Potassium Carbonate → 3-{[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-methyl-amino}-3-methyl-azetidine-1-carboxylic acid

HRID 519161Notes

Reaction equation

HRID 519161 reaction equation
C(=O)([O-])[O-].[K+].[K+].C([O:11][C:12]([N:14]1[CH2:17][C:16]([N:19]([C:21]2[CH:22]=[C:23]3[C:32](=[CH:33][C:34]=2Br)[O:31][CH2:30][C:29]2[N:24]3[C@H:25]([CH3:37])[C:26](=[O:36])[NH:27][N:28]=2)[CH3:20])([CH3:18])[CH2:15]1)=[O:13])(C)(C)C.C(OC(N1CC(NC2C=C3C(=CC=2Br)OCC2N3[C@H](C)C(=O)NN=2)(C)C1)=O)(C)(C)C.[F:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1B(O)O>O1CCOCC1.O.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>[F:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1[C:34]1[CH:33]=[C:32]2[C:23]([N:24]3[C:29]([CH2:30][O:31]2)=[N:28][NH:27][C:26](=[O:36])[C@H:25]3[CH3:37])=[CH:22][C:21]=1[N:19]([CH3:20])[C:16]1([CH3:18])[CH2:17][N:14]([C:12]([OH:11])=[O:13])[CH2:15]1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 27343542-Fluorophenylboronic acidHCID 867275233-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-3-methyl-azetidine-1-carboxylic acid tert-butyl esterHCID 86727559HCID 86727559, compound

Product 1

HCID 867275583-{[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-methyl-amino}-3-methyl-azetidine-1-carboxylic acid

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A degassed solution of potassium carbonate (0.432 g, 3.13 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.255 g, 0.313 mmol), 3-[((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-methyl-amino]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (prepared from 3-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (Example #148, Step G) using the similar procedure detailed in Example #102, Step A), 0.618 g, 1.25 mmol) and (2-fluorophenyl)boronic acid (0.262 g, 1.875 mmol) in 1,4-dioxane (15 mL) and water (3 mL) were heated at 90° C. for 4 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 25% EtOAc in petroleum ether) to afford 3-{[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-methyl-amino}-3-methyl-azetidine-1-carboxylic acid ten-butyl ester (0.540 g, 85%). 1H NMR (CDCl3, 400 MHz): δ 8.14 (s, 1H), 7.35-7.26 (m, 2H), 7.19-7.10 (m, 2H), 6.94 (s, 1H), 6.54 (s, 1H), 4.71-4.56 (m, 3H), 3.86-3.78 (m, 2H), 3.48 (m, 2H), 2.41 (s, 3H). 1.54 (d, J=6.8 Hz, 3H), 1.42 (s, 9H), 1.26 (s, 3H). LC/MS (Table 1, Method 25) Rt=0.913 min., MS m/z: 510 [M+H]+

Workup

  1. temperatureThe reaction mixture was cooled to rt
  2. concentrationconcentrated in vacuo
  3. customThe residue was purified by column chromatography on silica gel (eluting with 25% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-2c44c2ecd9704a9a8e1eef3cf62a6d5a
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

Loading…