CN1199403A - 5－o－德糖胺基－6－o－甲基红诺霉素a的新型衍生物,其制法及其在制备生物活性产品中的应用 - Google Patents
5－o－德糖胺基－6－o－甲基红诺霉素a的新型衍生物,其制法及其在制备生物活性产品中的应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
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Abstract
本发明涉及通式(Ⅰ)的化合物,式中R代表含多至18个碳原子的羧酸残基。式(Ⅰ)产物可用于制备抗生素。
Description
本发明涉及5-O-德糖胺基-6-O-甲基红诺霉素A的新型衍生物，其制法及其在制备生物活性产品中的应用。
本发明涉及通式(I)的化合物：式中R代表含多至18个碳原子的羧酸残基。
所述的羧酸残基举例如：尤其是乙酰基、丙酰基、丁酰基、异丁酰基、正戊酰基、异戊酰基、叔戊酰基和新戊酰基。
更具体而言，本发明涉及其中R代表乙酰基的式(I)化合物。
本发明同样涉及一种制备方法，其特征在于使式(II)的化合物：与能选择性激活11位羟基的试剂反应；式(II)中R具有前述的意义；然后使之与碱反应以制得式(III)化合物：；使式(III)化合物与羰基二咪唑反应，再与肼反应，以制得相应的式(I)化合物。
式(II)化合物是公知的，并可按照欧洲专利申请619319所述的方法制备之。
在一种优选的实施方案中：
-所述能选择性激活11位羟基的试剂是磺酸衍生物，例如甲磺酸酐、对甲苯磺酸酐和三氟甲磺酸酐；或者是亚硫酰氯，它与12位羟基形成亚硫酸酯环；
-所采用的碱用以产生双键10(11)，是二氮杂二环十一碳烯，例如DBU(即1，8-二氮杂二环[5，4，0]十一碳-7-烯)，或DBN(即1，5-二氮杂-二环[4，3，0]壬-5-烯)，或2，6-二甲基吡啶、2，4，6-三甲基吡啶、四甲基胍；
-式(III)化合物与羰基二咪唑的反应在上述碱存在下进行，或者在氢化钠、三乙胺、碳酸钠(钾)、碳酸氢钠(钾)、NaN(SiMe3)2或LiN(SiMe3)2存在下进行；
-所用肼为水合肼。
制得的式(III)化合物本身即是新型产物，构成本发明的一部分。
因此本发明也涉及式(III)的化学产物，更具体而言涉及其中R代表乙酰基的式(III)化合物。
式(I)化合物是有用的中间体，它尤其可用于制备欧洲专利申请0,676,409中说明和要求保护的抗生素。
本发明特别涉及式(I)化合物的应用，其特征在于使式(I)化合物与被保护羟基的解离试剂反应，制得式(IV)化合物：
使式(IV)化合物与式(V)的醛反应：式中R1′代表氢原子或含多至23个碳原子的饱和或不饱和烃基，任选地被一个或多个杂原子间断，并任选地带有一个或多个官能基；反应得到式(VI)化合物：使式(VI)化合物与3位羟基的氧化剂反应，然后与2′位羟基的解离试剂反应，制得式(VII)化合物：
使式(VII)化合物与还原剂反应以制得相应的式(VIII)化合物：
式中R1′具有前述意义。
在一种优选的实施方案中：
-R1′代表
-被保护的羟官能基的解离反应通过对酯官能基皂化然后酸化实现；
-2′位羟官能基的酯化反应按常规方法进行；
-使用例如1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐的二亚胺，在DMSO存在下进行3位羟基的氧化反应；
-2′位羟基的解离反应通过甲醇解进行；
-所用还原剂是NaBH3CN或NaBH(OAc)3或者NaBH4，同时存在乙酸；或者使用氢，同时存在催化剂如铂、钯，且任选地存在有例如盐酸或乙酸的酸。
如欧洲专利申请0676409中所说明及要求保护的，通式(VII)产物具有有用的抗生素活性。
实施例12′，3-二乙酸11，12-二脱氧-3-脱(2，6-二脱氧-3-C-甲基-3-O-甲基-α-L-核己吡喃糖基)-11，12-(亚肼基(羰基氧))-6-O-甲基-红霉素酯步骤A：2′，3-二乙酸 11-脱氧-10，11-二脱氢-3-脱(2，6-二脱氧-3-C-甲基-3-O-甲基-α-L-核己吡喃糖基)-6-O-甲基-红霉素酯
使含有9.45克2′，3-二乙酸3-脱(2，6-二脱氧-3-C-甲基-3-O-甲基-α-L-核己吡喃糖基)-6-O-甲基-红霉素酯和112毫升吡啶的溶液在0℃下搅拌15分种。在10分钟内加入1.52毫升亚硫酰氯。室温下搅拌过夜。分离干燥之；将其倒入150毫升乙酸乙酯和200毫升碳酸氢钠混合物中，搅拌10分钟。将其倾析，用乙酸乙酯萃取并干燥。得产物10.7克。
将上述10.7克产物与124毫升二甲基甲酰胺混合物在50℃下搅拌，5分钟内加入2.53毫升DBU。50℃下搅拌48小时，倾入水中。加入100毫升乙酸乙酯。倾析，水洗(1.25升)，乙酸乙酯萃取(400毫升)，硫酸镁干燥，过滤，滤液挥发至干。加入约50毫升异丙醚，使之结晶72小时，过滤，洗涤并干燥。得到目的产物5.514克，熔点为174℃。步骤B：2′，3-二乙酸11，12-二脱氧-3-脱(2，6-二脱氧-3-C-甲基-3-O-甲基-α-L-核己吡喃糖基)-11，12-(亚肼基(羰基氧))-6-O-甲基-红霉素酯
搅拌含如下成份的混合物：2.623克上一步骤制备的产物；972毫克羰基二咪唑；30毫升二氯甲烷和60微升DBU。搅拌4小时。加入404微升水合肼。搅拌24小时，加入50毫升酸式磷酸钠溶液(0.5M)。倾析，用二氯甲烷萃取，干燥。再溶于异丙醚。使之结晶过夜。过滤，用异丙醚洗涤，干燥。得到2.415克目的产物。NMR CDCl3 ppm0.84(t) CH3-CH21.00(d) 1.10(d)1.12(d)-1.15(d) CH-Me峰1.23(d)1.28(s) 6和12Me1.40(s)2.09(s) OAc′s2.18(s)2.26(s) NMe22.61(m)(2H) H8和H′32.88(m) H2≡3.06(m) H103.02(s) C-OMe3.33(m) H′53.67(s) H113.69(d) H54.03(d) H′1ax4.53(bs)(2H) NH24.73(dd) H′2ax5.03(d) H35.13(dd) H13应用：11，12-二脱氧-3-脱((2，6-二脱氧-3-C-甲基-3-O-甲基-α-L-核己吡喃糖基)氧)-6-O-甲基-3-氧代-12，11-(氧羰基)-(2-(3-(4-喹啉基)-2-丙基)亚肼基)红霉素步骤A：11，12-二脱氧-3-脱(2，6-二脱氧-3-C-甲基-3-O-甲基-α-L-核己吡喃糖基)-11，12-(亚肼基(羰基氧)-6-O-甲基红霉素
搅拌含如下成份的混合物30分钟：714毫克实施例1步骤B的产物；7.5毫升异丙醇和2mlN苏打。反应混合物在室温下保持48小时。加入2毫升当量浓度的盐酸溶液。蒸发至干。产物用硅胶色谱分离，以乙酸乙酯-三乙胺(9∶1)混合物为洗脱剂。得到300毫克目的产物。步骤B：2′-乙酸11，12-二脱氧-3-脱(2，6-二脱氧-3-C-甲基-3-O-甲基-α-L-核己吡喃糖)-12，11-(氧羰基)-(3-(4-喹啉基)亚丙基)亚肼基)-6-O-甲基红霉素酯
氮气氛下搅拌下述物质的混合物4小时：281毫升4-喹啉基丙醛，10.2毫升甲苯；802毫克上一步骤的产物和306微升乙酸。蒸发至干。产物用硅胶色谱分离，洗脱剂先用乙酸乙酯/三乙胺混合物(95∶5)，再用(90∶10)的乙酸乙酯/三乙胺混合物。制得916毫克产物。
将839毫克产物、10毫升二氯甲烷和121微升乙酸酐的混合物搅拌过夜。加入8.55毫升氨水。搅拌10分钟，用二氯甲烷萃取并干燥。得846毫克目的产物。步骤C：11，12-二脱氧-3-脱((2，6-二脱氧-3-C-甲基-3-O-甲基-α-L-核己吡喃糖基)氧)-3-氧代-12，11-(氧羰基(3-(4-喹啉基)亚丙基)亚肼基)-6-O-甲基红霉素
将含下述成份的混合物搅拌15分钟：1.783克1-乙基-3-(3-二甲氨基丙基碳化二亚胺)盐酸盐，1.67毫升DMSO及11毫升二氯甲烷。加入上一步骤的产物781毫克和8毫升二氯甲烷。搅拌1.30小时并加入1.8克三氯乙酸吡啶鎓。室温下搅拌3小时并加入30毫升氨水。搅拌15分钟，用二氯甲烷萃取，硫酸镁干燥。硅胶色谱分离产物，洗脱剂为乙酸乙酯/三乙胺混合物(9∶1)。收集到647毫克产物。将566毫克该产物与18毫升甲醇的混合物搅拌过夜，得到540毫克目的产物。步骤D：11，12-二脱氧-3-脱((2，6-二脱氧-3-C-甲基-3-O-甲基-α-L-核己吡喃糖基)氧)-6-O-甲基-3-氧代-12，11-(氧羰基(2-(3-(4-喹啉基)-2-丙基)亚肼基))红霉素
向10毫升乙酸乙酯中加入前一步骤制得的产物0.38克及铂氧化物38毫克。剧烈搅拌下氢化24小时。过滤，乙酸乙酯洗涤，减压蒸发。得产物0.375克，再溶于5毫升甲醇、175微升乙酸和90毫克硼氢化钠。室温下搅拌3小时。驱尽甲醇，重溶于二氯甲烷-水混合物中。用28％氨水将pH值调节至8-9。倾析，水洗，干燥，过滤并挥发至干。得到0.37克产物，硅胶色谱柱分离之，以乙酸乙酯/三乙胺混合物(96∶4)为洗脱剂。得到127毫克产物(rf＝0.25)，分离，洗涤并干燥。得到90毫克目的产物，熔点189℃。NMR CDCl3 ppm，300 MHz1.34(s)-1.48(s)：6和12 CH3；2.30(s)：N(CH3)2；2.65(s)：6-OCH3；3.06(dq)：H4；3.19(q)：H10；3.74(s)：H11；5.50(流动t.)：NH-CH2；7.30(d)：H3喹啉；7.53-7.68(dt)：H6-H7喹啉；8.10(m)：H5-H8喹啉；8.79(d)：H2喹啉
Claims (7)
1.式(I)化合物：式中R代表含多至18个碳原子的羧酸残基。
2.权利要求1中的式(I)化合物，其中R代表乙酰基。
3.权利要求1或2定义的式(I)化合物的制备方法，其特征在于使式(II)的化合物：式中R具有前述定义；与能选择性激活11位羟基的试剂反应，然后与碱反应制得式(III)化合物：使式(III)化合物与羰基二咪唑反应，再与肼NH2NH2反应，制得相应的式(I)化合物。
4.权利要求3中作为化学品的式(III)化合物。
5.作为化学品的式(III)化合物，其中R代表乙酰基。
6.权利要求1或2定义的式(I)化合物的应用，其特征在于：使式(I)化合物与被保护羟基的解离试剂反应，制得式(IV)的化合物：；使式(IV)化合物与式(V)的醛反应：
式中R1′代表氢原子或含多至23个碳原子的饱和或不饱和烃基，任选地被一个或多个杂原子间断，且任选地带有一个或多个官能基，以得到式(VI)化合物：使式(VI)化合物与3位羟基的氧化剂反应，再与2′位羟基的解离试剂反应，制得式(VII)的化合物：
使式(VII)化合物与还原剂反应，制得相应的式(VIII)化合物：
式中R1′具有上述意义。
7.式(I)化合物的用途，用于制备式(VIII)化合物，式中R1′代表如下基团：
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| FR9511861A FR2739620B1 (fr) | 1995-10-09 | 1995-10-09 | Nouveaux derives de la 5-0-desosaminyl 6-o-methyl erythronolide a, leur procede de preparation et leur application a la preparation de produits biologiquement actifs |
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| FR2777282B1 (fr) * | 1998-04-08 | 2001-04-20 | Hoechst Marion Roussel Inc | Nouveaux derives de la 2-fluoro 3-de((2,6-dideoxy 3-c-methyl 3-0-methyl-alpha-l-ribohexopyranosyl) oxyl) 6-o-methyl 3-oxo erythromycine, leur procede de preparation et leur application a la synthese de principes actifs de medicaments |
| US6590083B1 (en) | 1999-04-16 | 2003-07-08 | Ortho-Mcneil Pharmaceutical, Inc. | Ketolide antibacterials |
| ATE340183T1 (de) * | 1999-04-16 | 2006-10-15 | Kosan Biosciences Inc | Antiinfektiöse makrolidderivate |
| WO2000062783A2 (en) | 1999-04-16 | 2000-10-26 | Ortho-Mcneil Pharmaceutical, Inc. | Ketolide antibacterials |
| GB0031312D0 (en) * | 2000-12-21 | 2001-02-07 | Glaxo Group Ltd | Macrolides |
| EP1638549A4 (en) | 2003-03-10 | 2011-06-15 | Optimer Pharmaceuticals Inc | NEW ANTIBACTERIAL AGENTS |
| EP2214484A4 (en) * | 2007-10-25 | 2013-01-02 | Cempra Pharmaceuticals Inc | PROCESS FOR PREPARING ANTIBACTERIAL MAKROLIDE AGENTS |
| US8796232B2 (en) * | 2008-10-24 | 2014-08-05 | Cempra Pharmaceuticals, Inc. | Methods for treating resistant diseases using triazole containing macrolides |
| US9937194B1 (en) | 2009-06-12 | 2018-04-10 | Cempra Pharmaceuticals, Inc. | Compounds and methods for treating inflammatory diseases |
| AU2010292010B2 (en) | 2009-09-10 | 2016-01-07 | Cempra Pharmaceuticals, Inc. | Methods for treating malaria, tuberculosis and MAC diseases |
| CN103080122A (zh) | 2010-03-22 | 2013-05-01 | 森普拉制药公司 | 大环内脂的结晶形式及其用途 |
| US9051346B2 (en) | 2010-05-20 | 2015-06-09 | Cempra Pharmaceuticals, Inc. | Process for preparing triazole-containing ketolide antibiotics |
| JP6042334B2 (ja) | 2010-09-10 | 2016-12-14 | センプラ ファーマシューティカルズ，インコーポレイテッド | 疾患治療のための水素結合形成フルオロケトライド |
| CN104470527B (zh) | 2012-03-27 | 2019-05-28 | 森普拉制药公司 | 用于施用大环内酯抗生素的肠胃外制剂 |
| WO2014152326A1 (en) | 2013-03-14 | 2014-09-25 | Cempra Pharmaceuticals, Inc. | Methods for treating respiratory diseases and formulations therefor |
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| US3923784A (en) * | 1973-09-10 | 1975-12-02 | Hoffmann La Roche | Erythromycin a derivatives |
| US4518590A (en) * | 1984-04-13 | 1985-05-21 | Pfizer Inc. | 9α-Aza-9α-homoerythromycin compounds, pharmaceutical compositions and therapeutic method |
| US4742049A (en) * | 1986-06-04 | 1988-05-03 | Abbott Laboratories | Semisynthetic erythromycin antibiotics |
| PT86800B (pt) * | 1987-02-24 | 1992-05-29 | Beecham Group Plc | Processo para a preparacao de derivados de eritromicina |
| US5523399A (en) * | 1991-12-27 | 1996-06-04 | Taisho Pharmaceutical Co., Ltd. | 5-O-desosaminylerythronolide derivatives |
| ATE135707T1 (de) * | 1992-04-22 | 1996-04-15 | Taisho Pharmaceutical Co Ltd | 5-0-desosaminylerythronolid a derivate |
| FR2692579B1 (fr) * | 1992-06-19 | 1995-06-02 | Roussel Uclaf | Nouveaux dérivés de la picromycine, leur procédé de préparation et leur application comme médicaments. |
| KR960700258A (ko) * | 1993-01-26 | 1996-01-19 | 우에하라 아키라 | 5-0-데소사미닐에리쓰로노라이드 유도체 |
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