Diisopropylethylamine → (R)-2-Fluoro-4-(5-{[1-(7-hydroxynaphthalen-1-yl)pyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile

HRID 2306206Notes

Reaction equation

HRID 2306206 reaction equation
Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4]1.[C:19]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][N:26]2[C:30]([CH:31]=O)=[CH:29][N:28]=[CH:27]2)=[CH:23][C:22]=1[F:35])#[N:20].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO>[F:35][C:22]1[CH:23]=[C:24]([CH2:25][N:26]2[C:30]([CH2:31][NH:2][C@@H:3]3[CH2:7][CH2:6][N:5]([C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=5)[CH:11]=[CH:10][CH:9]=4)[CH2:4]3)=[CH:29][N:28]=[CH:27]2)[CH:33]=[CH:34][C:21]=1[C:19]#[N:20]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 5003444Sodium cyanoborohydrideHCID 114247081-(4-Cyano-3-fluorobenzyl)-5-imidazolecarboxaldehydeHCID 70170706(R)-3-amino-1-[7-hydroxynaphthalen-1-yl]pyrrolidine hydrochloride

Product 1

HCID 70171501(R)-2-Fluoro-4-(5-{[1-(7-hydroxynaphthalen-1-yl)pyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

(R)-3-Amino-1-[7-hydroxynaphthalen-1-yl]pyrrolidine hydrochloride, as described in Step J, (85 mg, 0.32 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described in Example 1, Step G, (75 mg, 0.33 mmol), were stirred in MeOH (1 mL) and N,N-diisopropylethylamine was added dropwise to adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hour at ambient temperature then NaCNBH3 (26 mg, 0.42 mmol) was added and stirring was continued for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 (1 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (3 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted further with CH2Cl2 (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2—1% to 6% MeOH—0.1% to 0.6% NH4OH to yield the titled product as a colorless oil.

Workup

  1. stirringstirring
  2. waitwas continued for 18 hours
  3. customThe reaction was quenched with saturated aqueous NaHCO3 (1 mL) and most of the MeOH
  4. customwas removed under reduced pressure
  5. customThe residual solution was partitioned between saturated aqueous NaHCO3 (3 mL) and CH2Cl2 (10 mL)
  6. extractionThe aqueous layer was extracted further with CH2Cl2 (2×10 mL)
  7. dry with materialThe combined organic extracts were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe crude product was purified by flash column chromatography on silica
  11. washeluting with a gradient of CH2Cl2—1% to 6% MeOH—0.1% to 0.6% NH4OH

Sources & evidence

ORD record
ord-d03d9fd6fe6d4a6f9b59bd5e1c025f80
Source dataset
uspto-grants-2002_08
Patent number
US06441017B1

Reaction notes

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