Diisopropylethylamine → 1-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

HRID 572066Notes

Reaction equation

HRID 572066 reaction equation
ClC(Cl)(Cl)CO[C:5](=[O:16])[NH:6][C:7]1[O:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:10][N:11]=1.[CH:19]([C:22]1[N:26]2[CH:27]=[C:28]([O:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@@H:35]([NH2:42])[CH2:34][CH2:33]3)[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1)([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:12]([C:9]1[O:8][C:7]([NH:6][C:5]([NH:42][C@@H:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:32]([O:31][C:28]3[CH:29]=[CH:30][C:25]4[N:26]([C:22]([CH:19]([CH3:21])[CH3:20])=[N:23][N:24]=4)[CH:27]=3)[CH2:33][CH2:34]2)=[O:16])=[N:11][N:10]=1)([CH3:13])([CH3:14])[CH3:15]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 86686683(1S,4S)-4-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylamineHCID 86686684(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-carbamic acid 2,2,2-trichloro-ethyl ester

Product 1

HCID 715997931-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-3-[(1S,4S)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaYield 81.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A solution of Intermediate 5d (83.1 mg, 0.263 mmol), Intermediate 5c (80.6 mg, 0.250 mmol), and DIPEA (54.4 μL, 0.313 mmol) in DMF (2 mL) was stirred at 125° C. for 45 min. After cooling, the mixture was concentrated in vacuo to give a brown oil. This was suspended in water (5 mL) and extracted with DCM (2×5 mL). The combined organics were passed through a hydrophobic frit and concentrated under vacuum to leave a brown oil. Purification by FCC, using 0-8% MeOH in EtOAc, followed by trituration (diethyl ether) afforded a buff solid (99.6 mg). Further purification by HPLC (10-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a flocculent white solid (25.9 mg, 21%). LCMS (Method 5): Rt 3.77 min, m/z 490 [MH+]. 1H NMR (400 MHz, CDCl3): 1.39 (9H, s), 1.52 (3H, d), 1.55 (3H, d), 2.00 (1H, m), 2.21-2.36 (2H, m), 2.43 (1H, m), 3.32 (1H, sept), 5.28-5.34 (2H, m), 7.12 (1H, dd), 7.30-7.38 (3H, m), 7.47-7.50 (2H, m), 7.73 (1H, d), 8.35 (1H, br s), 8.49 (1H, br d).

Workup

  1. temperatureAfter cooling
  2. concentrationthe mixture was concentrated in vacuo
  3. customto give a brown oil
  4. extractionextracted with DCM (2×5 mL)
  5. concentrationconcentrated under vacuum
  6. customto leave a brown oil
  7. customPurification by FCC

Sources & evidence

ORD record
ord-7add9b6047664718b16f87d3fd1b7b7f
Source dataset
uspto-grants-2015_05
Patent number
US09029373B2

Reaction notes

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