Benzyl Alcohol → benzyl (5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-3-yl)carbamate

HRID 513053Notes

Reaction equation

HRID 513053 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:42])=CC=1.[CH2:52]([OH:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>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:28][C:32](=[O:42])[O:59][CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[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

6

Reactant 4

HCID 244Benzyl AlcoholHCID 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 60171693benzyl (5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-3-yl)carbamate

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. Benzyl alcohol (0.025 mL, 0.24 mmol) was added to the reaction and the mixture was heated to 65° C. for 3 days. Upon cooling to room temperature the reaction was partitioned with EtOAc and aqueous saturated NaHCO3. The organics were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel with an EtOAc/hexane gradient as eluant to yield benzyl (5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-3-yl)carbamate (X-21). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.2 Hz, 1 H), 7.78 (s, 1 H), 7.52-7.25 (m, 6 H), 7.01 (d, J=7.6 Hz, 1 H), 6.98-6.84 (m, 2 H), 6.13 (d, J=6.9 Hz, 2 H), 5.36 (d, J=52.9 Hz, 1 H), 5.20 (s, 2 H), 5.03-4.86 (m, 1 H), 4.17-3.93 (m, 1 H), 3.93-3.72 (m, 1 H), 2.92-2.73 (m, 1 H), 2.16-1.97 (m, 1 H). MS m/z 449.1 (M+1)+.

Workup

  1. temperaturethe mixture was heated to 65° C. for 3 days
  2. temperatureUpon cooling to room temperature the reaction
  3. customwas partitioned with EtOAc and aqueous saturated NaHCO3
  4. dry with materialThe organics were dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product was purified by column chromatography on silica gel with an EtOAc/hexane gradient as eluant

Sources & evidence

ORD record
ord-8264b9f8d1fc4b0c8c0ec88d982e0f5b
Source dataset
uspto-grants-2015_08
Patent number
US09102671B2

Reaction notes

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