CN105254721A - Purification salt conversion method of micafungin - Google Patents
Purification salt conversion method of micafungin Download PDFInfo
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- CN105254721A CN105254721A CN201410202172.7A CN201410202172A CN105254721A CN 105254721 A CN105254721 A CN 105254721A CN 201410202172 A CN201410202172 A CN 201410202172A CN 105254721 A CN105254721 A CN 105254721A
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- 0 CCCCCOc1ccc(C(*2)ONC2c2ccc(C(NC(C3)(*C3C(NC(C(C3(C(*)C4)NCC5C3C5)N4C(C3CC3)C(C(CC(N)=O)O)NC(C(C(C(c3cc(O*)c(C=N)cc3)O)O)NC(C(CC(C3)O)N3C(C3(*4)C=C)=O)=O)=O)=O)O)C4=*(C)C3(*C)O)O)cc2)cc1 Chemical compound CCCCCOc1ccc(C(*2)ONC2c2ccc(C(NC(C3)(*C3C(NC(C(C3(C(*)C4)NCC5C3C5)N4C(C3CC3)C(C(CC(N)=O)O)NC(C(C(C(c3cc(O*)c(C=N)cc3)O)O)NC(C(CC(C3)O)N3C(C3(*4)C=C)=O)=O)=O)=O)O)C4=*(C)C3(*C)O)O)cc2)cc1 0.000 description 1
Abstract
The present invention relates to a purification salt conversion method of micafungin. According to the present invention, the method is mainly characterized in that a buffer solution of a corresponding salt and a micafungin N, N-diisopropylethylamine salt are subjected to ion exchange on a reverse phase preparative chromatographic column so as to complete salt conversion, remove the related impurities, and achieve the purification effect; and the process has characteristics of stable and controllable process, easy and convenient operation, easy industrial production achieving, and easy product quality control.
Description
Technical field
The present invention relates to medicinal chemistry arts, be specifically related to the purifying of MFG salt and turn salt method.
Background of invention
FK463 is echinocandin class antimicrobial drug, by the synthesis of Antifungi cell walls, suppresses pathomycete to grow.Be used for the treatment of by aspergillus tubigensis and the microbial following infection of beads clinically: fungemia, fungus in respiratory tract is sick, gi tract mycosis.The anti-fungal infection power potent by means of it and drug safety, this medicine has been the choice drug of ICU invasive infections with fungi treatment, has wide market outlook.
How FK463 is developed by Japanese Astellas company, at present the list marketing.Its structural formula is as shown in chemical compounds I:
The multiple preparation about FK463 and purification process have been reported open, such as patent WO9611210, WO2004014879 and patent WO2012143293A1.
Wherein WO9611210 is compound patent, uses particular form purifying and ion-exchange to turn salt, is not suitable for industrial production.
Patent WO2004014879 discloses MFG DIPEA salt (its structural formula is as shown in compound ii) purifying crude and turns salt method: MFG DIPEA salt crude product passes through gama-alumina purification column purifying, methanol-eluted fractions.Be dissolved in water after chromatographic solution is concentrated, cross UBK510L ion exchange column, with methanol aqueous solution (methanol/water=75/25) wash-out.Then add sodium hydroxide solution, acetoneand ethyl acetate crystallization, obtain FK463.
This technique is by two step operations: purifying and turn salt, obtains FK463 finished product.
MFG compound is unstable, easily degrade, and consider from production quality control angle, the long meeting of operation causes sample quality controllability difficulty to increase, and is unfavorable for process implementing; Consider from environmental friendliness angle in addition, operation is long can increase solvent usage quantity, is unfavorable for environment protection.
Patent WO2012143293A1 discloses the technique that a kind of single step purification turns salt: MFG N, reverse phase preparative column (HP20SS) on the N-diisopropylethylamine salt crude product aqueous solution, rinse purifying with 90%v/v3MNaCl/0.1MNaAc (ph5.5) and 10%v/v methanol mixed solvent and turn salt, post is rushed again by 40% methanol/water, finally use 90% methanol/water wash-out, obtain FK463 and prepare liquid.
This technique is by anti-phase preparation system, and a step completes purifying and turns salt.But MFG is easily hydrolyzed preparing under environment, generates impurity compound III, IV (its structure is as follows), be unfavorable for production quality control.And use a large amount of sodium-chlor, have very strong corrodibility for preparation liquid phase systems, be unfavorable for industry's enlarging production.
Therefore, this area is in the urgent need to developing the FK463 preparation method of a kind of technique simple and stable, reliable product quality.
Summary of the invention
The object of the present invention is to provide a kind of technique simple and stable, reliable product quality, be applicable to the preparation method of industrial MFG salt.
Technical scheme of the present invention is realized by following manner:
First Compound II per (MFG DIPEA salt) and preparation filling adsorption, pass through Na while gradient elution impurity
+(K
+) react with it, carry out ion-exchange, obtain FK463 (potassium) salt, then desalination, use the organic solvent wash-out of high density afterwards, by purifying with turn salt and to a step.
Be suitable for industrial anti-phase purifying.
Wherein, M salt buffer is by A, B two phase composite.
A phase is selected from acetic acid/sodium acetate, acetic acid/potassium acetate, sodium phosphate salt, potassium phosphate salt, sodium carbonate salt, potash salt, citric acid/sodium citrate or citric acid/Tripotassium Citrate aqueous solution;
B phase is selected from methyl alcohol, acetonitrile and/or ethanol.
Preferably, A phase concentration controls at 0.05mol/L ~ 5mol/L, preferred 0.1mol/L ~ 1.0mol/L.
Preferably, A phase pH value controls 4.0 ~ 7.0, and preferable ph controls 5.0 ~ 6.0.
Wherein, elution flow is by C, D two phase composite.
C phase: water.
D phase is selected from methyl alcohol, acetonitrile and/or ethanol.
Preferably, purification process of the present invention comprises the following steps:
A. preparative column filler: C
18class filler.
B. preparative column absorption on the Compound II per aqueous solution/organic solvent, volume ratio: 100/0 ~ 50/50;
C. mobile phase A/Mobile phase B: 99/1 ~ 60/40 (volume ratio), elution amount >=3 times column volume;
D. Mobile phase B/moving phase C:70/30 ~ 1/99 (volume ratio), elution amount >=3 times column volume;
E. moving phase D/ moving phase C:100/0 ~ 70/30 (volume ratio), product elution, described organic solvent is selected from methyl alcohol, acetonitrile and/or ethanol.
Preferred further, in order to control the degraded of MFG on preparative column, the invention provides purifying and turn envrionment temperature control interval in salt process, the method for control temperature includes but not limited to: control moving phase temperature, control indoor environment temperature, control preparative column temperature etc.
Described temperature controlling range is at-20 ~ 20 DEG C, preferred, and temperature range is at 0 ~ 10 DEG C.
Particularly preferred, purification process of the present invention is:
By anti-phase purifying chromatogram, purifying and turn salt and carry out simultaneously, a step completes purifying and turns salt; Purifying and turn in salt process, system temperature span of control is at 0 ~ 10 DEG C; Described damping fluid is by A, B two phase composite:
A phase is selected from acetic acid/sodium acetate, acetic acid/potassium acetate, sodium phosphate salt, potassium phosphate salt, sodium carbonate salt, potash salt, citric acid/sodium citrate or citric acid/Tripotassium Citrate aqueous solution;
B phase is selected from methyl alcohol, acetonitrile and/or ethanol;
Wherein A phase concentration controls to control 5.0 ~ 6.0 in 0.1mol/L ~ 1.0mol/L, A phase pH value.
On this basis, further, on the Compound II per aqueous solution/organic solvent, during preparative column absorption, volume ratio is 100/0 ~ 50/50; Mobile phase A/Mobile phase B volume ratio is: 99/1 ~ 60/40, elution amount >=3 times column volume; Mobile phase B/moving phase C volume ratio is 70/30 ~ 1/99, elution amount >=3 times column volume; Moving phase D/ moving phase C volume ratio is 100/0 ~ 70/30, and product elution, described organic solvent is selected from methyl alcohol, acetonitrile and/or ethanol.
Sample purity and the foreign matter content that purifying of the present invention turns salt method is detected by high performance liquid phase method, result display is according to method of the present invention, MFG salt can be obtained in high purity ground, and, highly corrosive raw material is not used in method provided by the present invention, detrimentally affect can not be produced to the equipment of industrial product, meet suitability for industrialized production needs.
In addition, unexpectedly, contriver prepares system temperature by control, effectively reduces the generation of degradation impurity compound III, ensure that quality product.
Accompanying drawing explanation
Fig. 1 is that purifying turns sample (compound ii) RP-HPLC collection of illustrative plates before salt;
Fig. 2 is that near 30 DEG C, purifying prepares liquid RP-HPLC collection of illustrative plates after turning salt;
Fig. 3 is that near 0 ~ 10 DEG C, purifying prepares liquid RP-HPLC collection of illustrative plates after turning salt.
Embodiment
In order to further illustrate technical scheme of the present invention and acquired technique effect thereof, illustrate embodiment of the present invention below in conjunction with embodiment.But the present invention is not limited to specific embodiment.
Compound II per of the present invention (MFG DIPEA salt) is transformed by mold fermentation, actinomycetes to obtain FR179642 (see following formula), modifies and prepare with small carboxylic acid molecules.
The present invention RP-HPLC used detects sample purity.
Its chromatographic condition is as follows:
Instrument: Agilent1200 high performance liquid chromatography
Chromatographic column: C
18post, 5um, 4.6 × 250mm
Flow velocity: 1.0mL/min
Determined wavelength: 210nm
Moving phase: the SODIUM PHOSPHATE, MONOBASIC/sodium perchlorate aqueous solution/acetonitrile
The present invention's residue on ignition method detects sample and turns salt performance.To prepare micafungin sodium, turn in theory salt completely after, residue on ignition is 5.5%.
The preparation of embodiment 1:4-(5-(4-(amyl group oxygen base) phenyl) isoxzzole-3-base) phenylformic acid-1-benzotriazole ester
4-(5-(4-(amyl group oxygen base) phenyl) isoxzzole-3-base) phenylformic acid-1-phenylformic acid 0.61kg, DMF5L, THF5L, HOBt0.35kg and EDC.HCl0.61kg is added, room temperature reaction 3 ~ 3.5 hours in 30L glass reaction still.After reaction terminates, add 20L ethyl acetate and 5L purified water, filtration, drying, obtain white object product 680g.
Embodiment 2: the preparation of Compound II per
In 30L glass reaction still, add FR1796421.00kg (in anhydride) and DMF10L, after stirring and dissolving, add DIPEA (DIPEA) 0.21kg again.Reaction solution is cooled to 0 ~ 20 DEG C, adds step gained intermediate 1., controlling temperature of reaction is 0 ~ 20 DEG C.
After reaction terminates, reaction solution is poured into and is added in 100L ethyl acetate, and white solid is separated out, and filters to obtain white solid, obtains Compound II per 1500g after vacuum-drying.
Embodiment 3: turn salt purifying
Get 500g Compound II per purified water to dissolve, loading, according to the form below chromatographic condition wash-out, collect target components.
Liquid is prepared in collection, is evaporated to dry, obtains white product FK463, dry 235g.
Gained sample carries out RP-HPLC detection, purity: 99.1%, and its collection of illustrative plates as shown in Figure 3.
Gained sample residue on ignition: 5.5%.
Embodiment 4: turn salt purifying
Get 500g Compound II per purified water to dissolve, loading, according to the form below chromatographic condition wash-out, collect target components.
Liquid is prepared in collection, is evaporated to dry, obtains white product FK463, dry 226g.
Gained sample carries out RP-HPLC detection, purity: 98.3%.
Gained sample residue on ignition: 5.6%.
Embodiment 5: turn salt purifying
Get 500g Compound II per purified water to dissolve, loading, according to the form below chromatographic condition wash-out, collect target components.
Liquid is prepared in collection, is evaporated to dry, obtains white product FK463, dry 246g.
Gained sample carries out RP-HPLC detection, purity: 99.3%.
Gained sample residue on ignition: 5.4%.
Comparative example
According to the purification process of embodiment 3, difference is that moving phase temperature controls at about 30 DEG C, and gained sample carries out RP-HPLC detection, and collection of illustrative plates as shown in Figure 2.
Turn salt method by single step purification provided by the invention, the residue on ignition producing multiple batches of sample (sodium salt), all near 5.5%, conforms to theoretical value, shows that sample turns salt complete.
After being detected by high performance liquid phase, as can be seen from RP-HPLC profiling results, the degradation impurity content that purification process of the present invention produces reduces greatly.
Claims (10)
1. the purifying of a MFG turns salt method, it is characterized in that, described method is on reversed-phase preparative chromatography post, by the buffered soln of corresponding salt and MFG N, N-diisopropylethylamine salt generation ion-exchange, complete and turn salt, use high levels of organic solvents wash-out afterwards, purifying and turn salt and carry out simultaneously.
2. the purifying of MFG according to claim 1 turns salt method, it is characterized in that, purifying and turn in salt process, and system temperature span of control is at-20 ~ 20 DEG C, and preferably, temperature range is at 0 ~ 10 DEG C.
3. the purifying of MFG according to claim 2 turns salt method, it is characterized in that, the method for control temperature includes but not limited to: control moving phase temperature, control indoor environment temperature, control preparative column temperature etc.
4. the purifying of MFG according to claim 1 turns salt method, it is characterized in that, described purifying is sodium salt or sylvite damping fluid with turning salt moving phase.
5. the purifying of MFG according to claim 4 turns salt method, it is characterized in that, described damping fluid is by A, B two phase composite:
A phase is selected from acetic acid/sodium acetate, acetic acid/potassium acetate, sodium phosphate salt, potassium phosphate salt, sodium carbonate salt, potash salt, citric acid/sodium citrate or citric acid/Tripotassium Citrate aqueous solution;
B phase is selected from methyl alcohol, acetonitrile and/or ethanol.
6. the purifying of MFG according to claim 5 turns salt method, it is characterized in that, A phase concentration controls at 0.05mol/L ~ 5mol/L, preferred 0.1mol/L ~ 1.0mol/L.
7. the purifying of MFG according to claim 5 turns salt method, it is characterized in that, A phase pH value controls 4.0 ~ 7.0, and preferable ph controls 5.0 ~ 6.0.
8. the purifying of MFG according to claim 5 turns salt method, it is characterized in that, A phase exists with B phase wash-out ratio control: with volume basis for 99/1 ~ 60/40, elution amount >=3 times column volume.
9. the purifying of MFG according to claim 1 turns salt method, it is characterized in that, preparative column filler is C
18class filler.
10. the purifying of MFG according to claim 1 turns salt method, it is characterized in that, comprises the following steps:
A. preparative column filler: C
18class filler.
B. preparative column absorption on the Compound II per aqueous solution/organic solvent, volume ratio: 100/0 ~ 50/50;
C. mobile phase A/Mobile phase B: with volume basis for 99/1 ~ 60/40, elution amount >=3 times column volume;
D. Mobile phase B/moving phase C: with volume basis for 70/30 ~ 1/99, elution amount >=3 times column volume;
E. moving phase D/ moving phase C: with volume basis for 100/0 ~ 70/30, product elution, described organic solvent is selected from methyl alcohol, acetonitrile and/or ethanol.
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| CN104788545A (en) * | 2014-05-29 | 2015-07-22 | 上海天伟生物制药有限公司 | Crystal powder of cyclopeptide compound, and preparation method and application thereof |
| CN108250274A (en) * | 2016-12-28 | 2018-07-06 | 浙江华谱新创科技有限公司 | Mikafen high efficiency separation and purification method |
| CN108752430A (en) * | 2018-05-31 | 2018-11-06 | 杭州中美华东制药有限公司 | Mikafen sodium novel crystal form and preparation method thereof |
| CN109956994A (en) * | 2017-12-25 | 2019-07-02 | 江苏豪森药业集团有限公司 | The preparation method of micafungin sodium |
| CN114249800A (en) * | 2020-09-22 | 2022-03-29 | 深圳市星银医药有限公司 | Preparation method of pamoic acid polypeptide drug |
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Cited By (9)
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| CN109956994A (en) * | 2017-12-25 | 2019-07-02 | 江苏豪森药业集团有限公司 | The preparation method of micafungin sodium |
| CN109956994B (en) * | 2017-12-25 | 2022-09-30 | 江苏豪森药业集团有限公司 | Preparation method of micafungin sodium salt |
| CN108752430A (en) * | 2018-05-31 | 2018-11-06 | 杭州中美华东制药有限公司 | Mikafen sodium novel crystal form and preparation method thereof |
| CN113087775A (en) * | 2018-05-31 | 2021-07-09 | 杭州中美华东制药有限公司 | Novel micafungin sodium crystal form II and preparation method thereof |
| CN113087775B (en) * | 2018-05-31 | 2022-07-08 | 杭州中美华东制药有限公司 | Novel micafungin sodium crystal form II and preparation method thereof |
| CN114249800A (en) * | 2020-09-22 | 2022-03-29 | 深圳市星银医药有限公司 | Preparation method of pamoic acid polypeptide drug |
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