Hydrochloric Acid → 3-(8-Azabicyclo[3.2.1]oct-2-en-3-yl)-7-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-amine

HRID 911978Notes

Reaction equation

HRID 911978 reaction equation
C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11](B1OC(C)(C)C(C)(C)O1)[CH2:12]2)=O)(C)(C)C.Br[C:26]1[C:30]2[CH:31]=[N:32][C:33]([NH2:47])=[C:34]([O:35][C@@H:36]([C:38]3[C:43]([Cl:44])=[CH:42][CH:41]=[C:40]([F:45])[C:39]=3[Cl:46])[CH3:37])[C:29]=2[O:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[CH:9]12[NH:8][CH:13]([CH2:14][CH2:15]1)[CH2:12][C:11]([C:26]1[C:30]3[CH:31]=[N:32][C:33]([NH2:47])=[C:34]([O:35][C@@H:36]([C:38]4[C:43]([Cl:44])=[CH:42][CH:41]=[C:40]([F:45])[C:39]=4[Cl:46])[CH3:37])[C:29]=3[O:28][CH:27]=1)=[CH:10]2

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 53393373Tert-butyl 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo(3.2.1)oct-2-ene-8-carboxylateHCID 578127253-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine

Product 1

HCID 578125493-(8-Azabicyclo[3.2.1]oct-2-en-3-yl)-7-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-amine

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent2×HCID 18180031Water 1,2-dimethoxyethaneSolvent

Conditions

Temperature
100 °C

Procedure

In a microwave vessel were added 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (60 mg, 0.2 mmol), 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-furo[3,2-c]pyridin-6-ylamine (0.098 g, 0.23 mmol), potassium carbonate (0.074 g, 0.54 mmol), DME/Water (4:1) (5 mL), and the vessel was degassed 3×. Pd(PPh3)4 (0.01 g, 0.009 mmol) was then added and the reaction mixture was heated in a microwave reactor to 100° C. for 30 min. The crude reaction mixture was passed through SPE cartridge. The compound was then dissolved in dioxane and 4 M HCl in 1,4-Dioxane (0.4 mL) was added slowly at 0° C. The reaction mixture was warmed to rt and stirred overnight at rt. Purification by prep TLC using 9% NH3 in MeOH in DCM afforded the title compound. 1H NMR (400 MHz, CD3OD): δ=1.64-1.77 (m, 1H), 1.85 (d, 3H), 1.89-1.98 (m, 1H), 2.01-2.12 (m, 2H), 2.18 (d, J=16.9 Hz, 1H), 2.88 (dd, J=16.8, 4.2 Hz, 1H), 3.82 (ddd, J=17.1, 5.8, 5.7 Hz, 2H), 6.46 (q, 1H), 6.52 (d, J=5.6 Hz, 1H), 7.19 (t, J=8.6 Hz, 1H), 7.37 (dd, J=9.0, 4.9 Hz, 1H), 7.54 (s, 1H), 8.16 (s, 1H). MS (ES+): m/z 447.97/450.01 (30/21) [MH+]. HPLC: tR=2.14 min (ZQ3, polar—5 min).

Workup

  1. customthe vessel was degassed 3×
  2. customThe crude reaction mixture
  3. temperatureThe reaction mixture was warmed to rt
  4. customPurification by prep TLC

Sources & evidence

ORD record
ord-1db7db88331d47bb99fd3ca12c7bf21c
Source dataset
uspto-grants-2011_09
Patent number
US08022206B2

Reaction notes

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