1-Hydroxybenzotriazole → 1-{4'-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]-4-biphenylyl}ethanone hydrochloride

HRID 452878Notes

Reaction equation

HRID 452878 reaction equation
[ClH:1].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.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C=CC2N(O)N=NC=2C=1.[C:54]([C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][C:66]([C:69](O)=[O:70])=[CH:65][CH:64]=2)=[CH:59][CH:58]=1)(=[O:56])[CH3:55]>C(Cl)Cl.C(Cl)CCl>[ClH:1].[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:69]([C:66]3[CH:65]=[CH:64][C:63]([C:60]4[CH:61]=[CH:62][C:57]([C:54](=[O:56])[CH3:55])=[CH:58][CH:59]=4)=[CH:68][CH:67]=3)=[O:70])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 41999154'-Acetyl-biphenyl-4-carboxylic acidHCID 16212021N-benzyl-N-ethylethanamine;1,4-bis(ethenyl)benzene;styreneHCID 574239521-Cyclobutyl-1,4-diazepane dihydrochloride

Product 1

HCID 669301861-{4'-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]-4-biphenylyl}ethanone hydrochlorideYield 24.6%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 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) and 4′-acetyl-4-biphenylcarboxylic acid (0.13 g) in DCM (5 ml). EDC (0.16 g) was then added and the reaction 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 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 (E2) as a pale solid (0.055 g). MS electrospray (+ion) 377 (MH+). 1H NMR δ (DMSO-d6): 10.57 (1H, s), 9.07 (2H, d, J=6.4 Hz), 7.88 (4H, m), 7.60 (2H, d, J=7.6 Hz), 4.15 (1H, m), 3.82-3.33 (6H, m), 3.02 (2H, m), 2.62 (3H, s), 2.41-1.62 (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-73c4cc4b0cf64ee7869af740a1d29db0
Source dataset
uspto-grants-2013_07
Patent number
US08492375B2

Reaction notes

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