Process for preparation of (R)-4-aminoindane and corresponding amides
A trimethylindane and reaction technology, which is used in the field of preparing (R)-4-aminoindane and corresponding amides, can solve problems such as complex operations, large yield loss, and increased costs
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Embodiment 1
[0199] Example 1 - Operation Sequence A
[0200] a) Preparation of 1-acetyl-6-fluoro-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (IIIb)
[0201] The compound 1-acetyl-6-fluoro-2,2,4-trimethyl-1 in racemic form and containing acetyl as nitrogen protecting group was prepared and isolated following the procedure described in patent application WO2017 / 178868 , 2,3,4-tetrahydroquinoline.
[0202] b) Chiral separation of racemic 1-acetyl-6-fluoro-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (IIIb)
[0203] 1.7 g of racemic 1-acetyl-6-fluoro-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were dissolved in n-heptane and isopropanol (85:15 ) and subjected to chiral separation by preparative chromatography eluting with a mixture of n-heptane and isopropanol (99:1). Two enantiomers were obtained after evaporation of the solvent under reduced pressure: 0.84 g (4R)-1-acetyl-6-fluoro-2,2,4-trimethyl-1,2,3,4-tetra Hydroquinoline (IVb) (100% e.e; Yield = 50% ) and 0.84 g of (4S)-1-acetyl-...
Embodiment 2
[0214] a) 3-Difluoromethyl-N-[(3R)-7-fluoro-1,1,3-trimethyl-4-indanyl]-1-methyl-4-pyrazolecarboxamide (II ) preparation
[0215] 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid chloride (0.58 g, 3.0 mmol) obtained according to known organic chemistry procedures was added to the enantiomerically pure isomer A solution of the compound (3R)-7-fluoro-1,1,3-trimethylindan-4-ylamine (I) (0.58 g, 3.0 mmol) in heptane (11 mL), heated to 50 °C. The addition of acid chloride occurs by dropwise addition over about ten minutes, forming a precipitate. The reaction mixture was heated at reflux (95°C to 97°C internal) while releasing gaseous HCl. After 4 hours, the reaction was complete and the mixture was cooled to room temperature and basified to pH=8-10 with 2.5 wt% aqueous sodium hydroxide solution (5 mL).
[0216] The precipitate was filtered and the solid obtained was suspended in water (5 mL) at 45°C and filtered again. The solid was washed again on the filter with water (...
Embodiment 3
[0222] a) Preparation of 1-acetyl-6-fluoro-4-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (VII)
[0223] Make 0.80 g of (4S)-1-acetyl-6-fluoro-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (Vb) (3.40 mmol) in acetonitrile (10 mL) The solution was refluxed and 20 wt% KMnO was slowly added dropwise over 5 h 4 Aqueous solution (17.0 mmol), the mixture was kept at reflux and stirred vigorously. At the end of the dropwise addition, the mixture was refluxed for 3 hours.
[0224] After that, it was cooled to room temperature and isopropanol (1.0 mL) was added while stirring continued for 1 hour.
[0225] The heterogeneous mixture was filtered on celite to remove salts, and the filter was washed with ethyl acetate and water.
[0226] The phases were separated and the aqueous phase was re-extracted with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain 0.76 g of 1-acetyl...
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