Trifluoroacetic acid → N-[(1R,6R)-6-Amino-2,2-difluorocyclohexyl]-5-ethyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxamide

HRID 2046410Notes

Reaction equation

HRID 2046410 reaction equation
C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH:33]=[CH2:34])=[C:22]([C:24]2[N:28]3[N:29]=[CH:30][CH:31]=[CH:32][C:27]3=[N:26][CH:25]=2)[CH:23]=1)=[O:18])(C)(C)C.C([O-])=O.[NH4+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(O)CC.[Pd]>[NH2:7][C@H:8]1[C@@H:9]([NH:16][C:17]([C:19]2[S:20][C:21]([CH2:33][CH3:34])=[C:22]([C:24]3[N:28]4[N:29]=[CH:30][CH:31]=[CH:32][C:27]4=[N:26][CH:25]=3)[CH:23]=2)=[O:18])[C:10]([F:15])([F:14])[CH2:11][CH2:12][CH2:13]1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 516892Sodium BicarbonateHCID 2723923Ammonium formateHCID 91321603tert-Butyl[(1R,2R)-2-({[5-ethenyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate

Product 1

HCID 67123104N-[(1R,6R)-6-Amino-2,2-difluorocyclohexyl]-5-ethyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxamide

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 10311-PropanolSolvent

Conditions

Temperature
100 °C

Procedure

tert-Butyl[(1R,2R)-2-({[5-ethenyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (103 mg, 0.205 mmol), ammonium formate (128 mg, 2.04 mmol), and 10% Pd/C (109 mg, 0.102 mmol) were dissolved in n-propanol (4.1 mL) and left to stir at 100° C. for 18 h. The solution was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and taken up in dichloromethane (2 mL). Trifluoroacetic acid (1 mL, 13.0 mmol) was added to the mixture and stirred for 4 h at room temperature. The solution was then neutralized with aqueous saturated sodium bicarbonate and extracted with dichloromethane (×3). The organic layers were collected and dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by prep HPLC. The compound was neutralized by taking the fractions and adding an aqueous saturated sodium bicarbonate solution and extracting three times with dichloromethane. The combined organics were dried with magnesium sulfate, filtered, and concentrated to afford the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.60 (d, 1H); 8.22 (s, 1H); 8.21 (d, 1H); 7.95 (s, 1H); 7.90 (d, 114, br); 7.29 (dd, 1H); 4.56 (m, 1H); 3.08 (m, 1H); 2.83 (q, 2H); 2.10 (m, 1H); 1.86 (m, 1H); 1.71 (m, 1H); 1.59 (m, 2H); 1.44 (m, 1H); 1.20 (t, 3H). LRMS (APCI) calc'd for (C19H21F2N5OS) [M+H]+, 406.1. found 406.1.

Workup

  1. waitleft
  2. temperatureThe solution was cooled to room temperature
  3. filtrationfiltered through celite
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. stirringstirred for 4 h at room temperature
  6. extractionextracted with dichloromethane (×3)
  7. customThe organic layers were collected
  8. dry with materialdried with magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was then purified by prep HPLC
  12. additionadding an aqueous saturated sodium bicarbonate solution
  13. extractionextracting three times with dichloromethane
  14. dry with materialThe combined organics were dried with magnesium sulfate
  15. filtrationfiltered
  16. concentrationconcentrated

Sources & evidence

ORD record
ord-edd9db3a857145f7a72d97bdada80ccf
Source dataset
uspto-grants-2013_11
Patent number
US08592425B2

Reaction notes

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