CN114736207A - Preparation process of small molecule HER2 inhibitor - Google Patents
Preparation process of small molecule HER2 inhibitor Download PDFInfo
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Abstract
The invention provides a preparation process of a small molecule HER2 inhibitor, which adopts 3-iodine-1H-pyrazolo [3,4-d ] pyrimidine-4-amine which is easily available on the market as an initial material and is synthesized by alkylation, carbonylation, acylation, deprotection, cyclization and acylation reactions, thereby obtaining a target product, namely a compound shown in formula 1. The whole preparation process has no special reaction type and special reaction condition, mild reaction condition, few reaction steps, higher reaction yield in each step, simple post-treatment, mostly using extraction washing and recrystallization modes, not using a purification mode of column chromatography, and being applicable to the operation of industrial mass production.
Description
Technical Field
The invention belongs to the technical field of biological medicines, relates to a preparation process of a compound, and particularly relates to a preparation process of a small molecular HER2 inhibitor TAS-0728.
Background
TAS-0728 (also known as TPC-107) is a novel, orally-administrable, highly active and highly selective, highly selective covalent binding inhibitor of the new generation of small molecule HER2 kinase, developed by Taiho Pharmaceutical Co., Ltd. Compared with reported HER2 inhibitory compounds such as lapatinib (quinazolines), afatinib (quinazolines) and neratinib (cyanoquinolines), TAS-0728 has a unique chemical structure, which is represented by the following formula 1.
TAS0728 covalently binds to Cys in HER2 and inhibits kinase activity. Unlike lapatinib, the inhibitory activity of TAS-0728 on HER2 kinase is not affected by the presence of high concentrations of ATP after binding to HER2 kinase, a particular feature of covalently bound TKIs. TAS0728 has clinical activity that may exceed lapatinib as a single drug. TAS0728 showed high selectivity for HER2 with reduced activity for EGFR. Compared to afatinib, TAS0728 has a higher specificity for HER2 than for EGFR, which is demonstrated in a combination enzymatic, cytopharmacodynamic and cytotoxic assay. To date, various covalent inhibitors have been developed to treat cancers that overexpress HER 2. However, a common dose-limiting toxicity in EGFR inhibitory compounds is grade 3 diarrhea, which is usually caused by inhibition of wild-type EGFR. The high specificity of HER2 may prevent EGFR-related toxicity and enable more effective dosing in patients. TAS0728 does not cause diarrhea in mouse models during effective dose treatment (Irie H; Ito K; Fujioka F; et al. TAS0728, a constant-binding, HER2-selective kinase inhibitor present activity in clinical models. mol Cancer Ther,2019,18(4): 733-) 742). Pharmacodynamic analyses performed using MCF10A cells engineered to express various mutant HER2 genes showed that TAS-0728 effectively inhibited phosphorylation of mutant HER2 and wild-type HER 2. Furthermore, TAS-0728 shows a strong and sustained inhibitory effect on phosphorylation of HER2, HER3 and downstream effectors, thereby inducing apoptosis of HER2 expanded breast cancer cells and tumor tissue in tumor tissue of xenograft models. TAS-0728 induced tumor regression in a mouse xenograft model carrying HER2 signal-dependent tumors and showed survival benefit in a peritoneal mouse model carrying HER2 driven cancer cells without any significant toxicity.
Currently, clinical trials (NCT03410927) are underway on a First-in-Human (FIH), 2-segment, 1/2, open label, multi-center study design, to evaluate the safety, tolerability, PK, pharmacodynamics, PGx and efficacy of TAS 0728. The study included clinical phase 1 and clinical phase 2 trial fractions of advanced solid tumor subjects with HER2 or HER3 overexpression, amplification or mutation, who progressed despite standard treatment or had no standard treatment, in particular, urothelial cancer, biliary tract cancer, metastatic breast cancer, non-small cell lung cancer and colorectal cancer. In conclusion TAS0728 may be a promising, more effective therapeutic option for the treatment of cancers carrying HER2 gene abnormalities and would be expected to improve the current therapeutic window compared to current HER2 inhibitors.
WO2017/146116 and US2017/0217970A1, both published by Dapeng chemical industry Co., Ltd, mention the synthesis of the compound TAS0728 (Compound 1, also known as the compound of formula 1) from two starting materials in various ways.
(1) 4, 6-dichloro-5-pyrimidinecarbaldehyde is taken as an initial material, and a key intermediate a is generated after cyclization, halogenation, N-alkylation, amination and carbonylation reactions; 3-iodine-1H-pyrazolo [3,4-d ] pyrimidine-4-amine is used as a starting material, and a key intermediate a is synthesized through N-alkylation, carbonylation, deboc protection removal and N-acylation reaction. The key intermediate produces compound 1 in two ways: the first is that the key intermediate a is subjected to N-acylation and C-acylation reaction to obtain a target compound 1; the two are key intermediates a, and the target compound 1 is obtained directly through N-acylation reaction.
(2) Compound 1 was prepared by an alternative synthetic route starting from 3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-4-amine: the starting material is subjected to N-alkylation, carbonylation, N-acylation, deboc protection removal and N-acylation to obtain the compound 1.
In the reaction process, the used triphenylphosphine belongs to a highly toxic reagent, and the sample purification is required to be carried out in a column chromatography mode after the reaction; the amination reaction needs to be carried out in a stainless steel pressure-resistant pipe at high temperature and high pressure, so that the risk is high, and the requirements on reaction equipment and operators are high during industrialization. The above operations are not favorable for the application of the process route in mass production.
Therefore, the preparation process of the compound shown in formula 1 still needs to be improved.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide a novel synthesis route and a preparation process of TAS-0728. Compared with the prior art, the invention adopts a new synthesis process route innovatively, the whole preparation process has no special reaction type and special reaction condition, the reaction condition is mild, the reaction steps are few, the reaction yield of each step is higher, the post-treatment is simple, the modes of extraction, washing and recrystallization are mostly used, the purification mode of column chromatography is not used, and the preparation method is suitable for the operation of industrial mass production.
In one aspect of the invention, the invention provides a synthetic route and a preparation process for a compound TAS-0728 shown in formula 1. According to an embodiment of the invention, the preparation process comprises:
(1) contacting a compound represented by formula 2 with a compound represented by formula 3 to obtain a compound represented by formula 4;
(2) contacting a compound represented by formula 4 with an alcohol solvent and a palladium metal complex to obtain a compound represented by formula 5;
(3) contacting a compound represented by formula 5 with a compound represented by formula 6 to obtain a compound represented by formula 7;
(4) contacting a compound represented by formula 7 with an alcohol solvent and a hydrochloric acid solution to obtain a compound represented by formula 8;
(5) contacting a compound represented by formula 8 with a base to obtain a compound represented by formula 9;
(6) contacting a compound represented by formula 9 with a base and acryloyl chloride to obtain a compound represented by formula 1,
the inventor finds that the preparation process adopts 3-iodo-1H-pyrazolo [3,4-d ] pyrimidine-4-amine (CAS number: 151266-23-8, a compound shown in formula 2) which is easily available on the market as a starting material, and is synthesized by alkylation, carbonylation, acylation, deprotection, cyclization and acylation reactions, so that a target product, namely the compound TAS-0728 shown in formula 1, is obtained.
The term "contacting" as used herein is to be understood broadly and can be any means that enables at least two reactants to react chemically, e.g. mixing of two reactants under suitable conditions. The reactants to be contacted may be mixed with stirring as necessary, and thus, the type of stirring is not particularly limited, and may be, for example, mechanical stirring, that is, stirring under the action of a mechanical force.
The terms "first", "second" and "first" are used herein for descriptive purposes only and are not to be construed as indicating or implying relative importance or to implicitly indicate the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
According to an embodiment of the present invention, the above method for preparing the compound represented by formula 4, the compound represented by formula 5, the compound represented by formula 7, the compound represented by formula 8, the compound represented by formula 9, the compound represented by formula 1 may further have at least one of the following additional technical features:
the chemical reactions described herein may be performed according to any method known in the art, according to embodiments of the present invention. The source of the raw materials for preparing the compound represented by formula 4, the compound represented by formula 5, the compound represented by formula 7, the compound represented by formula 8, the compound represented by formula 9, and the compound represented by formula 1 is not particularly limited, and it may be prepared by any known method or commercially available.
According to an embodiment of the present invention, in the step (1), the compound represented by formula 2, the compound represented by formula 3, and the contacting manner with the base are not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 2, the compound shown in the formula 3 and alkali can be improved, the reaction speed is increased, the efficiency of preparing the compound shown in the formula 4 by using the method is further improved, and the synthetic route is as follows:
through Scifinder search, the compound shown in the formula 4 is a brand-new compound, and the compound shown in the formula 4 is used as a drug intermediate in the process of preparing the compound shown in the formula 1.
According to an embodiment of the present invention, in the step (1), the following steps are included: adding a solvent A into a reaction bottle, adding a compound shown as a formula 2, a compound shown as a formula 3 and an alkali under stirring, heating to 80-90 ℃, keeping the temperature and stirring for 3-5 hours, cooling to room temperature after the reaction is finished, adding water, stirring for crystallization for 1-3 hours, filtering, washing a filter cake twice with water, and drying the filter cake in vacuum to obtain a compound shown as a formula 4. Therefore, the efficiency of the contact reaction of the compound shown in the formula 2, the compound shown in the formula 3 and alkali can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 4 by using the method is further improved.
According to an embodiment of the present invention, in step (1), the solvent a is at least one selected from DMF, or DMAC.
According to an embodiment of the present invention, in step (1), the base is at least one selected from potassium carbonate, cesium carbonate, or sodium carbonate, preferably the base is selected from potassium carbonate.
According to an embodiment of the invention, in the step (1), the molar ratio of the compound represented by the formula 2 to the compound represented by the formula 3 to the base is 1 (1.0-1.1) to (2.5-3.5), and preferably the molar ratio of the compound represented by the formula 2 to the compound represented by the formula 3 to the base is 1:1.05: 3.0. Thus, the efficiency of preparing the compound represented by formula 4 using this method can be further improved.
According to the embodiment of the present invention, in the step (1), it is preferable that the reaction temperature of the contact stirring of the compound represented by formula 2, the compound represented by formula 3 and the base is 85 ℃ and the reaction time is 4 hours. Thus, the efficiency of the contact reaction of the compound represented by formula 2, the compound represented by formula 3, and the base can be improved, and the efficiency of the production of the compound represented by formula 4 by this method can be further improved.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: adding DMF (45ml) into a reaction bottle, adding a compound shown in a formula 2 (4.5g,17.24mmol), a compound shown in a formula 3 (8.06g,18.1mmol) and potassium carbonate (7.15g,51.72mmol) respectively under stirring, heating to 85 ℃, keeping the temperature and stirring for 4h, after the reaction is finished, cooling to room temperature, adding water (80ml), stirring for crystallization for 1h, filtering, washing a filter cake twice with water (80ml), and drying the filter cake under vacuum at 50 ℃ to obtain a compound shown in a formula 4 (8.61g) with the yield of 79.9%.
According to an embodiment of the present invention, in the step (2), the contacting manner of the compound represented by formula 4 with the alcohol solvent and the palladium metal complex is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 4 with an alcohol solvent and a palladium metal complex can be improved, the reaction speed is accelerated, the efficiency of preparing the compound shown in the formula 5 by using the method is further improved, and the synthetic route is as follows:
through Scifinder search, the compound shown in the formula 5 is a brand-new compound, and the compound shown in the formula 5 is used as a drug intermediate in the process of preparing the compound shown in the formula 1.
According to an embodiment of the present invention, in the step (2), the following steps are included: dissolving the compound represented by the formula 4, an alcohol solvent and a palladium metal complex in a solvent B, replacing the inside of the system with carbon monoxide, heating to 100 ℃ and 120 ℃, stirring for 3.5-4.5 hours, cooling the reaction mixture to room temperature, adding methanol, adding an alkali, stirring the mixture for 30 minutes, adding water, washing an aqueous layer with ethyl acetate, adjusting the pH to 3 with hydrochloric acid, filtering the obtained precipitate, washing the filtered precipitate with water, and drying a filter cake in vacuum to obtain the compound represented by the formula 5. Therefore, the efficiency of the contact reaction of the compound shown as the formula 4 with an alcohol solvent and a palladium metal complex can be improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown as the formula 5 by using the method is further improved.
According to an embodiment of the present invention, in the step (2), the alcohol solvent is an alcohol solvent selected from C1-C6, preferably the alcohol solvent is at least one selected from ethanol, methanol, propanol, or isopropanol.
According to an embodiment of the present invention, in step (2), the palladium metal complex is selected from Pd (PPh)3)2Cl2Or Pd (OAc)2, preferably the palladium metal complex is selected from Pd (PPh)3)2Cl2。
According to an embodiment of the present invention, in the step (2), the base is at least one selected from triethylamine, pyridine, or lutidine.
According to an embodiment of the present invention, in step (2), the solvent B is at least one selected from DMF, NMP, or DMAC.
According to the embodiment of the invention, in the step (2), the molar ratio of the compound represented by the formula 4 to the alcohol solvent and the palladium metal complex is 1 (1.0-1.2) to (0.03-0.08), and preferably the molar ratio of the compound represented by the formula 4 to the alcohol solvent and the palladium metal complex is 1:1.1: 0.05. Thus, the efficiency of preparing the compound represented by formula 5 using this method can be further improved.
According to the embodiment of the present invention, in the step (2), the reaction temperature of the contact stirring of the compound represented by the formula 4 with the alcoholic solvent and the palladium metal complex is 107-115 ℃, and the reaction time is 4 hours. Therefore, the efficiency of the contact reaction of the compound shown in the formula 4 with the alcohol solvent and the palladium metal complex can be improved, and the efficiency of preparing the compound shown in the formula 5 by using the method can be further improved.
According to a specific embodiment of the present invention, in the step (2), the following steps are included: a mixture of a compound represented by the formula 4 (8.6g,13.75mmol), ethanol (0.7g,15.19mmol) and Pd (PPh)3)2Cl2(0.48g,0.69mmol) was dissolved in 86mL of NMP, the inside of the system was replaced with carbon monoxide, and then heated to 107 ℃ and 115 ℃ and stirred for 4 hours, then the reaction mixture was cooled to room temperature, 43mL of methanol was added thereto, triethylamine (6.97g,68.9mmol) was further added, the mixture was stirred for 30 minutes, after water was added, the aqueous layer was washed with ethyl acetate and adjusted to pH 3 with hydrochloric acid, then the resulting precipitate was filtered, the filtered precipitate was washed with water, and then the filter cake was vacuum-dried at 50 ℃ to obtain the compound represented by formula 5 (5.53g) in a yield of 74.0%.
According to the embodiment of the present invention, in the step (3), the contacting manner of the compound represented by the formula 5 with the compound represented by the formula 6 (CAS number 2088324-12-1), the base, and the condensing agent is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 5, the compound shown in the formula 6, alkali and a condensing agent can be improved, the reaction speed is increased, the efficiency of preparing the compound shown in the formula 7 by using the method is further improved, and the synthetic route is as follows:
through Scifinder search, the compound shown in the formula 7 is a brand-new compound, and the compound shown in the formula 7 is used as a drug intermediate in the process of preparing the compound shown in the formula 1.
According to an embodiment of the present invention, in the step (3), the following steps are included: adding the compound shown as the formula 5, alkali, the compound shown as the formula 6 and DMF into a reaction bottle, starting stirring, stirring for 15min, adding a condensing agent, stirring overnight at room temperature, adding water after the reaction is finished, stirring for crystallization, filtering, recrystallizing a filter cake with methanol, and drying in vacuum to obtain the compound shown as the formula 7. Therefore, the efficiency of the contact reaction of the compound shown in the formula 5, the compound shown in the formula 6, the alkali and the condensing agent can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 7 by using the method is further improved.
According to an embodiment of the present invention, in the step (3), the base is at least one selected from DIPEA, DIEA, or DMAP.
According to an embodiment of the present invention, in the step (3), the condensing agent is at least one selected from TBTU, or HBTU.
According to the embodiment of the invention, in the step (3), the molar ratio of the compound shown in the formula 5 to the compound shown in the formula 6, the base and the condensing agent is 1 (1.05-1.15): 1:1, and preferably the molar ratio of the compound shown in the formula 5 to the compound shown in the formula 6, the base and the condensing agent is 1:1.1:1: 1. Thus, the efficiency of preparing the compound represented by formula 7 using this method can be further improved.
According to a specific embodiment of the present invention, in the step (3), the following steps are included: the compound represented by the formula 5 (5.50g,10.12mmol), DIPEA (1.31g,10.12mmol), the compound represented by the formula 6 (2.30g,11.13mmol) and DMF (220ml) were added to a reaction flask, stirring was started, stirring was continued for 15min, TBTU (3.26g,10.12mmol) was further added, stirring was continued overnight at room temperature, after the reaction was completed, water (880ml) was added, crystallization was stirred, filtration was carried out, the cake was recrystallized from methanol (110ml), and vacuum drying was carried out at 50 ℃ to obtain the compound represented by the formula 7 (6.22g), with a yield of 84.0%.
According to an embodiment of the present invention, in the step (4), the contacting manner of the compound represented by formula 7 with the alcohol solvent and the hydrochloric acid solution is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 7, an alcohol solvent and a hydrochloric acid solution can be improved, the reaction speed is increased, the efficiency of preparing the compound shown in the formula 8 by using the method is further improved, and the synthetic route is as follows:
through Scifinder search, the compound shown as the formula 8 is a brand new compound, and the compound shown as the formula 8 is used as a drug intermediate in the process of preparing the compound shown as the formula 1.
According to an embodiment of the present invention, in the step (4), the following steps are included: adding the compound shown in the formula 7 and an alcohol solvent into a reaction bottle, starting stirring until the compound and the alcohol solvent are dissolved, dropwise adding an HCl solution, stirring at room temperature for 3-8 h after the dropwise adding is finished, after the reaction is finished, concentrating the reaction liquid under reduced pressure, adding dichloromethane into the concentrated solution for dissolving, stirring, cooling, crystallizing for 2h, filtering, and drying a filter cake under reduced pressure to obtain the compound shown in the formula 8. Therefore, the efficiency of the contact reaction of the compound shown in the formula 7, the alcohol solvent and the hydrochloric acid solution can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 8 by using the method is further improved.
According to an embodiment of the present invention, in the step (4), the alcohol solvent is an alcohol solvent selected from C1-C6, preferably the alcohol solvent is at least one selected from ethanol, methanol, propanol, or isopropanol.
According to an embodiment of the invention, in step (4), the hydrochloric acid solution is selected from a 4N HCl solution.
According to the embodiment of the invention, in the step (4), the molar ratio of the compound represented by the formula 7 to the 4N hydrochloric acid solution is 1 (2.0-3.5), and the molar ratio of the compound represented by the formula 7 to the 4N hydrochloric acid solution is preferably 1: 2.2. Thus, the efficiency of preparing the compound represented by formula 8 by this method can be further improved.
According to a specific embodiment of the present invention, in the step (4), the following steps are included: adding a compound shown as a formula 7 (6.2g, 8.47mmol) and methanol (100ml) into a reaction bottle, starting stirring until the compounds are dissolved, dropwise adding 4N HCl solution (4.67ml, 18.64mmol), stirring at room temperature for 4h after the dropwise adding is finished, after the reaction is finished, concentrating the reaction liquid at 40 ℃ under reduced pressure, adding dichloromethane (50ml) into the concentrated liquid for dissolving, stirring, cooling, crystallizing for 2h, filtering, and drying a filter cake at 30 ℃ under reduced pressure to obtain a compound shown as a formula 8 (4.29g), wherein the yield is 95.3%.
According to an embodiment of the present invention, in step (5), the manner of contacting the compound represented by formula 8 and the base is not particularly limited. Therefore, the efficiency of the contact reaction between the compound shown in the formula 8 and alkali can be improved, the reaction speed is increased, the efficiency of preparing the compound shown in the formula 9 by using the method is further improved, and the synthetic route is as follows:
through Scifinder search, the compound shown as the formula 9 is a brand-new compound, and the compound shown as the formula 9 is used as a drug intermediate in the process of preparing the compound shown as the formula 1.
According to an embodiment of the present invention, in the step (5), the following steps are included: adding the compound shown in the formula 8 and acetonitrile into a reaction bottle, starting stirring, adding alkali, stirring overnight at room temperature, after the reaction is finished, concentrating the reaction liquid under reduced pressure, and carrying out post-treatment to obtain the compound shown in the formula 9. Therefore, the efficiency of the contact reaction of the compound shown in the formula 8, triethylamine and methanesulfonyl chloride can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 9 by using the method is further improved.
According to an embodiment of the present invention, in the step (5), the base is at least one selected from potassium carbonate, sodium hydroxide, or potassium hydroxide.
According to the embodiment of the invention, in the step (5), the molar ratio of the compound represented by the formula 8 to the base is 1 (1.0-1.2), and the molar ratio of the compound represented by the formula 8 to the base is preferably 1: 1.05. Thus, the efficiency of preparing the compound represented by formula 9 by this method can be further improved.
According to a specific embodiment of the present invention, in the step (5), the following steps are included: adding the compound represented by the formula 8 (4.20g, 7.90mmol) and acetonitrile (80ml) into a reaction bottle, starting stirring, adding potassium carbonate (1.15g, 8.30mmol), stirring overnight at room temperature, concentrating the reaction solution under reduced pressure at 45 ℃, adding water (60ml) into the concentrated solution, extracting twice with DCM (60ml), washing the organic phase with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, adding methyl tert-butyl ether (80ml) into the filtrate under stirring, stirring for crystallization, filtering, drying the filter cake under reduced pressure at 40 ℃ to obtain the compound represented by the formula 9 (2.39g), with the yield of 67.1%.
According to the embodiment of the present invention, in the step (6), the contacting manner of the compound represented by formula 9 with the base, and acryloyl chloride is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 9, alkali and acryloyl chloride can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 1 by using the method is further improved, wherein the synthetic route is as follows:
according to the embodiment of the present invention, in the step (6), the following steps are included: adding the compound shown in the formula 9 and dichloromethane into a reaction bottle, starting stirring, cooling to 0 ℃, adding alkali, controlling the temperature to be-10-0 ℃, dropwise adding acryloyl chloride, stirring at room temperature for 5-12 hours after dropwise adding is finished, and performing post-treatment after the reaction is finished to obtain the target product, namely the compound shown in the formula 1. Therefore, the efficiency of the contact reaction of the compound shown as the formula 9, alkali and acryloyl chloride can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown as the formula 1 by using the method is further improved.
According to an embodiment of the present invention, in the step (6), the base is at least one selected from triethylamine, sodium carbonate, or potassium carbonate.
According to the embodiment of the invention, in the step (6), the molar ratio of the compound represented by the formula 9 to the base and the acryloyl chloride is 1 (1.3-1.5) to (1.1-1.3), and the molar ratio of the compound represented by the formula 9 to the base and the acryloyl chloride is preferably 1:1.4: 1.21. Thus, the efficiency of preparing the compound represented by formula 1 using this method can be further improved.
According to a specific embodiment of the present invention, in the step (6), the following steps are included: adding a compound (2.35g, 5.22mmol) shown in the formula 9 and dichloromethane (50ml) into a reaction bottle, starting stirring, cooling to 0 ℃, adding triethylamine (0.74g, 7.31mmol), controlling the temperature to be-10-0 ℃, dropwise adding acryloyl chloride (0.57g, 6.30mmol), stirring at room temperature for 7h after dropwise adding, filtering until the reaction is finished, washing filtrate with a proper amount of sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution respectively, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate at room temperature to be dry, adding dichloromethane (20ml) into a residue, stirring to dissolve, cooling to below-5 ℃ for crystallization for 1h, filtering, drying a filter cake at 30 ℃ in vacuum to obtain a compound (1.87g) shown in the formula 1, wherein the yield is 71.0%, and the purity is 99.8% by HPLC.
According to an embodiment of the present invention, the synthetic route of the compound represented by formula 1 may be as follows:
in a second aspect of the invention, there is provided a pharmaceutical intermediate useful in the preparation of compound TAS-0728 of formula 1. The compound shown in the formula 4, the compound shown in the formula 5, the compound shown in the formula 7, the compound shown in the formula 8 and the compound shown in the formula 9 are all brand-new intermediate compounds.
Compared with the prior art, the preparation process of the TAS-0728 has at least the following beneficial effects:
(1) the synthetic route and the preparation process are developed by the applicant for preparing the TAS-0728, and the target product TAS-0728 is obtained by adopting 3-iodo-1H-pyrazolo [3,4-d ] pyrimidine-4-amine (a compound shown in a formula 2) which is easily available on the market as a starting material and carrying out 6 steps of alkylation, carbonylation, acylation, deprotection, cyclization and acylation reactions. The total reaction process comprises six steps: firstly, adopting halogenated hydrocarbon and amine to carry out N-alkylation reaction under the alkaline condition to synthesize a compound shown in a formula 4; secondly, the iodo group in the compound shown in the formula 4 is added with carbon monoxide to generate acetic acid under the catalysis of palladium metal complex and alcohol for carbonylation reaction to generate the compound shown in the formula 5; thirdly, performing an N-acylation reaction on a carboxyl group in the compound shown in the formula 5 and a primary amine in the compound shown in the formula 6 under the action of alkali and a condensing agent to generate a compound shown in the formula 7; fourthly, removing the N protecting group in the compound shown in the formula 7 under an acidic condition to generate a compound shown in a formula 8; fifthly, intramolecular cyclization is carried out on bromo groups and primary amine in the compound shown in the formula 8 under an alkaline condition to generate a compound shown in a formula 9; sixthly, the compound shown in the formula 9 is subjected to acylation reaction with acyl chloride under alkaline conditions to generate a target product TAS-0728.
(2) The synthetic routes and the processes of the invention are all brand new synthetic routes, and are not reported in documents, and the compounds shown in the formula 4, the formula 5, the formula 7, the formula 8 and the formula 9 are all brand new compounds.
(3) Compared with the prior art, the synthetic process route has the advantages that the whole preparation process has no special reaction type or special reaction condition, the reaction condition is mild, the reaction steps are few, the reaction yield of each step is higher, the post-treatment is simple, the modes of extraction washing and recrystallization are mostly used, the purification mode of column chromatography is not used, and the synthetic process route is suitable for the operation of industrial mass production.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 Synthesis of Compound represented by formula 4
Adding DMF (45ml) into a reaction bottle, adding a compound shown in the formula 2 (4.5g,17.24mmol), a compound shown in the formula 3 (8.06g,18.1mmol) and potassium carbonate (7.15g,51.72mmol) respectively under stirring, heating to 85 ℃, keeping the temperature and stirring for 4h, after the reaction is finished, cooling to room temperature, adding water (80ml), stirring for crystallization for 2h, filtering, washing a filter cake twice with water (80ml), and drying the filter cake under vacuum at 50 ℃ to obtain a compound shown in the formula 4 (8.61g) with the yield of 79.9%.
LC-MS(ESI):m/z＝625.05(M+1)+，627.05(M+3)+
Example 2 Synthesis of Compound represented by formula 4
Adding DMF (45ml) into a reaction bottle, adding a compound shown in the formula 2 (4.5g,17.24mmol), a compound shown in the formula 3 (7.68g,17.24mmol) and potassium carbonate (5.96g,43.10mmol) respectively under stirring, heating to 80 ℃, keeping the temperature and stirring for 5h, after the reaction is finished, cooling to room temperature, adding water (80ml), stirring for crystallization for 1h, filtering, washing a filter cake twice with water (80ml), and drying the filter cake under vacuum at 50 ℃ to obtain a compound shown in the formula 4 (8.17g) with the yield of 75.8%.
EXAMPLE 3 Synthesis of Compound represented by formula 4
DMAC (60ml) was added to the reaction flask, and the compound represented by the formula 2 (4.5g,17.24mmol), the compound represented by the formula 3 (8.44g,18.96mmol) and potassium carbonate (8.34g,60.34mmol) were added thereto under stirring, and the mixture was heated to 90 ℃ and stirred for 3 hours while maintaining the temperature. After the reaction was completed, the temperature was decreased to room temperature, and water (80ml) was added thereto, followed by stirring and crystallization for 3 hours, filtration, washing of the cake with water (80ml) twice, and vacuum drying of the cake at 50 ℃ to obtain the compound represented by formula 4 (8.41g) in a yield of 78.0%.
Example 4 Synthesis of Compound represented by formula 4
DMF (80ml) was added to a reaction flask, and the compound represented by formula 2 (4.5g,17.24mmol), the compound represented by formula 3 (8.06g,18.1mmol) and cesium carbonate (16.85g,51.72mmol) were added under stirring, and the mixture was heated to 85 ℃ and stirred under heat for 4 hours, after the reaction was completed, the temperature was lowered to room temperature, and water (100ml) was added, followed by crystallization under stirring for 2 hours, filtration, washing of the cake twice with water (100ml), and vacuum drying of the cake at 50 ℃ to give the compound represented by formula 4 (8.37g) with a yield of 77.6%.
EXAMPLE 5 Synthesis of Compound represented by formula 4
Adding DMF (50ml) into a reaction bottle, adding a compound shown in the formula 2 (4.5g,17.24mmol), a compound shown in the formula 3 (8.06g,18.1mmol) and sodium carbonate (5.48g,51.72mmol) respectively under stirring, heating to 85 ℃, keeping the temperature and stirring for 4h, after the reaction is finished, cooling to room temperature, adding water (80ml), stirring for crystallization for 1.5h, filtering, washing a filter cake twice with water (80ml), and drying the filter cake under vacuum at 50 ℃ to obtain a compound shown in the formula 4 (8.29g) with the yield of 76.9%.
EXAMPLE 6 Synthesis of Compound represented by formula 5
A mixture of a compound represented by the formula 4 (8.6g,13.75mmol), ethanol (0.7g,15.19mmol) and Pd (PPh)3)2Cl2(0.48g,0.69mmol) was dissolved in 86mL of NMP, the inside of the system was replaced with carbon monoxide, and then heated to 107 ℃ and 115 ℃ and after stirring for 4 hours, the reaction mixture was cooled toTo this was added 43mL of methanol at room temperature, triethylamine (6.97g,68.9mmol) was further added, the mixture was stirred for 30 minutes, after addition of water, the aqueous layer was washed with ethyl acetate and adjusted to pH 3 with hydrochloric acid, the resulting precipitate was filtered, the filtered precipitate was washed with water, and the cake was dried under vacuum at 50 ℃ to obtain the compound represented by formula 5 (5.53g) in 74.0% yield.
LC-MS(ESI):m/z＝543.15(M+1)+，545.15(M+3)+
Example 7 Synthesis of Compound represented by formula 5
A mixture of a compound represented by the formula 4 (8.6g,13.75mmol), ethanol (0.63g,13.75mmol) and Pd (PPh)3)2Cl2(0.29g,0.413mmol) was dissolved in 100mL of NMP, the inside of the system was replaced with carbon monoxide, then heated to 100 ℃ and stirred for 4.5 hours, the reaction mixture was cooled to room temperature, 50mL of methanol was added thereto, triethylamine (6.97g,68.9mmol) was further added, the mixture was stirred for 30 minutes, after adding water, the aqueous layer was washed with ethyl acetate and adjusted to pH 3 with hydrochloric acid, then the resulting precipitate was filtered, and after the filtered precipitate was washed with water, the cake was vacuum-dried at 50 ℃ to obtain the compound represented by formula 5 (5.34g) in 71.2% yield.
EXAMPLE 8 Synthesis of Compound represented by formula 5
A mixture of a compound represented by the formula 4 (8.6g,13.75mmol), ethanol (0.76g,16.5mmol) and Pd (PPh)3)2Cl2(0.772g,1.1mmol) was dissolved in 86mL of DMF, the inside of the system was replaced with carbon monoxide, then heated to 115 ℃ and stirred for 3.5 hours, then the reaction mixture was cooled to room temperature, 43mL of methanol was added thereto, triethylamine (6.97g,68.9mmol) was further added, the mixture was stirred for 30 minutes, after water was added, the aqueous layer was washed with ethyl acetate and adjusted to pH 3 with hydrochloric acid, then the resulting precipitate was filtered, the filtered precipitate was washed with water, and the cake was dried under vacuum at 50 ℃ to obtain the compound represented by formula 5 (5.46g) in 73.1% yield.
Example 9 Synthesis of Compound represented by formula 5
The compound represented by the formula 4 (8.6g,13.75mmol), propanol (0.91g,15.19mmol) and pd (oac)2(0.155g,0.69mmol) were dissolved in 95mL of NMP, the inside of the system was replaced with carbon monoxide, then, heated to 110-.
EXAMPLE 10 Synthesis of Compound represented by formula 5
The compound represented by the formula 4 (8.6g,13.75mmol), isopropyl alcohol (0.91g,15.19mmol) and pd (oac)2(0.155g,0.69mmol) were dissolved in 120mL of DMAC, the inside of the system was replaced with carbon monoxide, and then heated to 110-.
EXAMPLE 11 Synthesis of Compound represented by formula 7
The compound represented by the formula 5 (5.50g,10.12mmol), DIPEA (1.31g,10.12mmol), the compound represented by the formula 6 (2.30g,11.13mmol) and DMF (220ml) were added to a reaction flask, stirring was started, stirring was continued for 15min, TBTU (3.26g,10.12mmol) was further added, stirring was continued overnight at room temperature, after the reaction was completed, water (880ml) was added, crystallization was stirred, filtration was carried out, the cake was recrystallized from methanol (110ml), and vacuum drying was carried out at 50 ℃ to obtain the compound represented by the formula 7 (6.22g), with a yield of 84.0%.
LC-MS(ESI):m/z＝731.28(M+1)+，733.28(M+3)+
EXAMPLE 12 Synthesis of Compound represented by formula 7
The compound represented by the formula 5 (5.50g,10.12mmol), DIPEA (1.31g,10.12mmol), the compound represented by the formula 6 (2.20g,10.63mmol) and DMF (220ml) were added to a reaction flask, stirring was started, stirring was continued for 15min, TBTU (3.26g,10.12mmol) was further added, stirring was continued overnight at room temperature, after the reaction was completed, water (880ml) was added, crystallization was stirred, filtration was carried out, the cake was recrystallized from methanol (110ml), and vacuum drying was carried out at 50 ℃ to obtain the compound represented by the formula 7 (6.09g), with a yield of 82.2%.
Example 13 Synthesis of Compound represented by formula 7
The compound represented by the formula 5 (5.50g,10.12mmol), DIPEA (1.31g,10.12mmol), the compound represented by the formula 6 (2.40g,11.64mmol) and DMF (220ml) were added into a reaction flask, stirring was started, stirring was carried out for 15min, TBTU (3.26g,10.12mmol) was further added, stirring was carried out overnight at room temperature, after the reaction was completed, water (880ml) was added, crystallization was carried out by stirring, filtration was carried out, the cake methanol (110ml) was recrystallized, and vacuum drying was carried out at 50 ℃ to obtain the compound represented by the formula 7 (6.19g), yield 83.6%.
EXAMPLE 14 Synthesis of Compound represented by formula 7
The compound represented by the formula 5 (5.50g,10.12mmol), DIEA (1.31g,10.12mmol), the compound represented by the formula 6 (2.30g,11.13mmol) and DMF (220ml) were added to a reaction flask, stirring was started, stirring was continued for 15min, HBTU (3.84g,10.12mmol) was further added, stirring was continued overnight at room temperature, after the reaction was completed, water (880ml) was added, crystallization was stirred, filtration was carried out, the cake was recrystallized from methanol (110ml), and vacuum drying was carried out at 50 ℃ to obtain the compound represented by the formula 7 (6.10g), with a yield of 82.4%.
EXAMPLE 15 Synthesis of Compound represented by formula 7
Adding the compound shown in the formula 5 (5.50g,10.12mmol), DMAP (1.24g,10.12mmol), the compound shown in the formula 6 (2.30g,11.13mmol) and DMF (220ml) into a reaction bottle, starting stirring, stirring for 15min, adding HBTU (3.84g,10.12mmol), stirring overnight at room temperature, after the reaction is finished, adding water (880ml), stirring for crystallization, filtering, recrystallizing filter cake methanol (110ml), and drying in vacuum at 50 ℃ to obtain the compound shown in the formula 7 (6.15g) with the yield of 83.1%.
EXAMPLE 16 Synthesis of Compound represented by formula 8
Adding a compound shown as a formula 7 (6.2g, 8.47mmol) and methanol (100ml) into a reaction bottle, starting stirring until the compounds are dissolved, dropwise adding a 4N HCl solution (4.7ml, 18.64mmol), stirring at room temperature for 4h after the dropwise adding is finished, after the reaction is finished, concentrating the reaction liquid at 40 ℃ under reduced pressure, adding dichloromethane (50ml) into the concentrated liquid for dissolving, stirring, cooling, crystallizing for 2h, filtering, and drying a filter cake at 30 ℃ under reduced pressure to obtain a compound shown as a formula 8 (4.29g), wherein the yield is 95.3%.
LC-MS(ESI):m/z＝531.17(M+1)+，533.17(M+3)+
Example 17 Synthesis of Compound represented by formula 8
Adding a compound shown as a formula 7 (6.2g, 8.47mmol) and methanol (100ml) into a reaction bottle, starting stirring until the compounds are dissolved, dropwise adding 4N HCl solution (4.3ml, 16.94mmol), stirring at room temperature for 3h after the dropwise adding is finished, after the reaction is finished, concentrating the reaction liquid at 40 ℃ under reduced pressure, adding dichloromethane (50ml) into the concentrated liquid for dissolving, stirring, cooling, crystallizing for 2h, filtering, and drying a filter cake at 30 ℃ under reduced pressure to obtain a compound shown as a formula 8 (4.18g), wherein the yield is 92.9%.
EXAMPLE 18 Synthesis of Compound represented by formula 8
Adding a compound shown as a formula 7 (6.2g, 8.47mmol) and methanol (100ml) into a reaction bottle, starting stirring until the compounds are dissolved, dropwise adding 4N HCl solution (7.4ml, 29.65mmol), stirring at room temperature for 8h after the dropwise adding is finished, after the reaction is finished, concentrating the reaction liquid at 40 ℃ under reduced pressure, adding dichloromethane (50ml) into the concentrated liquid for dissolving, stirring, cooling, crystallizing for 2h, filtering, and drying a filter cake at 30 ℃ under reduced pressure to obtain a compound shown as a formula 8 (4.24g), wherein the yield is 94.3%.
EXAMPLE 19 Synthesis of Compound represented by formula 9
Adding the compound represented by the formula 8 (4.20g, 7.90mmol) and acetonitrile (80ml) into a reaction bottle, starting stirring, adding potassium carbonate (1.15g, 8.30mmol), stirring overnight at room temperature, concentrating the reaction solution under reduced pressure at 45 ℃, adding water (60ml) into the concentrated solution, extracting twice with DCM (60ml), washing the organic phase with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, adding methyl tert-butyl ether (80ml) into the filtrate under stirring, stirring for crystallization, filtering, drying the filter cake under reduced pressure at 40 ℃ to obtain the compound represented by the formula 9 (2.39g), with the yield of 67.1%.
LC-MS(ESI):m/z＝451.25(M+1)+
EXAMPLE 20 Synthesis of Compound represented by formula 9
The compound represented by formula 8 (4.20g, 7.90mmol) and acetonitrile (80ml) were added to a reaction flask, and stirring was turned on, potassium carbonate (1.09g, 7.90mmol) was added, and stirring was carried out at room temperature overnight. The reaction mixture was concentrated under reduced pressure at 45 ℃ and water (60ml) was added to the concentrate, followed by extraction with DCM (60ml) twice. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was added with methyl t-butyl ether (80ml) under stirring, crystallized under stirring, filtered, and the filter cake was dried under reduced pressure at 40 ℃ to give the compound represented by formula 9 (2.35g) in a yield of 66.0%.
EXAMPLE 21 Synthesis of Compound represented by formula 9
The compound represented by formula 8 (4.20g, 7.90mmol) and acetonitrile (80ml) were added to a reaction flask, stirring was turned on, sodium carbonate (1.31g, 9.48mmol) was added, and stirring was carried out overnight at room temperature. The reaction mixture was concentrated under reduced pressure at 45 ℃ and water (60ml) was added to the concentrate, followed by extraction with DCM (60ml) twice. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was added with methyl t-butyl ether (80ml) under stirring, crystallized under stirring, filtered, and the filter cake was dried under reduced pressure at 40 ℃ to give the compound represented by formula 9 (2.38g) in a yield of 66.8%.
EXAMPLE 22 Synthesis of Compound represented by formula 9
The compound represented by formula 8 (4.20g, 7.90mmol) and acetonitrile (80ml) were charged into a reaction flask, and stirring was turned on, and sodium hydroxide (0.33g, 8.30mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure at 45 ℃ and water (60ml) was added to the concentrate, followed by extraction with DCM (60ml) twice. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was added with methyl t-butyl ether (80ml) under stirring, crystallized under stirring, filtered, and the filter cake was dried under reduced pressure at 40 ℃ to give the compound represented by formula 9 (2.34g) in a yield of 65.6%.
EXAMPLE 23 Synthesis of Compound represented by formula 9
The compound represented by the formula 8 (4.20g, 7.90mmol) and acetonitrile (80ml) were charged into a reaction flask, and stirring was turned on, and potassium hydroxide (0.47g, 8.40mmol) was added thereto and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure at 45 ℃ and water (60ml) was added to the concentrate, followed by extraction with DCM (60ml) twice. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was added with methyl t-butyl ether (80ml) under stirring, crystallized under stirring, filtered, and the filter cake was dried under reduced pressure at 40 ℃ to give the compound represented by formula 9 (2.35g) in a yield of 66.0%.
EXAMPLE 24 Synthesis of Compound represented by formula 1
Adding a compound (2.35g, 5.22mmol) shown in the formula 9 and dichloromethane (50ml) into a reaction bottle, starting stirring, cooling to 0 ℃, adding triethylamine (0.74g, 7.31mmol), controlling the temperature to be-10-0 ℃, dropwise adding acryloyl chloride (0.57g, 6.30mmol), stirring at room temperature for 7h after dropwise adding, filtering until the reaction is finished, washing filtrate with a proper amount of sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution respectively, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate at room temperature to be dry, adding dichloromethane (20ml) into a residue, stirring to dissolve, cooling to below-5 ℃ for crystallization for 1h, filtering, drying a filter cake at 30 ℃ in vacuum to obtain a compound (1.87g) shown in the formula 1, wherein the yield is 71.0%, and the purity is 99.8% by HPLC.
LC-MS(ESI):m/z＝505.26(M+1)+
EXAMPLE 25 Synthesis of Compound represented by formula 1
Adding a compound (2.35g, 5.22mmol) shown in the formula 9 and dichloromethane (50ml) into a reaction bottle, starting stirring, cooling to 0 ℃, adding triethylamine (0.69g, 6.79mmol), controlling the temperature to be-10-0 ℃, dropwise adding acryloyl chloride (0.52g, 5.74mmol), stirring at room temperature for 5 hours after dropwise adding is finished, filtering until the reaction is finished, washing filtrate with a proper amount of sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution respectively, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate at room temperature to be dry, adding dichloromethane (20ml) into a residue, stirring to dissolve, cooling to below-5 ℃ for crystallization for 1 hour, filtering, drying a filter cake at 30 ℃ in vacuum to obtain a compound (1.74g) shown in the formula 1, wherein the yield is 68.5%, and the purity of HPLC is 99.4%.
EXAMPLE 26 Synthesis of Compound represented by formula 1
Adding a compound (2.35g, 5.22mmol) shown in the formula 9 and dichloromethane (50ml) into a reaction bottle, starting stirring, cooling to 0 ℃, adding triethylamine (0.79g, 7.83mmol), controlling the temperature to be-10-0 ℃, dropwise adding acryloyl chloride (0.62g, 6.85mmol), stirring at room temperature for 12 hours after dropwise adding, filtering until the reaction is finished, washing filtrate with a proper amount of sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution respectively, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate at room temperature to be dry, adding dichloromethane (20ml) into a residue, stirring to dissolve, cooling to below-5 ℃ for crystallization for 1 hour, filtering, drying a filter cake at 30 ℃ in vacuum to obtain a compound (1.85g) shown in the formula 1, wherein the yield is 70.2%, and the purity is 99.5% by HPLC.
EXAMPLE 27 Synthesis of Compound represented by formula 1
Adding a compound (2.35g, 5.22mmol) shown in formula 9 and dichloromethane (50ml) into a reaction bottle, starting stirring, cooling to 0 ℃, adding potassium carbonate (1.01g, 7.31mmol), controlling the temperature to be-10-0 ℃, dropwise adding acryloyl chloride (0.57g, 6.30mmol), stirring at room temperature for 7h after dropwise adding is finished, filtering until the reaction is finished, washing filtrate with a proper amount of sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution respectively, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate at room temperature to be dry, adding dichloromethane (20ml) into a residue, stirring to dissolve, cooling to below-5 ℃ for crystallization for 1h, filtering, drying a filter cake at 30 ℃ in vacuum to obtain a compound (1.80g) shown in formula 1, wherein the yield is 68.3%, and the purity of HPLC is 99.5%.
EXAMPLE 28 Synthesis of Compound represented by formula 1
Adding a compound (2.35g, 5.22mmol) shown in formula 9 and dichloromethane (50ml) into a reaction bottle, starting stirring, cooling to 0 ℃, adding sodium carbonate (0.77g, 7.31mmol), controlling the temperature to be-10-0 ℃, dropwise adding acryloyl chloride (0.57g, 6.30mmol), stirring at room temperature for 8h after dropwise adding is finished, filtering until the reaction is finished, washing filtrate with a proper amount of sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution respectively, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate at room temperature to be dry, adding dichloromethane (20ml) into a residue, stirring to dissolve, cooling to below-5 ℃ for crystallization for 1h, filtering, drying a filter cake at 30 ℃ in vacuum to obtain a compound (1.74g) shown in formula 1, wherein the yield is 68.5%, and the purity of HPLC is 99.6%.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Moreover, various embodiments or examples and features of various embodiments or examples described in this specification can be combined and combined by one skilled in the art without being mutually inconsistent.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A process for preparing a compound TAS-0728 of formula 1, comprising:
(1) contacting a compound represented by formula 2 with a compound represented by formula 3 to obtain a compound represented by formula 4;
(2) contacting a compound represented by formula 4 with an alcohol solvent and a palladium metal complex to obtain a compound represented by formula 5;
(3) contacting a compound represented by formula 5 with a compound represented by formula 6 to obtain a compound represented by formula 7;
(4) contacting a compound represented by formula 7 with an alcohol solvent and a hydrochloric acid solution to obtain a compound represented by formula 8;
(5) contacting a compound represented by formula 8 with a base to obtain a compound represented by formula 9;
(6) contacting a compound represented by formula 9 with a base and acryloyl chloride to obtain a compound represented by formula 1,
2. the method according to claim 1, wherein in step (1), the following steps are included: adding a solvent A into a reaction bottle, respectively adding a compound shown in a formula 2, a compound shown in a formula 3 and alkali under stirring, heating to 80-90 ℃, keeping the temperature and stirring for 3-5 hours, cooling to room temperature after the reaction is finished, adding water, stirring for crystallization for 1-3 hours, filtering, washing a filter cake twice with water, and drying the filter cake in vacuum to obtain a compound shown in a formula 4;
optionally, in step (1), the solvent a is at least one selected from DMF, or DMAC;
optionally, in step (1), the base is at least one selected from potassium carbonate, cesium carbonate, or sodium carbonate;
optionally, in the step (1), the molar ratio of the compound shown in the formula 2 to the compound shown in the formula 3 to the base is 1 (1.0-1.1) to (2.5-3.5).
3. The method according to claim 2, wherein in step (1), the compound represented by formula 2, the compound represented by formula 3 and the base are preferably in a molar ratio of 1:1.05: 3.0;
optionally, in the step (1), the reaction temperature of the contact stirring of the compound shown in the formula 2, the compound shown in the formula 3 and the base is preferably 85 ℃, and the reaction time is preferably 4 hours;
optionally, in step (1), preferably the base is selected from potassium carbonate.
4. The method of claim 1, wherein in step (2), the following steps are included: dissolving the compound represented by the formula 4, an alcohol solvent and a palladium metal complex in a solvent B, replacing the inside of the system with carbon monoxide, heating to 100-120 ℃, stirring for 3.5-4.5 hours, then cooling the reaction mixture to room temperature, adding methanol, adding an alkali, stirring the mixture for 30 minutes, adding water, washing an aqueous layer with ethyl acetate, adjusting the pH to 3 with hydrochloric acid, filtering the obtained precipitate, washing the filtered precipitate with water, and drying a filter cake in vacuum to obtain the compound represented by the formula 5;
optionally, in the step (2), the alcoholic solvent is an alcoholic solvent selected from C1-C6, preferably the alcoholic solvent is at least one selected from ethanol, methanol, propanol, or isopropanol;
optionally, in step (2), the palladium metal complex is selected from Pd (PPh)3)2Cl2Or Pd (OAc)2Preferably, the palladium metal complex is selected from Pd (PPh)3)2Cl2；
Optionally, in step (2), the base is at least one selected from triethylamine, pyridine, or lutidine;
optionally, in step (2), the solvent B is at least one selected from DMF, NMP, or DMAC;
optionally, in the step (2), the molar ratio of the compound shown in the formula 4 to the alcohol solvent and the palladium metal complex is 1 (1.0-1.2) to (0.03-0.08), preferably the molar ratio of the compound shown in the formula 4 to the alcohol solvent and the palladium metal complex is 1:1.1: 0.05;
optionally, in the step (2), the reaction temperature of the contact stirring of the compound represented by the formula 4 with the alcoholic solvent and the palladium metal complex is 107-115 ℃, and the reaction time is 4 hours.
5. The method of claim 1, wherein in step (3), the following steps are included: adding a compound shown as a formula 5, alkali, a compound shown as a formula 6 and DMF (dimethyl formamide) into a reaction bottle, starting stirring, stirring for 15min, adding a condensing agent, stirring overnight at room temperature, adding water after the reaction is finished, stirring for crystallization, filtering, recrystallizing a filter cake with methanol, and drying in vacuum to obtain a compound shown as a formula 7;
optionally, in step (3), the base is at least one selected from DIPEA, DIEA, or DMAP;
optionally, in step (3), the condensing agent is at least one selected from TBTU, or HBTU;
optionally, in the step (3), the molar ratio of the compound shown in the formula 5 to the compound shown in the formula 6, the base and the condensing agent is 1 (1.05-1.15) to 1:1, and the molar ratio of the compound shown in the formula 5 to the compound shown in the formula 6, the base and the condensing agent is preferably 1:1.1:1: 1.
6. The method according to claim 1, wherein in step (4), the following steps are included: adding a compound shown as a formula 7 and an alcohol solvent into a reaction bottle, starting stirring until the compound and the alcohol solvent are dissolved, dropwise adding an HCl solution, stirring at room temperature for 3-8 h after the dropwise adding is finished, after the reaction is finished, concentrating the reaction liquid under reduced pressure, adding dichloromethane into the concentrated solution for dissolving, stirring, cooling, crystallizing for 2h, filtering, and drying a filter cake under reduced pressure to obtain a compound shown as a formula 8;
optionally, in the step (4), the alcoholic solvent is an alcoholic solvent selected from C1-C6, preferably the alcoholic solvent is at least one selected from ethanol, methanol, propanol, or isopropanol;
optionally, in step (4), the hydrochloric acid solution is selected from a 4N HCl solution;
optionally, in the step (4), the molar ratio of the compound shown in the formula 7 to the 4N hydrochloric acid solution is 1 (2.0-3.5), and the molar ratio of the compound shown in the formula 7 to the 4N hydrochloric acid solution is preferably 1: 2.2.
7. The method according to claim 1, wherein in step (5), the following steps are included: adding the compound shown in the formula 8 and acetonitrile into a reaction bottle, starting stirring, adding alkali, stirring overnight at room temperature, after the reaction is finished, concentrating the reaction solution under reduced pressure, and performing post-treatment to obtain the compound shown in the formula 9;
optionally, in step (5), the base is at least one selected from potassium carbonate, sodium hydroxide, or potassium hydroxide;
optionally, in the step (5), the molar ratio of the compound shown in the formula 8 to the base is 1 (1.0-1.2), and preferably the molar ratio of the compound shown in the formula 8 to the base is 1: 1.05.
8. The method according to claim 1, wherein in step (6), the following steps are included: adding a compound shown as a formula 9 and dichloromethane into a reaction bottle, starting stirring, cooling to 0 ℃, adding alkali, controlling the temperature to be-10-0 ℃, dropwise adding acryloyl chloride, stirring at room temperature for 5-12 hours after dropwise adding is finished, and performing post-treatment after the reaction is finished to obtain a target product, namely a compound shown as a formula 1;
optionally, in step (6), the base is at least one selected from triethylamine, sodium carbonate, or potassium carbonate;
optionally, in the step (6), the molar ratio of the compound shown as the formula 9 to the base to the acryloyl chloride is 1 (1.3-1.5) to (1.1-1.3), and the molar ratio of the compound shown as the formula 9 to the base to the acryloyl chloride is preferably 1:1.4: 1.21.
9. The method according to claim 1, wherein in step (1), the following steps are included: adding DMF (45ml) into a reaction bottle, adding a compound shown in the formula 2 (4.5g,17.24mmol), a compound shown in the formula 3 (8.06g,18.1mmol) and potassium carbonate (7.15g,51.72mmol) respectively under stirring, heating to 85 ℃, keeping the temperature and stirring for 4h, after the reaction is finished, cooling to room temperature, adding water (80ml), stirring for crystallization for 1h, filtering, washing a filter cake twice with water (80ml), and drying the filter cake under vacuum at 50 ℃ to obtain a compound shown in the formula 4 (8.61g) with the yield of 79.9%;
in the step (2), the method comprises the following steps: a mixture of a compound represented by the formula 4 (8.6g,13.75mmol), ethanol (0.7g,15.19mmol) and Pd (PPh)3)2Cl2(0.48g,0.69mmol) was dissolved in 86mL of NMP, the inside of the system was replaced with carbon monoxide, and then heated to 107 ℃ and 115 ℃ and stirred for 4 hours, the reaction mixture was cooled to room temperature, 43mL of methanol was added thereto, triethylamine (6.97g,68.9mmol) was further added, the mixture was stirred for 30 minutes, after addition of water, the aqueous layer was washed with ethyl acetate and adjusted to pH 3 with hydrochloric acid, the resulting precipitate was filtered, the filtered precipitate was washed with water, and the filter cake was vacuum-dried at 50 ℃ to obtain the compound represented by formula 5 (5.53g) in a yield of 74.0%;
in the step (3), the method comprises the following steps: adding a compound shown as a formula 5 (5.50g,10.12mmol), DIPEA (1.31g,10.12mmol), a compound shown as a formula 6 (2.30g,11.13mmol) and DMF (220ml) into a reaction bottle, starting stirring, stirring for 15min, adding TBTU (3.26g,10.12mmol), stirring overnight at room temperature, after the reaction is finished, adding water (880ml), stirring for crystallization, filtering, recrystallizing filter cake methanol (110ml), and drying in vacuum at 50 ℃ to obtain a compound shown as a formula 7 (6.22g), wherein the yield is 84.0%;
in the step (4), the method comprises the following steps: adding a compound shown as a formula 7 (6.2g, 8.47mmol) and methanol (100ml) into a reaction bottle, starting stirring until the compounds are dissolved, dropwise adding 4N HCl (4.67ml, 18.64mmol), stirring at room temperature for 4h after the dropwise adding is finished, after the reaction is finished, concentrating the reaction liquid at 40 ℃ under reduced pressure, adding dichloromethane (50ml) into the concentrated liquid for dissolving, stirring, cooling, crystallizing for 2h, filtering, and drying a filter cake at 30 ℃ under reduced pressure to obtain a compound shown as a formula 8 (4.29g), wherein the yield is 95.3%;
in the step (5), the method comprises the following steps: adding a compound shown as a formula 8 (4.20g, 7.90mmol) and acetonitrile (80ml) into a reaction bottle, starting stirring, adding potassium carbonate (1.15g, 8.30mmol), stirring overnight at room temperature, concentrating a reaction solution at 45 ℃ under reduced pressure, adding water (60ml) into the concentrated solution, extracting twice with DCM (60ml), washing an organic phase with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, adding methyl tert-butyl ether (80ml) into a filtrate under stirring, stirring for crystallization, filtering, drying a filter cake at 40 ℃ under reduced pressure to obtain a compound shown as a formula 9 (2.39g), wherein the yield is 67.1%;
in the step (6), the method comprises the following steps: adding a compound (2.35g, 5.22mmol) shown in the formula 9 and dichloromethane (50ml) into a reaction bottle, starting stirring, cooling to 0 ℃, adding triethylamine (0.74g, 7.31mmol), controlling the temperature to be-10-0 ℃, dropwise adding acryloyl chloride (0.57g, 6.30mmol), stirring at room temperature for 7h after dropwise adding, filtering until the reaction is finished, washing filtrate with a proper amount of sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution respectively, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate at room temperature to be dry, adding dichloromethane (20ml) into a residue, stirring to dissolve, cooling to below-5 ℃ for crystallization for 1h, filtering, drying a filter cake at 30 ℃ in vacuum to obtain a compound (1.87g) shown in the formula 1, wherein the yield is 71.0%, and the purity is 99.8% by HPLC.
10. A compound shown as a formula 4 as a medicine intermediate in the process of preparing the compound shown as the formula 1,
optionally, a compound shown as a formula 5 as a medicine intermediate in the process of preparing the compound shown as the formula 1,
optionally, a compound shown as a formula 7 as a medicine intermediate in the process of preparing the compound shown as the formula 1,
optionally, a compound shown as a formula 8 as a medicine intermediate in the process of preparing the compound shown as the formula 1,
optionally, a compound shown as a formula 9 as a medicine intermediate in the process of preparing the compound shown as the formula 1,
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Denomination of invention: Preparation process of a small molecule HER2 inhibitor Effective date of registration: 20230704 Granted publication date: 20230331 Pledgee: Agricultural Bank of China Co.,Ltd. Wuhan Branch Business Department Pledgor: Wuhan Jiuzhou Yumin Medical Technology Co.,Ltd. Registration number: Y2023420000290 |