Ammonium Acetate → HCID 86706051, compound

Zinc dust (1.3 g, 20.3 mmol) was added to a solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (400 mg, 0.92 mmol) in tetrahydrofuran (20 mL). This suspension was treated with a solution of ammonium acetate (1.1 g, 13.9 mmol) in water (7 mL). After stirring at room temperature for 16 h, the zinc residues were filtered off and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and saturated potassium hydrogen sulfate solution, the aqueous layer was extracted with ethyl acetate (2×), the organic layers were combined and the volatiles were removed in vacuo. The residual acetic acid was azeotroped off with toluene (3×10 mL) to give crude (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid (280 mg, 99%) half of which (140 mg, 0.46 mmol) was combined with (R)-1-(7-bromo-quinolin-2-yl)-ethylamine hydrochloride (obtained from ASIBA Pharmatech, Inc.), (194 mg, 0.60 mmol) and N,N-diisopropylethylamine (0.400 mL, 2.3 mmol) in anhydrous acetonitrile (10 mL). This solution was then treated with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (227 mg, 0.60 mmol). After stirring at room temperature for 3 h, the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate and subsequently washed with saturated ammonium chloride solution and sodium bicarbonate solution. The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 1:1 to afford the title compound (136 mg, 55%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 0.83 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 1.38 (d, J=6.9 Hz, 3H), 1.60 (d, J=6.9 Hz, 3H), 1.65-1.75 (m, 3H), 1.87-1.96 (m, 1H), 2.02-2.12 (m, 2H), 2.87-3.00 (m, 1H), 3.55-3.62 (m, 1H), 3.81 (d, J=3.4 Hz, 1H), 4.24-4.34 (m, 1H), 5.18-5.28 (m, 1H), 5.31-5.40 (m, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.69 (dd, J=8.7, 1.8 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 8.26 (d, J=1.6 Hz, 1H), 8.33 (d, J=8.7 Hz, 1H). LCMS (m/z) 534.1, 536.1 [M+H], Tr=2.27 min.

1. filtrationthe zinc residues were filtered off
2. customthe volatiles were removed in vacuo
3. customThe residue was partitioned between ethyl acetate and saturated potassium hydrogen sulfate solution
4. extractionthe aqueous layer was extracted with ethyl acetate (2×)
5. customthe volatiles were removed in vacuo
6. customThe residual acetic acid was azeotroped off with toluene (3×10 mL)

ORD record

ord-885cce3595fd46d4902b7ce7227c768d

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09062092B2