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Preparation method of alectinib intermediate

An intermediate and tinib technology, which is applied in the field of preparation of alectinib intermediates, can solve the problems of poor product quality, expensive preparation costs of raw materials and reagents, and poor operational safety.

Active Publication Date: 2019-02-26
成都正善达生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This preparation method has a long route, and a large amount of dangerous reagents such as thionyl chloride and aluminum trichloride are used in the process, which will cause corrosion hazards to the reaction container equipment, and a large amount of corrosive sewage will be generated after post-treatment, which is not conducive to green and environmentally friendly industrial production.
[0011] In summary, the preparation method of alectinib intermediate 2-(4-ethyl-3-iodo)phenyl-2-methylpropionic acid disclosed in the prior art has a long preparation route and expensive raw materials and reagents High preparation costs, heavy metal residues in the target product, poor product quality, and a large amount of acid gas and waste water generated in the post-treatment stage cannot realize green and environmentally friendly industrial production, or the raw materials and reagents are dangerous reagents, and the operation safety is poor, which increases production efficiency. The safety level and production cost are not conducive to the promotion and application of industrialization

Method used

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  • Preparation method of alectinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0132] Embodiment 1, the preparation method of alectinib intermediate 2-(4-ethyl-3-iodo)phenyl-2-methylpropionic acid

[0133]1) Add 64.0g of diethyl malonate (compound A-2a) and 640mL of ethylene glycol dimethyl ether into the reaction flask, add 21.6g of sodium methoxide, heat up to 70-75°C for 0.5h, then add 7.6g of iodine Cuprous chloride and 5.8g cuprous bromide were stirred for 1h; 37.0g of bromoethylbenzene (compound A-1) was added and kept at 70-75°C for 10-12h. Add 50% sodium hydroxide aqueous solution, keep the pH>12, stir for 4 hours, filter, concentrate under reduced pressure to remove the solvent; add water and hydrochloric acid to adjust the pH to 1-2, stir, filter with suction, wash with water, dry, and recrystallize to obtain compound A- 3 (25.0 g, 76% yield).

[0134] 2) Add 20.0g of compound A-3, 100mL of methanol and 4mL of concentrated sulfuric acid into the reaction flask, heat up to reflux for 4-5h, concentrate under reduced pressure to remove methanol, ...

Embodiment 2

[0138] 1) Add 48.0g of diethyl malonate (compound A-2a) and 640mL of 1,4-dioxane into the reaction flask, add 12g of 60wt% sodium hydride, heat up to 70-75°C and react for 0.5h, Add 7.6g of cuprous iodide, add 37.0g of bromoethylbenzene (compound A-1) after stirring, and keep the reaction at 70-75°C for 10-12h. Add 50% sodium hydroxide aqueous solution, keep the pH > 12, stir for 4 hours, filter, concentrate under reduced pressure to remove the solvent; add water and hydrochloric acid to the residue to adjust the pH to 1-2, stir, filter with suction, wash with water, dry, and recrystallize to obtain Compound A-3 (24.7 g, yield 75%).

[0139] 2) Add 20.0g of compound A-3, 20mL of methanol and 3.5mL of concentrated sulfuric acid into the reaction flask, heat up to reflux for 4-5h, concentrate under reduced pressure to remove methanol, add water and ethyl acetate in turn, separate the layers, and combine the organic layers. After washing with saturated sodium bicarbonate, the or...

Embodiment 3

[0143] 1) Add 80.0g of diethyl malonate (compound A-2a) and 640mL of tetrahydrofuran into the reaction flask, add 56g of potassium tert-butoxide, heat up to 65-70°C and react for 0.5h, then add 17.2g of cuprous bromide, After stirring, 37.0 g of bromoethylbenzene (compound A-1) was added, and the reaction was maintained at 65-70° C. for 10-12 h. Then add 50% sodium hydroxide aqueous solution, keep the pH > 12 and stir for 4 hours, then filter, concentrate under reduced pressure to remove the solvent; add water and hydrochloric acid to the residue to adjust the pH to 1-2, after stirring, filter with suction, wash with water, dry, and weigh Crystallization gave compound A-3 (23.6 g, yield 72%).

[0144] 2) Add 20.0g of compound A-3, 200mL of methanol and 4mL of acetyl chloride into the reaction flask, raise the temperature to reflux for 4-5h, concentrate under reduced pressure to remove methanol, add water and ethyl acetate in sequence, separate the layers, combine the organic l...

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Abstract

The invention discloses a preparation method of 2-(4-ethyl-3-iodine) phenyl-2-methyl propionic acid as an alectinib intermediate. According to the preparation method, the operation danger class and production cost are reduced by optimizing and improving a preparation route method, optimizing reaction conditions and improving aftertreatment and purification methods; the requirement for the anti-corrosion class of container equipment for reaction is low, operation safety is good, aftertreatment is environmentally friendly, the impurity content of the obtained 2-(4-ethyl-3-iodine) phenyl-2-methylpropionic acid as the alectinib intermediate is low, the purity and quality of the intermediate product are greatly improved while the yield is improved, the difficulty of process control in an alectinib crude drug production process is reduced, and the quality and yield of the crude drug of alectinib are improved; and the various steps of the preparation method are operated simply, a solvent andprocess conditions are safe and easy to run, environmentally friendly production is realized, and the application prospect is wide.

Description

technical field [0001] The present invention relates to the technical field of synthesis of pharmaceutical intermediates, more specifically, to a preparation method of alectinib intermediates. Background technique [0002] The new anti-cancer drug Alectinib is a new inhibitor of anaplastic lymphoma kinase (ALK), which is used for the treatment of advanced or metastatic ALK-positive non-small cell lung cancer, and is suitable for those who are not resistant to crizotinib and patients who deteriorated after treatment. [0003] The key intermediate for the synthesis of alectinib, 2-(4-ethyl-3-iodo)phenyl-2-methylpropionic acid, has the molecular formula: C 12 h 15 IO 2 , the English name is: 2-(4-Ethyl-3-idodophenyl)-2-methylpropanoic acid, the structural formula is as follows: [0004] [0005] The preparation method of the existing disclosed 2-(4-ethyl-3-iodo)phenyl-2-methylpropionic acid, WO2004 / 046080 document uses 2-(4-bromophenyl)-2-methylpropionic acid As the sta...

Claims

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Application Information

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IPC IPC(8): C07C51/363C07C57/58
CPCC07C51/09C07C51/363C07C67/08C07C57/58C07C57/30C07C69/612
Inventor 庹世川陶建
Owner 成都正善达生物医药科技有限公司
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