A kind of preparation method of alectinib intermediate

An intermediate and tinib technology, applied in the field of preparation of alectinib intermediates, can solve the problems of expensive preparation cost of raw materials and reagents, long preparation route, corrosion hazards of container equipment and the like

Active Publication Date: 2021-04-13
成都正善达生物医药科技有限公司
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  • 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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  • A kind of preparation method of alectinib intermediate
  • A kind of preparation method of alectinib intermediate
  • A kind of preparation method of alectinib intermediate

Examples

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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 alectinib intermediate 2-(4-ethyl-3-iodo)phenyl-2-methylpropionic acid. The preparation method of the present invention improves the preparation route method by optimizing and optimizing the reaction Conditions, improved post-processing and purification methods, reduced operational risk levels and production costs; low requirements on the corrosion resistance of reaction vessel equipment, good operational safety, post-processing green environmental protection, the obtained Alectinib intermediate 2- (4-ethyl-3-iodo)phenyl-2-methylpropionic acid has low impurity content, greatly improves the purity and quality of intermediate products while increasing the yield, and improves the production process of Alectinib API The difficulty of process control and the improvement of the quality and pass rate of Alectinib's raw material drug; the preparation method is simple to operate, the solvent and process conditions are safe and easy to implement, and it realizes environmental protection and green production, and has broad application prospects.

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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Patent Type & Authority Patents(China)
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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