CN104876951B - Preparation method for puerarin morphine - Google Patents
Preparation method for puerarin morphine Download PDFInfo
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- CN104876951B CN104876951B CN201510274941.9A CN201510274941A CN104876951B CN 104876951 B CN104876951 B CN 104876951B CN 201510274941 A CN201510274941 A CN 201510274941A CN 104876951 B CN104876951 B CN 104876951B
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Abstract
The invention discloses a preparation method for puerarin morphine. The preparation method comprises the following steps: (1) the synthesis of puerarin, to be specific, 1) preparing a compound 2 by taking a compound 1 as a raw material; 2) modifying the compound 2 to prepare a compound 3; 3) removing hydroxide radicals of the compound 3 to prepare a compound 4; 4) enabling the compound 4 to react with p-methoxyphenylacetyl chloride to prepare a compound 5; 5) reducing the compound 5 into a compound 6 through boron tribromide; 6) synthesizing the puerarin by taking the compound 6 as a raw material; (2) the synthesis of puerarin morphine. Through the use of the puerarin morphine, the dosage of morphine is reduced, the addiction and tolerance of the morphine are reduced, side effects of the morphine in the aspects of the respiratory system, cardiovascular system and central nervous system are effectively slowed down, and the puerarin morphine can be used for pain treatment as a substitute for morphine.
Description
Technical field
The present invention relates to a kind of puerarin morphine, specifically a kind of preparation method of puerarin morphine.
Background technology
Pain is a kind of common sympton of numerous disease.In terms of the treatment of pain, clinical conventional medicine mainly includes
Narcosis analgesic, antipyretic analgesic, antineuralgic, five big class of antimigraine and spasmolytic analgesic.Narcosis analgesic
By the opiate receptor of excitomotor center nervous system specific part, analgesic activity is produced, while can keeping tensions down and uneasy emotion.
Typical Representative of the morphine as such medicine, can alleviate the pain of a variety of causes, the features such as with acting on strong, always clinical wide
The first-selected narcotic analgesic medicine of general application.However, life-time service morphine can produce serious toleration and additive.To understand
Determine this problem, studied and the structure of morphine has been modified in terms of the modification of function base and skeleton transform two respectively.
As a result find：Morphine molecule C3The additive reduction of upper phenolic hydroxyl group etherification product, but analgesic effect also reduced simultaneously；C3And C6Upper hydroxyl
The acylated derivatives analgesia of base is strong compared with morphine with anesthetic action, but toxicity is also big compared with morphine 5-10 times, additive and euphoria
It is even more serious；N17On methyl when being that other larger alkyl replace, general analgesic activity weakens；C7-C8Between double bond quilt
Reduction, then obtain the potent antagonist Allylnoroxymorphone of the analgesics such as morphine.By morphine skeleton structure morphine hydrocarbon is simplified,
A series of benzos can be synthesized to mutter skeleton derivative, the medicine that analgesic activity is remarkably reinforced is obtained.However, the studies above not from
Fundamentally solve the problems, such as that Morphinoid drug is additive strong.From additive and toleration the reason for angle analysis, morphine enters body
It is interior to form metabolite morphine ketone through liver metabolism.The material can be with the irreversible tight knot of the sulfydryl on opiate receptor
Close, so as to block the analgesic activity of morphine, cause tolerance and addiction.The further metabolism of hydromorphone, a part can also be transformed into
For hydromorphone albumen.The albumen still can be combined closely with opiate receptor and be produced tolerance and addiction.Therefore, hydromorphone is morphine
Tolerance and addicted key substance.From mechanism of action angle analysis, the additive mechanism of morphine includes three aspects：One is
The impact that coffee is discharged to enkephalin；Two is the impact that morphine and enkephalin discharge to blue speckle core；Three is that prolonged application morphine can press down
The release of the neurotransmitteies such as intracerebral norepinephrine processed, dopamine, 5-hydroxy tryptamine and cyclic adenosine monophosphate, so as to increase mediator pair
The sum of active acceptor is answered, receptor sensitivity is reduced, the effect decay of morphine is finally resulted in.
On the basis of the studies above, in order to solve the additive and problem of resistance of morphines analgesics, existing research
Main being made that in terms of transformation morphine structure synthesizes its derivant and use in conjunction other drugs carry out compound medicine two is tasted
Examination.It is additive strong that the synthesis of modification and series derivates to morphine framing structure does not inherently solve morphines analgesics
Problem.Polypharmacy cardinal principle be using other Chinese medicine monomer or other chemicalses suppress internal hydromorphones generation or
Blue speckle core electric discharge reduces morphine and addicted purpose.The medicine of achievable this purpose includes ginsenoside and Liang
The chemicalses such as the Chinese medicine monomer such as henbane alkali and clonidine, verapamil and Propranolol.Although this medication consideration can be reduced
The consumption of morphine, but the complexity of Drug use administration is increased, while preventing new side effect again.
So far, the additive strong problem of Morphinoid drug is still field of medicaments hot research urgently to be resolved hurrily.
The content of the invention
It is an object of the invention to provide a kind of preparation method of puerarin morphine, to solve to propose in above-mentioned background technology
Problem.
For achieving the above object, the present invention provides following technical scheme：
A kind of preparation method of puerarin morphine, comprises the following steps：
(1) synthesis step of puerarin：
1) with compound 1 as raw material prepare compound 2：In 500mL there-necked flasks add 300mL anhydrous methylene chlorides and
The compound 1 of 27.0g, 50.0mmol, under agitation, is dividedly in some parts 8.8g, 75.0mmol NMO, stirring reaction 20min, then
Add 0.88g, the catalyst of 2.5mmol continues stirring reaction 2h at room temperature, reactant liquor 500mL dchloromethanes,
Kieselguhr is filtered, and filtrate is washed 2 times with the hypo solution of excess saturation, then with saturated common salt water washing 1 time, anhydrous sulfur
Sour sodium is dried, and evaporated under reduced pressure, column chromatography purification obtain compound 2；
2) compound 2 is carried out modifying prepare compound 3：Polar non-solute is dissolved in the anhydrous THF of 200mL,
- 78 DEG C are cooled under nitrogen protection, the organolithium reagent solution of 2.5mol/L, 17.6mL are added dropwise in above solution at a slow speed,
And at -78 DEG C stirring reaction 1h, then rise at a slow speed 0 DEG C of stirring reaction 1h, reactant liquor is cooled to -78 DEG C, by 21.5g,
The compound 2 of 40.0mmol is dissolved in 100mL THF, and is dropped in above-mentioned solution at a slow speed, and reaction stirs 1h at -78 DEG C,
Then with the quenching reaction of saturation ammonium chloride solution, then room temperature is warming up to, continuously adds 200mL water, with 2 × 200mL ethyl acetate
Extraction, merges organic faciess, then with 200mL saturated common salt water washings, anhydrous Na2SO4It is dried, vacuum distillation, Purified on column chromatography
Purification obtains final product compound 3；
3) compound 3 sloughs hydroxyl prepare compound 4：In 500mL there-necked flasks add 300mL anhydrous methylene chlorides and
20.3g, 30.0mmol compound 3, and be cooled to -20 DEG C, under agitation, first adds at a slow speed 7.0g, the reducing agent of 60.0mmol,
Deca 34.2g at a slow speed, 300.0mmol trifluoroacetic acids, after completion of dropping, continue stirring at room temperature and terminate to reaction, reduce pressure again
Distillation, gained grease 200mL ethyl acetate are dissolved, and successively with 50mL saturated common salt water washings, 50mL saturated sodium carbonates are molten
Liquid is washed, then with 50mL saturated common salt water washings, evaporated under reduced pressure obtains compound 4；
4) compound 4 reacts prepare compound 5 with acetanisole chlorine：250mL is added in 500mL there-necked flasks
Anhydrous methylene chloride is simultaneously cooled to 0 DEG C, by 3.7g, 4 points of the compound of the anhydrous catalyst of 27.5mmol and 16.5g, 25.0mmol
Above-mentioned solution is not added, under agitation, is added to 5.1g at a slow speed, the 50mL dichloromethane of 27.5mmol methoxyphenylacetyl chlorides is molten
Liquid, after completion of dropping, is stirred at room temperature overnight, and reactant liquor is poured at a slow speed 200mL into and is cooled in 0 DEG C of 1NHC1 solution, separates
Organic faciess, water are mutually extracted with 200mL dichloromethane, merge organic faciess, with 2 × 100mL saturated common salt water washings, anhydrous sodium sulfate
It is dried, evaporated under reduced pressure, crude product column chromatography purification obtain compound 5；
5) 5 Jing Boron tribromides of compound are reduced to compound 6：16.2g, 20.0mmol are added in 500mL there-necked flasks
Compound 5 and 200mL anhydrous methylene chlorides are simultaneously cooled to -78 DEG C, under nitrogen protection by the BBr of 1.0mol/L, 200mL3Two
Chloromethanes solution is dropped in above-mentioned solution, after completion of dropping at a slow speed, reacts 1h, then be slowly warmed to room temperature at -78 DEG C, stirring
Reaction 2h, reactant liquor is poured in 400mL frozen water at a slow speed, separates organic faciess, and water is mutually extracted with 3 × 200mL dichloromethane, is merged
Organic faciess, with 2 × 200mL saturated common salt water washings, anhydrous sodium sulfate drying, evaporated under reduced pressure, crude product column chromatography purification must be changed
Compound 6；
6) with compound 6 as Material synthesis puerarin：4.1g, 10.0mmol compounds 6 are dissolved in 50mL DMF, are being stirred
Mix it is lower 10mL DMFDMA are dropped in above-mentioned solution, after adding at a slow speed, reaction is stirred at room temperature to reaction and terminates, and reduces pressure
Distillation, gained crude product column chromatography purification obtain puerarin；
(2) synthesis step of puerarin morphine：5mL anhydrous methylene chlorides, 292mg are sequentially added in 25mL flasks,
0.5mmol compounds 9,83mg, 0.6mmol bromoacetic acids, 77mg, 0.6mmol DIEA and 228mg, 0.6mmolHATU, in room temperature
Under be stirred overnight, vacuum distillation, crude product column chromatography are purified, and anhydrous 3mL DMF, 86mg are sequentially added in 8mL flasks,
0.3mmol morphines, 41mg, the K of 0.3mmol2CO3And 212mg, 0.3mmol compound 10A or compound 10B, stir at room temperature
Mix overnight, add 3mL methanol, continue to be stirred overnight, reactant liquor adjusts pH to 6.5-7.5 with 1N hydrochloric acid solutions, filter, filtrate subtracts
Pressure distillation, crude product thin layer chromatography or preparative liquid chromatography purification, obtain puerarin morphine compounds 11A and compound 11B.
As further scheme of the invention：Catalyst described in the synthesis step (1) of the puerarin is four oxidations
One kind in osmium, N-methylmorpholine N- oxides and TPAP or wherein combination in any, reaction substrate mol ratio are 1:30, reaction temperature
Spend for room temperature.
As further scheme of the invention：Organolithium reagent described in the synthesis step (2) of the puerarin is
It is a kind of in n-BuLi, lithium methide, phenyl lithium；Described polar non-solute is the one kind in a phenylene dimethyl ether and TMEDA
Or its combination, it is described between phenylene dimethyl ether be 6.1g, 44.0mmol, TMEDA are 5.1g, 44.0mmol, and reaction mol ratio is 1:1.
As further scheme of the invention：Reducing agent described in the synthesis step (3) of the puerarin is three second
One kind in base silane, tri-phenyl-silane and trimethyl silane.
As further scheme of the invention：Catalyst described in the synthesis step (4) of the puerarin is trichlorine
Change any one in aluminum, borontrifluoride yttrium or borontrifluoride dysprosium.
As further scheme of the invention：In the synthesis step of the puerarin morphine, the bromoacetic acid, DIEA,
Reaction mol ratio with HATU is 1:1:1.
As further scheme of the invention：The consumption using reduction morphine of the puerarin morphine, reduces morphine
Additive and toleration, effectively slow down side effect of the morphine in terms of respiratory system, cardiovascular system and central nervous system,
Puerarin morphine carries out the treatment of pain as the succedaneum of morphine.
Compared with prior art, the invention has the beneficial effects as follows：The puerarin morphine of the present invention is one and has brand-newization
The noval chemical compound of structure is learned, its analgesic activity is suitable with morphine, but can effectively reduce the consumption of morphine, so as to reduce morphine
The purpose of additive and tolerance, while can also reduce morphine in terms of respiratory system, cardiovascular system and central nervous system
Side effect.
Description of the drawings
Synthetic route charts of the Fig. 1 for puerarin.
Synthetic route charts of the Fig. 2 for puerarin morphine.
Specific embodiment
Below in conjunction with the accompanying drawing in the embodiment of the present invention, the technical scheme in the embodiment of the present invention is carried out clear, complete
Site preparation is described, it is clear that described embodiment is only a part of embodiment of the invention, rather than the embodiment of whole.It is based on
Embodiment in the present invention, it is every other that those of ordinary skill in the art are obtained under the premise of creative work is not made
Embodiment, belongs to the scope of protection of the invention.
Fig. 1～2 are referred to, in the embodiment of the present invention, a kind of preparation method of puerarin morphine is comprised the following steps：
(1) synthesis step of puerarin：
1) 300mL anhydrous methylene chlorides and 27.0g, 50.0mmol raw material 1 are added in 500mL there-necked flasks, in stirring
Under, 8.8g is dividedly in some parts, then 75.0mmol NMO, stirring reaction 20min add 0.88g, 2.5mmol TPAP, in room
Temperature is lower to continue stirring reaction 2h, and reactant liquor 500mL dchloromethanes, kieselguhr are filtered, and filtrate is thio with excessive saturation
Metabisulfite solution is washed 2 times, then with saturated common salt water washing 1 time, anhydrous sodium sulfate drying, evaporated under reduced pressure, column chromatography purification are obtained
Target product；
2) by 6.1g, between 44.0mmol, phenylene dimethyl ether and 5.1g, 44.0mmol TMEDA are dissolved in the anhydrous THF of 200mL,
- 78 DEG C are cooled under nitrogen protection, 2.5mol/L, the n-BuLi hexane solution of 17.6mL are added dropwise at a slow speed above solution
In, and stirring reaction 1h at -78 DEG C, then 0 DEG C of stirring reaction 1h is risen at a slow speed, and reactant liquor is cooled to -78 DEG C, by 21.5g,
40.0mmol raw materials 2 are dissolved in 100mL THF, and are dropped in above-mentioned solution at a slow speed, and 1h is stirred in reaction at -78 DEG C, then
Reacted with the quenching of saturation ammonium chloride solution, then be warming up to room temperature, continuously add 200mL water, extracted with 2 × 200mL ethyl acetate,
Merge organic faciess, then with 200mL saturated common salt water washings, anhydrous Na2SO4 is dried, vacuum distillation, Purified on column chromatography purification
Obtain final product target product；
3) addition 300mL anhydrous methylene chlorides and 20.3g, 30.0mmol raw material 3 in 500mL there-necked flasks, and cool down
To -20 DEG C, under agitation, 7.0g, 60.0mmol triethyl silicanes, then Deca 34.2g at a slow speed, 300.0mmol are added at a slow speed first
Trifluoroacetic acid, after completion of dropping, continues stirring at room temperature and terminates to reaction, vacuum distillation, gained grease 200mL acetic acid
Ethyl ester dissolves, successively with 50mL saturated common salt water washings, the washing of 50mL saturated sodium carbonate solutions, then washed with 50mL saturated common salts
Wash, evaporated under reduced pressure obtains target product；
4) add in 500mL there-necked flasks and 250mL anhydrous methylene chlorides be cooled to 0 DEG C, by anhydrous 3.7g,
27.5mmol AlCl3And 16.5g, 25.0mmol raw material 4 is separately added into above-mentioned solution, under agitation, added to 5.1g at a slow speed,
The 50mL dichloromethane solutions of 27.5mmol methoxyphenylacetyl chlorides, after completion of dropping, are stirred at room temperature overnight, and reactant liquor is slow
Speed is poured 200mL into and is cooled in 0 DEG C of 1N HC1 solution, separates organic faciess, and water is mutually extracted with 200mL dichloromethane, is associated with
Machine phase, with 2 × 100mL saturated common salt water washings, anhydrous sodium sulfate drying, evaporated under reduced pressure, crude product column chromatography purification obtain target
Product；
5) 16.2g, 20.0mmol raw materials 5 and 200mL anhydrous methylene chlorides are added in 500mL there-necked flasks and is cooled down
To -78 DEG C, under nitrogen protection by the BBr of 1.0mol/L, 200mL3Dichloromethane solution is dropped in above-mentioned solution at a slow speed, drop
Add after finishing, 1h is reacted at -78 DEG C, then is warmed to room temperature at a slow speed, stirring reaction 2h is poured at a slow speed 400mL frozen water by reactant liquor
In, separating organic faciess, water is mutually extracted with 23 × 200mL chloromethanes, merges organic faciess, with 2 × 200mL saturated common salt water washings,
Anhydrous sodium sulfate drying, evaporated under reduced pressure, crude product column chromatography purification obtain target product；
6) by 4.1g, 10.0mmol raw materials 6 are dissolved in 50mL DMF) in, under agitation 10mL DMFDMA are dropped at a slow speed
In above-mentioned solution, after adding, reaction is stirred at room temperature to reaction and terminates, and vacuum distillation, gained crude product column chromatography purification are obtained
Target product.
(2) synthesis step of puerarin morphine：5mL anhydrous methylene chlorides, 292mg are sequentially added in 25mL flasks,
0.5mmol compounds 9,83mg, 0.6mmol bromoacetic acids, 77mg, 0.6mmol DIEA and 228mg, 0.6mmolHATU, in room temperature
Under be stirred overnight, vacuum distillation, crude product column chromatography are purified, and anhydrous 3mL DMF, 86mg are sequentially added in 8mL flasks,
0.3mmol morphines, 41mg, the K of 0.3mmol2CO3And 212mg, 0.3mmol compound 10A or compound 10B, stir at room temperature
Mix overnight, add 3mL methanol, continue to be stirred overnight, reactant liquor adjusts pH to 6.5-7.5 with 1N hydrochloric acid solutions, filter, filtrate subtracts
Pressure distillation, crude product thin layer chromatography or preparative liquid chromatography purification, obtain puerarin morphine compounds 11A and compound 11B.
Neuropathic pain is treated using puerarin morphine compounds：
1st, experimental technique：
1.1st, the foundation of sciatic nerve spinal cord in chronic compression (CCI) model：Mouse peritoneal injection Ethylurethanm (1.4g/kg) is anaesthetized
Afterwards, right hind top skin is cut, blunt separation biceps femoris exposes sciatic nerve trunk.With 8-0 chromic sutures in ischium
3 unijunctions are gently ligatured on nerve, central spacer 1mm is ligatured, the tightness of ligation button slight shrinkage occurs with right hind and is advisable.
After the completion of operation, suture muscles and skin, the prevention infection of lumbar injection penicillin are layered.Carry out hot-plate within postoperative 1 week.
1.2nd, experiment packet and medication：CCI model mices are randomly divided into into 5 groups, 8 per group, respectively physiology salt
Water matched group, 10mg/kg injection of morphia groups, 5.0mg/kg puerarin injection of morphia groups, 10mg/kg puerarin injection of morphia groups,
20mg/kg puerarin injection of morphia groups.All medicines pass through lumbar injection.
1.3rd, hot-plate：CCI model mices are placed on the cold-hot plate dolorimeter that panel temperature is 55 ± 0.3 DEG C,
To lift foot or lick foot as pain reaction index, before the administration of dynamic measurement mice and 15,30,45,60,75 and 90min after administration
Paw withdrawal incubation period (s) of Ipsilateral sole.Each point survey observing time 3 times (interval 2min), takes its meansigma methods as pain threshold.
1.4th, statistical analysis：Experimental data is with mean ± standard errorRepresent, it is soft using Sigmastat 2.03
The One-way ANOVA analysis model group mices of part and the difference of the control group mice threshold of pain；Two way RM ANOVA
Difference between (Bonferroni t-test) statistical analysiss different dosing group and between different time points each group.P<0.05 is poor
It is different statistically significant.
2nd, experimental result：
2.1st, the thermal hyperalgesia of CCI inductions：After performing the operation 1 week, the average paw withdrawal of CCI model mices is determined using hot plate method
Incubation period is 6.76 ± 0.24s, hence it is evident that less than paw withdrawal 13.26 ± 0.48s incubation period of control group mice, One-way ANOVA
Analysis shows that difference has statistical significance (P<0.001), CCI neuropathic pain model mices are pointed out to be successfully established.
2.2nd, analgesic activity of the puerarin morphine compounds to CCI model mices：1 result of table shows that abdominal cavity is individually injected
10mg/kg morphines are remarkably improved paw withdrawal incubation period of CCI model mice Ipsilateral soles, produce obvious analgesic activity, with life
Statistically significant (the P of reason saline control group comparing difference<0.01).Lumbar injection variable concentrations puerarin morphine can dose-dependant
Property improve paw withdrawal incubation period of CCI model mices, the analgesic effect of wherein 5.0mg/kg puerarins morphine is weaker, hold time compared with
It is short, only there is obvious analgesic activity within 30 minutes upon administration；The analgesic effect of 10mg/kg puerarin morphines is stronger, during maintenance
Between it is longer, reach 60min；The analgesic effect of 20mg/kg puerarin morphines is most strong, holds time most long, reaches 75min, its town
Pain effect is higher than 10mg/kg injection of morphia groups, but its no significant difference (P>0.05).
Table 1：Puerarin morphine compounds to the analgesic activity of CCI model mices (N=8)
Note：Compare * P with saline control group<0.05, * * P<0.01, * * * P<0.001
In the process of clinical application of the narcosis analgesics such as morphine, additive and toleration is which is maximum not enough.This
Bright employing drug molecule split technology, the molecular structure of the molecular structure and puerarin of morphine is combined as a whole, it is proposed that one
Plant the compound puerarin morphine with brand new.The pharmaceutical research of the compound shows that there is stronger analgesia to make for which
With can effectively strengthen the specificity of morphine analgesia effect, hence it is evident that reduce morphine consumption, overcome morphine clinical practice additive strong and
The problem of large side effects, is applied to clinic as morphine succedaneum, compared with the analgesic effect of morphine, puerarin morphine with
The suitable analgesic activity of morphine.The use of puerarin morphine can greatly reduce the consumption of morphine, reduce the additive and resistance to of morphine
By property, while side effect of the morphine in terms of respiratory system, cardiovascular system and central nervous system effectively can be slowed down.Puerarin
Morphine can carry out the treatment of pain as the succedaneum of morphine.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of spirit or essential attributes without departing substantially from the present invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit is required rather than described above is limited, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.Any reference in claim should not be considered as and limit involved claim.
Moreover, it will be appreciated that although this specification is been described by according to embodiment, not each embodiment is only wrapped
Containing an independent technical scheme, this narrating mode of description is only that those skilled in the art should for clarity
Using description as an entirety, the technical scheme in each embodiment can also Jing it is appropriately combined, form those skilled in the art
Understandable other embodiment.
Claims (1)
1. a kind of preparation method of puerarin morphine, it is characterised in that comprise the following steps：(1) synthesis step of puerarin：
The synthetic route chemical formula of puerarin is as follows：
1) with compound 1 as raw material prepare compound 2：In 500mL there-necked flasks add 300mL anhydrous methylene chlorides and
The compound 1 of 27.0g, 50.0mmol, under agitation, is dividedly in some parts 8.8g, 75.0mmol NMO, stirring reaction 20min, then
0.88g, the TPAP of 2.5mmol are added, continues stirring reaction 2h, reactant liquor 500mL dchloromethanes, silicon at room temperature
Diatomaceous earth is filtered, and filtrate is washed 2 times with the hypo solution of excess saturation, then with saturated common salt water washing 1 time, anhydrous slufuric acid
Sodium is dried, and evaporated under reduced pressure, column chromatography purification obtain compound 2；
2) compound 2 is carried out modifying prepare compound 3：By between, phenylene dimethyl ether and TMEDA are dissolved in the anhydrous THF of 200mL, in nitrogen
- 78 DEG C are cooled under gas shielded, the n-BuLi solution of 2.5mol/L, 17.6mL is added dropwise in above solution at a slow speed, and in -78
Stirring reaction 1h at DEG C, then 0 DEG C of stirring reaction 1h is risen at a slow speed, reactant liquor is cooled to -78 DEG C, by 21.5g, the change of 40.0mmol
Compound 2 is dissolved in 100mL THF, and is dropped in above-mentioned solution at a slow speed, and 1h is stirred in reaction at -78 DEG C, then uses saturation chlorine
Change ammonia solution quenching reaction, then be warming up to room temperature, continuously add 200mL water, extracted with 2 × 200mL ethyl acetate, merge organic
Phase, then with 200mL saturated common salt water washings, anhydrous Na 2SO4 is dried, and vacuum distillation, Purified on column chromatography purification obtain final product chemical combination
Thing 3；
3) compound 3 sloughs hydroxyl prepare compound 4：In 500mL there-necked flasks add 300mL anhydrous methylene chlorides and
20.3g, 30.0mmol compound 3, and -20 DEG C are cooled to, under agitation, 7.0g, the EtSiH of 60.0mmol are added at a slow speed first,
Deca 34.2g at a slow speed, 300.0mmol trifluoroacetic acids, after completion of dropping, continue stirring at room temperature and terminate to reaction, reduce pressure again
Distillation, gained grease 200mL ethyl acetate are dissolved, and successively with 50mL saturated common salt water washings, 50mL saturated sodium carbonates are molten
Liquid is washed, then with 50mL saturated common salt water washings, evaporated under reduced pressure obtains compound 4；
4) compound 4 reacts prepare compound 5 with acetanisole chlorine：In 500mL there-necked flasks, add 250mL anhydrous
Dichloromethane is simultaneously cooled to 0 DEG C, by 3.7g, 27.5mmol AlCl3And the compound 4 of 16.5g, 25.0mmol is separately added into
Solution is stated, under agitation, 5.1g, the 50mL dichloromethane solutions of 27.5mmol acetanisole chlorine, Deca is added at a slow speed
After finishing, it is stirred at room temperature overnight, reactant liquor is poured at a slow speed 200mL into and is cooled in 0 DEG C of 1NHCL solution, separates organic faciess,
Water is mutually extracted with 200mL dichloromethane, merges organic faciess, and with 2 × 100mL saturated common salt water washings, anhydrous sodium sulfate drying subtracts
Pressure is evaporated, and crude product column chromatography purification obtains compound 5；
5) 5 Jing Boron tribromides of compound are reduced to compound 6：16.2g, 20.0mmol chemical combination are added in 500mL there-necked flasks
Thing 5 and 200mL anhydrous methylene chlorides are simultaneously cooled to -78 DEG C, under nitrogen protection by the BBr3 dichloromethanes of 1.0mol/L, 200mL
Alkane solution is dropped in above-mentioned solution, after completion of dropping at a slow speed, reacts 1h, then be slowly warmed to room temperature at -78 DEG C, stirring reaction
2h, reactant liquor is poured in 400mL frozen water at a slow speed, separates organic faciess, and water is mutually extracted with 3 × 200mL dichloromethane, is merged organic
Phase, with 2 × 200mL saturated common salt water washings, anhydrous sodium sulfate drying, evaporated under reduced pressure, crude product column chromatography purification obtain compound
6；
6) with compound 6 as Material synthesis puerarin：4.1g, 10.0mmol compounds 6 are dissolved in 50mL DMF, under agitation
10mL DMFDMA are dropped in above-mentioned solution, after adding at a slow speed, reaction is stirred at room temperature to reaction and terminates, vacuum distillation,
Gained crude product column chromatography purification obtains puerarin；
(2) synthesis step of puerarin morphine：The synthetic route chemical formula of puerarin morphine is as follows：
5mL anhydrous methylene chlorides, 292mg, 0.5mmol compounds 9,83mg, 0.6mmol bromine second are sequentially added in 25mL flasks
Acid, 77mg, 0.6mmol DIEA and 228mg, 0.6mmol HATU, are stirred at room temperature overnight, vacuum distillation, crude product post color
Spectrum purification, sequentially adds anhydrous 3mL DMF, 86mg in 8mL flasks, 0.3mmol morphines, 41mg, the K2CO3 of 0.3mmol and
212mg, 0.3mmol compound 10A or compound 10B, is stirred at room temperature overnight, and adds 3mL methanol, continues to be stirred overnight,
Reactant liquor 1N hydrochloric acid solutions adjust pH to 6.5-7.5, filtration, filtrate decompression distillation, crude product thin layer chromatography or preparation solution
Phase chromatogram purification, obtains puerarin morphine compounds 11A or compound 11B.
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| CN105601625B (en) * | 2015-11-20 | 2018-05-25 | 西安交通大学 | A kind of preparation process of Puerarin C16H25NO2 |
| CN110818664B (en) * | 2019-08-07 | 2022-04-15 | 四川省中医药科学院 | Puerarin novel derivative and preparation method and application thereof |
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| CN100571696C (en) * | 2005-01-05 | 2009-12-23 | 国防教育研究基金会 | Inhibitor and the promoter of uridine 5'-diphosphate-glucal acidic group invertase 2B (UGT2B) |
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| CN100571696C (en) * | 2005-01-05 | 2009-12-23 | 国防教育研究基金会 | Inhibitor and the promoter of uridine 5'-diphosphate-glucal acidic group invertase 2B (UGT2B) |
Non-Patent Citations (3)
| Title |
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| Total synthesis of puerarin, an isoflavone C-glycoside;David Y. W. Lee,et al.,;《Tetrahedron Letters》;20031231;第44卷;第6857-6859页 * |
| 葛根素与阿片类药物联合应用对神经病理性痛的镇痛作用;段美婷，et al.,;《西北药学杂志》;20150331;第30卷(第2期);第162-164页 * |
| 葛根素对神经病理性痛模型小鼠的镇痛作用;罗敬华等，;《西北药学杂志》;20130131;第28卷(第1期);第48-50页 * |
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