3-(4-Carboxyphenyl)propionic acid (50 g, 0.2577 mol), AlCl3 (240 g, 1.804 mol) and sodium chloride (24 g, 10% of the weighed portion of AlCl3) were mixed in a round-bottomed flask. The reaction mixture was heated for 1 hour at 190° C., cooled to 100° C. and carefully poured onto ice. The reaction mixture was acidified by means of 6 molar HCl (1200 ml) and extracted with ethyl acetate (4×800 ml). The org. phase was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was used in the next step without being purified further. Yield: 33% (15 g, 0.035 mol) Step 2: The product from step 1 (4 g, 0.022 mol) was dissolved in methanol (100 ml); concentrated sulfuric acid (0.5 ml) was added, and refluxing was carried out for 12 hours. After monitoring by thin-layer chromatography, the reaction mixture was concentrated to dryness and the residue was purified by column chromatography. Yield: 58% (2.5 g, 0.012 mol) Step 3: The product from step 2 (2.5 g, 0.012 mol) was dissolved in methanol (50 ml); hydroxylamine HCl (2.72 g, 0.0394 mol) and sodium acetate (6.4 g, 0.0786 mol) were added at RT, and the mixture was heated for 2 hours at boiling temperature. After monitoring by thin-layer chromatography, the reaction mixture was concentrated and the residue was taken up in ethyl acetate, washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was used in the next step without being purified further. Yield: 90% (2.5 g, 0.0198 mol) Step 4: The product from step 3 (21 g, 0.1024 mol) was dissolved in ethanol (300 ml); water (52 ml) and conc. HCl solution (105 ml) were added, and stirring was carried out for 15 minutes. The reaction solution was cooled, Zn powder (40.17 g, 0.1024 mol) was added carefully, and the mixture was heated for 1 hour at boiling temperature. The reaction mixture was cooled to RT, filtered over Celite and washed with ethanol. The filtrate was concentrated under reduced pressure, and the residue was taken up several times in toluene and dried again. The resulting crude amine (100 g) was taken up in 1,4-dioxane (300 ml) and cooled to 0° C., and triethylamine (67 ml, 0.66 mol) was added. Boc anhydride (70 g, 0.3165 mol) was added at the same temperature, and stirring was carried out for 12 hours at RT. The reaction mixture was concentrated and taken up in ethyl acetate (1500 ml) and water (1000 ml). The org. phase was separated off, washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography. A light-yellow solid was obtained. Yield: 53% (16 g, 0.054 mol) Step 5: The product from step 4 (2 g, 0.0068 mol) was dissolved in dichloromethane (70 ml); TFA (14 ml) was added dropwise at 0° C., and stirring was carried out for 2 hours at RT. The reaction solution was concentrated to yield the TFA salt of the amine. 2-Trifluoromethyl-pyridine-3-carboxylic acid (1.3 g, 0.0068 mol) was dissolved in dichloromethane (25 ml); HATU (3.87 g, 0.0102 mol) and DI PEA (4.8 ml, 0.0272 mol) were added at 0° C., and stirring was carried out for 15 minutes. The amine-TFA salt was dissolved in dichloromethane (25 ml) and DIPEA (1.5 ml, 0.086 mol), added dropwise at 0° C. to the reaction solution and stirred for 16 hours at RT. The mixture was then diluted with dichloromethane (100 ml), washed in succession with ammonium chloride solution (2×50 ml), sat. sodium hydrogen carbonate solution (2×50 ml), water (50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, MeOH/DCM). Yield: 66% (1.6 g, 0.0043 mol) Step 6: The product from step 5 (1.5 g, 0.0041 mol) was dissolved in a mixture of THF:MeOH:water (6:4:1, 27 ml) and cooled to 0° C.; LiOH H2O (0.519 g, 0.00123 mol, 3.0 eq.) was added in portions, and stirring was carried out for 8 hours at RT. The reaction mixture was concentrated under reduced pressure, taken up in a small amount of water and washed with diethyl ether. The aqueous phase was acidified at 0° C. with 2 molar HCl solution. A white solid precipitated, which was filtered off, washed with water and dried for 4 hours at 60° C. in vacuo. Yield: 90% (1.3 g, 0.0037 mol)
HCID 81531Diisopropylethylamine
HCID 168937Lithium hydroxide, monohydrate
HCID 27775472-(Trifluoromethyl)pyridine-3-carboxylic acid
HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)
HCID 21892291Methanol tetrahydrofuran water
