CN110628841B - 酶催化不对称合成右美沙芬关键中间体的新方法 - Google Patents
酶催化不对称合成右美沙芬关键中间体的新方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
- C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
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- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明公开了来源于Amycolatopsis thermoflava的亚胺还原酶AtIR(WP_027931121.1)或Streptomyces thermolilacinus的亚胺还原酶StIR(WP_023587323.1)或Prauserella marina的亚胺还原酶PmIR(WP_091804541.1)或Sciscionella marina的亚胺还原酶SmIR(WP_020496004.1)或Amycolatopsis alba的亚胺还原酶AaIR(WP_020635634.1)或Streptoalloteichus hindustanus的亚胺还原酶ShIR(SHE96216.1)，并利用该亚胺还原酶作为生物催化剂制备中枢性镇咳药右美沙芬的关键中间体(S)‑1‑(4‑甲氧基苄基)‑1,2,3,4,5,6,7,8‑八氢异喹啉。以相应亚胺还原酶可催化5‑50g/L的底物，转化率大于99％，本方法具有收率高、立体选择性好、反应条件温和等显著特点。
Description
技术领域
本发明涉及一种镇咳药关键中间体制备的新方法，属于生物化工领域。具体涉及酶催化不对称还原制备氢溴酸右美沙芬关键中间体(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉的新方法。
背景技术
氢溴酸右美沙芬又叫氢溴酸右甲吗喃，化学名为(+)-3-甲氧基-17-甲基-(9α,13α,14α)-吗啡喃氢溴酸一水合物，适用于感冒、急性或慢性支气管炎、支气管哮喘、咽喉炎、肺结核以及其它上呼吸道感染引起的干咳。
氢溴酸右美沙芬的合成方法很多，如中国专利CN201310041846、CN201310051880，CN201210405684、CN201310004262、CN201410169133以及文献[今日药学，2008,18(4)，63-64]、[Helv.Chim.Acta 1956,39,1376-1386]，大部分制备方法均需要使用中间体(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)。传统制备该中间体的方法是通过对消旋的1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉(2)进行手性拆分获得的，如中国专利CN201210073513、美国专利US8148527及文献[Helv.Chim.Acta 1956,39,1376-1386]；这些方法操作繁琐、产物收率较低，并产生大量的废水。使用金属不对称催化还原1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉(1)制备(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)的方法也有报道，如中国专利CN201410169133及文献[Tetrahedron:Asymmetry 1998,9,4043–4054]，这类方法中存在金属催化剂的微量残留问题。中国专利CN201510875024.6采用环己胺氧化酶及其突变体结合非选择性还原剂，实现了1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉(2)的动态动力学拆分。
我们发现目前存在的工艺中，尚没有利用酶催化不对称还原制备(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)的方法。
发明内容
本发明拟采用亚胺还原酶实现1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉(1)的不对称还原制备(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)，该过程具有工艺路线简单、反应条件温和、得率大幅提高、无污染等显著特点。
本发明的目的在于提供一种氢溴酸右美沙芬关键中间体(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)的制备新方法，以克服现有技术的缺陷。
所述的(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)的制备方法，其特征在于：
利用亚胺还原酶催化式化合物1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉(1)及其盐不对称还原制备(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)，反应式如下：
所述的亚胺还原酶，其序列包含了与来源于Amycolatopsis thermoflava的亚胺还原酶AtIR(WP_027931121.1)或Streptomyces thermolilacinus的亚胺还原酶StIR(WP_023587323.1)或Prauserella marina的亚胺还原酶PmIR(WP_091804541.1)或Sciscionella marina的亚胺还原酶SmIR(WP_020496004.1)或Amycolatopsis alba的亚胺还原酶AaIR(WP_020635634.1)或Streptoalloteichus hindustanus的亚胺还原酶ShIR(SHE96216.1)具有至少80％同一性的氨基酸序列，所述亚胺还原酶具有亚胺还原的活性。
本发明中所述的产亚胺还原酶的基因工程菌，具体的构建方法是：对Amycolatopsis thermoflava的亚胺还原酶AtIR(WP_027931121.1)或Streptomycesthermolilacinus的亚胺还原酶StIR(WP_023587323.1)或Prauserella marina的亚胺还原酶PmIR(WP_091804541.1)或Sciscionella marina的亚胺还原酶SmIR(WP_020496004.1)或Amycolatopsis alba的亚胺还原酶AaIR(WP_020635634.1)或Streptoalloteichushindustanus的亚胺还原酶ShIR(SHE96216.1)分别进行密码子优化后全合成相对应序列，并在基因两端加上相应的酶切位点，并将合成的基因构建到相应表达载体中，然后表达载体转入受体菌，即得到所述的产亚胺还原酶的基因工程菌IR1、IR2、IR3、IR4、IR5、IR6；并对基因工程菌进行发酵培养，实现了亚胺还原酶的高效异源表达。
本发明中所述产亚胺还原酶的基因工程菌所用到的载体系列包括：pET系列质粒、pTXB1系列、pGEX系列、pETduet系列、pTYB系列。
本发明中所述的产亚胺还原酶的基因工程菌，其特征在于所述的能高效表达外源基因的宿主菌为下列之一：BL21系列、Rosetta系列、Origami系列、Tuner系列。
在本发明中，由质粒转化宿主得到的转化体可以基于已知信息生长并产生本发明所述的亚胺还原酶。任何一种人工的或天然的含有合适碳源、氮源、无机和其他营养物质的介质，只要能满足宿主菌体的生长并且能够表达出目的蛋白均可使用。培养方法和培养条件没有明确的限制，可以根据培养方法和类型等的不同而进行适当的选择，只要能满足宿主生长并能产生相应活性的亚胺还原酶即可。
本发明的亚胺还原酶可以是上述亚胺还原酶基因工程重组菌的培养物，也可以是通过将培养基离心后得到的菌体细胞或其加工制品。其中加工制品指的是菌体得到的提取物、破碎液、或者对提取物腈水解酶进行的分离和/或纯化得到的分离产品，或者通过固定化提取物或者加工制品的固定化制品。
本发明涉及生物转化合成(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)的方法，反应中适用的溶剂可以是水或含有不同缓冲液的水介质或含部分有机溶剂的水介质，其所用的缓冲液可以是水中加入一种或几种适当磷酸盐、Tris盐酸盐、碳酸氢盐、碳酸盐等。
本发明所述的pH值优选能够保持在亚胺还原酶可以表达其活性的pH范围内，优选pH值为6.5～9.0。反应温度优选保持在亚胺还原酶可以表达其活性的温度范围内，优选20～40℃。
本发明所述的底物浓度没有限制，通常底物为5～50g/L，考虑到反应效果，底物浓度优选大于等于25g/L。
附图说明
图1产物(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)的核磁氢谱
图2产物(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)的核磁碳谱
具体实施方式
以下通过具体的实施例来进一步说明，其目的在于更好的理解发明内容，但是这些实施例不构成对本发明的限制。
实施例1：高表达基因工程菌的获得
全基因合成由上海旭冠公司完成。
根据Amycolatopsis thermoflava的基因AtIR(WP_027931121.1)、Streptomycesthermolilacinus的基因StIR(WP_023587323.1)、Prauserella marina的基因PmIR(WP_091804541.1)、Sciscionella marina的基因SmIR(WP_020496004.1)、Amycolatopsis alba的基因AaIR(WP_020635634.1)、Streptoalloteichus hindustanus的基因ShIR(SHE96216.1)分别进行密码子优化后，以期使基因能够在大肠杆菌表达宿主中进行表达，序列见附表。并在基因两端加上相应的酶切位点，构建到相应载体中，得到基因工程菌IR1、IR2、IR3、IR4、IR5、IR6。
将制备得到的重组载体用常规方法转化入大肠杆菌BL21、Rosetta或Origami中，以构建重组亚胺还原酶或亚胺还原酶与葡萄糖脱氢酶(GDH)共表达的基因工程菌，筛选出组建成功的基因工程菌，其中以大肠杆菌BL21为宿主菌的重组菌目的蛋白表达相对较好。以目的蛋白表达量不低于20％的工程菌，作为生产用工程菌菌种，并以甘油菌或牛奶冻干菌种形式保存。
实施例2基因工程菌的培养和静息细胞的制备
挑取平板上单菌落接种至5ml含相应抗生素的发酵培养基中，培养15h左右作为种子液，按照1％的接种量接种至含600ml的发酵培养基中，在37℃，200rpm的摇床上培养至OD600＝0.6～0.8左右，加入终浓度为0.1mM的IPTG进行诱导10h以上，以8000rpm离心培养液收集菌体。
实施例3利用IR1的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR1的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH 7.5)，加入葡萄糖(1g)、NADP+(5mg)、GDH酶粉(50mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(0.5g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全(液相色谱柱：Daicel CHIRALPAK OJ-H(250mm×4.6mm,5μm)，流动相：异丙醇(0.5％乙醇胺)/正己烷＝10:90，检测波长：230nm，流速：0.5mL/min)，10％碳酸钠溶液调节pH至9.0，乙酸乙酯萃取(100mL*3)，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)0.353g，收率80％，ee值>95％。1HNMR(600MHz,METHANOL-d4)δ＝7.15(d,J＝8.4Hz,2H),6.87(d,J＝8.4Hz,2H),3.76(s,3H),3.35(d,J＝9.5Hz,1H),3.05-3.00(m,2H),2.75-2.69(m,1H),2.53(dd,J＝10.3,13.9Hz,1H),2.19-2.09(m,1H),2.05-1.85(m,5H),1.79-1.67(m,2H),1.60-1.51(m,2H).13C NMR(150MHz,METHANOL-d4)δ＝158.59,130.40,129.87,128.73,128.28,113.78,58.17,54.29,39.56,36.98,29.90,29.32,26.68,22.83,22.49.
实施例4利用IR2的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR2的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH 7.5)，加入葡萄糖(1g)、NADP+(5mg)、GDH酶粉(50mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(0.5g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，10％碳酸钠溶液调节pH至9.0，乙酸乙酯萃取(100mL*3)，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)0.379g，收率86％，ee值>95％。
实施例5利用IR3的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR3的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH 7.5)，加入葡萄糖(2g)、NADP+(5mg)、GDH酶粉(50mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(1.0g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)0.723g，收率82％，ee值>95％。
实施例6利用IR4的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR4的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH 7.5)，加入葡萄糖(2g)、NADP+(5mg)、GDH酶粉(50mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(1.0g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，10％碳酸钠溶液调节pH至9.0，乙酸乙酯萃取(100mL*3)，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)0.688g，收率78％，ee值>95％。
实施例7利用IR5的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR5的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH 7.5)，加入葡萄糖(2g)、NADP+(5mg)、GDH酶粉(50mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(1.0g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，10％碳酸钠溶液调节pH至9.0，乙酸乙酯萃取(100mL*3)，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)0.706g，收率80％，ee值>95％。
实施例8利用IR6的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR6的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH 7.5)，加入葡萄糖(2g)、NADP+(5mg)、GDH酶粉(50mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(1.0g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，10％碳酸钠溶液调节pH至9.0，乙酸乙酯萃取(100mL*3)，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)0.732g，收率83％，ee值>95％。
实施例9利用IR3的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR3的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH 7.5)，加入葡萄糖(10g)、NADP+(5mg)、GDH酶粉(50mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(5.0g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，10％碳酸钠溶液调节pH至9.0，乙酸乙酯萃取(100mL*3)，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)3.748g，收率85％，ee值>95％。
实施例10利用IR6的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR6的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH 7.5)，加入葡萄糖(10g)、NADP+(5mg)、GDH酶粉(50mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(5.0g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，10％碳酸钠溶液调节pH至9.0，乙酸乙酯萃取(100mL*3)，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)3.528g，收率80％，ee值>95％。
实施例11利用IR1与GDH共表达工程菌的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR1与GDH共表达工程菌的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH7.5)，加入葡萄糖(1g)、NADP+(5mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(0.5g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，10％碳酸钠溶液调节pH至9.0，乙酸乙酯萃取(100mL*3)，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)0.362g，收率82％，ee值>95％。
实施例12利用IR2与GDH共表达工程菌的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR2与GDH共表达工程菌的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH7.5)，加入葡萄糖(1g)、NADP+(5mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(0.5g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，10％碳酸钠溶液调节pH至9.0，乙酸乙酯萃取(100mL*3)，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)0.348g，收率79％，ee值>95％。
实施例13利用IR3与GDH共表达工程菌的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR3与GDH共表达工程菌的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH7.5)，加入葡萄糖(2g)、NADP+(5mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(1.0g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)0.750g，收率85％，ee值>95％。
实施例14利用IR4与GDH共表达工程菌的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR4与GDH共表达工程菌的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH7.5)，加入葡萄糖(2g)、NADP+(5mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(1.0g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，10％碳酸钠溶液调节pH至9.0，乙酸乙酯萃取(100mL*3)，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)0.688g，收率78％，ee值>95％。
实施例15利用IR5与GDH共表达工程菌的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR5与GDH共表达工程菌的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH7.5)，加入葡萄糖(2g)、NADP+(5mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(1.0g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，10％碳酸钠溶液调节pH至9.0，乙酸乙酯萃取(100mL*3)，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)0.670g，收率76％，ee值>95％。
实施例16利用IR6与GDH共表达工程菌的静息细胞催化式(1)盐酸盐的不对称还原
取2.5g IR6与GDH共表达工程菌的静息细胞重悬于100mL磷酸钠缓冲液(100mM,pH7.5)，加入葡萄糖(2g)、NADP+(5mg)、1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉盐酸盐(1)(1.0g)，使用10％碳酸钠溶液控制pH 7.5，于25℃氮气保护下反应24小时，HPLC检测显示反应完全，10％碳酸钠溶液调节pH至9.0，乙酸乙酯萃取(100mL*3)，无水硫酸钠干燥后旋干，经柱层析分离纯化得到(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉((S)-2)0.706g，收率80％，ee值>95％。
序列表
<110> 中国科学院天津工业生物技术研究所
<120> 酶催化不对称合成右美沙芬关键中间体的新方法
<130> 2018-06-20
<141> 2018-06-25
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Claims (6)
1.一种氢溴酸右美沙芬关键中间体(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉的制备方法，其特征在于：利用亚胺还原酶催化式(1)化合物1-(4-甲氧基苄基)-3,4,5,6,7,8-六氢异喹啉及其盐不对称还原制备式(2) 化合物(S)-1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉，反应式如下：
其中，亚胺还原酶的氨基酸序列分别如SEQ ID No .1、SEQ ID No .2、SEQ ID No .3、SEQ ID No .4、SEQ ID No .5、SEQ ID No .6任意之一所示。
2.根据权利要求1所述的的方法，其特征在于，所述亚胺还原酶是重组表达该酶的转化体培养物或重组表达该酶转化体培养物离心分离后的转化体细胞或转化体细胞加工制品。
3.如权利要求2所述的方法，其特征在于，所述转化体细胞加工制品是由转化体细胞得到的提取物、或通过对提取物中的亚胺还原酶进行分离和/或纯化得到的分离产品，或者通过固定化转化体细胞、提取物、转化体的分离产品而得到的固定化制品。
4.如权利要求1所述的方法，其特征在于，反应的pH值为6.5～9.0，所述反应的温度为20～40℃，反应的时间为10～40h。
5.如权利要求1所述的方法，其特征在于，反应的pH值为7.5；反应的温度为25℃；反应的时间为24h。
6.如权利要求1所述的方法，其特征在于，反应的底物式(1)化合物的浓度为5～50g/L。
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| CN105524971A (zh) * | 2015-12-02 | 2016-04-27 | 中国科学院天津工业生物技术研究所 | 酶催化拆分1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉的新方法 |
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| CN104761495A (zh) * | 2014-01-08 | 2015-07-08 | 上海医药工业研究院 | 一种新化合物及其制备方法和用途 |
| CN105524971A (zh) * | 2015-12-02 | 2016-04-27 | 中国科学院天津工业生物技术研究所 | 酶催化拆分1-(4-甲氧基苄基)-1,2,3,4,5,6,7,8-八氢异喹啉的新方法 |
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