3-乙氧基-N 去甲基安定對映異構體在酸性乙醇中的親核取代和消旋作用   全文下載

Nucleophilic Substitution and Racemization of 3-Ethoxy- N-desmethyldiazepam Enantiomers in Acidic Ethanol

3-乙氧基N 去甲基安定（3-EtO-NDZ; diazepam = 安定）在含不同硫酸濃度的乙醇和乙?中的pKa1值用光譜法和旋光光譜法作了測定，其結果分別為3.4和0.63。3-EtO-NDZ 之對映異構體在含各種不同酸濃度的乙醇中與溫度相關的消旋過程，用旋光光譜儀選擇其圖二色譜在365 nm波長處強度的改變為時間函數的方法作了測定。發現其消旋反應屬於顯見一級動力學過程。消旋反應之熱力學參數分別為： Eact = 16.7 kcal／mol，及在25°C時ΔH++ = 16.1kcal／mol, ΔS++ = -22.0 cal／K／mol 和ΔG++ = 22.6 kcal／ mol。該消旋反應有一同位素效應（kH／kD），在42°C時為1.9。基於本文所報導的結果及文獻所記述之對映異構性在C3位有取代基時的1,4-苯并二氮?類的傾向構象，設想提出所觀察之現象是由正（P）或負（M）構象所致的一個親核性經溶劑化的C3陽碳離子為中間體。該中間體導致了3-EtO-NDZ對映異構體在酸性乙醇中所發生的立體選擇性親核取代反應及隨後的消旋過程。"

pKal values of 3-ethoxy-N-desmethyldiazepam (3-EtO-NDZ) in ethanol and acetonitrile containing various concentrations of sulfuric acid , determined by spectrophotometry and spectropolarimetry, were found to be 3.4 and 0.63 respectively. Temperature dependent racemization of enantiomeric 3-EtO-NDZ in ethanol containing various acid concentrations was studied by monitoring changes of ellipticity at 365 nm as a function of time on a spectropolarimeter. The racemization reactions were found to follow apparent first order kinetics. Thermodynamic parameters of the racemization reaction were: Eact = 16.7 kcal/mol, and at 25°C: ΔH++ = 16.1 kcal/moi, ΔS++ =-22.0 cai/K/mol , and ΔG++ =22.6 kcal/mol, respectively. The racemization had an isotope effect (kH/kD) of 1.9 at 42°C. Based on the results of this report and the results of literature reports on the preferred conformation of enantiomeric 3-substituted-1,4-benzodiazepines, a nucleophilically solvated C3 carbonium ion intermediate resulting from either a P (plus) or a M (minus) conformation is proposed to be an intermediate. This intermediate is responsible for the stereoselective nucleophilic substitution and the subsequent racemization of 3-EtO-NDZ enantiomers in acidic ethanol.