Hydrochloric Acid → 6-chloro-1-(cyclobutylmethyl)-3-methylpyrimidine-2,4(1H,3H)-dione

HRID 896041

Reaktionsgleichung

Reaktionsgleichung von HRID 896041
ClCC1N[C:7](=O)[NH:6][C:5](=[O:10])C=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1P(C1C=CC=CC=1)C1C=CC=CC=1.[CH:30]1([CH2:34][OH:35])CC[CH2:31]1.[ClH:36]>C1COCC1.O1CCOCC1.O1CCOCC1>[Cl:36][C:31]1[N:11]([CH2:16][CH:15]2[CH2:12][CH2:13][CH2:14]2)[C:5](=[O:10])[N:6]([CH3:7])[C:34](=[O:35])[CH:30]=1

Komponenten

7

Edukt 4

HCID 313Hydrochloric AcidHCID 732736-(Chloromethyl)-2,4(1H,3H)-pyrimidinedioneHCID 78130CyclobutylcarbinolHCID 6218932-Pyridyldiphenylphosphine

Produkt 1

HCID 223496026-chloro-1-(cyclobutylmethyl)-3-methylpyrimidine-2,4(1H,3H)-dione

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 312751,4-DioxaneLösungsmittelHCID 22018518Dioxane tetrahydrofuranLösungsmittel

Versuchsvorschrift

To a cooled (0° C.) slurry of 6-chloromethyluracil (2.0 g, 12 mmol) in THF/dioxan (1:1, 16 ml) is added 2-pyridyldiphenylphosphine (3.60 g, 13.7 mmol) and cyclobutanemethanol (1.3 ml, 13.8 mmol), followed by di-t-butylazodicarboxylate (3.15 g, 13.7 mmol). The reaction is stirred overnight at ambient temperature, treated with 4M HCl in dioxan (15 ml) and evaporated. The residue is taken up in dichloromethane, washed with 3.5M HCl, dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography (100:1 dichloromethane-methanol elution) to afford 6-chloro-1cyclobutylmethyl-3-methyl-1H-pyrimidine-2,4-dione, 1H NMR (400 MHz, CDCl3) δ1.70-2.0 (m 6H), 2.60 (m 1H), 3.20 (s 3H), 4.00 (d J 7 2H), 5.78 (s 1H), which is dissolved in n-butanol (50 ml). Veratrylamine (4 ml, 26.5 mmol) is added and the reaction heated to reflux for 16 hours. The solvent is evaporated and the residue taken into dichloromethane, washed with 1M aqueous HCl, dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography (50:1 dichloromethane-methanol elution) to afford 1-cyclobutylmethyl-6-(3,4-dimethoxy-benzylamino)-3-methyl-1H-pyrimidine-2,4-dione, 1H NMR (400 MHz, CDCl3) d 1.60-1.80 (m 4H), 1.80-2.00 (m 2H), 2.50 (m 1H), 3.21 (s 3H), 3.80 (s 6H), 3.85 (d J 7 2H), 4.11 (d J 5 1H), 4.25 (m 1H), 4.84 (s 1H), 6.74 (s 1H), 6.80 (s 2H), which is dissolved in formic acid (50 ml) and Pd black (0.26 g) added. The reaction is heated at 40° C. for 21 hours, filtered through Celite, evaporated and purified by preparative HPLC to afford 6-amino-1-cyclobutylmethyl-3-methyl-1H-pyrimidine-2,4-dione, M+209, which is converted using the general procedure for Intermediate 1 into 5,6-diamino-1-cyclobutylmethyl-3-methyl-1H-pyrimidine-2,4-dione, HPLC retention time 0.17 mins (30-95% acetonitrile water gradient in 4 minutes).

Aufarbeitung

  1. customevaporated
  2. washwashed with 3.5M HCl
  3. dry with materialdried over magnesium sulfate
  4. customevaporated
  5. customThe crude product is purified by flash chromatography (100:1 dichloromethane-methanol elution)

Quellen und Nachweise

ORD-Eintrag
ord-52cafbb6056846f4afea87175547cfc9
Quelldatensatz
uspto-grants-2005_07
Patentnummer
US06919337B2

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