Hydrochloric Acid → 4'-{[4-(1,4-Dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3'-fluorobiphenyl-2-carbonitrile

HRID 1688517Notes

Reaction equation

HRID 1688517 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][CH:42]=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.Cl>C(N(CC)C1C=CC=CC=1)C.C(OCC)(=O)C>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][C:11]=4[F:27])=[C:22]([CH2:23][CH2:24][CH3:25])[N:40]4[N:41]=[CH:42][N:43]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1

Participants

7

Reactant 4

HCID 313Hydrochloric Acid2×HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 57460949Ethyl 2-[(2'-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoateHCID 178420920N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine

Product 1

HCID 670090304'-{[4-(1,4-Dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3'-fluorobiphenyl-2-carbonitrileYield 84%

Reagents, catalysts & solvents 2

HCID 7061N,N-DiethylanilineSolvent2×HCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
180 °C

Procedure

A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (408 g) and N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (125 g) were dissolved in N,N-diethylaniline (1.5 L) at 160° C. (internal temperature). A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (38 mL) in N,N-diethylaniline (400 mL) was added dropwise over 30 min, and the mixture was stirred at 180° C. (internal temperature) for 22 hr. The reaction mixture was cooled to room temperature, and ethyl acetate (1 L) and 3M hydrochloric acid (1 L) were added. The mixture was transferred into a separatory funnel with ethyl acetate (2 L) and 3M hydrochlorid acid (1 L). The organic layer was successively washed with 3M hydrochloric acid (2 L) twice and brine (2 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound as a brown solid (246 g, 84%).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. washThe organic layer was successively washed with 3M hydrochloric acid (2 L) twice
  3. dry with materialbrine (2 L), dried over anhydrous magnesium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customThe obtained residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-1dbc04ff45504a5797d8503257c4621b
Source dataset
uspto-grants-2012_04
Patent number
US08148383B2

Reaction notes

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