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Preparation method for intermediate of Roxadustat

A technology for intermediates and compounds, which is applied in the preparation of acyl halides, carboxylic acid halides, sulfonamides, etc., can solve the problems of difficult quality purification of final product raw materials, cumbersome preparation process, and high preparation costs, and achieve operational Convenience, high reaction yield, easy access to raw materials

Inactive Publication Date: 2017-03-08
SHANGHAI XUNHE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation process is relatively cumbersome, requiring the use of special hydrogenation equipment, and the preparation cost is high
[0015] Method 4) The isoquinoline ring is obtained by the amino acid ring-closing method. In this method, the phenolic hydroxyl group is introduced into the phenyl group, which easily generates amino substitution product by-products, which brings purification difficulties to the quality of the final product bulk drug
And the introduction of the 4-hydroxyl group on the isoquinoline ring adopts the hydrogen peroxide oxidation method, which has a greater safety hazard in the industrial production process

Method used

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  • Preparation method for intermediate of Roxadustat
  • Preparation method for intermediate of Roxadustat
  • Preparation method for intermediate of Roxadustat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Preparation of 3-methyl-5-bromoisobenzofuran-1(3H)-one (I)

[0050]

[0051] In a 3L reaction flask, 2-hydroxy-5-bromoacetophenone (215g, 1mol), ethyl carbazate (104g, 1mol) and absolute ethanol (1.5L) were sequentially added. Heated to reflux and stirred for 5h, cooled to room temperature, and solid precipitated out. After filtering, the filter cake was washed with absolute ethanol (0.3 L), and dried in vacuum (50° C.) for 5 h to obtain Intermediate 3 (247.1 g, yield 82.1%).

[0052] In a 3L reaction flask, Intermediate 3 (245g, 0.8mol) was dissolved in dichloromethane (2L), at room temperature, iodophenyldiethyl ester (386g, 1.2mol) was added in batches within 10min, after the addition was complete, stir at room temperature Reaction 4h. The reaction solution was extracted with water (1 L), and the organic layer was concentrated to dryness under reduced pressure to obtain the crude intermediate 5, which was directly put into the next step without purification.

...

Embodiment 2

[0055] Preparation of 3-methyl-5-phenoxyisobenzofuran-1(3H)-one (II)

[0056]

[0057] In a 2L reaction flask, add phenol (188g, 2mol), 3-methyl-5-bromoisobenzofuran-1(3H)-one (1, 227g, 1mol), cuprous bromide (21.7g, 0.5 mol), acetylacetone (10 g, 0.1 mol), potassium carbonate (276 g, 2 mol) and N,N-dimethylformamide (1 L). Heated to an internal temperature of 120°C for 10 h, cooled to room temperature, poured the reaction solution into 2N cold aqueous hydrochloric acid (1.5 L), and stirred for 30 min. After filtration, the filter cake was washed with water (0.5 L), and dried in vacuum (60° C.) for 5 h to obtain the compound of formula II (197 g, yield 82%). MS m / z 241[M+H] + .

Embodiment 3

[0059] Preparation of 3-methyl-5-phenoxyisobenzofuran-1(3H)-one (II)

[0060] In a 2L reaction flask, add phenol (188g, 2mol), 3-methyl-5-bromoisobenzofuran-1(3H)-one (1, 227g, 1mol), cuprous chloride (49.5g, 0.5 mol), acetylacetone (10 g, 0.1 mol), cesium carbonate (652 g, 2 mol) and N-methylpyrrolidone (1 L). Heated to an internal temperature of 120°C for 10 h, cooled to room temperature, poured the reaction solution into 2N cold aqueous hydrochloric acid (1.5 L), and stirred for 30 min. After filtering, the filter cake was washed with water (0.5 L), and dried in vacuum (60° C.) for 5 h to obtain the compound of formula II (194 g, yield 80.8%).

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Abstract

The invention provides a preparation method for an intermediate VI of Roxadustat. The preparation method comprises the following steps: reacting 3-methyl-5-bromoisobenzofuran-1(3H)-one (I), which serves as a starting raw material, with phenol so as to prepare an intermediate II, then, subjecting the II to a ring-opening substitution reaction so as to prepare a compound III, and subjecting the compound III to a substitution reaction so as to prepare a key intermediate V; and subjecting the V to alkali condensation, deprotection and aromatization, thereby preparing the target intermediate VI. The preparation method for the intermediate VI of the Roxadustat, provided by the invention, has the advantages that the raw materials are readily available, the process is simple, the operation is convenient, the reaction yield is high, the atom utilization ratio is high, and the industrial production is facilitated. The reaction general formula is represented by the formulae shown in the description.

Description

technical field [0001] The invention relates to a preparation method of Roxadustat intermediate used for treating chronic anemia. Background technique [0002] Roxadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor originally developed by FibroGen in the United States and currently co-developed with AstraZeneca. The chemical name is N-[(4-hydroxy-1-methyl-7 -Phenoxy-3-isoquinolinyl)carbonyl]glycine, this product can be used for the treatment of chronic anemia, and is currently in Phase 3 clinical research stage in the US FDA. [0003] The method that prior art is used for preparing Roxadustat mainly contains: [0004] 1) The compound patent synthesis route of the original FibroGen company (CN102977015B, application date: 20040604), as shown in the following scheme: [0005] [0006] 2) Zhejiang Beida announced the following synthetic method (CN104024227B, application date: 20120723) to improve the patented method of the original research compo...

Claims

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Application Information

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IPC IPC(8): C07D217/26C07D307/88C07C67/14C07C69/92C07C303/40C07C311/19
CPCC07D217/26C07C51/58C07C67/14C07C303/40C07D307/88C07C69/92C07C65/21C07C311/19
Inventor 郑永勇金华周峰黄美花孟欣
Owner SHANGHAI XUNHE PHARMA TECH CO LTD
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