CN110698461B - Preparation method of third-generation EGFR inhibitor - Google Patents

Preparation method of third-generation EGFR inhibitor Download PDF

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CN110698461B
CN110698461B CN201910614211.7A CN201910614211A CN110698461B CN 110698461 B CN110698461 B CN 110698461B CN 201910614211 A CN201910614211 A CN 201910614211A CN 110698461 B CN110698461 B CN 110698461B
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CN110698461A (en
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苏熠东
匡远卓
包如迪
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

Abstract

The present invention relates to a method for preparing a third generation EGFR inhibitor. The invention discloses preparation and application of an EGFR inhibitor. In particular to a preparation method of a 4- (1-cyclopropyl-1H-indol-3-yl) -N-phenylpyrimidine-2-amine derivative with a compound structure shown in a formula (I). The method overcomes the defects existing in the prior art, greatly reduces the cost, and has the advantages of good purity, high yield, strong process operability and greatly improved process safety. Therefore, the preparation method and the application thereof are suitable for industrial application.

Description

Preparation method of third-generation EGFR inhibitor
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method and application of a 4- (1-cyclopropyl-1H-indol-3-yl) -N-phenylpyrimidine-2-amine derivative.
Background
EGFR (Epidermal Growth Factor Receptor) is a member of the erbB receptor family of transmembrane protein tyrosine kinases. EGFR may form homodimers on cell membranes by binding to its ligand, e.g., epidermal Growth Factor (EGF), or heterodimers with other receptors in the family, such as erbB2, erbB3, or erbB 4. The formation of these dimers can cause phosphorylation of critical tyrosine residues within EGFR cells, thereby activating multiple downstream signaling pathways within the cell. These intracellular signaling pathways play an important role in cell proliferation, survival and anti-apoptosis. Deregulation of EGFR signaling pathways, including increased expression of ligands and receptors, EGFR gene amplification, and mutations, can promote transformation of cells into malignant tumors, and play an important role in proliferation, invasion, metastasis, and angiogenesis of tumor cells. EGFR is therefore a rational target for the development of anticancer drugs.
First generation small molecule EGFR inhibitors, including gefitinib (Iressa TM) and erlotinib (Tarceim) TM ) Has shown better efficacy in lung cancer treatment, and has been used as a first-line drug for the treatment of non-small cell lung cancer NSCLC with EGFR activating mutations (New England Journal of Medicine (2008) vol.358,1160-74,Biochemical and Biophysical Research Communications (2004) vol.319, 1-11).
Activation of mutant EGFR (including L858R and deletion of exon 19E 746_A 750) has reduced affinity for Adenosine Triphosphate (ATP) and increased affinity for small molecule inhibitors relative to wild-type (WT) EGFR, resulting in increased sensitivity of tumor cells to first generation EGFR inhibitors such as gefitinib or erlotinib for targeted therapy (Science [2004] 304, 1497-500;New England Journalof medicine[2004] 350, 2129-39).
However, almost all NSCLC patients develop resistance to the first-generation small molecule EGFR inhibitors after 10-12 months of treatment with such small molecule inhibitors. Its drug resistance mechanism includes EGFR secondary mutation, bypass activation, etc. Wherein, the drug resistance of half patients is caused by secondary mutation of EGFR gatekeeper gene residue T790M, thereby reducing the affinity of the drug to the target point to generate drug resistance, and causing tumor recurrence or disease progression.
Given the importance and popularity of such mutations in lung cancer EGFR-targeted therapies to develop drug resistance, many drug development companies (gabion, BI, AZ, etc.) have attempted to develop second generation small molecule EGFR inhibitors to treat such drug resistant lung cancer patients by inhibiting the EGFR T790M mutant, all ending with failure due to poor selectivity. Even though afatinib has been approved by the FDA for the treatment of lung cancer, it is only used for first line treatment in patients with EGFR activating mutations; in contrast, afatinib has a stronger inhibitory effect on wild type EGFR in patients with EGFR T790M mutation, and causes severe skin and gastrointestinal toxicity, so that the administration dosage is limited, and no therapeutic effect is shown.
Therefore, there is a need to develop third generation small molecule EGFR inhibitors that can highly selectively inhibit EGFR T790M mutant, while having no or low activity against wild-type EGFR. Due to this high selectivity, damage to the skin and gastrointestinal tract caused by wild-type EGFR inhibition can be greatly reduced to achieve treatment of EGFR T790M secondary mutation resistant tumors. In addition, it is also significant to retain inhibitory activity against EGFR-activating mutants, including L858R EGFR, exon 19 deleted E746_A750. Because of weaker inhibition to wild-type EGFR, third-generation EGFR inhibitors have better safety than first-generation EGFR inhibitors, and are expected to be a first-line treatment, while treating NSCLC with EGFR activating mutations, also eliminating small amounts of EGFRT790T mutant that may be present in initially treated patients, to delay the onset of resistance.
Lung cancer is a major disease threatening human health, and lung cancer death has been the leading cause of all malignant tumors. In China, the incidence rate of lung cancer rises year by year, and the new incidence rate of lung cancer is nearly 70 ten thousand per year. In europe and america, cases of lung cancer accompanied by EGFR activating mutations account for about 10% of all NSCLCs; in China, this ratio is as high as 30%. Thus, china has a larger market for EGFR targets.
In 2015, jiangsu Haoshen corporation disclosed in patent PCT/CN2015/091189 (application date: 2015.09.30) a class of 4-substituted-2- (N- (5-allylamidophenyl) amino) pyrimidine derivatives, with representative chemical names: n- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide, prepared as follows:
the patent takes 3- (2-chloropyrimidine-4-yl) -1-cyclopropyl-1H-indole as a raw material to prepare N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, but the raw material is difficult to purchase on a large scale, specific preparation conditions are not given, and the preparation method is not optimized and is not suitable for industrial mass production.
Journal org. Lett.2008,10 (8), 1653-1655 discloses a method for preparing 1-cyclopropyl-1H-indole derivatives from cyclopropylboronic acid and 1H-indole derivatives, but the technique has the following drawbacks: the dosage of the cyclopropylboric acid is large, the price of the cyclopropylboric acid is high, the reaction cost is greatly increased, and the method is not suitable for large-scale production; the reaction uses copper acetate and DMAP as raw materials, but the DMAP has high toxicity and high irritation, is not suitable for large-scale use and increases environmental protection pressure; toluene is used as a solvent in the reaction, and has strong irritation; the reaction is carried out at a high temperature of 95 ℃ and the reaction conditions are severe.
Journal Journal of Organic Chemistry,2008,73 (16), 6441-6444 also discloses a process for preparing 1-cyclopropyl-1H-indole derivatives from cyclopropylboronic acid and 1H-indole derivatives, which also has the disadvantage of large amounts of cyclopropylboronic acid.
Disclosure of Invention
In order to solve the problems in the prior art, the inventor develops a novel method for preparing the compound shown in the formula (I) in the long-term research and development process, and the method has the advantages of mild reaction conditions, mature process and stable quality, and is very suitable for industrial application.
The invention provides a preparation method of a compound shown as a formula (III), which comprises the following steps: coupling the compound of formula (II) with indole to obtain the compound of formula (III)
As a preferred embodiment, the molar ratio of the compound of formula (II) to indole is 1:1-2, preferably 1:1-1.2.
Preferably, the reaction of the step is carried out in the presence of a catalyst, an alkaline agent and an organic solvent.
As a further preferred embodiment, the catalyst is selected from copper acetate and bipyridine, preferably from copper acetate and 2,2' -bipyridine.
As a further preferred embodiment, the alkaline agent is selected from potassium phosphate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, preferably sodium carbonate or potassium phosphate.
As a further preferred embodiment, the molar ratio of the compound of formula (ii), indole, copper acetate, bipyridine and basic reagent in said step is 1:1 to 1.2:1 to 1.2:1 to 1.2:2 to 2.4.
As a further preferred embodiment, the organic solvent is selected from acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, toluene or dioxane, preferably from dimethylformamide or dimethylsulfoxide.
Preferably, the reaction of the step further comprises a purification process, and the method further comprises the following steps: the compound of formula (III) is extracted with n-heptane, washed with water, dried, concentrated under reduced pressure, and separated by chromatography.
As a further preferred scheme, the mass volume ratio of the compound of formula (II) to the n-heptane is 1:4-8, preferably 1:6-7, the volume ratio of the n-heptane to the reaction solvent is 3:15:1, preferably 4:1, and the chromatographic eluent is petroleum ether.
Further, the invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps:
1) Coupling the compound of formula (II) with indole to obtain a compound of formula (III);
2) Coupling the compound of formula (III) with a compound of formula (IX) to obtain a compound of formula (IV);
3) Coupling the compound of formula (IV) with a compound of formula (X) to obtain a compound of formula (V);
4) Reacting a compound of formula (V) with N, N, N' -trimethylethylenediamine to obtain a compound of formula (VI);
5) Nitroreduction of the compound of formula (VI) to give the compound of formula (VII);
6) Reacting a compound of formula (VII) with a compound of formula (XI) to give a compound of formula (I);
the reaction formula is as follows:
wherein R is 1 Selected from hydrogen, deuterium, halogen, cyano, nitro, optionally substituted C 1-8 Alkyl, optionally substituted hydroxy, optionally substituted C 3-8 Cycloalkyl, -SO 2 R 5 、-C(O)R 6 、-C(O)OR 6 or-P (O) R 7 R 8 ；
R 2 Selected from C 1-8 Alkoxy or C 3-8 A cycloalkoxy group optionally further substituted with one or more substituents selected from halogen, hydroxy, aryl, heterocycloalkyl;
R 3 is halogen;
R 4 selected from hydroxyl or halogen;
R 5 selected from hydrogen, deuterium, optionally substituted C 1-8 Alkyl, C 3-8 Cycloalkyl, heterocycloalkyl, or aryl;
R 6 、R 7 、R 8 each independently selected from hydrogen, deuterium, optionally substituted C 1-8 Alkyl, C 3-8 Cycloalkyl, heterocycloalkyl or aryl.
Furthermore, the invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps:
1) Coupling the compound of formula (II) with indole to obtain a compound of formula (III);
2) Coupling the compound of formula (III) with a compound of formula (IX) to obtain a compound of formula (IV);
3) Coupling the compound of formula (IV) with a compound of formula (X) to obtain a compound of formula (V);
4) Reacting a compound of formula (V) with N, N, N' -trimethylethylenediamine to obtain a compound of formula (VI);
5) Nitroreduction of the compound of formula (VI) to give the compound of formula (VII);
6) Reacting a compound of formula (VII) with a compound of formula (XI) to give a compound of formula (I);
the reaction formula is as follows:
wherein R is 1 Selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, trifluoromethyl, trifluoromethoxy, -SO 2 R 5 、-C(O)R 6 、-C(O)OR 6 or-P (O) R 7 R 8 ；
R 2 Selected from C 1-8 Alkoxy or C 3-8 Cycloalkoxy, optionally further substituted with one or more groups selected from halogen, hydroxy, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Substituted with a substituent of a cycloalkoxy group;
R 3 is halogen;
R 4 selected from hydroxyl or chlorine;
R 5 selected from hydrogen, deuterium, C 1-8 Alkyl, C 3-8 Cycloalkyl, halogen substituted C 1-8 Alkyl, phenyl or p-methylphenyl;
R 6 、R 7 、R 8 each independently selected from hydrogen, deuterium, C 1-8 Alkyl, C 3-8 Cycloalkyl, halogen substituted C 1-8 Alkyl or hydroxy substituted C 1-8 An alkyl group.
As a preferred embodiment, R 1 Selected from hydrogen, deuterium, halogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, trifluoromethyl or trifluoromethoxy;
R 2 selected from methoxy, ethoxy, difluoromethoxy or trifluoromethoxy;
R 3 selected from fluorine or chlorine.
As a preferred embodiment, the reaction of step 1) is carried out in the presence of a catalyst, an alkaline agent and an organic solvent.
The preferable reaction temperature is 70-80 ℃;
as a further preferred embodiment, the catalyst is selected from copper acetate and bipyridine, preferably from copper acetate and 2,2' -bipyridine; the alkaline agent is selected from potassium phosphate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, preferably from sodium carbonate or potassium phosphate; the organic solvent is selected from acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, toluene or dioxane, preferably from dimethylformamide or dimethyl sulfoxide.
As a further preferred embodiment, the compound of formula (II), indole, copper acetate, bipyridine and basic reagent are added in step 1) in a molar ratio of 1:1 to 1.2:1 to 1.2:1 to 1.2:2 to 2.4.
Preferably, the reaction of the step further comprises a purification process, and the method further comprises the following steps: the compound of formula (III) is extracted with n-heptane, washed with water, dried, concentrated under reduced pressure, and separated by chromatography.
As a further preferred scheme, the mass volume ratio of the compound of formula (II) to the n-heptane is 1:4-8, preferably 1:6-7, the volume ratio of the n-heptane to the reaction solvent is 3:15:1, preferably 4:1, and the chromatographic eluent is petroleum ether.
Preferably, step 2) is carried out in the presence of a catalyst.
Preferably at a temperature of 60℃to 70℃and more preferably at a temperature of 65℃to 70 ℃.
As a further preferred embodiment, the reaction temperature is such that the catalyst is selected from aluminium trichloride, ferric trichloride or boron trichloride, preferably from aluminium trichloride.
As a preferred embodiment, the reaction of step 3) is carried out in the presence of an acidic reagent and an alcoholic solvent.
The reaction temperature is preferably 100℃to 120℃and preferably 110℃to 120 ℃.
As a further preferable embodiment, the acid is an organic acid or an inorganic acid; the organic acid is selected from trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid hydrate, o-toluenesulfonic acid, camphorsulfonic acid, formic acid, acetic acid or mixtures thereof; the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or mixtures thereof, preferably from methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid hydrate or o-toluenesulfonic acid.
As a further preferred embodiment, the alcoholic solvent is selected from methanol, ethanol, isopropanol, tert-butanol amyl alcohol, 2-pentanediol or mixtures thereof.
Preferably, step 4) is carried out in an alkaline environment at a temperature of 80℃to 90℃and preferably at a temperature of 85℃to 90 ℃.
As a further preferred embodiment, the base is selected from trimethylamine, triethylamine, pyridine, piperidine, diisopropylethylamine, morpholine or mixtures thereof, preferably from triethylamine or diisopropylethylamine.
As a preferred embodiment, step 5) is carried out in the presence of a reducing agent selected from Pd/C, raney-Ni, pd (OH) and hydrogen 2 Or PtO 2 Preferably from Raney-Ni.
Preferably, step 6) comprises an amidation and elimination reaction, said elimination reaction being carried out in an alkaline environment, further said amidation reaction being carried out at low temperature, preferably at a temperature of 0-5 ℃.
Preferably, step 6) is carried out in an alkaline environment at a temperature of from 0℃to 10℃and preferably at a temperature of from 0℃to 5 ℃.
As a further preferred embodiment, the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate or mixtures thereof, preferably from sodium hydroxide or potassium hydroxide.
In another aspect, the invention provides the use of a process for the preparation of a compound of formula (I) in the preparation of a pharmaceutically acceptable salt of a compound of formula (I), said pharmaceutically acceptable salt being selected from the group consisting of mesylate salts.
In a preferred embodiment, the formation of the mesylate of the compound of formula (I) is carried out in a solvent system of acetone and water, or in a solvent system of ethyl acetate and ethanol.
The preparation method uses the cyclopropylboric acid and the 1H-indole as raw materials, the raw materials are easy to obtain, compared with the prior art, the consumption of the cyclopropylboric acid is reduced, the reaction cost is greatly reduced, the purity of the intermediate (III) reaches more than 98%, the use of a solvent with high toxicity and high irritation is avoided, the environmental pressure is reduced, and the preparation method is favorable for large-scale reaction.
The method has the advantages that the post-treatment process of each step of reaction in the route is simple, most byproducts can be removed by filtering, washing with water or washing with common organic solvents, and the process operability is strong. The organic solvent can be collected and reused, thus greatly reducing the cost. The product obtained by the reaction has good purity and high yield, and the process safety is improved.
The method has simple operation of salifying reaction, and the obtained product has high purity and good quality, and is beneficial to subsequent drug development.
Detailed Description
Detailed description: unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
“C 1-8 Alkyl "refers to straight chain alkyl groups and branched alkyl groups comprising 1 to 4 carbon atoms, alkyl refers to saturated aliphatic hydrocarbon groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, and the like.
“C 1-8 Alkoxy "refers to an alkyl oxy group containing 1 to 8 carbons, non-limiting examples of which include methoxy, ethoxy, propoxy, butoxy, and the like.
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, "C 3-8 Cycloalkyl "refers to cycloalkyl groups comprising 3 to 8 carbon atoms.
"alcohol solvent" refers to an alkane compound containing hydroxyl groups in the molecule, such as methanol, ethanol, isopropanol.
The present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.
The invention is thatThe structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gi min i C150X 4.6mm column).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the present invention were carried out under continuous magnetic stirring without specific explanation.
Example 1
Indole (32.7 g), copper acetate (50.7 g), 2' -bipyridine (43.6 g), sodium carbonate (59.2 g), DMF (250 mL) were added to the three-necked flask, and the temperature was adjusted to 70 ℃. Cyclopropylboronic acid (20.0 g) was dissolved in DMF (50 mL) and added dropwise to a three-necked flask. After the addition was completed, the mixture was stirred at 70℃for 41 hours. Cooled to room temperature, saturated ammonium chloride solution (200 mL) and n-heptane (400 mL) were added, the organic phase and aqueous phase were separated, the organic phase was washed with saturated ammonium chloride solution (2X 200 mL), the aqueous phase was washed with n-heptane (2X 400 mL), the above organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel is filled in the chromatographic column, the crude product is diluted by petroleum ether, the crude product is directly put on the column, and the petroleum ether is eluted to obtain 1-cyclopropyl-1H-indole (20.2 g), the purity is 98.8%, and the yield is 55.2%.
Example 2
Under the protection of nitrogen, sequentially adding 1-cyclopropyl-1H-indole (71.2 g) and 2, 4-dichloropyrimidine (87.1 g) into a three-mouth bottle (2L), adding 1, 2-dichloroethane (720 mL), stirring, adding aluminum trichloride (78.5 g) after 30 minutes, internally heating to 30 ℃, regulating the temperature to 65 ℃ for reflux, stirring for 3 hours, cooling to the room temperature of 25 ℃, slowly adding the reaction solution into an ice/water (500 g) mixture, stirring for 15 minutes, adding dichloromethane (700 mL), stirring for 5 minutes, separating an underlying organic layer, adding dichloromethane (500 Ml) into a water layer, stirring for 5 minutes, separating the underlying organic layer, combining the organic layer, adding saturated sodium bicarbonate aqueous solution (500 Ml), stirring for 30 minutes, separating the underlying organic layer, adding saturated aqueous sodium chloride solution (500 mL), stirring for 5 min, separating the lower organic layer, adding anhydrous sodium sulfate (75 g) to the organic layer, stirring for 30 min, filtering, washing the filter cake with dichloromethane (100 mL), removing most of the solvent under reduced pressure, replacing the solvent with ethyl acetate (200 mL), adding ethyl acetate (200 mL) under reduced pressure to remove the solvent until the total volume is about 260mL (about 140mL of ethyl acetate), heating to 77 ℃ for reflux, slowly dropwise adding petroleum ether (500 mL), adding for 40 min, refluxing for 30 min, naturally cooling to 20 ℃ after 3H, stirring for 15H, regulating the temperature to 5 ℃ after 1H, filtering, washing the filter cake with a mixed solvent of petroleum ether and ethyl acetate (mixed solvent of 0 ℃, petroleum ether ethyl acetate=4:1, 150 mL) and then washed twice with petroleum ether (150 mL,100 mL). The filter cake was taken out and dried under vacuum at 55℃for 2 hours to constant weight to give 3- (2-chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole (95.1 g) with a purity of 98.5% and a yield of 77.8%.
Example 3
At 25deg.C under nitrogen protection, sequentially adding 3- (2-chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole (95 g) and 4-fluoro-2-methoxy-5-nitroaniline (68.8 g) into a three-necked flask (2L), sequentially adding 2-pentanol (800 mL) and TsOH.H 2 O (80.4 g), stirring is started, and the temperature is regulated to 110 ℃ for reflux; after stirring for 4 hours, cooling to 30 ℃, filtering, soaking and washing a filter cake with 2-amyl alcohol (200 mL), and washing twice with petroleum ether (300 mL multiplied by 2); the filter cake was taken out and dried under vacuum at 65℃for 2 hours to constant weight to give 4- (1-cyclopropyl-1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (132 g) with a purity of 99.5% and a yield of 89.4%.
Example 4
Under the protection of nitrogen, dimethylacetamide (400 mL) is added into a three-necked flask (3L) at the temperature of 25 ℃, and stirred, and the compound 4- (1-cyclopropyl-1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidine-2-amine (131 g), diisopropylethylamine (121 g) and N, N, N' -trimethylethylenediamine (48 g) are sequentially added, and the temperature is regulated to 85 ℃; slowly adding water (400 mL) after stirring for 3 hours, keeping the internal temperature at 80 ℃ for 2 hours, naturally cooling to 25 ℃, slowly adding water (1200 mL) after 16 hours, keeping the temperature and stirring for 1 hour, and adjusting the temperature to 5 ℃ and keeping the temperature for 1 hour; filtering, washing the filter cake with water (200 mL. Times.2) once and then with petroleum ether (200 mL. Times.2) twice; taking out the filter cake, and vacuum drying at 60 ℃ for 3 hours to constant weight to obtain the compound N 1 - (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -N 4 - (2- (dimethylamino) ethyl) -2-methoxy-N 4 Methyl-5-nitrobenzene-1, 4-diamine (138.7 g), yield 88.5%, purity 99.4%.
Example 5
Adding tetrahydrofuran (650 mL) and ethanol (350 mL) into a three-necked flask (2L) at 25deg.C, stirring, and sequentially adding compound N 1 - (4- (1-cyclopropane)1H-indol-3-yl) -pyrimidin-2-yl-N 4 - (2- (dimethylamino) ethyl) -2-methoxy-N 4 -methyl-5-nitrobenzene-1, 4-diamine (138.7 g), raney nickel (85 g), hydrogen displacement reaction system for three times, hydrogen bag protection; after stirring for 24 hours, stirring was stopped, filtration was performed, and the cake was washed twice with ethanol (100 mL. Times.2) and twice with tetrahydrofuran (100 mL. Times.2); adding active carbon (20 g) into the filtrate, regulating the temperature to 70 ℃, and stirring for 2 hours; filtering while the mixture is hot, and removing the solvent under reduced pressure to obtain a compound N 4 - (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methylbenzene-1, 2, 4-triamine (130 g).
Example 6
Tetrahydrofuran (1200 mL) and N are added under the protection of nitrogen at 25 DEG C 4 - (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 To a three-necked flask (3L) of methylbenzene-1, 2, 4-triamine (130 g), stirring was started, the temperature was regulated to 0℃and a solution of 3-chloropropionyl chloride (52.7 g) in tetrahydrofuran (100 mL) was slowly added, the temperature was regulated to 25℃and n-heptane (1300 mL) was slowly added, and stirring was continued for 30 minutes; filtering, washing the filter cake with n-heptane (500 mL), taking out the filter cake, transferring the filter cake to a three-necked flask (3L), adding tetrahydrofuran (1300 mL), adding aqueous solution (257 mL) of potassium hydroxide (93.1 g), and regulating the temperature to 70 ℃ for reflux; stirring for 25 hours, regulating the temperature to 25 ℃, separating an upper tetrahydrofuran layer, slowly adding a saturated ammonium chloride aqueous solution (450 mL) to the water layer until the pH of the water phase is=8, adding ethyl acetate (1.3L) for extraction, stirring for 5 minutes, and separating an upper organic layer; the organic layers were combined, washed with saturated aqueous sodium chloride (500 mL), dried over anhydrous sodium sulfate (100 g) and filtered, the filter cake was washed with ethyl acetate (100 mL), activated carbon (13 g) was added to the filtrate, and after refluxing for 2 hours, the filter cake was filtered and washed with ethyl acetate (100 mL); the filtrate is decompressed to remove the solvent to obtain the compound N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidine-2-yl) amino) -2- ((2 ](dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide (129 g), yield 88.8%, purity 99%.
1 H NMR(400MHz,CDCl 3 ):δ9.78(s,1H),9.74(s,1H),8.55(s,1H),8.39(d,J＝5.3Hz,1H),8.11(d,J＝7.0Hz,1H),7.74-7.55(m,2H),7.18(d,J＝5.3Hz,1H),6.76(s,1H),6.62(dd,J＝16.8,10.1Hz,1H),6.46(dd,J＝16.9,1.9Hz,1H),6.24(m,1H),5.80-5.59(m,1H),3.88(s,3H),3.55-3.34(m,1H),3.02(t,J＝5.8Hz,2H),2.68(s,3H),2.57(t,J＝5.7Hz,2H),2.42(s,6H),1.24-1.17(m,2H),1.14-1.04(m,2H)；
MS m/z(ESI):526.3[M+H] + 。
Example 7
N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide (111.9 g) is added to a three-necked flask (2L) under the protection of nitrogen, acetone (1000 mL) and water (22.4 mL) are added, the temperature is raised to an internal temperature of 55 ℃, all dissolved matters are completely dissolved, an acetone (110 mL) solution containing methanesulfonic acid (19.3 g) is slowly added dropwise, the internal temperature is kept at 55 ℃ during dropwise addition, and the mixture is kept at the temperature for 30 minutes; naturally cooling, cooling to 25 ℃ after 3 hours, preserving heat and stirring for 30 minutes, regulating the temperature to 5 ℃, preserving heat and stirring for 1 hour; the mixture was filtered, and the filter cake was washed twice with acetone (300 mL. Times.2), and dried under vacuum at 80℃for 5 hours to constant weight to give N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide mesylate (109 g), 82.3% yield, 99.4% purity.

Claims (32)

1. A process for the preparation of a compound of formula (iii), comprising the steps of: coupling the compound of formula (II) with indole to obtain a compound of formula (III),
the molar ratio of the compound of the formula (II) to the indole is 1:1-1.2;
the reaction of the step is carried out in the presence of a catalyst, an alkaline reagent and an organic solvent, wherein the organic solvent is dimethylformamide, and the catalyst is selected from copper acetate and bipyridine; the alkaline agent is selected from potassium phosphate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.
2. The process for the preparation of a compound of formula (iii) according to claim 1, characterized in that the catalyst is selected from copper acetate and 2,2' -bipyridine.
3. The process for the preparation of a compound of formula (iii) according to claim 1, characterized in that the alkaline agent is selected from sodium carbonate or potassium phosphate.
4. A process for the preparation of a compound of formula (i), comprising the steps of:
1) Coupling the compound of formula (II) with indole to obtain a compound of formula (III);
2) Coupling the compound of formula (III) with a compound of formula (IX) to obtain a compound of formula (IV);
3) Coupling the compound of formula (IV) with a compound of formula (X) to obtain a compound of formula (V);
4) Reacting a compound of formula (V) with N, N, N' -trimethylethylenediamine to obtain a compound of formula (VI);
5) Nitroreduction of the compound of formula (VI) to give the compound of formula (VII);
6) Reacting a compound of formula (VII) with a compound of formula (XI) to give a compound of formula (I);
the reaction formula is as follows:
wherein R is 1 Selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-8 Alkyl groupHydroxy, C 3-8 Cycloalkyl, -SO 2 R 5 、-C(O)R 6 、-C(O)OR 6 or-P (O) R 7 R 8 ；
R 2 Selected from C 1-8 Alkoxy or C 3-8 A cycloalkoxy group optionally further substituted with one or more substituents selected from halogen, hydroxy;
R 3 is halogen;
R 4 selected from hydroxyl or halogen;
R 5 selected from hydrogen, deuterium, C 1-8 Alkyl, C 3-8 Cycloalkyl;
R 6 、R 7 、R 8 each independently selected from hydrogen, deuterium, C 1-8 Alkyl, C 3-8 Cycloalkyl;
the reaction of step 1) is carried out in the presence of a catalyst, an alkaline agent and an organic solvent;
wherein the catalyst is selected from copper acetate and bipyridine; the alkaline reagent is selected from potassium phosphate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; the organic solvent is dimethylformamide; the molar ratio of the compound of formula (II), indole, copper acetate, bipyridine and alkaline agent added in step 1) is 1:1 to 1.2:1 to 1.2:1 to 1.2:2 to 2.4.
5. A process for the preparation of a compound of formula (i), comprising the steps of:
1) Coupling the compound of formula (II) with indole to obtain a compound of formula (III);
2) Coupling the compound of formula (III) with a compound of formula (IX) to obtain a compound of formula (IV);
3) Coupling the compound of formula (IV) with a compound of formula (X) to obtain a compound of formula (V);
4) Reacting a compound of formula (V) with N, N, N' -trimethylethylenediamine to obtain a compound of formula (VI);
5) Nitroreduction of the compound of formula (VI) to give the compound of formula (VII);
6) Reacting a compound of formula (VII) with a compound of formula (XI) to give a compound of formula (I);
the reaction formula is as follows:
wherein R is 1 Selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, trifluoromethyl, trifluoromethoxy, -SO 2 R 5 、-C(O)R 6 、-C(O)OR 6 or-P (O) R 7 R 8 ；
R 2 Selected from C 1-8 Alkoxy or C 3-8 Cycloalkoxy, optionally further substituted with one or more groups selected from halogen, hydroxy, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Substituted with a substituent of a cycloalkoxy group;
R 3 is halogen;
R 4 selected from hydroxyl or chlorine;
R 5 selected from hydrogen, deuterium, C 1-8 Alkyl, C 3-8 Cycloalkyl, halogen substituted C 1-8 Alkyl, phenyl or p-methylphenyl;
R 6 、R 7 、R 8 each independently selected from hydrogen, deuterium, C 1-8 Alkyl, C 3-8 Cycloalkyl, halogen substituted C 1-8 Alkyl or hydroxy substituted C 1-8 An alkyl group;
the reaction of step 1) is carried out in the presence of a catalyst, an alkaline agent and an organic solvent;
wherein the catalyst is selected from copper acetate and bipyridine; the alkaline reagent is selected from potassium phosphate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; the organic solvent is dimethylformamide;
the molar ratio of the compound of formula (II), indole, copper acetate, bipyridine and alkaline agent added in step 1) is 1:1 to 1.2:1 to 1.2:1 to 1.2:2 to 2.4.
6. According to claim 4 or 5A process for the preparation of a compound of formula (I), characterized in that R 1 Selected from hydrogen, deuterium, halogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, trifluoromethyl or trifluoromethoxy;
R 2 selected from methoxy, ethoxy, difluoromethoxy or trifluoromethoxy;
R 3 selected from fluorine or chlorine;
R 5 、R 6 、R 7 、R 8 as defined in claim 4 or 5.
7. The process for the preparation of compounds of formula (i) according to claim 4 or 5, characterized in that the reaction temperature of step 1) is 70 ℃ to 80 ℃.
8. A process for the preparation of a compound of formula (i) according to claim 4 or 5, wherein the catalyst is selected from copper acetate and 2,2' -bipyridine.
9. A process for the preparation of a compound of formula (i) according to claim 4 or 5, characterized in that the alkaline agent is selected from sodium carbonate or potassium phosphate.
10. The process for the preparation of compounds of formula (i) according to claim 4 or 5, characterized in that step 2) is carried out at a temperature of 60 ℃ to 70 ℃ in the presence of a catalyst.
11. The process for the preparation of compounds of formula (i) according to claim 10, characterized in that step 2) is carried out at a temperature of 65 ℃ to 70 ℃.
12. A process for the preparation of a compound of formula (i) according to claim 10, wherein the catalyst is selected from aluminium trichloride, ferric trichloride or boron trichloride.
13. A process for the preparation of a compound of formula (i) according to claim 12, wherein the catalyst is selected from aluminium trichloride.
14. The process for the preparation of compounds of formula (i) according to claim 4 or 5, characterized in that the reaction of step 3) is carried out in the presence of an acidic reagent and an alcoholic solvent at a temperature of 100 ℃ to 120 ℃.
15. The process for the preparation of a compound of formula (i) according to claim 14, wherein the reaction temperature is 110 ℃ to 120 ℃.
16. A process for the preparation of a compound of formula (i) according to claim 14, wherein the acid is an organic or inorganic acid; the organic acid is selected from trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid hydrate, o-toluenesulfonic acid, camphorsulfonic acid, formic acid, acetic acid or mixtures thereof; the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or mixtures thereof.
17. A process for the preparation of a compound of formula (i) according to claim 16, wherein the acid is selected from methane sulphonic acid, trifluoromethane sulphonic acid, p-toluene sulphonic acid hydrate or o-toluene sulphonic acid.
18. The process for the preparation of a compound of formula (i) according to claim 14, wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol, tert-butanol pentanol, 2-pentanediol or mixtures thereof.
19. The process for the preparation of compounds of formula (i) according to claim 4 or 5, characterized in that step 4) is carried out in an alkaline environment at a temperature of 80 ℃ to 90 ℃.
20. The process for the preparation of compounds of formula (i) according to claim 19, characterized in that step 4) is carried out at a temperature of 85 ℃ to 90 ℃.
21. A process for the preparation of a compound of formula (i) according to claim 19, wherein the base is selected from trimethylamine, triethylamine, pyridine, piperidine, diisopropylethylamine, morpholine or mixtures thereof.
22. A process for the preparation of a compound of formula (i) according to claim 21, wherein the base is selected from triethylamine or diisopropylethylamine.
23. The process for the preparation of a compound of formula (I) according to claim 4 or 5, characterized in that step 5) is carried out in the presence of a reducing agent selected from Pd/C, raney-Ni, pd (OH) and hydrogen 2 Or PtO 2 。
24. A process for the preparation of a compound of formula (i) according to claim 23, wherein the reducing agent is selected from Raney-Ni.
25. The process for the preparation of a compound of formula (i) according to claim 4 or 5, characterized in that step 6) comprises an amidation and elimination reaction, said amidation reaction being carried out at low temperature; the elimination reaction is carried out in an alkaline environment.
26. The process for the preparation of a compound of formula (i) according to claim 25, wherein the amidation reaction is carried out at 0-5 ℃.
27. The process for the preparation of compounds of formula (i) according to claim 4 or 5, characterized in that step 6) is carried out in an alkaline environment at a temperature of 0 ℃ to 10 ℃.
28. The process for the preparation of compounds of formula (i) according to claim 27, characterized in that step 6) is carried out at a temperature of 0 ℃ to 5 ℃.
29. A process for the preparation of a compound of formula (i) according to claim 27, wherein the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate or mixtures thereof.
30. A process for the preparation of a compound of formula (i) according to claim 29, wherein the base is selected from sodium hydroxide or potassium hydroxide.
31. The use of a process for the preparation of a compound of formula (i) according to any one of claims 4 to 30 for the preparation of a pharmaceutically acceptable salt of a compound of formula (i), wherein the pharmaceutically acceptable salt is selected from the group consisting of mesylate salts.
32. Use according to claim 31, characterized in that the salt formation of the mesylate of the compound of formula (i) is carried out in a solvent system of acetone with water or in a solvent system of ethyl acetate with ethanol.
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