Nitrogen → tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-cyclopropylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate

HRID 1396372Notes

Reaction equation

HRID 1396372 reaction equation
Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3[CH2:20][CH2:19]3)[N:13]=2)[CH:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].N#N>CN1CCCC1=O.CN(C1C=CN=CC=1)C>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:20][CH2:19]2)[N:13]=1)(=[O:9])[NH2:10]

Participants

6

Reactant 3

HCID 947NitrogenHCID 1514389(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protectedHCID 866897336-Chloro-4-(6-cyclopropylpyridin-2-ylamino)pyridazine-3-carboxamide

Product 1

HCID 86689734tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-cyclopropylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
150 °C

Procedure

To a stirred solution of 6-chloro-4-(6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide (104 mg, 359 mmol) in N-methyl-2-pyrrolidinone (5 mL) was added DMAP (47 mg, 377 μmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (154 mg, 718 μmol). The mixture was heated to 150° C. for 1.5 days, then a stream of N2 was blown into the flask while heating at 140° C. to evaporate the volatile solvents. The residue obtained was then purified by chromatography (silica, 50 μm, 60 g, Analogix, 97:2.75:0.15 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 30 min) to afford tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-cyclopropylpyridin-2-ylamino)pyridazin-3 ylamino)cyclohexylcarbamate (126 mg, containing some residual NMP) as a brown viscous oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 11.43 (br. s., 1H) 8.17 (br. s., 1H) 8.03 (br. s., 1H) 7.44 (br. s., 1H) 7.03 (br. s., 1H) 6.80 (br. s., 1H) 6.60 (br. s., 1H) 5.76 (br. s., 1H) 5.49 (br. s., 1H) 3.82 (br. s., 1H) 3.24 (br. s., 1H) 2.03 (br. s., 1H) 1.32-1.91 (m, 8H) 1.45 (s., 9H) 1.05 (d, J=16.62 Hz, 4H). LCMS (EI/CI) m/z: 468 [M+H]. This was used directly in the next step without further purification.

Workup

  1. temperaturewhile heating at 140° C.
  2. customto evaporate the volatile solvents
  3. customThe residue obtained
  4. customwas then purified by chromatography (silica, 50 μm, 60 g, Analogix, 97:2.75:0.15 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 30 min)

Sources & evidence

ORD record
ord-f9f15931f2bb4dc6aede33dcf2fb1257
Source dataset
uspto-grants-2014_12
Patent number
US08901124B2

Reaction notes

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