tert-Butyl methyl ether → HCID 136633737, compound

HRID 1027309Notes

Reaction equation

[Cl:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([OH:8])[CH:7]=1.Cl[C:19]1[N:20]=[N:21][C:22]([O:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)=[CH:23][CH:24]=1.CC(OC)(C)C>O.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>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:19]2[N:20]=[N:21][C:22]([O:25][CH:26]3[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]3)=[CH:23][CH:24]=2)=[C:6]([OH:8])[CH:7]=1

Participants

Conditions

Temperature: 89 °C

Procedure

To the solution containing 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.22 kg, 4.8 mol) from the previous step was added 3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (1.17 kg, 4.4 mol). K3PO4-3H2O (2.34 kg, 8.8 mol) was dissolved in water (5 L) then added to the above solution. The mixture was purged with nitrogen 3 times. Pd(PPh3)4 (500 g, 0.42 mol) was added under nitrogen, and the reaction mixture was heated to reflux at 89° C. for 16 hours. After 16 hours, HPLC showed that the reaction was complete. After cooling to room temperature, the mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. CH2Cl2 (10 L×3) and 10% K2CO3 solution (15 L) were added to the above residue. The organic layers were separated and combined, followed by washing with water twice (10 L×2) and concentration under reduced pressure to give yellow oil. MTBE (10 L) was used to dissolve the yellow oil. Petroleum ether (4 L) was added slowly with stirring. A few dark solids precipitated and were removed by filtration. The filtrate was concentrated under reduced pressure and dissolved in CH2Cl2 (20 L). 2N HCl (5 L) was added slowly and a large amount of precipitate formed. After stirring for another 1 hour, the solid was collected by filtration and washed with EtOAc (2 L). The solid was dried in vacuo at 50° C. to give 5-chloro-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol hydrochloride (0.9 kg, 2.2 mol). MS m/z 362.0 [M+H]+; 1H-NMR: (DMSO-d6, 400 MHz) δ 9.26 (d, J=11.6 Hz, 1H), 8.49 (d, J=12 Hz, 1H), 8.38 (d, J=9.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.44 (d, J=9.6 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 7.02 (dd, Ja=2 Hz, Jb=8.4 Hz, 1H), 5.73 (m, 1H), 2.31 (dd, Ja=4 Hz, Jb=13.2 Hz, 2H), 1.84 (dd, Ja=11.6 Hz, Jb=2 Hz, 2H), 1.51 (s, 6H), 1.49 (s, 6H).

Workup

additionthen added to the above solution
customThe mixture was purged with nitrogen 3 times
temperaturethe reaction mixture was heated
temperatureAfter cooling to room temperature
filtrationthe mixture was filtered through a pad of celite
concentrationthe filtrate was concentrated under reduced pressure
additionCH2Cl2 (10 L×3) and 10% K2CO3 solution (15 L) were added to the above residue
customThe organic layers were separated
washby washing with water twice (10 L×2) and concentration under reduced pressure
customto give yellow oil
dissolutionto dissolve the yellow oil
customA few dark solids precipitated
customwere removed by filtration
concentrationThe filtrate was concentrated under reduced pressure
dissolutiondissolved in CH2Cl2 (20 L)
addition2N HCl (5 L) was added slowly
customa large amount of precipitate formed
stirringAfter stirring for another 1 hour
filtrationthe solid was collected by filtration
washwashed with EtOAc (2 L)
customThe solid was dried in vacuo at 50° C.

Sources & evidence

ORD record: ord-6174f1e64c79466abb50ebef17cf0c28
Source dataset: uspto-grants-2014_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08729263B2

Reaction notes

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