CN1030422A - 9-去氧-9a-氮杂-9a-甲基-9a-高红霉素A二水合物 - Google Patents
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Abstract
本发明公开了不吸湿的azithromycin(9-去氧
-9a-氮杂-9a-甲基-9a-高红霉素A)二水合物及其
制备方法。
Description
本发明涉及一种有效的新颖形式的azithromycin(9-去氧-9a-氮杂-9a-甲基-9a-高红霉素A),即:它的不吸湿的二水合物形式。
Azithromycin(9-去氧-9a-氮杂-9a-甲基-9a-高红霉素A)的属名是U.S.A.N.,一种由红霉素A衍生的广谱抗菌素化合物。Azithromycin分别是由Bright在美国专利4,474,768号和Kobrehel等人在美国专利4,517,359号中披露的。在这些专利中,发明者用了“N-甲基-11-氮杂-10-去氧-10-二氢红霉素A”这一命名。本发明的更系统的命名基于“IUPAC Nomenclature of Organic Chemistry,1979 Edition”,Pergamon Press,1979,PP.68-70,459,500-503上的开环和置换命名原则。
如先有技术所述,azithromyciz是由乙醇和水结晶得到的(例如见美国专利4,474,768号中的实施例3),是吸湿的一水合物(详见下面制备例1)。由于其吸湿性,极难制备和维持具有恒定的、可再现的含水型的所述一水合物。在配制过程中尤难处理,因为在较高的相对湿度时,一般需要避免静电之麻烦(如:流速,带电位的起尘引起的爆炸);一水合物易吸收不定量的水份,其吸湿量取决于曝光时间和相对湿度的精确值(见下面制备例1)。本发明的稳定的二水合物解决了上述难点。在有益于配制azithromycin的相对湿度状态下,该二水合物基本上是不吸湿的。
本发明涉及一种有效的新颖形式的azithromycin,即:在至少为两摩尔当量的水的存在下,由四氢呋喃和脂族(C5-C7)烃结晶制得的结晶的不吸湿二水合物。
Azithromycin的结构式如下:
该化合物衍生于不含有不对称中心的红霉素A,因此在其每个如同红霉素A一样的这类中心(*),都存在立体化学结构。根据红霉素A衍生物的系统命名,该化合物称为9-去氧-9a-氮杂-9a-甲基-9a-高红霉素A。包含本发明的二水合物的Azithromycin具有广谱抗菌素活性,用于治疗易受细菌感染的哺乳动物(包括人)。
“脂族(C5-C7)烃”是指沸点较低的烃溶剂,通常为有特定的沸点范围如通常所指的“戊烷”、“己烷”、“己烷类”等一类的混合物,但也可以是基本上纯的正己烷、环己烷或甲基环己烷。优选的烃溶剂是所谓的“己烷”,其沸点接近于纯的正己烷的沸点。
本发明易于实施。把呈无定形态的Azithromycin(按上述Bright或Kobrehel等的方法制得)或呈一水合物(由于吸水性,可能含一摩尔当量以上的水份)的Azithromycin溶于四氢呋喃。因为本方法初速阶段所需的温度并不关键,所以通常采用室温,从而省掉了加热和冷却的费用。此外,为获得最高的收率,并使溶剂用量、劳动力和设备成本最低,将四氢呋喃的体积保持在接近于最低的水平上,例如每公斤基质使用2升溶剂。采用惯用的过滤法,可方便地除去此阶段中存在的任何不溶性杂质。必要时,可用活性炭将混合物脱色。为了便于处理,在需要时,先用一部分(C5-C7)烃将高度浓缩的混合物稀释,然后过滤。若进入主体的水份大大超过一摩尔当量,例如接近2摩尔当量,则最好用硫酸镁一类的干燥剂将混合物干燥一段时间,特别是烃溶剂是在过滤前加入的情况下。为获得结晶的二水合物,将一定量的水加到所形成的纯净溶液中,以便足以使总的含水量达到相当于至少为2摩尔当量的水平,一般不超过3-4摩尔当量。用标准的费歇尔(Kare Fischer)滴定法,可方便地监测系统中的含水量。先加水,继之以加烃溶剂(若过滤前混合物已经过稀释,则加入较多的烃溶剂),促使生成所期望的二水合物的结晶。这一步骤可在室温(如17-30℃)下实施,但为便于最初的结晶,最好于稍高温(如30-40℃)下进行。所采用的烃溶剂的总体积一般至少四倍于四氢呋喃。烃的体积较大,效果就理想,但为使成本最低,一般不这样做。一旦结晶完毕,通常于室温下粒化一段时间(如3-24小时),然后过滤收集产物。一般,将有机溶剂真空干燥(于20-40℃,一般于室温下进行较方便)后,得到产物。为避免水合过程中水份的损失,在干燥期间,一般要监测挥发组分和含水量,以便使四氢呋喃和烃的含量落在0.25%以下,含水量在理论值(4.6%)的0.3%偏差内。
按Bright在美国专利4,474,768号(这里用作对比文献)中详述的方法和剂量,配制与施用azithromycin二水合物,用以治疗易受细菌感染者。
本发明由以下实施例加以说明。然而,应该理解到,本发明不限于所述实施例的具体细节。
实施例1
不吸湿的Azithromycin二水合物
方法A
将制备例1的吸湿一水合物(100g;含水量3.1%),四氢呋喃(220ml)和硅藻土(5g)在500ml的锥形烧瓶中混合,搅拌30分钟,然后过滤并用20ml四氢呋喃洗涤。将合并的滤液和洗涤液转移到一个3升的圆底烧瓶中,强烈地搅拌该溶液,加入水(2.0ml)。5分钟后,用5分钟时间加入己烷(1800ml),同时继续剧烈搅拌。经过18小时的粒化后,过滤收集标题产物用1×10ml己烷洗涤,真空干燥至水份为4.6±0.2%(用费歇尔滴定法测定),得到产物89.5g。
方法B
将制备例1的吸湿一水合物(197.6g)和四氢呋喃(430ml)装入反应器中,将该混合物搅拌成乳白色的溶液。加入活性炭(10g)和硅藻土(10g),将混合物搅拌15分钟,然后用800ml己烷稀释,经硅藻土垫板抽吸过滤,并用250ml己烷洗涤。将滤液和洗涤液汇合起来,用己烷将此混合物稀释成2500ml,并加温至34℃。搅拌下,加进24.7ml水。使该混合物冷却至室温,粒化五小时,回收标题产物,如方法A那样干燥,得到177.8g产物。
126℃时,二水合物急剧熔化(加热程度为10℃/分钟);127℃时,差示扫描量热法(加热速率20%/分钟)显示吸热性;热重量分析(加热速率30℃/分钟)表明100℃时,减量1.8%,150℃时减量4.3%;
ir(KBr)3953,3553,3488,2968,2930,2888,2872,2827,2780,2089,1722,1664,1468,1426,1380,1359,1344,1326,1318,1282,1270,1252,1187,1167,1157,1123,1107,1082,1050,1004,993,977,955,930,902,986,879,864,833,803,794,775,756,729,694,671,661,637,598,571,526,495,459,399,374,321和207cm-1;[alpha]26 D=-41.4°(c=1,CHCl3).
C38H72N2O12·2H2O的分析计算值:
C,58.14;H,9.77;N,3.57;OCH3,3.95;H2O,4.59.
实测值:
C,58.62;H.9.66;N,3.56;OCH3,4.11;H2O,4.49。
中和当量(0.5N HCl,在1∶1CH3CN∶H2O中):
计算值:374.5,
实测值:393.4。
在33%,75%或100%的相对湿度下,将略经干燥至含水量为4.1%(少于理论值)的二水合物试样迅速吸水,达到二水合物的理论含水量(4.6%)。在33%和75%的相对湿度下,含水量基本上保持恒定,持续时间至少为4天。在100%的相对湿度下,含水量进一步上升至约5.2%,以后三天里,它基本保持稳定含水量。
维持在18%的相对湿度下的相同二水合物试样逐渐失水。在四天时间里,含水量为2.5%;十二天里,含水量为1.1%。
制备例1
吸湿的Azithromycin一水合物
基本上按Kobrehel等的美国专利4,517,359号的甲基化步骤和Bright的美国专利4,474,768号的结晶步骤,搅拌下,将9-去氧-9a-氮杂-9a-高红霉素A(先前称为11-氮杂-10-去氧-10-二氢红霉素A;100g,0.218mol)溶于400ml CHCl3。在4-5分钟内,加入甲酸(98%;10.4ml,0.436mol)和甲醛(37%;16.4ml,0.349mol),将该混合物加热回流20小时。将该混合物冷却至室温,用400ml水稀释,用50% NaOH将pH调整至10.5。分离水层,用新鲜的CHCl3(2×100ml)萃取。将有机层合并起来,真空汽提至350ml,两次用450ml乙醇稀释,再次汽提至350ml,最后,在一小时内,用1000ml水稀释,在加入约250ml水之后,随着淤浆体开始形成,中止(反应)15分钟。过滤回收标题产物,50℃下风干24小时,得到产物85g,mp136℃;差热分析(加热速率20℃/分)显示142℃时吸热;热重量分析(加热速率30℃/分钟)显示100℃时减量2.6%,150℃时减量4.5%;含水量3.92%;乙醇含量1.09%。
C38H2N2O12的分析计算值(对含乙醇和含水量的校正):
C,58.46;H,9.78;N,3.74;烷氧基,4.67。
实测值:C,58.40;H,9.29;N,3.50;烷氧基,4.52。
将一水合物试样(含水量3.2%)维持在18%的相对湿度下,时间为14天。在开始的24小时内,试样失水,产生理论含水量为2.35%的一水合物。在以后的14天内,含水量基本上保持恒定,即在14天里记录到2.26%的恒定值。
在33%的相对湿度下,同样的一水合物含水量迅速上升至5.6%,至少在三天内基本上维持该值。同样,在75%和100%的相对湿度下,含水量迅速上升,但保持在更高的水平,分别为6.6%和7.2%,至少稳定3天。
Claims (2)
1、一种制备结晶azitromycin二水合物的方法,该方法包括:在至少为2摩尔当量水的存在下,从四氢呋喃和(C5-C7)脂族烃的混合物中结晶。
2、按权利要求1的方法,其中的烃是己烷。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1987/001612 WO1989000576A1 (en) | 1987-07-09 | 1987-07-09 | Azithromycin dihydrate |
USPCT/US87/01612 | 1987-07-09 |
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CN1030422A true CN1030422A (zh) | 1989-01-18 |
CN1016785B CN1016785B (zh) | 1992-05-27 |
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Cited By (4)
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WO2010003319A1 (zh) * | 2008-07-10 | 2010-01-14 | Liu Li | 红霉素的盐的水合物及其制备方法和用途 |
CN102417531A (zh) * | 2011-12-20 | 2012-04-18 | 浙江国邦药业有限公司 | 一种阿奇霉素一水合物的制备方法 |
CN101787063B (zh) * | 2009-01-23 | 2012-12-19 | 刘力 | 抗感染药物及其制备和用途 |
CN102911219A (zh) * | 2011-08-03 | 2013-02-06 | 山东方明药业集团股份有限公司 | 一种阿齐霉素在水相直接结晶的方法 |
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US5189159A (en) * | 1992-04-02 | 1993-02-23 | Merck & Co., Inc. | 8a-AZA-8a-homoerythromycin cyclic iminoethers |
EP0539223A1 (en) * | 1991-10-25 | 1993-04-28 | Ono Pharmaceutical Co., Ltd. | Glycine derivative monosodium salt tetrahydrate having an inhibitory effect on elastase |
US5215980A (en) * | 1992-01-17 | 1993-06-01 | Merck & Co., Inc. | 10-AZA-9-deoxo-11-deoxy-erythromycin A and derivatives thereof |
US5210235A (en) * | 1992-08-26 | 1993-05-11 | Merck & Co., Inc. | Methods of elaborating erythromycin fragments into amine-containing fragments of azalide antibiotics |
US5332807A (en) * | 1993-04-14 | 1994-07-26 | Merck & Co., Inc. | Process of producing 8A- and 9A-azalide antibiotics |
CN1034734C (zh) * | 1993-12-10 | 1997-04-30 | 北京市集才药物研究所 | 一种新的阿齐红霉素结晶及其制备方法 |
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WO2010003319A1 (zh) * | 2008-07-10 | 2010-01-14 | Liu Li | 红霉素的盐的水合物及其制备方法和用途 |
US8470787B2 (en) | 2008-07-10 | 2013-06-25 | Li Liu | Hydrates of erythromycin salts, preparation and use thereof |
CN101787063B (zh) * | 2009-01-23 | 2012-12-19 | 刘力 | 抗感染药物及其制备和用途 |
CN102911219A (zh) * | 2011-08-03 | 2013-02-06 | 山东方明药业集团股份有限公司 | 一种阿齐霉素在水相直接结晶的方法 |
CN102417531A (zh) * | 2011-12-20 | 2012-04-18 | 浙江国邦药业有限公司 | 一种阿奇霉素一水合物的制备方法 |
CN102417531B (zh) * | 2011-12-20 | 2014-06-11 | 浙江国邦药业有限公司 | 一种阿奇霉素一水合物的制备方法 |
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