Piperidine → [3-(3-Chloro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutyl]-piperidin-1-yl-methanone

HRID 1943280Notes

Reaction equation

HRID 1943280 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:20])[CH2:15]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 8082PiperidineHCID 14798Sodium HydroxideHCID 111923Propylphosphonic anhydrideHCID 574858713-(3-Chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid

Product 1

HCID 67278995[3-(3-Chloro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutyl]-piperidin-1-yl-methanoneYield 46.1%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added piperidine (0.13 ml, 1.29 mmol) and T3P (50 wt % solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (113 mg, 46% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C21H29Cl N2 O2, 376.9, found, 377.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.47 (d, J=2.1 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.34 (dd, J=7.9, 1.7 Hz, 1H), 3.70 (s, 2H), 3.54-3.48 (m, 2H), 3.32-3.26 (m, 2H), 3.02-2.93 (m, 1H), 2.75-2.67 (m, 2H), 2.65-2.51 (m, 6H), 1.78-1.71 (m, 4H), 1.63-1.44 (m, 6H); 100 MHz 13C NMR (CDCl3) δ 173.5, 146.3, 135.4, 133.9, 130.8, 126.5, 123.7, 72.9, 56.7, 54.3, 46.8, 43.5, 41.0, 28.4, 26.8, 25.8, 24.7, 23.7.

Workup

  1. customThe resulting reaction mixture
  2. customthe layers were separated
  3. extractionThe aqueous layer was subjected to EtOAc extraction (2×60 ml) again
  4. dry with materialthe combined organic layers were dried over MgSO4
  5. customevaporated
  6. customThe residue was purified by flash column chromatography
  7. washeluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH
  8. additionThe product containing fractions
  9. customwere collected
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-f81fdb3a0f044fbd892e9c5b99a1cf96
Source dataset
uspto-grants-2013_03
Patent number
US08389743B2

Reaction notes

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