CID 406 → tert-Butyl 4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)piperidine-1-carboxylate

HRID 1666324Notes

Reaction equation

HRID 1666324 reaction equation
C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH:11]=1)(=O)OCC)C.C(O[K])(C)(C)C.O=[C:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.P(=O)([O-])[O-]>O1CCCC1>[C:43]([O:42][C:40]([N:37]1[CH2:38][CH2:39][C:34](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=3)[CH:11]=2)[CH2:35][CH2:36]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]

Participants

6

Reactant 4

HCID 406CID 406HCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 86623890Diethyl (3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)phosphonateHCID 178418922HCID 178418922, compound

Product 1

HCID 66875665tert-Butyl 4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)piperidine-1-carboxylateYield 49%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a stirred mixture of [3-(5-trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (155.7 g, 0.40 mol) in tetrahydrofuran (800 mL) at −10° C. was added dropwise over a 5 min period 1.0 M tBuOK in tetrahydrofuran (420.0 mL, 0.42 mol). The temperature rose to −3° C. during the addition. The resulting red mixture was stirred between −6° C. and −10° C. for 2.5 h. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (79.7 g, 0.40 mol) in tetrahydrofuran (300 mL) was added dropwise over a 5 min period. The temperature rose to 2° C. The resulting red mixture was stirred at temperatures reaching 21° C. over the next 16 h. TLC showed product with no phosphonate present. The mixture was poured into 3.5 L of stirred ice-water. The resulting suspension was stirred at ambient temperature for 2.5 h and then was extracted with successive 1.0 L and 0.6 L portions of dichloromethane. The combined extracts were washed with 500 mL of brine, dried over magnesium sulfate and concentrated in vacuo to a thick semi solid residue. 250 mL of methyl t-butyl ether was added. The suspension was stirred at −10° C. for 2 h and filtered. Drying in vacuo at 25° C. for 66 h provided 85 g (49%) of product. The filtrate was concentrated in vacuo to a damp solid residue. This was taken up in 100 mL of methyl t-butyl ether. To the stirred suspension was added 300 mL of heptane and the resulting suspension was stirred at −10° C. for 2 h. The solid was filtered off, rinsed with 50 mL of methyl t-butyl ether:heptane (1:3) and pressed dry under suction. Further drying in vacuo at 34° C. for 6 h provided an additional 34.2 g (19.5%) of product. Total yield=119.2 g (68.5%).

Workup

  1. additionThe temperature rose to −3° C. during the addition
  2. customrose to 2° C
  3. stirringThe resulting red mixture was stirred at temperatures
  4. customreaching 21° C. over the next 16 h
  5. stirringThe resulting suspension was stirred at ambient temperature for 2.5 h
  6. extractionwas extracted with successive 1.0 L and 0.6 L portions of dichloromethane
  7. washThe combined extracts were washed with 500 mL of brine
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated in vacuo to a thick semi solid residue
  10. addition250 mL of methyl t-butyl ether was added
  11. stirringThe suspension was stirred at −10° C. for 2 h
  12. filtrationfiltered
  13. customDrying in vacuo at 25° C. for 66 h

Sources & evidence

ORD record
ord-bf62db08eaaf461ab63794ef3ffd1c4b
Source dataset
uspto-grants-2011_10
Patent number
US08044052B2

Reaction notes

Loading…