Bromhydrol → HCID 46947036, compound

HRID 1910699Notes

Reaction equation

HRID 1910699 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:10]=3[N:11](CC3C=CC(OC)=CC=3)[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)=[CH:4][CH:3]=1.[Br-].[Al+3].[Br-].[Br-]>C1(OC)C=CC=CC=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:10]=3[NH:11][C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)=[CH:4][CH:3]=1

Participants

6

Reactant 2

HCID 166749Bromhydrol2×HCID 67283437HCID 67283437, compound

Product 1

HCID 46947036HCID 46947036, compoundYield 42%

Reagents, catalysts & solvents 3

HCID 7519AnisoleSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
80 °C

Procedure

5,7-Dichloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.10 g, 0.20 mmol) and 2-aminopyridine-5-boronic acid pinacol ester were reacted according to the corresponding procedure described in Example 12 to yield intermediate 5-(6-aminopyridin-3-yl)-7-chloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one. (77 mg, 69%). 5-(6-Aminopyridin-3-yl)-7-chloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (77 mg, 0.14 mmol) was dissolved in anhydrous anisole (2 mL) under a nitrogen atmosphere, and aluminum bromide (1M in dichloromethane, 0.70 mL, 0.70 mmol) was added. The mixture was heated to 80° C. for 1 hour then cooled to ambient temperature and an additional amount of aluminum bromide (1M in dichloromethane, 0.70 mL, 0.70 mmol) was added. The solution was heated to 80° C. for 1 hour, cooled, poured into ice, diluted with ethyl acetate and saturated sodium bicarbonate. The layers were separated and the organic layer dried with sodium sulfate, decanted and concentrated in the presence of silica gel. Column chromatography eluting with a gradient of 70-100% ethyl acetate in hexanes provided 5-(6-aminopyridin-3-yl)-7-chloro-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (25 mg, 42% yield). 1H NMR (300 MHz, d6-DMSO) δ 3.47 (m, 2H) 3.71 (m, 1H), 6.40-6.46 (m, 2H), 7.20-7.26 (m, 2H), 7.42-7.62 (m, 5H), 7.78-7.87 (m, 4H), 10.64 (s, 1H); ESI m/z measured 427.1324 [M+H]+. calculated 427.1326.

Workup

  1. temperaturethen cooled to ambient temperature
  2. temperatureThe solution was heated to 80° C. for 1 hour
  3. temperaturecooled
  4. additionpoured into ice
  5. customThe layers were separated
  6. dry with materialthe organic layer dried with sodium sulfate
  7. customdecanted
  8. concentrationconcentrated in the presence of silica gel
  9. washColumn chromatography eluting with a gradient of 70-100% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-48886348b80e414e8336fab9810ad612
Source dataset
uspto-grants-2013_12
Patent number
US08604023B2

Reaction notes

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