Triethylamine → HCID 178452529, compound

HRID 625619Notes

Reaction equation

HRID 625619 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[NH:16][C:15]([C@@H:17]3[CH2:22][C@@H:21]4[C@@H:19]([CH2:20]4)[N:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:14][CH:13]=1)[CH:6]=[CH:5]2.[C:30]([C:32]1[NH:36][C:35]([C@@H:37]2[CH2:42][C@@H:41]3[C@@H:39]([CH2:40]3)[N:38]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:34][CH:33]=1)#[CH:31].C(N(CC)CC)C>CN(C=O)C.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>[C:46]([O:45][C:43]([N:38]1[C@H:37]([C:35]2[NH:34][CH:33]=[C:32]([C:30]#[C:31][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([C:12]3[N:16]=[C:15]([C@@H:17]5[CH2:22][C@@H:21]6[C@@H:19]([CH2:20]6)[N:18]5[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[NH:14][CH:13]=3)[CH:6]=[CH:5]4)[N:36]=2)[CH2:42][C@@H:41]2[C@H:39]1[CH2:40]2)=[O:44])([CH3:49])([CH3:48])[CH3:47]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 58498700(1R,3S,5R)-tert-butyl 3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylateHCID 58498751(1R,3S,5R)-tert-butyl 3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Product 1

HCID 178452529HCID 178452529, compoundYield 104.5%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

Nitrogen was bubbled through a solution of (1R,3S,5R)-tert-butyl 3-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (400 mg, 0.880 mmol), (1R,3S,5R)-tert-butyl 3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (313 mg, 1.14 mmol) and Cu(I)I (8.4 mg, 0.044 mmol) in triethylamine (0.37 mL, 2.6 mmol) and DMF (8 mL) for 10 min. Then Pd(PPh3)4 (50.9 mg, 0.044 mmol) was added, nitrogen was bubbled through the reaction mixture for 1 min, and then the flask was sealed and heated at 50° C. for 16 h. The reaction was concentrated to under high vacuum) and the residual solids were triturated with EtOAc (˜5 mL) and collected by filtration (rinsing with EtOAc and hexanes) to yield tert-butyl (1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (595 mg) as a light yellow solid. The material was used without further purification. LC-MS retention time 3.140 min; m/z 647.35 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.

Workup

  1. customnitrogen was bubbled through the reaction mixture for 1 min
  2. customthe flask was sealed
  3. concentrationThe reaction was concentrated to under high vacuum) and the residual solids
  4. customwere triturated with EtOAc (˜5 mL)
  5. filtrationcollected by filtration (rinsing with EtOAc and hexanes)

Sources & evidence

ORD record
ord-554a815281a042918314fd40182881cc
Source dataset
uspto-grants-2016_04
Patent number
US09303007B2

Reaction notes

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