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Process for the preparation of highly pure 2-((5-bromo-4-(cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid, salts thereof and solid state forms thereof

IP.com Disclosure Number: IPCOM000247971D
Publication Date: 2016-Oct-14

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   Process for the preparation of highly pure 2-((5-bromo-4- (cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid, salts thereof and solid state forms thereof

Disclosed herein after is a process for preparation of2-((5-bromo-4- (cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid (referred herein as comound I), salts and solid state forms thereof

Preparation of compound I:

Preparation of Dicyclohexylamine 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)- 4H-1,2,4-triazol-3-yl)thio)acetate

Methyl 2-((5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (100 g) was taken in dichloromethane (1000 mL) at 25ºC. Added aqueous Hydrobromic acid (48%) (730-850 gms) at 20ºC. To the resulting solution aqueous sodium nitrite solution (196-240 gms,) dissolved in water (500 mL) was added and stirred reaction mass at -10 to -3ºC for 3 hours. After completion of reaction, aqueous sodium metabisulfite solution (30%) (1000 ml) was added followed by layer separation. Organic layer was washed with water and concentrated under vacuum at 40-45ºC to get Methyl 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate as oily mass. Added sodium hydroxide solution (16-30 g, dissolved in 400-600 ml water) to the obtained oily mass and stirred for 2 hours at 25-30ºC.Added ethyl acetate (500-1000 mL) and adjusted pH=0.50 to 3.50 by dilute hydrochloric acid (80 mL-150 ml) at 20- 30ºC. Layers were separated and distilled out ethyl acetate under vacuum at 40-45ºC till 100-300 mL of residue. Cooled reaction mass up to 20ºC and added methanol(200-400 mL) followed by addition of dicylcohexylamine(56.2-68.0g).Stirred reaction mass for 4-5 hours at 30-40ºC.Cooled to 0ºC and stirred for 2 hours at 0-5ºC.Filtered reaction mass at 0-5ºC and washed with ethyl acetate(500 mL).Dried under vacuum at 40-45ºC to get dicyclohexylamine 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3- yl)thio)acetate (107-120 g ).

Preparation of 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3- yl)thio)acetic acid

Dicyclohexylamine 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3- yl)thio) acetate(100 g ) was taken in ethyl acetate (1000 mL) at 25ºC. Added water (1000 mL) at 20ºC. Reaction mass was heated up to 40ºC.pH was adjusted to 0.50-3.50 by hydrochloric acid solution (80-130 mL) followed by stirring for 2.0 hours. Reaction mass was filtered through hyflo bed at 35-40ºC.Layers were separated and washed organic layer with water (500 mL) twice. Added activated carbon (10 g) to the organic layer and heated up to 60ºC .Stirred for 1.0 hour at 55-60ºC followed by filtration through hyflo bed and bed was washed with ethyl acetate (200 mL). Concentrated ethyl acetate under vacuum till 40-45ºC and stirred the resulting mass for 4-5 hours at 20- 25ºC followed by filtration and washing with ethyl acetate (100 mL) at 20-30ºC. Wet product is dried under vacuum ove...