CN107235943A - A kind of preparation method of high purity butylene phthalide - Google Patents
A kind of preparation method of high purity butylene phthalide Download PDFInfo
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- CN107235943A CN107235943A CN201710606891.9A CN201710606891A CN107235943A CN 107235943 A CN107235943 A CN 107235943A CN 201710606891 A CN201710606891 A CN 201710606891A CN 107235943 A CN107235943 A CN 107235943A
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- C—CHEMISTRY; METALLURGY
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- 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
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Abstract
The invention provides a kind of preparation method of high purity butylene phthalide, including：S1) using Raney's nickel as catalyst, butylidene phthalide is carried out after hydrogenation reaction, removal of solvent under reduced pressure in alcoholic solvent, the first intermediate is obtained；S2) by first intermediate, potassium hydroxide, tetrahydrofuran and water hybrid reaction, the crystallization that cools after terminating is reacted, the second intermediate is obtained；S3 second intermediate) is subjected to cyclization reaction in acid organic solvent, butylphenyl phthaleine is obtained.Compared with prior art, the present invention can effectively reclaim using alcoholic solvent, tetrahydrofuran as reaction dissolvent and solvent is cheap, greatly reduce production cost；Meanwhile, requirement reduction to production equipment rectifying column refined by hydrolysis, without rectifying repeatedly, saves the energy.
Description
Technical field
The invention belongs to technical field of medicine synthesis, more particularly to a kind of preparation method of high purity butylene phthalide.
Background technology
Butylphenyl phthaleine [(±)-NBP] is the first class national new drug that China has independent intellectual property right.It and celery
The structure of the left-handed Butylphthalide [(-)-(S)-NBP] extracted in rapeseed oil is identical, is its artificial synthesized racemization
Body, with wide spectrum anti-convulsant activity.Clinical study results show that butylphenyl phthaleine has to acute and convalescence ischemic cerebral stroke patients
Obvious therapeutic effect；Brain energy metabolism can be improved, increase ischemic region cerebral blood flow (CBF), improve brain blood supply, cerebral infarct size is reduced,
Protection and reparation ischemic region cranial nerve cell.Its structural formula is as follows：
Butylphenyl phthaleine (3-Butylphthalide) soft capsule is possessing for Enbipu Pharmacy Co., Ltd., Shiyao Group.'s listing
The national class anti-cerebral ischemia new drug of independent intellectual property right, brand-new chemical constitution, trade name " En Bipu ", it can pass through drop
Low arachidonic acid content, improves cerebrovascular endothelial NO and PGI2Level, suppress glutamic neuron, reduction intracellular Ca2+ it is dense
Degree, suppresses free radical and improves the mechanism such as activities of antioxidant enzymes and produce drug effect for multiple pathology links caused by cerebral ischemia and make
With.It can be clinically used for light, moderate acute ischemic cerebral apoplexy.
In the prior art, Li Shaobai, Zhang Shaoming etc. are delivered on nineteen ninety Lanzhou University's journal (natural science edition), with neighbour
Phthalate anhydride, sodium acetate, valeric anhydride are heated to reflux preparing butylidenephthalide crude product at 300 DEG C, and essence is carried out using silica gel column chromatography
System, yield 25%, yield is substantially relatively low.Using ether as hydrogenation solvent, Pd/C is catalyst, and butylphenyl phthaleine is made in reduction, is carried out
Column chromatography obtains the butylphenyl phthaleine step yield 95%.But this method is related to the use of high temperature and ether, and is adopted in subtractive process
With column chromatography, be not suitable for industrialized production.This method process route is as follows：
China Concord Medical Science University Zhan Yu lotus Ph.D. Dissertations refer to use phthalic anhydride, valeric anhydride, valeric acid
Sodium carries out the synthesis of butylidenephthalide, yield 60~65% after rectifying；Using ethanol as hydrogenation solvent, Pd/C is catalyst preparation fourth
Yield 90~95% after phthalide crude product, distillation, rectifying, rectifying are carried out by obtained cut on the vacuum distillation post of high reflux ratio
Yield 90~95%.This method instead of sodium acetate using natrium valericum, reduce reaction temperature, and avoid second in course of reaction
Pollution of the acid vapor to environment；Catalysis substitutes ether using ethanol, and security greatly improves, but its to still need high rectifying degree multiple
Distillation, energy resource consumption is big, and totle drilling cost is higher, is unfavorable for production.This method process route is as follows：
Publication No. CN105884726A Chinese patent discloses the synthetic method and purifying process of a kind of butylphenyl phthaleine, its
Adjacent formylbenzoate is used for initiation material, is that solvent and n-butylmagnesium chloride magnesium grignard reagent react using THF, is prepared after acid adjustment
Obtain butylphenyl phthaleine product；Processing is hydrolyzed with alkaline matter for butylphenyl phthaleine crude product, then solid is gone out by acid out, filters, obtains fourth
Phthalide intermediate, its major impurity is reacted and phthalide；Above-mentioned acid adjustment alkali tune process is repeated, is finally closed
Ring, decompression precipitation obtain the butylphenyl phthaleine of high-purity, and purifying yield is 48~52%.This method purifying process is simple to operate, is not required to
Want column chromatography and high temperature, high vacuum rectification under vacuum, it is easy to which industrial method is produced；But the intermediate plate separated out in acid adjustment process reclaimed water
Knot is difficult to release from reactor, and butylphenyl phthaleine intermediate is extremely unstable, itself cyclization can also occur in the case of solid, repeatedly
Acid adjustment alkali tune can cause yield relatively low, and totle drilling cost is higher.This method process route is as follows：
Publication No. CN105130934A Chinese patent discloses a kind of butylphenyl phthaleine bulk drug product and preparation method thereof,
Butylphenyl phthaleine crude product is hydrolyzed using potassium hydroxide in methyl alcohol, ether solvent is added after cooling, makes hydroxyl amyl group Potassium Benzoate
Salt out；The sylvite is soluble in water, add ether solvent stirring and crystallizing and refined；Sylvite after then will be refined is added to
In the mixed liquor of water and dichloromethane, control pH is acidified cyclization at 1.5~3.0,30~45 DEG C of temperature and obtains butylphenyl phthaleine crude product,
In rectifying column, 4~5mmHg of vacuum is controlled, 154~160 DEG C are warming up to, reflux ratio 3~7 is controlled:1, obtain butylphenyl phthaleine former
Expect medicine.Solubility of the hydroxyl amyl group Potassium Benzoate salt in water is high in this method, and it is low with ether solvent crystallization yield, and ethers
Solvent cost is higher, causes production cost higher.
Publication No. CN1136209C Chinese patent is reported uses alkaline matter such as hydroxide by racemization-butylphenyl phthaleine
Open loop is hydrolyzed in one kind in sodium, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, caustic alcohol, and it is molten that dissociation reaction is used
Agent includes one kind in methanol, ethanol, or water, or alcohol-water mixture.After acidifying acid-base neutralization preparation is carried out with optically active amines
Split into salt, after crystallization purifying by the optically active ammonium salt of individual isomer in 0~40 DEG C, pH value between 1.0~4.0
Again acidifying cyclization obtains (-)-butyl phthalide and (+)-butyl phthalide of high-purity optically active.But hydrolysis is mentioned in the patent
Using one kind in methanol, ethanol, or water, or alcohol-water mixture, the solubility to sylvite of these solvents is larger, and sylvite is difficult
To separate out.
The content of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of preparation method of high purity butylene phthalide, should
Method yield is higher and purity is higher.
The invention provides a kind of preparation method of high purity butylene phthalide, including：
S1) using Raney's nickel as catalyst, butylidene phthalide is subjected to hydrogenation reaction, removal of solvent under reduced pressure in alcoholic solvent
Afterwards, the first intermediate is obtained；
S2) by first intermediate, potassium hydroxide, tetrahydrofuran and water hybrid reaction, the crystallization that cools after terminating is reacted,
Obtain the second intermediate；
S3 second intermediate) is subjected to cyclization reaction in acid organic solvent, butylphenyl phthaleine is obtained.
It is preferred that, the step S1) in hydrogenation reaction temperature be 15 DEG C~50 DEG C；The pressure of hydrogenation reaction be 1~
10atm。
It is preferred that, the step S1) in butylidene phthalide and alcoholic solvent mass volume ratio be 1g：(2~20) ml；It is described
Step S1) in Raney's nickel quality be butylidene phthalide quality 5%~20%.
It is preferred that, the mass volume ratio of first intermediate, tetrahydrofuran and water is 1g：(2~20) ml：(0.03~
2.0)ml。
It is preferred that, the step S2) in the temperature of hybrid reaction be 10 DEG C~80 DEG C, time of hybrid reaction is 1~3h.
It is preferred that, the step S2) in crystallization temperature be -10 DEG C~35 DEG C.
It is preferred that, the step S3) in cyclization react temperature be 20 DEG C~40 DEG C；The step S3) in cyclization react
PH value be 1~4.
It is preferred that, the butylidene phthalide is prepared in accordance with the following methods：
By valeric anhydride, phthalic anhydride and part natrium valericum hybrid reaction, then add remaining natrium valericum and continue anti-
Should；
The pH value that reaction adjusts reaction system after terminating with ammoniacal liquor is alkalescence, then is extracted with dichloromethane, obtains cyclobutenyl
Phthalide.
It is preferred that, the step S2) be specially：
Tetrahydrofuran, water are mixed with potassium hydroxide, the first intermediate hybrid reaction is then added, after reaction receives
Cool crystallization, after filtering, is washed with tetrahydrofuran, obtains the second intermediate.
It is preferred that, the step S3) be specially：
Second intermediate is carried out in acid organic solvent after cyclization reaction, 0.5~2h of reaction, separated organic
Layer, then organic solvent is added, continue to react, finally merge organic layer, obtain organic phase；
The organic phase is washed through weakly alkaline solution successively, washed, after desiccant dryness, recycling design, last rectifying,
Obtain butylphenyl phthaleine.
The invention provides a kind of preparation method of high purity butylene phthalide, including：S1) using Raney's nickel as catalyst, by fourth
Alkenyl phthalide is carried out after hydrogenation reaction, removal of solvent under reduced pressure in alcoholic solvent, obtains the first intermediate；S2) by described first
Mesosome, potassium hydroxide, tetrahydrofuran and water hybrid reaction, react the crystallization that cools after terminating, obtain the second intermediate；S3) by institute
State the second intermediate and cyclization reaction is carried out in acid organic solvent, obtain butylphenyl phthaleine.Compared with prior art, the present invention is adopted
With alcoholic solvent, tetrahydrofuran as reaction dissolvent, it can effectively reclaim and solvent is cheap, greatly reduce production cost；
Meanwhile, requirement reduction to production equipment rectifying column refined by hydrolysis, without rectifying repeatedly, saves the energy.
Brief description of the drawings
Fig. 1 is the HPLC collection of illustrative plates of the butylidenephthalide obtained in the embodiment of the present invention 2；
Fig. 2 is the HPLC collection of illustrative plates of the first intermediate obtained in the embodiment of the present invention 4；
Fig. 3 is the HPLC collection of illustrative plates of the second intermediate obtained in the embodiment of the present invention 4；
Fig. 4 is the HPLC collection of illustrative plates of the butylphenyl phthaleine crude product obtained in the embodiment of the present invention 6；
Fig. 5 is the HPLC collection of illustrative plates of the butylphenyl phthaleine obtained in the embodiment of the present invention 6.
Embodiment
Below in conjunction with the embodiment of the present invention, the technical scheme in the embodiment of the present invention is clearly and completely described,
Obviously, described embodiment is only a part of embodiment of the invention, rather than whole embodiments.Based in the present invention
Embodiment, the every other embodiment that those of ordinary skill in the art are obtained under the premise of creative work is not made, all
Belong to the scope of protection of the invention.
The invention provides a kind of preparation method of high purity butylene phthalide, including：S1) using Raney's nickel as catalyst, by fourth
Alkenyl phthalide is carried out after hydrogenation reaction, removal of solvent under reduced pressure in alcoholic solvent, obtains the first intermediate；S2) by described first
Mesosome, potassium hydroxide, tetrahydrofuran and water hybrid reaction, react the crystallization that cools after terminating, obtain the second intermediate；S3) by institute
State the second intermediate and cyclization reaction is carried out in acid organic solvent, obtain butylphenyl phthaleine.
The present invention is not particularly limited to the source of all raw materials, is commercially available or self-control.
In the present invention, the butylidene phthalide is preferably prepared in accordance with the following methods：By valeric anhydride, phthalic anhydride with
Part natrium valericum hybrid reaction, then adds remaining natrium valericum and continues to react；Reaction adjusts reactant after terminating with ammoniacal liquor
The pH value of system is alkalescence, then is extracted with dichloromethane, obtains butylidene phthalide.
The synthesis of present invention progress butylidenephthalide by raw material of valeric anhydride, phthalic anhydride and natrium valericum, and by penta
Sour sodium is added portionwise, and reduces to react in heating process and aggravates to discharge the danger that a large amount of gases go out reactor suddenly；Its
In, the mol ratio of the valeric anhydride, phthalic anhydride and natrium valericum is preferably 1：(0.8~1.2)：(0.8~1.2), it is more excellent
Elect 1 as：(0.9~1.1)：(0.8~1), is further preferably 1：(1~1.1)：(0.8~0.9), most preferably 1：1.1：0.8.
By natrium valericum, phthalic anhydride and part natrium valericum hybrid reaction, the temperature of the reaction is preferably 160 DEG C~
180 DEG C, more preferably 165 DEG C~175 DEG C, be further preferably 170 DEG C；The time of the reaction is preferably 0.5~2h, more preferably
1~1.5h, is further preferably 1h；Then remaining natrium valericum is added to continue to react；The part natrium valericum and remaining natrium valericum
Mass ratio be preferably (1~2)：(1~2), more preferably 1：1；The temperature for continuing to react is preferably 170 DEG C~200 DEG C,
More preferably 180 DEG C~200 DEG C, be further preferably 185 DEG C~195 DEG C, most preferably 190 DEG C；The time for continuing to react is excellent
Elect 2~5h, more preferably 2~4h as, be further preferably 3h.
Continue that after reaction terminates, the temperature of reaction system preferably is down into 90 DEG C~110 DEG C, be more preferably down to 95 DEG C~
105 DEG C, 100 DEG C are further preferably down to, water is added, continues to heat progress back flow reaction.The volume that the water is added is preferably penta
1~4 times of acid anhydrides quality, more preferably 2~3 times, be further preferably 2 times；The time of the back flow reaction is preferably 0.5~2h,
More preferably 1~1.5h, is further preferably 1h.
Reaction terminate after, be preferably dropped to 20 DEG C~40 DEG C, be more preferably down to 20 DEG C~35 DEG C, be further preferably cooled to 25 DEG C~
30 DEG C, most preferably 25 DEG C, the pH value for adjusting reaction system with ammoniacal liquor is alkalescence, more preferably 8~10, further preferably for 8.5~
9.5, most preferably 9；Extracted again with dichloromethane；The number of times of the extraction is preferably 2~4 times, more preferably 3 times.
After extraction, preferably washed successively through weak aqua ammonia, deionized water is washed with after desiccant dryness, reclaiming dichloromethane,
Obtain butylidene phthalide；The number of times of the weak aqua ammonia washing is preferably 2~3 times；The number of times of the deionized water washing is preferably 2
~3 times；The drier is drier well known to those skilled in the art, is had no in special limitation, the present invention preferably
For anhydrous calcium chloride.
Obtained butylidene phthalide can directly carry out hydrogenation reaction without rectifying；Vacuum distillation can be also carried out, 140 are collected
~145 DEG C/2~3mmHg cuts, obtain yellow oily liquid, purity 98% or so, yield 70%~75%.
Using Raney's nickel as catalyst, butylidene phthalide is subjected to hydrogenation reaction in alcoholic solvent, preferably first by cyclobutenyl benzene
Phthalein is mixed with alcoholic solvent, adds Raney's nickel, carries out hydrogenation reaction；The alcoholic solvent is that alcohol well known to those skilled in the art is molten
Agent, it is preferably ethanol, more preferably absolute ethyl alcohol to have no in special limitation, the present invention；The butylidene phthalide and alcohol
The mass volume ratio of solvent is preferably 1g：(2~20) ml, more preferably 1g：(3~15) ml, is further preferably 1g：(3~10ml),
It is further preferably 1g：(3~8ml), most preferably 1g：(4~6ml)；The quality of the Raney's nickel is preferably butylidene phthalide quality
5%~20%, more preferably 10%~15%；The temperature of the hydrogenation reaction is preferably 15 DEG C~50 DEG C, more preferably 20
DEG C~40 DEG C, it is further preferably 25 DEG C~35 DEG C；The pressure of the hydrogenation reaction is preferably 1~10atm (1~10kg/cm2), more
Preferably 1~8atm, is further preferably 1.5~6atm, is further preferably 1.5~5atm, is further preferably 1.5~3.5atm, most preferably
For 2.5atm；To hydrogen is not inhaled, reaction terminates.
After reaction terminates, preferably remove after catalyst, then removal of solvent under reduced pressure, obtain pale yellow oily liquid in first
Mesosome, i.e. butylphenyl phthaleine crude product.
By first intermediate, potassium hydroxide, tetrahydrofuran and water hybrid reaction, preferably first by tetrahydrofuran, water with
Potassium hydroxide is mixed, and is then added the first intermediate hybrid reaction, is more preferably first mixed tetrahydrofuran with water, is then stirring
Potassium hydroxide is added portionwise under conditions of mixing, then the first intermediate hybrid reaction is added dropwise；The temperature of the hybrid reaction is preferably
10 DEG C~80 DEG C, more preferably 35 DEG C~backflow, be further preferably backflow；The time of the hybrid reaction is preferably 1~3h, more excellent
Elect 1.5~2.5h as, be further preferably 2h；The mass volume ratio of first intermediate, tetrahydrofuran and water is preferably 1g：(2~
20)ml：(0.03~2.0) ml, more preferably 1g：(2~15) ml：(0.03~1.5) ml, is further preferably 1g：(2~10) ml：
(0.05~1.0) ml, is further preferably 1g：(3~8) ml：(0.05~0.5) ml, most preferably 1g：(3~8) ml：(0.05~
0.2)ml。
After reaction terminates, cool crystallization, obtains the second intermediate；The temperature of the cooling crystallization is preferably -10 DEG C~35
DEG C, more preferably 5 DEG C~30 DEG C, be further preferably 15 DEG C~25 DEG C, most preferably 20 DEG C；It is described cooling crystallization time be preferably
0.5~3h, more preferably 1~2h；Preferably filtered after cooling crystallization, then filter cake is washed with tetrahydrofuran, obtain the second intermediate.
The mixed liquor of tetrahydrofuran and water is as reaction dissolvent, and also serving as sylvite after refining solvent, cooling can directly separate out, it is not necessary to enter one
One-step refining, and the second intermediate purity obtained by this step is more than 99.5%, maximum list is miscellaneous to be less than 0.1% (HPLC faces
Product normalization method).
Second intermediate is subjected to cyclization reaction in acid organic solvent, preferably first the second middle graph is dissolved in
In water, then add and cyclization reaction is carried out in the organic solvent of acidity；Wherein, the organic solvent is those skilled in the art
Well known organic solvent, it is preferably dichloromethane to have no in special limitation, the present invention；The acid organic solvent is excellent
Choosing provides acid condition using inorganic acid, more preferably provides acid condition using hydrochloric acid；In the present invention, it is preferred to first will be organic molten
Agent is adjusted to acidity, is heated to the temperature of cyclization reaction, then the second intermediate for being dissolved in water is added dropwise；The temperature of the cyclization reaction is excellent
Elect 20 DEG C~40 DEG C, more preferably 25 DEG C~35 DEG C as；The pH value of the cyclization reaction is preferably 1~4, and more preferably 1~3,
It is further preferably 1~2；In the present invention, the step is preferably specially：Second intermediate is entered in acid organic solvent
Row cyclization is reacted, and after 0.5~2h of reaction, is preferably reacted after 0.5~1h, separates organic layer, then adds organic solvent, continues anti-
Should, finally merge organic layer, obtain organic phase；The organic phase is washed through weakly alkaline solution successively, washed, desiccant dryness
Afterwards, recycling design.The time for continuing to react is preferably 0.5~2h, more preferably 0.5~1h；The weakly alkaline solution is
Weakly alkaline solution well known to those skilled in the art, it is preferably weak aqua ammonia to have no in special limitation, the present invention；It is described dry
Drying prescription is drier well known to those skilled in the art, and it is preferably anhydrous calcium chloride to have no in special limitation, the present invention；
The method of the recycling design is method well known to those skilled in the art, is had no in special limitation, the present invention preferably
For the recycling design that is concentrated under reduced pressure.In this step, the second intermediate is dissolved in water droplet and added, because reaction is in sour environment all the time
Under, the second intermediate is that the neutralization of hydroxyl amyl group Potassium Benzoate is the direct cyclization of hydroxyl amyl group benzoic acid, is not in substantial amounts of hydroxyl amyl group
Benzoic acid and influence stirring.
It is recovered under reduced pressure after solvent, obtains pale yellowish oil liquid, preferably carries out rectifying, obtain butylphenyl phthaleine.The rectifying
Method is method well known to those skilled in the art, has no preferred progress rectification under vacuum in special limitation, the present invention, receives
Collect 154 DEG C/4~5mmHg cuts, obtain colourless oil liquid i.e. butylphenyl phthaleine；The rectification under vacuum is preferred to use thorn type rectifying column,
More preferably use 40cm lunge type rectifying columns.
The present invention using alcoholic solvent, tetrahydrofuran as reaction or extractant, can effectively reclaim and solvent price just
Preferably, production cost is greatly reduced；Meanwhile, requirement reduction to production equipment rectifying column, without repeatedly refined by hydrolysis
Rectifying, saves the energy.
The preparation technology for the butylphenyl phthaleine that the present invention is provided is as follows：
The present invention is using tetrahydrofuran and water as hydrolysising solvent, and hydroxyl amyl group Potassium Benzoate can be separated out directly, while also rising
To refined effect, it is not necessary to further refine, acidifying cyclization or obtained butylphenyl phthaleine crude product purity can just reach 99.5%
More than, then by simple rectifying once, you can obtain the butylphenyl phthaleine for meeting formulation requirements for obtaining high-purity of higher yields, operation
Simply, it is not necessary to which high reflux ratio rectifying column can remove the impurity in butylphenyl phthaleine without rectifying repeatedly.Also, the present invention passes through
Lab scale, the process certification of pilot scale, can ensure that the product quality produced meets the requirement of bulk drug, the process recovery ratio is higher,
With good reappearance and feasibility.
In order to furtherly of the invention, the preparation of a kind of butylphenyl phthaleine provided with reference to embodiments the present invention and refined
Method is described in detail.
Reagent used is commercially available in following examples.
Embodiment 1：The preparation and distillation of butylidenephthalide (DBT-1)
By valeric anhydride 46.56g, phthalic anhydride 40.73g, natrium valericum 12.41g is added in 500ml reaction bulbs, stirred
Mix well mixed, be heated to 170 DEG C or so and carry out reaction 1h；Natrium valericum 12.41g then is added, 190 DEG C of left sides are then warming up to
The right side, continues insulation reaction 3h；Reaction is finished, and system is cooled into 100 DEG C or so, and 95.0ml deionized waters are added dropwise, continue to be heated to
Backflow, continues the 1h that flows back, and room temperature is down in cooling；Control system temperature adjusts pH to 9, dichloromethane at 25 DEG C or so using concentrated ammonia liquor
Alkane 186.0 is extracted three times, is washed twice using 124.0ml weak aqua ammonias (1%), 124.0ml deionized waters are washed twice, appropriate nothing
Water calcium chloride is dried；Suction filtration, removes drier, and concentration and recovery dichloromethane obtains dark red oil, 20cm lunge type rectifying
Post carries out vacuum distillation, obtains yellow oily liquid as butylidenephthalide.
The butylidenephthalide obtained in embodiment 1 is analyzed using high performance liquid chromatography, its HPLC spectrogram result is obtained,
Butylidenephthalide (Z/E) purity 99.154%, larger impurity is descending to be arranged as 0.563%, 0.117%, 0.056%, the step
Rapid yield 70.0%.
Embodiment 2：The preparation and distillation of butylidenephthalide (DBT-1)
By valeric anhydride 2.40kg, phthalic anhydride 2.10kg, natrium valericum 0.64kg is added in 20L reaction bulbs, stirring
It is well mixed, it is heated to 170 DEG C or so and carries out reaction 1h；Natrium valericum 0.64kg then is added, 190 DEG C or so are then warming up to,
Continue insulation reaction 3h；Reaction is finished, and system is cooled into 100 DEG C or so, and 4.8L deionized waters are added dropwise, and continues to be heated to backflow,
Continue the 1h that flows back, room temperature is down in cooling；Control system temperature adjusts pH to 9, dichloromethane at 25 DEG C or so using concentrated ammonia liquor
9.6L is extracted three times, is washed twice using 6.4L weak aqua ammonias (1%), 6.4L deionized waters are washed twice, 300g anhydrous calcium chlorides
Dry；Suction filtration, removes drier, and concentration and recovery dichloromethane obtains dark red oil, and 20cm lunge type rectifying columns are subtracted
Pressure distillation, collects 140~145 DEG C/2~3mmHg cuts, obtains yellow oily liquid as butylidenephthalide.
The butylidenephthalide obtained in embodiment 2 is analyzed using high performance liquid chromatography, its HPLC spectrogram such as Fig. 1 is obtained
It is shown.As shown in Figure 1, butylidenephthalide (Z/E) purity 98.058%, larger impurity is descending to be arranged as 1.259%,
0.367%th, 0.123%, 0.078%, the step yield 72.3%.
Embodiment 3：The preparation of hydroxyl amyl group Potassium Benzoate (DBT-2)
Absolute ethyl alcohol 100.0ml, butylidene phthalide (DBT-1) 25.00g are added into hydriding reactor, Raney's nickel (wet) is added
3.75g, is carried out 3 nitrogen and exchanges exclusion air, exchanged 3 times using hydrogen, 25~35 DEG C of controlling reaction temperature, Stress control
2.5 atmospheric pressure (2.5kg/cm2) carry out hydrogenation reaction, untill hydrogen is not inhaled, about 3h；Catalyst is removed, be concentrated under reduced pressure ethanol,
Pale yellow oily liquid is obtained, the first intermediate is obtained.HPLC analyses are carried out to the first intermediate using high performance liquid chromatography, can
Know butylphenyl phthaleine crude product purity 97.555% after hydrogenation, larger impurity is descending to be arranged as 0.524%, 0.480%, 0.420%,
0.202%th, 0.143%.
Tetrahydrofuran 125.0ml is added into 250ml there-necked flasks, 2.5ml deionized waters is added, under stirring, is added portionwise
82% hydroxide flake potassium 9.0g, is added dropwise above-mentioned pale yellow oily liquid；Backflow is heated to, potassium hydroxide gradually dissolves, then,
A large amount of solids are separated out, and react about 2h；Reaction is finished, and cools to 20 DEG C or so stirring and crystallizing 1h, suction filtration is washed with 25.0ml tetrahydrofurans
Filter cake is washed, its 45 DEG C are dried under reduced pressure, the second intermediate i.e. Hydroxy pentyl Potassium Benzoate (DBT-2), off-white powder is obtained
29.35g。
HPLC analyses are carried out to the second intermediate using high performance liquid chromatography, it is known that DBT-2 purity 98.480%, wherein,
Butylphenyl phthaleine 1.349% (sylvite in a solvent cyclization produce), impurity is descending to be arranged as 0.075%, 0.065%,
0.032%.Yield 89.7%.
Embodiment 4：The preparation of hydroxyl amyl group Potassium Benzoate (DBT-2)
Absolute ethyl alcohol 6.8L, butylidene phthalide (DBT-1) 1.70kg are added into hydriding reactor, Raney's nickel (wet) is added
204.0g, is carried out 3 nitrogen and exchanges exclusion air, exchanged 3 times using hydrogen, 25~35 DEG C of controlling reaction temperature, Stress control
2.5 atmospheric pressure (2.5kg/cm2) carry out hydrogenation reaction, untill hydrogen is not inhaled, about 3h；Catalyst is removed, be concentrated under reduced pressure ethanol,
Pale yellow oily liquid is obtained, the first intermediate is obtained.
Tetrahydrofuran 8.5L is added into 20L reactors, 170ml deionized waters is added, under stirring, is added portionwise 82%
Shape potassium hydroxide 636.4g, is added dropwise above-mentioned pale yellow oily liquid；Backflow is heated to, potassium hydroxide gradually dissolves, then, largely
Solid is separated out, and reacts about 2h；Reaction is finished, and cools to 20 DEG C or so stirring and crystallizing 1h, suction filtration washs filter with 1.7L tetrahydrofurans
Cake, its 45 DEG C are dried under reduced pressure, and obtain the second intermediate i.e. Hydroxy pentyl Potassium Benzoate (DBT-2), off-white powder 2.01kg.
The first intermediate obtained in embodiment 4 is analyzed using high performance liquid chromatography, its HPLC spectrogram is obtained such as
Shown in Fig. 2.Butylphenyl phthaleine crude product purity 95.864% after hydrogenating as shown in Figure 2, larger impurity is descending to be arranged as 1.907%,
1.001%th, 0.318%, 0.276%, 0.169%.
The second intermediate obtained in embodiment 4 is analyzed using high performance liquid chromatography, its HPLC spectrogram is obtained such as
Shown in Fig. 3.DBT-2 purity 99.794% as shown in Figure 3, impurity is descending to be arranged as 0.062%, 0.052%, 0.037%,
0.028%th, 0.027%.Yield 90.5%.
Embodiment 5：The preparation of butylphenyl phthaleine (DBT)
Hydrochloric acid, dichloromethane are added into 250ml reaction bulbs, is warming up between 25~35 DEG C；By Hydroxy pentyl benzoic acid
Potassium (DBT-2) 25.00g, which is dissolved in deionized water, to be allowed to dissolve, and is added drop-wise in reaction system, 25~35 DEG C of control system temperature it
Between；After completion of dropping, keep between pH 1~2, continue to react 30min.Dichloromethane layer is separated, continues to add dichloromethane,
Between 25~35 DEG C of control system temperature, between control pH 1~2, continue to react 30min.Merge organic layer, using weak aqua ammonia
Washing, deionized water washing, anhydrous calcium chloride is dried；Be concentrated under reduced pressure recycling design, obtains pale yellowish oil liquid as butylphenyl phthaleine
Crude product 19.06g.Its purity is 99.794%, and impurity is descending to be arranged as 0.102%, 0.051%, 0.027%.
Embodiment 6：The preparation and rectifying of butylphenyl phthaleine (DBT)
Hydrochloric acid, dichloromethane are added into 20L reaction bulbs, is warming up between 25~35 DEG C；By Hydroxy pentyl Potassium Benzoate
(DBT-2) it is dissolved in deionized water and is allowed to dissolve, be added drop-wise in reaction system, between 25~35 DEG C of control system temperature；It is added dropwise
After finishing, keep between pH 1~2, continue to react 30min.Dichloromethane layer is separated, continues to add dichloromethane, control system
Between 25~35 DEG C of temperature, between control pH 1~2, continue to react 30min.Merge organic layer, washed using weak aqua ammonia, go from
Sub- water washing, anhydrous calcium chloride is dried；Be concentrated under reduced pressure recycling design, and it is butylphenyl phthaleine crude product to obtain pale yellowish oil liquid.
Rectification under vacuum is carried out using 40cm lunge types rectifying column, 154 DEG C/4~5mmHg cuts is collected, obtains colorless oil liquid
Body is butylphenyl phthaleine, cyclization and distillation yield:82.2%.
The butylphenyl phthaleine crude product (DBT-CP) obtained in embodiment 6 is analyzed, its HPLC spectrogram is obtained as shown in Figure 4.
As shown in Figure 4, its purity is 99.853%, and impurity is descending to be arranged as 0.055%, 0.048%, 0.044%.
The butylphenyl phthaleine obtained in embodiment 6 is analyzed, its HPLC spectrogram is obtained as shown in Figure 5.As shown in Figure 5, its
Purity is 99.903%, and impurity is descending to be arranged as 0.040%, 0.037%, 0.012%.(press HPLC area normalization methods
Meter).
Claims (10)
1. a kind of preparation method of high purity butylene phthalide, it is characterised in that including：
S1) using Raney's nickel as catalyst, butylidene phthalide is carried out after hydrogenation reaction, removal of solvent under reduced pressure in alcoholic solvent, obtained
To the first intermediate；
S2) by first intermediate, potassium hydroxide, tetrahydrofuran and water hybrid reaction, the crystallization that cools after terminating is reacted, is obtained
Second intermediate；
S3 second intermediate) is subjected to cyclization reaction in acid organic solvent, butylphenyl phthaleine is obtained.
2. preparation method according to claim 1, it is characterised in that the step S1) in the temperature of hydrogenation reaction be 15
DEG C~50 DEG C；The pressure of hydrogenation reaction is 1~10atm.
3. preparation method according to claim 1, it is characterised in that the step S1) in butylidene phthalide and alcoholic solvent
Mass volume ratio be 1g：(2~20) ml；The step S1) in Raney's nickel quality for butylidene phthalide quality 5%~
20%.
4. preparation method according to claim 1, it is characterised in that the matter of first intermediate, tetrahydrofuran and water
Amount volume ratio is 1g：(2~20) ml：(0.03~2.0) ml.
5. preparation method according to claim 1, it is characterised in that the step S2) in the temperature of hybrid reaction be 10
DEG C~80 DEG C, the time of hybrid reaction is 1~3h.
6. preparation method according to claim 1, it is characterised in that the step S2) in crystallization temperature for -10 DEG C~
35℃。
7. preparation method according to claim 1, it is characterised in that the step S3) in the temperature reacted of cyclization be 20
DEG C~40 DEG C；The step S3) in cyclization react pH value be 1~4.
8. preparation method according to claim 1, it is characterised in that the butylidene phthalide is prepared in accordance with the following methods：
By valeric anhydride, phthalic anhydride and part natrium valericum hybrid reaction, then add remaining natrium valericum and continue to react；
The pH value that reaction adjusts reaction system after terminating with ammoniacal liquor is alkalescence, then is extracted with dichloromethane, obtains butylidene phthalide.
9. preparation method according to claim 1, it is characterised in that the step S2) be specially：
Tetrahydrofuran, water are mixed with potassium hydroxide, the first intermediate hybrid reaction is then added, reaction cools after receiving
Crystallization, after filtering, is washed with tetrahydrofuran, obtains the second intermediate.
10. preparation method according to claim 1, it is characterised in that the step S3) be specially：
Second intermediate is carried out in acid organic solvent after cyclization reaction, 0.5~2h of reaction, organic layer is separated,
Organic solvent is added again, is continued to react, is finally merged organic layer, obtain organic phase；
The organic phase is washed through weakly alkaline solution successively, washed, after desiccant dryness, recycling design, last rectifying is obtained
Butylphenyl phthaleine.
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| CN111377894A (en) * | 2018-12-29 | 2020-07-07 | 江苏先声药业有限公司 | Purification method of 3-n-butyl-l (3H) -isobenzofuranone |
| CN113024495A (en) * | 2019-12-25 | 2021-06-25 | 上海奥博生物医药技术有限公司 | Novel method for purifying butylphthalide |
| CN115745930A (en) * | 2022-12-27 | 2023-03-07 | 山东诚创蓝海医药科技有限公司 | Preparation method of butylphthalide |
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| CN105130934A (en) * | 2015-08-15 | 2015-12-09 | 石药集团恩必普药业有限公司 | Butyl phthalide raw material drug product and preparation method thereof |
| CN105859670A (en) * | 2016-04-19 | 2016-08-17 | 丽珠医药集团股份有限公司 | Preparation method of high-purity butylphthalide |
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| CN105859670A (en) * | 2016-04-19 | 2016-08-17 | 丽珠医药集团股份有限公司 | Preparation method of high-purity butylphthalide |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111377894A (en) * | 2018-12-29 | 2020-07-07 | 江苏先声药业有限公司 | Purification method of 3-n-butyl-l (3H) -isobenzofuranone |
| CN111377894B (en) * | 2018-12-29 | 2023-10-20 | 江苏先声药业有限公司 | Purification method of 3-n-butyl-l (3H) -isobenzofuranone |
| CN113024495A (en) * | 2019-12-25 | 2021-06-25 | 上海奥博生物医药技术有限公司 | Novel method for purifying butylphthalide |
| CN113024495B (en) * | 2019-12-25 | 2024-05-14 | 上海奥博生物医药股份有限公司 | Novel purification method of butylphthalide |
| CN115745930A (en) * | 2022-12-27 | 2023-03-07 | 山东诚创蓝海医药科技有限公司 | Preparation method of butylphthalide |
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