Ammonia → US11401286, Example 135

HRID 1508805Notes

Reaction equation

HRID 1508805 reaction equation
[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]CC)=O)=[CH:19][CH:18]=3)[CH:8]=2)[CH2:3]1.[NH3:29]>CO>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([NH2:29])=[O:26])=[CH:21][CH:22]=3)[CH:8]=2)[CH2:3]1

Participants

4

Reactant 2

HCID 222Ammonia2×HCID 90338478ethyl 2-(4-((2-(3-hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Product 1

HCID 90110206US11401286, Example 135Yield 67%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
100 °C

Procedure

A 10-mL vial was charged with ethyl 2-(4-((2-(3-hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (Diastereomer B, 0.056 g, 0.147 mmol), methanol (3 mL) and ammonia (4.2 mL, 7N in methanol, 29.4 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 23 h. LCMS analysis of the cooled reaction showed ˜66% conversion. Additional ammonia (1.0 mL, 7N in methanol, 7.0 mmol) was added and the mixture was heated at 100° C. for 2 h. The cooled reaction mixture solution was concentrated under reduced pressure. The residue was absorbed on silica (4 g) then purified by chromatography on silica using dichloromethane/(80:20:1 dichloromethane/methanol/conc. NH4OH) (10:0 to 0:10) as the eluent to afford the title compound (0.034 g, 67%) as an off-white solid. MW=351.44. M.p. 93-95° C. 1H NMR (DMSO-d6, 500 MHz) δ 7.95 (s, 1H), 7.42 (s, 1H), 7.24-7.20 (m, 2H), 7.13-7.09 (m, 2H), 6.85 (br s, 1H), 6.64 (s, 1H), 5.60 (br s, 1H), 4.13-4.07 (m, 1H), 3.33 (s, 2H), 3.03 (quin, J=7.7 Hz, 1H), 2.78 (t, J=7.5 Hz, 2H), 2.74 (t, J=7.0 Hz, 2H), 2.09-1.98 (m, 3H), 1.95-1.86 (m, 1H), 1.77-1.56 (m, 4H). MS: APCI, m/z 352 [M+H]+.

Workup

  1. customThe vial was sealed
  2. customLCMS analysis of the cooled reaction
  3. temperaturethe mixture was heated at 100° C. for 2 h
  4. customThe cooled reaction mixture solution
  5. concentrationwas concentrated under reduced pressure
  6. customThe residue was absorbed on silica (4 g)
  7. customthen purified by chromatography on silica

Sources & evidence

ORD record
ord-f6b14c1286ad44efb64640b247763d9b
Source dataset
uspto-grants-2015_12
Patent number
US09221843B2

Reaction notes

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