Potassium Carbonate → 2-(4-(3-Cyanoquinolin-7-yl)-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide

HRID 1525928Notes

Reaction equation

Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:52]1[CH:61]=[C:60]2[C:55]([CH:56]=[C:57]([C:62]#[N:63])[CH:58]=[N:59]2)=[CH:54][CH:53]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:62]([C:57]1[CH:58]=[N:59][C:60]2[C:55]([CH:56]=1)=[CH:54][CH:53]=[C:52]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]3[CH2:26][CH2:25][C:15]4([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]5[CH2:23][CH2:24]5)[CH2:16]4)[CH2:14][CH2:13]3)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1)[CH:61]=2)#[N:63]

Participants

Conditions

Temperature: 120 °C

Procedure

To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (125 mg, 0.28 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (72 mg, 0.28 mmol) in 1,4-dioxane (2.0 mL) was added potassium acetate (61 mg, 0.63 mmol) and PdCl2(dppf)-CH2Cl2 adduct (23 mg, 0.03 mmol). The reaction mixture was purged with nitrogen and heated at 120° C. for 4 h. The reaction mixture was cooled and 7-bromoquinoline-3-carbonitrile (66.2 mg, 0.28 mmol) and 2M aq K2CO3 (0.3 mL, 0.6 mmol) were added. The reaction mixture was purged with nitrogen and heated with stirring at 100° C. for 1 h. The cooled reaction mixture was diluted with dichloromethane (60 mL) and salts were filtered away. The organic mixture was filtered through a plug of celite and sodium sulfate and the filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min. The mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) and the appropriate fractions were collected, combined and concentrated in vacuo to give expected product as a racemate (87 mg, 60%). Chiral HPLC was performed on this material in Example 63a. MS(ES)+ m/e 514 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.56-0.66 (m, 2 H) 0.75-0.87 (m, 2 H) 1.64-1.70 (m, 1 H) 1.72-1.77 (m, 1 H) 1.85-1.97 (m, 2 H) 2.31 (td, J=11.24, 2.53 Hz, 1 H) 2.56-2.61 (m, 1 H) 2.62-2.74 (m, 2 H) 2.77-2.86 (m, 1 H) 3.15 (s, 2 H) 4.00 (d, J=2.02 Hz, 2 H) 4.55 (s, 1 H) 5.65 (d, J=4.29 Hz, 1 H) 7.27 (d, J=4.04 Hz, 1 H) 7.49 (t, J=7.71 Hz, 1 H) 7.56 (d, J=1.77 Hz, 1 H) 7.65 (dd, J=7.96, 1.89 Hz, 1 H) 8.00 (dd, J=8.34, 1.77 Hz, 1 H) 8.06 (d, J=8.34 Hz, 1 H) 8.39-8.47 (m, 1 H) 8.63 (dd, J=2.02, 0.76 Hz, 1 H) 9.10 (d, J=2.27 Hz, 1 H).

Workup

customThe reaction mixture was purged with nitrogen
temperatureThe reaction mixture was cooled
customThe reaction mixture was purged with nitrogen
temperatureheated
customThe cooled reaction mixture
filtrationwere filtered away
filtrationThe organic mixture was filtered through a plug of celite and sodium sulfate
additionthe filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min
filtrationThe mixture was filtered
concentrationconcentrated in vacuo
customThe residue was purified by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH)
customthe appropriate fractions were collected
concentrationconcentrated in vacuo

Sources & evidence

ORD record: ord-82bb954c532a42b2aa022fa2f4a03e35
Source dataset: uspto-grants-2015_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09084794B2

Reaction notes

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