CN111004291A - Etimicin derivative and synthetic method thereof - Google Patents
Etimicin derivative and synthetic method thereof Download PDFInfo
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- CN111004291A CN111004291A CN201911315833.6A CN201911315833A CN111004291A CN 111004291 A CN111004291 A CN 111004291A CN 201911315833 A CN201911315833 A CN 201911315833A CN 111004291 A CN111004291 A CN 111004291A
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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
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- 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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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
The invention discloses etimicin derivatives having the general formula (I), wherein R is selected from- (CH)2)2OH or- (CH)2)3And (5) OH. The synthesis steps comprise: mixing etimicin, methanol, zinc acetate dihydrate, (N-hydroxy-5-norbornene-2, 3-dicarboximidoyl) -N-PNZ-4-amino-2 (R) -benzoyl-butyrate and dichloromethane to obtain an intermediate 1 (6' -PNZ-etimicin); mixing the intermediate 1, methanol, N-diisopropylethylamine and Boc anhydride to obtain an intermediate 2(6 ' -PNZ-1,2 ', 3, 3 ' -4 Boc-etimicin); dissolving the intermediate 2 in methanol, adding concentrated ammonia water and ethyl acetate to obtain an intermediate 3(1,2 ', 3, 3' -4 Boc-etimicin); intermediate 3, N-dimethylformamide, CHO (CH)2)nMixing the mixed solution of OH dimer, sodium cyanoborohydride, methanol and acetic acid to obtain intermediate 4 (6' - (2-tert-butyldimethylsilyloxy-ethyl) -1,2', 3, 3 ' -4 Boc-etimicin and 6 ' - (2-tert-butyldimethylsilyloxy-propyl) -1,2 ', 3, 3 ' -4 Boc-etimicin; dissolving etimicin in water, and adding sulfuric acid to obtain etimicin sulfate.
Description
FIELD
The invention relates to the field of pharmaceutical chemistry, in particular to a novel etimicin derivative and a synthetic method thereof.
Background
Etimicin sulfate is a new generation of aminoglycoside antibiotics independently developed in China, and has the characteristics of low toxicity, high efficiency, drug-resistant bacteria resistance and the like.
Etimicin sulfate is suitable for various infections caused by Escherichia coli, Klebsiella pneumoniae, Serratia, Acetobacter trifoliatus, Enterobacter, Acinetobacter, Proteus, Haemophilus influenzae, Pseudomonas aeruginosa, Staphylococcus, etc., to which it is sensitive. Clinical research shows that the product has better curative effect on the following infections: such as acute bronchitis, acute attack of chronic bronchitis, community lung infection, etc. Kidney and urogenital infections: such as acute pyelonephritis, cystitis, chronic pyelonephritis or chronic cystitis.
With the wide clinical application of etimicin sulfate, toxic and side effects of etimicin sulfate are gradually shown, and the finding of a better aminosugar antibiotic has high application value.
SUMMARY
In one aspect, the disclosure relates to etimicin derivatives, including etimicin stereoisomers, pharmaceutically acceptable salts of etimicin, and etimicin prodrugs.
Wherein R is selected from H or-CHA (CH)2)n-OH, a is selected from H, cycloalkyl, alkyl, heteroalkyl, aryl or aralkyl, and n is 1-6.
In another aspect, the present disclosure relates to a method of synthesizing etimicin derivatives, comprising the steps of:
step 1: mixing etimicin, an organic solvent and zinc acetate dihydrate to obtain a reaction solution 1;
mixing (N-hydroxy-5-norbornene-2, 3-dicarboximido) -N-PNZ-4-amino-2 (R) -benzoyl-butyrate with dichloromethane to obtain a reaction solution 2; and
and mixing the reaction solution 1 and the reaction solution 2, and carrying out aftertreatment to obtain an intermediate 1 (6' -PNZ-etimicin).
Step 2: intermediate 1 was dissolved in methanol, N-diisopropylethylamine and Boc anhydride were added and worked up to give intermediate 2(6 ' -PNZ-1,2 ', 3, 3 ' -4 Boc-etimicin).
And step 3: intermediate 2 was dissolved in methanol and concentrated ammonia and ethyl acetate were added to give intermediate 3(1,2 ', 3, 3' -4 Boc-etimicin).
And 4, step 4: reacting intermediate 3, N-dimethylformamide with CHO (CH)2)nOH dimers are mixed to obtain a reaction solution 3, wherein n is 1 or 2;
mixing sodium cyanoborohydride with a mixed solution of methanol and acetic acid to obtain a reaction solution 4;
the reaction mixture 3 and the reaction mixture 4 were mixed to obtain intermediates 4(6 '- (2-tert-butyldimethylsilyloxy-ethyl) -1, 2', 3, 3 '-4 Boc-etimicin and 6' - (2-tert-butyldimethylsilyloxy-propyl) -1,2 ', 3, 3' -4 Boc-etimicin).
And 5: and mixing the intermediate 4, dichloromethane and trifluoroacetic acid to obtain etimicin.
Step 6: dissolving etimicin in water, and adding sulfuric acid to obtain etimicin sulfate.
Detailed description of the invention
In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.
Unless otherwise required by the disclosure, throughout the specification and the appended claims, the words "comprise", "comprising", and "have" are to be construed in an open, inclusive sense, i.e., "including but not limited to".
Reference throughout the specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that a particular reference element, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment, and furthermore, particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.
Definition of
In the present disclosure, the term "naphthenic base" is defined as the attribute of some natural mineral oil with special structure in the petroleum industry, is a mixture with naphthenic hydrocarbon as a main component, and is a naphthenic hydrocarbon substance from natural mineral naphthenic base crude oil.
In the present disclosure, the term "alkyl" is intended to include groups consisting of carbon atoms bonded to non-hydrogen radicals, such as haloalkyl (e.g., -CF3, -CH2CF3) and acyl (e.g., -C (O) CH3, -C (O) CF3, -C (O) CH2OCH3, and the like).
In the present disclosure, the term "heteroalkyl," by itself or in combination with another term, means a stable straight-chain, branched-chain hydrocarbon radical or combination thereof, consisting of a number of carbon atoms and at least one heteroatom.
In this disclosure, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent which may be mono-, di-, or poly-substituted, and which may be mono-, di-, or polyvalent, and which may be monocyclic or polycyclic (e.g., 1 to 3 rings; wherein at least one ring is aromatic), fused together, or covalently linked.
In this disclosure, the term "aralkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like), including those alkyl groups in which a carbon atom (e.g., methylene) has been replaced by, for example, an oxygen atom, such as phenoxymethyl, 2-pyridyloxymethyl 3- (1-naphthyloxy) propyl and the like.
In the present disclosure, the term "recrystallization" is a process of dissolving crystals in a solvent or melting and then recrystallizing from the solution or melt again. Recrystallization can purify impure materials or separate salts from each other when mixed together. Where it is the result of a physicochemical action.
In the present disclosure, the term "separation principle of silica gel chromatography" is to separate substances according to their different adsorption forces on silica gel, and in general, substances with relatively high polarity are easily adsorbed by silica gel, substances with relatively low polarity are not easily adsorbed by silica gel, and the whole chromatography process is adsorption, desorption, re-adsorption and re-desorption.
In the present disclosure, the term "elution" refers to the process in which, in an elution chromatography operation, a mobile phase carries the component to be measured forward in and out of a chromatography column, the mobile phase used being an eluent.
In the present disclosure, the term "spray drying" is a method of applying systematic technology to material drying, in which after the thin material is atomized in a drying chamber, the moisture is rapidly vaporized in contact with hot air, and then a dried product is obtained.
Detailed Description
In one aspect, the disclosure relates to etimicin derivatives, including etimicin stereoisomers, pharmaceutically acceptable salts of etimicin, and etimicin prodrugs.
Wherein R is selected from H or-CHA (CH)2)n-OH, a is selected from H, cycloalkyl, alkyl, heteroalkyl, aryl or aralkyl, and n is 1-6.
In certain embodiments, R is preferably- (CH)2)2OH、-(CH2)3OH or a mixture thereof.
In another aspect, the present disclosure relates to a method of synthesizing etimicin derivatives, comprising the steps of:
step 1: mixing etimicin, an organic solvent and zinc acetate dihydrate to obtain a reaction solution 1;
mixing (N-hydroxy-5-norbornene-2, 3-dicarboximido) -N-PNZ-4-amino-2 (R) -benzoyl-butyrate with dichloromethane to obtain a reaction solution 2; and
and mixing the reaction solution 1 and the reaction solution 2, and carrying out aftertreatment to obtain an intermediate 1 (6' -PNZ-etimicin).
Step 2: intermediate 1 was dissolved in methanol, N-diisopropylethylamine and Boc anhydride were added and worked up to give intermediate 2(6 ' -PNZ-1,2 ', 3, 3 ' -4 Boc-etimicin).
And step 3: intermediate 2 was dissolved in methanol and concentrated ammonia and ethyl acetate were added to give intermediate 3(1,2 ', 3, 3' -4 Boc-etimicin).
And 4, step 4: reacting intermediate 3, N-dimethylformamide with CHO (CH)2)nOH dimers are mixed to obtain a reaction solution 3, wherein n is 1 or 2;
mixing sodium cyanoborohydride with a mixed solution of methanol and acetic acid to obtain a reaction solution 4;
the reaction mixture 3 and the reaction mixture 4 were mixed to obtain intermediates 4(6 '- (2-tert-butyldimethylsilyloxy-ethyl) -1, 2', 3, 3 '-4 Boc-etimicin and 6' - (2-tert-butyldimethylsilyloxy-propyl) -1,2 ', 3, 3' -4 Boc-etimicin).
And 5: and mixing the intermediate 4, dichloromethane and trifluoroacetic acid to obtain etimicin.
Step 6: dissolving etimicin in water, and adding sulfuric acid to obtain etimicin sulfate.
In certain embodiments, etimicin derivatives may exist in specific geometric or stereoisomeric forms, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups.
In certain embodiments, prodrugs of etimicin compounds readily undergo chemical changes under physiological conditions to convert to etimicin. In addition, etimicin prodrugs can be converted to etimicin in the in vivo environment by chemical or biochemical means.
In certain embodiments, the organic solvent of step 1 is selected from methanol, ethanol, DMF, DMSO, or a mixture thereof, preferably the solvent is methanol.
In certain embodiments, in step 1, the post-treatment comprises:
concentrating the reaction solution treated in the step 1 under reduced pressure;
and (3) dissolving the solution in deionized water, and performing ion exchange resin column chromatography:
low temperature lyophilization gave the intermediate 1.
In certain embodiments, in step 1, the eluent from the treatment of ion exchange resin chromatography is selected from aqueous ammonia.
In certain embodiments, in step 1, the aqueous ammonia concentration is between 0.1% and 2% by mass.
In certain embodiments, in step 1, the concentration of ammonia is 0.5% by mass.
In certain embodiments, in step 2, the post-treatment comprises:
carrying out extraction and quenching reaction on the reaction liquid treated in the step 1 by using ice water, wherein the reaction time is 0-10 h, preferably 0-4 h, and more preferably 1 h;
adding ethyl acetate to extract and stratify;
adding saturated sodium bicarbonate and salt solution to wash the organic layer to neutrality;
adding anhydrous magnesium sulfate, drying, carrying out suction filtration, concentrating the filtrate, and carrying out silica gel chromatography to obtain the intermediate 2.
In certain embodiments, intermediate 3 is further purified by recrystallization in step 3, wherein the solvent is selected from tetrahydrofuran, water, methanol, ethanol, or mixtures thereof.
In certain embodiments, step 3 is further purified by recrystallization before intermediate 3 is obtained, the solvent being selected from a mixture of tetrahydrofuran and water.
In certain embodiments, the tetrahydrofuran to water volume ratio is 50: 1.
In certain embodiments, step 4, ion exchange resin column chromatography is used, and the eluent is selected from ammonia.
In certain embodiments, in step 4, the ammonia water is present at a concentration of 0.1% to 2% by mass.
In certain embodiments, in step 4, the concentration of ammonia is 0.6% by mass.
In certain embodiments, the sulfate salt is also spray dried prior to being obtained in step 5.
Example 1
This embodiment discloses
1. 6' -PNZ-etimicin (intermediate 1)
19.1g of etimicin was dissolved in 300ml of methanol, and 23.5g of zinc acetate dihydrate was added and stirred until dissolved. 15.5g (N-hydroxy-5-norbornene-2, 3-dicarboximido) -N-PNZ-4-amino-2 (R) -benzoyl-butyrate is dissolved in 2000ml dichloromethane and slowly dripped into the reaction solution, after the dripping is finished, the reaction solution is stirred overnight, the ion exchange resin column chromatography is carried out after the concentration, the eluent is 0.5% ammonia water, the product eluent is freeze-dried at low temperature to obtain 14.2g white solid, MS [ M +1 ]]+＝642.7
2. 6 ' -PNZ-1,2 ', 3, 3 ' -4 Boc-etimicin (intermediate 2)
Under the ice bath condition, 70g of the intermediate 1 is dissolved in 1L of methanol, 168ml of DIPEA is added, 220ml of Boc anhydride is added dropwise, the mixture is naturally heated to room temperature and stirred overnight, 300ml of ice water is used for quenching for 1h, the methanol is removed under reduced pressure, ethyl acetate is used for extraction for 3 times, organic layers are combined, saturated sodium bicarbonate and saline solution are respectively washed to be neutral, anhydrous magnesium sulfate is dried and then is filtered, and the filtrate is concentrated and directly subjected to the next reaction.
3. 1,2 ', 3, 3' -4 Boc-etimicin (intermediate 3)
16g of the intermediate 2 was dissolved in 300ml of methanol, 30ml of concentrated aqueous ammonia was further added, stirring was carried out at room temperature for 72 hours, 300ml of ethyl acetate was added, the organic layer after separation was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and then suction filtration was carried out, the filtrate was concentrated, and the residue was recrystallized from THF-water (1:2) to obtain 8.94g of a white solid.
4. 6 ' - (2-tert-Butyldimethylsilanyloxy-ethyl) -1,2 ', 3, 3 ' -4 Boc-etimicin (intermediate 4)
75g of intermediate 3 was dissolved in 500ml of DMF, and 15g of glycolaldehyde dimer was added thereto and the reaction was stirred at room temperature overnight. 70g of sodium cyanoborohydride is added into a mixed solution of 600ml of methanol and 150ml of acetic acid, the prepared solution is added into the reaction solution, the reaction is stirred at room temperature for 0.5h, 100ml of ice water is used for extraction, ethyl acetate is used for washing with saline solution after extraction to be neutral, and anhydrous magnesium sulfate is dried and then concentrated to be directly used for the next reaction.
5. 6' - (2-hydroxy-ethyl) -etimicin
32.8g of the intermediate 5 is dissolved in 1000ml of dichloromethane, 25ml of trifluoroacetic acid is dripped, the mixture is stirred and reacts for 2 hours at room temperature, the reaction solution is concentrated, the residue is dissolved in 500ml of water and then is subjected to ion exchange resin column chromatography, the eluent is 0.6% ammonia water, and the product is freeze-dried at low temperature to obtain 22.7g of white solid.
6. 6' - (2-hydroxy-ethyl) -etimicin sulfate
6' - (2-hydroxy-ethyl) -etimicin 28.3g was dissolved in 100ml water, magnetically stirred, slowly added dropwise with sulfuric acid 3.5ml, reacted at room temperature for 4h, concentrated under reduced pressure to remove most of the water, and the residue was spray dried to give a white solid 21.5g, MS [ M +1 ]]+＝523.7。
Example 2
5. 6 ' - (2-tert-Butyldimethylsilanyloxy-propyl) -1,2 ', 3, 3 ' -4 Boc-etimicin (intermediate 5)
76.8g of intermediate 3 was dissolved in 500ml of DMF, and 16.8g of propionaldehyde dimer was further added thereto, and the reaction was stirred at room temperature overnight. 70g of sodium cyanoborohydride is added into a mixed solution of 600ml of methanol and 150ml of acetic acid, the prepared solution is added into the reaction solution, the reaction is stirred at room temperature for 0.5h, 100ml of ice water is used for extraction, ethyl acetate is used for washing with saline solution after extraction to be neutral, and anhydrous magnesium sulfate is dried and then concentrated to be directly used for the next reaction.
6. 6' - (2-hydroxy-propyl) -etimicin
Dissolving 35.9g of the intermediate 5 in 1000ml of dichloromethane, dropwise adding 25ml of trifluoroacetic acid, stirring at room temperature for reacting for 2 hours, concentrating the reaction solution, dissolving the residue with 500ml of water, carrying out ion exchange resin column chromatography on the residue, carrying out low-temperature freeze-drying on the product to obtain 26.3g of a white solid, wherein the eluent is 0.6% ammonia water.
7. 6' - (2-hydroxy-propyl) -etimicin sulfate
6' - (2-hydroxy-propyl) -etimicin 29.9g was dissolved in 100ml of water, magnetically stirred, slowly added dropwise with sulfuric acid 3.5ml, reacted at room temperature for 4h, concentrated under reduced pressure to remove most of the water, and the residue was spray-dried to give a white solid 20.1g, MS [ M +1 ]]+＝537.7。
From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications or improvements may be made by those skilled in the art without departing from the spirit and scope of the disclosure, and that such modifications or improvements are intended to be within the scope of the appended claims.
Claims (10)
1. Etimicin derivatives having the general formula (I):
wherein R is selected from H or-CHA (CH)2)n-OH, a is selected from H, cycloalkyl, alkyl, heteroalkyl, aryl or aralkyl, and n is 1-6.
2. The etimicin derivative of claim 1, wherein R is selected from- (CH)2)2OH or- (CH)2)3OH。
3. The synthesis method of the etimicin derivative comprises the following steps:
step 1: mixing etimicin, an organic solvent and zinc acetate dihydrate to obtain a reaction solution 1;
mixing (N-hydroxy-5-norbornene-2, 3-dicarboximido) -N-PNZ-4-amino-2 (R) -benzoyl-butyrate with dichloromethane to obtain a reaction solution 2; and
and mixing the reaction solution 1 and the reaction solution 2, and carrying out aftertreatment to obtain an intermediate 1 (6' -PNZ-etimicin).
Step 2: intermediate 1 was dissolved in methanol, N-diisopropylethylamine and Boc anhydride were added and worked up to give intermediate 2(6 ' -PNZ-1,2 ', 3, 3 ' -4 Boc-etimicin).
And step 3: intermediate 2 was dissolved in methanol and concentrated ammonia and ethyl acetate were added to give intermediate 3(1,2 ', 3, 3' -4 Boc-etimicin).
And 4, step 4: the intermediate 3, N-dimethylFormamide and CHO (CH)2)nOH dimers are mixed to obtain a reaction solution 3, wherein n is 1 or 2;
mixing sodium cyanoborohydride with a mixed solution of methanol and acetic acid to obtain a reaction solution 4;
the reaction mixture 3 and the reaction mixture 4 were mixed to obtain intermediates 4(6 '- (2-tert-butyldimethylsilyloxy-ethyl) -1, 2', 3, 3 '-4 Boc-etimicin and 6' - (2-tert-butyldimethylsilyloxy-propyl) -1,2 ', 3, 3' -4 Boc-etimicin).
And 5: and mixing the intermediate 4, dichloromethane and trifluoroacetic acid to obtain etimicin.
Step 6: dissolving etimicin in water, and adding sulfuric acid to obtain etimicin sulfate.
4. The method for synthesizing etimicin derivative according to claim 3, wherein the organic solvent of step 1 is selected from methanol, ethanol, DMF, DMSO or a mixture thereof, preferably the solvent is selected from methanol.
5. The method for synthesizing an etimicin derivative as claimed in claim 3, wherein the post-treatment in the step 1 comprises:
concentrating the reaction solution treated in the step 1 under reduced pressure;
and (3) dissolving the solution in deionized water, and performing ion exchange resin column chromatography: and
low temperature lyophilization gave the intermediate 1.
6. The method for synthesizing etimicin derivative according to claim 3, wherein the eluent for the post-treatment ion exchange resin chromatography in step 1) is selected from ammonia, preferably ammonia with a concentration of 0.1 to 2% by mass, more preferably 0.5% by mass.
7. The method for synthesizing an etimicin derivative as claimed in claim 3, wherein the post-treatment in the step 2 comprises:
carrying out extraction and quenching reaction on the reaction liquid treated in the step 1 by using ice water, wherein the reaction time is 0-10 h, preferably 0-4 h, and more preferably 1 h;
adding ethyl acetate to extract and stratify;
adding saturated sodium bicarbonate and salt solution to wash the organic layer to neutrality; and
adding anhydrous magnesium sulfate, drying, carrying out suction filtration, concentrating the filtrate, and carrying out silica gel chromatography to obtain the intermediate 2.
8. The method for synthesizing etimicin derivative according to claim 3, wherein the intermediate 3 obtained in step 3 is further purified by recrystallization, and the solvent is selected from tetrahydrofuran, water, methanol, ethanol or a mixture thereof, preferably the solvent is selected from a mixture of tetrahydrofuran and water, more preferably the volume ratio of tetrahydrofuran to water is 50: 1.
9. The method for synthesizing etimicin derivative according to claim 3, wherein the step 4 is performed by ion exchange resin column chromatography, and the eluent is selected from ammonia, preferably ammonia with a concentration of 0.1 to 2% by mass, more preferably 0.6% by mass.
10. The method of synthesizing an etimicin derivative as claimed in claim 3, wherein the sulfate obtained in step 5 is further spray dried.
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| 李焕德等: "《抗菌药物临床应用指导手册》", 30 April 2014, 湖南科学技术出版社 * |
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