4-Methylmorpholine → (R/S)-N-(3-(3,3-difluoroazetidin-1-yl)-3-oxopropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide

HRID 77212

反応式

HRID 77212 の反応式
[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.[F:38][C:39]1([F:43])[CH2:42][NH:41][CH2:40]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:38][C:39]1([F:43])[CH2:42][N:41]([C:8](=[O:9])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:21]=[C:20]([C:22]4[O:26][N:25]=[C:24]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:23]=4[C:33]([F:35])([F:34])[F:36])[O:19][N:18]=3)=[CH:15][CH:16]=2)[CH2:40]1

参加物

6

反応物 4

HCID 79724-MethylmorpholineHCID 27582473,3-Difluoroazetidine hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 534964603-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid

生成物 1

HCID 53496465(R/S)-N-(3-(3,3-difluoroazetidin-1-yl)-3-oxopropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide収率 13.12%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

実験手順

(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Int-V, 25 mg, 0.050 mmol), 3,3-difluoroazetidine-HCl (6.45 mg, 0.050 mmol), 4-methylmorpholine (20.13 mg, 0.199 mmol), and HATU (24.60 mg, 0.065 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=10.6 min) to provide (R/S)-N-(3-(3,3-difluoroazetidin-1-yl)-3-oxopropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (5 mg, 6.53 μmol, 13.12% yield): LCMS=578.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.24 (2 H, m), 7.51-7.74 (7 H, m), 5.11 (1 H, s), 4.49 (2 H, td, J=11.77, 7.04 Hz), 4.29 (2 H, t, J=12.21 Hz), 3.45-3.58 (2 H, m), 2.38-2.52 (2 H, m); HPLC peak RT=9.4 min (Method A).

後処理

  1. customwas purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=10.6 min)

出典と根拠

ORDレコード
ord-d17bff185838476ab236e933c78d382e
出典データセット
uspto-grants-2014_09
特許番号
US08835470B2

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