1-Hydroxybenzotriazole → HCID 25177087, compound

HRID 1811746Notes

Reaction equation

HRID 1811746 reaction equation
C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][NH2:24])[N:13]=[C:12]([NH2:26])[N:11]=2)[C:7]([CH3:27])=[CH:6][C:5]=1[CH3:28].O.[OH-].[Li+].Cl.C(OCC)(=O)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.CO.O1CCCC1>[NH2:26][C:12]1[N:13]=[C:14]2[CH:15]=[C:10]([C:8]3[CH:9]=[C:4]([C:3](=[O:2])[NH:24][CH2:23][CH2:22][CH2:21][C:20](=[O:25])[NH:19][CH2:18][CH2:17][S:16]2)[C:5]([CH3:28])=[CH:6][C:7]=3[CH3:27])[N:11]=1

Participants

10

Reactant 6

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 168937Lithium hydroxide, monohydrateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 21866389Hydrogen chloride-ethyl acetateHCID 59224646HCID 59224646, compound

Product 1

HCID 25177087HCID 25177087, compoundYield 46%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

5-{2-Amino-6-[2-(4-aminobutyrylamino)ethylsulfanyl]pyrimidin-4-yl}-2,4-dimethylbenzoic acid methyl ester (153 mg, 0.37 mmol) obtained in Step 4 above was dissolved by adding tetrahydrofuran (2 ml), methanol (2 ml), and water (1 ml), and then lithium hydroxide monohydrate (160 mg, 3.82 mmol) was added thereto. The resulting mixture was stirred at room temperature for 8 hours. The reaction solution was cooled to 0° C., and 4N hydrochloric acid-ethyl acetate solution (2 ml) was added thereto. The solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (255 ml). (3-Dimethylaminopropyl)ethylcarbodiimide hydrochloride (736 mg, 3.84 mmol), N-hydroxybenzotriazole (519 mg, 3.84 mmol), and diisopropylethylamine (2.67 ml, 15.32 mmol) were added to the solution, and stirred at room temperature for 14 hours. The reaction solution was distilled off under reduced pressure. Water was added to the resulting residue, and extracted three times with ethyl acetate. The organic layers were combined together and washed with water and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. After filtration, anhydrous magnesium sulfate was washed with ethyl acetate. The filtrate and washing solution was combined together, and ethyl acetate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=20:1) to yield 4-amino-18,20-dimethyl-7-thia-3,5,10,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-11,16-dione (Compound 11) (65 mg, 46%).

Workup

  1. temperatureThe reaction solution was cooled to 0° C.
  2. distillationThe solvent was distilled off under reduced pressure
  3. dissolutionThe resulting residue was dissolved in dimethylformamide (255 ml)
  4. stirringstirred at room temperature for 14 hours
  5. distillationThe reaction solution was distilled off under reduced pressure
  6. additionWater was added to the resulting residue
  7. extractionextracted three times with ethyl acetate
  8. washwashed with water
  9. dry with materiala saturated aqueous sodium chloride solution, and then dried over magnesium sulfate
  10. filtrationAfter filtration, anhydrous magnesium sulfate
  11. washwas washed with ethyl acetate
  12. washThe filtrate and washing solution
  13. distillationethyl acetate was distilled off under reduced pressure
  14. customThe resulting residue was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=20:1)

Sources & evidence

ORD record
ord-f64483b962e84dd6a845369089da0cc3
Source dataset
uspto-grants-2013_01
Patent number
US08362236B2

Reaction notes

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