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Synthetic method for the preparation of an hydrazine compound

A technology for compounds and complexes, applied in the preparation of hydrazine, organic chemistry, etc., can solve problems such as providing effective methods that have not yet been met

Inactive Publication Date: 2021-05-25
MEREO BIOPHARMA 1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, it has not been satisfied to provide an effective method for producing 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide. Process and need for useful intermediate compounds suitable for commercial scale

Method used

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  • Synthetic method for the preparation of an hydrazine compound
  • Synthetic method for the preparation of an hydrazine compound
  • Synthetic method for the preparation of an hydrazine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0176] The method is described with respect to the introduced amount of compound 1 (1.0 eq).

[0177] Acetic anhydride (2.0 eq) was added to a mixture of 3-(cyanoacetyl)benzonitrile (Compound 1) (1.0 eq) in toluene (4.5 vol) and heated to 105°C. Slowly reduce the pressure to 800-900mbar until a slight reflux is obtained. Triethyl orthoformate (1.5 eq) was added during the distillation. The reaction was then stirred for 1 h. The reaction was cooled to 25°C and the product crystallized. n-Heptane (5 vol) was added within 0.5 h. The reaction was further cooled to less than 5 °C and stirred for 1 h. The product was filtered off, washed with n-heptane (2 x 2 vol) and dried under vacuum. 3-[2-Cyano-2-(ethoxymethylene)acetyl]benzonitrile (compound 2) was obtained as a red solid in 90% yield and 98% purity (HPLC, area %).

Embodiment 2

[0179] The method is described with respect to the introduced amount of compound 4 (1.0 eq).

[0180] Hydrochloric acid (30%, 3.7 eq) was added to a suspension of 3-amino-4-methylbenzoic acid (compound 4) (1.0 eq) in water (1.5 vol). The suspension was cooled to less than 10°C and stirred for 0.5 hours. A solution of sodium nitrite (1.1 eq) in water (0.85 vol) was added slowly while maintaining the temperature below 10°C. The reaction was then stirred for 0.5 hours. A cooled (<5°C) suspension of sodium sulfite (4.9 eq) in water (10 vol) was added to the reaction mixture while maintaining the temperature below 15°C. The reaction was then stirred for 1 hour. The resulting mixture was heated to 60 °C for 1 h. Hydrochloric acid (30%, 7.2eq) was added, and the mixture was stirred at 80°C for 2 hours. The mixture was cooled to 25°C. Aqueous sodium hydroxide solution (33%) was added (final pH: 5.6-5.8). The mixture was then stirred for 1 hour, filtered, washed with water (2×4 ...

Embodiment 3

[0183] The method is described relative to the introduced amount of Compound 2 (1.0 eq).

[0184] A solution of 3-[2-cyano-2-(ethoxymethylene)acetyl]benzonitrile (compound 2) (1.0 eq) in dimethyl sulfoxide (4 vol) was added at 105 °C over 1.5 h Into a solution of 3-hydrazino-4-methyl-benzoic acid (compound 3) (1.2 eq) in dimethyl sulfoxide (20 vol). The reaction was then stirred for 1 h. Water (24 vol) was added at 60°C within 1 hour and the mixture was then cooled to 20°C. The mixture was then stirred for 1 hour, filtered, washed with water (2 vol), washed with cold methanol (<5°C, 2 x 4 vol) and dried under vacuum. 3-[5-Amino-4-(3-cyanobenzoyl)-1H-pyrazol-1-yl]-4-methylbenzoic acid (compound 5) was obtained as pale yellow solid in 52% yield , purity 98% (HPLC, area %).

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Abstract

Provided is a process for preparing the compound 3 (3) or a salt or a solvate thereof, the process comprising the steps of a) Mixing the compound 4 with a mineral acid (4); b) Adding a nitrite salt or an organic nitrite derivative to the reaction mass to form a diazonium salt; c) Adding a sulfur-containing reducing agent to the reaction mass to form a hydrazyl sulfur complex, such as a hydrazyl sulfite complex; d) Hydrolysing the hydrazyl sulfur complex to provide the compound 3 or a salt or solvate thereof; and e) Optionally isolating the compound 3 or a salt or solvate thereof. Further provided is the use of the compound 3 in the synthesis of 3-[5-Amino-4- (3-Cyanobenzoyl)-Pyrazol-1-yl]-N-Cyclopropyl-4-Methylbenzamide.

Description

[0001] field of invention [0002] The invention discloses a new method for preparing 3-hydrazino-4-methyl-benzoic acid and its application in the synthesis of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl] -Use in N-cyclopropyl-4-methylbenzamide. [0003] Background of the invention [0004] The compound 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide was first disclosed in the international patent application WO2005 / 009973 Among them, various other pyrazole and imidazole compounds have cytokine inhibitory activity. WO2005 / 009973 discloses that such compounds are useful in the treatment of conditions associated with p38 kinases, especially p38α kinase and p38β kinase, including chronic obstructive pulmonary disease. WO2005 / 009973 discloses 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide as one such New pyrazole p38 kinase inhibitors. 3-[5-Amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide has the foll...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C241/02
CPCC07C241/02C07C243/22C07D231/38C07C2601/16C07C255/56
Inventor 李云中姜晓斌尼克·约翰内斯·朗德卡门·鲁伊斯杰罗姆·道弗涅
Owner MEREO BIOPHARMA 1
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