Ammonium Hydroxide → 1-(5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-3-yl)urea

HRID 513054Notes

Reaction equation

HRID 513054 reaction equation
[F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[CH:14][C:15](C(O)=O)=[C:9]3[CH:8]=2)[C@@H:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:3]1.CC[N:28]([CH:32](C)C)C(C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[NH4+:52].[Cl-].[NH4+].[OH-:55]>C1COCC1>[F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[CH:14][C:15]([NH:52][C:32]([NH2:28])=[O:55])=[C:9]3[CH:8]=2)[C@@H:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:3]1

Participants

7

Reactant 5

HCID 14923Ammonium HydroxideHCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 199401P,P-Diphenylphosphinic azideHCID 601713195-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Product 1

HCID 601716951-(5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-3-yl)urea

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (X-3) (50 mg, 0.15 mmol) and DIEA (0.052 mL, 0.30 mmol) in THF (0.75 mL) under N2 was added DPPA (0.035 mL, 0.17 mmol) and the reaction was stirred overnight at room temperature. NH4Cl (42 mg, 0.73 mmol) and NH4OH were added to the reaction and the mixture was heated to 65° C. overnight. Upon cooling to room temperature the reaction was concentrated, taken up in MeOH and filtered. The filtrate was purified by preparative LCMS and lyophilized to give 1-(5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-3-yl)urea (X-23). 1H NMR (400 MHz, MeOD) δ 8.19-8.08 (m, 1 H), 7.83-7.67 (m, 1 H), 7.35 (dd, J=7.8, 14.0 Hz, 1 H), 7.16 (d, J=7.6 Hz, 1H), 7.11-7.01 (m, 1 H), 6.97 (t, J=8.5 Hz, 1 H), 6.44 (bd, J=5.7 Hz, 1 H), 6.26 (bs, 1 H), 5.40 (d, J=52.9 Hz, 1 H), 5.12-4.99 (m, 1 H), 4.16 (dd, J=11.4, 35.7 Hz, 1 H), 3.87 (dd, J=12.0, 23.4 Hz, 1 H), 2.93-2.77 (m, 1 H), 2.24-2.04 (m, 1 H). MS m/z 358.1 (M+1)+.

Workup

  1. temperaturethe mixture was heated to 65° C. overnight
  2. temperatureUpon cooling to room temperature the reaction
  3. concentrationwas concentrated
  4. filtrationfiltered
  5. customThe filtrate was purified by preparative LCMS

Sources & evidence

ORD record
ord-5920b50221b943b3a769cd4e5d2822a0
Source dataset
uspto-grants-2015_08
Patent number
US09102671B2

Reaction notes

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