Tetrahydrofuran → HCID 178483558, compound

HRID 2274399Notes

Reaction equation

HRID 2274399 reaction equation
[N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)[CH:14]([CH3:16])[CH3:15])(C)C.Cl.C(N(CC)C([NH:25][C:26]1[C:27]([C:31]2[NH:35][C:34]3[CH:36]=[C:37]([O:41][CH2:42][CH2:43][CH2:44][N:45]4[CH2:50]CCC[CH2:46]4)[C:38]([F:40])=[CH:39][C:33]=3[N:32]=2)=[N:28][NH:29][CH:30]=1)=O)C.C(=O)(O)[O-].[Na+].C1C[O:61][CH2:60][CH2:59]1>>[CH3:50][N:45]([CH3:46])[CH2:44][CH2:43][CH2:42][O:41][C:37]1[C:38]([F:40])=[CH:39][C:33]2[N:32]=[C:31]([C:27]3[C:26]([NH:25][C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:8])=[CH:30][N:29]([CH:15]4[CH2:14][CH2:16][CH2:59][CH2:60][O:61]4)[N:28]=3)[NH:35][C:34]=2[CH:36]=1

Participants

6

Reactant 5

HCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 2420851-Piperidinecarbonyl chlorideHCID 516892Sodium BicarbonateHCID 178464318HCID 178464318, compound

Product 1

HCID 178483558HCID 178483558, compound

Conditions

Temperature
52 °C

Procedure

171.3 μL of piperidylcarbonyl chloride and 200 μL of N,N-diisopropylethylamine are added to a solution of 100 mg of intermediate 1 in 10 mL of THF. The reaction mixture is heated at 52° C. for 48 hours. The reaction medium is cooled to ambient temperature and then 20 mL of a saturated solution of sodium bicarbonate are added. The aqueous phase is extracted with 3 times 10 mL of EtOAc. The organic phases are dried over MgSO4, filtered and concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-4 cartridge. Elution is carried out with a dichloromethane/methanol mixture. 28 mg of piperidine-1-carboxylic acid [3-[6-(3-dimethylaminopropoxy)-5-fluoro-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide are obtained in the form of a brown resin. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.50 to 2.36 (m, 14H); 2.29 (broad s, 6H); 2.55 (m partially masked, 2H); 3.50 (m, 4H); 3.66 (m, 1H); 3.96 (m, 1H); 4.11 (m, 2H); 5.46 (broad d, J=10.0 Hz, 1H); from 7.08 to 7.55 (m, 2H); 8.14 (broad s, 1H); from 9.66 to 9.93 (m, 1H); 13.05 (m, 1H).

Workup

  1. temperatureThe reaction medium is cooled to ambient temperature
  2. extractionThe aqueous phase is extracted with 3 times 10 mL of EtOAc
  3. dry with materialThe organic phases are dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under vacuum in a rotary evaporator
  6. customThe reaction crude
  7. customis purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-4 cartridge
  8. washElution

Sources & evidence

ORD record
ord-85e78daf7aca4915a1c577dadd6878c3
Source dataset
uspto-grants-2015_09
Patent number
US09126969B2

Reaction notes

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