CN109134558A - A kind of synthetic method improving 1-N- ethyl gentamicinC la yield - Google Patents
A kind of synthetic method improving 1-N- ethyl gentamicinC la yield Download PDFInfo
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- CN109134558A CN109134558A CN201811106962.XA CN201811106962A CN109134558A CN 109134558 A CN109134558 A CN 109134558A CN 201811106962 A CN201811106962 A CN 201811106962A CN 109134558 A CN109134558 A CN 109134558A
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- 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
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- 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 present invention discloses a kind of raising 1-N- ethyl gentamicinClaThe synthetic method of yield, includes the following steps, 3,2 ' 6 '-N- triacetyl gentamicinCs are added into reaction flask1a, methylene chloride, fatty amine, at room temperature be added triphosgene DCM solution, react 4-6h after, ice water quenching reaction takes organic phase to be concentrated to get solid 1；Solid 1 is dissolved in methylene chloride, the concentrated sulfuric acid and silated reagent is added, compound 2 is concentrated to dryness to obtain after being heated to reflux；Compound 2 is dissolved in methylene chloride, acetaldehyde is added, buffer and potassium borohydride are added after being stirred to react, continues to stir, is concentrated to dryness to obtain compound 3；Etimicin finished product is obtained after compound 3 is post-processed.The present invention is directed to the amido of 3 " numbers positions and the hydroxyl of 4 " numbers positions is pre-processed, and then is protecting other amidos and hydroxyl, can significantly improve the yield of main reaction, the generation of side reaction is greatly reduced, improve target product yield.
Description
Technical field
The present invention relates to a kind of preparation methods of medicinal raw material, and in particular to a kind of raising 1-N- ethyl gentamicinC la
The synthetic method of yield.
Background technique
Etimicin Sulfate (Etimicinsulfate) is that China scientific research personnel voluntarily develops, and possesses independent intellectual production
Efficient, less toxic, antimicrobial agent a new generation of power partly prepares aminoglycoside antibiotics, is that unique first class national new drug that obtains is demonstrate,proved
The anti-infectives of book.Need to use intermediate 1-N- ethyl gentamicinC in Etimicin preparation process1a, in Chinese patent
Number be 201010132962.4 patent 1-N- ethyl gentamicinClaPreparation method in report for No. 3 positions, the position 2',
These three amidos of the position 6' and No. 5 positions, 2 " numbers positions, the safeguard measure of 4 " numbers these three hydroxyls of position, but not to the amine of 3 " numbers positions
Base is protected, so that in reductive amination process, the amido of 3 " numbers positions and the amido of No. 1 position form competitive reaction, produces pair
Reaction, causes the main reaction yield of No. 1 position amido to reduce, and reduces so as to cause the yield of target product, and yield only has 45% left side
It is right.
Fmoc- is used in a kind of preparation method of Etimicin Sulfate of patent that China Patent No. is CN104231016A
Cl protects gentamicinCla3,2', 6', 3 " bit aminos, it is purified, be evaporated after obtain four fluorenylmethyloxycarbonyl gentamicinCsla:
Then acetaldehyde solution N-ethylization is added in acid condition, then is restored using sodium triacetoxy borohydride；Finally
Piperidines/DMSO solution deprotection is added, this patent reports the safeguard measures of the amido and other amidos that are directed to 3 " numbers positions, but
Protective agent fluorenes methoxy dicarbonyl chloride can also be chemically reacted with No. 1 position amido and the production of other hydroxyls, to also result in No. 1 position amido
Main reaction yield reduce, so as to cause target product yield reduce.
Summary of the invention
It is a primary object of the present invention to overcome existing 1-N- ethyl gentamicinClaExisting for the synthetic method of yield
Defect provides a kind of raising 1-N- ethyl gentamicinClaThe synthetic method of yield, amido for 3 " numbers positions and 4 " numbers positions
Hydroxyl is pre-processed, and then is protecting other amidos and hydroxyl, can significantly improve the yield of main reaction, pair is greatly reduced
The generation of reaction improves target product yield, thus more suitable for practical, and with the utility value in industry.
The object of the invention to solve the technical problems adopts the following technical solutions to realize.
A kind of raising 1-N- ethyl gentamicinClaThe synthetic method of yield, includes the following steps:
3,2 ' 6 '-N- triacetyl gentamicinCs are added into reaction flask for step 11a, methylene chloride, fatty amine, at room temperature
The DCM solution of triphosgene is added, after reacting 4-6h, system uses ice water quenching reaction after reaction, take organic phase in clarification shape
It is concentrated to get solid 1；
The solid 1 that step 1 obtains is dissolved in methylene chloride by step 2, is added in three mouthfuls of reaction flasks with reflux unit, and stirring adds
Enter the concentrated sulfuric acid and silated reagent, heating reflux reaction 3-5h is concentrated to dryness to obtain compound 2；
The compound 2 that step 2 obtains is dissolved in methylene chloride by step 3, and acetaldehyde is added, and after being stirred to react 0.5-2h, buffering is added
Liquid and potassium borohydride continue after stirring 1.5h, are concentrated to dryness to obtain compound 3；
Sodium hydroxide solution is added into the compound 3 that step 3 obtains in step 4, is heated to reflux, and obtains the trip of product Etimicin
Obtained hydrolyzate is neutralized by the hydrolyzate from alkali, chromatographs to obtain desorbed solution using column, desorbed solution is concentrated to dryness
Obtain Etimicin finished product.
Preferably, fatty amine be diethylamine, it is triethylamine, isopropylamine, sec-butylamine, n-butylamine, cyclopropylamine, any in hexylamine
It is a kind of.
Preferably, silated reagent is hexamethyldisilazane, tetramethyl-disilazane, hexamethyl cyclotrisilazane, ring
Disilazane, first silicon substrate-ring-disilazane, trim,ethylchlorosilane, any one in bromo-silicane.
Preferably, 3,2 ' 6 '-N- triacetyl gentamicinC in step 11aIt is 2 with the molar ratio of organic amine and triphosgene:
4:1；According to 3,2 ' 6 '-N- triacetyl gentamicinCs1aDosage calculates, 3,2 ' 6 '-N- triacetyl gentamicin of 1mmol
C1aThe dosage of corresponding methylene chloride is 4-5ml.
Preferably, according to 3,2 ' 6 '-N- triacetyl gentamicinC in the step 11aDosage calculates, 1mmol 3,2 '
6 '-N- triacetyl gentamicinCs1aSilated reagent dosage is 4-6mmol in the corresponding step 2, in the corresponding step 2
The methylene chloride is 1-3ml.
Preferably, in step 3 buffer be pH=9-10 borate buffer, according in step 13,2 ' 6 '-N- triacetyls
Base gentamicinC1aDosage calculates, 3,2 ' 6 '-N- triacetyl gentamicinC of 1mmol1a, hydroboration described in corresponding step 3
The dosage of potassium is 0.1-0.2g, and the dosage of acetaldehyde described in corresponding step 3 is 0.1-0.3ml.
Preferably, the sodium hydroxide solution mass fraction in step 4 is 10%；By 3,2 ' 6 '-N- triacetyl in step 1
GentamicinC1aAmount calculate, 3,2 ' 6 '-N- triacetyl gentamicinC of 1mmol1aSodium hydroxide in the corresponding step 4
The dosage of solution is 1-3ml.
Preferably, the column chromatography in step 4 uses HD-II weakly acidic resin splitter, and purified water rushes column 8-10h, then uses
The parsing of 0.2mol/L ammonia spirit collects outlet purity >=90% purity until changing the parsing of 30% ethanol solution when outlet irrotationality light
Desorbed solution.
Preferably, the DCM solution by portions of triphosgene is added in step 1.
Preferably, after solid 1 obtained in step 1 uses column chromatographic purifying, then the behaviour of step 2, step 3, step 4 is carried out
Make.
By adopting the above technical scheme, can be realized following technology the utility model has the advantages that
(1) a kind of raising 1-N- ethyl gentamicinC provided by the inventionlaThe synthetic method of yield overcomes existing synthesis 1-N-
Ethyl gentamicinClaThe hydroxyl of the defect of method, amido and 4 " numbers positions for 3 " numbers positions is pre-processed, and 3 " numbers positions are made
Amido and the hydroxyls of 4 " numbers positions be cyclized, utilize 3,2 ' 6 '-N- triacetyl gentamicinCs1aThe amino and hydroxyl of itself
Ring is formed, achieve the purpose that amino and hydroxyl while being protected, 1-N- ethyl gentamicinC is effectively reducedlaIn synthesis process
Side reaction generation, improve 1-N- ethyl gentamicinClaYield；1-N- ethyl gentamicinC is simplified simultaneouslyla's
The step of amino and hydroxyl protection, reduces amino and hydroxyl protection adds venomous injurant caused by other protective agents in the process
The use of matter makes 1-N- ethyl gentamicinClaSynthesis technology it is safer.
(2) a kind of raising 1-N- ethyl gentamicinC provided by the inventionlaThe synthetic method of yield, it is complete using triphosgene
At the cyclisation of the hydroxyl of the amido and 4 " numbers positions of 3 " numbers positions, reaction condition is mild, and toxicity is low, and selectivity is good, is not susceptible to secondary anti-
It answers, and deprotection reaction is simple.
(3) a kind of raising 1-N- ethyl gentamicinC provided by the inventionlaThe synthetic method of yield selects rouge in step 1
The centre generated in step 1 reaction process is effectively reduced using the small feature of fatty amine steric hindrance as nucleopilic reagent in fat amine
The steric hindrance of body reduces the generation of side reaction to improve the selectivity of step 1 reaction.
(4) existing 1-N- ethyl gentamicinClaIn synthetic method, due to cloud density difference, three-dimensional effect is to hydroxyl
The selectivity and reaction rate of base protection are affected, and limitation is very big in the method for hydroxyl protection and the selection of reagent, leads to
The method of normal hydroxyl protection is complex, and reaction condition is harsher, and a kind of raising 1-N- ethyl celebrating provided by the invention is big mould
Plain ClaIn the synthetic method of yield, after the pretreatment of the hydroxyl of amido and 4 " numbers positions to 3 " numbers positions, effectively reduce subsequent
The generation of side reaction during hydroxyl protection, the selection of the method for selection and hydroxyl protection for later period hydroxy-protecting agent
It is more flexible.
Detailed description of the invention:
Attached drawing 1 is the reaction equation of embodiment 1.
Appended drawing reference
1- solid 1,2- compound 2,3- compound 3,4- Etimicin.
Specific embodiment
In order to further illustrate the present invention, combined with specific embodiments below to a kind of raising 1-N- ethyl provided by the invention
GentamicinClaThe synthetic method of yield is described in detail, but should not be construed as the limit to the scope of the present invention
It is fixed.
The present invention relates to solid 1, compound 2, compound 3 be the centre generated in the technical program implementation process
Compound.
Embodiment 1
3,2 ' 6 '-N- triacetyl gentamicinCs are added in step 1, reaction flask1a(1.15g, 2mmol), methylene chloride
The DCM(10ml of triphosgene (0.3g, 1mmol) is added portionwise at room temperature in (10ml), triethylamine (0.4g, 4mmol)) solution,
After reacting 4h, ice water quenching reaction is added after reaction, organic phase is taken to be concentrated to get solid 1 in clarification shape for system.
1.2g solid 1,5ml methylene chloride are added in three mouthfuls of reaction flasks with reflux unit step 2, and stirring is added dropwise 1
The concentrated sulfuric acid and 9.6mmol hexamethyldisilazane, heating reflux reaction 4h are dripped, compound 2 is concentrated to dryness to obtain.
Obtained compound 2 is dissolved in 5ml methylene chloride by step 3, and 0.5ml acetaldehyde is added dropwise, pH is added after being stirred to react 1h
For the borate buffer of 9-10,0.2g potassium borohydride is added, continues after stirring 1.5h, is concentrated to dryness to obtain compound 3.
Step 4,10% sodium hydroxide solution that obtained 3 system of compound is added to 4mL, heating reflux reaction
For 24 hours, the hydrolyzate of product Etimicin free alkali is obtained.Obtained hydrolyzate is neutralized, after be passed through HD-II weak acid
Property resin separating column in upper prop, purified water rushes column 9h, then parsed with 0.2mol/L ammonia spirit, to changing 30% when exporting irrotationality light
Ethanol solution parsing, collects outlet purity >=90% purity desorbed solution, is concentrated to dryness to obtain Etimicin finished product, yield 49.0%.
Embodiment 2
3,2 ' 6 '-N- triacetyl gentamicinCs are added in step 1, reaction flask1a(1.15g, 2mmol), methylene chloride
The DCM(10ml of triphosgene (0.3g, 1mmol) is added portionwise at room temperature in (8ml), diethylamine (0.29g, 4mmol)) solution,
After reacting 5h, ice water quenching reaction is added after reaction, organic phase is taken to be concentrated to get solid 1 in clarification shape for system.
1.2g solid 1,5ml methylene chloride are added in three mouthfuls of reaction flasks with reflux unit step 2, and stirring is added dropwise 1
The concentrated sulfuric acid and 9.6mmol tetramethyl-disilazane, heating reflux reaction 4h are dripped, compound 2 is concentrated to dryness to obtain.
Obtained compound 2 is dissolved in 5ml methylene chloride by step 3, and 0.5ml acetaldehyde is added dropwise, pH is added after being stirred to react 1h
For the borate buffer of 9-10,0.2g potassium borohydride is added, continues after stirring 1.5h, is concentrated to dryness to obtain compound 3.
Step 4,10% sodium hydroxide solution that obtained 3 system of compound is added to 4mL, heating reflux reaction
For 24 hours, the hydrolyzate of product Etimicin free alkali is obtained.Obtained hydrolyzate is neutralized, after be passed through HD-II weak acid
Property resin separating column in upper prop, purified water rushes column 9h, then parsed with 0.2mol/L ammonia spirit, to changing 30% when exporting irrotationality light
Ethanol solution parsing, collects outlet purity >=90% purity desorbed solution, is concentrated to dryness to obtain Etimicin finished product, yield 49.5%.
Embodiment 3
3,2 ' 6 '-N- triacetyl gentamicinC of 2mmol is added in step 1, reaction flask1a, 9ml methylene chloride, 4mmol it is different
The DCM solution of 10ml triphosgene is added portionwise at room temperature in propylamine, and wherein triphosgene is 1mmol, and after reacting 6h, system is in clear
Ice water quenching reaction is added after reaction, takes organic phase to be concentrated, solid 1 is obtained after being purified using silicagel column for clear shape.
1.2g solid 1 and 5ml methylene chloride are added in three mouthfuls of reaction flasks with reflux unit step 2, and stirring is added dropwise 1
The concentrated sulfuric acid and 9mmol trim,ethylchlorosilane, heating reflux reaction 4.5h are dripped, compound 2 is concentrated to dryness to obtain.
Obtained compound 2 is dissolved in 4ml methylene chloride by step 3, and 0.5ml acetaldehyde is added dropwise, pH is added after being stirred to react 1h
For the borate buffer of 9-10,0.2g potassium borohydride is added, continues after stirring 1h, is concentrated to dryness to obtain compound 3.
Step 4,10% sodium hydroxide solution that obtained 3 system of compound is added to 4mL, heating reflux reaction
For 24 hours, the hydrolyzate of product Etimicin free alkali is obtained.Obtained hydrolyzate is neutralized, after be passed through HD-II weak acid
Property resin separating column in upper prop, purified water rushes column 9h, then parsed with 0.2mol/L ammonia spirit, to changing 30% when exporting irrotationality light
Ethanol solution parsing, collects outlet purity >=90% purity desorbed solution, is concentrated to dryness to obtain Etimicin finished product, yield 49.3%.
Embodiment 4
3,2 ' 6 '-N- triacetyl gentamicinC of 2mmol is added in step 1, reaction flask1a, 10ml methylene chloride, 4mmol it is different
The DCM solution of 10ml triphosgene is added portionwise at room temperature in propylamine, and wherein triphosgene is 1mmol, and after reacting 5h, system is in clear
Ice water quenching reaction is added after reaction, takes organic phase to be concentrated, solid 1 is obtained after being purified using silicagel column for clear shape.
1.2g solid 1 and 5ml methylene chloride are added in three mouthfuls of reaction flasks with reflux unit step 2, and stirring is added dropwise 1
The concentrated sulfuric acid and 10mmol bromo-silicane, heating reflux reaction 5h are dripped, compound 2 is concentrated to dryness to obtain.
Obtained compound 2 is dissolved in 6ml methylene chloride by step 3, and 0.5ml acetaldehyde is added dropwise, pH is added after being stirred to react 1h
For the borate buffer of 9-10,0.2g potassium borohydride is added, continues after stirring 2h, is concentrated to dryness to obtain compound 3.
Step 4,10% sodium hydroxide solution that obtained 3 system of compound is added to 4mL, heating reflux reaction
For 24 hours, the hydrolyzate of product Etimicin free alkali is obtained.Obtained hydrolyzate is neutralized, after be passed through HD-II weak acid
Property resin separating column in upper prop, purified water rushes column 9h, then parsed with 0.2mol/L ammonia spirit, to changing 30% when exporting irrotationality light
Ethanol solution parsing, collects outlet purity >=90% purity desorbed solution, is concentrated to dryness to obtain Etimicin finished product, yield 48.8%.
Embodiment 5
3,2 ' 6 '-N- triacetyl gentamicinCs are added in step 1, reaction flask1a(1.15g, 2mmol), methylene chloride
The DCM(10ml of triphosgene (0.3g, 1mmol) is added portionwise at room temperature in (10ml), triethylamine (0.4g, 4mmol)) solution,
After reacting 4h, ice water quenching reaction is added after reaction, organic phase is taken to be concentrated to get solid 1 in clarification shape for system.
1.2g solid 1,5ml methylene chloride are added in three mouthfuls of reaction flasks with reflux unit step 2, and stirring is added dropwise 1
The concentrated sulfuric acid and 9.6mmol hexamethyldisilazane, heating reflux reaction 4h are dripped, compound 2 is concentrated to dryness to obtain.
Obtained compound 2 is dissolved in 5ml methylene chloride by step 3, and 0.5ml acetaldehyde is added dropwise, pH is added after being stirred to react 1h
For the borate buffer of 9-10,0.2g sodium borohydride is added, continues after stirring 1h, is concentrated to dryness to obtain compound 3.
Step 4,10% sodium hydroxide solution that obtained 3 system of compound is added to 4mL, heating reflux reaction
For 24 hours, the hydrolyzate of product Etimicin free alkali is obtained.Obtained hydrolyzate is neutralized, after be passed through HD-II weak acid
Property resin separating column in upper prop, purified water rushes column 9h, then parsed with 0.2mol/L ammonia spirit, to changing 30% when exporting irrotationality light
Ethanol solution parsing, collects outlet purity >=90% purity desorbed solution, is concentrated to dryness to obtain Etimicin finished product, yield 49.2%.
Embodiment 6
3,2 ' 6 '-N- triacetyl gentamicinCs are added in step 1, reaction flask1a(1.15g, 2mmol), methylene chloride
The DCM(10ml of triphosgene (0.3g, 1mmol) is added portionwise at room temperature in (8ml), diethylamine (0.29g, 4mmol)) solution,
After reacting 5h, ice water quenching reaction is added after reaction, organic phase is taken to be concentrated to get solid 1 in clarification shape for system.
1.2g solid 1,5ml methylene chloride are added in three mouthfuls of reaction flasks with reflux unit step 2, and stirring is added dropwise 1
The concentrated sulfuric acid and 9.6mmol tetramethyl-disilazane, heating reflux reaction 4h are dripped, compound 2 is concentrated to dryness to obtain.
Obtained compound 2 is dissolved in 5ml methylene chloride by step 3, and 0.5ml acetaldehyde is added dropwise, pH is added after being stirred to react 1h
For the borate buffer of 9-10,0.2g sodium borohydride is added, continues after stirring 1h, is concentrated to dryness to obtain compound 3.
Step 4,10% sodium hydroxide solution that obtained 3 system of compound is added to 4mL, heating reflux reaction
For 24 hours, the hydrolyzate of product Etimicin free alkali is obtained.Obtained hydrolyzate is neutralized, after be passed through HD-II weak acid
Property resin separating column in upper prop, purified water rushes column 9h, then parsed with 0.2mol/L ammonia spirit, to changing 30% when exporting irrotationality light
Ethanol solution parsing, collects outlet purity >=90% purity desorbed solution, is concentrated to dryness to obtain Etimicin finished product, yield 48.5%.
The above described is only a preferred embodiment of the present invention, be not intended to limit the present invention in any form, though
So the present invention has been disclosed as a preferred embodiment, and however, it is not intended to limit the invention, any technology people for being familiar with this profession
Member, without departing from the scope of the present invention, when the technology contents using the disclosure above are modified or are modified
For the equivalent embodiment of equivalent variations, but anything that does not depart from the technical scheme of the invention content, according to the technical essence of the invention
Any simple modification, equivalent change and modification to the above embodiments, all of which are still within the scope of the technical scheme of the invention.
Claims (10)
1. a kind of raising 1-N- ethyl gentamicinClaThe synthetic method of yield, which comprises the steps of:
3,2 ' 6 '-N- triacetyl gentamicinCs are added into reaction flask for step 11a, methylene chloride, fatty amine, at room temperature
The DCM solution of triphosgene is added, after reacting 4-6h, system uses ice water quenching reaction after reaction, take organic phase in clarification shape
It is concentrated to get solid 1；
The solid 1 that step 1 obtains is dissolved in methylene chloride by step 2, is added in three mouthfuls of reaction flasks with reflux unit, and stirring adds
Enter the concentrated sulfuric acid and silated reagent, heating reflux reaction 3-5h is concentrated to dryness to obtain compound 2；
The compound 2 that step 2 obtains is dissolved in methylene chloride by step 3, and acetaldehyde is added, and after being stirred to react 0.5-2h, buffering is added
Liquid and potassium borohydride continue after stirring 1.5h, are concentrated to dryness to obtain compound 3；
Sodium hydroxide solution is added into the compound 3 that step 3 obtains in step 4, is heated to reflux, and obtains the trip of product Etimicin
Obtained hydrolyzate is neutralized by the hydrolyzate from alkali, chromatographs to obtain desorbed solution using column, desorbed solution is concentrated to dryness
Obtain Etimicin finished product.
2. a kind of raising 1-N- ethyl gentamicinC according to claim 1laThe synthetic method of yield, which is characterized in that
The fatty amine is any one in diethylamine, triethylamine, isopropylamine, sec-butylamine, n-butylamine, cyclopropylamine or hexylamine.
3. a kind of raising 1-N- ethyl gentamicinC according to claim 1laThe synthetic method of yield, which is characterized in that
The silated reagent is hexamethyldisilazane, tetramethyl-disilazane, hexamethyl cyclotrisilazane, Cyclodisilazane, first
Any one in silicon substrate-ring-disilazane, trim,ethylchlorosilane or bromo-silicane.
4. a kind of raising 1-N- ethyl gentamicinC according to claim 1laThe synthetic method of yield, which is characterized in that
In the step 1,3,2 ' 6 '-N- triacetyl gentamicinCs1aMolar ratio with organic amine and the DCM solution of triphosgene is
2:4:1, according to 3,2 ' 6 '-N- triacetyl gentamicinCs1aDosage calculates, 1mmol3,2 ' 6 '-N- triacetyl gentamicins
C1aThe dosage of corresponding methylene chloride is 4-5ml.
5. a kind of raising 1-N- ethyl gentamicinC according to claim 1laThe synthetic method of yield, which is characterized in that
In the step 2, according to 3,2 ' 6 '-N- triacetyl gentamicinC in the step 11aDosage calculates, 1mmol3, and 2 ' 6 '-
N- triacetyl gentamicinC1aCorresponding silated reagent dosage is 4-6mmol, and the dosage of corresponding methylene chloride is 1-3ml, right
The dosage for answering the concentrated sulfuric acid is 0.01ml-0.03ml.
6. a kind of raising 1-N- ethyl gentamicinC according to claim 1laThe synthetic method of yield, which is characterized in that
In the step 3, the buffer is the borate buffer of pH=9-10, according to 3,2 ' 6 '-N- triacetyls in the step 1
Base gentamicinC1aDosage calculates, 1mmol3,2 ' 6 '-N- triacetyl gentamicinCs1a, the dosage of corresponding potassium borohydride is
The dosage of 0.1-0.2g, corresponding acetaldehyde are 0.1-0.3ml.
7. a kind of raising 1-N- ethyl gentamicinC according to claim 1laThe synthetic method of yield, which is characterized in that
In the step 4, sodium hydroxide solution mass fraction is 10%；It is big mould by 3,2 ' 6 '-N- triacetyls celebrating in the step 1
Plain C1aAmount calculate, 1mmol3,2 ' 6 '-N- triacetyl gentamicinCs1aThe dosage of corresponding sodium hydroxide solution is 1-3ml.
8. a kind of raising 1-N- ethyl gentamicinC according to claim 1laThe synthetic method of yield, which is characterized in that
Column chromatography in the step 4 uses HD-II weakly acidic resin splitter, and purified water rushes column 8-10h, then with 0.2mol/L ammonium hydroxide
Solution parsing collects the desorbed solution of outlet purity >=90% until changing the parsing of 30% ethanol solution when outlet irrotationality light.
9. a kind of synthetic method for improving 1-N- ethyl gentamicinC la yield according to claim 1, feature exist
In the DCM solution by portions of triphosgene described in the step 1 is added.
10. a kind of raising 1-N- ethyl gentamicinC described in any one according to claim 1 ~ 9laThe synthetic method of yield,
It is characterized in that, after solid 1 obtained in the step 1 uses column chromatographic purifying, then carry out the step 2, step 3, step 4
Operation.
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| 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 |
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| CN101928311A (en) * | 2010-03-26 | 2010-12-29 | 常州方圆制药有限公司 | Preparation method of 1-N-ethyl gentamicin Cla |
| WO2013124826A1 (en) * | 2012-02-24 | 2013-08-29 | Novartis Ag | Oxazolidin- 2 -one compounds and uses thereof as pi3ks inhibitors |
| CN105503972A (en) * | 2015-12-09 | 2016-04-20 | 无锡济民可信山禾药业股份有限公司 | Method for synthesizing 1-N-ethylgentamicin C1a by taking heteropolyacid as catalyst |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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