Diisopropylethylamine → 1-({2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetyl)azetidin-3-ol

HRID 1474727Notes

Reaction equation

HRID 1474727 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](O)=[O:32].Cl.[NH:35]1[CH2:38][CH:37]([OH:39])[CH2:36]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>[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[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[CH:5]=[C:4]([F:29])[C:3]=1[CH2:30][C:31]([N:35]1[CH2:38][CH:37]([OH:39])[CH2:36]1)=[O:32]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 27592903-Hydroxyazetidine hydrochlorideHCID 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 895837941-({2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetyl)azetidin-3-ol

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 (1.00 g, 2.17 mmol) in 8 ml anhydrous DMF at RT was added azetidin-3-ol hydrochloride (0.475 g, 4.33 mmol) and N,N-diisopropylethylamine (1.84 ml, 10.8 mmol). 0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.65 g, 4.33 mmol) was added and the mixture stirred at RT overnight. The mixture was filtered and purified by reverse-phase HPLC column chromatography (SunFire Prep C18 OBD Sum 19×100 mm column; 35-75% acetonitrile in 0.1% formic acid in water gradient) to afford the title compound. 1H NMR (CD3OD): δ 8.26 (s, 2H), 6.57 (d, J=9.4 Hz, 2H), 4.69 (t, J=12.5 Hz, 2H), 4.57-4.59 (m, 1H), 4.45-4.49 (m, 1H), 4.27 (s, 2H), 4.18-4.22 (m, 1H), 4.01-4.09 (m, 3H), 3.75-3.78 (m, 1H), 3.47 (s, 2H), 3.34 (s, 3H), 2.86-2.93 (m, 2H), 2.09-2.12 (m, 1H), 1.82-1.88 (m, 2H), 1.56-1.58 (m, 1H), 1.31-1.35 (m, 2H), 1.16-1.18 (m, 1H), 0.95-0.97 (m, 1H), 0.59-0.68 (m, 2H), −0.04 (m, 1H). LC/MS (m/z): 517.5 (M+H)+. Human EC50: 1.6 nM

Workup

  1. filtrationThe mixture was filtered
  2. custompurified by reverse-phase HPLC column chromatography (SunFire Prep C18 OBD Sum 19×100 mm column; 35-75% acetonitrile in 0.1% formic acid in water gradient)

Sources & evidence

ORD record
ord-4c45ffcc7b2e40ef9a2d96f15dc13d3a
Source dataset
uspto-grants-2015_04
Patent number
US09018224B2

Reaction notes

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