4-Methylmorpholine → (2R)-N-{(5R,6S,8S)-5-Methyl-6-phenyl-3-[1-(trifluoromethyl)cyclopropyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridine]-5-carboxamide

HRID 340178Notes

Reaction equation

HRID 340178 reaction equation
[CH3:1][C@H:2]1[N:7]2[C:8]([C:11]3([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]3)=[N:9][N:10]=[C:6]2[C@@H:5]([NH2:18])[CH2:4][C@H:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O:25]=[C:26]1[NH:34][C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[C@:27]21[CH2:42][C:41]1[C:36](=[CH:37][CH:38]=[C:39]([C:43](O)=[O:44])[CH:40]=1)[CH2:35]2.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH3:1][C@H:2]1[N:7]2[C:8]([C:11]3([C:14]([F:15])([F:16])[F:17])[CH2:13][CH2:12]3)=[N:9][N:10]=[C:6]2[C@@H:5]([NH:18][C:43]([C:39]2[CH:40]=[C:41]3[C:36](=[CH:37][CH:38]=2)[CH2:35][C@:27]2([C:28]4[C:29](=[N:30][CH:31]=[CH:32][CH:33]=4)[NH:34][C:26]2=[O:25])[CH2:42]3)=[O:44])[CH2:4][C@H:3]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1

Participants

8

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 86698235(5R,6S,8S)-5-Methyl-6-phenyl-3-[1-(trifluoromethyl)cyclopropyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-amine

Product 1

HCID 57405012(2R)-N-{(5R,6S,8S)-5-Methyl-6-phenyl-3-[1-(trifluoromethyl)cyclopropyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridine]-5-carboxamideYield 62.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of (5R,6S,8S)-5-methyl-6-phenyl-3-[1-(trifluoromethyl)cyclopropyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-amine (19.0 mg, 0.056 mmol) in N,N-dimethylformamide (565 μL) was added (2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (19.0 mg, 0.68 mmol), 1-hydroxy-7-azabenzotriazole (0.77 mg, 5.7 μmol), N-methylmorpholine (14.9 μL, 0.136 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.0 mg, 0.068 mmol). The mixture was stirred 30 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 (21 mg). HRMS 599.2367 (M+1). 1H NMR (400 MHz, DMSO): δ 11.12 (s, 1H); 9.19 (d, J=8.2 Hz, 1H); 8.08-8.05 (m, 1H); 7.85 (s, 1H); 7.82 (d, J=8.0 Hz, 1H); 7.41 (t, J=6.9 Hz, 3H); 7.36-7.27 (m, 3H); 7.23 (dd, J=7.3, 1.6 Hz, 1H); 6.89 (dd, J=7.3, 5.3 Hz, 1H); 5.43 (dt, J=10.7, 7.8 Hz, 1H); 4.69-4.61 (m, 1H); 3.70 (d, J=13.5 Hz, 1H); 3.43 (d, 16.3 Hz, 2H); 3.21 (d, J=16.3 Hz, 2H); 2.67-2.56 (m, 1H); 2.36-2.25 (m, 1H); 1.73 (d, J=10.3 Hz, 1H); 1.63-1.51 (m, 2H); 1.25 (d, J=9.3 Hz, 1H); 1.17 (t, J=6.5 Hz, 3H).

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-3114a354b4ff41fcac709491291184f2
Source dataset
uspto-grants-2014_11
Patent number
US08895572B2

Reaction notes

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