CN111662273A - Preparation method of tyrosine kinase inhibitor AZD3759 - Google Patents
Preparation method of tyrosine kinase inhibitor AZD3759 Download PDFInfo
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Abstract
The invention provides a preparation method of a tyrosine kinase inhibitor AZD3759, and relates to the field of pharmaceutical chemistry. The method takes 3, 4-dihydro-7-methoxy-4-oxo quinazoline-6-alcohol acetate as a raw material, and obtains 4-chloro-7-methoxy quinazoline-6-alcohol (a compound 3) through chlorination reaction and hydrolysis reaction; taking (R) - (-) -2-methylpiperazine as a raw material, and carrying out nucleophilic addition-elimination reaction and chloroformylation reaction to obtain (R) -4-chlorocarbonyl-3-tert-butyl formate (compound 6); carrying out esterification reaction on the compound 3 and the compound 6 to obtain a compound 7; carrying out Boc removal reaction and methylation reaction on the compound 7 to obtain a compound 9; the compound 9 and 2-fluoro-3-chloroaniline undergo alkylation reaction to obtain AZD 3759. The method has the advantages of cheap and easily obtained raw materials and low cost; sodium cyanoborohydride is not used in the reaction process, so that the method is more environment-friendly and is beneficial to industrial scale-up production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of a tyrosine kinase inhibitor AZD 3759.
Background
Brain metastasis is one of intracranial tumors, and most of tumor cells which are originally in other parts of a body are transferred into the cranium through a certain way and form new focuses in the cranium, and the incidence rate of the brain metastasis is 10 times that of the intracranial primary tumors. Of these, lung cancer is the most common primary tumor site, with about half of the brain metastases originating from lung cancer. About 85% of lung cancers are non-small cell lung cancers (NSCLC), and more seriously about 40-50% of NSCLC patients develop brain metastases in their course, with higher incidence of brain metastases in NSCLC patients with EGFR ("epidermal growth factor receptor") sensitive mutations. The occurrence of brain metastasis seriously affects the survival and life quality of patients, mainly because most chemotherapy drugs and TKI of the first generation have poor treatment effect on the focus of brain metastasis. Thus, there is a great need for more effective drugs to control NSCLC brain metastases.
AZD3759 (structural formula is shown in formula I) is a tyrosine kinase inhibitor, can effectively control NSCLC brain metastasis, is currently in second-stage clinical application, and has good economic benefit and social benefit if successfully marketed. The AZD3759 synthetic route disclosed in the document (J.Med.chem.2015,58,8200-8215) has the disadvantages of expensive starting materials and high cost; sodium cyanoborohydride is used in the reaction process, so that highly toxic gas hydrogen cyanide is easily generated, and the method is not suitable for industrial large-scale production.
Disclosure of Invention
In view of the above, the invention aims to provide a preparation method of a tyrosine kinase inhibitor AZD3759, which has the advantages of cheap and easily available raw materials and low cost; sodium cyanoborohydride is not used in the reaction process, so that the method is more environment-friendly; and the product yield is high, thereby being beneficial to industrial scale-up production.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of a tyrosine kinase inhibitor AZD3759, which does not use cyano sodium borohydride and comprises the following steps:
(1) mixing 3, 4-dihydro-7-methoxy-4-oxoquinazoline-6-alcohol acetate, DIEA and a first organic solvent, adding a chlorinating agent at the temperature of 50-70 ℃, and carrying out chlorination reaction at the temperature of 90-100 ℃ to obtain 4-chloro-7-methoxy quinazoline-6-acetate;
(2) mixing 4-chloro-7-methoxyquinazoline-6-acetate, an inorganic alkaline compound and a second organic solvent, heating and refluxing for hydrolysis reaction to obtain 4-chloro-7-methoxyquinazoline-6-ol;
(3) dissolving (R) - (-) -2-methylpiperazine in a third organic solvent to obtain a (R) - (-) -2-methylpiperazine solution, and dropwise adding Boc-anhydride into the (R) - (-) -2-methylpiperazine solution at the temperature of-5 ℃ to perform nucleophilic addition-elimination reaction to obtain (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester;
(4) dissolving (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester in a fourth organic solvent to obtain a (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester solution, adding triphosgene and pyridine into the (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester solution at the temperature of-30 ℃, and performing chloroformylation reaction at room temperature to obtain (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester;
(5) dissolving (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester in a fifth organic solvent to obtain a (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester solution, adding the 4-chloro-7-methoxyquinazoline-6-ol and an organic base into the (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester solution at the temperature of-5 to 5 ℃, and performing an esterification reaction at room temperature to obtain (R) -4-tert-butyl-1- (4-chloro-7-methoxyquinazolin-6-yl) -2-methylpiperazine-1, 4-dicarboxylic acid esters;
(6) mixing (R) -4-tert-butyl-1- (4-chloro-7-methoxyquinazolin-6-yl) -2-methylpiperazine-1, 4-dicarboxylate, HCl gas and a sixth organic solvent at room temperature to perform de-Boc reaction to obtain (R) -4-chloro-7-methoxyquinazolin-6-yl-2-methylpiperazine-1-formate;
(7) mixing (R) -4-chloro-7-methoxy quinazoline-6-yl-2-methylpiperazine-1-formate with a methylating agent, and carrying out methylation reaction at 90-100 ℃ to obtain (R) -4-chloro-7-methoxy quinazoline-6-yl-2, 4-dimethylpiperazine-1-formate; the methylation reagent is a formic acid/formaldehyde mixed reagent, a formic acid/paraformaldehyde mixed reagent or sodium triacetoxyborohydride;
(8) mixing (R) -4-chloro-7-methoxyquinazoline-6-yl-2, 4-dimethylpiperazine-1-formate, 2-fluoro-3-chloroaniline and a seventh organic solvent, and carrying out heating reflux to carry out alkylation reaction to obtain AZD 3759;
the steps (1) and (3) are not limited in time sequence.
Preferably, the chlorinating agent in the step (1) is thionyl chloride, oxalyl chloride or phosphorus oxychloride; the molar ratio of the 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate to the DIEA to the chlorinated reagent is 1: 1-10; the first organic solvent is toluene or dichloromethane; the time of the chlorination reaction is 2-3 h.
Preferably, the inorganic alkaline compound in the step (2) is one or more of ammonia, potassium carbonate and sodium carbonate; the molar ratio of the 4-chloro-7-methoxyquinazoline-6-acetate to the inorganic alkaline compound is 1: 1.5-10; the second organic solvent is isopropanol, ethanol, methanol, tert-butanol, n-butanol, acetonitrile, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, ethyl acetate, chloroform, acetone or butanone; the hydrolysis reaction time is 1-8 h.
Preferably, the molar ratio of (R) - (-) -2-methylpiperazine to Boc-anhydride in step (3) is 1: 1-10; the third organic solvent is dichloromethane, chloroform, tetrahydrofuran, ethyl acetate or acetonitrile; the time of the nucleophilic addition-elimination reaction is 1-5 h.
Preferably, the molar ratio of the (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester, the triphosgene and the pyridine in the step (4) is 1: 1-3: 2.5-4; the fourth organic solvent is dichloromethane, chloroform, tetrahydrofuran, ethyl acetate or acetonitrile; the time of the chloroformylation reaction is 15-48 h.
Preferably, after the chloroformylation reaction in the step (4), the method further comprises concentrating the obtained chloroformylation reaction solution to dryness under reduced pressure.
Preferably, the organic base in step (5) is N, N-diisopropylethylamine, triethylamine, tributylamine, trimethylamine, dodecyldimethylamine, hexadecyldimethylamine, dodecylbenzylmethylamine or N-methyldicyclohexylamine; the molar ratio of the 4-chloro-7-methoxyquinazoline-6-ol to the (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-tert-butyl formate to the organic base is 1: 1-2: 1.5 to 5; the fifth organic solvent is dimethylformamide, dimethylacetamide or N-methylpyrrolidone; the esterification reaction time is 12-36 h.
Preferably, the sixth organic solvent in the step (6) is methanol, 1, 4-dioxane, ethanol, isopropanol, tert-butanol, acetonitrile or tetrahydrofuran; the Boc removal reaction time is 12-24 h.
Preferably, in the step (7), the molar ratio of (R) -4-chloro-7-methoxyquinazolin-6-yl-2-methylpiperazine-1-carboxylate, formic acid and formaldehyde is 1: 5-15, (R) -4-chloro-7-methoxyquinazolin-6-yl-2-methylpiperazine-1-carboxylate, formic acid and paraformaldehyde is 1: 5-15, (R) -4-chloro-7-methoxyquinazolin-6-yl-2-methylpiperazine-1-carboxylate, sodium triacetoxyborohydride is 1: 5-15; the methylation reaction time is 1-3 h.
Preferably, the seventh organic solvent in the step (8) is isopropanol, ethanol, methanol, tert-butanol, n-butanol, acetonitrile, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, ethyl acetate, chloroform, acetone or butanone; the molar ratio of the (R) -4-chloro-7-methoxyquinazoline-6-yl-2, 4-dimethylpiperazine-1-formate to the 2-fluoro-3-chloroaniline is 1: 1-3; the time of the alkylation reaction is 1-8 h.
The invention provides a preparation method of a tyrosine kinase inhibitor AZD3759, which takes 3, 4-dihydro-7-methoxy-4-oxo quinazoline-6-alcohol acetate as a raw material to obtain 4-chloro-7-methoxy quinazoline-6-acetate (compound 2) through chlorination reaction; the compound 2 is hydrolyzed to obtain 4-chloro-7-methoxy quinazoline-6-alcohol (a compound 3); taking (R) - (-) -2-methylpiperazine (compound 4) as a raw material, and obtaining (R) -3-methylpiperazine-1-tert-butyl carboxylate (compound 5) through nucleophilic addition-elimination reaction; performing chloromethylation reaction on the compound 5 to obtain (R)4- (chlorocarbonyl) -3-methylpiperazine-1-tert-butyl formate (compound 6) and a compound 6; then carrying out esterification reaction on the compound 3 and the compound 6 to obtain (R) -4-tert-butyl-1- (4-chloro-7-methoxyquinazoline-6-yl) -2-methylpiperazine-1, 4-dicarboxylic ester (compound 7); the compound 7 is subjected to Boc removal reaction to obtain (R) -4-chloro-7-methoxy quinazoline-6-yl-2-methylpiperazine-1-formic ether (compound 8); obtaining (R) -4-chloro-7-methoxy quinazoline-6-yl-2, 4-dimethyl piperazine-1-formic ether (compound 9) by methylation reaction of the compound 8; the target compound AZD3759 is obtained by the alkylation reaction of the compound 9 and 2-fluoro-3-chloroaniline. The raw materials of 3, 4-dihydro-7-methoxy-4-oxo quinazoline-6-alcohol acetate and (R) - (-) -2-methylpiperazine adopted in the invention are cheap and easy to obtain, the operation is mild, and the production cost of AZD3759 is greatly reduced; the invention provides a synthetic method of 4-chloro-7-methoxyquinazoline-6-acetate (compound 2), which solves the problem that the 4-chloro-7-methoxyquinazoline-6-acetate (compound 2) has no commercial product, breaks through the problem of limiting industrial production, enables the subsequent reaction to be carried out smoothly, and has the advantages of shorter synthetic route, high yield and lower cost of the 4-chloro-7-methoxyquinazoline-6-acetate (compound 2); the (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (compound 5) is high in market price, and the compound 5 is synthesized by adopting (R) - (-) -2-methylpiperazine, so that the synthesis cost of AZD-3759 can be greatly reduced; according to the invention, the compound 5 is converted into (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-tert-butyl formate (compound 6) through chloroformylation by using triphosgene and pyridine, and then the subsequent reaction can be directly carried out by only carrying out reduced pressure concentration, so that the energy consumption is saved, and the production cost of the target product AZD3759 is reduced; in the invention, (R) -4-chloro-7-methoxyquinazoline-6-yl-2-methylpiperazine-1-formic ether (compound 8) and formic acid/formaldehyde, formic acid/paraformaldehyde or sodium triacetoxyborohydride which are methylation reagents are subjected to methylation reaction, so that the harsh condition of using sodium cyanoborohydride is successfully avoided, and virulent gas hydrogen cyanide is not generated in the reaction process, thus being more environment-friendly; the method adopts the steps of methylation and alkylation to prepare the AZD3759, can improve the reaction yield, and is favorable for obtaining a final product with higher purity. Therefore, the preparation method provided by the invention has low cost and is more environment-friendly; and the product yield is high, thereby being beneficial to industrial scale-up production.
The results of the examples show that AZD3759 is successfully prepared, and the structure is verified by nuclear magnetism and liquid quality, so that the structure is correct, and the HPLC purity is 99%.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a product prepared in example 2 of the present invention;
FIG. 2 is a LCMS spectrum of the product prepared in example 2 of the present invention.
Detailed Description
The invention provides a preparation method of a tyrosine kinase inhibitor AZD3759, which does not use cyano sodium borohydride and comprises the following steps:
(1) mixing 3, 4-dihydro-7-methoxy-4-oxoquinazoline-6-alcohol acetate (compound 1), DIEA and a first organic solvent, adding a chlorinating agent at the temperature of 50-70 ℃, and carrying out chlorination reaction at the temperature of 90-100 ℃ to obtain 4-chloro-7-methoxy quinazoline-6-acetate (compound 2);
(2) mixing 4-chloro-7-methoxyquinazoline-6-acetate (compound 2), an inorganic alkaline compound and a second organic solvent, heating and refluxing for hydrolysis reaction to obtain 4-chloro-7-methoxyquinazoline-6-ol (compound 3);
(3) dissolving (R) - (-) -2-methylpiperazine (compound 4) in a third organic solvent to obtain a (R) - (-) -2-methylpiperazine solution, and dropwise adding Boc-anhydride into the (R) - (-) -2-methylpiperazine mixed solution at the temperature of-5 ℃ to perform nucleophilic addition-elimination reaction to obtain (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (compound 5);
(4) dissolving the (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (compound 5) in a fourth organic solvent to obtain a (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester solution, adding triphosgene and pyridine to the (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester solution at-30 ℃, and performing chloroformylation reaction at room temperature to obtain (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (compound 6);
(5) dissolving (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (compound 6) in a fifth organic solvent to obtain a (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester solution, adding 4-chloro-7-methoxyquinazolin-6-ol (compound 3) and an organic base into the (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester solution at the temperature of-5 ℃, and performing an esterification reaction at room temperature to obtain (R) -4-tert-butyl-1- (4-chloro-7-methoxyquinazolin-6-yl) -2-methylpiperazine-1, 4-dicarboxylic acid ester (compound 7);
(6) mixing (R) -4-tert-butyl-1- (4-chloro-7-methoxyquinazolin-6-yl) -2-methylpiperazine-1, 4-dicarboxylate (compound 7), HCl gas and a sixth organic solvent at room temperature to perform de-Boc reaction to obtain (R) -4-chloro-7-methoxyquinazolin-6-yl-2-methylpiperazine-1-formate (compound 8);
(7) mixing (R) -4-chloro-7-methoxyquinazoline-6-yl-2-methylpiperazine-1-formate (compound 8) with a methylating agent, and carrying out methylation reaction at 90-100 ℃ to obtain (R) -4-chloro-7-methoxyquinazoline-6-yl-2, 4-dimethylpiperazine-1-formate (compound 9); the methylation reagent is a formic acid/formaldehyde mixed reagent, a formic acid/paraformaldehyde mixed reagent or sodium triacetoxyborohydride;
(8) mixing (R) -4-chloro-7-methoxyquinazoline-6-yl-2, 4-dimethylpiperazine-1-formate (compound 9), 2-fluoro-3-chloroaniline (compound 10) and a seventh organic solvent, and carrying out heating reflux to carry out alkylation reaction to obtain AZD 3759;
the steps (1) and (3) are not limited in time sequence.
The preparation method comprises the steps of mixing 3, 4-dihydro-7-methoxy-4-oxo quinazoline-6-alcohol acetate (compound 1), DIEA (N, N-diisopropylethylamine) and a first organic solvent, adding a chlorinating reagent at 50-70 ℃, and carrying out chlorination reaction at 90-100 ℃ to obtain 4-chloro-7-methoxy quinazoline-6-acetate (compound 2). In the present invention, the chlorinating agent is preferably thionyl chloride, oxalyl chloride or phosphorus oxychloride; the first organic solvent is preferably toluene or dichloromethane, and when the chlorinating reagent is thionyl chloride or oxalyl chloride, the first organic solvent is preferably dichloromethane; when the chlorinating agent is phosphorus oxychloride, the first organic solvent is preferably toluene. In the invention, the molar ratio of the 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate to the DIEA to the chlorinated reagent is preferably 1: 1-10, and more preferably 1: 3-7; the adding volume of the first organic solvent is preferably 3-10 of the feeding volume of the 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate. According to the invention, the 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate, DIEA and the first organic solvent are preferably mixed, and the mixture is stirred for 0.5h at the temperature of 50-70 ℃, preferably 55-65 ℃, and then chlorinated reagent is added. In the invention, the temperature of the chlorination reaction is preferably 94-96 ℃; after the chlorination reagent is added, heating the system to 90-100 ℃ to perform chlorination reaction; the temperature of the chlorination reaction is preferably 94-96 ℃; the time of the chlorination reaction is preferably 2-3 h, and more preferably 2.5 h. In the present invention, the chlorination reaction is preferably carried out under stirring. The progress of the reaction is preferably monitored by TLC (thin layer chromatography) in the present invention, and the reaction is considered complete when the point of 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate in the reaction solution disappears. In the present invention, the reaction formula of the chlorination reaction is shown as formula 1:
after the chlorination reaction, the method preferably carries out post-treatment on the obtained chlorination reaction liquid; the post-treatment preferably comprises: cooling the chlorination reaction liquid to room temperature, and then concentrating under reduced pressure to dryness to obtain a concentrate; mixing the concentrate with ethanol, stirring for 0.5h, and filtering; and drying the solid phase obtained by suction filtration at the temperature of 40-50 ℃ to obtain a compound 2. In the present invention, the volume of ethanol added is preferably 5 to 20 times the volume of the amount of compound 1 charged. The invention provides a synthetic method of the compound 2, which solves the problem that the raw material 2 has no products sold in the market, breaks through the problem of limiting industrial production, enables subsequent reaction to be carried out smoothly, has shorter synthetic route, high yield and lower cost of the compound 2, and can realize industrial scale-up production.
After 4-chloro-7-methoxyquinazoline-6-acetate (compound 2) is obtained, the compound 2, an inorganic alkaline compound and a second organic solvent are mixed, heated and refluxed for hydrolysis reaction, and 4-chloro-7-methoxyquinazoline-6-ol (compound 3) is obtained. In the invention, the inorganic alkaline compound is one or more of ammonia, potassium carbonate and sodium carbonate; wherein ammonia is added in the form of ammonia water, and the mass concentration of the ammonia water is preferably 25%; the molar ratio of the compound 2 to the inorganic basic compound is preferably 1: 1.5-10, more preferably 1: 3-8, and more preferably 1: 4-6. In the present invention, the second organic solvent is preferably isopropanol, ethanol, methanol, t-butanol, n-butanol, acetonitrile, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, ethyl acetate, chloroform, acetone, or butanone, more preferably methanol; the addition volume of the second organic solvent is preferably 3-20 times of the feeding volume of the compound 2. The method of mixing is not particularly required in the present invention, and a mixing method known to those skilled in the art may be employed, specifically, stirring and mixing. In the invention, the heating reflux temperature is preferably 60-80 ℃, and the hydrolysis reaction time is preferably 1-8 h, and more preferably 4-6 h. During the hydrolysis reaction, the present invention is preferably monitored by TLC, and the reaction is considered complete when the point of Compound 2 in the hydrolysis reaction solution disappears. In the present invention, the hydrolysis reaction is preferably carried out under stirring; the reaction formula of the hydrolysis reaction is shown as formula 2:
after the hydrolysis reaction, the invention preferably carries out post-treatment on the obtained hydrolysis reaction liquid; the post-treatment preferably comprises: and (3) carrying out suction filtration on the hydrolysis reaction liquid, and then drying the obtained filter cake at 40-50 ℃ to obtain the 4-chloro-7-methoxyquinazoline-6-ol (compound 3).
Dissolving (R) - (-) -2-methylpiperazine (compound 4) in a third organic solvent to obtain a (R) - (-) -2-methylpiperazine solution, dropwise adding Boc-anhydride into the (R) - (-) -2-methylpiperazine solution at-5 ℃ to perform nucleophilic addition-elimination reaction, and controlling the temperature of the reaction solution to be-5 ℃ to obtain (R) -3-methylpiperazine-1-tert-butyl carboxylate (compound 5). In the present invention, the third organic solvent is preferably dichloromethane, chloroform, tetrahydrofuran, ethyl acetate or acetonitrile, more preferably dichloromethane; the addition volume of the third organic solvent is preferably 5-20 times of the feeding volume of the compound 4. The Boc-anhydride is preferably dissolved in a third organic solvent in advance, and then the solution of the Boc-anhydride is dripped into the (R) - (-) -2-methylpiperazine solution; the invention has no special requirement on the dosage of the third organic solvent for dissolving the Boc-anhydride, and the Boc-anhydride can be fully dissolved; the dropping rate is preferably 60 drops/min. In the present invention, the molar ratio of (R) - (-) -2-methylpiperazine to Boc-anhydride in the step (3) is preferably 1: 0.5 to 2, more preferably 1: 0.5. in the invention, the time of the nucleophilic addition-elimination reaction is preferably 1-5 h, and more preferably 1 h; during the nucleophilic addition-elimination reaction, the progress of the reaction is preferably monitored by TLC, and the completion of the reaction is considered when the point of (R) - (-) -2-methylpiperazine in the nucleophilic addition-elimination reaction solution disappears. In the present invention, the nucleophilic addition-elimination reaction has the formula shown in formula 3:
after the nucleophilic addition-elimination reaction, the present invention preferably performs a post-treatment of the obtained nucleophilic addition-elimination reaction solution to obtain tert-butyl (R) -3-methylpiperazine-1-carboxylate (compound 5). The post-treatment preferably comprises: filtering the nucleophilic addition-elimination reaction solution, and spin-drying the filtrate to obtain a concentrate; adding a saturated potassium carbonate solution into the concentrate to perform a neutralization reaction to obtain a neutralization reaction solution; adding methyl tert-butyl ether into the neutralization reaction liquid for extraction, and collecting an organic phase; adding anhydrous sodium sulfate into the organic phase, and sequentially drying and filtering; adding petroleum ether into the organic phase obtained by filtering, stirring and crystallizing to obtain a crystal, namely the compound 5. The present invention has no special requirement on the specific operation method of the filtration and the spin-drying, and the corresponding operation method which is well known to those skilled in the art can be adopted. In the present invention, the saturated potassium carbonate solution is added in order to remove the unreacted Boc-anhydride; after addition of a saturated potassium carbonate solution, the solution is preferably stirred. In the invention, the adding volume of the methyl tert-butyl ether is preferably 3-20 times of the feeding volume of the compound 4, and more preferably 8-10 times of the feeding volume of the compound 4; the adding volume of the petroleum ether is preferably 1-10 times of the feeding volume of the compound 4, and more preferably 3-5 times of the feeding volume of the compound 4. In the invention, the crystallization temperature is preferably 0-10 ℃, and more preferably 2-5 ℃. The compound 5 is expensive in market price, the production cost is increased, and the synthesis cost of the AZD3759 can be greatly reduced by adopting (R) - (-) -2-methylpiperazine (compound 4) to synthesize the compound 5.
After the (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (compound 5) is obtained, the compound 5 is dissolved in a fourth organic solvent to obtain a compound 5 solution, triphosgene and pyridine are added into the compound 5 solution at the temperature of-30 ℃ to carry out chloroformylation reaction at room temperature, and the (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (compound 6) is obtained. In the present invention, the fourth organic solvent is preferably dichloromethane, chloroform, tetrahydrofuran, ethyl acetate or acetonitrile, more preferably dichloromethane; the addition volume of the fourth organic solution is preferably 5 to 20 times of the feeding volume of the compound 5, and more preferably 10 to 15 times of the feeding volume of the compound 5. In the invention, the molar ratio of the compound 5, triphosgene and pyridine is 1: 1-3: 2.5-4, and more preferably 1:1: 3-3.5. The triphosgene and the pyridine are preferably added into the compound 5 mixed solution at-30-0 ℃, more preferably at-20-0 ℃; preferably, triphosgene is added firstly, and pyridine is added after the triphosgene is added; the triphosgene and the pyridine are preferably added in 5 batches, and the feeding amount of each batch of the triphosgene and the pyridine is one fifth of the feeding amount of each batch of the triphosgene and the pyridine; after the triphosgene and the pyridine are added, the system is directly transferred to room temperature (15-30 ℃) to carry out chloromethylation reaction. In the invention, the time of the chloroformylation reaction is preferably 15-48 h, more preferably 20-35 h, and further preferably 25-30 h. In the present invention, the reaction formula of the chloroformylation reaction is shown as formula 4:
after the chloroformylation reaction, in the present invention, it is preferable to concentrate the resulting chloroformylation reaction solution under reduced pressure to dryness to obtain (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (compound 6). According to the invention, the compound 5 is converted into the compound 6 by using triphosgene and pyridine, and the reaction liquid can be directly put into the next reaction after being decompressed and concentrated to be dry without other additional treatment processes, so that the energy consumption is saved, and the production cost of the target product AZD3759 is reduced.
After the (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-tert-butyl formate (compound 6) is obtained, the compound 6 is dissolved in a fifth organic solvent to obtain a compound 6 solution, 4-chloro-7-methoxyquinazoline-6-ol (compound 3) and organic alkali are added into the compound 6 solution at the temperature of-5 ℃, and esterification reaction is carried out at room temperature to obtain (R) -4-tert-butyl-1- (4-chloro-7-methoxyquinazoline-6-yl) -2-methylpiperazine-1, 4-dicarboxylate (compound 7). In the present invention, the fifth organic solvent is preferably Dimethylformamide (DMF), Dimethylacetamide (DMA), or N-methylpyrrolidone (NMP), more preferably DMF; the addition volume of the fifth organic solvent is preferably 10 to 30 times of the feeding volume of the compound 3, and more preferably 20 to 25 times of the feeding volume of the compound 3. Preferably, after the compound 6 and a fifth organic solvent are mixed, cooling and stirring are carried out until the temperature is-5 ℃, and then the compound 3 and an organic base are added; after the compound 3 and the organic base are added, heating the system to room temperature for esterification reaction. In the present invention, the organic base is preferably DIEA (N, N-diisopropylethylamine), triethylamine, tributylamine, trimethylamine, dodecyldimethylamine, hexadecyldimethylamine, dodecylbenzylmethylamine, or N-methyldicyclohexylamine; the mol ratio of the compound 3 to the compound 6 to the organic base is preferably 1: 1-2: 1.5-5, more preferably 1: 1.5-2: 2 to 3. In the invention, the esterification reaction time is preferably 12-36 h, and more preferably 24 h; in the course of the esterification reaction, the present invention preferably monitors the progress of the reaction by TLC, and the completion of the reaction is considered when the spot of compound 3 in the esterification reaction liquid disappears. In the present invention, the reaction formula of the esterification reaction is shown as formula 5:
after the esterification reaction, the obtained esterification reaction liquid is preferably subjected to post-treatment to obtain a compound 7; the post-treatment preferably comprises: concentrating the esterification reaction liquid under reduced pressure, and evaporating most of the solvent (residual solvent is removed in subsequent treatment) to obtain a concentrated solution; adding purified water into the concentrated solution, stirring, standing for 12h, and performing suction filtration; and drying the filter cake obtained by suction filtration at 40-50 ℃ to obtain (R) -4-tert-butyl-1- (4-chloro-7-methoxyquinazoline-6-yl) -2-methylpiperazine-1, 4-dicarboxylic acid ester (compound 7).
After (R) -4-tert-butyl-1- (4-chloro-7-methoxyquinazolin-6-yl) -2-methylpiperazine-1, 4-dicarboxylate (compound 7) is obtained, the invention mixes the compound 7, HCl gas and a sixth organic solvent and carries out de-Boc reaction at room temperature to obtain (R) -4-chloro-7-methoxyquinazolin-6-yl-2-methylpiperazine-1-formate (compound 8). In the invention, the HCl gas is introduced into the reaction liquid through a steel cylinder filled with the HCl gas; the molar ratio of the HCl gas to the compound 7 is preferably 1: 1.5-3. In the present invention, the sixth organic solvent is preferably methanol, 1, 4-dioxane, ethanol, isopropanol, tert-butanol, acetonitrile or tetrahydrofuran; the addition volume of the sixth organic solvent is preferably 3-10 times of the feeding volume of the compound 7. In the invention, the time for removing Boc is preferably 12-24 h, and more preferably 12 h; during the Boc removal reaction, the present invention preferably monitors the progress of the reaction by TLC, and the reaction is considered complete when the point of compound 7 in the reaction solution disappears. In the present invention, the reaction formula of the Boc removal reaction is shown in formula 6:
after the Boc removal reaction, the method preferably performs post-treatment on the obtained Boc removal reaction liquid; the post-treatment preferably comprises: concentrating the Boc removal reaction liquid to be dry to obtain a concentrate; mixing the concentrate with purified water (the adding amount of the purified water is 2-5 times of the feeding amount of the compound 7 in volume), cooling the obtained mixed solution to 0-10 ℃, adding an alkaline solution while stirring to adjust the pH value of the mixed solution to 7-8, and separating out a solid; and (3) carrying out suction filtration on the mixed solution of the separated solids, and drying the filter cake at the temperature of 40-50 ℃ to obtain (R) -4-chloro-7-methoxyquinazoline-6-yl-2-methylpiperazine-1-formic ether (compound 8). In the invention, the alkaline solution is preferably a sodium carbonate solution, a potassium carbonate solution, a sodium bicarbonate solution, a potassium bicarbonate solution, a sodium hydroxide solution, a potassium hydroxide solution or ammonia water; the invention has no special requirements on the mass concentration of the alkaline solution, and the corresponding solution with the concentration well known to the skilled person can be adopted.
After the (R) -4-chloro-7-methoxy quinazoline-6-yl-2-methylpiperazine-1-formate (the compound 8) is obtained, the compound 8 is mixed with a methylating agent, and methylation reaction is carried out at 90-100 ℃ to obtain the (R) -4-chloro-7-methoxy quinazoline-6-yl-2, 4-dimethylpiperazine-1-formate (the compound 9). In the invention, the methylating agent is a formic acid/formaldehyde mixed reagent, a formic acid/paraformaldehyde mixed reagent or sodium triacetoxyborohydride; the molar ratio of the compound 8 to the formic acid to the formaldehyde is 1: 5-15, and more preferably 1: 8-12; the mol ratio of the compound 8 to the formic acid to the paraformaldehyde is preferably 1: 5-15, and more preferably 1: 8-12: 7-13; the molar ratio of the compound 8 to sodium triacetoxyborohydride is preferably 1: 5-15, and more preferably 1: 8-12. In the invention, the methylation reaction time is preferably 95-96 ℃; the methylation reaction time is preferably 1-3 h, and more preferably 1.5-2.5 h; during the methylation reaction, the present invention preferably monitors the progress of the reaction by TLC, and the reaction is considered complete when the point of compound 8 in the reaction solution disappears. In the present invention, the methylation reaction has a reaction formula shown in formula 7:
after the methylation reaction, the invention preferably carries out post-treatment on the obtained methylation reaction liquid to obtain (R) -4-chloro-7-methoxyquinazolin-6-yl-2, 4-dimethylpiperazine-1-formate (compound 9). In the present invention, the post-treatment preferably comprises the steps of:
(a) cooling the methylation reaction liquid to-20-10 ℃, adjusting the pH value of the reaction liquid to 9-10 by using an alkaline solution, separating out solids, and then carrying out suction filtration to obtain solids;
(b) adding ethyl acetate and a carbonate solution into the solid, stirring and separating liquid, and taking an organic phase;
(c) washing the organic phase with water, drying with anhydrous sodium sulfate, filtering, and concentrating the obtained dried organic phase under reduced pressure to obtain a concentrate;
(d) and adding an organic solvent into the concentrate, heating and refluxing for 0.5h, and sequentially cooling, crystallizing, filtering and drying a solid phase of the obtained reflux reaction solution to obtain a compound 9.
In the present invention, the alkaline solution in the step (a) is preferably a sodium carbonate solution, a potassium carbonate solution, a sodium bicarbonate solution, a potassium bicarbonate solution, a sodium hydroxide solution, a potassium hydroxide solution or ammonia water; the invention has no special requirements on the mass concentration of the alkaline solution, and the corresponding solution with the concentration well known to the skilled person can be adopted. In the invention, the adding volume of the ethyl acetate in the step (b) is preferably 3-10 times of the feeding volume of the compound 8; the carbonate solution is preferably K2CO3Solution of said K2CO3The solution preferably has a mass concentration of 10%, the K being2CO3The molar ratio of the methanol to formic acid in the methylating agent is preferably 1: 2-5. In the present invention, the organic solvent in step (d) is preferably ethyl acetate, diethyl ether, methyl tert-butyl ether, isopropyl ether, petroleum ether or a mixed solvent of ethyl acetate and petroleum ether; the adding volume of the organic solvent is preferably 3-10 times of the feeding volume of the compound 8. In the present invention, the temperature for drying the solid phase in the step (d) is preferably 40 to 50 ℃, and more preferably 45 ℃.
The methylation reaction step successfully avoids the harsh condition of using sodium cyanoborohydride, does not generate highly toxic gas hydrogen cyanide in the reaction process, is environment-friendly, does not need column chromatography treatment in the post-treatment process, and is suitable for large-scale production.
After the (R) -4-chloro-7-methoxyquinazolin-6-yl-2, 4-dimethylpiperazine-1-carboxylate (compound 9) is obtained, the compound 9, 2-fluoro-3-chloroaniline and a seventh organic solvent are mixed, heated and refluxed for alkylation reaction, and AZD3759((R) -4- (3-chloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yl 2, 4-dimethylpiperazine-1-carboxylate) is obtained. In the present invention, the seventh organic solvent is preferably isopropanol, ethanol, methanol, t-butanol, n-butanol, acetonitrile, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, ethyl acetate, chloroform, acetone, or butanone; the addition volume of the seventh organic solvent is preferably 3-10 times of the feeding volume of the compound 9. In the invention, the molar ratio of the compound 9 to the 2-fluoro-3-chloroaniline is preferably 1: 1-3, and more preferably 1: 1.5-2.5. In the invention, the time of the alkylation reaction is preferably 1-8 h, and more preferably 4-6 h; the progress of the reaction is preferably monitored by TLC in the present invention, and the reaction is considered complete when the spot of compound 9 in the reaction solution disappears. In the present invention, the reaction formula of the alkylation reaction is shown as formula 8:
after the alkylation reaction, preferably, the obtained alkylation reaction liquid is cooled to 0-40 ℃, filtered, the filter cake is dried at 40-50 ℃, then ethanol is added for refining, and the AZD3759 is obtained after filtering and drying again. In the invention, the temperature of the cooling is preferably 5-15 ℃; the temperature of the drying is preferably 45 ℃.
The preparation method provided by the invention has the advantages of cheap and easily available raw materials and low cost; sodium cyanoborohydride is not used in the reaction process, so that the method is more environment-friendly; and the product yield is high, thereby being beneficial to industrial scale-up production.
The following examples are provided to illustrate the preparation of AZD3759, a tyrosine kinase inhibitor, in accordance with the present invention, but should not be construed as limiting the scope of the present invention.
Example 1
The preparation method of the tyrosine kinase inhibitor AZD3759 comprises the following steps:
(1) preparation of 4-chloro-7-methoxyquinazoline-6-acetate (compound 2): adding 35g of 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate, 55g of DIEA and 320mL of toluene into a 1000mL reaction bottle, heating to 70 ℃, keeping the temperature and stirring for 0.5h, adding 65g of phosphorus oxychloride, then heating to 95 ℃, and stirring and reacting for 3h at the temperature; after TLC detection reaction is completed, cooling to room temperature, concentrating under reduced pressure to dryness, finally adding 60mL of ethanol, stirring at room temperature for 0.5h, filtering, and drying at 45 ℃ to obtain 33g of compound 2;
(2) preparation of 4-chloro-7-methoxyquinazolin-6-ol (Compound 3): adding 32.5g of compound 2, 32g of ammonia water (the mass concentration is 25%) and 100g of methanol into a reaction bottle, and stirring and reacting for 6 hours under the reflux condition; after TLC detection reaction is completed, carrying out suction filtration, and then drying at 40 ℃ to obtain 23g of a compound 3;
(3) (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (Compound 5) preparation: adding 16g of (R) - (-) -2-methylpiperazine and 150mL of dichloromethane into a reaction bottle, cooling to 0 ℃, dissolving 17g of Boc-anhydride in 100mL of dichloromethane, dripping into the reaction bottle, stirring for reacting for 1 hour, and monitoring by a point plate; after the reaction, filtering, spin-drying the filtrate, adding 11g of saturated potassium carbonate solution into the concentrate, stirring, extracting with methyl tert-butyl ether, drying the organic phase with anhydrous sodium sulfate, spin-drying, adding petroleum ether, cooling, stirring, and crystallizing to obtain 26g of compound 5;
(4) (R) -4- (Chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (Compound 6) preparation: stirring 26g of compound 5 and 300mL of dichloromethane, cooling to a temperature not higher than 0 ℃, adding 36.3g of triphosgene in batches, adding 28.9g of pyridine in batches at the temperature, heating to room temperature after the addition, reacting for 24 hours, concentrating the solution under reduced pressure until the solution is dried to obtain 35g of compound 6, and directly putting the compound 6 into the next reaction without other treatment;
(5) (R) -4-tert-butyl-1- (4-chloro-7-methoxyquinazolin-6-yl) -2-methylpiperazine-1, 4-dicarboxylate (Compound 7): adding the obtained compound 6 and 450mL of DMF into a reaction bottle, cooling and stirring to below 0 ℃, adding 23g of compound 3 and 34.5g of DIEA, heating to room temperature after adding, and reacting for 24 h; after TLC detection compound 3 completely reacts, concentrating under reduced pressure, evaporating most of solvent, adding 300mL of purified water, stirring, standing for 12h, performing suction filtration, and drying at 40 ℃ to obtain 51.7g of compound 7;
(6) (R) -4-chloro-7-methoxyquinazolin-6-yl-2-methylpiperazine-1-carboxylate (Compound 8): adding 51.5g of compound 7, 20g of HCl gas and 200mL of 1, 4-dioxane into a reaction bottle, and stirring at room temperature for 12 hours; after TLC detection reaction is finished, concentrating the reaction solution under reduced pressure to dryness, adding 200mL of purified water, cooling to 5 ℃, adding ammonia water while stirring to adjust the pH value to 8, separating out a solid, performing suction filtration, and drying at 45 ℃ to obtain 35.2g of a compound 8;
(7) (R) -4-chloro-7-methoxyquinazolin-6-yl-2, 4-dimethylpiperazine-1-carboxylate (Compound 9) preparation: adding 35.2g of compound 8, 31g of formic acid, 65g of 30% formaldehyde solution and 350mL of purified water into a reaction bottle, heating to 95 ℃, and stirring for reaction for 3 hours; after TLC detection reaction, cooling to 0 ℃, adjusting the pH value of the solution to 9 by using ammonia water, separating out a solid, performing suction filtration, adding 1.5L of ethyl acetate and 500mL of 10% K into the obtained solid2CO3Stirring and separating the solution, taking an organic phase, washing the organic phase with 500mL of water, drying the organic phase, filtering, concentrating under reduced pressure, adding 50mL of ethyl acetate and 50mL of petroleum ether into the residue, heating to reflux, stirring for 0.5h, cooling for crystallization, performing suction filtration, and drying at 45 ℃ to obtain 30.8g of a compound 9;
(8) preparation of AZD 3759: adding 30.8g of compound 9, 18.5g of 2-fluoro-3-chloroaniline and 300mL of isopropanol into a reaction bottle, and heating to reflux for reaction for 3 h; and after the TLC detection reaction is finished, cooling to 15 ℃, carrying out suction filtration, adding 100mL of ethanol into the filter cake, stirring at room temperature for 1-2 h, carrying out suction filtration, and drying to obtain 28.5g of AZD759 with high purity.
Example 2
The preparation method of the tyrosine kinase inhibitor AZD3759 comprises the following steps:
(1) preparation of 4-chloro-7-methoxyquinazoline-6-acetate (compound 2): adding 31g of 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate, 53g of DIEA and 300mL of toluene into a 1000mL reaction bottle, heating to 70 ℃, keeping the temperature and stirring for 0.5h, adding 60g of phosphorus oxychloride, then heating to 100 ℃, and stirring for reaction for 3h at the temperature; after TLC detection reaction is completed, cooling to room temperature, concentrating under reduced pressure to dryness, finally adding 60mL of ethanol, stirring at room temperature for 0.5h, filtering, and drying at 50 ℃ to obtain 31.5g of compound 2;
(2) preparation of 4-chloro-7-methoxyquinazolin-6-ol (Compound 3): adding 31.5g of compound 2, 30g of ammonia water (the mass concentration is 25%) and 100g of methanol into a reaction bottle, and stirring and reacting for 6 hours under the reflux condition; after TLC detection reaction is completed, carrying out suction filtration, and then drying at 50 ℃ to obtain 22g of compound 3;
(3) (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (Compound 5) preparation: adding 15g of (R) - (-) -2-methylpiperazine and 150mL of dichloromethane into a reaction bottle, cooling to 0 ℃, dissolving 16.5g of Boc-anhydride in 100mL of dichloromethane, dripping into the reaction bottle, stirring for reaction for 1 hour, and monitoring by a point plate; after the reaction is finished, filtering, spin-drying the filtrate, adding 10g of potassium carbonate saturated solution into the concentrate, stirring, extracting with methyl tert-butyl ether, drying with sodium sulfate, spin-drying, adding petroleum ether, cooling, stirring and crystallizing to obtain 25g of a compound 5;
(4) (R) -4- (Chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (Compound 6) preparation: stirring 25g of compound 5 and 300mL of dichloromethane, cooling to a temperature not higher than 0 ℃, adding 35.6g of triphosgene in batches, adding 28g of pyridine in batches at the temperature, heating to room temperature after the addition, reacting for 24 hours, concentrating the solution under reduced pressure until the solution is dried to obtain 33g of compound 6, and directly putting the compound 6 into the next reaction without other treatment;
(5) (R) -4-tert-butyl-1- (4-chloro-7-methoxyquinazolin-6-yl) -2-methylpiperazine-1, 4-dicarboxylate (Compound 7): adding the obtained compound 6 and 450mL of DMF into a reaction bottle, cooling and stirring to below 0 ℃, adding 26g of compound 3 and 35g of DIEA, heating to room temperature after adding, and reacting for 24 h; after TLC detection compound 3 completely reacts, concentrating under reduced pressure, evaporating to remove most of solvent, adding 300mL of purified water, stirring, standing for 12h, performing suction filtration, and drying at 50 ℃ to obtain 50g of compound 7;
(6) (R) -4-chloro-7-methoxyquinazolin-6-yl-2-methylpiperazine-1-carboxylate (Compound 8): adding 50g of compound 7, 20g of HCl gas and 200mL of 1, 4-dioxane into a reaction bottle, and stirring at room temperature for 12 hours; after TLC detection reaction is finished, concentrating the reaction solution under reduced pressure to dryness, adding 200mL of purified water, cooling to 5 ℃, adding ammonia water while stirring to adjust the pH value to 8, separating out a solid, performing suction filtration, and drying at 50 ℃ to obtain 34.5g of compound 8;
(7) (R) -4-chloro-7-methoxyquinazolin-6-yl-2, 4-dimethylpiperazine-1-carboxylate (preparation of compound 9: 34.5g of compound 8, 30g of formic acid, 65g of 30% formaldehyde solution and 350mL of purified water are added into a reaction flask, the temperature is increased to 100 ℃, the reaction is stirred for 3 hours, after the TLC detection reaction is finished, the temperature is reduced to 10 ℃, ammonia water is used for adjusting the pH value of the solution to 10, a solid is separated out and filtered, 1.5L of ethyl acetate and 500mL of 10% K are added into the obtained solid, and the mixture is stirred and reacted for 3 hours2CO3Stirring and separating the solution, taking an organic phase, washing the organic phase with 500mL of water, drying the organic phase, filtering, concentrating under reduced pressure, adding 50mL of ethyl acetate and 50m of petroleum ether into the residue, heating to reflux, stirring for 0.5h, cooling for crystallization, performing suction filtration, and drying at 50 ℃ to obtain 30g of a compound 9;
(8) preparation of AZD 3759: adding 30g of compound 9, 18.5g of 2-fluoro-3-chloroaniline and 300mL of isopropanol into a reaction bottle, and heating to reflux for reaction for 3 hours; after TLC detection reaction, cooling to 30 ℃, carrying out suction filtration, then drying at 50 ℃, carrying out suction filtration, adding 950mL of ethanol into a filter cake, stirring at room temperature for 2h, carrying out suction filtration, and drying to obtain 28.5g of AZD759 with higher purity.
The yield of the target compound AZD-3759 in this example was 83.1%, and the HPLC purity was 99.0%; the final product obtained in this example was characterized by nmr and LCMS (nmr hydrogen spectrum and LCMS spectrum are shown in fig. 1 and 2, respectively):1H-NMR(400MHz,CDCl3) 9.72(s, 1H),8.45(s, 1H),8.21(s, 1H),7.48(m, 2H),7.32(s, 1H),7.26(s, 1H),4.33(br, 1H),3.93(s, 3H),3.78(br, 1H),3.22(br, 1H),2.78(d, 1H),2.66(d, 1H),2.19(s, 3H),2.08(d, 1H),1.89(s, 1H),1.32(br, 3H); ESI molecular weight [ M ] determination+H+]460.1338。
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A preparation method of a tyrosine kinase inhibitor AZD3759 is characterized by comprising the following steps of, without using cyano sodium borohydride:
(1) mixing 3, 4-dihydro-7-methoxy-4-oxoquinazoline-6-alcohol acetate, DIEA and a first organic solvent, adding a chlorinating agent at the temperature of 50-70 ℃, and carrying out chlorination reaction at the temperature of 90-100 ℃ to obtain 4-chloro-7-methoxy quinazoline-6-acetate;
(2) mixing the 4-chloro-7-methoxyquinazoline-6-acetate, an inorganic alkaline compound and a second organic solvent, heating and refluxing for hydrolysis reaction to obtain 4-chloro-7-methoxyquinazoline-6-ol;
(3) dissolving (R) - (-) -2-methylpiperazine in a third organic solvent to obtain a (R) - (-) -2-methylpiperazine solution, and dropwise adding Boc-anhydride into the (R) - (-) -2-methylpiperazine solution at the temperature of-5 ℃ to perform nucleophilic addition-elimination reaction to obtain (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester;
(4) dissolving the (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester in a fourth organic solvent, mixing to obtain a (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester solution, adding triphosgene and pyridine into the (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester solution at the temperature of-30 ℃, and performing chloroformylation reaction at room temperature to obtain (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester;
(5) dissolving (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester in a fifth organic solvent to obtain a (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester solution, adding the 4-chloro-7-methoxyquinazoline-6-ol and an organic base into the (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester solution at the temperature of-5 to 5 ℃, and performing an esterification reaction at room temperature to obtain (R) -4-tert-butyl-1- (4-chloro-7-methoxyquinazolin-6-yl) -2-methylpiperazine-1, 4-dicarboxylic acid esters;
(6) mixing (R) -4-tert-butyl-1- (4-chloro-7-methoxyquinazolin-6-yl) -2-methylpiperazine-1, 4-dicarboxylate, HCl gas and a sixth organic solvent at room temperature to perform de-Boc reaction to obtain (R) -4-chloro-7-methoxyquinazolin-6-yl-2-methylpiperazine-1-formate;
(7) mixing (R) -4-chloro-7-methoxy quinazoline-6-yl-2-methylpiperazine-1-formate with a methylating agent, and carrying out methylation reaction at 90-100 ℃ to obtain (R) -4-chloro-7-methoxy quinazoline-6-yl-2, 4-dimethylpiperazine-1-formate; the methylation reagent is a formic acid-formaldehyde mixed reagent, a formic acid-paraformaldehyde mixed reagent or sodium triacetoxyborohydride;
(8) mixing (R) -4-chloro-7-methoxyquinazoline-6-yl-2, 4-dimethylpiperazine-1-formate, 2-fluoro-3-chloroaniline and a seventh organic solvent, and carrying out heating reflux to carry out alkylation reaction to obtain AZD 3759;
the steps (1) and (3) are not limited in time sequence.
2. The preparation method according to claim 1, wherein the chlorinating agent in the step (1) is thionyl chloride, oxalyl chloride or phosphorus oxychloride; the molar ratio of the 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate to the DIEA to the chlorinated reagent is 1: 1-10; the first organic solvent is toluene or dichloromethane; the time of the chlorination reaction is 2-3 h.
3. The preparation method according to claim 1, wherein the inorganic alkaline compound in the step (2) is one or more of ammonia, potassium carbonate and sodium carbonate; the molar ratio of the 4-chloro-7-methoxyquinazoline-6-acetate to the inorganic alkaline compound is 1: 1.5-10; the second organic solvent is isopropanol, ethanol, methanol, tert-butanol, n-butanol, acetonitrile, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, ethyl acetate, chloroform, acetone or butanone; the hydrolysis reaction time is 1-8 h.
4. The process according to claim 1, wherein the molar ratio of (R) - (-) -2-methylpiperazine to Boc-anhydride in step (3) is 1: 1-10; the third organic solvent is dichloromethane, chloroform, tetrahydrofuran, ethyl acetate or acetonitrile; the time of the nucleophilic addition-elimination reaction is 1-5 h.
5. The preparation method according to claim 1, wherein the molar ratio of the (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester, the triphosgene and the pyridine in the step (4) is 1:1 to 3:2.5 to 4; the fourth organic solvent is dichloromethane, chloroform, tetrahydrofuran, ethyl acetate or acetonitrile; the time of the chloroformylation reaction is 15-48 h.
6. The process according to claim 1 or 5, wherein the chloroformylation reaction in step (4) is followed by concentrating the resulting chloroformylation reaction solution to dryness under reduced pressure.
7. The method according to claim 1, wherein the organic base in the step (5) is N, N-diisopropylethylamine, triethylamine, tributylamine, trimethylamine, dodecyldimethylamine, hexadecyldimethylamine, dodecylbenzylmethylamine, or N-methyldicyclohexylamine; the molar ratio of the 4-chloro-7-methoxyquinazoline-6-ol to the (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-tert-butyl formate to the organic base is 1: 1-2: 1.5 to 5; the fifth organic solvent is dimethylformamide, dimethylacetamide or N-methylpyrrolidone; the esterification reaction time is 12-36 h.
8. The preparation method according to claim 1, wherein the sixth organic solvent in the step (6) is methanol, 1, 4-dioxane, ethanol, isopropanol, tert-butanol, acetonitrile or tetrahydrofuran; the Boc removal reaction time is 12-24 h.
9. The production method according to claim 1, wherein the molar ratio of (R) -4-chloro-7-methoxyquinazolin-6-yl-2-methylpiperazine-1-carboxylate, formic acid and formaldehyde in the step (7) is 1:5 to 15; the molar ratio of (R) -4-chloro-7-methoxyquinazolin-6-yl-2-methylpiperazine-1-carboxylate, formic acid and paraformaldehyde is 1: 5-15; the molar ratio of (R) -4-chloro-7-methoxyquinazoline-6-yl-2-methylpiperazine-1-formate to sodium triacetoxyborohydride is 1: 5-15; the methylation reaction time is 1-3 h.
10. The preparation method according to claim 1, wherein the seventh organic solvent in the step (8) is isopropanol, ethanol, methanol, t-butanol, n-butanol, acetonitrile, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, ethyl acetate, chloroform, acetone, or butanone; the molar ratio of the (R) -4-chloro-7-methoxyquinazoline-6-yl-2, 4-dimethylpiperazine-1-formate to the 2-fluoro-3-chloroaniline is 1: 1-3; the time of the alkylation reaction is 1-8 h.
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| CN105209456A (en) * | 2013-03-06 | 2015-12-30 | 阿斯利康(瑞典)有限公司 | Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor |
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| CN105209456A (en) * | 2013-03-06 | 2015-12-30 | 阿斯利康(瑞典)有限公司 | Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor |
| CN108658946A (en) * | 2017-03-28 | 2018-10-16 | 焦玉奇 | Novel quinazoline inhibitor |
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