4-Methylmorpholine → (6S)-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',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide

HRID 2179472Notes

Reaction equation

HRID 2179472 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[CH2:45][C:37]1=[N:38][CH:39]=[C:40]([C:42](O)=[O:43])[CH:41]=[C:36]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:42]([C:40]2[CH:41]=[C:36]3[CH2:35][C@@:27]4([C:28]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:34][C:26]4=[O:25])[CH2:45][C:37]3=[N:38][CH:39]=2)=[O:43])[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 68746980(S)-2'-oxo-1',2',5,7-tetrahydrospiro(cyclopenta(b)pyridine-6,3'-pyrrolo(2,3-b)-bipyridine)-3-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 86698906(6S)-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',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamideYield 65.5%

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) were added (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (19.1 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 (22 mg). HRMS 600.2347 (M+1). 1H NMR (400 MHz, DMSO): δ 11.13 (s, 1H); 9.39 (d, J=8.1 Hz, 1H); 8.91 (d, J=2.0 Hz, 1H); 8.15 (d, J=1.9 Hz, 1H); 8.10 (dd, J=5.3, 1.6 Hz, 1H); 7.48 (dd, J=7.3, 1.6 Hz, 1H); 7.42 (t, J=7.4 Hz, 2H); 7.38−7.29 (m, 3H); 6.94 (dd, J=7.3, 5.3 Hz, 1H); 5.49−5.40 (m, 1H); 4.70−4.62 (m, 1H); 3.72 (d, J=13.5 Hz, 1H); 3.50−3.32 (m, 4H); 2.62 (d, J=12.0 Hz, 1H); 2.36−2.28 (m, 1H); 174 (d, J=10.3 Hz, 1H); 1.64−1.52 (m, 2H); 1.27−1.20 (m, 1H); 1.18 (d, 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-f991879d987c4b5394486868cbbef593
Source dataset
uspto-grants-2015_06
Patent number
US09067941B2

Reaction notes

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