Morpholine → 5-((S)-6-Morpholin-4-yl-2,3,3a,4-tetrahydro-1H-5-oxa-7,9,9b-triaza-cyclopenta[a]naphthalen-8-yl)-pyrimidin-2-ylamine

HRID 334145Notes

Reaction equation

HRID 334145 reaction equation
Cl[C:2]1[N:11]=[C:10](Cl)[N:9]=[C:8]2[C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:15][CH2:14][CH2:13][N:7]12.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1([C:2]2[N:11]=[C:10]([C:37]3[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=3)[N:9]=[C:8]3[C:3]=2[O:4][CH2:5][C@@H:6]2[CH2:15][CH2:14][CH2:13][N:7]23)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1

Participants

7

Reactant 5

HCID 8083MorpholineHCID 8471TriethylamineHCID 10340Sodium CarbonateHCID 177502122-Aminopyrimidine-5-boronic acid, pinacol esterHCID 86667362(S)-6,8-dichloro-2,3,3a,4-tetrahydro-1H-5-oxa-7,9,9b-triaza-cyclopenta[a]naphthalene

Product 1

HCID 573856175-((S)-6-Morpholin-4-yl-2,3,3a,4-tetrahydro-1H-5-oxa-7,9,9b-triaza-cyclopenta[a]naphthalen-8-yl)-pyrimidin-2-ylamineYield 8%

Reagents, catalysts & solvents 1

HCID 178418476HCID 178418476, compoundCatalyst

Conditions

Temperature
140 °C

Procedure

A mixture of (S)-6,8-dichloro-2,3,3a,4-tetrahydro-1H-5-oxa-7,9,9b-triaza-cyclopenta[a]naphthalene (290 mg, 1.18 mmol), morpholine (275 μL, 3.14 mmol) and triethylamine (242 μL, 1.74 mmol) in IMS (11 mL) was heated at 140° C. for 20 mins in a microwave reactor, then concentrated in vacuo. The resulting residue re-dissolved in acetonitrile (2 mL) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (500 mg, 2.26 mmol), PdCl2(PPh3)2 (88 mg, 0.125 mmol) and sodium carbonate (4 mL, 4.0 mmol, 1M aqueous solution) were added. The reaction mixture was degassed and heated at 120° C. for 30 mins in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water gradient acetonitrile 5-60%) affording 122 as a white solid (30 mg, 8%). LCMS (method B): RT=3.34 min, [M+H]+=356. 1H NMR (400 MHz, CDCl3): δ 9.15 (2H, s), 5.14 (2H, broad s), 4.48 (1H, dd, J=10.4, 3.5 Hz), 3.87-3.68 (10H, m), 3.62 (1H, m), 3.31 (1H, t, J=10.1 Hz), 2.21-1.94 (3H, m), 1.50 (1H, m).

Workup

  1. concentrationconcentrated in vacuo
  2. dissolutionThe resulting residue re-dissolved in acetonitrile (2 mL)
  3. customThe reaction mixture was degassed
  4. temperatureheated at 120° C. for 30 mins in a microwave reactor
  5. washwas washed with methanol
  6. washthe product eluted with 2M ammonia in methanol
  7. concentrationconcentrated in vacuo
  8. customThe resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water gradient acetonitrile 5-60%)

Sources & evidence

ORD record
ord-42108a2e30f647408ae6a4af686c49b4
Source dataset
uspto-grants-2014_11
Patent number
US08883799B2

Reaction notes

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