(Diethylamino)sulfur trifluoride → (2R)-3-(((2-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamido)ethoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl dioleate

HRID 1055181Notes

Reaction equation

HRID 1055181 reaction equation
[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=O.C(N(S(F)(F)F)CC)C.[C:32]([O:51][CH2:52][C@H:53]([CH2:74][O:75][P:76]([O:79][CH2:80][CH2:81][NH2:82])([OH:78])=[O:77])[O:54][C:55](=[O:73])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]/[CH:63]=[CH:64]\[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(OCC)C>[C:32]([O:51][CH2:52][C@@H:53]([O:54][C:55](=[O:73])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]/[CH:63]=[CH:64]\[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:74][O:75][P:76]([O:79][CH2:80][CH2:81][NH:82][C:18](=[O:20])/[CH:17]=[C:16](\[CH3:21])/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:22])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])([OH:78])=[O:77])(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]

Participants

5

Reactant 3

HCID 123472(Diethylamino)sulfur trifluorideHCID 444795Retinoic AcidHCID 95467571,2-Dioleoyl-sn-glycero-3-phosphoethanolamine

Product 1

HCID 89381567(2R)-3-(((2-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamido)ethoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl dioleateYield 28.9%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Procedure

To a solution of retinoic acid (250 mg, 0.83 mmol) in diethyl ether stirring (20 mL) at −78° C., a solution of (diethylamino)sulfur trifluoride (130 μl, 0.90 mmol) in cold ether (20 mL) was added through a syringe. The reaction mixture was taken out of the cold bath and the stirring was continued at room temperature for an additional 2 hr. At the end, the solvent was removed by rotary evaporation. The residue was redissolved chloroform (50 mL) in the presence of solid Na2CO3 (50 mg). To this solution was added 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (600 mg, 0.81 mmol) and the reaction mixture was stirred at room temperature for an additional 24 hrs. The solvent was removed by rotary evaporation. The residue was purified by silica gel chromatography with a dichloromethane/methanol gradient to yield Z)-(2R)-3-(((2-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamido)ethoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl dioleate (240 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 0.87 (t, 6H, CH3), 1.01 (s, 6H, CH3) 1.20-1.40 (m, 40H, CH2), 1.40-1.60 (m, 8H, CH2), 1.70 (s, 3H, CH3—C═C), 1.80-2.10 (m, 8H), 2.32 (m, 4H, CH2C(═O)), 3.50 (m, 2H), 3.92-4.18 (m, 5H), 4.35 (m, 2H), 5.20 (m, 1H, NHC(═O)), 5.31 (m, 4H, CH═CH), 5.80-6.90 (m, 6H, CH═CH).

Workup

  1. customAt the end, the solvent was removed by rotary evaporation
  2. dissolutionThe residue was redissolved chloroform (50 mL) in the presence of solid Na2CO3 (50 mg)
  3. customThe solvent was removed by rotary evaporation
  4. customThe residue was purified by silica gel chromatography with a dichloromethane/methanol gradient

Sources & evidence

ORD record
ord-cef605ea2ef842bf8ff56ed608de08e0
Source dataset
uspto-grants-2016_07
Patent number
US09393315B2

Reaction notes

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