| 70% |
With caesium carbonate In N,N-dimethyl-formamide at 55℃; for 20h; |
1; 9; 14
A solution of 500 mg (2.75 mmol) 4,5-dimethoxy-3-hydroxybenzaldehyde and 860 μl (1.03 g, 5.50 mmol) 1 ,2-bis(2-chloroethoxy)ethane in 20 ml DMF was treated with 2.24 g (6.88 mmol) caesium carbonate and heated to 550C for 2Oh. After cooling the mixture was poured into 100 ml of ice water and extracted with chloroform. The organic extracts were washed with 50 ml of water twice and with brine, dried over sodium sulfate and evaporated. The resulting yellow oil (3-{2-[2-(2- chloroethoxy)ethoxy]-ethoxy}-4,5-dimethoxybenzaldehyde, 730 mg, 2.20 mmol, 80%) and 414 mg (2.20 mmol) phthalimide potassium salt were dissolved in 25 ml of DMF and stirred at 500C for 68h. After hydrolysis with 50 ml of ice water the mixture was extracted with chloroform, the combined organic phases were washed with water and brine and dried over sodium sulfate. Evaporation of the solvent yielded 932 mg of a yellow oil, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 1/1). The desired product accrued as a white powder (595 mg, 1.34 mmol, 61 %). 1H-NMR (CDCI3) δ = 9.85 (s, 1 H), 7.83 (m, 2H), 7.69 (m, 2H), 7.12 (m, 2H), 4.16 (m, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.89 (m, 2H), 3.83 (m, 2H), 3.75 (m, 2H), 3.67 (m, 4H) ppm. 13C-NMR δ = 190.9, 168.2, 153.8, 152.9, 144.4, 133.9, 132.2, 131.6, 123.2, 109.3, 106.6, 70.8, 70.3, 69.7, 69.0, 68.0, 61.0, 56.4, 37.3 ppm. MS: m/z = 466 [M+Na]+, 443 [M]+. Anal, calcd for C23H25NO8: C 62.30, H 5.68, N 3.16. Found C 61.97, H 5.76, N 3.10.; Example 9: Synthesis of model and precursor compoundsThe synthesis of the butenolide compounds 4,6 and 7 was accomplished via the route outlined in Figure 1. Ketoester 1 was synthesised as described by Patt et.al. by subsequent Aldol condensation, Michael addition and nitrile hydrolysis/esterification. Benzaldehyde 3 was accessible by reaction of 3,4-dimethoxy-5- hydroxybenzaldehyde with 1 ,2-bis(2-chloroethoxy)ethane and caesium carbonate in DMF. We found that the use of caesium- instead of potassium carbonate allows to perform the substitution reactions of these phenolic alcohols with nucleophiles at lower temperatures, thereby improving the yield of the desired ethers. Final addition of potassium phthalimide gives the product in 70% yield.The synthesis of benzaldehyde 5 started with the preparation of the PEG-spacer. This was conducted in accordance to the procedure described by Tahtaoui et.al. for EPO the corresponding PEG3-derivative. Subsequent reaction of triphenylmethanol and methanesulfonyl chloride with tetraethylene glycol yields the trityl protected, activated PEG derivative X, which is further converted to the azide Y by reaction with sodium azide in acetonitrile at reflux. The trityl group is then removed by action of TsOH in methanol, and the free hydroxy function was similarly activated with methanesulfonyl chloride. The coupling of the so modified PEG spacer 2 to 3,4-dimethoxy-5- hydroxybenzaldehyde is done by reaction of the compounds and caesium carbonate in DMF at 800C for 4 h.The final step includes the reaction of the ketoester 1 with the corresponding aldehyde. This is carried out by subsequently adding the ketoester and the aldehyde to a solution of sodium methylate in methanol at 00C and then refluxing the mixture for 12-15h under an inert atmosphere (argon). Finally, the addition of acetic acid and another 5-6h reflux is necessary to obtain the ring-closed butenolide products.Compound 6 is then converted to the free amine by staudinger reaction with triphenylphosphine and water in thf. In this special case we used polymer bound triphenylphosphine (polystyrene, 2% DVB) to remove the resulting oxides more easily. |
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