HCID 14441129, compound → (R)-[1-Methyl-2-(4-thiophen-2-yl-1,2,3,6-tetrahydropyrid-1-yl)ethyl]-pyrid-2-yl-amine

HRID 963258Notes

Reaction equation

HRID 963258 reaction equation
O[C:2]1([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:13][C@@H:14]1[CH2:18]OS(=O)(=O)[N:15]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN(C)C=O>[CH3:13][C@@H:14]([NH:15][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:18][N:5]1[CH2:6][CH:7]=[C:2]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:4]1

Participants

4

Reactant 2

HCID 14441129HCID 14441129, compoundHCID 22863100(R)-4-methyl-3-pyridin-2-yl[1,2,3]oxathiazolidine-2,2-dioxide

Product 1

HCID 18660712(R)-[1-Methyl-2-(4-thiophen-2-yl-1,2,3,6-tetrahydropyrid-1-yl)ethyl]-pyrid-2-yl-amineYield 80.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 4-hydroxy-4-thiophen-2-yl-piperidine (3.3 g, 18 mmol) and (R)-4-methyl-3-(pyrid-2-yl)-[1,2,3]-oxathiazolidine-2,2-dioxide (3.7 g, 17.5 mmol) was stirred in dimethylformamide (70 ml) at ambient temperature for 40 minutes, then evaporated to dryness in vacuo and the residue dissolved in tetrahydrofuran (30 m) and water (10 ml). Concentrated sulfuric acid (2.9 g) was dropwise added while maintaining room temperature. Thereafter sodium hydrogencarbonate (6.7 g) were added in a portion wise fashion and the resulting suspension stirred at ambient temperature overnight. Water (100 ml) and ethylacetate (100 ml) were added to the reaction mixture and the pH adjusted to 10 with the addition of 0.5N NaOH. The product was extracted with ethylacetate (3×100 ml) and the combined organic layer washed with brine (150 ml), dried over magnesium sulfate, filtered, and evaporated to dryness. The obtained residue was dissolved in acetic acid (300 ml) and heated to 140° C. bath temperature for 3 hours. After cooling to room temperature the mixture was evaporated in vacuo and the residue partitioned between chloroform and 5% aqueous sodium hydrogencarbonate. The organic layer was separated, dried over magnesium sulfate, filtered, and evaporated in vacuo. Column chromatography on 120 g of silica gel with 2% methanol/ethylacetate as eluant, followed by trituration in ether with the addition of two molequivalent of fumaric acid gave 4.2 g of the title compound as the fumarate salt hemihydrate, m.p. 63°-8° C.

Workup

  1. customevaporated to dryness in vacuo
  2. dissolutionthe residue dissolved in tetrahydrofuran (30 m)
  3. additionConcentrated sulfuric acid (2.9 g) was dropwise added
  4. additionThereafter sodium hydrogencarbonate (6.7 g) were added in a portion wise fashion
  5. additionWater (100 ml) and ethylacetate (100 ml) were added to the reaction mixture
  6. additionthe pH adjusted to 10 with the addition of 0.5N NaOH
  7. extractionThe product was extracted with ethylacetate (3×100 ml)
  8. washthe combined organic layer washed with brine (150 ml)
  9. dry with materialdried over magnesium sulfate
  10. filtrationfiltered
  11. customevaporated to dryness
  12. dissolutionThe obtained residue was dissolved in acetic acid (300 ml)
  13. temperatureheated to 140° C. bath temperature for 3 hours
  14. temperatureAfter cooling to room temperature the mixture
  15. customwas evaporated in vacuo
  16. customthe residue partitioned between chloroform and 5% aqueous sodium hydrogencarbonate
  17. customThe organic layer was separated
  18. dry with materialdried over magnesium sulfate
  19. filtrationfiltered
  20. customevaporated in vacuo
  21. additionColumn chromatography on 120 g of silica gel with 2% methanol/ethylacetate as eluant, followed by trituration in ether with the addition of two molequivalent of fumaric acid

Sources & evidence

ORD record
ord-08141eedc7de41bd828b32b2562e1884
Source dataset
uspto-grants-1998_06
Patent number
US05763460

Reaction notes

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