Trifluoroacetic acid methylene chloride → (r)-4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methyl ester

HRID 605539Notes

Reaction equation

HRID 605539 reaction equation
COC([CH:5]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=O.[C:28]([OH:34])(C(F)(F)F)=[O:29].[CH2:35](Cl)Cl>C(Cl)Cl>[CH3:35][O:34][C:28]([C@H:6]1[CH2:5][N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][N:12]=2)[CH2:9][CH2:8][NH:7]1)=[O:29]

Participants

4

Reactant 2

HCID 21863450Trifluoroacetic acid methylene chlorideHCID 57917724HCID 57917724, compound

Product 1

HCID 67045817(r)-4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methyl esterYield 94%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (110 mg, 0.28 mmol) was combined with 2.0 mL of 25% TFA/CH2Cl2 and was stirred at room temperature for 30 min. After this period the reaction mixture was diluted with CH2Cl2 (25 mL) and was washed with sat'd NaHCO3 (2×10 mL) and brine. The resulting CH2Cl2 layer was dried over anhydrous Na2SO4 and was evaporated in vacuo to yield crude amine. The crude amine was purified using flash silica chromatography (0-10% MeOH/CH2Cl2) to yield 77 mg (94%) of (R)-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methyl ester as a yellow residue. This material was combined with 6-Chlorosulfonyl-indan-1-carboxylic acid 4-nitro-benzyl ester from Step 2 (102 mg, 0.27 mmoles) and triethylamine (46 μL, 0.33 mmol) in 2.0 mL of anhydrous THF, and was stirred at 60° C. for 5 hours. After this period the reaction mixture was evaporated in vacuo and the resulting residue was combined with 30 mL of benzene. The resulting heterogeneous mixture was filtered with benzene washings. The filtrate was then evaporated in vacuo and purified using flash silica chromatography (0-30% EtOAc/Hexane) to yield 4-[3-(4-Nitro-benzyloxycarbonyl)-indane-5-sulfonyl]-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methyl ester.

Workup

  1. washwas washed with sat'd NaHCO3 (2×10 mL) and brine
  2. dry with materialThe resulting CH2Cl2 layer was dried over anhydrous Na2SO4
  3. customwas evaporated in vacuo
  4. customto yield crude amine
  5. customThe crude amine was purified

Sources & evidence

ORD record
ord-a7d168305f3e4e24b6c030f201009115
Source dataset
uspto-grants-2011_03
Patent number
US07915253B2

Reaction notes

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