CN1067401C - 5-o-德糖胺基-6-o-甲基红诺霉素a的新型衍生物及其制法 - Google Patents
5-o-德糖胺基-6-o-甲基红诺霉素a的新型衍生物及其制法 Download PDFInfo
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- 238000006243 chemical reaction Methods 0.000 claims description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
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- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
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- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
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- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
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- 150000003840 hydrochlorides Chemical class 0.000 description 1
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- CSYNQJPENMOLHR-UHFFFAOYSA-N n,n-diethylethanamine;ethyl acetate Chemical compound CCOC(C)=O.CCN(CC)CC CSYNQJPENMOLHR-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical class [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
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- NBBJYMSMWIIQGU-UHFFFAOYSA-N propionic aldehyde Natural products CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 150000003460 sulfonic acids Chemical group 0.000 description 1
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Classifications
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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
-
- 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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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
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。
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:
-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11,1 2-二脱氧-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2ml N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、1O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,300MHz1.34(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
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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 |
JP2002542197A (ja) | 1999-04-16 | 2002-12-10 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | ケトライド抗菌剤 |
DE60030847T2 (de) * | 1999-04-16 | 2007-04-19 | Kosan Biosciences, Inc., Hayward | Antiinfektiöse makrolidderivate |
US6590083B1 (en) | 1999-04-16 | 2003-07-08 | Ortho-Mcneil Pharmaceutical, Inc. | Ketolide antibacterials |
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ES2552682T3 (es) | 2003-03-10 | 2015-12-01 | Merck Sharp & Dohme Corp. | Agentes antibacterianos novedosos |
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EP2358379B1 (en) * | 2008-10-24 | 2015-12-16 | Cempra Pharmaceuticals, Inc. | Biodefenses using triazole-containing macrolides |
US9937194B1 (en) | 2009-06-12 | 2018-04-10 | Cempra Pharmaceuticals, Inc. | Compounds and methods for treating inflammatory diseases |
US9480679B2 (en) | 2009-09-10 | 2016-11-01 | Cempra Pharmaceuticals, Inc. | Methods for treating malaria, tuberculosis and MAC diseases |
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