CN107365359B - Synthesis method of vancomycin chiral functional monomer - Google Patents
Synthesis method of vancomycin chiral functional monomer Download PDFInfo
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- CN107365359B CN107365359B CN201710581060.0A CN201710581060A CN107365359B CN 107365359 B CN107365359 B CN 107365359B CN 201710581060 A CN201710581060 A CN 201710581060A CN 107365359 B CN107365359 B CN 107365359B
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- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 108010059993 Vancomycin Proteins 0.000 title claims abstract description 68
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 title claims abstract description 65
- 229960003165 vancomycin Drugs 0.000 title claims abstract description 63
- 239000000178 monomer Substances 0.000 title claims abstract description 24
- 238000001308 synthesis method Methods 0.000 title abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 18
- 150000001263 acyl chlorides Chemical class 0.000 claims abstract description 13
- 239000012074 organic phase Substances 0.000 claims abstract description 10
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 229920000642 polymer Polymers 0.000 abstract description 3
- 125000003342 alkenyl group Chemical group 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- -1 methylpropenyl Chemical group 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 230000001376 precipitating effect Effects 0.000 description 5
- MZFGYVZYLMNXGL-UHFFFAOYSA-N undec-10-enoyl chloride Chemical compound ClC(=O)CCCCCCCCC=C MZFGYVZYLMNXGL-UHFFFAOYSA-N 0.000 description 5
- 229960001572 vancomycin hydrochloride Drugs 0.000 description 5
- LCTORFDMHNKUSG-XTTLPDOESA-N vancomycin monohydrochloride Chemical compound Cl.O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 LCTORFDMHNKUSG-XTTLPDOESA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 3
- 238000001212 derivatisation Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001151 peptidyl group Chemical group 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- PSEVKFKRYVAODC-UHFFFAOYSA-N 11-chloroundec-1-ene Chemical compound ClCCCCCCCCCC=C PSEVKFKRYVAODC-UHFFFAOYSA-N 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000012644 addition polymerization Methods 0.000 description 1
- 125000002009 alkene group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
- C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
- C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention relates to a synthesis method of a vancomycin chiral functional monomer, and belongs to the technical field of organic synthesis and synthesis of functional high polymer intermediates. Completely dissolving vancomycin in an organic phase, and then adding an acyl chloride compound, wherein the molar ratio of the vancomycin to the acyl chloride compound is as follows: 1.0: 1.0-2.5, reacting for 0.5-4.0 h at the temperature of 0-80 ℃ to obtain vancomycin chiral functional monomer VanR, wherein Van represents vancomycin, and R represents a group substituted on vancomycin and is an alkylene group. The vancomycin derivative synthesized by the method contains terminal alkenyl in the structure, and can be used as a valuable functional monomer in the preparation of high molecular polymers.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and synthesis of functional high molecular polymer intermediates, and relates to a preparation method of a Levancomycin chiral functional monomer.
Background
Vancomycin (Van) molecules have a highly modified heptapeptide backbone[1]And having a hydrophilic glycosyl moiety and a hydrophobic peptidyl moiety, wherein the peptidyl moiety is cross-linked by seven amino acids to form a vancomycin tricyclic rigid backbone structure[2]The structure of the compound contains 7 peptide cores, 3 macrocycles and 18 stereoselective centers, and the molecular formula is C66N75C12N9024And the molecular mass is 1485.74. The structure schematic formula is as follows:
the vancomycin has a special structure, and the prepared stationary phase can have various interactions with analytes, such as hydrophobic effect, electrostatic effect, dipole superposition effect, hydrogen bond effect and the like in a solution system[3]Can be used for various separation modes such as reverse phase, normal phase, hydrophile and the like in chromatographic separation[4-5]. Vancomycin serving as a separation material is widely applied to the field of separation and analysis. The water solubility, the activity to sensitive bacteria and drug-resistant bacteria of the derivatized vancomycin are improved. Vancomycin has a complex structure and more functional groups, but the peptide skeleton is stable, and the vancomycin is in a moleculeThe primary amine group is relatively active, so derivatization can be realized by modifying the amine group at the tail end of the vancomycin and the amine group on the sugar ring. The modified vancomycin can also introduce a special action site under the condition of keeping the structure of a parent body unchanged. By introducing unsaturated alkyl group, vancomycin functional monomer with addition polymerization reaction can be formed.
At present, no commercially available vancomycin functional monomer exists, and vancomycin is mainly used as a chromatographic stationary phase.
[1] Kahne D, Leimkuhler C, Lu W, et al. Glycopeptide and lipoglycopeptide antibiotics. [J] Chemical Reviews, 2005, 105(2):425-48.
[2] Yan contest, Guo Shimur, Dingjunjie, Shenjinai, King Jixia, Kinggawa, Liangxin 28156vancomycin and its impurities hydrophilic interaction chromatography [ J ] chromatography 2015, 33(9): 951 956.
[3] Ilisz I, Berkecz R, Péter A. Retention mechanism of high-performance liquid chromatographic enantioseparation on macrocyclic glycopeptide-based chiral stationary phases[J]. Journal of Chromatography A, 2009, 1216(10): 1845-1860.
[4] Bosáková Z, Kloučková I, Tesařová E. Study of the stability of promethazine enantiomers by liquid chromatography using a vancomycin-bonded chiral stationary phase[J]. Journal of Chromatography B, 2002, 770(1/2): 63-69.
[5] Zhang X, Bao Y, Huang K, Barnettrundle K, Armstrong D. Evaluation of dalbavancin as chiral selector for HPLC and comparison with teicoplanin-based chiral stationary phases[J]. Chirality, 2010, 22(5): 495-513。
Disclosure of Invention
Aiming at the problems and the defects in the prior art, the invention provides a method for synthesizing a vancomycin chiral functional monomer. The method is carried out in an organic phase, has the advantages of mild reaction conditions, simple and convenient operation, low cost, small pollution and the like, and is realized by the following technical scheme.
A method for synthesizing vancomycin chiral functional monomer comprises the following steps:
completely dissolving vancomycin in an organic phase, and then adding an acyl chloride compound, wherein the molar ratio of the vancomycin to the acyl chloride compound is as follows: 1.0: 1.0-2.5, reacting for 0.5-4.0 h at the temperature of 0-80 ℃ to obtain vancomycin chiral functional monomer VanR, wherein Van represents vancomycin, and R represents a group substituted on vancomycin and is an alkylene group.
The organic phase is 25: 0.963 part of a mixed organic phase of N, N-dimethylformamide and triethylamine.
The number of carbon atoms in the acyl chloride compound is C3-C11.
And R represents an alkyl with a substituent group of C3-C11.
wherein: van is vancomycin and R is an alkene group.
The reaction of the present invention is well tolerant to functional groups, and the hydrocarbon chain of the acyl chloride may carry no or one substituent, and as in the above formula, R may contain only olefin or one other hydrocarbon group, and the hydrocarbon group may have any structure.
The above alkenyl group is preferably a hydrocarbon group having 3 to 11 carbon atoms, such as propenyl, methylpropenyl, undecenyl; more preferably a hydrocarbon group having 3 to 4 carbon atoms, and particularly preferably a propenyl group or a methylpropenyl group.
The organic solvent used in the method can be DMF (N, N-dimethylformamide), triethylamine and glacial acetic acid, and all the organic solvents are analytically pure.
The feeding molar ratio of the vancomycin to the acyl chloride compounds used in the method is 1.0: 1.0-2.5. The feeding mode of each raw material is preferably as follows: placing the dried round-bottom flask added with the stirrer and the vancomycin on a stirring device, and adding the organic phase mixed solvent for stirring; after the vancomycin is dissolved, adding acyl chloride compounds, and finally placing the reaction system in a water bath kettle at a certain temperature for reaction for a certain time.
The heating process can adopt a water bath or other heating methods.
The invention preferably carries out post-treatment on the reaction product after the reaction is finished, and comprises product concentration and purification.
The concentration process adopts a rotary evaporator vacuum concentration method of reduced pressure distillation, and can also adopt other evaporation methods, such as atmospheric distillation concentration.
The purification process adopts a recrystallization method to purify the product.
The invention has the beneficial effects that:
1. the vancomycin functional monomer is prepared by carrying out one-step reaction on vancomycin and acyl chloride compounds at a relatively low temperature, and the reaction condition is mild;
2. the derivatization reaction related to the method can be an organic phase, and the reaction is flexible and easy to operate and control;
3. the reaction involved in the method of the invention has good compatibility with other functional groups of parent compounds and is not influenced by derivatization reaction.
Detailed Description
The present invention will be further described with reference to the following embodiments.
Example 1
The synthesis method of the vancomycin chiral functional monomer comprises the following specific steps:
adding 0.825g of vancomycin hydrochloride (0.5 mmol) into a 50mL round-bottom flask, then adding 25mL of DMMF, stirring to dissolve completely, adding triethylamine (the volume ratio of N, N-dimethylformamide to triethylamine is 25: 0.963), dropwise adding 97 mu L (1 mmol) of methacryloyl chloride (the molar ratio of vancomycin to methacryloyl chloride is 1.0: 2.0) at room temperature, heating to 40 ℃ after dropwise adding, reacting for 2 hours, cooling to room temperature after the reaction is finished, adjusting to neutral with glacial acetic acid, adding 200mL of acetone, stirring, performing suction filtration, and collecting precipitates. Dissolving the precipitate with 30mL of methanol, and precipitating with 300mL of acetone; the process is repeated for 5 times to obtain vancomycin chiral functional monomer VanR, wherein Van represents vancomycin, R represents a group substituted on the vancomycin and is methacryloyl, and the molecular structural formula is as follows:
the compound is an off-white powder with a yield of 72.0% and the characterization data is as follows:
IR（KBr）：3414，2955，1651，1505，1399，1231，1127，1063，1026，893，848，818，712，616cm-1。
MS（ESI）m/z：1516[M+H]+、1538 [M+Na]+、1554[M+K]+。
example 2
The synthesis method of the vancomycin chiral functional monomer comprises the following specific steps:
adding 0.825g of vancomycin hydrochloride (0.5 mmol) into a 50mL round-bottom flask, then adding 25mL of DMMF, stirring to dissolve completely, adding triethylamine (the volume ratio of N, N-dimethylformamide to triethylamine is 25: 0.963), dropwise adding 81 mu L (1.0 mmol) of acryloyl chloride (the molar ratio of vancomycin to acryloyl chloride is 1.0: 2.0) at room temperature, heating to 40 ℃ after dropwise adding, reacting for 2 hours, cooling to room temperature after the reaction is finished, adjusting to neutral with glacial acetic acid, adding 200mL of acetone, stirring, performing suction filtration, and collecting precipitates. Dissolving the precipitate with 30ml methanol, and precipitating with 300ml acetone; the process is repeated for 5 times to obtain vancomycin chiral functional monomer VanR, wherein Van represents vancomycin, R represents a group substituted on the vancomycin and is an acryloyl group, and the molecular structural formula is shown as follows:
the compound was a white powder with a yield of 68.5%, and the characterization data were as follows:
IR（KBr）：3464，2962，1641，1505，1400，1231，1126，1064，1027，896，848，705，617cm-1。
MS（ESI）m/z：1525.41[M+Na]+。
example 3
The synthesis method of the vancomycin chiral functional monomer comprises the following specific steps:
adding 0.825g of vancomycin hydrochloride (0.5 mmol) into a 50mL round-bottom flask, then adding 25mL of DMMF, stirring to dissolve completely, adding triethylamine (the volume ratio of N, N-dimethylformamide to triethylamine is 25: 0.963), dropwise adding 214 mu L (1.0 mmol) of undecylenoyl chloride (the molar ratio of vancomycin to undecylenoyl chloride is 1.0: 2.0) at room temperature, heating to 40 ℃ after dropwise adding, reacting for 2 hours, cooling to room temperature after the reaction is finished, adjusting to neutral with glacial acetic acid, adding 200mL of acetone, stirring, performing suction filtration, and collecting precipitates. Dissolving the precipitate with 30ml methanol, and precipitating with 300ml acetone; the process is repeated for 5 times to obtain vancomycin chiral functional monomer VanR, wherein Van represents vancomycin, R represents that a group substituted on the vancomycin is undecylenoyl, and the molecular structural formula is as follows:
the compound is an off-white powder with a yield of 20.0% and the characterization data is as follows:
IR（KBr）：3426，2962，1650，1505，1399，1231，1127，1063，1017，893，850，819，712，617 cm-1。
MS（ESI）m/z：1637.5[M+Na]+、1653.5[M+K]+。
example 4
The synthesis method of the vancomycin chiral functional monomer comprises the following specific steps:
adding 0.825g of vancomycin hydrochloride (0.5 mmol) into a 50mL round-bottom flask, then adding 25mL of DMMF, stirring to dissolve completely, adding triethylamine (the volume ratio of N, N-dimethylformamide to triethylamine is 25: 0.963), dropwise adding 107 mu L (0.5 mmol) of undecylenyl chloride (the molar ratio of vancomycin to undecylenoyl chloride is 1.0: 1.0) at 0 ℃, heating to 80 ℃ after dropwise adding, reacting for 0.5h, cooling to room temperature after the reaction is finished, adjusting to neutral with glacial acetic acid, adding 200mL of acetone, stirring, performing suction filtration, and collecting precipitates. Dissolving the precipitate with 30ml methanol, and precipitating with 300ml acetone; the process is repeated for 5 times to obtain vancomycin chiral functional monomer VanR, wherein Van represents vancomycin, R represents that a group substituted on the vancomycin is undecylenoyl, and the molecular structural formula is as follows:
example 5
The synthesis method of the vancomycin chiral functional monomer comprises the following specific steps:
adding 0.825g of vancomycin hydrochloride (0.5 mmol) into a 50mL round-bottom flask, then adding 25mL of DMMF, stirring to dissolve completely, adding triethylamine (the volume ratio of N, N-dimethylformamide to triethylamine is 25: 0.963), dropwise adding 267.5 mu L (1.25 mmol) of undecylenic chloride (the molar ratio of vancomycin to undecylenoyl chloride is 1.0: 2.5) at 0 ℃, heating to 60 ℃ after dropwise adding, reacting for 4 hours, cooling to room temperature after the reaction is finished, adjusting to neutral by glacial acetic acid, adding 200mL of acetone, stirring, filtering, and collecting precipitates. Dissolving the precipitate with 30ml methanol, and precipitating with 300ml acetone; the process is repeated for 5 times to obtain vancomycin chiral functional monomer VanR3Wherein Van represents vancomycin, R3The group substituted on vancomycin is undecylenoyl, and the molecular structural formula is shown as follows:
while the present invention has been described in detail with reference to the specific embodiments thereof, the present invention is not limited to the embodiments described above, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.
Claims (1)
1. A method for synthesizing vancomycin chiral functional monomer is characterized by comprising the following steps:
completely dissolving vancomycin in an organic phase, and then adding an acyl chloride compound, wherein the molar ratio of the vancomycin to the acyl chloride compound is as follows: 1.0: 1.0-2.5, reacting for 0.5-4.0 h at 40 ℃ to obtain vancomycin chiral functional monomer VanR, wherein Van represents vancomycin, and R represents a group substituted on vancomycin and is an alkylene group;
the organic phase is 25: 0.963 of a mixed organic phase of N, N-dimethylformamide and triethylamine;
the number of carbon atoms in the acyl chloride compound is C3-C11.
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| WO2004058732A1 (en) * | 2002-12-30 | 2004-07-15 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Oxazolidine derivative, methods of preparation and uses |
| WO2006130418A1 (en) * | 2005-05-27 | 2006-12-07 | Wyeth | Tigecycline and methods of preparation |
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| US8362268B2 (en) * | 2008-05-30 | 2013-01-29 | University Of Notre Dame Du Lac | Anti-bacterial agents from benzo[d]heterocyclic scaffolds for prevention and treatment of multidrug resistant bacteria |
| CN103446894B (en) * | 2013-07-30 | 2015-09-30 | 云南师范大学 | Vancomycin chiral composite membrane and the application in phenylglycine racemate resolution thereof |
| CN107759672A (en) * | 2013-08-19 | 2018-03-06 | 南京爱斯药业有限公司 | Vancomycin derivatives, preparation method and applications |
| CN105085636B (en) * | 2014-05-19 | 2020-05-01 | 中国医学科学院药物研究所 | Vancomycin derivatives, preparation method thereof and application thereof in antibiosis |
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|---|---|---|---|---|
| WO2004058732A1 (en) * | 2002-12-30 | 2004-07-15 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Oxazolidine derivative, methods of preparation and uses |
| WO2006130418A1 (en) * | 2005-05-27 | 2006-12-07 | Wyeth | Tigecycline and methods of preparation |
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| Title |
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| 以万古霉素为手性选择剂的氨基酸对映体的毛细管电泳快速分离;康经武等;《分析化学》;万方;19991231;第27卷(第4期);第448-452页 * |
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