Lithium borohydride → (S)-2-(2-aminophenyl)-7-methoxy-8-(3-(((S)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-5,11a-dihydro-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl)oxy)propoxy)-pyrrolo[2,1-c][1,4]benzodiazepin-5(11aH)-one

HRID 594186Notes

Reaction equation

HRID 594186 reaction equation
[Li+].[B-](CC)(CC)CC.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH2:17][C@@H:18]2[N:24]([CH:25]=1)[C:23](=[O:26])[C:22]1[CH:27]=[C:28]([O:70][CH3:71])[C:29]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]3[C:67]([O:68][CH3:69])=[CH:66][C:39]4[C:40](=[O:65])[N:41]5[CH:56]=[C:55]([C:57]6[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=6)[CH2:54][C@H:42]5[C:43](=O)[N:44](COCC[Si](C)(C)C)[C:38]=4[CH:37]=3)=[CH:30][C:21]=1[N:20](COCC[Si](C)(C)C)[C:19]2=O.[BH4-].[Li+]>O1CCCC1>[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH2:17][C@@H:18]2[N:24]([CH:25]=1)[C:23](=[O:26])[C:22]1[CH:27]=[C:28]([O:70][CH3:71])[C:29]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]3[C:67]([O:68][CH3:69])=[CH:66][C:39]4[C:40](=[O:65])[N:41]5[CH:56]=[C:55]([C:57]6[CH:58]=[CH:59][C:60]([O:63][CH3:64])=[CH:61][CH:62]=6)[CH2:54][C@H:42]5[CH:43]=[N:44][C:38]=4[CH:37]=3)=[CH:30][C:21]=1[N:20]=[CH:19]2

Participants

5

Reactant 3

HCID 4148881Lithium borohydrideHCID 23712863Lithium triethylborohydrideHCID 86676192(S)-2-(2-aminophenyl)-7-methoxy-8-(3-(((S)-7-methoxy-2-(4-methoxyphenyl)-5,11-dioxo-10((2-(trimethylsilyl)ethoxy)methyl)-5,10,11,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl)oxy)propoxy)-10-((2-(trimethylsilyl)ethoxy)methyl)-pyrrolo[2,1-c][1,4]-benzodiazepine-5,11(10H,11aH)-dione

Product 1

HCID 86676193(S)-2-(2-aminophenyl)-7-methoxy-8-(3-(((S)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-5,11a-dihydro-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl)oxy)propoxy)-pyrrolo[2,1-c][1,4]benzodiazepin-5(11aH)-oneYield 14%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of Superhydride in dry tetrahydrofuran (1.0 M, 4.4 eq.) was added to a solution of the 2-analino compound 103 (300 mg) in dry tetrahydrofuran (5 mL) at −78° C. under an inert atmosphere. As reduction was proceeding slowly an aliquot of lithium borohydride (20 eq.) was added and the reaction mixture was allowed to return to room temperature. Water/ice was added to the reaction mixture to quench unreacted hydrides and the reaction was diluted with dichloromethane. The organic layer was washed sequentially with water (twice), citric acid and brine. Excess dichloromethane was removed by rotary evaporation under reduced pressure and the residue was redissolve in ethanol and water and treated with silica gel for 96 hours. The reaction mixture was vacuum filtered and the filtrate evaporated to dryness. The residue was subjected to flash column chromatography (silica gel, gradient chloroform/methanol). Pure fractions were collected and combined and excess eluent was removed by rotary evaporation under educed pressure to afford the pure product 104 (30 mg, 14% yield). LC/MS RT: 2.90 min, ES+726.09.

Workup

  1. additionwas added
  2. customto return to room temperature
  3. customto quench unreacted hydrides
  4. additionthe reaction was diluted with dichloromethane
  5. washThe organic layer was washed sequentially with water (twice), citric acid and brine
  6. customExcess dichloromethane was removed by rotary evaporation under reduced pressure
  7. dissolutionthe residue was redissolve in ethanol
  8. additionwater and treated with silica gel for 96 hours
  9. filtrationfiltered
  10. customthe filtrate evaporated to dryness
  11. customPure fractions were collected
  12. customexcess eluent was removed by rotary evaporation under educed pressure

Sources & evidence

ORD record
ord-c770348a5ca648f1b9537c8d735d1d01
Source dataset
uspto-grants-2016_01
Patent number
US09242013B2

Reaction notes

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