N-methyl-2-pyrrolidone → HCID 46938169, compound

HRID 655727Notes

Reaction equation

HRID 655727 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([O:18][C@@H:19]([CH2:30][O:31][C@H:32]([CH3:45])[CH2:33][O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=3)=[O:21])=[C:12]2[CH:11]=[N:10]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:88][N:89]1CCCC1=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:88]#[N:89])[C:3]=1[N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([O:18][C@@H:19]([CH2:30][O:31][C@H:32]([CH3:45])[CH2:33][O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=3)=[O:21])[C:12]=2[CH:11]=[N:10]1

Participants

6

Reactant 3

HCID 13387N-methyl-2-pyrrolidoneHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 57504702HCID 57504702, compound

Product 1

HCID 46938169HCID 46938169, compoundYield 79%

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
110 °C

Procedure

Tris(dibenzylideneacetone)dipalladium(0) (0.261 g, 0.29 mmol) was added in one portion to a de-gassed mixture of (2S)-2-(1-(2-bromo-6-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)-3-((2R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate BO1) (4.1 g, 5.70 mmol), zinc cyanide (0.335 g, 2.85 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.330 g, 0.57 mmol) in N-methylpyrrolidone (41 mL) at 20° C. under nitrogen. The resulting suspension was degassed under vacuum with inlet of nitrogen four times and then heated to 110° C. (internal temperature) for 1 hour. The mixture was cooled, poured into water (100 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined and washed with water (4×50 mL) and brine (50 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 100% EtOAc in isohexane to afford the product (3.0 g, 79%). 1H NMR (400.13 MHz, DMSO-d6) δ 0.90-1.08 (21H, m), 1.09-1.11 (3H, m), 2.45 (3H, s), 3.53-3.58 (1H, m), 3.60-3.66 (1H, m), 3.75-3.78 (1H, m), 4.10-4.15 (2H, m), 5.94-5.99 (1H, m), 7.87-7.91 (1H, m), 8.16-8.19 (2H, m), 8.31-8.33 (1H, m), 8.60-8.61 (1H, m), 8.73 (1H, s), 9.10-9.12 (1H, d), 11.20 (1H, s); m/z (ES−) (M−H)−=663; HPLC tR=3.79 min.

Workup

  1. customThe resulting suspension was degassed under vacuum with inlet of nitrogen four times
  2. temperatureThe mixture was cooled
  3. additionpoured into water (100 mL)
  4. extractionextracted with ethyl acetate (2×50 mL)
  5. washwashed with water (4×50 mL) and brine (50 mL)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. customThe crude product was purified by flash silica chromatography, elution gradient 30 to 100% EtOAc in isohexane

Sources & evidence

ORD record
ord-afe0f6055aa94198981fcb5dc992a7cf
Source dataset
uspto-grants-2011_12
Patent number
US08071608B2

Reaction notes

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