Sodium Iodide → 4-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-8-(3-morpholin-4-yl-propyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one, dihydrochloride

HRID 12368Notes

Reaction equation

HRID 12368 reaction equation
C(OC([N:8]1[CH2:38][CH2:37][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=3)[CH:12]2[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.[Cl:45][CH2:46][CH2:47][CH2:48]I.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C.CN(C=O)C>[ClH:45].[ClH:45].[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][CH:12]2[C:11]3([CH2:37][CH2:38][N:8]([CH2:46][CH2:47][CH2:48][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH2:9][CH2:10]3)[O:15][C:14](=[O:16])[N:13]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH3:27])[CH3:28])=[CH:20][CH:19]=2)=[CH:35][CH:34]=1

Participants

8

Reactant 5

HCID 5238Sodium IodideHCID 8083MorpholineHCID 11430Potassium CarbonateHCID 813631-Chloro-3-iodopropaneHCID 574260414-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester

Product 1

HCID 1317250184-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-8-(3-morpholin-4-yl-propyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one, dihydrochlorideYield 59.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
50 °C

Procedure

69NLS77 (300 mg, 0.57 mmol) was N-BOC deprotected as described in the preparation of 69NLS79-II and dissolved in acetonitrile (3 mL) and DMF (1 mL). To a solution of morpholine (65 μL, 0.74 mmol) in acetonitrile (3 mL) and DMF (1 mL) was added dropwise 1-chloro-3-iodopropane (73 μL, 0.68 mmol) and potassium carbonate (300 mg, 2.17 mmol). The mixture was heated at 50° C. for 3 h before the addition of the solution containing the deprotected spiropiperidine followed by sodium iodide (102 mg, 0.68 mmol). The mixture was stirred overnight at 50° C. and worked up as described for 69NLS79-II. Purification of the residue by silica gel column chromatography, eluting with a stepwise gradient of 0-6% methanol in dichloromethane, afforded the desired compound (127 mg, 40%) as a colorless oil. Treatment of the product in dichloromethane with 2 M HCl in diethylether as described for 69NLS75 gave the corresponding dihydrochloride salt as a colorless solid.

Workup

  1. customas described in the preparation of 69NLS79-II and
  2. customPurification of the residue by silica gel column chromatography
  3. washeluting with a stepwise gradient of 0-6% methanol in dichloromethane

Sources & evidence

ORD record
ord-5a2c7e9848a74cea8703403998e12834
Source dataset
uspto-grants-2010_06
Patent number
US07727999B2

Reaction notes

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