Pyrrolidine → HCID 67278301, compound

HRID 1943290Notes

Reaction equation

HRID 1943290 reaction equation
[Li]CCCC.Br[C:7]1[CH:18]=[C:17]([F:19])[C:10]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:9]([F:20])[CH:8]=1.[O:21]=[C:22]1[CH2:25][CH:24]([C:26]([OH:28])=O)[CH2:23]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[F:20][C:9]1[CH:8]=[C:7]([C:22]2([OH:21])[CH2:23][CH:24]([C:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])[CH2:25]2)[CH:18]=[C:17]([F:19])[C:10]=1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1

Participants

7

Reactant 5

HCID 31268PyrrolidineHCID 111923Propylphosphonic anhydrideHCID 49133583-Oxocyclobutane-1-carboxylic acidHCID 67278673HCID 67278673, compoundHCID 178418339Butyllithium

Product 1

HCID 67278301HCID 67278301, compoundYield 26.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A 2.5 M solution of n-BuLi in hexanes (4.34 ml, 10.9 mmol) was added over 15 min to a solution of intermediate 18, 1-(4-bromo-2,6-difluoro-benzyl)-pyrrolidine (3.0 g, 10.9 mmol) in absolute THF (20 ml) under a flow of nitrogen at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Then a −78° C. chilled solution of 3-oxocyclobutanecarboxylic acid (0.62 g, 5.43 mmol) in absolute THF (6 ml) was added drop wise at −78° C. The mixture was warmed to RT slowly and left stirring for 18 hrs. Pyrrolidine (0.674 ml, 8.15 mmol) and T3P (3.8 ml, 5.97 mmol, 50% solution in EtOAc) were added and stirred for 30 min and the reaction was then quenched with 1N NaOH (25 ml) and extracted with CH2Cl2 (3×100 ml) to recover 2.8 g of crude product. This was purified by flash column chromatography using a 120 g ISCO™ column and 5% and 8% MeOH/CH2Cl2 with 0.2% NH4OH to obtain the title compound (520 mg, 26% yield). Rf=0.75 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C20H26F2N2O2, 364.2, found, 365.4 (M+H) APCI; 1H-NMR (CDCl3) δ 7.03 (ddd, J=8.7, 3.7, 2.5 Hz, 2H), 3.76 (s, 2H), 3.51 (t, J=6.8 Hz, 2H), 3.47-3.40 (m, 4H), 3.13-3.06 (m, 1H), 2.80-2.73 (m, 2H), 2.60-2.50 (m, 5H), 2.00-1.90 (m, 2H), 1.90-1.83 (m, 2H), 1.76-1.72 (m, 4H).

Workup

  1. additionwas added drop wise at −78° C
  2. temperatureThe mixture was warmed to RT slowly
  3. waitleft
  4. stirringstirring for 18 hrs
  5. stirringstirred for 30 min
  6. customthe reaction was then quenched with 1N NaOH (25 ml)
  7. extractionextracted with CH2Cl2 (3×100 ml)
  8. customto recover 2.8 g of crude product
  9. customThis was purified by flash column chromatography

Sources & evidence

ORD record
ord-d2bdc490ce984ad9b8d63bc81d034cc9
Source dataset
uspto-grants-2013_03
Patent number
US08389743B2

Reaction notes

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