CN106866594A - The optimize technique of phenol sodium industrialized production is examined suitable for wheat - Google Patents
The optimize technique of phenol sodium industrialized production is examined suitable for wheat Download PDFInfo
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- CN106866594A CN106866594A CN201710088259.XA CN201710088259A CN106866594A CN 106866594 A CN106866594 A CN 106866594A CN 201710088259 A CN201710088259 A CN 201710088259A CN 106866594 A CN106866594 A CN 106866594A
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- Prior art keywords
- mycophenolic acid
- sodium
- reactor
- industrialized production
- optimize technique
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
Abstract
The invention discloses a kind of optimize technique that phenol sodium industrialized production is examined suitable for wheat, comprise the following steps：S101,3.8 4.2 times of methyl alcohol of MPA of addition to reactor, Mycophenolic Acid to reactor is added under agitation, heating mixed solution adds 4.8 5.2%W/W activated carbon to mixture, under agitation keeping temperature 20 30 minutes to 40 50 DEG C to solution clarification；S102, using methanol solution by diatomite, filtrate is collected in the reactor, washed using 1.8 2.2 times of methyl alcohol of Mycophenolic Acid, and collect in the reactor, cooling filtrate to room temperature adds 0.16 1.17 times of sodium methoxides of Mycophenolic Acid, prepare the methanol solution of sodium methoxide, wherein methanol quality is 4.8 5.2 times of sodium methoxides, under reactor normal temperature, sodium methoxide is added in Mycophenolic Acid, stir 55 65 minutes, 5 15 DEG C are cooled in pulpous state, are stirred 115 125 minutes, filter material；S103, with 8 12 times of amount acetone eluted materials of Mycophenolic Acid, discharging simultaneously checks weight in wet base, and dry matter is until humidity NMT1.8 2.2% in 40 50 DEG C.Present invention process is convenient, and reaction condition is gentle, and yield is high.
Description
Technical field
Phenol sodium preparation technology is examined the present invention relates to a kind of wheat, phenol sodium industrialized production is examined suitable for wheat more particularly, to one kind
Optimize technique.
Background technology
Prior art is based on the reaction of Mycophenolic Acid and sodium salt, it is possible to use sodium salt have 2- ethyl acetic acid sodium, hydroxide
Sodium, sodium methoxide.Representative patent has：
Bicon companies：Using 2- ethyl acetic acids sodium as sodium source, acetone is used as solvent.Teva companies：Use NaOH
Used as sodium source, acetonitrile is used as solvent.
If being encroached right with Bicon as sodium source using 2- ethyl acetic acids sodium；If using NaOH as sodium source,
The infringement with Teva companies can equally be run into；If Mycophenolic Acid and sodium methoxide react, it is also possible to obtain wheat and examine phenol sodium, but it
Synthetic route is identical with what south african patent No.6804959 was described.
If being synthesized as sodium source using first two material, the problem of infringement can be run into, if using the third material
The problem of low-yield can then be run into.
The content of the invention
The purpose of the present invention is exactly to solve the above problems, there is provided a kind of yield it is higher suitable for wheat examine phenol sodium industry
The optimize technique that metaplasia is produced.
To achieve these goals, the present invention is adopted the following technical scheme that：One kind examines phenol sodium industrialized production suitable for wheat
Optimize technique, comprise the following steps：
S101, the 3.8-4.2 times of methyl alcohol of MPA of addition to reactor, add Mycophenolic Acid to reaction under agitation
Device, heating mixed solution to 40-50 DEG C to solution clarification, protect under agitation to mixture by addition 4.8-5.2%W/W activated carbon
Hold temperature 20-30 minutes；
S102, using methanol solution by diatomite, filtrate is collected in the reactor, examine phenol using 1.8-2.2 times of wheat
The methyl alcohol washing of acid, and collect in the reactor, cooling filtrate to room temperature adds the 0.16-1.17 times of methyl alcohol of Mycophenolic Acid
Sodium, prepares the methanol solution of sodium methoxide, and wherein methanol quality is 4.8-5.2 times of sodium methoxide, and under reactor normal temperature, wheat examines phenol
Sodium methoxide is added in acid, is stirred 55-65 minutes, be cooled to 5-15 DEG C in pulpous state, stirred 115-125 minutes, filter material；
S103, with the 8-12 times of amount acetone eluted material of Mycophenolic Acid, discharging simultaneously checks weight in wet base, is done in 40-50 DEG C
Dry material obtains finished product until humidity NMT 1.8-2.2%.
Further：In step S101, the addition of methyl alcohol is 4 times of MPA additions in reaction vessel.
Further：Activated carbon addition is 5%W/W in step S101.
Further：In step S102,0.1688 times of sodium methoxide of Mycophenolic Acid is added after cooling filtrate to room temperature.
Further：In step S102, the methanol solution of sodium methoxide is prepared, wherein methanol quality is 5 times of sodium methoxides.
Further：In step S103, with 10 times of amount acetone eluted materials of Mycophenolic Acid
Further：In step S103, dry matter is until humidity NMT 2.0% in 40-50 DEG C.
Further, in step S102, washed using 2 times of methyl alcohol of Mycophenolic Acid, and collect in the reactor.
Compared with prior art, the present invention has the advantages that：(1) this Optimizing Technical is gentleer, cooling
10-15 DEG C of temperature (needs to cool down 1.5h at -15 DEG C) in patent document；(2) this optimize technique obtain product mode more
It is convenient, i.e. centrifugation plus acetone rinsing (recrystallization 1.5 hours are needed in patent document)；(3) this optimize technique yield is higher, reachable
94% (yield is 43% in patent document).
Specific embodiment
The invention discloses a kind of optimize technique that phenol sodium industrialized production is examined suitable for wheat, comprise the following steps：
S101, the 3.8-4.2 times of methyl alcohol of MPA (Mycophenolic Acid) of addition to reactor, add wheat and examine under agitation
Phenolic acid heats mixed solution to 40-50 DEG C to solution clarification to reactor, adds 4.8-5.2%W/W activated carbon to mixture,
Keeping temperature 20-30 minutes under agitation；
S102, using methanol solution by diatomite, filtrate is collected in the reactor, examine phenol using 1.8-2.2 times of wheat
The methyl alcohol washing of acid, and collect in the reactor, cooling filtrate to room temperature adds the 0.16-1.17 times of methyl alcohol of Mycophenolic Acid
Sodium, prepares the methanol solution of sodium methoxide, and wherein methanol quality is 4.8-5.2 times of sodium methoxide, and under reactor normal temperature, wheat examines phenol
Sodium methoxide is added in acid, 55-65 minutes (preferably 50 minutes) are stirred, 5-15 DEG C is cooled in pulpous state, stirred 115-125 minutes
(preferably 120 minutes), filter material；
S103, with the 8-12 times of amount acetone eluted material of Mycophenolic Acid, discharging simultaneously checks weight in wet base, is done in 40-50 DEG C
Dry material obtains finished product until humidity NMT 1.8-2.2%, checks dry weight and analyzes sample according to specification.
In embodiment：In step S101, the addition of methyl alcohol is 4 times of MPA additions in reaction vessel.
In embodiment：Activated carbon addition is 5%W/W in step S101.
In embodiment, in step S102, washed using 2 times of methyl alcohol of Mycophenolic Acid, and collect in the reactor.
In embodiment：In step S102,0.1688 times of sodium methoxide of Mycophenolic Acid is added after cooling filtrate to room temperature.
In embodiment：In step S102, the methanol solution of sodium methoxide is prepared, wherein methanol quality is 5 times of sodium methoxides.
In embodiment：In step S103, with 10 times of amount acetone eluted materials of Mycophenolic Acid
In embodiment：In step S103, dry matter is until humidity NMT 2.0% in 40-50 DEG C.
Specifically：Stage 1, the preparation of seed fermentation tank
Spore suspension is transferred to seed culture medium, is then cultivated 48-96 days at 24-30 DEG C.After the completion of incubation period, will
This nutrient growth of inoculation glass assembly that the vegetative cultures of growth are transferred to sterilizing is that laboratory inoculation whole process is nothing
Bacterium operates.The volume of inoculation is tested 1500 to 3000ml.The inoculation in laboratory is inoculated into 800-1000L seed culture mediums, plants
Sub- culture medium is in advance at 24 ± 3 DEG C and 1.0-1.5Kg/cm2Sterilized 20-60 minutes under pressure.
After inoculation, seed lot is hatched at 27 ± 3 DEG C, and rate of venting is 12-75m3/hr.Agitator speed keeps
In 100-300, counter-pressure is maintained at 0.2-1.0Kg/cm2Purity and form in seed fermentation tank are examined by batch cycle
Survey.After by the growth of 40-120 hours, the index in maturity period, such as PH [5.0to 7.0] and PMV [NLT have been obtained
10%], inoculum is transferred in fermentation tank (stage 02).
The fermentation in stage 2, Mycophenolic Acid
Mycophenolic Acid, is carried out in the fermentation tank containing 8-16KL aseptic culture mediums, culture medium in advance by 124 ±
3 DEG C of high temperature and t 1.0-1.5Kg/cm2Sterilized by 30-60 minutes under pressure, the fermentation period time is 150-300 hours, temperature
Degree is maintained at 27.0 ± 3.0 DEG C.Fermentation broth sample needs to be analyzed by HPLC, is periodically detected purity, and PH, PMV remain sugar amount
With the activity of Mycophenolic Acid.Agitator speed, Ventilation Rate, temperature and back pressure are held in regulation parameter.In fermentation period
In latter stage, batch is stopped and is transferred to the decline stage and is obtained product.
The separation in stage 3, Mycophenolic Acid (MPA)
The PH of liquid of receiving is adjusted to 4.00 ± 0.50, and product is extracted twice by isobutyl acetate (IBA), and IBA layers in 40-
60 DEG C of vacuum concentration.Toluene is added to concentrate and stirs 2-4 hours.Slurries obtain Mycophenolic Acid by centrifugation.Wheat
Examine phenolic acid and dry 10hours at 40-50 DEG C.
Stage 4, the purifying of Mycophenolic Acid crude product
Mycophenolic Acid is dissolved into isobutyl acetate (IBA) at 90-100 DEG C, and solution passes through decolorizing with activated carbon, by diatom
Soil filtering.IBA is heated to 90-100 DEG C in advance, then rinses diatomite.Filtrate is concentrated at 40-50 DEG C in a vacuum.Will
Slurries are cooled to 10-15 DEG C, and continue to stir and be centrifuged.Filter cake is rinsed by 10-15 DEG C of IBA- acetonitrile mixed solutions, then
It is dried in a vacuum to weightlessness and is not more than 1.5%, obtains pure Mycophenolic Acid.
Stage 5, wheat examines the generation of phenol sodium
Mycophenolic Acid sterling is dissolved into moisture and is not more than in 1.0% methyl alcohol, and is stirred at 40-50 DEG C to clear
Clearly.Activated carbon is added, and is filtered by diatomite, rinsed with the methyl alcohol for being heated to 40-50 DEG C afterwards.Sodium methoxide is dissolved alone in
Methanol solution, in the Mycophenolic Acid solution after addition filtering, and is stirred at room temperature, and reaction mixture is cooled to 10 DEG C -15 DEG C
And stir 2 hours.Afterwards, mixture is centrifuged and is washed with acetone.By wet crystal under the conditions of no more than 50 DEG C, in RCVD
Dry to moisture and be less than 2.0%.
Stage 6, wheat examines the purifying of phenol sodium
Diatomite is prepared by methyl alcohol in advance, and the wheat of acquisition is examined phenol sodium and is dissolved into methyl alcohol and is heated to 40-60 DEG C, addition work
Property carbon and at 40-60 DEG C stir 30 minutes, afterwards again in diatomite filter.Methyl alcohol distills under 35-50 DEG C of in vacuum.
The slurry of gained is cooled to 10-15 DEG C, and is stirred and is centrifuged.The acetone for being cooled to 10-15 DEG C in advance is added in filter cake, it
Filter cake is dried 5-20 hours in no more than 50 DEG C of vacuum afterwards, phenol sodium is examined until moisture is less than 2.0% and obtains wheat.
The preferred embodiment of the present invention is the foregoing is only, protection scope of the present invention is not limited in above-mentioned embodiment party
Formula, every technical scheme for belonging to the principle of the invention belongs to protection scope of the present invention.For those skilled in the art
Speech, some improvement carried out on the premise of principle of the invention is not departed from, these improvement also should be regarded as protection model of the invention
Enclose.
Claims (8)
1. a kind of optimize technique that phenol sodium industrialized production is examined suitable for wheat, it is characterised in that comprise the following steps：
S101, the 3.8-4.2 times of methyl alcohol of MPA of addition to reactor, add Mycophenolic Acid to reactor under agitation, plus
Hot mixing solution adds 4.8-5.2%W/W activated carbon to mixture, under agitation keeping temperature to 40-50 DEG C to solution clarification
20-30 minutes；
S102, using methanol solution by diatomite, filtrate is collected in the reactor, using 1.8-2.2 times of Mycophenolic Acid
Methyl alcohol is washed, and is collected in the reactor, cooling filtrate to room temperature, adds the 0.16-1.17 times of sodium methoxide of Mycophenolic Acid, system
The methanol solution of standby sodium methoxide, wherein methanol quality is 4.8-5.2 times of sodium methoxide, under reactor normal temperature, in Mycophenolic Acid
Addition sodium methoxide, stirs 55-65 minutes, is cooled to 5-15 DEG C in pulpous state, stirs 115-125 minutes, filter material；
S103, with the 8-12 times of amount acetone eluted material of Mycophenolic Acid, discharging simultaneously checks weight in wet base, the dried object in 40-50 DEG C
It is upright to humidity NMT 1.8-2.2%, obtain finished product.
2. the optimize technique that phenol sodium industrialized production is examined suitable for wheat according to claim 1, it is characterised in that：Step
In S101, the addition of methyl alcohol is 4 times of MPA additions in reaction vessel.
3. the optimize technique that phenol sodium industrialized production is examined suitable for wheat according to claim 1, it is characterised in that：Step
In S101, activated carbon addition is 5%W/W.
4. the optimize technique that phenol sodium industrialized production is examined suitable for wheat according to claim 1, it is characterised in that：Step
In S102, washed using 2 times of methyl alcohol of Mycophenolic Acid, and collect in the reactor.
5. the optimize technique that phenol sodium industrialized production is examined suitable for wheat according to claim 1, it is characterised in that：Step
In S102,0.1688 times of sodium methoxide of Mycophenolic Acid is added after cooling filtrate to room temperature.
6. the optimize technique that phenol sodium industrialized production is examined suitable for wheat according to claim 1, it is characterised in that：Step
In S102, the methanol solution of sodium methoxide is prepared, wherein methanol quality is 5 times of sodium methoxides.
7. the optimize technique that phenol sodium industrialized production is examined suitable for wheat according to claim 1, it is characterised in that：Step
In S103, with 10 times of amount acetone eluted materials of Mycophenolic Acid.
8. the optimize technique that phenol sodium industrialized production is examined suitable for wheat according to claim 1, it is characterised in that：Step
In S103, dry matter is until humidity NMT 2.0% in 40-50 DEG C.
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| CN201710088259.XA CN106866594A (en) | 2017-02-17 | 2017-02-17 | The optimize technique of phenol sodium industrialized production is examined suitable for wheat |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112645912A (en) * | 2020-12-27 | 2021-04-13 | 广东蓝宝制药有限公司 | Preparation method of high-purity M2 crystal form meclofenol sodium |
| CN114478452A (en) * | 2022-02-22 | 2022-05-13 | 广东蓝宝制药有限公司 | Preparation method of meclofenoxate sodium |
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| CN101014584A (en) * | 2004-07-20 | 2007-08-08 | 特瓦药厂私人有限公司 | Crystalline mycophenolate sodium |
| WO2010041269A1 (en) * | 2008-09-10 | 2010-04-15 | Ipca Laboratories Limited | Process for preparation of mycophenolic acid, its salt and ester derivatives |
| CN102464639A (en) * | 2010-11-16 | 2012-05-23 | 北京京卫信康医药科技发展有限公司 | Novel crystal forms of mycophenolate sodium and preparation method thereof |
| CN106350550A (en) * | 2016-11-28 | 2017-01-25 | 无锡福祈制药有限公司 | Method for preparing mycophenolate sodium from mycophenolic acid strains |
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| ZA684959B (en) * | 1967-11-22 | 1969-05-22 | Lilly Co Eli | Agents and methods for inhibiting the growth of malignant tumor cells in warm-blooded mammals |
| WO2004020426A1 (en) * | 2002-08-29 | 2004-03-11 | Biocon Limited | Process for the production of an immunosuppressant |
| CN101014584A (en) * | 2004-07-20 | 2007-08-08 | 特瓦药厂私人有限公司 | Crystalline mycophenolate sodium |
| CN101052631A (en) * | 2004-07-20 | 2007-10-10 | 特瓦药厂私人有限公司 | Crystalline mycophenolate sodium |
| WO2010041269A1 (en) * | 2008-09-10 | 2010-04-15 | Ipca Laboratories Limited | Process for preparation of mycophenolic acid, its salt and ester derivatives |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112645912A (en) * | 2020-12-27 | 2021-04-13 | 广东蓝宝制药有限公司 | Preparation method of high-purity M2 crystal form meclofenol sodium |
| CN114478452A (en) * | 2022-02-22 | 2022-05-13 | 广东蓝宝制药有限公司 | Preparation method of meclofenoxate sodium |
| CN114478452B (en) * | 2022-02-22 | 2024-02-06 | 广东蓝宝制药有限公司 | Preparation method of sodium mycophenolate |
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