CN113773304B - Preparation method of anti-drug-resistance anti-tumor EGFR inhibitor - Google Patents

Preparation method of anti-drug-resistance anti-tumor EGFR inhibitor Download PDF

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CN113773304B
CN113773304B CN202110935894.3A CN202110935894A CN113773304B CN 113773304 B CN113773304 B CN 113773304B CN 202110935894 A CN202110935894 A CN 202110935894A CN 113773304 B CN113773304 B CN 113773304B
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赵军军
孙长安
蓝月
徐丹丹
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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Abstract

The invention relates to a preparation method of an anti-drug-resistance anti-tumor EGFR inhibitor. Specifically, the invention relates to a preparation method of a 4- (1-cyclopropyl-1H-indol-3-yl) -N-phenyl pyrimidine-2-amine derivative with a compound structure shown as a general formula (IV). The method overcomes the defects in the prior art, greatly reduces the cost, and has the advantages of good product 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 anti-drug-resistance anti-tumor EGFR inhibitor
The application is a divisional application of the invention named as a preparation method of an anti-drug-resistance anti-tumor EGFR inhibitor, which is applied by Jiangsu Howesson pharmaceutical industry group Limited company, and has the application date of 2019, 25.02/2019 and the application number of 201910137524.8.
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method and application of a 4- (1-cyclopropyl-1H-indol-3-yl) -N-phenylpyrimidine-2-amine derivative.
Background
EGFR (epidemal Growth Factor Receptor) is a member of the erbB Receptor family of transmembrane protein tyrosine kinases. EGFR can 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 lead to phosphorylation of key tyrosine residues in EGFR cells, thereby activating multiple downstream signaling pathways in the cell. These intracellular signaling pathways play important roles in cell proliferation, survival, and resistance to apoptosis. Dysregulation of the EGFR signaling pathway, including increased expression of ligands and receptors, EGFR gene amplification and mutation, can promote cellular transformation to malignancy, and play an important role in proliferation, invasion, metastasis and angiogenesis of tumor cells. Therefore, EGFR is a rational target for anticancer drug development.
First generation small molecule EGFR inhibitors including gefitinib (Iressa Tm) and erlotinib (Tarceva) TM ) Has better curative effect in treating lung cancer and is used as a first-line medicament for treating non-small cell lung cancer NSCLC (New England) accompanied with EGFR activating mutation Journal of Medicine(2008)Vol.358,1160-74,Biochemical and Biophysical Research Communications(2004)Vol.319,1-11)。
Activating mutant EGFR (including L858R and exon 19 deletion del e746_ 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 purposes (Science [2004] stage 304, 1497-500 new England Journal of medicine [2004] stage 350, 2129-39.
However, almost all NSCLC patients develop resistance to small molecule inhibitors after 10-12 months of treatment with first generation small molecule EGFR inhibitors. The drug resistance mechanism comprises EGFR secondary mutation, bypass activation and the like. The drug resistance of half of patients is caused by the secondary mutation of the EGFR gatekeeping gene residue T790M, thereby reducing the affinity of the drug and the target spot to generate drug resistance, and causing the relapse of tumor or disease progression.
In view of the importance and prevalence of such mutations in EGFR-targeted therapies for lung cancer, several drug development companies (pfeiy, BI, AZ, etc.) have attempted to develop second generation small molecule EGFR inhibitors to treat patients with such resistant lung cancer by inhibiting the EGFR T790M mutant, all with poor selectivity and failure. Even though afatinib has been FDA approved for the treatment of lung cancer, it is only used for first line treatment in patients with EGFR activating mutations; in patients with EGFR T790M mutation, however, the dose was limited due to severe skin and gastrointestinal toxicity caused by the stronger inhibitory effect of afatinib on wild-type EGFR, and no therapeutic effect was shown.
Therefore, there is a need for the development of third generation small molecule EGFR inhibitors that inhibit EGFR T790M mutants with high selectivity and no or low activity against wild type EGFR. Due to the high selectivity, the damage of skin and gastrointestinal tract caused by the inhibition of wild EGFR can be greatly reduced, so that the EGFR T790M secondary mutation drug-resistant tumor can be treated. In addition, it is also of interest to retain inhibitory activity against EGFR activating mutants (including L858R EGFR, exon 19 deletion delE746_ A750). Because of weak inhibition on wild EGFR, the third-generation EGFR inhibitor has better safety than the first-generation EGFR inhibitor, and is expected to be used as a first-line treatment to treat NSCLC accompanied with EGFR activating mutation and clear a small amount of possible EGFR RT790T mutant strains of initially treated patients so as to delay the occurrence of drug resistance.
Lung cancer is a serious disease threatening human health, and lung cancer death accounts for the first of all malignant tumors. In China, the incidence of lung cancer is increasing year by year, and the number of new cases is nearly 70 million every year. In europe and the united states, lung cancer cases with EGFR activating mutations account for about 10% of all NSCLC; in China, this proportion is as high as 30%. Thus, china has a larger market for EGFR targets.
In 2015, the company Jiangsu Hawson disclosed a class of 4-substituted-2- (N- (5-allylamido) phenyl) amino) pyrimidine derivatives in patent WO2016054987, wherein the chemical name of the representative compound is: 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:
Figure BDA0003213126870000021
the patent takes 3- (2-chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole as a raw material to prepare N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloyl amide, but the raw material is difficult to purchase on a large scale and is not suitable for industrial mass production.
Journal J.org.Lett.2008,10,1653-1655 discloses a method for preparing 1-cyclopropyl-1H-indole derivatives by using cyclopropylboronic acid and 1H-indole derivatives as raw materials, but the method has the following defects: the consumption of the cyclopropyl boric acid is large, and the price of the cyclopropyl boric acid is high, so that the reaction cost is greatly improved, and the large-scale production is not suitable; copper acetate and DMAP are used as raw materials in the reaction, but the DMAP has high toxicity and high irritation, is not suitable for large-scale use and increases the environmental protection pressure; toluene is used as a solvent in the reaction, and the toluene also has strong irritation; the reaction is carried out at a high temperature of 95 ℃ and the reaction conditions are severe.
In order to solve the problems in the prior art, the inventor develops a novel method for preparing the compound shown in the general formula (IV) in a long-term research and development process.
Compared with the prior art, the invention has the following advantages:
1) The cyclopropanation reaction time is shortened, the reaction condition is simple, the water is not required to be controlled, and the convenience of the reaction is greatly improved;
2) The step of silica gel purification is removed, the purification is optimized to be the treatment after recrystallization, the operation period is greatly shortened, the generation amount of waste solid and waste liquid is greatly reduced, and the requirement of industrial batch amplification is met;
3) The yield and purity of each intermediate and final product are improved.
Disclosure of Invention
The invention relates to a method for preparing a compound shown as a general formula (I), which comprises the following steps:
Figure BDA0003213126870000031
coupling the compound shown in the general formula (II) with cyclopropylboronic acid to obtain a compound shown in the general formula (I);
wherein,
r is selected from hydrogen, deuterium, halogen and C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl or-S (O) 2 R a ；
R 1 Selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Cycloalkyl, trifluoromethyl or trifluoromethoxy; preferably hydrogen, halogen and trifluoromethyl;
R a selected from hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group; and is
y is 0,1, 2, 3 or 4.
The molar ratio of the compound represented by the general formula (II) to cyclopropylboronic acid is 1:1 to 5, preferably 1:1 to 2.5.
Further, the method comprises the following steps of,
Figure BDA0003213126870000041
1) Reacting the compound shown in the general formula (III) with indole to obtain a compound shown in a general formula (II);
2) Coupling the compound shown in the general formula (II) with cyclopropylboronic acid to obtain a compound shown in the general formula (I);
wherein,
R、R 1 and y is as defined for formula (I).
Also included in step 1) is a Grignard reagent selected from the group consisting of halogenated alkylated magnesium reagents, preferably methyl magnesium chloride or methyl magnesium bromide. More preferably, the molar ratio of the compound of formula (III) to the grignard reagent is 1:2 to 5, preferably 1:2 to 3;
the concentration of the Grignard reagent is 2-4 mol/L;
the reaction solvent is tetrahydrofuran or its derivative, preferably tetrahydrofuran or 2-methyl tetrahydrofuran.
As a further preferable scheme, in the preparation method of the compound shown in the general formula (I), the coupling reaction is carried out in the presence of a catalyst, an alkaline reagent and an organic solvent, and the reaction temperature is 50-65 ℃; preferably 60 deg.c.
In a further preferred embodiment, the catalyst in the coupling reaction is selected from copper acetate, copper halide or bipyridyl; preferably copper acetate and 2,2' -bipyridine; the alkaline reagent is selected from potassium phosphate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; sodium carbonate and potassium phosphate are preferred; the organic solvent is selected from acetonitrile, tetrahydrofuran, dimethyltetrahydrofuran, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, toluene or dioxane; acetonitrile, tetrahydrofuran, dimethyltetrahydrofuran, dimethylformamide and dimethyl sulfoxide are preferred. More preferably, the mass/volume ratio of the compound represented by the general formula (II) to the organic solvent is 1:5 to 20 (g/mL), preferably 1:8 to 15.
In a further preferred embodiment, in the method for preparing the compound represented by the general formula (I), the molar ratio of the compound represented by the general formula (II) added in the reaction to the cyclopropylboronic acid, the copper acetate, the bipyridine and the alkaline reagent is 1:1-1.2, 1-1.2 and 1:2-2.4.
The patent also relates to a process for the preparation of a compound of formula (IV) comprising the steps of,
Figure BDA0003213126870000042
reacting a compound shown in a general formula (V) with a compound shown in a general formula (VI) at a certain temperature in the presence of an alkali reagent to obtain a compound shown in a general formula (IV); optionally further reacting with an acidic reagent M to form a corresponding salt;
wherein,
x is 1,2, 3, 4 or 5;
m is selected from organic acid 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; preferably methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid hydrate or o-toluenesulfonic acid;
R 2 is selected from C 1-8 Alkoxy radical, C 1-8 Haloalkoxy or C 3-8 Cycloalkoxy, wherein said C 1-8 Alkoxy and C 3-8 Cycloalkoxy is optionally further substituted by one or more groups selected from halogen, hydroxy, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Cycloalkyl or C 3-8 Cycloalkoxy is substituted by a substituent;
R 3 selected from hydroxy or chlorine;
R、R 1 and y is as defined for formula (I);
the temperature is selected from-10 ℃ to 60 ℃; preferably from 0 ℃ to 30 ℃ and more preferably from 0 ℃ to 5 ℃.
The molar ratio of the compound of formula (V) to the compound of formula (VI) is 1:1 to 3, preferably 1:1.2 to 2.
The molar ratio of the compound of formula (VI) to M is 1:1 to 2, preferably 1:1 to 1.2.
The alkali reagent is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate or a mixture thereof; sodium hydroxide or potassium hydroxide is preferred.
The acidic reagent is selected from organic acid 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; methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid hydrate or o-toluenesulfonic acid is preferred.
As a further preferred embodiment, the process for producing a compound represented by the general formula (IV) comprises the steps of,
Figure BDA0003213126870000051
carrying out reduction reaction on the compound shown in the general formula (VII) in the presence of hydrogen and a reducing agent to obtain a compound shown in a general formula (V);
wherein,
R、R 1 and y is as described for formula (I);
R 2 as described in general formula (IV);
the reducing agent is selected from Pd/C, raney-Ni, pd (OH) 2 Or PtO 2 (ii) a Raney-Ni is preferred.
The weight ratio of the compound represented by the general formula (VII) to the reducing agent is 1 to 5:1, preferably 1.5 to 2:1, the reaction solvent is a mixed solution of tetrahydrofuran and ethanol, wherein the ratio of the tetrahydrofuran to the ethanol is 1.5-3: 1.
as a further preferred embodiment, the process for producing a compound represented by the general formula (IV) comprises the steps of,
Figure BDA0003213126870000061
reacting a compound shown in a general formula (VIII) with N, N, N' -trimethylethylenediamine at a certain temperature in the presence of an alkaline reagent to obtain a compound shown in a general formula (VII);
wherein,
R 4 such as selected from halogen; preferably a fluorine atom;
y、R、R 1 、R 2 and R 4 As described in general formula (IV);
the temperature is selected from 80 ℃ to 90 ℃; preferably at a temperature of from 85 ℃ to 90 ℃;
the alkaline reagent is selected from trimethylamine, triethylamine, pyridine, piperidine, diisopropylethylamine, morpholine or a mixture thereof; triethylamine and diisopropylethylamine are preferred.
As a further preferred embodiment, the process for producing a compound represented by the general formula (IV) comprises the steps of,
Figure BDA0003213126870000062
reacting a compound shown in a general formula (I) with a compound shown in a general formula (IX) at a certain temperature in the presence of an acid reagent and an alcohol solvent to obtain a compound shown in a general formula (VIII);
wherein,
y、R 1 、R 2 、R 3 and R 4 As described in general formula (IV);
the temperature is selected from 100 ℃ to 120 ℃; preferably 110 to 120 ℃;
the acid reagent is organic acid 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; preferably methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid hydrate or o-toluenesulfonic acid;
the molar ratio of the compound of formula (I) to the compound of formula (IX) is 1:1 to 1.2;
the molar ratio of the compound represented by the general formula (I) to the acid reagent is 1:1 to 1.5;
the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol amyl alcohol, 2-pentanediol or a mixture thereof.
As a further preferred embodiment, the process for producing a compound represented by the general formula (IV) comprises the steps of,
Figure BDA0003213126870000071
1) Coupling the compound shown in the general formula (II) with cyclopropylboronic acid to obtain a compound shown in the general formula (I);
2) Reacting a compound shown in a general formula (I) with a compound shown in a general formula (IX) at a certain temperature in the presence of an acid reagent and an alcohol solvent to obtain a compound shown in a general formula (VIII);
3) Reacting a compound shown in a general formula (VIII) with N, N, N' -trimethylethylenediamine at a certain temperature in the presence of an alkaline reagent to obtain a compound shown in a general formula (VII);
4) Carrying out reduction reaction on the compound shown in the general formula (VII) in the presence of hydrogen and a reducing agent to obtain a compound shown in a general formula (V);
5) Reacting a compound shown in a general formula (V) with a compound shown in a general formula (VI) at a certain temperature in the presence of an alkali reagent to obtain a compound shown in a general formula (IV), and optionally further reacting with an acid reagent to generate a corresponding salt;
wherein,
y、R、R 1 、R 2 、R 3 and R 4 As described in general formula (IV);
the definition of the acid reagent, the alcohol solvent, the alkaline reagent and the reducing agent in the above steps is as described in the same step in this patent.
As a further preferred embodiment, the process for preparing the compound represented by the general formula (IV) comprises the steps of preparing the compound represented by the general formula (I) according to claim 1, and the synthetic route is as follows,
Figure BDA0003213126870000081
1) Reacting the compound shown in the general formula (III) with indole or analogues thereof to obtain a compound shown in a general formula (II);
2) Coupling the compound shown in the general formula (II) with cyclopropylboronic acid to obtain a compound shown in the general formula (I);
3) Reacting a compound shown in a general formula (I) with a compound shown in a general formula (IX) at a certain temperature in the presence of an acid reagent and an alcohol solvent to obtain a compound shown in a general formula (VIII);
4) Reacting a compound shown in a general formula (VIII) with N, N, N' -trimethylethylenediamine at a certain temperature in the presence of an alkaline reagent to obtain a compound shown in a general formula (VII);
5) Carrying out reduction reaction on the compound shown in the general formula (VII) in the presence of hydrogen and a reducing agent to obtain a compound shown in a general formula (V);
6) Reacting a compound shown in a general formula (V) with a compound shown in a general formula (VI) at a certain temperature in the presence of an alkali reagent to obtain a compound shown in a general formula (IV), and optionally further reacting with an acid reagent to generate a corresponding salt;
wherein,
y、R、R 1 、R 2 、R 3 and R 4 As described in general formula (IV);
the definition of the acid reagent, the alcohol solvent, the alkaline reagent and the reducing agent in the above steps is as described in the same step in this patent.
The invention further relates to a method for preparing the compound shown in the general formula (IV), which can be further used for preparing pharmaceutically acceptable salts of the compound shown in the general formula (IV), wherein the pharmaceutically acceptable salts are mesylate.
The invention relates to a method for preparing pharmaceutically acceptable salts of a compound shown in a general formula (IV), wherein a solvent system in a salt forming process of mesylate of the compound shown in the general formula (IV) is a solvent system formed by acetone and water or a solvent system formed by ethyl acetate and ethanol.
In another aspect, the invention provides a process for the purification of a compound of formula (I), in particular 3- (2-chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole, by liquid-liquid extraction of the product with ethyl acetate and concentration to dryness. Adding ethanol, heating and refluxing to dissolve, cooling to room temperature, stirring and crystallizing.
Preferably, the weight to volume ratio of the compound of formula (II) to ethanol is 1:3 to 10 (g/mL).
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 a straight-chain alkyl group and a branched-chain alkyl group containing 1 to 8 carbon atoms, the alkyl refers to a saturated aliphatic hydrocarbon group, further includes a straight-chain alkyl group and a branched-chain alkyl group containing 1 to 6 carbon atoms, the alkyl refers to a saturated aliphatic hydrocarbon group, further includes a straight-chain alkyl group and a branched-chain alkyl group containing 1 to 3 carbon atoms, and the alkyl refers to a saturated aliphatic hydrocarbon group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, and the like.
“C 1-8 Alkoxy "means an alkyloxy group having 1 to 8 carbons, further an alkyloxy group having 1 to 6 carbons, further an alkyloxy group having 1 to 3 carbons, and non-limiting examples 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 a cycloalkyl group comprising 3 to 8 carbon atoms, further comprising 3 to 6 carbonsAn atomic cycloalkyl group.
"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, and polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"alcoholic solvent" means an alkane compound having a hydroxyl group in the molecule, such as methanol, ethanol, isopropanol.
The present invention will be described more fully with reference to the following examples, but the present invention is not limited thereto, and the present invention is not limited to the examples.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC measurements were carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gi min i C18X 4.6mm column).
The thin layer chromatography silica gel plate adopts a cigarette platform 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 a thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai 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 are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, and the solvent is a dry solvent, unless otherwise specified.
Example 1
Preparation of N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide methanesulfonate
Figure BDA0003213126870000101
The first step is as follows: preparation of 3- (2-chloropyrimidin-4-yl) -1H-indole
Figure BDA0003213126870000102
Indole (236.0 g, 2.02mol), tetrahydrofuran (1200 mL) was added to the reaction flask. After cooling to 0 ℃ and under nitrogen protection, methylmagnesium bromide (672mL, 3 mol/L2-methyltetrahydrofuran solution) was slowly added dropwise to the system. After the addition, the mixture was stirred for 1 hour. 2,4-dichloropyrimidine (120.0 g, 0.81mol) was added and stirred for 1 hour. Heating to internal temperature of 70 deg.C, stirring at the temperature for reaction for 5 hr, stopping heating, and cooling to room temperature. Ethyl acetate (600 mL) was added to the reaction flask, followed by saturated aqueous ammonium chloride (1200 mL). Stirring and layering, and reserving an organic phase. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, anhydrous sodium sulfate was added, stirring was carried out at room temperature, filtration was carried out, and the filtrate was concentrated to dryness under reduced pressure to obtain a yellow solid. Ethyl acetate (1200 mL) was added, the temperature was raised until the solid was clear, and n-heptane (1200 mL) was added dropwise thereto. After the dropwise addition, the mixture was cooled to room temperature. Filtration and drying gave 3- (2-chloropyrimidin-4-yl) -1H-indole (123.0 g) as a pale yellow solid in 66.5% yield and 99.6% HPLC purity.
1 HNMR(400MHz,DMSO-d 6 )δ12.11(s,1H),8.54-8.53(m,2H),8.45-8.42(m,1H),7.92(d,J＝5.6Hz,1H),7.53-7.50(m,1H),7.27-7.22(m,2H).
MS m/z(ESI):230[M+H] + .
The second step is that: preparation of 3- (2-chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole
Figure BDA0003213126870000111
3- (2-Chloropyrimidin-4-yl) -1H-indole (72.0g, 0.313mol), cyclopropylboronic acid (32.1g, 0.376 mol), copper acetate (57.0g, 0.313mol), 2,2' -bipyridine (49.2g, 0.313mol), sodium carbonate (66.6g, 0.626 mol), tetrahydrofuran (720 mL) were added to the reaction flask, and the temperature was raised to 60 ℃. The reaction was completed by stirring at this temperature for 10 hours. Filtering, washing a filter cake by using ethyl acetate, and concentrating the filtrate under reduced pressure to be dry. To the residue were added ethyl acetate (860 mL) and water (720 mL), and the mixture was stirred, separated into layers, and the organic phase was separated. To the organic phase was added a saturated sodium chloride solution (300 mL), stirred, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give a brown solid. Ethanol (300 mL) was added to the solid, heated to reflux, stirred to dissolve clear, slowly cooled to room temperature and stirred to crystallize. Filtering, drying the filter cake to obtain the product 3- (2-chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole with the purity of HPLC 99.9% and the yield of 72.6g of light yellow solid.
1 HNMR(400MHz,DMSO-d 6 )δ8.55-8.53(m,2H),8.45(d,J＝7.2Hz,1H),7.93(d,J＝5.6Hz,1H),7.69(d,J＝7.6Hz,1H),7.35-7.28(m,2H),3.65-3.60(m,1H),1.17-1.13(m,2H),1.11-1.06(m,2H).
MS m/z(ESI):270[M+H] + .
The third step: preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine
Figure BDA0003213126870000112
At 25 ℃ and under the protection of nitrogen, 3- (2-chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole (95 g) and 4-fluoro-2-methoxy-5-nitroaniline (68.8 g) are sequentially added into a three-necked bottle (2L), and 2-pentanol (800 mL) and TsOH. H are sequentially added 2 O (80.4 g), starting stirring, adjusting the temperature to the internal temperature of 110 ℃ and refluxing; stirring for 4 hr, cooling to 30 deg.C, filtering, soaking and washing the filter cake with 2-pentanol (200 mL), and washing twice with petroleum ether (300 mL × 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%.
The fourth step: n is a radical of 1 - (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -N 4 - (2- (dimethylamino) ethyl) -2-methoxy-N 4 Preparation of (E) -methyl-5-nitrobenzene-1,4-diamine
Figure BDA0003213126870000121
Adding dimethylacetamide (400 mL) into a three-necked flask (3L) at 25 ℃ under the protection of nitrogen, stirring, sequentially adding the compounds 4- (1-cyclopropyl-1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (131 g), diisopropylethylamine (121 g) and N, N, N' -trimethylethylenediamine (48 g), and adjusting the temperature to 85 ℃; stirring for 3 hours, slowly adding water (400 mL), keeping the internal temperature at 80 ℃, naturally cooling to 25 ℃ after 2 hours, slowly adding water (1200 mL) after 16 hours, keeping the temperature and stirring for 1 hour, adjusting the temperature to 5 ℃, and keeping the temperature for 1 hour; filtering, washing the filter cake with water (200 mL × 2), and adding petroleum ether (200 mL)2) Washing twice; taking out the filter cake, and vacuum drying at 60 ℃ for 3 hours to constant weight to obtain a 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%.
The fifth step: n is a radical of 4 - (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 Preparation of (E) -methylbenzene-1,2,4-triamine
Figure BDA0003213126870000122
Adding tetrahydrofuran (650 mL) and ethanol (350 mL) into a three-necked flask (2L) at 25 deg.C, stirring, and sequentially adding 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) and raney nickel (85 g), the hydrogen replacement reaction system is carried out for three times, and a hydrogen bag is protected; after stirring for 24 hours, stopping stirring, filtering, washing the filter cake twice with ethanol (100 mL × 2) and twice with tetrahydrofuran (100 mL × 2); adding active carbon (20 g) into the filtrate, adjusting the temperature to 70 ℃, and stirring for 2 hours; filtering while hot, decompressing and removing the solvent 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).
And a sixth step: preparation of N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide
Figure BDA0003213126870000131
Adding tetrahydrofuran (1200 mL) and N at 25 ℃ under the protection of nitrogen 4 - (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methyl radicalBenzene-1,2,4-triamine (130 g) is put into a three-necked bottle (3L), stirring is started, the temperature is adjusted to 0 ℃, a tetrahydrofuran (100 mL) solution of 3-chloropropionyl chloride (52.7 g) is slowly added, the temperature is adjusted to 25 ℃, n-heptane (1300 mL) is slowly added, and stirring is carried out for 30 minutes; filtering, washing the filter cake with n-heptane (500 mL), taking out the filter cake, transferring to a three-necked flask (3L), adding tetrahydrofuran (1300 mL), adding aqueous solution (257 mL) of potassium hydroxide (93.1 g), and adjusting the temperature to 70 ℃ for refluxing; after stirring for 25 hours, the temperature was adjusted to 25 ℃, the upper tetrahydrofuran layer was separated, a saturated aqueous ammonium chloride solution (450 mL) was slowly added to the aqueous layer until the aqueous phase pH =8, ethyl acetate (1.3L) was added for extraction, and after stirring for 5 minutes, the upper organic layer was separated; combining the above organic layers, adding saturated aqueous sodium chloride (500 mL) to the organic layer, washing, adding anhydrous sodium sulfate (100 g) to the separated organic layer, drying, filtering, washing the filter cake with ethyl acetate (100 mL), adding activated carbon (13 g) to the filtrate, refluxing for 2 hours, filtering, and washing the filter cake with ethyl acetate (100 mL); the solvent was removed from the filtrate under reduced pressure to give the compound N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-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] + 。
The seventh step: preparation of N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide methanesulfonate
Figure BDA0003213126870000141
Adding N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloyl amide (111.9 g) into a three-necked bottle (2L) at 25 ℃ under the protection of nitrogen, adding acetone (1000 mL) and water (22.4 mL), heating to 55 ℃ of the internal temperature, completely dissolving, slowly dropwise adding an acetone (110 mL) solution containing methanesulfonic acid (19.3 g), keeping the internal temperature of 55 ℃ while dropwise adding, and keeping the temperature and stirring for 30 minutes; naturally cooling, cooling to 25 ℃ after 3 hours, keeping the temperature and stirring for 30 minutes, adjusting the temperature to 5 ℃, keeping the temperature and stirring for 1 hour; the mixture was filtered, and the filter cake was washed twice with acetone (300 mL × 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 methanesulfonate (109 g) in 82.3% yield and 99.4% purity.
Example 2
Preparation of N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (meth) amino) phenyl) acryloyl amide
Figure BDA0003213126870000142
The first step is as follows: preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -N- (2- (difluoromethoxy) -4-fluoro-5-nitrophenyl) pyrimidin-2-amine
Figure BDA0003213126870000143
3- (2-Chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole (80mg, 0.29mmol) and 2- (difluoromethoxy) -4-fluoro-5-nitroaniline (64mg, 0.29mmol) were dissolved in 2-pentanol, heated to 1 hour by microwave reaction, cooled to room temperature, the solvent was evaporated off, and the residue was isolated and purified by preparative thin layer chromatography to give 4- (1-cyclopropyl-1H-indol-3-yl) -N- (2- (difluoromethoxy) -4-fluoro-5-nitrophenyl) pyrimidin-2-amine (76 mg).
MS m/z(ESI):456.1[M+H] + 。
The second step is that: preparation of N1- (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -2- (difluoromethoxy) -N4- (2- (dimethylamino) ethyl) -N4-methyl-5-nitrobenzene-1,4-diamine
Figure BDA0003213126870000151
4- (1-cyclopropyl-1H-indol-3-yl) -N- (2- (difluoromethoxy) -4-fluoro-5-nitrophenyl) pyrimidin-2-amine (76 mg) was dissolved in N, N-dimethylacetamide, and trimethylethylenediamine (0.1 g) was added to the solution, and the mixture was heated to reflux for 2 hours. Cooled to room temperature and the solvent evaporated to give N1- (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -2- (difluoromethoxy) -N4- (2- (dimethylamino) ethyl) -N4-methyl-5-nitrophenyl-1,4-diamine (50 mg).
MS m/z(ESI):538.3[M+H] + 。
The third step: preparation of N4- (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -5- (difluoromethoxy) -N1- (2- (dimethylamino) ethyl) -N1-methylbenzene-1,2,4-triamine
Figure BDA0003213126870000152
N1- (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -2- (difluoromethoxy) -N4- (2- (dimethylamino) ethyl) -N4-methyl-5-nitrobenzene-1,4-diamine (50 mg) was dissolved in 6mL of an ethanol-water mixed solvent (5:1), 65mg of iron powder and 50mg of ammonium chloride were added, and the mixture was heated to reflux and reacted for 2 hours. Cooling to room temperature, filtering and collecting filtrate. The ethanol in the filtrate was concentrated under reduced pressure, and water and dichloromethane-methanol (20. The organic phase was separated, dried and concentrated to give a crude product (20 mg).
MS m/z(ESI):508.3[M+H] + 。
The fourth step: preparation of N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -4- (difluoromethoxy) -2- ((2- (dimethylamino) ethyl) (meth) amino) phenyl) acryloyl amide
Figure BDA0003213126870000153
N4- (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -5- (difluoromethoxy) -N1- (2- (dimethylamino) ethyl) -N1-methylbenzene-1,2,4-triamine (20 mg) was dissolved in anhydrous tetrahydrofuran, protected with nitrogen, DIPEA (0.1 mL) was added at 0 ℃, and 1M 3-chloropropionyl chloride tetrahydrofuran solution (0.2 mL) was added dropwise. The reaction was carried out at 0 ℃ for 1 hour. Adding water and dichloromethane into the reaction solution, separating the water phase from the organic phase, extracting the water phase with dichloromethane for three times, combining the organic phases, drying and concentrating, and preparing a thin layer chromatography to separate to obtain a crude product. The crude product was further purified by reverse phase column (water: methanol =25 = 75) to obtain a final product (6.2 mg).
1 H NMR(400MHz,CD 3 OD)δ8.56(s,1H)，8.26(m,2H),8.08(d,1H),7.71(d,1H),7.50(d,1H)，7.32(m,3H),6.96(m,1H),6.79(m,1H),6.44(dd,1H),5.85(d,1H),3.62(m,1H),3.52(m,2H),3.40(m,2H),2.94(s,6H),2.82(s,3H),1.24(m,2H),1.14(m,2H)；
19 F NMR(376MHz,CD 3 OD)δ-83.26；
MS m/z(ESI):562.2[M+H] + .
Example 3
Preparation of N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- (trifluoromethoxy) phenyl) propenylamide
Figure BDA0003213126870000161
Preparation of N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- (trifluoromethoxy) phenyl) acryloyl amide was analogous to example 1.
1 H NMR(400MHz,CD 3 OD)δ9.56(s,1H),8.89(s,1H),8.56(m,1H),8.08(d,1H),7.71(d,1H),7.50(d,1H)，7.32(m,3H),6.96(m,1H),6.79-6.43(m,2H),6.09(dd,1H),5.85(d,1H),3.62(m,2H),2.75(m,3H),2.40-2.50(m,3H),2.94(s,6H),1.24(m,2H),1.14(m,2H)；
MS m/z(ESI):580.6[M+H] + .
Example 4
Preparation of N- (5- ((4- (1-cyclopropyl-4,6-dimethyl-5- (methylsulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) propenylamide
Figure BDA0003213126870000162
N- (5- ((4- (1-cyclopropyl-4,6-dimethyl-5- (methylsulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) propenylamide was prepared in analogy to example 1.
1 H NMR(400MHz,CD 3 OD)δ10.06(s,1H),8.89(s,1H),8.56(m,1H),8.08(d,1H),7.36(d,1H),7.19(s,1H),7.12(s,1H),6.48-6.43(m,2H),6.09(dd,1H),5.85(d,1H),3.82(m,3H),3.45(m,2H),3.32(s,3H),2.72-2.75(m,6H),2.64(s,3H),2.40-2.50(m,3H),2.21(s,6H),1.24(m,2H),1.14(m,2H)；
MS m/z(ESI):632.8[M+H] + .
Example 5
Preparation of N- (5- ((4- (1,5-bicyclopropyl-4,6-difluoro-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide
Figure BDA0003213126870000171
N- (5- ((4- (1,5-bicyclopropyl-4,6-difluoro-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) propenylamide was prepared in analogy to example 1.
1 H NMR(400MHz,CD 3 OD)δ10.06(s,1H),8.89(s,1H),8.56(m,1H),7.36(d,1H),7.19(s,1H),7.12(s,1H),7.06(s,1H),6.48(m,1H),6.43(s,1H),6.09(dd,1H),5.85(d,1H),3.82(s,3H),3.45(m,2H),2.75(s,3H),2.40-2.50(m,3H),2.21(s,6H),1.85(m,1H),1.24(m,2H),1.14(m,2H),1.00(m,2H),0.75(m,2H),；
MS m/z(ESI):602.8[M+H] + .
Example 6
Preparation of N- (5- ((4- (1-cyclopropyl-5,7-difluoro-6- (oxetan-3-yl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloyl amide
Figure BDA0003213126870000172
The preparation of N- (5- ((4- (1-cyclopropyl-5,7-difluoro-6- (oxetan-3-yl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloyl amide was analogous to example 1.
1 H NMR(400MHz,CD 3 OD)δ10.06(s,1H),8.89(s,1H),8.56(d,1H),7.61(m,1H),7.36(d,1H),7.19(s,1H),7.12(s,1H),6.48(m,1H),6.43(s,1H),6.09(dd,1H),5.75(d,1H),5.14(m,2H),4.89(m,2H),4.0(m,H),3.82(s,3H),3.45(m,2H),2.75(s,3H),2.40-2.50(m,3H),2.21(s,6H),1.00(m,2H),0.75(m,2H)；
MS m/z(ESI):618.7[M+H] + .
Example 7
Preparation of N- (5- ((4- (1-cyclopropyl-6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) propenylamide
Figure BDA0003213126870000181
N- (5- ((4- (1-cyclopropyl-6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) -4-methoxyphenyl) acryloylamide was prepared in analogy to example 1.
TFA salt of N- (5- ((4- (1-cyclopropyl-6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloyl amide 1 H NMR(400MHz,CD 3 OD):δ8.41(s,1H),8.15(br,1H),7.98(d,J＝6.8Hz,1H),7.89(s,1H),7.40(d,J＝6.8Hz,1H),7.17(d,J＝2.4Hz,1H),7.06(s,1H)，6.87(m,1H),6.50(m,2H),5.87(m,1H),3.95(s,3H),3.88(s,3H),3.55(m,3H),3.35(m,2H),2.92(s,6H),2.80(s,3H),1.22(m,2H),0.90(m,2H)；
MS m/z(ESI):556.2[M+H] + .
Example 8
Preparation of N- (5- ((5-chloro-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) -4-methoxyphenyl) acryloylamide
Figure BDA0003213126870000182
N- (5- ((5-chloro-4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) -4-methoxyphenyl) acryloylamide was prepared in analogy to example 1.
1 H NMR(400MHz,CD 3 OD)δ8.68(s,1H),8.41(s,1H),8.19(d,J＝7.8Hz,1H),7.82(s,1H),7.67(d,J＝8.2Hz,1H),7.26(t,J＝7.6Hz,1H),7.14(t,J＝7.5Hz,1H),6.99(s,1H),6.44(dt,J＝14.3,7.1Hz,2H),5.85(dd,J＝9.2,2.6Hz,1H),4.01(s,3H),3.60–3.44(m,3H),3.29(t,J＝5.6Hz,2H),2.87(s,6H),2.71(s,3H),1.25–1.18(m,2H),1.06–0.98(m,2H)；
MS m/z(ESI):561.1[M+H] + .
Example 9
Preparation of N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) propenylamide
Figure BDA0003213126870000191
N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide was prepared in analogy to example 1.
1 H NMR(400MHz,CD 3 OD)δ8.68(s,1H),8.41(s,1H),8.19(d,J＝7.8Hz,1H),7.82(s,1H),7.67(d,J＝8.2Hz,1H),7.26(t,J＝7.6Hz,1H),7.14(t,J＝7.5Hz,1H),6.99(s,1H),6.44(dt,J＝14.3,7.1Hz,2H),5.85(dd,J＝9.2,2.6Hz,1H),4.01(s,3H),3.60–3.44(m,3H),3.29(t,J＝5.6Hz,2H),2.87(s,6H),2.71(s,3H),1.25–1.18(m,2H),1.06–0.98(m,2H)；
MS m/z(ESI):594.3[M+H] + .
EXAMPLE 10 preparation of 3- (2-Chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole
3- (2-Chloropyrimidin-4-yl) -1H-indole (72.0g, 0.313mol), cyclopropylboronic acid (32.1g, 0.376mol), copper bromide (71.4g, 0.32mol), 2,2' -bipyridine (50.3g, 0.313mol), sodium carbonate (66.6g, 0.626 mol), acetonitrile (720 mL) were added to the reaction flask and warmed to 55 ℃. The reaction was completed by stirring at this temperature for 10 hours. Filtering, washing a filter cake by using ethyl acetate, and concentrating the filtrate under reduced pressure to be dry. To the residue were added ethyl acetate (860 mL) and water (720 mL), and the mixture was stirred, separated into layers, and the organic phase was separated. To the organic phase was added a saturated sodium chloride solution (300 mL), stirred, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give a brown solid. Ethanol (400 mL) was added to the solid, heated to reflux, stirred to dissolve, slowly cooled to room temperature and stirred to crystallize. Filtering, drying the filter cake to obtain the product 3- (2-chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole with the yield of 88.2 percent and the HPLC purity of 99.9 percent, wherein 74.7g of light yellow solid is obtained.

Claims (12)

1. A process for the preparation of a compound of formula (I) comprising the steps of:
Figure FDA0003954829980000011
coupling a compound shown as a general formula (II) with cyclopropylboronic acid to obtain a compound shown as a general formula (I);
the method for preparing the compound shown in the general formula (II) further comprises the following steps:
Figure FDA0003954829980000012
a compound of the formula (III) and
Figure FDA0003954829980000013
reacting to obtain a compound shown as a general formula (II);
r is selected from hydrogen, deuterium, halogen and C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl or-S (O) 2 R a ；
R 1 Selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Cycloalkyl, trifluoromethyl or trifluoromethoxy;
R a selected from hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group; and is
y is 0,1, 2, 3 or 4.
2. The method for preparing the compound of formula (I) according to claim 1, wherein R is 1 Selected from hydrogen, halogen and trifluoromethyl.
3. The method of claim 1, wherein the method further comprises a halogenated magnesium alkyl reagent.
4. The method of claim 3, wherein the method further comprises a methyl magnesium chloride reagent or a methyl magnesium bromide reagent.
5. The process for preparing the compound represented by the general formula (I) according to claim 1, wherein the coupling reaction is carried out in the presence of a catalyst, a basic agent and an organic solvent.
6. The method of claim 5, wherein the catalyst is selected from the group consisting of copper acetate and 2,2 '-bipyridine, copper halide and 2,2' -bipyridine.
7. The method of claim 6, wherein the catalyst is selected from the group consisting of copper acetate and 2,2' -bipyridine.
8. The process for preparing the compound represented by the general formula (I) according to claim 5, wherein the basic agent is selected from potassium phosphate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.
9. The process for preparing the compound of formula (I) according to claim 8, wherein the alkaline agent is selected from sodium carbonate or potassium phosphate.
10. The process according to claim 5, wherein the organic solvent is selected from acetonitrile, tetrahydrofuran, dimethyltetrahydrofuran, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, toluene or dioxane.
11. The method according to claim 10, wherein the organic solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, dimethyltetrahydrofuran, dimethylformamide, and dimethylsulfoxide.
12. The process for preparing the compound of formula (I) according to claim 1, wherein the purification of the compound of formula (I) comprises the steps of: performing liquid-liquid extraction by using ethyl acetate/water, concentrating to dryness, adding ethanol, heating and refluxing to dissolve, cooling to room temperature, stirring and crystallizing, wherein the weight-volume ratio of a compound shown in a formula (II) and ethanol as starting materials is 1g:3 to 10mL.
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