2,6-Lutidine → (R)-N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide

HRID 546198Notes

Reaction equation

HRID 546198 reaction equation
[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]1)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[CH:25]1([CH2:30][C@H:31]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)[C:32](Cl)=[O:33])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:32](=[O:33])[C@@H:31]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)[CH2:30][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[N:10]1)([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 79372,6-LutidineHCID 593449471-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamineHCID 866180523-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride

Product 1

HCID 67188509(R)-N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamideYield 77%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

In a round bottom flask was placed 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 86 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 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 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (prepared as in Example 102, ˜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 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, 20% ethyl acetate/hexanes) afforded (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (128 mg, 77%) as a white foam: [α]30589=−74.3° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C25H37N3O2SiCl2 (M+H)+ 510.2105, observed 510.2105; 1H NMR (300 MHz, DMSO-d6) δ −0.09 (s, 6H, 2×SiCH3), 0.77 (s, 9H, 3×CH3), 1.10 (m, 2H, CH2), 1.35-1.80 (m, 8H, 4×CH2), 2.05 (m, 1H, CH), 3.81 (m, 1H, ArCHCO), 3.84 (t, J=5.4 Hz, 2H, OCH2), 4.04 (t, J=5.4 Hz, 2 H, NCH2), 6.40 (d, J=2.3 Hz, 1H, Ar), 7.34 (dd, Jm=2.1 Hz, Jo=8.3 Hz, 1H, Ar), 7.51 (d, J=2.3 Hz, 1H, Ar), 7.58 (d, Jo=8.3 Hz, 1H, Ar), 7.59 (d, Jm=2.1 Hz, 1H, Ar), 10.68 (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, 20% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-036d2d80e0d04679b6fe45c5f04623c7
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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