Propylene Oxide → HCID 67469643, compound

HRID 1522652Notes

Reaction equation

HRID 1522652 reaction equation
[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:32][CH:33]1[CH2:35][O:34]1>CN(C=O)C>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:17]4[C:18](=[CH:22][N:23]([CH2:32][C@@H:33]([OH:34])[CH3:35])[N:24]=4)[N:19]=[CH:20][CH:21]=3)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 6378Propylene OxideHCID 10796Cesium carbonateHCID 67469580HCID 67469580, compound

Product 1

HCID 67469643HCID 67469643, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

N-(3′-Fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (374 mg, 1.119 mmol) and Cs2CO3 (364 mg, 1.119 mmol) were stirred in DMF (6 mL) for 10 minutes. 2-Methyloxirane (0.079 mL, 1.119 mmol) was added, the vessel sealed and the mixture was heated in a microwave at 120° C. for 30 minutes. The reaction mixture was cooled and purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 10-25% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to separate the regioisomers which in turn were further purified using a Chiralcel AD-H (5 um, 20×150 mm) column eluting with CO2: 15% EtOH+0.1% DEA at 50 mL/min to give (S)-1-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-ol 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.21 (d, J=4 Hz, 3H) 2.44 (s, 3H) 2.56 (s, 3H) 4.20-4.33 (m, 1H) 4.37 (dd, J=12, 8 Hz, 1H) 4.49 (dd, J=16, 4 Hz, 1H) 6.99 (d, J=4 Hz, 1H) 7.35 (dd, J=8, 4 Hz, 1H) 7.60 (dd, J=12, 8 Hz, 1H) 7.92 (s, 1H) 8.28 (d, J=4 Hz, 1H) 8.37 (s, 1H) 8.49 (s, 1H), MS [M+H] found 393.4; (R)-1-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-ol 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.22 (d, J=4 Hz, 3H) 2.46 (s, 3H) 2.57 (s, 3H) 4.21-4.34 (m, 1H) 4.39 (dd, J=12, 8 Hz, 1H) 4.51 (dd, J=12, 4 Hz, 1H) 7.01 (d, J=4 Hz, 1H) 7.36 (dd, J=8, 4 Hz, 1H) 7.61 (dd, J=8, 4 Hz, 1H) 7.93 (s, 1H) 8.29 (d, J=4 Hz, 1H) 8.38 (s, 1H) 8.50 (s, 1H), MS [M+H] found 393.4; (R)-1-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-ol 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.22 (d, J=8 Hz, 3H) 2.46 (s, 3H) 2.58 (s, 3H) 4.14-4.34 (m, 1H) 4.34-4.43 (m, 1H) 4.51 (m, 1H) 7.01 (d, J=4 Hz, 1H) 7.37 (dd, J=8, 4 Hz, 1H) 7.61 (dd, J=12, 12 Hz, 1H) 7.94 (s, 1H) 8.29 (d, J=4 Hz, 1H) 8.39 (s, 1H) 8.50 (s, 1H), MS [M+H] found 393.4; and (S)-1-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-ol 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.21 (d, J=8 Hz, 3H) 2.46 (s, 3H) 2.57 (s, 3H) 4.19-4.34 (m, 1H) 4.38 (m, 1H) 4.50 (m, 1H) 7.00 (d, J=4 Hz, 1H) 7.36 (dd, J=8, 4 Hz, 1H) 7.61 (dd, J=8, 8 Hz, 1H) 7.93 (s, 1H) 8.29 (d, J=4 Hz, 1H) 8.38 (s, 1H) 8.50 (s, 1H), MS [M+H] found 393.4.

Workup

  1. customthe vessel sealed
  2. temperatureThe reaction mixture was cooled
  3. custompurified by preparative HPLC
  4. washeluting with a gradient of 10-25% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA)
  5. customto separate the regioisomers which in turn
  6. customwere further purified
  7. washeluting with CO2

Sources & evidence

ORD record
ord-55eb8d3e8b2f42f5814d30785014ac07
Source dataset
uspto-grants-2015_07
Patent number
US09073918B2

Reaction notes

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