2,6-Lutidine → (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide

HRID 546211Notes

Reaction equation

HRID 546211 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]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].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>CN(C)C=O.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:14]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][CH2:36][CH2:37][OH:38])[N:31]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 509897073-(3-amino-1H-pyrazol-1-yl)propan-1-olHCID 67189998(R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid

Product 1

HCID 67191846(R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamideYield 68%

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 (prepared in Example 114, 65 mg, 0.20 mmol), methylene chloride (2 mL) and N,N-dimethylformamide (2 drops). To this solution was then added a solution of oxalyl chloride in methylene chloride (2.0 M solution, 110 μL, 0.22 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 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, 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, 50% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (60 mg, 68%) as a white foam: [α]25589=−6.2° (c=0.21, methanol); ES-HRMS m/e calcd for C22H28N4O4S (M+H)+ 445.1904, observed 445.1903; 1H NMR (300 MHz, DMSO-d6) δ 1.11 (m, 2H, CH2), 1.38-1.90 (m, 10H, 5×CH2), 2.12 (m, 1H, CH), 3.33 (brm, 2H, OCH2), 3.36 (s, 3H, SO2CH3), 3.98 (m, 1H, ArCHCO), 4.02 (t, J=7.1 Hz, 2H, NCH2), 4.56 (t, J=5.0 Hz, 1H, OH), 6.40 (d, J=2.2 Hz, 1H, Ar), 7.55 (d, J=2.2 Hz, 1H, Ar), 7.94 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 8.10 (d, Jm=1.6 Hz, 1H, Ar), 8.10 (d, Jo=8.2 Hz, 1H, Ar), 10.83 (s, 1H, NH).

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 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, 50% ethyl acetate/hexanes to 10% methanol/ethyl acetate)

Sources & evidence

ORD record
ord-e5ce810be47f4387ab8531c4370cf851
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

Loading…