Tributylphosphine → (R)-1-[5-(4-chlorophenoxy)pyrazin-2-yl]-5-(3-methoxyphenyl)pyrrolidin-2-one

Tri-n-butylphosphine (0.178 mL, 0.72 mmol) is added to a solution of di-tert-butyl azodicarboxylate (167 mg, 0.72 mmol) in dry THF (1.5 mL) at room temperature. The resulting mixture is stirred for 5 min at room temperature, then added dropwise to a solution of (S)—N-[5-(4-chlorophenoxy)pyrazin-2-yl]-4-hydroxy-4-(3-methoxyphenyl) butanamide (194 mg, 0.47 mmol) in THF (1.5 mL) at 0° C. and under argon. The reaction mixture is allowed to warm slowly to ambient temperature and stirred for 1.5 h, then partitioned between saturated aqueous NaHCO3 (5 mL) and CH2Cl2 (10 mL). The aqueous layer is extracted with CH2Cl2 (3×10 mL). The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is then purified on silica gel (0-33% ethyl acetate in hexane) to give (R)-1-[5-(4-chlorophenoxy)pyrazin-2-yl]-5-(3-methoxyphenyl)pyrrolidin-2-one (130 mg, 70%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 9.11 (d, J=1.2 Hz), 7.99 (d, J=1.6 Hz, 1H), 7.37-7.31 (m, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.07-7.02 (m, 2H), 6.81-6.72 (m, 3H), 5.68 (dd, J=8.2, 3.8 Hz, 1H), 3.77 (s, 3H), 2.89-2.74 (m, 1H), 2.72-2.57 (m, 2H), 2.10-1.99 (m, 1H). HPLC-MS calculated C21H18ClN3O3 (M+H+): 396.11, found: 396.10.

1. temperatureto warm slowly to ambient temperature
2. stirringstirred for 1.5 h
3. custompartitioned between saturated aqueous NaHCO3 (5 mL) and CH2Cl2 (10 mL)
4. extractionThe aqueous layer is extracted with CH2Cl2 (3×10 mL)
5. dry with materialThe combined organic extracts are dried over Na2SO4
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customThe residue is then purified on silica gel (0-33% ethyl acetate in hexane)

ORD record

ord-24d4391b1f20491480978ad9d40d9cd5

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08431607B2