1,2-Dichloroethane → 5-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-cyclobutyl-4-methylbenzamide

HRID 1487844Notes

Reaction equation

HRID 1487844 reaction equation
Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:28]([C:31]1[C:32]([CH:41]2[CH2:44][CH2:43][CH2:42]2)=[CH:33][C:34]([CH3:40])=[C:35]([CH:39]=1)[C:36](O)=[O:37])(=[O:30])[NH2:29].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([CH:4]2[CH2:5][N:2]([C:36]([C:35]3[C:34]([CH3:40])=[CH:33][C:32]([CH:41]4[CH2:44][CH2:43][CH2:42]4)=[C:31]([CH:39]=3)[C:28]([NH2:29])=[O:30])=[O:37])[CH2:3]2)=[CH:7][CH:8]=1)#[N:11]

Participants

8

Reactant 5

HCID 111,2-Dichloroethane2×HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 552549914-(Azetidin-3-yl)benzonitrile hydrochloride2×HCID 900214605-Carbamoyl-4-cyclobutyl-2-methylbenzoic acid2×

Product 1

HCID 900211065-(3-(4-Cyanophenyl)azetidine-1-carbonyl)-2-cyclobutyl-4-methylbenzamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a 4-mL vial was added 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 27 mg, ˜90% pure, 0.13 mmol), HOBt (20 wt % H2O) (22 mg, 0.13 mmol), EDC (27 mg, 0.14 mmol). A solution of 5-carbamoyl-4-cyclobutyl-2-methylbenzoic acid (compound 6.5, 28 mg, 0.12 mmol) in DMF (500.4) was added followed by DIEA (83 μL, 0.48 mmol). The mixture was sealed and stirred at room temperature for 18 hours. Additional amine (3 mg, ˜0.015 mmol) and EDC (5 mg, ˜0.026 mmol) were added and the mixture was stirred at room temperature for an additional 27 hours. The mixture was diluted with ethyl acetate (5 mL) and washed with brine (8 mL). The aqueous was extracted with ethyl acetate (2 mL) and the combined organics was washed with brine, 1 M NaH2PO4, saturated NaHCO3 and brine (7 mL each). The product began precipitating out of solution after the final brine wash, so the organics was diluted with DCM (3 mL) and MeOH (˜200 μL). The organics was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was triturated with Et2O (1.5 mL), filtered, and washed with Et2O (0.5 mL) to yield the title compound as an off white powder (41.4 mg, 92%). m/z (ES+) 374 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 7.67 (d with fine str., J=8.4 Hz, 2H), 7.40 (d with fine str., J=8.4 Hz, 2H), 7.32 (s, 1H), 7.25 (s, 1H), 5.79 (br s, 1H), 5.70 (br s, 1H), 4.67-4.57 (m, 1H), 4.39-4.30 (m, 1H), 4.28-4.18 (m, 1H), 4.00-3.86 (m, 3H), 2.46 (s, 3H), 2.42-2.31 (m, 2H), 2.19-1.96 (m, 3H), 1.88-1.77 (m, 1H).

Workup

  1. customThe mixture was sealed
  2. stirringthe mixture was stirred at room temperature for an additional 27 hours
  3. washwashed with brine (8 mL)
  4. extractionThe aqueous was extracted with ethyl acetate (2 mL)
  5. washthe combined organics was washed with brine, 1 M NaH2PO4, saturated NaHCO3 and brine (7 mL each)
  6. customThe product began precipitating out of solution after the final brine
  7. washwash
  8. additionso the organics was diluted with DCM (3 mL) and MeOH (˜200 μL)
  9. dry with materialThe organics was dried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe crude product was triturated with Et2O (1.5 mL)
  13. filtrationfiltered
  14. washwashed with Et2O (0.5 mL)

Sources & evidence

ORD record
ord-0665220f0055475189ab3c8e21df9238
Source dataset
uspto-grants-2016_08
Patent number
US09428502B2

Reaction notes

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