1,1-Dichloroethane → HCID 178479173, compound

HRID 849410Notes

Reaction equation

HRID 849410 reaction equation
[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][CH2:11][C@@H:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]([C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:8][C:7]=2[CH:29]=1)#[N:2].[CH:30]([C:32]1[N:33]=[CH:34][NH:35][CH:36]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:51]C(Cl)C>CC(O)=O.C(Cl)(Cl)Cl.[NH4+].[OH-].C([O-])(O)=O.[Na+]>[ClH:51].[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:30][C:32]3[N:33]=[CH:34][NH:35][CH:36]=3)[CH2:11][C@@H:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]([C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:8][C:7]=2[CH:29]=1)#[N:2]

Participants

9

Reactant 4

HCID 63651,1-DichloroethaneHCID 764281H-Imidazole-4-carbaldehydeHCID 5049666Sodium triacetoxyborohydride2×HCID 53636257(R)-7-cyano-2,3,4,5-tetrahydro-4-(phenylacetyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine2×

Product 1

HCID 178479173HCID 178479173, compound

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 6212ChloroformSolventHCID 14923Ammonium HydroxideSolventHCID 516892Sodium BicarbonateSolvent

Procedure

To a refluxing solution of (R)-7-cyano-2,3,4,5-tetrahydro-4-(phenylacetyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine (prepared from Compound C of Example 248 by EDC/HOAt coupling with phenylacetic acid, 0.100 g, 0.26 mmol) and 4-formylimidazole (0.025 g, 0.26 mmol) in AcOH (0.3 mL) and dichloroethane (0.5 mL) with 3 A sieves was added sodium triacetoxyborohydride (0.055 g, 0.26 mmol). The mixture was stirred 16 hr, and then for 3 days, with additional aldehyde and sodium triacetoxyborohydride (3×1 eq each) added each day. The mixture was diluted with CHCl3 (10 mL), NH4OH (5 mL) and NaHCO3 (5 mL), and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl3 (2×20 mL). The combined organic extracts were washed with NaHCO3, water and brine, dried over MgSO4, filtered and concentrated. The product was purified by preparative HPLC (gradient of 20-90% aqueous methanol with 1% TFA) and the HCl salt formed to afford Example 300 as a light yellow solid (4 mg, 3%). MS (M+H)+ =462+

Workup

  1. waitfor 3 days
  2. stirringstirred for 30 min
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with CHCl3 (2×20 mL)
  5. washThe combined organic extracts were washed with NaHCO3, water and brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe product was purified by preparative HPLC (gradient of 20-90% aqueous methanol with 1% TFA)

Sources & evidence

ORD record
ord-8d58fb358b114384943d818760f94b02
Source dataset
uspto-grants-2000_01
Patent number
US06011029

Reaction notes

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