Sodium Carbonate → Phenylmethyl 2-(butylamino)4-((2R)-2-{[[(2S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-(phenyloxy)propyl](phenylmethyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl)benzoate

HRID 47692Notes

Reaction equation

CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][C@@H:14]([CH2:19][N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:21][C@H:22]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:12]3)O1.C([O-])([O-])=O.[Na+].[Na+].Br[C:54]1[CH:69]=[CH:68][C:57]([C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])=[C:56]([NH:70][CH2:71][CH2:72][CH2:73][CH3:74])[CH:55]=1>C1(C)C=CC=CC=1.O1CCCC1.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]>[CH2:71]([NH:70][C:56]1[CH:55]=[C:54]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][C@@H:14]([CH2:19][N:20]([CH2:21][C@H:22]([O:31][Si:32]([C:35]([CH3:37])([CH3:38])[CH3:36])([CH3:34])[CH3:33])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:13][CH2:12]3)[CH:69]=[CH:68][C:57]=1[C:58]([O:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)=[O:59])[CH2:72][CH2:73][CH3:74]

Participants

Conditions

Temperature: 85 °C

Procedure

Argon gas was bubbled through a solution of (2S)-N-{[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N-(phenylmethyl)-3-(phenyloxy)-1-propanamine (Example 88, 92 mg, 0.14 mmol) in toluene (1.25 mL), tetrahydrofuran (0.25 mL), and aqueous Na2CO3 (0.50 mL of a 2M solution) for 10 minutes. Pd(dppf)Cl2 (10 mg, 0.014 mmol, 0.1 eq.) and phenylmethyl 4-bromo-2-(butylamino)benzoate (Example 193, 52 mg, 0.14 mmol, 1.0 eq.) were added, and argon was bubbled through the mixture for an additional 5 minutes before the mixture was stirred vigorously at 85° C. for 3 hours. The reaction mixture was cooled and filtered through a pad of Celite® with the aid of ethyl acetate. The filtrate was transferred to a separatory funnel where the water layer was removed. The organic layer was dried (MgSO4) and concentrated in vacuo to a crude oil. The crude was purified by flash chromatography on silica gel eluted on a gradient from 100:0 to 90:10 hexanes/ethyl acetate to provide the title compound as a colorless oil (47 mg, 42%): 1H NMR (300 MHz, CDCl3) δ7.95 (d, 1 H)7.69 (t, 1 H), 7.43-7.27 (m, 8 H), 7.23-7.19 (m, 6 H), 6.89 (t, 1 H), 6.84-6.80 (m, 3H), 6.75 (s, 1 H), 6.70 (d, 1 H), 5.29 (s, 2 H), 4.17-4.07 (m, 3 H), 3.83-3.66 (m, 3 H), 3.23 (q, 2 H), 2.93-2.64 (m, 6 H), 2.01-1.96 (m, 1 H), 1.72-1.63 (m, 3 H), 1.50-1.41 (m, 2 H), 0.95 (t, 3 H), 0.84 (s, 9 H), 0.07 (s, 3 H), 0.03 (s, 3 H); MS m/z 799.3 (MH+).

Workup

customargon was bubbled through the mixture for an additional 5 minutes before the mixture
temperatureThe reaction mixture was cooled
filtrationfiltered through a pad of Celite® with the aid of ethyl acetate
customThe filtrate was transferred to a separatory funnel
customwhere the water layer was removed
dry with materialThe organic layer was dried (MgSO4)
concentrationconcentrated in vacuo to a crude oil
customThe crude was purified by flash chromatography on silica gel
washeluted on a gradient from 100:0 to 90:10 hexanes/ethyl acetate

Sources & evidence

ORD record: ord-a4293d8179a84d63b485202db3f13317
Source dataset: uspto-grants-2004_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06699860B2

Reaction notes

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