4-(6-Amino-5-bromopyridin-3-yl)-1-methylpyrrolidin-2-one → 4-(2-amino-5-(1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide

HRID 595926Notes

Reaction equation

[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][C:3]=1Br.[Cl:16][C:17]1[CH:18]=[C:19]([C@H:23]([NH:26][C:27](=[O:44])[C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:29]=2[F:43])[CH2:24][OH:25])[CH:20]=[CH:21][CH:22]=1>>[NH2:1][C:2]1[C:3]([C:31]2[CH:32]=[CH:33][C:28]([C:27]([NH:26][C@@H:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=3)[CH2:24][OH:25])=[O:44])=[C:29]([F:43])[CH:30]=2)=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:14])[N:11]([CH3:13])[CH2:12]2)=[CH:6][N:7]=1

Participants

Reactant 2

HCID 1180455874-(6-Amino-5-bromopyridin-3-yl)-1-methylpyrrolidin-2-one

HCID 131734605(S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Product 1

HCID 1180461604-(2-amino-5-(1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide

Procedure

Following Step 6 in Scheme 50, using 4-(6-amino-5-bromopyridin-3-yl)-1-methylpyrrolidin-2-one and (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, 4-(2-amino-5-(1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was obtained as a diastereomeric mixture (33.3%). LCMS (m/z): 483.3 (MH+), 0.59 min; 1H NMR (400 MHz, CD3OD) δ ppm 8.79-8.61 (m, 1H) 7.97 (d, J=1.96 Hz, 1H) 7.93-7.82 (m, 2H) 7.48-7.39 (m, 3H) 7.39-7.25 (m, 3H) 5.25-5.14 (m, 1H) 3.95-3.76 (m, 3H) 3.69 (quin, J=8.22 Hz, 1H) 3.50 (dd, J=9.78, 7.43 Hz, 1H) 2.89 (s, 3H) 2.80 (dd, J=16.82, 9.00 Hz, 1H) 2.56 (dd, J=16.82, 8.22 Hz, 1H). The diastereomeric mixture was separated by chiral SFC (ChiralPak 5mic AD column, 4.6×100 (mm), IPA+0.1% DEA=40%, 5 mL/min). The polar diastereomer, 4-(2-amino-5-((R)-1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide, was obtained at Rt=1.41 min. LCMS (m/z): 483.3 (MH+), 0.586 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=1.56 Hz, 1H) 7.74 (t, J=7.83 Hz, 1H) 7.35 (d, J=2.35 Hz, 2H) 7.33-7.15 (m, 5H) 5.09 (t, J=5.87 Hz, 1H) 4.48 (s, 1H)) 3.83-3.63 (m, 3H) 3.50 (quint, J=8.22 Hz, 1H) 3.36 (dd, J=9.39, 7.43 Hz, 1H) 2.78 (s, 3H) 2.67 (dd, J=16.82, 9.00 Hz, 1H) 2.42 (dd, J=16.63, 8.41 Hz, 1H). The less polar diastereomer, 4-(2-amino-5-((S)-1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide, was obtained at Rt=2.16 min. LCMS (m/z): 483.3 (MH+), 0.585 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (d, J=2.35 Hz, 1H) 7.84 (t, J=8.02 Hz, 1H) 7.51-7.21 (m, 7H) 5.18 (t, J=5.87 Hz, 1H) 3.94-3.72 (m, 3H) 3.59 (quin, J=8.22 Hz, 1H) 3.50-3.42 (m, 1H) 2.88 (s, 3H) 2.82-2.70 (m, 1H) 2.51 (dd, J=16.82, 8.61 Hz, 1H).

Sources & evidence

ORD record: ord-73b18aacef0a4e5595aeef20137dd63e
Source dataset: uspto-grants-2016_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09242996B2

Reaction notes

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