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

HRID 546208Notes

Reaction equation

HRID 546208 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[C:29]([Si:33]([CH3:44])([CH3:43])[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]1)([CH3:32])([CH3:31])[CH3:30].N1C(C)=CC=CC=1C>CN(C)C=O.C(Cl)Cl>[C:29]([Si:33]([CH3:44])([CH3:43])[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][C:39]([NH:42][C:14](=[O:15])[C@@H:13]([C:5]2[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[N:38]1)([CH3:32])([CH3:31])[CH3:30]

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 593449471-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamineHCID 67189998(R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid

Product 1

HCID 67190407(R)-N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamideYield 84%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

In a round bottom flask was placed (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (75 mg, 0.23 mmol), methylene chloride (2 mL) and N,N-dimethylformamide (3 drops). To this solution was then added a solution of oxalyl chloride in methylene chloride (2.0 M solution, 130 μL, 0.26 mmol). Upon addition there was gas evolution. This was stirred for 30 min at 25° C. after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 56 mg, 0.23 mmol), 2,6-lutidine (55 μL, 0.46 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 2 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 40% ethyl acetate/hexanes) to afford (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (105 mg, 84%) as a white foam: [α]24589=−11.0° (c=0.20, methanol); ES-HRMS m/e calcd for C27H40N4O4SSi (M+H)+ 545.2613, observed 545.2603; 1H NMR (400 MHz, CDCl3) δ −0.05 (s, 6H, 2×SiCH3), 0.84 (s, 9H, 3×CH3), 1.14 (m, 2H, CH2), 1.46-1.94 (m, 8H, 4×CH2), 2.24 (m, 1H, CH), 3.27 (s, 3H, SO2CH3), 3.59 (t, J=7.6 Hz, 1H, ArCH), 3.87 (t, J=5.3 Hz, 2H, OCH2), 4.08 (t, J=5.3 Hz, 2H, NCH2), 6.62 (d, J=2.2 Hz, 1H, Ar), 7.35 (d, J=2.2 Hz, 1H, Ar), 7.84 (dd, Jm=1.8 Hz, Jo=8.3 Hz, 1H, Ar), 7.91 (brs, 1H, NH), 7.97 (d, Jm=1.8 Hz, 1H, Ar), 8.15 (d, Jo=8.3 Hz, 1H, Ar).

Workup

  1. customIn a round bottom flask was placed
  2. additionUpon addition there
  3. concentrationwas concentrated in vacuo
  4. dissolutionThe residue was then dissolved in methylene chloride (2 mL)
  5. temperatureto warm to 25° C.
  6. stirringstirred for 2 h
  7. customAfter this time, the reaction was quenched with a small amount of methanol
  8. concentrationconcentrated with silica gel (2 g) in vacuo
  9. custompurified on Biotage Flash chromatography system (40S column, silica gel, 40% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-38f310f32764428485c0386d37ef0d46
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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