Anisole → 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

HRID 513051Notes

Reaction equation

HRID 513051 reaction equation
S(O)(C(F)(F)F)(=O)=O.C1(OC)C=CC=CC=1.[C:17]([C:19]1[CH:20]=[C:21]([C@H:26]2[CH2:30][C@H:29]([F:31])[CH2:28][N:27]2[C:32]2[CH:37]=[CH:36][N:35]3[N:38]=[CH:39][C:40]([C:41]([N:43](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[O:42])=[C:34]3[CH:33]=2)[CH:22]=[C:23]([F:25])[CH:24]=1)#[N:18]>C(Cl)Cl>[C:17]([C:19]1[CH:20]=[C:21]([C@H:26]2[CH2:30][C@H:29]([F:31])[CH2:28][N:27]2[C:32]2[CH:37]=[CH:36][N:35]3[N:38]=[CH:39][C:40]([C:41]([NH2:43])=[O:42])=[C:34]3[CH:33]=2)[CH:22]=[C:23]([F:25])[CH:24]=1)#[N:18]

Participants

5

Reactant 3

HCID 7519AnisoleHCID 62406Trifluoromethanesulfonic acidHCID 682823175-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide

Product 1

HCID 601713175-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-20 °C

Procedure

A flask was charged with TfOH (136.4 g, 909 mmol) and DCM (505 mL) and cooled to −20° C. Anisole (45 g, 416 mmol) was added followed by a solution of 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-53) (101 g, 166 mmol) in DCM (303 mL). The mixture was warmed to 20° C., and maintained for 15 hours. HPLC showed consumption of (I-53). The reaction was cooled to <0° C. and DCM (1 L) and an aqueous saturated K2CO3 (1 L) was added (aqueous layer pH=9-10). The aqueous layer was separated and extracted with DCM (500 mL). The rag layer was filtered through Celite and the two layers were separated. The organic layers were combined and concentrated to dryness. The resulting solid was triturated with TBME (250 mL) at 20° C. to yield 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (X-10). Melting point: 140° C. (dec.). 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=8.0 Hz, 1 H), 8.23 (s, 1 H), 7.61-7.58 (m, 1 H), 7.48-7.42 (m, 1 H), 7.03 (d, J=2.4 Hz, 1 H), 6.52 (dd, J=2.8, 7.6 Hz, 1 H), 5.42 (d, J=52.4 1 H), 5.14 (dd, J=7.2, 9.6 Hz, 1 H), 4.21 (ddd, J=3.2, 12.0, 36.8 Hz, 1 H), 3.94 (ddd, J=2.0, 12.3, 23.8 Hz, 1 H), 2.98-2.85 (m, 1 H), 2.16 (dddd, J=3.6, 9.6, 14.0, 40.4 Hz, 1 H).

Workup

  1. temperatureThe mixture was warmed to 20° C.
  2. temperaturemaintained for 15 hours
  3. customconsumption of (I-53)
  4. temperatureThe reaction was cooled to <0° C.
  5. additionDCM (1 L) and an aqueous saturated K2CO3 (1 L) was added (aqueous layer pH=9-10)
  6. customThe aqueous layer was separated
  7. extractionextracted with DCM (500 mL)
  8. filtrationThe rag layer was filtered through Celite
  9. customthe two layers were separated
  10. concentrationconcentrated to dryness
  11. customThe resulting solid was triturated with TBME (250 mL) at 20° C.

Sources & evidence

ORD record
ord-9748787645b645d0a4102984afb301a5
Source dataset
uspto-grants-2015_08
Patent number
US09102671B2

Reaction notes

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