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Process for the preparation of roxadustat intermediates

An intermediate and solvent technology, which is applied in the preparation of imino compounds, organic chemistry, etc., can solve the problems of difficult quality purification of the final product API, cumbersome preparation process, and high preparation cost, so as to achieve easy availability of raw materials and high reaction yield , the effect of less operation steps

Active Publication Date: 2020-04-21
SHANGHAI XUNHE PHARMA TECH CO LTD
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  • 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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  • Process for the preparation of roxadustat intermediates
  • Process for the preparation of roxadustat intermediates
  • Process for the preparation of roxadustat intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of 1-(3-phenoxyphenyl)ethylamine (I)

[0035]

[0036] In a 2L reaction flask, add phenol (188g, 2mol), 3-bromoacetophenone (1,199g, 1mol), cuprous bromide (21.7g, 0.5mol), acetylacetone (10g, 0.1mol), Potassium carbonate (276 g, 2 mol) and N,N-dimethylformamide (1 L). Heated to an internal temperature of 120°C for 7 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), dried in vacuum (60° C.) for 5 h, and the compound of formula 2 (188.7 g, yield 89%) was obtained. MS m / z213[M+H] + .

[0037] In the 2L reaction flask, add formula 2 compound (188.7g, 0.89mol), hydroxylamine hydrochloride (74.2g, 1.07mol), sodium hydroxide (71.2g, 1.78mol) and absolute ethanol (0.8L) successively, heat to 60 ℃ reaction 3h, the reaction is complete. After cooling down to room temperature, sodium borohydride (67.6 g, 1.78 mol) wa...

Embodiment 2

[0039] Preparation of Dimethyl 2-(1-(3-phenoxyphenyl)ethylimino)malonate(III)

[0040]

[0041] In the 2L reaction flask, add 1-(3-phenoxyphenyl) ethylamine (1, 175g, 0.82mol), dimethyl ketomalonate (120g, 0.82mol), p-toluenesulfonic acid (7g) successively , 41 mmol) and toluene (1 L). Heated to reflux for 8 hours, cooled to room temperature, added water (0.5L) for extraction, and concentrated the organic layer to dryness under reduced pressure to obtain a crude product, which was recrystallized by adding absolute ethanol (0.5L) to obtain 2-(1-( Dimethyl 3-phenoxyphenyl)ethylimino)malonate (III, 274.5 g, yield 98%). MS m / z 342[M+H] + . 1 H NMR (400Hz, DMSO-d 6 )δ1.25 (d, J=3.2Hz, 3H), 2.95 (m, 1H), 3.71 (s, 6H), 6.98-7.03 (m, 3H), 7.15-7.19 (m, 4H), 7.38-7.41 (m, 2H).

Embodiment 3

[0043] Preparation of Diethyl 2-(1-(3-phenoxyphenyl)ethylimino)malonate(III)

[0044]

[0045] In the 2L reaction flask, add 1-(3-phenoxyphenyl) ethylamine (1, 175g, 0.82mol), diethyl ketomalonate (143g, 0.82mol), methanesulfonic acid (4g) successively , 41 mmol) and xylene (1 L). Heat to 130°C for 6 hours, cool to room temperature, add water (0.5L) for extraction, and concentrate the organic layer to dryness under reduced pressure to obtain a crude product, which is recrystallized by adding absolute ethanol (0.5L) to obtain 2-(1- Diethyl (3-phenoxyphenyl)ethylimino)malonate (III, 291 g, yield 96%). MS m / z 370[M+H] + . 1 H NMR (400Hz, DMSO-d 6 )δ1.21(d, J=3.2Hz, 3H), 1.29(m, 6H), 2.93(m, 1H), 4.22(m, 4H), 6.97-7.01(m, 3H), 7.14-7.17(m , 4H), 7.39-7.41 (m, 2H).

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Abstract

The invention provides a preparation method of Roxadustat intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate (IV), comprising the step of subjecting 2-(1-(3-phenoxyphenyl)ethylimide)dimalonate (III) as a starting material to condensation and cyclization. The preparation method of the Roxadustat intermediate IV has the advantages that material is easy to obtain, operating steps are few, the process is simple, the reaction yield is high, atom utilization rate is high, and the method is easy for industrial production. The reaction general formula is shown in the specification.

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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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/26C07C249/02C07C251/08
CPCC07C249/02C07D217/26C07C251/08
Inventor 周峰金华郑永勇黄美花孟欣
Owner SHANGHAI XUNHE PHARMA TECH CO LTD
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