CN111500652B - 一种制备氟苯尼考的方法 - Google Patents
一种制备氟苯尼考的方法 Download PDFInfo
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- CN111500652B CN111500652B CN201910387166.6A CN201910387166A CN111500652B CN 111500652 B CN111500652 B CN 111500652B CN 201910387166 A CN201910387166 A CN 201910387166A CN 111500652 B CN111500652 B CN 111500652B
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Abstract
本发明公开了一种制备氟苯尼考的方法，其特征在于，以式Ⅰ化合物为原料，加入酮还原酶，在酮还原酶催化还原酮羰基的同时动态动力学拆分得到式Ⅱ化合物，再将式Ⅱ化合物的三元环进行开环氟化和可选的进行去保护、二氯乙酰化反应制得氟苯尼考。
Description
技术领域
本发明属于生物制药和生物化工技术领域，具体涉及一种氟苯尼考的制备方法。
背景技术
氟苯尼考又称氟甲砜霉素是一种动物专用的广谱抗生素，主要用于牛、猪、鸡鸭、鱼等动物的细菌性疾病。氟苯尼考结构与甲砜霉素相似，但抗菌活性是甲砜霉素的10倍之多；并且抗菌广谱性及不良反应方面明显优于甲砜霉素。目前氟苯尼考已经成为动物类的主要抗菌药物。鉴于其优良的药效，其应用前景非常广阔。因此氟苯尼考的合成一直受到很大的重视。
氟苯尼考，其结构式如下所示：
目前工业制备氟苯尼考主要是以对甲砜基苯甲醛、甘氨酸等为起始原料，通过缩合、酯化、拆分等步骤制备(2S,3R)-对甲砜基苯丝氨酸乙酯(D-乙酯)。再在D-乙酯为原料的基础上，通过还原、与苄腈反应制备噁唑啉、Ishikawa试剂作用下氟化、水解以及二氯乙酰化等步骤生产，其合成线路如下所示：
目前的氟苯尼考的工业化生产路线必须使用到关键中间体D-乙酯，而生产D-乙酯需要硫酸铜络合制备氨基酸铜盐以及手性拆分等步骤，生产过程中产生大量的硫酸铜废水，并且手性拆分过程浪费了50％的原料，此方法不仅对环境危害大，成本也比较高。另外此工艺在D-乙酯的还原步骤会产生大量的含硼盐废水，处理比较困难，环境负担比较大。在氟化反应步骤需要使用当量的Ishikawa试剂，这类试剂氟原子利用率比较低，成本比较高，对设备的腐蚀性也比较大。综上所述，现有的氟苯尼考生产路线存在生产成本高、环境污染严重等缺陷，因此寻找更合适的工业化生产路线是很有价值的。
鉴于此，化学工作者发展了一些不对称合成氟苯尼考的方法。最近有专利报道了利用对[氮丙啶-2-基][4-(甲砜基)苯基]甲酮进行还原得到的相应的醇中间体，再利用氮丙啶三元环在酸性环境容易开环的性质合成氟苯尼考。比如：
中国专利(公开号CN102827042A)报道了利用手性配体-金属钌催化剂催化氢化制备氮丙啶-2-基][4-(甲砜基)苯基]甲醇，再通过三元环开环制备氟苯尼考。反应过程如下所示：
该方法，利用不对称催化还原避免了手性拆分，原子经济性较高。但是此方法存在催化剂价格昂贵、需要特殊的高压设备反应器等缺点，导致此方法很难实现工业化。
中国专利(公开号CN103936638A)报道了从手性[氮丙啶-2-基][4-(甲砜基)苯基]甲酮出发，通过选择性还原、醇的构型反转、三元环开环等步骤制备氟苯尼考，反应过程如下所示：
该方法，手性原料价格昂贵，反应步骤多，生产成本较高导致此方法工业化价值不大。
中国专利(公开号CN 106316898 A)报道了从手性[氮丙啶-2-基][4-(甲砜基)苯基]甲酮出发，通过在低温条件下利用大位阻还原剂还原得到所需构型的中间体醇、再经过三元环开环、脱保护、二氯乙酰化等步骤制备氟苯尼考，反应过程如下所示：
该方法，手性原料、大位阻的还原剂价格都比较昂贵，反应过程需要低温进行，生产成本较高导致此方法工业化价值不大。
发明内容
本发明针对现有技术的不足，提供了一种简单易行的合成氟苯尼考的新方法，该方法操作简单，条件温和，大幅度降低了生产的成本，适合大规模的工业化生产。
本发明的公开了一种制备氟苯尼考的方法，其特征在于，以式Ⅰ化合物为原料，
加入酮还原酶，在酮还原酶催化还原酮羰基的同时动态动力学拆分得到式Ⅱ化合物式Ⅰ、式Ⅱ中，R为保护基，
再将式Ⅱ化合物的三元环进行开环氟化和可选的进行去保护、二氯乙酰化反应制得氟苯尼考。
优选的，所述R为乙酰基、苄基或-COCHCl2；
优选的，所述开环氟化的步骤通过加入三乙胺氢氟酸盐完成；
优选的，所述酶反应过程中，添加辅酶烟酰胺腺嘌呤双核苷酸作为再生体系；
优选的，添加葡萄糖和葡萄糖脱氢酶实现辅酶烟酰胺腺嘌呤双核苷酸的再生；
优选的，添加异丙醇和可选的添加醇脱氢酶实现辅酶烟酰胺腺嘌呤双核苷酸的再生。
本发明的反应过程如下：
其中，酮还原-动态拆分过程如下：
优选的，当保护基R为COCHCl2时，只需要两步反应即可完成，反应过程如下：
具体实施方式
下面结合具体实施例对本发明做进一步详细的说明，但本发明并不限于以下实施例。
实施例1-5中，R＝乙酰基，反应路线如下：
实施例1：合成化合物(R)-[(R)-1-乙酰基氮丙啶-2-基][4-(甲砜基)苯基]甲醇
在500mL反应瓶中加入0.05M的磷酸缓冲液(pH＝7.5)240g，在搅拌下加入26.7g1-乙酰基-2-(4-甲砜基苯基)甲酰基氮丙啶，20克异丙醇。控制体系温度至35℃，搅拌均匀，在搅拌下依次加入60mg烟酰胺腺嘌呤双核苷酸、1.4g酮还原酶酶粉(购自苏州引航生物科技有限公司，商品编号为YH2068)。开始搅拌反应，20小时后取样HPLC检测，转化率98％以上，反应结束。体系中加入240mL乙酸乙酯，搅拌1小时，过滤(硅藻土助滤除酶)。滤液分层取有机层，水层用乙酸乙酯萃取(3×100mL)，合并有机相，干燥脱溶得到粗品24.8g。收率93％，ee>99％，de 96％产品无需纯化直接用于下一步反应。
实施例2：合成化合物(R)-[(R)-1-乙酰基氮丙啶-2-基][4-(甲砜基)苯基]甲醇
1-乙酰基-2-(4-甲砜基苯基)甲酰基氮丙啶26.7g、葡萄糖20g置于500mL的三口烧瓶，加入270mL pH＝7.5，0.05M的磷酸缓冲液。将三口烧瓶放入反应锅中，设置转速850rpm,温度35℃。然后分别加入60mg烟酰胺腺嘌呤双核苷酸,1.5g葡萄糖脱氢酶(采购自苏州引航生物科技有限公司：商品编号YH1901，或其他已知的葡萄糖脱氢酶)、以及1.5g酮还原酶粉(采购自苏州引航生物科技有限公司：商品编号YH2068)。开始反应，反应过程中用2M的NaOH溶液将pH维持在7.5左右，HPLC监测反应。24小时后反应转化率>98％。反应完毕，反应体系中加入240mL乙酸乙酯，搅拌1小时，过滤(硅藻土助滤除酶)。滤液分层取有机层，水层用乙酸乙酯萃取(3×100mL)，合并有机相，干燥脱溶得到粗品25.2g。收率94.3％，ee>99％，de98％产品无需纯化直接用于下一步反应。
实施例1-2所述YH2068酮还原酶，具有SEQ ID NO.1所示氨基酸序列，其核苷酸序列为SEQ ID NO.2。
实施例3：合成(1R,2S)-3-氟-1-[4-(甲砜基)苯基]-2-乙酰氨基-1-丙醇
将26.9g(R)-[(R)-1-乙酰基氮丙啶-2-基][4-(甲砜基)苯基]甲醇溶解在300ml氯仿中置于500mL的三口烧瓶中，称取30克无水三乙胺氢氟酸盐加入溶液中，加热回流24小时，HPLC监测反应，反应完全后体系降至室温。反应体系中加入200克冰水，用碳酸氢钠调节PH＝8-9,分液，取氯仿层，水相用氯仿萃取(2×100mL)，合并有机相，干燥脱溶得到粗品。粗品用乙醇重结晶得到产品23.4克。
实施例4：合成氟苯尼考氨基物
将28.9g(1R,2S)-3-氟-1-[4-(甲砜基)苯基]-2-乙酰氨基-1-丙醇甲醇溶解在300mL甲醇与100mL 2M KOH的混合溶液中，反应体系加热回流24小时，HPLC监测反应。待反应完全后甲醇蒸去，用二氯甲烷萃取，取有机层，合并有机相，干燥脱溶得到粗品。粗品结晶得到21.2g产品。
实施例5：合成氟苯尼考
在装有搅拌器、回流冷凝器、温度计的100mL三颈瓶中，加入氟苯尼考氨基物24.5g，甲醇100mL和二氯乙酸甲酯20mL。在60-65℃搅拌反应过夜，随后加入活性炭2.5g，保温脱色30min，趁热过滤，向滤液中滴加蒸馏水至有少量结晶析出时停止加水，稍停片刻，继续加入剩余蒸馏水(共350mL)。冷至室温，放置30min，抽滤，滤饼用蒸馏水洗涤，抽干，即得氟苯尼考31g。
实施例6-10中，R＝苄基，反应路线如下：
实施例6：合成化合物(R)-[(R)-1-苄基氮丙啶-2-基][4-(甲砜基)苯基]甲醇
在500mL反应瓶中加入0.05M的磷酸缓冲液(pH＝7.5)300g，在搅拌下加入31.5g1-苄基-2-(4-甲砜基苯基)甲酰基氮丙啶，30克异丙醇。控制体系温度至35℃，搅拌均匀，在搅拌下依次加入63mg烟酰胺腺嘌呤双核苷酸、1.6g酮还原酶酶粉(购自苏州引航生物科技有限公司，商品编号为YH2077)。开始搅拌反应，20小时后取样HPLC检测，转化率97％以上，反应结束。体系中加入300mL乙酸乙酯，搅拌1小时，过滤(硅藻土助滤除酶)。滤液分层取有机层，水层用乙酸乙酯萃取(3×100mL)，合并有机相，干燥脱溶得到粗品29g。收率92％，ee>99％，de 94％产品无需纯化直接用于下一步反应。
实施例7：合成化合物(R)-[(R)-1-苄基氮丙啶-2-基][4-(甲砜基)苯基]甲醇
1-苄基-2-(4-甲砜基苯基)甲酰基氮丙啶31.5g、葡萄糖20g置于500mL的三口烧瓶，加入320mL pH＝7.5，0.05M的磷酸缓冲液。将三口烧瓶放入反应锅中，设置转速850rpm,温度35℃。然后分别加入63mg烟酰胺腺嘌呤双核苷酸,1.6g葡萄糖脱氢酶(采购自苏州引航生物科技有限公司：商品编号YH1901，或其他已知的葡萄糖脱氢酶)、以及1.6g酮还原酶粉(采购自苏州引航生物科技有限公司：商品编号YH2077)。开始反应，反应过程中用2M的NaOH溶液将pH维持在7.5左右，HPLC监测反应。24小时后反应转化率>98％。反应完毕，反应体系中加入300mL乙酸乙酯，搅拌1小时，过滤(硅藻土助滤除酶)。滤液分层取有机层，水层用乙酸乙酯萃取(3×100mL)，合并有机相，干燥脱溶得到粗品28.2g。收率88.9％，ee>99％，de95％产品无需纯化直接用于下一步反应。
实施例6-7所述YH2077酮还原酶，具有SEQ ID NO.3所示氨基酸序列，其核苷酸序列为SEQ ID NO.4。
实施例8：合成(1R,2S)-3-氟-1-[4-(甲砜基)苯基]-2-苄氨基-1-丙醇
将31.7g(R)-[(R)-1-苄基氮丙啶-2-基][4-(甲砜基)苯基]甲醇溶解在300ml氯仿中置于500mL的三口烧瓶中，称取30克无水三乙胺氢氟酸盐加入溶液中，加热回流24小时，HPLC监测反应，反应完全后将至室温。反应体系中加入200克冰水，用碳酸氢钠调节PH＝8-9,分液，取氯仿层，水相用氯仿萃取(2×100mL)，合并有机相，干燥脱溶得到粗品。粗品用乙醇重结晶得到产品24.9克。
实施例9：合成氟苯尼考氨基物
将33.7g(1R,2S)-3-氟-1-[4-(甲砜基)苯基]-2-苄氨基-1-丙醇甲醇溶解在300mL甲醇，体系中加入3.5g 5％的湿Pd/C，常压通入氢气，常温反应5小时，HPLC监测反应。反应完全后，干燥脱溶得到粗品25g。
实施例10：合成氟苯尼考
在装有搅拌器、回流冷凝器、温度计的100mL三颈瓶中，加入氟苯尼考氨基物粗品25g，甲醇100mL和二氯乙酸甲酯20mL。在60-65℃搅拌反应过夜，随后加入活性炭2.5g，保温脱色30min，趁热过滤，向滤液中滴加蒸馏水至有少量结晶析出时停止加水，稍停片刻，继续加入剩余蒸馏水(共350mL)。冷至室温，放置30min，抽滤，滤饼用蒸馏水洗涤，抽干，即得氟苯尼考29g。
实施例11-13中，R＝COCHCl2，反应路线如下：
实施例11：合成化合物(R)-[(R)-1-二氯乙酰基氮丙啶-2-基][4-(甲砜基)苯基]甲醇
在500mL反应瓶中加入0.05M的磷酸缓冲液(pH＝7.5)300mL，在搅拌下加入33.6g1-二氯乙酰基-2-(4-甲砜基苯基)甲酰基氮丙啶，30克异丙醇。控制体系温度至35℃，搅拌均匀，在搅拌下依次加入68mg烟酰胺腺嘌呤双核苷酸、1.7g酮还原酶酶粉(购自苏州引航生物科技有限公司，商品编号为YH2045)。开始搅拌反应，20小时后取样HPLC检测，转化率99％以上，反应结束。体系中加入300mL乙酸乙酯，搅拌1小时，过滤(硅藻土助滤除酶)。滤液分层取有机层，水层用乙酸乙酯萃取(3×100mL)，合并有机相，干燥脱溶得到粗品31.9g。收率95％，ee>99％，de 98％产品无需纯化直接用于下一步反应。
实施例12：合成化合物(R)-[(R)-1-二氯乙酰基氮丙啶-2-基][4-(甲砜基)苯基]甲醇
二氯乙酰基-2-(4-甲砜基苯基)甲酰基氮丙啶33.6g、葡萄糖20g置于500mL的三口烧瓶，加入340mL pH＝7.5，0.05M的磷酸缓冲液。将三口烧瓶放入反应锅中，设置转速850rpm,温度35℃。然后分别加入68mg烟酰胺腺嘌呤双核苷酸,1.7g葡萄糖脱氢酶(采购自苏州引航生物科技有限公司：商品编号YH1901，或其他已知的葡萄糖脱氢酶)、以及1.7g酮还原酶粉(采购自苏州引航生物科技有限公司：商品编号YH2045)。开始反应，反应过程中用2M的NaOH溶液将pH维持在7.5左右，HPLC监测反应。24小时后反应转化率>98％。反应完毕，反应体系中加入300mL乙酸乙酯，搅拌1小时，过滤(硅藻土助滤除酶)。滤液分层取有机层，水层用乙酸乙酯萃取(3×100mL)，合并有机相，干燥脱溶得到粗品31.5g。收率94％，ee>99％，de 98％产品无需纯化直接用于下一步反应。
实施例11-12所述YH2045酮还原酶，具有SEQ ID NO.5所示氨基酸序列，其核苷酸序列为SEQ ID NO.6。
实施例13：合成氟苯尼考
将33.8g(R)-[(R)-1-二氯乙酰基氮丙啶-2-基][4-(甲砜基)苯基]甲醇溶解在350ml氯仿中置于500mL的三口烧瓶中，称取30克无水三乙胺氢氟酸盐加入溶液中，加热回流24小时，HPLC监测反应，反应完全后降至室温。反应体系中加入200克冰水，用碳酸氢钠调节PH＝8-9,分液，取氯仿层，水相用氯仿萃取(2×100mL)，合并有机相，干燥脱溶得到粗品。粗品用甲醇-水重结晶得到产品氟苯尼考28.9克。
实施例14：重组酮还原酶摇瓶表达
上述酮还原酶基因序列通过普通的分子克隆手段构建到pET30a表达质粒中。重组质粒被转化至大肠杆菌BL21(DE3)细胞中得到重组菌。接种单克隆至含有50μg/mL卡那霉素的LB培养基(蛋白胨10g/L，酵母粉5g/L，NaCl 10g/L，pH7.0)中，37度培养过夜。过夜培养物转接至TB培养基(蛋白胨12g/L，酵母提取物24g/L，甘油4mL/L，磷酸二氢钾2.31g/L，磷酸氢二钾12.54g/L)，37度培养至OD600到0.6-0.8，加入终浓度为0.4mM的IPTG，30度诱导表达过夜。离心收集细胞后重悬于20mM pH7.0的磷酸缓冲液，超声破碎细胞，离心，取上清做反应或冻存于-20度以下。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
序列表
<110> 苏州引航生物科技有限公司
<120> 一种制备氟苯尼考的方法
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caacacgatg cttctgatga agccggctgg actaagttgt ttgatacgac tgaagaagca 240
tttggcccag ttaccacggt tgtcaacaat gccggaattg cggtcagcaa gagtgttgaa 300
gataccacaa ctgaagaatg gcgcaagctg ctctcagtta acttggatgg tgtcttcttc 360
ggtacccgtc ttggaatcca acgtatgaag aataaaggac tcggagcatc aatcatcaat 420
atgtcatcta tcgaaggttt tgttggtgat ccaactctgg gtgcatacaa cgcttcaaaa 480
ggtgctgtca gaattatgtc taaatcagct gccttggatt gcgctttgaa ggactacgat 540
gttcgggtta acactgttca tccaggttat atcaagacac cattggttga cgatcttgaa 600
ggggcagaag aaatgatgtc acagcggacc aagacaccaa tgggtcatat cggtgaacct 660
aacgatatcg cttggatctg tgtttacctg gcatctgacg aatctaaatt tgccactggt 720
gcagaattcg ttgtcgatgg tggatacact gctcaataa 759
<210> 3
<211> 252
<212> PRT
<213> 人工序列()
<400> 3
Met Thr Asp Arg Leu Lys Gly Lys Val Ala Ile Val Thr Gly Gly Thr
1 5 10 15
Leu Gly Ile Gly Leu Ala Ile Ala Asp Lys Phe Val Glu Glu Gly Ala
20 25 30
Lys Val Val Ile Thr Gly Arg His Ala Asp Val Gly Glu Lys Ala Ala
35 40 45
Lys Ser Ile Gly Gly Thr Asp Val Ile Arg Phe Val Gln His Asp Ala
50 55 60
Ser Asp Glu Ala Gly Trp Thr Lys Leu Phe Asp Thr Thr Glu Glu Ala
65 70 75 80
Phe Gly Pro Val Thr Thr Val Val Asn Asn Ala Gly Ile Ala Val Ser
85 90 95
Asn Ser Val Glu Asp Thr Thr Thr Glu Glu Trp Arg Lys Leu Leu Ser
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 Thr Pro 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 Glu Gly Ala Glu Glu Met Met Ser Gln
195 200 205
Arg Thr Lys Thr Pro Met Gly His Ile Gly Glu Thr Asn Asp Ile Ala
210 215 220
Trp Ile Cys Val Tyr Leu Ala Ser Asp Glu Ser Lys Phe Ala Thr Gly
225 230 235 240
Ala Glu Phe Val Val Asp Gly Gly Tyr Thr Ala Gln
245 250
<210> 4
<211> 759
<212> DNA
<213> 人工序列()
<400> 4
atgactgatc gtttaaaagg caaagtagca attgtaactg gcggtacctt gggaattggc 60
ttggcaatcg ctgataagtt tgttgaagaa ggcgcaaagg ttgttattac cggccgtcac 120
gctgatgtag gtgaaaaagc tgccaaatca atcggcggca cagacgttat ccgttttgtc 180
caacacgatg cttctgatga agccggctgg actaagttgt ttgatacgac tgaagaagca 240
tttggcccag ttaccacggt tgtcaacaat gccggaattg cggtcagcaa tagtgttgaa 300
gataccacaa ctgaagaatg gcgcaagctg ctctcagtta acttggatgg tgtcttcttc 360
ggtacccgtc ttggaatcca acgtatgaag aataaaggac tcggagcatc aatcatcaat 420
atgtcatcta tcgaaggttt tgttggtgat ccaactccgg gtgcatacaa cgcttcaaaa 480
ggtgctgtca gaattatgtc taaatcagct gccttggatt gcgctttgaa ggactacgat 540
gttcgggtta acactgttca tccaggttat atcaagacac cattggttga cgatcttgaa 600
ggggcagaag aaatgatgtc acagcggacc aagacaccaa tgggtcatat cggtgaaact 660
aacgatatcg cttggatctg tgtttacctg gcatctgacg aatctaaatt tgccactggt 720
gcagaattcg ttgtcgatgg tggatacact gctcaataa 759
<210> 5
<211> 252
<212> PRT
<213> 人工序列()
<400> 5
Met Thr Asp Arg Leu Lys Gly Lys Val Ala Ile Val Thr Gly Gly Thr
1 5 10 15
Leu Gly Ile Gly Leu Ala Ile Ala Asp Lys Phe Val Glu Glu Gly Ala
20 25 30
Lys Val Val Ile Thr Gly Arg His Ala Asp Val Gly Glu Lys Ala Ala
35 40 45
Lys Ser Ile Gly Gly Thr Asp Val Ile Arg Phe Val Gln His Asp Ala
50 55 60
Ser Asp Glu Ala Gly Trp Thr Lys Leu Phe Asp Thr Thr Glu Glu Ala
65 70 75 80
Phe Gly Pro Val Thr Thr Val Val Asn Asn Ala Gly Ile Ala Val Ser
85 90 95
Asn Ser Val Glu Asp Thr Thr Thr Glu Glu Trp Arg Lys Leu Leu Ser
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 Thr Pro 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 Glu Gly Ala Glu Glu Met Met Ser Gln
195 200 205
Arg Thr Lys Thr Pro Met Gly His Ile Gly Glu Thr Asn Asp Ile Ala
210 215 220
Trp Ile Cys Val Tyr Leu Ala Ser Asp Glu Ser Lys Phe Ala Thr Gly
225 230 235 240
Ala Glu Phe Val Val Asp Gly Gly Tyr Thr Ala Gln
245 250
<210> 6
<211> 759
<212> DNA
<213> 人工序列()
<400> 6
atgactgatc gtttaaaagg caaagtagca attgtaactg gcggtacctt gggaattggc 60
ttggcaatcg ctgataagtt tgttgaagaa ggcgcaaagg ttgttattac cggccgtcac 120
gctgatgtag gtgaaaaagc tgccaaatca atcggcggca cagacgttat ccgttttgtc 180
caacacgatg cttctgatga agccggctgg actaagttgt ttgatacgac tgaagaagca 240
tttggcccag ttaccacggt tgtcaacaat gccggaattg cggtcagcaa tagtgttgaa 300
gataccacaa ctgaagaatg gcgcaagctg ctctcagtta acttggatgg tgtcttcttc 360
ggtacccgtc ttggaatcca acgtatgaag aataaaggac tcggagcatc aatcatcaat 420
atgtcatcta tcgaaggttt tgttggtgat ccaactccgg gtgcatacaa cgcttcaaaa 480
ggtgctgtca gaattatgtc taaatcagct gccttggatt gcgctttgaa ggactacgat 540
gttcgggtta acactgttca tccaggttat atcaagacac cattggttga cgatcttgaa 600
ggggcagaag aaatgatgtc acagcggacc aagacaccaa tgggtcatat cggtgaaact 660
aacgatatcg cttggatctg tgtttacctg gcatctgacg aatctaaatt tgccactggt 720
gcagaattcg ttgtcgatgg tggatacact gctcaataa 759
Claims (5)
1.一种制备氟苯尼考的方法，其特征在于，以式Ⅰ化合物为原料，加入酮还原酶，在酮还原酶催化还原酮羰基的同时动态动力学拆分得到式Ⅱ化合物，式Ⅰ、式Ⅱ中，R为乙酰基、苄基或-COCHCl2，
当R为-COCHCl2时，将式Ⅱ化合物的三元环进行开环氟化反应制得氟苯尼考，当R不为-COCHCl2时，将式Ⅱ化合物的三元环进行开环氟化反应,再进行去保护、二氯乙酰化反应制得氟苯尼考，所述酮还原酶具有SEQ ID NO.1、3或5所示氨基酸序列。
2.如权利要求1所述的方法，其特征在于，所述开环氟化的步骤通过加入三乙胺氢氟酸盐完成。
3.如权利要求1所述的方法，其特征在于，所述酶反应过程中，添加辅酶烟酰胺腺嘌呤双核苷酸作为再生体系。
4.如权利要求3所述的方法，其特征在于，添加葡萄糖和葡萄糖脱氢酶实现辅酶烟酰胺腺嘌呤双核苷酸的再生。
5.如权利要求3所述的方法，其特征在于，添加异丙醇和添加醇脱氢酶实现辅酶烟酰胺腺嘌呤双核苷酸的再生。
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| WO2015157927A1 (zh) * | 2014-04-16 | 2015-10-22 | 湖北美天生物科技有限公司 | 氟苯尼考的合成方法 |
| CN106316898A (zh) * | 2016-08-04 | 2017-01-11 | 湖北美天生物科技股份有限公司 | 氟苯尼考的合成方法 |
| CN109207531A (zh) * | 2017-07-03 | 2019-01-15 | 上海医药工业研究院 | 甲砜霉素与氟苯尼考关键中间体的生物制备方法 |
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| WO2015157927A1 (zh) * | 2014-04-16 | 2015-10-22 | 湖北美天生物科技有限公司 | 氟苯尼考的合成方法 |
| CN106316898A (zh) * | 2016-08-04 | 2017-01-11 | 湖北美天生物科技股份有限公司 | 氟苯尼考的合成方法 |
| CN109207531A (zh) * | 2017-07-03 | 2019-01-15 | 上海医药工业研究院 | 甲砜霉素与氟苯尼考关键中间体的生物制备方法 |
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