1,4-Dioxane → HCID 178420026, compound

HRID 707331Notes

Reaction equation

HRID 707331 reaction equation
[CH:1]1([C:4]([C:6]2[C:7](F)=[N:8][CH:9]=[CH:10][CH:11]=2)=O)[CH2:3][CH2:2]1.Cl.Cl.[NH:15]([C@H:17]1[CH2:20][C@H:19]([NH:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH2:18]1)[NH2:16].C([O-])(=O)C.[K+].O1CCOCC1>C1(C)C=CC=CC=1.C(O)C>[CH:1]1([C:4]2[C:6]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:15]([C@H:17]3[CH2:18][C@H:19]([NH:21][C:22]4[S:23][C:24]5[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=5[N:26]=4)[CH2:20]3)[N:16]=2)[CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 517044Potassium Acetate2×HCID 86694137HCID 86694137, compound2×HCID 178478861HCID 178478861, compound2×

Product 1

HCID 178420026HCID 178420026, compoundYield 28.8%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
105 °C

Procedure

Cyclopropyl(2-fluoropyridin-3-yl)methanone (intermediate 53, 0.270 g, 1.635 mmol), N-(trans-3-hydrazinylcyclobutyl)benzo[d]thiazol-2-amine dihydrochloride (intermediate 52, 0.502 g, 1.635 mmol), and potassium acetate (0.462 ml, 7.39 mmol) were suspended in a mixture of dry dioxane (5 mL), dry ethanol (5 mL), and dry toluene (5 mL) and heated at 105° C. for 30 minutes. The temperature was lowered to 90° C. and additional potassium acetate (1.2 g, 6.6 eq) was added. The mixture was stirred for another 90 minutes. After another 3 hours the reaction was evaporated to dryness under reduced pressure. Purification using silica chromatography (0-10% (2 N ammonia in methanol) in dichloromethane gradient) followed by repurification using reverse phase HPLC and free basing (ethyl acetate/saturated sodium bicarbonate) gave the desired N-(trans-3-(3-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)benzo[d]thiazol-2-amine (0.170 g, 0.470 mmol, 28.8% yield) as a white solid. M+1: 362.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87-1.20 (m, 4 H) 2.12-2.22 (m, 1 H) 2.49-2.71 (m, 2 H) 3.00-3.26 (m, 2 H) 4.36-4.58 (m, 1 H) 5.63 (quin, J=7.24 Hz, 1 H) 6.61 (br. s., 1 H) 6.89-7.12 (m, 2 H) 7.21 (br. s., 1 H) 7.53 (m, J=7.80 Hz, 2 H) 7.94 (dd, J=7.82, 1.17 Hz, 1 H) 8.39 (dd, J=4.40, 1.08 Hz, 1 H).

Workup

  1. customwas lowered to 90° C.
  2. customAfter another 3 hours the reaction was evaporated to dryness under reduced pressure
  3. customPurification
  4. customfollowed by repurification

Sources & evidence

ORD record
ord-73ea98bc6c6c42a6bce7ee038b4e3db2
Source dataset
uspto-grants-2015_11
Patent number
US09174992B2

Reaction notes

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