CN113234698B - 一种氰基还原酶和加巴喷丁的制备方法 - Google Patents
一种氰基还原酶和加巴喷丁的制备方法 Download PDFInfo
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0012—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7)
- C12N9/0044—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on other nitrogen compounds as donors (1.7)
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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
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/005—Amino acids other than alpha- or beta amino acids, e.g. gamma amino acids
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Life Sciences & Earth Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明涉及药物合成技术领域，特别涉及一种氰基还原酶和加巴喷丁的制备方法。该方法包括如下步骤：以氢化钠为催化剂，环己甲氰与2‑溴乙酸乙酯发生缩合反应，生成2‑氰基‑2‑环己烷基乙酸乙酯；在碱性条件下，2‑氰基‑2‑环己烷基乙酸乙酯发生水解反应，得到2‑氰基‑2‑环己烷基乙酸；2‑氰基‑2‑环己烷基乙酸在氰基还原酶的作用下转化成加巴喷丁。本发明针对文献方案的缺陷(加巴喷丁传统化学制备的问题)，通过引进氰基还原酶，系统优化了路线，不仅减少了反应步骤，同时使得反应条件更温和、环保。该路线不仅可以显著提升加巴喷丁整体收率，同时也使得其更符合当今绿色生产的需求。
Description
技术领域
本发明涉及药物合成技术领域，特别涉及一种加巴喷丁的制备方法。
背景技术
加巴喷丁是一种治疗局部癫痫的药物，同时它也是糖尿病神经炎、疱疹后剧痛等神经性病痛治疗的首选药物。
传统的加巴喷丁制备方法如下：
路线I:多篇文章及专利报道了该制备方法，Dipak Varal等人{Chem.Sci.Trans,5,442-446(2016)},Ashok Kumar mubai等人(Patent US20080103334A1),Delogu Pietro等人(Patent EP 2368872A1),Wolfram Geibel等人(Patent US005091567A)。环己酮先与氰乙酸乙酯缩合，然后在强酸高温下水解，醋酐成酯，氨解，最后Hofmann重排五步得加巴喷丁；
路线II:Gareth Griffiths等人{Helv.Chim.Acta,74,309-314(1991)}，KlausSteiner等人(Patent US5068413)报道首先利用环己酮在重金属四氯化钛的催化下与丙二酸二乙酯缩合，然后加氰基，酯水解，酸性脱羧后Raney镍氢化得加巴喷丁；
路线III:Xue Yaping等人{Catal.Commun,66,121-125(2015)；Biochem.Eng.J.125,190-195(2017)},Xu zhe等人{Bioprocess Biosys.Eng.42,455-463(2019)}尝试将氰水解酶(Nitrilase)应用到加巴喷丁制备工艺里，其路线是环己酮在重金属四氯化钛催化下与氰乙酸乙酯缩合，然后氰基加成脱羧，氰水解酶选择性水解以及最后的Raney镍氢化得加巴喷丁。
从以上加巴喷丁传统制备路线可以看出，路线I、II需要五步反应才能完成，在制备过程中涉及到重金属四氯化钛的使用，硫酸高温水解，Hofmann在液溴参与下重排，Raney镍氢化等昂贵、效率低、危险系数高的化学品使用，因此其规模化生产中的环境成本与安全成本很高。路线III虽然加入了氰水解酶的使用，这使得制备路线缩短到四步，但由于重金属四氯化钛、危化品氰化钠以及Raney镍高压氢化的使用，这使得该路线相比于路线I、II并无明显优势。
随着国家对环保的愈加重视，以及医药品采购价格的不断压低，因此开发一种更为绿色、更为经济的加巴喷丁生产工艺迫在眉睫。
发明内容
有鉴于此，本发明提供了一种氰基还原酶和加巴喷丁的制备方法。该方法制备路线短，收率高，是一种绿色、经济的生产工艺。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种加巴喷丁的制备方法，包括如下步骤：
步骤A：以氢化钠为催化剂，环己甲氰与2-溴乙酸乙酯发生缩合反应，生成2-氰基-2-环己烷基乙酸乙酯；
步骤B：在碱性条件下，2-氰基-2-环己烷基乙酸乙酯发生水解反应，得到2-氰基-2-环己烷基乙酸；
步骤C：2-氰基-2-环己烷基乙酸在氰基还原酶的作用下转化成加巴喷丁；
所述氰基还原酶由酶A和酶B组成，所述酶A为序列如SEQ ID NO：1所示的NR-I或序列如SEQ ID NO：2所示的NR-II中的一种或两种，所述酶B为PTDH或ADH中的一种或两种。
本发明采用环己甲氰为原料，以四氢呋喃做溶剂，在氢化钠催化下与2-溴乙酸乙酯缩合生成2-氰基-2-环己烷基乙酸乙酯，然后碱性条件下酯水解得2-氰基-2-环己烷基乙酸，最后在氰基还原酶(EC 1.7.1.13)作用下转化成加巴喷丁。
本专利通过引入氰基还原酶，从而系统的优化了制备路线(缩短到三步反应)，与此同时，在制备过程中还有效排除了重金属四氯化钛、有毒化学品氰化钠以及Raney镍高压氢化反应，从而大大提高最终收率、降低了其规模化生产的环境及安全成本。
本专利化学-酶法制备路线：
该路线利用环己甲氰为起始原料，在碱性条件下与2-溴乙酸乙酯缩合，然后酯水解后用氰基还原酶(Nitrile reductase)还原，共计三步简单反应制备加巴喷丁。
作为优选，步骤A中缩合反应的溶剂为四氢呋喃。
作为优选，步骤A具体为：环己甲氰与四氢呋喃混合，冷却至-15～-5℃并保持，加入氢化钠搅拌5～15min后，滴入2-溴乙酸乙酯，搅拌10～20min，升温至15～25℃，搅拌50～70min，加入冰水终止反应，用乙酸乙酯萃取产物，硫酸钠干燥，浓缩除溶剂，在乙酸乙酯/乙醇混合液中结晶。
作为优选，乙酸乙酯/乙醇混合液中，乙酸乙酯与乙醇的体积比为1:(2～4)。
优选地，乙酸乙酯/乙醇混合液中，乙酸乙酯与乙醇的体积比为1:3。
作为优选，环己甲氰、2-溴乙酸乙酯与氢化钠的摩尔比为(40～60):(60～90):(50～70)。
作为优选，步骤B具体为：将15％～25％乙醇水溶液的pH值调至11～14，加入2-氰基-2-环己烷基乙酸乙酯，在45～55℃下搅拌1.5～2.5小时后，冷却至15～25℃，用乙酸乙酯萃取产物，干燥，浓缩。
作为优选，氰基还原酶由酶A和酶B组成，酶A为NR-I或NR-II中的一种或两种，酶B为PTDH或ADH中的一种或两种。
在本发明中，PTDH序列如SEQ ID NO：3所示，ADH序列如SEQ ID NO：4所示。
优选地，氰基还原酶为NR-I/PTDH、NR-I/ADH或NR-II/ADH。
作为优选，氰基还原酶为NR-I/PTDH时，步骤C具体为：在缓冲液中加入2-氰基-2-环己烷基乙酸、β-烟酰胺腺嘌呤二核苷酸磷酸单钠盐、亚磷酸钠、异丙醇，调节pH值至8.0后，加入NR-I和PTDH进行催化反应，催化反应的温度为10～30℃，时间为3～5小时，pH值为7.0～8.5；反应结束后调节pH值至1.5，离心除蛋白杂质；然后调节溶液pH至7.0后利用反渗透除盐，抽干后粗品用乙醇/水结晶；
2-氰基-2-环己烷基乙酸、β-烟酰胺腺嘌呤二核苷酸磷酸单钠盐、亚磷酸钠、异丙醇、NR-I与PTDH的用量比为(40～60mM)：(0.1～0.3mM)：(100～150mM)：(20～30mL)：(500～1500U)：(2500～3500U)。
作为优选，氰基还原酶为NR-I/ADH时，步骤C具体为：在缓冲液中加入2-氰基-2-环己烷基乙酸、β-烟酰胺腺嘌呤二核苷酸磷酸单钠盐、异丙醇，调节pH值至7.5后，加入NR-I和ADH进行催化反应，催化反应的温度为10～30℃，时间为1～3小时，pH值为6.8～8.0；反应结束后调节pH值至1.5，离心除蛋白杂质；然后调节溶液pH至7.0后利用D201阴离子交换树酯除含磷酸杂质，抽干后粗品用乙醇/水结晶；
2-氰基-2-环己烷基乙酸、β-烟酰胺腺嘌呤二核苷酸磷酸单钠盐、异丙醇、NR-I与ADH的用量比为(40～60mM)：(0.1～0.3mM)：(30～50mL)：(500～1500U)：(1500～2500U)。
作为优选，氰基还原酶为NR-II/ADH时，步骤C具体为：在缓冲液中加入2-氰基-2-环己烷基乙酸、β-烟酰胺腺嘌呤二核苷酸磷酸单钠盐、异丙醇，调节pH值至7.5后，加入NR-II和ADH进行催化反应，催化反应的温度为10～30℃，时间为2～4小时，pH值为6.8～8.0，反应结束后调节pH值至1.5，离心除蛋白杂质；然后调节溶液pH至7.0后利用D201阴离子交换树酯除含磷酸杂质，抽干后粗品用乙醇/水结晶；
2-氰基-2-环己烷基乙酸、β-烟酰胺腺嘌呤二核苷酸磷酸单钠盐、异丙醇、NR-II与ADH的用量比为(40～60mM)：(0.1～0.3mM)：(30～50mL)：(1500～2500U)：(1500～2500U)。
本发明还提供了一种氰基还原酶，该氰基还原酶由酶A和酶B组成，所述酶A为序列如SEQ ID NO：1所示的NR-I或序列如SEQ ID NO：2所示的NR-II中的一种或两种，所述酶B为PTDH或ADH中的一种或两种。
在本发明中，PTDH序列如SEQ ID NO：3所示，ADH序列如SEQ ID NO：4所示。
本发明提供了一种氰基还原酶和加巴喷丁的制备方法。该方法包括如下步骤：以氢化钠为催化剂，环己甲氰与2-溴乙酸乙酯发生缩合反应，生成2-氰基-2-环己烷基乙酸乙酯；在碱性条件下，2-氰基-2-环己烷基乙酸乙酯发生水解反应，得到2-氰基-2-环己烷基乙酸；2-氰基-2-环己烷基乙酸在氰基还原酶的作用下转化成加巴喷丁。本发明具有如下技术效果：
本发明针对文献方案的缺陷(加巴喷丁传统化学制备的问题)，通过引进氰基还原酶，系统优化了路线，不仅减少了反应步骤，同时使得反应条件更温和、环保。该路线不仅可以显著提升加巴喷丁整体收率，同时也使得其更符合当今绿色生产的需求。
具体实施方式
本发明公开了一种氰基还原酶和加巴喷丁的制备方法，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明中，酶相关信息如下：
NR-I,NR-II是nitrile reductase，它们是霍乱弧菌(Vibrio choleraeserotype)体内的酶改造而来的(Uniprot ID:Q9KTK0,EC 1.7.1.13)；
PTDH是施氏假单胞菌(Pseudomonas stutzeri)体内一个亚磷酸脱氢酶改造而来的(Uniprot ID:O69054,EC 1.20.1.1)；
ADH是短乳杆菌Lactobacillus brevis体内的一个醇脱氢酶，(Uniprot ID:Q84EX5,EC 1.1.1.1)。
上述酶的氨基酸和DNA序列如下：
表1酶的氨基酸序列
注：表1中加粗的氨基酸是NR-I与NR-II氨基酸序列的改造位点。原有酶无法完成第三步反应。
表2酶的DNA序列
相关酶的制备：
以上酶所需要的基因是通过公司直接合成的(安徽通用生物)，然后以NdeI/XhoI酶切位点亚克隆到pET28a质粒上。构建好的质粒转入E.coli(BL21)菌株(通用生物)，平板培养后挑单克隆转入5mL含50μM卡那霉素的LB培养液中(37℃)进行培养，当细胞生长至对数期后(OD～0.6)加入0.5mM异丙基-β-D-硫代吡喃半乳糖苷(IPTG)诱导蛋白表达4小时，最后通过细胞收集、破碎及高速离心得上清液，然后利用十二烷基磺酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)确认蛋白表达正确后菌体可以逐级接入到5L培养发酵罐里进行37℃生长、0.5mM IPTG诱导表达6小时，最终获得湿细胞45-70g。在制备加巴喷丁前，将含酶湿细胞与三羟甲基氨基甲烷盐酸(Tris.HCl)缓冲液(50mM，pH 8.0)在冰上混合均匀(10克湿细胞与200mL缓冲液混合)，然后高压破碎细胞壁，高速离心(16000rpm，45min)后获得含酶清液直接使用。(酶活力在120-300U/mL，U是室温一分钟转化1μmol所需酶量)LB培养基构成为：1％胰蛋白胨、0.5％酵母粉，1％NaCl，1％磷酸氢二钾、1％磷酸氢二钾以及5％的甘油。
本发明中所用原料或试剂均可由市场购得。
下面结合实施例，进一步阐述本发明：
实施例1：2-氰基-2-环己烷基乙酸乙酯的合成
首先环己甲氰(5.45g,50mmol)与无水的四氢呋喃(200mL)混合加入三口圆底烧瓶，冰盐浴冷却到-10℃，然后分批加入氢化钠固体(1.44g,62mmol)，维持混合液低温(-10℃)搅拌10分钟后，缓慢滴入2-溴乙酸乙酯(9.7mL，75mmol)。低温搅拌15分钟后升至室温搅拌60分钟，加入冰水(200mL)终止反应，用乙酸乙酯萃取产物，硫酸钠干燥，浓缩除溶剂得固体粗品，最后产物在乙酸乙酯/乙醇＝1:3(体积比)中结晶得白色固体7.2克，收率74％。
实施例2：2-氰基-2-环己烷基乙酸的合成
往离子水(200mL)与乙醇(50mL)混合溶剂中加入氢氧化钠(2.0g，50mmol)溶解完全，然后加入2-氰基-2-环己烷基乙酸乙酯(5.86g，30mmol)，50℃加热搅拌该混合溶液2小时后冷却至室温，最后用乙酸乙酯萃取、干燥、浓缩得5.4克粗品，直接进行下一步使用，无需纯化。
实施例3：加巴喷丁的合成路线I(NR-I与PTDH)
在500mL含有50mM pH 8.0的三羟甲基氨基甲烷盐酸(Tris.HCl)溶液中先后加入4.17克2-氰基-2-环己烷基乙酸(50mM)，765毫克β-烟酰胺腺嘌呤二核苷酸磷酸(NADP+)单钠盐(0.2mM)，12.96克五水亚磷酸钠(120mM)以及25mL异丙醇。调节反应pH值到8.0后，加入1000UNR-I以及3000U PTDH启动催化反应，反应在室温下缓慢搅拌4小时，在反应过程中通过添加HCl或NaOH水溶液维持体系pH值在7.0-8.5之间。反应结束后加酸沉淀蛋白(调节溶液pH值到1.5，并快速搅拌)，离心除去蛋白杂质；然后调节溶液pH到7.0后利用反渗透除盐，抽干后粗品用乙醇/水结晶得到2.86克白色固体(收率67％)。
实施例4：加巴喷丁的合成路线II(NR-I与ADH)
与实施例3类似，用的是ADH酶和异丙醇，不需要额外添加亚磷酸钠。在500mL含有50mM pH 7.5的三羟甲基氨基甲烷盐酸(Tris.HCl)溶液中先后加入4.17克2-氰基-2-环己烷基乙酸(50mM)，765毫克β-烟酰胺腺嘌呤二核苷酸磷酸(NADP+)单钠盐(0.2mM)以及40mL异丙醇。调节反应pH值到7.5后，加入1000UNR-I以及2000U ADH启动催化反应，反应在室温下缓慢搅拌2小时，在反应过程中通过添加HCl或NaOH水溶液维持体系pH值在6.8-8.0之间。反应结束后加酸沉淀蛋白(调节溶液pH值到1.5，并快速搅拌)，离心除去蛋白杂质；然后调节溶液pH到7.0后利用D201阴离子交换树酯除含磷酸杂质(用去离子水做洗脱液，产物与树脂结合弱直接流出)，含产物流出液抽干后用乙醇/水结晶得到3.85克白色固体(收率90％)。
实施例5：加巴喷丁的合成路线III(NR-II与ADH)
与实施例4相同，区别是用的NR-II酶，其活力与NR-I比较相差较大。在500mL含有50mM pH 7.5的三羟甲基氨基甲烷盐酸(Tris.HCl)溶液中先后加入4.17克2-氰基-2-环己烷基乙酸(50mM)，765毫克β-烟酰胺腺嘌呤二核苷酸磷酸(NADP+)单钠盐(0.2mM)以及40mL异丙醇。调节反应pH值到7.5后，加入2000U NR-II以及2000U ADH启动催化反应，反应在室温下缓慢搅拌3小时，在反应过程中通过添加HCl或NaOH水溶液维持体系pH值在6.8-8.0之间。反应结束后加酸沉淀蛋白(调节溶液pH值到1.5，并快速搅拌)，离心除去蛋白杂质；然后调节溶液pH到7.0后利用D201阴离子交换树酯除含磷酸杂质(用去离子水做洗脱液，产物与树脂结合弱直接流出)，含产物流出液抽干后用乙醇/水结晶得到3.12克白色固体(收率73％)。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
序列表
<110> 深圳瑞德林生物技术有限公司
<120> 一种氰基还原酶和加巴喷丁的制备方法
<130> S21P001097
<160> 8
<170> SIPOSequenceListing 1.0
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Met Ser Lys Tyr Ser Asp Ala Lys Glu Leu Ala Ser Leu Thr Leu Gly
1 5 10 15
Lys Lys Thr Glu Tyr Ala Asn Gln Tyr Asp Pro Ser Leu Leu Gln Pro
20 25 30
Val Pro Arg Ser Leu Asn Arg Asn Asp Leu His Leu Ser Ala Thr Leu
35 40 45
Pro Phe Gln Gly Cys Asp Ile Trp Thr Leu Tyr Glu Leu Ser Trp Leu
50 55 60
Asn Gln Lys Gly Leu Pro Gln Val Ala Ile Gly Glu Val Ser Ile Pro
65 70 75 80
Ala Thr Ser Ala Asn Leu Ile His Gly Lys Ser Phe Lys Leu Tyr Leu
85 90 95
Asn Ser Tyr Asn Gln Thr Arg Phe Ala Ser Trp Asp Glu Val Gln Thr
100 105 110
Arg Leu Val His Asp Leu Ser Ala Cys Ala Gly Glu Thr Val Thr Val
115 120 125
Asn Val Lys Ser Leu Asn Glu Tyr Thr Ala Glu Pro Ile Val Thr Met
130 135 140
Gln Gly Glu Cys Ile Asp Asp Gln Asp Ile Glu Ile Ala Asn Tyr Glu
145 150 155 160
Phe Asp Asp Ala Leu Leu Gln Gly Ala Ala Gln Gly Glu Glu Val Ser
165 170 175
Glu Val Leu His Ser His Leu Leu Lys Ser Asn Cys Leu Ile Thr Asn
180 185 190
Gln Pro Asp Trp Gly Ser Val Glu Ile Ala Tyr His Gly Ala Lys Met
195 200 205
Asn Arg Glu Ala Leu Leu Arg Tyr Leu Val Ser Phe Arg Glu His Asn
210 215 220
Glu Phe Leu Phe Gln Cys Val Glu Arg Ile Phe Thr Asp Ile Met Arg
225 230 235 240
Tyr Cys Gln Pro Gln Ser Leu Thr Val Tyr Ala Arg Tyr Thr Arg Arg
245 250 255
Gly Gly Leu Asp Asp Asn Pro Phe Arg Ser Ser His Gln Ser Ala Pro
260 265 270
Asn His Asn Gln Arg Met Ala Arg Gln
275 280
<210> 2
<211> 281
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Met Ser Lys Tyr Ser Asp Ala Lys Glu Leu Ala Ser Leu Thr Leu Gly
1 5 10 15
Lys Lys Thr Glu Tyr Ala Asn Gln Tyr Asp Pro Ser Leu Leu Gln Pro
20 25 30
Val Pro Arg Ser Leu Asn Arg Asn Asp Leu His Leu Ser Ala Thr Leu
35 40 45
Pro Phe Gln Gly Cys Asp Ile Trp Thr Leu Tyr Glu Leu Ser Trp Leu
50 55 60
Asn Gln Lys Gly Leu Pro Gln Val Ala Ile Gly Glu Val Ser Ile Pro
65 70 75 80
Ala Thr Ser Ala Asn Leu Ile His Ala Lys Ser Phe Lys Leu Tyr Leu
85 90 95
Asn Ser Tyr Asn Gln Thr Arg Phe Ala Ser Trp Asp Glu Val Gln Thr
100 105 110
Arg Leu Val His Asp Leu Ser Ala Cys Ala Gly Glu Thr Val Thr Val
115 120 125
Asn Val Lys Ser Leu Asn Glu Tyr Thr Ala Glu Pro Ile Val Thr Met
130 135 140
Gln Gly Glu Cys Ile Asp Asp Gln Asp Ile Glu Ile Ala Asn Tyr Glu
145 150 155 160
Phe Asp Asp Ala Leu Leu Gln Gly Ala Ala Gln Gly Glu Glu Val Ser
165 170 175
Glu Val Leu His Ser His Leu Leu Lys Ser Asn Cys Leu Ile Thr Asn
180 185 190
Gln Pro Asp Trp Gly Ser Val Glu Ile Ala Tyr His Gly Ala Lys Met
195 200 205
Asn Arg Glu Ala Leu Leu Arg Tyr Leu Val Ser Phe Arg Glu His Asn
210 215 220
Glu Phe Leu Tyr Gln Cys Val Glu Arg Ile Phe Thr Asp Ile Met Arg
225 230 235 240
Tyr Cys Gln Pro Gln Ser Leu Thr Val Tyr Ala Arg Tyr Thr Arg Arg
245 250 255
Gly Gly Leu Asp Glu Asn Pro Phe Arg Ser Ser His Gln Ser Ala Pro
260 265 270
Asn His Asn Gln Arg Met Ala Arg Gln
275 280
<210> 3
<211> 336
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met Leu Pro Lys Leu Val Ile Thr His Arg Val His Asp Glu Ile Leu
1 5 10 15
Gln Leu Leu Ala Pro His Cys Glu Leu Met Thr Asn Gln Thr Asp Ser
20 25 30
Thr Leu Thr Arg Glu Glu Ile Leu Arg Arg Cys Arg Asp Ala Gln Ala
35 40 45
Met Met Ala Phe Met Pro Asp Arg Val Asp Ala Asp Phe Leu Gln Ala
50 55 60
Cys Pro Glu Leu Arg Val Ile Gly Cys Ala Leu Lys Gly Phe Asp Asn
65 70 75 80
Phe Asp Val Asp Ala Cys Thr Ala Arg Gly Val Trp Leu Thr Phe Val
85 90 95
Pro Asp Leu Leu Thr Val Pro Thr Ala Glu Leu Ala Ile Gly Leu Ala
100 105 110
Val Gly Leu Gly Arg His Leu Arg Ala Ala Asp Ala Phe Val Arg Ser
115 120 125
Gly Lys Phe Arg Gly Trp Gln Pro Arg Phe Tyr Gly Thr Gly Leu Asp
130 135 140
Asn Ala Thr Val Gly Phe Leu Gly Met Gly Ala Ile Gly Leu Ala Met
145 150 155 160
Ala Asp Arg Leu Gln Gly Trp Gly Ala Thr Leu Gln Tyr His Glu Arg
165 170 175
Lys Ala Leu Asp Thr Gln Thr Glu Gln Arg Leu Gly Leu Arg Gln Val
180 185 190
Ala Cys Ser Glu Leu Phe Ala Ser Ser Asp Phe Ile Leu Leu Ala Leu
195 200 205
Pro Leu Asn Ala Asp Thr Leu His Leu Val Asn Ala Glu Leu Leu Ala
210 215 220
Leu Val Arg Pro Gly Ala Leu Leu Val Asn Pro Cys Arg Gly Ser Val
225 230 235 240
Val Asp Glu Ala Ala Val Leu Ala Ala Leu Glu Arg Gly Gln Leu Gly
245 250 255
Gly Tyr Ala Ala Asp Val Phe Glu Met Glu Asp Trp Ala Arg Ala Asp
260 265 270
Arg Pro Gln Gln Ile Asp Pro Ala Leu Leu Ala His Pro Asn Thr Leu
275 280 285
Phe Thr Pro His Ile Gly Ser Ala Val Arg Ala Val Arg Leu Glu Ile
290 295 300
Glu Arg Cys Ala Ala Gln Asn Ile Leu Gln Ala Leu Ala Gly Glu Arg
305 310 315 320
Pro Ile Asn Ala Val Asn Arg Leu Pro Lys Ala Glu Pro Ala Ala Cys
325 330 335
<210> 4
<211> 252
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Met Ser Asn Arg Leu Asp Gly Lys Val Ala Ile Ile Thr Gly Gly Thr
1 5 10 15
Leu Gly Ile Gly Leu Ala Ile Ala Thr Lys Phe Val Glu Glu Gly Ala
20 25 30
Lys Val Met Ile Thr Gly Arg His Ser Asp Val Gly Glu Lys Ala Ala
35 40 45
Lys Ser Val Gly Thr Pro Asp Gln Ile Gln Phe Phe Gln His Asp Ser
50 55 60
Ser Asp Glu Asp Gly Trp Thr Lys Leu Phe Asp Ala Thr Glu Lys Ala
65 70 75 80
Phe Gly Pro Val Ser Thr Leu Val Asn Asn Ala Gly Ile Ala Val Asn
85 90 95
Lys Ser Val Glu Glu Thr Thr Thr Ala Glu Trp Arg Lys Leu Leu Ala
100 105 110
Val Asn Leu Asp Gly Val Phe Phe Gly Thr Arg Leu Gly Ile Gln Arg
115 120 125
Met Lys Asn Lys Gly Leu Gly Ala Ser Ile Ile Asn Met Ser Ser Ile
130 135 140
Glu Gly Phe Val Gly Asp Pro Ser Leu Gly Ala Tyr Asn Ala Ser Lys
145 150 155 160
Gly Ala Val Arg Ile Met Ser Lys Ser Ala Ala Leu Asp Cys Ala Leu
165 170 175
Lys Asp Tyr Asp Val Arg Val Asn Thr Val His Pro Gly Tyr Ile Lys
180 185 190
Thr Pro Leu Val Asp Asp Leu Pro Gly Ala Glu Glu Ala Met Ser Gln
195 200 205
Arg Thr Lys Thr Pro Met Gly His Ile Gly Glu Pro Asn Asp Ile Ala
210 215 220
Tyr Ile Cys Val Tyr Leu Ala Ser Asn Glu Ser Lys Phe Ala Thr Gly
225 230 235 240
Ser Glu Phe Val Val Asp Gly Gly Tyr Thr Ala Gln
245 250
<210> 5
<211> 846
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
atgagcaaat atagcgatgc gaaagaactg gcgagcctga ccctgggcaa aaaaaccgaa 60
tatgcgaacc agtatgatcc gagcctgctg cagccggtgc cgcgcagcct gaaccgcaac 120
gatctgcatc tgagcgcgac cctgccgttt cagggctgcg atatttggac cctgtatgaa 180
ctgagctggc tgaaccagaa aggcctgccg caggtggcga ttggcgaagt gagcattccg 240
gcgaccagcg cgaacctgat tcatggcaaa agctttaaac tgtatctgaa cagctataac 300
cagacccgct ttgcgagctg ggatgaagtg cagacccgcc tggtgcatga tctgagcgcg 360
tgcgcgggcg aaaccgtgac cgtgaacgtg aaaagcctga acgaatatac cgcggaaccg 420
attgtgacca tgcagggcga atgcattgat gatcaggata ttgaaattgc gaactatgaa 480
tttgatgatg cgctgctgca gggcgcggcg cagggcgaag aagtgagcga agtgctgcat 540
agccatctgc tgaaaagcaa ctgcctgatt accaaccagc cggattgggg cagcgtggaa 600
attgcgtatc atggcgcgaa aatgaaccgc gaagcgctgc tgcgctatct ggtgagcttt 660
cgcgaacata acgaatttct gtttcagtgc gtggaacgca tttttaccga tattatgcgc 720
tattgccagc cgcagagcct gaccgtgtat gcgcgctata cccgccgcgg cggcctggat 780
gataacccgt ttcgcagcag ccatcagagc gcgccgaacc ataaccagcg catggcgcgc 840
cagtga 846
<210> 6
<211> 846
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
atgagcaaat atagcgatgc gaaagaactg gcgagcctga ccctgggcaa aaaaaccgaa 60
tatgcgaacc agtatgatcc gagcctgctg cagccggtgc cgcgcagcct gaaccgcaac 120
gatctgcatc tgagcgcgac cctgccgttt cagggctgcg atatttggac cctgtatgaa 180
ctgagctggc tgaaccagaa aggcctgccg caggtggcga ttggcgaagt gagcattccg 240
gcgaccagcg cgaacctgat tcatgcgaaa agctttaaac tgtatctgaa cagctataac 300
cagacccgct ttgcgagctg ggatgaagtg cagacccgcc tggtgcatga tctgagcgcg 360
tgcgcgggcg aaaccgtgac cgtgaacgtg aaaagcctga acgaatatac cgcggaaccg 420
attgtgacca tgcagggcga atgcattgat gatcaggata ttgaaattgc gaactatgaa 480
tttgatgatg cgctgctgca gggcgcggcg cagggcgaag aagtgagcga agtgctgcat 540
agccatctgc tgaaaagcaa ctgcctgatt accaaccagc cggattgggg cagcgtggaa 600
attgcgtatc atggcgcgaa aatgaaccgc gaagcgctgc tgcgctatct ggtgagcttt 660
cgcgaacata acgaatttct gtatcagtgc gtggaacgca tttttaccga tattatgcgc 720
tattgccagc cgcagagcct gaccgtgtat gcgcgctata cccgccgcgg cggcctggat 780
gaaaacccgt ttcgcagcag ccatcagagc gcgccgaacc ataaccagcg catggcgcgc 840
cagtga 846
<210> 7
<211> 1011
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
atgttaccga aattagttat cacgcacaga gtgcacgacg aaatccttca attgctggcc 60
cctcattgtg agttgatgac caaccaaacc gattctaccc tgacgagaga agagatactg 120
cgccgttgca gagacgcaca agccatgatg gcgtttatgc cggaccgtgt agatgcagac 180
tttcttcaag cttgcccgga acttcgggtc attggttgtg ctttgaaagg gttcgacaac 240
tttgacgtgg atgcgtgtac tgcacgcggg gtatggctta cttttgtacc tgacttattg 300
acggttccca ctgccgagct tgctattggc ctggccgtcg gattaggccg ccatttacgt 360
gcggcagatg cgttcgtacg gagtgggaag tttcggggct ggcaaccgcg attctacggg 420
actggattgg ataacgccac tgtaggtttc cttgggatgg gtgccatagg tttagctatg 480
gcagatagat tacaggggtg gggagctacc cttcaatatc atgagcgtaa agcattggat 540
acacaaacag aacagcgctt gggtcttaga caggtcgcgt gctcggaact tttcgcttcc 600
tcagacttca tactgttggc cttgccactt aacgctgaca ctctacattt ggtaaacgct 660
gaattgctgg ctttggtacg tcccggcgca ctgttagtta atccgtgccg gggctcggtg 720
gtagacgagg cagccgtgct ggcagcgctt gagagagggc aacttggcgg atatgctgca 780
gacgtgttcg agatggaaga ctgggcccgc gcggaccgtc cacagcaaat cgatcctgcg 840
ttgttggccc accctaatac tttatttact ccgcacatcg gatcagcggt gagagcggtg 900
cggcttgaga ttgagcgttg cgcagctcag aacatcctcc aggcgctggc aggagaacgt 960
ccaattaatg ctgtaaatcg tttaccgaag gctgaaccag cagcttgttg a 1011
<210> 8
<211> 759
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
atgtctaacc gtttggatgg taaggtagca atcattacag gtggtacgtt gggtatcggt 60
ttagctatcg ccacgaagtt cgttgaagaa ggggctaagg tcatgattac cggccggcac 120
agcgatgttg gtgaaaaagc agctaagagt gtcggcactc ctgatcagat tcaatttttc 180
caacatgatt cttccgatga agacggctgg acgaaattat tcgatgcaac ggaaaaagcc 240
tttggcccag tttctacatt agttaataac gctgggatcg cggttaacaa gagtgtcgaa 300
gaaaccacga ctgctgaatg gcgtaaatta ttagccgtca accttgatgg tgtcttcttc 360
ggtacccgat tagggattca acggatgaag aacaaaggct taggggcttc catcatcaac 420
atgtcttcga tcgaaggctt tgtgggtgat cctagcttag gggcttacaa cgcatctaaa 480
ggggccgtac ggattatgtc caagtcagct gccttagatt gtgccctaaa ggactacgat 540
gttcgggtaa acactgttca ccctggctac atcaagacac cattggttga tgacctacca 600
ggggccgaag aagcgatgtc acaacggacc aagacgccaa tgggccatat cggtgaacct 660
aacgatattg cctacatctg tgtttacttg gcttctaacg aatctaaatt tgcaacgggt 720
tctgaattcg tagttgacgg tggctacact gctcaatag 759
Claims (8)
1.一种加巴喷丁的制备方法，其特征在于，包括如下步骤：
步骤A：以氢化钠为催化剂，环己甲氰与2-溴乙酸乙酯发生缩合反应，生成2-氰基-2-环己烷基乙酸乙酯；
步骤B：在碱性条件下，2-氰基-2-环己烷基乙酸乙酯发生水解反应，得到2-氰基-2-环己烷基乙酸；
步骤C：2-氰基-2-环己烷基乙酸在氰基还原酶的作用下转化成加巴喷丁；
所述氰基还原酶由酶A和酶B组成，所述酶A为序列如SEQ ID NO：1所示的NR-I或序列如SEQ ID NO：2所示的NR-II中的一种或两种，所述酶B为PTDH或ADH中的一种或两种；
步骤A中所述缩合反应的溶剂为四氢呋喃；
所述PTDH序列如SEQ ID NO：3所示，所述ADH序列如SEQ ID NO：4所示。
2.根据权利要求1所述的制备方法，其特征在于，步骤A具体为：环己甲氰与四氢呋喃混合，冷却至-15～-5℃并保持，加入氢化钠搅拌5～15min后，滴入2-溴乙酸乙酯，搅拌10～20min，升温至15～25℃，搅拌50～70min，加入冰水终止反应，用乙酸乙酯萃取产物，硫酸钠干燥，浓缩除溶剂，在乙酸乙酯/乙醇混合液中结晶。
3.根据权利要求1或2所述的制备方法，其特征在于，环己甲氰、2-溴乙酸乙酯与氢化钠的摩尔比为(40～60):(60～90):(50～70)。
4.根据权利要求1所述的制备方法，其特征在于，步骤B具体为：将15％～25％乙醇水溶液的pH值调至11～14，加入2-氰基-2-环己烷基乙酸乙酯，在45～55℃下搅拌1.5～2.5小时后，冷却至15～25℃，用乙酸乙酯萃取产物，干燥，浓缩。
5.根据权利要求1所述的制备方法，其特征在于，所述氰基还原酶为NR-I/PTDH、NR-I/ADH或NR-II/ADH。
6.根据权利要求5所述的制备方法，其特征在于，所述氰基还原酶为NR-I/PTDH，步骤C具体为：在缓冲液中加入2-氰基-2-环己烷基乙酸、β-烟酰胺腺嘌呤二核苷酸磷酸单钠盐、亚磷酸钠、异丙醇，调节pH值至8.0后，加入NR-I和PTDH进行催化反应，所述催化反应的温度为10～30℃，时间为3～5小时，pH值为7.0～8.5；反应结束后调节pH值至1.5，离心除蛋白杂质；然后调节溶液pH至7.0后利用反渗透除盐，抽干后粗品用乙醇/水结晶；2-氰基-2-环己烷基乙酸、β-烟酰胺腺嘌呤二核苷酸磷酸单钠盐、亚磷酸钠、异丙醇、NR-I与PTDH的用量比为(40～60mM)：(0.1～0.3mM)：(100～150mM)：(20～30mL)：(500～1500U)：(2500～3500U)；
所述氰基还原酶为NR-I/ADH，步骤C具体为：在缓冲液中加入2-氰基-2-环己烷基乙酸、β-烟酰胺腺嘌呤二核苷酸磷酸单钠盐、异丙醇，调节pH值至7.5后，加入NR-I和ADH进行催化反应，所述催化反应的温度为10～30℃，时间为1～3小时，pH值为6.8～8.0；反应结束后调节pH值至1.5，离心除蛋白杂质；然后调节溶液pH至7.0后利用D201阴离子交换树酯除含磷酸杂质，抽干后粗品用乙醇/水结晶；2-氰基-2-环己烷基乙酸、β-烟酰胺腺嘌呤二核苷酸磷酸单钠盐、异丙醇、NR-I与ADH的用量比为(40～60mM)：(0.1～0.3mM)：(30～50mL)：(500～1500U)：(1500～2500U)；
所述氰基还原酶为NR-II/ADH，步骤C具体为：在缓冲液中加入2-氰基-2-环己烷基乙酸、β-烟酰胺腺嘌呤二核苷酸磷酸单钠盐、异丙醇，调节pH值至7.5后，加入NR-II和ADH进行催化反应，所述催化反应的温度为10～30℃，时间为2～4小时，pH值为6.8～8.0，反应结束后调节pH值至1.5，离心除蛋白杂质；然后调节溶液pH至7.0后利用D201阴离子交换树酯除含磷酸杂质，抽干后粗品用乙醇/水结晶；2-氰基-2-环己烷基乙酸、β-烟酰胺腺嘌呤二核苷酸磷酸单钠盐、异丙醇、NR-II与ADH的用量比为(40～60mM)：(0.1～0.3mM)：(30～50mL)：(1500～2500U)：(1500～2500U)。
7.一种氰基还原酶，其特征在于，所述氰基还原酶由酶A和酶B组成，所述酶A为序列如SEQ ID NO：1所示的NR-I或序列如SEQ ID NO：2所示的NR-II中的一种或两种，所述酶B为PTDH或ADH中的一种或两种。
8.根据权利要求7所述的氰基还原酶，其特征在于，所述PTDH序列如SEQ ID NO：3所示，所述ADH序列如SEQ ID NO：4所示。
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