Proton sponge → (2R,5R)-2-Methoxymethyl-5-methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester

HRID 1475283Notes

Reaction equation

HRID 1475283 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@@H:10]([CH2:25][OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.C[O+](C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@@H:10]([CH2:25][O:26][CH3:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 88675Proton sponge2×HCID 93245TrimethyloxoniumHCID 867239281-Benzyl 4-(tert-butyl) (2R,5R)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate

Product 1

HCID 86723929(2R,5R)-2-Methoxymethyl-5-methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl esterYield 69.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
5 °C

Procedure

(2R,5R)-2-Hydroxymethyl-5-methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (25 g, 68 mmol) in DCM (823 mL) was cooled to 4° C. (ice bath). 1,8-bis(dimethylamino)naphthalene (72 g, 337 mmol) was added in one portion followed by trimethyl oxonium tetrifluoroborate (50 g, 337 mmol) portionwise over 5 min. The mixture was stirred for 35 min at 5° C., the ice bath removed, then warmed from 5-17° C. over 1 h. After stirring for a further 20 min., saturated aqueous ammonium chloride (300 mL) was added slowly and reaction stirred for 10 min. The organic layer was separated and the aqueous phase extracted with DCM (2×300 mL). The combined organic extracts were washed with 1.0 M HCl (3×1.5 L), saturated sodium bicarbonate solution (3×1.5 L), dried over sodium sulfate, filtered and concentrated. The oil was dissolved in DCM and petrol added until precipitation of 1,8-bis(dimethylamino)naphthalene occurred. Purification by column chromatography (silica gel, 0-0%, 0-100%, EtOAc/petrol) gave an oil which contained 1,8-bis(dimethylamino)naphthalene as a contaminant. The remaining 1,8-bis(dimethylamino)naphthalene was captured during filtration through a SCX-2 column eluting with MeOH, to give the title compound (18 g, 52% over two steps) as a pale yellow oil. 1H NMR (Me-d3-OD): 7.46-7.26 (5H, m), 5.26-5.07 (2H, m), 4.31 (2H, d), 4.04-3.85 (1H, m), 3.79 (1H, d), 3.46 (2H, s), 3.28-3.09 (2H, m), 1.48 (9H, s), 1.15 (3H, dd).

Workup

  1. customthe ice bath removed
  2. temperaturewarmed from 5-17° C. over 1 h
  3. stirringAfter stirring for a further 20 min.
  4. additionsaturated aqueous ammonium chloride (300 mL) was added slowly
  5. customreaction
  6. stirringstirred for 10 min
  7. customThe organic layer was separated
  8. extractionthe aqueous phase extracted with DCM (2×300 mL)
  9. washThe combined organic extracts were washed with 1.0 M HCl (3×1.5 L), saturated sodium bicarbonate solution (3×1.5 L)
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated
  13. dissolutionThe oil was dissolved in DCM
  14. additionpetrol added until precipitation of 1,8-bis(dimethylamino)naphthalene
  15. customPurification by column chromatography (silica gel, 0-0%, 0-100%, EtOAc/petrol)
  16. customgave an oil which
  17. filtrationThe remaining 1,8-bis(dimethylamino)naphthalene was captured during filtration through a SCX-2 column
  18. washeluting with MeOH

Sources & evidence

ORD record
ord-ae5338069fdb402095eea890c83925ac
Source dataset
uspto-grants-2015_04
Patent number
US09018214B2

Reaction notes

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