Hydrochloric Acid → (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole-6-carboxylic acid

HRID 1692012Notes

Reaction equation

HRID 1692012 reaction equation
[N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].C(OCC)(=O)C.CO.Cl>O1CCCC1.CO.O.O1CCOCC1>[N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 168937Lithium hydroxide, monohydrateHCID 21584119Ethylacetate methanolHCID 44124706(R)-ethyl 2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole-6-carboxylate

Product 1

HCID 44124707(R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole-6-carboxylic acid

Reagents, catalysts & solvents 4

HCID 887MethanolSolvent2×HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of (R)-ethyl 2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole-6-carboxylate (Example 53, 1.38 g, 3.85 mmol) in tetrahydrofuran (50 mL) and methanol (25 mL) was added to a stirred solution of lithium hydroxide monohydrate (0.504 g, 12.00 mmol) in water (20 mL). The reaction mixture was stirred at ambient temperature for 19 hours. An aliquot was checked by TLC (99:1 ethyl acetate/methanol). A lower Rf spot was apparent, however, considerable starting ester remained, so the reaction mixture was heated to 40° C. for 7 hours. Starting ester was still present so the reaction mixture was stirred at ambient temperature for approximately 65 hours. Starting ester appeared to be consumed so the reaction mixture was concentrated under reduced pressure. The residue was treated with methanol (100 mL), water (200 mL), and three equivalents (3.0 mL, 12.0 mmol) of 4 M HCl in dioxane. This mixture was stirred overnight at ambient temperature. A precipitate had formed overnight. Most of the methanol was removed under reduced pressure, then the mixture was diluted with additional water and the precipitate was collected by filtration. This solid was azeotroped with benzene to remove residual water then dried in a vacuum oven to provide the title compound as the dihydrate. 1H NMR (300 MHz, CD3OD) δ ppm 8.27 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 3.96-3.83 (m, 1H), 3.81-3.68 (m, 1H), 3.62-3.36 (m, 3H), 2.94-2.69 (m, 4H), 2.51-2.36 (m, 1H), 2.23-2.06 (m, 1H), 1.83-1.68 (m, 4H), 1.66-1.50 (m, 2H); MS (DCI/NH3) m/z 332 (M+H)+.

Workup

  1. temperaturewas heated to 40° C. for 7 hours
  2. stirringwas stirred at ambient temperature for approximately 65 hours
  3. customto be consumed so the reaction mixture
  4. concentrationwas concentrated under reduced pressure
  5. stirringThis mixture was stirred overnight at ambient temperature
  6. customA precipitate had formed overnight
  7. customMost of the methanol was removed under reduced pressure
  8. additionthe mixture was diluted with additional water
  9. filtrationthe precipitate was collected by filtration
  10. customThis solid was azeotroped with benzene
  11. customto remove residual water
  12. customthen dried in a vacuum oven

Sources & evidence

ORD record
ord-b269b335d88545cda3849bd504153aa3
Source dataset
uspto-grants-2012_04
Patent number
US08153813B2

Reaction notes

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