2,6-Lutidine → HCID 67191237, compound

HRID 546224Notes

Reaction equation

HRID 546224 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]([OH:14])=O)=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][CH2:36][CH2:37][OH:38])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[OH:38][CH2:37][CH2:36][CH2:35][N:32]1[CH:33]=[CH:34][C:30]([NH:29][C:12](=[O:14])[C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[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:31]1

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 509897073-(3-amino-1H-pyrazol-1-yl)propan-1-olHCID 67191851HCID 67191851, compound

Product 1

HCID 67191237HCID 67191237, compoundYield 83%

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 (prepared in Example 122, 65 mg, 0.20 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 110 μL, 0.21 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 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 29 mg, 0.20 mmol), 2,6-lutidine (46 μL, 0.40 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 diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)—N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (74 mg, 83%) as a colorless gum: [α]32589=−23.3° (c=0.15, methanol); ES-HRMS m/e calcd for C22H29N3O5S (M+H)+ 448.1901, observed 448.1901; 1H NMR (300 MHz, DMSO-d6) δ 1.50 (m, 1H, CH), 1.76-2.29 (m, 10H, 5×CH2), 2.62 (s, 3H, ArCH3), 3.18 (s, 3H, SO2CH3), 3.33 (m, 2H, OCH2), 3.90 (m, 1H, ArCHCO), 4.01 (t, J=6.9 Hz, 2H, NCH2), 4.56 (t, J=5.1 Hz, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.45 (brs, 1H, Ar), 7.46 (brd, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.85 (d, Jo=8.6 Hz, 1H, Ar), 10.78 (s, 1H, NH).

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. additiondiluted with methylene chloride
  9. concentrationconcentrated with silica gel (2 g) in vacuo
  10. custompurified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes to 10% methanol/ethyl acetate)

Sources & evidence

ORD record
ord-12a549897c0d4697bb3e01c8e5a6e7f7
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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