CN110845554A - Synthesis method of etimicin sulfate - Google Patents
Synthesis method of etimicin sulfate Download PDFInfo
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- CN110845554A CN110845554A CN201911316438.XA CN201911316438A CN110845554A CN 110845554 A CN110845554 A CN 110845554A CN 201911316438 A CN201911316438 A CN 201911316438A CN 110845554 A CN110845554 A CN 110845554A
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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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- 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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Abstract
The invention discloses a method for synthesizing etimicin sulfate. The method comprises the following steps: etimicin, an organic solvent, zinc acetate dihydrate and (N-hydroxy-5-norbornene-2, 3-dicarboximidoyl) -N-PNZ-4-amino-2 (R) -benzoyl-butyrate are mixed with dichloromethane to obtain an intermediate 1; mixing the intermediate 1, methanol, a metal chelate and carbonic acid (N-hydroxy-5-norbornene-2, 3-formylimine tert-butyl ester) to obtain an intermediate 2, mixing the intermediate 2, THF, (N-hydroxy-5-norbornene-2, 3-diformylimide) -9-fluorene-acetate, N-methylmorpholine and Boc anhydride to obtain an intermediate 3, mixing the intermediate 3, dichloromethane and N, N-diisopropylethylamine in an ice bath to obtain an intermediate 4, mixing the intermediate 4, tetrahydrofuran and acetaldehyde, adding a reducing agent to obtain an intermediate 5, mixing the intermediate 5 with a hydrogen chloride saturated ethyl acetate solution, adjusting the pH to 6.5-7 to obtain etimicin, and reacting the etimicin with sulfuric acid to obtain etimicin sulfate, wherein the synthesis method disclosed by the invention has less side reaction, the product has high purity and is easy for industrial production.
Description
FIELD
The invention relates to the field of pharmaceutical chemistry, in particular to a synthesis method of etimicin sulfate.
Background
Etimicin sulfate is a highly effective, low-toxicity, strong drug-resistant bacteria-resistant semisynthetic glucosamine antibiotic which is independently developed in China and has complete intellectual property rights, and is the only anti-infective drug which can obtain a new drug certificate in China.
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.
The prior art has certain defects, mainly including a large amount of product impurities, low yield and the like. With the improvement of drug detection standards, there is an urgent need to further optimize the synthesis method of etimicin sulfate.
SUMMARY
The present disclosure relates to a method for synthesizing etimicin sulfate, which mainly comprises the following steps:
1) mixing etimicin, an organic solvent and zinc acetate dihydrate to obtain a first reaction solution;
mixing (N-hydroxy-5-norbornene-2, 3-dicarboximido) -N-PNZ-4-amino-2 (R) -benzoyl-butyrate with dichloromethane to obtain a second reaction solution; and
mixing the first reaction solution and the second reaction solution, and carrying out aftertreatment to obtain an intermediate 1, wherein the intermediate 1 has the following structural formula:
2) mixing the intermediate 1, methanol and metal chelate, adding carbonic acid (N-hydroxy-5-norbornene-2, 3-formylimine tert-butyl ester) into the reaction solution, and carrying out aftertreatment to obtain an intermediate 2, wherein the structural formula of the intermediate 2 is as follows:
3) intermediate 2, THF and 2.7g (N-hydroxy-5-norbornene-2, 3-dicarboxylimide) -9-fluorene-acetate were mixed, and N-methylmorpholine and Boc anhydride were added to the reaction solution, followed by workup to give intermediate 3, wherein intermediate 3 has the following structural formula:
4) and mixing the intermediate 3, dichloromethane and N, N-diisopropylethylamine in an ice bath to obtain an intermediate 4, wherein the intermediate 4 has the following structural formula:
5) mixing the intermediate 4, tetrahydrofuran and acetaldehyde, and adding a reducing agent into the reaction solution for reduction to obtain an intermediate 5, wherein the intermediate 5 has the following structural formula:
6) mixing the intermediate 5 with a hydrogen chloride saturated ethyl acetate solution, and adjusting the pH to 6.5-7 to obtain etimicin, wherein the structure formula of the etimicin is as follows:
7) dissolving etimicin in deionized water to obtain an etimicin aqueous solution, and mixing the etimicin aqueous solution with concentrated sulfuric acid; mixing an etimicin aqueous solution with concentrated sulfuric acid, and performing spray drying to obtain etimicin sulfate, wherein the etimicin sulfate has a structural formula as follows:
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 "reversed-phase high performance liquid chromatography (RP-HPLC)" refers to a high performance liquid chromatography in which the surface of the stationary phase particles is a non-polar material (e.g., containing C18 chains) and the mobile phase is polar. High performance liquid chromatography, which is broadly referred to as reversed phase liquid chromatography, provided that the mobile phase has a polarity greater than that of the stationary phase. Molecules passing through such reverse phase chromatography columns move according to their polarity, with greater polarity moving more rapidly.
In the present disclosure, the term "concentration" is a unit operation that removes a portion of the solvent from the solution, a process in which the solute and solvent are partially separated.
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.
In the present disclosure, the term "macroporous adsorbent resin column chromatography" refers to the principle of adsorption and screening, and organic substances are eluted by a certain solvent on macroporous adsorbent resin according to different adsorption forces and molecular weights, so as to achieve different purposes of separation, purification, impurity removal, concentration, and the like.
In the present disclosure, the term "vacuum freeze-drying" is a drying technique that uses the principle of sublimation to dehydrate a material. After the material is rapidly frozen, it is heated in a vacuum (below the triple point pressure of water).
In the present disclosure, the term "vacuum drying", also known as resolution drying, is a drying method in which a material is placed under negative pressure and is dried by heating to reach a boiling point under a negative pressure state or by cooling to solidify the material and then passing through a melting point.
In the present disclosure, the term "spray drying" is a method in which a systematic technique is applied to the drying of a material. After the thin material is atomized in the drying chamber, the water content is quickly vaporized in the contact of the thin material and hot air, and then the dried product is obtained. The method can directly dry the solution or emulsion into powder or granular product, and can omit the procedures of evaporation, pulverization, etc.
Detailed Description
The present disclosure relates to a method for synthesizing etimicin sulfate, which mainly comprises the following steps:
1) mixing etimicin, an organic solvent and zinc acetate dihydrate to obtain a first reaction solution;
mixing (N-hydroxy-5-norbornene-2, 3-dicarboximido) -N-PNZ-4-amino-2 (R) -benzoyl-butyrate with dichloromethane to obtain a second reaction solution; and
mixing the first reaction solution and the second reaction solution, and carrying out aftertreatment to obtain an intermediate 1, wherein the intermediate 1 has the following structural formula:
2) mixing the intermediate 1, methanol and a metal chelate, adding carbonic acid (N-hydroxy-5-norbornene-2, 3-formylimine tert-butyl ester) into a reaction solution, and carrying out aftertreatment to obtain an intermediate 2, wherein the structural formula of the intermediate 2 is as follows:
3) intermediate 2, THF and 2.7g (N-hydroxy-5-norbornene-2, 3-dicarboxylimide) -9-fluorene-acetate were mixed, and N-methylmorpholine and Boc anhydride were added to the reaction solution, followed by workup to give intermediate 3, wherein intermediate 3 has the following structural formula:
4) and mixing the intermediate 3, dichloromethane and N, N-diisopropylethylamine in an ice bath to obtain an intermediate 4, wherein the intermediate 4 has the following structural formula:
5) mixing the intermediate 4, tetrahydrofuran and acetaldehyde, and adding a reducing agent into the reaction solution for reduction to obtain an intermediate 5, wherein the intermediate 5 has the following structural formula:
6) mixing the intermediate 5 with a hydrogen chloride saturated ethyl acetate solution, and adjusting the pH to 6.5-7 to obtain etimicin, wherein the structure formula of the etimicin is as follows:
7) dissolving etimicin in deionized water to obtain an etimicin aqueous solution, and mixing the etimicin aqueous solution with concentrated sulfuric acid; mixing an etimicin aqueous solution with concentrated sulfuric acid, and performing spray drying to obtain etimicin sulfate, wherein the etimicin sulfate has a structural formula as follows:
in certain embodiments, in step 1), the organic solvent is selected from methanol, ethanol, DMF, DMSO, or a mixture thereof.
In certain embodiments, in step 1), the organic solvent is selected from methanol.
In certain embodiments, in step 1), the post-treatment comprises:
concentrating the reaction solution treated in the step 1);
performing ion exchange resin column chromatography;
and (5) carrying out low-temperature freeze-drying to obtain the intermediate 1.
In certain embodiments, in step 1), the eluent from the post-treatment ion exchange resin chromatography is selected from aqueous ammonia having a concentration of 0.1% to 2%.
In certain embodiments, in step 1), the eluent from the post-treatment ion exchange resin chromatography is selected from aqueous ammonia having a concentration of 0.5%.
In certain embodiments, in step 2), the carbonic acid (N-hydroxy-5-norbornene-2, 3-and formylimine tert-butyl ester is added in portions in the following mass ratios: 1:1.2.
In certain embodiments, in step 2), the metal chelating agent is selected from zinc acetate, copper acetate, zinc pivalate, or a mixture thereof.
In certain embodiments, in step 2), the metal chelator selected from the metal chelators is zinc acetate.
In certain embodiments, in step 2), the post-treatment comprises:
quenching the reaction liquid ice water treated in the step 2);
removing the solvent under reduced pressure;
washing and drying to obtain the intermediate 2.
In certain embodiments, in step 2), the ice water extraction time is from 0 to 10 h.
In certain embodiments, in step 2), the ice water extraction time is from 0 to 4 h.
In certain embodiments, in step 2), the ice water extraction time is 2 h.
In certain embodiments, in step 3), (N-hydroxy-5-norbornene-2, 3-dicarboxylimide) -9-fluorene-acetate is added in portions, in the following mass ratios: 1:1.5.
In certain embodiments, in step 3), the post-treatment comprises:
quenching the reaction liquid ice water treated in the step 2);
removing tetrahydrofuran under reduced pressure;
washing with water; and
concentrating and recrystallizing to obtain the intermediate 3.
In certain embodiments, in step 3), the ice water extraction time is from 0 to 30 h.
In certain embodiments, in step 3), the ice water extraction time is from 4 to 12 h.
In certain embodiments, in step 3), the ice water extraction time is 8 h.
In certain embodiments, in step 3), the recrystallization solvent is selected from acetone: water, methanol, ethanol or mixtures thereof.
In certain embodiments, the recrystallization solvent is selected from acetone and water mixtures.
In certain embodiments, the acetone to water volume ratio is 1: 6.
In certain embodiments, in step 5), the reaction temperature is controlled to be 0 to 30 ℃ during the addition of acetaldehyde.
In certain embodiments, in step 5), the reaction temperature is controlled to be 0 to 17 ℃ during the addition of acetaldehyde.
In certain embodiments, in step 5), the reducing agent is selected from sodium cyanoborohydride, red aluminum, sodium borohydride, sodium triacetoxyborohydride, potassium borohydride, borane, lithium aluminum hydride, or mixtures thereof.
In certain embodiments, in step 5), the reducing agent is selected from sodium borohydride.
In certain embodiments, in step 5), the temperature is further reduced before reduction, and the temperature is controlled to be 0 to 10 ℃.
In certain embodiments, in step 5), the temperature is further reduced before reduction, and the temperature is controlled to be 0 to 5 ℃.
In some embodiments, step 6) further comprises subjecting etimicin to macroporous adsorbent resin column chromatography, wherein the eluent is selected from ammonia water, and the mass percent concentration of the eluent is 0.1-2%.
In some embodiments, step 6) further comprises subjecting etimicin to macroporous adsorbent resin column chromatography, wherein the eluent is selected from ammonia water and has a mass percent concentration of 0.5%.
Example 1
This embodiment discloses
1. 6' -PNZ-gentamicin C1a (intermediate 1)
19.1g of etimicin was dissolved in 3000ml 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-2' 3-di-Boc gentamicin C1a (intermediate 2)
5.86g of intermediate 1 was dissolved in 100ml of methanol, 5.5g of zinc acetate was further added, the mixture was stirred at room temperature until the solid was completely dissolved, 5g of (N-hydroxy-5-norbornene-2, 3-carboximidot-butyl) carbonate was added in portions, after stirring overnight, 1.5g of (N-hydroxy-5-norbornene-2, 3-carboximidot-butyl) carbonate was further added, the reaction was further stirred for 24 hours, quenched with ice water for 2 hours, the solvent was removed under reduced pressure, the ethyl acetate solvent was removed as a residue, washed with ammonia water, dried over anhydrous magnesium sulfate, and concentrated and used directly in the next reaction.
3. 6 '-PNZ-2' 3,3 "-TriBoc-1-Fmoc-gentamicin C1a
7.38g of intermediate 2 are dissolved in 200ml of THF, 2.7g of (N-hydroxy-5-norbornene-2, 3-dicarboximide) -9-fluorene-acetate are added, stirring is continued for 2h, 1g of (N-hydroxy-5-norbornene-2, 3-dicarboximide) -9-fluorene-acetate are added, stirring is continued for 3h, 1ml of N-methylmorpholine and 5g of Boc anhydride are added, reaction is carried out at room temperature for 5g, quenching is carried out with ice water for 8h, THF is removed under reduced pressure, freezing is carried out overnight, the product is collected at the bottom of the flask, the aqueous layer is poured off, the residue is washed with dichloromethane solvent and water, and after concentration acetone: water (1:6) was recrystallized to give 5.92g of a white solid.
4. 6 '-PNZ-2' 3,3 "-Tris Boc-gentamicin C1a
15g of the intermediate 3 is dissolved in 500ml of dichloromethane, 18.2ml of N, N-diisopropylethylamine is slowly dripped after ice bath, the mixture is stirred and reacted for 2 hours, the reaction solution is respectively washed by saturated saline and phosphate buffer solution, anhydrous magnesium sulfate is dried, and the product is subjected to silica gel column chromatography after concentration to obtain 12.1g of white-like solid.
5. 6 '-PNZ-2' 3,3 "-Tris Boc-1- (N-ethyl) gentamicin C1a
Dissolving 11g of the intermediate 4 in 100ml of tetrahydrofuran, adjusting the pH value to 5-6, reducing the temperature to below 12 ℃, dropwise adding acetaldehyde, controlling the reaction temperature to be not higher than 17 ℃ in the process, reacting at room temperature for 2 hours after dropwise adding, reducing the temperature to 0-5 ℃, adding 1.7g of sodium borohydride in batches, continuing to react for 5 hours, dropwise adding ice water for extraction and extinction, removing tetrahydrofuran under reduced pressure, pouring out a water layer, dissolving and drying a product dichloromethane, and concentrating the product to be directly used for the next reaction.
6. Etimicin
Dissolving 12.4g of the intermediate 5 in 100ml of ethyl acetate, adding 50ml of ethyl acetate solution saturated with hydrogen chloride, keeping the temperature of the reaction solution not higher than 20 ℃ in the process, reacting at room temperature overnight after the addition is finished, adjusting the pH value to 6.5-7 by using 2M sodium hydroxide solution, removing the organic solvent under reduced pressure, separating a water layer by using macroporous resin, taking 0.5% ammonia water as an eluent, and freeze-drying the product at low temperature to obtain 5.5g of a white solid.
7. Etimicin sulfate
Dissolving 10g of etimicin in 25ml of deionized water, magnetically stirring, carrying out ice bath, slowly dropwise adding 2.4ml of concentrated sulfuric acid, magnetically stirring for 3h, and carrying out spray drying on the reaction solution to obtain 10.4g of the product.
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. The synthesis method of etimicin sulfate comprises the following steps:
1) mixing etimicin, an organic solvent and zinc acetate dihydrate to obtain a first reaction solution;
mixing (N-hydroxy-5-norbornene-2, 3-dicarboximido) -N-PNZ-4-amino-2 (R) -benzoyl-butyrate with dichloromethane to obtain a second reaction solution; and
mixing the first reaction solution and the second reaction solution, and carrying out aftertreatment to obtain an intermediate 1, wherein the intermediate 1 has the following structural formula:
2) mixing the intermediate 1, methanol and metal chelate, adding carbonic acid (N-hydroxy-5-norbornene-2, 3-formylimine tert-butyl ester) into the reaction solution, and carrying out aftertreatment to obtain an intermediate 2, wherein the structural formula of the intermediate 2 is as follows:
3) mixing the intermediate 2, THF and (N-hydroxy-5-norbornene-2, 3-diformylimide) -9-fluorene-acetate, adding N-methylmorpholine and Boc anhydride into the reaction solution, and carrying out post-treatment to obtain an intermediate 3, wherein the structural formula of the intermediate 3 is as follows:
4) and mixing the intermediate 3, dichloromethane and N, N-diisopropylethylamine in an ice bath to obtain an intermediate 4, wherein the intermediate 4 has the following structural formula:
5) mixing the intermediate 4, tetrahydrofuran and acetaldehyde, and adding a reducing agent into the reaction solution for reduction to obtain an intermediate 5, wherein the intermediate 5 has the following structural formula:
6) mixing the intermediate 5 with a hydrogen chloride saturated ethyl acetate solution, and adjusting the pH to 6.5-7 to obtain etimicin, wherein the structure formula of the etimicin is as follows:
7) dissolving etimicin in deionized water to obtain an etimicin aqueous solution, mixing the etimicin aqueous solution with concentrated sulfuric acid, and performing spray drying to obtain etimicin sulfate, wherein the etimicin sulfate has a structural formula as follows:
2. the method for synthesizing etimicin as claimed in claim 1, wherein the organic solvent is selected from methanol, ethanol, DMF, DMSO or a mixture thereof in step 1), preferably the organic solvent is selected from methanol.
3. The method for synthesizing etimicin as claimed in claim 1, wherein the post-treatment in step 1) comprises:
concentrating the reaction solution treated in the step 1);
performing ion exchange resin column chromatography;
and (5) carrying out low-temperature freeze-drying to obtain the intermediate 1.
Wherein the eluent for ion exchange resin chromatography is selected from ammonia water with concentration of 0.1-2%, preferably 0.5%.
4. The method for synthesizing etimicin as claimed in claim 1, wherein the metal chelating agent used in step 2) is selected from zinc acetate, copper acetate, zinc pivalate or a mixture thereof, preferably the metal chelating agent is selected from zinc acetate.
5. The method of synthesizing etimicin as claimed in claim 1, wherein the post-processing in step 2) comprises:
quenching the reaction liquid ice water treated in the step 2);
removing the solvent under reduced pressure; and
washing and drying to obtain the intermediate 2.
Wherein the ice water extraction and extinction time is 0 to 10 hours, preferably 0 to 4 hours, and more preferably 2 hours.
6. The method of synthesizing etimicin as claimed in claim 1, wherein the post-processing in step 3) comprises:
quenching the reaction liquid ice water treated in the step 2);
removing tetrahydrofuran under reduced pressure;
washing with water; and
concentrating and recrystallizing to obtain the intermediate 3.
7. The method for synthesizing etimicin according to claim 1, wherein in the step 3), the ice water extraction time is 0 to 30 hours, preferably 4 to 12 hours, and more preferably 8 hours; the recrystallization solvent is selected from acetone, water, methanol, ethanol or a mixture of acetone, preferably a mixture of acetone and water, and more preferably the volume ratio of acetone to water is 1: 6.
8. The method for synthesizing etimicin as claimed in claim 1, wherein the reaction temperature is controlled to be 0 to 30 ℃, preferably 0 to 17 ℃ during the dropping of acetaldehyde in the step 5); the reducing agent is selected from sodium cyanoborohydride, red aluminum, sodium borohydride, sodium triacetoxyborohydride, potassium borohydride, borane, lithium aluminum hydride or mixtures thereof, preferably sodium borohydride.
9. The method for synthesizing etimicin as claimed in claim 1, wherein the step 5) is further performed by cooling before reduction, and the temperature is controlled to be 0 to 10 ℃, preferably 0 to 5 ℃.
10. The method for synthesizing etimicin as claimed in claim 1, wherein the etimicin obtained in step 6) is further subjected to macroporous adsorbent resin column chromatography, and the eluent is selected from ammonia water, preferably the mass percent concentration of ammonia water is 0.1% to 2%, more preferably the mass percent concentration of ammonia water is 0.5%.
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