Hydrochloric Acid → HCID 58010006, compound

HRID 2204584Notes

Reaction equation

HRID 2204584 reaction equation
S([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25](C(OCC5C6C=CC=CC=6C6C5=CC=CC=6)=O)[CH2:24]4)=[CH:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].Cl.[C:49]([C:51]1([C:54]([OH:56])=O)[CH2:53][CH2:52]1)#[N:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1.CN(C=O)C>[CH:13]1[C:14]2[N:19]3[C:20]([C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:54]([C:51]5([C:49]#[N:50])[CH2:53][CH2:52]5)=[O:56])[CH2:24]4)=[CH:21][N:22]=[C:18]3[CH:17]=[N:16][C:15]=2[NH:11][CH:12]=1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 27332591-Cyanocyclopropanecarboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58010039HCID 58010039, compound

Product 1

HCID 58010006HCID 58010006, compoundYield 9.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
100 °C

Procedure

To a solution of (R)-(9H-fluoren-9-yl)methyl 3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate (0.20 g, 0.32 mmol) in 1,4-dioxane (3 mL) was added aqueous NaOH (2 N, 0.97 mL, 1.9 mmol). The reaction mixture was heated at about 100° C. for about 3 h before it was allowed to cool to ambient temperature. The reaction was neutralized with 4N HCl in 1,4-dioxane (0.5 mL) and was concentrated under reduced pressure. To the residue was added MeCN (25 mL) before it was concentrated under reduced pressure. This procedure was repeated before the addition of 1-cyanocyclopropanecarboxylic acid (0.072 g, 0.65 mmol), HATU (0.111 g, 0.291 mmol) and DMF (2 mL) followed by DIEA (0.170 mL, 0.971 mmol). After stirring at room temperature for about 3 h, the reaction was partitioned between EtOAc (2×50 mL) and aqueous NaHCO3 (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction was purified by RP-HPLC (Table 2, Method j). The combined product-containing fractions were concentrated under reduced pressure to remove MeCN and then lyophilized to give (R)-1-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile as a white solid (0.010 g, 9%): LC/MS (Table 2, Method a) Rt=1.67 min; MS m/z: 335 (M+H)+.

Workup

  1. temperatureto cool to ambient temperature
  2. concentrationwas concentrated under reduced pressure
  3. additionTo the residue was added MeCN (25 mL) before it
  4. concentrationwas concentrated under reduced pressure
  5. customthe reaction was partitioned between EtOAc (2×50 mL) and aqueous NaHCO3 (50 mL)
  6. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe crude reaction
  10. customwas purified by RP-HPLC (Table 2, Method j)
  11. additionThe combined product-containing fractions
  12. concentrationwere concentrated under reduced pressure
  13. customto remove MeCN

Sources & evidence

ORD record
ord-4b858ae69b6b437a87d3332581493ef4
Source dataset
uspto-grants-2016_06
Patent number
US09365579B2

Reaction notes

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