Ammonia → US11401286, Example 133

HRID 1508796Notes

Reaction equation

HRID 1508796 reaction equation
C(O[C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[N:20](C(OC(C)(C)C)=O)[CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]3[CH2:31][CH2:32][CH2:33][C:14]=23)=[CH:8][CH:7]=1)C.[NH3:35]>CO>[NH:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]1[N:16]=[C:15]2[CH2:31][CH2:32][CH2:33][C:14]2=[C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([NH2:35])=[O:34])=[CH:11][CH:10]=2)[CH:18]=1

Participants

4

Reactant 2

HCID 222AmmoniaHCID 90338568tert-butyl 2-(4-((4-(2-ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-pyrrole-1-carboxylate

Product 1

HCID 90338445US11401286, Example 133Yield 38%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
100 °C

Procedure

A 20-mL vial was charged with tert-butyl 2-(4-((4-(2-ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-pyrrole-1-carboxylate (0.110 g, 0.24 mmol, 1.0) and methanol (3 mL). To this solution was added NH3 (6.8 mL, 7N in methanol, 476 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 65 h. After this time, the crude reaction solution was concentrated under reduced pressure. The residue was adsorbed onto silica then purified by chromatography on silica using dichloromethane/(90:10:0.25 dichloromethane/methanol/aq. NH4OH) (10:0 to 0:10) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford 2-(4-((2-(1H-pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide (0.030 g, 38%) as a brown solid. MW=332.40. 1H NMR (DMSO-d6, 500 MHz) δ 11.16 (br s, 1H), 7.93 (br s, 1H), 7.42 (br s, 1H), 7.26-7.22 (m, 2H), 7.17-7.13 (m, 2H), 7.03 (s, 1H), 6.85 (s, 1H), 6.74-6.71 (m, 1H), 6.39 (s, 1H), 6.05-6.20 (m, 1H), 3.34 (s, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.05 (quin, J=7.5 Hz, 2H). MS: ESI, m/z 333 [M+H]+. Treatment with 1.25M HCl in methanol afforded the title compound (0.035 g, 100%) as an off-white solid. MW=368.86. M.p. 163-165° C. 1H NMR (DMSO-d6, 500 MHz) δ 13.43 (br s, 1H), 12.06 (br s, 1H), 9.46 (br s, 1H), 7.52 (br s, 1H), 7.40-7.36 (m, 2H), 7.32-7.28 (m, 2H), 7.12-7.09 (m, 1H), 7.08 (s, 1H), 7.06-7.03 (m, 1H), 6.92 (br s, 1H), 6.29-6.25 (m, 1H), 3.43 (s, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H); APCI MS m/z 333 [M+H]+.

Workup

  1. customThe vial was sealed
  2. customAfter this time, the crude reaction solution
  3. concentrationwas concentrated under reduced pressure
  4. customthen purified by chromatography on silica

Sources & evidence

ORD record
ord-455d4aed5e8f4fea8c8fe5ce48f7d091
Source dataset
uspto-grants-2015_12
Patent number
US09221843B2

Reaction notes

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