Hydrochloric Acid → HCID 178454371, compound

HRID 628427Notes

Reaction equation

HRID 628427 reaction equation
[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:45]=[C:46]([Cl:48])[CH:47]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29](Cl)=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:34]1[N:38](C2CCCCO2)[N:37]=[CH:36][CH:35]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:49]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52].C([O-])([O-])=O.[Cs+].[Cs+].Cl.O1CCOCC1>C1(C)C=CC=CC=1.C(Cl)Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:45]=[C:46]([Cl:48])[CH:47]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29]([N:49]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[NH:50][C:51]([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:34]1[CH:35]=[CH:36][NH:37][N:38]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 85431Di-tert-butyl bicarbamate3×HCID 123348242HCID 123348242, compound

Product 1

HCID 178454371HCID 178454371, compound

Reagents, catalysts & solvents 3

HCID 178439015HCID 178439015, compoundCatalyst2×HCID 1140TolueneSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
140 °C

Procedure

A mixture of 1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-5-chloro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[3,2-b]pyridine (2.7 g, 3.9 mmol, from Step 2), di-tert-butyl hydrazine-1,2-dicarboxylate (0.99 g, 4.3 mmol, Aldrich), Cs2CO3 (2.5 g, 7.8 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.30 g, 0.39 mmol, Aldrich) in toluene (25 mL) was degassed and heated at 140° C. for 3 hours. Additional di-tert-butyl hydrazine-1,2-dicarboxylate (0.50 g, 2.2 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.30 g, 0.38 mmol) were added and heating was continued for 1 hour. After addition of more di-tert-butyl hydrazine-1,2-dicarboxylate (0.20 g, 0.86 mmol) and heating for another 40 minutes, the mixture was cooled to room temperature and diluted with DCM, filtered and concentrated. The intermediate thus obtained was isolated by flash chromatography, eluting with a gradient from 0-25% EtOAc in hexanes (2.5 g). A solution of the intermediate in DCM (80 mL) at 0° C. was treated with 4.0 M HCl in dioxane (3.9 mL, 16 mmol). After stirring for 15 minutes, the reaction was quenched with aqueous ammonia. The reaction mixture was diluted with water, and the aqueous solution was extracted with three portions of EtOAc. The combined organic extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated. The title product was purified by flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes. Yield: (1.1 g, 35%).

Workup

  1. customwas degassed
  2. temperatureheating
  3. temperatureheating for another 40 minutes
  4. temperaturethe mixture was cooled to room temperature
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe intermediate thus obtained
  8. customwas isolated by flash chromatography
  9. washeluting with a gradient from 0-25% EtOAc in hexanes (2.5 g)
  10. customthe reaction was quenched with aqueous ammonia
  11. additionThe reaction mixture was diluted with water
  12. extractionthe aqueous solution was extracted with three portions of EtOAc
  13. washThe combined organic extracts were washed sequentially with water and brine
  14. dry with materialdried over sodium sulfate
  15. filtrationfiltered
  16. concentrationconcentrated
  17. customThe title product was purified by flash chromatography
  18. washeluting with a gradient from 0-50% EtOAc in hexanes

Sources & evidence

ORD record
ord-168740a3e7424702a8da8153fdf7b74c
Source dataset
uspto-grants-2016_04
Patent number
US09309246B2

Reaction notes

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