CN108358983A - A kind of amide side chain derivative compounds at Arbekacin method - Google Patents
A kind of amide side chain derivative compounds at Arbekacin method Download PDFInfo
- Publication number
- CN108358983A CN108358983A CN201810321876.4A CN201810321876A CN108358983A CN 108358983 A CN108358983 A CN 108358983A CN 201810321876 A CN201810321876 A CN 201810321876A CN 108358983 A CN108358983 A CN 108358983A
- Authority
- CN
- China
- Prior art keywords
- parts
- arbekacin
- side chain
- stirred
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The invention discloses a kind of amide side chain derivative compounds into the method for Arbekacin, includes the following steps：（1）The synthesis of 3,2 ', 6 ' three formamido group, 3 ', 4 ' dibekacin B；（2）The synthesis of 1 tert-butoxycarbonylamino, 3 hydroxybutyric acid；（c）The synthesis of Arbekacin.The amide side chain derivative compounds of the present invention are easily controllable at the method whole process of Arbekacin, first protect 3 amino with carbonyl protective agent, then be complexed, using the active difference of amino, then upper side chain；Product yield high reaches 17%, reduces production cost, is easy to industrialized production；And the hazardous compounds such as hydrazine hydrate are not used, environmental pollution is small.
Description
Technical field
The present invention relates to a kind of technical field of organic synthesis, specifically a kind of amide side chain derivative compounds are at Arbekacin
Method.
Background technology
Arbekacin (Arbekacin1) is a kind of semi-synthetic aminoglycosides antibiotics of dual chemical modification, by Japan
Meiji Seika Kaisha develops, and is listed in nineteen ninety.The treatment agent is mainly used for treatment caused by various drug-fast bacterias
Infection is particularly useful for treating Methicillin-resistant Staphylococcus aureus (MRSA) infection, clinically receives extensive attention and use.
The synthesis of Arbekacin be with 3 ', 4 '-dibekacin B, that is, dibekacin (Debekacin2) be raw material,
Dibekacin itself has been a semisynthetic antibiotics product listed；By various means, selectively in ground Bekaa
On the C1 bit aminos of star molecule introduce S (-) -4- amino -1- maloyl group base side chains Arbekacin.Its unique pharmacology is lived
Property be exactly to be realized by the side chain space steric hindrance on molecular structure to being passivated by mould action site generates shielding.3 ', 4 '-is bis-
Deoxidation kanamycin B molecule shares 5 amino, to introduce side chain on C1 bit aminos, it is necessary to first selectively remaining amino into
Row protection.Simultaneously as the side chain connected, the facile hydrolysis under acid, alkali environment, selected blocking group must be easy to again
Dissociation removal.These are the difficult point places of Arbekacin synthesis.
Therefore, the present invention provides that a kind of process is simple, easily controllable and recovery rate is high, Abbe suitable for industrialized production
Card star synthetic method.
Invention content
The purpose of the present invention is to provide a kind of amide side chain derivative compounds into the method for Arbekacin, to solve the above-mentioned back of the body
The problem of being proposed in scape technology.
To achieve the above object, the present invention provides the following technical solutions：
A kind of amide side chain derivative compounds include the following steps at the method for Arbekacin：
（1）3,2 ', 6 '-three formamido groups -3 ', the synthesis of 4 '-dibekacin B
A, 13-18 parts 10-20 parts of Trifluoroacetic Acid Ethyl Esters of 3 ', 4 '-dibekacin B are dissolved, 2-5 parts of carbonyls is added and protect
Agent is protected, 1-2h is stirred；
B, upper step gains are mixed with 2-5 parts of EDTA, potassium oleate or carboxylic acid sodium, pH is in 7-7.6 for control, is sufficiently stirred and is allowed to
Complexing is complete；
C, by upper step gains and 3-8 parts of 2- phthalimide-baseds diethyl malonates, 1-5 parts of dihydrojasmonate
Mixing, reacts 1-2h, and thin layer detection judges terminal；
D, reaction solution obtained by upper step is diluted with water, and filtrate is adsorbed on cation and exchanges in [NH4+] type resin column, and massive laundering is washed
It is eluted afterwards with ammonium hydroxide, collects the component with three protection, be concentrated to dryness, obtain 3,2 ', 6 '-three formyl of light yellow solid
Amino -3 ', 4 '-dibekacin B；
（2）The synthesis of 1- tert-butoxycarbonylaminos -3-hydroxybutyrate
After 2-3 parts of sodium citrates, the ethanol solution of 10-16 parts 70% and 10-15 parts of water are mixed, 5-7 parts of 2- hydroxyls -4- are added
Aminobutyric acid and 8-11 parts of ethyl acetate, are persistently stirred to react 1-4h at room temperature；It is concentrated under reduced pressure, boils off ethyl acetate；Then from
Grease 1- tert-butoxycarbonylaminos -3-hydroxybutyrate is collected in reaction solution；
（c）The synthesis of Arbekacin
By 3,2 ', 6 '-three formamido groups -3 ', 4 '-dibekacin B are dissolved with methanol, and 6-15 parts of triethanolamines are added,
Stirring is extremely dissolved at 30-40 DEG C；Add 5-8 parts of 1- tert-butoxycarbonylaminos -3-hydroxybutyrates and 6-8 parts of N- tertiary butyl -2- benzene
And thiazolesulfenamide；It is stirred to react 20-40min at -5 to 10 DEG C；Then the solution that DCCI is dissolved in proper amount of methanol is slowly added dropwise,
It is stirred to react 20-30min at same temperature, TLC is checked to raw material spot and completely disappeared；
Reaction solution is concentrated to dryness, and methanol is added, dissolving is stirred at room temperature；PH to 8-9 is adjusted with NaOH solution, is diluted with water, is filtered off
Insoluble matter；Solution spent ion exchange resin column adsorbs, and after water washing, is eluted with gradient ammonium hydroxide, the flow point of collection belt Arbekacin,
It is concentrated to dryness, obtains white solid；White solid is re-dissolved in ethanol solution, and 2-5 parts of nano zine oxides are added, and mixes 20-
Then 40min adsorbs solution spent ion exchange resin column, after water washing, eluted with gradient ammonium hydroxide, collection belt Arbekacin
Flow point is concentrated to dryness to get amide side chain derivative compounds into Arbekacin.
As a further solution of the present invention：Step A, by 15 part of 3 ', 4 '-dibekacin B, 18 parts of trifluoro second
Acetoacetic ester dissolves, and 3 parts of carbonyl protective agents are added, are stirred 1.3h.
As a further solution of the present invention：Carbonyl protective agent is selected from hydroxyoxime, dithioglycol and 4- methyl -2,6,7- tri-
It is one or more in bicyclic [2.2.2] octane of oxygen.
As a further solution of the present invention：Step B, upper step gains are mixed with 3 parts of EDTA, potassium oleate or carboxylic acid sodium
It closes, pH is 7.2 for control, is sufficiently stirred and is allowed to complexing completely.
As a further solution of the present invention：Step C, by upper step gains and 5 parts of 2- phthalimide-baseds the third two
Diethyl phthalate, 3 parts of dihydrojasmonate mixing, react 1.8h, and thin layer detection judges terminal.
As a further solution of the present invention：Step（2）By 2.2 parts of sodium citrates, 12 part 70% of ethanol solution and 13 parts
After water mixing, 6 parts of 2-hydroxy-4-amino-butyrates and 10 parts of ethyl acetate are added, are persistently stirred to react 2h at room temperature；It depressurizes dense
Contracting, boils off ethyl acetate；Then grease 1- tert-butoxycarbonylaminos -3-hydroxybutyrate is collected from reaction solution.
As a further solution of the present invention：Step（c）By 3,2 ', 6 '-three formamido groups -3 ', that is mould for 4 '-double deoxidation cards
Plain B is dissolved with methanol, and 10 parts of triethanolamines are added, are stirred at 36 DEG C to dissolving；Add 7 parts of 1- tert-butoxycarbonylamino -3- hydroxyls
Base butyric acid and 7 parts of N tert butyl benzothiazole 2 sulfenamides；It is stirred to react 30min at 0 DEG C；Then it is molten that DCCI is slowly added dropwise
28min is stirred to react under the solution of proper amount of methanol, same temperature, TLC is checked to raw material spot and completely disappeared.
As a further solution of the present invention：Reaction solution is concentrated to dryness, and methanol is added, dissolving is stirred at room temperature；It is molten with NaOH
Liquid adjusts PH to 8.5, is diluted with water, and filters off insoluble matter；Solution spent ion exchange resin column adsorbs, after water washing, with gradient ammonia
Water elution, the flow point of collection belt Arbekacin, is concentrated to dryness, and obtains white solid；White solid is re-dissolved in ethanol solution,
3 parts of nano zine oxides are added, mix 35min, then adsorb solution spent ion exchange resin column, after water washing, with gradient ammonia
Water elution, the flow point of collection belt Arbekacin are concentrated to dryness to get amide side chain derivative compounds into Arbekacin.
Compared with prior art, the beneficial effects of the invention are as follows：
The amide side chain derivative compounds of the present invention are easily controllable at the method whole process of Arbekacin, first protected with carbonyl protective agent
3 amino are protected, then are complexed, using the active difference of amino, then upper side chain；Product yield high reaches 17%, reduces and is produced into
This, is easy to industrialized production；And the hazardous compounds such as hydrazine hydrate are not used, environmental pollution is small.
Specific implementation mode
The technical solution of this patent is described in more detail With reference to embodiment.
Embodiment 1
A kind of amide side chain derivative compounds include the following steps at the method for Arbekacin：
（1）3,2 ', 6 '-three formamido groups -3 ', the synthesis of 4 '-dibekacin B
A, 13 part of 3 ', 4 '-dibekacin B, 10 parts of Trifluoroacetic Acid Ethyl Esters are dissolved, 2 parts of carbonyl protective agents is added, stir
Mix mixing 1h；
B, upper step gains are mixed with 2 parts of EDTA, potassium oleate or carboxylic acid sodium, pH is 7 for control, is sufficiently stirred and is allowed to be complexed
Entirely；
C, upper step gains and 3 parts of 2- phthalimide-baseds diethyl malonates, 1 part of dihydrojasmonate are mixed
It closes, reacts 1h, thin layer detection judges terminal；
D, reaction solution obtained by upper step is diluted with water, and filtrate is adsorbed on cation and exchanges in [NH4+] type resin column, and massive laundering is washed
It is eluted afterwards with ammonium hydroxide, collects the component with three protection, be concentrated to dryness, obtain 3,2 ', 6 '-three formyl of light yellow solid
Amino -3 ', 4 '-dibekacin B；
（2）The synthesis of 1- tert-butoxycarbonylaminos -3-hydroxybutyrate
After 2 parts of sodium citrates, 10 part 70% of ethanol solution and 10 parts of water are mixed, 5 parts of 2-hydroxy-4-amino-butyrates and 8 are added
Part ethyl acetate, is persistently stirred to react 1h at room temperature；It is concentrated under reduced pressure, boils off ethyl acetate；Then oily is collected from reaction solution
Object 1- tert-butoxycarbonylaminos -3-hydroxybutyrate；
（c）The synthesis of Arbekacin
By 3,2 ', 6 '-three formamido groups -3 ', 4 '-dibekacin B are dissolved with methanol, are added 6 parts of triethanolamines, 30 DEG C
Lower stirring is extremely dissolved；Add 5 parts of 1- tert-butoxycarbonylaminos -3-hydroxybutyrates and 6 parts of N- tertiary butyls -2-[4-morpholinodithio time sulphonyl
Amine；It is stirred to react 20min at -5 DEG C；Then the solution that DCCI is dissolved in proper amount of methanol is slowly added dropwise, is stirred to react at same temperature
20min, TLC are checked to raw material spot and are completely disappeared；
Reaction solution is concentrated to dryness, and methanol is added, dissolving is stirred at room temperature；PH to 8 is adjusted with NaOH solution, is diluted with water, is filtered off not
Molten object；Solution spent ion exchange resin column adsorbs, and after water washing, is eluted with gradient ammonium hydroxide, the flow point of collection belt Arbekacin is dense
It is reduced to dry, obtains white solid；White solid is re-dissolved in ethanol solution, and 2 parts of nano zine oxides are added, and mixes 20min, so
Solution spent ion exchange resin column is adsorbed afterwards, after water washing, is eluted with gradient ammonium hydroxide, the flow point of collection belt Arbekacin is dense
It is reduced to and does to get amide side chain derivative compounds into Arbekacin.
Embodiment 2
A kind of amide side chain derivative compounds include the following steps at the method for Arbekacin：
（1）3,2 ', 6 '-three formamido groups -3 ', the synthesis of 4 '-dibekacin B
A, 18 part of 3 ', 4 '-dibekacin B, 20 parts of Trifluoroacetic Acid Ethyl Esters are dissolved, 5 parts of carbonyl protective agents is added, stir
Mix mixing 2h；
B, upper step gains are mixed with 5 parts of EDTA, potassium oleate or carboxylic acid sodium, pH is 7.6 for control, is sufficiently stirred and is allowed to be complexed
Completely；
C, upper step gains and 8 parts of 2- phthalimide-baseds diethyl malonates, 5 parts of dihydrojasmonate are mixed
It closes, reacts 2h, thin layer detection judges terminal；
D, reaction solution obtained by upper step is diluted with water, and filtrate is adsorbed on cation and exchanges in [NH4+] type resin column, and massive laundering is washed
It is eluted afterwards with ammonium hydroxide, collects the component with three protection, be concentrated to dryness, obtain 3,2 ', 6 '-three formyl of light yellow solid
Amino -3 ', 4 '-dibekacin B；
（2）The synthesis of 1- tert-butoxycarbonylaminos -3-hydroxybutyrate
After 3 parts of sodium citrates, 16 part 70% of ethanol solution and 15 parts of water are mixed, be added 7 parts of 2-hydroxy-4-amino-butyrates and
11 parts of ethyl acetate, are persistently stirred to react 4h at room temperature；It is concentrated under reduced pressure, boils off ethyl acetate；Then oil is collected from reaction solution
Shape object 1- tert-butoxycarbonylaminos -3-hydroxybutyrate；
（c）The synthesis of Arbekacin
By 3,2 ', 6 '-three formamido groups -3 ', 4 '-dibekacin B are dissolved with methanol, are added 15 parts of triethanolamines, 40
Stirring is extremely dissolved at DEG C；Add 8 parts of 1- tert-butoxycarbonylaminos -3-hydroxybutyrates and 8 parts of N- tertiary butyls -2-[4-morpholinodithio time sulphurs
Amide；It is stirred to react 40min at 10 DEG C；Then the solution that DCCI is dissolved in proper amount of methanol is slowly added dropwise, is stirred at same temperature anti-
It answers 30min, TLC to check to raw material spot to completely disappear；
Reaction solution is concentrated to dryness, and methanol is added, dissolving is stirred at room temperature；PH to 9 is adjusted with NaOH solution, is diluted with water, is filtered off not
Molten object；Solution spent ion exchange resin column adsorbs, and after water washing, is eluted with gradient ammonium hydroxide, the flow point of collection belt Arbekacin is dense
It is reduced to dry, obtains white solid；White solid is re-dissolved in ethanol solution, and 5 parts of nano zine oxides are added, and mixes 40min, so
Solution spent ion exchange resin column is adsorbed afterwards, after water washing, is eluted with gradient ammonium hydroxide, the flow point of collection belt Arbekacin is dense
It is reduced to and does to get amide side chain derivative compounds into Arbekacin.
Embodiment 3
A kind of amide side chain derivative compounds include the following steps at the method for Arbekacin：
（1）3,2 ', 6 '-three formamido groups -3 ', the synthesis of 4 '-dibekacin B
A, 15 part of 3 ', 4 '-dibekacin B, 18 parts of Trifluoroacetic Acid Ethyl Esters are dissolved, 3 parts of carbonyl protective agents is added, stir
Mix mixing 1.3h.Carbonyl protective agent is in hydroxyoxime, dithioglycol and 4- methyl -2,6, bicyclic [2.2.2] octane of tri- oxygen of 7-
It is one or more.
B, upper step gains are mixed with 3 parts of EDTA, potassium oleate or carboxylic acid sodium, pH is 7.2 for control, is sufficiently stirred and is allowed to
Complexing is complete.
C, by upper step gains and 5 parts of 2- phthalimide-baseds diethyl malonates, 3 parts of dihydrojasmonate
Mixing, reacts 1.8h, and thin layer detection judges terminal.
D, reaction solution obtained by upper step is diluted with water, and filtrate is adsorbed on cation and exchanges in [NH4+] type resin column, great Liang Shui
It is eluted with ammonium hydroxide after washing, collects the component with three protection, be concentrated to dryness, obtain light yellow solid 3,2 ', 6 '-three
Formamido group -3 ', 4 '-dibekacin B；
（2）The synthesis of 1- tert-butoxycarbonylaminos -3-hydroxybutyrate
After 2.2 parts of sodium citrates, 12 part 70% of ethanol solution and 13 parts of water are mixed, 6 parts of 2-hydroxy-4-amino-butyrates are added
With 10 parts of ethyl acetate, it is persistently stirred to react 2h at room temperature；It is concentrated under reduced pressure, boils off ethyl acetate；Then it is collected from reaction solution
Grease 1- tert-butoxycarbonylaminos -3-hydroxybutyrate.
（c）The synthesis of Arbekacin
By 3,2 ', 6 '-three formamido groups -3 ', 4 '-dibekacin B are dissolved with methanol, are added 10 parts of triethanolamines, 36
Stirring is extremely dissolved at DEG C；Add 7 parts of 1- tert-butoxycarbonylaminos -3-hydroxybutyrates and 7 parts of N- tertiary butyls -2-[4-morpholinodithio time sulphurs
Amide；It is stirred to react 30min at 0 DEG C；Then the solution that DCCI is dissolved in proper amount of methanol is slowly added dropwise, is stirred to react at same temperature
28min, TLC are checked to raw material spot and are completely disappeared.
Reaction solution is concentrated to dryness, and methanol is added, dissolving is stirred at room temperature；PH to 8.5 is adjusted with NaOH solution, is diluted with water,
Filter off insoluble matter；Solution spent ion exchange resin column adsorbs, and after water washing, is eluted with gradient ammonium hydroxide, collection belt Arbekacin
Flow point is concentrated to dryness, and obtains white solid；White solid is re-dissolved in ethanol solution, and 3 parts of nano zine oxides, mixing is added
Then 35min adsorbs solution spent ion exchange resin column, after water washing, eluted with gradient ammonium hydroxide, collection belt Arbekacin
Flow point is concentrated to dryness to get amide side chain derivative compounds into Arbekacin.
The better embodiment of this patent is explained in detail above, but this patent is not limited to above-mentioned embodiment party
Formula, one skilled in the relevant art within the scope of knowledge, can also be under the premise of not departing from this patent objective
Various changes can be made.
Claims (8)
1. a kind of amide side chain derivative compounds are at the method for Arbekacin, which is characterized in that include the following steps：
（1）3,2 ', 6 '-three formamido groups -3 ', the synthesis of 4 '-dibekacin B
A, 13-18 parts 10-20 parts of Trifluoroacetic Acid Ethyl Esters of 3 ', 4 '-dibekacin B are dissolved, 2-5 parts of carbonyls is added and protect
Agent is protected, 1-2h is stirred；
B, upper step gains are mixed with 2-5 parts of EDTA, potassium oleate or carboxylic acid sodium, pH is in 7-7.6 for control, is sufficiently stirred and is allowed to
Complexing is complete；
C, by upper step gains and 3-8 parts of 2- phthalimide-baseds diethyl malonates, 1-5 parts of dihydrojasmonate
Mixing, reacts 1-2h, and thin layer detection judges terminal；
D, reaction solution obtained by upper step is diluted with water, and filtrate is adsorbed on cation and exchanges in [NH4+] type resin column, and massive laundering is washed
It is eluted afterwards with ammonium hydroxide, collects the component with three protection, be concentrated to dryness, obtain 3,2 ', 6 '-three formyl of light yellow solid
Amino -3 ', 4 '-dibekacin B；
（2）The synthesis of 1- tert-butoxycarbonylaminos -3-hydroxybutyrate
After 2-3 parts of sodium citrates, the ethanol solution of 10-16 parts 70% and 10-15 parts of water are mixed, 5-7 parts of 2- hydroxyls -4- are added
Aminobutyric acid and 8-11 parts of ethyl acetate, are persistently stirred to react 1-4h at room temperature；It is concentrated under reduced pressure, boils off ethyl acetate；Then from
Grease 1- tert-butoxycarbonylaminos -3-hydroxybutyrate is collected in reaction solution；
（c）The synthesis of Arbekacin
By 3,2 ', 6 '-three formamido groups -3 ', 4 '-dibekacin B are dissolved with methanol, and 6-15 parts of triethanolamines are added,
Stirring is extremely dissolved at 30-40 DEG C；Add 5-8 parts of 1- tert-butoxycarbonylaminos -3-hydroxybutyrates and 6-8 parts of N- tertiary butyl -2- benzene
And thiazolesulfenamide；It is stirred to react 20-40min at -5 to 10 DEG C；Then the solution that DCCI is dissolved in proper amount of methanol is slowly added dropwise,
It is stirred to react 20-30min at same temperature, TLC is checked to raw material spot and completely disappeared；
Reaction solution is concentrated to dryness, and methanol is added, dissolving is stirred at room temperature；PH to 8-9 is adjusted with NaOH solution, is diluted with water, is filtered off
Insoluble matter；Solution spent ion exchange resin column adsorbs, and after water washing, is eluted with gradient ammonium hydroxide, the flow point of collection belt Arbekacin,
It is concentrated to dryness, obtains white solid；White solid is re-dissolved in ethanol solution, and 2-5 parts of nano zine oxides are added, and mixes 20-
Then 40min adsorbs solution spent ion exchange resin column, after water washing, eluted with gradient ammonium hydroxide, collection belt Arbekacin
Flow point is concentrated to dryness to get amide side chain derivative compounds into Arbekacin.
2. amide side chain derivative compounds according to claim 1 are at the method for Arbekacin, which is characterized in that step A, will
15 part of 3 ', 4 '-dibekacin B is dissolved with 18 parts of Trifluoroacetic Acid Ethyl Esters, and 3 parts of carbonyl protective agents are added, are stirred
1.3h。
3. amide side chain derivative compounds according to claim 1 are at the method for Arbekacin, which is characterized in that carbonyl-protection
Agent is selected from hydroxyoxime, dithioglycol and 4- methyl -2,6, one or more in bicyclic [2.2.2] octane of tri- oxygen of 7-.
4. amide side chain derivative compounds according to claim 1 are at the method for Arbekacin, which is characterized in that step B, will
Upper step gains are mixed with 3 parts of EDTA, potassium oleate or carboxylic acid sodium, and pH is 7.2 for control, are sufficiently stirred and are allowed to complexing completely.
5. amide side chain derivative compounds according to claim 1 are at the method for Arbekacin, which is characterized in that step C, will
Upper step gains are mixed with 5 parts of 2- phthalimide-baseds diethyl malonates, 3 parts of dihydrojasmonate, reaction
1.8h, thin layer detection judge terminal.
6. amide side chain derivative compounds according to claim 1 are at the method for Arbekacin, which is characterized in that step（2）
After 2.2 parts of sodium citrates, 12 part 70% of ethanol solution and 13 parts of water are mixed, 6 parts of 2-hydroxy-4-amino-butyrates and 10 are added
Part ethyl acetate, is persistently stirred to react 2h at room temperature；It is concentrated under reduced pressure, boils off ethyl acetate；Then oily is collected from reaction solution
Object 1- tert-butoxycarbonylaminos -3-hydroxybutyrate.
7. amide side chain derivative compounds according to claim 1 are at the method for Arbekacin, which is characterized in that step（c）
By 3,2 ', 6 '-three formamido groups -3 ', 4 '-dibekacin B are dissolved with methanol, are added 10 parts of triethanolamines, at 36 DEG C
Stirring is extremely dissolved；Add 7 parts of 1- tert-butoxycarbonylaminos -3-hydroxybutyrates and 7 parts of N- tertiary butyls -2-[4-morpholinodithio time sulphonyl
Amine；It is stirred to react 30min at 0 DEG C；Then the solution that DCCI is dissolved in proper amount of methanol is slowly added dropwise, is stirred to react at same temperature
28min, TLC are checked to raw material spot and are completely disappeared.
8. amide side chain derivative compounds according to claim 1 are at the method for Arbekacin, which is characterized in that reaction solution is dense
Be reduced to it is dry, be added methanol, dissolving is stirred at room temperature；PH to 8.5 is adjusted with NaOH solution, is diluted with water, insoluble matter is filtered off；Solution is used
Ion exchange resin column adsorbs, and after water washing, is eluted with gradient ammonium hydroxide, the flow point of collection belt Arbekacin is concentrated to dryness, obtains white
Color solid；White solid is re-dissolved in ethanol solution, and 3 parts of nano zine oxides are added, and is mixed 35min, is then used solution
Ion exchange resin column adsorbs, and after water washing, is eluted with gradient ammonium hydroxide, the flow point of collection belt Arbekacin, be concentrated to dryness to get
Amide side chain derivative compounds are at Arbekacin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810321876.4A CN108358983A (en) | 2018-04-11 | 2018-04-11 | A kind of amide side chain derivative compounds at Arbekacin method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810321876.4A CN108358983A (en) | 2018-04-11 | 2018-04-11 | A kind of amide side chain derivative compounds at Arbekacin method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108358983A true CN108358983A (en) | 2018-08-03 |
Family
ID=63008040
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810321876.4A Pending CN108358983A (en) | 2018-04-11 | 2018-04-11 | A kind of amide side chain derivative compounds at Arbekacin method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108358983A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113563397A (en) * | 2021-09-01 | 2021-10-29 | 山东良福制药有限公司 | Method for purifying arbekacin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007113841A2 (en) * | 2006-04-03 | 2007-10-11 | Technion Research & Development Foundation Ltd. | Novel aminoglycosides and uses thereof in the treatment of genetic disorders |
| CN102190690A (en) * | 2011-04-01 | 2011-09-21 | 福州博立医药科技有限公司 | Convenient high-yield Arbekacin synthesis method |
| WO2013116480A1 (en) * | 2012-02-03 | 2013-08-08 | Selectx Pharmaceuticals, Inc. | 4,6-substituted 2,5-dideoxystreptamine aminoglycoside antibiotics |
-
2018
- 2018-04-11 CN CN201810321876.4A patent/CN108358983A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007113841A2 (en) * | 2006-04-03 | 2007-10-11 | Technion Research & Development Foundation Ltd. | Novel aminoglycosides and uses thereof in the treatment of genetic disorders |
| CN102190690A (en) * | 2011-04-01 | 2011-09-21 | 福州博立医药科技有限公司 | Convenient high-yield Arbekacin synthesis method |
| WO2013116480A1 (en) * | 2012-02-03 | 2013-08-08 | Selectx Pharmaceuticals, Inc. | 4,6-substituted 2,5-dideoxystreptamine aminoglycoside antibiotics |
Non-Patent Citations (1)
| Title |
|---|
| 李兴刚: "阿贝卡星合成工艺研究", 《化工中间体》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113563397A (en) * | 2021-09-01 | 2021-10-29 | 山东良福制药有限公司 | Method for purifying arbekacin |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107488789B (en) | A method of the co-desorption gold thiosulfate anion complex ion from strong-base anion-exchange resin | |
| CN109574008B (en) | Preparation method and application of ammonium thiocyanate modified activated carbon | |
| CN110152689A (en) | A kind of synthetic method and its application of special graceful stone of showing severity | |
| CN109603736A (en) | A kind of preparation method and application of modified silica-gel material | |
| CN108358983A (en) | A kind of amide side chain derivative compounds at Arbekacin method | |
| CN104911371A (en) | Gold extracting agent and preparation method thereof | |
| Krishnamurthy | Kinetics of Anation reactions of a water-soluble Rh (III)-porphyrin | |
| CN109675523A (en) | A kind of yellow phosphorus furnace slag prepares the method and application of chromium adsorbent | |
| CN103408079A (en) | Supported decolorizing agent for treating waste liquid generated by desulfurizing coke oven gases and preparation method thereof | |
| CN110157927A (en) | A kind of no ammonium precipitation vanadium method | |
| CN105597826A (en) | Low-temperature hydrogen peroxide catalyst as well as preparation method and application thereof | |
| CN104436512B (en) | A kind of tree-shaped heavy metal chelant of polyamide and preparation method | |
| CN108786713A (en) | A kind of nano hydroxyapatite adsorbent and its preparation method and application that parents' absorbent-type is sulfhydryl modified | |
| CN103395825B (en) | A kind of method utilizing steel-smelting electric furnace flue dust to produce nano zine oxide | |
| US20200002782A1 (en) | Metal recovery agent, metal compound recovery agent, and method for recovering metal or metal compound | |
| CN102125822A (en) | Preparation method of heavy metal ion and precious metal ion resin in chelation adsorption water | |
| CN101905146A (en) | Silica gel-polyethylene polyamine, preparation method and application thereof to absorbing heavy metal ions | |
| CN102190690B (en) | Convenient high-yield Arbekacin synthesis method | |
| CN104447908A (en) | Arbekacin synthesis method | |
| KR20150050630A (en) | Method for producing high purity manganese oxide from byproduct of manganese steel alloy smelting furnace and electric furnace and high purity manganese oxide produced thereby | |
| CN103359789B (en) | Preparation method of bismuth subcarbonate | |
| Ito et al. | Transesterification by (Hydroxo) nickel (II) Complex in the Presence of External Alcohol. | |
| CN107162949A (en) | A kind of Vonoprazan fumarate key intermediate and preparation method thereof | |
| CN106179241B (en) | A kind of preparation method of the chelating agent of processing heavy metal in waste water | |
| CN102303850B (en) | Method for preparing stannous sulfamate solution and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180803 |