CN1016785B - 9-去氧-9a-氮杂-9a-甲基-高红霉素A二水合物的制备方法 - Google Patents

9-去氧-9a-氮杂-9a-甲基-高红霉素A二水合物的制备方法

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CN1016785B
CN1016785B CN88104331A CN88104331A CN1016785B CN 1016785 B CN1016785 B CN 1016785B CN 88104331 A CN88104331 A CN 88104331A CN 88104331 A CN88104331 A CN 88104331A CN 1016785 B CN1016785 B CN 1016785B
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azithromycin
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道格拉斯·约翰·梅尔德伦·艾伦
凯文·迈克尔·内普弗
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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***的命名基于“IUPAC    Nomenclature    of    Organic    Chemistry，1979    Edition”，Perg-amon    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，azithromycin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***）;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（C-C）烃结晶制得的结晶 的不吸湿二水合物。
Azithromycin的结构式如下：
Figure 88104331_IMG1
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***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***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9-去氧-9a-氮杂-9a-甲基-9a-高红霉素A二水合物的方法，该方法包括：将吸湿的9-去氧-9a-氮杂-9a-甲基-9a-高红霉素A一水合物在至少为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。
CN88104331A 1987-07-09 1988-07-08 9-去氧-9a-氮杂-9a-甲基-高红霉素A二水合物的制备方法 Expired CN1016785B (zh)

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PCT/US1987/001612 WO1989000576A1 (en) 1987-07-09 1987-07-09 Azithromycin dihydrate
USPCT/US87/01612 1987-07-09

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1308361C (zh) * 2004-08-09 2007-04-04 大连振邦氟涂料股份有限公司 乙烯－三氟氯乙烯共聚物的制备方法
CN100366686C (zh) * 2006-01-12 2008-02-06 济南瑞氟化工科技有限公司 一种氟硅超双疏不粘涂料

Families Citing this family (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HRP20020231A2 (en) * 2002-03-18 2003-12-31 Pliva D D ISOSTRUCTURAL PSEUDOPOLYMORPHS OF 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A
US5912331A (en) * 1991-03-15 1999-06-15 Merck & Co., Inc. Process for the preparation of 9-deoxo-9(Z)-hydroxyiminoerythromycin A
US5985844A (en) * 1992-03-26 1999-11-16 Merck & Co., Inc. Homoerythromycin A derivatives modified at the 4"-and 8A-positions
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
US5605889A (en) 1994-04-29 1997-02-25 Pfizer Inc. Method of administering azithromycin
JP2977907B2 (ja) 1994-05-06 1999-11-15 ファイザー・インコーポレーテッド アジスロマイシンの放出調節された剤形
ES2122905B1 (es) * 1996-07-11 1999-11-16 Astur Pharma Sa Sintesis de 11,12-hidrogenoortoborato de 9-desoxo-9a-aza-11,12-desoxi-9a-metil-9a-homoeritromicina a. un procedimiento para la preparacion de 9-desoxo-9a-aza-9a-metil-9a-homoeritromicina a dihidrato (azitromicina dihidrato).
US6369035B1 (en) * 1997-10-16 2002-04-09 Pliva, Farmaceutska Industrja, Dioni{Haeck Over (C)}Ko Dru{Haeck Over (S)}Tvo 3,6-hemiketals from the class of 9A-azalides
US6861411B1 (en) 1997-12-02 2005-03-01 Pfizer, Inc. Method of treating eye infections with azithromycin
PT102130A (pt) * 1998-03-13 1999-09-30 Hovione Sociedade Quimica S A Processo de preparacao de dihidrato de azitromicina
TW546302B (en) * 1998-05-08 2003-08-11 Biochemie Sa Improvements in macrolide production
CA2245398C (en) 1998-08-21 2002-01-29 Apotex Inc. Azithromycin monohydrate isopropanol clathrate and methods for the manufacture thereof
PT1152765E (pt) * 1998-11-30 2004-12-31 Teva Pharma Etanolato de azitromicina, processo de preparacao e composicoes farmaceuticas que os contem
US7056893B2 (en) 1999-03-31 2006-06-06 Insite Vision, Inc. Topical treatment for prevention of ocular infections
US6239113B1 (en) 1999-03-31 2001-05-29 Insite Vision, Incorporated Topical treatment or prevention of ocular infections
OA11876A (en) * 1999-05-18 2006-03-27 Pfizer Prod Inc Novel crystalline forms of a macrolide antibiotic.
KR100700475B1 (ko) 1999-06-29 2007-03-28 바이오케미 에스.에이. 마크롤라이드
ES2177373B1 (es) * 1999-11-26 2003-11-01 Astur Pharma Sa Preparacion de azitromicina en su forma no cristalina
DE60133083D1 (de) 2000-01-04 2008-04-17 Teva Pharma Verfahren zur herstellung von azithromycin-dihydrat
ES2162764B1 (es) * 2000-05-17 2003-04-01 Ercros Ind Sa Forma polimorfica del dihidrato de azitromicina, y su procedimiento deobtencion.
DE60026718T2 (de) 2000-07-25 2006-11-16 Laboratorio Silanes, S.A. De C.V. Einstufiges verfahren zur herstellung von 7,16-deoxy-2-aza-10-o-cladinosil-12-o-desosaminil-4,5-dihydroxi-6-ethyl-3,5,9,11,13,15-hexamethylbicycle(11.2.11)hexadeca-1(2)-en-8-ona undeine neue form von 9-desoxo-9a-methyl-9a-aza-9a-homoerythromycin a
ES2172417B1 (es) * 2000-07-31 2003-09-16 Sint Quimica Sa Nueva forma mejorada de azitromicina monohidrato de menor higroscopicidad, procedimiento de preparacion y composiciones farmaceuticas que la comprenden.
ATE306491T1 (de) 2000-08-23 2005-10-15 Wockhardt Ltd Verfahren zur herstellung von wasserfreiem azithromycin
CZ303343B6 (cs) * 2000-11-27 2012-08-08 Sandoz Ag Zpusob prípravy azithromycinu ve forme monohydrátu
IN190080B (zh) * 2001-01-29 2003-06-07 Alembic Ltd
KR100491183B1 (ko) * 2001-03-21 2005-05-25 한미약품 주식회사 아지트로마이신의 제조방법 및 이 방법에 사용되는9-데옥소-9에이-아자-9에이-호모에리트로마이신 에이의결정성 수화물
EP1671979B1 (en) 2001-05-22 2008-08-13 Pfizer Products Inc. New Cristal Form of Azithromycin
EA007618B1 (ru) 2001-05-22 2006-12-29 Пфайзер Продактс Инк. Кристаллический полуторогидрат азитромицина, содержащая его фармацевтическая композиция и способ лечения на его основе
US6861413B2 (en) 2001-05-22 2005-03-01 Pfizer Inc. Stable non-dihydrate azithromycin oral suspensions
SK1012004A3 (sk) * 2001-08-21 2005-04-01 Pfizer Products Inc. Použitie azitromycínu na výrobu liečiva na liečenie respiračných infekcií u človeka
BR0215175A (pt) * 2001-12-21 2004-12-28 Pfizer Prod Inc Métodos para a granulação úmida de azitromicina
NZ532707A (en) * 2001-12-21 2006-07-28 Pfizer Prod Inc Directly compressible formulations of azithromycin
JP2005526020A (ja) * 2002-02-01 2005-09-02 ファイザー・プロダクツ・インク アジスロマイシンの乾式造粒配合物
US7376064B2 (en) 2002-02-25 2008-05-20 Samsung Electronics Co., Ltd. Method and apparatus for recording data on optical recording medium
ITMI20021209A1 (it) * 2002-06-04 2003-12-04 Chemi Spa Processo di preparazione di azitromicina ad elevata purezza
US6855813B2 (en) * 2002-07-19 2005-02-15 Alembic Limited Process for the preparation of azithromycin monohydrate
HRP20020614A2 (en) 2002-07-22 2004-06-30 PLIVA-ISTRAŽIVAČKI INSTITUT d.o.o. Rhombic pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin a
GB2395482A (en) * 2003-07-03 2004-05-26 Jubilant Organosys Ltd Process for preparing non-hygroscopic azithromycin dihydrate
US20050013835A1 (en) * 2003-07-15 2005-01-20 Pfizer Inc. Stable non-dihydrate azithromycin oral suspensions
CA2549225A1 (en) * 2003-12-04 2005-06-16 Pfizer Products Inc. Spray-congeal process using an extruder for preparing multiparticulate crystalline drug compositions containing preferably a poloxamer and a glyceride
RU2006119453A (ru) * 2003-12-04 2007-12-20 Пфайзер Продактс Инк. (Us) Получение посредством основанных на применении жидкостей способов лекарственные формы азитромицина с большим количеством частиц
US6984403B2 (en) * 2003-12-04 2006-01-10 Pfizer Inc. Azithromycin dosage forms with reduced side effects
WO2005053639A2 (en) * 2003-12-04 2005-06-16 Pfizer Products Inc. Controlled release multiparticulates formed with dissolution enhancers
EP1691787B1 (en) * 2003-12-04 2008-07-02 Pfizer Products Inc. Method for making pharmaceutical multiparticulates
WO2005053653A1 (en) * 2003-12-04 2005-06-16 Pfizer Products Inc. Spray-congeal process using an extruder for preparing multiparticulate azithromycin compositions containing preferably a poloxamer and a glyceride
WO2005053652A1 (en) 2003-12-04 2005-06-16 Pfizer Products Inc. Multiparticulate crystalline drug compositions containing a poloxamer and a glyceride
BRPI0416534A (pt) * 2003-12-04 2007-01-09 Pfizer Prod Inc composições multiparticuladas com estabilidade melhorada
US7468428B2 (en) * 2004-03-17 2008-12-23 App Pharmaceuticals, Llc Lyophilized azithromycin formulation
US20060116336A1 (en) * 2004-03-17 2006-06-01 American Pharmaceutical Partners, Inc. Lyophilized azithromycin formulation
US7235646B2 (en) 2004-06-28 2007-06-26 Alembic Limited Process for the preparation of azithromycin monohydrate isopropanol clathrate
US7683162B2 (en) * 2004-08-30 2010-03-23 Taro Pharmaceutical Industries Limited Process of preparing a crystalline azithromycin monohydrate
TWI315310B (en) * 2004-12-01 2009-10-01 Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag Methods of preparing pimecrolimus
US20080199527A1 (en) * 2004-12-21 2008-08-21 Pfizer Inc. Enteric Coated Azithromycin Multiparticulates
US8546423B2 (en) 2005-05-18 2013-10-01 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
JP2009539866A (ja) * 2006-06-05 2009-11-19 オースペックス・ファーマシューティカルズ・インコーポレイテッド 置換エリスロマイシンアナログの調製および有用性
US7704959B2 (en) 2006-10-03 2010-04-27 Dow Pharmaceutical Sciences Azithromycin for the treatment of nodular acne
US20090062220A1 (en) * 2007-08-29 2009-03-05 Protia, Llc Deuterium-enriched azithromycin
CN101177441B (zh) * 2007-12-05 2012-05-23 浙江耐司康药业有限公司 一种稳定的阿奇霉素一水合物结晶的制备方法
CN101624412B (zh) * 2008-07-10 2012-07-04 刘力 大环内酯类衍生物及其制备和用途
NZ592717A (en) 2008-10-07 2013-03-28 Mpex Pharmaceuticals Inc Aerosol fluoroquinolone formulations for improved pharmacokinetics comprising levofloxacin or ofloxacin and a di- or trivalent cation
SI2346509T1 (sl) 2008-10-07 2020-08-31 Horizon Orphan Llc Inhalacija levofloksacina za zmanjšanje vnetja pljuč
CN101418026B (zh) * 2008-10-09 2011-05-18 南京工业大学 一种晶型和粒度可控的阿奇霉素结晶工艺
CN101787063B (zh) * 2009-01-23 2012-12-19 刘力 抗感染药物及其制备和用途
BRPI1009823A2 (pt) 2009-03-13 2019-09-24 Da Volterra Assistance Publique Hopitaux De Paris E Univ Paris Diderot Paris 7 "composição compreendendo um sistema de dispensação de droga, conjunto de uma primeira e uma segunda composição, e, kit."
RU2563809C2 (ru) 2009-09-04 2015-09-20 Мпекс Фармасьютикалс, Инк. Применение левофлоксацина в форме аэрозоля для лечения муковисцидоза
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
CN103159811A (zh) * 2011-12-10 2013-06-19 山东方明药业集团股份有限公司 一种阿齐霉素中间体9a-脱氧-9a-氮杂-9a-高红霉素A的制备方法
WO2013088274A1 (en) 2011-12-14 2013-06-20 Wockhardt Limited Anhydrous amorphous azithromycin composition free of azithromycin dihydrate
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

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4020270A (en) * 1974-05-02 1977-04-26 Societa' Farmaceutici Italia S.P.A. L-lyxohex-1-enopyranose derivative
US4219641A (en) * 1979-06-14 1980-08-26 The Upjohn Company Process for preparing erythromycin succinate
SI8110592A8 (en) 1981-03-06 1996-06-30 Pliva Pharm & Chem Works Process for preparing of n-methyl-11-aza-10-deoxo-10-dihydroerythromycine a and derivatives thereof
US4474768A (en) * 1982-07-19 1984-10-02 Pfizer Inc. N-Methyl 11-aza-10-deoxo-10-dihydro-erytromycin A, intermediates therefor
US4526889A (en) * 1982-11-15 1985-07-02 Pfizer Inc. Epimeric azahomoerythromycin A derivative, intermediates and method of use
PH19293A (en) * 1982-11-15 1986-03-04 Pfizer Epimeric azahomoerythromycin,pharmaceutical composition containing the same and method of use thereof
US4512982A (en) * 1984-04-13 1985-04-23 Pfizer Inc. 9α-Aza-9α-homoerythromycin compounds, pharmaceutical composition and therapeutic method
YU43402B (en) * 1985-03-04 1989-06-30 Pliva Pharm & Chem Works Process for preparation of 11-aza-10-deoxo-10-dihydroeritromycin "a" by using electro-chemical reduction
WO1989002271A1 (en) 1987-09-10 1989-03-23 Pfizer Azithromycin and derivatives as antiprotozoal agents

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1308361C (zh) * 2004-08-09 2007-04-04 大连振邦氟涂料股份有限公司 乙烯－三氟氯乙烯共聚物的制备方法
CN100366686C (zh) * 2006-01-12 2008-02-06 济南瑞氟化工科技有限公司 一种氟硅超双疏不粘涂料

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