CN108864125B - Preparation method of antibacterial drug - Google Patents
Preparation method of antibacterial drug Download PDFInfo
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- CN108864125B CN108864125B CN201710338972.5A CN201710338972A CN108864125B CN 108864125 B CN108864125 B CN 108864125B CN 201710338972 A CN201710338972 A CN 201710338972A CN 108864125 B CN108864125 B CN 108864125B
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- 229940124350 antibacterial drug Drugs 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 229940126062 Compound A Drugs 0.000 claims abstract description 66
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 66
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 54
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 255
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 99
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 93
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 79
- 238000006243 chemical reaction Methods 0.000 claims description 62
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 51
- 238000010791 quenching Methods 0.000 claims description 50
- 230000000171 quenching effect Effects 0.000 claims description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- 238000003756 stirring Methods 0.000 claims description 46
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 44
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 44
- 239000012046 mixed solvent Substances 0.000 claims description 35
- 239000003960 organic solvent Substances 0.000 claims description 29
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 26
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical group CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- 239000003242 anti bacterial agent Substances 0.000 claims description 22
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical group FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 18
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000003638 chemical reducing agent Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 13
- 235000019253 formic acid Nutrition 0.000 claims description 13
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 8
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 7
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 claims description 7
- ZWDGGNOBARRAPI-UHFFFAOYSA-N C(C)(C)[AlH]C(C)C.[Li] Chemical group C(C)(C)[AlH]C(C)C.[Li] ZWDGGNOBARRAPI-UHFFFAOYSA-N 0.000 claims description 6
- -1 lithium tri-t-butoxyaluminum hydride Chemical class 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000007363 ring formation reaction Methods 0.000 abstract description 4
- 238000007142 ring opening reaction Methods 0.000 abstract description 4
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000006722 reduction reaction Methods 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 196
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 180
- 239000012074 organic phase Substances 0.000 description 147
- 239000000243 solution Substances 0.000 description 140
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 102
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 74
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- 229910052938 sodium sulfate Inorganic materials 0.000 description 51
- 235000011152 sodium sulphate Nutrition 0.000 description 51
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 49
- 238000005160 1H NMR spectroscopy Methods 0.000 description 49
- 238000010898 silica gel chromatography Methods 0.000 description 48
- 238000001514 detection method Methods 0.000 description 43
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- 238000001914 filtration Methods 0.000 description 37
- 229920006395 saturated elastomer Polymers 0.000 description 35
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- 238000001035 drying Methods 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 238000001816 cooling Methods 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 239000007864 aqueous solution Substances 0.000 description 26
- 238000010438 heat treatment Methods 0.000 description 25
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 238000002156 mixing Methods 0.000 description 15
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 14
- 239000012295 chemical reaction liquid Substances 0.000 description 13
- 230000000844 anti-bacterial effect Effects 0.000 description 11
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 11
- 238000005406 washing Methods 0.000 description 10
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000001476 sodium potassium tartrate Substances 0.000 description 8
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 241000191967 Staphylococcus aureus Species 0.000 description 6
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 6
- 108010059993 Vancomycin Proteins 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 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 description 6
- 229960003165 vancomycin Drugs 0.000 description 6
- 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 description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000007195 tryptone soya broth Substances 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 2
- 241000194031 Enterococcus faecium Species 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- 240000005125 Myrtus communis Species 0.000 description 2
- 235000013418 Myrtus communis Nutrition 0.000 description 2
- 241000191963 Staphylococcus epidermidis Species 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- HTBVGZAVHBZXMS-UHFFFAOYSA-N lithium;tris[(2-methylpropan-2-yl)oxy]alumane Chemical compound [Li].[Al+3].CC(C)(C)[O-].CC(C)(C)[O-].CC(C)(C)[O-] HTBVGZAVHBZXMS-UHFFFAOYSA-N 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000943303 Enterococcus faecalis ATCC 29212 Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 241000102542 Kara Species 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000012137 tryptone Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of an antibacterial drug. The preparation method of the antibacterial drug comprises the steps of using sodium methoxide with the structural formula as
The compound A and methyl iodide are used as initial raw materials, and reduction reaction, ring-closing reaction, oxidation reaction, ring-opening reaction and other steps are carried out, so that the compound A with the structural formula shown in the specification is obtained
The antibacterial drug is prepared by a chemical synthesis method, so that the sources of the antibacterial drug are increased, and the wider application of the antibacterial drug is facilitated.
Description
Technical Field
The invention relates to a preparation method of an antibacterial drug.
Background
Myrtucommuacetalone was extracted and isolated from myrtle (myrtucommuini lin.) by the farzana shaheen group of University of kara in 2013, and was found to have a strong T cell proliferation inhibitory activity (IC)50<0.5 μ g/mL) and inhibiting ROS production activity, but other biological activities, especially antibacterial activities, have not been screened to date due to the low amount of the compound extracted from the plant. The structural formula of the compound myrtucommuacetalone extracted from myrtle is shown in the specification
The compound of (4) and found that the substance has a good antibacterial activity, however, the yield of the substance extracted and isolated from plants is low, which limits the practical application of the compound.
Disclosure of Invention
Therefore, there is a need for a method for preparing an antibacterial agent, which can be obtained by chemical synthesis to increase its source.
Under the condition of no water and 50-80 ℃, sodium methoxide with the structural formula as shown in the specification
The compound A and methyl iodide react in alcohol to obtain the compound with the structural formula
The compound B of (1), wherein the molar ratio of the sodium methoxide to the compound A is 5-12: 1, and the molar ratio of the methyl iodide to the compound A is 7-16: 1;
under the conditions of anhydrous temperature and-70 to-78 ℃, a reducing agent reacts with the compound B in a first organic solvent to obtain a compound with a structural formula of
The compound C of (1), wherein the molar ratio of the reducing agent to the compound B is 0.5-2.5: 1;
reacting the compound A, the compound C and protonic acid in a second organic solvent at the temperature of between 0 and 40 ℃ to obtain a compound with a structural formula ofThe compound D of (1), wherein the molar ratio of the compound A to the compound C is 0.2-0.5: 1;
reacting the compound C with organic alkali and trifluoromethanesulfonylation reagent in a third organic solvent at the temperature of 40-90 ℃ to obtain a compound with a structural formula
The molar ratio of the organic base to the compound C is 1-2: 1, the trifluoromethanesulfonylation reagent is trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride, and the trifluoromethanesulfonyl chloride is prepared fromThe molar ratio of the acylation reagent to the compound C is 1-2: 1, and OTf represents trifluoromethanesulfonyloxy;
reacting the compound E, triethylamine and formic acid in a fourth organic solvent under the condition of a catalyst at the temperature of 50-80 ℃ to obtain a compound with a structural formula of
The compound F of (1), wherein the molar ratio of the triethylamine to the compound E is 1-3: 1, and the molar ratio of the formic acid to the compound E is 1-3: 1;
reacting the compound D, the compound F and p-toluenesulfonic acid in a fifth organic solvent at 50-110 ℃ to obtain a compound with a structural formula
The compound G of (1), wherein the molar ratio of the compound F to the compound D is 1: 1-2, and the molar ratio of the p-toluenesulfonic acid to the compound D is 0.25-1.5: 1; and
reacting the compound G with strong alkaline hydroxide in a mixed solvent of water and alcohol at the temperature of between 50 and 90 ℃ to obtain the compound with the structural formula shown in the specification
The antibacterial agent of (1), wherein the molar ratio of the strongly basic hydroxide to the compound G is 50-150: 1.
The preparation method of the antibacterial drug takes sodium methoxide, the compound A and methyl iodide as initial raw materials, and then the antibacterial drug is obtained through reduction reaction, ring-closing reaction, oxidation reaction and ring-opening reaction, namely the antibacterial drug is prepared by a chemical synthesis method, so that the sources of the antibacterial drug are increased, and the wider application of the antibacterial drug is facilitated.
In one embodiment, the step of reacting sodium methoxide, compound a, and methyl iodide in alcohol under anhydrous conditions at 50-80 ℃ is specifically: dissolving the compound A in the alcohol under the anhydrous condition and the temperature of 0-40 ℃ to obtain an alcohol solution of the compound A, then adding the sodium methoxide into the alcohol solution of the compound A, adding the methyl iodide at the temperature of-10-5 ℃, reacting at the temperature of 50-80 ℃ for 6-15 hours, and then quenching the reaction.
In one embodiment, in the step of reacting sodium methoxide, compound a and methyl iodide in an alcohol, the alcohol is at least one of methanol, ethanol and propanol.
In one embodiment, the step of reacting the reducing agent with the compound B in the first organic solvent under anhydrous conditions at-70 ℃ to-78 ℃ is specifically: dissolving the compound B in the first organic solvent at the temperature of 0-40 ℃ to obtain an organic solution of the compound B; adding the reducing agent into the organic solution of the compound B at the temperature of-70 ℃ to-78 ℃, stirring and reacting for 5 minutes to 60 minutes, and then quenching the reaction.
In one embodiment, the reducing agent is lithium diisopropylaluminum hydride or lithium tri-t-butoxyaluminum hydride.
In one embodiment, the protic acid is trifluoroacetic acid or p-toluenesulfonic acid.
In one embodiment, the organic base is 2, 6-lutidine, pyridine, or triethylamine.
In one embodiment, the strong basic strong oxide is potassium hydroxide or sodium hydroxide.
In one embodiment, the step of reacting the compound G and the strongly basic hydroxide in the mixed solvent of water and alcohol is specifically: dissolving the compound G in the mixed solvent of water and alcohol at 0-40 ℃, adding the strong alkaline hydroxide, and reacting at 50-90 ℃.
In one embodiment, the catalyst consists of palladium acetate and triphenylphosphine in a molar ratio of 1: 2-4, or the catalyst is tetrakis (triphenylphosphine) palladium.
Drawings
Fig. 1 is a flowchart of a method for preparing an antibacterial agent according to an embodiment.
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
As shown in fig. 1, a method for preparing an antibacterial agent according to an embodiment includes the steps of:
step S110: under the condition of no water and 50-80 ℃, sodium methoxide with the structural formula as shown in the specificationThe compound A and methyl iodide react in alcohol to obtain the compound with the structural formulaCompound B of (1).
Wherein the molar ratio of sodium methoxide to compound A is 5-12: 1; the molar ratio of the methyl iodide to the compound A is 7-16: 1.
Specifically, the step of reacting sodium methoxide, a compound A and methyl iodide in alcohol under the anhydrous condition at 50-100 ℃ specifically comprises the following steps: dissolving a compound A in alcohol under the conditions of no water and 0-40 ℃ to obtain an alcohol solution of the compound A, then adding sodium methoxide into the alcohol solution of the compound A, adding methyl iodide at-10-5 ℃, reacting at 50-80 ℃ for 6-15 hours, and quenching the reaction. Wherein, the reagent used for quenching reaction is hydrochloric acid.
Wherein, the alcohol in step S110 is selected from at least one of absolute methanol, absolute ethanol and absolute propanol, preferably absolute methanol, and the absolute methanol can provide step S110 with high yield; the sodium methoxide is anhydrous sodium methoxide.
Wherein, after step S110, a step of purifying compound B is further included: extracting the reaction liquid obtained after quenching reaction with ethyl acetate, washing the organic phase with a saturated sodium sulfite aqueous solution, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain a purified compound B. The iodine in the extracted organic phase was removed by washing the organic phase with an aqueous solution of saturated sodium sulfite.
Step S120: under the conditions of anhydrous temperature and-70 to-78 ℃, a reducing agent reacts with a compound B in a first organic solvent to obtain a compound with a structural formula of
Compound (2) of (1).
Specifically, the step of reacting the reducing agent with the compound B in the first organic solvent under the anhydrous condition at-70 ℃ to-78 ℃ is specifically as follows: dissolving a compound B in a first organic solvent at the temperature of 0-40 ℃ to obtain an organic solution of the compound B; adding a reducing agent into the organic solution of the compound B at the temperature of-70 ℃ to-78 ℃, stirring and reacting for 5 minutes to 60 minutes, and then quenching the reaction. Wherein the reagent used for quenching the reaction is ethyl acetate.
Wherein the first organic solvent is tetrahydrofuran, dichloromethane or toluene; tetrahydrofuran is preferred to provide a higher yield in step S120.
Wherein the molar ratio of the reducing agent to the compound B is 0.2-0.5: 1. The reducing agent is lithium diisopropylaluminum hydride or lithium tri-tert-butoxyaluminum hydride.
After step S120, a purification step of compound C is also included: adding saturated sodium potassium tartrate aqueous solution into reaction liquid after quenching reaction at the temperature of between 0 and 40 ℃, extracting by using ethyl acetate, washing an organic phase by using saturated anhydrous sodium sulfite aqueous solution and drying by using anhydrous sodium sulfate in sequence, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and carrying out chromatography and purification by using a silica gel column layer. Because lithium diisopropylhydride and lithium tri-tert-butoxyhydride contain aluminum ions, the quenched reaction solution is colloidal and is not beneficial to purification, and the saturated aqueous solution of sodium potassium tartrate can dissolve out aluminum in the reaction solution to dissolve the sol and separate the reaction solution, thereby facilitating subsequent extraction.
Step S130: reacting the compound A, the compound C and protonic acid in a second organic solvent at the temperature of between 0 and 40 ℃ to obtain a compound with a structural formula ofCompound D of (1).
Wherein the molar ratio of the compound A to the compound C is 0.2-0.5: 1.
Specifically, the step of reacting the compound a, the compound C and the protonic acid in the second organic solvent at 0 ℃ to 40 ℃ specifically comprises: dissolving the compound A and the compound C in a second organic solvent, stirring and reacting for 10-12 hours at the temperature of 0-40 ℃, and then quenching the reaction. Wherein, the reagent used for quenching reaction is saturated sodium bicarbonate water solution.
Wherein, step S130 is a dehydration ring closure reaction, and the protonic acid plays a role in promoting ring closure in step S130. The protonic acid is trifluoroacetic acid or p-toluenesulfonic acid. The molar ratio of the protonic acid to the compound A is 0.05-1.5: 1.
Wherein the second organic solvent is toluene, chloroform, dichloromethane or dichloroethane.
Step S140: reacting the compound C with organic alkali and trifluoromethanesulfonylation reagent in a third organic solvent at the temperature of 40-90 ℃ to obtain a compound with a structural formula
Compound E of (1). Wherein OTf represents trifluoromethanesulfonyloxy.
Wherein the molar ratio of the organic base to the compound C is 1-2: 1. Specifically, the organic base is 2, 6-lutidine, pyridine or triethylamine. The organic base enolates the carbonyl group of compound C and shifts the double bond.
Wherein the trifluoromethanesulfonylation reagent is trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride; the molar ratio of the trifluoromethanesulfonylation reagent to the compound C is 1-2: 1. The triflic anhydride, triflyl chloride, acts to sulfonylate the enol hydroxyl group.
Wherein the third organic solvent is 1,2 dichloroethane, dichloromethane, chloroform or toluene.
Specifically, step S140 specifically includes: dissolving the compound C in a third organic solvent to obtain an organic solution of the compound C, adding an organic base and a trifluoromethanesulfonylation reagent into the organic solution of the compound C at the temperature of 0-40 ℃, stirring and reacting for 3-12 hours at the temperature of 40-90 ℃, and then quenching the reaction at the temperature of 0-40 ℃. Wherein, the reagent used for quenching reaction is saturated sodium bicarbonate water solution.
Step S150: reacting the compound E, triethylamine and formic acid in a fourth organic solvent under the condition of a catalyst at the temperature of between 50 and 80 ℃ to obtain a compound with a structural formula of
Compound F of (1).
Wherein the molar ratio of triethylamine to the compound E is 1-3: 1; the molar ratio of formic acid to the compound E is 1-3: 1. The catalyst is composed of palladium acetate and triphenylphosphine in a molar ratio of 1: 2-4, or the catalyst is tetrakis (triphenylphosphine) palladium. The fourth organic solvent is N, N-dimethylformamide or tetrahydrofuran.
Step S160: reacting the compound D, the compound F and p-toluenesulfonic acid in a fifth organic solvent at 50-110 ℃ to obtain a compound with a structural formula
Compound G of (1).
Wherein the molar ratio of the compound F to the compound D is 1-2: 1; the molar ratio of the p-toluenesulfonic acid to the compound D is 0.25-1.5: 1. The fifth organic solvent is an organic substance with a boiling point not lower than that of chloroform. For example, chloroform, dichloroethane, toluene, etc.
Step S170: reacting compound G and strong alkaline hydroxide in a mixed solvent of water and alcohol at the temperature of 60-90 ℃ to obtain the compound with the structural formula of
The antibacterial agent of (1).
Specifically, the step of reacting compound G and a strongly basic hydroxide in a mixed solvent of water and an alcohol at 60 ℃ to 90 ℃ comprises: dissolving the compound G in a mixed solvent of water and alcohol at 0-40 ℃, adding strong alkaline hydroxide, and reacting at 60-90 ℃. Wherein the molar ratio of the strong basic hydroxide to the compound G is 50-150: 1. The strong alkaline hydroxide is potassium hydroxide or sodium hydroxide; the strong basic hydroxide promotes the ring-opening reaction in step S170.
Wherein the alcohol in step S170 is ethanol, methanol or propanol; preferably ethanol, which enables a higher yield in step S170. Specifically, the volume ratio of water to alcohol in the mixed solvent of water and alcohol is 50: 1-150: 1.
The preparation method of the antibacterial drug takes sodium methoxide, the compound A and methyl iodide as initial raw materials, and then the antibacterial drug is obtained through reduction reaction, ring-closing reaction, oxidation reaction and ring-opening reaction, namely the antibacterial drug is prepared by a chemical synthesis method, so that the sources of the antibacterial drug are increased, and the wider application of the antibacterial drug is facilitated.
The following are specific examples:
example 1
The preparation process of the antibacterial agent of this example is as follows:
(1) dissolving compound A (102mmol) in 240 ml of anhydrous methanol to obtain a methanol solution of compound A; adding anhydrous sodium methoxide powder (816mmol) into methanol solution of compound A at 25 deg.C, stirring and mixing for 0.5 hr, cooling to 0 deg.C, and addingAdding iodomethane (1430mmol), stirring and mixing for 0.5 hour, heating to 64 ℃, reacting at 64 ℃ for 8 hours, cooling to 25 ℃, then quenching the reaction with 2mol/L hydrochloric acid, extracting the obtained reaction liquid with ethyl acetate, washing the organic phase with a saturated sodium sulfite aqueous solution, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 23.1g of a compound B with a yield of 90%, wherein the detection data of the compound B are as follows: IR (film) lambdamax3412，2962，2940，2876，1724，1672，1558，1474，1420，1314，1049，939；1H NMR(400MHz，CDCl3)δ3.84–3.74(m，1H)，1.43(s，6H)，1.35(s，6H)，1.17(s，3H)，1.16(s，3H)；13C NMR(100MHz，CDCl3)δ209.9，208.6，199.3，196.9，108.2，56.9，52.2，35.2，24.3，23.9，19.1；HRMS(ESI)C14H19O4[(M-H)-]Calculated molecular weight is 251.1289, found molecular weight is 251.1287. Wherein, the synthetic route of the compound B is as follows, Me in the formula represents methyl, and the following is the same:
(2) compound B (19.8mmol) was dissolved in 200 ml of tetrahydrofuran at 25 ℃ to give a tetrahydrofuran solution of compound B; lithium diisopropylaluminum hydride (23.8mmol) was added to a tetrahydrofuran solution of compound B at-78 deg.c, stirred for 20 minutes, then quenched with ethyl acetate, warmed to 25 deg.c, saturated aqueous sodium potassium tartrate solution was added, the resulting reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, and finally the concentrated organic phase was purified by silica gel column chromatography to give 4.2g of compound C in 91% yield, wherein the assay data for compound C is as follows: IR (film) lambdamax 2974，2938，2872，1717，1690，1676，1609，1464，1422，1385，1258，1098，945，804；1H NMR(400MHz，CDCl3)δ7.29(d，J＝1.0Hz，1H)，3.42–3.33(m，1H)，1.34(s，6H)，1.33(s，6H)，1.13(d，J＝6.6Hz，6H)；13C NMR(100MHz，CDCl3)δ208.8，199.8，196.6，164.9，130.6，58.5，58.2，28.6，22.3，21.9，21.8；HRMS(ESI)C14H21O3[(M+H)+]237.1483 as a calculated molecular weight value; the molecular weight was found to be 237.1491. The synthetic route of the compound C is as follows:
(3) dissolving compound A (40mmol) and compound C (80mmol) in 80 ml of chloroform to obtain chloroform solution of compound A and compound C, adding p-toluenesulfonic acid (40mmol) to react for 10 hours under stirring at 25 ℃, then quenching with saturated aqueous sodium bicarbonate, extracting the obtained reaction solution with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase under vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 13.5g of compound D with 81% yield, wherein the detection data of compound D are as follows: IR (film) lambdamax3240，2969，2930，2870，1719，1624，1591，1396，1383，1229，1155，1001，833；1H NMR(400MHz，CDCl3)δ13.38(s，1H)，7.30(s，1H)，6.32(s，1H)，4.38(d，J＝3.2Hz，1H)，3.92–3.87(m，1H)，1.95–1.90(m，1H)，1.62(s，3H)，1.46(s，3H)，1.43(s，3H)，1.39(s，3H)，1.25(t，J＝6.5Hz，6H)，0.83(d，J＝6.8Hz，3H)，0.78(d，J＝6.6Hz，3H)；13C NMR(100MHz，CDCl3)δ211.8，208.9，198.8，168.2，164.7，159.6，153.4，112.1，103.8，103.8，100.7，56.2，47.3，39.7，34.8，31.5，25.2，25.0，25.0，24.1，20.9，18.9，18.7，17.7；HRMS(ESI)C24H31O6[(M+H)+]415.2115 as a calculated molecular weight value; the molecular weight was found to be 415.2107. The synthetic route of the compound D is as follows:
(4) dissolving compound C (25mmol) in 100ml of 1, 2-dichloroethane to obtain a 1, 2-dichloroethane solution of compound C; adding 2, 6-lutidine (37.5mmol) and trifluoromethanesulfonic anhydride (37.5mmol) into a 1, 2-dichloroethane solution of compound C at 25 deg.C, heating to 84 deg.C, stirring for 3 hours, cooling to 25 deg.C, quenching with saturated aqueous sodium bicarbonate solution, extracting the obtained reaction solution with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, vacuum concentrating the organic phase, and purifying the concentrated organic phase with silica gel column chromatography to obtain 6.45g of compound E with a yield of 70%, wherein the detection data of compound E are as follows: IR (film) lambdamax2986，2944，2877，1730，1690，1633，1470，1449，1420，1176，1136，1020，936，837；1H NMR(500MHz，CDCl3)δ5.62(s，1H)，1.86(s，3H)，1.55(s，3H)，1.46(s，6H)，1.39(s，6H)；13C NMR(125MHz，CDCl3)δ208.8，197.7，162.3，144.4，127.1，122.2，119.7，117.1，114.6，113.6，57.4，49.0，25.6，24.6，23.5，20.0；HRMS(ESI)C15H20F3O5S[(M+H)+]369.0978 as a calculated molecular weight value; molecular weight found 369.0971. Synthesis route for Compound E is as follows:
(5) dissolving the compound E (15mmol) in 15 ml of tetrahydrofuran to obtain a tetrahydrofuran solution of the compound E; at 25 ℃, palladium acetate (0.3mmol), triphenylphosphine (0.6mmol), triethylamine (30mmol) and formic acid (30mmol) are respectively added into a tetrahydrofuran solution of E, the temperature is raised to 66 ℃, the mixture is stirred for 8 hours, the temperature is reduced to 25 ℃, then saturated aqueous sodium bicarbonate solution is used for quenching, the obtained reaction solution is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the sodium sulfate is removed by filtration, the organic phase is concentrated in vacuum, and finally the concentrated organic phase is purified by silica gel column chromatography to obtain 2.97g of a compound F, wherein the detection data of the compound F are as follows: IR (film) lambdamax2976，2936，2870，1719，1676，1638，1468，1379，1360，1302，1250，1042，854；1H NMR(400MHz，CDCl3)δ6.50(s，1H)，5.93(s，1H)，1.87(s，3H)，1.75(s，3H)，1.35(s，6H)，1.34(s，6H)；13C NMR(100MHz，CDCl3)δ213.4，201.1，149.3，138.5，132.5，118.9，57.5，45.1，27.5，26.6，23.7，19.5；HRMS(ESI)C14H21O2[(M+H)+]221.1536 as a calculated molecular weight value; the molecular weight was found to be 221.1533. The synthetic route for compound F is as follows:
(6) dissolving a compound F (9.6mmol) and a compound D (4.8mmol) in 48 ml of toluene to obtain a toluene solution of the compound F and the compound D; p-toluenesulfonic acid (1.2mmol) was added to a toluene solution of compound F and compound D at 25 ℃, then warmed to 60 ℃, stirred for 48 hours, then quenched with a saturated aqueous solution of sodium bicarbonate, the resulting reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, the concentrated organic phase was purified by silica gel column chromatography, and finally recrystallized in a mixed solution of methanol and dichloromethane to give 1.3G of compound G with a yield of 44%, wherein the detection data of compound G are as follows: rf＝0.35(hexane/ethyl acetate＝8/1)；IR(film)λmax3422，2955，2864，1717，1625，1598，1557，1431，1277，865；1H NMR(600MHz，CDCl3)δ14.05(s，1H)，4.15(d，J＝3.1Hz，1H)，3.91–3.84(m，1H)，3.44–3.40(m，1H)，3.39(d，J＝3.0Hz，1H)，1.94–1.90(m，1H)，1.88(dd，J＝12.1，6.6Hz，1H)，1.56(s，3H)，1.50(m，1H)，1.39(s，3H)，1.38(s，6H)，1.35(s，3H)，1.34(s，3H)，1.34(s，3H)，1.28(s，3H)，1.26(s，3H)，1.22(d，J＝6.9Hz，3H)，1.20(d，J＝7.0Hz，3H)，0.92(s，3H)，0.82(d，J＝7.0Hz，3H)，0.63(d，J＝6.9Hz，3H)；13C NMR(150MHz，CDCl3)δ218.1，212.5，209.3，197.6，167.5，163.4，154.6，151.7，113.1，110.8，105.8，104.7，102.8，85.3，56.1，54.1，51.3，47.5，39.7，39.1 37.4，35.0，34.7，31.2，29.8，28.7，28.7，25.6，25.3，25.2，25.0，24.2，24.0，21.2，21.1，19.5，18.1，16.9；HRMS(ESI)C38H51O8[(M+H)+]Calculated molecular weight: 635.3578, respectively; molecular weight found: 635.3575. the synthetic route for compound G is as follows:
(7) dissolving a compound G (0.24mmol) in 15 ml of a mixed solvent of ethanol and water (wherein the volume ratio of ethanol to water in the mixed solvent of ethanol and water is 6:1) to obtain a mixed solvent of ethanol and water of the compound G; adding potassium hydroxide (36mmol) into a mixed solvent of ethanol and water of a compound G at 25 ℃, then heating to 80 ℃, stirring for 6 hours, cooling to 25 ℃, then quenching with 1mol/L hydrochloric acid, extracting the obtained reaction liquid with ethyl acetate, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 70mg of the antibacterial drug, wherein the yield is 45%, and the detection data of the antibacterial drug are as follows: rf＝0.3(hexane/ethyl acetate＝8/1)；IR(film)λmax2977，2937，2874，1720，1703，1595，1556，1467，1384，1299，1092；1H NMR(500MHz，CDCl3)δ14.24(s，1H)，11.75(s，1H)，8.55(s，1H)，4.17–4.09(m，1H)，3.43(dd，J＝7.5，2.7Hz，1H)，3.38(d，J＝2.8Hz，1H)，3.27(d，J＝10.7Hz，1H)，2.89–2.80(m，1H)，1.91(dd，J＝12.2，7.0Hz，1H)，1.58–1.52(m，1H)，1.51(s，3H)，1.48(s，3H)，1.39(s，3H)，1.39(s，3H)，1.38(s，3H)，1.36(s，3H)，1.34(s，3H)，1.33(s，3H)，1.28(s，3H)，1.19(d，J＝6.8Hz，3H)，1.14(s，3H)，1.04(s，3H)，0.78(d，J＝6.4Hz，3H)，0.69(d，J＝6.4Hz，3H)；13C NMR(125MHz，CDCl3)δ217.6，212.6，212.4，202.7，176.6，163.8，159.7，156.3，115.5，114.6，106.0，104.4，100.4，86.1，55.1，53.6，50.4，48.6，41.7，39.8，38.9，37.1，35.3，30.7，28.7，28.6，27.4，25.7，25.7，25.6，25.4，24.8，24.0，22.2，21.9，20.3，19.8，19.4；HRMS(ESI)C38H53O9[(M+H)+]Calculated molecular weight: 653.3684, respectively; molecular weight found: 653.3672. the synthetic route of the antibacterial drug is as follows:
and (3) testing antibacterial activity:
1. the strain is as follows: staphylococcus aureus s.aureus ATCC 29213; methicillin-resistant staphylococcus aureus s.aureus ATCC33591 (MASA); vancomycin intermediate resistant staphylococcus aureus s.aureus Mu50 (VISA); staphylococcus epidermidis s ATCC 12228; enterococcus faecalis e.faecalis ATCC 29212; enterococcus faecium ATCC700221, from institute of medical and biotechnology, china academy of medical sciences.
2. Strain culture: the bacterial strains were cultured in Mueller-Hinton (MH) broth, and when they grew for 8-12 hours to about 0.5 Mcfarland concentration (1X 10)8CFU), obtaining a bacterial liquid for later use.
3. The experimental method comprises the following steps:
(1) dissolving the antibacterial agent of the present example in absolute ethanol, diluting to 1000. mu.g/mL with Tryptone Soya Broth (TSB) Broth, and continuing to dilute with the Broth to make the concentration of the antibacterial agent range from 256. mu.g/mL to 0.25. mu.g/mL to obtain a liquid medicine; in addition, vancomycin was prepared at a concentration ranging from 256. mu.g/mL to 0.25. mu.g/mL as a positive control.
(2) Adding 100 μ L of the medicinal liquid with concentration ranging from 256 μ g/mL to 0.25 μ g/mL and 100 μ L of the bacterial liquid into each well of a 96-well plate to make the final antibacterial drug concentration 5 × 104CFU, using tryptone soy broth medium plus bacteria solution as negative control (TSB medium, bacterial solution each 100 μ L), using TSB broth medium without bacteria solution as blank control (TSB medium 200 μ L), sealing 96-well plate, and placing at 37 deg.CIncubate for 20 hours in a warm incubator.
(3) Under the precondition that bacteria in the negative control holes obviously grow, the minimum inhibitory concentration of the drug is the minimum concentration of the drug, which is observed by naked eyes and has no obvious growth of the bacteria in the holes after the drug liquid is added, the experiment is repeated for three times in parallel, and the average value is taken.
4. Results of the experiment
Table 1 shows the in vitro antibacterial activity data of the antibacterial agent of this example and vancomycin as a positive control:
TABLE 1
As can be seen from Table 1, the antibacterial agent of the present example has significant antibacterial activity against enterococcus faecium, and the MIC value is 8 μ g/mL, which is stronger than the antibacterial activity of vancomycin, a positive control drug; the antibacterial agent has obvious antibacterial activity on staphylococcus aureus, methicillin-resistant staphylococcus aureus and vancomycin intermediate drug-resistant staphylococcus aureus, the MIC values are 1 mug/mL, 1 mug/mL and 2 mug/mL respectively, and the antibacterial activity of the antibacterial agent is equivalent to that of a positive control vancomycin; the antibacterial drug of the embodiment has moderate and strong antibacterial activity to staphylococcus epidermidis and enterococcus faecalis, and the MIC values are both 16 mug/mL, namely the antibacterial drug of the embodiment has good antibacterial activity and antibacterial effect.
Example 2
The preparation process of the antibacterial agent of this example is as follows:
(1) dissolving a compound A (102mmol) in 200 ml of absolute ethanol to obtain an ethanol solution of the compound A; adding anhydrous sodium methoxide powder (1224mmol) into an ethanol solution of the compound A at 35 ℃, stirring and mixing for 0.5 hour, cooling to-10 ℃, then adding methyl iodide (1632mmol), stirring and mixing for 0.5 hour, heating to 78 ℃, reacting at 78 ℃ for 12 hours, cooling to 35 ℃, then quenching the reaction by using 2mol/L hydrochloric acid, extracting the obtained reaction solution by using ethyl acetate, washing an organic phase by using saturated anhydrous sodium sulfite, drying the anhydrous sodium sulfate, filtering to remove the sodium sulfate, concentrating the organic phase in vacuum, and finally, adding anhydrous sodium methoxide powder (1224mmol) into the ethanol solution of the compound A, stirring and mixing for 0.5 hour, cooling to-10 ℃, then adding methylThe concentrated organic phase was purified by silica gel column chromatography to give 12.8g of compound B in 50% yield, wherein the detection data for compound B are as follows: IR (film) lambdamax3412，2962，2940，2876，1724，1672，1558，1474，1420，1314，1049，939；1H NMR(400MHz，CDCl3)δ3.84–3.74(m，1H)，1.43(s，6H)，1.35(s，6H)，1.17(s，3H)，1.16(s，3H)；13C NMR(100MHz，CDCl3)δ209.9，208.6，199.3，196.9，108.2，56.9，52.2，35.2，24.3，23.9，19.1；HRMS(ESI)C14H19O4[(M-H)-]Calculated molecular weight is 251.1289, found molecular weight is 251.1287. The synthetic route of the compound B is as follows:
(2) compound B (19.8mmol) was dissolved in 100ml of dichloromethane at 0 ℃ to give a dichloromethane solution of compound B; lithium diisopropylaluminum hydride (9.9mmol) was added to a dichloromethane solution of compound B at-78 deg.c, stirred for 60 minutes, then quenched with ethyl acetate, warmed to 0 deg.c, saturated aqueous sodium potassium tartrate solution was added, the resulting reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, and finally the concentrated organic phase was purified by silica gel column chromatography to give 1.4g of compound C in 30% yield, wherein the assay data for compound C is as follows: IR (film) lambdamax 2974，2938，2872，1717，1690，1676，1609，1464，1422，1385，1258，1098，945，804；1H NMR(400MHz，CDCl3)δ7.29(d，J＝1.0Hz，1H)，3.42–3.33(m，1H)，1.34(s，6H)，1.33(s，6H)，1.13(d，J＝6.6Hz，6H)；13C NMR(100MHz，CDCl3)δ208.8，199.8，196.6，164.9，130.6，58.5，58.2，28.6，22.3，21.9，21.8；HRMS(ESI)C14H21O3[(M+H)+]237.1483 as a calculated molecular weight value; the molecular weight was found to be 237.1491. The synthetic route of the compound C is as follows:
(3) dissolving compound A (40mmol) and compound C (80mmol) in 80 ml of toluene to obtain a toluene solution of compound A and compound C, adding p-toluenesulfonic acid (2mmol), stirring at 25 ℃ for 10 hours, quenching with saturated aqueous sodium bicarbonate, extracting the obtained reaction solution with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, vacuum concentrating the organic phase, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 5.9g of compound D with a yield of 35%, wherein the detection data of compound D are as follows: IR (film) lambdamax3240，2969，2930，2870，1719，1624，1591，1396，1383，1229，1155，1001，833；1H NMR(400MHz，CDCl3)δ13.38(s，1H)，7.30(s，1H)，6.32(s，1H)，4.38(d，J＝3.2Hz，1H)，3.92–3.87(m，1H)，1.95–1.90(m，1H)，1.62(s，3H)，1.46(s，3H)，1.43(s，3H)，1.39(s，3H)，1.25(t，J＝6.5Hz，6H)，0.83(d，J＝6.8Hz，3H)，0.78(d，J＝6.6Hz，3H)；13C NMR(100MHz，CDCl3)δ211.8，208.9，198.8，168.2，164.7，159.6，153.4，112.1，103.8，103.8，100.7，56.2，47.3，39.7，34.8，31.5，25.2，25.0，25.0，24.1，20.9，18.9，18.7，17.7；HRMS(ESI)C24H31O6[(M+H)+]415.2115 as a calculated molecular weight value; the molecular weight was found to be 415.2107. The synthetic route of the compound D is as follows:
(4) dissolving compound C (25mmol) in 100ml of 1, 2-dichloroethane to obtain a 1, 2-dichloroethane solution of compound C; adding pyridine (25mmol) and trifluoromethanesulfonic anhydride (37.5mmol) into 1, 2-dichloroethane solution of compound C at 25 deg.C, heating to 84 deg.C, stirring for 3 hr, cooling to 25 deg.C, and quenching with saturated aqueous solution of sodium bicarbonate to obtain the final productThe reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, and finally the concentrated organic phase was purified by silica gel column chromatography to give 4.1g of compound E, with a yield of 45%, wherein the detection data for compound E are as follows: ir (film) λ max2986, 2944, 2877, 1730, 1690, 1633, 1470, 1449, 1420, 1176, 1136, 1020, 936, 837;1H NMR(500MHz，CDCl3)δ5.62(s，1H)，1.86(s，3H)，1.55(s，3H)，1.46(s，6H)，1.39(s，6H)；13C NMR(125MHz，CDCl3)δ208.8，197.7，162.3，144.4，127.1，122.2，119.7，117.1，114.6，113.6，57.4，49.0，25.6，24.6，23.5，20.0；HRMS(ESI)C15H20F3O5S[(M+H)+]369.0978 as a calculated molecular weight value; the molecular weight was found to be 369.0971. The synthetic route for compound E is as follows:
(5) dissolving the compound E (15mmol) in 150 ml of N, N-dimethylformamide to obtain an N, N-dimethylformamide solution of the compound E; at 25 ℃, palladium acetate (0.3mmol), triphenylphosphine (0.6mmol), triethylamine (30mmol) and formic acid (30mmol) are respectively added into an N, N-dimethylformamide solution of E, the temperature is raised to 60 ℃, stirring is carried out for 8 hours, the temperature is reduced to 25 ℃, then saturated sodium bicarbonate aqueous solution is used for quenching, the obtained reaction solution is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, sodium sulfate is removed by filtration, the organic phase is concentrated in vacuum, and finally the concentrated organic phase is purified by silica gel column chromatography to obtain 1.19g of compound F, wherein the detection data of the compound F are as follows: IR (film) lambdamax2976，2936，2870，1719，1676，1638，1468，1379，1360，1302，1250，1042，854；1H NMR(400MHz，CDCl3)δ6.50(s，1H)，5.93(s，1H)，1.87(s，3H)，1.75(s，3H)，1.35(s，6H)，1.34(s，6H)；13C NMR(100MHz，CDCl3)δ213.4，201.1，149.3，138.5，132.5，118.9，57.5，45.1，27.5，26.6，23.7，19.5；HRMS(ESI)C14H21O2[(M+H)+]221.1536 as a calculated molecular weight value; the molecular weight was found to be 221.1533. The synthetic route for compound F is as follows:
(6) dissolving compound F (7.2mmol) and compound D (4.8mmol) in 48 ml of dichloroethane to give a dichloroethane solution of compound F and compound D; p-toluenesulfonic acid (7.2mmol) was added to a dichloroethane solution of compound F and compound D at 30 ℃, then warmed to 50 ℃, stirred for 18 hours, then quenched with a saturated aqueous solution of sodium bicarbonate, the resulting reaction solution was extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, the concentrated organic phase was purified by silica gel column chromatography, and finally recrystallized in a mixed solution of methanol and dichloromethane to give 274mg of compound G with a yield of 9%, wherein the detection data of compound G are as follows: rf＝0.35(hexane/ethyl acetate＝8/1)；IR(film)λmax3422，2955，2864，1717，1625，1598，1557，1431，1277，865；1H NMR(600MHz，CDCl3)δ14.05(s，1H)，4.15(d，J＝3.1Hz，1H)，3.91–3.84(m，1H)，3.44–3.40(m，1H)，3.39(d，J＝3.0Hz，1H)，1.94–1.90(m，1H)，1.88(dd，J＝12.1，6.6Hz，1H)，1.56(s，3H)，1.50(m，1H)，1.39(s，3H)，1.38(s，6H)，1.35(s，3H)，1.34(s，3H)，1.34(s，3H)，1.28(s，3H)，1.26(s，3H)，1.22(d，J＝6.9Hz，3H)，1.20(d，J＝7.0Hz，3H)，0.92(s，3H)，0.82(d，J＝7.0Hz，3H)，0.63(d，J＝6.9Hz，3H)；13C NMR(150MHz，CDCl3)δ218.1，212.5，209.3，197.6，167.5，163.4，154.6，151.7，113.1，110.8，105.8，104.7，102.8，85.3，56.1，54.1，51.3，47.5，39.7，39.1 37.4，35.0，34.7，31.2，29.8，28.7，28.7，25.6，25.3，25.2，25.0，24.2，24.0，21.2，21.1，19.5，18.1，16.9；HRMS(ESI)C38H51O8[(M+H)+]Calculated molecular weight: 635.3578, respectively; molecular weight found: 635.3575. the synthetic route for compound G is as follows:
(7) dissolving a compound G (0.24mmol) in 15 ml of a mixed solvent of methanol and water (wherein the volume ratio of methanol to water is 6:1) to obtain a mixed solvent of methanol and water of the compound G; adding potassium hydroxide (36mmol) into a mixed solvent of methanol and water of a compound G at 40 ℃, then heating to 80 ℃, stirring for 12 hours, cooling to 40 ℃, then quenching with 1mol/L hydrochloric acid, extracting the obtained reaction liquid with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering to remove the sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 46.7mg of the antibacterial drug with the yield of 30%, wherein the detection data of the antibacterial drug are as follows: rf＝0.3(hexane/ethyl acetate＝8/1)；IR(film)λmax2977，2937，2874，1720，1703，1595，1556，1467，1384，1299，1092；1H NMR(500MHz，CDCl3)δ14.24(s，1H)，11.75(s，1H)，8.55(s，1H)，4.17–4.09(m，1H)，3.43(dd，J＝7.5，2.7Hz，1H)，3.38(d，J＝2.8Hz，1H)，3.27(d，J＝10.7Hz，1H)，2.89–2.80(m，1H)，1.91(dd，J＝12.2，7.0Hz，1H)，1.58–1.52(m，1H)，1.51(s，3H)，1.48(s，3H)，1.39(s，3H)，1.39(s，3H)，1.38(s，3H)，1.36(s，3H)，1.34(s，3H)，1.33(s，3H)，1.28(s，3H)，1.19(d，J＝6.8Hz，3H)，1.14(s，3H)，1.04(s，3H)，0.78(d，J＝6.4Hz，3H)，0.69(d，J＝6.4Hz，3H)；13C NMR(125MHz，CDCl3)δ217.6，212.6，212.4，202.7，176.6，163.8，159.7，156.3，115.5，114.6，106.0，104.4，100.4，86.1，55.1，53.6，50.4，48.6，41.7，39.8，38.9，37.1，35.3，30.7，28.7，28.6，27.4，25.7，25.7，25.6，25.4，24.8，24.0，22.2，21.9，20.3，19.8，19.4；HRMS(ESI)C38H53O9[(M+H)+]Calculated molecular weight: 653.3684, respectively; is divided intoMeasured values of the quantum: 653.3672. the synthetic route of the antibacterial drug is as follows:
example 3
The preparation process of the antibacterial agent of this example is as follows:
(1) dissolving a compound A (102mmol) in 240 ml of a mixed solution of anhydrous methanol and anhydrous ethanol (the volume ratio of the anhydrous methanol to the anhydrous ethanol is 1:1) to obtain an organic solution of the compound A; adding anhydrous sodium methoxide powder (816mmol) into an organic solution of the compound A at the temperature of 20 ℃, stirring and mixing for 0.5 hour, cooling to 0 ℃, then adding iodomethane (1430mmol), stirring and mixing for 0.5 hour, heating to 75 ℃, reacting at 75 ℃ for 8 hours, cooling to 20 ℃, then quenching the reaction by using 2mol/L hydrochloric acid, extracting the obtained reaction solution by using ethyl acetate, washing an organic phase by using an aqueous solution of saturated sodium sulfite, drying anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by using a silica gel column chromatography to obtain 15.4g of the compound B with the yield of 60%, wherein the detection data of the compound B are as follows: IR (film) lambdamax3412，2962，2940，2876，1724，1672，1558，1474，1420，1314，1049，939；1H NMR(400MHz，CDCl3)δ3.84–3.74(m，1H)，1.43(s，6H)，1.35(s，6H)，1.17(s，3H)，1.16(s，3H)；13C NMR(100MHz，CDCl3)δ209.9，208.6，199.3，196.9，108.2，56.9，52.2，35.2，24.3，23.9，19.1；HRMS(ESI)C14H19O4[(M-H)-]Calculated molecular weight is 251.1289, found molecular weight is 251.1287. The synthetic route of the compound B is as follows:
(2) compound B (19.8mmol) was dissolved in 200 ml of toluene at 40 ℃ to give a toluene solution of compound B; lithium diisopropylhydride (49) was added at-78 deg.C5mmol) of compound B in toluene was added, stirred for 20 minutes, then quenched with ethyl acetate, warmed to 35 ℃, saturated aqueous sodium potassium tartrate solution was added, the resulting reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, and finally the concentrated organic phase was purified by silica gel column chromatography to give 1.89g of compound C, 41% yield, wherein the detection data of compound C are as follows: IR (film) lambdamax 2974，2938，2872，1717，1690，1676，1609，1464，1422，1385，1258，1098，945，804；1H NMR(400MHz，CDCl3)δ7.29(d，J＝1.0Hz，1H)，3.42–3.33(m，1H)，1.34(s，6H)，1.33(s，6H)，1.13(d，J＝6.6Hz，6H)；13C NMR(100MHz，CDCl3)δ208.8，199.8，196.6，164.9，130.6，58.5，58.2，28.6，22.3，21.9，21.8；HRMS(ESI)C14H21O3[(M+H)+]237.1483 as a calculated molecular weight value; the molecular weight was found to be 237.1491. The synthetic route of the compound C is as follows:
(3) dissolving a compound A (40mmol) and a compound C (200mmol) in 100ml of dichloromethane to obtain a chloroform solution of the compound A and the compound C, then adding p-toluenesulfonic acid (60mmol), stirring and reacting at 25 ℃ for 10 hours, then quenching with a saturated aqueous solution of sodium bicarbonate, extracting the obtained reaction solution with dichloromethane, drying an organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 13.2g of a compound D with a yield of 79%, wherein the detection data of the compound D are as follows: IR (film) lambdamax3240，2969，2930，2870，1719，1624，1591，1396，1383，1229，1155，1001，833；1H NMR(400MHz，CDCl3)δ13.38(s，1H)，7.30(s，1H)，6.32(s，1H)，4.38(d，J＝3.2Hz，1H)，3.92–3.87(m，1H)，1.95–1.90(m，1H)，1.62(s，3H)，1.46(s，3H)，1.43(s，3H)，1.39(s，3H)，1.25(t，J＝6.5Hz，6H)，0.83(d，J＝6.8Hz，3H)，0.78(d，J＝6.6Hz，3H)；13C NMR(100MHz，CDCl3)δ211.8，208.9，198.8，168.2，164.7，159.6，153.4，112.1，103.8，103.8，100.7，56.2，47.3，39.7，34.8，31.5，25.2，25.0，25.0，24.1，20.9，18.9，18.7，17.7；HRMS(ESI)C24H31O6[(M+H)+]415.2115 as a calculated molecular weight value; the molecular weight was found to be 415.2107. The synthetic route of the compound D is as follows:
(4) dissolving compound C (25mmol) in 100ml of 1, 2-dichloroethane to obtain a 1, 2-dichloroethane solution of compound C; adding triethylamine (50mmol) and trifluoromethanesulfonic anhydride (37.5mmol) into a 1, 2-dichloroethane solution of a compound C at 25 ℃, heating to 90 ℃, stirring for 3 hours, cooling to normal temperature, then quenching with a saturated aqueous solution of sodium bicarbonate, extracting the obtained reaction solution with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 3.87g of a compound E with a yield of 70%, wherein the detection data of the compound E are as follows: IR (film) lambdamax2986，2944，2877，1730，1690，1633，1470，1449，1420，1176，1136，1020，936，837；1H NMR(500MHz，CDCl3)δ5.62(s，1H)，1.86(s，3H)，1.55(s，3H)，1.46(s，6H)，1.39(s，6H)；13C NMR(125MHz，CDCl3)δ208.8，197.7，162.3，144.4，127.1，122.2，119.7，117.1，114.6，113.6，57.4，49.0，25.6，24.6，23.5，20.0；HRMS(ESI)C15H20F3O5S[(M+H)+]369.0978 as a calculated molecular weight value; the molecular weight was found to be 369.0971. The synthetic route for compound E is as follows:
(5) dissolving the compound E (15mmol) in 150 ml of tetrahydrofuran to obtain a tetrahydrofuran solution of the compound E; at 25 ℃, palladium acetate (0.3mmol), triphenylphosphine (0.6mmol), triethylamine (30mmol) and formic acid (30mmol) are respectively added into a tetrahydrofuran solution of E, the temperature is raised to 50 ℃, the mixture is stirred for 8 hours, the temperature is reduced to 25 ℃, then saturated aqueous sodium bicarbonate solution is used for quenching, the obtained reaction solution is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the sodium sulfate is removed by filtration, the organic phase is concentrated in vacuum, and finally the concentrated organic phase is purified by silica gel column chromatography to obtain 2.6g of compound F, the yield is 79%, wherein the detection data of the compound F are as follows: IR (film) lambdamax2976，2936，2870，1719，1676，1638，1468，1379，1360，1302，1250，1042，854；1H NMR(400MHz，CDCl3)δ6.50(s，1H)，5.93(s，1H)，1.87(s，3H)，1.75(s，3H)，1.35(s，6H)，1.34(s，6H)；13C NMR(100MHz，CDCl3)δ213.4，201.1，149.3，138.5，132.5，118.9，57.5，45.1，27.5，26.6，23.7，19.5；HRMS(ESI)C14H21O2[(M+H)+]221.1536 as a calculated molecular weight value; the molecular weight was found to be 221.1533. The synthetic route for compound F is as follows:
(6) dissolving a compound F (7.2mmol) and a compound D (4.8mmol) in 48 ml of toluene to obtain a toluene solution of the compound F and the compound D; p-toluenesulfonic acid (4.8mmol) was added to a toluene solution of compound F and compound D at 0 ℃, then warmed to 110 ℃, stirred for 15 minutes, then quenched with a saturated aqueous solution of sodium bicarbonate, the resulting reaction solution was extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, the concentrated organic phase was purified by silica gel column chromatography, and finally recrystallized in a mixed solution of methanol and dichloromethane to give 186mg of compound G with a yield of 6.2%, wherein the detection data for compound G are as follows: rf＝0.35(hexane/ethyl acetate＝8/1)；IR(film)λmax3422，2955，2864，1717，1625，1598，1557，1431，1277，865；1H NMR(600MHz，CDCl3)δ14.05(s，1H)，4.15(d，J＝3.1Hz，1H)，3.91–3.84(m，1H)，3.44–3.40(m，1H)，3.39(d，J＝3.0Hz，1H)，1.94–1.90(m，1H)，1.88(dd，J＝12.1，6.6Hz，1H)，1.56(s，3H)，1.50(m，1H)，1.39(s，3H)，1.38(s，6H)，1.35(s，3H)，1.34(s，3H)，1.34(s，3H)，1.28(s，3H)，1.26(s，3H)，1.22(d，J＝6.9Hz，3H)，1.20(d，J＝7.0Hz，3H)，0.92(s，3H)，0.82(d，J＝7.0Hz，3H)，0.63(d，J＝6.9Hz，3H)；13C NMR(150MHz，CDCl3)δ218.1，212.5，209.3，197.6，167.5，163.4，154.6，151.7，113.1，110.8，105.8，104.7，102.8，85.3，56.1，54.1，51.3，47.5，39.7，39.1 37.4，35.0，34.7，31.2，29.8，28.7，28.7，25.6，25.3，25.2，25.0，24.2，24.0，21.2，21.1，19.5，18.1，16.9；HRMS(ESI)C38H51O8[(M+H)+]Calculated molecular weight: 635.3578, respectively; molecular weight found: 635.3575. the synthetic route for compound G is as follows:
(7) dissolving a compound G (0.24mmol) in 5 ml of a mixed solvent of propanol and water (wherein, the volume ratio of the propanol to the water is 6:1) to obtain the mixed solvent of the propanol and the water of the compound G; adding potassium hydroxide (12mmol) into a mixed solvent of propanol and water of a compound G at 40 ℃, heating to 90 ℃, stirring for 3 hours, cooling to 40 ℃, then quenching with 1mol/L hydrochloric acid, extracting the obtained reaction solution with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering to remove the sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 31mg of the antibacterial agent with the yield of 20%, wherein the detection data of the antibacterial agent are as follows: rf＝0.3(hexane/ethyl acetate＝8/1)；IR(film)λmax2977，2937，2874，1720，1703，1595，1556，1467，1384，1299，1092；1H NMR(500MHz，CDCl3)δ14.24(s，1H)，11.75(s，1H)，8.55(s，1H)，4.17–4.09(m，1H)，3.43(dd，J＝7.5，2.7Hz，1H)，3.38(d，J＝2.8Hz，1H)，3.27(d，J＝10.7Hz，1H)，2.89–2.80(m，1H)，1.91(dd，J＝12.2，7.0Hz，1H)，1.58–1.52(m，1H)，1.51(s，3H)，1.48(s，3H)，1.39(s，3H)，1.39(s，3H)，1.38(s，3H)，1.36(s，3H)，1.34(s，3H)，1.33(s，3H)，1.28(s，3H)，1.19(d，J＝6.8Hz，3H)，1.14(s，3H)，1.04(s，3H)，0.78(d，J＝6.4Hz，3H)，0.69(d，J＝6.4Hz，3H)；13C NMR(125MHz，CDCl3)δ217.6，212.6，212.4，202.7，176.6，163.8，159.7，156.3，115.5，114.6，106.0，104.4，100.4，86.1，55.1，53.6，50.4，48.6，41.7，39.8，38.9，37.1，35.3，30.7，28.7，28.6，27.4，25.7，25.7，25.6，25.4，24.8，24.0，22.2，21.9，20.3，19.8，19.4；HRMS(ESI)C38H53O9[(M+H)+]Calculated molecular weight: 653.3684, respectively; molecular weight found: 653.3672. the synthetic route of the antibacterial drug is as follows:
example 4
The preparation process of the antibacterial agent of this example is as follows:
(1) dissolving compound A (102mmol) in 240 ml of anhydrous propanol to obtain a propanol solution of compound A; adding anhydrous sodium methoxide powder (816mmol) into propanol solution of compound A at 0 deg.C, stirring and mixing for 0.5 hr, adding iodomethane (1430mmol), stirring and mixing for 0.5 hr, heating to 80 deg.C, reacting at 80 deg.C for 8 hr, cooling to 0 deg.C, quenching with 2mol/L hydrochloric acid to obtain reaction solution, extracting with ethyl acetate, washing organic phase with saturated aqueous solution of sodium sulfite, drying anhydrous sodium sulfate, filtering to remove sodium sulfate, vacuum concentrating the organic phase, and purifying the concentrated organic phase with silica gel column chromatography to obtain 12.0g of compound B with 46% yield, wherein the detection data of compound B such asThe following: IR (film) lambdamax3412，2962，2940，2876，1724，1672，1558，1474，1420，1314，1049，939；1H NMR(400MHz，CDCl3)δ3.84–3.74(m，1H)，1.43(s，6H)，1.35(s，6H)，1.17(s，3H)，1.16(s，3H)；13C NMR(100MHz，CDCl3)δ209.9，208.6，199.3，196.9，108.2，56.9，52.2，35.2，24.3，23.9，19.1；HRMS(ESI)C14H19O4[(M-H)-]Calculated molecular weight is 251.1289, found molecular weight is 251.1287. The synthetic route of the compound B is as follows:
(2) compound B (19.8mmol) was dissolved in 200 ml of tetrahydrofuran at 25 ℃ to give a tetrahydrofuran solution of compound B; lithium aluminum tri-tert-butoxyhydride (20mmol) was added to a tetrahydrofuran solution of compound B at-78 deg.c, stirred for 20 minutes, then quenched with ethyl acetate, warmed to 25 deg.c, a saturated aqueous solution of sodium potassium tartrate was added, the resulting reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, and finally the concentrated organic phase was purified by silica gel column chromatography to give 3.5g of compound C, in 75% yield, wherein the assay data for compound C is as follows: IR (film) lambdamax 2974，2938，2872，1717，1690，1676，1609，1464，1422，1385，1258，1098，945，804；1H NMR(400MHz，CDCl3)δ7.29(d，J＝1.0Hz，1H)，3.42–3.33(m，1H)，1.34(s，6H)，1.33(s，6H)，1.13(d，J＝6.6Hz，6H)；13C NMR(100MHz，CDCl3)δ208.8，199.8，196.6，164.9，130.6，58.5，58.2，28.6，22.3，21.9，21.8；HRMS(ESI)C14H21O3[(M+H)+]237.1483 as a calculated molecular weight value; the molecular weight was found to be 237.1491. The synthetic route of the compound C is as follows:
(3) dissolving a compound A (40mmol) and a compound C (80mmol) in 120 ml of dichloromethane to obtain a dichloromethane solution of the compound A and the compound C, adding p-toluenesulfonic acid (60mmol), stirring and reacting at 0 ℃ for 12 hours, then quenching with a saturated aqueous solution of sodium bicarbonate, extracting the obtained reaction solution with dichloromethane, drying an organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 9.8g of a compound D with a yield of 63%, wherein the detection data of the compound D are as follows: IR (film) lambdamax3240，2969，2930，2870，1719，1624，1591，1396，1383，1229，1155，1001，833；1H NMR(400MHz，CDCl3)δ13.38(s，1H)，7.30(s，1H)，6.32(s，1H)，4.38(d，J＝3.2Hz，1H)，3.92–3.87(m，1H)，1.95–1.90(m，1H)，1.62(s，3H)，1.46(s，3H)，1.43(s，3H)，1.39(s，3H)，1.25(t，J＝6.5Hz，6H)，0.83(d，J＝6.8Hz，3H)，0.78(d，J＝6.6Hz，3H)；13C NMR(100MHz，CDCl3)δ211.8，208.9，198.8，168.2，164.7，159.6，153.4，112.1，103.8，103.8，100.7，56.2，47.3，39.7，34.8，31.5，25.2，25.0，25.0，24.1，20.9，18.9，18.7，17.7；HRMS(ESI)C24H31O6[(M+H)+]415.2115 as a calculated molecular weight value; the molecular weight was found to be 415.2107. The synthetic route of the compound D is as follows:
(4) dissolving compound C (25mmol) in 100ml of dichloromethane to obtain a dichloromethane solution of compound C; adding 2, 6-dimethylpyridine (37.5mmol) and trifluoromethanesulfonyl chloride (50mmol) into dichloromethane solution of compound C at 25 deg.C, heating to 40 deg.C, stirring for 15 hr, cooling to room temperature, quenching with saturated aqueous solution of sodium bicarbonate, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, and collecting the organic phaseThe phases are concentrated in vacuo and the concentrated organic phase is finally purified by column chromatography on silica gel to give 4.5g of compound E in 49% yield, where the data for the detection of compound E are as follows: IR (film) lambdamax2986，2944，2877，1730，1690，1633，1470，1449，1420，1176，1136，1020，936，837；1H NMR(500MHz，CDCl3)δ5.62(s，1H)，1.86(s，3H)，1.55(s，3H)，1.46(s，6H)，1.39(s，6H)；13C NMR(125MHz，CDCl3)δ208.8，197.7，162.3，144.4，127.1，122.2，119.7，117.1，114.6，113.6，57.4，49.0，25.6，24.6，23.5，20.0；HRMS(ESI)C15H20F3O5S[(M+H)+]369.0978 as a calculated molecular weight value; the molecular weight was found to be 369.0971. The synthetic route for compound E is as follows:
(5) dissolving the compound E (15mmol) in 150 ml of tetrahydrofuran to obtain a tetrahydrofuran solution of the compound E; at 25 ℃, palladium acetate (0.3mmol), triphenylphosphine (0.6mmol), triethylamine (45mmol) and formic acid (45mmol) are respectively added into a tetrahydrofuran solution of E, the temperature is raised to 50 ℃, the mixture is stirred for 15 hours, the temperature is reduced to 25 ℃, then saturated aqueous sodium bicarbonate solution is used for quenching, the obtained reaction solution is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the sodium sulfate is removed by filtration, the organic phase is concentrated in vacuum, and finally the concentrated organic phase is purified by silica gel column chromatography to obtain 2.54g of a compound F, wherein the detection data of the compound F are as follows: IR (film) lambdamax2976，2936，2870，1719，1676，1638，1468，1379，1360，1302，1250，1042，854；1H NMR(400MHz，CDCl3)δ6.50(s，1H)，5.93(s，1H)，1.87(s，3H)，1.75(s，3H)，1.35(s，6H)，1.34(s，6H)；13C NMR(100MHz，CDCl3)δ213.4，201.1，149.3，138.5，132.5，118.9，57.5，45.1，27.5，26.6，23.7，19.5；HRMS(ESI)C14H21O2[(M+H)+]221.1536 as a calculated molecular weight value; actual measurement of molecular weightValue 221.1533. The synthetic route for compound F is as follows:
(6) dissolving a compound F (9.6mmol) and a compound D (4.8mmol) in 48 ml of chloroform to obtain a chloroform solution of the compound F and the compound D; p-toluenesulfonic acid (7.2mmol) was added to a chloroform solution of compound F and compound D at 40 ℃, then warmed to 50 ℃, stirred for 18 hours, then quenched with a saturated aqueous solution of sodium bicarbonate, the resulting reaction solution was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, the concentrated organic phase was purified by silica gel column chromatography, and finally recrystallized in a mixed solution of methanol and dichloromethane to give 296mg of compound G with a yield of 10%, wherein the detection data of compound G are as follows: rf＝0.35(hexane/ethyl acetate＝8/1)；IR(film)λmax3422，2955，2864，1717，1625，1598，1557，1431，1277，865；1H NMR(600MHz，CDCl3)δ14.05(s，1H)，4.15(d，J＝3.1Hz，1H)，3.91–3.84(m，1H)，3.44–3.40(m，1H)，3.39(d，J＝3.0Hz，1H)，1.94–1.90(m，1H)，1.88(dd，J＝12.1，6.6Hz，1H)，1.56(s，3H)，1.50(m，1H)，1.39(s，3H)，1.38(s，6H)，1.35(s，3H)，1.34(s，3H)，1.34(s，3H)，1.28(s，3H)，1.26(s，3H)，1.22(d，J＝6.9Hz，3H)，1.20(d，J＝7.0Hz，3H)，0.92(s，3H)，0.82(d，J＝7.0Hz，3H)，0.63(d，J＝6.9Hz，3H)；13C NMR(150MHz，CDCl3)δ218.1，212.5，209.3，197.6，167.5，163.4，154.6，151.7，113.1，110.8，105.8，104.7，102.8，85.3，56.1，54.1，51.3，47.5，39.7，39.137.4，35.0，34.7，31.2，29.8，28.7，28.7，25.6，25.3，25.2，25.0，24.2，24.0，21.2，21.1，19.5，18.1，16.9；HRMS(ESI)C38H51O8[(M+H)+]Calculated molecular weight: 635.3578, respectively; molecular weight found: 635.3575. the synthetic route for compound G is as follows:
(7) dissolving a compound G (0.24mmol) in 12 ml of a mixed solvent of ethanol and water (wherein, the volume ratio of ethanol to water is 5:1) to obtain the mixed solvent of ethanol and water of the compound G; adding potassium hydroxide (36mmol) into a mixed solvent of ethanol and water of a compound G at the temperature of 0 ℃, then heating to 80 ℃, stirring for 12 hours, cooling to 0 ℃, then quenching with 1mol/L hydrochloric acid, extracting the obtained reaction liquid with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering to remove the sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 54.4mg of the antibacterial drug with the yield of 35%, wherein the detection data of the antibacterial drug are as follows: rf＝0.3(hexane/ethyl acetate＝8/1)；IR(film)λmax2977，2937，2874，1720，1703，1595，1556，1467，1384，1299，1092；1H NMR(500MHz，CDCl3)δ14.24(s，1H)，11.75(s，1H)，8.55(s，1H)，4.17–4.09(m，1H)，3.43(dd，J＝7.5，2.7Hz，1H)，3.38(d，J＝2.8Hz，1H)，3.27(d，J＝10.7Hz，1H)，2.89–2.80(m，1H)，1.91(dd，J＝12.2，7.0Hz，1H)，1.58–1.52(m，1H)，1.51(s，3H)，1.48(s，3H)，1.39(s，3H)，1.39(s，3H)，1.38(s，3H)，1.36(s，3H)，1.34(s，3H)，1.33(s，3H)，1.28(s，3H)，1.19(d，J＝6.8Hz，3H)，1.14(s，3H)，1.04(s，3H)，0.78(d，J＝6.4Hz，3H)，0.69(d，J＝6.4Hz，3H)；13C NMR(125MHz，CDCl3)δ217.6，212.6，212.4，202.7，176.6，163.8，159.7，156.3，115.5，114.6，106.0，104.4，100.4，86.1，55.1，53.6，50.4，48.6，41.7，39.8，38.9，37.1，35.3，30.7，28.7，28.6，27.4，25.7，25.7，25.6，25.4，24.8，24.0，22.2，21.9，20.3，19.8，19.4；HRMS(ESI)C38H53O9[(M+H)+]Calculated molecular weight: 653.3684, respectively; molecular weight found: 653.3672. the synthetic route of the antibacterial drug is as follows:
example 5
The preparation process of the antibacterial agent of this example is as follows:
(1) dissolving compound A (102mmol) in 240 ml of anhydrous methanol to obtain a methanol solution of compound A; adding anhydrous sodium methoxide powder (510mmol) into a methanol solution of the compound A at the temperature of 25 ℃, stirring and mixing for 0.5 hour, cooling to 5 ℃, adding iodomethane (714mmol), stirring and mixing for 0.5 hour, then heating to 50 ℃, reacting at 50 ℃ for 15 hours, cooling to 25 ℃, then quenching the reaction by using 2mol/L hydrochloric acid, extracting the obtained reaction liquid by using ethyl acetate, washing an organic phase by using an aqueous solution of saturated sodium sulfite, drying anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by using a silica gel column chromatography to obtain 12.3g of the compound B with the yield of 48%, wherein the detection data of the compound B are as follows: IR (film) lambdamax3412，2962，2940，2876，1724，1672，1558，1474，1420，1314，1049，939；1H NMR(400MHz，CDCl3)δ3.84–3.74(m，1H)，1.43(s，6H)，1.35(s，6H)，1.17(s，3H)，1.16(s，3H)；13C NMR(100MHz，CDCl3)δ209.9，208.6，199.3，196.9，108.2，56.9，52.2，35.2，24.3，23.9，19.1；HRMS(ESI)C14H19O4[(M-H)-]Calculated molecular weight is 251.1289, found molecular weight is 251.1287. The synthetic route of the compound B is as follows:
(2) compound B (19.8mmol) was dissolved in 120 ml of tetrahydrofuran at 10 ℃ to give a tetrahydrofuran solution of compound B; adding lithium diisopropylhydride aluminum (23.8mmol) into tetrahydrofuran solution of compound B at-70 deg.C, stirring for 20 min, quenching with ethyl acetate, heating to 25 deg.C, adding saturated aqueous solution of sodium potassium tartrate, extracting the obtained reaction solution with ethyl acetate to obtain extractThe organic phase is dried over anhydrous sodium sulfate, filtered to remove the sodium sulfate, the organic phase is concentrated in vacuo and the concentrated organic phase is finally purified by column chromatography on silica gel to give 3.8g of compound C in 82% yield, where the data for the detection of compound C are as follows: IR (film) lambdamax 2974，2938，2872，1717，1690，1676，1609，1464，1422，1385，1258，1098，945，804；1H NMR(400MHz，CDCl3)δ7.29(d，J＝1.0Hz，1H)，3.42–3.33(m，1H)，1.34(s，6H)，1.33(s，6H)，1.13(d，J＝6.6Hz，6H)；13C NMR(100MHz，CDCl3)δ208.8，199.8，196.6，164.9，130.6，58.5，58.2，28.6，22.3，21.9，21.8；HRMS(ESI)C14H21O3[(M+H)+]237.1483 as a calculated molecular weight value; the molecular weight was found to be 237.1491. The synthetic route of the compound C is as follows:
(3) dissolving a compound A (40mmol) and a compound C (80mmol) in 100ml of dichloromethane to obtain a dichloromethane solution of the compound A and the compound C, stirring for 5 hours, adding trifluoroacetic acid (40mmol), stirring at 25 ℃ for reaction for 10 hours, quenching with saturated aqueous sodium bicarbonate, extracting the obtained reaction solution with dichloromethane, drying an organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 4.8g of a compound D with a yield of 29%, wherein the detection data of the compound D are as follows:
IR(film)λmax3240，2969，2930，2870，1719，1624，1591，1396，1383，1229，1155，1001，833；1H NMR(400MHz，CDCl3)δ13.38(s，1H)，7.30(s，1H)，6.32(s，1H)，4.38(d，J＝3.2Hz，1H)，3.92–3.87(m，1H)，1.95–1.90(m，1H)，1.62(s，3H)，1.46(s，3H)，1.43(s，3H)，1.39(s，3H)，1.25(t，J＝6.5Hz，6H)，0.83(d，J＝6.8Hz，3H)，0.78(d，J＝6.6Hz，3H)；13C NMR(100MHz，CDCl3)δ211.8，208.9，198.8，168.2，164.7，159.6，153.4，112.1，103.8，103.8，100.7，56.2，47.3，39.7，34.8，31.5，25.2，25.0，25.0，24.1，20.9，18.9，18.7，17.7；HRMS(ESI)C24H31O6[(M+H)+]415.2115 as a calculated molecular weight value; the molecular weight was found to be 415.2107.
The synthetic route of the compound D is as follows:
(4) dissolving compound C (25mmol) in 100ml of chloroform to obtain a chloroform solution of compound C; adding 2, 6-lutidine (37.5mmol) and trifluoromethanesulfonic anhydride (25mmol) into chloroform solution of compound C at 40 ℃, heating to 60 ℃, stirring for 3 hours, cooling to normal temperature, then quenching with saturated aqueous sodium bicarbonate solution, extracting the obtained reaction solution with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, vacuum concentrating the organic phase, and finally purifying the concentrated organic phase with silica gel column chromatography to obtain 5.53g of compound E with a yield of 60%, wherein the detection data of compound E are as follows: IR (film) lambdamax2986，2944，2877，1730，1690，1633，1470，1449，1420，1176，1136，1020，936，837；1H NMR(500MHz，CDCl3)δ5.62(s，1H)，1.86(s，3H)，1.55(s，3H)，1.46(s，6H)，1.39(s，6H)；13C NMR(125MHz，CDCl3)δ208.8，197.7，162.3，144.4，127.1，122.2，119.7，117.1，114.6，113.6，57.4，49.0，25.6，24.6，23.5，20.0；HRMS(ESI)C15H20F3O5S[(M+H)+]369.0978 as a calculated molecular weight value; the molecular weight was found to be 369.0971. The synthetic route for compound E is as follows:
(5) compound E (15mmol) was dissolved in 150 ml of N, N-dimethylformamide to give N, N-dimethyl of Compound EFormamide; adding tetra (triphenylphosphine) palladium (0.6mmol), triethylamine (15mmol) and formic acid (15mmol) into N, N-dimethylformamide of E respectively at 25 ℃, heating to 80 ℃, stirring for 8 hours, cooling to 25 ℃, then quenching with saturated aqueous sodium bicarbonate, extracting the obtained reaction liquid with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 493mg of compound F with the yield of 15%, wherein the detection data of the compound F are as follows: IR (film) lambdamax2976，2936，2870，1719，1676，1638，1468，1379，1360，1302，1250，1042，854；1H NMR(400MHz，CDCl3)δ6.50(s，1H)，5.93(s，1H)，1.87(s，3H)，1.75(s，3H)，1.35(s，6H)，1.34(s，6H)；13C NMR(100MHz，CDCl3)δ213.4，201.1，149.3，138.5，132.5，118.9，57.5，45.1，27.5，26.6，23.7，19.5；HRMS(ESI)C14H21O2[(M+H)+]221.1536 as a calculated molecular weight value; the molecular weight was found to be 221.1533. The synthetic route for compound F is as follows:
(6) dissolving a compound F (4.8mmol) and a compound D (4.8mmol) in 48 ml of toluene to obtain a toluene solution of the compound F and the compound D; p-toluenesulfonic acid (4.8mmol) was added to a toluene solution of compound F and compound D at 25 ℃, then warmed to 80 ℃, stirred for 6 hours, then quenched with saturated aqueous sodium bicarbonate, the resulting reaction was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, the concentrated organic phase was purified by silica gel column chromatography, and finally recrystallized in a mixed solution of methanol and dichloromethane to give 88.6mg of compound G with 3% yield, wherein the assay data for compound G is as follows: rf＝0.35(hexane/ethyl acetate＝8/1)；IR(film)λmax3422，2955，2864，1717，1625，1598，1557，1431，1277，865；1H NMR(600MHz，CDCl3)δ14.05(s，1H)，4.15(d，J＝3.1Hz，1H)，3.91–3.84(m，1H)，3.44–3.40(m，1H)，3.39(d，J＝3.0Hz，1H)，1.94–1.90(m，1H)，1.88(dd，J＝12.1，6.6Hz，1H)，1.56(s，3H)，1.50(m，1H)，1.39(s，3H)，1.38(s，6H)，1.35(s，3H)，1.34(s，3H)，1.34(s，3H)，1.28(s，3H)，1.26(s，3H)，1.22(d，J＝6.9Hz，3H)，1.20(d，J＝7.0Hz，3H)，0.92(s，3H)，0.82(d，J＝7.0Hz，3H)，0.63(d，J＝6.9Hz，3H)；13C NMR(150MHz，CDCl3)δ218.1，212.5，209.3，197.6，167.5，163.4，154.6，151.7，113.1，110.8，105.8，104.7，102.8，85.3，56.1，54.1，51.3，47.5，39.7，39.137.4，35.0，34.7，31.2，29.8，28.7，28.7，25.6，25.3，25.2，25.0，24.2，24.0，21.2，21.1，19.5，18.1，16.9；HRMS(ESI)C38H51O8[(M+H)+]Calculated molecular weight: 635.3578, respectively; molecular weight found: 635.3575. the synthetic route for compound G is as follows:
(7) dissolving a compound G (0.24mmol) in 9.2 ml of a mixed solvent of ethanol and water (wherein, the volume ratio of ethanol to water in the mixed solvent of ethanol and water is 6:1) to obtain the mixed solvent of ethanol and water of the compound G; adding sodium hydroxide (24mmol) into a mixed solvent of ethanol and water of a compound G at 28 ℃, then heating to 80 ℃, stirring for 12 hours, cooling to 40 ℃, then quenching with 1mol/L hydrochloric acid, extracting the obtained reaction liquid with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering to remove the sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 42mg of the antibacterial drug with the yield of 27%, wherein the detection data of the antibacterial drug are as follows: rf＝0.3(hexane/ethyl acetate＝8/1)；IR(film)λmax2977，2937，2874，1720，1703，1595，1556，1467，1384，1299，1092；1H NMR(500MHz，CDCl3)δ14.24(s，1H)，11.75(s，1H)，8.55(s，1H)，4.17–4.09(m，1H)，3.43(dd，J＝7.5，2.7Hz，1H)，3.38(d，J＝2.8Hz，1H)，3.27(d，J＝10.7Hz，1H)，2.89–2.80(m，1H)，1.91(dd，J＝12.2，7.0Hz，1H)，1.58–1.52(m，1H)，1.51(s，3H)，1.48(s，3H)，1.39(s，3H)，1.39(s，3H)，1.38(s，3H)，1.36(s，3H)，1.34(s，3H)，1.33(s，3H)，1.28(s，3H)，1.19(d，J＝6.8Hz，3H)，1.14(s，3H)，1.04(s，3H)，0.78(d，J＝6.4Hz，3H)，0.69(d，J＝6.4Hz，3H)；13C NMR(125MHz，CDCl3)δ217.6，212.6，212.4，202.7，176.6，163.8，159.7，156.3，115.5，114.6，106.0，104.4，100.4，86.1，55.1，53.6，50.4，48.6，41.7，39.8，38.9，37.1，35.3，30.7，28.7，28.6，27.4，25.7，25.7，25.6，25.4，24.8，24.0，22.2，21.9，20.3，19.8，19.4；HRMS(ESI)C38H53O9[(M+H)+]Calculated molecular weight: 653.3684, respectively; molecular weight found: 653.3672. the synthetic route of the antibacterial drug is as follows:
example 6
The preparation process of the antibacterial agent of this example is as follows:
(1) dissolving compound A (102mmol) in 240 ml of anhydrous methanol to obtain a methanol solution of compound A; adding anhydrous sodium methoxide powder (918mmol) into a methanol solution of the compound A at the temperature of 15 ℃, stirring and mixing for 0.5 hour, cooling to 0 ℃, adding iodomethane (1430mmol), stirring and mixing for 0.5 hour, then heating to 70 ℃, reacting at 70 ℃ for 6 hours, cooling to 25 ℃, then quenching the reaction by using 2mol/L hydrochloric acid, extracting the obtained reaction liquid by using ethyl acetate, washing an organic phase by using an aqueous solution of saturated sodium sulfite, drying anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by using a silica gel column chromatography to obtain 21.6g of the compound B, wherein the detection data of the compound B are as follows: IR (film) lambdamax3412，2962，2940，2876，1724，1672，1558，1474，1420，1314，1049，939；1H NMR(400MHz，CDCl3)δ3.84–3.74(m，1H)，1.43(s，6H)，1.35(s，6H)，1.17(s，3H)，1.16(s，3H)；13C NMR(100MHz，CDCl3)δ209.9，208.6，199.3，196.9，108.2，56.9，52.2，35.2，24.3，23.9，19.1；HRMS(ESI)C14H19O4[(M-H)-]Calculated molecular weight is 251.1289, found molecular weight is 251.1287. The synthetic route of the compound B is as follows:
(2) compound B (19.8mmol) was dissolved in 200 ml of tetrahydrofuran at 30 ℃ to give a tetrahydrofuran solution of compound B; lithium aluminum tri-tert-butoxyhydride (24mmol) was added to a tetrahydrofuran solution of compound B at-75 ℃, stirred for 20 minutes, then quenched with ethyl acetate, warmed to 40 ℃, saturated aqueous sodium potassium tartrate solution was added, the resulting reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, and finally the concentrated organic phase was purified by silica gel column chromatography to give 3.7g of compound C in 80% yield, wherein the assay data for compound C is as follows: IR (film) lambdamax 2974，2938，2872，1717，1690，1676，1609，1464，1422，1385，1258，1098，945，804；1H NMR(400MHz，CDCl3)δ7.29(d，J＝1.0Hz，1H)，3.42–3.33(m，1H)，1.34(s，6H)，1.33(s，6H)，1.13(d，J＝6.6Hz，6H)；13C NMR(100MHz，CDCl3)δ208.8，199.8，196.6，164.9，130.6，58.5，58.2，28.6，22.3，21.9，21.8；HRMS(ESI)C14H21O3[(M+H)+]237.1483 as a calculated molecular weight value; the molecular weight was found to be 237.1491. The synthetic route of the compound C is as follows:
(3) compound A (40mmol) and compound C (80mmol) were dissolved in 80 mlTo toluene to give a toluene solution of compound a and compound C, then p-toluenesulfonic acid (10mmol) was added, the reaction was stirred at 40 ℃ for 10 hours, followed by quenching with saturated aqueous sodium bicarbonate, the resulting reaction solution was extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, sodium sulfate was removed by filtration, the organic phase was concentrated in vacuo, and finally the concentrated organic phase was purified by silica gel column chromatography to give 8.9g of compound D with a yield of 53%, wherein the detection data of compound D are as follows: IR (film) lambdamax3240，2969，2930，2870，1719，1624，1591，1396，1383，1229，1155，1001，833；1H NMR(400MHz，CDCl3)δ13.38(s，1H)，7.30(s，1H)，6.32(s，1H)，4.38(d，J＝3.2Hz，1H)，3.92–3.87(m，1H)，1.95–1.90(m，1H)，1.62(s，3H)，1.46(s，3H)，1.43(s，3H)，1.39(s，3H)，1.25(t，J＝6.5Hz，6H)，0.83(d，J＝6.8Hz，3H)，0.78(d，J＝6.6Hz，3H)；13C NMR(100MHz，CDCl3)δ211.8，208.9，198.8，168.2，164.7，159.6，153.4，112.1，103.8，103.8，100.7，56.2，47.3，39.7，34.8，31.5，25.2，25.0，25.0，24.1，20.9，18.9，18.7，17.7；HRMS(ESI)C24H31O6[(M+H)+]415.2115 as a calculated molecular weight value; the molecular weight was found to be 415.2107. The synthetic route of the compound D is as follows:
(4) dissolving the compound C (25mmol) in 100mL of toluene to obtain a toluene solution of the compound C; adding 2, 6-lutidine (37.5mmol) and trifluoromethanesulfonyl chloride (50mmol) into a 1, 2-dichloroethane solution of a compound C at 0 ℃, heating to 40 ℃, stirring for 12 hours, cooling to 0 ℃, then quenching with a saturated aqueous solution of sodium bicarbonate, extracting the obtained reaction solution with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 2.86g of a compound E with a yield of 31%, wherein the detection data of the compound E are as follows:IR(film)λmax2986，2944，2877，1730，1690，1633，1470，1449，1420，1176，1136，1020，936，837；1H NMR(500MHz，CDCl3)δ5.62(s，1H)，1.86(s，3H)，1.55(s，3H)，1.46(s，6H)，1.39(s，6H)；13C NMR(125MHz，CDCl3)δ208.8，197.7，162.3，144.4，127.1，122.2，119.7，117.1，114.6，113.6，57.4，49.0，25.6，24.6，23.5，20.0；HRMS(ESI)C15H20F3O5S[(M+H)+]369.0978 as a calculated molecular weight value; the molecular weight was found to be 369.0971. The synthetic route for compound E is as follows:
(5) dissolving the compound E (15mmol) in 150 ml of tetrahydrofuran to obtain a tetrahydrofuran solution of the compound E; at 25 ℃, palladium acetate (0.3mmol), triphenylphosphine (1.2mmol), triethylamine (30mmol) and formic acid (30mmol) are respectively added into a tetrahydrofuran solution of E, the temperature is raised to 66 ℃, the mixture is stirred for 8 hours, the temperature is reduced to 25 ℃, then saturated aqueous sodium bicarbonate solution is used for quenching, the obtained reaction solution is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, the sodium sulfate is removed by filtration, the organic phase is concentrated in vacuum, and finally the concentrated organic phase is purified by silica gel column chromatography to obtain 2.67g of a compound F with the yield of 81%, wherein the detection data of the compound F are as follows: IR (film) lambdamax2976，2936，2870，1719，1676，1638，1468，1379，1360，1302，1250，1042，854；1H NMR(400MHz，CDCl3)δ6.50(s，1H)，5.93(s，1H)，1.87(s，3H)，1.75(s，3H)，1.35(s，6H)，1.34(s，6H)；13C NMR(100MHz，CDCl3)δ213.4，201.1，149.3，138.5，132.5，118.9，57.5，45.1，27.5，26.6，23.7，19.5；HRMS(ESI)C14H21O2[(M+H)+]221.1536 as a calculated molecular weight value; the molecular weight was found to be 221.1533. The synthetic route for compound F is as follows:
(6) dissolving a compound F (7.2mmol) and a compound D (4.8mmol) in chloroform to obtain a chloroform solution of the compound F and the compound D; p-toluenesulfonic acid (7.2mmol) was added to a chloroform solution of compound F and compound D at 15 ℃, then warmed to 60 ℃, stirred for 18 hours, then quenched with a saturated aqueous solution of sodium bicarbonate, the resulting reaction solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, the concentrated organic phase was purified by silica gel column chromatography, and finally recrystallized in a mixed solution of methanol and dichloromethane to give 281mg of compound G with a yield of 9.5%, wherein the detection data of compound G are as follows: rf＝0.35(hexane/ethyl acetate＝8/1)；IR(film)λmax3422，2955，2864，1717，1625，1598，1557，1431，1277，865；1H NMR(600MHz，CDCl3)δ14.05(s，1H)，4.15(d，J＝3.1Hz，1H)，3.91–3.84(m，1H)，3.44–3.40(m，1H)，3.39(d，J＝3.0Hz，1H)，1.94–1.90(m，1H)，1.88(dd，J＝12.1，6.6Hz，1H)，1.56(s，3H)，1.50(m，1H)，1.39(s，3H)，1.38(s，6H)，1.35(s，3H)，1.34(s，3H)，1.34(s，3H)，1.28(s，3H)，1.26(s，3H)，1.22(d，J＝6.9Hz，3H)，1.20(d，J＝7.0Hz，3H)，0.92(s，3H)，0.82(d，J＝7.0Hz，3H)，0.63(d，J＝6.9Hz，3H)；13C NMR(150MHz，CDCl3)δ218.1，212.5，209.3，197.6，167.5，163.4，154.6，151.7，113.1，110.8，105.8，104.7，102.8，85.3，56.1，54.1，51.3，47.5，39.7，39.1 37.4，35.0，34.7，31.2，29.8，28.7，28.7，25.6，25.3，25.2，25.0，24.2，24.0，21.2，21.1，19.5，18.1，16.9；HRMS(ESI)C38H51O8[(M+H)+]Calculated molecular weight: 635.3578, respectively; molecular weight found: 635.3575. the synthetic route for compound G is as follows:
(7) compound G (0.24mmol) was dissolvedObtaining a mixed solvent of ethanol and water of a compound G in 10 ml of mixed solvent of ethanol and water (wherein, the volume ratio of ethanol to water in the mixed solvent of ethanol and water is 4: 1); adding potassium hydroxide (36mmol) into a mixed solvent of ethanol and water of a compound G at the temperature of 20 ℃, then heating to 60 ℃, stirring for 12 hours, cooling to 20 ℃, then quenching with 1mol/L hydrochloric acid, extracting the obtained reaction liquid with ethyl acetate, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 28mg of the antibacterial drug with the yield of 18%, wherein the detection data of the antibacterial drug are as follows: rf＝0.3(hexane/ethyl acetate＝8/1)；IR(film)λmax2977，2937，2874，1720，1703，1595，1556，1467，1384，1299，1092；1H NMR(500MHz，CDCl3)δ14.24(s，1H)，11.75(s，1H)，8.55(s，1H)，4.17–4.09(m，1H)，3.43(dd，J＝7.5，2.7Hz，1H)，3.38(d，J＝2.8Hz，1H)，3.27(d，J＝10.7Hz，1H)，2.89–2.80(m，1H)，1.91(dd，J＝12.2，7.0Hz，1H)，1.58–1.52(m，1H)，1.51(s，3H)，1.48(s，3H)，1.39(s，3H)，1.39(s，3H)，1.38(s，3H)，1.36(s，3H)，1.34(s，3H)，1.33(s，3H)，1.28(s，3H)，1.19(d，J＝6.8Hz，3H)，1.14(s，3H)，1.04(s，3H)，0.78(d，J＝6.4Hz，3H)，0.69(d，J＝6.4Hz，3H)；13C NMR(125MHz，CDCl3)δ217.6，212.6，212.4，202.7，176.6，163.8，159.7，156.3，115.5，114.6，106.0，104.4，100.4，86.1，55.1，53.6，50.4，48.6，41.7，39.8，38.9，37.1，35.3，30.7，28.7，28.6，27.4，25.7，25.7，25.6，25.4，24.8，24.0，22.2，21.9，20.3，19.8，19.4；HRMS(ESI)C38H53O9[(M+H)+]Calculated molecular weight: 653.3684, respectively; molecular weight found: 653.3672. the synthetic route of the antibacterial drug is as follows:
example 7
The preparation process of the antibacterial agent of this example is as follows:
(1) dissolving compound A (102mmol) in 200 ml of anhydrous methanol to obtain a methanol solution of compound A; adding anhydrous sodium methoxide powder (816mmol) into a methanol solution of the compound A at the temperature of 10 ℃, stirring and mixing for 0.5 hour, cooling to 0 ℃, then adding iodomethane (1430mmol), stirring and mixing for 0.5 hour, heating to 64 ℃, reacting at 64 ℃ for 8 hours, cooling to 10 ℃, then quenching the reaction by using 2mol/L hydrochloric acid, extracting the obtained reaction liquid by using ethyl acetate, washing an organic phase by using a saturated sodium sulfite aqueous solution, drying anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by using a silica gel column chromatography to obtain 23.1g of the compound B with the yield of 90%, wherein the detection data of the compound B are as follows: IR (film) lambdamax3412，2962，2940，2876，1724，1672，1558，1474，1420，1314，1049，939；1H NMR(400MHz，CDCl3)δ3.84–3.74(m，1H)，1.43(s，6H)，1.35(s，6H)，1.17(s，3H)，1.16(s，3H)；13C NMR(100MHz，CDCl3)δ209.9，208.6，199.3，196.9，108.2，56.9，52.2，35.2，24.3，23.9，19.1；HRMS(ESI)C14H19O4[(M-H)-]Calculated molecular weight is 251.1289, found molecular weight is 251.1287. The synthetic route of the compound B is as follows:
(2) compound B (19.8mmol) was dissolved in 20 ml of tetrahydrofuran at 20 ℃ to give a tetrahydrofuran solution of compound B; adding lithium diisopropylaluminum hydride (23.8mmol) into tetrahydrofuran solution of compound B at-78 deg.C, stirring for 5 min, quenching with ethyl acetate, heating to 25 deg.C, adding saturated aqueous solution of sodium potassium tartrate solution, extracting the obtained reaction solution with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, vacuum concentrating the organic phase, and purifying the concentrated organic phase with silica gel column chromatography to obtain 3.8g of compound C with 81% yieldThe detection data for C are as follows: IR (film) lambdamax 2974，2938，2872，1717，1690，1676，1609，1464，1422，1385，1258，1098，945，804；1H NMR(400MHz，CDCl3)δ7.29(d，J＝1.0Hz，1H)，3.42–3.33(m，1H)，1.34(s，6H)，1.33(s，6H)，1.13(d，J＝6.6Hz，6H)；13C NMR(100MHz，CDCl3)δ208.8，199.8，196.6，164.9，130.6，58.5，58.2，28.6，22.3，21.9，21.8；HRMS(ESI)C14H21O3[(M+H)+]237.1483 as a calculated molecular weight value; the molecular weight was found to be 237.1491. The synthetic route of the compound C is as follows:
(3) dissolving a compound A (40mmol) and a compound C (80mmol) in 80 ml of dichloromethane to obtain a dichloromethane solution of the compound A and the compound C, then adding p-toluenesulfonic acid (20mmol), stirring and reacting at 30 ℃ for 10 hours, then quenching with saturated aqueous sodium bicarbonate, extracting the obtained reaction solution with dichloromethane, drying an organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 10.8g of a compound D with a yield of 65%, wherein the detection data of the compound D are as follows: IR (film) lambdamax3240，2969，2930，2870，1719，1624，1591，1396，1383，1229，1155，1001，833；1H NMR(400MHz，CDCl3)δ13.38(s，1H)，7.30(s，1H)，6.32(s，1H)，4.38(d，J＝3.2Hz，1H)，3.92–3.87(m，1H)，1.95–1.90(m，1H)，1.62(s，3H)，1.46(s，3H)，1.43(s，3H)，1.39(s，3H)，1.25(t，J＝6.5Hz，6H)，0.83(d，J＝6.8Hz，3H)，0.78(d，J＝6.6Hz，3H)；13C NMR(100MHz，CDCl3)δ211.8，208.9，198.8，168.2，164.7，159.6，153.4，112.1，103.8，103.8，100.7，56.2，47.3，39.7，34.8，31.5，25.2，25.0，25.0，24.1，20.9，18.9，18.7，17.7；HRMS(ESI)C24H31O6[(M+H)+]415.2115 as a calculated molecular weight value; the molecular weight was found to be 415.2107. The synthetic route of the compound D is as follows:
(4) dissolving compound C (25mmol) in 100ml of 1, 2-dichloroethane to obtain a 1, 2-dichloroethane solution of compound C; adding 2, 6-lutidine (37.5mmol) and trifluoromethanesulfonic anhydride (37.5mmol) into a 1, 2-dichloroethane solution of compound C at 30 ℃, heating to 70 ℃, stirring for 3 hours, cooling to normal temperature, then quenching with saturated aqueous sodium bicarbonate, extracting the obtained reaction solution with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 5.62g of compound E with a yield of 61%, wherein the detection data of compound E are as follows: IR (film) lambdamax2986，2944，2877，1730，1690，1633，1470，1449，1420，1176，1136，1020，936，837；1H NMR(500MHz，CDCl3)δ5.62(s，1H)，1.86(s，3H)，1.55(s，3H)，1.46(s，6H)，1.39(s，6H)；13C NMR(125MHz，CDCl3)δ208.8，197.7，162.3，144.4，127.1，122.2，119.7，117.1，114.6，113.6，57.4，49.0，25.6，24.6，23.5，20.0；HRMS(ESI)C15H20F3O5S[(M+H)+]369.0978 as a calculated molecular weight value; the molecular weight was found to be 369.0971. The synthetic route for compound E is as follows:
(5) dissolving the compound E (15mmol) in 150 ml of N, N-dimethylformamide to obtain an N, N-dimethylformamide solution of the compound E; respectively adding tetrakis (triphenylphosphine) palladium (0.3mmol), triethylamine (30mmol) and formic acid (30mmol) into an N, N-dimethylformamide solution of E at 25 ℃, heating to 60 ℃, stirring for 12 hours, cooling to 25 ℃, and dissolving with saturated sodium bicarbonate waterQuenching the solution, extracting the obtained reaction solution with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 0.99g of compound F with the yield of 30%, wherein the detection data of the compound F are as follows: IR (film) lambdamax2976，2936，2870，1719，1676，1638，1468，1379，1360，1302，1250，1042，854；1H NMR(400MHz，CDCl3)δ6.50(s，1H)，5.93(s，1H)，1.87(s，3H)，1.75(s，3H)，1.35(s，6H)，1.34(s，6H)；13C NMR(100MHz，CDCl3)δ213.4，201.1，149.3，138.5，132.5，118.9，57.5，45.1，27.5，26.6，23.7，19.5；HRMS(ESI)C14H21O2[(M+H)+]221.1536 as a calculated molecular weight value; the molecular weight was found to be 221.1533. The synthetic route for compound F is as follows:
(6) dissolving a compound F (7.2mmol) and a compound D (4.8mmol) in 48 ml of toluene to obtain a toluene solution of the compound F and the compound D; p-toluenesulfonic acid (7.2mmol) was added to a toluene solution of compound F and compound D at 10 ℃, then warmed to 70 ℃, stirred for 18 hours, then quenched with saturated aqueous sodium bicarbonate, the resulting reaction was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the organic phase was concentrated in vacuo, the concentrated organic phase was purified by silica gel column chromatography and finally recrystallized in a mixed solution of methanol and dichloromethane to give 118.4mg of compound G, with a 4% yield, wherein the assay data for compound G is as follows: rf＝0.35(hexane/ethyl acetate＝8/1)；IR(film)λmax3422，2955，2864，1717，1625，1598，1557，1431，1277，865；1H NMR(600MHz，CDCl3)δ14.05(s，1H)，4.15(d，J＝3.1Hz，1H)，3.91–3.84(m，1H)，3.44–3.40(m，1H)，3.39(d，J＝3.0Hz，1H)，1.94–1.90(m，1H)，1.88(dd，J＝12.1，6.6Hz，1H)，1.56(s，3H)，1.50(m，1H)，1.39(s，3H)，1.38(s，6H)，1.35(s，3H)，1.34(s，3H)，1.34(s，3H)，1.28(s，3H)，1.26(s，3H)，1.22(d，J＝6.9Hz，3H)，1.20(d，J＝7.0Hz，3H)，0.92(s，3H)，0.82(d，J＝7.0Hz，3H)，0.63(d，J＝6.9Hz，3H)；13C NMR(150MHz，CDCl3)δ218.1，212.5，209.3，197.6，167.5，163.4，154.6，151.7，113.1，110.8，105.8，104.7，102.8，85.3，56.1，54.1，51.3，47.5，39.7，39.137.4，35.0，34.7，31.2，29.8，28.7，28.7，25.6，25.3，25.2，25.0，24.2，24.0，21.2，21.1，19.5，18.1，16.9；HRMS(ESI)C38H51O8[(M+H)+]Calculated molecular weight: 635.3578, respectively; molecular weight found: 635.3575. the synthetic route for compound G is as follows:
(7) dissolving a compound G (0.24mmol) in 5.3 ml of a mixed solvent of ethanol and water (wherein, the volume ratio of ethanol to water in the mixed solvent of ethanol and water is 7: 1) to obtain the mixed solvent of ethanol and water of the compound G; adding sodium hydroxide (12mmol) into a mixed solvent of ethanol and water of a compound G at the temperature of 10 ℃, then heating to 80 ℃, stirring for 12 hours, cooling to 10 ℃, then quenching with 1mol/L hydrochloric acid, extracting the obtained reaction liquid with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering to remove the sodium sulfate, concentrating the organic phase in vacuum, and finally purifying the concentrated organic phase by silica gel column chromatography to obtain 35.8mg of the antibacterial drug with the yield of 23%, wherein the detection data of the antibacterial drug are as follows: rf＝0.3(hexane/ethyl acetate＝8/1)；IR(film)λmax2977，2937，2874，1720，1703，1595，1556，1467，1384，1299，1092；1H NMR(500MHz，CDCl3)δ14.24(s，1H)，11.75(s，1H)，8.55(s，1H)，4.17–4.09(m，1H)，3.43(dd，J＝7.5，2.7Hz，1H)，3.38(d，J＝2.8Hz，1H)，3.27(d，J＝10.7Hz，1H)，2.89–2.80(m，1H)，1.91(dd，J＝12.2，7.0Hz，1H)，1.58–1.52(m，1H)，1.51(s，3H)，1.48(s，3H)，1.39(s，3H)，1.39(s，3H)，1.38(s，3H)，1.36(s，3H)，1.34(s，3H)，1.33(s，3H)，1.28(s，3H)，1.19(d，J＝6.8Hz，3H)，1.14(s，3H)，1.04(s，3H)，0.78(d，J＝6.4Hz，3H)，0.69(d，J＝6.4Hz，3H)；13C NMR(125MHz，CDCl3)δ217.6，212.6，212.4，202.7，176.6，163.8，159.7，156.3，115.5，114.6，106.0，104.4，100.4，86.1，55.1，53.6，50.4，48.6，41.7，39.8，38.9，37.1，35.3，30.7，28.7，28.6，27.4，25.7，25.7，25.6，25.4，24.8，24.0，22.2，21.9，20.3，19.8，19.4；HRMS(ESI)C38H53O9[(M+H)+]Calculated molecular weight: 653.3684, respectively; molecular weight found: 653.3672. the synthetic route of the antibacterial drug is as follows:
the technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The preparation method of the antibacterial drug is characterized by comprising the following steps:
under the condition of no water and 50-80 ℃, sodium methoxide with the structural formula as shown in the specification
The compound A and methyl iodide react in alcohol to obtain the compound with the structural formula
The compound B of (1), wherein the molar ratio of the sodium methoxide to the compound A is 5-12: 1, and the molar ratio of the methyl iodide to the compound A is 7-16: 1;
under the conditions of anhydrous temperature and-70 to-78 ℃, a reducing agent reacts with the compound B in a first organic solvent to obtain a compound with a structural formula of
The compound C of (1), wherein the molar ratio of the reducing agent to the compound B is 0.5-2.5: 1;
reacting the compound A, the compound C and protonic acid in a second organic solvent at the temperature of between 0 and 40 ℃ to obtain a compound with a structural formula of
The compound D of (1), wherein the molar ratio of the compound A to the compound C is 0.2-0.5: 1;
reacting the compound C with organic alkali and trifluoromethanesulfonylation reagent in a third organic solvent at the temperature of 40-90 ℃ to obtain a compound with a structural formulaThe compound E of (1), wherein the molar ratio of the organic base to the compound C is 1-2: 1, the trifluoromethanesulfonylation reagent is trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride, the molar ratio of the trifluoromethanesulfonylation reagent to the compound C is 1-2: 1, and OTf represents trifluoromethanesulfonyloxy;
reacting the compound E, triethylamine and formic acid in a fourth organic solvent under the condition of a catalyst at the temperature of 50-80 ℃ to obtain a compound with a structural formula of
The compound F of (1), wherein the molar ratio of the triethylamine to the compound E is 1-3: 1, and the molar ratio of the formic acid to the compound E is 1-3: 1;
reacting the compound D, the compound F and p-toluenesulfonic acid in a fifth organic solvent at 50-110 ℃ to obtain a compound with a structural formula
The compound G of (1), wherein the molar ratio of the compound F to the compound D is 1-2: 1, and the molar ratio of the p-toluenesulfonic acid to the compound D is 0.25-1.5: 1; and
reacting the compound G with strong alkaline hydroxide in a mixed solvent of water and alcohol at the temperature of 60-90 ℃ to obtain the compound with the structural formula shown in the specification
The antibacterial agent of (1), wherein the molar ratio of the strongly basic hydroxide to the compound G is 50-150: 1.
2. The method for preparing an antibacterial drug according to claim 1, wherein the step of reacting sodium methoxide, compound a and methyl iodide in alcohol under anhydrous conditions at 50-80 ℃ is specifically: dissolving the compound A in the alcohol under the anhydrous condition and the temperature of 0-40 ℃ to obtain an alcohol solution of the compound A, then adding the sodium methoxide into the alcohol solution of the compound A, adding the methyl iodide at the temperature of-10-5 ℃, reacting at the temperature of 50-80 ℃ for 6-15 hours, and then quenching the reaction.
3. The method of claim 1, wherein the step of reacting sodium methoxide, compound a, and methyl iodide in an alcohol, wherein the alcohol is at least one of methanol, ethanol, and propanol.
4. The method for preparing the antibacterial drug according to claim 1, wherein the step of reacting the reducing agent with the compound B in the first organic solvent under the conditions of anhydrous temperature and-70 ℃ to-78 ℃ is specifically as follows: dissolving the compound B in the first organic solvent at the temperature of 0-40 ℃ to obtain an organic solution of the compound B; adding the reducing agent into the organic solution of the compound B at the temperature of-70 ℃ to-78 ℃, stirring and reacting for 5 minutes to 60 minutes, and then quenching the reaction.
5. The method of claim 1, wherein the reducing agent is lithium diisopropylaluminum hydride or lithium tri-t-butoxyaluminum hydride.
6. The method for preparing an antibacterial agent according to claim 1, wherein the protic acid is trifluoroacetic acid or p-toluenesulfonic acid.
7. The method of claim 1, wherein the organic base is 2, 6-lutidine, pyridine or triethylamine.
8. The method of claim 1, wherein the strongly basic hydroxide is potassium hydroxide or sodium hydroxide.
9. The method for producing an antibacterial drug according to claim 1, characterized in that the step of reacting the compound G with a strongly basic hydroxide in a mixed solvent of water and an alcohol is specifically: dissolving the compound G in the mixed solvent of water and alcohol at 0-40 ℃, adding the strong alkaline hydroxide, and reacting at 60-90 ℃.
10. The preparation method of the antibacterial drug according to claim 1, wherein the catalyst is composed of palladium acetate and triphenylphosphine in a molar ratio of 1: 2-4, or the catalyst is tetrakis (triphenylphosphine) palladium.
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| CN108853078B (en) * | 2017-05-15 | 2020-12-22 | 南方科技大学 | Preparation method of antibacterial drug |
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