Acetic Acid → 4-[2-(5-Bromo-pyrazin-2-ylamino)-ethyl]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

HRID 2401109Notes

Reaction equation

HRID 2401109 reaction equation
[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:9]([O:11][C:12]([C:14]1([CH2:27][CH:28]=O)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:14]1([CH2:27][CH2:28][NH:8][C:5]2[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 5995392-Amino-5-bromopyrazineHCID 5049666Sodium triacetoxyborohydrideHCID 584784234-(2-Oxoethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

Product 1

HCID 866775664-[2-(5-Bromo-pyrazin-2-ylamino)-ethyl]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl esterYield 92.5%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 63651,1-DichloroethaneSolvent2×

Procedure

To a solution of 5-bromo-2-pyrazinamine (0.35 g, 2.01 mmol) in 1-2 dichloroethane (DCE, 5.0 mL) was added a solution of 4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.722 g, 2.41 mmol) in DCE (2.0 mL), acetic acid (3.1 eq) and allowed to stir at room temperature for an hour. NaBH(OAc)3 (3.0 eq.) was then added in one portion and reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was then diluted with DCM (5 mL), quenched with 2 M of NH4OH in water. The layers were separated, and the aqueous layer was extracted with DCM (5.0 mL×2). The combined organic layers were washed with aqueous NaHCO3 (15 mL), brine (30 mL), and dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluting with methanol in dichloromethane (0-10%) afforded 0.85 g (77%) of title compound.

Workup

  1. stirringto stir at room temperature for 16 hours
  2. customquenched with 2 M of NH4OH in water
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with DCM (5.0 mL×2)
  5. washThe combined organic layers were washed with aqueous NaHCO3 (15 mL), brine (30 mL)
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated under vacuum
  8. customPurification by column chromatography on silica gel eluting with methanol in dichloromethane (0-10%)

Sources & evidence

ORD record
ord-ec8a1160b5994817aaf87f514b51ff93
Source dataset
uspto-grants-2014_08
Patent number
US08796278B2

Reaction notes

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