(S)-(+)-2-(Methoxymethyl)pyrrolidine → (S)-N-(4-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine

HRID 555807Notes

Reaction equation

HRID 555807 reaction equation
Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:25][O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>CS(C)=O>[CH3:25][O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1

Participants

4

Reactant 2

HCID 671217(S)-(+)-2-(Methoxymethyl)pyrrolidineHCID 59351351N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine

Product 1

HCID 46208828(S)-N-(4-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (180 mg, 0.51 mmol) in DMSO (2 mL) was added (s)-(+)-2-(methoxymethyl)-pyrrolidine (0.29 mL, 2.55 mmol). The reaction mixture was heated at 80° C. for 16 h. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organics were dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 40% EtOAc in hexanes, followed by reverse-phase preparative HPLC using a Phenomena Gemini™ column (10 micron, C18, 110 Å, 150×30 mm), 0.1% TFA in CH3CN/H2O as mobile phase, gradient 10% to 90% over 15 min., then treated with Si-carbonate resin to provide (S)—N-(4-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as off-white solid. MS (ESI, pos. ion) m/z: 434.1 (M+1). IC50 (uM) +++++.

Workup

  1. customThe reaction mixture was partitioned between EtOAc and brine
  2. extractionThe aqueous layer was back extracted with EtOAc (2×)
  3. dry with materialthe combined organics were dried (Na2SO4)
  4. concentrationconcentrated
  5. customThe crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g)
  6. washeluting with a gradient of 0% to 40% EtOAc in hexanes
  7. customover 15 min.
  8. additiontreated with Si-carbonate resin

Sources & evidence

ORD record
ord-19df78cfd73445659d9e57a636d47f27
Source dataset
uspto-grants-2011_11
Patent number
US08053438B2

Reaction notes

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