Trifluoroacetic acid → 1-[4-(3-Pyrrolidin-1-ylmethyl-cyclobutyl)-benzyl]-pyrrolidine

HRID 1241518Notes

Reaction equation

HRID 1241518 reaction equation
[N:1]1([CH2:6][CH:7]2[CH2:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)(O)[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[N:1]1([CH2:6][CH:7]2[CH2:8][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:16][CH:17]=3)[CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

4

Reactant 3

HCID 6422Trifluoroacetic acidHCID 12052TriethylsilaneHCID 219348323-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanol

Product 1

HCID 113125751-[4-(3-Pyrrolidin-1-ylmethyl-cyclobutyl)-benzyl]-pyrrolidineYield 31%

Procedure

Alternatively, to a stirring solution of 3-pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanol (Example 8, General procedure B, Step D) (1.1 g, 3.5 mmol) in TFA (5.4 mL, 70.1 mmol) was added triethyl silane (5.6 mL, 35.0 mmol). The reaction was then heated to 75 □C (oil bath) for 14 hours. The reaction was then cooled to rt and concentrated under reduced pressure. The residual was taken up in CH2Cl2 and washed with NaHCO3. The aqueous layer was back extracted with 3:1 (CH3Cl:isopropanol). The combined organic layers were dried over MgSO4, filtered though a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a 40 M Biotage column, eluting with a gradient of 10%–20% MeOH/CH2Cl2 with 0.3% NH4OH. The product containing fractions were collected and concentrated to give the title compound (324 mg, 18%) as the bis-TFA salt. To this material in EtOAc was added a solution of HCl (2 eq, 2M THF). The resulting solution was stirred over night, and then filtered through a fritted funnel. The solid was collected and dried under reduced pressure to yield the title compound as the bis-HCl salt and as a mixture of isomers.

Workup

  1. temperatureThe reaction was then heated to 75 □C (oil bath) for 14 hours
  2. concentrationconcentrated under reduced pressure
  3. washwashed with NaHCO3
  4. extractionThe aqueous layer was back extracted with 3:1 (CH3Cl:isopropanol)
  5. dry with materialThe combined organic layers were dried over MgSO4
  6. filtrationfiltered though a fritted funnel
  7. concentrationconcentrated under reduced pressure
  8. customPurification of this material
  9. washeluting with a gradient of 10%–20% MeOH/CH2Cl2 with 0.3% NH4OH
  10. additionThe product containing fractions
  11. customwere collected
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-d806a69db99249e29d565ef27f84049c
Source dataset
uspto-grants-2006_10
Patent number
US07115600B2

Reaction notes

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