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Eltrombopag intermediate and preparation method therefor and application thereof

An Eltrombopag and reaction technology, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve problems such as many steps, unsuitable for large-scale industrial production, etc., and achieve a simple preparation method and high safety. , cost saving effect

Inactive Publication Date: 2015-11-25
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires the use of highly toxic and difficult to purchase methyl iodide, many steps, the suzuki coupling yield is only 47%, and the total yield is only 28%, which is not suitable for large-scale industrial production

Method used

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  • Eltrombopag intermediate and preparation method therefor and application thereof
  • Eltrombopag intermediate and preparation method therefor and application thereof
  • Eltrombopag intermediate and preparation method therefor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-3

[0027] Example 1-3: Preparation of 2-benzyloxy-1-bromo-3-nitrobenzene

[0028] 10.9g (50mmol) of 2-nitro-6-bromophenol, 9g (52mmol) of benzyl bromide, 7.6g (55mmol) of potassium carbonate were mixed in acetonitrile (120ml) and reacted under reflux for 3 hours until the reaction is complete. Cool to room temperature and filter Concentrate to dryness to obtain a concentrate, add ethyl acetate (100ml) to dissolve, wash with water (50ml), saturated brine (50ml), dry, and concentrate to dryness to obtain 15g of yellow crystals with a yield of 97.4%.

[0029] Mix 2-nitro-6-bromophenol (4.36g), benzyl bromide (3.6g), potassium carbonate (4.14g) and tetrahydrofuran (50ml), stir under reflux for 3 hours, cool, filter, and concentrate the filtrate to dryness. Add ethyl acetate (30ml) and water (50ml), separate the layers, extract the aqueous layer with ethyl acetate (30ml×2), combine the organic layers, wash with water, washed with saturated brine, dry, filter, and concentrate to obtain the ...

Embodiment 4-5

[0031] Example 4-5: Preparation of 3'-nitro-2'-benzyloxy-[1,1'-biphenyl]-3-carboxylic acid

[0032] The compound obtained in Example 1 was 12.32g (40mmol), 3-carboxyphenylboronic acid 7.97g (48mmol), potassium carbonate 8.28g (60mmol), [1,1'-bis(diphenylphosphine)ferrocene] Palladium dichloride 2.04g (2.8mmol), mixed in 1,4-dioxane (200ml) and water (40ml) at 60°C under nitrogen protection for 4 hours, cooled and filtered, and concentrated to remove 1,4-dioxane Ring, add water (100ml), adjust the pH to acidity with 1mol / L dilute hydrochloric acid, a solid precipitated out, and filtered to obtain 14g of a dark brown solid. It was recrystallized with isopropanol (60ml) and water (20ml), and finally 11.5g of light brown solid was obtained with a yield of 82.4%. 1 HNMR(400MHz,CDCl3)δ8.30(s,1H), 8.18(d,J=7.7Hz,1H), 7.85(d,J=7.7Hz,1H), 7.81(dd,J=8.1,1.4Hz, 1H), 7.62(dd,J=7.6,1.3Hz,1H), 7.55(t,J=7.7Hz,1H), 7.33(t,J=7.9Hz,1H), 7.26–7.20(m,3H), 7.05(dd,J=6.6,2.5Hz,2H),4.66(s,2H).ESI-MS(...

Embodiment 6-7

[0034] Example 6-7: Preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid

[0035] Dissolve 10.47g (30mmol) of the compound obtained in Example 4 in ethyl acetate (350ml), add 1.05g of 10% palladium on carbon, react with hydrogen under pressure at 50°C for 10 hours, cool, filter, and concentrate to dryness to obtain yellow Solid 6.6g. The yield was 96%. 1 HNMR(400MHz,DMSO-d 6 )δ8.08(s,1H),7.93(d,J=7.7Hz,1H), 7.73(d,J=7.8Hz,1H), 7.58(t,J=7.7Hz,1H),7.44(dd, J=7.8Hz,1H),7.26(dd,J=7.7,1.4Hz,1H),7.04(t,J=7.8Hz,1H).ESI-MS(m / z):228[MH] -

[0036] Dissolve 10.47g (30mmol) of the compound obtained in Example 4 in ethyl acetate (350ml), add 2.1g of 10% palladium on carbon, and react with hydrogen under pressure at 50°C for 8 hours, cool, filter, and concentrate to dryness to obtain yellow Solid 6.7g. The yield was 97.5%.

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Abstract

The present invention provides a novel preparation method for an eltrombopag intermediate. The raw materials of the intermediate is easily available, and the preparation method therefor is simple and high in safety; According to a reaction step section for preparing eltrombopag by using a novel intermediate, the yield is as twice as that in the prior art, so that the cost is lowered significantly, and the method is suitable for large-scale industrial production application. (img file='DDA0000503880400000011.TIF'wi='488'he='336' / ).

Description

Technical field [0001] The invention relates to the technical field of preparation methods of Eltrombopag. Background technique [0002] Eltrombopag is a small molecule, non-peptide thrombopoietin (TPO) receptor agonist that stimulates the proliferation and differentiation of megakaryocytes. Eltrombopag is in the form of diethanolamine salt by GlaxoSmithKline and LigandPharmaceuticals under the trade name Sold to treat diseases that cause thrombocytopenia. The chemical name of Eltrombopag is 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro- 4H-pyrazole-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid has the following chemical structure: [0003] [0004] US Patent US2004019190A1 discloses a synthetic method of Eltrombopag, and its synthetic route is as follows: [0005] [0006] This method is based on 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (compound of formula 1) as the raw material, diazotizing under acidic conditions to obtain diazonium sa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C205/59C07C201/12C07D231/46
Inventor 徐浩吴雪松岑均达
Owner SHANGHAI INST OF PHARMA IND CO LTD
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