Trifluoroacetic acid → (S)-1-((S)-2-tert-Butoxycarbonylamino-3-pyrazol-1-yl-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

To (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl)ester (909 mg, 1.97 mmol) in anhydrous dichloromethane (6 mL) at room temperature and under an atmosphere of nitrogen was added trifluoroacetic acid (6 mL, 173 mmol). The solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated in vacuo and the residue co-evaporated from toluene (3×). The resulting brown viscous oil was dissolved in anhydrous acetonitrile (2 mL) and added to a solution of L-N-Boc-3-pyrazol-1-yl-alanine (500 mg, 1.97 mmol), N,N-diisopropylethylamine (1.4 mL, 7.87 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (747 mg, 1.97 mmol) in anhydrous acetonitrile (10 mL) that had been previously stirred at 0° C. for 20 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was cooled to 0° C. diluted with ethyl acetate and quenched with 1 M hydrochloric acid. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×). The organic layer was then dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 then 2:1 to give the title compound (999 mg, 95%) as a white foam, as a 2:1 mixture of diastereoisomers. LCMS (m/z) 500.1 [M+H], Tr=2.71 min.

1. concentrationThe reaction was concentrated in vacuo
2. dissolutionThe resulting brown viscous oil was dissolved in anhydrous acetonitrile (2 mL)
3. stirringhad been previously stirred at 0° C. for 20 minutes
4. temperatureThe reaction was warmed to room temperature
5. stirringstirred for 16 h
6. temperatureThe reaction was cooled to 0° C.
7. customquenched with 1 M hydrochloric acid
8. customThe organic layer was separated
9. washwashed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×)
10. customThe organic layer was then dried through a hydrophobic frit
11. concentrationconcentrated in vacuo
12. customThe residue was purified by silica gel chromatography

ORD record

ord-87f61f8412c14c1588e147d80c7d84ee

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09145441B2