Acetic Acid → methyl (7R)-7-[[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate

HRID 1669465Notes

Reaction equation

HRID 1669465 reaction equation
[CH3:1]C(O)=O.O=[C:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1.[NH2:18][C@@H:19]1[CH2:26][N:25]2[C:27]3[CH:28]=[C:29]([C:40]([O:42][CH3:43])=[O:41])[CH:30]=[CH:31][C:32]=3[C:33]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:24]2[C:23]2[CH:44]=[CH:45][CH:46]=[CH:47][C:22]=2[O:21][CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C=O.O.[BH3-][C:66]#[N:67].[Na+]>ClCCCl.CCOC(C)=O.CO>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C@H:6]([N:18]([CH3:1])[C@@H:19]2[CH2:26][N:25]3[C:27]4[CH:28]=[C:29]([C:40]([O:42][CH3:43])=[O:41])[CH:30]=[CH:31][C:32]=4[C:33]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[C:24]3[C:23]3[CH:44]=[CH:45][CH:46]=[CH:47][C:22]=3[O:21][CH2:20]2)[CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15].[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C@@H:6]([N:67]([CH3:66])[C@@H:19]2[CH2:26][N:25]3[C:27]4[CH:28]=[C:29]([C:40]([O:42][CH3:43])=[O:41])[CH:30]=[CH:31][C:32]=4[C:33]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[C:24]3[C:23]3[CH:44]=[CH:45][CH:46]=[CH:47][C:22]=3[O:21][CH2:20]2)[CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]

Participants

12

Reactant 7

HCID 176Acetic Acid2×HCID 712FormaldehydeHCID 962WaterHCID 471360Tert-butyl 3-oxopyrrolidine-1-carboxylateHCID 5003444Sodium cyanoborohydrideHCID 5049666Sodium triacetoxyborohydrideHCID 50994751Methyl(7r)-7-amino-14-cyclohexyl-7,8-dihydro-6h-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate

Product 2

HCID 67346364methyl (7R)-7-[[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylateYield 43%HCID 67346772Methyl (7r)-7-[[(3r)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino]-14-cyclohexyl-7,8-dihydro-6h-indolo[1,2-e][1,5]benzoxazocine-11-carboxylateYield 43%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

AcOH (4 eq) was added to a stirred mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (1.5 eq) and methyl (7R)-7-amino-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (1 eq, prepared as described in Example 1, Step 4) in dry DCE (1M); after 30 min Na(OAc)3BH (1.8 eq) was added and the mixture was stirred at RT for 4 h. Evaporation to dryness gave a residue that was taken in EtOAc, washed with sat. aq. NaHCO3 and brine, dried and concentrated in vacuo. AcOH (4 eq) was added to a stirred mixture of foregoing crude (1 eq) and a 37% solution of HCHO in H2O (2 eq) in dry MeOH (1M); NaCNBH3 (1.6 eq) was added and the mixture was stirred at RT for 3 h. Evaporation to dryness gave a residue that was taken in EtOAc, washed with sat. aq. NaHCO3 and brine, then dried and concentrated in vacuo. The crude material was purified by FC (Biotage, PE:EtOAc:toluene, 4:3:3) to afford methyl (7R)-7-[[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (43%) and its diastereoisomer methyl (7R)-7-[[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (43%). (ES+) m/z 588 (M+H)+.

Workup

  1. customEvaporation to dryness
  2. customgave a residue that
  3. washwashed with sat. aq. NaHCO3 and brine
  4. customdried
  5. concentrationconcentrated in vacuo
  6. stirringthe mixture was stirred at RT for 3 h
  7. customEvaporation to dryness
  8. customgave a residue that
  9. washwashed with sat. aq. NaHCO3 and brine
  10. customdried
  11. concentrationconcentrated in vacuo
  12. customThe crude material was purified by FC (Biotage, PE:EtOAc:toluene, 4:3:3)

Sources & evidence

ORD record
ord-5a6c23b70f524c1d9c730c45697cf15f
Source dataset
uspto-grants-2011_08
Patent number
US07989438B2

Reaction notes

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