Diisopropylethylamine → 4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)-6-(1-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877770Notes

Reaction equation

HRID 877770 reaction equation
CCN(C(C)C)C(C)C.[C:10]([C:13]1[CH:18]=[N:17][N:16]2[CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)[CH:21]=[C:15]2[C:14]=1[NH:31][C@H:32]1[C@@H:36]([CH3:37])[CH2:35][N:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][N:39]=2)[CH2:33]1)(=[O:12])[NH2:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:71][C:72]1([F:76])[CH2:75][NH:74][CH2:73]1>>[C:44]([C:41]1[CH:42]=[CH:43][C:38]([N:34]2[CH2:35][C@H:36]([CH3:37])[C@H:32]([NH:31][C:14]3[C:15]4[N:16]([CH:19]=[C:20]([C:22]5[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:74]6[CH2:75][C:72]([F:76])([F:71])[CH2:73]6)=[O:29])[CH:26]=5)[CH:21]=4)[N:17]=[CH:18][C:13]=3[C:10]([NH2:11])=[O:12])[CH2:33]2)=[N:39][CH:40]=1)#[N:45]

Participants

5

Reactant 4

HCID 81531DiisopropylethylamineHCID 27582473,3-Difluoroazetidine hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 682916422-(4-(3-carbamoyl-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)acetic acid

Product 1

HCID 601945414-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)-6-(1-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamideYield 17.8%

Procedure

Hunig's base (0.014 mL, 0.079 mmol) was added to a stirred solution of crude 2-(4-(3-carbamoyl-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)acetic acid (20 mg, from Step 2) and HATU (20.05 mg, 0.053 mmol). After 2.5 h at room temperature, 3,3-difluoroazetidine hydrochloride (6.83 mg, 0.053 mmol) was added. After 40 min at room temperature, the reaction was complete. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 7-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (4.1 mg). 1H NMR (500 MHz, chloroform-d/methanol-d4) δ ppm 8.31 (br. s., 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.63 (dd, J=8.9, 1.5 Hz, 1H), 6.99 (d, J=1.5 Hz, 1H), 6.49 (d, J=8.9 Hz, 1H), 4.99-4.91 (m, 3H), 4.46 (t, J=11.9 Hz, 2H), 4.39 (t, J=11.9 Hz, 2H), 3.94 (br. s., 2H), 3.41 (br. s., 1H), 2.84 (br. s., 1H), 1.29 (d, J=6.9 Hz, 3H); MS (ES+) m/z: 561.1 (M+H); LC retention time: 1.24 min (analytical LCMS Method I).

Workup

  1. waitAfter 40 min at room temperature
  2. customThe crude material was purified via preparative LC/MS with the following conditions
  3. waitGradient: 5-100% B over 15 minutes
  4. customa 7-minute hold
  5. additionFractions containing the desired product
  6. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-dc1381ac7fff451b97b19fb5f1370f50
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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