CN114213471A - Synthesis method of etimicin - Google Patents
Synthesis method of etimicin Download PDFInfo
- Publication number
- CN114213471A CN114213471A CN202111616538.1A CN202111616538A CN114213471A CN 114213471 A CN114213471 A CN 114213471A CN 202111616538 A CN202111616538 A CN 202111616538A CN 114213471 A CN114213471 A CN 114213471A
- Authority
- CN
- China
- Prior art keywords
- etimicin
- reaction
- synthesizing
- concentrating
- ice
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- VEGXETMJINRLTH-ALRICIOSSA-N etimicin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@H](O)[C@H]1O[C@@H]1[C@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N VEGXETMJINRLTH-ALRICIOSSA-N 0.000 title claims abstract description 39
- 229950009953 etimicin Drugs 0.000 title claims abstract description 39
- 238000001308 synthesis method Methods 0.000 title description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- DNYGXMICFMACRA-UHFFFAOYSA-N gentamicin C1A Natural products O1C(CNC)CCC(N)C1OC1C(O)C(OC2C(C(NC)C(C)(O)CO2)O)C(N)CC1N DNYGXMICFMACRA-UHFFFAOYSA-N 0.000 claims abstract description 9
- VEGXETMJINRLTH-BOZYPMBZSA-N gentamycin C1a Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N VEGXETMJINRLTH-BOZYPMBZSA-N 0.000 claims abstract description 8
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000004246 zinc acetate Substances 0.000 claims abstract description 5
- 238000010189 synthetic method Methods 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 14
- 239000003480 eluent Substances 0.000 claims description 13
- 239000005457 ice water Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000012044 organic layer Substances 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 238000005342 ion exchange Methods 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012024 dehydrating agents Substances 0.000 claims description 6
- 239000011347 resin Substances 0.000 claims description 6
- 229920005989 resin Polymers 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 5
- 239000002808 molecular sieve Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000013375 chromatographic separation Methods 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000012267 brine Substances 0.000 claims description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000010010 raising Methods 0.000 claims description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 abstract description 6
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003638 chemical reducing agent Substances 0.000 abstract description 3
- 235000019253 formic acid Nutrition 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 239000012279 sodium borohydride Substances 0.000 abstract description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract description 2
- 238000010511 deprotection reaction Methods 0.000 abstract description 2
- 230000006872 improvement Effects 0.000 description 5
- 230000003115 biocidal effect Effects 0.000 description 4
- 241000191940 Staphylococcus Species 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- DNYGXMICFMACRA-XHEDQWPISA-N Gentamicin C2b Chemical compound O1[C@H](CNC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N DNYGXMICFMACRA-XHEDQWPISA-N 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 229960004744 micronomicin Drugs 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
- C07H15/236—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthetic method of etimicin, wherein gentamicin C1a firstly reacts with zinc acetate and acetic anhydride to obtain an intermediate P1, the intermediate P1 reacts with acetaldehyde under the action of formic acid to obtain an intermediate P2, the intermediate P2 is subjected to alkali deprotection of sodium hydroxide to obtain the etimicin, the novel synthetic method of the etimicin avoids the existing route from using reducing agents such as sodium borohydride and the like to carry out heterogeneous reaction, the preparation process is easy to operate, the method is more environment-friendly and convenient for large-scale production, the prepared etimicin has high purity, and the synthetic route of the etimicin is as follows:
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a synthetic method for preparing etimicin from gentamicin C1 a.
Background
Etimicin (Etimicin), the chemical name is O-2-amino-2, 3, 4, 6-tetradeoxy-6-amino-alpha-D-erythro-hexopyranosyl- (1 → 4) -O- [ 3-deoxy-4-C-methyl-3 (methylamino) -beta-L-arabinopyranosyl- (1 → 6) ] -2-deoxy-N-ethyl-L-streptomycin, the molecular formula is C21H43N5O7, and the Etimicin is a novel semi-synthetic water-soluble antibiotic and belongs to aminoglycosides.
The etimicin mechanism of action is to inhibit the normal protein synthesis of sensitive bacteria. The antibiotic is a broad-spectrum antibiotic, has good antibacterial action on most of G + and G-bacteria, has higher antibacterial activity on escherichia coli, klebsiella pneumoniae, serratia, proteus mirabilis, salmonella, haemophilus, staphylococcus and the like, and has MIC value in vitro in a blood concentration range of therapeutic dose of the product on part of gentamycin, micronomicin and cefazolin resistant staphylococcus aureus, escherichia coli and klebsiella. It also has antibacterial activity against part of Staphylococcus producing penicillinase and part of Staphylococcus with low-level Methicillin Resistance (MRSA).
Etimicin is a second-generation amino sugar antibiotic, the existing etimicin synthesis needs to use reducing agents such as sodium borohydride and the like for heterogeneous reaction, and in the preparation process, the number of impurities is large, the separation is difficult, the amount of waste liquid is large, the environmental protection pressure is large, the main problems of the existing production method are solved, and the large-scale production is not convenient.
Disclosure of Invention
In order to solve the problems, the invention provides a synthesis method of etimicin, which is easy to operate and more convenient for large-scale production, and the prepared etimicin has high purity.
According to one aspect of the present invention, there is provided a method for synthesizing etimicin, comprising the steps of:
the method comprises the following steps: adding methanol into gentamicin C1a, and stirring and mixing to obtain gentamicin C1a methanol solution;
step two: adding zinc acetate and acetic anhydride into the solution obtained in the step one, reacting in ice bath for a certain time, adding ice water, stirring to obtain a reaction solution 1, concentrating the reaction solution 1 under reduced pressure, performing chromatographic separation, eluting with ammonia water to obtain an eluent 1, concentrating the eluent 1, and performing freeze-drying to obtain an intermediate P1, wherein the intermediate P1 is a white solid, and the intermediate P1 has the following structural formula:
step three: adding the intermediate P1 obtained in the step two and a reaction reagent into a reaction bottle, adding a dehydrating agent and acetaldehyde, dropwise adding anhydrous formaldehyde, carrying out ice-bath reaction, heating, raising the temperature, naturally cooling to room temperature, adding ice water, stirring, extracting with dichloromethane, washing and separating the obtained organic layer, drying the organic layer with anhydrous sodium sulfate, and concentrating to obtain an intermediate P2, wherein the intermediate P2 has the following structural formula:
step four: adding water to fully dissolve the intermediate P2 obtained in the third step, adding sodium hydroxide, heating and refluxing for a certain time, adding acid to adjust the pH value to be neutral to obtain a reaction solution 2, concentrating the reaction solution 2 under reduced pressure, separating, eluting with ammonia water to obtain an eluent 2, concentrating the eluent 2, and freeze-drying to obtain etimicin, wherein the structural formula of the etimicin is as follows:
in the second step, the ice-bath reaction time is 4 hours, the stirring time after adding ice water is 30min, and the chromatographic separation adopts an ion exchange column which is HD-2 resin.
As a further improvement of the invention, in the third step, the reaction reagent is selected from one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane, DMF and DMSO.
As a further development of the invention, the reactant is preferably DMF.
As a further improvement of the invention, in the third step, the dehydrating agent is selected from one or more of anhydrous magnesium sulfate, anhydrous sodium sulfate and molecular sieve.
As a further development of the invention, the dehydrating agent is preferably a molecular sieve.
In the third step, after ice-bath reaction for 2 hours, heating to 70 ℃ for reaction for 24 hours, then naturally cooling to room temperature, adding ice water, stirring for 30 minutes, extracting with dichloromethane for 3 times, washing an organic layer with ice water, brine and saturated sodium bicarbonate in sequence, separating liquid, drying the organic layer with anhydrous sodium sulfate, and concentrating to obtain an intermediate P2.
As a further improvement of the invention, the intermediate P2 obtained in the third step is directly used in the reaction in the fourth step without purification.
As a further improvement of the invention, in the fourth step, the heating reflux reaction time is 3h, dilute hydrochloric acid is adopted for adjusting the pH, and an ion exchange column is adopted for separation, wherein the ion exchange column is HD-2 resin.
As a further improvement of the invention, 1% ammonia water is adopted for elution in the second step, and 0.5% ammonia water is adopted for elution in the fourth step.
Compared with the prior art, the invention has the beneficial effects that: the novel synthesis method of etimicin disclosed by the invention avoids the heterogeneous reaction of reducing agents such as sodium borohydride and the like in the existing route, the preparation process is easy to operate, less waste liquid is generated, the novel synthesis method is more environment-friendly, large-scale production is facilitated, the prepared etimicin is high in purity, and the purity of the etimicin synthesized by the method disclosed by the invention can reach 97.5% through detection of a high performance liquid chromatograph.
Detailed Description
The present invention is described in detail below with reference to various embodiments, but it should be understood that these embodiments are not intended to limit the present invention, and those skilled in the art should be able to make modifications and substitutions on the functions, methods, or structures of these embodiments without departing from the scope of the present invention.
According to the synthesis method of etimicin in one embodiment of the invention, gentamicin C1a firstly reacts with zinc acetate and acetic anhydride to obtain an intermediate P1, the intermediate P1 reacts with acetaldehyde under the action of formic acid to perform reductive amination to obtain an intermediate P2, and the intermediate P2 is subjected to sodium hydroxide alkali deprotection to obtain etimicin, wherein the synthesis route is as follows:
the synthesis method of etimicin comprises the following specific operation steps:
dissolving gentamicin C1a (22.5g,50mmol) in 100ml methanol, magnetically stirring for 10min, adding 37g zinc acetate and 25ml acetic anhydride, reacting in ice bath for 4h, adding 100ml ice water, stirring for 30min to obtain reaction liquid 1, concentrating the reaction liquid 1 under reduced pressure, separating by ion exchange column (HD-2 resin) chromatography, eluting with 1% ammonia water to obtain eluent 1, concentrating the eluent 1, and freeze-drying to obtain intermediate P1 as a white solid, wherein 17.2g of the intermediate P1 is obtained.
Adding 17.2g of intermediate P1 and 50ml of DMF into a reaction bottle, continuously adding 100g of dried 4A molecular sieve and 22g of acetaldehyde, dropwise adding 5ml of anhydrous formic acid, carrying out ice-bath reaction for 2h, heating to 70 ℃ for reaction for 24h, naturally cooling to room temperature, adding 50ml of ice water, stirring for 30min, extracting with dichloromethane for 3 times, sequentially washing the obtained organic layer with ice water, saline water and saturated sodium bicarbonate, separating the liquid, drying the organic layer with anhydrous sodium sulfate, concentrating into paste to obtain intermediate P2, and directly using the intermediate P2 for the next reaction without refining.
Dissolving the intermediate P2 obtained by the reaction in the previous step in 40ml of water, continuously adding 6g of sodium hydroxide, heating and refluxing for reaction for 3h, adjusting the pH value to be neutral by using dilute hydrochloric acid to obtain a reaction solution 2, separating the residue after the reaction solution 2 is concentrated under reduced pressure by using an ion exchange column (HD-2 resin), eluting by using 0.5% ammonia water to obtain an eluent 2, concentrating the eluent 2 under reduced pressure, adding water to dissolve and freeze-dry the eluent to obtain 7.5g of etimicin, and detecting by using a High Performance Liquid Chromatograph (HPLC) to synthesize the etimicin with the purity of 97.5%.
The foregoing describes only some embodiments of the present invention and modifications and variations thereof will be apparent to those skilled in the art without departing from the spirit and scope of the invention.
Claims (10)
1. A synthetic method of etimicin is characterized by comprising the following steps:
the method comprises the following steps: adding methanol into gentamicin C1a, and stirring and mixing to obtain gentamicin C1a methanol solution;
step two: adding zinc acetate and acetic anhydride into the solution obtained in the step one, reacting in ice bath for a certain time, adding ice water, stirring to obtain a reaction solution 1, concentrating the reaction solution 1 under reduced pressure, performing chromatographic separation, eluting with ammonia water to obtain an eluent 1, concentrating the eluent 1, and performing freeze-drying to obtain an intermediate P1, wherein the intermediate P1 is a white solid, and the intermediate P1 has the following structural formula:
step three: adding the intermediate P1 obtained in the step two and a reaction reagent into a reaction bottle, adding a dehydrating agent and acetaldehyde, dropwise adding anhydrous formaldehyde, carrying out ice-bath reaction, heating, raising the temperature, naturally cooling to room temperature, adding ice water, stirring, extracting with dichloromethane, washing and separating the obtained organic layer, drying the organic layer with anhydrous sodium sulfate, and concentrating to obtain an intermediate P2, wherein the intermediate P2 has the following structural formula:
step four: adding water to fully dissolve the intermediate P2 obtained in the third step, adding sodium hydroxide, heating and refluxing for a certain time, adding acid to adjust the pH value to be neutral to obtain a reaction solution 2, concentrating the reaction solution 2 under reduced pressure, separating, eluting with ammonia water to obtain an eluent 2, concentrating the eluent 2, and freeze-drying to obtain etimicin, wherein the structural formula of the etimicin is as follows:
2. the method for synthesizing etimicin according to claim 1, wherein in the second step, the ice-bath reaction time is 4h, the stirring time after adding ice water is 30min, and the chromatographic separation adopts an ion exchange column which is HD-2 resin.
3. The method for synthesizing etimicin according to claim 1, wherein the reaction reagent in step three is selected from one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane, DMF and DMSO.
4. A method of synthesizing etimicin according to claim 3, wherein the reaction reagent is preferably DMF.
5. The method for synthesizing etimicin according to claim 1, wherein in the third step, the dehydrating agent is one or more selected from anhydrous magnesium sulfate, anhydrous sodium sulfate and molecular sieves.
6. The method for synthesizing etimicin according to claim 5, wherein the dehydrating agent is preferably a molecular sieve.
7. The method for synthesizing etimicin according to claim 1, wherein in the third step, after 2 hours of ice-bath reaction, heating to 70 ℃ for 24 hours of reaction, then naturally cooling to room temperature, adding ice water, stirring for 30 minutes, extracting with dichloromethane for 3 times, washing the organic layer with ice water, brine and saturated sodium bicarbonate in sequence, separating the liquid, drying the organic layer with anhydrous sodium sulfate, and concentrating to paste to obtain the intermediate P2.
8. The method of synthesizing etimicin according to claim 7, wherein the intermediate P2 obtained in the third step is used in the reaction in the fourth step without purification.
9. The method for synthesizing etimicin according to claim 1, wherein in the fourth step, the heating reflux reaction is performed for 3 hours, dilute hydrochloric acid is used for adjusting the pH, and an ion exchange column is used for separation, wherein the ion exchange column is HD-2 resin.
10. The method for synthesizing etimicin according to claim 1, wherein 1% ammonia water is used for the elution in the second step, and 0.5% ammonia water is used for the elution in the fourth step.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111616538.1A CN114213471A (en) | 2021-12-27 | 2021-12-27 | Synthesis method of etimicin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111616538.1A CN114213471A (en) | 2021-12-27 | 2021-12-27 | Synthesis method of etimicin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114213471A true CN114213471A (en) | 2022-03-22 |
Family
ID=80706232
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111616538.1A Pending CN114213471A (en) | 2021-12-27 | 2021-12-27 | Synthesis method of etimicin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114213471A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103833804A (en) * | 2014-03-22 | 2014-06-04 | 烟台只楚药业有限公司 | Synthetic method of etimicin sulfate |
| CN105503972A (en) * | 2015-12-09 | 2016-04-20 | 无锡济民可信山禾药业股份有限公司 | Method for synthesizing 1-N-ethylgentamicin C1a by taking heteropolyacid as catalyst |
| CN110372760A (en) * | 2019-08-14 | 2019-10-25 | 无锡济民可信山禾药业股份有限公司 | A kind of synthetic method of 3-N- ethyl Gentamicin C1a |
-
2021
- 2021-12-27 CN CN202111616538.1A patent/CN114213471A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103833804A (en) * | 2014-03-22 | 2014-06-04 | 烟台只楚药业有限公司 | Synthetic method of etimicin sulfate |
| CN105503972A (en) * | 2015-12-09 | 2016-04-20 | 无锡济民可信山禾药业股份有限公司 | Method for synthesizing 1-N-ethylgentamicin C1a by taking heteropolyacid as catalyst |
| CN110372760A (en) * | 2019-08-14 | 2019-10-25 | 无锡济民可信山禾药业股份有限公司 | A kind of synthetic method of 3-N- ethyl Gentamicin C1a |
Non-Patent Citations (1)
| Title |
|---|
| 张悦，等: "《医用化学》", 华中科技大学出版社 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101786971B (en) | Preparation process of doxycycline hydrochloride | |
| CN107311875A (en) | The synthetic method of aramine | |
| CN113549042B (en) | Preparation method of dapagliflozin | |
| CN106749447B (en) | A kind of intermediate of epirubicin hydrochloride compound | |
| CN106749446A (en) | A kind of intermediate of epirubicin hydrochloride compound V | |
| CN103833714A (en) | Semi-synthesis method of luteolin and galuteolin as well as luteolin rutinoside | |
| CN106749445A (en) | A kind of intermediate of epirubicin hydrochloride compound III | |
| CN108191925A (en) | The industrial manufacturing process of gemcitabine key intermediate sulfonation sugar | |
| CN114213471A (en) | Synthesis method of etimicin | |
| CN107043362B (en) | A kind of intermediate of epirubicin hydrochloride compounds Ⅳ | |
| CN103113430B (en) | Method for preparing etimicin sulfate | |
| CN105524129A (en) | Etimicin sulfate preparation method | |
| CN109293722B (en) | Azithromycin related substance and preparation method thereof | |
| CN112679570B (en) | Synthesis and purification method of tildipirosin | |
| CN106432388A (en) | Preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine | |
| CN110229111B (en) | Ambroxol impurity and preparation method and application thereof | |
| CN114149473B (en) | Synthesis method of epirubicin hydrochloride and intermediate thereof | |
| CN101152195A (en) | Application of aminoglycoside antibiotic in preparing pharmaceutical composition for treating drug-fast bacteria infection | |
| CN101054398B (en) | Method of synthesizing 2-deoxy-5-iodo-beta-uridine | |
| CN111362997A (en) | Synthesis of androstenedione (2,2,4,6,6,16, 16-D) by deuterium exchange7) Method (2) | |
| CN101993464A (en) | Preparation method of capecitabine | |
| CN111454214B (en) | Synthetic method of 2-methoxy-1-pyrimidineethylamine hydrochloride | |
| CN111087410A (en) | Preparation method of amoxicillin impurity G | |
| CN111040007A (en) | Synthetic method of 1, 3, 2' -N, N, N-triacetyl gentamicin C1a | |
| JP2016515589A (en) | Synthesis method of dibekacin and arbekacin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220322 |