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

HRID 546186Notes

Reaction equation

HRID 546186 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.[Cl:25][C:26]1[CH:27]=[C:28]([C@@H:36]([CH2:40][C@H:41]2[CH2:45][CH2:44][C:43](=[O:46])[CH2:42]2)[C:37](Cl)=[O:38])[CH:29]=[CH:30][C:31]=1[S:32]([CH3:35])(=[O:34])=[O:33]>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:37](=[O:38])[C@@H:36]([C:28]2[CH:29]=[CH:30][C:31]([S:32]([CH3:35])(=[O:33])=[O:34])=[C:26]([Cl:25])[CH:27]=2)[CH2:40][C@H:41]2[CH2:45][CH2:44][C:43](=[O:46])[CH2:42]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 86618051(R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride

Product 1

HCID 67188652(R)-N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-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, 54 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, 50% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (88 mg, 77%) as a yellow foam: [α]30589=−74.3° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C26H38N3O5SSiCl (M+H)+ 568.2063, observed 568.2063; 1H NMR (300 MHz, DMSO-d6) δ −0.09 (s, 6H, 2×SiCH3), 0.77 (s, 9H, 3×CH3), 1.51 (m, 1H, CH), 1.79-2.29 (m, 8 H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.84 (m, 2H, OCH2), 3.96 (m, 1H, ArCHCO), 3.96 (m, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.53 (d, J=2.2 Hz, 1H, Ar), 7.61 (dd, Jo=8.2 Hz, Jm=1.4 Hz, 1H, Ar), 7.73 (d, Jm=1.4 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.83 (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, 50% ethyl acetate/hexanes to 70% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-c965b3fc9d33492c9f62f855a3bc31ac
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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