Methanol → (1S,2R)-2-(bromomethyl)-4'-(4-chlorophenyl)-2',3',9'-trimethylspiro-[cyclopropane-1,6'-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]

HRID 1772335Notes

Reaction equation

HRID 1772335 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26][O:27]C)[N:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)[Br:30].CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26][OH:27])[N:9]=2)=[CH:6][CH:7]=1.[Br:30][CH2:26][C@H:24]1[C@@:10]2([N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)[CH2:25]1

Participants

7

Reactant 4

HCID 887MethanolHCID 25134Boron tribromideHCID 516892Sodium BicarbonateHCID 57345408(2'R,9S)-7-(4-chlorophenyl)-2'-(methoxymethyl)-4,5,13-trimethylspiro[3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene-9,1'-cyclopropane]2×

Product 2

HCID 57404762(1S,2R)-2-(bromomethyl)-4'-(4-chlorophenyl)-2',3',9'-trimethylspiro-[cyclopropane-1,6'-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]HCID 57404763((1S,2R)-4'-(4-chlorophenyl)-2',3',9'-trimethylspiro[cyclopropane-1,6'-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin]-2-yl)methanol

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (1S,2R)-4′-(4-chlorophenyl)-2-(methoxymethyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine] (2.35 g, 5.69 mmol) in DCM (70 mL) at −78° C. was added a solution of boron tribromide (1M in DCM) (Compound 202; 17.07 mmol). The reaction was warmed to rt for 30 min before MeOH was added followed by sat. aq. NaHCO3. The product was extracted with DCM (repeated 4 times), dried over a cotton plug and concentrated to dryness under vacuum. The residue was purified by flash chromatography (MeOH/DCM 0.5:99.5 to 5:95) to give ((1S,2R)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin]-2-yl)methanol (Compound 203) (1.9 g) as a white solid and (1S,2R)-2-(bromomethyl)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine] (Compound 237) (449 mg) as a side product. LRMS (M+H)+: 399 m/z. 1H NMR (two conformers detected in ˜1:1 ratio) (400 MHz, DMSO-d6) δ 7.41-7.53 (m, 4H), 4.64 (t, J=5.72 Hz, 0.5H), 4.51 (t, J=5.38 Hz, 0.5H), 3.95 (quin, J=6.20 Hz, 0.5H), 3.69 (quin, J=6.20 Hz, 0.5H), 3.10-3.18 (m, 0.5H), 3.01-3.09 (m, 0.5H), 2.60 (s, 3H), 2.39 (s, 1.5H), 2.38 (s, 1.5H), 2.14-2.23 (m, 0.5H), 1.96-2.04 (m, 0.5H), 1.57 (s, 1.5H), 1.55 (s, 1.5H), 1.32-1.37 (m, 0.5H), 1.25-1.32 (m, 0.5H), 0.96 (dd, J=5.26, 9.16 Hz, 0.5H), 0.58 (t, J=6.20 Hz, 0.5H).

Workup

  1. additionwas added
  2. extractionThe product was extracted with DCM (repeated 4 times)
  3. customdried over a cotton plug
  4. concentrationconcentrated to dryness under vacuum
  5. customThe residue was purified by flash chromatography (MeOH/DCM 0.5:99.5 to 5:95)

Sources & evidence

ORD record
ord-2e372954a61041b49b6366aca76f1948
Source dataset
uspto-grants-2016_02
Patent number
US09249161B2

Reaction notes

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