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Novel method for preparing Eltrombopag intermediate

A compound and a defined technology, applied in the field of preparation of Eltrombopag intermediates, can solve problems such as difficult handling, high production costs, and inability to apply mechanically, and achieve the effects of reducing three wastes emissions, reducing material costs, and ingenious design

Active Publication Date: 2016-11-23
JIANGSU VCARE PHARMATECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] There are also well-known problems in the above four routes, that is, the problem of the Suzuki coupling reaction itself. The conventional coupling reagent itself has no effective method to recycle and apply mechanically. The cost is high; even if it is palladium acetate, after mixing with other solid or liquid materials, it cannot be effectively recovered, and it cannot be applied mechanically; tetrakistriphenylphosphine palladium is an important and representative Suzuki coupling reagent, and the triphenylphosphine that it introduces Phosphine-related impurities are difficult to remove
Therefore the deficiency of above method has restricted the large-scale industrialized production and cost reduction of formula I compound, therefore it is necessary to develop new synthetic method

Method used

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  • Novel method for preparing Eltrombopag intermediate
  • Novel method for preparing Eltrombopag intermediate
  • Novel method for preparing Eltrombopag intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063]

[0064] Acetic acid (7.5L) and 4-chloro-2-bromophenol (1500.0g, 7.2mol) were added successively in the reaction flask and stirred thoroughly; sodium nitrate (1229.0g, 14.5mol) and concentrated sulfuric acid (1418.0g, 14.5mol) were added dropwise at room temperature ) aqueous solution (1.4L); after dropping, control the temperature at 25-30°C and react for about 20-30min; stop the reaction, pour the reaction solution into ice water (7.5L), and stir thoroughly for 20min; filter with suction, and wash the filter cake with water Until the filtrate is nearly neutral (PH 6-7); the filter cake is dried to obtain a yellow solid: 1742g, yield: 95%. mp 122~124℃; 1 H NMR (400MHz, DMSO) δ8.11(d, J=2.6Hz, 1H), 8.05(d, J=2.6Hz, 1H); ESI-MS(m / z): 250[M-H] - .

Embodiment 2

[0066]

[0067] In the reaction flask, add DMF (2.5L) successively, compound II (500.0g, 1.98mol) potassium carbonate (821.2g, 5.9mol), fully stir; dropwise add benzyl bromide (508.1g, 3.0mol), dropwise process without Obvious exothermic phenomenon; after dripping, react at 20-25°C for 4-6h, pour the reaction solution into water (12.5L), stir well, filter with suction, rinse the filter cake with water, and dry the filter cake to obtain a light yellow solid: 598g, Yield 88%. mp 74~76℃; 1 H NMR (300MHz, DMSO) δ8.26 (d, J=2.7Hz, 1H), 8.16 (d, J=2.7Hz, 1H), 7.39-7.47 (m, 5H), 5.11 (s, 2H).

Embodiment 3

[0069]

[0070] In the reaction flask, add compound III-1 (500.0g, 1.46mol), methanol (2.5L), sodium carbonate (309.0g, 2.91mol), water (2.5L), 3-carboxyphenylboronic acid (242.0g, 1.46mol), 10% palladium carbon (50.0g), nitrogen replacement three times, reflux reaction for 24h. Stop the reaction, suction filter while it is hot, rinse the palladium-carbon filter cake with hot methanol, and recover the palladium-carbon. Combine the filtrates, control the temperature below 20°C, add concentrated hydrochloric acid dropwise to adjust to acidity (pH=1-2); filter with suction, rinse the filter cake with water, wash the filter cake with methanol / ethyl acetate (V / V, 1 / 2) Beat, filter, and dry the filter cake to obtain a light yellow solid: 487g, yield: 87%, purity 99.14% [HPLC method: chromatographic column ODS-C 18 (150*4.6mm, 5um); column temperature 35°C; flow rate 1mL / min; mobile phase A: 10mM sodium dihydrogen phosphate (PH=3), flow B: acetonitrile (gradient elution: 0→10min,...

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Abstract

The invention provides a method for preparing a compound shown as the formula I (please see the formula in the description). The method specifically comprises the following steps that 1, a compound shown as the formula (II) (please see the formula in the description) reacts with a compound shown as formula (V) (please see the formula in the description) under the alkaline condition to generate a compound shown as the formula (III) (please see the formula in the description); 2, the compound shown as the formula (III) (please see the formula in the description) reacts with a compound shown as the formula (VI) (please see the formula in the description) under the alkaline condition in the presence of palladium carbon to generate a compound shown as the formula (IV) (please see the formula in the description); 3, the compound shown as the formula (IV) (please see the formula in the description) reacts in the presence of palladium carbon and a hydrogen source under the alkaline condition to generate the compound shown as the formula (I) (please see the formula in the description). According to the method, design is ingenious, protecting group removal, dechlorination and nitro reduction are together completed in the final hydrogenation process, and the purity of the obtained compound shown as the formula (I) (please see the formula in the description) is high; the most important thing is that compared with other Suzuki coupling agents, cost of palladium carbon is lower, a source of palladium carbon is wide and easy to obtain, palladium carbon can be directly recycled and reused after being simply filtered and separated, and therefore the material cost is greatly reduced; meanwhile, emission of three wastes is reduced, and the method is quite suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new method for preparing an intermediate of Eltrombopag. Background technique [0002] Immune thrombocytopenia (ITP) is a rare blood disorder characterized by damaged or insufficient platelet counts, putting patients at increased risk of bruising or bleeding. The chemical name of Eltrombopag is 3′-{(2Z)-2-[1-(3,4-xylyl)-3-methyl-5-oxo-1,5-dihydro- 4H-pyrazole-4-ylidene]hydrazino}-2′-hydroxy-3-biphenylcarboxylic acid-2-aminoethanol salt (1:2), is a thrombopoietin receptor jointly developed by GlaxoSmithKline and Ligand Pharmaceuticals In 2008, the FDA approved its marketing in the United States. The trade name is Promacta. It is used for the treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP) after glucocorticoids, immunoglobulin therapy or splenectomy. decrease in platelets. This product can induce the proliferation and differentiation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/52C07C227/04C07C205/59C07C205/37C07C201/12
CPCY02P20/55
Inventor 周西朋沙波龚彦春吕伏生袁方刘永强
Owner JIANGSU VCARE PHARMATECH
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