2,6-Lutidine → (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide

HRID 546184Notes

Reaction equation

HRID 546184 reaction equation
[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:30]([CH2:34][C@H:35]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]2)[C:31](Cl)=[O:32])[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:30]([CH2:34][C@H:35]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]2)[C:31]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=2)=[O:32])[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27]

Participants

5

Reactant 3

HCID 79372,6-LutidineHCID 451167281-(2-methoxyethyl)-1H-pyrazol-3-amineHCID 86618051(R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride

Product 1

HCID 67190470(R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamideYield 76%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

In a round bottom flask was placed 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 32 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (prepared as in Example 96, ˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then 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 (4 g column, 60% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (71 mg, 76%) as a white foam: [α]30589=−90.0° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C21H26N3O5SCl (M+H)+ 468.1355, observed 468.1354; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.79-2.29 (m, 8 H, 4×CH2), 3.19 (s, 3H, OCH3), 3.34 (s, 3H, SO2CH3), 3.61 (t, J=5.1 Hz, 2H, OCH2), 3.95 (m, 1H, ArCHCO), 4.12 (t, J=5.1 Hz, 2H, NCH2), 6.42 (d, J=2.0 Hz, 1H, Ar), 7.55 (d, J=2.0 Hz, 1H, Ar), 7.62 (d, Jo=8.1 Hz, 1H, Ar), 7.73 (s, 1H, Ar), 8.02 (d, Jo=8.1 Hz, 1H, Ar), 10.85 (s, 1H, NH).

Workup

  1. customIn a round bottom flask was placed
  2. customtransferred to a separatory funnel
  3. washwashed with a saturated aqueous sodium bicarbonate solution (10 mL)
  4. dry with materiala 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification on an AnaLogix Intelliflash system (4 g column, 60% ethyl acetate/hexanes to 100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-c6b7f5fb94684a239584ed0f23a70dd4
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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