CN112159404A - Preparation method of tocaintinib - Google Patents
Preparation method of tocaintinib Download PDFInfo
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- CN112159404A CN112159404A CN202011108695.7A CN202011108695A CN112159404A CN 112159404 A CN112159404 A CN 112159404A CN 202011108695 A CN202011108695 A CN 202011108695A CN 112159404 A CN112159404 A CN 112159404A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention relates to a preparation method of tacrolinib, which comprises the steps of taking 4-hydroxy-6-chloroquinazoline as a raw material, firstly carrying out copper-catalyzed C-N cross coupling reaction with 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole, then activating 4-hydroxy of quinazolinone by adopting a Kate condensing agent (BOP), and carrying out nucleophilic substitution reaction with 4- ([1,2,4] triazolo [1,5-a ] pyridine-7-oxy) -3-methylaniline to obtain the tacrolinib. The route avoids using high-corrosivity and high-toxicity reagents, has low requirements on equipment, reduces the operation difficulty and the environmental protection requirements, and has high product yield and high purity; the route is simple and environment-friendly, and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of tocaintinib.
Background
Tourtinib (Tucatinib; Irbinitinib, ARRY-380, ONT-380) is a small molecule oral Tyrosine Kinase (TKI) inhibitor, and has highly specific targeting selectivity for human epidermal growth factor receptor 2(HER 2). The FDA approved tocaintinib in combination with chemotherapy (trastuzumab and capecitabine) for the treatment of adult patients with advanced HER2 positive breast cancer who cannot be surgically resected or metastasized on day 4, month 17 of 2020. Tukatinib, originally developed by Array Biopharma, was marketed by Seattle Genetics Inc. after being assigned to Oncothyron (ONTY) and after being repurposed to Cascaden Therapeutics, Seattle Genetics Inc. The Tucanitinib has good blood brain barrier permeability, has important significance for treating HER2 positive breast cancer brain metastasis, selectively inhibits HER2, has relatively small side effect, and is good in tolerance of patients.
The chemical name of the Tourtinib is as follows: n4- (4- ([1,2, 4)]Triazolo [1,5-a]Pyridine-7-oxy) -3-methylphenyl) -N6- (4, 4-dimethyl-4, 5-dihydrooxazol-2-yl) quinazoline-4, 6-diamine having a CAS number of 937263-43-9 and a molecular formula of C26H24N8O2Molecular weight is 480.52, and the formula is as follows:
the synthesis of tocatinib was first disclosed in patent WO2007059257 from the company Array BioPharma by a synthetic method, the synthetic route being as follows:
according to the method, 2-amino-5-nitrobenzonitrile (5) is used as a starting material, firstly, the starting material reacts with DMF-DMA to generate an imine intermediate (6), then palladium carbon is used for catalytic hydrogenation reduction of nitro, the reaction is carried out with 2-amino-2-methyl-1-propanol (8) and N, N' -Thiocarbonyldiimidazole (TCDI) to obtain a thiourea intermediate (9), then the reaction is carried out with 4- ([1,2,4] triazolo [1,5-a ] pyridine-7-oxy) -3-methylaniline (4) to construct a quinazoline intermediate (10) through Dimroth rearrangement, and finally, a thiourea side chain is cyclized into an oxazoline ring at room temperature to obtain the target product of the staurtinib. The other two patents WO2013142875 and WO2013056108 also adopt the same synthesis method. The route involves multistep high temperature reactions, and the purification process is basically completed by column chromatography, and is only suitable for milligram-scale preparation in a laboratory to provide the API required for pharmaceutical research, and the original research company does not further disclose a synthetic process route capable of realizing large-scale preparation.
Domestic patent CN109942576A discloses another synthetic method of tocaintinib, the route is as follows:
cyclization of 2-amino-2-methyl-1-propanol (8) with 1,1' -Thiocarbonyldiimidazole (TCDI) affords 4, 4-dimethyloxazolidine-2-thione (11) which is subsequently treated with methyl trifluoromethanesulfonate to give 4, 4-dimethyl-2-methylthiooxazolines trifluoromethanesulfonate (12), which is unstable at room temperature and requires immediate further reaction. The intermediate (6) of nitroformamidine and the intermediate amine (4) are subjected to Dimroth rearrangement reaction to construct a quinazoline intermediate (13), then palladium carbon is used for reducing nitro to obtain an aromatic amine intermediate (14), and finally the intermediate and 4, 4-dimethyl-2-methylthio oxazoline triflate (12) are heated to 125 ℃ in DMF by taking cesium carbonate as alkali to react for 20 hours to obtain the target product of the tacalcinib. The total yield of the route is obviously improved, the purification step and purity of the product meet the requirements of API, but the route relates to a malodorous thio-compound intermediate, an expensive palladium-carbon catalyst and a methylation reagent methyl trifluoromethanesulfonate with high toxicity are used, the final step needs high-temperature reaction, the purity and yield of the product are influenced, and the reaction also generates the odorous methyl mercaptan, so that the environmental protection requirement of industrial production cannot be met.
Disclosure of Invention
The invention aims to provide a preparation method of the tocaininib, which has mild reaction conditions, avoids using high-risk or high-price reaction reagents, is simple and convenient to operate, has high product purity, and is suitable for industrial production.
The technical scheme adopted by the invention for solving the technical problems is as follows: a preparation method of tocaintinib comprises the following steps:
(1) dissolving 4-hydroxy-6-chloroquinazoline in an organic solvent, adding catalysts of cuprous bromide, potassium phosphate and an amide ligand, and performing coupling reaction with 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole to obtain 4-hydroxy-6- (4, 4-dimethyl-4, 5-dihydrooxazole-2-amino) quinazoline;
(2) 4-hydroxy-6- (4, 4-dimethyl-4, 5-dihydro-oxazole-2-amido) quinazoline and benzotriazole-1-methoxy tris (dimethylamino) phosphonium hexafluorophosphate (Kate condensing agent, BOP) are dissolved in an organic solvent, firstly react at 5-80 ℃ under the action of organic base, and then undergo nucleophilic substitution reaction with 4- ([1,2,4] triazolo [1,5-a ] pyridine-7-oxyl) -3-methylaniline to obtain the Tukatinib.
The reaction equation is as follows:
further, the organic solvent in the step (1) is one or a mixture of several of N, N-dimethylformamide, dimethyl sulfoxide, N-butanol, N-pentanol, ethylene glycol or ethylene glycol monomethyl ether.
Further, in the step (1), the amide-based ligand is one of nicotinamide, N-methylnicotinamide and N-methylbenzamide.
Further, in the step (1), the molar ratio of the 4-hydroxy-6-chloroquinazoline, the cuprous bromide catalyst, the potassium phosphate, the amide ligand and the 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole is 1.0:0.01-0.05:1.0-1.5:0.02-0.1: 1.0-2.0.
Further, the coupling reaction in the step (1) is carried out in a nitrogen atmosphere, the reaction temperature is 100-150 ℃, and the reaction time is 10-30 hours.
Further, the organic solvent in the step (2) is one or a mixture of more of acetonitrile, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and N, N-dimethylformamide.
Further, the organic base in the step (2) is one of diisopropylethylamine, triethylamine, methylmorpholine, pyridine, N-dimethylaminopyridine and 1, 8-diazabicycloundecen-7-ene.
Further, in the step (2), the molar ratio of 4-hydroxy-6- (4, 4-dimethyl-4, 5-dihydrooxazole-2-amino) quinazoline, benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, organic base and 4- ([1,2,4] triazolo [1,5-a ] pyridin-7-yloxy) -3-methylaniline is 1.0:1.0-2.0: 1.0-2.0.
Further, the reaction time of 5-80 ℃ in the step (2) is 0.1-1 hour, and the reaction time of nucleophilic substitution is 10-24 hours.
The starting materials 4-hydroxy-6-chloroquinazoline (1) and 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole of the present invention are commercially available and 4- ([1,2,4] triazolo [1,5-a ] pyridin-7-yloxy) -3-methylaniline can be prepared according to the method of patent document WO 2007059257. The first step of reaction is a copper-catalyzed C-N coupling Ullmann reaction of aromatic chloride and amine, a plurality of catalyst ligands are screened, and finally the highest yield is found when N-methylnicotinamide is used as the ligand; the second step of reaction is 4-position substitution reaction of quinazolinone, the conventional method is to chlorinate heterocyclic hydroxyl through phosphorus oxychloride, oxalyl chloride and the like, and then the reaction is carried out with amines to construct 4-position carbon nitrogen bond of quinazoline structure.
The preparation method comprises the steps of taking 4-hydroxy-6-chloroquinazoline as a raw material, firstly carrying out copper-catalyzed C-N cross coupling reaction with 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole, then activating the 4-hydroxy of quinazolinone by adopting a Kate condensing agent (BOP), and carrying out nucleophilic substitution reaction with 4- ([1,2,4] triazolo [1,5-a ] pyridine-7-oxy) -3-methylaniline to obtain the Tukatinib. The route avoids using highly corrosive and highly toxic reagents, has low requirements on equipment, reduces the operation difficulty and the environmental protection requirements, has high product yield and high purity, is concise and environment-friendly, and is suitable for large-scale production.
Detailed Description
The following are specific examples of the present invention and further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
Example 1
Under the protection of nitrogen, 0.1mol of 4-hydroxy-6-chloroquinazoline is dissolved in 200ml of N, N-dimethylformamide, 0.003mol of cuprous bromide, 0.11mol of potassium phosphate, 0.006mol of N-methylnicotinamide and 0.15mol of 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole are sequentially added, and then the reaction solution is heated to 120 ℃ for reaction for 20 hours. After cooling, the solvent was removed by concentration under reduced pressure, 200ml of methylene chloride and a saturated aqueous solution of ammonium chloride were added, the mixture was separated, the organic phase was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Concentration under reduced pressure and recrystallization of the residue from methanol and water gave the product as a white solid in 82.1% yield.
0.05mol of 4-hydroxy-6- (4, 4-dimethyl-4, 5-dihydrooxazole-2-amino) quinazoline and 0.06mol of Kate condensing agent BOP0 are dissolved in 200ml of acetonitrile, 0.075mol of N, N-dimethylamino pyridine is added, the mixture is stirred and reacted for 0.5 hour at room temperature, and then 0.06mol of 4- ([1,2,4] triazolo [1,5-a ] pyridine-7-oxy) -3-methylaniline is added, and the mixture is stirred and reacted for 18 hours at room temperature. Concentrating under reduced pressure, adding ethyl acetate and water, separating the layers, washing the organic phase successively with saturated aqueous ammonium chloride, aqueous sodium bicarbonate and brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove the solvent, and recrystallizing the residue with water to give the product as a white solid in 78.2% yield, HPLC 99%.
Example 2
Under the protection of nitrogen, 0.1mol of 4-hydroxy-6-chloroquinazoline is dissolved in 200ml of ethylene glycol monomethyl ether, 0.001mol of cuprous bromide, 0.14mol of potassium phosphate, 0.004mol of N-methylbenzamide and 0.18mol of 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole are sequentially added, and then the reaction solution is heated to 100 ℃ for reaction for 25 hours. After cooling, the solvent was removed by concentration under reduced pressure, 200ml of methylene chloride and a saturated aqueous solution of ammonium chloride were added, the mixture was separated, the organic phase was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Concentration under reduced pressure and recrystallization of the residue from methanol and water gave the product as a white solid in 86.2% yield.
0.05mol of 4-hydroxy-6- (4, 4-dimethyl-4, 5-dihydrooxazole-2-amino) quinazoline and 0.075mol of a Kate condensing agent BOP0.075 are dissolved in 200ml of tetrahydrofuran, 0.06mol of diisopropylethylamine is added, the mixture is stirred and reacted at 40 ℃ for 0.7 hour, and then 0.09mol of 4- ([1,2,4] triazolo [1,5-a ] pyridine-7-oxy) -3-methylaniline is added, and the mixture is stirred and reacted at 40 ℃ for 10 hours. Concentrating under reduced pressure, adding ethyl acetate and water, separating the layers, washing the organic phase successively with saturated aqueous ammonium chloride, aqueous sodium bicarbonate and brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove the solvent, and recrystallizing the residue with water to give the product as a white solid in 74.4% yield, HPLC 99%.
Example 3
Under the protection of nitrogen, 0.1mol of 4-hydroxy-6-chloroquinazoline is dissolved in 200ml of mixed solvent of dimethyl sulfoxide and ethylene glycol, 0.005mol of cuprous bromide, 0.1mol of potassium phosphate, 0.002mol of N-methylnicotinamide and 0.1mol of 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole are sequentially added, and then the reaction solution is heated to 150 ℃ for reaction for 10 hours. After cooling, the solvent was removed by concentration under reduced pressure, 200ml of methylene chloride and a saturated aqueous solution of ammonium chloride were added, the mixture was separated, the organic phase was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Concentration under reduced pressure and recrystallization of the residue from methanol and water gave the product as a white solid in 84.7% yield.
0.05mol of 4-hydroxy-6- (4, 4-dimethyl-4, 5-dihydrooxazole-2-amino) quinazoline and 0.1mol of Kate condensing agent BOP0 are dissolved in 200ml of glycol dimethyl ether, 0.1mol of triethylamine is added, the mixture is stirred and reacted for 0.1 hour at the temperature of 5 ℃, and then 0.1mol of 4- ([1,2,4] triazolo [1,5-a ] pyridine-7-oxy) -3-methylaniline is added, stirred and reacted for 24 hours at the temperature of 5 ℃. Concentrating under reduced pressure, adding ethyl acetate and water, separating, washing the organic phase with saturated aqueous ammonium chloride solution, aqueous sodium bicarbonate solution and brine in sequence, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove the solvent, and recrystallizing the residue with water to obtain the product as a white solid with yield of 77.1% and HPLC 99%.
Example 4
Under the protection of nitrogen, 0.1mol of 4-hydroxy-6-chloroquinazoline is dissolved in 200ml of mixed solvent of n-butanol and n-pentanol, 0.002mol of cuprous bromide, 0.15mol of potassium phosphate, 0.001mol of nicotinamide and 0.2mol of 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole are sequentially added, and then the reaction solution is heated to 140 ℃ for reaction for 30 hours. After cooling, the solvent was removed by concentration under reduced pressure, 200ml of methylene chloride and a saturated aqueous solution of ammonium chloride were added, the mixture was separated, the organic phase was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Concentration under reduced pressure and recrystallization of the residue with methanol and water gave the product as a white solid in 85.9% yield.
0.05mol of 4-hydroxy-6- (4, 4-dimethyl-4, 5-dihydrooxazole-2-amino) quinazoline and 0.05mol of Kate condensation agent BOP0 are dissolved in 200ml of N, N-dimethylformamide, 0.05mol of 1, 8-diazabicycloundecen-7-ene is added, the mixture is stirred and reacted for 1 hour at 80 ℃, and then 0.05mol of 4- ([1,2,4] triazolo [1,5-a ] pyridine-7-oxy) -3-methylaniline is added, and the mixture is stirred and reacted for 20 hours at 80 ℃. Concentrating under reduced pressure, adding ethyl acetate and water, separating, washing the organic phase with saturated aqueous ammonium chloride solution, aqueous sodium bicarbonate solution and brine in sequence, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove the solvent, and recrystallizing the residue with water to obtain the product as a white solid with yield of 75.9% and HPLC 99%.
Comparative example 1
4-hydroxy-6- (4, 4-dimethyl-4, 5-dihydrooxazol-2-amino) quinazoline was prepared as in example 1.
The preparation of the tocaininib adopts phosphorus oxychloride: 0.05mol of 4-hydroxy-6- (4, 4-dimethyl-4, 5-dihydrooxazole-2-amido) quinazoline is added into 100ml of phosphine oxide trichloride for reflux reaction for 6 hours; the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 200ml of tetrahydrofuran, and 0.2mol of triethylamine and 0.06mol of 4- ([1,2,4] triazolo [1,5-a ] pyridin-7-yloxy) -3-methylaniline were added to the mixture and the mixture was stirred at room temperature for 18 hours. Concentrating under reduced pressure, adding ethyl acetate and water, separating, washing the organic phase with saturated aqueous ammonium chloride solution, aqueous sodium bicarbonate solution and brine in sequence, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove the solvent, and recrystallizing the residue with water to obtain the product as a white solid with a yield of 45.3% and HPLC 98%.
Claims (9)
1. The preparation method of the tocaintinib is characterized by comprising the following steps of:
(1) dissolving 4-hydroxy-6-chloroquinazoline in an organic solvent, adding catalysts of cuprous bromide, potassium phosphate and an amide ligand, and performing coupling reaction with 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole to obtain 4-hydroxy-6- (4, 4-dimethyl-4, 5-dihydrooxazole-2-amino) quinazoline;
(2) 4-hydroxy-6- (4, 4-dimethyl-4, 5-dihydro-oxazole-2-amido) quinazoline and benzotriazole-1-oxyl tris (dimethylamino) phosphonium hexafluorophosphate are dissolved in an organic solvent, react at 5-80 ℃ under the action of organic base, and then undergo nucleophilic substitution reaction with 4- ([1,2,4] triazolo [1,5-a ] pyridine-7-oxyl) -3-methylaniline to obtain the tocainide.
2. The preparation method of the same as claimed in claim 1, wherein the organic solvent in the step (1) is one or a mixture of N, N-dimethylformamide, dimethyl sulfoxide, N-butanol, N-pentanol, ethylene glycol or ethylene glycol monomethyl ether.
3. The method for preparing the same as in claim 1, wherein the amide-based ligand in the step (1) is one of nicotinamide, N-methylnicotinamide and N-methylbenzamide.
4. The method of preparing tacrolinib of claim 1, wherein the molar ratio of the 4-hydroxy-6-chloroquinazoline, the cuprous bromide catalyst, the potassium phosphate, the amide-based ligand, and the 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole in the step (1) is 1.0:0.01-0.05:1.0-1.5:0.02-0.1: 1.0-2.0.
5. The method for preparing the same as claimed in claim 1, wherein the coupling reaction in the step (1) is performed under a nitrogen atmosphere at a temperature of 100 ℃ and 150 ℃ for a time of 10-30 hours.
6. The preparation method of the tocaintinib as claimed in claim 1, wherein the organic solvent in step (2) is one or a mixture of acetonitrile, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and N, N-dimethylformamide.
7. The method for preparing tocaintinib according to claim 1, wherein in step (2), the organic base is one of diisopropylethylamine, triethylamine, methylmorpholine, pyridine, N-dimethylaminopyridine, and 1, 8-diazabicycloundecen-7-ene.
8. The method for preparing tocaintinib according to claim 1, wherein the molar ratio of 4-hydroxy-6- (4, 4-dimethyl-4, 5-dihydrooxazol-2-amino) quinazoline, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, organic base, 4- ([1,2,4] triazolo [1,5-a ] pyridin-7-yloxy) -3-methylaniline in step (2) is 1.0:1.0-2.0: 1.0-2.0.
9. The method for preparing tocaintinib according to claim 1, wherein in step (2), the reaction time at 5-80 ℃ is 0.1-1 hour, and the nucleophilic substitution reaction time is 10-24 hours.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112898298A (en) * | 2021-01-26 | 2021-06-04 | 上海法默生物科技有限公司 | Preparation method of tocaintinib intermediate |
| CN114262327A (en) * | 2021-12-30 | 2022-04-01 | 武汉九州钰民医药科技有限公司 | Preparation process of HER2 small-molecule inhibitor picatinib |
| CN115340541A (en) * | 2022-07-01 | 2022-11-15 | 上海艾洋化学科技有限公司 | Preparation method of tocaintinib intermediate |
| WO2024003929A1 (en) * | 2022-06-28 | 2024-01-04 | Dr Reddys Laboratories | Process for the preparation of tucatinib |
-
2020
- 2020-10-16 CN CN202011108695.7A patent/CN112159404B/en active Active
Non-Patent Citations (3)
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| DAVID J. BERNHARDSON，ET AL.: "Cu-Catalyzed Couplings of Heteroaryl Primary Amines and (Hetero)aryl Bromides with 6‑Hydroxypicolinamide Ligands", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| LINGFENG YIN，ET AL.: "New Synthetic Route to Tucatinib", 《SYNTHESIS》 * |
| ZHAO-KUI WAN，ET AL.: "The Scope and Mechanism of Phosphonium-Mediated SNAr Reactions in Heterocyclic Amides and Ureas", 《J. ORG. CHEM》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112898298A (en) * | 2021-01-26 | 2021-06-04 | 上海法默生物科技有限公司 | Preparation method of tocaintinib intermediate |
| CN114262327A (en) * | 2021-12-30 | 2022-04-01 | 武汉九州钰民医药科技有限公司 | Preparation process of HER2 small-molecule inhibitor picatinib |
| WO2024003929A1 (en) * | 2022-06-28 | 2024-01-04 | Dr Reddys Laboratories | Process for the preparation of tucatinib |
| CN115340541A (en) * | 2022-07-01 | 2022-11-15 | 上海艾洋化学科技有限公司 | Preparation method of tocaintinib intermediate |
| CN115340541B (en) * | 2022-07-01 | 2024-01-30 | 上海艾洋化学科技有限公司 | Preparation method of tocartinib intermediate |
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