CN104693251A - Preparation method of gamithromycin or 13-descladinosylation compound serving as precursor of gamithromycin - Google Patents
Preparation method of gamithromycin or 13-descladinosylation compound serving as precursor of gamithromycin Download PDFInfo
- Publication number
- CN104693251A CN104693251A CN201510087675.9A CN201510087675A CN104693251A CN 104693251 A CN104693251 A CN 104693251A CN 201510087675 A CN201510087675 A CN 201510087675A CN 104693251 A CN104693251 A CN 104693251A
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- acid
- add
- descladinosylation
- preparation
- presoma
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 title claims abstract description 21
- VWAMTBXLZPEDQO-UZSBJOJWSA-N (2r,3s,4r,5s,8r,10r,11r,12s,13s,14r)-11-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-7-propyl-1-oxa-7-azacyclopentadeca Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@H](CC)[C@@](C)(O)[C@H](O)[C@@H](C)CN([C@@H](C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)C)CCC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 VWAMTBXLZPEDQO-UZSBJOJWSA-N 0.000 title abstract description 11
- 229960002314 gamithromycin Drugs 0.000 title abstract description 10
- 239000002243 precursor Substances 0.000 title abstract 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000003756 stirring Methods 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 16
- 239000000758 substrate Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 12
- 150000002576 ketones Chemical class 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001408 amides Chemical class 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- 239000012141 concentrate Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 6
- 239000011707 mineral Substances 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 4
- YHVUVJYEERGYNU-UHFFFAOYSA-N 4',8-Di-Me ether-5,7,8-Trihydroxy-3-(4-hydroxybenzyl)-4-chromanone Natural products COC1(C)CC(O)OC(C)C1O YHVUVJYEERGYNU-UHFFFAOYSA-N 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- AJSDVNKVGFVAQU-BIIVOSGPSA-N cladinose Chemical compound O=CC[C@@](C)(OC)[C@@H](O)[C@H](C)O AJSDVNKVGFVAQU-BIIVOSGPSA-N 0.000 abstract description 2
- 229910001873 dinitrogen Inorganic materials 0.000 abstract 1
- 239000011159 matrix material Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 3
- MQTOSJVFKKJCRP-HHZDEWPHSA-N Azythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@H]([C@@]([C@H](O)[C@H](C)N(C)C[C@@H](C)C[C@](C)(O)[C@@H](O[C@@H]2[C@H]([C@@H](C[C@H](C)O2)N(C)C)O)[C@@H]1C)(C)O)CC)[C@@H]1C[C@](C)(OC)[C@H](O)[C@@H](C)O1 MQTOSJVFKKJCRP-HHZDEWPHSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000006049 ring expansion reaction Methods 0.000 description 2
- KYTWXIARANQMCA-RWJQBGPGSA-N (3r,4s,5s,6r,7r,9r,11s,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-10-hydroxyimino-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecan-2 Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=NO)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 KYTWXIARANQMCA-RWJQBGPGSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241001581234 Histophilus Species 0.000 description 1
- 241001293418 Mannheimia haemolytica Species 0.000 description 1
- 241000606856 Pasteurella multocida Species 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- -1 cladinose compound Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940051027 pasteurella multocida Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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 preparation method of gamithromycin or a 13-descladinosylation compound serving as a precursor of gamithromycin, belonging to the field of chemical synthesis. The method comprises the steps of adding a reaction substrate and a solvent into a high-pressure kettle, wherein the reaction substrate is gamithromycin or the precursor thereof, and the solvent is low-grade amide, low-grade ketone or low-grade alcohol; adding acid, and controlling the pH value of a reaction system at 0.5-5; introducing nitrogen gas to the high-pressure kettle, and keeping the pressure at 0.1-0.8Mpa; and controlling the reaction temperature at 0-35 DEG C and stirring for 1-12 hours. The preparation method is simple in process and high in selectivity, and the yield of gamithromycin or the 13-descladinosylation compound serving as the precursor of gamithromycin is high. Gamithromycin or the precursor thereof contains hydroxyls, ester groups and a plurality of ether bonds; and the reaction substrate of gamithromycin and the precursor thereof in the method disclosed by the invention selectively breaks the ether bonds at the juncture of cladinose and a matrix under an acid condition, but the hydroxyls and the ester groups are unchanged under the reaction condition, so that the selectivity is high.
Description
Technical field
The present invention relates to the field of chemical synthesis, particularly a kind of preparation method adding meter mycin or its presoma 13-descladinosylation compound.
Background technology
Adding a meter mycin (Gamithromycin) CAS:145435-72-9 molecular structural formula is:
Adding meter mycin is a kind of novel s-generation Macrolide veterinary antibiotic medicine.It is the same with Azythromycin synthetic intermediate that synthesis adds meter mycin intermediate, and be all ring expansion derivative obtained after a kind of erythromycin A-9 oxime ring expansion, just both are isomerss.Add meter mycin and be mainly used in treating the cattle infected disease that the bacterial pathogens such as pasteurella haemolytica, pasteurella multocida, Histophilus causes.
In recent years, along with the universal of novel equipment together etc. and the increase of China's science research input, the raising work of China's pharmaceutical standards is also more and more deep.The raising of pharmacopeia Chinese traditional medicine the standard not only directly standard of the specification medicine such as bulk drug, injection itself and safe medication, and for the production of medicine, there is indirectly directive function, for superseded old technique, facilitated technique raising and process modification by immeasurable meaning.
Add meter mycin or its presoma 13-descladinosylation adds the major impurity compound in meter mycin or its presoma, the preparation of impurity correlative should become the basis that standards of pharmacopoeia improves.About the preparation method adding meter mycin or its presoma 13-descladinosylation impurity thing has no report.
Application publication number discloses the preparation technology that a kind of Azythromycin or azithromycin intermediate slough cladinose compound for the Chinese invention patent of " CN 103232501 A ".But the productive rate that this invented technology prepares descladinosylation compound only has 44.4%-52.0%.
Summary of the invention
For making up above deficiency, the invention provides and a kind ofly add preparation method of meter mycin or its presoma 13-descladinosylation compound and preparation method thereof.
Technical scheme of the present invention is:
A kind of preparation method adding meter mycin or its presoma 13-descladinosylation compound, to add meter mycin or to add meter mycin presoma for reaction substrate, with rudimentary acid amides, lower ketones or lower alcohol for solvent, reaction substrate and solvent are placed in autoclave, add acid as catalyzer and to control reaction system pH be 0.5-5, in autoclave, pass into nitrogen and keep pressure to be 0.1-0.8Mpa, control temperature of reaction is 0-35 DEG C, stirring reaction 1-12h; Concrete reaction formula is as follows:
Wherein, R
1for H or CH
2cH
2cH
3, R
2for H or OH, R
3for H or CH
3, R
4for CH
3, H, COCH
2cH
3, or SO
2c
6h
4cH
3.
Preferably, the mass ratio of solvent and reaction substrate is 1:1-1:10.
Preferably, reaction terminates, and method of purification is specially: add the one in halohydrocarbon, lower member ester or rudimentary ether and water under normal pressure, be 8.5-10.5 by sodium hydroxide solution adjust ph, phase inversion concentrates to organic layer, and enriched material adds lower alcohol or lower ketones crystallization, centrifuging.
Preferably, described rudimentary acid amides is DMF or N,N-dimethylacetamide; Lower ketones is C
3-C
6ketone; Lower alcohol is C
1-C
4alcohol.
Further, described lower ketones is acetone, methylethylketone or methyl iso-butyl ketone (MIBK); Described lower alcohol is methyl alcohol, ethanol, n-propyl alcohol.
As preferably, described acid is the mixed acid aqueous solution of the organic acid of 10wt%-60 wt%, mineral acid or organic acid and mineral acid; Described organic acid is formic acid, acetic acid, oxalic acid, propionic acid, butyric acid; Described mineral acid is hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid.
Preferably, described halohydrocarbon is C
1-C
4halohydrocarbon; Described lower member ester is C
2-C
6ester; Described rudimentary ether is C
2-C
6ether.
Further, described halohydrocarbon is methylene dichloride, chloroform, tetracol phenixin or 1,2-ethylene dichloride; Described lower member ester is ethyl formate, ethyl acetate or isopropyl acetate; Described rudimentary ether is ether, propyl ether, isopropyl ether or methyl tertiary butyl ether.
Preferably, in method of purification, the mass ratio of halohydrocarbon, lower member ester or rudimentary ether and reaction substrate is 1:1-1:10; The mass ratio of water and reaction substrate is 1:1-1:10.
As preferably, reaction system pH is 1.5-3, and pressure is 0.3-0.6Mpa, and temperature of reaction is 25-30 DEG C, stirring reaction 6-10h.
Beneficial effect of the present invention is:
The preparation method adding meter mycin or its presoma 13-descladinosylation compound of the present invention, technique is simple, selectivity is high, add meter mycin or its presoma 13-descladinosylation compound yield is high.
Add in meter mycin and presoma thereof and comprise hydroxyl, ester group and several ehter bonds, but add meter mycin and presoma reaction substrate thereof in the inventive method in acid condition, the ehter bond that selectivity fracture cladinose is connected with parent, and hydroxyl, ester group do not react under the reaction conditions, selectivity is high.
Embodiment
Embodiment 1
In the autoclave of 250ml, add a meter mycin 7.8g(10mmol), methyl alcohol 20ml, stirring and dissolving, drips the aqueous hydrochloric acid of 4mol/L, and regulate pH between 1.5-2.0, autoclave passes into N
2, keep pressure 0.3Mpa, control temperature 25 DEG C, add methylene dichloride and each 50ml of water after stirring 8h, regulate pH=9.8 with the sodium hydroxide solution of 4mol/L, separatory obtains organic phase and concentrates, and concentration residue adds 35ml acetone stirring and crystallizing and filters.The vacuum drying white solid B 5.4g of filter cake 50 DEG C, yield 86.0%, purity is 99.5%.
Embodiment 2
In the autoclave of 250ml, add 9-deoxidation-8 α-azepine-8 α-homoerythromycin A 7.4g(10mmol), methyl alcohol 20ml, stirring and dissolving, drips the aqueous hydrochloric acid of 4mol/L, and regulate pH between 1.5-2.0, autoclave passes into N
2, keep pressure 0.5Mpa, control temperature 30 DEG C, add methylene dichloride and each 50ml of water after stirring 5h, regulate pH=9.6 with the sodium hydroxide solution of 4mol/L, separatory obtains organic phase and concentrates, and concentration residue adds 35ml ethanol stirring and crystallizing and filters.The vacuum drying white solid B 5.0g of filter cake 50 DEG C, yield 83.7%, purity is 98.4%.
Embodiment 3:
In the autoclave of 250ml, add a meter mycin 7.8g(10mmol), acetone 70ml, drip the sulfuric acid of 4mol/L, regulate pH between 2.5-3.0, autoclave passes into N
2, control temperature 30 DEG C, keeps pressure 0.4Mpa, adds methylene dichloride and each 50ml of water after stirring 8h, regulates pH=9.8 with the sodium hydroxide solution of 4mol/L, and separatory obtains organic phase and concentrates, and concentration residue adds 35ml ethanol stirring and crystallizing and filters.The vacuum drying white solid B 5.1g of filter cake 50 DEG C, yield 82.0%, purity is 99.6%.
Embodiment 4:
In the autoclave of 250ml, add a meter mycin 7.8g(10mmol), methyl alcohol 20ml, drip the hydrochloric acid of 4mol/L, regulate pH between 1.5-2.0, autoclave passes into N
2, control temperature 35 DEG C, keeps pressure 0.3Mpa, adds methyl tertiary butyl ether and each 50ml of water after stirring 8h, regulates pH=9.8 with the sodium hydroxide solution of 4mol/L, and separatory obtains organic phase and concentrates, and concentration residue adds 35ml ethanol stirring and crystallizing and filters.The vacuum drying white solid B 5.2g of filter cake 50 DEG C, yield 84.0%, purity is 96.6%.
Embodiment 5:
In the autoclave of 250ml, add a meter mycin 7.8g(10mmol), methyl alcohol 20ml, add water 80ml under stirring, drip the mixing acid of phosphoric acid and oxalic acid, regulate pH between 1.0-1.5, autoclave passes into N
2, control temperature 25 DEG C, keeps pressure 0.6Mpa, adds ethyl acetate and each 50ml of water after stirring 8h, regulates pH=9.8 with the sodium hydroxide solution of 4mol/L, and separatory obtains organic phase and concentrates, and concentration residue adds 35ml methyl alcohol stirring and crystallizing and filters.The vacuum drying white solid B 5.1g of filter cake 50 DEG C, yield 81.6%, purity is 99.5%.
Embodiment 6:
In the autoclave of 250ml, add a meter mycin 7.8g(10mmol), DMF 20ml, add water 80ml under stirring, drip hydrochloric acid, regulate pH between 2.0-2.5, autoclave passes into N
2, control temperature 35 DEG C, keeps pressure 0.5Mpa, adds ethyl acetate and each 50ml of water after stirring 6h, regulates pH=9.7 with the sodium hydroxide solution of 4mol/L, and separatory obtains organic phase and concentrates, and concentration residue adds 35ml methyl alcohol stirring and crystallizing and filters.The vacuum drying white solid B 5.2g of filter cake 50 DEG C, yield 80.9%, purity is 98.9%.
Claims (10)
1. one kind adds the preparation method of meter mycin or its presoma 13-descladinosylation compound, it is characterized in that: to add meter mycin or to add meter mycin presoma for reaction substrate, with rudimentary acid amides, lower ketones or lower alcohol for solvent, reaction substrate and solvent are placed in autoclave, add acid as catalyzer and to control reaction system pH be 0.5-5, in autoclave, pass into nitrogen and keep pressure to be 0.1-0.8Mpa, control temperature of reaction is 0-35 DEG C, stirring reaction 1-12h; Concrete reaction formula is as follows:
Wherein, R
1for H or CH
2cH
2cH
3, R
2for H or OH, R
3for H or CH
3, R
4for CH
3, H, COCH
2cH
3, or SO
2c
6h
4cH
3.
2. add the preparation method of meter mycin or its presoma 13-descladinosylation compound as claimed in claim 1, it is characterized in that: the mass ratio of solvent and reaction substrate is 1:1-1:10.
3. add the preparation method of meter mycin or its presoma 13-descladinosylation compound as claimed in claim 1, it is characterized in that, reaction terminates, method of purification is specially: add the one in halohydrocarbon, lower member ester or rudimentary ether and water under normal pressure, be 8.5-10.5 by sodium hydroxide solution adjust ph, phase inversion concentrates to organic layer, and enriched material adds lower alcohol or lower ketones crystallization, centrifuging.
4. as described in claim 1 or 3, add the preparation method of meter mycin or its presoma 13-descladinosylation compound, it is characterized in that: described rudimentary acid amides is DMF or N,N-dimethylacetamide; Lower ketones is C
3-C
6ketone; Lower alcohol is C
1-C
4alcohol.
5. add the preparation method of meter mycin or its presoma 13-descladinosylation compound as claimed in claim 4, it is characterized in that: described lower ketones is acetone, methylethylketone or methyl iso-butyl ketone (MIBK); Described lower alcohol is methyl alcohol, ethanol, n-propyl alcohol.
6. add the preparation method of meter mycin or its presoma 13-descladinosylation compound as claimed in claim 1, it is characterized in that: described acid is the mixed acid aqueous solution of the organic acid of 10wt%-60 wt%, mineral acid or organic acid and mineral acid; Described organic acid is formic acid, acetic acid, oxalic acid, propionic acid, butyric acid; Described mineral acid is hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid.
7. add the preparation method of meter mycin or its presoma 13-descladinosylation compound as claimed in claim 3, it is characterized in that: described halohydrocarbon is C
1-C
4halohydrocarbon; Described lower member ester is C
2-C
6ester; Described rudimentary ether is C
2-C
6ether.
8. add the preparation method of meter mycin or its presoma 13-descladinosylation compound as claimed in claim 7, it is characterized in that: described halohydrocarbon is methylene dichloride, chloroform, tetracol phenixin or 1,2-ethylene dichloride; Described lower member ester is ethyl formate, ethyl acetate or isopropyl acetate; Described rudimentary ether is ether, propyl ether, isopropyl ether or methyl tertiary butyl ether.
9. add the preparation method of meter mycin or its presoma 13-descladinosylation compound as claimed in claim 3, it is characterized in that: in method of purification, the mass ratio of halohydrocarbon, lower member ester or rudimentary ether and reaction substrate is 1:1-1:10; The mass ratio of water and reaction substrate is 1:1-1:10.
10. add the preparation method of meter mycin or its presoma 13-descladinosylation compound as claimed in claim 1, it is characterized in that: reaction system pH is 1.5-3, pressure is 0.3-0.6Mpa, and temperature of reaction is 25-30 DEG C, stirring reaction 6-10h.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993250A (en) * | 2011-07-06 | 2013-03-27 | 洛阳惠中兽药有限公司 | C-3 substituted-9-deoxidized-9A-aza-9A-high erythromycin A derivative |
| CN103232501A (en) * | 2013-04-11 | 2013-08-07 | 宜昌东阳光药业股份有限公司 | A preparation process for compounds of azithromycin or azithromycin intermediates with cladinose removed |
| CN104119413A (en) * | 2014-07-29 | 2014-10-29 | 华中农业大学 | Synthesis method of tulathromycin residue marker |
-
2015
- 2015-02-26 CN CN201510087675.9A patent/CN104693251B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993250A (en) * | 2011-07-06 | 2013-03-27 | 洛阳惠中兽药有限公司 | C-3 substituted-9-deoxidized-9A-aza-9A-high erythromycin A derivative |
| CN103232501A (en) * | 2013-04-11 | 2013-08-07 | 宜昌东阳光药业股份有限公司 | A preparation process for compounds of azithromycin or azithromycin intermediates with cladinose removed |
| CN104119413A (en) * | 2014-07-29 | 2014-10-29 | 华中农业大学 | Synthesis method of tulathromycin residue marker |
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| SULEJMAN ALIHODZIC, ET AL.,: "Synthesis and Antibacterial Activity of Isomeric 15-Membered Azalides.", 《J.ANTIBIOT》 * |
| ZORICA MARUSIC ISTUK, ET AL.,: "Novel 9a-carbamoyl- and 9a-thiocarbamoyl-3-decladinosyl-6-hydroxy and 6-methoxy derivatives of 15-membered macrolides.", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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