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

HRID 1943264Notes

Reaction equation

HRID 1943264 reaction equation
[F:1][C:2]1[CH:13]=[C:12]([C:14]2(O)[CH2:17][CH:16]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:15]2)[CH:11]=[CH:10][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.COCCN(S(F)(F)[F:36])CCOC.C(Cl)[Cl:40]>>[ClH:40].[F:1][C:2]1[CH:13]=[C:12]([C:14]2([F:36])[CH2:17][CH:16]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:15]2)[CH:11]=[CH:10][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1

Participants

4

Reactant 3

HCID 6344DichloromethaneHCID 2734690(Bis(2-methoxyethyl)amino)sulfur trifluorideHCID 67279201N-{2-fluoro-4-[1-hydroxy-3-(pyrrolidin-1-ylcarbonyl)cyclobutyl]benzyl}-pyrrolidine

Product 1

HCID 67279052N-{2-fluoro-4-[1-fluoro-3-(pyrrolidin-1-ylcarbonyl)cyclobutyl]benzyl}-pyrrolidine hydrochlorideYield 67%

Conditions

Temperature
-75 °C

Procedure

A 2-L 3-neck RB flask, equipped a magnetic stirring bar, thermometer, addition funnel and nitrogen gas inlet was charged with Example 8, N-{2-fluoro-4-[1-hydroxy-3-(pyrrolidin-1-ylcarbonyl)cyclobutyl]benzyl}-pyrrolidine (43.0 g, 0.124 mol) and 1 L of anhydrous DCM under nitrogen. The mixture was cooled to −75° C. with a dry ice/acetone bath, then Deoxo-Fluor (Aldrich, 33.0 g, 27.5 mL, 0.149 mol) was added dropwise. The mixture was warmed to 0° C. and stirred for 30 min at this temperature. Then the mixture was quenched with 350 mL of sat. Na2CO3, and extracted with DCM (3×300 mL). The extract was dried over Na2SO4 and evaporated. The resulting crude oil was purified by column (silica gel, ether 60%, hexane 30%, MeOH 5%, Et3N 5%, Rf=0.37 in ether 60%, hexane 30%, MeOH 5%, NH4OH 5%) to give 29.0 g (67%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.39 (t, J=7.64 Hz, 1H), 7.21 (d, J=7.92 Hz, 1H), 7.14 (d, J=10.9 Hz, 1H), 3.67 (s, 2H), 3.40-3.61 (m, 5H), 2.66-3.00 (m, 4H), 2.50-2.55 (m, 4H), 1.80-2.00 (m, 4H), 1.75-1.80 (m, 4H).

Workup

  1. customA 2-L 3-neck RB flask, equipped a magnetic stirring bar
  2. additionthermometer, addition funnel and nitrogen gas inlet
  3. temperatureThe mixture was warmed to 0° C.
  4. customThen the mixture was quenched with 350 mL of sat. Na2CO3
  5. extractionextracted with DCM (3×300 mL)
  6. dry with materialThe extract was dried over Na2SO4
  7. customevaporated
  8. customThe resulting crude oil was purified by column (silica gel, ether 60%, hexane 30%, MeOH 5%, Et3N 5%, Rf=0.37 in ether 60%, hexane 30%, MeOH 5%, NH4OH 5%)

Sources & evidence

ORD record
ord-31b0dbb3ae0d41798a2b6bf05faef0ea
Source dataset
uspto-grants-2013_03
Patent number
US08389743B2

Reaction notes

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