3-Chloropropanesulphonyl chloride → 2-{[4-(4-[(1-isopropylpiperidin-4-yl)oxy]phenyl)tetrahydro-2H-pyran-4-yl]methyl}isothiazolidine 1,1-dioxide

HRID 272960Notes

Reaction equation

HRID 272960 reaction equation
[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)C(C)C)(C)C.CC(C)([O-])C.[K+]>ClCCl.O1CCCC1>[NH3:4].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][N:24]4[CH2:26][CH2:27][CH2:28][S:29]4(=[O:31])=[O:30])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 154103-Chloropropanesulphonyl chlorideHCID 81531DiisopropylethylamineHCID 23665647Potassium tert-butoxideHCID 68576458(4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine

Product 2

HCID 222AmmoniaHCID 598374072-{[4-(4-[(1-isopropylpiperidin-4-yl)oxy]phenyl)tetrahydro-2H-pyran-4-yl]methyl}isothiazolidine 1,1-dioxideYield 29%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

A solution of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine (100 mg, 0.30 mmol), 3-chloropropanesulphonyl chloride (51 μl, 0.40 mmol) and N,N-diisopropylethylamine (521 μl, 0.30 mmol) in dichloromethane (2 ml) was stirred at room temperature for 18 hrs. The reaction mixture was concentrated in vacuo and then partitioned between dichloromethane (10 ml) and sodium bicarbonate solution (10 ml). The aqueous layer was extracted with a further 10 ml dichloromethane and the combined organics dried over sodium sulphate and concentrated in vacuo to give an oil. This was dissolved in tetrahydrofuran (2 ml). Potassium tert-butoxide (65 mg, 0.60 mmol) was added to the solution and the reaction mixture stirred at 40° C. for 18 hrs. This was then concentrated in vacuo and partitioned between diethyl ether (10 ml) and water (10 ml). The aqueous layer was extracted with a further 10 ml diethyl ether and the combined organics dried over sodium sulphate and concentrated in vacuo to give a pale yellow oil. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 96:4:0.4 to give the title compound as a pale yellow oil (19 mg, 15%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.90 (d, 2H), 4.26 (m, 2H), 3.80 (m, 2H), 3.58 (m, 2H), 3.15 (s, 2H), 2.99 (t, 2H), 2.80 (m, 2H), 2.75 (m, 2H), 2.40 (t, 2H), 2.38 (m, 2H), 2.16 (m, 2H), 2.02 (m, 4H), 1.90 (m, 2H) 1.81 (m, 2H), 1.03 (d, 6H); HRMS (ESI+) 437.2457 (M+H)+.

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. custompartitioned between dichloromethane (10 ml) and sodium bicarbonate solution (10 ml)
  3. extractionThe aqueous layer was extracted with a further 10 ml dichloromethane
  4. dry with materialthe combined organics dried over sodium sulphate
  5. concentrationconcentrated in vacuo
  6. customto give an oil
  7. concentrationThis was then concentrated in vacuo
  8. custompartitioned between diethyl ether (10 ml) and water (10 ml)
  9. extractionThe aqueous layer was extracted with a further 10 ml diethyl ether
  10. dry with materialthe combined organics dried over sodium sulphate
  11. concentrationconcentrated in vacuo
  12. customto give a pale yellow oil
  13. customThe compound was purified by column chromatography on Biotage® silica gel
  14. washeluting with dichloromethane

Sources & evidence

ORD record
ord-3bfbb32fbcba4203bc7c061aa556851a
Source dataset
uspto-grants-2008_11
Patent number
US07456164B2

Reaction notes

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