2-Fluoro-3-(trifluoromethyl)benzaldehyde → 2-fluoro-3-(trifluoromethyl)benzyl-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine

HRID 23274

Reaction equation

HRID 23274 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(OC(C)(C)C)=O)[CH2:18][C@@H:5]23)[CH:10]=1.[F:26][C:27]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C(O)(=O)C>[F:26][C:27]1[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][CH:14]1[N:7]2[C:8]3[C:4]([CH:5]4[CH2:18][NH:17][CH2:16][CH2:15][CH:6]42)=[CH:3][C:2]([NH2:1])=[CH:10][C:9]=3[CH2:11][O:12][CH2:13]1

Participants

6

Reactant 3

HCID 5179782-Fluoro-3-(trifluoromethyl)benzaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 86586438Tert-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

Product 1

HCID 867595982-fluoro-3-(trifluoromethyl)benzyl-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6342AcetonitrileSolvent

Procedure

To 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 (35 mg, 0.10 mmol) in 5 mL of acetonitrile was added 2-fluoro-3-(trifluoromethyl)benzaldehyde (38 mg, 0.20 mmol) and three drops of glacial acetic acid. The reaction was stirred at ambient temperature for 1 h and then there was added sodium triacetoxyborohydride (64 mg, 0.30 mmol). The reaction was stirred at ambient temperature for 3 h and then was quenched by the addition of aq ammonium hydroxide. The mixture was extracted with methylene chloride, washed with brine, dried (K2CO3) and concentrated. The residue was taken up in 10 mL of methylene chloride and then there was added 5 mL of trifluoroacetic acid. The reaction was allowed to stir at ambient temperature for 3 h and then was concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product containing fractions were concentrated, free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 126. 1H NMR (CDCl3) δ: 7.55-7.40 (m, 2H), 7.12 (t, 1H, J=7.7 Hz), 6.31 (d, 1H, J=2.0 Hz), 6.15 (d, 1H, J=1.9 Hz), 4.48 (ABq, 2H, JAB 14.3 Hz), 4.32 (s, 2H), 4.12 (app d, 1H), 3.63 (app t, 1H), 3.30-3.20 (m, 2H), 3.18-2.98 (m, 4H), 2.56 (app t, 1H), 2.43 (app t, 1H), 2.05-1.92 (m, 2H). LRMS (ES)+: 422.3 (M+H)+.

Workup

  1. stirringThe reaction was stirred at ambient temperature for 3 h
  2. customwas quenched by the addition of aq ammonium hydroxide
  3. extractionThe mixture was extracted with methylene chloride
  4. washwashed with brine
  5. dry with materialdried (K2CO3)
  6. concentrationconcentrated
  7. additionthere was added 5 mL of trifluoroacetic acid
  8. stirringto stir at ambient temperature for 3 h
  9. concentrationwas concentrated in vacuo
  10. customThe residue was purified by preparative HPLC (
  11. washC18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product
  12. additioncontaining fractions
  13. concentrationwere concentrated, free-based with aq ammonium hydroxide
  14. extractionextracted with chloroform
  15. washwashed with brine
  16. dry with materialdried (K2CO3)
  17. concentrationconcentrated

Sources & evidence

ORD record
ord-18df519ac6be428a9d14b1b3635a8293
Source dataset
uspto-grants-2005_02
Patent number
US06849619B2

Linked notes

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