本研究為探討21-Bromo-3α-hydroxy-3β-methoxymethyl-5α- pregnan-20-one(7)的親核性取代反應機構。在反應過程利用TLC與HPLC偵測分析，顯示出取代反應過程中有一特殊的中間物存在並順利鑑別出其反應機構。當進行21-Bromo-3α-hydroxy-3β-methoxy-methyl-5α-pregnan-20-one與Lithium imidazole的取代反應時，起始物反應完成後，親核性試劑包括n-Butyllithium, Methyllithium, Lithium piperidine 和 Lithium pyrrolidine再加入反應溶液中，與Lithium imidazole進行競爭反應。從單離的產物分析中發現，共有二種產物：α-Imidazolylcarbonyl 化合物和強親核性的加合物存在。因此提出兩種可能進行的反應路徑來探討：第一種路徑為直接進行SN2的取代反應，由親核性試劑的Imidazolyl陰離子攻擊α-碳原子位置直接取代溴原子；另一路徑則為Imidazole 陰離子攻擊Carbonyl的位置，形成環氧化物的中間產物，接著再由多餘的Imidazole陰離子或額外添加的強親核性試劑攻擊環氧化物之立體阻礙小的位置而得到相對取代的產物。

A study regarding the nucleophilic substitution of reacting 21-Bromo-3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one (compound 7) with lithium imidazole was described.
TLC and HPLC were employed to monitor the reaction profile and an intermediate was observed in this reaction. The HPLC analysis of the reaction profile found that the reaction yield of this intermediate increased eith the decrease of reaction temperature. The identification of this intermediate was proposed based on the experiment that after the reaction of compound 7 went into completion, other nuceophiles, such as n-butyllithium, methyllithium, lithiumpiperidine, and lithium pyrrolidine were add respectively to the reaction mixture, a major product compound 8 and another nucleophile respectively replaced compound were obtained. This results together with the literature explanation proposed by Pearson and Weinstein in similar reaction leaded to this conclusion that the reaction of compound 7 with nucleophile lithium imidazole proceeded in two ways.
The major reaction route is the nucleophilic replacement of bromide with imidazole anion to give compound 7 as the major product；another temperature dependent minor route is going through nucleophilic addition of imidazole anion to the carbonyl carbon followed by ring cyclization to give a three membered oxided as the intermediate. This intermediate was ustable as to be hydrolyzed to give a α-hydroxyl- ketone adduct (compound 20) during the product worked out procedure or react respectively with the nucleophiles added before the product been worked out to give compound 21-24.

1.Hogenkamp DJ, Tahir SH, Hawison JE, Upasani RB, Alauddin M, Kimbrough CL, Acosta-Burruel M, Whittemore ER, Woodward RM, Lan NC, Gee KW, Bolger MB. Synthesis and in vitro activity of 3β-substituted-3α-hydroxypregnan-20-ones:allosteric modulators of the GABA-A receptor. J. Med. Chem. 1997;40,61–72.
2.The manufactured process and pharmacological activity of 3α-hydroxy-21-(1'-imidazolyl)-3β-methoxymethyl-5α-pregnan-20-one (7) are preparing for patent and submission.
3.Moshe Gavish, Idit Bachman, Rami Shoukrun, Yeshayahu Katz, Leo Veenman, Gary Weisinger, and Abraham Weizman. Enigma of the peripheral benzodiazepine receptor. Pharmacological Review. 1999;51,629–650
4.Olsen, R. W. and Avoli, M. GABA and epileptogenesis. Epilepsia 1997;38,399-407
5.Ong J, Kerr DI. Recent advances in GABAB receptors : from pharmacology to molecular biology. Acta Pharmacologica Sinica 2000;21,111–123.
6.(a) Tanitame A, Oyamada Y, Ofuji K, Fujimoto M, Suzuki K, Ueda T, Terauchi H, Kawasaki M, Nagai K, Wachi M, Yamagishi J-i. Synthesis and antibacterial activity of novel and potent DNA gyrase inhibitors with azole ring. Bioorg. Med. Chem. 2004;12,5515–5524. (b) Clausen CA, Yang VM. Azole-based antimycotic agents inhibit mold on unseasoned pine. Int. Biodeter. Biodeg. 2005;55,99–102. (c) Hackett JC, Kim Y-W, Su B, Brueggemeier RW. Synthesis and charaterization of azole isoflavone inhibitors of aromatase. Bioorg. Med. Chem. 2005;13,4063–4070.
7.Njar CO Vincent. High-yield synthesis of novel imidazoles and triazoles from alcohols and phenols. Synthesis 2000;14,2019– 2028.
8.Thompson SK, Murthy KHM, Zhao B, Winborne E, Green DW, Fisher SM, DesJarlais RL, Jr. Tomaszek TA, Meek TD, Gleason JG, Abdel-Meguid SS. Rational design, synthesis, and crystallographic analysis of a hydroxyethylene-based HIV-1 protease inhibitor containing a heterocyclic P1’–P2’ amide bond isostere. J. Med. Chem. 1994;37,3100–3107.
9.Boyle FT, Costello GF. Cancer therapy : a move to the molecular level. Chem. Soc. Rev. 1998;27,251–262.
10.Njar CO Vincent, Brodie MH Angela. Comprehensive pharmacology and clinical efficacy of aromatase inhibitors. Drugs 1999;58,233–257.
11.Kamijo T, Yamamoto R, Harada H, Iizuka K. An improved and convenient procedure for the synthesis of 1-substituted imidazoles. Chem. Pharm. Bull. 1983;31,1213–1221.
12.(a)March J. In Advanced Organic Chemistry, Reaction, Mechanisms and Structure. Wiley/Interscience, New York, 1985. (b)Edenborough M. In Organic Reaction Mechanism. A Step by Step Approach. Taylopr and Francis, London, 1999.
13.Carroll FA. In Perspectives on Structure and Mechanism in Organic Chemistry. Brooks/Cole, Pacific Grove, 1998.
14.Hughes ED. Mechanism and kinetics of substitution at a saturated carbon atom. Trans Faraday Soc 1941;37, 603–630.
15.Evans DP, Baker, JW. Mechanism and kinetics of substitution at a saturated carbon atom：General discussion. Trans Faraday Soc 1941;37,645–648.
16.Pearson RG, Langer SH, Williams FV, McGuire WJ. Mechanism of the reaction of α-haloketones with weakly basic nucleophilic reagents. J Am Chem Soc 1952;74, 5130–5132.
17.Winstein S, Grunwald E, Jones HW. The correlation of solvolysis rates and the classification of solvolysis reaction into mechanistic categories. J Am Chem Soc 1951;73,2700–2707.
18.Stevens CL, Maik W, Patt R. Isolation of epoxyether from the reaction of an α-haloketone with base. J Am Chem Soc 1950;72,4758–4760.
19.Dewar MJS. In The Electronic Theory of Organic Chemistry. Clarendon Press, Oxford. 1949.