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Preparation method of ALK inhibitor Brigatinib

A technology of tini and acid application, applied in the field of medicine, can solve the problems of unsuitability for large-scale or industrialized production, low reaction yield, expensive raw materials, etc., and achieve the maximum benefit generation of industrialization, easy availability of reaction raw materials, post-processing convenient effect

Active Publication Date: 2020-05-12
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In its published patents WO2016065028 (A1), WO2017016410A1, and WO2009070740 (A2), three synthetic routes of the drug and its intermediates are introduced. Regarding the synthesis method of Brigatinib, the patent WO2016065028 (A1) provides the original process synthesis method, because Its synthetic route is simple and the most widely used, but the reaction yield of each step is low, and the final product yield is less than 25%. The post-treatment is generally through the column, which is not suitable for process treatment, and there is no specific mention of possible impurities in the process. (Scheme 1)
The first disadvantage of the synthesis method given in patent WO2017016410A1 is that the raw materials are expensive, and it is not suitable for large-scale or industrial production in today’s fierce competition for generic drug raw materials, and cyanamide is unstable and reacts with acids to produce toxic gases; the second disadvantage is the last One-step chlorination often produces a large number of by-products 17 (about 11.7%), which are similar in structure to the product and difficult to remove or avoid
The first disadvantage of the synthetic method given by patent WO2009070740 (A2) is that this process is not profitable in the highly competitive generic drug market due to the use of expensive reagents in the long-term production
The second disadvantage is that when compound 14 undergoes a condensation reaction with urea, the chlorine atom on 14 is very unstable and is easily substituted by the amino group on urea.
The third disadvantage is that the reaction requires at least 7 steps, resulting in a lower yield (10.7%)
[0019] There are disadvantages such as expensive raw materials, low product yield, many impurities, and low purity when all the above-mentioned routes are produced on a large scale.

Method used

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  • Preparation method of ALK inhibitor Brigatinib
  • Preparation method of ALK inhibitor Brigatinib
  • Preparation method of ALK inhibitor Brigatinib

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Experimental program
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Embodiment 1

[0048] Synthesis of intermediate 1 (2,5-dichloro-N-(2-(dimethylphosphino)phenyl)pyrimidin-4-amine).

[0049]

[0050] 2,4,5-trichloropyrimidine (AP-2) (15.2g, 83mmol), 2,4,5-trichloropyrimidine and 2-(dimethylphosphoryl)aniline (AP-1) (9.4 g, 55.6 mmol, ) and K 2 HPO 4 (15.3 g, 110 mmol) in DMF (55 mL) was stirred at 65°C for 4 hours. After cooling, the reaction mixture was filtered, the filter cake was washed with ethyl acetate (20ml) and the filtrate was evaporated. The residue was dissolved in ethyl acetate (50ml), extracted three times with saturated sodium chloride solution (3×100ml), the organic matter was combined, concentrated by rotation to a yellow-white solid, and beaten three times with PE (3×20ml) to obtain the obtained The desired product 12.0g AP-3 is a yellow-white solid. Yield: 90.3%, HPLC purity >98.0%. ESI-MS(m / z): 316.0[M+H] + ,631.0[2M+H] +

Embodiment 2

[0052] Synthesis of 1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)4-methylpiperazine

[0053]

[0054] 2-nitro-5-fluoroanisole (17.1 g, 0.1 mol) and 1-methyl-4-(4-piperidinyl)-piperazine (18.3 g, 0.1 mol) in MeCN (65 mL) solvent , Potassium carbonate (27.6g, 0.2mol) was used as an acid application agent, stirred at reflux for 4.5 hours, cooled to room temperature and filtered with suction, and the filter cake was washed with DCM (20mL). The filtrates were combined and concentrated, the concentrated solid was dissolved in DCM (50ml), extracted three times with 1mol / L HCl solution (3×15ml), the aqueous layer was collected and adjusted to pH=8.0 with potassium carbonate, and then extracted three times with DCM (3×20ml) . It was dried over sodium sulfate, filtered, and concentrated in vacuo to obtain the desired product AP-6 as 29.34 g of bright yellow powder, with a yield of 87.8% and a purity of >99.8% by HPLC. ESI-MS (m / z): 335.2[M+H]+, 669.4[2M+H]+

Embodiment 3

[0056] Synthesis of Intermediate 2 (2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperazinyl]-aniline)

[0057]

[0058] Dissolve 1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)4-methylpiperazine (AP-6) (20 g, 0.06 mol) in EtOH (800 mL) After neutralization, catalytic hydrogenation (10 psi H 2 ) 2.5 hours. The mixture was filtered through celite and the filtrate was concentrated to give a purple solid. Yield: 17.3 g, 95% yield, >99.8% purity. ESI-MS(m / z):305.2[M+H]+609.4[2M+H]+

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Abstract

The invention relates to the technical field of medicines, and relates to a preparation method of a medicine ALK inhibitor AP26113. The method comprises the following steps: (1) carrying out substitution reaction of aromatic amine on 2,4,5-trichloropyrimidine and 2-(dimethyloxyphosphate)aniline under the action of an acid applying agent to obtain an intermediate 1 (2,5-dichloro-N-(2-(dimethylphosphine)phenyl)pyrimidine-4-amine), and pulping the intermediate; (2) carrying out aromatic amine substitution reaction on 2-nitro-5-fluoroanisole and 1-methyl-4-(4-piperidyl)-piperazine under the actionof an acid applying agent to obtain a compound 1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)4-methylpiperazine, dissolving the compound with an organic solvent, and extracting the compound with an acidic solvent; (3) carrying out palladium-carbon catalytic hydrogenation on the product obtained in the step (2) to obtain an intermediate 2 (2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperazinyl]-aniline); (4) carrying out amine substitution reaction on the intermediate 1 and the intermediate 2 under an acidic catalytic condition to obtain a crude product of Brigatinib. The yield of the Brigatinibreaches 50% or above, and the purity of the Brigatinib reaches 99.9% or above.

Description

technical field [0001] The invention relates to the technical field of medicines, and relates to a preparation method of the drug ALK inhibitor Brigatinib AP26113 (Brigatinib), and also relates to intermediates and impurities in the preparation process. Background technique [0002] The new drug Brigatinib (AP26113) invented by Ariad was launched in the United States in 2017. The drug is a second-generation ALK inhibitor. Patients who develop intolerance after treatment with crizotinib. In other words, this new targeted drug can reverse the drug resistance of crizotinib. In its published patents WO2016065028 (A1), WO2017016410A1, and WO2009070740 (A2), three synthetic routes of the drug and its intermediates are introduced. Regarding the synthesis method of Brigatinib, the patent WO2016065028 (A1) provides the original process synthesis method, because Its synthetic route is simple and the most widely used, but the reaction yield of each step is low, and the final product ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558
CPCC07F9/65583
Inventor 沙宇郭奥锋张乾坤张峻铭陈佳乐陈家奇
Owner SHENYANG PHARMA UNIVERSITY
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