CN107216298A - A kind of preparation method of butylphenyl phthaleine - Google Patents
A kind of preparation method of butylphenyl phthaleine Download PDFInfo
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- CN107216298A CN107216298A CN201710606003.3A CN201710606003A CN107216298A CN 107216298 A CN107216298 A CN 107216298A CN 201710606003 A CN201710606003 A CN 201710606003A CN 107216298 A CN107216298 A CN 107216298A
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- WMBOCUXXNSOQHM-FLIBITNWSA-N CCC/C=C(/c1ccccc11)\OC1=O Chemical compound CCC/C=C(/c1ccccc11)\OC1=O WMBOCUXXNSOQHM-FLIBITNWSA-N 0.000 description 3
- LKHZIZSYUWCUAW-UHFFFAOYSA-N C[O](C(c1ccccc11)=O)C1=O Chemical compound C[O](C(c1ccccc11)=O)C1=O LKHZIZSYUWCUAW-UHFFFAOYSA-N 0.000 description 2
- 0 CCCC*C(c1ccccc11)OC1=O Chemical compound CCCC*C(c1ccccc11)OC1=O 0.000 description 1
- HJXMNVQARNZTEE-UHFFFAOYSA-N CCCCC(c1c2cccc1)OC2=O Chemical compound CCCCC(c1c2cccc1)OC2=O HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 description 1
- IEZTYUMJKFZPEW-UHFFFAOYSA-N CCCCC(c1ccccc1C(O)=O)O Chemical compound CCCCC(c1ccccc1C(O)=O)O IEZTYUMJKFZPEW-UHFFFAOYSA-N 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N O=C(c1ccccc11)OC1=O Chemical compound O=C(c1ccccc11)OC1=O LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- YSZZIRWBOXXOIJ-UHFFFAOYSA-N O=C1OCC2C1=CC=CC2 Chemical compound O=C1OCC2C1=CC=CC2 YSZZIRWBOXXOIJ-UHFFFAOYSA-N 0.000 description 1
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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
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Abstract
The invention provides a kind of preparation method of butylphenyl phthaleine, 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, sodium hydroxide and water hybrid reaction, then with dichloromethane washing reaction system, alcoholic solvent is added, after acid adjustment reaction, 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 is used as reaction or extractant using alcoholic solvent, dichloromethane, it can effectively be reclaimed and cheap, greatly reduce production cost, pass through hydrolysising purification, acid adjustment Purification by filtration again, the butylphenyl phthaleine for meeting formulation requirements for obtaining high-purity of higher yields can be obtained, it is simple to operate without rectification under vacuum step.
Description
Technical field
The invention belongs to technical field of medicine synthesis, more particularly to a kind of preparation method of butylphenyl phthaleine.
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.
A kind of preparation method of high purity butylene phthalide is disclosed in Publication No. CN105859670A Chinese patent, by fourth
Phthalide crude product is depressurized under vacuum 1-2mbar, collects 130~140 DEG C of cuts；The cut is added inorganic base is used in methanol
Hydrolysis, concentration removes methanol, and addition dichloromethane stirring separates out solid and obtains hydroxyl amyl group benzoate；Sylvite after then will be refined
It is added to the water, cyclization is acidified at 30~45 DEG C of temperature and obtains butylphenyl phthaleine, HPLC purity >=99.90%.But this method still needs to lead to
A rectification under vacuum is crossed, qualified butylphenyl phthaleine is obtained passing through into salt, dichloromethane washing, is not avoided that the mistake of rectification under vacuum
Journey.
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 butylphenyl phthaleine, and this method is received
Rate is higher, purity is higher and without rectifying.
The invention provides a kind of preparation method of butylphenyl phthaleine, 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, sodium hydroxide and water hybrid reaction, then with dichloromethane washing reaction system,
Alcoholic solvent is added, after acid adjustment reaction, the second intermediate is obtained；
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 and water is 1g：(2~20) ml；First intermediate and alcohol are molten
The mass volume ratio of agent is 1g：(0.1~1) ml；The mass volume ratio of the butylidene phthalide and dichloromethane is 1g：(2~
20)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) it is middle using glacial acetic acid acid adjustment；Acid adjustment to pH value is 4~6；The temperature of acid adjustment reaction is 0
DEG C~20 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：
First intermediate, sodium hydroxide and water are blended in 10 DEG C~80 DEG C reactions, reaction makes system temperature after terminating
Spend for 10 DEG C~30 DEG C, then with dichloromethane washing reaction system, add alcoholic solvent, after acid adjustment reaction, obtain in second
Mesosome.
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 obtains butylbenzene
Phthalein.
The invention provides a kind of preparation method of butylphenyl phthaleine, including：S1) using Raney's nickel as catalyst, by cyclobutenyl benzene
Phthalein is carried out after hydrogenation reaction, removal of solvent under reduced pressure in alcoholic solvent, obtains the first intermediate；S2) by first intermediate, hydrogen
Sodium oxide molybdena and water hybrid reaction, then with dichloromethane washing reaction system, add alcoholic solvent, after acid adjustment reaction, obtain the
Two intermediates；S3 second intermediate) is subjected to cyclization reaction in acid organic solvent, butylphenyl phthaleine is obtained.With it is existing
Technology is compared, the present invention using alcoholic solvent, dichloromethane as reaction or extractant, its can effectively reclaim and price just
Preferably, production cost is greatly reduced, then by hydrolysising purification, acid adjustment Purification by filtration, you can obtain higher yields obtains high-purity
The butylphenyl phthaleine for meeting formulation requirements, it is simple to operate without rectification under vacuum step.
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 4；
Fig. 2 is the HPLC collection of illustrative plates of the first intermediate obtained in the embodiment of the present invention 5；
Fig. 3 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 butylphenyl phthaleine, including：S1) using Raney's nickel as catalyst, by cyclobutenyl benzene
Phthalein is carried out after hydrogenation reaction, removal of solvent under reduced pressure in alcoholic solvent, obtains the first intermediate；S2) by first intermediate, hydrogen
Sodium oxide molybdena and water hybrid reaction, then with dichloromethane washing reaction system, add alcoholic solvent, after acid adjustment reaction, obtain the
Two intermediates；S3 second intermediate) is subjected to cyclization reaction in acid organic solvent, butylphenyl phthaleine is obtained.
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, sodium hydroxide and water hybrid reaction, preferably first sodium hydroxide is mixed with water, Ran Hou
Under conditions of stirring, the first intermediate is added dropwise；The mass volume ratio of first intermediate and water is preferably 1g：(2~20) ml,
More preferably 1g：(3~15) ml, is further preferably 1g：(3~10ml), is further preferably 1g：(3~8ml), most preferably 1g：(4~
6ml)；The temperature of the hybrid reaction is preferably 10 DEG C~80 DEG C, and more preferably 35 DEG C~80 DEG C, be further preferably 50 DEG C~60
℃；The time of the hybrid reaction is preferably 1~3h, more preferably 2~3h, is further preferably 2h.
After reaction terminates, preferably make the temperature of reaction system for 10 DEG C~30 DEG C, more preferably 20 DEG C~30 DEG C, further preferably
For 20 DEG C~25 DEG C, then with dichloromethane washing reaction system, yellow clear liquid is obtained；Alcoholic solvent is added, acid adjustment carries out anti-
Should；The alcoholic solvent is alcoholic solvent well known to those skilled in the art, and it is preferably second to have no in special limitation, the present invention
Alcohol, more preferably absolute ethyl alcohol；The mass volume ratio of first intermediate and alcoholic solvent is preferably 1g：(0.1~1) ml, more
Preferably 1g：(0.2~0.8) ml, is further preferably 1g：(0.3~0.5) ml；The acid adjustment is preferred to use organic acid progress, more excellent
Choosing uses glacial acetic acid；The acid adjustment preferably makes the pH value of reaction system be 4~6, more preferably 5~6, is further preferably 6；It is described to adjust
The temperature of acid reaction is preferably 0 DEG C~20 DEG C, and more preferably 0 DEG C~15 DEG C, be further preferably 0 DEG C~10 DEG C.Acid adjustment reaction terminates
Afterwards, preferably filter, more preferably carry out rejection filter, obtain the second intermediate, i.e. hydroxyl amyl group benzoic acid.
Second intermediate is subjected to cyclization reaction in acid organic solvent；Wherein, the organic solvent is this
Organic solvent known to art personnel, it is preferably dichloromethane to have no in special limitation, the present invention；The acidity
Organic solvent preferably use inorganic acid provide acid condition, more preferably using hydrochloric acid provide acid condition；The cyclization reaction
Temperature be preferably 20 DEG C~40 DEG C, more preferably 25 DEG C~35 DEG C；The pH value of the cyclization reaction is preferably 1~4, more preferably
It is further preferably 1~2 for 1~3；In the present invention, the step is preferably specially：By second intermediate in the organic of acidity
Carried out in solvent after cyclization reaction, 0.5~2h of reaction, preferably react after 0.5~1h, separate organic layer, then add organic solvent,
Continue to react, finally merge organic layer, obtain organic phase；The organic phase is washed through weakly alkaline solution successively, washed, is dried
After agent is dried, recycling design obtains butylphenyl phthaleine.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, is had no excellent in special limitation, the present invention
Elect weak aqua ammonia as；The drier is drier well known to those skilled in the art, is had no in special limitation, the present invention
Preferably anhydrous calcium chloride；The method of the recycling design is method well known to those skilled in the art, and it is special to have no
It is preferably the recycling design that is concentrated under reduced pressure in limitation, the present invention.In this step, the second intermediate is added portionwise, because reaction is begun
It is in eventually under sour environment, the direct cyclization of the second intermediate does not interfere with stirring.
The present invention goes the removal of impurity using water as hydrolysis solvent by dichloromethane extraction, then by ethanol acid adjustment analysis
Go out the second intermediate, Purification by filtration also functions to Refinement, be not required to further refine, can obtain meeting system after acidifying cyclization
The butylphenyl phthaleine bulk drug of agent requirement.
The preparation technology for the butylphenyl phthaleine that the present invention is provided is as follows：
The present invention is using alcoholic solvent, dichloromethane as reaction or extractant, and it can effectively be reclaimed and cheap,
Production cost is greatly reduced, then by hydrolysising purification, acid adjustment Purification by filtration, you can obtain the symbol for obtaining high-purity of higher yields
The butylphenyl phthaleine of formulation requirements is closed, it is simple to operate without rectification under vacuum step.Also, the present invention is tested by lab scale, the technique of pilot scale
Card, 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, a kind of preparation method of the butylphenyl phthaleine provided with reference to embodiments the present invention is entered
Row is described in detail.
Reagent used is commercially available in following examples.
The preparation and distillation of the butylidenephthalide of embodiment 1 (DBT-1)
By valeric anhydride 93.12g, phthalic anhydride 111.09g, natrium valericum 24.82g is added in 1L reaction bulbs, stirring
It is well mixed, it is heated to 170 DEG C or so and carries out reaction 1h；Then add natrium valericum 24.82g, then be warming up to 190 DEG C or so, after
Continuous insulation reaction 3h；Reaction is finished, and system is cooled into 100 DEG C or so, and 186mL deionized waters are added dropwise, and continues to be heated to backflow, after
Room temperature is down in continuous backflow 1h, cooling；Control system temperature adjusts pH to 9, dichloromethane 450mL at 25 DEG C or so using concentrated ammonia liquor
Extract three times, washed twice using 150mL weak aqua ammonias (1%), 150mL deionized waters are washed twice, anhydrous calcium chloride is dried；Take out
Filter, removes drier, and concentration and recovery dichloromethane obtains dark red oil, and 20cm lunge types rectifying column carries out vacuum distillation,
140~145 DEG C/2~3mmHg cuts are collected, 62.88g yellow oily liquids, as butylidenephthalide (DBT-1) is obtained.
The butylidenephthalide (DBT-1) obtained in embodiment 1 is analyzed using high performance liquid chromatography, its (Z/E) purity
98.196% (HPLC) left and right, larger impurity is descending to be arranged as 1.083%, 0.449%, 0.058%, the step yield
74.8%.
The preparation of the hydroxyl amyl group benzoic acid (DBT-2) of embodiment 2
Absolute ethyl alcohol 240mL, butylidene phthalide (DBT-1) 60.00g are added into 1L hydriding reactors, Raney's nickel (wet) is added
9.00g, carries out 4 hydrogen and exchanges exclusion air.Temperature is heated to 25~35 DEG C, 2.5 atmospheric pressure (2.5kg/ of Stress control
cm2) carry out hydrogenation reaction, untill hydrogen is not inhaled, about 2h；Catalyst is removed, be concentrated under reduced pressure ethanol, obtains pale yellow oily liquid
As the first intermediate, purity 96.324%.
300ml deionized waters, sodium hydroxide 13.20g are added into 1L reaction bulbs, stirring and dissolving is added above-mentioned faint yellow
Oily liquids, 50~60 DEG C of temperature control reacts about 2h；Reaction is finished, and is cooled to 20 DEG C or so and is extracted three times with 300ml dichloromethane,
30mL absolute ethyl alcohols are added in aqueous phase, pH=6 is adjusted with glacial acetic acid, suction filtration obtains the second intermediate (DBT- with 30ml water washing filter cakes
2)。
The preparation and rectifying of the butylphenyl phthaleine of embodiment 3 (DBT)
120ml 2N hydrochloric acid, 120ml dichloromethane are added into 1L reaction bulbs, pH=1~2 are adjusted, 25~35 DEG C of temperature control it
Between；It is that the second intermediate (DBT-2) is added in reaction system in batches by Hydroxy pentyl benzoic acid, 25~35 DEG C of control system temperature
Between, react 30min.Dichloromethane layer is separated, continues to add between 120ml dichloromethane, 25~35 DEG C of control system temperature,
Control between pH 1~2, continue to react 30min.Merge organic layer, washed using weak aqua ammonia, deionized water washing, anhydrous chlorination
Calcium is dried；Be concentrated under reduced pressure recycling design, obtains 26.43g pale yellowish oils liquid as butylphenyl phthaleine.
The butylphenyl phthaleine obtained in embodiment 3 is analyzed using high performance liquid chromatography, its purity 99.718% is obtained, most
It is big by single miscellaneous 0.070%.Refined yield：43.6%.
The preparation and distillation of the butylidenephthalide of embodiment 4 (DBT-1)
By valeric anhydride 441.41g, phthalic anhydride 386.59g, natrium valericum 117.81g is added in 5L reaction bulbs, stirred
Mix well mixed, be heated to 170 DEG C or so and carry out reaction 1h；Then add natrium valericum 118.00g, then be warming up to 190 DEG C or so,
Continue insulation reaction 3h；Reaction is finished, and system is cooled into 100 DEG C or so, and 1L deionized waters are added dropwise, and continues to be heated to backflow, after
Room temperature is down in continuous backflow 1h, cooling；Control system temperature adjusts pH to 9, dichloromethane 2.5L at 25 DEG C or so using concentrated ammonia liquor
Extract three times, washed twice using 1L weak aqua ammonias (1%), 1L deionized waters are washed twice, 100g anhydrous calcium chlorides are dried；Take out
Filter, removes drier, and concentration and recovery dichloromethane obtains dark red oil, and 20cm lunge types rectifying column carries out vacuum distillation,
140~145 DEG C/2~3mmHg cuts are collected, 339.66g yellow oily liquids, as butylidenephthalide (DBT-1) is obtained.
The butylidenephthalide (DBT-1) obtained in embodiment 1 is analyzed using high performance liquid chromatography, its HPLC figures are obtained
Spectrum, as shown in Figure 1.As shown in Figure 1, its (Z/E) purity 98.367% (HPLC) left and right, larger impurity is descending to be arranged as
0.870%th, 0.116%, 0.471%, the step yield 76.1%.
The preparation of the hydroxyl amyl group benzoic acid (DBT-2) of embodiment 5
Absolute ethyl alcohol 1300mL, butylidene phthalide (DBT-1) 325.00g are added into hydriding reactor, Raney's nickel (wet) is added
48.75g, carries out 4 hydrogen and exchanges exclusion air.Temperature is heated to 25~35 DEG C, 2.5 atmospheric pressure of Stress control
(2.5kg/cm2) carry out hydrogenation reaction, untill hydrogen is not inhaled, about 3h；Catalyst is removed, be concentrated under reduced pressure ethanol, obtains faint yellow
Oily liquids is the first intermediate, purity 97.893%.
1600ml deionized waters, sodium hydroxide 71.20g are added into 3L reaction bulbs, stirring and dissolving is added above-mentioned faint yellow
Oily liquids, 50~60 DEG C of temperature control reacts about 2h；Reaction is finished, and is cooled to 20 DEG C or so and is extracted three times with 1600ml dichloromethane,
160mL absolute ethyl alcohols are added in aqueous phase, pH=6 is adjusted with glacial acetic acid, suction filtration obtains the second intermediate with 160ml water washing filter cakes
(DBT-2)。
The first intermediate obtained in embodiment 2 is analyzed using high performance liquid chromatography, its HPLC collection of illustrative plates is obtained, such as
Shown in Fig. 2.
The preparation and rectifying of the butylphenyl phthaleine of embodiment 6 (DBT)
650ml 2N hydrochloric acid, 650ml dichloromethane are added into 2L reaction bulbs, pH=1~2 are adjusted, 25~35 DEG C of temperature control it
Between；It is that the second intermediate (DBT-2) is added in reaction system in batches by Hydroxy pentyl benzoic acid, 25~35 DEG C of control system temperature
Between, react 30min.Dichloromethane layer is separated, continues to add between 325ml dichloromethane, 25~35 DEG C of control system temperature,
Control between pH 1~2, continue to react 30min.Merge organic layer, washed using weak aqua ammonia, deionized water washing, anhydrous chlorination
Calcium is dried；Be concentrated under reduced pressure recycling design, obtains 190.2g pale yellowish oils liquid as butylphenyl phthaleine.
The butylphenyl phthaleine obtained in embodiment 3 is analyzed using high performance liquid chromatography, its HPLC collection of illustrative plates, such as Fig. 3 is obtained
It is shown.From the figure 3, it may be seen that its purity 99.823%, maximum single miscellaneous 0.088%, total miscellaneous 0.177%.Refined yield：57.9%.
Claims (10)
1. a kind of preparation method of butylphenyl phthaleine, 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, sodium hydroxide and water hybrid reaction, then with dichloromethane washing reaction system, then add
Enter alcoholic solvent, after acid adjustment reaction, obtain the 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 mass volume ratio of first intermediate and water is
1g：(2~20) ml；The mass volume ratio of first intermediate and alcoholic solvent is 1g：(0.1~1) ml；The butylidene phthalide and two
The mass volume ratio of chloromethanes is 1g：(2~20) 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) it is middle using glacial acetic acid acid adjustment；Acid adjustment
It is 4~6 to pH value；The temperature of acid adjustment reaction is 0 DEG C~20 DEG C.
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：
First intermediate, sodium hydroxide and water are blended in 10 DEG C~80 DEG C reactions, reaction makes the system temperature be after terminating
10 DEG C~30 DEG C, then with dichloromethane washing reaction system, alcoholic solvent is added, after acid adjustment reaction, the second intermediate is obtained.
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 obtains butylphenyl phthaleine.
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| 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 |
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| CN114073694A (en) * | 2020-08-14 | 2022-02-22 | 北京科莱博医药开发有限责任公司 | Butylphthalide preparation and preparation method thereof |
| CN114073694B (en) * | 2020-08-14 | 2024-03-12 | 北京科莱博医药开发有限责任公司 | Butylphthalide preparation and preparation method thereof |
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