N,N'-Dicyclohexylurea → (3,5-Di-tert-butyl-4-hydroxy-phenyl)-(2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]dec-3-yl)-methanone

HRID 574624Notes

Reaction equation

HRID 574624 reaction equation
C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[C:23](O)=[O:24])([CH3:19])([CH3:18])[CH3:17].C(NC1CCCCC1)(NC1CCCCC1)=O.ON1C2C=CC=CC=2N=N1.[CH3:60][CH:61]1[NH:65][CH2:64][C:63]2([CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]2)[S:62]1>ClCCl.O>[C:30]([C:27]1[CH:26]=[C:22]([C:23]([N:65]2[CH2:64][C:63]3([CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]3)[S:62][CH:61]2[CH3:60])=[O:24])[CH:21]=[C:20]([C:16]([CH3:19])([CH3:17])[CH3:18])[C:28]=1[OH:29])([CH3:31])([CH3:33])[CH3:32]

Participants

8

Reactant 5

HCID 4277N,N'-DicyclohexylureaHCID 10868DicyclohexylcarbodiimideHCID 150073,5-Di-tert-butyl-4-hydroxybenzoic acidHCID 757711-HydroxybenzotriazoleHCID 669939622,8-Dimethyl-1-thia-3,8-diazaspiro[4.5]decane

Product 1

HCID 46846802(3,5-Di-tert-butyl-4-hydroxy-phenyl)-(2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]dec-3-yl)-methanone

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

A solution of dicyclohexylcarbodiimide (985 mg, 4.77 mmol) in dry and distilled dichloromethane (10 ml) was added to a stirred solution of 3,5-di-tert-butyl-4-hydroxybenzoic acid (1.14 g, 4.55 mmol) in dichloromethane (15 ml) at room temperature under an argon atmosphere. Dicyclohexylurea began to precipitate as a white solid. 1-Hydroxybenzotriazole (645 mg, 4.77 mmol) was added and the resulting solution was stirred at room temperature for 5 min. 2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (846 mg, 4.55 mmol) in dichloromethane (5 ml) was then added and the resulting mixture was kept at room temperature overnight. The next day mixture was heated at 30° C. (temperature of water bath) for 5 hrs and then kept at room temperature for another 4 days. The resulting suspension was filtered and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 140/10/1) to give two fractions: AF723 (224 mg, 99.16% chemical purity) and a mixture of AF723 with a by-product (943 mg). The mixture of AF723 with by-product was purified by flash chromatography in a COMBI-flash system using linear gradient (silica, CH2Cl2/EtOH/NH4OH 220/10/1 to 140/10/1). After evaporation and drying under vacuum, AF723 (516 mg, 100% chemical purity) was obtained as a white solid. 1H NMR (CDCl3, 500 MHz) δ 7.27 (s, 2H, arom CH), 5.55 (m, 1H, CH—S), 5.44 (s, 1H, OH), 4.10 (m, 1H, CHH—N—CO), 3.40 (m, 1H, CHH—N—CO), 2.60 (m, 2H, CH2—NCH3), 2.28 (m, 1H, CHH—NCH3), 2.25 (s, 3H, NCH3), 2.11 (m, 1H, CHH—NCH3), 1.95-1.66 (m, 4H, two CH2—CS), 1.60 (d, J=6.15 Hz, 3H, CH3—CH), 1.44 (s, 18H, t-butyl) ppm; 13C NMR (CDCl3, 500 MHz) δ 170.78 (C═O), 155.52 (C), 135.93 (two C), 127.39 (C), 124.30 (two CH), 59.56 (C), 58.00 (CH), 56.40 (CH2), 54.23 (CH2), 52.82 (CH2), 45.88 (CH3), 37.68 (CH2), 36.50 (CH2), 34.28 (C), 30.21 (CH3), 23.99 (CH3) ppm; FTIR (HATR) 2943.89, 1619.92, 1388.67 cm−1; GC-MS (EI) 7.31 min m/z: 419 (M+1).

Workup

  1. distillationdistilled dichloromethane (10 ml)
  2. customto precipitate as a white solid
  3. waitthe resulting mixture was kept at room temperature overnight
  4. waitkept at room temperature for another 4 days
  5. filtrationThe resulting suspension was filtered
  6. customthe solvent evaporated under reduced pressure
  7. customThe residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 140/10/1)
  8. customto give two fractions
  9. additionThe mixture of AF723 with by-product
  10. customwas purified by flash chromatography in a COMBI-flash system
  11. customAfter evaporation
  12. customdrying under vacuum
  13. customAF723 (516 mg, 100% chemical purity) was obtained as a white solid
  14. customGC-MS (EI) 7.31 min m/z

Sources & evidence

ORD record
ord-cdc27705f3bb47dca1d78a752643d45d
Source dataset
uspto-grants-2015_05
Patent number
US09034891B2

Reaction notes

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