Dichloromethane → L-Proline, N-(methoxycarbonyl)-L-valyl-4-hydroxy-, methyl ester, (4R)-

HRID 709361Notes

Reaction equation

HRID 709361 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl.Cl.[OH:41][C@H:42]1[CH2:46][NH:45][C@H:44]([C:47]([O:49][CH3:50])=[O:48])[CH2:43]1>C([O-])(O)=O.[Na+]>[OH:41][C@H:42]1[CH2:46][N:45]([C:7](=[O:9])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]([CH3:12])[CH3:11])[C@H:44]([C:47]([O:49][CH3:50])=[O:48])[CH2:43]1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 10942966(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acidHCID 114353194-Hydroxy-L-proline methyl ester hydrochloride

Product 1

HCID 58313116L-Proline, N-(methoxycarbonyl)-L-valyl-4-hydroxy-, methyl ester, (4R)-Yield 79.9%

Reagents, catalysts & solvents 1

HCID 516892Sodium BicarbonateSolvent

Procedure

In a 500 mL round-bottomed flask, (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (2.90 g, 16.6 mmol) and HATU (6.29 g, 16.6 mmol) were combined with CH2Cl2 (300 ml) to give a colorless suspension. TEA (5.03 g, 6.92 ml, 49.7 mmol) was added and stirred at rt for 30 min. (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate HCl (3.01 g, 16.6 mmol) was added and stirred at room temperature for 5 hr. It was diluted with NaHCO3 (sat. solution, 100 ml) and organic phase was separated. The aqueous layer was extracted with CH2Cl2 (2×100 ml) and the organic layer was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by a silica gel column (CH2Cl2, 20%, 40%, 60%, 80% EtOAc/CH2Cl2) to afford (2S,4R)-methyl 4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylate as an oil (4.0 g, 79.9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (dd, J=17.32, 6.78 Hz, 17H) 1.75-1.96 (m, 5H) 2.10 (br. s., 3H) 3.46-3.62 (m, 16H) 3.63-3.77 (m, 5H) 4.33 (d, J=8.03 Hz, 5H) 5.21 (d, J=3.76 Hz, 3H) 7.30 (d, J=8.78 Hz, 2H)

Workup

  1. customto give a colorless suspension
  2. additionwas added
  3. customwas separated
  4. extractionThe aqueous layer was extracted with CH2Cl2 (2×100 ml)
  5. dry with materialthe organic layer was dried with MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude material was purified by a silica gel column (CH2Cl2, 20%, 40%, 60%, 80% EtOAc/CH2Cl2)

Sources & evidence

ORD record
ord-bbec11073871468d994cae801752dbde
Source dataset
uspto-grants-2015_11
Patent number
US09180193B2

Reaction notes

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