CN112552283A - Preparation method of novel tinib medicine - Google Patents
Preparation method of novel tinib medicine Download PDFInfo
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- CN112552283A CN112552283A CN202011437586.XA CN202011437586A CN112552283A CN 112552283 A CN112552283 A CN 112552283A CN 202011437586 A CN202011437586 A CN 202011437586A CN 112552283 A CN112552283 A CN 112552283A
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- boc
- ethanol
- tinib
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- hctu
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
Abstract
The invention provides a preparation method of a novel tinib drug, which takes N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (imatinib amine) and BOC-L-nitroarginine as raw materials, and obtains the novel tinib drug with high purity by condensation, palladium catalytic hydrogenation reduction, Boc removal of methanesulfonic acid to form salt, and recrystallization and refining.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a preparation method of a novel tinib medicine.
Background
Imatinib is an oral drug used for the treatment of acute, accelerated and chronic phases of adult patients with philadelphia chromosome (be-Abl) positive chronic myelogenous leukemia (CML for short). CML is a hematopoietic stem cell disease caused by DNA abnormalities of stem cells in the bone marrow. DNA abnormalities produce abnormal proteins that interfere with the normal production of leukocytes in the bone marrow, ultimately leading to a dramatic increase in the number of leukocytes. The CML is divided into three stages of a chronic stage, an accelerated stage and a crisis stage, and the average survival time of a patient in the crisis stage is only 2-3 months. Imatinib is also effective in treating gastrointestinal stromal tumor, and the effective rate is about 50%. Although imatinib has a significant effect, there are also significant side effects, the main side effects include: neutropenia, thrombocytopenia, anemia, headache, dyspepsia, edema, weight gain, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. The severity of these events was mild to moderate, and only 2-5% of patients had a permanent termination of treatment due to the development of drug-related adverse events.
In order to improve the tolerance of the human body to the tinib drugs and reduce the toxic and side effects, a novel tinib drug needs to be developed. In order to achieve the aim, natural amino acid-L-arginine is introduced into the structure, and a novel tinib medicament is prepared.
Disclosure of Invention
The method provided by the invention comprises the following steps: n- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (imatinib amine) and BOC-L-nitroarginine are subjected to condensation reaction in an N, N-Dimethylformamide (DMF) solvent by taking HCTU as a condensing agent and N, N-Diisopropylethylamine (DIPEA) as an organic base, palladium-carbon catalytic hydrogenation and denitrification are carried out in an ethanol solution, finally methane sulfonic acid is subjected to Boc removal to form a salt in ethanol, and the new tinib drug is obtained after recrystallization.
Among them, in the above step, the preferred condensing agent is HCTU.
In the above step, the organic base is preferably N, N-diisopropylethylamine.
Wherein in the step, the molar ratio of BOC-L-nitroarginine, HCTU, DIPEA and N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine is 1.0-1.2: 1.1-1.2: 1.2-1.4: 1.
In the step, the pH value of the system after the ammonia water is alkalized is 9-10.
Wherein, in the step, the weight ratio of the 10 percent palladium carbon to the fifth palladium carbon is 5 to 15 percent.
Wherein in the step, the molar ratio of the methanesulfonic acid to the substrate is 1.0-1.2: 1.
In the above steps, ethanol is preferably used as a solvent in the Boc removal salt formation of methanesulfonic acid.
The preferred synthetic route of the present invention is as follows:
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the technical scheme of the invention is further explained by the specific embodiments, but the protection scope of the invention is not limited. For convenience of description, the examples omit necessary or conventional technical conditions or steps, such as weighing, feeding, etc., which are considered to be conventional or readily known to those skilled in the art.
Example 1:
27.7g (0.1mol, 1.0eq) of N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (1), 35.1g (0.11mol, 1.1eq) of BOC-L-nitroarginine (2) and 250mL of Dimethylformamide (DMF) were placed in a 1L three-necked flask equipped with a mechanical stirrer and a thermometer, and the temperature of the ice-water bath was lowered to 10-20 ℃ with stirring. Then, 45.5g (0.11mol, 1.1eq) of HCTU and 15.5g (0.12mol, 1.2eq) of DIPEA were added and the reaction was allowed to proceed for 3 hours. Naturally heating to room temperature, and continuing to react for 2h until the N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (1) is reacted. Adding 500mL of water into a reaction bottle to quench and react, adjusting the pH value to 9-10 with ammonia water, separating out a solid, continuously stirring for 1 hour, performing suction filtration, and leaching the obtained solid with 100mL of water to obtain a crude product. Adding the crude product into 200mL ethyl acetate, heating to reflux and dissolve, cooling to 20-25 ℃ by using a water bath, stirring and crystallizing for 1 hour, carrying out suction filtration, and drying in a forced air drying oven at 50-60 ℃ for 4 hours to obtain 50.4g of an intermediate 3, wherein the yield is 87%, and the purity is 99.2% (HPLC).
46.3g (0.08mol, 1.0eq) of intermediate 3, 4.8g (0.08mol, 1.0eq) of acetic acid and 300mL of ethanol were added to a 1L hydrogenation flask, 4.6g (10% w/w) of 10% palladium on carbon was added, the mixture was evacuated and charged with nitrogen twice, the evacuation and charging with hydrogen were repeated twice, the reaction was stopped by keeping the hydrogen pressure at 50psi and at 20-30 ℃ for 2 hours. Vacuumizing, filling nitrogen, and filtering to remove the Pd/C catalyst. And adding 200mL of water into the filtrate, adjusting the pH value of the solution to 9-10 by using ammonia water, separating out a solid, continuously stirring for 1 hour, carrying out suction filtration, and leaching the obtained solid by using 100mL of water to obtain a crude product. Adding the crude product into 200mL of ethanol, heating until the crude product is dissolved by reflux, cooling to 0-5 ℃ by using an ice water bath, stirring and crystallizing for 1 hour, carrying out suction filtration, and drying for 4 hours in a forced air drying oven at 50-60 ℃ to obtain 39.3g of intermediate 4, wherein the yield is 92%, and the purity is 99.5% (HPLC).
32.0g (0.06mol, 1.0eq) of intermediate 4 and 480mL of ethanol were charged in a 1L three-necked flask equipped with a mechanical stirrer and a thermometer, and after stirring at room temperature for 1 hour, 5.8g (0.06mol, 1.0eq) of methanesulfonic acid was added to the system. After stirring at room temperature for 1 hour, the temperature is raised to 75-80 ℃ for reaction for 2 hours. Cooling to 0-5 deg.C with ice water bath, stirring for crystallizing for 1 hr, vacuum filtering, recrystallizing the crude product with 400mL ethanol, and drying the refined product in a vacuum drying oven at 50-60 deg.C for 6 hr to obtain 27.1g white crystalline solid product 5 with yield of 85.2% and purity of 99.8% (HPLC).
Example 2:
27.7g (0.1mol, 1.0eq) of N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (1), 38.3g (0.12mol, 1.2eq) of BOC-L-nitroarginine (2) and 250mL of Dimethylformamide (DMF) were placed in a 1L three-necked flask equipped with a mechanical stirrer and a thermometer, and the temperature of the ice-water bath was lowered to 10-20 ℃ with stirring. Then, 49.6g (0.12mol, 1.2eq) of HCTU and 18.1g (0.14mol, 1.4eq) of DIPE were added and the reaction was incubated for 3 hours. Naturally heating to room temperature, and continuing to react for 2h until the N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (1) is reacted. Adding 500mL of water into a reaction bottle to quench and react, adjusting the pH value to 9-10 with ammonia water, separating out a solid, continuously stirring for 1 hour, performing suction filtration, and leaching the obtained solid with 100mL of water to obtain a crude product. Adding the crude product into 200mL ethyl acetate, heating to reflux and dissolve, cooling to 20-25 ℃ by using a water bath, stirring and crystallizing for 1 hour, carrying out suction filtration, and drying in a forced air drying oven at 50-60 ℃ for 4 hours to obtain 52.1g of intermediate 3, wherein the yield is 90%, and the purity is 99.4% (HPLC).
46.3g (0.08mol, 1.0eq) of intermediate 3, 4.8g (0.08mol, 1.0eq) of acetic acid and 300mL of ethanol were added to a 1L hydrogenation flask, 6.9g (15% w/w) of 10% palladium on carbon was added, the mixture was evacuated and charged with nitrogen twice, the evacuation and charging with hydrogen were repeated twice, the reaction was stopped by keeping the hydrogen pressure at 50psi and at 20-30 ℃ for 2 hours. Vacuumizing, filling nitrogen, and filtering to remove the Pd/C catalyst. And adding 200mL of water into the filtrate, adjusting the pH value of the solution to 9-10 by using ammonia water, separating out a solid, continuously stirring for 1 hour, carrying out suction filtration, and leaching the obtained solid by using 100mL of water to obtain a crude product. Adding the crude product into 200mL of ethanol, heating until the crude product is dissolved by reflux, cooling to 0-5 ℃ by using an ice water bath, stirring and crystallizing for 1 hour, carrying out suction filtration, and drying for 4 hours in a forced air drying oven at 50-60 ℃ to obtain 38.4g of intermediate 4, wherein the yield is 90%, and the purity is 99.6% (HPLC).
32.0g (0.06mol, 1.0eq) of intermediate 4 and 480mL of ethanol were charged in a 1L three-necked flask equipped with a mechanical stirrer and a thermometer, and after stirring at room temperature for 1 hour, 6.4g (0.066mol, 1.1eq) of methanesulfonic acid was added to the system. After stirring at room temperature for 1 hour, the temperature is raised to 75-80 ℃ for reaction for 2 hours. Cooling to 0-5 deg.C with ice water bath, stirring for crystallizing for 1 hr, vacuum filtering, recrystallizing the crude product with 400mL ethanol, and drying the refined product in a vacuum drying oven at 50-60 deg.C for 6 hr to obtain 27.6g white crystalline solid product 5 with yield of 87% and purity of 99.7% (HPLC).
Example 3:
27.7g (0.1mol, 1.0eq) of N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (1), 31.9g (0.1mol, 1.0eq) of BOC-L-nitroarginine (2) and 250mL of Dimethylformamide (DMF) were placed in a 1L three-necked flask equipped with a mechanical stirrer and a thermometer, and the temperature of the ice-water bath was lowered to 10-20 ℃ with stirring. Then, 45.5g (0.1mol, 1.1eq) of HCTU and 15.5g (0.1mol, 1.2eq) of DIPE were added and the reaction was allowed to proceed for 3 hours. Naturally heating to room temperature, and continuing to react for 2h until the N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (1) is reacted. Adding 500mL of water into a reaction bottle to quench and react, adjusting the pH value to 9-10 with ammonia water, separating out a solid, continuously stirring for 1 hour, performing suction filtration, and leaching the obtained solid with 100mL of water to obtain a crude product. Adding the crude product into 200mL ethyl acetate, heating to reflux and dissolve, cooling to 20-25 ℃ by using a water bath, stirring and crystallizing for 1 hour, carrying out suction filtration, and drying in a forced air drying oven at 50-60 ℃ for 4 hours to obtain 48.0g of intermediate 3, wherein the yield is 83%, and the purity is 99.1% (HPLC).
46.3g (0.08mol, 1.0eq) of intermediate 3, 4.8g (0.08mol, 1.0eq) of acetic acid and 300mL of ethanol were added to a 1L hydrogenation flask, 2.3g (5% w/w) of 10% palladium on carbon was added, the mixture was evacuated and charged with nitrogen twice, the evacuation and charging with hydrogen were repeated twice, the reaction was stopped by keeping the hydrogen pressure at 50psi and at 20-30 ℃ for 4 hours. Vacuumizing, filling nitrogen, and filtering to remove the Pd/C catalyst. And adding 200mL of water into the filtrate, adjusting the pH value of the solution to 9-10 by using ammonia water, separating out a solid, continuously stirring for 1 hour, carrying out suction filtration, and leaching the obtained solid by using 100mL of water to obtain a crude product. Adding the crude product into 200mL ethanol, heating to reflux and dissolve, cooling to 0-5 ℃ with ice water bath, stirring and crystallizing for 1 hour, filtering, and drying in a forced air drying oven at 50-60 ℃ for 4 hours to obtain 38.0g of intermediate 4, wherein the yield is 89%, and the purity is 99.5% (HPLC).
32.0g (0.06mol, 1.0eq) of intermediate 4 and 480mL of ethanol were charged in a 1L three-necked flask equipped with a mechanical stirrer and a thermometer, and after stirring at room temperature for 1 hour, 7.0g (0.06mol, 1.2eq) of methanesulfonic acid was added to the system. After stirring at room temperature for 1 hour, the temperature is raised to 75-80 ℃ for reaction for 2 hours. Cooling to 0-5 deg.C with ice water bath, stirring for crystallizing for 1 hr, vacuum filtering, recrystallizing the crude product with 400mL ethanol, and drying the refined product in a vacuum drying oven at 50-60 deg.C for 6 hr to obtain 26.4g white crystalline solid product 5 with yield of 83% and purity of 99.9% (HPLC).
The invention has been described with reference to specific embodiments. The invention can be used for other purposes by those skilled in the art by appropriately changing the raw materials, the process conditions and the like without departing from the content of the invention, and all similar substitutes and modifications obvious to those skilled in the art are deemed to be included in the scope of the invention.
Claims (8)
1. A preparation method of a novel tinib medicament comprises the following steps: carrying out condensation reaction on N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (imatinib amine) and BOC-L-nitroarginine in a N, N-Dimethylformamide (DMF) solvent by taking HCTU as a condensing agent and N, N-Diisopropylethylamine (DIPEA) as an organic base, then carrying out catalytic hydrogenation and denitrification on palladium-carbon in an ethanol solution, finally removing Boc salt from methanesulfonic acid in ethanol, and recrystallizing to obtain the compound.
2. The process of claim 1, wherein the preferred condensing agent is HCTU.
3. The process according to claim 1, characterized in that the organic base is preferably N, N-diisopropylethylamine.
4. The process of claim 1, wherein the molar ratio of BOC-L-nitroarginine, HCTU, DIPEA to N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine is 1.0 to 1.2: 1.1-1.2: 1.2-1.4: 1.
5. the method as claimed in claim 1, wherein the pH of the system after the ammonia water alkalization is 9-10.
6. The method of claim 1, wherein the weight ratio of 10% palladium on carbon to the fifth is 5% to 15%.
7. The method according to claim 6, wherein the molar ratio of methanesulfonic acid to substrate is 1.0 to 1.2: 1.
8. the process of claim 1, wherein the preferred solvent for the Boc removal of methane sulfonic acid into salt is ethanol.
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CN115232105A (en) * | 2022-08-23 | 2022-10-25 | 天津羲泽润科技有限公司 | Teninil small molecule compound and preparation method thereof |
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CN101985442A (en) * | 2010-09-19 | 2011-03-16 | 南京卡文迪许生物工程技术有限公司 | Convenient and quick method for preparing high-purity imatinib and mesylate thereof |
CN105294669A (en) * | 2014-10-24 | 2016-02-03 | 山东凯森制药有限公司 | Tenth factor inhibitor and preparation method and application thereof |
WO2016172528A1 (en) * | 2015-04-23 | 2016-10-27 | Inhibikase Therapeutics, Inc. | Compositions and methods for inhibiting kinases |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN101985442A (en) * | 2010-09-19 | 2011-03-16 | 南京卡文迪许生物工程技术有限公司 | Convenient and quick method for preparing high-purity imatinib and mesylate thereof |
CN105294669A (en) * | 2014-10-24 | 2016-02-03 | 山东凯森制药有限公司 | Tenth factor inhibitor and preparation method and application thereof |
WO2016172528A1 (en) * | 2015-04-23 | 2016-10-27 | Inhibikase Therapeutics, Inc. | Compositions and methods for inhibiting kinases |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN115232105A (en) * | 2022-08-23 | 2022-10-25 | 天津羲泽润科技有限公司 | Teninil small molecule compound and preparation method thereof |
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