Hexane → Spiro[piperidine-4,7′-[7H]thieno[2,3-c]pyran]-1-carboxylic acid, 2′-fluoro-4′,5′-dihydro-, 1,1-dimethylethyl ester

HRID 1517556Notes

Reaction equation

HRID 1517556 reaction equation
CC1(C)CCCC(C)(C)N1.C([Li])CCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Li].[N:33]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:38][CH2:37][C:36]2([C:43]3[S:44][CH:45]=[CH:46][C:42]=3[CH2:41][CH2:40][O:39]2)[CH2:35][CH2:34]1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:64])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1.O>[F:64][C:45]1[S:44][C:43]2[C:36]3([O:39][CH2:40][CH2:41][C:42]=2[CH:46]=1)[CH2:35][CH2:34][N:33]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:38][CH2:37]3

Participants

10

Reactant 7

HCID 8058HexaneHCID 130352,2,6,6-TetramethylpiperidineHCID 25517Ammonium ChlorideHCID 588007N-FluorobenzenesulfonimideHCID 52951550HCID 52951550, compoundHCID 5741988838227-87-1HCID 178418339Butyllithium

Product 1

HCID 52951551Spiro[piperidine-4,7′-[7H]thieno[2,3-c]pyran]-1-carboxylic acid, 2′-fluoro-4′,5′-dihydro-, 1,1-dimethylethyl esterYield 50%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

2,2,6,6-Tetramethylpiperidine (18.7 mL, 110.5 mmol) is added over tetrahydrofuran (200 mL), and solution is cooled under nitrogen at −78° C. 2.5 M solution of butyl lithium in hexane (37.2 mL, 93 mmol) is added and mixture is stirred for 30 min at −78° C. Over the fresh lithium 2,2,6,6-tetramethylpiperidine solution is added a solution of tert-butyl spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate (20 g, 58.2 mmol) in tetrahydrofuran (90 mL) keeping temperature below −70° C. After 20 min. a solution of N-fluorobenzenesulfonimide (30.26 g, 93.07 mmol) in tetrahydrofuran (200 mL) previously cooled under nitrogen at −20° C. is added via cannula. After 1 hr. stirring, water (20 mL) and aqueous solution of ammonium chloride (50 mL) are added. Then, organic layer is separated and the aqueous is washed twice with methyl t-butyl ether (2×25 mL). Organics are combined and solvent is evaporated under reduced pressure. Crude material is purified by normal phase HPLC using hexane/methyl t-butyl ether as solvents to give tert-butyl 2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate in 50% yield. MS (m/z): 328 (M+1).

Workup

  1. customtemperature below −70° C
  2. additionis added via cannula
  3. waitAfter 1 hr
  4. stirringstirring
  5. customThen, organic layer is separated
  6. washthe aqueous is washed twice with methyl t-butyl ether (2×25 mL)
  7. customsolvent is evaporated under reduced pressure
  8. customCrude material is purified by normal phase

Sources & evidence

ORD record
ord-c44c99884bb340a0b9018788e9040858
Source dataset
uspto-grants-2012_07
Patent number
US08232289B2

Reaction notes

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