4-Methylmorpholine → 1-[5-(5-fluoro-2-{1-[2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3-thiazol-2-yl]cyclobutanol

HRID 2362690Notes

Reaction equation

HRID 2362690 reaction equation
[F:1][C:2]1[C:3]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17](O)=[O:18])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:30][N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CS(C)=O>[F:1][C:2]1[C:3]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]([N:34]4[CH2:35][CH2:36][CH2:37][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:18])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 2283491-MethylhomopiperazineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 670037172-(4-(5-fluoro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid

Product 1

HCID 546730971-[5-(5-fluoro-2-{1-[2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3-thiazol-2-yl]cyclobutanol

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-(4-(5-fluoro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid (Example 65B) (100 mg, 0.242 mmol) in N,N-dimethylformamide (783 μl) was added 1-methyl-1,4-diazepane (35.9 mg, 0.314 mmol), 4-methylmorpholine (80 μl, 0.726 mmol), 1-hydroxybenzotriazole hydrate (55.6 mg, 0.363 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (69.6 mg, 0.363 mmol). The reaction was cooled to room temperature and diluted with dimethyl sulfoxide (1 mL). The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, 19×150 mm Atlantis Prep T3 OBD 5 um column, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile containing 0.1% v/v trifluoroacetic acid) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.29 (bs, 1H), 8.43 (s, 1H), 8.29 (s, 1H), 8.20 (d, J=3.6 Hz, 1H), 8.10 (s, 1H), 7.05 (s, 1H), 6.65 (s, 1H), 5.22-5.17 (m, 2H), 3.67-3.41 (m, 4H), 2.67-2.34 (m, 6H), 2.32-2.23 (m, 3H), 2.05-1.71 (m, 4H); MS ESI(+) m/z 510.1 [M+H]+.

Workup

  1. customThe resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, 19×150 mm Atlantis Prep T3 OBD 5 um column
  2. washeluting with a gradient of 5% B in A to 75% B in A over 25 minutes

Sources & evidence

ORD record
ord-b8acefd9ad42471fbff6b8718ae54708
Source dataset
uspto-grants-2014_04
Patent number
US08691810B2

Reaction notes

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