Triethylamine → (R)-6-methoxy-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole dihydrochloride

HRID 1692003Notes

Reaction equation

HRID 1692003 reaction equation
[NH:1]1[CH2:5][CH2:4][C@@H:3]([N:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:2]1.[Cl:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=2[N:17]=1.C(N(CC)CC)C>CN(C)C=O.O.C(OCC)(=O)C>[ClH:12].[ClH:12].[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([N:1]3[CH2:5][CH2:4][C@@H:3]([N:6]4[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]4)[CH2:2]3)[S:14][C:15]=2[CH:21]=1

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 2731322-Chloro-6-methoxybenzothiazoleHCID 7176312(R)-1-(pyrrolidin-3-yl)piperidine

Product 1

HCID 66905516(R)-6-methoxy-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole dihydrochloride

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
150 °C

Procedure

A mixture of (R)-1-(pyrrolidin-3-yl)piperidine (freebase of Reference Example 5C, 0.721 g, 4.668 mmol), 2-chloro-6-methoxybenzo[d]thiazole (0.848 g, 4.244 mmol), and triethylamine (1.77 mL, 12.73 mmol) in N,N-dimethylformamide (10 mL) was heated to 150° C. under microwave irradiation for 1.5 hours. The reaction mixture was diluted with water (350 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with brine (2×200 mL) then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on an Analogix IF-280 (Analogix SF40-120 g, 98:2 ethyl acetate/methanol). Fractions containing product were combined and concentrated under reduced pressure to give a solid. The solid was dissolved in hot ethyl acetate, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and a crystallization attempt was set up with ethyl acetate and diethyl ether. A gummy solid formed. The remaining solution was decanted free of this solid and the decant was treated with excess 4 M HCl in dioxane to provide the title compound as a precipitate that was collected by filtration. 1H NMR (300 MHz, CD3OD) δ ppm 7.53 (d, J=5.8 Hz, 1H), 7.52 (s, 1H), 7.16 (dd, J=2.5, 9.0 Hz, 1H), 4.36-4.21 (m, 2H), 4.20-3.99 (m, 2H), 3.93-3.79 (m, 1H), 3.86 (s, 3H), 3.74-3.51 (m, 2H), 3.25-3.06 (m, 2H), 2.84-2.55 (m, 2H), 2.07-1.82 (m, 5H), 1.68-1.49 (m, 1H); MS (DCI/NH3) m/z 318 (M+H)+.

Workup

  1. extractionextracted with ethyl acetate (3×75 mL)
  2. washThe combined organic extracts were washed with brine (2×200 mL)
  3. dry with materialthen dried (MgSO4)
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customThe residue was purified by column chromatography on an Analogix IF-280 (Analogix SF40-120 g, 98:2 ethyl acetate/methanol)
  7. additionFractions containing product
  8. concentrationconcentrated under reduced pressure
  9. customto give a solid
  10. dry with materialdried (MgSO4)
  11. filtrationfiltered
  12. concentrationThe filtrate was concentrated under reduced pressure
  13. customA gummy solid formed
  14. customThe remaining solution was decanted free of this solid
  15. additionthe decant was treated with excess 4 M HCl in dioxane

Sources & evidence

ORD record
ord-29dd6f99679f4d96a4c9c27efc4faf52
Source dataset
uspto-grants-2012_04
Patent number
US08153813B2

Reaction notes

Loading…