2,2-Difluoro-1,3-benzodioxole-5-carbonyl chloride → 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic Acid [4-((S)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide

HRID 1183900Notes

Reaction equation

HRID 1183900 reaction equation
[NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])=[C:4]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)[CH:3]=1.[F:26][C:27]1([F:39])[O:31][C:30]2[CH:32]=[CH:33][C:34]([C:36](Cl)=[O:37])=[CH:35][C:29]=2[O:28]1>C(Cl)Cl>[NH2:10][C@@H:8]([CH3:9])[CH2:7][O:6][C:5]1[CH:18]=[CH:19][C:2]([NH:1][C:36]([C:34]2[CH:33]=[CH:32][C:30]3[O:31][C:27]([F:39])([F:26])[O:28][C:29]=3[CH:35]=2)=[O:37])=[CH:3][C:4]=1[C:20]1[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=1

Participants

4

Reactant 2

HCID 27740642,2-Difluoro-1,3-benzodioxole-5-carbonyl chlorideHCID 86633183tert-butyl(S)-1-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)propan-2-ylcarbamate

Product 1

HCID 578145452,2-Difluoro-benzo[1,3]dioxole-5-carboxylic Acid [4-((S)-2-amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of tert-butyl(S)-1-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)propan-2-ylcarbamate (40.0 mg, 115 μmol) in DCM was added 2,2-difluorobenzo[d][1,3]dioxole-5-carbonyl chloride (28.0 mg, 127 μmol) followed by TEA (32.2 μl, 231 μmol). The reaction was mixed in a rotary shaker at 25° C. for 1 hour then quenched with MeOH (100 μl). After mixing for 20 minutes TFA (400 μl) was added and the resulting mixture was heated to 40° C. and mixed for 1 hour. The organic solvent was removed under vacuum; the crude residue was dissolved in acetonitrile (0.5 mL), neutralized with saturated bicarbonate and subjected to purification by preparative LCMS. The proper fractions were pooled, frozen and lyophilized to afford the title compound as an off white solid (16.7% yield). LCMS m/z=431.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.82 Hz, 3 H), 3.48-3.58 (m, 1 H), 3.71 (s, 3 H), 3.99-4.08 (m, 2 H), 6.36 (d, J=1.77 Hz, 1 H), 7.25 (d, J=9.09 Hz, 1 H), 7.50 (d, J=1.77 Hz, 1 H), 7.60 (d, J=8.59 Hz, 1 H), 7.71 (d, J=2.53 Hz, 2 H), 7.82-7.91 (m, 2 H), 10.35 (s, 1 H).

Workup

  1. additionThe reaction was mixed in a rotary shaker at 25° C. for 1 hour
  2. customthen quenched with MeOH (100 μl)
  3. additionAfter mixing for 20 minutes TFA (400 μl)
  4. additionwas added
  5. additionmixed for 1 hour
  6. customThe organic solvent was removed under vacuum
  7. dissolutionthe crude residue was dissolved in acetonitrile (0.5 mL)
  8. customsubjected to purification by preparative LCMS
  9. temperaturefrozen

Sources & evidence

ORD record
ord-35b8a49dc9f347a7b0fa1dfbe13974f4
Source dataset
uspto-grants-2014_03
Patent number
US08664258B2

Reaction notes

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