Preparation method of dacotinib key intermediate

Abstract

The invention relates to a preparation method of a key intermediate P of Dacrotinib. The method has the advantages of short steps, environmental friendliness, simplicity in operation, safety, high total yield, mild reaction, low cost and high economic benefit, is more suitable for industrial production, and has a very good application prospect.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a method for preparing a key intermediate of dacomitinib, a lung cancer targeted drug. Background Technology

[0002] Dacomitinib is a second-generation targeted therapy for lung cancer, jointly developed by Pfizer and Warner Lamb. It irreversibly inhibits three different ERBB family members, including EGFR (HER1), HER2, and HER4. In June 2019, dacomitinib was approved for marketing in China for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion mutations or exon 21 L858R substitution mutations. In addition, in vitro studies have shown that dacomitinib has a significant growth inhibitory effect in HER2-amplified gastric cancer cells (SNU216, N87), and in most sensitive cell lines, dacomitinib can induce apoptosis through G0 / G1 phase arrest, thereby exerting its anti-proliferative effect.

[0003]

[0004] Compound P is a key intermediate in the preparation of dacomitinib, and its structure is as follows:

[0005]

[0006] Chinese patent CN112707846 A discloses a method for preparing a key intermediate P of dacomitinib as follows:

[0007]

[0008] Step 1: React compound PO5-10A, an acid-binding agent, and an acetylation reagent in an organic solvent to obtain compound PO5-10A-1A;

[0009] Step 2: Add nitrifying agent and dehydrating agent to compound P05-10A-1A to react and obtain compound P05-10A-2A;

[0010] Step 3: Compound PO5-10A-2A reacts with a base or acid in an organic solvent to give compound PO5-10A-3A;

[0011] Step 4: Compound P05-10A-3A and the reagent for preparing acyl chloride are dissolved in an organic solvent and reacted. After the reaction, ammonia water is added to react and give compound P05-10A-4A.

[0012] Step 5: React compound PO5-10A-4A and a dehydrating agent in an organic solvent to obtain compound PO5-4A;

[0013] Step 6: React compound PO5-4A and N,N-dimethylformamide dimethyl acetal in an organic solvent to obtain the dacomitinib intermediate.

[0014] This synthetic route is lengthy, has a long synthesis cycle, low overall yield, and involves harsh reaction conditions and highly irritating reagents, such as the acetylation reagent used in step 1, the nitration reagent used in step 2, the chlorination reagent used in step 4, and the dehydrating agent used in step 5. Therefore, it is not suitable for large-scale industrial production.

[0015] Therefore, improving the existing process for preparing intermediate P has significant practical value. Summary of the Invention

[0016] The problem the invention aims to solve

[0017] To address the aforementioned problems in the existing technology, this invention provides a method for preparing intermediate P that is shorter in steps, more environmentally friendly, simple and safe to operate, has a high overall yield and mild reaction, is low in cost and economically efficient, is more suitable for industrial production, and has excellent application prospects.

[0018] Solution for solving the problem

[0019] A method for preparing dacomitinib intermediate compound P, characterized by comprising the following steps:

[0020]

[0021] Step S2: Compound P1 undergoes an ammoniation reaction to obtain compound P2;

[0022] Step S3: Compound P2 undergoes an acetal reaction to yield compound P.

[0023] Preferably, step S2 is carried out in the presence of amination reagent C.

[0024] Preferably, the ammoniation reagent C is selected from... One or more of the following, wherein X is selected from N, O, S and CH, and R is selected from halogen, nitro, hydroxyl, alkoxy and alkyl.

[0025] Preferably, the ammoniation reagent C is selected from... One or more of them.

[0026] Preferably, step S2 is a reaction that occurs in the presence of a base.

[0027] Preferably, the alkali in step S2 is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, and cesium fluoride.

[0028] Preferably, the alkali in step S2 is selected from one or more of sodium tert-butoxide and potassium tert-butoxide.

[0029] Preferably, step S2 involves a reaction occurring in a solvent.

[0030] Preferably, the solvent in step S2 is selected from organic solvents.

[0031] Preferably, the solvent in step S2 is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, acetone and dimethyl sulfoxide.

[0032] Preferably, the solvent in step S2 is selected from one or more of acetone and dimethyl sulfoxide.

[0033] Preferably, in step S2, the molar ratio of compound P1 to amination reagent C is 1.0:1.0 to 5.0.

[0034] Preferably, in step S2, the molar ratio of compound P1 to amination reagent C is 1.0:1.0 to 3.0.

[0035] Preferably, in step S2, the molar ratio of compound P1 to the base is 1.0:1.0 to 5.0.

[0036] Preferably, in step S2, the molar ratio of compound P1 to base is 1.0:2.5-4.0.

[0037] Preferably, in step S2, the mass-to-volume ratio of compound P1 to solvent is 1.0:0.5 to 20.0, in g / mL.

[0038] Preferably, in step S2, the mass-to-volume ratio of compound P1 to solvent is 1.0:10.0 to 20.0, in g / mL.

[0039] Preferably, step S3 is a reaction that occurs in the presence of N,N-dimethylformamide dimethyl acetal.

[0040] Preferably, step S3 involves a reaction occurring in a solvent.

[0041] Preferably, the solvent in step S3 is selected from organic solvents.

[0042] Preferably, the solvent in step S3 is selected from one or more of 2-methyltetrahydrofuran, n-heptane, ethylene glycol dimethyl ether, m-xylene, and toluene.

[0043] Preferably, the solvent in step S3 is selected from one or more of toluene and m-xylene.

[0044] Preferably, the molar ratio of compound P2 to N,N-dimethylformamide dimethyl acetal is 1.0:1.0 to 10.0.

[0045] Preferably, the molar ratio of compound P2 to N,N-dimethylformamide dimethyl acetal is 1.0:4.0 to 8.0.

[0046] Preferably, the mass-to-volume ratio of compound P2 to solvent is 1.0:0.5 to 20.0, in g / mL.

[0047] Preferably, the mass-to-volume ratio of compound P2 to solvent is 1.0:8.0 to 18.0, in g / mL;

[0048] Preferably, the reaction temperature in step S3 is 20–140°C.

[0049] Preferably, the reaction temperature in step S3 is 60–120°C.

[0050] Preferably, the reaction temperature in step S3 is 105–115°C.

[0051] Preferably, the method further includes the following steps:

[0052]

[0053] Step S1: Compound A undergoes an etherification reaction to give compound P1.

[0054] Preferably, step S1 is a reaction that occurs in the presence of a base.

[0055] Preferably, the alkali in step S1 is selected from methanol base, and more preferably from one or more of sodium methoxide, potassium methoxide and calcium methoxide.

[0056] Preferably, the alkali in step S1 is selected from sodium methoxide.

[0057] Preferably, step S1 involves a reaction occurring in a solvent.

[0058] Preferably, the solvent in step S1 is selected from organic solvents.

[0059] Preferably, the solvent in step S1 is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0060] Preferably, the solvent in step S1 is one or more of N,N-dimethylformamide and N,N-dimethylacetamide.

[0061] Preferably, the molar ratio of compound A to base is 1.0:1.0 to 5.0.

[0062] Preferably, the molar ratio of compound A to base is 1.0:1.0 to 3.0.

[0063] Preferably, the mass-to-volume ratio of compound A to solvent is 1.0:5.0 to 15.0, in g / mL.

[0064] Preferably, the mass-to-volume ratio of compound A to solvent is 1.0:10.0 to 15.0, in g / mL.

[0065] Preferably, the post-processing step S1 includes adding water to the reaction solution after the reaction is completed, filtering, and drying the filter cake to obtain product P1.

[0066] Preferably, the mass-volume ratio of compound A to water is 1.0:1.0 to 30.0, in g / mL.

[0067] Preferably, the mass-volume ratio of compound A to water is 1.0:10.0 to 15.0, in g / mL.

[0068] Preferably, the post-processing step S2 includes adding water to the reaction solution after the reaction is completed, extracting with an organic solvent, and removing the solvent from the organic layer to obtain the crude product.

[0069] Preferably, the crude product is recrystallized using a purification organic solvent to obtain product P2, wherein the purification organic solvent is selected from one or more of toluene, dichloromethane, methyl acetate, ethyl acetate, butyl acetate, petroleum ether, diethyl ether, methyl tert-butyl ether, n-pentane, n-hexane, and n-heptane.

[0070] Preferably, the crude product is dissolved in dichloromethane, then petroleum ether is added, the product is precipitated, filtered, and the filter cake is dried to obtain product P2.

[0071] Preferably, the post-processing step S3 includes adding water to the reaction solution after the reaction is completed, filtering, and drying the filter cake to obtain the crude product.

[0072] Preferably, the crude product is recrystallized using a purification organic solvent to obtain product P, wherein the purification organic solvent is selected from one or more of methanol, ethanol, and isopropanol.

[0073] Preferably, the crude product is dissolved in ethanol, cooled, precipitated, filtered, and the filter cake is dried to obtain product P.

[0074] The effects of the invention

[0075] (1) The method for preparing intermediate P in this invention involves only three steps, which is short, has a high overall yield, and is economically efficient.

[0076] (2) The present invention utilizes an amination reagent to directly add an amino group. The reaction conditions are mild. This preparation method has obvious advantages, such as reducing reaction steps, avoiding the use of dangerous reagents, and simplifying post-processing steps, making it suitable for industrial production. Attached Figure Description

[0077] Figure 1 For intermediate P1 1 H NMR spectrum.

[0078] Figure 2 For intermediate P2 1 H NMR spectrum.

[0079] Figure 3 For intermediate P 1 H NMR spectrum. Detailed Implementation

[0080] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0081] This invention provides a method for preparing dacomitinib intermediate compound P, comprising the following steps:

[0082]

[0083] Step S2: Compound P1 undergoes an ammoniation reaction to obtain compound P2;

[0084] Step S3: Compound P2 undergoes an acetal reaction to yield compound P.

[0085] In some embodiments, step S2 occurs in the presence of amination reagent C.

[0086] In some embodiments, the amination reagent C in step S2 is selected from... One or more of the following, wherein X is selected from N, O, S and CH, and R is selected from halogen, nitro, hydroxyl, alkoxy and alkyl.

[0087] In some embodiments, the amination reagent C is selected from... One or more of them.

[0088] In some embodiments, step S2 is a reaction that occurs in the presence of a base.

[0089] In some embodiments, the base in step S2 is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, and cesium fluoride.

[0090] In some embodiments, the base in step S2 is selected from one or more of sodium tert-butoxide and potassium tert-butoxide.

[0091] In some embodiments, the base mentioned in step S2 is selected from sodium tert-butoxide.

[0092] In some embodiments, step S2 is a reaction that occurs in a solvent.

[0093] In some embodiments, the solvent in step S2 is selected from organic solvents.

[0094] In some embodiments, the solvent in step S2 is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, acetone, and dimethyl sulfoxide.

[0095] In some embodiments, the solvent in step S2 is selected from one or more of acetone and dimethyl sulfoxide.

[0096] In some embodiments, the solvent in step S2 is selected from dimethyl sulfoxide.

[0097] In some embodiments, the molar ratio of compound P1 to amination reagent C in step S2 is 1.0:1.0 to 5.0.

[0098] In some embodiments, the molar ratio of compound P1 to amination reagent C in step S2 is 1.0:1.0 to 3.0.

[0099] In some embodiments, the molar ratio of compound P1 to base in step S2 is 1.0:1.0 to 5.0.

[0100] In some embodiments, the molar ratio of compound P1 to base in step S2 is 1.0:2.5 to 4.0.

[0101] In some embodiments, the mass-to-volume ratio of compound P1 to solvent in step S2 is 1.0:0.5 to 20.0, in g / mL.

[0102] In some embodiments, the mass-to-volume ratio of compound P1 to solvent in step S2 is 1.0:10.0-20.0, in g / mL.

[0103] In some embodiments, the post-processing step S2 includes adding water to the reaction solution after the reaction is complete, extracting with an organic solvent, and removing the solvent from the organic layer to obtain the crude product.

[0104] In some embodiments, the crude product in the post-processing step S2 is recrystallized using a purification organic solvent to obtain product P2, wherein the purification organic solvent is selected from one or more of toluene, dichloromethane, methyl acetate, ethyl acetate, butyl acetate, petroleum ether, diethyl ether, methyl tert-butyl ether, n-pentane, n-hexane, and n-heptane.

[0105] In some embodiments, in the post-processing step of step S2, the crude product is dissolved in dichloromethane, then petroleum ether is added, precipitated, filtered, and the filter cake is dried to obtain product P2.

[0106] In some embodiments, the post-processing steps of step S2 include adding an appropriate amount of water and stirring after the reaction is complete, extracting with an organic solvent, drying to remove the solvent, dissolving in dichloromethane, adding petroleum ether to precipitate, filtering, and drying the filter cake at a temperature of 45°C and a vacuum of -0.08MPa to 0.01MPa to obtain product P2.

[0107] In some embodiments, step S3 is a reaction that occurs in the presence of N,N-dimethylformamide dimethyl acetal.

[0108] In some embodiments, step S3 is a reaction that occurs in a solvent.

[0109] In some embodiments, the solvent in step S3 is selected from organic solvents.

[0110] In some embodiments, the solvent in step S3 is selected from one or more of 2-methyltetrahydrofuran, n-heptane, ethylene glycol dimethyl ether, m-xylene, and toluene.

[0111] In some embodiments, the solvent in step S3 is selected from toluene.

[0112] In some embodiments, the molar ratio of compound P2 and N,N-dimethylformamide dimethyl acetal in step S3 is 1.0:1.0 to 10.0.

[0113] In some embodiments, the molar ratio of compound P2 and N,N-dimethylformamide dimethyl acetal in step S3 is 1.0:4.0 to 8.0.

[0114] In some embodiments, the mass-to-volume ratio of compound P2 to solvent in step S3 is 1.0:0.5 to 20.0, in g / mL.

[0115] In some embodiments, the mass-to-volume ratio of compound P2 to solvent in step S3 is 1.0:8.0 to 18.0, in g / mL.

[0116] In some embodiments, the reaction temperature of step S3 is 20–140°C.

[0117] In some embodiments, the reaction temperature of step S3 is 60–120°C.

[0118] In some embodiments, the reaction temperature of step S3 is 105–115°C.

[0119] In some embodiments, the post-processing step S3 includes adding water to the reaction solution after the reaction is complete, filtering, and drying the filter cake to obtain the crude product.

[0120] In some embodiments, the crude product in the post-processing step S3 is recrystallized using a purification organic solvent to obtain product P, wherein the purification organic solvent is selected from one or more of methanol, ethanol and isopropanol.

[0121] In some embodiments, in the post-processing step of step S3, the crude product is dissolved in ethanol, cooled, precipitated, filtered, and the filter cake is dried to obtain product P.

[0122] In some embodiments, the post-processing step S3 includes adding an appropriate amount of water and stirring after the reaction is complete, adding water to the reaction solution, precipitating a solid, filtering to obtain a crude product, adding ethanol to the crude product, stirring at 80°C for 1 hour, cooling, filtering, and drying the filter cake at 45°C and a vacuum of -0.08MPa to 0.01MPa to obtain product P.

[0123] In some embodiments, the method further includes the following steps:

[0124]

[0125] Step S1: Compound A undergoes an etherification reaction to give compound P1.

[0126] In some implementations, step S1 is a reaction that occurs in the presence of a base.

[0127] In some embodiments, the base mentioned in step S1 is selected from methanol base.

[0128] In some embodiments, the base in step S1 is selected from one or more of sodium methoxide, potassium methoxide, and calcium methoxide.

[0129] In some embodiments, the base mentioned in step S1 is selected from sodium methoxide.

[0130] In some embodiments, step S1 is a reaction that occurs in a solvent.

[0131] In some embodiments, the solvent in step S1 is selected from organic solvents.

[0132] In some embodiments, the solvent in step S1 is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0133] In some embodiments, the solvent in step S1 is selected from one or more of N,N-dimethylformamide and N,N-dimethylacetamide.

[0134] In some embodiments, the solvent in step S1 is selected from N,N-dimethylformamide.

[0135] In some embodiments, the molar ratio of compound A to base in step S1 is 1.0:1.0 to 5.0.

[0136] In some embodiments, the molar ratio of compound A to base in step S1 is 1.0:1.0 to 3.0.

[0137] In some embodiments, the mass-to-volume ratio of compound A to solvent in step S1 is 1.0:5.0 to 15.0, in g / mL.

[0138] In some embodiments, the mass-to-volume ratio of compound A to solvent in step S1 is 1.0:10.0 to 15.0, in g / mL.

[0139] In some embodiments, the post-processing step S1 includes adding water to the reaction solution after the reaction is complete, filtering, and drying the filter cake to obtain product P1.

[0140] In some embodiments, the mass-volume ratio of compound A to water in the post-processing step S1 is 1.0:1.0 to 30.0, in g / mL.

[0141] In some embodiments, the mass-volume ratio of compound A to water in the post-processing step S1 is 1.0:10.0 to 15.0, in g / mL.

[0142] In some embodiments, the post-processing step S1 includes adding an appropriate amount of water and stirring after the reaction is complete, causing product P1 to precipitate, filtering, washing the filter cake with water, and drying at a temperature of 45°C and a vacuum degree of -0.08MPa to 0.01MPa to obtain product P1.

[0143] This invention provides a method for preparing dacomitinib intermediate compound P, comprising the following steps:

[0144]

[0145] Step S1: Compound A undergoes an etherification reaction to give compound P1;

[0146] Step S2: Compound P1 undergoes an ammoniation reaction to obtain compound P2;

[0147] Step S3: Compound P2 undergoes an acetal reaction to yield compound P.

[0148] In some implementations, step S1 is a reaction that occurs in the presence of a base.

[0149] In some embodiments, the base mentioned in step S1 is selected from methanol base.

[0150] In some embodiments, the base in step S1 is selected from one or more of sodium methoxide, potassium methoxide, and calcium methoxide.

[0151] In some embodiments, the base mentioned in step S1 is selected from sodium methoxide.

[0152] In some embodiments, step S1 is a reaction that occurs in a solvent.

[0153] In some embodiments, the solvent in step S1 is selected from organic solvents.

[0154] In some embodiments, the solvent in step S1 is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0155] In some embodiments, the solvent in step S1 is selected from one or more of N,N-dimethylformamide and N,N-dimethylacetamide.

[0156] In some embodiments, the solvent in step S1 is selected from N,N-dimethylformamide.

[0157] In some embodiments, the molar ratio of compound A to base in step S1 is 1.0:1.0 to 5.0.

[0158] In some embodiments, the molar ratio of compound A to base in step S1 is 1.0:1.0 to 3.0.

[0159] In some embodiments, the mass-to-volume ratio of compound A to solvent in step S1 is 1.0:5.0 to 15.0, in g / mL.

[0160] In some embodiments, the mass-to-volume ratio of compound A to solvent in step S1 is 1.0:10.0 to 15.0, in g / mL.

[0161] In some embodiments, the post-processing step S1 includes adding water to the reaction solution after the reaction is complete, filtering, and drying the filter cake to obtain product P1.

[0162] In some embodiments, the mass-volume ratio of compound A to water in the post-processing step S1 is 1.0:1.0 to 30.0, in g / mL.

[0163] In some embodiments, the mass-volume ratio of compound A to water in the post-processing step S1 is 1.0:10.0 to 15.0, in g / mL.

[0164] In some embodiments, the post-processing step S1 includes adding an appropriate amount of water and stirring after the reaction is complete, precipitating product P1, filtering, washing the filter cake with water, and drying it at a temperature of 45°C and a vacuum degree of -0.08MPa to 0.01MPa to obtain product P1.

[0165] In some embodiments, step S2 occurs in the presence of amination reagent C.

[0166] In some embodiments, the amination reagent C in step S2 is selected from... One or more of the following, wherein X is selected from N, O, S and CH, and R is selected from halogen, nitro, hydroxyl, alkoxy and alkyl.

[0167] In some embodiments, the amination reagent C is selected from... One or more of them.

[0168] In some embodiments, step S2 is a reaction that occurs in the presence of a base.

[0169] In some embodiments, the base in step S2 is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, and cesium fluoride.

[0170] In some embodiments, the base in step S2 is selected from one or more of sodium tert-butoxide and potassium tert-butoxide.

[0171] In some embodiments, the base mentioned in step S2 is selected from sodium tert-butoxide.

[0172] In some embodiments, step S2 is a reaction that occurs in a solvent.

[0173] In some embodiments, the solvent in step S2 is selected from organic solvents.

[0174] In some embodiments, the solvent in step S2 is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, acetone, and dimethyl sulfoxide.

[0175] In some embodiments, the solvent in step S2 is selected from one or more of acetone and dimethyl sulfoxide.

[0176] In some embodiments, the solvent in step S2 is selected from dimethyl sulfoxide.

[0177] In some embodiments, the molar ratio of compound P1 to amination reagent C in step S2 is 1.0:1.0 to 5.0.

[0178] In some embodiments, the molar ratio of compound P1 to amination reagent C in step S2 is 1.0:1.0 to 3.0.

[0179] In some embodiments, the molar ratio of compound P1 to base in step S2 is 1.0:1.0 to 5.0.

[0180] In some embodiments, the molar ratio of compound P1 to base in step S2 is 1.0:2.5 to 4.0.

[0181] In some embodiments, the mass-to-volume ratio of compound P1 to solvent in step S2 is 1.0:0.5 to 20.0, in g / mL.

[0182] In some embodiments, the mass-to-volume ratio of compound P1 to solvent in step S2 is 1.0:10.0-20.0, in g / mL.

[0183] In some embodiments, the post-processing step S2 includes adding water to the reaction solution after the reaction is complete, extracting with an organic solvent, and removing the solvent from the organic layer to obtain the crude product.

[0184] In some embodiments, the crude product in the post-processing step S2 is recrystallized using a purification organic solvent to obtain product P2, wherein the purification organic solvent is selected from one or more of toluene, dichloromethane, methyl acetate, ethyl acetate, butyl acetate, petroleum ether, diethyl ether, methyl tert-butyl ether, n-pentane, n-hexane, and n-heptane.

[0185] In some embodiments, in the post-processing step of step S2, the crude product is dissolved in dichloromethane, then petroleum ether is added, precipitated, filtered, and the filter cake is dried to obtain product P2.

[0186] In some embodiments, the post-processing step S2 includes adding an appropriate amount of water and stirring after the reaction is complete, extracting with an organic solvent, drying the organic layer to remove the solvent and obtain a residue, dissolving the residue with dichloromethane, precipitating it with petroleum ether, filtering, and drying the filter cake at a temperature of 45°C and a vacuum of -0.08MPa to 0.01MPa to obtain product P2.

[0187] In some embodiments, step S3 is a reaction that occurs in the presence of N,N-dimethylformamide dimethyl acetal.

[0188] In some embodiments, step S3 is a reaction that occurs in a solvent.

[0189] In some embodiments, the solvent in step S3 is selected from organic solvents.

[0190] In some embodiments, the solvent in step S3 is selected from one or more of 2-methyltetrahydrofuran, n-heptane, ethylene glycol dimethyl ether, m-xylene, and toluene.

[0191] In some embodiments, the solvent in step S3 is selected from toluene.

[0192] In some embodiments, the molar ratio of compound P2 and N,N-dimethylformamide dimethyl acetal in step S3 is 1.0:1.0 to 10.0.

[0193] In some embodiments, the molar ratio of compound P2 and N,N-dimethylformamide dimethyl acetal in step S3 is 1.0:4.0 to 8.0.

[0194] In some embodiments, the mass-to-volume ratio of compound P2 to solvent in step S3 is 1.0:0.5 to 20.0, in g / mL.

[0195] In some embodiments, the mass-to-volume ratio of compound P2 to solvent in step S3 is 1.0:8.0 to 18.0, in g / mL.

[0196] In some embodiments, the reaction temperature of step S3 is 20–140°C.

[0197] In some embodiments, the reaction temperature of step S3 is 60–120°C.

[0198] In some embodiments, the reaction temperature of step S3 is 105–115°C.

[0199] In some embodiments, the post-processing step S3 includes adding water to the reaction solution after the reaction is complete, filtering, and drying the filter cake to obtain the crude product.

[0200] In some embodiments, the crude product in the post-processing step S3 is recrystallized using a purification organic solvent to obtain product P, wherein the purification organic solvent is selected from one or more of methanol, ethanol and isopropanol.

[0201] In some embodiments, in the post-processing step of step S3, the crude product is dissolved in ethanol, cooled, precipitated, filtered, and the filter cake is dried to obtain product P.

[0202] In some embodiments, the post-processing step S3 includes cooling after the reaction is complete, adding water to the reaction solution to precipitate the solid, filtering to obtain a crude product, adding ethanol to the crude product, stirring at 80°C for 1 hour, cooling, filtering, and drying the filter cake at 45°C and a vacuum of -0.08MPa to 0.01MPa to obtain product P.

[0203] The method of the present invention will be described below through specific embodiments. It should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0204] The following examples 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0205] TLC: Thin-layer chromatography. Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for TLC. The silica gel plates used in TLC have a diameter of 0.2mm-0.3mm, while those used for separating and purifying products are 0.4mm-0.5mm.

[0206] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0207] In the following examples, unless otherwise specified, all temperatures are in Celsius; unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods; commercially available materials and reagents are used directly without further purification; unless otherwise specified, commercially available manufacturers include, but are not limited to, Sinopharm Group, Bailingwei Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd., and Shanghai Mairui Chemical Technology Co., Ltd.

[0208] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0209] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0210] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, or the developing solvent system for TLC included: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate. The volume ratio of the solvent varied depending on the polarity of the compound and could also be adjusted by adding a small amount of acidic or basic reagents, such as acetic acid or triethylamine.

[0211] Example 1

[0212]

[0213] 20.0 g (172 mmol) of 4-fluoro-3-nitrobenzene (compound A) was added to 240.0 mL of N,N-dimethylformamide at 20-30 °C and stirred until dissolved. 10 g (186 mmol) of sodium methoxide was slowly added, and the reaction was maintained at 20-25 °C for 2 h after the addition was complete. 300 mL of water was added, and product P1 precipitated. The product was filtered, the filter cake was washed with water, dried under vacuum, and the solid was dried at 45 °C. 19.5 g of bright yellow solid (intermediate P1) was obtained, with a molar yield of 91.0%.

[0214] 18.0 g (101 mmol) of 4-methoxy-3-nitrobenzene (intermediate P1) and 8.5 g (101 mmol) of 4H-1,2,4-triazol-4-amine were dissolved in 120 mL of dimethyl sulfoxide and stirred. 24.3 g (253 mmol) of sodium tert-butoxide was dissolved in 120 mL of dimethyl sulfoxide and added dropwise. The reaction color deepened with the addition of sodium tert-butoxide solution. After the addition was complete, the reaction was maintained at 20–25 °C for 2 h. The reaction was quenched with water, extracted with ethyl acetate, dried, dissolved in dichloromethane, and precipitated with petroleum ether. The precipitate was dried under vacuum, and the solid was dried at 45 °C to give 14.3 g of a yellow solid (intermediate P2), with a molar yield of 73.3%.

[0215] 13.0 g (67 mmol) of 2-amino-4-methoxy-5-nitrobenzenenitrile (intermediate P2), 40.1 g (337 mmol) of N,N-dimethylformamide dimethyl acetal, and 160 mL of toluene were added, and the mixture was heated to 105–115 °C and maintained at this temperature for 4 h. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, and 50 mL of water was added to the reaction solution. A solid precipitated, was filtered, and dried under vacuum to obtain the crude product. 160 mL of ethanol was added to the crude product, and the mixture was stirred at 80 °C for 1 h. The mixture was then cooled to room temperature, filtered, and dried under vacuum. The solid was dried overnight at 45 °C to give 14.3 g of a yellow solid (intermediate P), with a molar yield of 85.5%.

[0216] Example 2

[0217]

[0218] 200.0 g (1.72 mol) of 4-fluoro-3-nitrobenzenenitrile (compound A) was added to 2.4 L of N,N-dimethylformamide at 20-30 °C and stirred until dissolved. 100 g (1.86 mol) of sodium methoxide was slowly added, and the reaction was maintained at 20-25 °C for 3 h. 3 L of water was added, and product P1 precipitated. The product was filtered, the filter cake was washed with water, dried under vacuum, and the solid was dried at 45 °C. 193.2 g of bright yellow solid (intermediate P1) was obtained, with a molar yield of 90.1%.

[0219] 190.0 g (1.07 mol) of 4-methoxy-3-nitrobenzene (intermediate P1) and 89.7 g (1.07 mol) of 4H-1,2,4-triazol-4-amine were dissolved in 1.2 L of dimethyl sulfoxide and stirred. 256.5 g (2.67 mol) of sodium tert-butoxide was dissolved in 1.2 L of dimethyl sulfoxide and added dropwise. The reaction color deepened with each addition of sodium tert-butoxide solution. After the addition was complete, the reaction was maintained at 20–25 °C for 2 h. The reaction was then quenched with water, extracted with ethyl acetate, dried, dissolved in dichloromethane, and precipitated with petroleum ether. The precipitate was dried under vacuum, and the solid was dried at 45 °C to give 146.7 g of a yellow solid (intermediate P2), with a molar yield of 70.7%.

[0220] 140.0 g (725 mmol) of 2-amino-4-methoxy-5-nitrobenzenenitrile (intermediate P2), 431.8 g (3.63 mol) of N,N-dimethylformamide dimethyl acetal, and 1.75 L of toluene were added, and the mixture was heated to 105–115 °C and maintained at this temperature for 4 h. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, and 540 mL of water was added to the reaction solution. A solid precipitated, was filtered, and dried under vacuum to obtain the crude product. 1725 mL of ethanol was added to the crude product, and the mixture was stirred at 80 °C for 1 h. The mixture was then cooled to room temperature, filtered, and dried under vacuum. The solid was dried overnight at 45 °C to give 155.3 g of a yellow solid (intermediate P), with a molar yield of 86.3%.

[0221] Example 3

[0222]

[0223] 35.0 g (302 mmol) of 4-fluoro-3-nitrobenzene (compound A) was added to 500 mL of N,N-dimethylformamide at 20-30 °C and stirred until dissolved. 20 g (370 mmol) of sodium methoxide was slowly added, and the reaction was maintained at 20-25 °C for 2 h after the addition was complete. 525 mL of water was added, and product P1 precipitated. The product was filtered, the filter cake was washed with water, dried under vacuum, and the solid was dried at 45 °C. 34.7 g of bright yellow solid (intermediate P1) was obtained, with a molar yield of 92.4%.

[0224] 30.0 g (169 mmol) of 4-methoxy-3-nitrobenzene (intermediate P1) and 42.5 g (507 mmol) of 4H-1,2,4-triazol-4-amine were dissolved in 300 mL of acetone and stirred. 75 g (670 mmol) of potassium tert-butoxide was suspended in 300 mL of acetone and added dropwise. The reaction color deepened with the addition of potassium tert-butoxide solution. After the addition was complete, the reaction was maintained at 20–25 °C for 2 h. The reaction was quenched with water, extracted with ethyl acetate, dried, dissolved in dichloromethane, and precipitated with petroleum ether. The precipitate was dried under vacuum and the solid was dried at 45 °C to give 24.3 g of a yellow solid (intermediate P2), with a molar yield of 74.6%.

[0225] 20.0 g (104 mmol) of 2-amino-4-methoxy-5-nitrobenzenenitrile (intermediate P2), 93.2 g (783 mmol) of N,N-dimethylformamide dimethyl acetal, and 350 mL of m-xylene were added, and the mixture was heated to 105–115 °C and maintained at this temperature for 4 h. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, and 77 mL of water was added to the reaction solution. A solid precipitated, was filtered, and dried under vacuum to obtain the crude product. 250 mL of ethanol was added to the crude product, and the mixture was stirred at 80 °C for 1 h. The mixture was then cooled to room temperature, filtered, and dried under vacuum. The solid was dried overnight at 45 °C to give 21.5 g of a yellow solid (intermediate P), with a molar yield of 83.8%.

[0226] Example 4

[0227]

[0228] 35.0 g (302 mmol) of 4-fluoro-3-nitrobenzene (compound A) was added to 450 mL of N,N-dimethylacetamide at 20-30 °C and stirred until dissolved. 35 g (648 mmol) of sodium methoxide was slowly added, and the reaction was maintained at 20-25 °C for 2 h after the addition was complete. 500 mL of water was added, and product P1 precipitated. The product was filtered, the filter cake was washed with water, dried under vacuum, and the solid was dried at 45 °C. 48.3 g of bright yellow solid (intermediate P1) was obtained, with a molar yield of 89.9%.

[0229] 20.0 g (112 mmol) of 4-methoxy-3-nitrobenzene (intermediate P1) and 18.0 g (165 mmol) of O-phenylhydroxylamine were dissolved in 150 mL of N,N-dimethylformamide and stirred. 31.6 g (329 mmol) of sodium tert-butoxide was dissolved in 150 mL of N,N-dimethylformamide and added dropwise. The reaction color deepened with the addition of sodium tert-butoxide solution. After the addition was complete, the reaction was maintained at 20–25 °C for 2 h. The reaction was quenched with water, extracted with ethyl acetate, dried, dissolved in dichloromethane, and precipitated with petroleum ether. The precipitate was dried under vacuum, and the solid was dried at 45 °C to give 17.6 g of a yellow solid (intermediate P2), with a molar yield of 81.3%.

[0230] 16.0 g (83 mmol) of 2-amino-4-methoxy-5-nitrobenzenenitrile (intermediate P2), 40.0 g (336 mmol) of N,N-dimethylformamide dimethyl acetal, and 160 mL of toluene were added, and the mixture was heated to 105–115 °C and maintained at this temperature for 4 h. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, and 50 mL of water was added to the reaction solution. A solid precipitated, was filtered, and dried under vacuum to obtain the crude product. 160 mL of ethanol was added to the crude product, and the mixture was stirred at 80 °C for 1 h. The mixture was then cooled to room temperature, filtered, and dried under vacuum. The solid was dried overnight at 45 °C to give 17.9 g of a yellow solid (intermediate P), with a molar yield of 87.2%.

[0231] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A method for preparing dacomitinib intermediate compound P, characterized in that, Includes the following steps: Step S2: Compound P1 undergoes an ammoniation reaction to obtain compound P2; Step S3: Compound P2 undergoes an acetal reaction to yield compound P.

2. The method for preparing dacomitinib intermediate compound P according to claim 1, characterized in that, Step S2 is a reaction that occurs in the presence of amination reagent C. Preferably, the ammoniation reagent C is selected from... One or more of the following, wherein X is selected from N, O, S and CH, and R is selected from halogen, nitro, hydroxyl, alkoxy and alkyl, preferably. One or more of the following; Preferably, step S2 is a reaction that occurs in the presence of a base; Preferably, the alkali is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, and cesium fluoride, and more preferably one or more of sodium tert-butoxide and potassium tert-butoxide; Preferably, step S2 involves a reaction occurring in a solvent; Preferably, the solvent is selected from organic solvents, more preferably from one or more of N,N-dimethylformamide, N-methylpyrrolidone, acetone and dimethyl sulfoxide, and more preferably from one or more of acetone and dimethyl sulfoxide; Preferably, in step S2, the molar ratio of compound P1 to amination reagent C is 1.0:1.0 to 5.0, more preferably 1.0:1.0 to 3.0; Preferably, in step S2, the molar ratio of compound P1 to the base is 1.0:1.0 to 5.0, more preferably 1.0:2.5 to 4.0; Preferably, in step S2, the mass-to-volume ratio of compound P1 to solvent is 1.0:0.5 to 20.0, more preferably 1.0:10.0 to 20.0, in g / mL.

3. The method for preparing dacomitinib intermediate compound P according to any one of claims 1-2, characterized in that, Step S3 is a reaction that occurs in the presence of N,N-dimethylformamide dimethyl acetal. Preferably, step S3 involves a reaction occurring in a solvent; Preferably, the solvent is selected from organic solvents, more preferably from one or more of 2-methyltetrahydrofuran, n-heptane, ethylene glycol dimethyl ether, m-xylene and toluene, and more preferably from one or more of toluene and m-xylene; Preferably, the molar ratio of compound P2 to N,N-dimethylformamide dimethyl acetal is 1.0:1.0 to 10.0, more preferably 1.0:4.0 to 8.0; Preferably, the mass-to-volume ratio of compound P2 to solvent is 1.0:0.5 to 20.0, more preferably 1.0:8.0 to 18.0, in g / mL; Preferably, the reaction temperature in step S3 is 20–140°C, more preferably 60–120°C, and most preferably 105–115°C.

4. The method for preparing dacomitinib intermediate compound P according to any one of claims 1-3, characterized in that, The method further includes the following steps: Step S1: Compound A undergoes an etherification reaction to give compound P1.

5. The method for preparing dacomitinib intermediate compound P according to any one of claims 1-4, characterized in that, Step S1 is a reaction that occurs in the presence of a base; Preferably, the alkali is selected from methanol base, more preferably from one or more of sodium methoxide, potassium methoxide and calcium methoxide, and more preferably from sodium methoxide; Preferably, step S1 involves a reaction occurring in a solvent; Preferably, the solvent is selected from organic solvents, more preferably from one or more of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, and more preferably from one or more of N,N-dimethylformamide and N,N-dimethylacetamide; Preferably, the molar ratio of compound A to base is 1.0:1.0 to 5.0, more preferably 1.0:1.0 to 3.0; Preferably, the mass-volume ratio of compound A to solvent is 1.0:5.0 to 15.0, more preferably 1.0:10.0 to 15.0, in g / mL.

6. The method for preparing dacomitinib intermediate compound P according to any one of claims 4-5, characterized in that, The post-processing steps of step S1 include adding water to the reaction solution after the reaction is completed, filtering, and drying the filter cake to obtain product P1. Preferably, the mass-volume ratio of compound A to water is 1.0:1.0-30.0, more preferably 1.0:10.0-15.0, in g / mL.

7. The method for preparing dacomitinib intermediate compound P according to any one of claims 1-6, characterized in that, The post-processing steps of step S2 include adding water to the reaction solution after the reaction is completed, extracting with an organic solvent, and removing the solvent from the organic layer to obtain the crude product. Preferably, the crude product is recrystallized using a purification organic solvent to obtain product P2, wherein the purification organic solvent is selected from one or more of toluene, dichloromethane, methyl acetate, ethyl acetate, butyl acetate, petroleum ether, diethyl ether, methyl tert-butyl ether, n-pentane, n-hexane, and n-heptane. Preferably, the crude product is dissolved in dichloromethane, then petroleum ether is added, the product is precipitated, filtered, and the filter cake is dried to obtain product P2.

8. The method for preparing dacomitinib intermediate compound P according to any one of claims 1-7, characterized in that, The post-processing steps in step S3 include adding water to the reaction solution after the reaction is complete, filtering, and drying the filter cake to obtain the crude product. Preferably, the crude product is recrystallized using a purification organic solvent to obtain product P, wherein the purification organic solvent is selected from one or more of methanol, ethanol, and isopropanol; Preferably, the crude product is dissolved in ethanol, cooled, precipitated, filtered, and the filter cake is dried to obtain product P.

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