4-Methylmorpholine → (2R)-N-[(6S,8S)-6-(2,3-Difluorophenyl)-3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl]-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridine]-5-carboxamide

HRID 340168Notes

Reaction equation

HRID 340168 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH2:23])[CH2:10]1.[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C@:26]21[CH2:41][C:40]1[C:35](=[CH:36][CH:37]=[C:38]([C:42](O)=[O:43])[CH:39]=1)[CH2:34]2.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH:23][C:42]([C:38]2[CH:39]=[C:40]3[C:35](=[CH:36][CH:37]=2)[CH2:34][C@:26]2([C:27]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:33][C:25]2=[O:24])[CH2:41]3)=[O:43])[CH2:10]1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 69965156(R)-2'-Oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridine]-5-carboxylic acidHCID 86698230(6S,8S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-amine

Product 1

HCID 57407113(2R)-N-[(6S,8S)-6-(2,3-Difluorophenyl)-3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl]-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridine]-5-carboxamideYield 76.9%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a solution of (6S,8S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-amine (7.0 mg, 0.023 mmol) in N,N-dimethylforinamide (105 μL) was added (2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (6.5 mg, 0.023 mmol), 1-hydroxy-7-azabenzotriazole (0.3 mg, 2.1 μmol), N-methylmorpholine (2.56 μL, 0.023 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.46 mg, 0.023 mmol). The mixture was stirred 25 min. Water was added, and the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→15% water/acetonitrile with 0.1% trifluoroacetic acid) giving the title compound (10.5 mg). HRMS 594.1931 (M+1). 1H NMR (500 MHz, DMSO): δ 11.10 (s, 1H); 8.84 (d, J=8.6 Hz, 1H); 8.07 (dd, J=5.3, 1.6 Hz, 1H); 7.83 (s, 1H); 7.79 (d, J=8.0 Hz, 1H); 7.40-7.36 (m, 2H); 7.32-7.28 (m, 2H); 7.22 (dd, J=7.3, 1.6 Hz, 1H); 6.92 (s, 1H); 6.88 (dd, J=7.3, 5.3 Hz, 1H); 4.34 (d, J=7.9 Hz, 1H); 3.80 (t, J=10.3 Hz, 4H); 3.40 (d, J=16.3 Hz, 2H); 3.19 (dd, J=16.4, 3.5 Hz, 2H); 2.33-2.29 (m, 2H).

Workup

  1. customthe mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→15% water/acetonitrile with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-1263bcb459ac4cf1907d402be913e2c4
Source dataset
uspto-grants-2014_11
Patent number
US08895572B2

Reaction notes

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