Sulfuric Acid → HCID 66788567, compound

HRID 2409390Notes

Reaction equation

HRID 2409390 reaction equation
S(=O)(=O)(O)O.[N:6]1[CH:7]=[N:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=3)[CH2:18][NH:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)O)[CH:12]=[CH:11][C:10]=12.[NH4+].[OH-].CS(O)(=O)=O>C(Cl)Cl.CCOC(C)=O>[N:6]1[CH:7]=[N:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]4[C:31]([CH:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=5)[CH2:20][NH:19][CH2:18]4)=[CH:32][CH:33]=3)[CH:12]=[CH:11][C:10]=12.[N:6]1[CH:7]=[N:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]4[C:31]([CH:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=5)[CH2:20][NH:19][CH2:18]4)=[CH:32][CH:33]=3)[CH:12]=[CH:11][C:10]=12

Participants

7

Reactant 4

HCID 1118Sulfuric AcidHCID 6395Methanesulfonic AcidHCID 14923Ammonium HydroxideHCID 59580336HCID 59580336, compound

Product 1

HCID 66788567HCID 66788567, compoundYield 54%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of concentrated sulfuric acid (500 g, 5.0 mol) in a 3 L round bottom flask was cooled to 0° C. with an ice bath. To the flask was added dropwise a solution of 2-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzylamino)-1-(3,4-dichlorophenyl)ethanol (79 g, 0.191 mol) in DCM (250 mL). The addition was finished in 30 min and the reaction temperature was controlled in the range of 10-20° C. DCM was blown away with nitrogen gas during the addition. The evaporation of DCM helped to lower the reaction temperature. The mixture solution was stirred at RT overnight. HPLC indicated no remaining starting material. The HPLC area ratio of 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and 5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline was 75:25. The reaction mixture was cooled to 0° C. Isopropanol (2 L) was added to the solution slowly, maintaining temperature <0° C. The solid (desired isomer 92% purity) was obtained by filtration. The solid was then dissolved in AcOEt (1 L) and the pH adjusted to 10 with NH4OH. The water layer was extracted with EtOAc twice. The combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue was dissolved in EtOH (250 mL) and then 1.1 eq of methanesulfonic acid (20.20 g, 0.21 mol) was added and the solution stirred overnight. The resulting precipitate methanesulfonic acid salt (98% purity) was filtered. This was dissolved in water and the pH adjusted with NH4OH to 10, then extracted with AcOEt twice. The combined extracts were washed with water and dried over Na2SO4. After removal of solvent, 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline was obtained in an amorphous state (40.8 g, 54% yield): m/z=395.0 [M+1]; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.05 (dd, J=12.00, 8.00 Hz, 1H), 3.40 (dd, J=12.00, 4.00 Hz, 1H), 4.05-4.25 (m, 3H), 6.96 (m, 2H), 7.25-7.35 (m, 4H), 7.70-7.80 (m, 2H), 8.32 (s, 1H), 8.74(s, 1H).

Workup

  1. additionThe addition
  2. customwas controlled in the range of 10-20° C
  3. customThe evaporation of DCM
  4. temperatureThe reaction mixture was cooled to 0° C
  5. additionIsopropanol (2 L) was added to the solution slowly
  6. temperaturemaintaining temperature <0° C
  7. customThe solid (desired isomer 92% purity) was obtained by filtration
  8. extractionThe water layer was extracted with EtOAc twice
  9. washThe combined organic layers were washed with water
  10. dry with materialdried over Na2SO4
  11. concentrationconcentrated
  12. dissolutionThe residue was dissolved in EtOH (250 mL)
  13. stirringthe solution stirred overnight
  14. filtrationThe resulting precipitate methanesulfonic acid salt (98% purity) was filtered
  15. dissolutionThis was dissolved in water
  16. extractionextracted with AcOEt twice
  17. washThe combined extracts were washed with water
  18. dry with materialdried over Na2SO4
  19. customAfter removal of solvent

Sources & evidence

ORD record
ord-c0f653ec03ce4ab78e49d381f50bab1d
Source dataset
uspto-grants-2014_08
Patent number
US08815894B2

Reaction notes

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