Formic Acid → 1-(4-{2-[(1S,2R)-2-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl]cyclopropyl}ethoxy}phenyl)imidazolidin-2-one

HRID 1850738Notes

Reaction equation

HRID 1850738 reaction equation
[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:38][CH2:39][N:40]=[C:41]=[O:42].CC([O-])(C)C.[Na+].C(O)=O>C1COCC1>[CH3:2][CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:27]=[CH:26][C:24]([N:25]4[CH2:38][CH2:39][NH:40][C:41]4=[O:42])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3]

Participants

7

Reactant 5

HCID 284Formic AcidHCID 160352-Chloroethyl isocyanateHCID 81531DiisopropylethylamineHCID 23676156Sodium t-butoxideHCID 867111874-(2-{(1S,2R)-2-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]cyclopropyl}ethoxy)aniline

Product 1

HCID 665631431-(4-{2-[(1S,2R)-2-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl]cyclopropyl}ethoxy}phenyl)imidazolidin-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 4-(2-{(1S,2R)-2-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]cyclopropyl}ethoxy)aniline (82 mg, 0.221 mmol) in THF (2.5 ml) at room temperature under nitrogen was added DIPEA (0.155 ml, 0.885 mmol), followed by 2-chloroethyl isocyanate (0.038 ml, 0.443 mmol) and the resulting mixture stirred at room temperature for 1 hour. The mixture was then cooled to 0° C. and NaOtBu (2M solution in THF) (0.443 ml, 0.885 mmol) was added dropwise. The ice bath was removed and the mixture was stirred for 30 minutes at room temperature. The mixture was quenched with formic acid (0.068 ml, 1.771 mmol) and then concentrated under reduced pressure. The residue was dissolved in DMF and filtered. The residue in DMF was then purified by RP HPLC on a Gilson, SunFire-5C18 OBD 19×150 mm column, eluting with a gradient of MeCN in water (0.1% HCOOH) from 10% to 100% over 8 minutes, hold at 100% for 1 minute, at 20 ml/min flow rate. The fractions containing product were combined, frozen and then lyophilized from MeCN/water to afford the title compound.

Workup

  1. temperatureThe mixture was then cooled to 0° C.
  2. customThe ice bath was removed
  3. stirringthe mixture was stirred for 30 minutes at room temperature
  4. concentrationconcentrated under reduced pressure
  5. dissolutionThe residue was dissolved in DMF
  6. filtrationfiltered
  7. customThe residue in DMF was then purified by RP HPLC on a Gilson
  8. washOBD 19×150 mm column, eluting with a gradient of MeCN in water (0.1% HCOOH) from 10% to 100% over 8 minutes
  9. waithold at 100% for 1 minute, at 20 ml/min flow rate
  10. additionThe fractions containing product
  11. temperaturefrozen

Sources & evidence

ORD record
ord-0fbff00bc9a84d9094b1cf3917befd71
Source dataset
uspto-grants-2015_02
Patent number
US08957062B2

Reaction notes

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