CN105503972B - One kind synthesizes 1-N- ethyl gentamicinCs by catalyst of heteropoly acid1aMethod - Google Patents
One kind synthesizes 1-N- ethyl gentamicinCs by catalyst of heteropoly acid1aMethod Download PDFInfo
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- CN105503972B CN105503972B CN201510908458.1A CN201510908458A CN105503972B CN 105503972 B CN105503972 B CN 105503972B CN 201510908458 A CN201510908458 A CN 201510908458A CN 105503972 B CN105503972 B CN 105503972B
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- 239000003054 catalyst Substances 0.000 title description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 27
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims abstract description 22
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 239000000706 filtrate Substances 0.000 claims abstract description 18
- 238000010438 heat treatment Methods 0.000 claims abstract description 15
- 238000010992 reflux Methods 0.000 claims abstract description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000010189 synthetic method Methods 0.000 claims abstract description 10
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 239000011964 heteropoly acid Substances 0.000 claims abstract description 9
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 9
- 239000011591 potassium Substances 0.000 claims abstract description 9
- 238000004321 preservation Methods 0.000 claims abstract description 9
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 8
- 238000011068 loading method Methods 0.000 claims abstract description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 239000000843 powder Substances 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- 229910052750 molybdenum Inorganic materials 0.000 claims description 4
- 229910052758 niobium Inorganic materials 0.000 claims description 4
- 229910052710 silicon Inorganic materials 0.000 claims description 4
- 229910052715 tantalum Inorganic materials 0.000 claims description 4
- 229910052721 tungsten Inorganic materials 0.000 claims description 4
- 229910052720 vanadium Inorganic materials 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 6
- UQXKXGWGFRWILX-UHFFFAOYSA-N ethylene glycol dinitrate Chemical compound O=N(=O)OCCON(=O)=O UQXKXGWGFRWILX-UHFFFAOYSA-N 0.000 claims 3
- 238000000034 method Methods 0.000 abstract description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 2
- 125000003047 N-acetyl group Chemical group 0.000 abstract 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229950009953 etimicin Drugs 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- OEBISAUVQBGQKC-ZIZSAZPJSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4-amino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]oxy-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;sulfuric acid Chemical compound OS(O)(=O)=O.O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](NC)[C@@](C)(O)CO1)O)NCC)[C@H]1O[C@H](CN)CC[C@H]1N OEBISAUVQBGQKC-ZIZSAZPJSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- VEGXETMJINRLTH-ALRICIOSSA-N etimicin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@H](O)[C@H]1O[C@@H]1[C@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N VEGXETMJINRLTH-ALRICIOSSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 241000589291 Acinetobacter Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940126678 chinese medicines Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- VYQNWZOUAUKGHI-UHFFFAOYSA-N monobenzone Chemical compound C1=CC(O)=CC=C1OCC1=CC=CC=C1 VYQNWZOUAUKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000002444 silanisation Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
- C07H15/236—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of 1 N ethyl gentamicinCs1aSynthetic method, this method comprises the following steps：Glycol dimethyl ether is taken, hexamethyldisilazane after concentrated sulfuric acid mixing, adds in 3,2 ', 6 ' three N acetyl group gentamicinCs1aDry powder is heated to flowing back, steams partial solvent；10 DEG C are cooled to, puts into dichloromethane, puts into heteropoly acid, then under the conditions of 5~10 DEG C of heat preservation, acetaldehyde is added dropwise, is stirred to react.Add potassium borohydride, add borate buffer, be stirred to react, normal heating steams partial solvent, adds in 20% sodium hydroxide solution, is heated to reflux, and cools down, and vacuum filters to obtain filtrate.Filtrate is diluted with salt-free water, is passed through loading in chromatography column, collects active ingredient, and concentration freezes to obtain 1 N ethyl gentamicinCs of target compound1a。
Description
Technical field
It is specifically a kind of to be celebrated with 3,2 ', 6 '-three-N- acetyl group the present invention relates to a kind of organic chemical synthesis method
Big mycin C1aSynthesize 1-N- ethyl gentamicinCs1aMethod, be one kind on the basis of traditional Acetaldehyde add heteropoly acid urge
It is combined to 1-N- ethyl gentamicinCs1aMethod.
Background technology
Etimicin Sulfate (Etimicin sulfate) is that China scientific research personnel voluntarily develops, and possesses independent intellectual production
Efficient, less toxic, antimicrobial agent the semi-synthetic aminoglycoside antibiotics of a new generation of power is that unique first class national new drug that obtains is demonstrate,proved
The anti-infectives of book.Its mechanism of action is the normal albumen synthesis for resisting sensitive bacteria, to Escherichia coli, citric acid lung
Scorching bacillus, Enterobacter, Serratia, proteus mirabilis, Salmonella, haemophilus influenzae and staphylococcus etc. have higher
Antibacterial activity, to part Pseudomonas alba, acinetobacter etc. have certain antibacterial activity, to part gentamicin, small promise
The mycin and drug resistant staphylococcus aureus of cephazoline, Escherichia coli and Klebsiella pneumoniae, MIC value still exist
In the range of the blood concentration of the product therapeutic dose.To generating the part staphylococcus of penicillase and part low-level methoxy west
The drug resistant grape ball (MRSA) of woods also has certain antibacterial activity.
It needs to use intermediate 1-N- ethyl gentamicinCs in Etimicin building-up process1a, prior art discloses three kinds
Synthetic method.
Chinese patent 93112412.3 describes following methods：
By 3,2 ', 6 '-three-N- acetyl group gentamicinCs1aN- ethylizations are carried out with acetaldehyde, are obtained with sodium borohydride reduction
To 3,2 ', 6 '-three-N- acetyl group -1-N- ethyl gentamicinCs1a, then obtained when 100 DEG C of back hydrolysis 48 are small with sodium hydroxide
To 1-N- ethyl gentamicinCs1aHydrating solution, by II macroporous resin column of 732 strong acidic ion resin columns and YPR- respectively
Purifying, obtains 1-N- ethyl gentamicinCs1a.Sulfuric acid is added in after desorbed solution is concentrated under reduced pressure, then at 60 DEG C with activated carbon decolorizing,
It finally freezes and obtains 1-N- ethyl gentamicinCs1aSulfate, weight yield are 30% or so.
Chinese patent 201010132962.4, and Chinese patent 201010132963.9 is to 1-N- ethyl gentamicinCs1a's
Synthesis is improved：First with 3,2 ', 6 '-three-N- acetyl group gentamicinCs1aIt is molten in chloroform with hexamethyldisilazane
In agent, it is heated to flowing back under the catalytic action of the concentrated sulfuric acid and 3,2 ', 6 '-three-N- acetyl group -5 of generation occurs, 2 ", 4 "-three
(trimethyl silicon substrate) gentamicinC1aSilanization reaction, until the reaction is complete.It is ethylized again with acetaldehyde afterwards.Finally weigh
It is 45% or so to measure yield.
The defects of existing process, is that the ammonification reduction reaction conditions of acetaldehyde are more sensitive for pH, the intermediate of imines
Side reaction that is unstable and entirely reacting is more.Therefore there are yield is relatively low, the later stage is not readily separated purifying, technical process is cumbersome
A series of problems, such as.
The present invention is adjusted existing process route, effectively improves the yield of product, while is greatly reduced impurity
Content.
The content of the invention
It is an object of the invention to provide a kind of easy to operate, energy conservation and environmental protection simultaneously can synthesize Etimicin with higher yield
(1-N- ethyl gentamicinCs1a) method.
1-N- ethyls gentamicinC of the present invention1aSynthetic method, comprise the following steps：
A, by glycol dimethyl ether, hexamethyldisilazane after concentrated sulfuric acid mixing, adds in 3,2 ', 6 '-three-N- acetyl group
GentamicinC1aDry powder is heated to flowing back, steams partial solvent；
B, 10 DEG C are cooled to, adds in dichloromethane, heteropoly acid then under the conditions of 5~10 DEG C of heat preservation, is added dropwise acetaldehyde, stirs
Reaction is mixed, adds potassium borohydride, adds borate buffer, is stirred to react, normal heating steams partial solvent；
C, 20% sodium hydroxide solution is added in, is heated to reflux, is cooled down, vacuum filters to obtain filtrate, filtrate water dilution, through layer
Active ingredient, concentration, dry 1-N- ethyl gentamicinCs are collected in analysis separation1a。
Wherein, the heteropoly acid is by certain by hetero atom (P, Si, Fe, Co) and polyatom (Mo, W, V, Nb, Ta)
The oxygen-containing polyacid of one kind that structure is made up of oxygen atom ligand bridging.
Wherein, the hetero atom is P, Si, Fe, Co；The polyatom is Mo, W, V, Nb, Ta.
Wherein, with 3,2 ', 6 '-three-N- acetyl group gentamicinCs1aGauge, the dosage of heteropoly acid is 1-100mg/g.
The source of heteropoly acid and trade name：R grades of Shanghai Chinese medicines group reagent A
In order to further illustrate beneficial effects of the present invention, the detection method of the present invention is compared with existing method
Compared with：
The present invention reduces the use of solvent for existing method, shortens the reaction time, reduces into production cost, together
When the present invention also greatly improve the yield and purity of product, show extraordinary effect.
Specific embodiment
By specific examples below, the present invention is further illustrated, but without limitation.
Embodiment 1
In three mouthfuls of reaction bulbs are dried equipped with the 500mL of the reflux condensing tube with drying tube, agitating device, ethylene glycol is put into
Dimethyl ether 100mL, hexamethyldisilazane 19g, concentrated sulfuric acid 0.1mL after stirring evenly, add in 3,2 ', 6 '-three-N- acetyl group
GentamicinC1aOvendry power 15g is heated to flowing back, and reacts 5h.It is changed to distilling apparatus normal heating and steams solvent about 90mL；Cooling
To 10 DEG C, dichloromethane 80mL is put into, puts into 25mg heteropoly acids, then under the conditions of 5~10 DEG C of heat preservation, acetaldehyde 1.6g is added dropwise,
Stir 0.5h.Add potassium borohydride 1.9g, react 0.5h, adding borate buffer 20mL, (31g boric acid adds deionized water 1L stirrings molten
Solution adjusts pH=10 with sodium hydroxide), 1h is stirred, normal heating is distilled to 100 DEG C of liquid temperature, steams partial solvent；Add in 20%
Sodium hydroxide solution 100mL is heated to reflux for 24 hours, being cooled to 30 DEG C, vacuum filters to obtain filtrate.Filtrate is diluted with salt-free water, is passed through
Loading in chromatography column, collects active ingredient, and concentration freezes to obtain target compound 1-N- ethyl gentamicinCs1a.Concentration is frozen
Do to obtain product 12.3g.Yield is 82%, purity 94%.
Embodiment 2
In three mouthfuls of reaction bulbs are dried equipped with the 500mL of the reflux condensing tube with drying tube, agitating device, ethylene glycol is put into
Dimethyl ether 100mL, hexamethyldisilazane 19g, concentrated sulfuric acid 0.1mL after stirring evenly, add in 3,2 ', 6 '-three-N- acetyl group
GentamicinC1aOvendry power 15g is heated to flowing back, and reacts 5h.It is changed to distilling apparatus normal heating and steams solvent about 90mL；Cooling
To 10 DEG C, dichloromethane 80mL is put into, puts into 75mg heteropoly acids, then under the conditions of 5~10 DEG C of heat preservation, acetaldehyde 1.6g is added dropwise,
Stir 0.5h.Add potassium borohydride 1.9g, react 0.5h, adding borate buffer 20mL, (31g boric acid adds deionized water 1L stirrings molten
Solution adjusts pH=10 with sodium hydroxide), 1h is stirred, normal heating is distilled to 100 DEG C of liquid temperature, steams partial solvent；Add in 20%
Sodium hydroxide solution 100mL is heated to reflux for 24 hours, being cooled to 30 DEG C, vacuum filters to obtain filtrate.Filtrate is diluted with salt-free water, is passed through
Loading in chromatography column, collects active ingredient, and concentration freezes to obtain target compound 1-N- ethyl gentamicinCs1a.Concentration is frozen
Do to obtain product 12.6g.Yield is 84%, purity 95%.
Embodiment 3
In three mouthfuls of reaction bulbs are dried equipped with the 500mL of the reflux condensing tube with drying tube, agitating device, ethylene glycol is put into
Dimethyl ether 100mL, hexamethyldisilazane 19g, concentrated sulfuric acid 0.1mL after stirring evenly, add in 3,2 ', 6 '-three-N- acetyl group
GentamicinC1aOvendry power 15g is heated to flowing back, and reacts 5h.It is changed to distilling apparatus normal heating and steams solvent about 90mL；Cooling
To 10 DEG C, dichloromethane 80mL is put into, puts into 100mg heteropoly acids, then under the conditions of 5~10 DEG C of heat preservation, acetaldehyde 1.6g is added dropwise,
Stir 0.5h.Add potassium borohydride 1.9g, react 0.5h, adding borate buffer 20mL, (31g boric acid adds deionized water 1L stirrings molten
Solution adjusts pH=10 with sodium hydroxide), 1h is stirred, normal heating is distilled to 100 DEG C of liquid temperature, steams partial solvent；Add in 20%
Sodium hydroxide solution 100mL is heated to reflux for 24 hours, being cooled to 30 DEG C, vacuum filters to obtain filtrate.Filtrate is diluted with salt-free water, is passed through
Loading in chromatography column, collects active ingredient, and concentration freezes to obtain target compound 1-N- ethyl gentamicinCs1a.Concentration is frozen
Do to obtain product 13.3g.Yield is 88%, purity 95%.
Claims (7)
1. a kind of 1-N- ethyls gentamicinC1aSynthetic method, comprise the following steps：
A, by glycol dimethyl ether, after concentrated sulfuric acid mixing, it is big to add in the celebrating of 3,2 ', 6 '-three-N- acetyl group for hexamethyldisilazane
Mycin C1aDry powder is heated to flowing back, steams partial solvent；
B, 10 DEG C are cooled to, adds in dichloromethane, then under the conditions of 5~10 DEG C of heat preservation, acetaldehyde is added dropwise in heteropoly acid, and stirring is anti-
Should, add potassium borohydride, add borate buffer, be stirred to react, normal heating steams partial solvent；
C, 20% sodium hydroxide solution is added in, is heated to reflux, is cooled down, filtrate, filtrate water dilution, through chromatography point is filtered by vacuum to obtain
From collecting active ingredient, concentration, dry 1-N- ethyl gentamicinCs1a。
2. synthetic method according to claim 1, which is characterized in that the heteropoly acid is by hetero atom：P、Si、Fe、
Co and polyatom：Mo, W, V, Nb, Ta, the oxygen-containing polyacid of one kind being made up of by certain structure oxygen atom ligand bridging.
3. synthetic method according to claim 2, which is characterized in that the hetero atom is P, Si, Fe, Co；Described
Polyatom is Mo, W, V, Nb, Ta.
4. 1-N- ethyls gentamicinC according to claim 1 or 21aSynthetic method, which is characterized in that with 3,2 ',
6 '-three-N- acetyl group gentamicinCs1aGauge, the dosage of heteropoly acid is 1-100mg/g.
5. synthetic method according to claim 1, which is characterized in that comprise the following steps：
In three mouthfuls of reaction bulbs are dried equipped with the 500mL of the reflux condensing tube with drying tube, agitating device, glycol dinitrate is put into
After stirring evenly, it is big to add in the celebrating of 3,2 ', 6 '-three-N- acetyl group by ether 100mL, hexamethyldisilazane 19g, concentrated sulfuric acid 0.1mL
Mycin C1aOvendry power 15g is heated to flowing back, and reacts 5h, is changed to distilling apparatus normal heating and steams solvent about 90mL；It is cooled to 10
DEG C, dichloromethane 80mL is put into, puts into 25mg heteropoly acids, then under the conditions of 5~10 DEG C of heat preservation, acetaldehyde 1.6g, stirring is added dropwise
0.5h adds potassium borohydride 1.9g, reacts 0.5h, adds borate buffer 20mL, stirs 1h, and normal heating is distilled to 100 DEG C of liquid temperature,
Steam partial solvent；20% sodium hydroxide solution 100mL is added in, is heated to reflux for 24 hours, being cooled to 30 DEG C, filtrate is filtered by vacuum to obtain,
Filtrate is diluted with salt-free water, is passed through loading in chromatography column, collects active ingredient, concentration, freeze to get.
6. synthetic method according to claim 1, which is characterized in that comprise the following steps：
In three mouthfuls of reaction bulbs are dried equipped with the 500mL of the reflux condensing tube with drying tube, agitating device, glycol dinitrate is put into
After stirring evenly, it is big to add in the celebrating of 3,2 ', 6 '-three-N- acetyl group by ether 100mL, hexamethyldisilazane 19g, concentrated sulfuric acid 0.1mL
Mycin C1aOvendry power 15g is heated to flowing back, and reacts 5h, is changed to distilling apparatus normal heating and steams solvent about 90mL；It is cooled to 10
DEG C, dichloromethane 80mL is put into, puts into 75mg heteropoly acids, then under the conditions of 5~10 DEG C of heat preservation, acetaldehyde 1.6g, stirring is added dropwise
0.5h adds potassium borohydride 1.9g, reacts 0.5h, adds borate buffer 20mL, stirs 1h, and normal heating is distilled to 100 DEG C of liquid temperature,
Steam partial solvent；20% sodium hydroxide solution 100mL is added in, is heated to reflux for 24 hours, being cooled to 30 DEG C, filtrate is filtered by vacuum to obtain,
Filtrate is diluted with salt-free water, is passed through loading in chromatography column, collects active ingredient, concentration, freeze to get.
7. synthetic method according to claim 1, which is characterized in that comprise the following steps：
In three mouthfuls of reaction bulbs are dried equipped with the 500mL of the reflux condensing tube with drying tube, agitating device, glycol dinitrate is put into
After stirring evenly, it is big to add in the celebrating of 3,2 ', 6 '-three-N- acetyl group by ether 100mL, hexamethyldisilazane 19g, concentrated sulfuric acid 0.1mL
Mycin C1aOvendry power 15g is heated to flowing back, and reacts 5h, is changed to distilling apparatus normal heating and steams solvent about 90mL；It is cooled to 10
DEG C, dichloromethane 80mL is put into, puts into 100mg heteropoly acids, then under the conditions of 5~10 DEG C of heat preservation, acetaldehyde 1.6g, stirring is added dropwise
0.5h adds potassium borohydride 1.9g, reacts 0.5h, adds borate buffer 20mL, stirs 1h, and normal heating is distilled to 100 DEG C of liquid temperature,
Steam partial solvent；20% sodium hydroxide solution 100mL is added in, is heated to reflux for 24 hours, being cooled to 30 DEG C, filtrate is filtered by vacuum to obtain,
Filtrate is diluted with salt-free water, is passed through loading in chromatography column, collects active ingredient, concentration, freeze to get.
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| CN106866756A (en) * | 2017-01-10 | 2017-06-20 | 苏利制药科技江阴有限公司 | A kind of method for synthesizing 1 N Netilmicins |
| CN107652334A (en) * | 2017-09-13 | 2018-02-02 | 无锡济民可信山禾药业股份有限公司 | The synthetic method of 3 N ethyl Gentamicin C1as |
| CN109134558A (en) * | 2018-09-21 | 2019-01-04 | 常州方圆制药有限公司 | A kind of synthetic method for improving the yield of 1-N-ethyl gentamicin Cla |
| CN113185561A (en) * | 2021-04-24 | 2021-07-30 | 无锡济煜山禾药业股份有限公司 | Method for obtaining 1-N-ethyl gentamicin C1a by pipeline reaction hydrolysis |
| CN114213471A (en) * | 2021-12-27 | 2022-03-22 | 无锡福祈制药有限公司 | Synthesis method of etimicin |
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