CN1051803C - 制备6－羟基含氮六元环化合物的方法 - Google Patents

制备6－羟基含氮六元环化合物的方法 Download PDF

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CN1051803C
CN1051803C CN93103482A CN93103482A CN1051803C CN 1051803 C CN1051803 C CN 1051803C CN 93103482 A CN93103482 A CN 93103482A CN 93103482 A CN93103482 A CN 93103482A CN 1051803 C CN1051803 C CN 1051803C
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安田磨理
大岸治行
佐藤胜利
森本裕纪
长泽透
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Abstract

制备下式的6－羟基含氮六元环化合物的方法：
其中R1表示氰基、氨基甲酰基、甲酰基，该方法包括使下式的化合物
其中R1如上定义，与微生物在含水介质中反应。在吩嗪甲硫酸酯的存在下该反应可提高上述反应的效率。

Description

制备6-羟基含氮六元环化合物的方法
本发明涉及制备6-羟基含氮六元环化合物的方法。更具体地说，本发明涉及制备6-羟基吡啶衍生物及6-羟基吡嗪衍生物的方法，它们利用微生物反应，作为制备药物、农药、染料或其类似物的中间体是有用的。
各种含氮六元环化合物如二氢吡啶、烟酸等，可以作为制备药物、农药、染料或其类似物的重要合成中间体。例如，最近研究了一种作用于烟酸受体的新型杀虫剂，和由下面通式所表示的lmidacloprid(Nippon Tokushu Noyaku Co.)是这种新杀虫剂其中之一
Figure C9310348200041
作为制备Imidacloprid的中间体，3-氯甲基-6-氯吡啶是非常重要的。
迄今制备在3-及6-位上有取代基的吡啶的各种合成路线已被深入研究，然而，没有方法是采用有机化学方法在3-取代吡啶上选择性地引入6-位取代基。另一方面，采用属于假单胞菌属、芽孢杆菌属或无色杆菌属的微生物，在烟酸6-位上引入羟基基团的方法——该方法可以分解烟酸，已在日本专利公开(KOKAI)Nos.60-196193及60-196194中有叙述。然而，在上述方法应用于实际用途中时，有必要更有效率地表示活性。对于其它3-取代含氮六元环化合物没有报导。
本发明目的在于制备具有下面通式(II)的6-羟基含氮六元环化合物的方法：
Figure C9310348200051
其中R1表示羧基、氨基甲酰基、氰基、甲酰基、C1-C5羟烷基、C2-C6烷氧羰基、羧乙烯基、羧甲基或躬基；R2表示氢原子或羧基；A表示碳原子或氮原子，条件是当R2是氢原子而A是碳原子时，R1不为羧基。该方法包括使具有下面通式(1)的含氮6-元环化合物：
Figure C9310348200052
其中R1、R2及A的定义如通式(II)在含水介质中与微生物或物理化学处理过的微生物反应。
本发明将详述如下。
按本发明制备的6-羟基含氮六元环化合物由上面的通式(II)表示。R1所定义的C1-C5羟烷基举例包括羟甲基、1-羟乙基、2-羟乙基、3-羟乙基、3-羟丙基、4-羟丁基等；而C2-C6烷氧羰基包括甲氧羰基、乙氧羰基、正丙氧羰基、异丙氧羰基、正丁氧羰基等。
通式(I)的起始含氮六元环化合物包括烟酰胺、3-氰基吡啶、喹啉酸、烟碱醛、吡嗪酰胺等。所对应的6-羟基含氮六元环化合物可以按照本发明的方法制备。
本发明采用的优选的微生物举例包括选自属于土壤杆菌属(Genus Agrobacterium)、节杆菌属(Genus Arthrobacter)、博代氏(杆)菌属(Genus Bordetella)、短杆菌属(Genus Brevibacterium)、假单胞菌属(Genus Pseudomonas)、无色杆菌属(Genus Achr-omobacter)、Comamonas菌属、欧文氏菌属(Genus Erwinia)、无芽胞杆菌属(Genus Bacterium)、棒状杆菌属(Genus Corynebac-terium)、沙雷菌属(Genus Serratia)、八叠球菌属(GenusSarcina)、黄色杆菌属(Genus Xanthobacter)、产碱菌属(GenusAlcaligenes)、产黄菌属(Genus Flavobacterium)及小球菌属(GenusMicrococcus)的微生物。这些微生物经物理化学处理过的也可采用。本发明上述方法中使用的微生物不应局限于上面列出的有机体，只要它们具有向通式(I)的含氮六元环化合物6-位选择性地引入羟基的能力就可以。
属于土壤杆菌属的微生物举例包括放射形土壤杆菌、根癌病土壤杆菌、Agrobacterium Viscosum等。更具体地举例：放射形土壤杆菌NRRL B-11291(Agricultural Research Service CultureCollection)，根癌病土壤杆菌1AM 13129(Research Institute of Ap-plied Microbiology，Tokyo University)，A.viscosumIFO 13652(Insti-tute for Fermentation，Osaka)等。
属于节杆菌属的微生物举例包括Arthrobacter globiformis，Arthrobacter fragilis等。更具体地举例：A.globiformis IFO 12137(Institute for Fermentation，Osaka)，A.fragilis FERM P-4350(Fermentation Research Institute，Agency of Industral Science andTechnology)等。
属于博代氏(杆)菌属的微生物举例包括支气管败血性博代氏(杆)菌等。更具体地举例：支气管败血性博代氏(杆)菌ATCC 4617(Ameriean Type Culture Collection)等。
属于短杆菌属的微生物举例包括Brevibacterium butanicum，Brevibacterium ketoglutamicum等。更具体地举例：B.butani-cumATCC 21196(American Type Culture Collection)，B.ketoglu-tamicum ATCC 15587(American Type Culture Collection)等。
属于假单胞菌属的微生物举例包括Pseudomonas dacunhae，嗜麦芽假单胞菌，Pseudomonas chlororaphis，Pseudomonas hydan-toinophilum，恶臭假单胞菌、荧光假单胞菌等。更具体地举例：P.dacunhae ATCC 13261(American Type Culture Collection)，嗜麦芽假单胞菌ATCC 13637(American Type Culture Collection)，P.chlororaphis IFO 3904(Institute for Fermentation，Osaka)，P.hydantoinopbilumFERM P-4347(Fermentation Research Insti-tute，Agency of Industrial Science and Tehnology)，恶臭假单胞菌ATCC 21244(American Type Culture Collection)，荧光假单胞菌IFO 3903(Institute for Fermentation，Osaka)等。
属于无色杆菌属的微生物举例包括Achromobacter Xerosis等。更具体地举例：A.xerosisIFO 12668(Institute for Fermenta-tion，Osaka)等。
属于Comamonas属的微生物举例包括Comamonas aci-dovorans，Comamonas testosteroni等。更具体地举例：C.acidovo-rans NCIMB 9289(National Collection of Industrial And MarineBacteria Ltd.)，C.testosteroni ATCC 11996(American Type CultureCollection)等。
属于欧文氏菌属的微生物举例包括草生欧文氏菌等。更具体地举例：草生欧文氏菌ATCC 21434(American Type CultureCollection)等。
属于无芽胞杆菌属的微生物举例包括Bacterium cyclo-oxy-dans等。更具体地举例：B.cyclo-oxydansATCC 12673(AmericanType Culture Collection)等。
属于棒状杆菌属的微生物举例包括干燥棒状杆菌等。更具体地举例：干燥棒状杆菌NCTC 9755(National Collection of TypeCultures)等。
属于沙雷菌属的微生物举例包括Serratia liquefaciens，粘质沙雷菌等。更具体地举例：S.liquefaciens IFO 12979(Institute forFermentation，Osaka)，粘质沙雷菌IFO 3054(Institure for Fermen-tation，Osaka)，粘质沙雷菌IFO 12648(Institure for Fermentation，Osaka)等。
属于八叠球菌属的微生物举例包括Sarcina lutea等。更具体地举例：S.luteaATCC 9341(American Type Culture Collection)等。
属于黄色杆菌属的微生物举例包括Xanthobacter flavus等。更具体地举例：X，flavusNCIMB 10071(National Collections of In-dustrial And Marine Bacteria Ltd.)等。
属于产碱菌属的微生物举例包括Alcaligenes eutrophus、Alc-aligenes aquamarinus、粪产碱菌等。更具体地举例：A.eutrophusATCC 17699(American Type Culture Collection)、A.aquamarinusFERM P-4229(Fermentation Research Institute，Aqency of Indus-trial Science and Technology)、粪产碱菌IFO 13111(Institute forFermentation，Osaka)等。
属于产黄菌属的微生物举例包括Flavobacterium Suaveolens、Flavobacterium aminogenes、Flavobacterium arborescens，Flavobac-terium dehydrogenans，Flavobacterium heparinum等。更具体地举例：F.suaveolensIFO 3752(Institute for Fermentation，Osaka)、F.aminogenes FERM P-3134(Permentation Resesrch Institute，Agen-cy of Industrial Science and Technology)、F.arborescens IFO 3750(Institute for Fermentation，Osaka)、F.dehydtogenansATCC 13930(American Type Culture Collection)、F.heparinum IFO 12017(In-stitute for Fermentation、Osaka)等。
属于小球菌属的微生物举例包括Micrococcus varians、Micrococcus morrhuae等。更具体地举例：M.varians IAM 1314(Institute of Applied Microbiology，The University ofTokyo)、M.morrhuae IAM 1711(Institute of AppliedMicrobiology，The University of Tokyo)等。
对培养这些微生物的营养必需品没有限制，用于微生物的常规的营养必需品就可以使用。例如，碳源包括糖如葡萄糖、蔗糖、果糖、甘油、山梨(糖)醇、糖蜜、淀粉水解液或类似物，而有机酸比如乙酸、富马酸或类似物；氮源包括硝酸盐、铵盐、玉米浆、酵母抽提物、肉提取物、酵母粉、大豆水解产物、棉籽粉、多胨(polypeptone)、Benton等；矿物质包括磷酸钾、磷酸钙、磷酸钠、硫酸镁、硫酸锰、氯化钠等。矿物质如铁离子、钴离子、铜离子或其类似物源加到培养物中对诱导酶的产生是有利的。
培养在需氧条件20-40℃温度下，优选在30-35℃，pH4.0-9.0，优选pH5.0-7.0时进行是有利的，经过20-24小时一段时间直到微生物种群增加到约OD6605到OD66040。
用物理化学处理过的微生物在本发明中是指微生物提取物、粉碎的微生物及它们的纯化产品。该纯化产品通过已知的方法得到，如用硫酸铵分离、离子交换色谱、硅胶过滤或类似方法。在本发明方法中，含氮六元环化合物(I)可与微生物本身(活细胞或干细胞)或物理化学处理过的微生物反应。
通过培养得到的微生物或物理化学处理过的微生物可固定于凝胶上，如聚丙烯酰胺凝胶、光致交联树脂、carrageenan或类似物，然后可以与含氮六元环化合物(I)反应。
当化合物(I)与微生物自身可以反应时，化合物(I)可以加到已充分生长的微生物中。含氮六元环化合物(I)的合适的浓度在0.1％重量及饱和浓度之间，优选1.0到5.0％重量。反应在20-50℃、优选30-40℃，pH4.0-9.0、优选5.0-7.0，在2-24小时通常20-24小时一段时间内、在需氧条件和搅拌下进行。
当化合物(I)可以与物理化学处理过的微生物反应时，化合物加到水溶液中，如含约2-15mg(蛋白质重量)微生物提取物或粉碎的微生物的0.01到1M磷酸盐缓冲液(pH6-9)。
当微生物自身或处理过的微生物固定后，含氮六元环化合物(I)在上述条件下，在一装有搅拌器的反应器中，与被固定的微生物反应。或者，含有含氮六元环化合物的液体通过装填着被固定微生物的柱。
羟基化的效率在本发明中可通过在吩嗪甲硫酸酯(phenaz-ine methosulfate)的存在下进行反应来提高。在这种情况下，吩嗪甲硫酸酯(N-甲基吩嗪鎓甲硫酸酯或5-甲基吩嗪鎓甲基硫酸酯)需要存在于反应混合物中。更具体地说，吩嗪甲硫酸酯可与化合物(I)一起、在与微生物自身或处理过的微生物反应时同时加入。在反应混合物中合适的吩嗪甲硫酸酯的浓度为1-100mM，优选5-100mM。
本发明中使用的含水介质可为水或缓冲液如醋酸盐缓冲液、磷酸盐缓冲液等。对于化合物(I)过量的所说的含水介质作为底物是优选的。
这样得到的6-羟基含氮六元环化合物可由反应混合物中、采用常规的方式萃取，所用的溶剂如甲醇、水或类似物，并可通过装有ODS树脂或类似物的柱色谱纯化。
得自本发明的6-羟基合氮六元环化合物(II)如3-氰基-6-羟基吡啶，作为制备药物、农药、染料或类似物的中间体是有用的。例如，3-氰基-6-羟基吡啶采用常规的方法可以很容易地转化成3-氯甲基-6-羟基吡啶，它是农药的中间体。
提出下面详细的实施例说明本发明某些特定的内容。这些实施例只是代表性的而不应作为任何方面的限制。实施例1
向装备有脐(navels)的锥形烧瓶中，加入含1g酵母抽提物、1g葡萄糖、0.3g K2HPO4、0.1g KH2PO4、1mg FeSO4、50mg MgSO4、1mg MnSO4及100ml水的营养液，所得的混合物在120℃消毒20分钟，冷却到30℃后，混合物加入各自消毒的1mg CuSO4及0.2g 3-氰基吡啶作为诱导剂。表1中所列的微生物之一在营养琼脂培养基中孵育24小时后，用铂环接种到上述混合物中，采用160rpm的旋转摇动器使混合物在30℃孵育24小时。24小时后、肉汤回收并离心。分离的细胞悬浮并用0.02mol醋酸盐缓冲液(pH5.5)洗涤，再离心得到剩余细胞。向100ml反应器中加入20ml 1.0％3-氰基吡啶(pH5.5)，混合物加热到30℃并与上面得到的剩余细胞混合。所得的混合物充分搅拌24小时得到3-氰基-6-羟基吡啶。产物通过HPLC、IR及1H-NMR鉴定。表I给出了结果。
表1
             所用微生物     产量(mg)
  Achromobacter xerosis(IFO 12668)Agrobacterium radiobacter(NRRL B-11291)Alcaligenes eutrophus(ATCC 17699)Alcaligenes aquamarinus(FERM P-4229)Alcaligenes faecalis(IFO 13111)Arthrobacter globiformis(IFO 12137)Arthrobacter fragilis(FERM P-4350)Bacterium cvclo-oxvdans(ATCC 12673)Bordetella bronchiseptica(ATCC 4617)Brevibacterium butanicum(ATCC 21196)Brevibacterium ketoglutamicum(ATCC 15587)Corvnebacterium xerosis(NCTC 9755)Erwinia herbicola(ATCC 21434)Flavobacterium suaveolens(IFO 3752)Micrococcus varians(IAM 1314)Micrococcus morrhuae(IAM 1711)Comamonas acidovorans(NCIMB9289)Comamonas testosteroni(ATCC 11996)Pseudomonas dacunhae(ATCC 13261)Pseudomonas maltophila(ATCC 13637)Pseudomonas chlororaphis(IFO 3904)Pseudomonas hydantoinophilum(FERMP-4347)Pseudomonas putida(ATCC 21244)Sarcina lutea(ATCC 9341)Serratia liquefaciens(IFO  12979)Serratia marcescens(IFO  3054)Serratia marcescens(IFO  12648)Xanthobacter flavus(NCIMB 10071)     2.01.03.02.02.03.02.013.010.012.02.019.02.01.01.01.072.024.012.019.01.05.01.03.01.01.02.01.0
1H-NMR(DMSO-d6)δ：6.42(1H，d，J4.5＝9.9Hz，H-5)，7.67(1H，dd，J4.5＝9.9Hz，J2，4＝2.4Hz，H-4)，8.26(1H，d，J2，4＝2.4Hz，H-2)，12.40(1H，bs，OH)实施例2
将含1g肉提取物、1g苹果酸、0.1g K2HPO4、1g烟酸、500mgMgSO4·7H2O及100ml水的营养溶液(pH7.0)加到Sakaguchi烧瓶中，内容物在120℃消毒20分钟。冷却到30℃后，加入2ml消毒的金属溶液(如表2所示)。在营养琼脂培养基中孵育24小时后，粘质沙雷菌(IFO 12648)及荧光假单胞菌(IFO 3903)各自用铂环接种，在一往复振动器中于30℃孵育36小时。回收培养的产物后，细胞离心。分离的细胞悬浮并用0.1mol磷酸盐缓冲液(pH7.0)洗涤并离心得到细胞。所得的细胞通过超声波磨成粉状并采用超离心。所得沉淀混合并悬浮于置于冰上的0.3％Triton X及0.1％十六(烷)基吡啶鎓氯化物中1小时，再超离心。上清液作为粗酶溶液使用。沉淀再经过同样的步骤，并将上清液加到粗酶溶液中。粗酶溶液通过在DEAE Sephacel，Phenyl Sepharose，Butyl Toyopearl或类似物上的柱色谱纯化。
反应由100μl酶溶液与1.5mM DCIP(2，6-二氯靛酚)、2.0ml 0.1M磷酸盐缓冲液(pH7.0)、100μl 3.0mM PMS(吩嗪甲硫酸酯)及500μl 2mM-5mM如表2所示的底物溶液混合而开始。30℃完成该反应1分钟后，通过测量600nm处吸光度的变化测定活性。表3表示出试验结果。
表2.金属溶液的组成金属                    /L of DWCaCl2·2H2O            400mgH3BO3                  500mgCuSO4·5H2O            40mgKI                        100mgFeSO4·7H2O            200mgMnSO4·7H2O            400mgZnSO4·7H2O            400mgH2MoO4·2H2O          200mgHCl                       20ml
                  表3.
                粘质沙雷菌  莹光假单胞菌底物
                  IFO 12648    IFO 3903
                    μM           μM烟酰胺                  213           701吡嗪2，3-二羧酸         19            3烟碱醛                  463           825吡啶基甲醇              72            857吡啶基丙醇              N.D           7烟酸乙酯                461           539喹啉酸                  39            15反-3-(3-吡啶基)丙烯酸   206           0.33-吡啶基乙酸            91            47酰氨基吡嗪              17            143-吡啶乙醛肟            293           3333-氰基吡啶              33            11N.D.：不确定
从实施例1及2的结果可以发现，通过所采用的微生物的作用，可以在含氮六元环化合物的6-位选择性地引入羟基。

Claims (4)

1.制备下式的6-羟基-3-氰基吡啶的方法：
Figure C9310348200021
该方法包括使下式的3-氰基吡啶
Figure C9310348200022
与微生物在含水介质中反应且将得到的产物从所述的介质中回收，其中所述的微生物选自Achromobacter xerosis，Agrobacteriumradiobacter，Alcaligenes eutrophus，Alcaligenes aquamarinus，Alcaligenes faecalis，Arthrobacter globiformis，Arthrobacterfragilis，Bacterium cyclo-oxydans，Bordetella bronchiseptica，Brevibacterium butanicum，Brevibacterium ketoglutamicum，Corynebacterium xerosis，Erwinia herbicola，Flavobacteriumsuaveolens，Micrococcus varians，Micrococcus morrhuae，Comamonas acidovorans，Comamonas testosteroni，Pseudomonasdacunhae，Pseudomonas maltophila，Pseudomonas chlororaphis，Pseudomonas hydantoinophilum，Pseudomonas putida，Sarcianlutea， Serratia liquefaciens，Serratia marcescens，Xanthobacter flavus和Pseudomonas fluorescens，且所述的反应在搅拌、有氧、pH4.0-9.0及20-50℃的温度下进行。
2.按权利要求1的方法，其中所述的反应在吩嗪甲硫酸酯的存在下进行。
3.制备下式的6-羟基-3-氨基甲酰基吡啶或6-羟基-3-甲酰基吡啶的方法：
Figure C9310348200031
其中R1表示氨基甲酰基或甲酰基，该方法包括使下式的3-氨基甲酰基吡啶或3-甲酰基吡啶
Figure C9310348200032
与微生物在含水介质中反应且将得到的产物从所述的介质中回收，其中所述的微生物选自Serratia marcescens和Pseudomonas fluorescens，且所述的反应在搅拌、有氧、pH4.0-9.0及20-50℃的温度下进行。
4.按权利要求3的方法，其中所述的反应在吩嗪甲硫酸酯的存在下进行。
CN93103482A 1992-02-26 1993-02-26 制备6－羟基含氮六元环化合物的方法 Expired - Fee Related CN1051803C (zh)

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