Diisopropylethylamine → n-{5-[(1r)-1-({3-Cyano-6-[(5-cyclopropyl-1h-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamide

HRID 2189872Notes

Reaction equation

HRID 2189872 reaction equation
[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.NC(C1C=CC(F)=C([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])C=1)C.CCN(C(C)C)C(C)C>C(O)CCC>[C:14]([C:13]1[C:12]([NH:19][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:23]=2)[CH3:21])=[N:11][C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[C:17]([F:18])[CH:16]=1)#[N:15]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 11646595(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrileHCID 67426606N-[5-(1-aminoethyl)-2-fluorophenyl]methanesulfonamide

Product 1

HCID 67425688n-{5-[(1r)-1-({3-Cyano-6-[(5-cyclopropyl-1h-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamideYield 20.2%

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Conditions

Temperature
150 °C

Procedure

To a 10-ml microwave vessel was added, 2-chloro-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoronicotinonitrile (Method 1, 600 mg, 2.3 mmol), N-[5-(1-aminoethyl)-2-fluorophenyl]methanesulfonamide (Method 61, 500 mg, 2.3 mmol), DIEA (0.5 ml, 2.76 mmol), and n-butanol (5 ml). The vessel was sealed and subjected to microwave heating at 150° C. for 5 hours (CEM Discover System). The resulting mixture was then purified by silica gel chromatography using 5% MeOH/DCM. The racemic product obtained was then chirally purified by HPLC on Chiralcel OJ column (500×50 mm, 20 microns) using 50:25:25:0.1% of hexane/MeOH/EtOH/diethylamine at 118 ml/min. The chiral purification gave 220 mg of N-{5-[(1R)-1-({3-cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamide 1H NMR: δ 11.77-12.26 (br s, 1H), 9.51 (s, 1H), 9.34-9.48 (br s, 1H), 7.62 (d, J=10.55 Hz, 1H), 7.39 (d, J=8.29 Hz, 1H), 7.02-7.23 (m, 3H), 6.00 (s, 1H), 5.07-5.24 (m, 1H), 2.95 (s, 3H), 1.81-1.95 (m, 1H), 1.49 (d, J=7.54 Hz, 3H), 0.88-0.97 (m, 2H), 0.57-0.68 (m, 2H). MS: Calcd.: 473. Found: [M+H]+ 474 and 223 mg of N-{5-[(1S)-1-({3-cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}methanesulfonamidel; 1H NMR: 11.73-12.38 (br s, 1H), 9.42 (s, 1H), 8.41-9.12 (br s, 1H), 7.61 (d, J=11.30 Hz, 1H), 7.37 (d, J=7.54 Hz, 1H), 6.96-7.24 (m, 3H), 6.02 (s, 1H), 5.05-5.26 (m, 1H), 2.90 (s, 3H), 1.79-1.96 (m, 1H), 1.49 (d, J=6.78 Hz, 3H), 0.89-0.98 (m, 2H), 0.59-0.67 (m, 2H). MS: Calcd.: 473. Found: [M+H]+ 474.

Workup

  1. additionTo a 10-ml microwave vessel was added
  2. customThe vessel was sealed
  3. customThe resulting mixture was then purified by silica gel chromatography
  4. customThe racemic product obtained
  5. customwas then chirally purified by HPLC on Chiralcel OJ column (500×50 mm, 20 microns)
  6. customThe chiral purification

Sources & evidence

ORD record
ord-421ad42dcd924662892b7579ab8ac717
Source dataset
uspto-grants-2012_12
Patent number
US08324252B2

Reaction notes

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