CN111606889B - Process for the preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -N-phenylpyrimidin-2-amine derivatives - Google Patents
Process for the preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -N-phenylpyrimidin-2-amine derivatives Download PDFInfo
- Publication number
- CN111606889B CN111606889B CN202010114126.7A CN202010114126A CN111606889B CN 111606889 B CN111606889 B CN 111606889B CN 202010114126 A CN202010114126 A CN 202010114126A CN 111606889 B CN111606889 B CN 111606889B
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- general formula
- preparation
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a preparation method of a 4- (1-cyclopropyl-1H-indole-3-yl) -N-phenyl pyrimidine-2-amine derivative. 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 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
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 (Epidermal 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, amplification and mutation of EGFR genes, etc., can promote transformation of cells into malignant tumor cells, 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 effects 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 Biophysical Research Communications (2004) Vol.319, 1-11) which is a non-small cell lung cancer accompanied by mutation of EGFR activation.
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 gatekeeper gene residue T790M, thereby reducing the affinity of the drug and the target spot to generate drug resistance, and causing the recurrence of the tumor or the 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 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 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 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 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 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 WO2016054987, wherein the chemical names of the representative compounds are: 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 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 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 silica gel purification step is removed, the optimization is the recrystallization post-treatment, 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:
coupling a compound shown in a general formula (II) with cyclopropylboronic acid to obtain a compound shown in a general formula (I);
wherein the content of the first and second substances,
r is selected from hydrogen, deuterium, halogenElement, 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, more preferably 1:1 to 1.5.
Further, the method comprises the following steps:
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 the content of the first and second substances,
R、R 1 and y is as defined for formula (I).
Step 1) further comprises a Grignard reagent selected from halogenated alkylated magnesium reagents, preferably methyl magnesium chloride or methyl magnesium bromide, more preferably, the molar ratio of the compound represented by the general formula (III) to the Grignard reagent is 1:2 to 5, preferably 1:2 to 3, more preferably 1;
the concentration of the Grignard reagent is 2 to 4mol/L;
the reaction solvent is tetrahydrofuran or its derivative, preferably tetrahydrofuran or 2-methyl tetrahydrofuran.
As a further preferable scheme, the coupling reaction in the step 2) 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 dimethylsulfoxide 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.
More preferably, the molar ratio of the compound of formula (II) to the catalyst is 1:1 to 5, preferably 1:1 to 2, more preferably 1:1.
more preferably, the molar ratio of the compound represented by the general formula (II) to the basic agent is 1:1 to 5, preferably 1:1 to 2, more preferably 1:1.
as a further preferred embodiment, in the preparation method of 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 basic agent is 1 to 1.2, 1.
The present patent also relates to a process for the preparation of a compound of formula (IV), comprising the steps of:
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 the content of the first and second substances,
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; wherein the content of the first and second substances,
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 and substituted;
R 3 selected from hydroxy or chlorine;
R、R 1 and y is as defined for formula (I);
the temperature is selected from 0 ℃ to 10 ℃; preferably 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) further comprises the step of producing a compound represented by the general formula (V) from a compound represented by the general formula (VII),
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 the content of the first and second substances,
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 and 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,
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, the first and the second end of the pipe are connected with each other,
R 4 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 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,
reacting a compound of formula (I) with a compound of formula (IX) to give a compound of formula (VIII);
wherein the content of the first and second substances,
y、R 1 、R 2 、R 3 and R 4 As described in general formula (IV).
As a further preferable mode, the method for producing the compound represented by the general formula (IV) comprises the steps of,
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 the content of the first and second substances,
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,
1) Coupling a compound shown in a general formula (II) with cyclopropylboronic acid to obtain a compound shown in a 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 the content of the first and second substances,
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 method for preparing the compound shown in the general formula (IV) comprises the steps of preparing the compound shown in the general formula (I), and the synthetic route is as follows:
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 a compound shown in a general formula (II) with cyclopropylboronic acid to obtain a compound shown in a 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 the content of the first and second substances,
y、R、R 1 、R 2 、R 3 and R 4 As described in general formula (IV);
the definitions of the acid reagent, the alcohol solvent, the alkaline reagent and the reducing agent in the above steps are as described in the same step in the 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 including 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 including a straight-chain alkyl group and a branched-chain alkyl group containing 1 to 3 carbon atoms, 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 The cycloalkyl group "means a cycloalkyl group including 3 to 8 carbon atoms, and further includes a cycloalkyl group of 3 to 6 carbon atoms.
"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 pyrrolidinylImidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, and polycyclic heterocyclic groups include spiro-, fused-and bridged-ring 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 rings.
"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 units of parts per million (ppm). NMR was measured by 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. The 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 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 a dry nitrogen or argon atmosphere with continuous magnetic stirring, without specific mention, the solvent being a dry solvent.
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
The first step is as follows: preparation of 3- (2-chloropyrimidin-4-yl) -1H-indole
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 thereto, and the mixture was 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
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' -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 a filtrate under reduced pressure to be dry. Ethyl acetate (860 mL), water (720 mL) was added to the residue, stirred, the layers separated and the organic phase 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
25℃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) were added in sequence to a three-necked flask (2L), and 2-pentanol (800 mL) and TsOH. H. 2 O (80.4 g), 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 (200 mL), and washing twice with petroleum ether (300 mL × 2); the filter cake was taken out and dried in vacuo 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 99.5% purity and 89.4% yield.
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-nitrophenyl-1, 4-diamine
Adding dimethylacetamide (400 mL) 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 (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 a filter cake once by using water (200 mL multiplied by 2), and washing twice by using petroleum ether (200 mL multiplied by 2); taking out the filter cake, and drying the filter cake for 3 hours at 60 ℃ in vacuum 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-nitrophenyl-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
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 used for protection; 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
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 -methylbenzene-1, 2, 4-triamine (130 g) into a three-necked flask (3L), with stirring switched on, the temperature was adjusted to 0 ℃, a solution of 3-chloropropionyl chloride (52.7 g) in tetrahydrofuran (100 mL) was added slowly, the temperature was adjusted to 25 ℃, n-heptane (1300 mL) was added slowly, and stirring was 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, saturated aqueous ammonium chloride solution (450 mL) was slowly added to the aqueous layer until the aqueous phase pH =8, and then the mixture was addedExtracting with ethyl acetate (1.3L), stirring for 5 min, and separating the upper organic layer; 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
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. 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 (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) (methyl) amino) phenyl) acryloylamide
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
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
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, trimethylethylenediamine (0.1 g) was added, and the reaction was heated to reflux for 2 hours. Cooled to room temperature and the solvent was 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
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). 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
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, purged with nitrogen, DIPEA (0.1 mL) was added at 0 ℃, and a solution of 1M 3-chloropropionyl chloride in tetrahydrofuran (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 water phase from organic phase, extracting the water phase with dichloromethane for three times, combining the organic phases, drying, concentrating, and preparing a crude product by thin layer chromatography separation. 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
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
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) propenylamide
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) propenylamide is analogous 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) propenylamide
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) (meth) amino) -4-methoxyphenyl) propenylamide is 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) acryloylamide
N- (5- ((4- (1-cyclopropyl-6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide was prepared in analogy to example 1.
TFA salts 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
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) acryloylamide
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 is analogous 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, 0.376 mol), copper bromide (71.4g, 0.32mol), 2' -bipyridine (50.3g, 0.313mol), sodium carbonate (66.6g, 0.626 mol), acetonitrile (720 mL) were added to the reaction flask, and the temperature was raised 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 a 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. And filtering, and drying a filter cake to obtain the product 3- (2-chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole, wherein 74.7g of a light yellow solid is obtained, the yield is 88.2%, the HPLC purity is 99.9%, and the mass spectrum and nuclear magnetism data of the product are consistent with the spectrum data of the step 2 in the example 1.
Claims (32)
1. A process for the preparation of a compound of formula (I), comprising the steps of:
coupling the compound of the general formula (II) with cyclopropylboronic acid to give a compound of the general formula (I);
wherein the content of the first and second substances,
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 provided with
y is 0,1, 2, 3 or 4.
2. Process for the preparation of compounds of general formula (I) according to claim 1, characterized in that R 1 Selected from hydrogen, halogen and trifluoromethyl.
3. The process for the preparation of the compound of formula (I) according to claim 1, characterized in that it comprises the following steps:
1) Reacting the compound of the general formula (III) with indole or an analogue thereof to obtain a compound of a general formula (II);
2) Coupling the compound of the general formula (II) with cyclopropylboronic acid to give a compound of the general formula (I);
wherein, the first and the second end of the pipe are connected with each other,
R、R 1 and y is as defined in claim 1.
4. The process of claim 3, wherein step 1) further comprises a Grignard reagent selected from the group consisting of halogenated magnesium alkylates.
5. The method of claim 3, wherein step 1) further comprises a Grignard reagent selected from methyl magnesium chloride or methyl magnesium bromide.
6. The process for the preparation of compounds of general formula (I) according to any one of claims 1 to 3, characterized in that the coupling reaction is carried out in the presence of a catalyst, a basic reagent and an organic solvent.
7. The process for the preparation of the compounds of formula (I) according to claim 6, characterized in that the catalyst is selected from copper acetate, copper halides or bipyridines.
8. The process for the preparation of the compounds of general formula (I) according to claim 6, characterized in that the catalyst is selected from copper acetate and 2,2' -bipyridine.
9. Process for the preparation of the compounds of general formula (I) according to claim 6, characterized in that the alkaline agent is chosen from potassium phosphate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.
10. Process for the preparation of the compounds of general formula (I) according to claim 6, characterized in that the alkaline agent is chosen from sodium carbonate or potassium phosphate.
11. Process for the preparation of the compounds of general formula (I) according to claim 6, characterized in that the organic solvent is chosen from acetonitrile, tetrahydrofuran, dimethyltetrahydrofuran, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, toluene or dioxane.
12. The process for the preparation of the compound of formula (I) according to claim 6, characterized in that the organic solvent is selected from acetonitrile, tetrahydrofuran, dimethyltetrahydrofuran, dimethylformamide or dimethylsulfoxide.
13. A process for the preparation of a compound of formula (VIII) comprising the preparation of a compound of formula (I) according to claim 1 or 2:
the compound of the general formula (I) is reacted with a compound of the general formula (IX) to give a compound of the general formula (VIII),
wherein the content of the first and second substances,
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 oneOr more are 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 4 selected from halogens.
14. The process for preparing a compound of formula (VIII) according to claim 13,
R 2 is selected from C 1-3 An alkoxy group; r 4 Selected from fluorine atoms.
15. The process for the preparation of compounds of formula (VIII) according to claim 13 or 14, characterized in that R 2 Selected from methoxy.
16. A process for the preparation of a compound of formula (VIII) comprising the preparation of a compound of formula (I) according to claim 1 or 2:
reacting the compound of the general formula (I) with the compound of the general formula (IX) in the presence of an acid reagent and an alcohol solvent to obtain a compound of the general formula (VIII),
wherein R is 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 4 Selected from halogens.
17. The process of claim 16, wherein R is a compound of formula (VIII) 4 Is a fluorine atom.
18. The process for preparing a compound of formula (VIII) according to claim 16 or 17, wherein the acid reagent 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.
19. The process for preparing the compound of general formula (VIII) according to claim 16 or 17, wherein the acid reagent is methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid hydrate or o-toluenesulfonic acid.
20. The method for preparing the compound of formula (VIII) according to claim 16 or 17, wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol, t-butanol amyl alcohol, 2-pentanediol or a mixture thereof.
21. A process for the preparation of a compound of formula (VII) comprising the preparation of a compound of formula (VIII) according to any one of claims 13 to 16:
the compound of the general formula (VIII) reacts with N, N, N' -trimethylethylenediamine in the presence of an alkaline reagent to obtain a compound of the general formula (VII).
22. The process for the preparation of the compound of formula (VII) according to claim 21, characterized in that the basic reagent is selected from trimethylamine, triethylamine, pyridine, piperidine, diisopropylethylamine, morpholine or mixtures thereof.
23. The process for the preparation of the compound of formula (VII) according to claim 21, characterized in that the basic reagent is selected from triethylamine and diisopropylethylamine.
24. A process for the preparation of a compound of formula (V) comprising the preparation of a compound of formula (VII) as claimed in any one of claims 21 to 23:
and (5) carrying out reduction reaction on the compound of the general formula (VII) in the presence of hydrogen and a reducing agent to obtain the compound of the general formula (V).
25. The process for the preparation of compounds of general formula (V) according to claim 24, characterized in that said reducing agent is selected from Pd/C, raney-Ni, pd (OH) 2 Or PtO 2 。
26. The process for the preparation of compounds of formula (V) according to claim 24, characterized in that the reducing agent is selected from Raney-Ni.
27. A process for the preparation of a compound of formula (IV), which comprises the preparation of a compound of formula (V) according to any one of claims 24 to 26:
reacting a compound shown in a general formula (V) with a compound shown in a general formula (VI) 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;
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;
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 in claim 1.
28. The process of claim 27, wherein M is selected from methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid hydrate, or o-toluenesulfonic acid.
29. The process of claim 27, wherein M is methanesulfonic acid.
30. The process for the preparation of the compound of formula (IV) according to claim 27, wherein the alkaline agent 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.
31. The process of claim 27, wherein the alkaline reagent is selected from sodium hydroxide or potassium hydroxide.
32. The process for preparing the compound of formula (IV) according to any one of claims 27 to 31, wherein the solvent system for the salt formation of the compound of formula (IV) is a solvent system of acetone and water or a solvent system of ethyl acetate and ethanol.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2019101371853 | 2019-02-25 | ||
| CN201910137185 | 2019-02-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111606889A CN111606889A (en) | 2020-09-01 |
| CN111606889B true CN111606889B (en) | 2023-03-07 |
Family
ID=72198114
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010114126.7A Active CN111606889B (en) | 2019-02-25 | 2020-02-24 | Process for the preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -N-phenylpyrimidin-2-amine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111606889B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109761960B (en) * | 2019-02-25 | 2021-08-31 | 江苏豪森药业集团有限公司 | Preparation method of anti-drug-resistance anti-tumor EGFR inhibitor |
| CN112457299B (en) * | 2020-12-14 | 2021-12-17 | 江苏豪森药业集团有限公司 | Purification method of EGFR inhibitor |
| CN114057695A (en) * | 2021-10-20 | 2022-02-18 | 湖南润星制药有限公司 | Synthesis method and application of key intermediate of amitinib |
Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102325764A (en) * | 2008-12-22 | 2012-01-18 | 阿斯利康(瑞典)有限公司 | Pyrimidine indole derivatives for treating cancer |
| WO2013014448A1 (en) * | 2011-07-27 | 2013-01-31 | Astrazeneca Ab | 2 - (2, 4, 5 - substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN105461695A (en) * | 2014-09-29 | 2016-04-06 | 齐鲁制药有限公司 | Pyrimidine or triazine derivative, and preparation method and use thereof |
| WO2016054987A1 (en) * | 2014-10-11 | 2016-04-14 | 上海翰森生物医药科技有限公司 | Egfr inhibitor, and preparation and application thereof |
| CN106559991A (en) * | 2014-06-19 | 2017-04-05 | 阿里亚德医药股份有限公司 | For the heteroaryl compound of kinase inhibition |
| CN106967050A (en) * | 2017-05-11 | 2017-07-21 | 北京工业大学 | A kind of AZD9291 preparation method |
| CN106995437A (en) * | 2016-01-22 | 2017-08-01 | 齐鲁制药有限公司 | Substituted indole or indazole pyrimidine derivatives and its production and use |
| WO2018045956A1 (en) * | 2016-09-07 | 2018-03-15 | 江苏豪森药业集团有限公司 | Benzimidazole compound kinase inhibitor, preparation method therefor and application thereof |
| CN107935997A (en) * | 2017-12-01 | 2018-04-20 | 南京奇可药业有限公司 | A kind of difficult to understand this replaces the synthetic method of Buddhist nun |
| WO2018139903A1 (en) * | 2017-01-26 | 2018-08-02 | 한미약품 주식회사 | Pyrimidine compound and pharmaceutical use thereof |
| CN109761960A (en) * | 2019-02-25 | 2019-05-17 | 江苏豪森药业集团有限公司 | The preparation method of the antitumor EGFR inhibitor of overriding resistance |
| CN110606842A (en) * | 2018-06-15 | 2019-12-24 | 上海艾力斯医药科技有限公司 | Process for producing pyridylamino pyrimidine derivative and intermediate thereof |
| CN110698461A (en) * | 2018-07-09 | 2020-01-17 | 上海翰森生物医药科技有限公司 | Preparation method of third-generation EGFR inhibitor |
-
2020
- 2020-02-24 CN CN202010114126.7A patent/CN111606889B/en active Active
Patent Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102325764A (en) * | 2008-12-22 | 2012-01-18 | 阿斯利康(瑞典)有限公司 | Pyrimidine indole derivatives for treating cancer |
| WO2013014448A1 (en) * | 2011-07-27 | 2013-01-31 | Astrazeneca Ab | 2 - (2, 4, 5 - substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN106559991A (en) * | 2014-06-19 | 2017-04-05 | 阿里亚德医药股份有限公司 | For the heteroaryl compound of kinase inhibition |
| CN105461695A (en) * | 2014-09-29 | 2016-04-06 | 齐鲁制药有限公司 | Pyrimidine or triazine derivative, and preparation method and use thereof |
| WO2016054987A1 (en) * | 2014-10-11 | 2016-04-14 | 上海翰森生物医药科技有限公司 | Egfr inhibitor, and preparation and application thereof |
| CN106995437A (en) * | 2016-01-22 | 2017-08-01 | 齐鲁制药有限公司 | Substituted indole or indazole pyrimidine derivatives and its production and use |
| WO2018045956A1 (en) * | 2016-09-07 | 2018-03-15 | 江苏豪森药业集团有限公司 | Benzimidazole compound kinase inhibitor, preparation method therefor and application thereof |
| WO2018139903A1 (en) * | 2017-01-26 | 2018-08-02 | 한미약품 주식회사 | Pyrimidine compound and pharmaceutical use thereof |
| CN110214138A (en) * | 2017-01-26 | 2019-09-06 | 韩美药品株式会社 | Pyrimidine compound and its medicinal usage |
| CN106967050A (en) * | 2017-05-11 | 2017-07-21 | 北京工业大学 | A kind of AZD9291 preparation method |
| CN107935997A (en) * | 2017-12-01 | 2018-04-20 | 南京奇可药业有限公司 | A kind of difficult to understand this replaces the synthetic method of Buddhist nun |
| CN110606842A (en) * | 2018-06-15 | 2019-12-24 | 上海艾力斯医药科技有限公司 | Process for producing pyridylamino pyrimidine derivative and intermediate thereof |
| CN110698461A (en) * | 2018-07-09 | 2020-01-17 | 上海翰森生物医药科技有限公司 | Preparation method of third-generation EGFR inhibitor |
| CN109761960A (en) * | 2019-02-25 | 2019-05-17 | 江苏豪森药业集团有限公司 | The preparation method of the antitumor EGFR inhibitor of overriding resistance |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111606889A (en) | 2020-09-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113773304B (en) | Preparation method of anti-drug-resistance anti-tumor EGFR inhibitor | |
| CN110698461B (en) | Preparation method of third-generation EGFR inhibitor | |
| CN107840846B (en) | Pyrimidine ring-containing compound, EGFR inhibitor and application thereof | |
| CN111606889B (en) | Process for the preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -N-phenylpyrimidin-2-amine derivatives | |
| EP3409674B1 (en) | Process for preparing compositions useful for treating disorders related to kit | |
| TWI585088B (en) | Imidazo[1,2-b]pyridazine analogues as kinase inhibitors | |
| JP5415403B2 (en) | 9- (pyrazol-3-yl) -9H-purin-2-amine and 3- (pyrazol-3-yl) -3H-imidazo [4,5-B] pyridin-5-amine derivatives and for the treatment of cancer Their use of | |
| ES2905973T3 (en) | Process for the preparation of 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine dihydrochloride -2,4-diamine | |
| WO2016015453A1 (en) | Pyridine amidopyrimidine derivative, preparation method and use thereof | |
| WO2018017983A1 (en) | Compounds useful for treating disorders related to ret | |
| CN111171000A (en) | EGFR inhibitor and preparation and application thereof | |
| CN110041333B (en) | Bromodomain inhibitor compounds and uses thereof | |
| JP2021512161A (en) | 2H-indazole derivatives as CDK4 and CDK6 inhibitors and their therapeutic use | |
| JP5498396B2 (en) | 4-Aminopyrimidine derivatives as histamine H4 receptor antagonists | |
| EP3287463A1 (en) | Condensed-ring pyrimidylamino derivative, preparation method therefor, and intermediate, pharmaceutical composition and applications thereof | |
| WO2018183712A1 (en) | Pyrrolo[1,2-b]pyridazine compounds and compositions useful for treating disorders related to kit and pdgfr | |
| CN111961034A (en) | Compounds useful as RET kinase inhibitors and uses thereof | |
| EP2673268A1 (en) | Method of inhibiting hamartoma tumor cells | |
| TW201738236A (en) | Method for preparing tyrosine kinase inhibitor and derivatives thereof | |
| CN110546145B (en) | Azaaryl derivative, preparation method and pharmaceutical application thereof | |
| AU2017282903B2 (en) | Crystals of aniline pyrimidine compound serving as EGFR inhibitor | |
| CN109593102B (en) | Preparation method and crystal form of deuterated diphenylaminopyrimidine compound | |
| KR20220007111A (en) | Compounds used as kinase inhibitors and their applications | |
| CN112313207A (en) | Cyano-substituted pyridine and cyano-substituted pyrimidine compounds, and preparation methods and applications thereof | |
| WO2021129841A1 (en) | Compound used as ret kinase inhibitor and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |