【作者】 何洪华；

【导师】 韦萍； 龚大春；

【作者基本信息】 南京工业大学 ， 生物化工， 2005， 硕士

【摘要】 手性氨基醇是一类由α-氨基酸经过手性源还原得到的具有光学活性的氨基醇。目前,手性氨基醇已广泛用于医药、精细化工、材料和不对称催化的有机合成中。在医药领域主要应用在多肽类药物和喹诺酮类手性药物中,在不对称催化领域手性氨基醇以其来源广泛,结构多样化而备受关注,主要用作金属手性配体和手性助剂的手性源。因此,研究手性氨基醇的制备对建立低成本、规模制备手性氨基醇,具有很强的实际应用价值。本文对手性氨基醇的应用和制备进展进行了较全面的论述。根据氨基酸水溶性差异,采用NaBH₄ 体系和催化加氢的方法,系统研究了脂溶性和水溶性氨基酸衍生的手性氨基醇的制备方法;对NaBH4 的各种还原体系在手性氨基醇制备中的应用进行了工艺优化和成本分析。首次建立了以Fmoc 保护氨基酸为原料,利用NaBH₄/N-甲基吗啉/氯甲酸异丁酯体系合成Fmoc-苏氨醇、Fmoc-亮氨醇等系列手性氨基醇的新路线。首先,深入研究了NaBH₄-LiCl、NaBH₄-CH₃OH、NaBH₄-H₂SO₄和NaBH₄-I₂等4 个还原体系在脂溶性氨基酸衍生的手性氨基醇制备中的应用。利用这4 个体系分别制备了L-苯丙氨醇、L-苯甘氨醇、L-亮氨醇、L-异亮氨醇、L-缬氨醇和L-脯氨醇等6 个氨基醇。在每个体系中,对影响氨基醇收率的主要反应条件,如还原剂用量、反应时间和温度等方面采用单因素分析法进行优化。收率比相关文献普遍高出10-30%。在各体系最佳反应条件下,得到6 个氨基醇的收率有所不同。NaBH₄-LiCl 体系:L-苯丙氨醇81.5%、L-苯甘氨醇90.2%、L-亮氨醇84.9%、L-异亮氨醇85.6%、L-缬氨醇81.1%、L-脯氨醇41.5%;NaBH₄-CH₃OH 体系:L-苯丙氨醇84.3%、L-苯甘氨醇85.6%、L-亮氨醇92.7%、L-异亮氨醇88.1%、L-缬氨醇86.8%、L-脯氨醇50.2%;NaBH₄-H₂SO₄体系:L-苯丙氨醇87.9%、L-苯甘氨醇82.6%、L-亮氨醇78.4%、L-异亮氨醇80.2%、L-缬氨醇84.5%、L-脯氨醇31.6%;NaBH₄-I2 体系:L-苯丙氨醇97.5%、L-苯甘氨醇91.1%、L-亮氨醇98.9%、L-异亮氨醇98.9%、L-缬氨醇90.8%、L-脯氨醇88.4%。对每个体系下6 种氨基醇的生产成本进行了原料成本核算。从成本因素考虑,L-苯甘氨醇用NaBH₄-LiCl体系制备最好,L-苯丙氨醇、L-亮氨醇、L-异亮氨醇和L-缬氨醇用NaBH₄-H₂SO₄体系为宜,L-脯氨醇用NaBH₄-I₂体系制备最佳。更多还原

【Abstract】 Chiral amino alcohols are a class of optically active amino alcohols obtained by the reduction of α-amino acids as starting materials. At present, the application of chiral amino alcohols has been attracted due to their importance in asymmetric synthesis, pharmaceutical, fine chemicals, materials, etc. In the field of pharmacy, chiral amino alcohols have been applied in peptides and quinolone pharmaceuticals. In the filed of asymmetric catalysis, much attention has been attracted to chiral amino alcohols due to its extensive sources and diversified structures. Accordingly, study on the high efficiency, low cost and larger scale preparation of chiral amino alcohols has important practical value . The comprehensive review about the application and preparation of chiral amino alcohols was reported. Bases on dissolvability of amino acids, the preparation method of amino alcohols of lipophilicity and hydrophilicity was systemically studied using NaBH₄ system and catalytic hydrogenation. The process was optimized and the cost of each amino alcohol was estimated according to each NaBH₄ system. The new synthetic route of chiral amino alcohols, such as Fmoc-threoninol and Fmoc-leucinol, utilizing NaBH₄-NMM-iBuOCOCl using Fmoc protecting amino acid as starting materials was developed. Firstly, chiral amino alcohols was prepared by the reduction of four reductive methods, such as NaBH₄-LiCl, NaBH₄-CH₃OH, NaBH₄-H₂SO₄, NaBH₄-I₂ from lipophilic amino acids as starting matericals,. Six amino alcohols, such as L-phenylalaninol, L-phenylglycinol, L-leucinol, L-isoleucinol, L-valinol, L-prolinol were synthesized. Using single factor analysis, the chief conditions, such as reaction time and temperature were optimized. Six amino alcohols L-phenylalaninol （yield 81.5%）, L-phenylglycinol （yield 90.2%）, L-leucinol （yield 84.9%）, L-isoleuciol （yield 85.6%）, L-valinol （yield 81.1%） and L-prolinol （yield 41.5%） were prepared using NaBH₄-LiCl reduction system. The yields of six amino alcohols using other reduction system were obtained. The cost of six amino alcohols was estimated according to each system. In the matter of cost, the best reduction method of L-phenylglycinol was NaBH4-LiCl system, the best reduction method of L-prolinol was NaBH4-I2 system and other amino alcohols were obtained by NaBH4-H2SO4 system. Secondly, reduction process of hydrophilicity amino acids was studied. The aqueous-phase hydrogenation of L-alanine to L-alaninol was studied in the presence of 5% Ru/C catalyst. This facile hydrogenation constituted a new “green”route for producing chiral amino alcohols. Direct aqueous-phase catalytic hydrogenation of free amino acids offered an alternative that is atom-economical and amenable to continuous processing, obviates the need for intermediate esterification and use of organic solvents, and avoids byproduct waste streams. The L43 optium conditions were obtained .Under the conditions of the molar ratio of phosphorus acid and alanine 0.5:1, 120℃,8MPa for 12h with the 97.5% converting yield of L-alanine and 98.1% e.e. Under the same conditions, the converting yield of L-threoninol was 90% and the optical yield was 97%. All hydrophilic amino alcohols could be prepared utilizing this method. Finally, N-protected amino alcohols Fmoc-Threoninol （yield 86.3%）, Fmoc-Leucinol （yield 96.1%）, Fmoc-Alaninol （yield 90.6%）, Fmoc-Valinol （yield 95.4%）, Boc-Alaninol （yield 75.3%）, Fmoc-Serinol（tBu） （yield 94.3%） and Boc-Phenylalaninol （yield 96.4%） were prepared using NaBH4-NMM-iBuOCOCl reduction system and Boc-hydroxyprolinol （yield 90.1%） was synthesized using NaBH4-LiCl reduction system.更多还原