CN114736207B - Preparation process of small molecule HER2 inhibitor - Google Patents
Preparation process of small molecule HER2 inhibitor Download PDFInfo
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- CN114736207B CN114736207B CN202210470505.9A CN202210470505A CN114736207B CN 114736207 B CN114736207 B CN 114736207B CN 202210470505 A CN202210470505 A CN 202210470505A CN 114736207 B CN114736207 B CN 114736207B
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- 238000002360 preparation method Methods 0.000 title abstract description 17
- 229940125497 HER2 kinase inhibitor Drugs 0.000 title abstract description 5
- 150000003384 small molecules Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 329
- 238000006243 chemical reaction Methods 0.000 claims abstract description 118
- 238000005406 washing Methods 0.000 claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 claims abstract description 18
- 238000003756 stirring Methods 0.000 claims description 129
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 79
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 53
- 238000001914 filtration Methods 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 43
- 239000012065 filter cake Substances 0.000 claims description 41
- 239000002585 base Substances 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 39
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- 238000001035 drying Methods 0.000 claims description 32
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- 239000000047 product Substances 0.000 claims description 7
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- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
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- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 3
- 229960004891 lapatinib Drugs 0.000 description 3
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- 239000000376 reactant Substances 0.000 description 3
- HQAIUXZORKJOJY-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound NC1=NC=NC2=NNC(I)=C12 HQAIUXZORKJOJY-UHFFFAOYSA-N 0.000 description 2
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a preparation process of a small molecular HER2 inhibitor, which adopts 3-iodine-1H-pyrazolo [3,4-d ] pyrimidine-4-amine which is easily obtained in the market as an initial material, and is synthesized through 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 (alias: TPC-107) is a novel, orally-administrable, highly active and highly selective, new generation of highly selective covalent binding inhibitors of the small molecule HER2 kinase, developed by the Nippon Roc Pharmaceutical Co., ltd. (Taiho Pharmaceutical Co., ltd., abbreviated as TAIHO). 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 and reduced activity for EGFR. Compared with 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 HER2 over-expressed cancers. 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 covalence-binding, HER2-selective kinase inhibitor phosphor powder activity in clinical models. Mol Cancer Ther,2019,18 (4): 733-742). Pharmacodynamic analyses using MCF10A cells engineered to express various mutant HER2 genes showed that TAS-0728 effectively inhibited the phosphorylation of mutant HER2 and wild-type HER 2. Furthermore, TAS-0728 shows a strong and sustained inhibitory effect on the phosphorylation of HER2, HER3 and downstream effectors, thereby inducing apoptosis of HER 2-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 HER 2-driven cancer cells without any significant toxicity.
Currently, clinical trials (NCT 03410927) are underway on a First-in-Human (FIH), 2-part, phase 1/2, open label, multicenter study design, to assess the safety, tolerability, PK, pharmacodynamics, PGx and efficacy of TAS 0728. The study included clinical stage 1 and clinical stage 2 trial fractions of patients with advanced solid tumors 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 is expected to improve the current therapeutic window compared to current HER2 inhibitors.
WO2017/146116 and US2017/0217970A1, both published by the university of penc drug industry co, mention the synthesis of the compound TAS0728 (compound 1, alternatively referred to as the compound of formula 1) from two starting materials in a variety of ways.
(1) Taking 4, 6-dichloro-5-pyrimidinecarbaldehyde as an initial material, and carrying out cyclization, halogenation, N-alkylation, amination and carbonylation reactions to generate a key intermediate a; 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: one 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) An alternative synthetic route starting from 3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-4-amine was prepared as compound 1: 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 represented by formula 1 still needs to be improved.
Disclosure of Invention
The present invention is directed to solving, at least in part, 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 can be 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 the 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-iodine-1H-pyrazolo [3,4-d ] pyrimidine-4-amine (CAS number: 151266-23-8, compound shown in formula 2) which is easily available on the market as a starting material, and the target product, namely the compound TAS-0728 shown in formula 1, is synthesized through alkylation, carbonylation, acylation, deprotection, cyclization and acylation reactions.
The term "contacting" as used herein is to be understood broadly and can be any means that enables a chemical reaction of at least two reactants, such as mixing the two reactants under appropriate conditions. The reactants to be contacted may be mixed with stirring as needed, 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, and 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 material for producing 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 is not particularly limited, and it may be produced 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 manner of contacting 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 accelerated, 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 as the formula 4 is a brand-new compound, and the compound shown as the formula 4 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 (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 h, cooling to room temperature after the reaction is finished, adding water, stirring for crystallization for 1-3 h, filtering, washing a filter cake twice with water, and drying the filter cake in vacuum to obtain the compound shown in the 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 the embodiment of the invention, 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), preferably the molar ratio of the compound shown in the formula 2 to the compound shown in the formula 3 to the base is 1.05. 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: DMF (45 ml) 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 potassium carbonate (7.15g, 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 (80 ml) was added, followed by crystallization under stirring for 1 hour, filtration, washing of the cake twice with water (80 ml), and drying of the cake under vacuum at 50 ℃ to give the compound represented by formula 4 (8.61 g) with a 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 as the formula 5 is a brand-new compound, and the compound shown as the formula 5 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 (2), the following steps are included: dissolving a compound represented by formula 4, an alcohol solvent and a palladium metal complex in a solvent B, displacing the inside of the system with carbon monoxide, then heating to 100-120 ℃, stirring for 3.5-4.5 hours, then cooling the reaction mixture to room temperature, adding methanol thereto, adding a base thereto, stirring the mixture for 30 minutes, adding water, washing the aqueous layer with ethyl acetate, adjusting to pH =3 with hydrochloric acid, then filtering the resulting precipitate, washing the filtered precipitate with water, and vacuum-drying the filter cake to obtain a compound represented by formula 5. 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, the reaction speed is increased, and the efficiency of preparing the compound shown in 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 selected from C1-C6 alcohol solvents, preferably the alcohol solvent is at least one selected from ethanol, methanol, propanol, or isopropanol.
According to an embodiment of the present invention, in the step (2), the palladium metal complex is selected from Pd (PPh) 3 ) 2 Cl 2 Or Pd (OAc) 2, preferablyThe palladium metal complex is selected from Pd (PPh) 3 ) 2 Cl 2 。
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 alcoholic 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 alcoholic solvent and the palladium metal complex is 1.1. 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 formula 4 with the alcoholic solvent and the palladium metal complex is 107 to 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 compound represented by formula 4 (8.6 g, 13.75mmol), ethanol (0.7 g, 15.19mmol) and Pd (PPh) 3 ) 2 Cl 2 (0.48g, 0.69mmol) was dissolved in 86mL of NMP, the inside of the system was replaced with carbon monoxide, and then it was heated to 107-115 ℃ and stirred for 4 hours, then the reaction mixture was cooled to room temperature, 43mL of methanol was added thereto, triethylamine (6.97g, 68.9 mmol) 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 filter cake was vacuum-dried at 50 ℃ to obtain the compound represented by formula 5 (5.53 g), yield 74.0%.
According to an embodiment of the present invention, in the step (3), the contacting manner of the compound represented by formula 5 with the compound represented by formula 6 (CAS No. 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 accelerated, 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 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, 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. 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: a compound represented by the formula 5 (5.50g, 10.12mmol), DIPEA (1.31g, 10.12mmol), a compound represented by the formula 6 (2.30g, 11.13mmol) and DMF (220 ml) were charged into a reaction flask, and stirred with stirring for 15min, and then TBTU (3.26g, 10.12mmol) was added thereto, and stirred overnight at room temperature, after completion of the reaction, water (880 ml) was added, followed by crystallization with stirring, filtration, recrystallization from a cake of methanol (110 ml), and vacuum drying at 50 ℃ to obtain a compound represented by the formula 7 (6.22 g), 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 the 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 as the formula 7, the alcohol solvent and the hydrochloric acid solution can be improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown as 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 selected from C1-C6 alcohol solvents, 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 an embodiment of the present invention, in step (4), the molar ratio of the compound represented by formula 7 to the 4N hydrochloric acid solution is 1 (2.0 to 3.5), and preferably the molar ratio of the compound represented by formula 7 to the 4N hydrochloric acid solution is 1. 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 (100 ml) into a reaction bottle, starting stirring until the mixture is dissolved, dropwise adding 4N HCl solution (4.67ml, 18.64mmol), stirring at room temperature for 4 hours after the dropwise adding is finished, after the reaction is finished, concentrating the reaction liquid at 40 ℃ under reduced pressure, adding dichloromethane (50 ml) into the concentrated liquid for dissolving, stirring, cooling, crystallizing for 2 hours, filtering, drying a filter cake at 30 ℃ under reduced pressure, and obtaining a compound shown as a formula 8 (4.29 g), wherein the yield is 95.3%.
According to an embodiment of the present invention, in the step (5), the contacting manner of 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 accelerated, 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 performing post-treatment to obtain the compound shown in the formula 9. Therefore, the efficiency of the contact reaction of the compound shown as the formula 8, triethylamine and methanesulfonyl chloride can be improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown as 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 an embodiment of the present invention, in the step (5), the molar ratio of the compound represented by formula 8 to the base is 1 (1.0 to 1.2), and preferably the molar ratio of the compound represented by formula 8 to the base is 1.05. Thus, the efficiency of preparing the compound represented by formula 9 using this method can be further improved.
According to a specific embodiment of the present invention, in the step (5), the following steps are included: a compound represented by the formula 8 (4.20g, 7.90mmol) and acetonitrile (80 ml) were added to a reaction bottle, stirring was started, potassium carbonate (1.15g, 8.30mmol) was added, stirring was carried out overnight at room temperature, the reaction solution was concentrated under reduced pressure at 45 ℃, water (60 ml) was added to the concentrate, extraction was carried out twice with DCM (60 ml), the organic phase was washed with a saturated sodium chloride solution, drying was carried out with anhydrous sodium sulfate, filtration was carried out, methyl tert-butyl ether (80 ml) was added to the filtrate with stirring, crystallization was carried out with stirring, filtration was carried out, and the filter cake was dried under reduced pressure at 40 ℃ to give a compound represented by the formula 9 (2.39 g), yield 67.1%.
According to an embodiment of the present invention, in 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 an embodiment of the present invention, in step (6), the molar ratio of the compound represented by formula 9 to the base and acryloyl chloride is 1 (1.3-1.5) to (1.1-1.3), preferably the molar ratio of the compound represented by formula 9 to the base and acryloyl chloride is 1.4. Thus, the efficiency of preparing the compound represented by formula 1 using the 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 (50 ml) 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 7 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 (20 ml) 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 the compound (1.87 g) 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, the invention provides a pharmaceutical intermediate useful in the preparation of the compound TAS-0728 of formula 1. The compound shown as the formula 4, the compound shown as the formula 5, the compound shown as the formula 7, the compound shown as the formula 8 and the compound shown as 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 shown in the formula 1 is obtained by adopting 3-iodine-1H-pyrazolo [3,4-d ] pyrimidine-4-amine (shown in the 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 and acyl chloride generate acylation reaction under alkaline condition 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 disclosed by the invention 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 operation of industrial mass production.
Detailed Description
The following describes in detail embodiments of the present invention. The following examples are illustrative only and are not to be construed as limiting the invention. The examples do not specify particular techniques or conditions, and are performed according to techniques or conditions described in literature in the art or according to the product specification. The reagents or instruments used are conventional products which are commercially available, and are not indicated by manufacturers.
Example 1 Synthesis of Compound represented by formula 4
DMF (45 ml) 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 potassium carbonate (7.15g, 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 (80 ml) was added, followed by crystallization under stirring for 2 hours, filtration, washing of the cake twice with water (80 ml), and vacuum drying of the cake at 50 ℃ to give the compound represented by formula 4 (8.61 g) with a 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
DMF (45 ml) was added into a reaction flask, and the compound represented by formula 2 (4.5g, 17.24mmol), the compound represented by formula 3 (7.68g, 17.24mmol) and potassium carbonate (5.96g, 43.10 mmol) were added respectively with stirring, and the mixture was heated to 80 ℃ and stirred at constant temperature for 5 hours, after completion of the reaction, the temperature was lowered to room temperature, and water (80 ml) was added, followed by crystallization with stirring for 1 hour, filtration, the cake was washed twice with water (80 ml), and dried under vacuum at 50 ℃ to obtain the compound represented by formula 4 (8.17 g) with a yield of 75.8%.
Example 3 Synthesis of Compound represented by formula 4
DMAC (60 ml) 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 (80 ml) was added thereto, followed by stirring and crystallization for 3 hours, filtration, washing of the cake with water (80 ml) twice, and vacuum drying of the cake at 50 ℃ to obtain the compound represented by formula 4 (8.41 g) in a yield of 78.0%.
Example 4 Synthesis of Compound represented by formula 4
DMF (80 ml) is added into a reaction bottle, a compound shown in a formula 2 (4.5g, 17.24mmol), a compound shown in a formula 3 (8.06g, 18.1mmol) and cesium carbonate (16.85g, 51.72mmol) are respectively added under stirring, the temperature is raised to 85 ℃, the mixture is kept and stirred for 4 hours, after the reaction is finished, the temperature is lowered to room temperature, water (100 ml) is added, the mixture is stirred and crystallized for 2 hours, the mixture is filtered, a filter cake is washed twice by water (100 ml), and the filter cake is dried under vacuum at 50 ℃ to obtain a compound shown in a formula 4 (8.37 g), wherein the yield is 77.6%.
EXAMPLE 5 Synthesis of Compound represented by formula 4
DMF (50 ml) is added into a reaction bottle, a compound shown in a formula 2 (4.5g, 17.24mmol), a compound shown in a formula 3 (8.06g, 18.1mmol) and sodium carbonate (5.48g, 51.72mmol) are respectively added under stirring, the temperature is raised to 85 ℃, the mixture is kept and stirred for 4 hours, after the reaction is finished, the temperature is lowered to room temperature, water (80 ml) is added, the mixture is stirred and crystallized for 1.5 hours, the mixture is filtered, a filter cake is washed twice by water (80 ml), and the filter cake is dried under vacuum at 50 ℃ to obtain a compound shown in a formula 4 (8.29 g), wherein the yield is 76.9%.
Example 6 Synthesis of Compound represented by formula 5
A compound represented by formula 4 (8.6 g, 13.75mmol), ethanol (0.7 g, 15.19mmol) and Pd (PPh) 3 ) 2 Cl 2 (0.48g, 0.69mmol) was dissolved in 86mL of NMP, the inside of the system was replaced with carbon monoxide, then it was heated to 107-115 ℃ and after stirring for 4 hours, the reaction mixture was cooled to room temperature, 43mL of methanol was added thereto, triethylamine (6.97g, 68.9 mmol) 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, then the resulting precipitate was filtered, the filtered precipitate was washed with water, and the filter cake was dried under vacuum at 50 ℃ to obtain the compound represented by formula 5 (5.53 g) in a yield of 74.0%.
LC-MS(ESI):m/z＝543.15(M+1) + ，545.15(M+3) +
Example 7 Synthesis of Compound represented by formula 5
A compound represented by the formula 4 (8.6 g, 13.75mmol), ethanol (0.63g, 13.75mmol) and Pd (PPh) 3 ) 2 Cl 2 (0.29g, 0.413mmol) was dissolved in 100mL of NMP, the inside of the system was replaced with carbon monoxide, then heated to 100 to 107 ℃ and after stirring for 4.5 hours, the reaction mixture was cooled to room temperature, 50mL of methanol was added thereto, and triethylamine was further added(6.97g, 68.9 mmol), the mixture was stirred for 30 minutes, water was added, and after the aqueous layer was washed with ethyl acetate and adjusted to pH =3 with hydrochloric acid, the resulting precipitate was filtered, and after the filtered precipitate was washed with water, the filter cake was vacuum-dried at 50 ℃ to obtain the compound represented by formula 5 (5.34 g) with a yield of 71.2%.
Example 8 Synthesis of Compound represented by formula 5
A compound represented by the formula 4 (8.6 g, 13.75mmol), ethanol (0.76g, 16.5mmol) and Pd (PPh) 3 ) 2 Cl 2 (0.772 g,1.1 mmol) was dissolved in 86mL of DMF, the inside of the system was replaced with carbon monoxide, and then heated to 115-120 ℃ and stirred for 3.5 hours, then the reaction mixture was cooled to room temperature, 43mL of methanol was added thereto, triethylamine (6.97g, 68.9 mmol) 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 in vacuo at 50 ℃ to obtain the compound represented by formula 5 (5.46 g) in a yield of 73.1%.
Example 9 Synthesis of Compound represented by formula 5
The compound represented by formula 4 (8.6 g, 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 to 115 ℃, and after stirring for 4 hours, the reaction mixture was cooled to room temperature, 43mL of methanol was added thereto, lutidine (6.41g, 68.9mmol) was further added, the mixture was stirred for 30 minutes, after adding water, the water layer was washed with ethyl acetate, and adjusted to pH =3 with hydrochloric acid, then the resulting precipitate was filtered, and after washing with water, the filter cake was dried in vacuum at 50 ℃, thereby obtaining the compound represented by formula 5 (5.38 g) in a yield of 72.0%.
Example 10 Synthesis of Compound represented by formula 5
The compound represented by formula 4 (8.6 g, 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, then heated to 110 to 115 ℃, stirred for 4 hours, the reaction mixture was cooled to room temperature, 43mL of methanol was added thereto, pyridine (5.45g, 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, after the filtered precipitate was washed with water, the cake was dried under vacuum at 50 ℃ to obtain the compound represented by formula 5 (5.44 g) in a yield of 72.8%.
Example 11 Synthesis of Compound represented by formula 7
A compound represented by the formula 5 (5.50g, 10.12mmol), DIPEA (1.31g, 10.12mmol), a compound represented by the formula 6 (2.30g, 11.13mmol) and DMF (220 ml) were charged into a reaction flask, stirred with stirring, stirred for 15min, and TBTU (3.26g, 10.12mmol) was further added, stirred overnight at room temperature, after completion of the reaction, water (880 ml) was added, stirred for crystallization, filtered, cake methanol (110 ml) was recrystallized, and vacuum-dried at 50 ℃ to obtain a compound represented by the formula 7 (6.22 g), yield 84.0%.
LC-MS(ESI):m/z＝731.28(M+1) + ，733.28(M+3) +
EXAMPLE 12 Synthesis of Compound represented by formula 7
A compound represented by the formula 5 (5.50g, 10.12mmol), DIPEA (1.31g, 10.12mmol), a compound represented by the formula 6 (2.20g, 10.63mmol) and DMF (220 ml) were charged into 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 completion of the reaction, water (880 ml) was added, crystallization was carried out under stirring, filtration was carried out, cake-methanol (110 ml) was recrystallized, and vacuum-dried at 50 ℃ to obtain a compound represented by the formula 7 (6.09 g), yield 82.2%.
Example 13 Synthesis of Compound represented by formula 7
A compound represented by formula 5 (5.50g, 10.12mmol), DIPEA (1.31g, 10.12mmol), a compound represented by formula 6 (2.40g, 11.64mmol) and DMF (220 ml) were charged into a reaction flask, stirred with stirring, stirred for 15min, TBTU (3.26g, 10.12mmol) was further added, stirred overnight at room temperature, after completion of the reaction, water (880 ml) was added, stirred for crystallization, filtered, cake methanol (110 ml) was recrystallized, and vacuum-dried at 50 ℃ to obtain a compound represented by formula 7 (6.19 g), yield 83.6%.
Example 14 Synthesis of Compound represented by formula 7
A compound represented by the formula 5 (5.50g, 10.12mmol), DIEA (1.31g, 10.12mmol), a compound represented by the formula 6 (2.30g, 11.13mmol) and DMF (220 ml) were charged into a reaction flask, and stirred with stirring for 15min, HBTU (3.84g, 10.12mmol) was further added thereto, and the mixture was stirred overnight at room temperature, after completion of the reaction, water (880 ml) was added thereto, followed by crystallization with stirring, filtration, cake-like methanol (110 ml) recrystallization, and vacuum drying at 50 ℃ to obtain a compound represented by the formula 7 (6.10 g), with a yield of 82.4%.
EXAMPLE 15 Synthesis of Compound represented by formula 7
A compound represented by the formula 5 (5.50g, 10.12mmol), DMAP (1.24g, 10.12mmol), a compound represented by the formula 6 (2.30g, 11.13mmol) and DMF (220 ml) were charged in a reaction flask, and stirred for 15min, HBTU (3.84g, 10.12mmol) was further added thereto, and stirred overnight at room temperature, after completion of the reaction, water (880 ml) was added, followed by stirred crystallization, filtration, cake methanol (110 ml) recrystallization, and vacuum drying at 50 ℃ to give a compound represented by the formula 7 (6.15 g), with a 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 (100 ml) into a reaction bottle, starting stirring until the mixture is 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 (50 ml) 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 (4.29 g), 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 (6.2 g, 8.47mmol) and methanol (100 ml) into a reaction bottle, starting stirring until the mixture is dissolved, dropwise adding a 4N Cl solution (4.3 ml, 16.94mmol), stirring at room temperature for 3h after the dropwise adding is finished, after the reaction is finished, concentrating the reaction solution at 40 ℃ under reduced pressure, adding dichloromethane (50 ml) into the concentrated solution 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 (4.18 g), 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 (100 ml) into a reaction bottle, starting stirring until the mixture is dissolved, dropwise adding 4N HCl solution (7.4 ml, 29.65mmol), stirring at room temperature for 8 hours after the dropwise adding is finished, after the reaction is finished, concentrating the reaction liquid at 40 ℃ under reduced pressure, adding dichloromethane (50 ml) into the concentrated liquid for dissolving, stirring, cooling, crystallizing for 2 hours, filtering, drying a filter cake at 30 ℃ under reduced pressure, and obtaining the compound shown as the formula 8 (4.24 g), wherein the yield is 94.3%.
Example 19 Synthesis of Compound represented by formula 9
Adding a compound represented by the formula 8 (4.20g, 7.90mmol) and acetonitrile (80 ml) into a reaction bottle, starting stirring, adding potassium carbonate (1.15g, 8.30mmol), stirring at room temperature overnight, concentrating the reaction liquid at 45 ℃ under reduced pressure, adding water (60 ml) into the concentrated liquid, extracting with DCM (60 ml) twice, washing the organic phase with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, adding methyl tert-butyl ether (80 ml) into the filtrate while stirring, stirring for crystallization, filtering, and drying a filter cake at 40 ℃ under reduced pressure to obtain a compound represented by the formula 9 (2.39 g) with the yield of 67.1%.
LC-MS(ESI):m/z＝451.25(M+1) +
EXAMPLE 20 Synthesis of Compound represented by formula 9
A compound represented by the formula 8 (4.20g, 7.90mmol) and acetonitrile (80 ml) were added to a reaction flask, and stirring was started, and potassium carbonate (1.09g, 7.90mmol) was added thereto and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure at 45 ℃ and water (60 ml) was added to the concentrate, followed by extraction with DCM (60 ml) 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 (80 ml) 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 (2.35 g) in a yield of 66.0%.
EXAMPLE 21 Synthesis of Compound represented by formula 9
A compound represented by the formula 8 (4.20g, 7.90mmol) and acetonitrile (80 ml) were charged in a reaction flask, and stirring was started, and sodium carbonate (1.31g, 9.48mmol) was added thereto and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure at 45 ℃ and water (60 ml) was added to the concentrate, followed by extraction with DCM (60 ml) 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 (80 ml) under stirring, stirred to crystallize, filtered, and the filter cake was dried under reduced pressure at 40 ℃ to give the compound represented by formula 9 (2.38 g) in a yield of 66.8%.
Example 22 Synthesis of Compound represented by formula 9
A compound represented by the formula 8 (4.20g, 7.90mmol) and acetonitrile (80 ml) were charged in a reaction flask, and stirring was started, and sodium hydroxide (0.33g, 8.30mmol) was added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure at 45 ℃ and water (60 ml) was added to the concentrate, which was then extracted twice with DCM (60 ml). 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 (80 ml) with stirring, crystallized with stirring, filtered, and the filter cake was dried under reduced pressure at 40 ℃ to give the compound represented by formula 9 (2.34 g) in a yield of 65.6%.
Example 23 Synthesis of Compound represented by formula 9
A compound represented by the formula 8 (4.20g, 7.90mmol) and acetonitrile (80 ml) were charged in a reaction flask, and stirring was started, and potassium hydroxide (0.47g, 8.40mmol) was added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure at 45 ℃ and water (60 ml) was added to the concentrate, followed by extraction with DCM (60 ml) 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 (80 ml) under stirring, stirred to crystallize, filtered, and the filter cake was dried under reduced pressure at 40 ℃ to give the compound represented by formula 9 (2.35 g) 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 (50 ml) 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 7 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 (20 ml) 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 the compound (1.87 g) 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 (50 ml) 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 (20 ml) 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 the compound (1.74 g) shown in the formula 1, wherein the yield is 68.5%, and the purity is 99.4% by HPLC.
Example 26 Synthesis of Compound represented by formula 1
Adding a compound (2.35g, 5.22mmol) shown in the formula 9 and dichloromethane (50 ml) 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 is finished, filtering after 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 (20 ml) 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 the compound (1.85 g) 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 the formula 9 and dichloromethane (50 ml) into a reaction bottle, starting stirring, cooling to 0 ℃, adding potassium carbonate (1.01g, 7.31mmol), controlling the temperature to be minus 10-0 ℃, dropwise adding acryloyl chloride (0.57g, 6.30mmol), stirring at room temperature for 7 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 (20 ml) into a residue, stirring to dissolve, cooling to below minus 5 ℃ for crystallization for 1 hour, filtering, drying a filter cake at 30 ℃ in vacuum to obtain the compound (1.80 g) shown in the formula 1, wherein the yield is 68.3%, and the purity is 99.5% by HPLC.
Example 28 Synthesis of Compound represented by formula 1
Adding a compound (2.35g, 5.22mmol) shown in the formula 9 and dichloromethane (50 ml) 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 8 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 proper amount of 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 (20 ml) into a residue, stirring to dissolve, cooling to below-5 ℃ for crystallization for 1 hour, filtering, and drying a filter cake at 30 ℃ in vacuum to obtain the compound shown in the formula 1 (1.74 g), wherein the purity is 68.5% and the HPLC (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. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, 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 (20)
1. A process for preparing a compound 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 the 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 the 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 production process according to claim 1, characterized by comprising, in step (1), the steps of: 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 h, cooling to room temperature after the reaction is finished, adding water, stirring for crystallization for 1-3 h, filtering, washing a filter cake twice with water, drying the filter cake in vacuum to obtain a compound shown in a formula 4,
in step (1), the solvent A is at least one selected from DMF or DMAC;
in the step (1), the base is at least one selected from potassium carbonate, cesium carbonate and sodium carbonate;
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 alkali is 1 (1.0-1.1) to (2.5-3.5).
3. The process according to claim 2, wherein in the step (1), the base is potassium carbonate.
4. The process according to claim 2, wherein in step (1), the molar ratio of the compound represented by formula 2 to the compound represented by formula 3 to the base is 1.05.
5. The process according to claim 2, wherein in the step (1), the reaction temperature of the contact stirring of the compound represented by the formula 2, the compound represented by the formula 3 and the base is 85 ℃ and the reaction time is 4 hours.
6. The production process according to claim 1, characterized by comprising, in the step (2), the steps of: dissolving a compound represented by formula 4, an alcohol solvent and a palladium metal complex in a solvent B, displacing the inside of the system with carbon monoxide, then heating to 100-120 ℃, stirring for 3.5-4.5 hours, then cooling the reaction mixture to room temperature, adding methanol thereto, adding a base thereto, stirring the mixture for 30 minutes, adding water thereto, washing the aqueous layer with ethyl acetate, adjusting to pH =3 with hydrochloric acid, then filtering to obtain a precipitate, washing the filtered precipitate with water, and vacuum-drying the filter cake to obtain a compound represented by formula 5,
in the step (2), the alcohol solvent is selected from C1-C6 alcohol solvents;
in the step (2), the palladium metal complex is selected from Pd (PPh) 3 ) 2 Cl 2 Or Pd (OAc) 2;
in the step (2), the solvent B is at least one selected from DMF, NMP and DMAC;
in the step (2), the base is at least one selected from triethylamine, pyridine and lutidine;
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.
7. The production process according to claim 6, wherein in the step (2), the alcohol solvent is at least one selected from the group consisting of ethanol, methanol, propanol and isopropanol.
8. The production process according to claim 6, wherein in the step (2), the palladium metal complex is Pd (PPh) 3 ) 2 Cl 2 。
9. The production process according to claim 6, wherein in step (2), the molar ratio of the compound represented by formula 4 to the alcoholic solvent and the palladium metal complex is 1.1.
10. The process according to claim 6, wherein 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 to 115 ℃ and the reaction time is 4 hours.
11. The production process according to claim 1, characterized by comprising, in step (3), the steps of: adding a compound shown as a formula 5, alkali, a compound shown as a 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, drying in vacuum to obtain a compound shown as a formula 7,
in the step (3), the base is at least one selected from DIPEA, DIEA and DMAP;
in the step (3), the condensing agent is at least one selected from TBTU or HBTU;
in the step (3), the molar ratio of the compound represented by the formula 5 to the compound represented by the formula 6, the base and the condensing agent is 1 (1.05-1.15): 1.
12. The production process according to claim 11, wherein in step (3), the molar ratio of the compound represented by formula 5 to the compound represented by formula 6, the base, and the condensing agent is 1.1.
13. The production process according to claim 1, characterized by comprising, in step (4), the steps of: 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 a 4N 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, drying a filter cake under reduced pressure to obtain a compound shown as a formula 8,
in the step (4), the alcohol solvent is selected from C1-C6 alcohol solvents;
in the step (4), the molar ratio of the compound represented by the formula 7 to the 4N HCl solution is 1 (2.0 to 3.5).
14. The production process according to claim 13, wherein in the step (4), the alcohol solvent is at least one selected from the group consisting of ethanol, methanol, propanol and isopropanol.
15. The process according to claim 13, wherein in step (4), the molar ratio of the compound represented by formula 7 to the 4N HCl solution is 1.
16. The production process according to claim 1, wherein 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 at room temperature overnight, after the reaction is finished, concentrating the reaction liquid under reduced pressure, performing post-treatment to obtain the compound shown in the formula 9,
in the step (5), the base is at least one selected from potassium carbonate, sodium hydroxide and potassium hydroxide;
in the step (5), the molar ratio of the compound represented by the formula 8 to the base is 1 (1.0 to 1.2).
17. The process according to claim 16, wherein in the step (5), the molar ratio of the compound represented by formula 8 to the base is 1.
18. The production process according to claim 1, wherein in the 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, performing post-treatment after reaction is finished to obtain a target product, namely a compound shown as a formula 1,
in the step (6), the base is at least one selected from triethylamine, sodium carbonate and potassium carbonate;
in the step (6), the molar ratio of the compound shown in the formula 9 to the alkali and the acryloyl chloride is 1 (1.3-1.5) to 1.1-1.3.
19. The process according to claim 18, wherein in step (6), the molar ratio of the compound represented by formula 9 to the base to acryloyl chloride is 1.4.
20. The production process according to claim 1, characterized by comprising, in step (1), the steps of: adding 45ml of DMF into a reaction bottle, respectively adding 4.5g of the compound shown in the formula 2, 8.06g of the compound shown in the formula 3 and 7.15g of potassium carbonate while stirring, heating to 85 ℃, keeping the temperature and stirring for 4 hours, cooling to room temperature after the reaction is finished, adding 80ml of water, stirring for crystallization for 1 hour, filtering, washing a filter cake twice by using 80ml of water, and performing vacuum drying on the filter cake at 50 ℃ to obtain 8.61g of the compound shown in the formula 4 with the yield of 79.9%;
in the step (2), the method comprises the following steps: 8.6g of the compound represented by the formula 4, 0.7g of ethanol and 0.48g of Pd (PPh) 3 ) 2 Cl 2 Dissolving in 86mL of NMP, displacing the inside of the system with carbon monoxide, then heating to 107-115 ℃, after stirring for 4 hours, cooling the reaction mixture to room temperature, adding 43mL of methanol thereto, further adding 6.97g of triethylamine, stirring the mixture for 30 minutes, after adding water, washing the aqueous layer with ethyl acetate, adjusting to pH =3 with hydrochloric acid, and then filtering to obtainWashing the filtered precipitate with water, and vacuum-drying the filter cake at 50 ℃ to obtain 5.53g of the compound shown in the formula 5 with the yield of 74.0%;
in the step (3), the method comprises the following steps: adding 5.50g of a compound shown as a formula 5, 1.31g of DIPEA, 2.30g of a compound shown as a formula 6 and 220ml of DMF into a reaction bottle, starting stirring, stirring for 15min, adding 3.26g of TBTU, stirring overnight at room temperature, after the reaction is finished, adding 880ml of water, stirring for crystallization, filtering, recrystallizing a filter cake by using 110ml of methanol, and drying in vacuum at 50 ℃ to obtain 6.22g of a compound shown as a formula 7 with the yield of 84.0%;
in the step (4), the method comprises the following steps: adding 6.2g of the compound shown in the formula 7 and 100ml of methanol into a reaction bottle, starting stirring until dissolving, dropwise adding 4.67ml of 4N HCl, stirring at room temperature for 4 hours after dropwise adding is finished, after the reaction is finished, concentrating the reaction liquid at 40 ℃ under reduced pressure, adding 50ml of dichloromethane into the concentrated solution for dissolving, stirring, cooling, crystallizing for 2 hours, filtering, and drying a filter cake at 30 ℃ under reduced pressure to obtain 4.29g of the compound shown in the formula 8, wherein the yield is 95.3%;
in the step (5), the method comprises the following steps: adding 4.20g of the compound shown in the formula 8 and 80ml of acetonitrile into a reaction bottle, starting stirring, adding 1.15g of potassium carbonate, stirring at room temperature overnight, concentrating the reaction solution at 45 ℃ under reduced pressure, adding 60ml of water into the concentrated solution, extracting twice with 60ml of DCM, washing an organic phase with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, adding 80ml of methyl tert-butyl ether into the filtrate under stirring, stirring for crystallization, filtering, and drying a filter cake at 40 ℃ under reduced pressure to obtain 2.39g of the compound shown in the formula 9 with the yield of 67.1%;
in the step (6), the method comprises the following steps: adding 2.35g of the compound shown as the formula 9 and 50ml of dichloromethane into a reaction bottle, starting stirring, cooling to 0 ℃, adding 0.74g of triethylamine, controlling the temperature to-10-0 ℃, dropwise adding 0.57g of acryloyl chloride, stirring at room temperature for 7h after the dropwise adding is finished, filtering until the reaction is finished, washing the filtrate with a proper amount of sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution respectively, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate at room temperature under reduced pressure to dryness, adding 20ml of dichloromethane into the residue, stirring to dissolve, cooling to below-5 ℃, crystallizing for 1h, filtering, and drying the filter cake at 30 ℃ in vacuum to obtain 1.87g of the compound shown as the formula 1, wherein the yield is 71.0%, and the HPLC purity is 99.8%.
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| WO2009023978A1 (en) * | 2007-08-17 | 2009-02-26 | Oncalis Ag | Pyrazolo [3,4 -d] pyrimidine compounds and their use as modulators of protein kinase |
| CN110885331A (en) * | 2018-09-11 | 2020-03-17 | 中国药科大学 | Preparation and application of novel 6-amino-1H-pyrazolo [3, 4-d ] pyrimidine JAK kinase inhibitor |
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