dried; even more preferably, the solid after toluene slurrying is further decolorized with activated carbon and dried to obtain the compound of formula (III).

[0032] The inventors found that when the equivalent ratio of the compound of formula (II):CDI:diethyl phosphonoacetate is 1.0:1.5:1.7, DMF is used as the reaction solvent, and the mass ratio of the compound of formula (II) to the first solvent is 1:(9.0 - 9.2), the reaction in step S2 is carried out at room temperature. Under this preferred combination of conditions, the yield of the compound of formula (III) prepared can reach up to 97%, and the purity can reach 97%, which can significantly improve the yield.

[0033] Preferably, in the step S3, the equivalent ratio of the compound of formula (III), anhydrous lithium chloride, and potassium hydroxide is 1:(1.5 - 2.5):(1.5 - 2.5); further preferably, the equivalent ratio of the compound of formula (III), anhydrous lithium chloride, and potassium hydroxide is 1:2.0:2.0.

[0034] Preferably, in the step S3, the second solvent is tetrahydrofuran.

[0035] Preferably, in the step S3, the equivalent ratio of the compound of formula (III) to the compound of formula (IV) is 1:(2 - 5).

[0036] Preferably, in the step S3, the temperature is lowered to -15°C to -25°C; the reaction temperature is -10°C to 0°C.

[0037] On the other hand, the present invention provides an intermediate of the aminoquinazoline tyrosine kinase inhibitor compound (A), and the structural formula of the intermediate is as follows:

[0038]

[0039] The compound of formula (III) can be used as an intermediate for synthesizing compound (A), and can react with the compound of formula (IV) in one step to generate compound (A); in addition, compared with the method for synthesizing compound (A) in CN 104119350A, it is more environmentally friendly.

[0040] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides a method for synthesizing the aminoquinazoline tyrosine kinase inhibitor compound (A). By optimizing the process routes and process conditions of each step in the compound, the yield and purity of the compound are ultimately greatly improved. The synthesis method has a high raw material conversion efficiency and can achieve scale-up production. In addition, compared with the prior art, the synthesis method is safe, simple, has low requirements for equipment, and is more suitable for industrial production. Detailed implementation manners

[0041] The following further elaborates the present invention in detail with reference to specific embodiments. The embodiments are only used to explain the present invention and are not used to limit the scope of the present invention. The test methods used in the following embodiments are all conventional methods unless otherwise specified; the materials, reagents, etc. used are, unless otherwise specified, reagents and materials that can be obtained from commercial channels.

[0042] The equivalent ratio in the present invention is the molar equivalent ratio, and the equivalent unit is eq. For example, the equivalent ratio of the compound of formula (I) and ammonium sulfide is 1:(5.5 - 10), which means that when the amount of the compound of formula (I) is 1 mol, the amount of ammonium sulfide is 5.5 - 10 mol. When expressing the relative amounts of the two in equivalents, the amount of the compound of formula (I) is 1 eq, and the amount of ammonium sulfide is 5.5 - 10 eq.

[0043] The low-resolution mass spectrometry (MS) data was determined by a spectrometer of Agilent 6320 series LC-MS equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.

[0044] The low-resolution mass spectrometry (MS) data was determined by a spectrometer of Agilent 6120 series LC-MS equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 °C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.

[0045] Both of the above spectrometers were equipped with an Agilent Zorbax SB-C18 column, sized 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; the HPLC peaks were recorded and read at UV-Vis wavelengths of 210 nm and 254 nm. The mobile phase was a 0.1% formic acid acetonitrile solution (phase A) and a 0.1% formic acid ultrapure water solution (phase B).

[0046] Nuclear magnetic resonance spectral data were determined using a Bruker Avance 400 nuclear magnetic resonance spectrometer or a Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, with CDC13, DMSO-d6, CD3OD or Acetone-d6 as solvents (reported in ppm), using TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks appeared, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartet), br (broadened), dd (double of doublets), dt (doublet of triplets), dq (doublet of quartets), ddd (doublet of doublet of doublets), ddt (doublet of doublet of triplets), dddd (doublet of doublet of doublet of doublets). The coupling constant was expressed in hertz (Hz).

[0047] The purity of the compound was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), with UV detection at 210 nm and 254 nm, a Zorbax SB-C18 column, sized 2.1×30 mm, 4 μm, for 10 minutes, a flow rate of 0.6 mL / min, 5 - 95% of (0.1% formic acid acetonitrile solution) of (0.1% formic acid aqueous solution), and the column temperature maintained at 40 °C.

[0048] The following abbreviations were used throughout the specification: DMF: N,N-dimethylformamide, THF: tetrahydrofuran, DME: ethylene glycol dimethyl ether.

[0049] Preparation of Intermediate Compound (IV)

[0050]

[0051] Step (1). Dissolve (IV-1) (10 g, 1 eq) in water (30 mL), put it into a reaction kettle, slowly dropwise add an aqueous solution of potassium hydroxide (8.5 g, 2.5 eq) in water (10 mL). After completion, add a phase transfer catalyst 18-crown-6 (18-crown ether-6) (0.32 g, 0.02 eq), dropwise add bromoacetaldehyde diethyl acetal (1.3 eq). After dropping, raise the temperature to 100 °C, start GC monitoring after reacting for 5.0 h, and then sample and detect once every 1.0 h until the compound (IV-1) ≤ 1.0%. Stop heating, add sodium chloride to saturation, stir and then let it stand for layer separation. Take the upper organic phase, dissolve the organic phase in water, extract the water layer with n-hexane three times (to remove impurities), discard the n-hexane layer, continue to extract the water layer with dichloromethane (to extract the product compound (IV-2)), dry the dichloromethane layer, and concentrate to obtain 12.1 g of compound (IV-2), with a yield of 82.0% and a purity of 94.1%. MS (ESI, pos. ion) m / z: 246.2 [M + 1] + ; 1 HNMR (400 MHz, CDCl3): δ 4.54 (t, 1H), 4.05 (s, 2H), 3.75 (m, 2H), 3.68 (m, 2H), 3.54 (m, 4H), 2.88 (m, 2H), 2.80 (m, 2H), 2.65 (d, 2H), 1.21 (t, 6H).

[0052] Step (2). At 0 °C ± 10 °C, dissolve compound (IV-2) (12.1 g) in an equal mass of water, and put this aqueous solution into concentrated hydrochloric acid (1.2 times the mass of compound (IV-2)). Under nitrogen protection, raise the temperature to 35 °C ± 5 °C and react for 5.0 h, then start HPLC monitoring. After that, sample and send for inspection once every 1.0 h until the compound (IV-2) ≤ 10.5%. Stop the reaction to obtain compound (IV). The reaction solution is directly used for the next step without any treatment, and the yield is recorded as 100%. MS (ESI, pos. ion) m / z: 172.2 [M + 1] + 。

[0053] Synthesis of the aminoquinazoline tyrosine kinase inhibitor compound (A) in Example 1

[0054]

[0055] Step (1). At 25 °C ± 5 °C, add 12 g of sec-butanol into a reaction flask, then add 10 g (1.0 eq) of the compound of formula (I) and ammonium sulfide (40 - 48% aqueous solution, 10 eq). Stir at 25 °C ± 5 °C for 1.0 h and start HPLC monitoring. When the remaining amount of the compound of formula (I) ≤ 0.1%, continue to heat up to 70 °C for reaction. Start HPLC monitoring 3 hours after adding ammonium sulfide and send samples for inspection every hour. When the remaining amount of the hydroxylamine intermediate state of the compound of formula (I) ≤ 2.5%, end the reaction after 5 h. Add water, cool to room temperature, precipitate solids, filter, wash with water, and dry (60 °C ± 5 °C) until the water content ≤ 0.9% to obtain the compound of formula (II) as an off-white solid with a purity of 90% and a yield of 85%. MS (ESI, pos. ion) m / z: 322.2 [M + 1] + 。

[0056] Step (2). At 25 °C ± 10 °C, dissolve diethylphosphonoacetic acid in N,N-dimethylformamide (6.57 g), add N,N'-carbonyldiimidazole (CDI), and continue to stir at room temperature (25 °C ± 10 °C) for 1.0 h. Then add 0.73 g of the compound of formula (II). The equivalent ratio of the compound of formula (II), N,N'-carbonyldiimidazole (CDI), and diethylphosphonoacetic acid is 1.0 eq: 1.5 eq: 1.7 eq. Start timing after adding all the materials. Start HPLC monitoring from the 1st hour of the reaction and send samples for inspection every 0.5 hour. When the compound of formula (II) ≤ 0.30% (after 15 h of reaction), pour the reaction solution into ice water, precipitate solids, filter, and slurry the filter cake with EA:Hexane = 1:2 without controlling the temperature for 12 hours, then filter and dry. Heat the solid to reflux with toluene until S ≤ 0.5% (to remove the residual elemental sulfur from the previous step), cool, dry, and the slurried solid is red. Decolorize the color with activated carbon (the decolorizing solvent is a mixed solvent of ethyl acetate and methanol), filter, concentrate, and dry (60 °C ± 5 °C) until the water content ≤ 3.0% to obtain the compound of formula (III) as an off-white solid with a purity of 96% and a yield of 94%.

[0057] Step (3). Add the compound of formula (III) (10 g, 1 eq) into a reaction flask containing tetrahydrofuran (100 mL), cool it to -20 °C ± 5 °C, and slowly add anhydrous lithium chloride (2.0 eq) and an aqueous solution of 25% potassium hydroxide (2.0 eq) in sequence. After the addition is complete, slowly drip the compound of formula (IV) (3.0 eq). After the dripping is complete, warm the temperature to -5 °C ± 5 °C and stir the reaction until (I-3) ≤ 0.85%. Then warm the temperature to 25 °C ± 5 °C, add water to precipitate a solid, stir, filter, dry (60 °C ± 5 °C), slurry with acetone, filter, and dry (60 °C ± 5 °C) until the water content ≤ 5.0% to obtain the product (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(methoxy-d3)quinazolin-6-yl)-4-((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)but-2-enamide, which is the aminoquinazoline tyrosine kinase inhibitor compound (A). 8.8 g of the product is obtained as a pale white solid, with a yield of 85% and a purity of 96.8%. The spectral data of the aminoquinazoline tyrosine kinase inhibitor compound (A) are as follows: MS (ESI, pos.ion) m / z: 517.9 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 10.90 (s, 1H), 9.45 (s, 1H), 8.92 (s, 1H), 8.12 (dd, J1 = 6.8 Hz, J2 = 2.6 Hz, 1H), 7.76 (s, 1H), 7.58 (s, 1H), 7.57 (t, J = 8.4 Hz, 1H), 6.77 - 6.67 (m, 1H), 6.59 (d, J = 16.2 Hz, 1H), 3.78 (t, J = 6.2 Hz, 4H), 3.26 (t, J = 4.4 Hz, 2H), 3.20 (dd, J1 = 7.8 Hz, J2 = 2.6 Hz, 2H), 2.26 (d, J = 4.6 Hz, 4H).

[0058] Comparison of the process of step (1) in Example 2 for preparing the aminoquinazoline tyrosine kinase inhibitor compound (A) with the process of step (1) in Example 1

[0059] This example refers to the process of step (1) in Example 1, with the difference being the different reaction conditions. The reaction conditions and reaction results are shown in Table 1 below.

[0060] Table 1

[0061]

[0062]

[0063] Note: "N / A" in the table indicates that the HPLC purity of compound (III) in the reaction solution after the reaction ends is too low or the HPLC of the reaction solution shows a large number of impurities (the HPLC purity is far lower than 40%).

[0064] The above table shows that when the molar ratio of the compound of formula (I) to ammonium sulfide is 1eq:6eq, using sec-butanol as the solvent and the reaction temperature is 70 °C, the yield of the compound of formula (II) is the highest, the purity is the best, the highest yield can reach 85%, and the purity can reach 90%.

[0065] Comparison of Process 3-1-3-19 in Step (2) for Preparing the Aminoketolide Tyrosine Kinase Inhibitor Compound (A) in Example 3 with the Process in Step (2) of Example 1

[0066] This example refers to the process of Step (2) in Example 1, the difference lies in the different reaction conditions. The reaction conditions and reaction results are shown in Table 2 below.

[0067] Table 2

[0068]

[0069]

[0070] It can be seen from the above table that when using DMF as the reaction solvent, when the molar ratio of the compound of formula (I) to CDI to diethyl phosphonoacetate is 1.0eq:1.5eq:1.7eq, the yield is as high as 97% and the purity is 97%.

[0071] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made on the basis of the above description and ideas. It is not necessary and impossible to list all the implementation manners here. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing an aminoquinazoline tyrosine kinase inhibitor compound (A), characterized in that, It includes the following steps: S1. Mix and stir the compound of formula (I), an alcohol solvent, and ammonium sulfide, and then heat to 70 - 80 °C for reaction to obtain the compound of formula (II); S2. Mix and stir diethylphosphonoacetic acid, a first solvent, and N,N'-carbonyldiimidazole, add the compound of formula (II) for reaction, and obtain the compound of formula (III) after post-treatment; S3. Mix the compound of formula (III) with a second solvent, cool down, add anhydrous lithium chloride, a potassium hydroxide solution, and the compound of formula (IV) for reaction to obtain the aminoquinazoline tyrosine kinase inhibitor compound (A); In the step S1, the equivalent ratio of the compound of formula (I) to ammonium sulfide is 1:(6 - 10); The equivalent ratio of the compound of formula (II), N,N'-carbonyldiimidazole, and diethylphosphonoacetic acid is 1:1.5:(1.5 - 1.7); The reaction formula of the synthesis method is as follows: 。 2. The synthesis method according to claim 1, characterized in that, In the step S1, the alcohol solvent is n-propanol, isopropanol, n-butanol, or sec-butanol.

3. The synthesis method according to claim 1, wherein In the step S1, the equivalent ratio of the compound of formula (I) to ammonium sulfide is 1:(6 - 6.2); the alcohol solvent is sec-butanol.

4. The synthesis method according to claim 3, wherein In the step S1, the mass ratio of the compound of formula (I) to the alcohol solvent is 1:(12 - 13).

5. The synthesis method according to claim 3, characterized in that, The equivalent ratio of the compound of formula (II), N,N'-carbonyldiimidazole, and diethylphosphonoacetic acid is 1:1.5:1.

5.

6. The synthesis method according to claim 1, characterized in that, In the step S2, the first solvent is selected from one or more of N,N-dimethylformamide, tetrahydrofuran, or ethylene glycol dimethyl ether.

7. The synthesis method according to claim 6, characterized in that, The first solvent is N,N-dimethylformamide.

8. The synthesis method according to claim 1, characterized in that, In the step S3, cool down to -15 °C - -25 °C; the reaction temperature is -10 °C - 0 °C.

9. The synthesis method according to claim 1 or 8, characterized in that In the step S3, the equivalent ratio of the compound of formula (III), anhydrous lithium chloride, and potassium hydroxide is 1:(1.5 - 2.5):(1.5 - 2.5).

10. The synthesis method according to claim 9, wherein, The equivalent ratio of the compound of formula (III), anhydrous lithium chloride, and potassium hydroxide is 1:2.0:2.0.

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