Dichloromethane → (2S,4S)-4-{4-[6-Amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-2-carboxylic acid dimethylamide

HRID 1926321Notes

Reaction equation

HRID 1926321 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C@@H:13]3[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=O)[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[C:28]([Cl:31])[CH:27]=[CH:26][C:25]=2[F:32].C(Cl)Cl.Cl.[CH3:37][NH:38][CH3:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH3:37][N:38]([CH3:39])[C:18]([C@@H:15]1[CH2:14][C@H:13]([N:11]2[CH:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:21]4[N:22]=[CH:23][C:24]5[C:29]([CH:30]=4)=[C:28]([Cl:31])[CH:27]=[CH:26][C:25]=5[F:32])[CH:4]=3)[CH:9]=[N:10]2)[CH2:17][NH:16]1)=[O:20]

Participants

6

Reactant 5

HCID 6344DichloromethaneHCID 10473Dimethylamine, hydrochlorideHCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 67521202(2S,4S)-4-{4-[6-amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-2-carboxylic acid

Product 1

HCID 44160251(2S,4S)-4-{4-[6-Amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-2-carboxylic acid dimethylamide

Procedure

To a solution of (2S,4S)-4-{4-[6-amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-2-carboxylic acid (5.00 mg, 0.00889 mmol) in DCM (2 mL, 0.02 mol) was added dimethylamine hydrochloride (20 mg, 0.2 mmol) and DIPEA (0.2 mL, 1.0 mmol), and stirred for 1 min. TBTU (5.71 mg, 0.0178 mmol) was then added, and the solution was stirred at rt for 10 min. The material was transferred to a separatory funnel. The organic layer was washed with water, and concentrated in vacuo. The material was loaded onto a prep TLC plate, eluting with 6% (7N NH3 in MeOH/DCM. The band containing the product was collected and the product was eluted with 1:1 MeOH/DCM. The solution was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.15-2.22 (m, 1H), 2.82-2.90 (m, 1H), 2.99 (s, 3H), 3.10-3.13 (m, 3H), 3.21-3.26 (m, 1H), 3.49 (dd, J=12.3, 3.2 Hz, 1H), 4.15 (t, J=8.2 Hz, 1H), 4.99-5.05 (m, 1H), 7.38 (dd, J=9.6, 8.3 Hz, 1H), 7.84-7.91 (m, 2H), 8.13-8.17 (m, 2H), 8.27 (d, J=2.3 Hz, 1H), 8.43 (s, 1H), 9.60 (s, 1H). MS (ES+): m/z=480.13/482.11 (100/36) [MH+]. HPLC: tR=1.89 min (ZQ2, polar—5 min).

Workup

  1. stirringthe solution was stirred at rt for 10 min
  2. customThe material was transferred to a separatory funnel
  3. washThe organic layer was washed with water
  4. concentrationconcentrated in vacuo
  5. washeluting with 6% (7N NH3 in MeOH/DCM
  6. additionThe band containing the product
  7. customwas collected
  8. washthe product was eluted with 1:1 MeOH/DCM
  9. concentrationThe solution was concentrated in vacuo

Sources & evidence

ORD record
ord-5865998f94864e5aaee92e3dc646fd59
Source dataset
uspto-grants-2012_05
Patent number
US08178668B2

Reaction notes

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