tert-butyl 3-fluoro-4-[(6-{[(2R)-2-hydroxypropanoyl]amino}thieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate → tert-butyl 3-fluoro-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidine-1-carboxylate

HRID 711970Notes

Reaction equation

HRID 711970 reaction equation
[F:1][CH:2]1[CH:7]([NH:8][C:9]2[C:14]([NH:15][C:16](=O)[C@H:17]([OH:19])[CH3:18])=[CH:13][N:12]=[C:11]3[CH:21]=[CH:22][S:23][C:10]=23)[CH2:6][CH2:5][N:4]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:3]1>C(O)(=O)C>[F:1][CH:2]1[CH:7]([N:8]2[C:9]3=[C:10]4[S:23][CH:22]=[CH:21][C:11]4=[N:12][CH:13]=[C:14]3[N:15]=[C:16]2[C@H:17]([OH:19])[CH3:18])[CH2:6][CH2:5][N:4]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:3]1

Participants

3

Reactant 1

HCID 86717438tert-butyl 3-fluoro-4-[(6-{[(2R)-2-hydroxypropanoyl]amino}thieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate

Product 1

HCID 86717439tert-butyl 3-fluoro-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidine-1-carboxylateYield 10%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

To a mixture of tert-butyl 4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-3-fluoropiperidine-1-carboxylate (0.21 g, 0.57 mmol) and (R)-2-hydroxypropanoic acid (0.059 g, 0.65 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.23 g, 0.60 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water, concentrated and purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give tert-butyl 3-fluoro-4-[(6-{[(2R)-2-hydroxypropanoyl]amino}thieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate (0.155 g, 62%). LCMS calculated for C20H28FN4O4S (M+H)+: m/z=439.2. Found: 439.1. A solution of the amide intermediate in acetic acid (1 mL) was heated at reflux for 2 h. The resulting mixture was purified on silica gel (eluting with 0-10% MeOH in dichloromethane) to give tert-butyl 3-fluoro-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidine-1-carboxylate (16 mg, 10%). LCMS calculated for C20H26FN4O3S (M+H)+: m/z=421.2. Found: 421.1. The Boc protected intermediate was treated with trifluoroacetic acid (0.1 mL, 1 mmol) in methylene chloride (0.2 mL) at room temperature for 1 h. The mixture was concentrated and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give two desired products. First peak retention time 0.253 min. LCMS calculated for C15H18FN4OS (M+H)+: m/z=321.1. Found: 321.1. Second peak retention time 0.514 min. LCMS calculated for C15H18FN4OS (M+H)+: m/z=321.1. Found: 321.1.

Workup

  1. temperatureat reflux for 2 h
  2. customThe resulting mixture was purified on silica gel (eluting with 0-10% MeOH in dichloromethane)

Sources & evidence

ORD record
ord-0cb9d2a651134c58b59482b6e47aedfc
Source dataset
uspto-grants-2015_11
Patent number
US09181271B2

Reaction notes

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