CN106256824A - A kind of preparation method of high-purity De Lasha star meglumine salt - Google Patents
A kind of preparation method of high-purity De Lasha star meglumine salt Download PDFInfo
- Publication number
- CN106256824A CN106256824A CN201510339691.2A CN201510339691A CN106256824A CN 106256824 A CN106256824 A CN 106256824A CN 201510339691 A CN201510339691 A CN 201510339691A CN 106256824 A CN106256824 A CN 106256824A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- lasha star
- lasha
- star
- 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.)
- Granted
Links
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 239000002904 solvent Substances 0.000 claims abstract description 29
- 229960003194 meglumine Drugs 0.000 claims abstract description 12
- 238000000746 purification Methods 0.000 claims abstract description 11
- 230000007062 hydrolysis Effects 0.000 claims abstract description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 7
- 230000008025 crystallization Effects 0.000 claims abstract description 7
- 238000001816 cooling Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- -1 isobutyryl Chemical group 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- 125000001589 carboacyl group Chemical group 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- 238000007670 refining Methods 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 238000001035 drying Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000010583 slow cooling Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000003541 multi-stage reaction Methods 0.000 description 2
- 238000005498 polishing Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- QOPAMSBHSSXKGC-UHFFFAOYSA-N [F].C1=CC=C2NC(=O)C=CC2=C1 Chemical class [F].C1=CC=C2NC(=O)C=CC2=C1 QOPAMSBHSSXKGC-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- DYDCPNMLZGFQTM-UHFFFAOYSA-N delafloxacin Chemical compound C1=C(F)C(N)=NC(N2C3=C(Cl)C(N4CC(O)C4)=C(F)C=C3C(=O)C(C(O)=O)=C2)=C1F DYDCPNMLZGFQTM-UHFFFAOYSA-N 0.000 description 1
- 229950006412 delafloxacin Drugs 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- FZRNJOXQNWVMIH-UHFFFAOYSA-N lithium;hydrate Chemical class [Li].O FZRNJOXQNWVMIH-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical class [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000007517 polishing process Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to belong to the process for purification of De Lasha star intermediate formula 1 compound, be dissolved in good solvent including formula 1 compound, then mix with poor solvent, heated and stirred, cooling crystallization, isolate crystallization.Formula 1 compound hydrolysis being refining to obtain is obtained high-purity De Lasha star, reacts into De Lasha star meglumine salt, the purity of the latter with meglumine 99.5%.The method of the present invention can effectively go the removal of impurity, is simultaneously introduced solvent and reagent is few, and yield is high, and technical process is simple to operate, effectively reduces preparation cost.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to process for purification and the De Lasha star Portugal of De Lasha star intermediate
The preparation method of methylamine salt.
Background technology
De Lasha star (Delafloxacin), chemistry is entitled: 1-(6-amino-3,5-difluoro pyridine-2-base) the chloro-6-of-8-
Fluoro-7-(3-hydroxy azetidine-1-base)-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, as indicated with 2, it is corresponding for structural formula
Meglumine salt structure as shown in Equation 3:
。
De Lasha star be by Japan Wakunaga pharmaceutical Co. Ltd develop a kind of fluorine quinolone compounds, at present by
Melinta treats company and develops, it is thus achieved that the QIDP qualification of U.S. FDA, is in III phase clinical investigation phase.It acts on machine
Making identical with other fluoroquinolones, act on Bacterial DNA gyrase and topoisomerase I V, prominent Inhibiting enzyme activity can
Reduce the selectivity of bacterial resistance sudden change, be expected to become treatment respiratory tract, urinary tract infection, acute bacterial skin and skin knot
Structure infects the drug candidate of diseases such as (ABSSSI).
WO9711068 and WO2006015194 discloses the synthetic method of De Lasha star, mainly has two kinds of methods:
Method one (WO9711068):
This route is with 2, and 4,5-trifluoros, 2-chlorobenzoic acid is starting material, obtains compound a, compound a and nitrogen through multistep reaction
Azetidine is condensed to yield De Lasha star.
Method two (WO2006015194):
This route is with 2, and 4,5-trifluoro-benzoic acids are starting material, prepares compound 1 through multistep reaction, then hydrolysis obtains De Lasha
Star, finally becomes De Lasha star meglumine salt with meglumine.
Owing to De Lasha star meglumine salt synthesis step is long, impurity is more, and conventional method is difficult to reach the requirement of pharmaceutical grade.
The polishing purification of the most not mentioned intermediate of preparation method of two process routes disclosed above and the polishing purification of finished product, institute
The purity obtaining finished product is difficult to reach pharmaceutical grade requirement.
WO2001034595 discloses a kind of De Lasha star and refines way, by by alkali gold such as De Lasha star and Lithium hydrates
Belong to hydroxide reaction and generate alkali metal salt, then acidifying retrieves De Lasha star to reach refined purpose, at this method increase
Reason process, operation complexity, reduce product yield.CN201310021838.4 discloses the purification way of a kind of improvement, passes through
Prepare the ester compounds before De Lasha star carboxyl does not hydrolyzes, directly react with alkali metal and prepare highly purified De Lasha star alkali metal
Salt solid compounds, the more prepared high-purity De Lasha star of acidifying, the method by directly being prepared De Lasha star alkali gold by intermediate
Belong to salt, the method comparing WO2001034595, decrease step, relatively improve yield.But this method needs to introduce highly basic all the time
And acid, integrated operation still aobvious complexity, there is the risk introducing residue, simultaneously because there is the process of twice soda acid, yield is the most on the low side, no
It is beneficial to industrial amplification production.
CN201310124425.9 discloses the refined way of another kind of De Lasha star.By De Lasha star is added to non-matter
In sub-solvent, adding water, heated and stirred recrystallization is so as to get highly purified De Lasha star.The solvent such as N-N dimethyl that this method introduces
Acetamide boiling point is high, is difficult to eliminate, has the risk of dissolvent residual, and temperature is higher simultaneously, and energy consumption is big, and yield is the highest.
Although above-mentioned 3 kinds of methods lead to refined De Lasha star thus obtain the De Lasha star meglumine salt of pharmaceutical grade, but still
Have that yield is on the low side, have residual solvent, energy consumption big and be not suitable for the defect of industrialized production, accordingly, it would be desirable to seek more to optimize
Method is to obtain the De Lasha star meglumine salt of pharmaceutical grade.
Summary of the invention
The purpose of the present invention obtains a kind of method of high-purity De Lasha star meglumine salt, the De Lasha star that the method obtains
Meglumine salt yield is high, purity high, meets medicinal requirements, and the method simple economy, it is suitable for industrialized production.
De Lasha star has been made research by inventor herein, finds that its dissolubility is poor, except in the non-matter of minority polarity
Sub-solvent such as DMF, NMP etc. has outside preferable dissolubility, and in the common solvent such as alcohols, esters and aralkyl hydrocarbon, dissolubility is low or not
Molten.Formula 1 compound before the hydrolysis of De Lasha star is also made systematic study simultaneously, has found that compound 1 is in alcohols, esters and second
In the common solvent such as nitrile, acetone, dissolubility is preferable.Present inventors have surprisingly found that, after carrying out formula 1 compound refining, then hydrolyze
Obtaining De Lasha star, be then converted into De Lasha star meglumine salt, De Lasha star is without repurity therebetween, it is possible to obtain high-purity
De Lasha star meglumine salt, and meet medicinal requirements.
For realizing the purpose of the present invention, it is provided that following embodiment.
In one embodiment, the present invention provides a kind of method of polishing purification formula 1 compound, including:
It is dissolved in good solvent including by formula 1 compound, then mixes with poor solvent, heated and stirred, cooling crystallization, isolate knot
Crystalline substance,
In formula 1, R1 is alkyl, and R2 is alkanoyl.
In the above-described embodiment, the method for the present invention, wherein, R1 is the alkyl of C1～C4, preferably ethyl, and R2 is C1
～the alkanoyl of C6, preferably isobutyryl.
In the above-described embodiment, the method for the present invention, described good solvent selected from methanol, ethanol, isopropanol, n-butyl alcohol,
In acetonitrile, oxolane, acetone, ethyl acetate, methyl acetate, n-butyl acetate and isopropyl acetate one or more, preferably
Methanol, ethanol or ethyl acetate；Described poor solvent is a kind of or many in water, petroleum ether, normal hexane, hexamethylene and normal heptane
Kind, preferably water, petroleum ether, formula 1 compound is 1:1～1:10g/ml with the mass volume ratio of good solvent, preferably 1:2～1:
6g/ml；Formula 1 compound is 1:0～1:10g/ml with the mass volume ratio of poor solvent, is preferably.For 1:2～1:5g/ml.
In the above-described embodiment, the method for the present invention, during heated and stirred, solution system is molten clear or insoluble clear state.Add
The temperature of heat is 30～100 DEG C, and preferably 40～70 DEG C, the heated and stirred time is 0.5～5h.
In one embodiment, the process for purification of formula 1 compound of the present invention, suitable including formula 1 compound is added
The good solvent of equivalent and poor solvent, gradually cool after heated and stirred 0.5～5h crystallize, separates solid.
In formula 1 compound, R1 is the alkyl of alkyl, preferably C1～C4, more preferably ethyl, and R2 refers to alkanoyl, excellent
Elect the alkanoyl of C1～C6, more preferably isobutyryl as.
In above-mentioned specific embodiments, the method for the present invention, described good solvent is selected from methanol, ethanol, isopropanol, positive fourth
In alcohol, acetonitrile, oxolane, acetone, ethyl acetate, methyl acetate, n-butyl acetate and isopropyl acetate, one or more, excellent
Elect methanol, ethanol or ethyl acetate as；Described poor solvent is selected from water, petroleum ether, normal hexane, hexamethylene and normal heptane
Plant or multiple, preferably water or petroleum ether.Formula 1 compound is 1:1～1:10g/ml with the mass volume ratio of good solvent, is preferably
1:2～1:6g/ml；Formula 1 compound is 1:0～1:10g/ml, preferably 1:2～1:5g/ with the mass volume ratio of poor solvent
ml.Heating-up temperature is 30～100 DEG C, preferably 40～70 DEG C.The heated and stirred time is 1～3h.The cooling crystallization time be 1～
20h, preferably 3～10h.
Herein, formula 1 compound is a kind of known compound, can be prepared by the following technical solutions.
Reference is introduced in full according to WO2006015194() published method, formula 1 compound can be made by the following method
Standby and obtain:
In another embodiment, the present invention provides a kind of method preparing De Lasha star meglumine salt, comprises the following steps:
1) include being dissolved in good solvent formula 1 compound, then mix with poor solvent, heated and stirred, cooling crystallization, isolate knot
Brilliant, it is thus achieved that highly purified formula 1 compound；
2) highly purified for upper step formula 1 compound hydrolysis is obtained De Lasha star；
3) the De Lasha star of upper acquisition is reacted with meglumine obtain De Lasha star meglumine salt.
Concrete reaction equation is as follows:
Preferably, the method preparing De Lasha star meglumine salt of the present invention, it is refining to obtain including the method through the invention described above
Formula 1 compound dissolution in alcoholic solution, add strong base solution, acidifying crystallize i.e. obtains De Lasha star, then is existed by De Lasha star
Water becomes salt get De Lasha star meglumine salt with meglumine.
The present invention has the positive effect that:
Existing disclosed De Lasha star preparation method is not if refined, and the De Lasha star purity prepared is the highest, it is difficult to reach medicinal
Requirement.In published process for purification, mainly realize its meglumine salt by purification De Lasha star and meet pharmaceutical grade, and have
Relate to condition and the processes such as soda acid, high boiling solvent, high temperature recrystallization, the shortcoming that yield is the highest.The method of the present invention overcomes
Disadvantage mentioned above, is refined by formula 1 compound preferable to dissolubility, yield > 90%, then hydrolysis obtains high-purity moral and draws
Sha Xing (purity > 99.0%), the De Lasha star obtained can not be re-refined and directly become salt i.e. to obtain high-purity De Lasha with meglumine
Star meglumine salt (purity > 99.5%), yield > and 90%, the method refining effect is notable, simple to operate, it is to avoid use high boiling point molten
Agent and strong acid and strong base, yield is high, is suitable for amplifying industrialized production.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described, and those skilled in the art can be made more fully to manage
Solve the present invention, but limit the scope of the present invention never in any form.
The preparation of embodiment 1 formula 1 compound, wherein, R1 is ethyl, and R2 is isobutyryl, and reaction equation is as follows:
In 100L reactor, it is sequentially added into 5.0Kg (9.9mol) formula 4 compound, 25Kg ethyl acetate and 500g sulphuric acid, room temperature
Stirring, is slowly added dropwise 1.7KgNCS (12.8mol) and is dissolved in the solution of 25Kg methyl acetate.Dripping complete rear chamber temperature, to stir 5 little
Time, more respectively with sodium bicarbonate solution, sodium sulfite solution and saturated aqueous common salt washing, organic facies is concentrated to dryness and i.e. obtains formula 1 and change
Compound crude product 5.0Kg, purity 97%.
Refining of embodiment 2 formula 1 compound
The formula 1 crude compound 1Kg that embodiment 1 prepares is added in 20L reaction bulb, adds 2L methanol, 3L water, be heated to 50
DEG C, close heating after stirring 1 hour, Slow cooling is down to room temperature, ice-water bath crystallize 5h, sucking filtration, and filter cake is washed with a small amount of cold methanol
Washing, drain, filter cake drying under reduced pressure, to constant weight, obtains pale yellow powder 930g, yield 93%, HPLC purity: 99.1%.
Embodiment 3 changes the refined of formula 1 compound
The formula 1 crude compound 1Kg that example 1 prepares is added in 20L reaction bulb, adds 6L ethanol, 2L water, be heated to 60 DEG C and stir
Closing heating after mixing 1 hour, Slow cooling is down to room temperature, ice-water bath crystallize 7h, sucking filtration, and filter cake, by a small amount of cold washing with alcohol, is taken out
Dry, filter cake drying under reduced pressure, to constant weight, obtains pale yellow powder 900g, yield 90%, HPLC purity: 99.3%.
Embodiment 4, changes the refined of formula 1 compound
The formula 1 crude compound 1Kg that example 1 prepares is added in 20L reaction bulb, adds 5L ethyl acetate, be heated to 60 DEG C, stir
Mixing dissolving, add 5L petroleum ether, close heating, system Slow cooling is down to room temperature, ice-water bath crystallize 8h, sucking filtration, and filter cake is with few
Amount cold ethyl acetate washing, drains, and filter cake drying under reduced pressure, to constant weight, obtains pale yellow powder 840g, yield 84%, HPLC purity:
99.5%。
Embodiment 5, the preparation of De Lasha star
The formula 1 compound 1 highly finished product 500g that embodiment 2 prepares is added in 20L reaction bulb, adds isopropanol 10L, stir molten
Solving, be slowly added dropwise the sodium hydroxide solution 4L of mass fraction 4%, after stirring to hydrolysis completely, the acetic acid of dropping mass fraction 12% is molten
Liquid 5L.Fully leaching solid after crystallize, water washs, and drying under reduced pressure obtains pale yellow powder 384g, yield 94%, purity 99.3%.
The preparation of embodiment 6 De Lasha star
The formula 1 compound highly finished product 500g that embodiment 4 prepares is added in 20L reaction bulb, addition isopropanol 10L, stirring and dissolving,
It is slowly added dropwise the sodium hydroxide solution 4L of mass fraction 4%, after stirring to hydrolysis completely, drips the acetic acid solution of mass fraction 12%
5L.Fully leaching solid after crystallize, water washs, and drying under reduced pressure obtains pale yellow powder 380g, yield 93%, purity 99.6%.
Comparative example 1, the preparation of De Lasha star
The formula 1 crude compound 500g that embodiment 1 prepares is added in 20L reaction bulb, adds isopropanol 10L, stirring and dissolving, delay
The slow sodium hydroxide solution 4L dripping mass fraction 4%, drips the acetic acid solution 5L of mass fraction 12% after stirring to hydrolysis completely.
Fully leaching solid after crystallize, water washs, and drying under reduced pressure obtains pale yellow powder 375g, yield 92%, purity 97.9%
The preparation of embodiment 7 De Lasha star meglumine salt
De Lasha star 200g embodiment 5 prepared and 120g meglumine add in 2L reaction bulb, add 1L water, and agitating heating is molten clearly
Rear slow cooling cools down, and crystallize filters the most afterwards, and cold water washs, and is dried to obtain micro-yellow powder 237g, yield 82%, HPLC purity
99.7%。
Embodiment 8, the preparation of De Lasha star meglumine salt
De Lasha star 200g embodiment 6 prepared and 120g meglumine add in 2L reaction bulb, add 1L water, and agitating heating is molten clearly
Rear slow cooling cools down, and crystallize filters the most afterwards, and cold water washs, and is dried to obtain micro-yellow powder 237g, yield 82%, HPLC purity
99.8%。
The preparation of comparative example 2 De Lasha star meglumine salt
De Lasha star 200g comparative example 1 prepared and 120g meglumine add in 2L reaction bulb, add 1L water, and agitating heating is molten clearly
Rear slow cooling cools down, and crystallize filters the most afterwards, and cold water washs, and is dried to obtain micro-yellow powder 240g, yield 83%, HPLC purity
98.6%。
Claims (10)
1. the process for purification of Yi Zhong De Lasha star intermediate compound of formula I, is dissolved in good solvent including compound of formula I, then with not
Good solvent mixes, and heated and stirred, cooling crystallization isolate crystallization, and in Formulas I, R1 is alkyl, and R2 is alkanoyl.
2. the method for claim 1, R1 is the alkyl of C1～C4, preferably ethyl, and R2 is the alkanoyl of C1～C6, excellent
Elect isobutyryl as.
3. the method for claim 1, described good solvent is selected from methanol, ethanol, isopropanol, n-butyl alcohol, acetonitrile, tetrahydrochysene furan
Mutter, in acetone, ethyl acetate, methyl acetate, n-butyl acetate and isopropyl acetate one or more.
4. the method for claim 1, described poor solvent is in water, petroleum ether, normal hexane, hexamethylene and normal heptane
One or more.
5. the method for claim 1, during heated and stirred, solution system is molten clear or insoluble clear state.
6. the mass volume ratio of preparation method, compound of formula I and good solvent is 1:1～1:10g/ml as claimed in claim 1, excellent
Elect 1:2～1:6g/ml as.
7. the method for claim 1, compound of formula I is 1:0～1:10g/ml with the mass volume ratio of poor solvent, excellent
Elect 1:2～1:5g/ml as.
8. the method for claim 1, the temperature of heating is 30～100 DEG C, preferably 40～70 DEG C.
9. the method for claim 1, the heated and stirred time is 0.5～5h.
10. the method preparing De Lasha star meglumine salt, comprises the following steps:
1) the method purification compound of formula I according to claim 1-9, obtains highly purified compound of formula I；
2) hydrolysis of highly purified for upper step compound of formula I is obtained De Lasha star；
3) the De Lasha star upper step obtained reacts with meglumine and obtains De Lasha star meglumine salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510339691.2A CN106256824B (en) | 2015-06-18 | 2015-06-18 | Preparation method of high-purity delafloxacin meglumine salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510339691.2A CN106256824B (en) | 2015-06-18 | 2015-06-18 | Preparation method of high-purity delafloxacin meglumine salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106256824A true CN106256824A (en) | 2016-12-28 |
| CN106256824B CN106256824B (en) | 2020-10-27 |
Family
ID=57713827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510339691.2A Active CN106256824B (en) | 2015-06-18 | 2015-06-18 | Preparation method of high-purity delafloxacin meglumine salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106256824B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831723A (en) * | 2017-02-15 | 2017-06-13 | 鲁南制药集团股份有限公司 | A kind of process for purification of improved De Lasha stars |
| CN110467600A (en) * | 2018-05-10 | 2019-11-19 | 上海度德医药科技有限公司 | A kind of De Lasha star meglumine salt crystal form L and preparation method thereof |
| CN111718330A (en) * | 2019-03-23 | 2020-09-29 | 南京海润医药有限公司 | A kind of delafloxacin impurity III and product refining method |
| CN111718329A (en) * | 2019-03-23 | 2020-09-29 | 南京海润医药有限公司 | A kind of delafloxacin impurity IV and product refining method |
| CN111718331A (en) * | 2019-03-23 | 2020-09-29 | 南京海润医药有限公司 | Impurities I and II of Delafloxacin and product refining method |
| CN113527262A (en) * | 2021-06-22 | 2021-10-22 | 安徽普利药业有限公司 | Refining method of delafloxacin and meglumine salt thereof |
| WO2023137966A1 (en) * | 2022-01-20 | 2023-07-27 | 海南普利制药股份有限公司 | New crystal form of delafloxacin meglumine and preparation method therefor |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6136823A (en) * | 1996-11-28 | 2000-10-24 | Wakunaga Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivatives or salts thereof and drugs containing the same as the active ingredient |
| WO2006015194A2 (en) * | 2004-07-30 | 2006-02-09 | Abbott Laboratories | Preparation of pyridonecarboxylic acid antibacterials |
| US20100286397A1 (en) * | 2004-10-08 | 2010-11-11 | Zhang Geoff G Z | Salt and crystalline forms thereof of a drug |
| CN102164912A (en) * | 2008-09-24 | 2011-08-24 | Rib-X制药有限公司 | Process for preparing quinolones |
| CN103936717A (en) * | 2013-01-22 | 2014-07-23 | 上海医药工业研究院 | Intermediate of delafloxacin and preparation method thereof |
| CN104098548A (en) * | 2013-04-11 | 2014-10-15 | 上海医药工业研究院 | Delafloxacin purifying method |
-
2015
- 2015-06-18 CN CN201510339691.2A patent/CN106256824B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6136823A (en) * | 1996-11-28 | 2000-10-24 | Wakunaga Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivatives or salts thereof and drugs containing the same as the active ingredient |
| WO2006015194A2 (en) * | 2004-07-30 | 2006-02-09 | Abbott Laboratories | Preparation of pyridonecarboxylic acid antibacterials |
| US20100286397A1 (en) * | 2004-10-08 | 2010-11-11 | Zhang Geoff G Z | Salt and crystalline forms thereof of a drug |
| CN102164912A (en) * | 2008-09-24 | 2011-08-24 | Rib-X制药有限公司 | Process for preparing quinolones |
| CN103936717A (en) * | 2013-01-22 | 2014-07-23 | 上海医药工业研究院 | Intermediate of delafloxacin and preparation method thereof |
| CN104098548A (en) * | 2013-04-11 | 2014-10-15 | 上海医药工业研究院 | Delafloxacin purifying method |
Non-Patent Citations (2)
| Title |
|---|
| ANTHONY R. HAIGHT等: "Synthesis of the Quinolone ABT-492: Crystallizations for Optimal Processing，Organic Process Research & Development，Synthesis of the Quinolone ABT-492: Crystallizations for Optimal Processing", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| BARNES, DAVID M等: "Chlorination at the 8-Position of a Functionalized Quinolone and the Synthesis of Quinolone Antibiotic", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831723A (en) * | 2017-02-15 | 2017-06-13 | 鲁南制药集团股份有限公司 | A kind of process for purification of improved De Lasha stars |
| CN106831723B (en) * | 2017-02-15 | 2020-07-28 | 鲁南制药集团股份有限公司 | Improved refining method of delafloxacin |
| CN110467600A (en) * | 2018-05-10 | 2019-11-19 | 上海度德医药科技有限公司 | A kind of De Lasha star meglumine salt crystal form L and preparation method thereof |
| CN111718330A (en) * | 2019-03-23 | 2020-09-29 | 南京海润医药有限公司 | A kind of delafloxacin impurity III and product refining method |
| CN111718329A (en) * | 2019-03-23 | 2020-09-29 | 南京海润医药有限公司 | A kind of delafloxacin impurity IV and product refining method |
| CN111718331A (en) * | 2019-03-23 | 2020-09-29 | 南京海润医药有限公司 | Impurities I and II of Delafloxacin and product refining method |
| CN113527262A (en) * | 2021-06-22 | 2021-10-22 | 安徽普利药业有限公司 | Refining method of delafloxacin and meglumine salt thereof |
| WO2023137966A1 (en) * | 2022-01-20 | 2023-07-27 | 海南普利制药股份有限公司 | New crystal form of delafloxacin meglumine and preparation method therefor |
| CN116514775A (en) * | 2022-01-20 | 2023-08-01 | 海南普利制药股份有限公司 | A new crystal form of delafloxacin meglumine salt and its preparation method |
| CN116514775B (en) * | 2022-01-20 | 2024-11-29 | 安徽普利药业有限公司 | A new crystal form of delafloxacin meglumine salt and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106256824B (en) | 2020-10-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106256824A (en) | A kind of preparation method of high-purity De Lasha star meglumine salt | |
| CN111511722B (en) | Method for preparing oxa-goril intermediate and composition thereof | |
| CN101941969B (en) | Preparation method of moxifloxacin hydrochloride | |
| CN105085522A (en) | Method for preparing high-purity moxifloxacin hydrochloride | |
| CN101486753A (en) | Novel method for synthesizing finasteroid | |
| CN103664912B (en) | A kind of synthesis technique of prucalopride | |
| CN103360350B (en) | A kind of preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection | |
| CN114634441A (en) | Novel method for synthesizing 6, 6-dimethyl-3-azabicyclo [3,1,0] hexane | |
| CN106831723B (en) | Improved refining method of delafloxacin | |
| CN101270124B (en) | Novel method for purifying and preparing high-purity fluorandiol and fluorandiol salt | |
| CN109553550B (en) | Method for synthesizing dihydrooat alkaloid | |
| CN105440054B (en) | A kind of technique preparing cefathiamidine | |
| CN103787924A (en) | New purification method of antitumor drug Belinostat | |
| CN102924436A (en) | Refining method of fasudil hydrochloride | |
| WO2020182228A1 (en) | Method of refining sodium taurocholate | |
| CN103665084A (en) | Method for preparing abiraterone acetate | |
| CN105254629A (en) | Preparation method of moxifloxacin hydrochloride | |
| CN104557877A (en) | Avanafil intermediate as well as preparation method and application thereof | |
| CN107074834A (en) | Purification method of emtricitabine | |
| CN107879979A (en) | A kind of preparation method of Dexmedetomidine | |
| WO2021056382A1 (en) | Preparation method for alpha-penta-o-acetyl mannose | |
| CN106117212A (en) | A kind of sldenafil synthesis technique of improvement | |
| CN104230825B (en) | The preparation method of Erlotinib alkali monohydrate crystal form Form I | |
| CN110563721A (en) | Preparation method of azasetron hydrochloride | |
| CN108863946B (en) | Preparation method of dibazole impurity reference substance |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |