CN1062867C - 12,13－环氧－泰乐菌素的衍生物及其制备方法 - Google Patents
12,13－环氧－泰乐菌素的衍生物及其制备方法 Download PDFInfo
- Publication number
- CN1062867C CN1062867C CN96109447A CN96109447A CN1062867C CN 1062867 C CN1062867 C CN 1062867C CN 96109447 A CN96109447 A CN 96109447A CN 96109447 A CN96109447 A CN 96109447A CN 1062867 C CN1062867 C CN 1062867C
- Authority
- CN
- China
- Prior art keywords
- represent
- epoxy
- tylosin
- mycaminose
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000004182 Tylosin Substances 0.000 title claims abstract description 39
- 229960004059 tylosin Drugs 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 10
- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical group O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 claims abstract description 25
- 239000004593 Epoxy Substances 0.000 claims abstract description 15
- -1 oxime derivatives of tylosin Chemical class 0.000 claims abstract description 13
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 238000006146 oximation reaction Methods 0.000 claims abstract description 4
- DIOQKPOBSJVSJS-UHFFFAOYSA-N 3,6-Dideoxy-3-dimethylamino-beta-D-glucose Natural products CC1OC(O)C(O)C(N(C)C)C1O DIOQKPOBSJVSJS-UHFFFAOYSA-N 0.000 claims description 39
- IJUPCLYLISRDRA-UHFFFAOYSA-N Mycaminose Natural products CC(O)C(O)C(N(C)C)C(O)C=O IJUPCLYLISRDRA-UHFFFAOYSA-N 0.000 claims description 39
- IJUPCLYLISRDRA-ULAWRXDQSA-N mycaminose Chemical compound C[C@@H](O)[C@@H](O)[C@H](N(C)C)[C@@H](O)C=O IJUPCLYLISRDRA-ULAWRXDQSA-N 0.000 claims description 32
- 229930194936 Tylosin Natural products 0.000 claims description 23
- 235000019375 tylosin Nutrition 0.000 claims description 23
- 239000002585 base Substances 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229960001866 silicon dioxide Drugs 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 5
- 125000004036 acetal group Chemical group 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000013375 chromatographic separation Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 150000002191 fatty alcohols Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 150000002923 oximes Chemical class 0.000 abstract description 3
- 239000003242 anti bacterial agent Substances 0.000 abstract 1
- 229940088710 antibiotic agent Drugs 0.000 abstract 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 56
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229930184158 Maridomycin Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FFXJTOKFQATYBI-RUTGJBPVSA-N [(1s,3r,7r,8s,9s,10r,12r,13r,14e,16s)-9-[(2s,3r,4r,5s,6r)-4-(dimethylamino)-3-hydroxy-5-[(2s,4r,5s,6s)-4-hydroxy-4,6-dimethyl-5-propanoyloxyoxan-2-yl]oxy-6-methyloxan-2-yl]oxy-13-hydroxy-8-methoxy-3,12-dimethyl-5-oxo-10-(2-oxoethyl)-4,17-dioxabicyclo[14.1 Chemical compound C1[C@](O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C[C@@H]3O[C@H]3/C=C/[C@H](O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C FFXJTOKFQATYBI-RUTGJBPVSA-N 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 229950002784 maridomycin Drugs 0.000 description 3
- QRPHLEPFYLNRDA-NLGRAQRVSA-N 2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4s,5s,6r)-4-(dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13-trimethyl-2,10-dioxo-1-oxacyclohexadeca-11,1 Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O QRPHLEPFYLNRDA-NLGRAQRVSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 150000001993 dienes Chemical class 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- IUPCWCLVECYZRV-JZMZINANSA-N rosaramicin Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H]([C@@H]2O[C@@]2(C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O IUPCWCLVECYZRV-JZMZINANSA-N 0.000 description 2
- 229950001447 rosaramicin Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- IUPCWCLVECYZRV-ZRDIBKRKSA-N rosamicin Chemical compound O=CCC1CC(C)C(=O)\C=C\C2(C)OC2C(C)C(CC)OC(=O)CC(O)C(C)C1OC1OC(C)CC(N(C)C)C1O IUPCWCLVECYZRV-ZRDIBKRKSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Epoxy Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及12，13-环氧-泰乐菌素(tylosin)衍生物，一种来源于泰乐菌素基团的新型半合成抗菌素，以及制备这些衍生物的方法。根据本发明，对12，13-环氧-泰乐菌素衍生物进行氢化后肟化，得到以下泰乐菌素衍生物；10，11-二氢-12，13-环氧，对应地，10，11-二氢-12，13-环氧肟。
直接肟化12，13-环氧泰乐菌素衍生物给出泰乐菌素的12，13-环氧肟衍生物。
Description
本发明涉及泰乐菌素(tylosin)衍生物，这是一种显示抗菌活性的大环内酯类新型合成产物。更具体而言，本发明涉及通式Ⅰ的12，13-环氧-泰乐菌素的衍生物：
其中，R代表O，R1代表CHO或CH(OCH3)2，R2代表H或碳霉糖基，且…代表单键；或者R代表NOH，R1代表CHO或CH(OCH3)2，R2代表H或碳霉糖基，且…代表单键或双键；以及涉及通式Ⅱ的化合物
其中，R代表H或碳霉糖基。本发明还涉及制备这些化合物的方法。
人们已经对16-元泰乐菌素环的二烯部分进行了一系列的改进。已知硫羟基加成得到泰乐菌素的硫醚(S.Omura美国专利4，594，338)。还已知通过催化氢化二烯和C-9及C-10位的肟化，制得了泰乐菌素10，11，12，13-四氢衍生物，及各相应的肟(A.Naranda美国专利5，023，240)。
已知泰乐菌素的选择性氧化可得到12，13-环氧衍生物(A.K.Mallams美国专利4，808，575)。另外，还制备了具有12，13-环氧结构的其他16-元大环内酯的二氢和四氢衍生物。还已知的是麦里多霉素(maridomycin)的催化氢化得到13-羟基-10，11，12，13-四氢麦里多霉素(M.Muroi，Chem.Pharm.Bull.24，(1976)450)，其中，C10-C11双键的还原反应伴随着环氧乙烷环的开环，而蔷薇霉素(rosamycin)的催化氢化却给出了保留12，13-环氧结构的10，11-二氢衍生物。还已知通过蔷薇霉素和其12，13-二氢环氧衍生物的肟化制得了C-20乙醛肟(H.Reinmann的美国专利4，056，616)。
在迄今已知的现有技术中，尚未对12，13-环氧泰乐菌素的10，11-二氢衍生物和其C-9肟、12，13-环氧-泰乐菌素肟及其具有9，11-环氧桥的10，11-二氢-12，13-环氧化合物进行过描述，也没有对这里所提及的泰乐菌素衍生物的制各方法进行过描述。
已发现通式Ⅰ的12，13-环氧-泰乐菌素的衍生物
其中，R代表O，R1代表CHO或CH(OCH3)2，R2代表H或碳霉糖基，且…代表单键；或者R代表NOH，R1代表CHO或CH(OCH3)2，R2代表H或碳霉糖基，且…代表单键或双键；以及通式Ⅱ的化合物
其中，R代表H或碳霉糖基，可以以如下方式制备，即，将通式Ⅲ的化合物A/其中，R代表CHO或CH(OCH3)2，R1代表H或碳霉糖基，且当R1代表H时，R2代表N(CH3)2或N-O(CH3)2；置于主要为低级C1-C3脂族醇的有机溶剂中，用2-5％w/w钯-炭和0.2-0.5MPa的氢压，在室温下氢化5-8小时，然后任选地将所得的通式Ⅰ的化合物，其中，R代表O，R1代表CHO或CH(OCH3)2，R2代表H或碳霉糖基，且…代表单键，在吡啶或加有碱例如(或Na2CO3)的低级醇中，在氮气气流和室温或回流温度下用3-6当量的盐酸胲肟化3-7小时。然后任选地在室温下，在乙腈和0.2N HCl(1∶1)的混合物中或乙腈与在水中的1％三氟乙酸(1∶2)的混合物中水解乙缩醛基团2小时；B/其中，R代表CH(OCH3)2，R1代表H或碳霉糖基，且R2代表N(CH3)2按上述进行肟化反应，且在硅胶柱中用色谱分离所得的产物：通式Ⅰ的化合物，其中R代表NOH，R1代表CH(OCH3)2，R2代表H或碳霉糖基，且…代表双键，和通式Ⅱ的化合物，其中R代表H或碳霉糖基，然后任选地按所述的方式进行缩醛基团水解。
在本发明中，新化合物可用卤代烃，例如用四氯化碳、氯仿或二氯甲烷，通过常规的萃取法从碱性水溶液中分离出来，并蒸发至干残渣。
如果必要，用于光谱分析的反应产物的分离或纯化可在硅胶柱(分别是Silicagel 60 Merck Co.，230-400目/ASTH，60-230目/ASTH)在溶剂系统：二氯甲烷-甲醇-氢氧化氨；A(90∶9∶1.5)或B(90∶9∶0.5)中进行。
新化合物的辨识采用UV和NMR光谱。
新化合物显示抗菌活性，并能在新泰乐菌素衍生物的制备中用作中间体。
本发明用下述实施例来说明，但不限制本发明的范围。
实施例110，11-二氢-12，13-环氧泰乐菌素2-二甲缩醛(1)
在240ml乙醇中溶解12，13-环氧-泰乐菌素20-二甲缩醛(2.4g，2.4mmol)，加入10％Pd/C(0.72g)，并将混合物在室温、氢压为0.2MPa下氢化8小时。反应完全后，滤去催化剂，减压下蒸去乙醇得干产物，然后，在硅胶柱上用色谱分离所得的产物。产量：1.25g(52％)Rf(A)0.651H-NMR(CDCl3)ppm 5.10(1H,d,1″),4.58(1H,d,1),4.24(1H,d,1＇),3.64(3H,s,3OMe),3.51(3H,s,2OMe),3.39(3H,s,20-OMe),3.24(3H,s,20-OMe),2.52(6H,s,NMe2),1.34(3H,s,12-CH3)13C-NMR(CDCl3)ppm 212.31(s,C-9),170.48(s，C-1)，103.27(d，C-1＇)，102.94(d，C-20),99.36(d,C-1),96.54(d,C-1″),60.66(q,3OMe),59.28(s,C-12),58.30(q,2OMe),58.27(d,C-13),53.21(q,20-OMe),50.43(q,20-OMe),33.87(t,C-10),28.95(t,C-11),18.36(q,C-22)实施例210，11-二氢-12，13-环氧-泰乐菌素(2)
将12，13-环氧-泰乐菌素(2g，2.1mmol)溶解于200ml乙醇中，加入10％Pd/C(0.4g)，并在室温及氢气压力为0.4MPa下氢化7小时。产物按实施例1分离。产量：0.92g(46％)Rf(A)0.541H-NMR(CDCl3)ppm 9.67(1H,s,CHO),5.09(1H,d,1″),4.58(1H,d,1),4.25(1H,D,1＇),3.65(3H,s,3OMe),3.50(3H,s,2OMe),2.51(6H,s,NMe2),1.23(3H,s,12-CH3)13C-NMR(CDCl3)ppm 212.33(s,C-9),202.86(d,C-20),170.46(s,C-1),103.25(d,C-1＇),99.36(d,C-1),96.74(d,C-1″),60.66(q,3OMe),59.29(s,C-12),58.37(q,2OMe；d，C-13),33.87(t,C-10),28.95(t,C-11),18.36(q，C-22)
实施例310，11-二氢-12，13-环氧-去碳霉糖泰乐菌素20-二甲缩醛(3)方法A
在250ml乙醇中溶解12，13-环氧-去碳霉糖泰乐菌素(desmycosin)N-氧化20-二甲缩醛(2.5g，2.9mmol)，加入1.25g 10％Pd/C，并在室温及氢气压为0.5MPa下氢化7小时。产物按实施例1分离。产量：1.27g(52％)Rf(A)0.571H-NMR(CDCl3)ppm 4.56(1H,d,1),4.25(1H,d,1＇),3.64(3H,s,3OMe),3.51(3H,s,2OMe),3.38(3H,s,20-OMe),3.22(3H,s,20-OMe),2.52(6H,s,NMe2),1.33(3H,s,12-CH3)13C-NMR(CDCl3)ppm 212.31(s,C-9),170.25(s，C-1),103.23(d,C-1＇),102.80(d,C-20),99.34(d,C-1),60.45(q,3OMe),59.27(s,C-12),58.28(q,2OMe),58.23(d,C-13),53.25(q,20-OMe),50.45(q,20-OMe),33.88(t,C-10),28.99(t,C-11),18.38(q,C-22)方法B
在250ml乙醇中溶解12，13-环氧-去碳霉糖泰乐菌素(desmycosin)20-二甲缩醛(3g，3.6mmo1)，加入0.6g 10％Pd/C，并在室温及氢气压为0.5MPa下氢化8小时。按实施例1分离得到的产物与采用方法A得到的产物相同。
实施例410，11-二氢-12，13-环氧-去碳霉糖泰乐菌素(4)
在100ml乙醇中溶解12，13-环氧-去碳霉糖泰乐菌素(2.4g，3mmol)，加入0.72g10％Pd/C，并在室温及氢气压力为0.3MPa下氢化8小时。产物按实施例1分离。产量：1.3g(54％)Rf(A)0.451H-NMR(CDCl3)ppm 9.65(1H,s,CHO),4.55(1H,d,1),4.24(1H,d,1＇),3.64(3H,s,3OMe),3.51(3H,s,2OMe),2.51(6H,s,NMe2),1.34(3H,s,12-CH3)13C-NMR(CDC13)ppm 212.30(s,C-9),202.36(d,C-20),170.27(s,C-1),103.29(d,C-1＇),99.34(d,C-1),60.47(q,3OMe),59.28(s,C-12),58.27(q,2OMe；d,C-13),33.89(t,C-10),28.97(t,C-11),18.37(q,C-22)
实施例510，11-二氢-12，13-环氧-泰乐菌素肟20-二甲缩醛(5)
在39ml吡啶中溶解化合物1(3g，3mmol)，加入盐酸胲(1.25g 18mmol)，在室温、氮气气流下搅拌7小时。反应液用150ml水稀释，用NaOH碱化至pH9，并减压蒸馏至三分之一体积。用氯仿进行萃取(2x60ml至pH6，2x60ml至pH9.5)。合并pH9.5的萃取液，用饱和NaHCO3溶液洗涤，干燥(K2CO3)并蒸发至干残渣。产量：1.83g(61.3％)Rf(A)0.451H-NMR(DMSO)ppm 10.23(1H,s,9-NOH,在与D2O混合时消失),4.99(1H,d,1″),4.45(1H,d,1),4.22(1H,d,1＇),3.49(3H,s,3OMe),3.45(3H,s,2OMe),3.23(3H,s,20-OMe),3.14(3H,s,20-OMe),2.46(6H,s,NMe2),1.25(3H,s,12-CH3)13C-NMR(CDCl3)ppm 173.19(s，C-1),161.69(s,C-9),104.17(d,C-1＇),102.06(d,C-20),100.64(d,C-1),96.65(d,C-1″),62.30(s,C-12),61.69(d,C-13),61.43(q,3OMe),59.09(q,2OMe),16.32(q,C-22)实施例610，11-二氢-12，13-环氧-去碳霉糖泰乐菌素肟20-二甲缩醛(6)
在20ml甲醇中溶解化合物3(2g，2.4mmol)，加入0.64g Na2CO3和盐酸胲(0.84g 12.3mmol)，在回流温度、氮气气流下搅拌3小时。反应液倾入60ml水中，用如实施例5所述的pH梯度萃取进行分离。产量：1.1g(54％)Rf(A)0.31H-NMR(DMSO)ppm 10.22(1H,s,9-NOH,在与D2O混合时消失),4.43(1H,d,1),4.19(1H,d,1＇),3.47(3H,s,3OMe),3.43(3H,s,2OMe),3.21(3H,s,20-OMe),3.12(3H,s,20-OMe),2.42(6H,s,NMe2),1.24(3H,s,12-CH3)13C-NMR(CDCl3)ppm 172.98(s,C-1),161.62(s,C-9),103.98(d,C-1′),102.05(d,C-20),100.51(d,C-1),62.27(s,C-12),61.73(d,C-13),61.42(q,3OMe),59.09(q,2OMe),16.30(q,C-22)
实施例710，11-二氢-12，13-环氧-泰乐菌素肟(7)10，11-二氢-12，13-环氧-去碳霉糖泰乐菌素肟(8)
在20ml乙腈和20ml 0.2N HCl的混合液中溶解化合物5(2g，2mmol)，在室温下搅拌2小时。反应液用20ml水稀释，用NaOH碱化至pH9，用氯仿进行萃取(2x30ml)，干燥(K2CO3)并蒸发至干残渣。粗产物在硅胶柱中用色谱进行分离。产量：0.64 g(34％)化合物7；Rf(B)0.301H-NMR(DMSO)ppm 10.23(1H,s,9-NOH,在与D2O混合时消失),9.67(1H,s,CHO),4.95(1H,d,1″),4.45(1H,d,1),4.21(1H,d,1＇),3.49(3H,s，3OMe),3.45(3H,s,2OMe),2.47(6H,s,NMe2),1.25(3H,s,12-CH3)13C-NMR(CDCl3)ppm 203.11(d,C-20),173.18(s,C-1),161.65(s,C-9),104.15(d,C-1＇),100.62(d,C-1),96.63(d,C-1″),62.30(s,C-12),61.76(d，C-13),61.42(q,3OMe),59.25(q,2OMe),16.46(q,C-22)和0.35 g(23％)化合物8；Rf(B)0.221H-NMR(DMSO)ppm 10.21(1H,s,9-NOH,在与D2O混合时消失),9.68(1H,s,CHO),4.43(1H,d,1),4.18(1H,d,1＇),3.46(3H,s,3OMe),3.43(3H,s,2OMe),2.45(6H,s,NMe2),1.22(3h,s,12-CH3)13C-NMR(CDCl3)ppm 202.98(d,C-20),172.97(s,C-1),161.63(s,C-9),103.98(d,C-1＇),100.33(d,C-1),62.29(d,C-12),61.73(s,C-13),61.40(q,3OMe),59.23(q,2OMe),16.45(q,C-22)
实施例810，11-二氢-12，13-环氧-去碳霉糖泰乐菌素肟(8)
在13ml乙腈和26ml 1％三氟乙酸的混合物水溶液中溶解化合物6(1．3g，1.5mmol)，在室温下搅拌2小时。产物按实施例7所述进行分离。产量：1g(81％)与实施例7的化合物8的光谱特征相同的化合物。
实施例912，13-环氧-去碳霉糖泰乐菌素肟20-二甲缩醛(9)9-羟基-10，11-二氢-12，13-环氧-9，11-(环氧亚氨基)-去碳霉糖泰乐菌素肟20-二甲缩醛(10)
在16ml吡啶中溶解12，13-环氧-去碳霉糖泰乐菌素20-二甲缩醛(2g，2.4mmol)，并加入盐酸胲(1.0g，14.4mmol)，在氮气气流和室温下搅拌4小时。反应液中加入160ml水，用10％NaOH碱化至pH9，用氯仿进行萃取(2x80ml)，合并的萃取液被干燥和蒸发至干残渣。粗产物用硅胶柱在溶剂系统A中用色谱进行分离。产量：0.43 g(24％)化合物9；Rf(A)0.381H-NMR(DMSO)ppm 10.42(1H,s,9-NOH，在与D2O混合时消失)，6.58(1H,d,11),6.43(1H,d,10),4.46(1H,d,1),4.23(1H,d,1＇),3.50(3H,s，3OMe),3.45(3H,s,2OMe),3.23(3H,s,20-OMe),3.14(3H,s,20-OMe),2.47(6H,s,NMe2)13C-NMR(CDCl3)ppm 172.82(s,C-1),158.86(s,C-9),136.33(d,C-11),115.86(d,C-10),104.15(d,C-1＇),102.12(d,C-20),100.58(d,C-1),63.94(d,C-13),61.43(q,3OMe),59.38(s,C-12),59.11(q,2OMe),14.81(s,C-22)和0.83g(47％)化合物10，Rf(A)0.321H-NMR(DMSO)ppm 4.45(1H,d,1),4.22(1H,d,1＇),3.49(3H,s,3OMe),3.45(3H,s,2OMe),3.23(3H,s,20-OMe),3.14(3H,s,20-OMe),2.46(6H,s,NMe2)13C-NMR(CDCl3)ppm 170.04(s,C-1),110.23(s,C-9),104.08(d,C-1＇),102.51(d,C-20),100.24(d,C-1),63.37(d,C-13),61.44(q,3OMe),60.67(s，C-12),59.13(q,2OMe),54.34(d,C-11),15.24(s,C-22)
Claims (4)
1、具有通式Ⅰ的12，13-环氧-泰乐菌素衍生物其中，R代表O，R1代表CHO或CH(OCH3)2，R2代表H或碳霉糖基，且…代表单键；或者R代表NOH，R1代表CHO或CH(OCH3)2，R2代表H或碳霉糖基，且…代表单键或双键；
其中，R代表H或碳霉糖基。
2、如权利要求1所述的泰乐菌素衍生物，其是选自于以下组中：10，11-二氢-12，13-环氧-泰乐菌素20-二甲缩醛，10，11-二氢-12 13-环氧-泰乐菌素，10，11-二氢-12 13-环氧去碳霉糖泰乐菌素20-二甲缩醛，10，11-二氢-12 13-环氧-去碳霉糖泰乐菌素，10，11-二氢-12 13-环氧-泰乐菌素肟20-二甲缩醛，10，11-二氢-12 13-环氧-去碳霉糖泰乐菌素20-二甲缩醛，10，11-二氢-12 13-环氧-泰乐菌素肟，9、10，11-二氢-12，13-环氧-去碳霉糖泰乐菌素肟，12，13-环氧-去碳霉糖泰乐菌素肟20-二甲缩醛，9-羟基-10，11-二氢-12，13-环氧-9，11-(环氧亚氨基)去碳霉糖泰乐菌素20-二甲缩醛。
3、制备通式Ⅰ的12，13-环氧-泰乐菌素的衍生物和通式Ⅱ的化合物的方法，其中，R代表O，R1代表CHO或CH(OCH3)2，R2代表H或碳霉糖基，且…代表单键；或者R代表NOH，R1代表CHO或CH(OCH3)2，R2代表H或碳霉糖基，且…代表
其中，R代表H或碳霉糖基，所述方法的特征在于，将通式Ⅲ的化合物
A/其中R代表CHO或CH(OCH3)2，R1代表H或碳霉糖基，且当R1代表H时，R2代表N(CH3)2或N-O(CH3)2；置于低级C1-C3脂族醇的有机溶剂中，用2-5％w/w钯-炭和0.2-0.5MPa的氢压在室温下氢化5-8小时；然后任选地将所得的通式Ⅰ的化合物，其中R代表O，R1代表CH(OCH3)2，R2代表H或碳霉糖基，且…代表单键，在吡啶或加有碱的低级醇中，在氮气气流和室温或回流温度下用3-6当量的盐酸胲肟化3-7小时，接着任选地在室温下水解乙缩醛基团；B/其中R代表CH(OCH3)2，R1代表H或碳霉糖基，且R2代表N(CH3)2，按上述进行肟化反应，然后在硅胶柱中用色谱分离所得的产物--通式Ⅰ的化合物，其中R代表NOH，R1代表CH(OCH3)2，R2代表H或碳霉糖基，且…代表双键，和通式Ⅱ的化合物，其中R代表H或碳霉糖基，接着任选地进行缩醛基团水解。
4、如权利要求3所述的方法，其中，水解是在乙腈和0.2N HCl的1∶1混合物中或在乙腈与1％三氟乙酸的1∶2混合物的水溶液中，在室温下进行2小时。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HR950449A HRP950449A2 (en) | 1995-08-14 | 1995-08-14 | Derivatives of 12, 13-epoxy-tylosin and processes of manufacture thereof |
| HRP950449A | 1995-08-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1148047A CN1148047A (zh) | 1997-04-23 |
| CN1062867C true CN1062867C (zh) | 2001-03-07 |
Family
ID=10946293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96109447A Expired - Fee Related CN1062867C (zh) | 1995-08-14 | 1996-08-14 | 12,13－环氧－泰乐菌素的衍生物及其制备方法 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5688924A (zh) |
| EP (1) | EP0792885A3 (zh) |
| JP (1) | JPH09183790A (zh) |
| CN (1) | CN1062867C (zh) |
| BA (1) | BA96113A (zh) |
| BG (1) | BG63309B1 (zh) |
| CA (1) | CA2183049A1 (zh) |
| CZ (1) | CZ229096A3 (zh) |
| HR (1) | HRP950449A2 (zh) |
| HU (1) | HUP9602080A3 (zh) |
| PL (1) | PL182429B1 (zh) |
| RO (1) | RO115526B1 (zh) |
| SI (1) | SI9600250A (zh) |
| SK (1) | SK282511B6 (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HRP960509A2 (en) * | 1996-10-30 | 1998-06-30 | Pliva Pharm & Chem Works | Novel polyhydro tylosin derivatives and a process for the preparation thereof |
| HRP980496B1 (en) * | 1998-09-10 | 2007-03-31 | GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. | New thilozine hydroxy derivatives and a process for the preparation thereof |
| US7247617B2 (en) * | 2004-07-13 | 2007-07-24 | Kosan Biosciences Incorporated | Sixteen-member macrolide antiinfective agents |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1038674A (zh) * | 1988-06-17 | 1990-01-10 | 奥西蒙特公司 | 用作为阴极电解液的全氟化合物导电性水包油型微滴乳液 |
| CN1060847A (zh) * | 1990-10-25 | 1992-05-06 | 美露香株式会社 | 泰乐菌素衍生物及其制备方法 |
| CN1022981C (zh) * | 1989-09-09 | 1993-12-08 | 中国科学院广州化学所 | 二醋酸纤维素微孔滤膜的制造方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4056616A (en) * | 1976-03-05 | 1977-11-01 | Schering Corporation | Rosamicin derivatives and method of using same |
| AU551142B2 (en) * | 1981-07-09 | 1986-04-17 | Zaidan Hojin Biseibutsu Kagaku Kenkyukai | Tylosin derivatives |
| US4808575A (en) * | 1986-06-23 | 1989-02-28 | Schering Corporation | 12,13-oxoderivatives of macrolides |
-
1995
- 1995-08-14 HR HR950449A patent/HRP950449A2/hr not_active Application Discontinuation
-
1996
- 1996-07-25 BA BA960113A patent/BA96113A/bs unknown
- 1996-07-29 HU HU9602080A patent/HUP9602080A3/hu unknown
- 1996-07-29 EP EP96112219A patent/EP0792885A3/en not_active Withdrawn
- 1996-08-01 CZ CZ962290A patent/CZ229096A3/cs unknown
- 1996-08-09 SK SK1047-96A patent/SK282511B6/sk unknown
- 1996-08-09 CA CA002183049A patent/CA2183049A1/en not_active Abandoned
- 1996-08-12 BG BG100779A patent/BG63309B1/bg unknown
- 1996-08-13 PL PL96315675A patent/PL182429B1/pl unknown
- 1996-08-13 SI SI9600250A patent/SI9600250A/sl unknown
- 1996-08-13 RO RO96-01642A patent/RO115526B1/ro unknown
- 1996-08-13 US US08/696,178 patent/US5688924A/en not_active Expired - Fee Related
- 1996-08-14 JP JP8232518A patent/JPH09183790A/ja active Pending
- 1996-08-14 CN CN96109447A patent/CN1062867C/zh not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1038674A (zh) * | 1988-06-17 | 1990-01-10 | 奥西蒙特公司 | 用作为阴极电解液的全氟化合物导电性水包油型微滴乳液 |
| CN1022981C (zh) * | 1989-09-09 | 1993-12-08 | 中国科学院广州化学所 | 二醋酸纤维素微孔滤膜的制造方法 |
| CN1060847A (zh) * | 1990-10-25 | 1992-05-06 | 美露香株式会社 | 泰乐菌素衍生物及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| SK282511B6 (sk) | 2002-10-08 |
| CZ229096A3 (en) | 1997-03-12 |
| CA2183049A1 (en) | 1997-02-15 |
| HRP950449A2 (en) | 1997-12-31 |
| SI9600250A (en) | 1997-04-30 |
| BA96113A (bs) | 2000-05-02 |
| BG63309B1 (bg) | 2001-09-28 |
| EP0792885A2 (en) | 1997-09-03 |
| HU9602080D0 (en) | 1996-09-30 |
| EP0792885A3 (en) | 1998-01-14 |
| HUP9602080A2 (en) | 1997-05-28 |
| SK104796A3 (en) | 1997-04-09 |
| JPH09183790A (ja) | 1997-07-15 |
| US5688924A (en) | 1997-11-18 |
| BG100779A (en) | 1997-09-30 |
| HUP9602080A3 (en) | 1998-04-28 |
| PL315675A1 (en) | 1997-02-17 |
| PL182429B1 (pl) | 2002-01-31 |
| RO115526B1 (ro) | 2000-03-30 |
| CN1148047A (zh) | 1997-04-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0109253B1 (en) | Epimeric azahomoerythromycin a derivative and intermediates therefor | |
| Reher et al. | Triterpenoids from plants of the Sanguisorbeae | |
| EP0827965A2 (en) | Synthesis of 9-deoxo- 9a-aza 11,12-deoxy- 9a-methyl-9a-homoerythromycin A 11,12- hydrogenorthoborate dihydrate | |
| CN1062867C (zh) | 12,13－环氧－泰乐菌素的衍生物及其制备方法 | |
| EP0287082B1 (en) | Derivatives of tylosin and 10,11,12,13-tetrahydro tylosin, methods of manufacture thereof and their use in pharmaceuticals and in the manufacture thereof | |
| EP0985679B1 (en) | New hydroxy derivatives of tylosin and process for their preparation | |
| Hart et al. | The alkaloids of Lamprolobium fruticosum Benth.(family Leguminosae) | |
| US5922684A (en) | Polyhydro derivatives of tylosine and process for their preparation | |
| RU2173689C2 (ru) | Производные 12,13-эпокситилозина и способы их получения | |
| RU2234510C2 (ru) | Производные класса олеандомицина и способ их получения | |
| CZ20014362A3 (cs) | 4´-Demykarosyl-8a-aza-8a-homotylosiny a způsob jejich výroby | |
| EP1175428B1 (en) | 3-deoxy-desmycosin derivatives and process for their preparation | |
| Naranda et al. | New Dihydro and Tetrahydro Derivatives of Desmycosin III. The Opening of Oxirane Ring of 12, 13-Epoxydesmycosin | |
| Elix et al. | The Identification and Synthesis of Two New β-Orcinol para-Depsides in the Lichen Pseudocyphellaria norvegica | |
| RO111684B1 (ro) | Derivati de 10,11,12,13-tetrahidrodesmicosina si procedeu pentru prepararea acestora | |
| CN1224724A (zh) | 一种鞘类脂糖苷化合物及其提取方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |