Synthesis
General procedure for the synthesis of 2-methyl-6-quinoline carboxylic acid from p-aminobenzoic acid and trans-2-butenal:
Intermediate 13: Synthesis of (2-methylquinolin-6-yl)methylamine:
Step 1: Preparation of 2-methylquinoline-6-carboxylic acid: 6N hydrochloric acid (73 ml) was added to 4-aminobenzoic acid (5 g, 36.45 mmol) and heated to reflux for 2 hours. Subsequently, crotonaldehyde (3.06 g, 43.75 mmol) was added slowly and dropwise over 45 min. After 12 hours of reaction, the reaction mixture was cooled to 0 °C and the pH was adjusted to 3-5 with aqueous ammonia solution. the aqueous phase was extracted with dichloromethane, the organic phases were combined and acidified with 2N hydrochloric acid, the precipitate was collected by filtration and dried under vacuum to afford 2-methyl-6-quinolinecarboxylic acid as a brown solid (3.0 g, 44% yield).
References
[1] Patent: WO2013/144737, 2013, A2. Location in patent: Paragraph 252
[2] Patent: US2015/57309, 2015, A1. Location in patent: Paragraph 0524
[3] Journal of Medicinal Chemistry, 2002, vol. 45, # 21, p. 4647 - 4654
[4] Chemistry - A European Journal, 2018, vol. 24, # 61, p. 16368 - 16378
[5] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6138 - 6141
