Diisopropylamine → (6-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-((2R,6S)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)(1-methyl-1H-imidazol-2-yl)methanol

HRID 577850Notes

Reaction equation

HRID 577850 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[Si:21]([O:38][CH2:39][C:40]1[C:45]([N:46]2[CH2:51][C@H:50]([CH3:52])[O:49][C@H:48]([CH3:53])[CH2:47]2)=[C:44]([Cl:54])[C:43]([F:55])=[CH:42][N:41]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:56][N:57]1[CH:61]=[CH:60][N:59]=[C:58]1[CH:62]=[O:63]>C1COCC1>[Si:21]([O:38][CH2:39][C:40]1[N:41]=[C:42]([CH:62]([C:58]2[N:57]([CH3:56])[CH:61]=[CH:60][N:59]=2)[OH:63])[C:43]([F:55])=[C:44]([Cl:54])[C:45]=1[N:46]1[CH2:51][C@H:50]([CH3:52])[O:49][C@H:48]([CH3:53])[CH2:47]1)([C:34]([CH3:37])([CH3:35])[CH3:36])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1

Participants

7

Reactant 5

HCID 7912DiisopropylamineHCID 1395751-Methyl-2-imidazolecarboxaldehydeHCID 2724682Lithium diisopropylamideHCID 67319975(2R,6S)-4-(2-((tert-Butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine2×HCID 178418339Butyllithium

Product 1

HCID 67357736(6-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-((2R,6S)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)(1-methyl-1H-imidazol-2-yl)methanolYield 66%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

Diisopropylamine (0.868 mL, 6.14 mmol) was added dropwise to a stirring solution of 2.5M butyllithium in hexanes (2.339 mL, 5.85 mmol) in THF (20 mL) at −78° C. The solution was warmed to 0° C. for 10 minutes and then cooled again to −78° C. Cannulation of the LDA at −78° C. into (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45, 1.5 g, 2.92 mmol) in THF (10 mL) at −78° C. Allowed dark solution to stir for 20 minutes then cannulated into a stirring solution of 1-methyl-1H-imidazole-2-carbaldehyde (0.644 g, 5.85 mmol) in THF (10 mL) at −78° C. The solution was allowed to warm to −50° C. then quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and washed resulting organics with brine. After drying the organics over sodium sulfate, filtering, and evacuating the filtrate under vacuum, a crude yellow oil was obtained. The crude oil was purified on silica using 40% ethyl acetate in n-hexane to give 1.2 g (66%) of the title compound as oil.

Workup

  1. temperaturecooled again to −78° C
  2. customat −78° C.
  3. customat −78° C
  4. temperatureto warm to −50° C.
  5. customthen quenched with saturated ammonium chloride solution
  6. extractionThe mixture was extracted with ethyl acetate
  7. washwashed
  8. customresulting organics with brine
  9. dry with materialAfter drying the organics over sodium sulfate
  10. filtrationfiltering
  11. customevacuating the filtrate under vacuum
  12. customa crude yellow oil was obtained
  13. customThe crude oil was purified on silica using 40% ethyl acetate in n-hexane

Sources & evidence

ORD record
ord-055d5848e8c04432aa7996113570ffef
Source dataset
uspto-grants-2015_05
Patent number
US09040528B2

Reaction notes

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