Azetidine → 1-(azetidin-1-yl)-2-(3-fluoro-4-((((1R,2R)-2-(1-(5-(methoxymethyl) pyrimidin-2-yl)piperidin-4-yl)cyclopropyl)methoxy)methyl)phenyl)ethanone

HRID 1468877Notes

Reaction equation

HRID 1468877 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30](O)=[O:31])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=2)[CH2:16][CH2:15]1.O.O[N:35]1[C:39]2C=CC=[CH:43][C:38]=2N=N1.Cl.C(/N=N/CCCN(C)C)C.N1CCC1>C(Cl)Cl>[N:35]1([C:30](=[O:31])[CH2:29][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=4)[CH2:18][CH2:19]3)=[C:2]([F:1])[CH:3]=2)[CH2:43][CH2:38][CH2:39]1

Participants

6

Reactant 4

HCID 10422AzetidineHCID 27960291-Hydroxybenzotriazole hydrateHCID 867178062-(3-fluoro-4-((((1R,2R)-2-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)cyclopropyl)methoxy)methyl)phenyl)acetic acidHCID 178465607HCID 178465607, compound

Product 1

HCID 711366761-(azetidin-1-yl)-2-(3-fluoro-4-((((1R,2R)-2-(1-(5-(methoxymethyl) pyrimidin-2-yl)piperidin-4-yl)cyclopropyl)methoxy)methyl)phenyl)ethanoneYield 76.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

2-(3-Fluoro-4-((((1R,2R)-2-(1-(5-(methoxymethyl)pyrimidin-2-yl)piperidin-4-yl)cyclopropyl)methoxy)methyl)phenyl)acetic acid (Step D product, 70 mg, 0.158 mmol), 1-HYDROXYBENZOTRIAZOLE HYDRATE (36.3 mg, 0.237 mmol) and (E)-3-(ETHYLDIAZENYL)-N,N-DIMETHYLPROPAN-1-AMINE HYDROCHLORIDE (42.5 mg, 0.237 mmol) were dissolved in CH2Cl2 (3 ml). The mixture was stirred at RT for 10 min., to which was added AZETIDINE (0.016 ml, 0.237 mmol). The reaction mixture was stirred at RT overnight. TLC and LC-MS showed the SM was completely consumed. The mixture was diluted with DCM, washed with water, dried over MgSO4, and evaporated to dryness. The crude product was purified by prep TLC (pure EtOAc) to afford 58.2 mg (76%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 8.30 (S, 2H), 7.38 (m, 1H), 7.05 (m, 2H), 4.70 (m, 2H), 4.60-4.50 (m, 2H), 4.25 (s, 2H), 4.10˜4.00 (m, 4H), 3.70 (m, 1H), 3.40 (m, 3H), 3.32 (s, 3H), 2.83 (m, 2H), 2.25 (m, 2H), 2.05 (m, 2H), 1.82 (m, 1H), 1.40-1.20 (m, 3H), 1.05 (m, 1H), 0.70 (m, 2H), 0.40 (m, 1H). LC/MS (m/z): 483 (M+H)+, GPR119 Human EC50: 5.16 nM.

Workup

  1. stirringThe reaction mixture was stirred at RT overnight
  2. customwas completely consumed
  3. additionThe mixture was diluted with DCM
  4. washwashed with water
  5. dry with materialdried over MgSO4
  6. customevaporated to dryness
  7. customThe crude product was purified by prep TLC (pure EtOAc)

Sources & evidence

ORD record
ord-8ff19329d1954ee7840bdd25b7d8f2ef
Source dataset
uspto-grants-2015_04
Patent number
US09006228B2

Reaction notes

Loading…