Tetrahydrofuran → ((R)-3-Hydroxy-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

HRID 1514108Notes

Reaction equation

HRID 1514108 reaction equation
[CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].Cl.[OH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[OH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22]1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 8082PiperidineHCID 2759333(3R)-piperidin-3-ol hydrochlorideHCID 252109975-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid

Product 1

HCID 25211286((R)-3-Hydroxy-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanoneYield 45%

Reagents, catalysts & solvents 1

HCID 8471TriethylamineSolvent

Procedure

Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (R)-(+)-3-hydroxypiperidine hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine (containing and additional 1.1 eq. to neutralize the piperdinyl hydrochloride salt) and piperdine derivative. The reaction mixture was evaporated to an oil and partitioned between EtOAc (5 mL) and water (5 mL). The organic fraction was further washed with brine (2×5 mL), dried over MgSO4, filtered, and evaporated to an oil. The crude product was then chromatographed on silica gel with EtOAc/hexanes (50 then 75 then 100%) as eluant to afford product as a colorless solid (41 mg, 45%). 1H NMR (CDCl3) 1.56-1.62 (m, 1 H), 1.62-1.80 (m, 1 H), 1.83-2.10 (m, 2 H), 2.36 (d, J=1.3, 3 H), 2.86 (br, 1 H), 3.50-3.76 (m, 4 H), 3.82-3.98 (m, 2 H), 7.39 (br d, J=4.0, 1 H), 7.44 (d, J=4.0, 1 H). 13C NMR 7.9, 22.6, 32.5, ˜48 (br), ˜52 (br), 66.2, 114.7, 118.7 (q, J=271), 128.0, 129.6, 131.3, 140.1, 155.2 (q, J=40), 157.9, 163.5. 19F NMR −63.2. LC/MS 5.65 min, [M+1]+ 361.

Workup

  1. additioncontaining
  2. customThe reaction mixture was evaporated to an oil
  3. custompartitioned between EtOAc (5 mL) and water (5 mL)
  4. washThe organic fraction was further washed with brine (2×5 mL)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. customevaporated to an oil
  8. customThe crude product was then chromatographed on silica gel with EtOAc/hexanes (50

Sources & evidence

ORD record
ord-f75736ec015643aaaa109883feed8d13
Source dataset
uspto-grants-2012_07
Patent number
US08222243B2

Reaction notes

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