1,2-Dichloroethane → 4'-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]-4-biphenylcarbonitrile hydrochloride

HRID 2261233Notes

Reaction equation

HRID 2261233 reaction equation
Cl.Cl.[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.CC[N:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)CC.C=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C=CC1C=CC(C=C)=CC=1.C1C=CC2N([OH:53])N=NC=2C=1.C(Cl)C[Cl:56]>C(Cl)Cl>[ClH:56].[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:27]([C:28]3[CH:33]=[CH:32][C:31]([C:23]4[CH:22]=[CH:21][C:20]([C:19]#[N:16])=[CH:25][CH:24]=4)=[CH:30][CH:29]=3)=[O:53])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 16212021N-benzyl-N-ethylethanamine;1,4-bis(ethenyl)benzene;styreneHCID 574239521-Cyclobutyl-1,4-diazepane dihydrochloride

Product 1

HCID 669303334'-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]-4-biphenylcarbonitrile hydrochlorideYield 90.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

1-(Cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) (0.15 g) was stirred with diethylaminomethyl polystyrene (1.0 g), HOBT (0.045 g), 4′-cyano-4-biophenylcarboxylic acid (0.16 g) in DCM (5 ml). EDC (0.16 g) was then added and the reaction was stirred at rt for 16 h. The polymer supported base was filtered off and the filtrate was diluted with DCM (10 ml) and washed with saturated sodium hydrogen carbonate (2×15 ml). The organic layer was then loaded directly onto a silica column eluting with 0-10% MeOH (containing 10% 0.880 ammonia solution)/DCM. The isolated free base product was dissolved in DCM (5 ml) and treated with excess 1N HCl/diethyl ether solution (1 ml) and stirred for 10 min. The mixture was evaporated (co-evaporated with acetone 2×10 ml), triturated with acetone, then dried at 50° C. under high vacuum for 16 h to yield the title compound (E1) as a pale solid (0.119 g). MS electrospray (+ion) 360 (MH+). 1H NMR δ (DMSO-d6): 10.60 (1H, s), 7.97 (4H, m), 7.86 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=7.6 Hz), 4.18 (1H, m), 3.89-3.37 (6H, m), 3.10 (2H, m), 2.40-1.59 (8H, m).

Workup

  1. filtrationwas filtered off
  2. additionthe filtrate was diluted with DCM (10 ml)
  3. washwashed with saturated sodium hydrogen carbonate (2×15 ml)
  4. washeluting with 0-10% MeOH (containing 10% 0.880 ammonia solution)/DCM
  5. dissolutionThe isolated free base product was dissolved in DCM (5 ml)
  6. additiontreated with excess 1N HCl/diethyl ether solution (1 ml)
  7. stirringstirred for 10 min
  8. customThe mixture was evaporated (co-evaporated with acetone 2×10 ml)
  9. customtriturated with acetone
  10. customdried at 50° C. under high vacuum for 16 h

Sources & evidence

ORD record
ord-e28251f9e76b46e58c35baec14a66ef9
Source dataset
uspto-grants-2010_12
Patent number
US07846922B2

Reaction notes

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