WO2020177044A1 - 一类井冈羟胺a的酯化物及其制备和抑菌应用 - Google Patents

一类井冈羟胺a的酯化物及其制备和抑菌应用 Download PDF

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WO2020177044A1
WO2020177044A1 PCT/CN2019/076786 CN2019076786W WO2020177044A1 WO 2020177044 A1 WO2020177044 A1 WO 2020177044A1 CN 2019076786 W CN2019076786 W CN 2019076786W WO 2020177044 A1 WO2020177044 A1 WO 2020177044A1
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hydroxylamine
jinggang
reaction
add
preparation
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范永仙
陆跃乐
陈小龙
蔡晓青
李剑锋
杨珊珊
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浙江工业大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom

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  • the invention relates to an esterified compound of Jinggang hydroxylamine A and its preparation method and antibacterial application.
  • Validamycin is a pseudotrisaccharide compound, which was isolated from the secondary metabolites of Streptomyce hygroscopicus var.lemonesus in 1970 and was named Validamycin.
  • the Shanghai Institute of Pesticides discovered and screened the strains of Streptomyces hygroscopicus var.jinggangensis that can inhibit rice sheath blight (Rhizoctonia solani) in the soils of Jinggangshan in Jiangxi and Hangzhou, Zhejiang.
  • the chemical structure of the extracted active compound is consistent with that of effective mycin, and its effective ingredient is named jinggangmycin (jinggangmycin).
  • Jinggangmycin can effectively inhibit rice sheath blight, and has a certain bactericidal effect on vegetable seedling wilt. In addition, it has long-term efficacy, low toxicity, low residue, high safety, and low environmental pollution advantages, making it popular in my country The largest area and the lowest cost per mu of pollution-free biological pesticides.
  • Jinggangmycin A is the most important and most important component of Jinggangmycin compounds. Its molecular structure contains Jinggang hydroxylamine A and a D-glucopyranose group, which is a kind of pseudotrisaccharide compound.
  • Jinggang Hydroxylamine A is similar to that of trehalose (as shown below). It is considered to be a class of natural trehalase competitive inhibitors with high activity. It has a novel structure, good in vitro bactericidal effect, and strong selectivity. The inhibitory effect of the enzyme can reach 10 -8 -10 -9 mol/L. In addition, it is highly safe to mammals and higher plants, and has good application prospects.
  • Jinggang Hydroxylamine A has a strong in vitro trehalase inhibitory activity, but it is difficult to enter the organism. Therefore, it is necessary to modify the structure of Jinggang Hydroxylamine A to increase its ability to enter the organism to solve the problem of "injection".
  • ester synthesis has become a preferred solution.
  • the number of hydroxyl groups on Jinggang hydroxylamine A is large, and it is difficult for conventional chemical synthesis methods to accurately control the esterification sites.
  • the lipase-catalyzed synthesis method used in the present invention can accurately control the reaction sites and finally obtain high-purity derivatization. Things. Further studies on its biological activity have shown that it has good biological activity, and some of its derivatives have surpassed Jinggangmycin A in antibacterial activity, and can be developed into a new type of fungicide.
  • the first object of the present invention is to provide a class of esterified Jinggang hydroxylamine A with good biological activity, especially good antibacterial activity.
  • the second object of the present invention is to provide a method for preparing the esterification of Jinggang hydroxylamine A, which can accurately control the reaction sites and obtain high purity esterification.
  • the third object of the present invention is to provide the application of the esterified Jinggang hydroxylamine A in the preparation of antibacterial agents, which has a good inhibitory effect.
  • the present invention provides a series of esters of Jinggang hydroxylamine A, the structure of which is as follows:
  • R 1 -R 8 wherein R 1 is RCO-, R 2 is RCO- or H, wherein R is a C 1 -C 21 aliphatic hydrocarbon group or halogenated aliphatic hydrocarbon group, and the other groups are H.
  • R is a C 1 -C 21 saturated aliphatic hydrocarbon group.
  • R is a C 1 -C 21 unsaturated aliphatic hydrocarbon group.
  • R is a C 1 -C 21 halogenated saturated aliphatic hydrocarbon group.
  • the present invention provides a preparation method of the esterified Jinggang hydroxylamine A
  • the preparation method is: Jinggang hydroxylamine A and fatty acid RCOOH react under the action of a biocatalyst to prepare the esterified Jinggang hydroxylamine A;
  • the biocatalyst is a lyophilized powder obtained by lyophilizing the wet cells of Acinetobacter zjutfet-1 through slant culture, seed culture, and fermentation culture, and then freeze-drying; the feeding mole of the fatty acid RCOOH and Jinggang hydroxylamine A
  • the ratio is not higher than 0.5 or not lower than 1.
  • the resulting product is an ester, i.e. R 1 is RCO-, R 2 is H, to increase the yield of an ester
  • the molar ratio of fatty acid RCOOH to Jinggang hydroxylamine A is 0.5.
  • the feeding molar ratio of the fatty acid RCOOH to the Jinggang hydroxylamine A is not less than 1, the product obtained is a diester, that is, R 1 and R 2 are both RCO-.
  • the fatty acid RCOOH and the Jinggang hydroxylamine A are preferred The molar ratio of feed is 1.
  • the Acinetobacter aureus zjutfet-1 of the present invention is described in Chinese patent CN105385621A, and the conditions of slope culture, seed culture, and fermentation culture during the preparation of the biocatalyst can be referred to this patent.
  • the preparation method of the biocatalyst is:
  • the final concentration of the seed culture medium is 8-10g/L peptone, 5-8g/L yeast extract, NaCl 8-10g/L, solvent is distilled water, pH value is 6.5-7.0;
  • the fermentation medium is composed of peptone 8-10g/L, sucrose 5-8g/L, dipotassium hydrogen phosphate 8-10g/L, and magnesium sulfate 0.5-0.6g/L , Olive oil 20-50g/L, solvent is distilled water, pH value is 6.5-7.0.
  • the preparation method is specifically implemented as follows: Put Jinggang hydroxylamine A, fatty acid RCOOH and reaction solvent in a reaction vessel and mix thoroughly at 15-45°C, and then add the biocatalyst for shaking reaction at 25-45°C, and after full reaction Add chloroform to stop the reaction, filter the reaction mixture, evaporate the solvent, then add water and adjust the pH value to neutral with sodium hydroxide, separate through a macroporous adsorption resin column, and use an ethanol aqueous solution with a volume concentration of 0%-55% For gradient elution of the elution reagents, the target solution is collected, concentrated and dried to obtain the esterification of Jinggang hydroxylamine A; wherein the reaction solvent is a mixture of cyclohexane and tert-butanol.
  • the reaction solvent is a mixture of cyclohexane and tert-butanol.
  • the volume ratio of cyclohexane to tert-butanol in the reaction solvent is 1:1.
  • the amount of the reaction solvent is 5-10 mL/mmol based on the number of moles of Jinggang hydroxylamine A.
  • the amount of the biocatalyst is 0.5-2 g/mmol based on the number of moles of Jinggang hydroxylamine A.
  • the developer is iodine vapor and ninhydrin solution
  • the present invention provides the application of the esterified Jinggang hydroxylamine A in the preparation of antibacterial agents.
  • the esterified Jinggang hydroxylamine A prepared by the invention has higher biological activity, especially antibacterial activity.
  • the bacteriostatic agent is a bacteriostatic agent against Rhizoctonia solani.
  • the present invention has the following beneficial effects:
  • the present invention provides a class of esterified Jinggang hydroxylamine A, which has relatively high biological activity, especially antibacterial activity, especially for rice sheath blight bacteria, has a good inhibitory effect, and is expected to become a new generation of antibacterial Agent.
  • the present invention provides a method for preparing the esterification of Jinggang hydroxylamine A with good selectivity.
  • the selected biocatalyst can efficiently catalyze the esterification reaction, and can accurately control the reaction site, while controlling the reaction Time and reaction substrate to obtain high purity ester.
  • Acinetobacter jonesii zjutfet-1 preserved at the China Type Culture Collection, the preservation date is September 6, 2015, the preservation number is CCTCC NO.M2015511, and the preservation address is Wuhan University, Wuhan, China, postcode 430072
  • the cultivation method of this bacteria is as follows:
  • Acinetobacter agarii zjutfet-1 was inoculated into a slant medium, and cultured at 35° C. for 20 hours to obtain slant colonies; the final concentration of the slant medium was composed of: LB medium + 2% agar powder.
  • the slant colonies were inoculated into a seed culture medium and cultured at 30°C for 6 hours to obtain a seed liquid.
  • the final concentration of the seed culture medium was peptone 10g/L, yeast extract 5g/L, NaCl 10g/L, and the solvent was distilled water, pH The value is 7.0;
  • the seed solution was inoculated into the fermentation medium with a volume concentration of 0.2% inoculum, and cultured at 30°C and 180 rpm for 48 hours.
  • the fermentation broth was centrifuged, and the supernatant was discarded to obtain wet cells, which were then freeze-dried to obtain the following Freeze-dried powder of bacteria.
  • the fermentation medium is composed of peptone 10g/L, sucrose 5g/L, dipotassium hydrogen phosphate 10g/L, magnesium sulfate 0.5g/L, olive oil 50g/L, the solvent is distilled water, and the pH is 7.0.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and acetic acid (0.120 g, 2.0 mmol) were sequentially added to a 50 mL conical flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34g, 4.0mmol) and propionic acid (0.148g, 2.0mmol) were sequentially added to a 50mL Erlenmeyer flask, and 10mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and butyric acid (0.176 g, 2.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and valeric acid (0.204 g, 2.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and hexanoic acid (0.232 g, 2.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and heptanoic acid (0.260 g, 2.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and caprylic acid (0.288 g, 2.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 minutes. After the reaction system is fully balanced, add freeze-dried bacteria powder (1g). At 45°C, shake on a shaker for 48 hours.
  • Jinggang hydroxylamine A (1.34g, 4.0mmol) and nonanoic acid (0.316g, 2.0mmol) were sequentially added to a 50mL Erlenmeyer flask, and 10mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and capric acid (0.344 g, 2.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34g, 4.0mmol) and n-undecanoic acid (0.372g, 2.0mmol) were sequentially added to a 50mL Erlenmeyer flask, and 10mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and n-dodecanoic acid (0.400 g, 2.0 mmol) were sequentially added to a 50 mL conical flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and n-tridecanoic acid (0.428 g, 2.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and n-pentadecanoic acid (0.484 g, 2.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and n-hexadecanoic acid (0.512 g, 2.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and n-octadecanoic acid (0.568 g, 2.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 min. After the reaction system is fully equilibrated, add freeze-dried bacteria powder (1g), and shake on a shaker for 48 hours at 45°C.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and caprylic acid (0.58 g, 4.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 minutes. After the reaction system is fully balanced, add freeze-dried bacteria powder (1g). At 45°C, shake on a shaker for 72 hours.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and 7,8-octenic acid (0.28 g, 2.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added. At 45°C, shake on a shaker for 30 minutes. After the reaction system is fully balanced, add freeze-dried bacteria powder (1g). At 45°C, shake on a shaker for 72 hours.
  • Jinggang hydroxylamine A (1.34 g, 4.0 mmol) and trichlorooctanoic acid (0.50 g, 2.0 mmol) were sequentially added to a 50 mL Erlenmeyer flask, and 10 mL each of cyclohexane and tert-butanol were added.
  • trichlorooctanoic acid (0.50 g, 2.0 mmol
  • the measurement method used is the mycelial growth rate method. Specific operation: Take the activated R. solani plate from the edge of the potato culture medium with a hole punch with a diameter of 6.0mm, and inoculate the plate with the hyphae face down and inoculate the plate with medicated agar medium and the control group respectively. The center of the base plate is cultured in a constant temperature incubator at 25°C. When the diameter of the control colony is between 50mm and 80mm (R.solani generally takes 36h), use a vernier caliper to measure, calculate the colony diameter from the average of the data, and finally calculate it Inhibition rate.
  • the calculation formula of mycelial growth inhibition rate 4-1 (length unit: mm) is as follows:
  • the inhibition rate obtained by diluting multiple test agents to a concentration of 1000 ⁇ g/mL as a reference. If the inhibition rate is 0, discard it. On the contrary, if the inhibition rate is greater than 0, use 500 ⁇ g/mL, 250 ⁇ g/mL , 125 ⁇ g/mL, 62.5 ⁇ g/mL, 31.25 ⁇ g/mL and other concentration gradients for antibacterial activity determination.
  • the regression equation of drug virulence and the calculation of effective concentration EC 50 and EC 5 The virulence of the drug to R.solani is expressed by the mycelial growth inhibition rate. The inhibition rate of mycelial growth is converted into the inhibition probability value (y), and the concentration of the agent is converted into the concentration logarithm (x). According to the least square method, the regression equation determination coefficient R of the inhibition probability value of the drug to R.solani is obtained, according to the toxicity The force regression equation was used to calculate the EC 5 and EC 50 values of the concentration of the drug to inhibit mycelial growth.

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Abstract

本发明公开了一类井冈羟胺A的酯化物及其制备和抑菌应用。所述井冈羟胺A的酯化物的结构如下所示，其中，R 1-R 8中，其中R 1为RCO-，R 2为RCO-或H，其中R为C 1-C 21的脂烃基或者卤代脂烃基，其他基团为H。本发明提供了所述井冈羟胺A的酯化物的制备方法，该方法可准确控制反应位点，得到高纯度的酯化物。本发明提供了所述井冈羟胺A的酯化物在制备针对水稻纹枯病菌的抑菌剂中的应用，其对于水稻纹枯病菌，具有很好的抑制作用。

Description

一类井冈羟胺A的酯化物及其制备和抑菌应用 技术领域
本发明涉及一类井冈羟胺A的酯化物及其制备方法和抑菌应用。
技术背景
井冈霉素(Validamycin)是一种假三糖类化合物，于1970年在吸水链霉菌柠檬变种(Streptomyce hygroscopicus var.lemonesus)的次生代谢产物中分离得到，被命名为有效霉素。1973年上海市农药研究所在江西井冈山以及浙江杭州的土壤中发现并筛选出能够抑制水稻纹枯病(Rhizoctonia solani)的吸水链霉菌井冈变种(S.hygroscopicus var.jinggangensis)菌株，经研究，从中提取的活性化合物化学结构与有效霉素是一致的，其有效成分被命名为井冈霉素(jinggangmycin)。井冈霉素能高效地抑制水稻纹枯病，对蔬菜幼苗枯萎病也具有一定的杀菌效果，另外具有长久药效，低毒性，低残留，高安全，环境污染小的优势使其成为我国推广使用面积最大、亩用成本最低的无公害生物源农药。
井冈霉素A是井冈霉素类化合物中最重要也是最主要的组分，其分子结构包含井冈羟胺A和一个D型吡喃葡萄糖基，是一类假三糖类化合物。
井冈羟胺A化学结构同海藻糖类似(如下所示)，被认为是一类具有高活性的天然海藻糖酶竞争性抑制剂，其结构新颖，离体杀菌效果好，选择性强，对海藻糖酶的抑制效果能达到10 -8-10 -9mol/L，另外其对哺乳动物以及高等植物的安全性高，具有很好的应用前景。
Figure PCTCN2019076786-appb-000001
井冈羟胺A具有较强的离体海藻糖酶抑制活性，但很难进入生物体内，因此，有必要通过修饰井冈羟胺A的结构，增加其进入生物体内的能力，以此解决靠“注射”才能发挥其杀虫、杀菌活性的问题，而酯合成则成为了一个首选的方案。但是，井冈羟胺A上羟基数量较多，常规的化学合成法很难精准控制酯化位点，而本发明采用的脂肪酶催化合成法，可准确控制反应位点，并最终得到高纯度的衍生物。进一步对其生物活性进行研究，研究表明，其具有很好的生物活性，部分衍生物抑菌活性超过了井冈霉素A，可开发成为新型杀菌剂。
发明内容
本发明的第一个目的是提供一类具有良好生物活性尤其是良好抑菌活性的井冈羟胺A的酯化物。
本发明的第二个目的是提供一种井冈羟胺A的酯化物的制备方法，该方法可准确控制反应位点，得到高纯度的酯化物。
本发明的第三个目的是提供所述井冈羟胺A的酯化物在制备抑菌剂中的应用，具有很好的抑制作用。
为实现上述发明目的，本发明采用如下技术方案：
一方面，本发明提供了一系列井冈羟胺A的酯化物，其结构如下所示：
Figure PCTCN2019076786-appb-000002
其中，R 1-R 8中，其中R 1为RCO-，R 2为RCO-或H，其中R为C 1-C 21的脂烃基或者卤代脂烃基，其他基团为H。
作为优选，R为C 1-C 21的饱和脂烃基。
作为进一步的优选，R 1＝C nH 2n+1CO-，其中n＝1-21，R 2-R 8＝H。更进一步优选n＝8-18，再更进一步优选n＝10-18，特别优选10-17。
作为进一步的优选，R 1＝R 2＝C nH 2n+1CO-，其中n＝1-21，R 3-R 8＝H。更进一步优选n＝3-18，再更进一步优选n＝5-18，特别优选n＝7-18，如R 1＝R 2＝CH 3CH 2CH 2CH 2CH 2CH 2CH 2CO-。
作为优选，R为C 1-C 21的不饱和脂烃基。
作为进一步的优选，R 1＝C nH 2n-1CO-，其中n＝1-21，R 2-R 8＝H。更进一步优选n＝3-18，再更进一步优选n＝5-18，特别优选n＝7-18，如R 1＝CH 2＝CHCH 2CH 2CH 2CH 2CH 2CO-。
作为优选，R为C 1-C 21的卤代饱和脂烃基。
作为进一步的优选，R 1＝C nH 2n+1-mX mCO-，其中n＝1-21，m≤2n+1，R 2-R 8＝H，X＝F、Cl、Br或I。更进一步优选n＝3-18，再更进一步优选n＝5-18，特别优选n＝7-18。更进一步优选X＝Cl。特别优选R 1＝CCl 3CH 2CH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H。
第二方面，本发明提供了一种所述井冈羟胺A的酯化物的制备方法，所述制备方法为：井冈羟胺A和脂肪酸RCOOH在生物催化剂的作用下反应制得井 冈羟胺A的酯化物；所述生物催化剂为琼式不动杆菌zjutfet-1经斜面培养、种子培养、发酵培养得到的湿菌体再经冷冻干燥获得的菌体冻干粉；所述脂肪酸RCOOH与井冈羟胺A的投料摩尔比不高于0.5或者不低于1。
本发明中，当所述脂肪酸RCOOH与井冈羟胺A的投料摩尔比不高于0.5时，得到的产物为一酯，即R 1为RCO-，R 2为H，为提高一酯的收率，优选脂肪酸RCOOH与井冈羟胺A的投料摩尔比为0.5。当所述脂肪酸RCOOH与井冈羟胺A的投料摩尔比不小于1时，得到的产物为二酯，即R 1和R 2均为RCO-，为兼顾收率和成本，优选脂肪酸RCOOH与井冈羟胺A的投料摩尔比为1。
本发明所述的琼式不动杆菌zjutfet-1记载于中国专利CN105385621A，所述生物催化剂制备过程中的斜面培养、种子培养、发酵培养的条件均可参考该专利。作为优选，所述生物催化剂的制备方法为：
(1)将琼氏不动杆菌zjutfet-1接种至斜面培养基，在20-35℃培养20-36h，获得斜面菌落；所述斜面培养基终浓度组成为：LB培养基+2％琼脂粉；
(2)将斜面菌落接种于种子培养基，在25-30℃培养6h，获得种子液，所述种子培养基终浓度组成为蛋白胨8-10g/L，酵母提取物5-8g/L，NaCl 8-10g/L，溶剂为蒸馏水，pH值为6.5-7.0；
(3)将种子液以体积浓度0.2-0.5％接种量接种于发酵培养基，在25-35℃、180rpm的条件下培养36-48h，将发酵液离心，弃上清液，获得湿菌体，随后进行冷冻干燥获得菌体冻干粉；所述发酵培养基组成蛋白胨8-10g/L、蔗糖5-8g/L、磷酸氢二钾8-10g/L、硫酸镁0.5-0.6g/L，橄榄油20-50g/L，溶剂为蒸馏水，pH值为6.5-7.0。
作为优选，所述制备方法具体按照如下实施：将井冈羟胺A、脂肪酸RCOOH和反应溶剂置于反应容器中于15-45℃充分混合，然后加入生物催化剂在25-45℃ 振荡反应，充分反应后加入三氯甲烷使反应停止，将反应混合物过滤、蒸除溶剂，然后加水并用氢氧化钠调节pH值至中性，通过大孔吸附树脂柱分离，以体积浓度为0％-55％的乙醇水溶液为洗脱试剂进行梯度洗脱，收集目标液，浓缩干燥得到井冈羟胺A的酯化物；其中，所述反应溶剂为环己烷与叔丁醇的混合液。作为进一步的优选，所述反应溶剂中环己烷与叔丁醇的体积比为1:1。作为进一步的优选，所述反应溶剂的用量以井冈羟胺A的摩尔数计为5-10mL/mmol。
作为优选，所述生物催化剂的用量以井冈羟胺A的摩尔数计为0.5-2g/mmol。
本发明中合成井冈羟胺A的酯化物的反应过程采用薄板层析(展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液)进行监控并确定反应终点，如制备一酯时，产生除一酯外的化合物时即停止反应。
第三方面，本发明提供了所述井冈羟胺A的酯化物在制备抑菌剂中的应用。本发明制备的井冈羟胺A的酯化物具有较高的生物活性尤其是抑菌活性。
作为优选，所述的抑菌剂是针对水稻纹枯病菌的抑菌剂。
与现有技术相比，本发明的有益效果在于：
(1)本发明提供了一类井冈羟胺A的酯化物，其具有较高的生物活性尤其是抑菌活性，特别对水稻纹枯病菌，具有很好的抑制作用，有望成为新一代抑菌剂。
(2)本发明提供了一种具有很好选择性的井冈羟胺A的酯化物的制备方法，所选用的生物催化剂可高效催化该酯化反应，且可准确控制反应位点，同时通过控制反应时间和反应底物，得到高纯度的酯化物。
具体实施方式
下面结合具体实施例对本发明进行进一步描述，但本发明的保护范围并不仅限于此。
实施例1：产脂肪酶菌株的发酵
本发明将琼氏不动杆菌zjutfet-1(保藏于中国典型培养物保藏中心，保藏日期为2015年9月6日，保藏编号CCTCC NO.M2015511，保藏地址为中国武汉武汉大学，邮编430072)，应用于所述化合物的合成。该菌的培养方法如下文所述：
将琼氏不动杆菌zjutfet-1接种至斜面培养基，在35℃培养20h，获得斜面菌落；所述斜面培养基终浓度组成为：LB培养基+2％琼脂粉。
将斜面菌落接种于种子培养基，在30℃培养6h，获得种子液，所述种子培养基终浓度组成为蛋白胨10g/L，酵母提取物5g/L，NaCl 10g/L，溶剂为蒸馏水，pH值为7.0；
将种子液以体积浓度0.2％接种量接种于发酵培养基，在30℃、180rpm的条件下培养48h，将发酵液离心，弃上清液，获得湿菌体，随后进行冷冻干燥获得下文所述的菌体冻干粉。所述发酵培养基组成蛋白胨10g/L、蔗糖5g/L、磷酸氢二钾10g/L、硫酸镁0.5g/L，橄榄油50g/L，溶剂为蒸馏水，pH值为7.0。
实施例2：乙酸井冈羟胺A酯(化合物1)的制备(R 1＝CH 3CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和乙酸(0.120g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱(上海华震科技有限公司，HZ-801)分离，洗脱液为0％-55％的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到0.38g乙酸井冈羟胺A酯，纯度98.8％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1(体积比)，显色剂为碘蒸气与茚三酮溶 液。
1H NMR(600MHz,DMSO)δ5.58(dd,J＝6.2,0.6Hz,1H),4.74(d,J＝0.9Hz,2H),4.06(s,1H),3.72(dd,J＝2.5,1.5Hz,1H),3.57–3.54(m,1H),3.52(dd,J＝12.2,8.0Hz,1H),3.35(t,J＝8.3Hz,1H),3.27(dd,J＝12.4,8.2Hz,1H),3.17(dd,J＝7.9,1.8Hz,1H),3.13–3.11(m,1H),3.09(dd,J＝9.2,6.3Hz,1H),2.08(d,J＝1.0Hz,1H),2.07(dd,J＝6.5,4.1Hz,1H),2.01(s,3H),1.76(s,1H),1.33–1.31(m,1H),1.07–1.05(m,1H).ESI-MS:[M+H]:378.1719.
实施例3：丙酸井冈羟胺A酯(化合物2)的制备(R 1＝CH 3CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和丙酸(0.148g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到丙酸井冈羟胺A酯0.42g，纯度98.5％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.58(dd,J＝6.2,0.6Hz,1H),4.72(d,J＝0.6Hz,2H),4.06(dd,J＝4.2,0.7Hz,1H),3.85(dt,J＝5.5,3.7Hz,1H),3.70(dd,J＝9.4,4.3Hz,1H),3.60(dd,J＝9.3,4.2Hz,1H),3.52(dd,J＝12.4,7.6Hz,1H),3.27(dd,J＝12.4,7.6Hz,1H),3.19–3.14(m,2H),3.09(dd,J＝6.2,4.4Hz,1H),2.88–2.81(m,1H),2.48(dd,J＝7.5,2.9Hz,1H),2.46–2.42(m,2H),1.68(s,1H),1.37–1.26(m,1H),1.20(t,J＝6.8Hz,3H),1.09(dd,J＝8.2,3.6Hz,1H).
ESI-MS:[M+H] +:392.1867.
实施例4：丁酸井冈羟胺A酯(化合物3)的制备(R 1＝CH 3CH 2CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和丁酸(0.176g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到丁酸井冈羟胺A酯0.45g，纯度98.2％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ4.73(d,J＝13.9Hz,2H),4.56(s,1H),4.41(dd,J＝9.5,5.8Hz,1H),4.31(s,1H),3.77(t,J＝8.4Hz,1H),3.53(dd,J＝10.4,3.8Hz,1H),3.49–3.41(m,1H),3.41–3.23(m,6H),3.09(t,J＝8.7Hz,1H),2.13(dt,J＝11.2,6.9Hz,1H),1.89(s,5H),1.87–1.80(m,1H),1.53(ddd,J＝14.9,11.7,5.8Hz,1H).
ESI-MS[M+H] +406.2067,[M+Na] +428.1890
实施例5：戊酸井冈羟胺A酯(化合物4)的制备(R 1＝CH 3CH 2CH 2CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和戊酸(0.204g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然 后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到戊酸井冈羟胺A酯0.46g，纯度99.1％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.76(s,1H),5.44(s,1H),4.65(s,5H),4.17(dd,J＝10.6,2.8Hz,1H),4.09–3.86(m,3H),3.70(d,J＝4.7Hz,1H),2.28(t,J＝7.3Hz,2H),2.03–1.93(m,1H),1.77(d,J＝14.1Hz,1H),1.51(dt,J＝15.0,7.4Hz,2H),1.38–1.03(m,4H),0.86(t,J＝7.3Hz,3H).
ESI-MS[M+H] +420.2227,[M+Na] +442.2040
实施例6：己酸井冈羟胺A酯(化合物5)的制备(R 1＝CH 3CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和己酸(0.232g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到己酸井冈羟胺A酯0.45g，纯度98.4％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.81(dd,J＝37.3,3.0Hz,1H),4.68(d,J＝13.1Hz,2H),4.35(d,J＝13.2Hz,1H),3.96(d,J＝17.8Hz,1H),3.69(dd,J＝11.3,5.7Hz,1H),3.49(d,J＝3.8Hz,31H),3.46–3.17(m,6H),3.11–3.02(m,1H),2.31(dt, J＝22.2,7.3Hz,1H),2.15(t,J＝7.4Hz,1H),1.74(dd,J＝14.1,3.2Hz,1H),1.56–1.36(m,2H),1.36–1.03(m,6H),,0.89(t,J＝6.9Hz,3H).
ESI-MS[M+H] +434.2381,[M+Na] +456.2189
实施例7：庚酸井冈羟胺A酯(化合物6)的制备
(R 1＝CH 3CH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和庚酸(0.260g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到庚酸井冈羟胺A酯0.48g，纯度98.5％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.79(dd,J＝37.3,3.0Hz,1H),4.62(d,J＝13.1Hz,2H),4.33(d,J＝13.2Hz,1H),3.94(d,J＝17.8Hz,1H),3.71(dd,J＝11.3,5.7Hz,1H),3.45(d,J＝3.8Hz,31H),3.43–3.17(m,6H),3.11–3.01(m,1H),2.31(dt,J＝22.2,7.3Hz,1H),2.18(t,J＝7.4Hz,1H),1.71(dd,J＝14.1,3.2Hz,1H),1.56–1.38(m,2H),1.36–1.03(m,8H),0.91(t,J＝6.9Hz,3H).
ESI-MS[M+H] +448.2532,[M+Na] +470.2341
实施例8：辛酸井冈羟胺A酯(化合物7)的制备
(R 1＝CH 3CH 2CH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和辛酸(0.288g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反 应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到辛酸井冈羟胺A酯0.51g，纯度98.3％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.81(dd,J＝37.3,3.0Hz,1H),4.65(d,J＝13.1Hz,2H),4.31(d,J＝13.2Hz,1H),3.94(d,J＝17.8Hz,1H),3.71(dd,J＝11.3,5.7Hz,1H),3.45(d,J＝3.8Hz,31H),3.40–3.17(m,6H),3.11–3.01(m,1H),2.30(dt,J＝22.2,7.3Hz,1H),2.18(t,J＝7.4Hz,1H),1.74(dd,J＝14.1,3.2Hz,1H),1.56–1.40(m,2H),1.36–1.01(m,10H),0.91(t,J＝6.9Hz,3H).
ESI-MS[M+H] +462.2686,[M+Na] +484.2492
实施例9：壬酸井冈羟胺A酯(化合物8)的制备
(R 1＝CH 3CH 2CH 2CH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和壬酸(0.316g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到壬酸井冈羟胺A酯0.49g，纯度98.9％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.79(dd,J＝37.3,3.0Hz,1H),4.66(d,J＝13.1Hz,2H),4.45(d,J＝13.2Hz,1H),3.97(d,J＝17.8Hz,1H),3.71(dd,J＝11.3,5.7Hz,1H),3.48(d,J＝3.8Hz,31H),3.45–3.18(m,6H),3.13–3.04(m,1H),2.29(dt,J＝22.2,7.3Hz,1H),2.17(t,J＝7.4Hz,1H),1.76(dd,J＝14.1,3.2Hz,1H),1.58–1.40(m,2H),1.24(s,10H),1.16–1.00(m,2H),0.86(t,J＝6.9Hz,3H).
ESI-MS[M+H] +476.2856,[M+Na] +498.2616
实施例10：癸酸井冈羟胺A酯(化合物9)的制备
(R 1＝CH 3CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和癸酸(0.344g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到癸酸井冈羟胺A酯0.55g，纯度98.4％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.86(dd,J＝37.6,3.5Hz,1H),4.62(d,J＝13.0Hz,1H),4.48(d,J＝13.2Hz,1H),3.92(d,J＝18.1Hz,1H),3.65(dd,J＝11.0,5.7Hz,1H),3.43(d,J＝3.6Hz,1H),3.40–3.13(m,6H),3.11–3.04(m,1H),2.29(dt,J＝22.2,7.1Hz,1H),2.17(t,J＝7.7Hz,1H),1.81(dd,J＝14.5,3.6Hz,1H),1.58–1.42(m,2H),1.24(s,12H),1.16–0.98(m,2H),0.86(t,J＝6.5Hz,3H).
m/z(ESI-MS):[M+H] +490.3008,[M+Na] +512.2746.
实施例11：正十一烷酸井冈羟胺A酯(化合物10)的制备
(R 1＝CH 3CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和正十一烷酸(0.372g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到正十一烷酸井冈羟胺A酯0.52g，纯度98.1％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.92(dd,J＝37.8,3.7Hz,1H),4.71(d,J＝13.5Hz,1H),4.48(d,J＝13.7Hz,1H),3.98(d,J＝17.2Hz,1H),3.71(dd,J＝11.8,5.4Hz,1H),3.46(d,J＝3.4Hz,1H),3.42–3.18(m,6H),3.13–3.06(m,1H),2.30(dt,J＝22.2,7.2Hz,1H),2.21(t,J＝7.4Hz,1H),1.85(dd,J＝14.0,3.2Hz,1H),1.56–1.42(m,2H),1.20(s,14H),1.16–0.98(m,2H),0.86(t,J＝6.3Hz,3H).
m/z(ESI-MS):[M+H] +504.3161,[M+Na] +527.1816.
实施例12：正十二烷酸井冈羟胺A酯(化合物11)的制备：
(R 1＝CH 3CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H)
井冈羟胺A(1.34g，4.0mmol)和正十二烷酸(0.400g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离， 洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到正十二烷酸井冈羟胺A酯0.54g，纯度98.2％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.95(dd,J＝36.5,4.1Hz,1H),4.77(d,J＝12.8Hz,1H),4.50(d,J＝12.8Hz,1H),3.41(d,J＝17.8Hz,1H),3.768(dd,J＝11.3,5.7Hz,1H),3.43(d,J＝3.8Hz,1H),3.40–3.18(m,6H),3.13–3.06(m,1H),2.32(dt,J＝22.2,7.3Hz,1H),2.25(t,J＝7.4Hz,1H),1.86(dd,J＝14.1,3.2Hz,1H),1.56–1.42(m,2H),1.23(s,12H),1.16–0.92(m,4H),0.81(t,J＝6.8Hz,3H).
m/z(ESI-MS):[M+H] +518.3310,[M+Na] +540.2876.
实施例13：正十四烷酸井冈羟胺A酯(化合物12)的制备：
(R 1＝CH 3CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H)
井冈羟胺A(1.34g，4.0mmol)和正十三烷酸(0.428g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到正十四烷酸井冈羟胺A酯0.49g，纯度98.6％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.93(dd,J＝37.3,3.0Hz,1H),4.70(d,J＝13.1Hz,1H),4.50(d,J＝13.2Hz,1H),3.94(d,J＝17.4Hz,1H),3.72(dd,J＝11.3,5.7Hz,1H),3.48(d,J＝4.2Hz,1H),3.44–3.17(m,6H),3.13–3.02(m,1H),2.31(dt,J ＝22.2,7.3Hz,1H),2.24(t,J＝7.4Hz,1H),1.87(dd,J＝14.1,3.2Hz,1H),1.65–1.40(m,2H),1.18(s,12H),1.15–0.81(m,6H),0.74(t,J＝6.4Hz,3H).
m/z(ESI-MS):[M+H] +546.3624,[M+Na] +568.3201
实施例14：正十五烷酸井冈羟胺A酯(化合物13)的制备
(R 1＝CH 3CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和正十五烷酸(0.484g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，过滤除去析出的脂肪酸钠，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到正十五烷酸井冈羟胺A酯0.58g，纯度98.4％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.58(dd,J＝6.2,0.6Hz,1H),4.76(d,J＝0.9Hz,2H),4.06(dd,J＝7.3,0.6Hz,1H),3.75(dd,J＝9.2,7.4Hz,1H),3.70(t,J＝8.8Hz,1H),3.52(dd,J＝12.4,7.1Hz,1H),3.27(dd,J＝12.4,7.1Hz,1H),3.19(t,J＝8.9Hz,1H),3.13–3.06(m,2H),2.83(dd,J＝10.5,8.7Hz,1H),2.61(dd,J＝16.9,7.8Hz,1H),2.36(t,J＝8.0Hz,2H),2.02(t,J＝7.9Hz,1H),1.97(s,1H),1.69(p,J＝7.8Hz,2H),1.40–1.29(m,23H),1.21–1.16(m,1H),0.99(t,J＝6.4Hz,3H).
m/z(ESI-MS):[M+H] +560.3833,[M+Na] +582.3432
实施例15：正十六烷酸井冈羟胺A酯(化合物14)的制备
(R 1＝CH 3CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CO-， R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和正十六烷酸(0.512g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，过滤除去析出的脂肪酸钠，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到正十六烷酸井冈羟胺A酯0.56g，纯度98.4％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.58(dd,J＝6.2,0.6Hz,1H),4.74(d,J＝0.6Hz,2H),4.06(dd,J＝4.4,0.9Hz,1H),3.75(dd,J＝9.2,4.4Hz,1H),3.55–3.49(m,2H),3.27(dd,J＝12.4,7.0Hz,1H),3.22–3.17(m,1H),3.14–3.07(m,2H),2.83(dd,J＝10.3,8.1Hz,1H),2.49(dt,J＝9.3,7.6Hz,1H),2.32(t,J＝8.2Hz,2H),2.19(t,J＝8.0Hz,1H),1.71(p,J＝8.0Hz,2H),1.51(s,1H),1.41–1.26(m,25H),1.18(t,J＝7.9Hz,1H),0.99(t,J＝6.4Hz,3H).
m/z(ESI-MS):[M+H] +574.4101,[M+Na] +596.3614
实施例16：正十八烷酸井冈羟胺A酯(化合物15)的制备
(R 1＝CH 3CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和正十八烷酸(0.568g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡48h。 反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，过滤除去析出的脂肪酸钠，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到正十八烷酸井冈羟胺A酯0.54g，纯度98.6％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(500MHz,Chloroform)δ5.58(dd,J＝6.2,0.6Hz,1H),4.74(d,J＝0.9Hz,2H),4.06(dd,J＝4.2,0.6Hz,1H),3.75(dd,J＝8.9,4.3Hz,1H),3.52(dd,J＝12.4,7.6Hz,1H),3.50–3.46(m,1H),3.27(dd,J＝12.4,7.6Hz,1H),3.18–3.13(m,1H),3.12–3.07(m,2H),2.83(dd,J＝10.4,8.1Hz,1H),2.59(dt,J＝9.2,7.7Hz,1H),2.26(dt,J＝11.2,8.1Hz,3H),1.70(p,J＝8.0Hz,2H),1.43–1.30(m,29H),1.17(s,1H),1.11(t,J＝8.0Hz,1H),0.99(t,J＝6.5Hz,3H).
m/z(ESI-MS):[M+H] +602.4508,[M+Na] +624.5136
实施例17：辛酸井冈羟胺A二酯(化合物16)的制备
(R 1＝R 2＝CH 3CH 2CH 2CH 2CH 2CH 2CH 2CO-，R 3-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和辛酸(0.58g，4.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡72h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到辛酸井冈羟胺A二酯0.54g，纯度96.8％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.58(dd,J＝6.2,0.6Hz,1H),4.75–4.70(m,2H),4.24(dd,J＝12.4,7.1Hz,1H),4.06(dd,J＝8.0,0.7Hz,1H),3.93(dd,J＝12.4,7.1Hz,1H),3.75(dd,J＝9.2,8.0Hz,1H),3.58(d,J＝5.2Hz,1H),3.54–3.46(m,1H),3.38–3.28(m,2H),3.21(dd,J＝8.1,3.9Hz,1H),3.09(dd,J＝8.2,6.2Hz,1H),2.39(dt,J＝15.9,6.9Hz,4H),2.03(dq,J＝10.7,3.6Hz,1H),1.87(dt,J＝12.5,3.7Hz,1H),1.81–1.69(m,5H),1.51(s,1H),1.39–1.27(m,16H),0.98(t,J＝6.3Hz,6H).
m/z(ESI-MS):[M+H] +572.4102,[M+Na] +594.4423.
实施例18：7,8-辛烯酸井冈羟胺A酯(化合物17)的制备(R 1＝
CH 2＝CHCH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和7,8-辛烯酸(0.28g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡72h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到7,8-辛烯酸井冈羟胺A酯0.62g，纯度97.9％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(600MHz,DMSO)δ5.65(ddt,J＝16.3,10.0,6.1Hz,1H),5.58(dd,J＝6.2,0.6Hz,1H),5.02–4.97(m,1H),4.97–4.93(m,1H),4.77(d,J＝0.9Hz,2H),4.06(d,J＝1.3Hz,1H),3.77–3.72(m,2H),3.52(dd,J＝12.5,7.5Hz,1H),3.35(s,1H),3.27(dd,J＝12.5,7.5Hz,1H),3.22–3.17(m,1H),3.14–3.11(m,1H),3.09(t,J＝4.3Hz,1H),2.36(dt,J＝9.8,7.9Hz,3H),2.08(t,J＝8.0Hz,1H),2.02(dd,J＝ 14.2,7.8Hz,2H),1.74–1.66(m,3H),1.38–1.34(m,4H),1.34–1.30(m,1H),1.15(t,J＝7.9Hz,1H).
m/z(ESI-MS):[M+H] +:460.2506
实施例19：三氯辛酸井冈羟胺A酯(化合物18)的制备(R 1＝
CCl 3CH 2CH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H)：
井冈羟胺A(1.34g，4.0mmol)和三氯辛酸(0.50g，2.0mmol)依次加入到50mL的锥形烧瓶中，加入环己烷与叔丁醇各10mL。45℃下，摇床振荡30min，反应体系充分平衡后加入菌体冻干粉(1g)，45℃下，摇床振荡72h。反应结束后，加入20mL三氯甲烷停止反应，反应液过滤，旋蒸，加入20mL去离子水，然后加入1M氢氧化钠溶液至pH＝7，然后通过大孔吸附树脂柱分离，洗脱液为0％-55％浓度梯度的乙醇水溶液进行梯度洗脱，收集目标液，浓缩干燥，得到三氯辛酸井冈羟胺A酯0.49g，纯度98.1％。TLC检测浓缩液，展开剂为正丙醇：水：乙酸＝4:1:1，显色剂为碘蒸气与茚三酮溶液。
1H NMR(500MHz,Chloroform)δ5.58(dd,J＝6.2,0.6Hz,1H),4.74(d,J＝0.6Hz,2H),4.06(dd,J＝2.6,0.6Hz,1H),4.00(dd,J＝7.0,3.3Hz,1H),3.74(t,J＝3.1Hz,1H),3.52(dd,J＝12.4,7.1Hz,1H),3.35(t,J＝8.3Hz,1H),3.27(dd,J＝12.4,7.1Hz,1H),3.21–3.15(m,1H),3.11–3.06(m,1H),2.82(dd,J＝10.3,8.3Hz,1H),2.43(dt,J＝9.2,7.7Hz,1H),2.37–2.28(m,4H),1.90(t,J＝7.9Hz,1H),1.73(p,J＝8.0Hz,2H),1.51(s,1H),1.42–1.32(m,6H),1.31(d,J＝4.1Hz,1H),1.24(t,J＝7.9Hz,1H).
m/z(ESI-MS):[M+H] +:565.1462
实施例20：抗菌活性的测定
采用的测定方法是菌丝生长速率法。具体操作：用直径为6.0mm的打孔器在土豆培养基的边缘取活化好的R.solani菌碟，将菌碟菌丝面朝下，分别接种至含药琼脂培养基平板和对照组培养基平板的正中央，于25℃的恒温培养箱中培养，待对照菌落直径在50mm和80mm之间时(R.solani一般需要36h)利用游标卡尺测量，由数据的平均值计算菌落直径，最终算得抑制率。菌丝生长抑制率计算公式4-1(长度单位：mm)如下：
Figure PCTCN2019076786-appb-000003
实验过程中，先以多个待测试剂稀释到1000μg/mL的浓度得到的抑制率做参照，若抑制率为0则舍弃，相反，若抑制率大于0，则以500μg/mL、250μg/mL、125μg/mL、62.5μg/mL、31.25μg/mL等浓度梯度做抑菌活性测定。
药物毒力回归方程和有效中浓度EC 50与EC 5的计算：以菌丝生长抑制率表示药物对R.solani的毒力。对菌丝生长的抑制率换算成抑制几率值(y)，药剂浓度换算成浓度对数(x)，按最小二乘法求出药物对R.solani抑制几率值的回归方程决定系数R，根据毒力回归方程分别计算药物对菌丝生长的抑制中浓度EC 5和EC 50值。
表4-3 不同药物对R.solani的毒力方程
Table 4-3 Poisonous force equation of different drugs on R.solani.
Figure PCTCN2019076786-appb-000004
Figure PCTCN2019076786-appb-000005
从上表可见，该类化合物具有很好的生物活性，其中，部分化合物对水稻纹枯病的抑制作用超过了井冈霉素A，甚至最低作用效果相较于井冈霉素A或 井冈羟胺A，低2-3个数量级。因此，该类化合物具有巨大的应用前景和商业价值，有望开发成为替代井冈霉素的新型高效、绿色杀菌剂。

Claims (13)

  1. 井冈羟胺A的酯化物，其结构如下所示：
    Figure PCTCN2019076786-appb-100001
    其中，R 1-R 8中，其中R 1为RCO-，R 2为RCO-或H，其中R为C 1-C 21的脂烃基或者卤代脂烃基，其他基团为H。
  2. 如权利要求1所述的井冈羟胺A的酯化物，其特征在于：R为C 1-C 21的饱和脂烃基。
  3. 如权利要求2所述的井冈羟胺A的酯化物，其特征在于：R 1＝C nH 2n+1CO-，其中n＝1-21，R 2-R 8＝H；优选n＝8-18，进一步优选n＝10-18，特别优选10-17
  4. 如权利要求2所述的井冈羟胺A的酯化物，其特征在于：R 1＝R 2＝C nH 2n+1CO-，其中n＝1-21，R 3-R 8＝H；优选n＝3-18，进一步优选n＝5-18，特别优选n＝7-18。
  5. 如权利要求1所述的井冈羟胺A的酯化物，其特征在于：R为C 1-C 21的不饱和脂烃基。
  6. 如权利要求5所述的井冈羟胺A的酯化物，其特征在于：R 1＝C nH 2n-1CO-，其中n＝1-21，R 2-R 8＝H；优选n＝3-18，进一步优选n＝5-18，特别优选n＝7-18，如R 1＝CH 2＝CHCH 2CH 2CH 2CH 2CH 2CO-。
  7. 如权利要求1所述的井冈羟胺A的酯化物，其特征在于：R为C 1-C 21的卤代饱和脂烃基。
  8. 如权利要求7所述的井冈羟胺A的酯化物，其特征在于：R 1＝C nH 2n+1-mX mCO-，其中n＝1-21，m≤2n，R 2-R 8＝H，X＝F、Cl、Br或I；优选 n＝3-18，进一步优选n＝5-18，特别优选n＝7-18；特别优选R 1＝CCl 3CH 2CH 2CH 2CH 2CH 2CH 2CO-，R 2-R 8＝H。
  9. 一种如权利要求1所述的井冈羟胺A的酯化物的制备方法，所述制备方法为：井冈羟胺A和脂肪酸RCOOH在生物催化剂的作用下反应制得井冈羟胺A的酯化物；所述生物催化剂为琼式不动杆菌zjutfet-1经斜面培养、种子培养、发酵培养得到的湿菌体再经冷冻干燥获得的菌体冻干粉；所述脂肪酸RCOOH与井冈羟胺A的投料摩尔比不高于0.5或者不低于1；RCOOH中的R的定义同权利要求1。
  10. 如权利要求9所述的制备方法，其特征在于：所述制备方法具体按照如下实施：将井冈羟胺A、脂肪酸RCOOH和反应溶剂置于反应容器中于15-45℃充分混合，然后加入生物催化剂在25-45℃振荡反应，充分反应后加入三氯甲烷使反应停止，将反应混合物过滤、蒸除溶剂，然后加水并用氢氧化钠调节pH值至中性，通过大孔吸附树脂柱分离，体积浓度为0％-55％的乙醇水溶液为洗脱试剂进行梯度洗脱，收集目标液，浓缩干燥得到井冈羟胺A的酯化物；其中，所述反应溶剂为环己烷与叔丁醇的混合液。
  11. 如权利要求10所述的制备方法，其特征在于：所述生物催化剂的用量以井冈羟胺A的摩尔数计为0.5-2g/mmol；所述反应溶剂的用量以井冈羟胺A的摩尔数计为5-10mL/mmol。
  12. 如权利要求1所述的井冈羟胺A的酯化物在制备抑菌剂中的应用。
  13. 如权利要求12所述的应用，其特征在于：所述的抑菌剂是针对水稻纹枯病菌的抑菌剂。
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