Trifluoroacetic acid → 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide

HRID 1396348Notes

Reaction equation

HRID 1396348 reaction equation
ClC1N=[N:6]C(C(N)=[O:9])=C(NC2C=CC=C(C(C)C)N=2)C=1.N[C@@H]1CCCC[C@@H]1NC(=O)OC(C)(C)C.[C:36]([C:39]1[N:44]=[N:43][C:42]([NH:45][C@@H:46]2[CH2:51][CH2:50][CH2:49][CH2:48][C@@H:47]2[NH:52]C(=O)OC(C)(C)C)=[CH:41][C:40]=1[NH:60][C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH:67]([CH3:69])[CH3:68])[N:62]=1)(=[O:38])[NH2:37].N[C@H]1CCCC[C@H]1NC1N=NC(C(N)=O)=C(NC2C=CC=C(C(C)C)N=2)C=1.C(O)(C(F)(F)F)=O>CN1CCCC1=O.ClCCl>[NH4+:6].[OH-:9].[NH2:52][C@H:47]1[CH2:48][CH2:49][CH2:50][CH2:51][C@H:46]1[NH:45][C:42]1[N:43]=[N:44][C:39]([C:36]([NH2:37])=[O:38])=[C:40]([NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([CH:67]([CH3:69])[CH3:68])[N:62]=2)[CH:41]=1

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected2×HCID 716268226-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamideHCID 866897176-Chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamideHCID 86689718tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate

Product 2

HCID 14923Ammonium HydroxideHCID 716268226-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamideYield 9%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
150 °C

Procedure

To a solution of 6-chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (102 mg, 350 μmol) in N-methyl-2-pyrrolidinone (6 ml) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (150 mg, 699 μmol) and the mixture heated to 150° C. for 3 d. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (150 mg, 699 μmol) was added and the reaction heated to 150° C. for an additional 2 d, then cooled, concentrated, and purified by chromatography (silica, 50 μm, 40 g, Analogix, 96:3.8:0.2 to 84:15.2:0.8; dichloromethane:MeOH:NH4OH) to give a mixture of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate and 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (33 mg). This mixture was dissolved in dichloromethane (2 mL) then TFA (370 mg, 250 μL, 3.24 mmol) was added. After 18 h, the mixture was concentrated in vacuo and the residue obtained was purified by chromatography (spherical silica, 20-45 μm, 25 g, Versaflash Supelco, 96:3.8:0.2 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 25 min gradient to afford 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (12 mg, 9%) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.35 (br. s., 1H) 8.33 (s, 1H) 7.96 (br. s., 1H) 7.44 (t, J=7.83 Hz, 1H) 6.70 (d, J=7.58 Hz, 1H) 6.61 (d, J=8.08 Hz, 1H) 5.61 (br. s., 1H) 5.31 (br. s., 1H) 3.75 (br. s., 1H) 3.19 (d, J=3.28 Hz, 1H) 2.89-3.01 (m, 1H) 1.32-1.80 (m, 8H) 1.27 (d, J=6.82 Hz, 6H). LCMS (EI/CI) m/z: 370 [M+H].

Workup

  1. temperaturethe reaction heated to 150° C. for an additional 2 d
  2. temperaturecooled
  3. concentrationconcentrated
  4. custompurified by chromatography (silica, 50 μm, 40 g, Analogix, 96:3.8:0.2 to 84:15.2:0.8; dichloromethane:MeOH:NH4OH)
  5. customto give
  6. concentrationthe mixture was concentrated in vacuo
  7. customthe residue obtained
  8. customwas purified by chromatography (spherical silica, 20-45 μm, 25 g, Versaflash Supelco, 96:3.8:0.2 to 84:15.2:0.8 dichloromethane

Sources & evidence

ORD record
ord-fdf30e5f435c4f2fb1f7349c01e3406b
Source dataset
uspto-grants-2014_12
Patent number
US08901124B2

Reaction notes

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