Sodium hydride → (3S,4R)-3-[(cyclohexylmethyl-methyl-carbamoyloxy)-methyl]-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1158421Notes

Reaction equation

HRID 1158421 reaction equation
[H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@@H:13]([CH2:15][N:16]([CH:33]([CH3:35])[CH3:34])[C:17](=[O:32])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=2)[C@H:12]([CH2:36][OH:37])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH:38]1([CH2:44][N:45]([CH3:49])[C:46](Cl)=[O:47])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@@H:13]([CH2:15][N:16]([CH:33]([CH3:34])[CH3:35])[C:17](=[O:32])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=2)[C@H:12]([CH2:36][O:37][C:46](=[O:47])[N:45]([CH2:44][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH3:49])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 59512299(3S,4R)-3-Hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl esterHCID 59512492N-(cyclohexylmethyl)-N-methylcarbamoyl chloride

Product 1

HCID 68616733(3S,4R)-3-[(cyclohexylmethyl-methyl-carbamoyloxy)-methyl]-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Procedure

To a stirred suspension of NaH (60% oily dispersion, 17 mg, 0.42 mmol) in THF (2 mL) is added at 0° C. (3S,4R)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (160 mg, 0.303 mmol) in THF (3 mL). The resulting solution is stirred 30 min before the addition of a solution of cyclohexylmethyl-methyl-carbamoyl chloride (80 mg, 0.421 mmol) in THF (3 mL). The mixture is further stirred overnight at RT and poured into an aqueous solution of NH4Cl. AcOEt is added, the layers are separated and the aqueous one extracted twice with AcOEt. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 95:5). TLC, Rf (CH2Cl2/MeOH 95:5)=0.25. MS (LC-MS): 648 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.83 min.

Workup

  1. customthe layers are separated
  2. extractionthe aqueous one extracted twice with AcOEt
  3. dry with materialThe combined organic extracts are dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 95:5)
  7. customtR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min)
  8. custom6.83 min.

Sources & evidence

ORD record
ord-c95618d511fa44028c1406caa03056b3
Source dataset
uspto-grants-2010_10
Patent number
US07807709B2

Reaction notes

Loading…