Pyrazole → tert-butyl 2-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-5-yl]phenyl]-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate

HRID 929196Notes

Reaction equation

HRID 929196 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:25][C@H:26]4[C@H:30]5[O:31][CH2:32][C@@H:33]([OH:34])[C@H:29]5[O:28][CH2:27]4)[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.[N:36]1[NH:37][CH:38]=[C:39]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41][C:40]=12.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.N1C=CC=N1>[Cu]I.CCOC(C)=O.CCCCCC.O1CCOCC1>[OH:34][C@@H:33]1[CH2:32][O:31][C@@H:30]2[C@H:26]([O:25][C:15]3[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]4[C:12]([N:14]=3)=[N:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:37]5[CH:38]=[C:39]6[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41][C:40]6=[N:36]5)=[CH:3][CH:4]=3)=[C:9]([Cl:35])[CH:10]=4)[CH2:27][O:28][C@H:29]12

Participants

9

Reactant 5

HCID 1048PyrazoleHCID 62657Potassium Phosphate, TribasicHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 86684749HCID 86684749, compoundHCID 178451520HCID 178451520, compound

Product 1

HCID 131735091tert-butyl 2-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-5-yl]phenyl]-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 312751,4-DioxaneSolventHCID 21226206Ethyl acetate hexaneSolvent

Conditions

Temperature
100 °C

Procedure

A vial was charged with (3R,3aR,6R,6aR)-6-[5-(4-bromophenyl)-6-chloro-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (501.8 mg, 0.861 mmol), tert-butyl 4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-carboxylate (240.3 mg, 1.148 mmol), tripotassium phosphate (581.6 mg, 2.74 mmol), and copper (I) iodide (37.2 mg, 0.195 mmol). The vial was evacuated (3×) and backfilled with nitrogen. Trans-N,N′-dimethylcyclohexane-1,2-diamine (55 μl, 0.348 mmol) and dioxane (1.7 ml) were added to the vial to give a hazy suspension that was heated to 100° C. for 24 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (100 ml) and water (100 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a pale green residue. Flash chromatography of the residue utilizing a 40 g silica RediSep Rf® column and employing a 0-100% EtOAc/hexane gradient afforded a mixture of the two pyrazole linked regioisomers as a pale amber foam. LC-MS: calculated for C34H43ClN6O7Si 710.27 observed m/e: 711.29 (M+H)+ (Rt 1.30/2 min)

Workup

  1. customThe vial was evacuated (3×)
  2. customto give a hazy suspension that
  3. temperatureThe reaction mixture was cooled to room temperature
  4. custompartitioned between EtOAc (100 ml) and water (100 ml)
  5. extractionThe aqueous layer was extracted with EtOAc (2×50 ml)
  6. washwashed with brine (1×30 ml)
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. customevaporated under reduced pressure
  10. customto give a pale green residue
  11. customgradient afforded
  12. custom2 min

Sources & evidence

ORD record
ord-ff57cc68511a45d794873d7fe1eedc6a
Source dataset
uspto-grants-2016_03
Patent number
US09290517B2

Reaction notes

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