Azetidine → 1-(azetidin-1yl)-2-(2,6-difluoro-4-{2[(1S,2R)-2-{1-[5-(methoxylmethyl)pyrimidin-2yl]piperidin-4-yl}cyclopropyl]ethoxyl}phenyl)ethanone

HRID 1474728Notes

Reaction equation

HRID 1474728 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]=[C:4]([F:29])[C:3]=1[CH2:30][C:31]([OH:33])=O.[NH:34]1[CH2:37][CH2:36][CH2:35]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:34]1([C:31](=[O:33])[CH2:30][C:3]2[C:2]([F:1])=[CH:7][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:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=4)[CH2:16][CH2:15]3)=[CH:5][C:4]=2[F:29])[CH2:37][CH2:36][CH2:35]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 89583798{2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid

Product 1

HCID 895840341-(azetidin-1yl)-2-(2,6-difluoro-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 {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy}phenyl]acetic acid (5.00 g, 10.8 mmol) in 8 ml anhydrous DMF at RT was added azetidine (0.928 g, 16.3 mmol) and N,N-diisopropylethylamine (3.78 ml, 21.7 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.18 g, 16.3 mmol) was added to the solution and the mixture stirred at RT for 4 hrs. The residue was purified by preparative biotage reverse phase (C-18) (100 g column), eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%). The solid was purified by column chromatography on silica gel (Biotage 40M), eluting with EtOAc/hexanes (30% to 90%). The product was further purified by preparative biotage Reverse phase (C-18)(100 g), eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 2H), 6.67 (d, J=9.4 Hz, 2H), 4.67 (t, J=13.9 Hz, 2H), 4.18 (m, 4H), 4.06 (m, 211), 3.85 (t, J=7.8 Hz, 2H), 3.38 (s, 2H), 3.23 (s, 3H), 2.85 (m, 2H), 2.20 (m, 211), 2.03 (m, 1H), 1.75 (t, J=14.2 Hz, 2H), 1.51 (m, 114), 1.21-1.25 (m, 3H), 0.87 (m, 1H), 0.57 (m, 2H), −0.08 (m, 1H). LC/MS (m/z): 501.4 (M+H)+. GPR119 Human EC50: 0.18 nM

Workup

  1. customThe residue was purified by preparative biotage reverse phase (C-18) (100 g column)
  2. washeluting with Acetonitrile/Water+0.1% formic acid (35% to 90%)
  3. customThe solid was purified by column chromatography on silica gel (Biotage 40M)
  4. washeluting with EtOAc/hexanes (30% to 90%)
  5. customThe product was further purified by preparative biotage Reverse phase (C-18)(100 g)
  6. washeluting with Acetonitrile/Water+0.1% formic acid (35% to 90%)

Sources & evidence

ORD record
ord-e809f35430b14ba39cec12ec10619d00
Source dataset
uspto-grants-2015_04
Patent number
US09018224B2

Reaction notes

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