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Preparation method for ARV-110 intermediate

A technology of oxo and ethoxy, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of many by-products, complex reactions, and difficulties in scale-up production, and achieve the effects of mild reaction conditions, simple operation, and good repeatability

Inactive Publication Date: 2020-02-28
SUZHOU GUOKUANG PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The inventor of this patent found that when repeating this reaction: the repeatability of this reaction is not good, the conversion rate of raw materials is low, there are many by-products, and the reaction is more complicated, and although adding sodium triacetoxy borohydride many times, the reaction does not fail. No improvement, low yield (<20%), difficult to scale up

Method used

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  • Preparation method for ARV-110 intermediate
  • Preparation method for ARV-110 intermediate
  • Preparation method for ARV-110 intermediate

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preparation example Construction

[0031] The invention provides a kind of preparation method of 4-((5-(2-(tert-butoxy)-2-oxoethoxy) pentyl) amino) methyl benzoate, described method comprises following two step:

[0032] (1) Compound p-aminobenzoic acid 2 and aliphatic aldehyde 3 in BH 3 Under the action of the compound 4-((5-(2-(tert-butoxy)-2-oxoethoxy)phenyl)pentylamino)benzoic acid 4;

[0033] (2) compound 4-((5-(2-(tert-butoxy)-2-oxoethoxy) phenyl) amino) benzoic acid 4 is esterified in the system of halide / alkali, The compound methyl 4-((5-(2-(tert-butoxy)-2-oxoethoxy)pentyl)amino)benzoate 1 was obtained.

[0034] The reaction synthesis route is:

[0035]

[0036] In a preferred embodiment, in step (1), the reaction solvent is a common organic solvent in the art, preferably, the reaction solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methanol, ethanol , acetonitrile, ethyl acetate, isopropyl acetate and one or more of methyl tert-butyl ether.

[...

Embodiment 1

[0047] Preparation of 4-((5-(2-(tert-butoxy)-2-oxoethoxy)phenyl)amino)benzoic acid

[0048]

[0049] P-aminobenzoic acid (100g, 0.73moL, purchased from Biide Pharmaceuticals) and BH 3Tetrahydrofuran complex solution (800 mL, 1.0 M, 0.80 moL, purchased from Anaiji Chemical) was added to tetrahydrofuran (2.5 L). After the addition, stir at room temperature for 30 minutes, and then add aliphatic aldehyde (174.0g, 0.80moL, self-made according to the method provided on page 169 of CN201680014250.8). Stir at room temperature overnight, spot plate detection reaction is complete, add water to quench the reaction. The solvent was evaporated under reduced pressure, water (2.0 L) was added to the residue, and the pH value was adjusted to 12 with 4N NaOH solution. Add ethyl acetate (500mL) and separate the layers. The aqueous phase was collected, and the pH value of the aqueous phase was adjusted back to about 3 with concentrated hydrochloric acid. Extract with ethyl acetate (2 x 1...

Embodiment 2

[0051] Preparation of 4-((5-(2-(tert-butoxy)-2-oxoethoxy)phenyl)amino)benzoic acid

[0052]

[0053] Except that the reaction solvent was replaced by 2-methyltetrahydrofuran, the operation of Example 2 was the same as that of Example 1, and the yield was 89%.

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Abstract

The invention provides a preparation method for an ARV-110 intermediate. The ARV-110 intermediate is 4-((5-(2-(tert-butoxy)-2-oxoethoxy)amyl)amino)methyl benzoate. The method comprises the following two steps: (1) allowing a compound, namely p-aminobenzoic acid 2 to react with fatty aldehyde 3 under the action of BH3 so as to obtain a compound, namely 4-((5-(2-(tert-butoxy)-2-oxoethoxy)phenyl)amylamino)benzoic acid 4; and (2) esterifying the compound, namely the 4-((5-(2-(tert-butoxy)-2-oxoethoxy)phenyl)amylamino)benzoic acid 4 in a halomethane / alkali system so as to obtain a compound, namely4-((5-(2-(tert-butoxy)-2-oxoethoxy)amyl)amino)methyl benzoate 1. The reaction synthesis route is described in the specification.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a kind of methyl 4-((5-(2-(tert-butoxy)-2-oxoethoxy)pentyl)amino)benzoate method of preparation. Background technique [0002] ARV-110 is a new type of anti-prostate cancer drug developed by Arvinas Company of the United States based on PROTAC protein degradation technology, and is currently in the clinical research stage. In the in vivo and in vitro models of this drug, whether it is AR mutation or overexpression (both are common reasons for the failure of AR targeted therapy), this new drug has an excellent degradation effect on AR. ARV-110 has been granted fast-track qualification by the US FDA. [0003] Methyl ((5-(2-(tert-butoxy)-2-oxoethoxy)pentyl)amino)benzoate (Compound 1) is an important intermediate for the preparation of ARV-110. The preparation method of compound 1 is reported on page 169 of CN201680014250.8: milligram-level methyl 4-aminoben...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C229/60
CPCC07C227/18C07C229/60
Inventor 梅德盛孙靖刘爱风汪奎孙高睿杨坤肖程陈林瑞
Owner SUZHOU GUOKUANG PHARMTECH CO LTD
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