Triethylamine → (2S,3S,5R)-4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol

HRID 2357733Notes

Reaction equation

HRID 2357733 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@:9]2([OH:17])[O:14][CH2:13][C@@H:12]([CH3:15])[NH:11][C@H:10]2[CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[NH2:25][S:26]([C:29]1[C:30]([Cl:47])=[CH:31][C:32]([NH:40][CH2:41][C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[C:33]([CH:39]=1)[C:34]([O:36][CH2:37]Cl)=[O:35])(=[O:28])=[O:27]>C(#N)C>[NH2:25][S:26]([C:29]1[C:30]([Cl:47])=[CH:31][C:32]([NH:40][CH2:41][C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[C:33]([CH:39]=1)[C:34]([O:36][CH2:37][N:11]1[C@H:12]([CH3:15])[CH2:13][O:14][C@:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)([OH:17])[C@@H:10]1[CH3:16])=[O:35])(=[O:27])=[O:28]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 60829ManifaxineHCID 14421522Chloromethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate

Product 1

HCID 58916391(2S,3S,5R)-4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

A solution of free base of (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (20a) (0.023 mole) (U.S. Pat. No. 5,104,870), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate (15) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give (2S,3S,5R)-4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (520). See eg., U.S. Pat. No. 5,104,870) and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).

Workup

  1. temperaturewith cooling on an ice bath
  2. additionAfter the addition
  3. temperaturethe reaction is heated
  4. temperatureto reflux for 2 hours
  5. temperatureThe reaction is cooled
  6. customthe volatiles removed by spin evaporation
  7. customthe residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate
  8. washThe organic layer is washed with water
  9. dry with materialThe organic layer is dried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customto give crude product, which
  13. custommay be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent
  14. customspin evaporated in vacuo
  15. customto give a solid
  16. customthat may be recrystallized

Sources & evidence

ORD record
ord-083c011a7e6a4f798ea5a973cd647900
Source dataset
uspto-grants-2010_07
Patent number
US07763612B2

Reaction notes

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