CN110372760A - A kind of synthetic method of 3-N- ethyl Gentamicin C1a - Google Patents
A kind of synthetic method of 3-N- ethyl Gentamicin C1a Download PDFInfo
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- 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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Abstract
The present invention relates to a kind of synthetic methods of 3-N- ethyl Gentamicin C1a, method includes the following steps: step 1) 2 ", 6 "-N, N- diacetyl Gentamicin C1a and zinc acetate react to obtain zinc complex；Step 2) its protected zinc complex of amino is reacted to obtain with di-tert-butyl dicarbonate；Step 3) is reacted with sodium oxalate again unlocks complexing；Step 4) obtains the product that amino is acetylation after acetic anhydride is added；Step 5) plus hydrochloric acid are deprotected to obtain 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1as；Step 6) 1; 2 "; 6 "-N; N; N- triacetyl Gentamicin C1a is added glycol dimethyl ether, hexamethyldisilazane and strong sulfuric acid response and forms silane; methylene chloride and acetaldehyde reaction are added, potassium borohydride then is added and borate buffer reacts to obtain ethide, obtains 3-N- ethyl Gentamicin C1a with sodium hydroxide solution hydrolysising silane is purified again.
Description
Technical field:
The present invention relates to field of medicinal chemistry, a kind of preparation method of glucoside-containing component is specifically a kind of
The synthetic method of 3-N- ethyl Gentamicin C1a.
Background technique:
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 preparation Etimicin Sulfate injection is suitable for its sensitive Escherichia coli, Klebsiella pneumoniae, sand
Lei Shi Bacillus, citrobacter, Enterobacter, acinetobacter, Proteus, bloodthirsty Bacillus influenzae, Pseudomonas aeruginosa and
Various infection caused by staphylococcus etc..Clinical studies show this product has a better effect following infection.Respiratory tract infection: such as
Acute bronchitis, acute exacerbation of chronic bronchitis, community's pulmonary infection etc.；Kidney and urogenital infections: as suddenly
Property pyelonephritis, cystitis, chronic pyelonephritis or chronic cystitis acute attack etc.；Skin soft tissue and other infection: such as
Skin and soft tissue infection, wound, the infection of wound and postpartum of performing the operation and the infection of other sensitive bacterias.
The adverse reaction that drug generates in clinical use has outside the Pass in addition to the pharmacological activity with drug itself, raw with drug
The impurity generated in production also has certain relationship.Raising drug quality and clinical application are pacified so impurity is separately separated research
Full property makes great sense.
3-N- ethyl Gentamicin C1a, structural formula are as follows:
3-N- ethyl Gentamicin C1a is one of remaining major impurity in Etimicin Sulfate bulk pharmaceutical chemicals and preparation,
Due to similar to Etimicin structure, property is close, it is extremely difficult to separate from production.Both at home and abroad without 3-N- ethyl gentamicin
The standard items of C1a are sold.
At present about the patent of 3-N- ethyl Gentamicin C1a preparation method (Chinese Patent Application No.:
201710823129.6), key step are as follows: by glycol dimethyl ether, hexamethyldisilazane, the concentrated sulfuric acid, 2 ", 6 "-N, N-
Diacetyl Gentamicin C1a, which is put into round-bottomed flask, to flow back, and dissolves to reactant, steams partial solvent.Dichloromethane is added
Alkane is placed at 10 DEG C and stirs, and acetaldehyde is added dropwise.After reaction plus potassium borohydride, borate buffer are stirred to react, and normal pressure steams
Partial solvent.10%~20% sodium hydroxide solution is added, is heated to reflux, is cooled to room temperature, reaction system is concentrated.Desalination,
Pass through isolated target compound 3-N- ethyl Gentamicin C1a.The preparation method, which exists, cannot be distinguished 1-C- amino and 3-
C- amino causes that side reaction must be generated in preparation process, a large amount of Etimicin and other associated byproducts is generated, because being difficult to
It separates and leads to problems such as low yield or purity low.
Summary of the invention:
The purpose of the present invention is to provide a kind of preparation methods of 3-N- ethyl Gentamicin C1a.This method has exclusive
The advantages of good side reaction of property is few, is easy to purifies and separates.
Preparation method of the present invention, comprising the following steps:
Step 1) 2 ", 6 "-N, N- diacetyl Gentamicin C1a and zinc acetate react to obtain zinc complex.
Step 2) its protected zinc complex of amino is reacted to obtain with di-tert-butyl dicarbonate.
Step 3) is reacted with sodium oxalate again unlocks complexing.
Step 4) obtains the product that amino is acetylation after acetic anhydride is added.
Step 5) plus hydrochloric acid are deprotected to obtain 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1as.
Step 6) 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a addition glycol dimethyl ethers, two silicon nitrogen of hexamethyl
Alkane and strong sulfuric acid response form silane, add methylene chloride and acetaldehyde reaction, potassium borohydride and borate buffer is then added
Reaction obtains ethide, obtains 3-N- ethyl Gentamicin C1a with sodium hydroxide solution hydrolysising silane is purified again.
The synthetic route of the method for the invention, as follows:
Preferably, synthetic method of the invention, steps are as follows:
Step 1) takes 2 ", " celebrating of-N, N- diacetyl is big mould for 6 "-N, N- diacetyl Gentamicin C1a are dissolved according to 2 ", 6
In the methanol of plain 5~10 times of proportional volumes of C1a weight solution 1, be added according to 2 in solution 1 ", 6 " celebrating of-N, N- diacetyl is big
The anhydrous zinc acetate of mycin C1a 0.5~2 times of ratio of weight, stirring and dissolving stir 1~3 hour, obtain reaction solution 1.
Step 2) reaction solution 1 is cooled to 0~10 DEG C, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a weight 1
The triethylamine of~2 times of ratios and according to 2 ", 6 " two carbon of 2~3 times of ratios of amount of-N, N- diacetyl Gentamicin C1a substance
Sour di tert butyl carbonate stirs 2~5 hours, obtains reaction solution 2.
Solvent is removed in the concentration of step 3) reaction solution 2, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a weight 10~
The water dissolution of 15 times of proportional volumes, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a 0.5~2 times of ratio of weight
Sodium oxalate stirs 3~5 hours, precipitating filtering, obtains filtrate, and filtrate concentration is removed solvent, is added according to 2 ", 6 "-N, N- diacetyls
The methanol of 5~10 times of ratios of Gentamicin C1a weight dissolves, and obtains solution 2.
Step 4) solution 2 is cooled to 0~10 DEG C, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a weight 1~
The triethylamine of 2 times of ratios and according to 2 ", 6 " acetic anhydride of-N, N- diacetyl Gentamicin C1a 0.2~1 times of ratio of quality, is stirred
It mixes 1~2 hour, obtains reaction solution 3.
Solvent is removed in the concentration of step 5) reaction solution 3, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a weight 10~
The concentration of 15 times of proportional volumes is 1~6 mole of every liter of hydrochloric acid, stirs 1~2 hour, obtains reaction solution 4, reaction solution 4 is with sodium hydroxide
Solution adjusts pH 8~9, and after solvent is removed in concentration, with silica gel column chromatography post separation, obtaining 1,2, the celebrating of ", 6 "-N, N, N- triacetyl is big
Mycin C1a.
Step 6) 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a are added according to 1,2 ", 6 "-N, N, N- triacetyls
The glycol dimethyl ether of 8~12 times of proportional volumes of Gentamicin C1a weight, 1,2 ", 6 "-N, N, N- triacetyl gentamicins
The hexamethyldisilazane of 4~6 times of proportional volumes of C1a weight and according to 1,2 ", 6 "-N, N, N- triacetyl gentamicins
The concentrated sulfuric acid of 0.05~0.5 times of ratio of the amount of C1a substance is heated to 90~100 DEG C of dissolutions and flows back 2~4 hours, obtains reaction solution
5；The concentration of reaction solution 5 boils off most of solvent, with 1,2 ", 6 " 8~12 times of-N, N, N- triacetyl Gentamicin C1a weight
The methylene chloride of proportional volume dissolves, and obtains solution 3；Tri- second of-N, N, N- that solution 3 is cooled to 0~10 DEG C, is added according to 1,2 ", 6 "
40% acetaldehyde of 0.3~0.5 times of proportional volume of acyl group Gentamicin C1a weight stirs 1~2 hour, obtains reaction solution 6；Reaction
It is added in liquid 6 according to 1,2 ", 6 " potassium borohydride of-N, N, N- triacetyl Gentamicin C1a 0.6~0.8 times of ratio of weight, is stirred
It mixes 0.5~3 hour, obtains reaction solution 7；It is added in reaction solution 7 according to 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a weight
The pH of 2~3 times of proportional volumes is 9~11 borate buffers, stirs 2~12 hours, obtains reaction solution 8；In reaction solution 8 be added according to
1,2 ", 6 " 10% sodium hydroxide solution of 5~8 times of proportional volumes of-N, N, N- triacetyl Gentamicin C1a weight, concentration are steamed
Methylene chloride is removed, is added according to 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a 10~15 times of proportional volumes of weight
20% sodium hydroxide solution is warming up to 100~120 DEG C of reflux, stirs 24~36 hours, obtains reaction solution 9；Reaction solution 9 is with macropore
Resin adsorption collects the eluent of purity > 95%, vacuum concentration with salt-free water desalination with 5%~40% ethanol gradient elution
After obtain 3-N- ethyl Gentamicin C1a.
Preparation method of the invention has the advantages that for existing technique
1-C- amino is complexed using zinc acetate as complexing agent by the present invention, protects 3-C- amino with di-tert-butyl dicarbonate, then
Zinc is settled out with sodium oxalate and disconnects complexing, 1-C- amino is protected with acetic anhydride, then 3-N- tertiary butyloxycarbonyl is selectively sloughed with hydrochloric acid
Base protecting group obtains 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1as, is allowed to the site that subsequent acetaldehyde participates in reaction and only has
3-C- amino.And protection is not distinguished application No. is 201710823129.6 patent, and cause side reaction serious.Pass through
The 3-N- ethyl Gentamicin C1a that method of the invention is prepared has the good side reaction of specificity few, and product is easily isolated purifying,
The features such as yield is high.For improving drug quality, the safety for improving clinical application is of great significance.
Beneficial effects of the present invention are further illustrated below by way of comparison:
Specific embodiment:
The present invention is further illustrated by the following examples, but not as limitation of the present invention.
Embodiment 1
", 6 "-N, N- diacetyl the Gentamicin C1a 1.0g that takes 2 is dissolved in methanol 10mL obtaining solution 1.It is added in solution 1
Anhydrous zinc acetate 0.86g, stirring and dissolving stir 2 hours, obtain reaction solution 1.Reaction solution 1 is cooled to 0~10 DEG C, and triethylamine is added
The di-tert-butyl dicarbonate 0.82g of 2mL and 2.0 equivalents stir 3 hours, obtain reaction solution 2.Solvent is removed in the concentration of reaction solution 2, is added
Water 15mL dissolution, is added sodium oxalate 0.79g, stirs 3 hours, and precipitating filtering obtains filtrate.Solvent is removed in filtrate concentration, and methanol is added
10mL dissolution, obtains solution 2.Solution 2 is cooled to 0~10 DEG C, and triethylamine 2mL and acetic anhydride 0.27mL is added, and stirs 1 hour, obtains
Reaction solution 3.Solvent is removed in the concentration of reaction solution 3, and 6 moles of every liter of hydrochloric acid 12mL are added, and stirs 2 hours, obtains reaction solution 4.Reaction solution 4 with
Sodium hydroxide solution adjusts pH 8~9, after solvent is removed in concentration, tri- second of ", 6 "-N, N, N- that with silica gel column chromatography post separation, obtains 1,2
Acyl group Gentamicin C1a.1,2 ", 6 " glycol dimethyl ether 5mL, six is added in-N, N, N- triacetyl Gentamicin C1a 0.6g
Methyl disilazane 2.4mL and concentrated sulfuric acid 0.01mL is heated to 90 DEG C of dissolutions and flows back 2 hours, obtains reaction solution 5.Reaction solution 5 is concentrated
Most of solvent is boiled off, with methylene chloride 5.4mL dissolution, obtains solution 3.Solution 3 is cooled to 0~10 DEG C, and 40% acetaldehyde is added
0.24mL stirs 1 hour, obtains reaction solution 6.Potassium borohydride 0.36g is added in reaction solution 6, stirs 1 hour, obtains reaction solution 7.Instead
The borate buffer 1.44mL that addition pH is 10 in liquid 7 is answered (to add deionized water 30mL stirring and dissolving by 10.0g boric acid, use hydrogen-oxygen
Change sodium adjusting pH=10 to be made), it stirs 5 hours, obtains reaction solution 8.10% sodium hydroxide solution 5mL is added in reaction solution 8, is concentrated
Steaming vibrating dichloromethane adds 20% sodium hydroxide 12mL solution, is warming up to 110 DEG C of reflux, stirs 24 hours, obtains reaction solution 9.
Reaction solution 9 rinses desalination with macroporous resin adsorption, with salt-free water, with 5%~40% ethanol gradient elution, collects purity > 95%
Eluent, obtain 3-N- ethyl Gentamicin C1a, purity 97% after vacuum concentration.
Embodiment 2
", 6 "-N, N- diacetyl the Gentamicin C1a 3.0g that takes 2 is dissolved in methanol 30mL obtaining solution 1.It is added in solution 1
Anhydrous zinc acetate 2.58g, stirring and dissolving stir 2 hours, obtain reaction solution 1.Reaction solution 1 is cooled to 0~10 DEG C, and triethylamine is added
The di-tert-butyl dicarbonate 3.7g of 6mL and 3.0 equivalents stir 3 hours, obtain reaction solution 2.Solvent is removed in the concentration of reaction solution 2, and water is added
30mL dissolution, is added sodium oxalate 2.37g, stirs 3 hours, and precipitating filtering obtains filtrate.Solvent is removed in filtrate concentration, and methanol is added
30mL dissolution, obtains solution 2.Solution 2 is cooled to 0~10 DEG C, and triethylamine 6mL and acetic anhydride 1.6mL is added, and stirs 0.5 hour, obtains
Reaction solution 3.Solvent is removed in the concentration of reaction solution 3, and 6 moles of every liter of hydrochloric acid 40mL are added, and stirs 2 hours, obtains reaction solution 4.Reaction solution 4 with
Sodium hydroxide solution adjusts pH 8~9, after solvent is removed in concentration, tri- second of ", 6 "-N, N, N- that with silica gel column chromatography post separation, obtains 1,2
Acyl group Gentamicin C1a.1,2 ", 6 " glycol dimethyl ether 15mL, six is added in-N, N, N- triacetyl Gentamicin C1a 1.6g
Methyl disilazane 6.4mL and concentrated sulfuric acid 0.02mL is heated to 95 DEG C of dissolutions and flows back 3 hours, obtains reaction solution 5.Reaction solution 5 is concentrated
Most of solvent is boiled off, with methylene chloride 15mL dissolution, obtains solution 3.Solution 3 is cooled to 0~10 DEG C, and 40% acetaldehyde is added
0.8mL stirs 1 hour, obtains reaction solution 6.Potassium borohydride 0.96g is added in reaction solution 6, stirs 1 hour, obtains reaction solution 7.Reaction
The borate buffer 3.84mL that pH is 10 is added in liquid 7 (to add deionized water 30mL stirring and dissolving by 10.0g boric acid, use hydroxide
Sodium adjusts pH=10 and is made), it stirs 3 hours, obtains reaction solution 8.10% sodium hydroxide solution 8mL is added in reaction solution 8, concentration is steamed
Methylene chloride is removed, 20% sodium hydroxide 20mL solution is added, is warming up to 115 DEG C of reflux, stirs 30 hours, obtains reaction solution 9.Instead
It answers liquid 9 with macroporous resin adsorption, desalination is rinsed with salt-free water, with 5%~40% ethanol gradient elution, collect purity >'s 95%
Eluent obtains 3-N- ethyl Gentamicin C1a, purity 98% after vacuum concentration.
Embodiment 3
", 6 "-N, N- diacetyl the Gentamicin C1a 5.3g that takes 2 is dissolved in methanol 70mL obtaining solution 1.It is added in solution 1
Anhydrous zinc acetate 4.55g, stirring and dissolving stir 3 hours, obtain reaction solution 1.Reaction solution 1 is cooled to 0~10 DEG C, and triethylamine is added
The di-tert-butyl dicarbonate 6.54g of 10.6mL and 3.0 equivalents stir 2 hours, obtain reaction solution 2.Solvent is removed in the concentration of reaction solution 2, adds
Enter water 100mL dissolution, sodium oxalate 4.2g is added, stir 3 hours, precipitating filtering obtains filtrate.Solvent is removed in filtrate concentration, and first is added
Alcohol 70mL dissolution, obtains solution 2.Solution 2 is cooled to 0~10 DEG C, and triethylamine 12mL and acetic anhydride 2.8mL is added, and stirs 1 hour,
Obtain reaction solution 3.Solvent is removed in the concentration of reaction solution 3, and 3 moles of every liter of hydrochloric acid 70mL are added, and stirs 3 hours, obtains reaction solution 4.Reaction solution 4
PH 8~9, which is adjusted, with sodium hydroxide solution, with silica gel column chromatography post separation, obtains 1,2 after solvent is removed in concentration ", 6 "-N, N, N- tri-
Acetyl group Gentamicin C1a.1,2 ", 6 " glycol dimethyl ether 16mL, six is added in-N, N, N- triacetyl Gentamicin C1a 2g
Methyl disilazane 8mL and concentrated sulfuric acid 0.02mL is heated to 90 DEG C of dissolutions and flows back 3 hours, obtains reaction solution 5.The concentration of reaction solution 5 is steamed
Most of solvent is removed, with methylene chloride 18mL dissolution, obtains solution 3.Solution 3 is cooled to 0~10 DEG C, and 40% acetaldehyde 0.8mL is added,
Stirring 1 hour, obtains reaction solution 6.Potassium borohydride 1.2g is added in reaction solution 6, stirs 1.5 hours, obtains reaction solution 7.In reaction solution 7
The borate buffer 4.8mL that pH is 10 is added (to add deionized water 30mL stirring and dissolving by 10.0g boric acid, adjusted with sodium hydroxide
PH=10 is made), it stirs 5 hours, obtains reaction solution 8.10% sodium hydroxide solution 10mL is added in reaction solution 8, concentration boils off two
Chloromethanes adds 20% sodium hydroxide 25mL solution, is warming up to 115 DEG C of reflux, stirs 36 hours, obtains reaction solution 9.Reaction solution
9 rinse desalination with macroporous resin adsorption, with salt-free water, with 5%~40% ethanol gradient elution, collect the elution of purity > 95%
Liquid obtains 3-N- ethyl Gentamicin C1a, purity 98% after vacuum concentration.
Embodiment 4
A kind of synthetic method of 3-N- ethyl Gentamicin C1a, which comprises the following steps:
Step 1 takes 2 ", 6 "-N, N- diacetyl Gentamicin C1a is dissolved in a certain proportion of methanol solution 1.
A certain proportion of anhydrous zinc acetate is added in step 2, solution 1, stirring and dissolving stirring a period of time, obtains reaction solution 1.
Step 3, reaction solution 1 are cooled to 0~10 DEG C, and a certain proportion of triethylamine and di-tert-butyl dicarbonate is added, stirring
For a period of time, reaction solution 2 is obtained.
Solvent is removed in step 4, the concentration of reaction solution 2, and a certain proportion of water dissolution is added, a certain proportion of sodium oxalate is added, stirs
It mixes a period of time, precipitating filtering obtains filtrate.
Solvent is removed in step 5, filtrate concentration, and a certain proportion of methanol dissolution is added, obtains solution 2.
Step 6, solution 2 are cooled to 0~10 DEG C, and a certain proportion of triethylamine and acetic anhydride is added, stirring a period of time, obtains
Reaction solution 3.
Solvent is removed in step 7, the concentration of reaction solution 3, and a certain proportion of hydrochloric acid is added, stirring a period of time, obtains reaction solution 4.
Step 8, reaction solution 4 adjust pH 8~9 with sodium hydroxide solution, after solvent is removed in concentration, with silica gel column chromatography post separation,
Obtain 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1as.
Step 9,1,2 ", 6 " a certain proportion of glycol dimethyl ethers of-N, N, N- triacetyl Gentamicin C1a addition, six
Methyl disilazane and the concentrated sulfuric acid dissolve by heating reflux a period of time, obtain reaction solution 5.
Step 10, the concentration of reaction solution 5 boil off most of solvent, with the dissolution of certain proportion methylene chloride, obtain solution 3.
Step 11, solution 3 are cooled to 0~10 DEG C, and a certain proportion of 40% acetaldehyde is added, stirring a period of time, must react
Liquid 6.
A certain proportion of potassium borohydride is added in step 12, reaction solution 6, stirring a period of time, obtains reaction solution 7.
A certain proportion of borate buffer is added in step 13, reaction solution 7, stirring a period of time, obtains reaction solution 8.
It is added a certain proportion of 10% sodium hydroxide solution in step 14, reaction solution 8, is concentrated steaming vibrating dichloromethane, then plus
Enter a certain proportion of 20% sodium hydroxide solution, is warming up to reflux, stirring a period of time, obtains reaction solution 9.
Step 15, reaction solution 9 are separated through macroporous resin adsorption desalination, obtain target product 3-N- ethyl Gentamicin C1a.
Wherein, the addition volume ratio of solvent methanol is 2 in step 1 ", 6 "-N, N- diacetyl Gentamicin C1a weight
5~10 times.
Wherein, the additional proportion of anhydrous zinc acetate is 2 in step 2 ", 6 "-N, N- diacetyl Gentamicin C1a substance
0.5~2 times of equivalent of amount, mixing time are 1~3 hour.
Wherein, the additional proportion of triethylamine is 2 in step 3 ", 6 " the 1~2 of-N, N- diacetyl Gentamicin C1a weight
Times, the additional proportion of di-tert-butyl dicarbonate is 2 ", 6 " 2~3 times of the amount of-N, N- diacetyl Gentamicin C1a substance are worked as
Amount, mixing time are 2~5 hours.
Wherein, the additional proportion of water is 2 in step 4 ", 6 " the 10~15 of-N, N- diacetyl Gentamicin C1a weight
Times, the additional proportion of sodium oxalate is 2 ", 6 " 0.5~2 times of equivalent of-N, N- diacetyl Gentamicin C1a weight, mixings time
It is 3~5 hours.
Wherein, the addition volume ratio of solvent methanol is 2 in step 5 ", 6 "-N, N- diacetyl Gentamicin C1a weight
5~10 times.
Wherein, the additional proportion of triethylamine is 2 in step 6 ", 6 " the 1~2 of-N, N- diacetyl Gentamicin C1a weight
Times, the additional proportion of acetic anhydride is 2 ", 6 " 0.2~1 times of equivalent of-N, N- diacetyl Gentamicin C1a quality, mixings time
It is 1~2 hour.
Wherein, concentration of hydrochloric acid is 1~6 mole every liter in step 7, and it is 2 that volume ratio, which is added, ", 6 "-N, N- diacetyl celebratings
10~15 times of big mycin C1a weight, mixing time are 1~2 hour.
Wherein, the addition volume ratio of glycol dimethyl ether is that 1,2 ", 6 "-N, N, N- triacetyl celebratings are big mould in step 9
8~12 times of plain C1a weight, the addition volume ratio of hexamethyldisilazane are 1,2 ", 6 " celebrating of-N, N, N- triacetyl is big mould
4~6 times of plain C1a weight, the additional proportion of the concentrated sulfuric acid are 1,2 ", the 6 " amounts of-N, N, N- triacetyl Gentamicin C1a substance
0.05~0.5 times, reflux temperature be 90~100 DEG C, return time be 2~4 hours.
Wherein, the addition volume ratio of methylene chloride is 1,2 in step 10 ", 6 "-N, N, N- triacetyl gentamicins
8~12 times of C1a weight.
Wherein, the addition volume ratio of 40% acetaldehyde is 1,2 in step 11 ", 6 "-N, N, N- triacetyl gentamicins
0.3~0.5 times of C1a weight, mixing time are 1~2 hour.
Wherein, the additional proportion of potassium borohydride is 1,2 in step 12 ", 6 "-N, N, N- triacetyl Gentamicin C1a weights
0.6~0.8 times of amount, mixing time are 0.5~3 hour.
Wherein, the pH of borate buffer is 9~11 in step 13, additional proportion 1,2 ", 6 "-N, N, N- triacetyl celebratings
Big 2~3 times of weight of mycin C1a, mixing time are 2~12 hours.
Wherein, the addition volume ratio of 10% sodium hydroxide solution is 1,2 in step 14 ", 6 "-N, N, N- triacetyl celebratings
5~8 times of big mycin C1a weight, the addition volume ratio of 20% sodium hydroxide solution are 1,2 ", 6 "-N, N, N- triacetyls
10~15 times of Gentamicin C1a weight, reflux temperature are 100~120 DEG C, and return time is 24~36 hours.
Wherein, separation is, with salt-free water desalination, to be washed with macroporous resin adsorption with 5%~40% ethanol gradient in step 15
It is de-, the eluent of purity > 95% is collected, obtains 3-N- ethyl Gentamicin C1a after vacuum concentration.
Embodiment 5
Step 1 takes 2 ", " celebrating of-N, N- diacetyl is big mould for 6 "-N, N- diacetyl Gentamicin C1a are dissolved according to 2 ", 6
Solution 1 is obtained in the methanol of plain 5~10 times of proportional volumes of C1a weight.
It is added in step 2, solution 1 according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a 0.5~2 times of ratio of weight
Anhydrous zinc acetate, stirring and dissolving stir 1~3 hour, obtain reaction solution 1.
Step 3, reaction solution 1 are cooled to 0~10 DEG C, are added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a weight 1
The triethylamine of~2 times of ratios and according to 2 ", 6 " two carbon of 2~3 times of ratios of amount of-N, N- diacetyl Gentamicin C1a substance
Sour di tert butyl carbonate stirs 2~5 hours, obtains reaction solution 2.
Solvent is removed in step 4, the concentration of reaction solution 2, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a weight 10~
The water dissolution of 15 times of proportional volumes, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a 0.5~2 times of ratio of weight
Sodium oxalate stirs 3~5 hours, and precipitating filtering obtains filtrate.
Solvent is removed in step 5, filtrate concentration, is added according to 2 ", 6 " 5~10 times of weight of-N, N- diacetyl Gentamicin C1a
The methanol of ratio dissolves, and obtains solution 2.
Step 6, solution 2 are cooled to 0~10 DEG C, are added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a weight 1~
The triethylamine of 2 times of ratios and according to 2 ", 6 " acetic anhydride of-N, N- diacetyl Gentamicin C1a 0.2~1 times of ratio of quality, is stirred
It mixes 1~2 hour, obtains reaction solution 3.
Solvent is removed in step 7, the concentration of reaction solution 3, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a weight 10~
The concentration of 15 times of proportional volumes is 1~6 mole of every liter of hydrochloric acid, stirs 1~2 hour, obtains reaction solution 4.
Step 8, reaction solution 4 adjust pH 8~9 with sodium hydroxide solution, after solvent is removed in concentration, with silica gel column chromatography post separation,
Obtain 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1as.
Step 9,1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a are added according to 1,2 ", 6 "-N, N, N- triacetyls
The glycol dimethyl ether of 8~12 times of proportional volumes of Gentamicin C1a weight, 1,2 ", 6 "-N, N, N- triacetyl gentamicins
The hexamethyldisilazane of 4~6 times of proportional volumes of C1a weight and according to 1,2 ", 6 "-N, N, N- triacetyl gentamicins
The concentrated sulfuric acid of 0.05~0.5 times of ratio of the amount of C1a substance is heated to 90~100 DEG C of dissolutions and flows back 2~4 hours, obtains reaction solution
5。
Step 10, the concentration of reaction solution 5 boil off most of solvent, with 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1as
The methylene chloride of 8~12 times of proportional volumes of weight dissolves, and obtains solution 3.
Step 11, solution 3 are cooled to 0~10 DEG C, are added according to 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a weights
40% acetaldehyde of 0.3~0.5 times of proportional volume of amount stirs 1~2 hour, obtains reaction solution 6.
It is added in step 12, reaction solution 6 according to 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a weight 0.6~0.8
The potassium borohydride of times ratio stirs 0.5~3 hour, obtains reaction solution 7.
2~3 multiple proportions of ", 6 "-N, N, N- triacetyl Gentamicin C1a weight is added according to 1,2 in step 13, reaction solution 7
The pH of example volume is 9~11 borate buffers, stirs 2~12 hours, obtains reaction solution 8.
5~8 multiple proportions of ", 6 "-N, N, N- triacetyl Gentamicin C1a weight is added according to 1,2 in step 14, reaction solution 8
10% sodium hydroxide solution of example volume, is concentrated steaming vibrating dichloromethane, adds according to 1,2 ", 6 "-N, N, N- triacetyl celebratings
20% sodium hydroxide solution of big mycin C1a 10~15 times of proportional volumes of weight, is warming up to 100~120 DEG C of reflux, stir 24~
36 hours, obtain reaction solution 9.
Step 15, reaction solution 9 are received with macroporous resin adsorption with salt-free water desalination with 5%~40% ethanol gradient elution
Collect the eluent of purity > 95%, obtains 3-N- ethyl Gentamicin C1a after vacuum concentration.
Claims (9)
1. a kind of preparation method of 3-N- ethyl Gentamicin C1a, which is characterized in that pass through following steps,
Step 1) 2 ", 6 "-N, N- diacetyl Gentamicin C1a and zinc acetate react to obtain zinc complex；
Step 2) its protected zinc complex of amino is reacted to obtain with di-tert-butyl dicarbonate；
Step 3) is reacted with sodium oxalate again unlocks complexing；
Step 4) obtains the product that amino is acetylation after acetic anhydride is added；
Step 5) plus hydrochloric acid are deprotected to obtain 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1as；
Step 6) 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a be added glycol dimethyl ether, hexamethyldisilazane and
Strong sulfuric acid response forms silane, adds methylene chloride and acetaldehyde reaction, and potassium borohydride and borate buffer reaction is then added
Ethide is obtained, obtains 3-N- ethyl Gentamicin C1a with sodium hydroxide solution hydrolysising silane is purified again.
2. preparation method according to claim 1, which is characterized in that wherein
Step 1) method is as follows: taking 2 ", 6 "-N, N- diacetyl Gentamicin C1a are dissolved according to 2 ", 6 "-N, N- diacetyls
Solution 1 is obtained in the methanol of 5~10 times of proportional volumes of Gentamicin C1a weight, is added in solution 1 according to 2 ", 6 "-N, N- diacetyl
The anhydrous zinc acetate of base Gentamicin C1a 0.5~2 times of ratio of weight, stirring and dissolving stir 1~3 hour, obtain reaction solution 1.
3. preparation method according to claim 1, which is characterized in that wherein
Step 2) method is as follows: reaction solution 1 is cooled to 0~10 DEG C, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1as
The triethylamine of 1~2 times of ratio of weight and according to 2 ", 6 " 2~3 times of ratios of amount of-N, N- diacetyl Gentamicin C1a substance
Di-tert-butyl dicarbonate stirs 2~5 hours, obtains reaction solution 2.
4. preparation method according to claim 1, which is characterized in that wherein
Step 3) method is as follows: solvent is removed in the concentration of reaction solution 2, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a weights
The water dissolution of 10~15 times of proportional volumes of amount, is added according to 2 ", 6 " 0.5~2 times of weight of-N, N- diacetyl Gentamicin C1a
The sodium oxalate of ratio stirs 3~5 hours, precipitating filtering, obtains filtrate, and filtrate concentration is removed solvent, is added according to 2 ", 6 "-N, N- bis-
The methanol of 5~10 times of ratios of acetyl group Gentamicin C1a weight dissolves, and obtains solution 2.
5. preparation method according to claim 1, which is characterized in that wherein
Step 4) method is as follows: solution 2 is cooled to 0~10 DEG C, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a weights
Measure the triethylamine of 1~2 times of ratio and according to 2 ", the 6 " acetic acid of-N, N- diacetyl Gentamicin C1a 0.2~1 times of ratio of quality
Acid anhydride stirs 1~2 hour, obtains reaction solution 3.
6. preparation method according to claim 1, which is characterized in that wherein
Step 5) method is as follows: solvent is removed in the concentration of reaction solution 3, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a weights
The concentration for measuring 10~15 times of proportional volumes is 1~6 mole of every liter of hydrochloric acid, stirs 1~2 hour, obtains reaction solution 4, reaction solution 4 is with hydrogen
Sodium hydroxide solution adjusts pH8~9 and, with silica gel column chromatography post separation, obtains 1,2 after solvent is removed in concentration ", 6 "-N, N, N- triacetyls
Gentamicin C1a.
7. preparation method according to claim 1, which is characterized in that wherein
Step 6) method is as follows: 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a are added according to 1,2 ", 6 "-N, N, N- tri-
The glycol dimethyl ether of 8~12 times of proportional volumes of acetyl group Gentamicin C1a weight, 1,2 ", 6 "-N, N, N- triacetyl celebratings
The hexamethyldisilazane of 4~6 times of proportional volumes of big mycin C1a weight and according to 1,2 ", 6 " celebrating of-N, N, N- triacetyl is big
The concentrated sulfuric acid of 0.05~0.5 times of ratio of the amount of mycin C1a substance is heated to 90~100 DEG C of dissolutions and flows back 2~4 hours, obtains instead
Answer liquid 5；The concentration of reaction solution 5 boils off most of solvent, with 1,2 ", 6 " the 8 of-N, N, N- triacetyl Gentamicin C1a weight~
The methylene chloride dissolution of 12 times of proportional volumes, obtains solution 3；Solution 3 is cooled to 0~10 DEG C, is added according to 1,2 ", 6 "-N, N, N-
40% acetaldehyde of 0.3~0.5 times of proportional volume of triacetyl Gentamicin C1a weight stirs 1~2 hour, obtains reaction solution 6；
It is added in reaction solution 6 according to 1,2 ", the 6 " hydroborations of-N, N, N- triacetyl Gentamicin C1a 0.6~0.8 times of ratio of weight
Potassium stirs 0.5~3 hour, obtains reaction solution 7；It is added in reaction solution 7 according to 1,2 ", 6 "-N, N, N- triacetyl gentamicins
The pH of 2~3 times of proportional volumes of C1a weight is 9~11 borate buffers, stirs 2~12 hours, obtains reaction solution 8；In reaction solution 8
It is added according to 1,2 ", 6 " 10% sodium hydroxide of-N, N, N- triacetyl Gentamicin C1a 5~8 times of proportional volumes of weight is molten
Steaming vibrating dichloromethane is concentrated in liquid, adds according to 1,2 10~15 multiple proportions of ", 6 "-N, N, N- triacetyl Gentamicin C1a weight
20% sodium hydroxide solution of example volume, is warming up to 100~120 DEG C of reflux, stirs 24~36 hours, obtains reaction solution 9；Reaction solution
9 collect the eluent of purity > 95% with macroporous resin adsorption, with salt-free water desalination with 5%~40% ethanol gradient elution,
3-N- ethyl Gentamicin C1a is obtained after vacuum concentration.
8. a kind of synthetic method of 3-N- ethyl Gentamicin C1a, which comprises the following steps:
Step 1 takes 2 ", 6 "-N, N- diacetyl Gentamicin C1a is dissolved in a certain proportion of methanol solution 1；
A certain proportion of anhydrous zinc acetate is added in step 2, solution 1, stirring and dissolving stirring a period of time, obtains reaction solution 1；
Step 3, reaction solution 1 are cooled to 0~10 DEG C, and a certain proportion of triethylamine and di-tert-butyl dicarbonate is added, and stir one section
Time obtains reaction solution 2；
Solvent is removed in step 4, the concentration of reaction solution 2, and a certain proportion of water dissolution is added, a certain proportion of sodium oxalate, stirring one is added
Section time, precipitating filtering obtain filtrate；
Solvent is removed in step 5, filtrate concentration, and a certain proportion of methanol dissolution is added, obtains solution 2；
Step 6, solution 2 are cooled to 0~10 DEG C, and a certain proportion of triethylamine and acetic anhydride is added, stirring a period of time, must react
Liquid 3；
Solvent is removed in step 7, the concentration of reaction solution 3, and a certain proportion of hydrochloric acid is added, stirring a period of time, obtains reaction solution 4；
Step 8, reaction solution 4 adjust pH8~9 with sodium hydroxide solution and, with silica gel column chromatography post separation, obtain after solvent is removed in concentration
1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a；
Step 9,1,2 ", 6 " a certain proportion of glycol dimethyl ethers of-N, N, N- triacetyl Gentamicin C1a addition, hexamethyl
Disilazane and the concentrated sulfuric acid dissolve by heating reflux a period of time, obtain reaction solution 5；
Step 10, the concentration of reaction solution 5 boil off most of solvent, with the dissolution of certain proportion methylene chloride, obtain solution 3；
Step 11, solution 3 are cooled to 0~10 DEG C, and a certain proportion of 40% acetaldehyde is added, stirring a period of time, obtains reaction solution 6；
A certain proportion of potassium borohydride is added in step 12, reaction solution 6, stirring a period of time, obtains reaction solution 7；
A certain proportion of borate buffer is added in step 13, reaction solution 7, stirring a period of time, obtains reaction solution 8；
A certain proportion of 10% sodium hydroxide solution is added in step 14, reaction solution 8, steaming vibrating dichloromethane is concentrated, adds one
20% sodium hydroxide solution of certainty ratio is warming up to reflux, stirring a period of time, obtains reaction solution 9；
Step 15, reaction solution 9 are separated through macroporous resin adsorption desalination, obtain target product 3-N- ethyl Gentamicin C1a.
9. preparation method according to claim 8, which is characterized in that steps are as follows:
Step 1 takes 2 ", 6 "-N, N- diacetyl Gentamicin C1a are dissolved according to 2 ", 6 "-N, N- diacetyl gentamicins
Solution 1 is obtained in the methanol of 5~10 times of proportional volumes of C1a weight；
The anhydrous of according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a 0.5~2 times of ratio of weight is added in step 2, solution 1
Zinc acetate, stirring and dissolving stir 1~3 hour, obtain reaction solution 1；
Step 3, reaction solution 1 are cooled to 0~10 DEG C, are added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a weight 1~2
The triethylamine of times ratio and according to 2 ", 6 " two carbonic acid two of 2~3 times of ratios of amount of-N, N- diacetyl Gentamicin C1a substance
The tert-butyl ester stirs 2~5 hours, obtains reaction solution 2；
Solvent is removed in step 4, the concentration of reaction solution 2, is added according to 2 ", 6 " 10~15 times of weight of-N, N- diacetyl Gentamicin C1a
The water of proportional volume dissolves, and is added according to 2 ", the 6 " oxalic acid of-N, N- diacetyl Gentamicin C1a 0.5~2 times of ratio of weight
Sodium stirs 3~5 hours, and precipitating filtering obtains filtrate；
Solvent is removed in step 5, filtrate concentration, is added according to 2 ", 6 "-N, N- diacetyl Gentamicin C1a 5~10 times of ratios of weight
Methanol dissolution, obtain solution 2；
Step 6, solution 2 are cooled to 0~10 DEG C, are added according to 2 ", 6 " 1~2 times of weight of-N, N- diacetyl Gentamicin C1a
The triethylamine of ratio and ", 6 " acetic anhydride of-N, N- diacetyl Gentamicin C1a 0.2~1 times of ratio of quality according to 2, stirring 1
~2 hours, obtain reaction solution 3；
Solvent is removed in step 7, the concentration of reaction solution 3, is added according to 2 ", 6 " 10~15 times of weight of-N, N- diacetyl Gentamicin C1a
The concentration of proportional volume is 1~6 mole of every liter of hydrochloric acid, stirs 1~2 hour, obtains reaction solution 4；
Step 8, reaction solution 4 adjust pH8~9 with sodium hydroxide solution and, with silica gel column chromatography post separation, obtain after solvent is removed in concentration
1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a；
Step 9,1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a are added according to 1,2 ", 6 " celebrating of-N, N, N- triacetyl is big
The glycol dimethyl ether of 8~12 times of proportional volumes of mycin C1a weight, 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1as
The hexamethyldisilazane of 4~6 times of proportional volumes of weight and according to 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a objects
The concentrated sulfuric acid of 0.05~0.5 times of ratio of the amount of matter is heated to 90~100 DEG C of dissolutions and flows back 2~4 hours, obtains reaction solution 5；
Step 10, the concentration of reaction solution 5 boil off most of solvent, with 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a weight
8~12 times of proportional volumes methylene chloride dissolution, obtain solution 3；
Step 11, solution 3 are cooled to 0~10 DEG C, are added according to 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a weight
40% acetaldehyde of 0.3~0.5 times of proportional volume stirs 1~2 hour, obtains reaction solution 6；
0.6~0.8 multiple proportions of ", 6 "-N, N, N- triacetyl Gentamicin C1a weight is added according to 1,2 in step 12, reaction solution 6
The potassium borohydride of example stirs 0.5~3 hour, obtains reaction solution 7；
It is added in step 13, reaction solution 7 according to 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a 2~3 times of ratio bodies of weight
Long-pending pH is 9~11 borate buffers, stirs 2~12 hours, obtains reaction solution 8；
It is added in step 14, reaction solution 8 according to 1,2 ", 6 "-N, N, N- triacetyl Gentamicin C1a 5~8 times of ratio bodies of weight
Steaming vibrating dichloromethane is concentrated in 10% long-pending sodium hydroxide solution, and it is big mould to add according to 1,2 the celebrating of ", 6 "-N, N, N- triacetyl
20% sodium hydroxide solution of 10~15 times of proportional volumes of plain C1a weight, is warming up to 100~120 DEG C of reflux, and stirring 24~36 is small
When, obtain reaction solution 9；
Step 15, reaction solution 9 are collected pure with salt-free water desalination with 5%~40% ethanol gradient elution with macroporous resin adsorption
The eluent of > 95% is spent, obtains 3-N- ethyl Gentamicin C1a after vacuum concentration.
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