2,6-Lutidine → HCID 67188036, compound

HRID 546203Notes

Reaction equation

HRID 546203 reaction equation
[CH3:1][O:2][C:3]([CH3:12])([CH3:11])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]([CH2:36][C@H:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:33](Cl)=[O:34])[CH:25]=[CH:26][C:27]=1[S:28]([CH3:31])(=[O:30])=[O:29]>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]([CH2:36][C@H:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:33]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][C:3]([O:2][CH3:1])([CH3:12])[CH3:11])[N:6]=2)=[O:34])[CH:25]=[CH:26][C:27]=1[S:28]([CH3:31])(=[O:30])=[O:29]

Participants

5

Reactant 3

HCID 79372,6-LutidineHCID 668999341-(2-methoxy-2-methylpropyl)-1H-pyrazol-3-amineHCID 86618053HCID 86618053, compound

Product 1

HCID 67188036HCID 67188036, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

In a round bottom flask was placed 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in Example 94, 61 mg, 0.36 mmol), 2,6-lutidine (54 μL, 0.49 mmol) and methylene chloride (10 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionyl chloride (prepared as in Example 106, ˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then diluted with methylene chloride (10 mL) transferred to a separatory funnel and the layers separated. The aqueous layer was then extracted methylene chloride (3×10 mL). The organics were combined and then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 35% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (as a mixture of two diastereomers, 130 mg, 77%) as an off-white foam: ES-HRMS m/e calcd for C23H30N3O4SClF2 (M+H)+ 518.1687, observed 518.1684; 1H NMR (300 MHz, DMSO-d6) δ 1.04 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.42 (m, 1H, CH), 1.64-2.31 (m, 8H, 4×CH2), 3.14 (s, 3H, OCH3), 3.34 (s, 3H, SO2CH3), 3.91 (m, 1 H, ArCHCO), 3.97 (s, 2 H, NCH2), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.48 (d, J=2.2 Hz, 1H, Ar), 7.60 (d, Jo=8.2 Hz, 1H, Ar), 7.71 (s, 1H, Ar), 8.02 (d, Jo=8.2 Hz, 1H, Ar), 10.84 (s, 1H, NH).

Workup

  1. customIn a round bottom flask was placed
  2. customAfter this time the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL)
  3. additiondiluted with methylene chloride (10 mL)
  4. customtransferred to a separatory funnel
  5. customthe layers separated
  6. washwashed with a 1 N aqueous hydrochloric acid solution (10 mL)
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification on an AnaLogix Intelliflash system (12 g column, 35% ethyl acetate/hexanes to 70% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-6e5307881f1a4b338855fe2f25258970
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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