2-Methyltetrahydrofuran → 4-(4-Chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine
Reaction equation
[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18](Cl)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CC1OCCC1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]Participants
Reactant 3
Product 1
Reagents, catalysts & solvents 1
Conditions
- Temperature
- 20 °C
Procedure
7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (15.2 g, 41.16 mmoles) is charged into a 250 mL 3-necked round bottomed flask, followed by addition of 2-MeTHF (61 mL, 4.0 volumes), the yellowish brown slurry is stirred at about 20° C. for 5 min. Then morpholine (19 g, 218.18 mmoles) is added over 2-5 minutes. Contents are heated to reflux and maintained at reflux for 12 hr. The slurry is cooled to 25° C., followed by addition of 2-MeTHF (53 mL, 3.5 volumes) and water (38 mL 2.5 volumes). The reaction mixture is warmed to 40° C., where upon a homogenous solution with two distinct layers formed. The layers are separated, the organic layer is filtered and concentrated to ˜3 volumes at atmospheric pressure. Four volumes 2-propanol (61 mL) are added. The solution is concentrated to ˜3 volumes followed by addition of 4 volumes 2-propanol (61 mL), re-concentrated to ˜3 volumes, followed by addition of another 6 volumes 2-propanol (91 mL), and refluxed for 15 min. The clear solution is gradually cooled to 75° C., seeded with 0.45 g 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine slurried in 2 mL 2-propanol, rinsed with an additional 2 mL 2-propanol and transferred to a crystallization flask. The slurry is cooled to between 0-5° C., maintained for 1 hr, filtered and the product rinsed with 2-propanol (30 mL, 2 volumes). The solid is dried at 60° C. in a vacuum oven to afford 16.92 g 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine. Purity of product by HPLC assay is 100.00%. XRPD and DSC data of product is consistant with reference sample. MS (ES)=420 (M+1).
Workup
- temperatureContents are heated
- temperatureto reflux
- temperaturemaintained
- temperatureat reflux for 12 hr
- temperatureThe slurry is cooled to 25° C.
- temperatureThe reaction mixture is warmed to 40° C.
- customwhere upon a homogenous solution with two distinct layers formed
- customThe layers are separated
- filtrationthe organic layer is filtered
- concentrationconcentrated to ˜3 volumes at atmospheric pressure
- additionFour volumes 2-propanol (61 mL) are added
- concentrationThe solution is concentrated to ˜3 volumes
- additionfollowed by addition of 4 volumes 2-propanol (61 mL)
- concentrationre-concentrated to ˜3 volumes
- additionfollowed by addition of another 6 volumes 2-propanol (91 mL)
- temperaturerefluxed for 15 min
- temperatureThe clear solution is gradually cooled to 75° C.
- washrinsed with an additional 2 mL 2-propanol
- customtransferred to a crystallization flask
- temperatureThe slurry is cooled to between 0-5° C.
- temperaturemaintained for 1 hr
- filtrationfiltered
- washthe product rinsed with 2-propanol (30 mL, 2 volumes)
- customThe solid is dried at 60° C. in a vacuum oven
Sources & evidence
- ORD record
- ord-670908793ea44b2e83766e2307c50175
- Source dataset
- uspto-grants-2013_10
- Patent number
- US08563718B2
Reaction notes
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