Citric Acid → HCID 71735778, compound

HRID 2172304Notes

Reaction equation

HRID 2172304 reaction equation
[S:1]1[C:5]([NH2:6])=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[S:14](Cl)(Cl)(=[O:16])=[O:15].Cl.[Br:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH2:34][NH:35][CH2:36]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C1COCC1>[Br:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH2:34][N:35]([S:14]([NH:6][C:5]1[S:1][N:2]=[CH:3][N:4]=1)(=[O:16])=[O:15])[CH2:36]2

Participants

8

Reactant 5

HCID 311Citric AcidHCID 8471Triethylamine2×HCID 24648Sulfuryl chlorideHCID 2902745-Amino-1,2,4-thiadiazoleHCID 89813562HCID 89813562, compound2×

Product 1

HCID 71735778HCID 71735778, compound

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A suspension of 1,2,4-thiadiazol-5-amine (2.67 g, 26.4 mmol) in 20 mL DCM was treated with triethylamine (3.68 ml, 26.4 mmol) and was allowed to stir for 10 minutes. The reaction mixture was then cooled to −78° C. and was treated with 1 equivalent of sulfuryl chloride. After stirring for 5 minutes, the cooling bath was removed, and the reaction mixture was allowed to stir for an additional hour. LC/MS showed mostly product so the reaction mixture was filtered then concentrated. The resulting residue was dissolved in 10 mL THF and was added to a solution of 5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate D, 4.70 g, 13.20 mmol) and triethylamine (4.05 ml, 29.0 mmol) in 10 mL THF. After stirring for an additional 4 hours, the reaction mixture was poured into 1 N citric acid solution and was extracted with EtOAc. The organics were washed with brine, dried over MgSO4 and concentrated. The resulting residue was triturated with DCM providing a white solid. The washings were purified by silica gel column chromatography (0 to 100% EtOAc/heptane) and combined with the white solid yielding 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (6.90 g, 13.29 mmol). [M+H]+=518.9 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.04 (s, 1H), 7.97 (s, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.22 (d, J=7.1 Hz, 1H), 7.01 (d, J=6.1 Hz, 1H), 4.34 (s, 2H), 3.30 (m, 2H), 2.47-2.58 (m, 2H)

Workup

  1. stirringAfter stirring for 5 minutes
  2. customthe cooling bath was removed
  3. stirringto stir for an additional hour
  4. filtrationwas filtered
  5. concentrationthen concentrated
  6. dissolutionThe resulting residue was dissolved in 10 mL THF
  7. stirringAfter stirring for an additional 4 hours
  8. extractionwas extracted with EtOAc
  9. washThe organics were washed with brine
  10. dry with materialdried over MgSO4
  11. concentrationconcentrated
  12. customThe resulting residue was triturated with DCM providing a white solid
  13. customThe washings were purified by silica gel column chromatography (0 to 100% EtOAc/heptane)

Sources & evidence

ORD record
ord-8a1155b435bb4ee387742e6ebd919be8
Source dataset
uspto-grants-2015_06
Patent number
US09051311B2

Reaction notes

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