Prodrugs of vitamine K
A halogen and alkyl technology, used in the synthesis of these prodrugs, can solve the problem of vitamin K2 being unstable to oxygen and light
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Embodiment 1
[0143]
[0144] 2-((2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctadecane-2,6,10,14,18,22 ,26-hepten-1-yl)-3-methylnaphthalene-1,4-dione (2-((2E,6E,10E,14E,18E,22E)-3,7,11,15,19 ,23,27-Heptamethylloctacosa-2,6,10,14,18,22,26-heptaen-1-yl)-3-methylnaphthalene-1,4-dione) (1.00g, 1.34mmol), benzoic anhydride ( 6.00 g, 26.52 mmol), NaOAc (0.134 g, 1.64 mmol) and Zn powder (0.31 g, 4.74 mmol) were added together and heated to 140°C. After 1 h at 140 °C, the reaction mixture was cooled to room temperature (r.t.) and diluted with THF (40 mL). Join Et 2 NH (20 mL) and the reaction mixture was stirred for another hour, then heptane (50 mL) was added. The obtained mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (heptane:EtOAc gradient) to give 0.58 (50%) of 2-((2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23, 27-Heptamethyl-octadecane-2,6,10,14,18,22,26-hepten-1-yl)-3-methylnaphthalene-1,4-diyl dibe...
Embodiment 2
[0149]
[0150] LiOH.H 2 O (1.84g, 443.8mmol) was added to 2-((2E,6E,10E,14E,18E,22E)-3,7,11,15,19 in a mixture of THF (75mL) and water (20mL) ,23,27-Heptamethyloctadecane-2,6,10,14,18,22,26-hepten-1-yl)-3-methylnaphthalene-1,4-diylbenzidine Ester (2-((2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethylloctacosa-2,6,10,14,18,22,26- heptaen-1-yl)-3-methylnaphthalene-1,4-diyl dibenzoate) solution. The resulting solution was degassed in an ultrasonic bath for 5 min and stirred at 50° C. for 20 h, then 3M HCl (solution) was added until pH 2. The resulting mixture was extracted with EtOAc (2 x 250 mL). The organic layers were combined and dried (Na 2 SO 4 ), filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (heptane:EtOAc gradient) to afford 2.30 g (50%) of 2-((2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23 ,27-Heptamethyloctadecane-2,6,10,14,18,22,26-hepten-1-yl)-4-hydroxy-3-methylnaphthalen-1-ylbenzoate (A) a...
Embodiment 3
[0159]
[0160] 2-((2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctadecane-2,6,10,14,18,22 ,26-Hepten-1-yl)-4-hydroxy-3-methylnaphthalen-1-ylbenzoate (2-((2E,6E,10E,14E,18E,22E)-3,7, 11,15,19,23,27-Heptamethylloctacosa-2,6,10,14,18,22,26-heptaen-1-yl)-4-hydroxy-3-methylnaphthalen-1-yl benzoate) (0.21g, 0.28mmol) dissolved in CH 2 Cl 2 (10 mL) and cooled to 0 °C. To this solution was added diethyl chlorophosphate (60 μL, 0.42 mmol) and Et 3 N (59 μL, 0.42 mmol). The reaction mixture was stirred at room temperature for 20 h, then the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (heptane:EtOAc gradient) to afford 70 mg (29%) of 4-((diethoxyphosphoryl)oxy)-2-((2E,6E,10E,14E,18E, 22E)-3,7,11,15,19,23,27-heptamethyloctadecane-2,6,10,14,18,22,26-hepten-1-yl)-3-meth Naphthalene-1-ylbenzoate, a colorless oil.
[0161] 1 H NMR (400MHz, CDCl 3 )δ8.31(d, J=8.0, 2H), 8.21(d, J=8.5, 1H), 7.70–7.64(m, 2H), 7.55(t, J=...
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