CN1041523C - 结晶态取代的阿佛曼菌素苯甲酸盐及其制备方法与应用 - Google Patents

结晶态取代的阿佛曼菌素苯甲酸盐及其制备方法与应用 Download PDF

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CN1041523C
CN1041523C CN94193136A CN94193136A CN1041523C CN 1041523 C CN1041523 C CN 1041523C CN 94193136 A CN94193136 A CN 94193136A CN 94193136 A CN94193136 A CN 94193136A CN 1041523 C CN1041523 C CN 1041523C
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R·韦托维奇
R·迪查克
J·A·麦考利
R·J·瓦沙龙纳
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Abstract

通过从含有受控量水的有机溶剂中结晶，得到热力学上最稳定的结晶态4”-脱氧-4”-表甲氨基阿佛曼菌素Bla/Blb苯甲酸盐半水合物。

Description

结晶态取代的阿佛曼菌素苯甲酸盐及其制备方法与应用
发明背景
4”-脱氧-4”-表甲氨基阿佛曼菌素(avermectin)Bla／Blb的苯甲酸盐是已知的。如欧洲专利公开EP0465121-A1所述，它是一种稳定的盐，相对于以前描述的盐酸盐而言，其稳定性增强了，这大大提高了这种重要的农用杀虫剂的货架寿命。
发明概述
本发明涉及4”-脱氧-4”-表甲氨基阿佛曼菌素Bla／Blb苯甲酸盐(一种已知的农用杀虫剂)的四种结晶形态中之最稳定者及其制备方法。
已鉴定出的四种结晶态称为A型、B型、C型和D型，其中有三种是水化的(B、C和D)。热力学上最稳定的结晶态是半水合物B。了解最稳定的结晶态并设计该形态产品的生产方法是极为重要的，因为它能提供具有结晶均一性的大块物质，这种物质在贮存时不会转变成另一种结晶惯态。
生产B型结晶的新方法包括：从含有受控量水的有机溶剂中结晶出化合物。
发明详述
本发明的新化合物是基本纯净形式的结晶-4”-脱氧-4”-表甲氨基阿佛曼菌素Bla／Blb苯甲酸盐半水合物，其结构式如下：
Figure 9419313600061
其中R是-CH3(Bla)或-H(Blb)。该化合物称为B型结晶或类似的名称。
在开杯中在氮气流下以20℃／分的加热速度测定的差示扫描量热(DSC)曲线的特征是：有一个峰值温度为74℃的相对较宽的失水吸热峰和一个峰值温度为155℃的主要熔解／分解吸热峰，外推的起始温度为150℃，缔合热为56焦耳／克。B型的X-射线粉末衍射图形的特征是：d间距为18．13、9．08、8．68、5．03、4．61、4．53、3．97和3．82。水溶解性依赖于pH。在pH5的乙酸盐缓冲液中，其溶解度为0．32mg／ml。
本发明的新方法包括：从含水有机溶剂中重结晶任何高能态的化合物。
用于该新方法的含水有机溶剂优选为含2-4％w／w水的乙腈、含0．5-0．8％w／w水的甲基叔丁基醚(MTBE)、或含0．1-0．3％w／w水的异丙醇(IPA)。
将结晶态A、C或D的化合物于约50-60℃溶解于用必要量的水处理过的有机溶剂中，用B型结晶接种，冷却到约15-30℃并在该温度下老化约2-4小时，用约1-2小时的时间进一步冷却到约5℃。
用过滤器收集结晶产物并真空干燥。
本文所述的苯甲酸盐及其游离碱的用途和使用方法是本领域技术人员公知的，在科技文献和专利文献(如EP0465121)中有详细的叙述。
该化合物具有显著的杀寄生物活性，可在人和动物卫生及农业中作为抗蠕虫剂、杀外寄生虫剂、杀昆虫剂和杀鸟剂。作为农用除害剂，它对以下害虫有活性：贮存谷物的昆虫害虫(如拟谷盗、粉甲)、农作物的昆虫害虫如螨类(红叶螨)、蚜虫(无网长管蚜)；迁移直翅目昆虫(如蝗虫)以及生活在植物组织上的未成熟期昆虫。该化合物可作为杀线虫剂用于控制土壤线虫和植物寄生虫，如在农业上有重要意义的根结线虫。该化合物对其他植物害虫如亚热带粘虫和墨西哥豆瓢虫也有活性。
化合物用已知技术，以喷雾剂、粉尘剂、乳剂等形式施用于生长着的作物或贮存作物，从而实现对上述农业害虫的防护。处理生长着的作物时，化合物的施用率约为5-50克／公顷。防护贮存作物时，通常是用含0．1-10ppm化合物的溶液喷雾施用。
实施例
B型产品的制备
材料                                       量A型物质(从甲基叔丁基醚中结晶得到) 3．59kg    94．2％(重量)
                            2．33kg    95．7％(重量)
                            5．92kg(测定为5．61kg)乙腈(HPLC级)                     40升(KF=0．2mg／ml)去离子水                         570ml
步骤
给一个50升四颈圆底烧瓶配备机械搅拌器、N2入口、热电偶和漏斗。用N2吹扫容器后，加入乙腈(12升，KF=0．2mg／ml)并温热至50-55℃，装入A型物质。加完(30分钟)后，使混合物在氮气氛下再老化10分钟，得到透明的红棕色溶液。
再加乙腈(6升)稀释该批物料，加入水(270ml)，然后于45℃下加入B型晶种(10g)。晶体在45℃下立即开始迅速生长。为确保形成B型晶体，结晶过程必须在＞35℃起始，并主要在＞35℃进行。
用45分钟时间使该批物料冷却到20℃，并老化2．5小时。在此期间结晶浆液稠化，难以进行搅拌。再加乙腈(2升)，用1小时将浆液冷却到5℃。在5℃下老化30分钟后，将浆液过滤到衬有纸和聚丙烯的直径为22英寸的Cenco-Lapp漏斗上。母液循环回到结晶容器中，以冲洗和转移剩余的产品。滤饼用冷的(2℃)湿乙腈洗涤(5×4升，每份含1．5％(v／v)水)。使氮气流通过滤饼30分钟使滤饼部分干燥，然后转移到Hull干燥器中。
将滤饼于30℃下真空干燥(25英寸)3天，达到恒重，用气相色谱法(GC)测得的乙腈含量＜0．1％(重量)。该批产物为4．95kgB型物质。
无水Bla分析分子量             1008．26分子式             C56H81NO15CFA：              米色粉末X-射线             结晶B型水合物HPLC*             95．9％(重量)
               97．8％(面积)TLC                单点滴定*            100％(高氯酸)UV*              A％333、245nm(甲醇)KF              1．08％(重量)GC              CH3CN      ＜0．01％己烷            ＜0．01％
            甲基叔丁基醚    未测，＜0．01％
            乙酸异丙酯      未测，＜0．01％
*经KF、GC校正

Claims (5)

1．化合物4”-脱氧-4”-表甲氨基阿佛曼菌素Bla／Blb苯甲酸盐半水合物的结晶态B，其特征在于，所述化合物具有下列结构式：
其中对于Bla而言，R为-CH3，或对于Blb而言，R为-H；
所述化合物的差示扫描量热曲线表明，在峰温度为约75℃时的相对宽的浅的吸热峰(endotherm)相应于失水，在峰温度为约155℃时的第二个吸热峰相应于伴随着所述化合物的分解的融化(melting)；
所述化合物的X-射线粉末衍射具有下述特征：其中X-轴代表角度2-theta，而Y-轴代表以计数(count)／秒表示的强度，该X-射线粉末衍射是用CuKαX-射线辐射获得的，
角度          d-间距      相对强度(角度2-theta)    (A°)      (I／Imax)4．92          17．947         136．07          14．549         216．50          13．587         228．82          10．018         239．84           8．982         4810．3           8．581         4411．2           7．894         6112．1           7．309         5313．0           6．805         8013．9           6．366         4714．7           6．022         8015．7           5．640         1416．7           5．304         7216．9           5．242         6917．7           5．007         9318．1           4．897         5419．3           4．595         9720．4           4．350         2521．5           4．130         4322．4           3．966        10023．4           3．799         8024．7           3．602         2625．3           3．517         1926．2           3．399         4128．3           3．151         2529．0           3．077         3830．5           2．929         2531．1           2．873         1432．7           2．736         1134．0           2．635         1135．6           2．520         3139．6           2．274         22
2．一种制备基本纯净形式的结晶化合物4”-脱氧-4”-表甲氨基阿佛曼菌素Bla／Blb苯甲酸盐半水合物(B型)的方法，该方法包括：用以下方法从含水有机溶剂中重结晶任何其他形式或这些形式的混合物：于50-60℃下将起始原料溶解于加有约0．1-4％w／w水的有机溶剂中；冷却到约45-35℃；用B型晶体接种；放置到结晶基本完全；冷却到15-30℃并在该温度放置约2-4小时；用1-2小时的时间冷却到约5℃；收集固体并干燥。
3．权利要求2的方法，其中含水有机溶剂是含2-4％w／w水的乙腈。
4．一种防治农业昆虫的方法，该方法包括在受所述农业昆虫侵染的区域施用有效量的权利要求1的稳定盐。
5．一种用于防治植物或植物产品昆虫侵染的组合物，该组合物含有惰性载体和有效量的权利要求1的稳定盐。
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Families Citing this family (6)

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US6486195B1 (en) * 1993-08-19 2002-11-26 Merck & Co., Inc. Thermodynamically stable crystal form of 4″-deoxy-4″-epi-methylamino avermectin B1a/B1b benzoic acid salt and processes for its preparation
CR6574A (es) 2001-02-27 2004-10-28 Syngenta Participations Ag Sales de avermectinas substituidas en la posicion 4 con propiedades plaguicidas
ES2523758T3 (es) * 2010-02-23 2014-12-01 Nippon Kayaku Co., Ltd. Forma cristalina estable de carbonato de 2-etil-3,7-dimetil-6-(4-(trifluorometoxi)fenoxi)quinolin-4-il-metilo, método de producción de la misma, y composición química agrícola que contiene cristales de la misma
CN106995476B (zh) * 2017-05-16 2018-03-13 河北美荷药业有限公司 一种甲氨基阿维菌素b2苯甲酸盐的制备方法
CN108840893A (zh) * 2018-07-01 2018-11-20 李万强 一种甲氨基阿维菌素苯甲酸盐的新晶型及其制备方法
CN109912671B (zh) * 2019-04-12 2022-04-26 宁夏泰益欣生物科技有限公司 一种利用阿维菌素结晶母液提取阿维菌素B2a的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0465121A1 (en) * 1990-06-28 1992-01-08 Merck & Co. Inc. Stable salts of 4"-deoxy-4"-epimethylamino avermectin B1a/B1b

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57212200A (en) * 1981-06-23 1982-12-27 Takeda Chem Ind Ltd Preparation of echinoside a
GB8518422D0 (en) * 1985-07-22 1985-08-29 Beecham Group Plc Compounds
IT1216059B (it) * 1988-03-11 1990-02-22 Crc Ricerca Chim Procedimento per la separazione di diastereomeri macrociclici.
JPH0631302B2 (ja) * 1988-11-16 1994-04-27 日本化薬株式会社 エトポシド−２−ジメチルアミノ体塩酸二水和結晶及びその製造法
JPH0615557B2 (ja) * 1990-02-19 1994-03-02 ヤマサ醤油株式会社 ２’―デオキシ―２’―メチリデンシチジンの２水和物結晶
JPH0446192A (ja) * 1990-06-12 1992-02-17 Nippon Kayaku Co Ltd オキセタノシンｇ無水物結晶及びその製造法
JP2652272B2 (ja) * 1990-12-31 1997-09-10 住化ファインケム株式会社 １−（４−アミノ−６，７−ジメトキシ−２−キナゾリニル）−４−（２−テトラヒドロフロイル）ピペラジン塩酸塩の新規な結晶体および該結晶体の製造方法
RU2057132C1 (ru) * 1991-05-15 1996-03-27 Яманоути Фармасьютикал Ко., Лтд. Моногидрат (-)-(s)-2,8-диметил-3-метилен-1-окса-8-азаспиро[4,5]-декана l-тартрата и способ его получения
JP2848721B2 (ja) * 1991-08-09 1999-01-20 森永乳業株式会社 結晶ラクチュロース三水和物とその製造法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0465121A1 (en) * 1990-06-28 1992-01-08 Merck & Co. Inc. Stable salts of 4"-deoxy-4"-epimethylamino avermectin B1a/B1b

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EP0714400A1 (en) 1996-06-05
GR3032164T3 (en) 2000-04-27
EP0714400B1 (en) 1999-12-15
CZ45996A3 (en) 1996-05-15
RU2133753C1 (ru) 1999-07-27
DE69422182T2 (de) 2000-06-21
FI110783B (fi) 2003-03-31
FI960725A (fi) 1996-02-16
KR960703936A (ko) 1996-08-31

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