Trifluoroacetic acid → 4-(4-Fluoro-3-trifluoromethyl-benzylamino)-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide

HRID 550824Notes

Reaction equation

HRID 550824 reaction equation
FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:11]2[N:18]=[C:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]3)=[O:21])[S:16][C:12]=2[N:13]=[CH:14][N:15]=1.C(N(CC)C(C)C)(C)C.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][C:40]=1[C:47]([F:50])([F:49])[F:48].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)C.O.C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[C:11]2[N:18]=[C:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([NH:28][CH2:43][C:42]4[CH:45]=[CH:46][C:39]([F:38])=[C:40]([C:47]([F:50])([F:48])[F:49])[CH:41]=4)[CH2:24][CH2:23]3)=[O:21])[S:16][C:12]=2[N:13]=[CH:14][N:15]=1

Participants

11

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 5222694-Fluoro-3-(trifluoromethyl)benzaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 590119524-Amino-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide

Product 1

HCID 866165074-(4-Fluoro-3-trifluoromethyl-benzylamino)-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amideYield 25.4%

Reagents, catalysts & solvents 5

HCID 176Acetic AcidSolventHCID 887MethanolSolventHCID 962WaterSolventHCID 1140TolueneSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
25 °C

Procedure

A suspension of the trifluoroacetic acid salt of 4-amino-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (1.82 g, 4.30 mmol) in methanol was treated with N,N-diisopropylethylamine (1.5 mL, 6.50 mmol), 4-fluoro-3-(trifluoromethyl)benzaldehyde (1.3 mL, 6.50 mmol) and toluene. The resulting mixture was stirred at 25° C. for 1 h and was then concentrated in vacuo. This procedure was repeated until the reaction mixture became homogenous when dissolved in toluene. After the final concentration to remove toluene, the reaction mixture was diluted with dichloroethane (100 mL) and then was treated with acetic acid (0.26 g) and sodium triacetoxyborohydride (2.73 g, 13 mmol). The resulting reaction mixture was allowed to stir at 25° C. overnight. At this time, the reaction mixture was poured into water and extracted into ethyl acetate. The organics were washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, gradient elution 1:1 ethyl acetate/hexanes) afforded a colorless oil. The oil was dissolved in diethyl ether and then was concentrated in vacuo to afford 4-(4-fluoro-3-trifluoromethyl-benzylamino)-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (530 mg, 25%) as a white, foamy solid; ES-HRMS m/e calcd for C20H20F4N6O2S (M+H)+ 485.1378, found 485.1378.

Workup

  1. concentrationwas then concentrated in vacuo
  2. dissolutiondissolved in toluene
  3. concentrationAfter the final concentration
  4. customto remove toluene
  5. additionthe reaction mixture was diluted with dichloroethane (100 mL)
  6. customThe resulting reaction mixture
  7. stirringto stir at 25° C. overnight
  8. extractionextracted into ethyl acetate
  9. washThe organics were washed with a saturated aqueous sodium bicarbonate solution
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. washFlash chromatography (Merck Silica gel 60, 230-400 mesh, gradient elution 1:1 ethyl acetate/hexanes)
  14. customafforded a colorless oil
  15. concentrationwas concentrated in vacuo

Sources & evidence

ORD record
ord-84090f0c3b994d27ae2f724312becaa1
Source dataset
uspto-grants-2011_05
Patent number
US07947692B2

Reaction notes

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