High purity preparation method of Afatinib intermediate

A compound and reaction technology, which is applied in the field of preparation of -N4--7-oxyl)-quinazoline-4,6-diamine, can solve the problems of difficult industrialization, high purity of dehalogenated impurities, and post-processing troubles and other problems, to achieve the effect of convenient preparation, lower production cost, and short route

Active Publication Date: 2015-09-23
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis of the compound of formula (II) reported in previous patents and literatures is obtained by reducing the nitro compound of formula (VII), but the reported method is either troublesome in post-processing and difficult to industrialize, or it will produce dehalogenated impurities during the reaction and it is difficult to obtain high Purity of compound of formula (II)

Method used

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  • High purity preparation method of Afatinib intermediate
  • High purity preparation method of Afatinib intermediate
  • High purity preparation method of Afatinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add the compound of formula (III) (50g) into acetonitrile (200ml), slowly add phosphorus oxychloride (41.25g), then drop into triethylamine (27g), heat to reflux, and maintain reflux for 5h, drop into formula ( IV) A mixed solution of the compound (38.75 g) dissolved in 1,4-dioxane (250 ml). After dripping, continue to reflux for 1 hour, cool down to room temperature and add water (200ml), adjust the pH to 7-8 with 5N sodium hydroxide solution, stir for 1 hour, filter, wash the filter cake with water (200ml×2), drain, and solid After drying in a blast oven at 50°C for 12 hours, 72 g of the compound of the yellow formula (V) was obtained.

Embodiment 2

[0032] Add the compound of formula (VI) (13.6g) into DMF (385ml), stir in an ice bath and add potassium tert-butoxide (48g) in batches. And react at room temperature for 2 hours, slowly add water (2L), adjust the pH to 7-8 with 2N hydrochloric acid solution, stir at room temperature for 1 hour, filter, and dry the solid in a blast oven at 50°C for 12 hours to obtain 47g of a yellow compound of formula (VII).

Embodiment 3

[0034] Mix 1.5L THF, 100g of the compound of formula (VII), 10g of activated carbon, FeCl 3 1g and 100g of hydrazine hydrate were poured into the reaction flask in turn, refluxed for 3 hours, filtered, the filtrate was stirred at room temperature for 4 hours, filtered, and the solid was dried in a blast oven at 50°C. 88 g of off-white solid was obtained, the molar yield was 95%, and the HPLC was 99.57%. The structure confirmation map of the obtained final product is as follows: figure 1 shown.

[0035] 1 H-NMR(DMSO-d6)δ:2.13(m,1H),2.33(m,1H),3.80(m,1H),3.96(m,3H),5.24(br,1H),5.38(s,2H ),7.06(s,1H),7.39(s,1H),7.81(m,1H),8.20(m,1H),8.38(s,1H),9.39(s,1H).

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Abstract

The present invention relates to a high purity preparation method of Afatinib intermediate, and particularly relates to a high purity preparation method of an antineoplastic treatment medicine maleate Afatinib intermediate (II) compound, the method comprises the following steps: an objective product is obtained sequentially through substitution in two steps, reduction reaction and the like of 6-amino-7-fluoro-3,4-dihydro-quinazolin-4-one. The method is simple in process, economic and environmental-friendly, and suitable for industrial amplification requirements, and the manufactured finished product is high in purity.

Description

technical field [0001] The present invention relates to the fields of organic chemistry and medicinal chemistry, in particular to (S)-N 4 The preparation method of -(3-chloro-4-fluorophenyl)-7-((tetrahydrofuran-3-yl)oxy)-quinazoline-4,6-diamine. Background technique [0002] Afatinib maleate is a multi-targeted oral small-molecule drug developed by Boehringer Inheim in Germany. It is an epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) receptor Irreversible inhibitor of amino acid kinases. It is a second-generation highly potent dual irreversible tyrosine kinase inhibitor. The drug was approved by the US FDA on July 12, 2013. The trade name is Gilotrif. [0003] Afatinib maleate (I), the chemical name is 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1- Oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate. [0004] [0005] [0006] Among the many synthetic methods of afatinib maleate, the compoun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 陈安丰杨勇张亮周炳城陈亭亭
Owner JIANGSU HANSOH PHARMA CO LTD
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