Triethylamine → 2-(4-Bromo-2,6-difluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide

HRID 1525935Notes

Reaction equation

HRID 1525935 reaction equation
[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9](O)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.Cl.[CH:33]1([N:36]2[CH2:41][C:40]3([CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[O:39][CH2:38][C:37]2=[O:47])[CH2:35][CH2:34]1>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([N:44]2[CH2:45][CH2:46][C:40]3([O:39][CH2:38][C:37](=[O:47])[N:36]([CH:33]4[CH2:34][CH2:35]4)[CH2:41]3)[CH2:42][CH2:43]2)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1

Participants

7

Reactant 5

HCID 8471Triethylamine2×HCID 31297Methanesulfonyl chlorideHCID 85257MethanesulfonateHCID 69083351HCID 69083351, compoundHCID 712710952-(4-Bromo-2,6-difluorophenyl)-2-hydroxyacetamide

Product 1

HCID 712712402-(4-Bromo-2,6-difluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamideYield 16.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of 2-(4-bromo-2,6-difluorophenyl)-2-hydroxyacetamide (4.56 g, 17.1 mmol) and triethylamine (7.17 mL, 51.4 mmol) in anhydrous acetonitrile (25 mL) was added neat methanesulfonyl chloride (1.7 mL, 22.3 mmol). The reaction mixture was stirred vigorously at 40° C. for 3 h, at which point the reaction had proceeded to completion. To the mesylate intermediate was added more triethylamine (7.2 mL, 51.4 mmol) followed by 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (4.23 g, 17.1 mmol). The reaction was heated at 90° C. for 3 h until starting material was consumed. The reaction was diluted with water (25 mL) then the phases were separated and the aqueous phase was extracted with ether (3×25 mL). The combined ether phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (65-100% of 10% methanol in dichloromethane:dichloromethane) provided the title product (1.26 g, 16% yield). MS(ES)+ m/e 458 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.59-0.69 (m, 2 H) 0.75-0.86 (m, 2 H) 1.61-1.74 (m, 2 H) 1.85-1.95 (m, 2 H) 2.21 (s, 1 H) 2.53-2.64 (m, 2 H) 2.66-2.76 (m, 3 H) 2.79 (br. s., 1 H) 3.96 (s, 2 H) 4.68 (s, 1 H) 5.64 (br. s., 1 H) 7.16-7.26 (m, 2 H) 7.35 (br. s., 1 H).

Workup

  1. temperatureThe reaction was heated at 90° C. for 3 h
  2. customwas consumed
  3. additionThe reaction was diluted with water (25 mL)
  4. customthe phases were separated
  5. extractionthe aqueous phase was extracted with ether (3×25 mL)
  6. dry with materialThe combined ether phases were dried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification of the residue by flash chromatography (65-100% of 10% methanol in dichloromethane:dichloromethane)

Sources & evidence

ORD record
ord-0736d810f23f47d7bf9ffe30ab3afde3
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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