Dichloromethane → (2R,3R)-3-(tert-Butyldimethylsilanyloxy)-2-hydroxymethyl-2-methylpyrrolidine-1-carboxylic acid (3-chloro-4-cyano-2-methyl-phenyl)-amide

HRID 501607Notes

Reaction equation

HRID 501607 reaction equation
FC(F)(F)[C:3]([OH:5])=O.[Si:8]([O:15][C@@H:16]1[CH2:20][CH2:19][NH:18][C@@:17]1([CH2:22][OH:23])[CH3:21])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].CC[N:26](C(C)C)C(C)C.Cl[C:34]1[C:35](C)=[C:36]([CH2:40][C:41]([NH2:43])=O)C=[CH:38][CH:39]=1.[CH2:45]([Cl:47])Cl>>[Cl:47][C:45]1[C:39]([CH3:38])=[C:34]([NH:26][C:3]([N:18]2[CH2:19][CH2:20][C@@H:16]([O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[C@:17]2([CH2:22][OH:23])[CH3:21])=[O:5])[CH:35]=[CH:36][C:40]=1[C:41]#[N:43]

Participants

5

Reactant 4

HCID 6344DichloromethaneHCID 81531DiisopropylethylamineHCID 684549373-Chloro-2-methylphenylacetamideHCID 68459451(2R,3R)-[3-(tert-Butyldimethylsilanyloxy)-2-methylpyrrolidin-2-yl]methanol trifluoroacetic acid salt

Product 1

HCID 59754220(2R,3R)-3-(tert-Butyldimethylsilanyloxy)-2-hydroxymethyl-2-methylpyrrolidine-1-carboxylic acid (3-chloro-4-cyano-2-methyl-phenyl)-amide

Procedure

To a solution of (2R,3R)-[3-(tert-Butyldimethylsilanyloxy)-2-methylpyrrolidin-2-yl]methanol trifluoroacetic acid salt (58C) (167 mg, 0.61 mmol) in CH2Cl2 (2.5 mL) at 0° C. were added molecular sieves followed by Hunig's base (0.21 mL, 1.22 mL). After stirring for 15 min, 2-Chloro-4-isocyanato-3-methylbenzonitrile (23A) was added and the ice bath was removed. After 10 min, the reaction was stirred for 2 h and then diluted with water and CH2Cl2. The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The resulting solid was purified via preparative HPLC (Luna C-18, 250×21.2 mm, eluting with 60-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 15 min; Flow rate at 10 mL/min; UV detection at 220 nm) to provide the title compound (17 mg) as a white film (LC/MS m/z 438 [M+H]+) and di-acylated product (80 mg) as a white solid (LC/MS m/z 630 [M+H]+). The di-acylated product (80 mg, 0.13 mmol) was dissolved in EtOH (2 mL) and treated with 21% NaOEt (48 □L, 0.13 mmol) at rt for 4 h. The reaction was concentrated under reduced pressure then diluted with water and EtOAc. The layers were separated, and the aqueous layer acidified with 1 N HCl then re-extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via preparative HPLC (Luna C-18, 100×21.2 mm, eluting with 40-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (43 mg) as a white film. LC/MS m/z 438 [M+H]+.

Workup

  1. customthe ice bath was removed
  2. waitAfter 10 min
  3. stirringthe reaction was stirred for 2 h
  4. additiondiluted with water and CH2Cl2
  5. customThe layers were separated
  6. washthe organic layer was washed with brine
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe resulting solid was purified via preparative HPLC (Luna C-18, 250×21.2 mm
  11. washeluting with 60-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 15 min

Sources & evidence

ORD record
ord-a6a5f87f010c46b49f55fbbad2dc24a2
Source dataset
uspto-grants-2010_08
Patent number
US07772267B2

Reaction notes

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