CN106866650A - A kind of synthesis of MFG and method of purification - Google Patents
A kind of synthesis of MFG and method of purification Download PDFInfo
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- CN106866650A CN106866650A CN201710012242.6A CN201710012242A CN106866650A CN 106866650 A CN106866650 A CN 106866650A CN 201710012242 A CN201710012242 A CN 201710012242A CN 106866650 A CN106866650 A CN 106866650A
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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Abstract
The present invention relates to the preparation method of pharmaceutical intermediate, the synthesis of specially a kind of MFG intermediate and method of purification.Of the invention mainly obtaining compound III, compound III and compound IV using hydroxy-acid group acyl chloride reaction to compound II carries out condensation reaction, and crystallization and purification obtains the MFG intermediate compound I of high-purity.Preparation method process is simple of the invention, reagent is cheap, and solvent-oil ratio is few, substantially reduces production cost, and the purity and yield of product are higher, it is easy to accomplish industrialized production.
Description
Technical field
The present invention relates to the preparation method field of pharmaceutical intermediate, specially a kind of synthesis of MFG intermediate with carry
Pure method.
Background technology
MFG (Micafungin) is transformed by the natural products to Coleophoma empetri, chemistry
The new echinocandin antifungal agent thing that synthesis is obtained；It is to candida albicans such as candida albicans, Candida glabrata, heat for beads
Bacterium, candida krusei and Candida parapsilosis have preferable inhibitory activity, also there is good external inhibitory activity for aspergillus, but
For the unrestraints such as neogenesis cryptococcus, sickle-like bacteria, zygomycete and Fructus Atriplicis Sibiricae trichosporon bacteria activity.MFG (Micafungin)
Developed by Japanese Teng Ze companies, listed in Japan in December, 2002, trade name Fungusrd, in March, 2005 passes through the U.S.
FDA certifications, are only approved for treatment esophageal candidiasis, bone-marrow transplantation and ADS patient's neutrophilic granulocytopenia at present
Prophylactic treatment.
Micafungin precursor compound II:
Micafungin precursor compound IV:
Compound 1 is reacted using carbodiimide type condensing agent method mainly for MFG synthesis at present, is such as existed
There are N, N'- dicyclohexyls carbon two sub- (DCC, EDCl) etc., also O-phthalic in CN103917531A, CN103145810B patent
Acyl fourth monooctyl ester (BOP), hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl (PyBOP) etc., in order to prevent racemization from also adding
Enter auxiliary reagent N- hydroxybenzotriazoles ester (HOBt).Post processing purifying is needed using ion exchange resin and column chromatography method
Carry out post processing purifying.These methods are all defective, and the reagent for being used all costly, and is generated more useless molten
Agent, and the product purity of gained is relatively low.
The content of the invention
Synthesis and method of purification it is an object of the invention to provide a kind of MFG intermediate, to solve above-mentioned background
The problem proposed in technology.
To achieve the above object, the present invention provides following technical scheme：A kind of synthesis of MFG intermediate and purification
Method, comprises the following steps：
S1：Compound II carries out acyl chloride reaction chemical equation under catalyst action with thionyl chloride：
After reaction is qualified, add dichloromethane and pyridinium dissolution cooling stand-by；
S2：Under low temperature, compound III and compound IV is added dropwise carries out condensation reaction, and the chemical equation of reaction is：
After reaction is qualified, sodium carbonate is quenched, layering, and water is added to winestone acid for adjusting pH value, ethyl acetate extraction, organic phase
Washing concentrating obtains crude product；
S3：Crystallization：Crude product and water are stirred, and sodium hydrate aqueous solution is added dropwise, and adjust pH, add ethanol, separate out solid, are taken out
Filter, drying.Drying solid and water stirring and dissolving, add ethanol, and secondary crystallization, filtering, drying is obtained in the middle of sterling MFG
Body I.
Preferably, the catalyst for being used in the step S1 is pyridine, triethylamine and imidazoles, more preferably pyridine.
Preferably, the solvent for being used in the step S1 is dichloromethane or chloroform.
Preferably, the dropping temperature for being used in the step S1 is 20~25 DEG C.
Preferably, the amount of the pyridine for being used in the step S1 and the amount ratio of compound II are 0.02:1~0.03:1,
Thionyl chloride is 1.25 with compound II mol ratios:1~1.3:1.
Preferably, reacted in the step S1 it is qualified after the amount ratio of the amount of pyridine that uses and compound II be 0.5:1
~0.7:1, the usage amount of dichloromethane and the amount ratio of compound II are 15:1~14:1, temperature is -15~-10 DEG C.
Preferably, the cryogenic conditions for being reacted in the step S2 are -45~-40 DEG C, and mode is added dropwise for spraying is added dropwise.
Preferably, the compound IV for being used in the step S2 is 1.1 with compound III mol ratios:1~1:1.
Preferably, the reagent of regulation pH used is tartaric acid, mandelic acid and citric acid, preferably winestone in the step S2
Acid, the scope for adjusting pH is 3~4.
Preferably, the step S1, the concentration condition used in S2 is 40~45 DEG C of temperature, vacuum≤- 0.08Mpa.
Preferably, the reagent that pH is adjusted in the step S3 is 10% sodium hydrate aqueous solution, and the scope of pH is 8~9.
Preferably, it is 5 that the volume of water and the ratio of crude product weight are added in the step S3:1~2:1, added
The volume of ethanol and the ratio of crude product weight are 10:1~8:1.
Preferably, the drying condition in the step S3 is 25~30 DEG C of temperature, vacuum≤- 0.09Mpa.
Compared with prior art, the beneficial effects of the invention are as follows：The present invention is mainly used to the carboxylic acid on compound II
Acyl chlorides is activated, and is obtained compound III and compound IV and is condensed, and obtains MFG intermediate, and this programme avoids adopting
With expensive reagent, and the generation of solvent slop can be reduced；Purified by way of dilution crystallization afterwards, purity can be obtained
MFG higher.
Brief description of the drawings
Fig. 1 is the molecular structural formula of MFG intermediate obtained in the present invention；
Fig. 2 is process chart of the invention；
Fig. 3 is the HPLC collection of illustrative plates of embodiment one；
Fig. 4 is the HPLC collection of illustrative plates of embodiment two；
Fig. 5 is the HPLC collection of illustrative plates of embodiment three.
Specific embodiment
The technical scheme in the embodiment of the present invention will be clearly and completely described below, it is clear that described implementation
Example is only a part of embodiment of the invention, rather than whole embodiments.Based on the embodiment in the present invention, this area is common
The every other embodiment that technical staff is obtained under the premise of creative work is not made, belongs to the model of present invention protection
Enclose.
Refer to Figure of description 1-5.
Embodiment one
The present invention provides a kind of technical scheme：A kind of synthesis of MFG intermediate and method of purification, including following step
Suddenly：
100ml dichloromethane, 7.1g (20mmol, 1.0eq) compound II and 0.2g pyridines are added in 250ml flasks,
Stirring and dissolving, heats up 22 DEG C, and 3.0g (0.25mol, 1.25eq) thionyl chloride is added dropwise, after completion of the reaction, dense after being kept for 5 hours
Contract to obtain 8.2g oily liquids, continuously add 100ml dichloromethane dissolving, and add 4.0g pyridines stir cool to -10 DEG C it is stand-by,
Obtain the dichloromethane solution of compound III.
To 100ml dichloromethane and 18g (19.1mmol, 1.0eq) compound IV is added in 500ml flasks, stirring is lowered the temperature
To -42 DEG C, spraying is added dropwise the solution of compound III, 3.5 hours completion of dropping；Then kept for 8 hours at -43 DEG C；Reaction is closed
After lattice, reaction liquid is slowly added drop-wise in 5% sodium carbonate liquor of 100ml, and be stirred at room temperature 5 hours, stratification, divided and go
Organic phase, water is mutually added dropwise tartaric acid solution, adjusts pH value 3.7 or so, adds ethyl acetate stirring, stratification, organic addition
Enter 100ml water washings, stratification controls 42 DEG C, and vacuum≤- 0.08Mpa is concentrated to give 24.7g crude products.
To in 500mL flasks, 24.7g crude products and 80ml water are added, 10% sodium hydroxide solution is added dropwise, solid progressively disappears
Lose, regulation pH value is stirred 4 hours 8.2, and 200ml ethanol solutions are added dropwise thereto, progressively there are a large amount of solids to separate out, and suction filtration is obtained
To solid 19.2g.
To in 500mL flasks, 19.2g solids and 50ml water stirring and dissolvings are added, after 4 hours, 200ml second is added dropwise thereto
Alcoholic solution, progressively has a large amount of solids to separate out, and suction filtration, dries to obtain compound I solids 17.4g.
HPLC detection methods：Chromatographic column model 150 × 4.6mm × 3.5 μm, wavelength 210nm, 30 DEG C of column temperature, sample size
10ul, flow velocity 1.0ml/min, diluent is acetonitrile：Water=70:30, isocratic elution, wherein mobile phase A are that sodium dihydrogen phosphate is molten
Liquid：Acetonitrile (30:70), Mobile phase B acetonitrile；Ratio is mobile phase A：Mobile phase B=70:30.HPLC collection of illustrative plates is as shown in Figure 3.
Embodiment two
100ml dichloromethane, 7.1g (20mmol, 1.0eq) compound II and 0.2g pyridines are added in 250ml flasks,
Stirring and dissolving, heats up 22 DEG C, and 3.6g (0.30mol, 1.50eq) thionyl chloride is added dropwise, after completion of the reaction, dense after being kept for 5 hours
Contract to obtain 8.3g oily liquids, continuously add 100ml dichloromethane dissolving, and add 4.5g pyridines stir cool to -10 DEG C it is stand-by,
Obtain the dichloromethane solution of compound III.
To 100ml dichloromethane and 18g (19.1mmol, 1.0eq) compound IV is added in 500ml flasks, stirring is lowered the temperature
To -45 DEG C, spraying is added dropwise the solution of compound III, 3 hours completion of dropping；Then kept for 8 hours at -42 DEG C；Reaction is qualified
Afterwards, reaction liquid is slowly added drop-wise in 5% sodium carbonate liquor of 100ml, and is stirred at room temperature 5 hours, stratification, divided and gone
Machine phase, water is mutually added dropwise tartaric acid solution, adjusts pH value 3.5 or so, adds ethyl acetate stirring, stratification, organic to be added to
100ml water washings, stratification controls 42 DEG C, and vacuum≤- 0.08Mpa is concentrated to give 24.9g crude products.
To in 500mL flasks, 24.9g crude products and 80ml water are added, 10% sodium hydroxide solution is added dropwise, solid progressively disappears
Lose, regulation pH value is stirred 4 hours 8.4, and 200ml ethanol solutions are added dropwise thereto, progressively there are a large amount of solids to separate out, and suction filtration is obtained
To solid 19.0g.
To in 500mL flasks, 19.2g suction filtrations solid and 50ml water stirring and dissolvings are added, after 4 hours, be added dropwise thereto
200ml ethanol solutions, progressively have a large amount of solids to separate out, and suction filtration dries to obtain compound I solids 17.0g.HPLC collection of illustrative plates such as Fig. 4 institutes
Show.
Embodiment three
100ml dichloromethane, 7.1g (20mmol, 1.0eq) compound II and 0.2g pyridines are added in 250ml flasks,
Stirring and dissolving, heats up 25 DEG C, and 3.0g (0.30mol, 1.25eq) thionyl chloride is added dropwise, after completion of the reaction, dense after being kept for 5 hours
Contract to obtain 8.2g oily liquids, continuously add 100ml dichloromethane dissolving, and add 5.0g pyridines stir cool to -10 DEG C it is stand-by,
Obtain the dichloromethane solution of compound III.
To 100ml dichloromethane and 18g (19.1mmol, 1.0eq) compound IV is added in 500ml flasks, stirring is lowered the temperature
To -45 DEG C, spraying is added dropwise the solution of compound III, 4 hours completion of dropping；Then kept for 8 hours at -45 DEG C；Reaction is qualified
Afterwards, reaction liquid is slowly added drop-wise in 5% sodium carbonate liquor of 100ml, and is stirred at room temperature 5 hours, stratification, divided and gone
Machine phase, water is mutually added dropwise tartaric acid solution, adjusts pH value 3.9 or so, adds ethyl acetate stirring, stratification, organic to be added to
100ml water washings, stratification controls 42 DEG C, and vacuum≤- 0.08Mpa is concentrated to give 24.7g crude products.
To in 500mL flasks, 24.7g crude products and 100ml water are added, 10% sodium hydroxide solution is added dropwise, solid progressively disappears
Lose, regulation pH value is stirred 4 hours 8.1, and 200ml ethanol solutions are added dropwise thereto, progressively there are a large amount of solids to separate out, and suction filtration is obtained
To solid 19.4g.
To in 500mL flasks, 19.4g suction filtrations solid and 60ml water stirring and dissolvings are added, after 4 hours, be added dropwise thereto
200ml ethanol solutions, progressively have a large amount of solids to separate out, and suction filtration dries to obtain compound I 17.7g.HPLC collection of illustrative plates is as shown in Figure 5.
The solution of the present invention is that the carboxylic acid on compound II is activated using acyl chlorides, obtains compound III and chemical combination
Thing IV is condensed, and obtains MFG intermediate I, it is to avoid is used expensive reagent, and can be reduced the generation of solvent slop；Afterwards
Treatment is purified by way of dilution crystallization, can obtain purity MFG intermediate higher, is worthy to be popularized.
Although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
Understanding can carry out various changes, modification, replacement to these embodiments without departing from the principles and spirit of the present invention
And modification, the scope of the present invention be defined by the appended.
Claims (13)
1. a kind of synthesis of MFG intermediate and method of purification, it is characterised in that comprise the following steps：
S1：Compound II carries out acyl chloride reaction chemical equation under catalyst action with thionyl chloride：
After reaction is qualified, add dichloromethane and pyridinium dissolution cooling stand-by；
S2：Under low temperature, compound III and compound IV is added dropwise carries out condensation reaction, and the chemical equation of reaction is：
After reaction is qualified, sodium carbonate is quenched, layering, and water is added to winestone acid for adjusting pH value, ethyl acetate extraction, organic phase washing
It is concentrated to give crude product；
S3：Crystallization：Crude product and water are stirred, and sodium hydrate aqueous solution is added dropwise, and adjust pH, add ethanol, separate out solid, and suction filtration dries
It is dry.Drying solid and water stirring and dissolving, add ethanol, and secondary crystallization, filtering, drying obtains sterling MFG intermediate compound I.
2. a kind of synthesis of MFG intermediate according to claim 1 and method of purification, it is characterised in that：The step
The catalyst used in rapid S1 is pyridine, triethylamine and imidazoles, more preferably pyridine.
3. a kind of synthesis of MFG intermediate according to claim 1 and method of purification, it is characterised in that：The step
The solvent used in rapid S1 is dichloromethane or chloroform.
4. a kind of synthesis of MFG intermediate according to claim 1 and method of purification, it is characterised in that：The step
The dropping temperature used in rapid S1 is 20~25 DEG C.
5. a kind of intermediate of MFG according to claim 1 synthesizes and method of purification, it is characterised in that：The step
The amount of the pyridine used in rapid S1 and the amount ratio of compound II are 0.02:1~0.03:1, II moles of thionyl chloride and compound
Than being 1.25:1~1.3:1.
6. a kind of intermediate of MFG according to claim 1 synthesizes and method of purification, it is characterised in that：The step
Reacted in rapid S1 it is qualified after the amount of pyridine that uses and the amount ratio of compound II be 0.5:1~0.7:1, the use of dichloromethane
Amount is 15 with the amount ratio of compound II:1~14:1, temperature is -15~-10 DEG C.
7. a kind of synthesis of MFG intermediate according to claim 1 and method of purification, it is characterised in that：The step
The cryogenic conditions reacted in rapid S2 are -45~-40 DEG C, and mode is added dropwise for spraying is added dropwise.
8. a kind of synthesis of MFG intermediate according to claim 1 and method of purification, it is characterised in that：The step
The compound IV used in rapid S2 is 1.1 with compound III mol ratios:1~1:1.
9. a kind of synthesis of MFG intermediate according to claim 1 and method of purification, it is characterised in that：The step
The reagent of regulation pH used is tartaric acid, mandelic acid and citric acid, preferably tartaric acid in rapid S2, the scope for adjusting pH is 3~
4。
10. a kind of synthesis of MFG intermediate according to claim 1 and method of purification, it is characterised in that：It is described
Step S1, the concentration condition used in S2 is 40~45 DEG C of temperature, vacuum≤- 0.08Mpa.
A kind of synthesis of 11. MFG intermediates according to claim 1 and method of purification, it is characterised in that：It is described
The reagent that pH is adjusted in step S3 is 10% sodium hydrate aqueous solution, and the scope of pH is 8~9.
A kind of synthesis of 12. MFG intermediates according to claim 1 and method of purification, it is characterised in that：It is described
It is 5 that the volume of water and the ratio of crude product weight are added in step S3:1~2:1, volume and the crude product weight of the ethanol for being added
Ratio be 10:1~8:1.
A kind of synthesis of 13. MFG intermediates according to claim 1 and method of purification, it is characterised in that：It is described
Drying condition in step S3 is 25~30 DEG C of temperature, vacuum≤- 0.09Mpa.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN111606901A (en) * | 2020-06-16 | 2020-09-01 | 大桐制药（中国）有限责任公司 | Synthetic method of micafungin side chain intermediate |
| CN112710753A (en) * | 2020-12-18 | 2021-04-27 | 卓和药业集团有限公司 | Method for analyzing micafungin related substances |
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| CN103492409A (en) * | 2011-04-04 | 2014-01-01 | 赛利亚医药公司 | Methods for manufacturing an antifungal agent |
| CN103917531A (en) * | 2011-09-09 | 2014-07-09 | 桑多斯股份公司 | Preparation of micafungin intermediates |
| WO2016056023A2 (en) * | 2014-10-07 | 2016-04-14 | Alaparthi Lakshmi Prasad | Intermediates and processes to prepare micafungin |
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| WO2004014879A1 (en) * | 2002-08-08 | 2004-02-19 | Fujisawa Pharmaceutical Co., Ltd. | New process |
| CN103492409A (en) * | 2011-04-04 | 2014-01-01 | 赛利亚医药公司 | Methods for manufacturing an antifungal agent |
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| 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 |
| CN111606901A (en) * | 2020-06-16 | 2020-09-01 | 大桐制药（中国）有限责任公司 | Synthetic method of micafungin side chain intermediate |
| CN112710753A (en) * | 2020-12-18 | 2021-04-27 | 卓和药业集团有限公司 | Method for analyzing micafungin related substances |
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