4-Methylpyrazole → 4-((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-ylamino)-6-(4-methyl-1H-pyrazol-1-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877797Notes

Reaction equation

HRID 877797 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([C:19]4([C:22]#[N:23])[CH2:21][CH2:20]4)=[O:18])[CH2:12]3)=[C:8]([C:24]([NH2:26])=[O:25])[CH:7]=[N:6][N:5]2[CH:27]=1.C1(C(C#N)C(O)=O)CC1.C(=O)([O-])[O-].[K+].[K+].[CH3:43][C:44]1[CH:45]=[N:46][NH:47][CH:48]=1.CN[C@H]1CCCC[C@@H]1NC>[Cu](I)I.O1CCOCC1>[C:22]([C:19]1([C:17]([N:13]2[CH2:14][C@H:15]([CH3:16])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:27]=[C:2]([N:46]5[CH:45]=[C:44]([CH3:43])[CH:48]=[N:47]5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:24]([NH2:26])=[O:25])[CH2:12]2)=[O:18])[CH2:20][CH2:21]1)#[N:23]

Participants

8

Reactant 5

HCID 34064-MethylpyrazoleHCID 11430Potassium CarbonateHCID 13822957(1S,2S)-(+)-N,N'-Dimethylcyclohexane-1,2-diamineHCID 184753102-Cyano-2-cyclopropylacetic acidHCID 682917116-bromo-4-((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 682912074-((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-ylamino)-6-(4-methyl-1H-pyrazol-1-yl)pyrrolo[1,2-b]pyridazine-3-carboxamideYield 34.2%

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

The title compound was prepared from 20 mg (0.046 mmol) of 6-bromo-4-((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (prepared from the product of Step 1 of Example 158 using the methods previously described in Step 1 of Example 191 by replacing cyanoacetic acid with cyclopropylcyanoacetic acid), potassium carbonate (32.0 mg, 0.232 mmol), 4-methyl-1H-pyrazole (15.2 mg, 0.18 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (13.2 mg, 0.09 mmol) and dioxane (0.30 mL). The resulting mixture was sparged with argon for ˜5 min. then copper iodide (17.7 mg, 0.09 mmol) was added and the mixture was heated at 100° C. for 3 h. After cooling to rt, the mixture was purified by preparative LC/MS using the following conditions: (column: Waters XBridge C18, 19×250 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: 10-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 6.8 mg of the title compound. Analytical LCMS (method H) retention time=1.98 min. (MH+ 433.2). 1H NMR (500 MHz, METHANOL-d4, appeared as rotomers) δ 8.39-8.32 (m, 1H), 8.14 (s, 1H), 8.07 (dd, J=12.4, 1.5 Hz, 1H), 7.98 (d, J=7.4 Hz, 1H), 7.69-7.64 (m, 1H), 7.34-7.24 (m, 1H), 5.20-5.00 (m, 2H), 4.55-4.41 (m, 3H), 4.13-3.90 (m, 3H), 3.04-2.80 (m, 1H), 2.34 (s, 3H), 1.99-1.65 (m, 4H), 1.49-1.38 (m, 4H).

Workup

  1. customThe resulting mixture was sparged with argon for ˜5 min.
  2. temperatureAfter cooling to rt
  3. customthe mixture was purified by preparative LC/MS
  4. customa 5-minute hold
  5. additionFractions containing the desired product
  6. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-884ca3c18d464004bd4fc7eae392f4bb
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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