CN112708644A - 氟苯尼考中间体的制备方法 - Google Patents
氟苯尼考中间体的制备方法 Download PDFInfo
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- CN112708644A CN112708644A CN201911022454.8A CN201911022454A CN112708644A CN 112708644 A CN112708644 A CN 112708644A CN 201911022454 A CN201911022454 A CN 201911022454A CN 112708644 A CN112708644 A CN 112708644A
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- Prior art keywords
- reduction reaction
- compound
- nadph
- nadh
- ketoreductase
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Abstract
本发明公开了一种氟苯尼考中间体的制备方法。本发明的制备方法包括以下步骤:在反应体系中,在pH值为7.0的条件下,在酮还原酶和辅酶存在下,将化合物3进行如下式的还原反应,得到化合物1,即可;其中,所述的还原反应温度30℃;所述的酮还原酶的氨基酸序列为如SEQ ID NO.1所示,“和/或”,与如SEQ ID NO.1所示同源性为96%以上的氨基酸序列。该方法在较短时间内转化率可达100%,且立体选择性较高。
Description
技术领域
本发明涉及一种氟苯尼考中间体的制备方法。
背景技术
氟苯尼考又称氟甲砜霉素、氯砜尼可等,为新一代的动物专用广谱抗菌药,其结构类似于甲砜霉素,但其抗菌能力可达甲砜霉素的10倍之多,而且它抗菌谱广,杀菌作用强大,安全高效,没有再生障碍性贫血、致畸、致癌和致突变作用,故其被广泛应用。目前,世界上已有20多个国家批准并允许其销售使用。在国内氟苯尼考已被批准用于猪、禽、鱼等多种动物。(1R,2R)-2-氨基-1-(4-(甲磺酰基)苯基)-1,3-丙二醇是氟苯尼考重要中间体,其结构式为其关键是手性中心的构建。
复旦大学专利CN105152989B公开了由2-(N-叔丁氧甲酰胺基)-3-(4-甲砜基苯基)-3-氧代丙酸乙酯经重排获得2-叔丁氧甲酰胺基-3-(4-甲砜基苯基)-3-氧代丙酸乙酯,再经钌催化剂催化不对称氢化伴随动态动力学拆分,制得(2S,3S)-3-羟基-2-(叔丁氧甲酰胺基)-3-(4-甲砜基苯基)丙酸乙酯,再经甲磺酰氯酯化,硼氢化钠还原,和脱保护制得(1R,2R)-2-氨基-1-(4-(甲磺酰基)苯基)-1,3-丙二醇。
此方法中关键手性中心的建立是采用化学催化法,需要昂贵的金属催化剂,以及产生重金属污染,对环境污染严重,不利于工业化生产。
因此,亟须提供一种对对环境友好的氟苯尼考中间体的制备方法。
发明内容
本发明所要解决的技术问题是为了克服现有技术中在化学催化方法中构建氟苯尼考重要中间体手性中心,需要昂贵的金属催化剂,转化率较低的缺陷,而提供了一种氟苯尼考中间体的制备方法。本发明的制备方法在较短时间内转化率可达100%,且立体选择性较高。
本发明通过以下技术方案解决上述问题。
本发明提供了一种氟苯尼考中间体的制备方法,其包括以下步骤:溶剂中,在pH值为7.0的条件下,在酮还原酶和辅酶存在下,将化合物3进行如下式的还原反应,得到化合物1,即可;
其中,所述的还原反应的温度30℃;所述的酮还原酶的氨基酸序列为如SEQ IDNO.1所示,“和/或”,与如SEQ ID NO.1所示同源性为96%以上的氨基酸序列;
所述的还原反应中,所需要的pH值可通过使用缓冲液来调节和控制。其中,所述的缓冲液的浓度可以为0.09~0.12mol/L,还可以为0.1mol/L。所述的缓冲液可以本领域常规的缓冲液,还可以为磷酸盐缓冲液,进一步可以为磷酸二氢钠-磷酸氢二钠缓冲液。
所述的还原反应中,所述的反应体系还可以包括助溶剂。所述的助溶剂的可以为本领常规的助溶剂,还可以为二甲亚砜(DMSO)。所述的助溶剂与所述的反应体系的体积比可以为0.01:1~0.1:1,还可以为0.05:1。
所述的还原反应中,所述的酮还原酶的氨基酸序列可以为与如SEQ ID NO.1所示同源性为96%以上所示,还进一步可以为如SEQ ID NO.2所示。
所述的还原反应中,所述的酮还原酶的浓度可以为0.1~10U/mL,还可以为0.3~3.25U/ml,又可以为0.3U/ml或3.25U/ml。
所述的还原反应中,所述的辅酶可为本领域此类反应中常规的辅酶,还可以为NADH和/或NADPH。
所述的还原反应中,所述的辅酶的与化合物3的摩尔比可以为1:200-1:2,又可以为1:13。
所述的还原反应中,所述的辅酶可以采用辅酶再生系统原位生成辅酶,辅酶再生系统可以为本领域中常规的辅酶再生系统。当所述的辅酶为NADH和/或NADPH时,所述NADH和/或NADPH的制备方法可以包括以下步骤:在脱氢酶以及供氢体的存在下,将NAD+和/或NADP+进行还原反应,得到所述的NADH和/或NADPH即可。
所述NADH和/或NADPH的制备方法中,所述的脱氢酶可以为葡萄糖脱氢酶、醇脱氢酶或甲酸脱氢酶,还可以为醇脱氢酶,还进一步可为氨基酸序列的NCBI登录号为BAN05992.1。
所述NADH和/或NADPH的制备方法中,所述的供氢体可以为葡萄糖、异丙醇或甲酸盐,还可以为异丙醇。
所述NADH和/或NADPH的制备方法中,当所述的供氢体为异丙醇时,所述的醇脱氢酶的浓度可以为1~20U/mL,还可以为7.5U/mL。
所述NADH和/或NADPH的制备方法中,所述的供氢体与所述的化合物3的摩尔比可以为1:1~20:1,还可以为1:1~10:1,又可以为10:1。
所述的还原反应中,所述的化合物3的浓度可以为10~100mg/mL,还可以为10~15mg/mL,又可以为10mg/ml。
所述的还原反应可以在摇床进行,所述摇床的转速可以为100~300rpm,还可以为220rpm。
所述还原反应的进程可采用本领域此类反应中常规的监测方法进行监测(例如HPLC、LCMS)。一般以所述化合物3消失时作为反应的终点。所述还原反应的时间可为2~6小时,还可以为6小时。
在本发明一技术方案中,所述的氟苯尼考中间体的制备方法,其优选包括下列步骤:
步骤1、将所述的化合物3、所述的缓冲溶液和助溶剂混合,得一混合液;
步骤2、将所述的辅酶和所述的酮还原酶与步骤1得到的混合液混合,进行所述的还原反应。
其中,所述的缓冲溶液、所述的助溶剂、所述的辅酶和所述的酮还原酶均同前所述。
本发明中,浓度若无特殊说明,均为反应前所述化合物占整个反应体系的终浓度。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明的酮还原酶、辅酶和化合物3均为自制,其它所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明的制备方法用于制备氟苯尼考中间体,转化率可达100%,ee值可达99%以上,且反应时间较短。
附图说明
图1为化合物1对照品的HPLC图谱。
图2为实施例3中化合物3的HPLC图谱。
图3为实施例4反应液的HPLC图谱。
图4为实施例5反应液的HPLC图谱。
图5为对照品DL-对甲砜基苯丝氨酸乙酯的手性图谱。
图6为实施例4中化合物1的ee值检测的图谱。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
以下实施例中的酮还原酶、辅酶和化合物3为自制,其仅为一个举例,其他来源的只要能符合酮还原酶、辅酶和化合物3的要求,也适用于本发明。对照品DL-对甲砜基苯丝氨酸乙酯为实验室自行合成,合成方法参考CN102442930A。
本发明中的实验方法如无特别说明均为常规方法。
分析方法
手性分析及浓度分析通过柱前衍生化高效液相色谱进行,具体的条件为:
色谱条件:色谱柱Agilent ZORBAX Eclipse plus C18(4.6mm×150mm,3.5μm);梯度洗脱:流动相A:0.1%TFA+H2O,流动相B:0.1%TFA+ACN(乙腈),10%B(0.01min),100%B(10min),100%B(11min),10%B(11.5min),stop(16min);检测波长:254nm;流速:1.0mL/min;柱温:25℃;进样量:10μL。
手性色谱条件:CHIRALPAK IG(4.6mm×250mm,5μm);流动相:正己烷:乙醇:DEA(40:60:0.1);检测波长:210nm;流速:0.8mL/min;柱温:25℃;进样量:5μL。
实施例1酮还原酶的制备
从NCBI检索到酮还原酶基因和根据专利WO2013062878A1中记载的酮还原酶基因序列全合成酮还原酶基因。合成公司为苏州金唯智生物科技有限公司,江苏省南京市江北新区研创园浦滨路211号。
将合成的酮还原酶基因连pET28a,酶切位点NdeI&HindIII,将酶连好的载体转化至宿主E.coli BL21(DE3)感受态细胞,得到含有酮还原酶的工程菌株。
将含有酮还原酶基因的工程菌株在经平皿划线活化后,挑单菌落接种至含50μg/ml卡那霉素的5ml LB液体培养基中,37℃震荡培养12h。将菌种按2%接种量接种至150ml含50μg/ml卡那霉素TB培养基,37℃震荡至OD600达到0.8左右时,加入IPTG至其终浓度为0.5mM,18℃诱导培养16h。培养结束后,将培养液10000rpm离心10min,弃上清液,收集菌体,置于-80℃超低温冰箱中保存,待用。相关酶信息如表1。
表1
编号 | 类型 | 来源 | NCBI登录号 | 氨基酸序列 |
K111(3) | Oxidoreductase | Exiguobacterium sp.MH3 | NP_012630.1 | SEQ ID NO.1 |
K112(4) | Oxidoreductase | Exiguobacterium sp. | HCV53802 | SEQ ID NO.2 |
将培养结束后收集到的菌体3g,用30mL50mM pH8.0磷酸缓冲液洗涤两次,之后重悬于30mLpH8.0的磷酸缓冲液中,均质破碎,破碎液离心去除沉淀,得到上清液,上清液为含有K111(3)酮还原酶的粗酶液以及含有K112(4)酮还原酶的粗酶液。
酶活检测方法:200μL反应体系,在180μL 0.1M含5%DMSO的pH7.0的磷酸氢二钠-磷酸二氢钠盐缓冲液中,加底物NHBoc-乙酯终浓度为0.7%(质量体积比mg/μL),加入NADH/NADPH至终浓度1mM,加入20μL的粗酶液,25℃测340nm波长的光吸收,做酶动力学曲线,根据NADH/NADPH标准曲线计算酶活。
单位酶活定义:在特定反应条件(25℃,pH7.0)下,每分钟消耗1μmol NADPH/NADH所需的酶量,具体地见表2。
表2
编号 | 类型 | 来源 | NCBI登录号 | 辅酶 | 酶活(U/mL) |
K111(3) | Oxidoreductase | Exiguobacterium sp.MH3 | WP_023468191.1 | NADPH | 1.2 |
K112(4) | Oxidoreductase | Exiguobacterium sp | HCV53802 | NADPH | 13 |
实施例2醇脱氢酶的制备
醇脱氢酶基因的获取与表达
根据来源于Lactobacillus brevis KB290(NCBI登录号为(BAN05992.1)的醇脱氢酶基因,全合成醇脱氢酶基因。
醇脱氢酶基因酶连pET28a,酶切位点NdeI&HindIII,将酶连好的载体,转化宿主大肠杆菌BL21感受态细胞。菌种接种TB培养基于37℃下,200rpm摇床,加入IPTG浓度0.1mM诱导过夜,收菌。菌株加入终浓度为25%的无菌甘油后,编号,置于-80℃低温冰箱保藏备用。
醇脱氢酶菌株的培养与粗酶液的制备
LB液体培养基组成:蛋白胨10g/L,酵母粉5g/L,NaCl 10g/L,用去离子水溶解后定容,121℃灭菌20min,待用。
将含有醇脱氢酶基因的工程菌在经平皿划线活化后,挑单菌落接种至含50μg/ml卡那霉素的5ml LB液体培养基中,37℃震荡培养12h。按2%接种量转接至50ml同样含50μg/ml卡那霉素的新鲜LB液体培养基中,37℃震荡至OD600达到0.8左右时,加入IPTG至其终浓度为0.5mM,18℃诱导培养16h。培养结束后,将培养液10000rpm离心10min,弃上清液,收集菌体,置于-80℃超低温冰箱中保存,待用。
将培养结束后收集到的菌体3g,用50mM pH7.0磷酸缓冲液洗涤菌体两次,之后将菌体重悬于pH7.0的30mL磷酸缓冲液中,超声破碎,破碎液离心去除沉淀,得到上清液含重组醇脱氢酶的粗酶液,测得酶活为75U/mL。
酶活检测方法:1mL反应体系,25℃条件下,先加980μL的pH 7.0 50mM磷酸氢二钠-磷酸二氢钠缓冲液(含异丙醇200mM),再加10μL NADP+(25mM),最后加10μL适量的粗酶液,紫外分光光度计测定340nm处OD值。
单位酶活定义:在特定反应条件(25℃,pH 7.0)下,每分钟产生1μmol NADPH所需要的酶量。
实施例3原料化合物3的制备
化合物7的制备
将4-甲磺酰基苯甲酸(化合物8)(10.0g,49.95mmol)和催化量的DMF置于250mL的单口圆底瓶中,加入DCM(100mL)搅拌溶解,随后慢慢加入SOCl2(11.9g,2.0eq),加毕,升温至45℃回流搅拌过夜。TLC显示原料消失,减压浓缩反应液得11.2g白色固体4-甲磺酰基苯甲酰氯(化合物7),无需纯化直接投下一步。
化合物5的制备
向500mL的三口瓶中依次加入碳酸(7.9g,74.92mmol),EA(180mL)和H2O(100mL),冰盐浴冷却降温至0℃,分批加入甘氨酸乙酯盐酸盐(化合物6),加毕搅拌10min;然后分批加入4-甲磺酰基苯甲酰氯(化合物7),约20min加完。撤去冰浴,室温搅拌反应2h,反应液先浑浊后逐渐澄清。TLC点板显示原料消失,分层,有机相无水硫酸钠干燥,过滤,脱溶得13.8g白色固体化合物5,收率:96.8%。
化合物4的制备
向500mL单口瓶中依次加入化合物5(13.8g,48.37mmol),Boc2O酸酐(15.8g,72.55mmol)和DMAP(0.30g,2.42mmol),接着加入乙腈200mL,氮气保护下升温至70℃搅拌2h,TLC(PE:EA=2:1)显示原料消失反应结束。反应液直接硅胶拌样快速柱纯化(PE:EA=4:1~1:1),得18.1g淡黄色固体化合物4,收率:96.8%。
化合物3的制备
将化合物4(19.4g,50.33mmol)置于夹套反应瓶中,加入2-Me-THF(190mL)搅拌溶解,氮气保护下冷却降温至0℃,滴加叔丁醇钾(7.3g,65.43mmol)的2-Me-THF(100mL)溶液(约40min滴完);加毕反应保温1h,TLC(PE:EA=3:1)显示反应完全。滴加10%的柠檬酸水溶液调节pH=7,接着加入饱和氯化钠溶液洗涤,有机相无水硫酸钠干燥抽滤,减压脱溶得11.2g油状物粗品,收率57.7%。经HPLC检测(保留时间为t为8.489min,具体地见图2)。
实施例4化合物1的制备
在0.1M的pH7.0的磷酸氢二钠-磷酸二氢钠盐缓冲液中,加入100mg化合物3的0.5mL的DMSO溶液至终浓度为26mM,再加入异丙醇200μl(10eq),2mM NAD+/NADP+,实施例1得到的编号为K111(3)的酮还原酶的粗酶液2.5ml(终浓度为0.3U/ml)、醇脱氢酶1mL(终浓度为7.5U/mL),反应体系10ml。在30℃下,220rpm,摇床反应6h,HPLC检测只有产物峰,化学脱Boc,测ee值。
反应结束后,经检测,其MS:M+1为388;HPLC检测,保留时间t为7.284min,具体地见图3(其对照品保留时间t为7.271min(具体地见图1),化合物3保留时间t为8.489min(具体地见图2)),转化率为100%,其ee值为99.82%(具体地见图6)。
实施例5化合物1的制备
按照实施例4的制备方法,将酮还原酶替换为编号为K112(4)酮还原酶的粗酶液(2.5ml,终浓度为3.25U/ml),得到化合物1。
经MS检测,M+1为388;经HPLC检测,保留时间为t为7.273min(具体地见图4),转化率为100%,其ee值为99.9%。
SEQ ID NO 1
1 mkytvitgas sgigyetakl lagkgkslvl varrtselek lrdevkqisp dsdvilksvd
61 ladnqnvhdl yeglkeldie twinnagfgd fdlvqdielg kiekmlrlni ealtilsslf
121 vrdhhdiegt tlvnissagg yrivpnavty catkfyvsay teglaqelqk ggaklrakvl
181 apaatetefa drsrgeagfd ysknvkkyht aaemagflhq liesdaivgi vdgetyefel
241 rgplfnyag
SEQ ID NO 2
1 mkytvitgas sgigyetakl lagkgrslvl varrtselek lrdevkqisp dsdvilksid
61 lsdnqnvhdl yeglneleie twinnagfgd fdlvqdidlg kiekmlrlni ealtilsslf
12 1vrdhhdvegt tlvnissagg yrivpnavty catkfyvsay teglaqelqk ggaklrakvl
181 apaatetefa drsrgevgfd ysknvkkyht aaemagflhq liesdaivgi vdgetyefel
241 rgplfnyag
SEQUENCE LISTING
<110> 上海弈柯莱生物医药科技有限公司
<120> 氟苯尼考中间体的制备方法
<130> P180116974C
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 249
<212> PRT
<213> Exiguobacterium sp. MH3
<400> 1
Met Lys Tyr Thr Val Ile Thr Gly Ala Ser Ser Gly Ile Gly Tyr Glu
1 5 10 15
Thr Ala Lys Leu Leu Ala Gly Lys Gly Lys Ser Leu Val Leu Val Ala
20 25 30
Arg Arg Thr Ser Glu Leu Glu Lys Leu Arg Asp Glu Val Lys Gln Ile
35 40 45
Ser Pro Asp Ser Asp Val Ile Leu Lys Ser Val Asp Leu Ala Asp Asn
50 55 60
Gln Asn Val His Asp Leu Tyr Glu Gly Leu Lys Glu Leu Asp Ile Glu
65 70 75 80
Thr Trp Ile Asn Asn Ala Gly Phe Gly Asp Phe Asp Leu Val Gln Asp
85 90 95
Ile Glu Leu Gly Lys Ile Glu Lys Met Leu Arg Leu Asn Ile Glu Ala
100 105 110
Leu Thr Ile Leu Ser Ser Leu Phe Val Arg Asp His His Asp Ile Glu
115 120 125
Gly Thr Thr Leu Val Asn Ile Ser Ser Ala Gly Gly Tyr Arg Ile Val
130 135 140
Pro Asn Ala Val Thr Tyr Cys Ala Thr Lys Phe Tyr Val Ser Ala Tyr
145 150 155 160
Thr Glu Gly Leu Ala Gln Glu Leu Gln Lys Gly Gly Ala Lys Leu Arg
165 170 175
Ala Lys Val Leu Ala Pro Ala Ala Thr Glu Thr Glu Phe Ala Asp Arg
180 185 190
Ser Arg Gly Glu Ala Gly Phe Asp Tyr Ser Lys Asn Val Lys Lys Tyr
195 200 205
His Thr Ala Ala Glu Met Ala Gly Phe Leu His Gln Leu Ile Glu Ser
210 215 220
Asp Ala Ile Val Gly Ile Val Asp Gly Glu Thr Tyr Glu Phe Glu Leu
225 230 235 240
Arg Gly Pro Leu Phe Asn Tyr Ala Gly
245
<210> 2
<211> 249
<212> PRT
<213> Exiguobacterium sp
<400> 2
Met Lys Tyr Thr Val Ile Thr Gly Ala Ser Ser Gly Ile Gly Tyr Glu
1 5 10 15
Thr Ala Lys Leu Leu Ala Gly Lys Gly Arg Ser Leu Val Leu Val Ala
20 25 30
Arg Arg Thr Ser Glu Leu Glu Lys Leu Arg Asp Glu Val Lys Gln Ile
35 40 45
Ser Pro Asp Ser Asp Val Ile Leu Lys Ser Ile Asp Leu Ser Asp Asn
50 55 60
Gln Asn Val His Asp Leu Tyr Glu Gly Leu Asn Glu Leu Glu Ile Glu
65 70 75 80
Thr Trp Ile Asn Asn Ala Gly Phe Gly Asp Phe Asp Leu Val Gln Asp
85 90 95
Ile Asp Leu Gly Lys Ile Glu Lys Met Leu Arg Leu Asn Ile Glu Ala
100 105 110
Leu Thr Ile Leu Ser Ser Leu Phe Val Arg Asp His His Asp Val Glu
115 120 125
Gly Thr Thr Leu Val Asn Ile Ser Ser Ala Gly Gly Tyr Arg Ile Val
130 135 140
Pro Asn Ala Val Thr Tyr Cys Ala Thr Lys Phe Tyr Val Ser Ala Tyr
145 150 155 160
Thr Glu Gly Leu Ala Gln Glu Leu Gln Lys Gly Gly Ala Lys Leu Arg
165 170 175
Ala Lys Val Leu Ala Pro Ala Ala Thr Glu Thr Glu Phe Ala Asp Arg
180 185 190
Ser Arg Gly Glu Val Gly Phe Asp Tyr Ser Lys Asn Val Lys Lys Tyr
195 200 205
His Thr Ala Ala Glu Met Ala Gly Phe Leu His Gln Leu Ile Glu Ser
210 215 220
Asp Ala Ile Val Gly Ile Val Asp Gly Glu Thr Tyr Glu Phe Glu Leu
225 230 235 240
Arg Gly Pro Leu Phe Asn Tyr Ala Gly
245
Claims (10)
2.如权利要求1所述的制备方法,其特征在于,所述的还原反应中,所述的酮还原酶的浓度为0.1~10U/mL;
和/或,所述的还原反应中,所述的辅酶的与化合物3的摩尔比为1:200-1:2;
和/或,所述的还原反应中,所述的化合物3的浓度为10~100mg/mL;
和/或,所述的酮还原酶的氨基酸序列如SEQ ID NO.2所示;
和/或,所述的还原反应的时间为2~6小时。
3.如权利要求2所述的制备方法,其特征在于,所述的还原反应中,所述的酮还原酶的浓度为0.3~3.25U/ml;
和/或,所述的还原反应中,所述的辅酶的与化合物3的摩尔比为1:13;
和/或,所述的还原反应中,所述的化合物3的浓度为10~15mg/mL;
和/或,所述还原反应的时间为6小时。
4.如权利要求3所述的制备方法,其特征在于,所述的还原反应中,所述的酮还原酶的浓度为0.3U/ml或3.25U/ml;
和/或,所述的还原反应中,所述的化合物3的浓度为10mg/ml。
5.如权利要求1所述的制备方法,其特征在于,所述的还原反应中pH值通过使用缓冲液来控制和调节;
和/或,所述的还原反应中还包括助溶剂;
和/或,所述的还原反应中,所述的酮还原酶的氨基酸序列为SEQ ID NO.1所示同源性为96%以上的氨基酸序列;
和/或,所述的还原反应中,所述的辅酶为NADH和/或NADPH;
和/或,所述的还原反应在摇床中进行。
6.如权利要求5所述的制备方法,其特征在于,所述的缓冲液的浓度为0.09~0.12mol/L;
和/或,所述的缓冲液为磷酸盐缓冲液;
和/或,所述的助溶剂为二甲亚砜;
和/或,所述的助溶剂与所述的反应体系的体积比为0.01:1~0.1:1;
和/或,当所述的辅酶为NADH和/或NADPH时,所述NADH和/或NADPH的制备方法包括下列步骤:在脱氢酶以及供氢体的存在下,将NAD+和/或NADP+进行还原反应,得到所述的NADH和/或NADPH即可。
7.如权利要求6所述的制备方法,其特征在于,所述的缓冲液的浓度为0.1mol/L;
和/或,所述的缓冲液磷酸二氢钠-磷酸氢二钠缓冲液;
和/或,所述的助溶剂与所述的反应体系的体积比为0.05:1;
和/或,所述NADH和/或NADPH的制备方法中,所述的脱氢酶为葡萄糖脱氢酶、醇脱氢酶或甲酸脱氢酶;
和/或,所述NADH和/或NADPH的制备方法中,所述的供氢体为葡萄糖、异丙醇或甲酸盐;
和/或,所述的供氢体与所述的化合物3的摩尔比为1:1~20:1。
8.如权利要求7所述的制备方法,其特征在于,所述NADH和/或NADPH的制备方法中,所述的脱氢酶为醇脱氢酶;
和/或,所述NADH和/或NADPH的制备方法中,所述的供氢体为异丙醇;
和/或,所述NADH和/或NADPH的制备方法中,所述的供氢体与所述的化合物3的摩尔比为1:1~10:1。
9.如权利要求8所述的制备方法,其特征在于,所述NADH和/或NADPH的制备方法中,当所述的供氢体为异丙醇时,所述的醇脱氢酶的浓度为1~20U/mL;
和/或,所述NADH和/或NADPH的制备方法中,当所述的脱氢酶为醇脱氢酶时,所述的醇脱氢酶氨基酸序列的NCBI登录号为BAN05992.1;
和/或,所述NADH和/或NADPH的制备方法中,所述的供氢体与所述的化合物3的摩尔比为10:1。
10.如权利要求1~9任一项所述的制备方法,其特征在于,所述的氟苯尼考中间体的制备方法,其包括下列步骤:
步骤1、将所述的化合物3、所述的缓冲溶液和助溶剂混合,得一混合液;
步骤2、将所述的辅酶和所述的酮还原酶与步骤1得到的混合液混合,进行所述的还原反应。
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