Dimethylacetamide → 2-({5-Amino-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxyphenyl}amino)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile

HRID 1842774Notes

Reaction equation

HRID 1842774 reaction equation
Cl[C:2]1[C:3]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=23)=[N:4][C:5]([NH:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([N:17]3[CH2:21][CH2:20][C@@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18]3)=[C:11]([NH2:25])[CH:10]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.C[C:70]([N:72](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn]>[NH2:25][C:11]1[C:12]([N:17]2[CH2:21][CH2:20][C@@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18]2)=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[C:2]([C:70]#[N:72])=[CH:7][N:6]=2)[CH:10]=1

Participants

6

Reactant 3

HCID 31374DimethylacetamideHCID 21081571Dicyclohexyl(2',4',6'-tripropyl-[1,1'-biphenyl]-2-yl)phosphineHCID 86677235N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine2×

Product 1

HCID 894144842-({5-Amino-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxyphenyl}amino)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrileYield 65%

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 23994ZincCatalyst

Conditions

Temperature
95 °C

Procedure

A mixture of N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 18, 250 mg, 0.52 mmol), zinc cyanide (36.8 mg, 0.31 mmol), zinc powder (3.41 mg, 0.05 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (‘XPhos’ 49.8 mg, 0.10 mmol) was stirred in DMA (2 mL) and purged with N2 for 0.25 h. Tris(dibenzylidene-acetone)dipalladium(0) (47.8 mg, 0.05 mmol) was then added and the mixture was heated at 95° C. for 2 h. The cooled mixture was then absorbed onto an SCX column, washed with CH3OH and eluted with 7M methanolic ammonia solution. Appropriate fractions were combined and concentrated in vacuo. The resulting residue was suspended in CH3OH then the mixture was filtered. The collected solid was dried on the filter to give the title compound (160 mg, 65%) as a tan powder; 1H NMR: (100° C.) 1.78-1.92 (1H, m), 2.00-2.15 (1H, m), 2.26 (6H, s), 2.95-3.02 (1H, m), 3.02-3.07 (1H, m), 3.07-3.13 (1H, m), 3.16-3.27 (2H, m), 3.68 (3H, s), 6.74 (1H, s), 6.95 (1H, s), 7.13 (1H, td), 7.33-7.43 (1H, m), 8.37 (1H, d), 8.64 (1H, s), 8.77 (1H, dt), 8.84 (1H, s), 8.91 (1H, s); m/z: ES+ MH+ 470.60.

Workup

  1. custompurged with N2 for 0.25 h
  2. customThe cooled mixture was then absorbed onto an SCX column
  3. washwashed with CH3OH
  4. washeluted with 7M methanolic ammonia solution
  5. concentrationconcentrated in vacuo
  6. filtrationthe mixture was filtered
  7. customThe collected solid was dried on the
  8. filtrationfilter

Sources & evidence

ORD record
ord-e0060ea1d2d04373ae9f5fc7d7658d85
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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