3-Oxocyclobutane-1-carboxylic acid → 3-(3-Fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-hydroxycyclobutanecarboxylic acid

HRID 1694399Notes

Reaction equation

HRID 1694399 reaction equation
Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:4]([F:14])[CH:3]=1.[Li]CCCC.[O:20]=[C:21]1[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]1>C1COCC1>[F:14][C:4]1[CH:3]=[C:2]([C:21]2([OH:20])[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]2)[CH:13]=[CH:12][C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1

Participants

5

Reactant 3

HCID 49133583-Oxocyclobutane-1-carboxylic acidHCID 222667231-(4-Bromo-2-fluorobenzyl)pyrrolidineHCID 178418339Butyllithium

Product 1

HCID 672787123-(3-Fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-hydroxycyclobutanecarboxylic acid

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-85 °C

Procedure

A 2-L 3-neck RB flask, equipped a mechanical stirrer, addition funnel, thermometer and nitrogen gas inlet was charged with Intermediate 8, 1-(4-bromo-2-fluorobenzyl)pyrrolidine (69.86 g, 0.27 mol) and 700 mL of anhydrous THF. The system was flushed with nitrogen and cooled to −85° C. with liquid nitrogen with an ether/MeOH (1:1) bath. Then n-BuLi (10M in hexane, 30 mL, 0.298 mol) was added dropwise through an addition funnel at T<−80° C. The mixture was stirred at this temperature for an additional 15 min, then a solution of 3-oxocyclobutanecarboxylic acid (dried under vacuum for 2 days, 15.4 g, 0.135 mol) in 300 mL of anhydrous THF was added dropwise through an addition funnel keeping T<−80° C. The mixture was allowed to warm to RT and evaporated. The residue was mixed with 500 mL of water and washed with ether (2×300 mL). Then the aqueous solution was acidified to pH 1 with conc. HCl and washed with ether (2×300 mL). Then the aqueous solution was neutralized to pH 6-5 with NaOH and coevaporated three times with iPrOH (300 mL each time). Then the mixture was coevaporated with THF (200 mL) and dried to give gummy residue containing the product with inorganic salts LCMS (M+H): 294.4

Workup

  1. customA 2-L 3-neck RB flask, equipped
  2. additiona mechanical stirrer, addition funnel
  3. customThe system was flushed with nitrogen
  4. customT<−80° C
  5. temperatureto warm to RT
  6. customevaporated
  7. additionThe residue was mixed with 500 mL of water
  8. washwashed with ether (2×300 mL)
  9. washwashed with ether (2×300 mL)
  10. customdried
  11. customto give gummy residue
  12. additioncontaining the product with inorganic salts LCMS (M+H)

Sources & evidence

ORD record
ord-3e8ec5747d65498982679fafd0e0e6d5
Source dataset
uspto-grants-2012_04
Patent number
US08158673B2

Reaction notes

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