CN110698461A - Preparation method of third-generation EGFR inhibitor - Google Patents

Preparation method of third-generation EGFR inhibitor Download PDF

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CN110698461A
CN110698461A CN201910614211.7A CN201910614211A CN110698461A CN 110698461 A CN110698461 A CN 110698461A CN 201910614211 A CN201910614211 A CN 201910614211A CN 110698461 A CN110698461 A CN 110698461A
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CN110698461B (en
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苏熠东
匡远卓
包如迪
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Jiangsu Hausen Pharmaceutical Group Co Ltd
Shanghai Hansen Biological Medicine Technology Co Ltd
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Shanghai Hansen Biological Medicine Technology Co Ltd
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    • 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

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Abstract

The invention relates to a preparation method of a third-generation EGFR inhibitor. The invention discloses preparation and application of an 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 in a formula (I). 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 third-generation EGFR inhibitor
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 cells. 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) They show better therapeutic effect in lung cancer treatment and have been used as first-line drugs for treating NSCLC (New England Journal of Medicine (2008) Vol.358,1160-74, Biochemical and biological Research Communications (2004) Vol.319,1-11) which is a non-small cell lung cancer accompanied by mutation of EGFR activation.
Activation of mutant EGFR (including L858R and the exon 19 deletion del E746_ A750) with decreased affinity for Adenosine Triphosphate (ATP) and increased affinity for small molecule inhibitors, relative to wild-type (WT) EGFR, resulted 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. In half of patients, the drug resistance is caused by the secondary mutation of the EGFR gatekeeper gene residue T790M, thereby reducing the affinity of the drug and the target point to generate drug resistance, and causing the recurrence or disease progression of the tumor.
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 lung cancer patients with such resistance by inhibiting the EGFR T790M mutant, all with poor selectivity. Even though afatinib has been FDA approved for the treatment of lung cancer, it is only used for first line treatment of 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 the EGFR T790M mutant 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 as to treat EGFR T790M secondary mutation drug-resistant tumor. 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 to 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 790T mutant strain of an initial treatment patient so as to delay the occurrence of drug resistance.
Lung cancer is a serious disease threatening human health, and death of lung cancer accounts for the first place of all malignant tumors. In China, the incidence rate of lung cancer is rising year by year, and the number of new cases is nearly 70 ten thousand 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 PCT/CN2015/091189 (application date: 2015.09.30), 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:
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 no specific preparation condition is given, so that the preparation method is not optimized and is not suitable for industrial mass production.
Journal org.Lett.2008,10(8), 1653-doped 1655 disclose 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.
Journal of Organic Chemistry,2008,73(16),6441-6444 also discloses a method for preparing 1-cyclopropyl-1H-indole derivatives from cyclopropylboronic acid and 1H-indole derivatives, which has the disadvantage of large dosage 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 a long-term research and development process.
The invention provides a preparation method of a compound shown in a formula (III), which comprises the following steps: coupling reaction of a compound of formula (II) and indole to obtain a compound of formula (III)
Figure BDA0002123359390000041
Preferably, the molar ratio of the compound of the formula (II) to the indole is 1: 1-2, and preferably 1: 1-1.2.
Preferably, the reaction of said step is carried out in the presence of a catalyst, an alkaline agent and an organic solvent.
As a further preferred version, 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 agent in said step is 1: 1-1.2: 1-1.2: 1-1.2: 2 to 2.4.
As a further preferred version, the organic solvent is selected from acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, toluene or dioxane, preferably from dimethylformamide or dimethyl sulfoxide.
Preferably, the reaction of the step further comprises a purification process, and further comprises the following steps: extracting the compound of formula (III) with n-heptane, washing with water, drying, concentrating under reduced pressure, and separating with chromatography column.
In a further preferred embodiment, the mass-to-volume ratio of the compound of formula (II) to n-heptane is 1: 4-8, preferably 1: 6-7, the volume ratio of n-heptane to the reaction solvent is 3:15:1, preferably 4:1, and the chromatographic eluent is petroleum ether.
Further, the present invention provides a process for the preparation of a compound of formula (i), comprising the steps of:
1) coupling reaction of a compound of a formula (II) and indole to obtain a compound of a formula (III);
2) coupling reaction of the compound of the formula (III) and the compound of the formula (IX) to obtain a compound of the formula (IV);
3) obtaining a compound of formula (V) from the coupling reaction of a compound of formula (IV) and a compound of formula (X);
4) reacting the compound shown in the formula (V) with N, N, N' -trimethylethylenediamine to obtain a compound shown in a formula (VI);
5) reducing the nitro group of the compound of the formula (VI) to obtain a compound of a formula (VII);
6) reacting a compound of formula (VII) with a compound of formula (XI) to obtain a compound of formula (I);
the reaction formula is as follows:
wherein R is1Selected from hydrogen, deuterium, halogen, cyano, nitro, optionally substituted C1-8Alkyl, optionally substituted hydroxy, optionally substituted C3-8Cycloalkyl, -SO2R5、-C(O)R6、-C(O)OR6or-P (O) R7R8；
R2Is selected from C1-8Alkoxy or C3-8Cycloalkoxy, optionally further substituted with one or more substituents selected from halogen, hydroxy, aryl, heterocycloalkyl;
R3is halogen;
R4selected from hydroxy or halogen;
R5selected from hydrogen, deuterium, optionally substituted C1-8Alkyl radical, C3-8Cycloalkyl, heterocycloalkyl, or aryl;
R6、R7、R8each independently selected from hydrogen, deuterium, optionally substituted C1-8Alkyl radical, C3-8Cycloalkyl, heterocycloalkyl, or aryl.
Further, the present invention provides a process for the preparation of a compound of formula (i), comprising the steps of:
1) coupling reaction of a compound of a formula (II) and indole to obtain a compound of a formula (III);
2) coupling reaction of the compound of the formula (III) and the compound of the formula (IX) to obtain a compound of the formula (IV);
3) obtaining a compound of formula (V) from the coupling reaction of a compound of formula (IV) and a compound of formula (X);
4) reacting the compound shown in the formula (V) with N, N, N' -trimethylethylenediamine to obtain a compound shown in a formula (VI);
5) reducing the nitro group of the compound of the formula (VI) to obtain a compound of a formula (VII);
6) reacting a compound of formula (VII) with a compound of formula (XI) to obtain a compound of formula (I);
the reaction formula is as follows:
Figure BDA0002123359390000061
wherein R is1Selected from hydrogen, deuterium, halogen, cyano, nitro, C1-8Alkyl radical, C1-8Alkoxy radical, C3-8Cycloalkyl, trifluoromethyl, trifluoromethoxy, -SO2R5、-C(O)R6、-C(O)OR6or-P (O) R7R8；
R2Is selected from C1-8Alkoxy or C3-8Cycloalkoxy, optionally further substituted by one or more groups selected from halogen, hydroxy, C1-8Alkyl radical, C1-8Alkoxy radical, C3-8Cycloalkyl or C3-8Cycloalkoxy is substituted by a substituent;
R3is halogen;
R4selected from hydroxy or chlorine;
R5selected from hydrogen, deuterium, C1-8Alkyl radical, C3-8Cycloalkyl, halo-substituted C1-8Alkyl, phenyl or p-methylphenyl;
R6、R7、R8each independently selected from hydrogen, deuterium and C1-8Alkyl radical, C3-8Cycloalkyl, halo-substituted C1-8Alkyl or hydroxy substituted C1-8An alkyl group.
As a preferred embodiment, R1Selected from hydrogen, deuterium, halogen, C1-8Alkyl radical, C1-8Alkoxy radical, C3-8Cycloalkyl, trifluoromethyl or trifluoromethoxy;
R2selected from methoxy, ethoxy, difluoromethoxy or trifluoromethoxy;
R3selected from fluorine or chlorine.
Preferably, the reaction of step 1) is carried out in the presence of a catalyst, an alkaline agent and an organic solvent.
The reaction temperature is preferably 70-80 ℃;
as a further preferred version, 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 molar ratio of the compound of formula (ii), indole, copper acetate, bipyridine and alkaline agent added in step 1) is 1: 1-1.2: 1-1.2: 1-1.2: 2 to 2.4.
Preferably, the reaction of the step further comprises a purification process, and further comprises the following steps: extracting the compound of formula (III) with n-heptane, washing with water, drying, concentrating under reduced pressure, and separating with chromatography column.
In a further preferred embodiment, the mass-to-volume ratio of the compound of formula (II) to n-heptane is 1: 4-8, preferably 1: 6-7, the volume ratio of 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 from 60 ℃ to 70 ℃, more preferably at a temperature of from 65 ℃ to 70 ℃.
As a further preferred embodiment, the reaction temperature is selected from the group consisting of aluminum trichloride, ferric trichloride, and boron trichloride, preferably from aluminum trichloride.
Preferably, 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 mode, 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, t-butanol amyl alcohol, 2-pentanediol or a mixture thereof.
Preferably, step 4) is carried out at a temperature of from 80 ℃ to 90 ℃ in an alkaline environment, preferably at a temperature of from 85 ℃ to 90 ℃.
As a further preferred embodiment, the base is selected from trimethylamine, triethylamine, pyridine, piperidine, diisopropylethylamine, morpholine or a mixture thereof, preferably from triethylamine or diisopropylethylamine.
Preferably, step 5) is carried out in the presence of a reducing agent selected from the group consisting of Pd/C, Raney-Ni, Pd (OH) and hydrogen2Or PtO2Preferably from Raney-Ni.
As a preferable mode, the step 6) includes amidation and elimination, the elimination is performed in an alkaline environment, and further, the amidation is performed under a low temperature condition, preferably at a temperature of 0 to 5 ℃.
Preferably, step 6) is carried out at a temperature of 0 ℃ to 10 ℃ in an alkaline environment, preferably at a temperature of 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 a further 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 mesylate salts.
Preferably, the salt formation of the mesylate salt 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 takes the cyclopropylboronic acid and the 1H-indole as raw materials, the raw materials are easy to obtain, compared with the prior art, the consumption of the cyclopropylboronic acid is reduced, the reaction cost is greatly reduced, the purity of the intermediate (III) reaches more than 98%, the use of a high-toxicity and high-irritation solvent is avoided, the environmental pressure is relieved, and the large-scale reaction is facilitated.
The invention has simple post-treatment process of each step of reaction, can remove most by-products by filtering, washing with water or washing with common organic solvent, and has strong process operability. The organic solvent can be collected for repeated use, thereby greatly reducing the cost. The product obtained by the reaction has good purity and high yield, and the process safety is also improved.
The salifying reaction is simple to operate, 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.
“C1-8Alkyl "refers to straight and branched alkyl groups comprising 1 to 4 carbon atoms, alkyl refers to a saturated aliphatic hydrocarbon group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, and the like.
“C1-8Alkoxy "means an alkyloxy group having 1 to 8 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, "C3-8Cycloalkyl "refers to cycloalkyl groups comprising 3 to 8 carbon atoms.
The "alcohol solvent" refers to 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)3OD) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gi min i C18150X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco 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. 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 continuous magnetic stirring without specific mention.
Example 1
Figure BDA0002123359390000091
Indole (32.7g), copper acetate (50.7g), 2' -bipyridine (43.6g), sodium carbonate (59.2g), and DMF (250mL) were added to a three-necked flask, and the temperature was adjusted to 70 ℃. Cyclopropylboronic acid (20.0g) was dissolved in DMF (50mL) and added dropwise to a three-necked flask. After the addition was complete, the mixture was stirred at 70 ℃ for 41 hours. After cooling to room temperature, a saturated ammonium chloride solution (200mL) and n-heptane (400mL) were added, and the organic phase and the aqueous phase were separated, washed with a saturated ammonium chloride solution (2X 200mL) and the aqueous phase with n-heptane (2X 400mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel is filled in a chromatographic column, the crude product is diluted by petroleum ether and is directly loaded on the column, and the petroleum ether is used for elution to obtain the 1-cyclopropyl-1H-indole (20.2g), the purity is 98.8 percent, and the yield is 55.2 percent.
Example 2
Figure BDA0002123359390000092
Adding 1-cyclopropyl-1H-indole (71.2g) and 2, 4-dichloropyrimidine (87.1g) into a three-necked flask (2L) at 25 ℃ in sequence under the protection of nitrogen, adding 1, 2-dichloroethane (720mL), starting stirring, after 30 minutes, adding aluminum trichloride (78.5g), raising the internal temperature to 30 ℃, adjusting the internal temperature to 65 ℃, refluxing, stirring for 3 hours, cooling to room temperature of 25 ℃, slowly adding the reaction solution into an ice/water (500g) mixture, stirring for 15 minutes, adding dichloromethane (700mL), stirring for 5 minutes, separating out a lower organic layer, adding dichloromethane (500Ml) into an aqueous layer, stirring for 5 minutes, separating out a lower organic layer, combining the organic layers, adding a saturated aqueous sodium bicarbonate solution (500Ml), stirring for 30 minutes, separating out a lower organic layer, adding a saturated aqueous chlorinated solution (500Ml), stirring for 5 minutes, separating a lower organic layer, adding anhydrous sodium sulfate (75g) to the organic layer, stirring for 30 minutes, filtering, washing a filter cake with dichloromethane (100mL), removing most of the solvent under reduced pressure, adding ethyl acetate (200mL) to replace the solvent once, adding ethyl acetate (200mL) to remove the solvent under reduced pressure until the total volume of the solvent is about 260mL (about 140mL of ethyl acetate), heating to 77 ℃ for refluxing, slowly dropwise adding petroleum ether (500mL), adding the petroleum ether for 40 minutes, refluxing for 30 minutes, cooling to 20 ℃ after 3 hours, stirring for 15 hours, adjusting the temperature to 5 ℃, filtering after 1 hour, washing the filter cake with a mixed solvent of petroleum ether and ethyl acetate (0 ℃ mixed solvent, petroleum ether: ethyl acetate 4:1, 150mL), and washing twice with petroleum ether (150mL, 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 (95.1g) with a purity of 98.5% and a yield of 77.8%.
Example 3
At 25 ℃, under the protection of nitrogen, 3- (2-chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole (95g) and 4-fluoro-2-methoxy-5-nitroaniline (68.8g) are sequentially added into a three-necked bottle (2L), and 2-pentanol (800mL) and TsOH2O (80.4g), starting stirring, and adjusting the temperature to the internal temperature of 110 ℃ for refluxing; stirring for 4 hr, cooling to 30 deg.C, filtering, soaking and washing the filter cake with 2-pentanol (200mL), and washing twice with petroleum ether (300mL × 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 (132g) with a purity of 99.5% and a yield of 89.4%.
Example 4
Figure BDA0002123359390000111
Adding dimethylacetamide (400mL) into a three-necked flask (3L) at the temperature of 25 ℃ under the protection of nitrogen, stirring, sequentially adding a compound 4- (1-cyclopropyl-1H-indol-3-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (131g), diisopropylethylamine (121g) and N, N, N' -trimethylethylenediamine (48g), and adjusting the temperature to 85 ℃; stirring for 3 hours, slowly adding water (400mL), keeping the internal temperature at 80 ℃, naturally cooling to 25 ℃ after 2 hours, slowly adding water (1200mL) 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 a filter cake once by using water (200mL multiplied by 2), and washing twice by using petroleum ether (200mL multiplied by 2); taking out the filter cake, and vacuum drying at 60 ℃ for 3 hours to constant weight to obtain a compound N1- (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -N4- (2- (dimethylamino) ethyl) -2-methoxy-N4-methyl-5-nitrobenzene-1, 4-Diamine (138.7g), yield 88.5%, purity 99.4%.
Example 5
Figure BDA0002123359390000112
Adding tetrahydrofuran (650mL) and ethanol (350mL) into a three-necked flask (2L) at 25 deg.C, stirring, and sequentially adding compound N1- (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -N4- (2- (dimethylamino) ethyl) -2-methoxy-N4Methyl-5-nitrobenzene-1, 4-diamine (138.7g), raney nickel (85g), hydrogen replacement reaction system three times, hydrogen bag protection; after stirring for 24 hours, stopping stirring, filtering, washing the filter cake twice with ethanol (100mL × 2) and twice with tetrahydrofuran (100mL × 2); adding active carbon (20g) 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 N4- (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methylbenzene-1, 2, 4-triamine (130 g).
Example 6
Figure BDA0002123359390000121
Adding tetrahydrofuran (1200mL) and N at 25 ℃ under the protection of nitrogen4- (4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) -N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methylbenzene-1, 2, 4-triamine (130g) was added to a three-necked flask (3L), stirring was started, the temperature was adjusted to 0 ℃, a solution of 3-chloropropionyl chloride (52.7g) in tetrahydrofuran (100mL) was slowly added, the temperature was adjusted to 25 ℃, n-heptane (1300mL) was slowly added, and stirring was carried out for 30 minutes; filtering, washing the filter cake with n-heptane (500mL), taking out the filter cake, transferring to a three-necked flask (3L), adding tetrahydrofuran (1300mL), adding aqueous solution (257mL) of potassium hydroxide (93.1g), 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 (450mL) was slowly added to the aqueous layer until the pH of the aqueous phase became 8, ethyl acetate (1.3L) was added for extraction, and after stirring for 5 minutes, the upper tetrahydrofuran layer was separatedAn upper organic layer; combining the above organic layers, adding saturated aqueous sodium chloride (500mL) to the organic layer, washing, adding anhydrous sodium sulfate (100g) to the separated organic layer, drying, filtering, washing the filter cake with ethyl acetate (100mL), adding activated carbon (13g) 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 (129g), yield 88.8%, purity 99%.
1H NMR(400MHz,CDCl3):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
Figure BDA0002123359390000131
Adding N- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloyl amide (111.9g) into a three-necked bottle (2L) at 25 ℃ under the protection of nitrogen, adding acetone (1000mL) and water (22.4mL), heating to 55 ℃ of the internal temperature, completely dissolving, slowly dropwise adding an acetone (110mL) solution containing methanesulfonic acid (19.3g), 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. 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 methanesulfonate (109g) in 82.3% yield and 99.4% purity.

Claims (22)

1. A process for the preparation of a compound of formula (iii), comprising the steps of: coupling reaction of the compound of the formula (II) and indole to obtain a compound of a formula (III),
Figure FDA0002123359380000011
2. the method for preparing the compound of formula (iii) according to claim 1, wherein the molar ratio of the compound of formula (ii) to indole is 1: 1-2, preferably 1: 1-1.2.
3. The process for the preparation of the compound of formula (iii) according to claim 1 or 2, characterized in that the reaction of step (hi) is carried out in the presence of a catalyst 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.
4. A process for the preparation of a compound of formula (i) comprising the steps of:
1) coupling reaction of a compound of a formula (II) and indole to obtain a compound of a formula (III);
2) coupling reaction of the compound of the formula (III) and the compound of the formula (IX) to obtain a compound of the formula (IV);
3) obtaining a compound of formula (V) from the coupling reaction of a compound of formula (IV) and a compound of formula (X);
4) reacting the compound shown in the formula (V) with N, N, N' -trimethylethylenediamine to obtain a compound shown in a formula (VI);
5) reducing the nitro group of the compound of the formula (VI) to obtain a compound of a formula (VII);
6) reacting a compound of formula (VII) with a compound of formula (XI) to obtain a compound of formula (I);
the reaction formula is as follows:
Figure FDA0002123359380000021
wherein R is1Selected from hydrogen, deuterium, halogen, cyano, nitro, optionally substituted C1-8Alkyl, optionally substituted hydroxy, optionally substituted C3-8Cycloalkyl, -SO2R5、-C(O)R6、-C(O)OR6or-P (O) R7R8；
R2Is selected from C1-8Alkoxy or C3-8Cycloalkoxy, optionally further substituted with one or more substituents selected from halogen, hydroxy, aryl, heterocycloalkyl;
R3is halogen;
R4selected from hydroxy or halogen;
R5selected from hydrogen, deuterium, optionally substituted C1-8Alkyl radical, C3-8Cycloalkyl, heterocycloalkyl, or aryl;
R6、R7、R8each independently selected from hydrogen, deuterium, optionally substituted C1-8Alkyl radical, C3-8Cycloalkyl, heterocycloalkyl, or aryl.
5. A process for the preparation of a compound of formula (i) comprising the steps of:
1) coupling reaction of a compound of a formula (II) and indole to obtain a compound of a formula (III);
2) coupling reaction of the compound of the formula (III) and the compound of the formula (IX) to obtain a compound of the formula (IV);
3) obtaining a compound of formula (V) from the coupling reaction of a compound of formula (IV) and a compound of formula (X);
4) reacting the compound shown in the formula (V) with N, N, N' -trimethylethylenediamine to obtain a compound shown in a formula (VI);
5) reducing the nitro group of the compound of the formula (VI) to obtain a compound of a formula (VII);
6) reacting a compound of formula (VII) with a compound of formula (XI) to obtain a compound of formula (I);
the reaction formula is as follows:
Figure FDA0002123359380000031
wherein R is1Selected from hydrogen, deuterium, halogen, cyano, nitro, C1-8Alkyl radical, C1-8Alkoxy radical, C3-8Cycloalkyl, trifluoromethyl, trifluoromethoxy, -SO2R5、-C(O)R6、-C(O)OR6or-P (O) R7R8；
R2Is selected from C1-8Alkoxy or C3-8Cycloalkoxy, optionally further substituted by one or more groups selected from halogen, hydroxy, C1-8Alkyl radical, C1-8Alkoxy radical, C3-8Cycloalkyl or C3-8Cycloalkoxy is substituted by a substituent;
R3is halogen;
R4selected from hydroxy or chlorine;
R5selected from hydrogen, deuterium, C1-8Alkyl radical, C3-8Cycloalkyl, halo-substituted C1-8Alkyl, phenyl or p-methylphenyl;
R6、R7、R8each independently selected from hydrogen, deuterium and C1-8Alkyl radical, C3-8Cycloalkyl, halo-substituted C1-8Alkyl or hydroxy substituted C1-8An alkyl group.
6. A process for the preparation of a compound of formula (I) according to claim 4 or 5, wherein R is1Selected from hydrogen, deuterium, halogen, C1-8Alkyl radical, C1-8Alkoxy radical, C3-8Cycloalkyl, trifluoromethyl or trifluoromethoxy;
R2selected from methoxy, ethoxy, difluoromethoxy or trifluoromethoxy;
R3selected from fluorine or chlorine;
R5、R6、R7、R8as defined in claim 1.
7. The process for preparing the compound of formula (i) according to claim 4 or 5, wherein the reaction of step 1) is carried out in the presence of a catalyst, a basic agent and an organic solvent at a temperature of 70 ℃ to 80 ℃.
8. The process for the preparation of the compound of formula (i) according to claim 7, wherein the catalyst is selected from the group consisting of 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.
9. The process for preparing a compound of formula (i) according to claim 8, wherein the compound of formula (ii), indole, copper acetate, bipyridine and basic agent are added in step 1) in a molar ratio of 1: 1-1.2: 1-1.2: 1-1.2: 2 to 2.4.
10. The process for the preparation of the 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, preferably at a temperature of 65 ℃ to 70 ℃.
11. Process for the preparation of the compound of formula (i) according to claim 10, characterized in that the catalyst is selected from aluminum trichloride, ferric trichloride or boron trichloride, preferably from aluminum trichloride.
12. The process for the preparation of the compound of formula (i) according to claim 4 or 5, wherein the reaction of step 3) is carried out in the presence of an acidic reagent and an alcoholic solvent at a temperature of from 100 ℃ to 120 ℃, preferably from 110 ℃ to 120 ℃.
13. The process for the preparation of the compound of formula (i) according to claim 12, wherein 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.
14. The process of claim 12, wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol, t-butanol amyl alcohol, 2-pentanediol or mixtures thereof.
15. The process for the preparation of the compound of formula (i) according to claim 4 or 5, characterized in that step 4) is carried out in a basic environment at a temperature of 80 ℃ to 90 ℃, preferably at a temperature of 85 ℃ to 90 ℃.
16. Process for the preparation of compounds of formula (i) according to claim 15, characterized in that the base is selected from trimethylamine, triethylamine, pyridine, piperidine, diisopropylethylamine, morpholine or mixtures thereof, preferably from triethylamine or diisopropylethylamine.
17. The process for the preparation of the compound of formula (i) according to claim 4 or 5, wherein step 5) is carried out in the presence of a reducing agent selected from Pd/C, Raney-Ni, Pd (OH) and hydrogen2Or PtO2Preferably from Raney-Ni.
18. The process for the preparation of the compound of formula (i) according to claim 4 or 5, characterized in that step 6) comprises amidation and elimination reactions, the amidation reaction being carried out at low temperature, preferably at a temperature of 0-5 ℃; the elimination reaction is carried out in an alkaline environment.
19. The process for the preparation of the compound of formula (i) according to claim 4 or 5, characterized in that step 6) is carried out in a basic environment at a temperature of 0 ℃ to 10 ℃, preferably at a temperature of 0 ℃ to 5 ℃.
20. Process for the preparation of compounds of formula (i) according to claim 19, characterized in that 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.
21. Use of a process for the preparation of a compound of formula (i) as claimed in any one of claims 4 to 20 in 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 the mesylate salt.
22. Use according to claim 21, characterized in that the salification of the mesylate salt of the compound of formula (i) is carried out in a solvent system formed from acetone and water, or in a solvent system formed from ethyl acetate and ethanol.
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