2,6-Lutidine → HCID 67189552, compound

HRID 546221Notes

Reaction equation

HRID 546221 reaction equation
[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)[C:12](O)=[O:13])=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].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>C(Cl)Cl.CN(C)C=O>[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:12](=[O:13])[C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([CH3:22])[CH:7]=2)[CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]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 67191851HCID 67191851, compound

Product 1

HCID 67189552HCID 67189552, compoundYield 77%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

(R)-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (85 mg, 0.26 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 140 μL, 0.27 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes 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, 63 mg, 0.26 mmol), 2,6-lutidine (62 μL, 0.52 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 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, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) to afford (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (109 mg, 77%) as a yellow oil: [α]25589=−50.0° (c=0.21, methanol); ES-HRMS m/e calcd for C27H41N3O5SSi (M+H)+ 548.2609, observed 548.2609; 1H NMR (300 MHz, CDCl3) δ −0.06 (s, 6H, 2×SiCH3), 0.84 (s, 9H, 3×CH3), 1.57 (m, 1H, CH), 1.82-2.47 (m, 8H, 4×CH2), 2.72 (s, 3H, ArCH3), 3.09 (s, 3H, SO2CH3), 3.55 (t, J=7.3 Hz, 1H, ArCHCO), 3.85 (t, J=5.3 Hz, 2H, OCH2), 4.06 (t, J=5.3 Hz, 2H, NCH2), 6.64 (d, J=2.2 Hz, 1H, Ar), 7.35 (m, 3H, Ar), 7.75 (brs, 1H, NH), 8.03 (d, Jo=8.2 Hz, 1H, Ar).

Workup

  1. customat 25° C.
  2. customproduced gas evolution and it
  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 1 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, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-1c5ad097e9e248a5a87832d813406a6b
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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