密灭汀A3 | 51596-10-2

• 物质功能分类: 有机原料 - 羧酸类化合物及衍生物
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯类和类似物
• 中文名称: 密灭汀A3
• 中文别名: 密灭汀
• 英文名称: Milbemectin
• 英文别名: (10E,14E,16E)-(1R,4S,5'S,6R,6'R,8R,13R,20R,21R,24S)-6'-ethyl-21,24-dihydroxy-5',11,13,22-tetramethyl-(3,7,19- trioxatetracyclo[15.6.1.1⁴'⁸.0²⁰'²⁴]pentacosa-10,14,16,22-tetraene)-6-spiro-2'-(tetrahydropyran)-2-one；milbemycin α₁；milbemycin A₃；milbemycin α1；milbemectin A3；milbemycin A3；(1R,4S,5'S,6R,6'R,8R,10E,13R,14E,16E,20R,21R,24S)-21,24-dihydroxy-5',6',11,13,22-pentamethylspiro[3,7,19-trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene-6,2'-oxane]-2-one
• CAS: 51596-10-2
• 化学式: C₃₁H₄₄O₇
• 分子量: 528.686
• InChiKey: ZLBGSRMUSVULIE-GSMJGMFJSA-N

物化性质

• 熔点：
  212-215°; mp 192-194°
• 比旋光度：
  D20 +106° (c = 0.25 in acetone) (Aoki); D20 +106° (acetone) (Hirama)
• 沸点：
  725.5±60.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)
• 溶解度：
  DMF：可溶； DMSO：可溶；乙醇：可溶；甲醇：可溶
• 颜色/状态：
  White, crystalline powder (Technical grade)
• 闪点：
  43 °C (Closed cup) /Ultiflora Miticide/
• 蒸汽压力：
  9.8X10-11 mm Hg at 20 °C

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  38
• 可旋转键数：
  0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  94.4
• 氢给体数：
  2
• 氢受体数：
  7

ADMET

代谢

广泛代谢（在动物中，低剂量时粪便或胆汁中没有母化合物）主要通过羟基化，也有证据表明存在较小的葡萄糖醛酸化途径。（来自表格）

Extensively metabolised /in animals/ (no parent compound in faeces or bile at low dose) mainly by hydroxylation, also evidence for minor glucuronidation pathway. /From table/

来源:Hazardous Substances Data Bank (HSDB)

代谢

53只Fischer 344大鼠（每组5只/性别）通过口服灌胃方式给予(14)C-Milbemycin A4 ((14)C-E187) ... 在血浆、肝脏和肾脏样本中发现的 主要代谢物是13-羟基 A4，分别占放射性残留总量的60.2%、52.4%和66.7%。从粪便中鉴定出的代谢物包括：二羟基化的A4s（3种代谢物）；和三羟基化的A4s（2种代谢物）。主要的尿液代谢物是二羟基化的A4s（占给药剂量的0.95%至4.38%）。

Fifty-three Fischer 344 rats (5/sex/group) were dosed with (14)C-Milbemycin A4 ((14)C-E187) orally by gavage ... The major metabolite found in plasma, liver, and kidney samples was 13-hydroxy A4, accounting for up to 60.2, 52.4, and 66.7% of the total radioactive residue, respectively. The following metabolites were characterized from the feces: dihydroxylated A4s (3 metabolites); and trihydroxylated A4s (2 metabolites). The major urinary metabolite was dihydroxylated A4s (0.95 to 4.38% of admin dose).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。通过非重复呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的呕吐反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒物A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最小流量/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：急性暴露/可能会引起轻微的眼睛刺激。不是皮肤刺激物。不是皮肤致敏剂。/Ultiflora杀螨剂/

/LABORATORY ANIMALS: Acute Exposure/ May cause slight eye irritation. Not a dermal irritant. Not a skin sensitizer. /Ultiflora Miticide/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：亚慢性或前慢性暴露/ E-187（...纯度=93.7%）通过明胶胶囊以0（空胶囊）、3、10或30毫克/千克/天的剂量水平每天一次，每周7天，连续13周，给予每性别4只比格犬。没有动物死亡。在30毫克/千克/天的剂量下，两个性别都观察到了治疗相关的前震颤、镇静、流涎、蹒跚步态和眼部分泌物。在30毫克/千克/天的剂量下，雄性动物观察到治疗相关的体重下降和治疗相关的平均相对肾上腺重量增加。显微镜检查显示，在30毫克/千克/天的剂量下，雌性动物出现了治疗相关的C细胞增生。可能的不良效应：头部震颤。根据临床体征，NOEL（男/女）= 10毫克/千克/天。

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ E-187 ( ... purity = 93.7%) was admin to 4 beagle dogs per sex per dose by gelatin capsule at dose levels of 0 (empty capsule), 3, 10, or 30 mg/kg/day once a day 7 days/wk for 13 wk. No animals died. Treatment-related tremor of the head, sedation, salivation, staggering gait, and eye discharge were observed in both sexes at 30 mg/kg/day. A treatment-related decr in bw and a treatment-related incr in mean relative adrenal weight were observed in males at 30 mg/kg/day. Microscopic examination revealed treatment-related C-cell hyperplasia in females at 30 mg/kg/day. Possible adverse effect: tremor of the head. NOEL (M/F)= 10 mg/kg/day based on clinical signs.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

吸收、分布、排泄和哺乳动物中的代谢：至少47%（在单一低剂量2.5毫克/千克时）被吸收，根据胆汁和尿液排泄数据。广泛分布；肾上腺、肾脏、胰腺、淋巴结和生殖脂肪中残留最高。没有累积的证据。24小时排泄：尿液5%至9%，粪便85%至100%。（来自表格）

Absorption, distribution, excretion and metabolism in mammals: At least 47% /absorbed/ at single low dose (2.5 mg/kg), based on biliary and urinary excretion. Widely distributed; highest residues in adrenals, kidneys, pancreas, lymph nodes, and reproductive fat. No evidence for accumulation. /24 hr excretion/ urinary 5 to 9%; fecal 85 to 100%. /From table/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

费舍尔344大鼠（每组每性别5只）通过口服灌胃的方式给予（14）C-Milbemycin A4（14C-E187），剂量水平为2.5 mg/kg（低剂量）和25 mg/kg（高剂量），按照以下方案进行：1）单次低剂量；2）14天重复非标记剂量后给予单次碳-14低剂量；3）单次高剂量；4）单次低剂量以监测药代动力学；5）单次高剂量用于药代动力学。使用每组每性别9只大鼠进行组织分布研究，通过给予单次口服低剂量和高剂量。使用每组每性别4只大鼠进行胆汁插管研究，通过给予单次口服低剂量和高剂量。对于单次口服低剂量和高剂量以及重复剂量组，给予的（14）C的平均总回收率在93.7%到106%之间，其中81.5%到100%通过粪便排出，3.28%到9.29%通过尿液排出。剩余组织中的量小于总放射性残留物（TRR）的0.44%。碳-14的排泄是迅速的，大多数在给药后24小时内排出。胆汁和尿液中检测到的碳-14量表明，大约50%（在低剂量时）和30%（在高剂量时）的碳-14被吸收。口服给药后，碳-14在血浆中的浓度在给药后2到3小时达到峰值。组织中大部分的碳-14发现存在于胃肠道或肝脏中...

Fischer 344 rats (5/sex/group) were dosed with (14)C-Milbemycin A4 (14C-E187) orally by gavage at dose levels of 2.5 mg/kg (low dose) and 25 mg/kg (high dose) according to the following regimen: (1) single low dose; (2) 14-day repeated nonlabelled dose followed by a single carbon-14 low dose; (3) single high dose; (4) single low dose to monitor pharmacokinetics; and (5) single high dose for pharmacokinetics. Tissue distribution studies were conducted using 9 rats/sex/group by administering single oral low and high doses. Bile cannulation studies were conducted using 4 rats/sex/group by admin single oral low and high doses. For the single oral low and high dose and repeated dose groups, the mean total recoveries of the admin (14)C ranged from 93.7 to 106%, with 81.5 to 100% eliminated in feces and 3.28 to 9.29% in urine. The amt in the remaining tissues were < 0.44% of the total radioactive residue (TRR). Excretion of carbon-14 was rapid with most being excreted within 24 hr of admin. The amt of carbon-14 detected in bile and urine indicated that ca 50% (at low dose) and 30% (at high dose) of carbon-14 was absorbed. Following the oral dose, the plasma concn of carbon-14 peaked after 2 to 3 hr post-dose. Most of the carbon-14 in tissues was found in the gastrointestinal tract or in the liver ...

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险品运输编号：
  UN 2588
• 包装等级：
  III
• 危险类别：
  6.1(b)

制备方法与用途

弥拜菌素简介

弥拜菌素（milbemectin），试验代号B41、E187、S1-8601，商品名称包括Koromite、Matsuguard、Mesa、Milbeknock、Ultiflora和密灭汀。该化合物是由日本三共化学公司开发的一种抗生素类杀虫、杀螨剂。

理化性质

弥拜菌素A3原药纯度≥95%，为白色粉末，熔点212~215℃，密度（25℃）：1.1270，蒸气压（20℃）：1.3×10-5mPa，KowlgP：5.3，Henry常数<9.93×10-4Pa·m³/mol。水中溶解度（20℃，mg/L）：0.88，在有机溶剂中溶解性较好，如甲醇64.8、乙醇41.9、丙酮66.1、乙酸乙酯69.5、苯143.1、正己烷1.4。

应用 适用作物与防治对象

• 适用作物：蔬菜（茄子等）、水果（苹果、梨、草莓、柑橘等）、茶叶、松树等。
• 防治对象：朱砂叶螨、二斑叶螨、神泽氏叶螨、柑橘红蜘蛛、苹果红蜘蛛、柑橘锈壁虱，对线虫如松材线虫也有效。

残留量与安全施药

在土壤中DT516~33d。对皮肤轻度刺激，对鱼剧毒，禁用水域、空中施药或大面积使用。

应用技术

• 对害虫的各个阶段均有效。
• 活性与阿维菌素相似，但毒性低，比阿维菌素更安全。

使用方法

在世界范围内弥拜菌素推荐使用剂量为5.6~28g/hm²。具体用药量如下：

1. 1%弥拜菌素乳油防治神泽氏叶螨：每公顷用药1kg,稀释1000倍，害螨发生时施药，接收前6d停止施药。
2. 防治柑橘红蜘蛛：每公顷用药1.3kg,稀释1500倍，害虫密度每叶达5只时，施药一次，接收前6d停止施药。
3. 防治梨二点叶螨：每公顷用药0.6~0.8kg,稀释1500倍，叶螨发生时施药一次，隔14d再施药一次，接收前6d停止施药。
4. 防治度枣轮斑病：每公顷用药0.6~0.8kg,稀释1500倍，叶螨发生时施药一次，接收前6d停止施药。
5. 防治十字花科蔬菜蚜虫：每公顷用药0.5~0.7kg,稀释1500倍，害虫发生时施药一次，隔7d再施药一次，接收前6d停止施药。
6. 防治水蜜桃二点叶螨：每公顷用药2kg,稀释1000倍，害虫发生时施药一次，接收前15d停止施药。

作用机理

弥拜菌素是从土壤微生物链霉菌（streptomyces hygroscopicus subsp. aureolacrimosus）的发酵物中提取而得到。

毒性

• 急性经口LD50(mg/kg)：雄大鼠762，雌大鼠456，雄小鼠324，雌小鼠313。
• 大、小鼠急性经皮LD50>5000mg/kg。对兔皮肤和眼睛无刺激性，对豚鼠皮肤无致敏性。
• 大鼠吸入LC50(4h,mg/kg)：雄性1.90，雌性2.80。
• NOEL[mg/(kg·d)]：雄大鼠6.81，雌大鼠8.77，雄小鼠18.9，雌小鼠19.6。
• ADI(EC)0.03mg/kg[2005],(FSC)0.03mg/kg。无致畸、致突变、致癌作用。

反应信息

• 作为反应物：
  描述：

  密灭汀A3 在 manganese(IV) oxide 、 盐酸羟胺 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 丙酮 为溶剂， 反应 6.0h， 生成 5-ketomilbemycin A₃ 5-oxime
  参考文献：
  名称：

  Synthesis of 5-Keto-5-oxime Derivatives of Milbemycins and Their Activities against Microfilariae.

  摘要：

  从米尔贝霉素 D (1)、米尔贝霉素 A4 (2) 和米尔贝霉素 A3 (3)开始，通过对 5-酮基米尔贝霉素的 α、β-共轭羰基功能进行选择性氧化，合成了一系列 5-酮基-5-肟衍生物 (4-6)。研究人员在感染了软下二鞭毛虫微丝蚴的狗身上研究了合成化合物的活性。米尔贝霉素 D (7)、A4 (8) 和 A3 (9) 的 5-酮-5-肟对控制微丝蚴具有相当高的效力，且效力高于其母体，而 5-O-酰基肟 (11-15) 也表现出很高的活性。

  DOI：

  10.1271/bbb1961.55.2615
• 作为产物：
  描述：

  [(2R,4S,6R,8R,9S)-2-[(2E,5R,6E,8E)-8-[(3aS,4R,6S,7R,7aR)-7-benzoyloxy-4-formyl-3a-hydroxy-6-methyl-5,6,7,7a-tetrahydro-4H-1-benzofuran-3-ylidene]-3,5-dimethylocta-2,6-dienyl]-8,9-dimethyl-1,7-dioxaspiro[5.5]undecan-4-yl] benzoate 在 吡啶 、 sodium chlorite 、 sodium tetrahydroborate 、 potassium dihydrogenphosphate 、 cerium(III) chloride 、 四丙基高钌酸铵 、 2-甲基-2-丁烯 、 4 A molecular sieve 、 2,4,6-三氯苯甲酰氯 、 氢氟酸 、 3-(4-nitrophenyl)-2-(phenylsulfonyl)-1,2-oxaziridine 、 sodium methylate 、 4-吡咯烷基吡啶 、 三乙胺 、 zinc(II) chloride 、 叔丁醇 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 71.33h， 生成 密灭汀A3
  参考文献：
  名称：

  螺酮缩醇大环内酯的全合成（+）米尔倍霉素α 1

  摘要：

  抗寄生虫螺酮缩醇大环内酯的总合成（+）米尔倍霉素α 1被报告，以下朱莉娅砜阴离子的砜的耦合3与北半球醛2和随后的官能团的阐述。

  DOI：

  10.1016/s0040-4039(00)60158-2

文献信息

• 13β-Hydroxylation of Milbemycins by Selenium Dioxide
  作者：Yoshihisa Tsukamoto、Kazuo Sato、Takao Kinoto、Toshiaki Yanai

  DOI：10.1246/bcsj.65.3300

  日期：1992.12

  Introduction of a hydroxyl group to milbemycin nucleus was examined. Starting from 5-oxo-5-deoxymilbemycins, 13β-hydroxy-5-oxo-5-deoxymilbemycins were obtained stereo- and regioselectively by selenium dioxide oxidation in formic acid and subsequent acidic hydrolysis. The stereochemistry of the hydroxyl group was elucidated by 1H NMR study.

  对 milbemycin 核心引入羟基进行了研究。从 5-氧-5-脱氧milbemycin 开始，通过在甲酸中用二氧化硒氧化，随后进行酸性水解，获得了 13β-羟基-5-氧-5-脱氧milbemycin，具有立体选择性和区域选择性。通过 1H NMR 研究阐明了羟基的立体化学。
• Bioconversion of Milbemycin-related Compounds. Isolation and Utilization of Non-producer, Strain RNBC-5-51.
  作者：KOICHI NONAKA、TAKAHIRO TSUKIYAMA、KAZUO SATO、CHIEKO KUMASAKA、FUMIO MARUYAMA、HIROJI YOSHIKAWA

  DOI：10.7164/antibiotics.52.620

  日期：——

  A non-producing strain, the so-called strain RNBC-5-51 SANK 60198, was isolated during a screening program of strain improvement in the milbemycin production. Strain RNBC-5-51 indicated almost the same characteristics as those in the parent strain, that is, the abundant spore formation on agar media and the good growth in liquid media. But it does not produce any kind of milbemycins. In addition, strain RNBC-5-51 accumulated precursor-like compounds of milbemycin-polyketide, the production of which were inhibited by the addition of cerulenin. In the bioconversion experiments, strain RNBC-5-51 converted milbemycin β6 and A4 to milbemycin α14, and milbemycin β7 and A3 to milbemycin α11, respectively. This strain also converted milbemycin D and avermectin Bla, to 26-(3-methyl-2-butenoyloxy)milbemycin D and 26-(3-methyl-2-butenoyloxy)avermectin Bla, respectively. These results suggest that milbemycin α11 is biosynthesized through the same route as milbemycin α14, and the mutated step in strain RNBC-5-51 might be in the polyketide synthetic pathway of milbemycins. Strain RNBC-5-51 loses the ability for de novo synthesis of milbemycins, but it retains the ability to bioconvert the milbemycin skeleton. This strain might be useful for C-26 modification of milbemycin-related compounds.

  在米尔贝霉素生产的菌株改良筛选计划中，分离出了一株不生产米尔贝霉素的菌株，即所谓的 RNBC-5-51 SANK 60198 菌株。菌株 RNBC-5-51 与母本菌株的特征几乎相同，即在琼脂培养基上有大量孢子形成，在液体培养基中生长良好。但它不产生任何种类的米贝菌素。此外，菌株 RNBC-5-51 积累了类似于米尔贝菌素聚酮的前体化合物，而加入神经鞘氨醇可抑制其产生。 在生物转化实验中，菌株 RNBC-5-51 分别将米尔贝霉素 β6 和 A4 转化为米尔贝霉素 α14，将米尔贝霉素 β7 和 A3 转化为米尔贝霉素 α11。该菌株还能将小米霉素 D 和阿维菌素 Bla 分别转化为 26-（3-甲基-2-丁烯酰氧基）小米霉素 D 和 26-（3-甲基-2-丁烯酰氧基）阿维菌素 Bla。 这些结果表明，米尔贝霉素α11与米尔贝霉素α14的生物合成途径相同，菌株RNBC-51的突变步骤可能是米尔贝霉素的多酮合成途径。菌株 RNBC-5-51 失去了从头合成米尔贝霉素的能力，但保留了生物转化米尔贝霉素骨架的能力。该菌株可能有助于米尔贝霉素相关化合物的 C-26 改造。
• Diastereoselective Microbial Hydroxylation of Milbemycin Derivatives
  作者：Gerardo M. Ramos Tombo、Oreste Gmsalba、Hans-Peter Schär、Bruno Frei、Peter Maienfisch、Anthony C. O’Sullivan

  DOI：10.1080/00021369.1989.10869540

  日期：1989.6

  The diastereoselective hydroxylation of milbemycin A4 (1) at the 13/f-position (-*2) was performed by cultures of Streptomyces violascens (ATCC 31560). 14,15-epoxymilbemycin A4 (3) was formed via a parallel reaction as a byproduct. The conversion and the product ratio, 2/3, were improved by the addition of organic solvents. The best results, i.e., 91 % conversion with 92 % 2 and 8 % 3, were obtained by adding 2.5% DMSO to the culture broth. Oxime 7 was also hydroxylated at the 13β-position by S. violascens under similar conditions. In the case of milbemycin A3 (9) and D (10), the main products after treatment with S. violascens were the corresponding 14,15-epoxides, 13 and 14, respectively.

  米尔贝霉素 A4 (1) 在 13/f 位 (-*2) 的非对映选择性羟基化反应是由 Streptomyces violascens (ATCC 31560) 培养物进行的。14,15-epoxymilbemycin A4 (3) 作为副产品通过平行反应生成。通过添加有机溶剂，提高了转化率和产品比率（2/3）。在培养液中加入 2.5% 的二甲基亚砜（DMSO）可获得最佳结果，即 91% 的转化率，92% 的 2 和 8% 的 3。在类似条件下，肟 7 也被 S. violascens 在 13β 位羟化。至于米尔贝霉素 A3（9）和 D（10），经 violascens 菌处理后的主要产物分别是相应的 14,15-环氧化物 13 和 14。
• METHOD FOR SYNTHESIZING MILBEMYCIN OXIME
  申请人：HUBEI HONCH PHARMACEUTICAL CO.,LTD

  公开号：US20170050977A1

  公开（公告）日：2017-02-23

  The present invention provides a method for synthesizing Milbemycin oxime. The method comprises the following steps. (1) Oxidizing reaction: oxidizing Milbemycin, using hypochlorite or chlorite as oxidizers and piperidine nitrogen oxygen free radicals as the catalyst and halide as the catalyst promoter. The oxidation reaction is conducted in a dichloromethane solvent for 0.5-4 hours at −5-15° C. to produce the intermediate product Milbemycin ketone. (2) Oximation reaction: reacting the Milbemycin ketone with a hydroxylamine hydrochloride oximation agent in a 1,4-dioxane reaction solvent for 10-16 hours at 25-35° C. to obtain Milbemycin oxime. The method provided by the present invention realized the industrial production of Milbemycin oxime for the first time domestically. Moreover, the yield of the prepared product is higher than competing products both at home and abroad.

  本发明提供了一种合成氧羟基妙巴蟛的方法。该方法包括以下步骤。 （1）氧化反应：氧化妙巴蟛，使用次氯酸盐或氯酸盐作为氧化剂，吡啶氮氧自由基作为催化剂和卤化物作为催化剂助剂。在二氯甲烷溶剂中，将氧化反应在-5至15°C下进行0.5-4小时，以生成中间产物妙巴蟛酮。 （2）氧化胺反应：将妙巴蟛酮与羟胺盐酸盐氧化剂在1,4-二氧六环反应溶剂中反应10-16小时，在25-35°C下获得氧羟基妙巴蟛。本发明提供的方法首次在国内实现了氧羟基妙巴蟛的工业生产。此外，所制备产品的产率高于国内外竞争产品。
• Synthesis of Milbemycins β₉and β₁₀from Milbemycins A₃and A₄and Their Biological Activities
  作者：Takahiro TSUKIYAMA、Ayako KINOSHITA、Reiji ICHINOSE、Kazuo SATO

  DOI：10.1271/bbb.66.1407

  日期：2002.1

  Chemical derivation methods were used to prepare milbemycins β9 and β10 from milbemycins A3 and A4. Their acaricidal activities were also assessed against the organophosphorus-sensitive two-spotted spider mite (Tetranychus urticae) on primary leaves of cowpea plants (Vigna sinesis Savi species) by spraying.

  采用化学衍生方法，从米贝菌素 A3 和 A4 制备了米贝菌素 β9 和 β10。此外，还通过喷洒方法评估了它们对豇豆（Vigna sinesis Savi species）主叶上有机磷敏感的二斑蜘蛛螨（Tetranychus urticae）的杀螨活性。