Pyrrolidine → N-{2-fluoro-4-[1-hydroxy-3-(pyrrolidin-1-ylcarbonyl)cyclobutyl]benzyl}-pyrrolidine

HRID 1694400Notes

Reaction equation

HRID 1694400 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.CC[N:24]([CH:28]([CH3:30])C)[CH:25]([CH3:27])C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.N1CCCC1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:15][CH:16]([C:18]([N:24]3[CH2:25][CH2:27][CH2:30][CH2:28]3)=[O:19])[CH2:17]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1

Participants

6

Reactant 4

HCID 31268PyrrolidineHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 672787123-(3-Fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-hydroxycyclobutanecarboxylic acid

Product 1

HCID 67279201N-{2-fluoro-4-[1-hydroxy-3-(pyrrolidin-1-ylcarbonyl)cyclobutyl]benzyl}-pyrrolidine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A 2-L 3-neck RB flask, equipped a mechanical stirrer, addition funnel and nitrogen gas inlet was charged with Intermediate 9, 3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-3-hydroxycyclobutanecarboxylic acid (0.135 mol, crude material from the above intermediate), 500 mL of anhydrous THF and DIEA (34.8 g, 0.27 mol). The initially insoluble mixture was stirred for 1.5 h until a uniform suspension formed. Then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% solution in EtOAc, 104.5 mL, 0.164 mol) was added and stirred for 5 min. (NOTE: exotherm was observed, reached ˜45-50° C.). Then pyrrolidine (28.2 mL, 24.0 g, 0.337 mol) was added. (NOTE: more exotherm was observed, reached ˜70-80° C. The mixture was stirring at RT for 12 h, then evaporated. The residue was mixed with 500 mL of sat. Na2CO3 and 200 mL of water. The mixture was extracted with DCM (5×300 mL), the extract was dried over Na2SO4, evaporated and dried to give 33.4 g (71% for two steps) of pure title compound (LCMS (M+H): 347.1. 1H NMR (300 MHz, CDCl3): δ 7.37 (t, J=7.37 Hz, 1H), 7.17-7.26 (m, 2H), 3.68 (s, 2H), 3.53 (t, J=6.78 Hz, 2H), 3.44 (t, J=6.58 Hz, 2H), 3.03-3.14 (m, 1H), 2.79-2.87 (m, 2H), 2.5-2.6 (m, 6H), 1.87-2.00 (m, 4H), 1.75-1.80 (m, 4H).

Workup

  1. customA 2-L 3-neck RB flask, equipped
  2. additiona mechanical stirrer, addition funnel and nitrogen gas inlet
  3. customformed
  4. stirringstirred for 5 min. (NOTE: exotherm was observed, reached ˜45-50° C.)
  5. customreached ˜70-80° C
  6. stirringThe mixture was stirring at RT for 12 h
  7. customevaporated
  8. additionThe residue was mixed with 500 mL of sat. Na2CO3 and 200 mL of water
  9. extractionThe mixture was extracted with DCM (5×300 mL)
  10. dry with materialthe extract was dried over Na2SO4
  11. customevaporated
  12. customdried

Sources & evidence

ORD record
ord-50f71345333742aeabe17b9b20c2b17d
Source dataset
uspto-grants-2012_04
Patent number
US08158673B2

Reaction notes

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