1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 4-[(5S*,9R*)-3-(3,5-Dichloro-phenyl)-1-methyl-2,4-dioxo-7-(quinoxaline-6-carbonyl)-1,3,7-triaza-spiro[4.4]non-9-yl]-benzonitrile

HRID 489249

Reaction equation

HRID 489249 reaction equation
[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:35][C:36]1[CH:37]=[C:38]([N:43]2[C:47](=[O:48])[C@@:46]3([C@H:52]([C:53]4[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=4)[CH2:51][NH:50][CH2:49]3)[N:45]([CH3:61])[C:44]2=[O:62])[CH:39]=[C:40]([Cl:42])[CH:41]=1>CN(C=O)C>[Cl:35][C:36]1[CH:37]=[C:38]([N:43]2[C:47](=[O:48])[C@@:46]3([C@H:52]([C:53]4[CH:54]=[CH:55][C:56]([C:57]#[N:58])=[CH:59][CH:60]=4)[CH2:51][N:50]([C:11]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[N:4]5)=[O:13])[CH2:49]3)[N:45]([CH3:61])[C:44]2=[O:62])[CH:39]=[C:40]([Cl:42])[CH:41]=1

Participants

6

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 674813Quinoxaline-6-carboxylic acidHCID 119947544-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile

Product 1

HCID 600547664-[(5S*,9R*)-3-(3,5-Dichloro-phenyl)-1-methyl-2,4-dioxo-7-(quinoxaline-6-carbonyl)-1,3,7-triaza-spiro[4.4]non-9-yl]-benzonitrileYield 24.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of quinoxaline-6-carboxylic acid (56.2 mg, 0.318 mmol) in 7 ml DMF were added EDCI (62 mg, 0.32 mmol), TEA (53.9 μl, 0.38 mmol) and HOBt (49.3 mg, 0.36 mmol). After 30 min, a solution of Example 15 (103.4 mg, 0.249 mmol) in 1 ml DMF was added. The reaction mixture was then stirred overnight at RT before evaporation to dryness. The residue was partitioned between DCM (50 ml) and 1N solution of HCl (20 ml). The DCM layer was washed with 10% solution of sodium carbonate (2×20 ml), dried over sodium sulfate, concentrated and purified by reverse phase HPLC (gradient from CH3CN/H2O/TFA: 5/95/0.05 to CH3CN/H2O/TFA: 80/20/0.05) to yield the titled compound (35 mg). Retention time: 2.16 min., 571 (M+1) (LCMS conditions: LC Micromass platform (APCI+, DAD (210-400 nm)), Column: TSK gel Super ODS 4.6 mm ID×5 cm, Flow rate: 2.75 mL/min, Gradient: from 100% eluent A to 100% eluent B in 2 min., with a plateau with 100% eluent B during 1 min. Eluent A: H2O (0.05% TFA), Eluent B: CH3CN/H2O/TFA (80/20/0.05)).

Workup

  1. customThe residue was partitioned between DCM (50 ml) and 1N solution of HCl (20 ml)
  2. washThe DCM layer was washed with 10% solution of sodium carbonate (2×20 ml)
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated
  5. custompurified by reverse phase HPLC (gradient from CH3CN/H2O/TFA: 5/95/0.05 to CH3CN/H2O/TFA: 80/20/0.05)

Sources & evidence

ORD record
ord-aa67af3149d9492bbfce663d49cc2839
Source dataset
uspto-grants-2005_12
Patent number
US06977267B2

Linked notes

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