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Compound, and preparation method and application thereof

A compound, afatinib technology, applied in the field of afatinib degradation of impurities and its preparation, to achieve the effect of simple reaction operation process, easy control of process operation, and cheap and easy-to-obtain raw materials

Inactive Publication Date: 2017-07-04
WATERSTONE PHARMA WUHAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the method for afatinib to degrade impurities shown in the compound of formula 1 still needs to be improved

Method used

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  • Compound, and preparation method and application thereof
  • Compound, and preparation method and application thereof
  • Compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] The steps of synthetic compound 5 are as follows:

[0042] (1) Add 125.1g of compound 4(S)-3-hydroxytetrahydrofuran and 1200ml of DMF to the three-necked flask, start stirring, cool down to 0°C in an ice-water bath, add 160g of potassium tert-butoxide, and stir for 1 hour;

[0043] (2) Add 120 g of compound 3 (N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine) and react at room temperature for 2-6 hours.

[0044] (3) Take a sample, quench the central control with water, pour the reaction solution into water, adjust the pH to 7 with hydrochloric acid, filter, wash with water, and dry to obtain 137 g of compound 5 with a yield of 95%.

[0045] The H NMR spectrum data of compound 5: 1 H-NMR (DMSO-d 6), 5.42(s,1H),7.42-7.46(t,J=10.8Hz,2H),7.77-7.79(t,J=2.8Hz,1H),8.13-8.14(d,J=4.8Hz,1H),8.65 (s,1H),9.20(s,1H),10.14(s,1H).

Embodiment 2

[0047] The steps of synthetic compound 6 are as follows:

[0048] (1) Add 100g of compound 5 to the three-necked flask: (4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy) -quinazoline), 2500mL ethyl acetate, add 500ml glacial acetic acid, 500ml water, 56g iron powder under stirring, heat up to 70°C for 1h;

[0049] (2) complete reaction, cooling and filtering, the filter cake is washed with ethyl acetate, the filtrate is allowed to stand for stratification, the water phase is retained, and the organic phase is placed;

[0050] (3) Add ethyl acetate to the aqueous phase, extract and separate the liquids, and combine the organic phases;

[0051] (4) Add 2L of water to the organic phase, adjust the pH to 8 with sodium hydroxide solution under cooling, let stand for stratification, wash with water, wash with saline, stand for stratification, dry and filter with anhydrous sodium sulfate. The filtrate was concentrated to dryness to obtain 84 g of compound ...

Embodiment 3

[0053] The steps of synthetic compound 8 are as follows:

[0054] (1) Add 350mL of tetrahydrofuran into the three-necked reaction flask, start stirring, and add 54.3g of 1,1-dicarbonylimidazole to form a white suspension. Raise the temperature to 40°C, dissolve 57.1g of diethylphosphonoacetic acid in tetrahydrofuran, add dropwise to the system, and stir at 40°C for 30-45min. Above-mentioned reaction mixture is solution A;

[0055] (2) Add 420 mL of tetrahydrofuran into the three-necked reaction flask, start stirring, and add 84.0 g of compound 6, which is a pale green solution. Raise the temperature to 40°C and the above solution is B, add the above solution A to the solution B dropwise, after the addition, the internal temperature drops to 30°C to react;

[0056] (3) Stir for 2 hours, and the reaction is complete. Add 420 mL of methyl tert-butyl ether and cool to room temperature. After stirring continuously for 30 minutes, the above white suspension is suction-filtered. ...

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Abstract

The invention relates to a compound, and a preparation method and application thereof. Specifically, the compound is as shown in a formula 1 which is described in the specification. The invention also provides the preparation method for the compound as shown in the formula 1. The preparation method comprises a step of contacting N-[4-[(3-chloro-4-fluorophenyl)amino]-7[[(3S)-tetrahydro-3-furyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butyleneamide with an alkaline aqueous solution in an organic solvent so as to obtain the compound as shown in the formula 1. The preparation method is simple to operate; a white powder product can be obtained through direct filtering after post-treatment; and the prepared compound has high purity, as high as 99% or above, and can be directly used as an impurity control substance for research on the quality of an afatinib bulk drug.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular, the invention relates to an afatinib degraded impurity and its preparation method and application. Background technique [0002] Afatinib (Afatinib) is a multi-targeted oral small molecule drug developed by Boehringer Ingelheim, Germany. It is an irreversible inhibitor of acid kinase and also a second-generation highly effective dual irreversible tyrosine kinase inhibitor. The drug was approved by the US FDA on July 12, 2013, and its trade name is Gilotrif. The main alkaline degradation impurity of afatinib is the compound shown in formula 1, which is often used as a reference substance in the quality research of afatinib pharmaceutical products and the quantitative control of impurities. [0003] [0004] At present, the method for preparing afatinib degrading impurities represented by the compound of formula 1 still needs to be improved. Contents of the invention [0005] Th...

Claims

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Application Information

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IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 徐助雄张倩钱丽娜崔健
Owner WATERSTONE PHARMA WUHAN
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