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

HRID 2046404Notes

Reaction equation

HRID 2046404 reaction equation
[N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([C:16]([OH:18])=O)[S:13][C:14]=2[CH3:15])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(OC(=O)[NH:52][C@@H:53]1[CH2:58][CH2:57][CH2:56][C:55]([F:60])([F:59])[C@@H:54]1[NH2:61])(C)(C)C.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>O.ClCCl>[NH2:52][C@H:53]1[C@@H:54]([NH:61][C:16]([C:12]2[S:13][C:14]([CH3:15])=[C:10]([C:3]3[N:4]4[N:5]=[CH:6][CH:7]=[CH:8][C:9]4=[N:1][CH:2]=3)[CH:11]=2)=[O:18])[C:55]([F:60])([F:59])[CH2:56][CH2:57][CH2:58]1

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 580464044-(Imidazo[1,2-b]pyridazin-3-yl)-5-methylthiophene-2-carboxylic acidHCID 59603811tert-Butyl ((1R,2R)-2-amino-3,3-difluorocyclohexyl)carbamate

Product 1

HCID 67123022N-[(1R,6R)-6-Amino-2,2-difluorocyclohexyl]-4-(imidazo[1,2-b]pyridazin-3-yl)-5-methylthiophene-2-carboxamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a mixture of 4-(imidazo[1,2-b]pyridazin-3-yl)-5-methylthiophene-2-carboxylic acid (0.06 g, 0.24 mmol) and BOP (0.16 g, 0.36 mmol) was added tert-butyl[(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (0.06 g, 0.26 mmol) followed by diisopropylethylamine (0.09 mL, 0.49 mmol). The mixture was allowed stir at room temperature overnight. The resulting solution was diluted with water and extracted three times with dichloromethane. The combined organic layers were dried with magnesium sulfate, filtered, concentrated and to the resulting residue was added dichloromethane and trifluoroacetic acid (1 mL, 53 mmol). The compound was 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 ethyl acetate. 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 8.62 (d, 1H); 8.28 (s, 1H); 8.21 (d, 1H); 7.99 (s, 1H); 7.90 (d, 1H); 7.29 (dd, 1H); 4.55 (m, 1H); 3.08 (m, 1H); 2.47 (s, 3H); 2.11 (m, 1H); 1.85 (m, 1H); 1.71 (m, TH); 1.59 (m, 2H); 1.45 (m, 1H). LRMS (APCI) calc'd for (C18H19F2N5OS) [M+H]+, 392.1. found 392.1.

Workup

  1. extractionextracted three times with dichloromethane
  2. dry with materialThe combined organic layers were dried with magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated and to the resulting residue
  5. customThe compound was purified by prep HPLC
  6. additionadding an aqueous saturated sodium bicarbonate solution
  7. extractionextracting three times with ethyl acetate
  8. dry with materialThe combined organics were dried with magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-e79a14bb9ee04b8991c360c531b23669
Source dataset
uspto-grants-2013_11
Patent number
US08592425B2

Reaction notes

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