Azetidine → 1-(azetidin-1yl)-2-(2-fluoro-4-{2[(1S,2R)-2-{1-[5-(methoxylmethyl)pyrimidin-2yl]piperidin-4-yl}cyclopropyl]ethoxyl}phenyl)ethanone

HRID 1474698Notes

Reaction equation

HRID 1474698 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([OH:32])=O.[NH:33]1[CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:33]1([C:30](=[O:32])[CH2:29][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=4)[CH2:16][CH2:15]3)=[CH:7][C:2]=2[F:1])[CH2:36][CH2:35][CH2:34]1

Participants

6

Reactant 4

HCID 10422AzetidineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 117678258[2-fluoro-4-(2-{(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl}ethoxy)phenyl]acetic acid

Product 1

HCID 895841181-(azetidin-1yl)-2-(2-fluoro-4-{2[(1S,2R)-2-{1-[5-(methoxylmethyl)pyrimidin-2yl]piperidin-4-yl}cyclopropyl]ethoxyl}phenyl)ethanone

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of {2-fluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid (500 mg, 1.13 mmol) in 8 ml of anhydrous DMF at RT was added azetidine (129 mg, 2.26 mmol) and N,N-diisopropylethylamine (0.591 ml, 3.38 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (643 mg, 1.69 mmol) was added to the solution and stirred at RT for 4 hrs. The mixture was purified by column chromatography by loading directly to a preparative biotage reverse phase column (C-18) (50 g column) and eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%). The material was further purified by column chromatography on silica gel Biotage 40S, eluting with EtOAc/hexanes (30% to 90%) to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.29 (s, 2H), 7.27 (t, J=8.4 Hz, 1H), 6.64 (d, J=2.1 Hz, 1H), 6.20 (d, J=2.3 Hz, 1H), 4.74 (t, J=13.2 Hz, 2H), 4.27 (s, 2H), 4.17 (t, J=7.7 Hz, 2H), 4.04 (m, 4H), 3.40 (s, 2H), 3.35 (s, 3H), 2.85 (m, 2H), 2.14-2.29 (m, 3H), 1.85 (m, 2H), 1.41 (m, 1H), 1.36 (m, 2H), 1.11 (m, 1H), 0.93 (m, 1H), 0.60-0.71 (m, 2H), −0.08 (m, 1H). LC/MS (m/z): 482.4 (M+H)+. GPR119 Human EC50: 0.77 nM

Workup

  1. customThe mixture was purified by column chromatography
  2. washeluting with Acetonitrile/Water+0.1% formic acid (35% to 90%)
  3. customThe material was further purified by column chromatography on silica gel Biotage 40S
  4. washeluting with EtOAc/hexanes (30% to 90%)

Sources & evidence

ORD record
ord-1792cd05c4094bec8357e0e1f2b8932d
Source dataset
uspto-grants-2015_04
Patent number
US09018224B2

Reaction notes

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