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Preparation method of osilodrostat

A technology of odes and benzonitrile, applied in the field of preparation of Cushing's syndrome drug odes, can solve the problems of low total yield, many reaction steps, restricting industrial production and the like, and achieves favorable conditions for industrial production and conditions. mild effect

Pending Publication Date: 2020-08-28
SUZHOU MIRACPHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this method also has defects such as many reaction steps and low overall yield, especially the chiral target product is obtained through the separation method of HPLC chiral column chromatography, which limits the industrial production of this product to varying degrees.

Method used

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  • Preparation method of osilodrostat
  • Preparation method of osilodrostat
  • Preparation method of osilodrostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Under nitrogen protection, 6-(6-trifluoromethyl-2-yl)-1,3,5-triazine-2,4-dione (II) (18g, 0.1mol), 1 , 3-dihydroxyacetone dimer (18g, 0.1mol), potassium thiocyanate (9.7g, 0.1mol), solvent acetonitrile 100mL and water 50mL, keep the temperature at 5-10°C, and react for 10 hours. The temperature was lowered to 0°C, 30% hydrogen peroxide (31 mL, 0.3 mol) was added, and the reaction was continued to stir for 2 hours, and the reaction was monitored by TLC to complete. The reaction was quenched with saturated sodium sulfite solution and adjusted to pH = 8-10 with solid sodium carbonate. Ethyl acetate was added to extract 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was recovered by distillation under reduced pressure, and the oily substance 4-[(1R)-(2-hydroxymethyl-1H-imidazol-1-yl)- 2-Hydroxyethyl]-3-fluoro-benzonitrile (III) 18.5g, yield 70.9%, EI-MS m / z: 262[M+H] + .

Embodiment 2

[0039] Add 4-[(1R)-(2-hydroxymethyl-1H-imidazol-1-yl)-2-hydroxyethyl]-3-fluoro-benzonitrile (III) (13g, 50mmol) into the three-necked flask, Manganese dioxide (13 g, 150 mmol) and dioxane 150 mL. The temperature was raised to 80°C, and the reaction was carried out for 8 hours, and the reaction was completed by TLC monitoring. Remove the solid by filtration with celite, and concentrate under reduced pressure to give a yellow oily substance 4-[(1R)-(2-formyl-1H-imidazol-1-yl)-2-hydroxyethyl]-3-fluoro-benzene Nitrile (IV) 10.4g, yield 80.3%, EI-MS m / z: 260[M+H] + .

Embodiment 3

[0041]Add 30mL of concentrated sulfuric acid and 15mL of water to the reaction flask under ice-cooling, and add 4-[(1R)-(2-formyl-1H-imidazol-1-yl)-2-hydroxyethyl]-3 - Fluoro-benzonitrile (IV) (7.8 g, 30 mmol) and sodium bromide (3.7 g, 36 mmol) and dioxane 30 mL. The temperature was raised to 90° C., and the reaction was carried out for 5 hours, and the reaction was monitored by TLC to complete. Stand still, take the supernatant, extract three times with ethyl acetate, combine the organic phases, wash with water, saturated sodium bicarbonate solution and water successively, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 8.8 g of yellow-red liquid 4-[(1R)-(2-formyl-1H-imidazol-1-yl)-2-bromo-ethyl]-3-fluoro-benzonitrile (V) was obtained, and the yield was 91.1 %, EI-MS m / z:323[M+H] + .

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Abstract

The invention discloses a preparation method of osilodrostat. 4-[(1R)-1-amino-2-hydroxyethyl]-3-fluorobenzonitrile is used as a raw material, and sequentially undergoes basic unit reactions such as cyclization, oxidation, bromination, Wittig and catalytic hydrogenation to generate the target product osilodrostat. The preparation method is simple in process, mild in condition, safe and environment-friendly, and provides a new synthesis way for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of Cushing's syndrome drug oderestat. Background technique [0002] Osilodrostat is a drug jointly developed by Novartis and Recordati for the treatment of Cushing's syndrome. The drug was approved by the EU EMA and the US FDA on January 15, 2020 and March 6, 2020, respectively, and was launched in Europe and the United States under the trade name Isturisa. Odyssestat is the first FDA-approved 11-beta hydroxylase inhibitor that directly blocks adrenal cortisol synthesis. Because the drug has not been officially listed in my country, and does not have a standard Chinese translation, the applicant transliterates it as "Odysstat" here. [0003] The chemical name of oderestat is: 4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluoro-benzonitrile. [0004] [0005] I...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04Y02P20/55
Inventor 许学农
Owner SUZHOU MIRACPHARMA TECH
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