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RET kinase inhibitor intermediates and preparation method thereof

A kinase inhibitor and preparation process technology, applied in the direction of organic chemistry, can solve the problems of high cost and poor stability of intermediates, and achieve the effects of improving production efficiency, simple waste liquid treatment, and reducing production costs

Inactive Publication Date: 2020-08-18
厦门云凡医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In order to solve the technical problems of certain aspects of the prior art such as high cost and poor stability of intermediates, the present invention provides a new synthetic route for synthesizing RET kinase inhibitor intermediates formula (5a) and formula (5b)

Method used

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  • RET kinase inhibitor intermediates and preparation method thereof
  • RET kinase inhibitor intermediates and preparation method thereof

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Embodiment 1

[0034] The synthesis of embodiment 1 compound 2a and 2b

[0035] Weigh 60g (322.5mmol) of 3-bromo-5-methoxypyridine, 180mL of water, and 36.5g (322.5mmol) of sulfamic acid into a 500mL flask, rise to 90°C for 30min, cool to room temperature, add Potassium carbonate 44.6g (322.5mmol) and absolute ethanol 130mL, ethyl propiolate 25.3g (257.9mmol) was added dropwise at room temperature, reacted overnight, filtered, washed with water, dried, red solid (2a and 2b mixture) 62.5g, Yield 81.0%.

Embodiment 2

[0036] The synthesis of embodiment 2 compound 3a and 3b

[0037] Weigh 50.0g (167.2mmol) of the mixture of 2a and 2b and 350mL of 48% HBr aqueous solution, add them to a 500mL single-necked bottle, raise the temperature to 80°C for 2.5h, cool down in an ice bath and stir, and add potassium carbonate to the mother liquor until there is no Bubbles were generated, filtered, washed with water, and separated by column chromatography to obtain 11.3g of 3b and 15.2g of 3a. The total yield of 3a and 3b was 96.8%, and the ratio of 3a and 3b was 1:2.4.

[0038] 3a hydrogen spectrum data: 1 H NMR (400MHz, CDCl 3 δppm): δ3.82(s, 3H, OCH 3 ), 6.57 (d, J = 1.9Hz, 1H, Ar-H), 7.18 (d, J = 1.8Hz, 1H, Ar-H), 7.87 (d, J = 2.2Hz, 1H, Ar-H), 8.04 (d, J=1.8Hz, 1H, Ar-H); 3b hydrogen spectrum data: 1 H NMR (400MHz, CDCl 2 δppm): δ 3.82 (s, 3H, OCH 3 ), 6.57(d, J=1.9Hz, 1H, Ar-H), 7.18(d, J=1.8Hz, 1H, Ar-H), 7.87(d, J=2.2Hz, 1H, Ar-H), 8.04 (m, 1H, Ar-H).

Embodiment 3

[0039] The synthesis of embodiment 3 compound 4a

[0040]Weigh 10.3g (45.4mmol) of 3a and 154.5mL of DMF, add them to a 250mL two-necked bottle respectively, cool down to 0°C, add 20.9g (136.1mmol) of phosphorus oxychloride dropwise, transfer to a 25°C water bath after adding React for 3 hours; pour the reaction liquid into 500 mL of ice water, add sodium hydroxide until the pH of the solution is 8.0-9.0, filter, wash with water, and dry to obtain 11.3 g of off-white solid 4a with a yield of 98.0%.

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Abstract

The invention discloses RET kinase inhibitor intermediates and a preparation method thereof, and relates to the field of medicinal chemistry, wherein the method for synthesizing RET kinase inhibitorsrepresented by a formula (5a) and a formula (5b) comprises the steps: (a) carrying out a reaction of compounds represented by a formula (4a) and a formula (4b) with hydroxylamine sulfonic acid to formthe compounds represented by the formula (5a) and the formula (5b); and (b) carrying out a reaction of the compounds represented by a formula (3a) and a formula (3b) with phosphorus oxychloride to form compounds represented by the formula (4a) and the formula (4b); and (c) allowing compounds represented by a formula (2a) and a formula (2b) to form the compounds represented by the formula (3a) andformula (3b) under the action of an acid; and (d) after the reaction of the mixture of 3-bromo-5-methoxypyridine, hydroxylamine sulfonic acid and water is finished at the temperature of 70-100 DEG C,adding an alcoholic solution of alkali at room temperature, dropwise adding propiolate, and after the reaction is finished at room temperature, obtaining the compounds represented by the formula (2a)and the formula (2b), wherein R is methyl, ethyl, propyl or butyl.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a RET kinase inhibitor intermediate and a preparation method thereof. Background technique [0002] Selpercatinib (LOXO-292) is a potent, oral, highly selective rearrangement during transfection (RET) kinase inhibitor indicated for the treatment of cancer patients with abnormal RET. The RET gene, a proto-oncogene that rearranges during transfection and hence its name, encodes a cell membrane receptor tyrosine kinase whose abnormality is a rare driver of many types of tumors. RET fusions are estimated to be present in approximately 2% of NSCLC, 10-20% of papillary thyroid carcinoma (PTC) and other types of thyroid cancer, and in subgroups of other cancers such as colorectal cancer; RET point mutations are present in approximately 60% of medullary thyroid cancer (MTC). RET fusion and RET point mutation cancers mainly depend on the activation of RET kinase to maintain their prol...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 叶兆宝罗善梅马友柠吴明昌
Owner 厦门云凡医药科技有限公司
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