Citric Acid → HCID 71736901, compound

HRID 2172325Notes

Reaction equation

HRID 2172325 reaction equation
Cl.[F:2][C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1.N1C=CN=C1.[S:14](Cl)(Cl)(=[O:16])=[O:15].[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=2[C:35]2[CH:44]=[CH:43][CH:42]=[C:41]3[C:36]=2[CH2:37][CH2:38][NH:39][CH2:40]3)[CH:24]=1.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.CCCCCCC>[F:2][C:3]1[S:7][C:6]([NH:8][S:14]([N:39]2[CH2:38][CH2:37][C:36]3[C:41](=[CH:42][CH:43]=[CH:44][C:35]=3[C:26]3[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[CH:30][C:25]=3[N:23]3[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]3)[CH2:40]2)(=[O:16])=[O:15])=[N:5][CH:4]=1

Participants

9

Reactant 6

HCID 311Citric AcidHCID 795ImidazoleHCID 24648Sulfuryl chlorideHCID 81531DiisopropylethylamineHCID 118589315-Fluoro-1,3-thiazol-2-amine hydrochlorideHCID 89813688HCID 89813688, compound

Product 1

HCID 71736901HCID 71736901, compoundYield 0.4%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8900HeptaneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 5-fluorothiazol-2-amine hydrochloride (Milestone Pharmatech, Brunswick, N.J., 0.692 g, 4.48 mmol) and imidazole (1.219 g, 17.91 mmol) in 10 mL DCM was cooled to −78° C. and was treated with sulfuryl chloride (0.364 ml, 4.48 mmol). After stirring for 10 minutes, the reaction mixture was placed in a 0° C. bath and was allowed to stir for one hour at which point about 3 mL heptane was added, and the organics were decanted off. The resulting solid was treated with a solution of 5-(2-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.800 g, 2.239 mmol) in 15 mL DCM followed by DIPEA (4.69 ml, 26.9 mmol) and was heated to 80° C. for 30 minutes. The reaction mixture was poured into 1N citric acid solution and was extracted with EtOAc. The organics were concentrated then purified directly by reverse phase column chromatography [RediSep Gold C18 150 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] yielding N-(5-fluorothiazol-2-yl)-5-(2-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.005 g, 9.30 μmol). [M+H]+=538.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 7.93 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.23 (s, 1H), 7.09-7.20 (m, 2H), 7.02 (d, J=7.0 Hz, 1H), 6.99 (d, J=0.7 Hz, 1H), 4.25-4.43 (m, 2H), 3.78-3.83 (m, 1H), 3.18-3.28 (m, 1H), 2.45-2.55 (m, 1H), 2.33-2.42 (m, 1H), 2.14 (s, 3H)

Workup

  1. customwas placed in a 0° C.
  2. additionwas added
  3. customthe organics were decanted off
  4. extractionwas extracted with EtOAc
  5. concentrationThe organics were concentrated
  6. customthen purified directly by reverse phase column chromatography [RediSep Gold C18 150 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)]

Sources & evidence

ORD record
ord-10fee5b7d24841348f0471777ba3431b
Source dataset
uspto-grants-2015_06
Patent number
US09051311B2

Reaction notes

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