(S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate → HCID 178451909, compound

HRID 625571Notes

Reaction equation

HRID 625571 reaction equation
[CH3:1][C:2]1([CH3:28])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[CH:10]=2)[O:3]1.I[C:30]1[NH:34][C:33]([C@@H:35]2[CH2:39][CH2:38][CH2:37][N:36]2[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[N:32][CH:31]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:28])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:30]2[N:34]=[C:33]([C@@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:32][CH:31]=2)[CH:13]=[CH:12]3)[O:5]1

Participants

6

Reactant 2

HCID 58498756(S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylateHCID 596108242,2'-(Naphthalene-2,6-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)

Product 1

HCID 178451909HCID 178451909, compoundYield 36.9%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
120 °C

Procedure

A 100 mL pressure vessel equipped with a magnetic stir bar was charged with 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (2.00 g, 5.26 mmol), (S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2.10 g, 5.79 mmol) and Pd(Ph3P)4 (0.058 g, 0.05 mmol) in DME (47.8 mL) and water (4.8 mL). The solution was degassed under vacuum for 5 min and the reactor was back filled with nitrogen. The vessel was sealed and the reaction mixture was heated overnight at 120° C. The reaction was cooled to room temperature and the volatiles were removed under. The residue was partitioned between water and EtOAc and the water layer was extracted with additional EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified with a BIOTAGE® (dry loaded onto a 90 g silica gel cartridge and eluted with a gradient of 0 to 30% EtOAc in DCM) and repurified with a BIOTAGE® (dry loaded onto a 80 g silica gel cartridge and eluted with a gradient of 0 to 50% EtOAc in DCM) to yield (S)-tert-butyl 2-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (949 mg) as a yellow solid. The material (contaminated with (2S,2′S)-tert-butyl 2,2′-(4,4′-(naphthalene-2,6-diyl)bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate) was used in the next step without further purification. LC-MS retention time 1.760 min; m/z 490.21 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.

Workup

  1. customA 100 mL pressure vessel equipped with a magnetic stir bar
  2. customThe solution was degassed under vacuum for 5 min
  3. additionthe reactor was back filled with nitrogen
  4. customThe vessel was sealed
  5. temperatureThe reaction was cooled to room temperature
  6. customthe volatiles were removed under
  7. customThe residue was partitioned between water and EtOAc
  8. extractionthe water layer was extracted with additional EtOAc
  9. dry with materialThe combined organic layers were dried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe crude product was purified with a BIOTAGE® (
  13. customdry
  14. washeluted with a gradient of 0 to 30% EtOAc in DCM) and
  15. customrepurified with a BIOTAGE® (
  16. customdry
  17. washeluted with a gradient of 0 to 50% EtOAc in DCM)

Sources & evidence

ORD record
ord-debc2f720b804a59a9a3981229c40936
Source dataset
uspto-grants-2016_04
Patent number
US09303007B2

Reaction notes

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