3-Bromo-2-methoxy-5-methylpyridine → tert-butyl (7bR,11aS)-6-(2-methoxy-5-methyl-3-pyridinyl)amino-1,2,7b, 10,11,11 a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate

HRID 23296Notes

Reaction equation

[NH2:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][O:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:5]23)[CH:10]=1.Br[C:27]1[C:28]([O:34][CH3:35])=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:35][O:34][C:28]1[C:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][O:12][CH2:13][CH2:14][N:7]4[C@H:6]4[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:5]34)[CH:10]=2)=[CH:32][C:31]([CH3:33])=[CH:30][N:29]=1

Participants

Conditions

Temperature: 50 °C

Procedure

A solution of tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4] oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)Carboxylate from Example 56, Part B (968 mg, 2.81 mmol), 3-bromo-2-methoxy-5-methylpyridine (515 mg, 2.55 mmol), and NaOt-Bu (404 mg, 4.20 mmol) in anhydrous toluene (40 mL) was stirred under an argon atmosphere in a sealable test tube. The mixture was degassed with argon at 85° C. for 30 min then cooled to 50° C. Tris(dibenzylideneacetone)dipalladium(0) (62 mg, 67 μmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (84.0 mg, 135 μmol) were added; the reaction was sealed and heated at 85° C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc, filtered through a bilayer pad of diatomaceous earth and silica gel, and concentrated. Purification of the residue by flash column chromatography (silica gel, 10-50% EtOAc/hexanes) provided tert-butyl (7bR,11aS)-6-(2-methoxy-5-methyl-3-pyridinyl)amino-1,2,7b, 10,11,11 a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate (1.16 g, 89%). A solution of the intermediate in CH2Cl2 (20 mL) at −10° C. was treated with TFA (6 mL) and stirred for 1 h. Upon concentration in vacuo, the residue was partitioned between a 1:1 solution of CH2Cl2/satd NaHCO3 (100 mL). The aqueous phase was extracted with CH2Cl2 (4×75 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography [silica gel, 5-50% (80:18:2 CHCl3/MeOH/concd NH4OH)/CH2Cl2]and trituration with CH2Cl2/Et2O/hexanes provided the title compound of Example 172 (590 mg, 65%) as a tan solid: mp 122-124° C.; 1H NMR (300 MHz, CDCl3) δ 7.40 (s, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.77 (s, 1H), 5.84 (br s, 1H), 4.75 (d, J=14.1 Hz, 1H), 4.58 (d, J=14.1 Hz, 1H), 4.3414.16 (m, 1H), 4.01 (s, 3H), 3.89-3.69 (m, 1H), 3.58-3.39 (m, 1H), 3.38-3.13 (m, 2H), 3.11-2.99 (m, 1H), 2.98-2.85 (m, 2H), 2.81-2.68 (m, 1H), 2.61-2.42 (m, 1H), 2.19 (s, 3H), 2.01-1.77 (m, 3H); ESI MS m/z 367 [C21H26N4O2+H]+.

Workup

customThe mixture was degassed with argon at 85° C. for 30 min
customthe reaction was sealed
temperatureheated at 85° C. for 16 h
temperatureThe reaction was cooled to room temperature
filtrationfiltered through a bilayer pad of diatomaceous earth and silica gel
concentrationconcentrated
customPurification of the residue by flash column chromatography (silica gel, 10-50% EtOAc/hexanes)

Sources & evidence

ORD record: ord-1e3bff6537dd4bb6b7aac09c5b41cd9c
Source dataset: uspto-grants-2005_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06849619B2

Reaction notes

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