1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid [1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-yl]-amide

HRID 23432Notes

Reaction equation

HRID 23432 reaction equation
[C:1]1([C:15]([OH:17])=O)[C:10]2[C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][CH2:5][C:4]=2[NH:3][N:2]=1.[N:18]1([CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]2)[CH2:21][CH2:20][CH2:19]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCCl.C(Cl)Cl>[N:18]1([CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][C:27]([NH:30][C:15]([C:1]3[C:10]4[C:9]5[N:11]=[CH:12][CH:13]=[CH:14][C:8]=5[CH2:7][CH2:6][CH2:5][C:4]=4[NH:3][N:2]=3)=[O:17])=[N:26]2)[CH2:19][CH2:20][CH2:21]1

Participants

7

Reactant 3

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 121330693,4,5,6-Tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acidHCID 121330701-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-ylamine

Product 1

HCID 101506503,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid [1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-yl]-amideYield 8.8%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent

Procedure

7.8 mL of 1.7 M of t-BuLi in pentane is added dropwise under argon to a stirred solution of 1-bromo-3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene (1.4 g) in 75 mL of anhydrous THF at −78° C. After addition, dry carbon dioxide is bubbled into the mixture at the same temperature for 2 hours. The reaction mixture is allowed to warm to room temperature, quenched with 1N HCl solution, and diluted with water. The mixture is basified with 1N NaOH to pH 8-9, and then extracted with EtOAc. The aqueous layer is then acidified with HOAc to pH 4-5 and extracted with CH2Cl2 eight times. The combined extracts are washed with water, dried, and concentrated to give 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid as a tan solid. 1H NMR(DMSO): 1.95(m, 2H), 2.96(m, 2H), 3.07(t, 2H), 7.45(m,1H), 7.97(d,1H), 8.52(d, 2H). LR-MS: MW 229.23, Found: 230.2(M+1). Step 6: A mixture of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid (80 mg), 1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-ylamine (68 mg), EDCI(85 mg) and DMAP(55 mg) in 10 mL of 1,2-dichloroethane is refluxed overnight, cooled and diluted with CH2Cl2. The mixture is washed with aqueous NaHCO3 solution, water, dried over Na2SO4 and concentrated under vacuum. Purification on a silica gel plate, eluting with 10% MeOH in CH2Cl2 yields 12 mg of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid [1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-yl]-amide as a colorless foam. 1H NMR (CDCl3): 2.01-2.31(m, 6H), 2.67-2.92(m, 8H), 3.63(m, 2H), 4.17(t, 2H), 6.65(d, 1H), 7.23(m, 1H), 7.33(d, 1H), 7.65(d, 1H), 8.62(d, 1H), 14.13(bs, 1H). LR-MS: MW 391.48, Found: 392.2 (M+1).

Workup

  1. temperatureis refluxed overnight
  2. temperaturecooled
  3. washThe mixture is washed with aqueous NaHCO3 solution, water
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated under vacuum
  6. customPurification on a silica gel plate
  7. washeluting with 10% MeOH in CH2Cl2

Sources & evidence

ORD record
ord-d58539adec3b44a386af32a93f6d3823
Source dataset
uspto-grants-2005_02
Patent number
US06852730B2

Reaction notes

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