CN109810115A - Isoflavone compound and the preparation method and application thereof - Google Patents
Isoflavone compound and the preparation method and application thereof Download PDFInfo
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Abstract
The present invention provides isoflavone compound and preparation method thereof, the structural formula of the isoflavone compound isWherein R isOr
Description
Technical field
The invention belongs to organic synthesis field of medicaments, are related to isoflavone compound and the preparation method and application thereof.
Background technique
Alzheimer disease (Alzheimer's disease, AD) is a kind of progressive neurodegenerative deficiency disorder, clinical
It shows as cognition and memory function constantly deteriorates, the decline of activity of daily living progressive, and have various neuropsychic symptoms and row
For obstacle.The disease is mostly brain primary disease, and onset is slow, and the course of disease is in progressive, has family history more, is drawn in elderly population
Play the dull-witted most common disease.The most significant europathology histologic characteristics of AD be senile plaque, Amyloid deposits and
Neurofibrillary tangles occur mainly in Basal forebrain, hippocampal tissue and cerebral cortex.
About AD pathogenesis, there are many different hypothesis at present, and wherein cholinergic nerve of centrum functional disturbance is considered
It is mostly important one kind.Acetylcholine (acetylcholine, ACh) is the neurotransmitter for promoting learning and memory, in intracerebral
It is destroyed by 2 kinds of cholinesterases, i.e. acetylcholinesterase (Acetylcholinesterase, AChE) and butyrylcholine esterase
(Butyrveholinesterase, BuChE).Anticholinesterase can delay the hydrolysis of ACh, therefore anticholinesterase
It can be improved AD patient ACh and generate curative effect in the content of synaptic cleft, be the current only drug therapy hand being commonly recognized
Section.It is mostly selective AChE inhibitor currently used for clinical anticholinesterase, periphery side effect is larger, long-term treatment effect
Fruit is undesirable.
In recent years, BuChE inhibitor has become the novel targets of AD therapeutic agent research and development.The study found that with AD disease
The activity of the development of journey, the horizontal degradation of patient's intracerebral AChE and BuChE rises with it, and BuChE plays intracerebral ACh at this time
Main hydrolysis.BuChE has also been proved in one AChE knock out mice experiment potential AChE to be replaced to carry out ACh
Hydrolysis.In vivo study confirms that intracerebral levels of acetylcholine can be improved in selective BuChE inhibitor, reduces A beta-aggregation, improves cognition
Function.Therefore, the result of study based on zoopery and clinical test above with respect to BuChE inhibitor develops specificity
BuChE inhibitor would be possible to improve the clinical treatment status of AD.
BuChE is also related with a variety of metabolism, including participation detoxification processes, removes the peptide for being rich in polyproline, adjusting
Blood serum metabolic relevant to obesity, diabetes and insulin resistance etc..Therefore, in order to probe into angle of the BuChE in these metabolism
Color develops selective BuChE inhibitor no less important.
Although many compounds show potential BuChE inhibitory activity, so has the BuChE inhibitor of good selectivity
Rare report, therefore develop and can selectively inhibit BuChE to AChE without obvious inhibitory activity, there is excellent selectivity
BuChE inhibitor have great importance.
Summary of the invention
It is an object of the invention to be improved for selectivity existing for the existing compound with BuChE inhibitory activity
Deficiency, an object of the present invention be to provide the activity for capableing of selective depression BuChE and to the activity of AChE without obvious suppression
Production use, isoflavone compound with excellent selectivity and preparation method thereof, it is described the second object of the present invention is to provide
Isoflavone compound is preparing the application in the drug using BuChE as target spot.
Shown in the structural formula of isoflavone compound provided by the invention such as formula (I),
In formula (I), R isOr
Isoflavone compound i.e. provided by the invention is specially structural formula four compounds as follows:
The present invention also provides above-mentioned isoflavone compound pharmaceutically acceptable salt, such as change shown in formula (I)
Close object and hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, Malaysia
The addition salts that acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or ferulic acid are formed.
The present invention also provides above-mentioned isoflavone compound pharmaceutically acceptable hydrates.
The present invention also provides above-mentioned isoflavone compound, above-mentioned isoflavone compound pharmaceutically acceptable salt
Or hydrate pharmaceutically acceptable polymorph.
Term " pharmaceutically acceptable " refer in reasonable medical judgment scope, can be adapted to for the mankind and other
The tissue of mammal contacts, without improper toxicity, stimulation, allergic reaction etc., when receptor is administered can directly or
Ground connection provides the prodrug of the compound of the present invention or compound.Term " hydrate " indicates osajin chemical combination provided by the invention
Object further passes through active force combination stoichiometry or the compound of non-stoichiometric water formation between Non-covalent molecular.Term
" polymorph " indicates compound provided by the invention or the solid crystallization way of its compound.
Above-mentioned isoflavone compound provided by the invention, above-mentioned isoflavone compound pharmaceutically acceptable salt or
Pharmaceutically acceptable hydrate can be formed the above-mentioned isoflavone compound of person with pharmaceutically acceptable complementary ingredient
Pharmaceutical composition, the common active effect for playing selective depression BuChE.The pharmaceutical composition can be using conventional medicine
Object formulation method is prepared into the form of liquid preparation or solid pharmaceutical preparation, and the liquid form can be aqueous solution form, described
Solid form can be powder, particle, tablet or freeze-dried powder form.The pharmaceutical composition can cooperate water for injection, salt water
Solution, glucose solution, injection/infusion salt water, injection/infusion glucose, Ge Linshi solution contain lactate
Ge Linshi solution is used together.
The present invention also provides the preparation methods of above-mentioned isoflavone compound, and the synthetic route and step of this method are such as
Under:
(1) dichloromethane solution of 3,4- dihydro -2H- pyrans is added dropwise to the two of raw material 1 and para-methylbenzenepyridinsulfonate sulfonate
In chloromethanes solution, it is stirred to react 4~6h, is extracted with dichloromethane after being cleaned with saturated sodium bicarbonate solution, organic phase is removed
In water, evaporating solvent under reduced pressure obtains intermediate 1；
Intermediate 1 is suspended in n,N-Dimethylformamide dimethylacetal, 3~5h of back flow reaction is cooled to room temperature,
Evaporating solvent under reduced pressure obtains intermediate 2；
Intermediate 2 is dissolved in CHCl3In, pyridine, I is added2, it is stirred to react 10~14h, saturation Na is added2S2O3Solution stirs
0.5~1h of reaction is mixed, uses CH later2Cl2Extraction removes the water in organic phase, is spin-dried for, and crosses silica gel chromatograph column separating purification, obtains
Intermediate 3；
Intermediate 3, p-methyl benzenesulfonic acid are added in the mixed solution of methanol and tetrahydrofuran, back flow reaction 1~2h is cold
But to room temperature, evaporating solvent under reduced pressure washes by products therefrom with ethyl acetate is dissolved in, removes moisture, be spin-dried for, obtain intermediate
4；
(2) 3- methyl-2-butene aldehyde, potassium acid sulfate and triethyl orthoformate are added in ethyl alcohol under conditions of 0 DEG C,
0 DEG C of 0.5~1h of reaction, is then stirred at room temperature 0.5~1h of reaction, filters and use ethanol washing for gained reaction solution, toward filter
Potassium carbonate is added in liquid and is stirred to react 1~3h, filters, filtrate decompression is concentrated, the crude product of intermediate 5 is obtained；
Intermediate 4, the crude product of intermediate 5,3- picoline are added in dimethylbenzene, 22~26h of back flow reaction is cooling
To room temperature, evaporating solvent under reduced pressure crosses silica gel chromatograph column separating purification, obtains intermediate 6；
(3) by intermediate 6, Na2CO3, (2- hydroxy phenyl) boric acid, Pd/C be added glycol dimethyl ether and water mixed liquor
In, in 45~50 DEG C of 0.5~1h of reaction, crosses diatomite and remove solid, gained filtrate is used into CH2Cl2Extraction removes in organic phase
Water, be spin-dried for, cross silica gel chromatograph column separating purification, obtain intermediate 7a；
By intermediate 6, Na2CO3, (3- hydroxy phenyl) boric acid, Pd/C be added in the mixed liquor of glycol dimethyl ether and water,
In 45~50 DEG C of 0.5~1h of reaction, crosses diatomite and remove solid, gained filtrate is used into CH2Cl2Extraction removes in organic phase
Water is spin-dried for, and is crossed silica gel chromatograph column separating purification, is obtained intermediate 7b；
(4) intermediate 8a, triethylamine are dissolved in methylene chloride, isocyanide heptyl heptylate is then added and reacts 5~7h, decompression
Concentration crosses silica gel chromatograph column separating purification, obtains compound 8a；
Compound 8b, potassium carbonate are added in the mixed solution of n,N-Dimethylformamide and acetonitrile and form mixed liquor A, it will
The acetonitrile solution dropwise of N, N- dimethylcarbamyl chloride is into mixed liquor A, 3~4h of back flow reaction, with dilute after being cooled to room temperature
Then salt acid elution plus water and is extracted with ethyl acetate, with saturated common salt water washing organic phase, remove the water in organic phase, subtract
Pressure concentration, crosses silica gel chromatograph column separating purification, obtains compound 8b；
Compound 8b, triethylamine are dissolved in methylene chloride, isocyanide heptyl heptylate is then added and reacts 5~7h, depressurizes dense
Contracting, through silica gel chromatograph column separating purification, obtains compound 8c；
Compound 8b, triethylamine are dissolved in methylene chloride, 2- phenethyl isocyanates is then added and reacts 5~7h,
It is concentrated under reduced pressure, through silica gel chromatograph column separating purification, obtains compound 8d.
In the preparation method of above-mentioned isoflavone compound, preferred technological parameter is as follows:
In step (1), when synthetic intermediate 1, the molar ratio of 3,4- dihydro -2H- pyrans and raw material 1 is (3~4): 1, it is right
The molar ratio of pyridinium p-toluenesulfonic acid and raw material 1 is (0.03~0.1)；When synthetic intermediate 2, n,N-Dimethylformamide diformazan
The additional amount of base acetal is 1.5~2 times of 1 mole of raw material；When synthetic intermediate 3, pyridine, I2Additional amount be respectively raw material
1.1~1.5 times, 2~2.5 times of 1 mole；When synthetic intermediate 4, intermediate 3 and the molar ratio of p-methyl benzenesulfonic acid are
(10~12): 1；
In step (2), when synthetic intermediate 5, the molar ratio of 3- methyl-2-butene aldehyde and triethyl orthoformate be 1:(1~
1.2), the molar ratio of potassium acid sulfate and 3- methyl-2-butene aldehyde is (0.05~0.1): 1；When synthetic intermediate 6, intermediate 4
Additional amount is 0.1~0.5 times of 3- methyl-2-butene aldehyde mole, and the molar ratio of 3- picoline and intermediate 4 is (0.03
~0.1): 1.
In step (3), when synthetic intermediate 7a, the molar ratio of (2- hydroxy phenyl) boric acid and intermediate 6 be 1:(1.1~
1.4), Na2CO3Additional amount be 3~4 times of 6 mole of intermediate, the additional amount of Pd/C should make the mole intermediate of Pd
The 5%~8% of 6 moles；When synthetic intermediate 7b, the molar ratio of (3- hydroxy phenyl) boric acid and intermediate 6 be 1:(1.1~
1.4), Na2CO3Additional amount be 3~4 times of 6 mole of intermediate, the additional amount of Pd/C should make the mole intermediate of Pd
The 5%~8% of 6 moles.
In step (4), when synthesizing compound 8a, the molar ratio of isocyanide heptyl heptylate, triethylamine and intermediate 7a be (1.1~
1.3): (1.1~1.3): 1；When synthesizing compound 8b, the molar ratio of intermediate 7b and N, N- dimethylcarbamyl chloride are 1:
(1.1~1.3), the additional amount of potassium carbonate are 3~4 times of intermediate 7b mole；When synthesizing compound 8c, isocyanide heptyl heptylate,
The molar ratio of triethylamine and intermediate 7 is (1.1~1.3): (1.1~1.3): 1；When synthesizing compound 8d, 2- phenethyl isocyanide
The molar ratio of acid esters, triethylamine and intermediate 7b is (1.1~1.3): (1.1~1.3): 1.
In the preparation method of above-mentioned isoflavone compound, the methanol that is used when preparing intermediate 3 and tetrahydrofuran
In mixed solution, the volume ratio of methanol and tetrahydrofuran is preferably 1:(0.8~1.2).
In the preparation method of above-mentioned isoflavone compound, in the mixed liquor of step (3) glycol dimethyl ether and water,
The volume ratio of glycol dimethyl ether and water is preferably 1:(0.8~1.2).
The present invention also provides above-mentioned isoflavone compound, above-mentioned isoflavone compound pharmaceutically acceptable salt
And pharmaceutically acceptable hydrate is being prepared using BuChE as the application in target drug above-mentioned isoflavone compound.
The drug for belonging to anti-senile dementia either anti-learning memory disorder using BuChE as target drug, can be used for anti-ageing year
Dull-witted or anti-learning memory disorder.
The present invention tests inhibition of the isoflavone compound provided by the invention to AChE and BuChE by experiment in vitro
Activity, the results showed that the activity of isoflavone compound energy selective depression BuChE provided by the invention and the activity to AChE
Without obvious inhibiting effect, there is excellent selectivity, isoflavone compound provided by the invention is to the inhibiting effect of BuChE
To 49.3~1339 times of AChE inhibiting effect, it is selectively significantly better than positive control medicine galanthamine (galantamine)
With Tacrine (tacrine).When inhibiting the activity of BuChE, the IC of isoflavone compound provided by the invention50It can be down to
(0.093 ± 0.001)~(0.681 ± 0.019) μm ol/L, the inhibitory activity with excellent BuChE.
Compared with prior art, technical solution of the present invention has technical effect beneficial below:
1. the activity of isoflavone compound energy selective depression BuChE provided by the invention and AChE is inhibited without obvious
Activity, selectivity is very excellent, can achieve 49.3 to the active rejection ability of AChE to the active rejection ability of BuChE
~1339 times, while IC of the isoflavone compound provided by the invention when inhibiting the activity of BuChE50It can be down to 0.093
± 0.001 μm of ol/L has excellent BuChE inhibitory activity.Inhibit to live based on above-mentioned excellent selectivity and efficient BuChE
Property, isoflavone compound provided by the invention can prepare the application in drug using BuChE as target spot, the present invention be Ah
The clinical application of the silent disease in Wurz sea provides a kind of new potential selection.
2. the preparation method of isoflavone compound provided by the invention is simple, reaction condition is mild, convenient for operation and control
System, energy consumption is small, and yield is high, at low cost, can be suitble to industrialization production, be conducive to promote and apply.
Specific embodiment
Isoflavone compound provided by the invention and the preparation method and application thereof is made by the following examples further
Explanation.It is necessary to note that following embodiment is served only for, the invention will be further described, should not be understood as protecting model to the present invention
The limitation enclosed, one of ordinary skill in the art make some nonessential modifications and adaptations according to foregoing invention content, to the present invention
It is embodied, still falls within the range of invention protection.
1~7 synthesis compound provided by the invention by the following examples Pass through comparative example 1
~6 synthesis 5 compounds similar with above-mentioned 4 compound structures provided by the invention
All compounds synthesized by 8 testing example of embodiment and comparative example are to the inhibitory activity of BuChE and AChE and calculate choosing
Selecting property.
Embodiment 1
In the present embodiment, synthetic intermediate 1, intermediate 2, intermediate 3 and intermediate 4, synthetic route and steps are as follows:
(1) by 3,4- dihydro -2H- pyrans (12mL, 155mmol) be added methylene chloride (64mL) in, and by the solution by
It is added dropwise in methylene chloride (128mL) solution of raw material 1 (6.086g, 40mmol) and para-methylbenzenepyridinsulfonate sulfonate (372mg),
Then reaction is stirred at room temperature, monitors extent of reaction with thin-layer chromatography, reaction terminates after 4 hours, then uses saturated sodium bicarbonate
Solution cleaning, is extracted with dichloromethane after cleaning, the organic phase of collection is filtered with anhydrous sodium sulfate, remove under reduced pressure later molten
Agent obtains intermediate 1.
(2) intermediate 1 is suspended in n,N-Dimethylformamide dimethylacetal (7.97mL, 60mmol), is then existed
95 DEG C of back flow reaction 3h stop reaction, are cooled to room temperature, evaporating solvent under reduced pressure, obtained red solid is intermediate 2.
(3) intermediate 2 is dissolved in CHCl3In, pyridine (3.54mL, 44mmol), I are sequentially added under stiring2(20.3 g,
80mmol), reaction 12h is then stirred at room temperature, saturation Na is added2S2O3Solution continues that reaction 30 minutes is stirred at room temperature, and stops
Reaction, by gained reaction solution CH2Cl2Extraction three times, merges organic phase, and anhydrous sodium sulfate is added and dries, filters, is spin-dried for, crosses silicon
Glue chromatography column separating purification, obtained white solid are intermediate 3, yield 74.70%.
Nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon spectrum detection are carried out to intermediate 3, as a result are as follows:1H NMR(CDCl3,400MHz)δ:1.55–
1.78(m,3H),1.89–2.03(m,3H),3.63–3.67(m,1H),3.80–3.86(m,1H),5.54-5.55(m,1H),
7.09-7.12 (m, 2H), 8.14 (d, 1H, J=9.6Hz), 8.22 (s, 1H)；13C NMR(CDCl3,400MHz)δ:18.4,
25.1,30.1,62.2,87.1,96.7,103.3,116.3,116.7,128,157.5,157.8,161.9,172.9。
(4) intermediate 3 (4.47g, 12mmol) and p-methyl benzenesulfonic acid (228mg, 1.2mmol) are thrown in reaction flask,
The volume ratio of the mixed solution 240mL of addition methanol and tetrahydrofuran, methanol and tetrahydrofuran is 1:1, is then flowed back at 60 DEG C
1h is reacted, stops reaction, is cooled to room temperature, evaporating solvent under reduced pressure, the residue obtained after solvent will be removed and be dissolved in 500mL second
It in acetoacetic ester, washes 2 times, anhydrous sodium sulfate is added and dries, filters, is spin-dried for, obtained yellow solid is intermediate 4, yield
It is 92.8%.
Nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon spectrum detection are carried out to intermediate 4, as a result are as follows:1H NMR(DMSO-d6,400MHz)δ:
6.86 (t, J=2Hz, 1H), 6.93-6.96 (m, 1H), 7.90 (dd, J=1.2Hz, 8.8Hz, 1H), 8.68 (d, J=
2.4Hz,1H), 10.93(s,1H)；13C NMR(DMSO-d6,100MHz)δ:18.4,25.1,30.1,62.2,87.1,96.7,
103.3,116.3, 116.7,128.0,157.5,157.8,161.9,172.9。
Embodiment 2
In the present embodiment, synthetic intermediate 5 and intermediate 6, synthetic route and steps are as follows:
(1) under conditions of 0 DEG C, 3- methyl-2-butene aldehyde is slowly added into the ethyl alcohol (24mL) under stirring
(7.72mL, 80 mmol), potassium acid sulfate (0.545g, 4mmol) and triethyl orthoformate (13.3mL, 80mmol), then 0
DEG C reaction 30 minutes, reaction 30 minutes is stirred at room temperature later, gained reaction solution is filtered to and use 5mL ethanol washing, past filtrate
Simultaneously reaction 2 hours is stirred at room temperature in middle addition potassium carbonate, later filters reaction solution, and gained filtrate is concentrated under reduced pressure at 35 DEG C,
It obtains the crude product of intermediate 5 and is directly used in the synthesis of next step.
(2) successively by intermediate 4 (2.304g, 8mmol), crude product (6mL) (1:3), the dimethylbenzene (46mL) of intermediate 5
It is placed in a reaction flask with 3- picoline (195 μ L, 0.25mmol), back flow reaction for 24 hours, is cooled to room temperature, and is removed under reduced pressure molten
Agent crosses silica gel chromatograph column separating purification and obtains intermediate 6, yield 48%.
Nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon spectrum detection are carried out to intermediate 6, as a result are as follows:1H NMR(CDCl3,400MHz)δ:1.49
(s, 6H), 5.72 (d, 1H, J=10.0Hz), 6.73 (d, 1H, J=10.0Hz), 6.86 (d, 1H, J=8.4Hz), 8.00 (d,
1H, J=8.4Hz), 8.23 (s, 1H)；13C NMR(CDCl3,100MHz)δ:28.3,78.1,87.3,109.2,114.8,
115.8,116.1, 127.1,130.8,152.4,157.0,157.8,172.8。
Embodiment 3
In the present embodiment, synthetic intermediate 7a, synthetic route and steps are as follows:
By intermediate 6 (17mg, 0.5mmol), Na2CO3(159mg, 1.5mmol), (2- hydroxy phenyl) boric acid (91.2mg,
0.6mmol), Pd/C (26.5mg, 5mol%) is placed in a reaction flask, and 3mL glycol dimethyl ether and 3mL water is added, then 45
DEG C reaction 1h, cross diatomite remove solid, filter cake CH2Cl2It washes, gained filtrate is used into CH2Cl2Extraction 3 times merges organic phase,
Anhydrous sodium sulfate is added to dry, filter, is spin-dried for, crosses silica gel chromatograph column separating purification and obtains intermediate 7a, yield 89%,
M.p.:149-151 DEG C, HPLC purity:99.2%.
Nucleus magnetic hydrogen spectrum, nuclear-magnetism carbon spectrum and Mass Spectrometer Method are carried out to intermediate 7a, as a result are as follows:1H NMR(CDCl3,400MHz)
δ: 1.50 (s, 6H), 5.76 (d, J=10.0Hz, 1H), 6.84 (d, J=10.0Hz, 1H), 6.93-6.99 (m, 2H), 7.10
(dd, J=1.2,8.0Hz, 1H), 7.17 (dd, J=1.6,7.6Hz, 1H), 7.33-7.37 (m, 1H), 8.11-8.14 (m,
2H)；13C NMR (CDCl3,400MHz)δ:28.4,78.3,109.1,114.7,116.4,117.2,119.8,120.8,
120.9,125.0,126.9, 129.7,130.6,130.8,152.4,155.2,156.7,158.3,178.8；MS(ESI):m/
z calcd.C20H17O4[M+H]+ 321.11,found 321.24。
Embodiment 3
In the present embodiment, synthetic intermediate 7b, synthetic route and steps are as follows:
By intermediate 6 (17mg, 0.5mmol), Na2CO3(159mg, 1.5mmol), (3- hydroxy phenyl) boric acid (91.2mg,
0.6mmol), Pd/C (26.5mg, 5mol%) is placed in a reaction flask, and 3mL glycol dimethyl ether and 3mL water is added, then 45
DEG C reaction 1h, cross diatomite remove solid, filter cake CH2Cl2It washes, gained filtrate is used into CH2Cl2Extraction 3 times merges organic phase,
Anhydrous sodium sulfate is added to dry, filter, is spin-dried for, crosses silica gel chromatograph column separating purification and obtains intermediate 7b, yield 41%, m.p.:
220-221 DEG C, HPLC purity:97.3%.
Nucleus magnetic hydrogen spectrum, nuclear-magnetism carbon spectrum and Mass Spectrometer Method are carried out to intermediate 7b, as a result are as follows:1H NMR(DMSO-d6,
400MHz) δ: 1.50 (s, 6H), 5.73 (d, J=10.0Hz, 1H), 5.80 (s, 1H), 6.81 (d, J=10.0Hz, 1H),
6.85-6.89 (m, 2H), 7.02 (d, J=7.6Hz, 1H), 7.20 (dd, J=2,2.4Hz, 1H), 7.29 (t, J=7.6Hz,
1H), 7.99 (s, 1H), 8.08 (d, J=8.8Hz, 1H)；13C NMR(CDCl3,100MHz)δ:27.6,77.9,109.0,
114.1,114.8,115.0,116.1, 117.9,119.5,123.7,126.1,129.1,131.4,133.0,151.6,
153.7,156.6,157.0,174.4；MS(ESI):m/z calcd.C20H17O4 +[M+H]+321.11,found 321.24。
Embodiment 4
In the present embodiment, compound 8a is synthesized, synthetic route and steps are as follows:
Under stiring, intermediate 7a (0.2mmol) and triethylamine (31 μ L, 0.22mmol) are added sequentially to the two of 3mL
It in chloromethanes, is stirred at room temperature 15 minutes, isocyanide heptyl heptylate (0.22mol) is added later and reacts 6 hours, gained is reacted mixed
It closes object to be concentrated under reduced pressure, obtains compound 8a after crossing silica gel chromatograph column separating purification, yield 56%, m.p.:89-91 DEG C, HPLC
Purity:99.1%.
Nucleus magnetic hydrogen spectrum, nuclear-magnetism carbon spectrum and Mass Spectrometer Method are carried out to compound 8a, as a result are as follows:1H NMR(CDCl3,400MHz)
δ: 0.78 (t, J=6.8Hz, 3H), 1.11-1.31 (m, 10H), 1.43 (s, 6H), 3.03 (q, J=6.8Hz, 2H), 5.02
(t, J=5.2 Hz, 1H), 5.65 (d, J=10.0Hz, 1H), 6.72 (d, J=10.0Hz, 1H), 6.78 (d, J=8.8Hz,
1H), 7.14-7.20 (m, 2H), 7.24 (dd, J=1.6,7.2Hz, 1H), 7.30-7.35 (m, 2H), 7.83 (s, 1H), 7.95
(d, J=8.8Hz, 1H)；13C NMR(CDCl3,100MHz)δ:14.2,22.7,26.6,28.3,28.9,29.7,31.8,
41.3,77.9,109.4,115.0,115.4, 118.2,122.3,123.0,125.6,125.7,126.7,129.8,130.4,
131.7,149.7,152.5,153.6,154.7,157.5, 175.3；MS(ESI):m/z calcd.C28H32NO5[M+H]+
462.23,found 462.23。
Embodiment 5
In the present embodiment, compound 8b is synthesized, synthetic route and steps are as follows:
By intermediate 7b (0.2mmol), potassium carbonate (0.6mmol) sequentially add N,N-dimethylformamide (1.5mL) with
Mixed liquor A is formed in the mixed solution of acetonitrile (0.6 mL), by N, N- dimethylcarbamyl chloride (0.22mmol) is added to
In 0.3mL acetonitrile and mixing forms N, the acetonitrile solution of N- dimethylcarbamyl chloride, then by N, N- dimethyl carbamoyl
The acetonitrile solution of chlorine is added dropwise in mixed liquor A, is heated to reflux 3h at 95 DEG C later, is cooled to room temperature, and dilute hydrochloric acid is added and washes
Wash, backward gained mixture 20mL water is added, be extracted with ethyl acetate three times, merge organic phase, then washed with saturated common salt
It washs 3 times, with being filtered after anhydrous sodium sulfate drying, gained filtrate decompression is concentrated, the residue being concentrated to get is crossed into silica gel chromatographic column
Obtain compound 8b after isolating and purifying, yield 65%, m.p.:234-236 DEG C, HPLC purity:97.6%.
Nucleus magnetic hydrogen spectrum, nuclear-magnetism carbon spectrum and Mass Spectrometer Method are carried out to compound 8b, as a result are as follows:1H NMR(CDCl3,600MHz)
δ: 1.51 (s, 6H), 3.01 (s, 3H), 3.11 (s, 3H), 5.73 (d, J=10.2Hz, 1H), 6.81 (d, J=9.6Hz, 1H),
6.87 (dd, J=0.6,9.0Hz, 1H), 7.13-7.15 (m, 1H), 7.36-7.38 (m, 2H), 7.41 (t, 1H), 8.00 (s,
1H), 8.06 (d, J=9.0 Hz, 1H)；13C NMR(CDCl3,100MHz)δ:28.3,36.6,36.8,77.9,109.3,
115.0,115.5,118.4,121.7, 122.6,124.4,125.7,126.8,129.4,130.5,133.3,151.6,
152.4,152.8,155.0,157.5,175.6；MS(ESI): m/z calcd.C23H22NO5 +(M+)392.15,found
392.18。
Embodiment 6
In the present embodiment, compound 8c is synthesized, synthetic route and steps are as follows:
Under stiring, intermediate 7b (0.2mmol) and triethylamine (31 μ L, 0.22mmol) are added sequentially to the two of 3mL
It in chloromethanes, is stirred at room temperature 15 minutes, isocyanide heptyl heptylate (0.22mol) is added later and reacts 6 hours, gained is reacted mixed
It closes object to be concentrated under reduced pressure, obtains compound 8c after crossing silica gel chromatograph column separating purification, yield 65%, m.p.:107-109 DEG C,
HPLC purity:96.8%.
Nucleus magnetic hydrogen spectrum, nuclear-magnetism carbon spectrum and Mass Spectrometer Method are carried out to compound 8c, as a result are as follows:1H NMR(CDCl3,400MHz)
δ: 0.89 (t, J=6.4Hz, 3H), 1.29-1.33 (m, 8H), 1.50-1.58 (m, 8H), 3.25 (q, J=6.4Hz, 2H),
5.01 (s, 1H), 5.72 (d, J=10.0Hz, 1H), 6.8 (d, J=10.0Hz, 1H), 6.86 (d, J=8.8Hz, 1H),
7.14-7.15 (m, 1H), 7.36-7.42 (m, 3H), 7.98 (s, 1H), 8.06 (d, J=8.8Hz, 1H)；13C NMR(CDCl3,
100MHz)δ:14.2,22.7, 26.9,28.3,29.1,30.0,31.9,41.4,77.9,109.3,115.0,115.5,
118.4,121.5,122.4,124.4,125.9,126.8, 129.4,130.5,133.3,151.2,152.4,152.7,
154.7,157.5,175.5；MS(ESI):m/z calcd.C28H32NO5 [M+H]+462.23,found 462.26。
Embodiment 7
In the present embodiment, compound 8d is synthesized, synthetic route and steps are as follows:
Under stiring, intermediate 7b (0.2mmol) and triethylamine (31 μ L, 0.22mmol) are added sequentially to the two of 3mL
It is stirred at room temperature in chloromethanes 15 minutes, 2- phenethyl isocyanates (0.22mol) is added later and reacts 6 hours, by gained
Reaction mixture is concentrated under reduced pressure, and obtains compound 8d, yield 82%, m.p.:145-147 after crossing silica gel chromatograph column separating purification
DEG C, HPLC purity:99.9%.
Nucleus magnetic hydrogen spectrum, nuclear-magnetism carbon spectrum and Mass Spectrometer Method are carried out to compound 8d, as a result are as follows:1H NMR(CDCl3,400MHz)
δ: 1.51 (s, 6H), 2.89 (t, J=6.8Hz, 2H), 3.53 (q, J=6.4Hz, 2H), 5.11 (s, 1H), 5.73 (d, J=
10.0Hz, 2H), 6.81 (d, J=10.0Hz, 1H), 6.87 (d, J=8.8Hz, 1H), 7.13 (d, J=6.4Hz, 1H),
7.23-7.27 (m, 3H), 7.32-7.48 (m, 5H), 7.99 (s, 1H), 8.06 (d, J=8.4Hz, 1H)；13C NMR(CDCl3,
100MHz)δ:28.3,36.1, 42.5,77.9,109.3,115.0,115.5,118.4,121.4,122.4,124.4,
125.9,126.8,126.9,128.9,129.0,129.4, 130.5,133.3,138.7,151.1,152.4,152.7,
154.6,157.5,175.5；MS(ESI):m/z calcd.C29H26NO5 [M+H]+468.18,found 468.22。
Comparative example 1
In this comparative example, compound 8e is synthesized, synthetic route and steps are as follows:
By intermediate 7a (0.2mmol), potassium carbonate (0.6mmol) sequentially add N,N-dimethylformamide (1.5mL) with
Mixed liquor A is formed in the mixed solution of acetonitrile (0.6 mL), by N, N- dimethylcarbamyl chloride (0.22mmol) is added to
In 0.3mL acetonitrile and mixing forms N, the acetonitrile solution of N- dimethylcarbamyl chloride, then by N, N- dimethyl carbamoyl
The acetonitrile solution of chlorine is added dropwise in mixed liquor A, is heated to reflux 3h at 95 DEG C later, is cooled to room temperature, and dilute hydrochloric acid is added and washes
Wash, backward gained mixture 20mL water is added, be extracted with ethyl acetate three times, merge organic phase, then washed with saturated common salt
It washs 3 times, with being filtered after anhydrous sodium sulfate drying, gained filtrate decompression is concentrated, the residue being concentrated to get is crossed into silica gel chromatographic column
Obtain compound 8e after isolating and purifying, yield 52%, m.p.:61-63 DEG C, HPLC purity:98.9%.
Nucleus magnetic hydrogen spectrum, nuclear-magnetism carbon spectrum and Mass Spectrometer Method are carried out to compound 8e, as a result are as follows:1H NMR(CDCl3,600MHz)
δ: 1.51 (s, 6H), 2.89 (s, 6H), 5.73 (d, J=10.2Hz, 1H), 6.82 (d, J=10.2Hz, 1H), 6.86 (d, J=
8.4Hz, 1H), 7.24-7.27 (m, 2H), 7.32 (dd, J=1.2,7.2Hz, 1H), 7.39-7.42 (m, 1H), 7.91 (s,
1H), 8.04 (d, J=9.0Hz)；13C NMR(CDCl3,400MHz)δ:28.3,36.5,36.7,77.9,109.4,115.0,
115.3,118.3,122.5, 123.2,125.4,125.5,126.7,129.7,130.4,131.5,150.0,152.5,
153.4,154.8,157.4,175.1；MS(EI): m/z calcd.C23H22NO5 +(M+)392.15,found 392.13。
Comparative example 2
In this comparative example, compound 8f is synthesized, synthetic route and steps are as follows:
By intermediate 7a (0.2mmol), potassium carbonate (0.6mmol) sequentially add N,N-dimethylformamide (1.5mL) with
Mixed liquor A is formed in the mixed solution of acetonitrile (0.6 mL), N- ethyl-N-methylamino formyl chloride (0.22mmol) is added to
In 0.3mL acetonitrile and the acetonitrile solution for forming N- ethyl-N-methylamino formyl chloride is mixed, then by N- ethyl-N-methyl ammonia
The acetonitrile solution of base formyl chloride is added dropwise in mixed liquor A, is heated to reflux 3h at 95 DEG C later, is cooled to room temperature, and is added
Dilute hydrochloric acid washing, it is backward gained mixture be added 20mL water, be extracted with ethyl acetate three times, merge organic phase, then be saturated
Brine It 3 times, with being filtered after anhydrous sodium sulfate drying, gained filtrate decompression is concentrated, the residue being concentrated to get is crossed into silicon
Obtain compound 8f after glue chromatography column separating purification, yield 56%, m.p.:65-67 DEG C, HPLC purity:98.2%.
Nucleus magnetic hydrogen spectrum, nuclear-magnetism carbon spectrum and Mass Spectrometer Method are carried out to compound 8f, as a result are as follows:1H NMR(CDCl3,600MHz)
δ: 0.88-0.92 (m, 3H), 1.50 (s, 6H), 2.78 (d, J=16.8Hz, 3H), 3.16-3.24 (m, 2H), 5.65 (d, J=
10.0Hz, 1H), 6.73 (d, J=10.0Hz, 1H), 6.78 (d, J=8.8Hz, 1H), 7.15-7.20 (m, 2H), 7.25 (d, J
=7.6Hz, 1H), 7.31-7.35 (m, 1H), 7.83 (s, 1H), 7.96 (d, J=8.8Hz, 1H)；13C NMR(CDCl3,
100MHz)δ:12.6,28.3, 34.0,44.0,77.8,109.4,115.0,115.3,118.3,122.5,123.1,125.4,
125.5,126.6,129.7,130.5,131.5, 150.0,152.5,153.5,154.4,157.4,175.1；MS(ESI):m/
z calcd.C24H24NO5[M+H]+406.16,found 406.13。
Comparative example 3
In this comparative example, compound 8g is synthesized, synthetic route and steps are as follows:
Intermediate 7b (0.2mmol), potassium carbonate potassium carbonate (0.6mmol) are sequentially added into N,N-dimethylformamide
Mixed liquor A is formed in the mixed solution of (1.5mL) and acetonitrile (0.6mL), by N- ethyl-N-methylamino formyl chloride
(0.22mmol) is added in 0.3mL acetonitrile and mixes the acetonitrile solution for forming N- ethyl-N-methylamino formyl chloride, then
The acetonitrile solution of N- ethyl-N-methylamino formyl chloride is added dropwise in mixed liquor A, is heated to reflux at 95 DEG C later
3h is cooled to room temperature, be added dilute hydrochloric acid washing, it is backward gained mixture be added 20mL water, be extracted with ethyl acetate three times, conjunction
And organic phase, then with saturated common salt water washing 3 times, with being filtered after anhydrous sodium sulfate drying, gained filtrate decompression is concentrated, it will be dense
The obtained residue of contracting, which is crossed after silica gel chromatograph column separating purification, obtains compound 8g, yield 31%, and m.p.:178-180 DEG C, HPLC
Purity:99.3%.
Nucleus magnetic hydrogen spectrum, nuclear-magnetism carbon spectrum and Mass Spectrometer Method are carried out to compound 8g, as a result are as follows:1H NMR(CDCl3,400MHz)
δ: 1.17-1.26 (m, 3H), 1.50 (s, 6H), 3.03 (d, J=34.4Hz, 3H), 3.38-3.51 (m, 2H), 5.72 (d, J=
10.0Hz, 1H), 6.8 (d, J=10.0Hz, 1H), 6.86 (dd, J=0.4,8.8Hz, 1H), 7.14 (d, J=8.0Hz, 1H),
7.35-7.41 (m, 3H), 8.00 (s, 1H), 8.05 (d, J=8.8Hz, 1H)；13C NMR(CDCl3,100MHz)δ:13.0,
28.3,34.2,44.2, 77.9,109.3,115.0,115.5,118.4,121.7,122.7,124.5,125.7,126.9,
129.4,130.5,133.3,151.6, 152.5,152.8,154.6,157.6,175.7；MS(ESI):m/z
calcd.C24H24NO5[M+H]+406.16,found 406.17。
Comparative example 4
In this comparative example, compound 8h is synthesized, synthetic route and steps are as follows:
Under stiring, intermediate 7a (0.2mmol) and triethylamine (31 μ L, 0.22mmol) are added sequentially to the two of 3mL
It in chloromethanes, is stirred at room temperature 15 minutes, 2- phenethyl isocyanates (0.22mol) is added later and reacts 6 hours, by gained
Reaction mixture is concentrated under reduced pressure, and obtains compound 8h, yield 60%, m.p.:123-125 after crossing silica gel chromatograph column separating purification
DEG C, HPLC purity:99.8%.
Nucleus magnetic hydrogen spectrum, nuclear-magnetism carbon spectrum and Mass Spectrometer Method are carried out to compound 8h, as a result are as follows:1H NMR(CDCl3,400MHz)
δ: 1.50 (s, 6H), 2.72 (t, J=6.4Hz, 2H), 3.41 (q, J=6.4Hz, 2H), 5.06 (s, 1H), 5.73 (d, J=
10.0Hz, 1H), 6.82 (d, J=10.0Hz, 1H), 6.88 (d, J=8.4Hz, 1H), 7.07 (d, J=7.2Hz, 2H),
7.16-7.22 (m, 4H), 7.26-7.34 (m, 2H), 7.41 (t, J=7.2Hz, 1H), 7.91 (m, 1H), 8.04 (d, J=
8.4Hz,1H)；13C NMR (CDCl3,100MHz)δ:28.3,36.1,42.5,77.9,109.4,115.0,115.4,118.3,
122.4,123.1,125.5,125.8, 126.6,126.8,128.7,128.8,129.8,130.6,131.8,138.6,
149.6,152.6,153.6,154.6,157.5,175.3；MS (ESI):m/z calcd.C29H26NO5[M+H]+468.18,
found 468.21。
Comparative example 5
In this comparative example, synthetic intermediate 7c, synthetic route and steps are as follows:
By intermediate 6 (17mg, 0.5mmol), Na2CO3(159mg, 1.5mmol), (the fluoro- 3- hydroxy phenyl of 2-) boric acid
(91.2mg, 0.6mmol), Pd/C (26.5mg, 5mol%) are placed in a reaction flask, and 3mL glycol dimethyl ether and 3mL water is added,
Then it in 45 DEG C of reaction 1h, crosses diatomite and removes solid, filter cake CH2Cl2It washes, gained filtrate is used into CH2Cl2Extraction 3 times is closed
And organic phase, anhydrous sodium sulfate is added and dries, filters, is spin-dried for, crosses silica gel chromatograph column separating purification and obtains compound 8c, yield is
60%, m.p.:214-216 DEG C, HPLC purity:99.2%.
Nucleus magnetic hydrogen spectrum, nuclear-magnetism carbon spectrum and Mass Spectrometer Method are carried out to intermediate 7c, as a result are as follows:1H NMR(DMSO-d6,
400MHz) δ: 1.51 (s, 6H), 5.73 (d, J=10.0Hz, 1H), 5.89 (s, 1H), 6.81 (d, J=10.0Hz, 1H),
6.87-6.92 (m, 2H), 6.97-7.02 (m, 1H), 7.06 (t, J=8.0Hz, 1H), 7.96 (s, 1H), 8.07 (d, J=
8.8Hz,1H)；13C NMR (DMSO-d6,100MHz)δ:27.6,77.9,109.1,114.1,115.2,117.5,117.8,
120.1,120.6,120.7,121.4, 123.9,125.9,131.5,145.0,145.1,151.7,154.5,156.8,
173.6；MS(ESI):m/z calcd.C20H16FO4 [M+H]+339.10,found 339.22。
Comparative example 6
In this comparative example, compound 8i is synthesized, synthetic route and steps are as follows:
Under stiring, intermediate 7c (0.2mmol) and triethylamine (31 μ L, 0.22mmol) are added sequentially to the two of 3mL
It in chloromethanes, is stirred at room temperature 15 minutes, isocyanide ester (0.22mol) is added later and reacts 6 hours, gained is reacted and is mixed
Object is concentrated under reduced pressure, and obtains compound 8i after silica gel column chromatography filters, yield 48%, and m.p.:183-185 DEG C, HPLC
Purity:98.2 %.
Nucleus magnetic hydrogen spectrum, nuclear-magnetism carbon spectrum and Mass Spectrometer Method are carried out to compound 8i, as a result are as follows:1H NMR(CDCl3,400MHz)
δ: 1.16 (d, J=7.2Hz, 6H), 1.43 (s, 6H), 2.77-2.84 (m, 1H), 5.65 (d, J=10.0Hz, 1H), 6.73
(d, J=10.0Hz, 1H), 6.79 (d, J=8.8Hz, 1H), 7.10-7.18 (m, 5H), 7.31 (d, J=7.6Hz, 2H),
7.49 (d, J=7.6 Hz, 2H), 7.87 (s, 1H), 8.0 (d, J=8.8Hz, 1H)；13C NMR(CDCl3,100MHz)δ:
24.2,28.3,33.7,77.9, 109.4,115.0,115.5,118.4,119.1,121.8,121.9,124.5,126.8,
127.1,129.4,130.2,130.5,135.2, 144.7,150.7,151.8,152.5,157.5,175.9；MS(ESI):m/
z calcd.C30H28NO5[M+H]+482.20,found 482.21。
Embodiment 8
In the present embodiment, according to document and optimize anticholinesterase screening model (be specifically shown in Tu Y, Zhong Y,
Du H, et al.Anticholinesterases and antioxidant alkamides from Piper nigrum
Fruits [J] .Natural Product Research, 2015,30 (17): 1945-1949.), to above-described embodiment and comparison
Compound 8a~8i of example synthesis carries out Activity determination, using galanthamine (galantamine) and Tacrine (tacrine) as
Positive control.
The results are shown in Table 1, and as shown in Table 1, compound 8a, 8b, 8c and 8d provided by the invention can selective depressions
The activity of BuChE and to the activity of AChE without obvious inhibiting effect, there is excellent selectivity, and have to the activity of BuChE
Good inhibiting effect.
1 compound of table inhibits the activity of AChE and BuChE in vitro
The inhibitory activity IC of a AChE50(μM) or 10 μM of inhibiting rate expression, IC50Value is independent experiment three times
Average value ± SEM, illustrates the IC of compound when being indicated with 10 μM of inhibiting rate50Be worth it is excessively high, without practical application value.
B selectivity=(IC50on BuChE)/(IC50on AChE) 。
Claims (10)
1. isoflavone compound, which is characterized in that shown in the structural formula of the isoflavone compound such as formula (I),
In formula (I), R isOr
2. the pharmaceutically acceptable salt of isoflavone compound described in claim 1.
3. the pharmaceutically acceptable hydrate of isoflavone compound described in claim 1.
4. the preparation method of isoflavone compound described in claim 1, which is characterized in that synthetic route and steps are as follows:
(1) dichloromethane solution of 3,4- dihydro -2H- pyrans is added dropwise to the dichloromethane of raw material 1 and para-methylbenzenepyridinsulfonate sulfonate
In alkane solution, it is stirred to react 4~6h, is extracted with dichloromethane after being cleaned with saturated sodium bicarbonate solution, is removed in organic phase
Water, evaporating solvent under reduced pressure obtain intermediate 1；
Intermediate 1 is suspended in n,N-Dimethylformamide dimethylacetal, 3~5h of back flow reaction is cooled to room temperature, decompression
Solvent is evaporated off, obtains intermediate 2；
Intermediate 2 is dissolved in CHCl3In, pyridine, I is added2, it is stirred to react 10~14h, saturation Na is added2S2O3Solution stirring is anti-
0.5~1h is answered, uses CH later2Cl2Extraction removes the water in organic phase, is spin-dried for, and crosses silica gel chromatograph column separating purification, obtains centre
Body 3；
Intermediate 3, p-methyl benzenesulfonic acid are added in the mixed solution of methanol and tetrahydrofuran, 1~2h of back flow reaction is cooled to
Room temperature, evaporating solvent under reduced pressure wash by products therefrom with ethyl acetate is dissolved in, remove moisture, be spin-dried for, obtain intermediate 4；
(2) 3- methyl-2-butene aldehyde, potassium acid sulfate and triethyl orthoformate are added in ethyl alcohol under conditions of 0 DEG C, at 0 DEG C
0.5~1h is reacted, 0.5~1h of reaction is then stirred at room temperature, gained reaction solution is filtered and used ethanol washing, into filtrate
Potassium carbonate is added and is stirred to react 1~3h, filters, filtrate decompression is concentrated, the crude product of intermediate 5 is obtained；
Intermediate 4, the crude product of intermediate 5,3- picoline are added in dimethylbenzene, 22~26h of back flow reaction is cooled to room
Temperature, evaporating solvent under reduced pressure cross silica gel chromatograph column separating purification, obtain intermediate 6；
(3) by intermediate 6, Na2CO3, (2- hydroxy phenyl) boric acid, Pd/C be added in the mixed liquor of glycol dimethyl ether and water,
45~50 DEG C of 0.5~1h of reaction cross diatomite and remove solid, gained filtrate is used CH2Cl2Extraction removes the water in organic phase,
It is spin-dried for, crosses silica gel chromatograph column separating purification, obtain intermediate 7a；
By intermediate 6, Na2CO3, (3- hydroxy phenyl) boric acid, Pd/C be added in the mixed liquor of glycol dimethyl ether and water, 45
~50 DEG C of 0.5~1h of reaction cross diatomite and remove solid, gained filtrate is used CH2Cl2Extraction removes the water in organic phase, rotation
It is dry, silica gel chromatograph column separating purification is crossed, intermediate 7b is obtained；
(4) intermediate 8a, triethylamine are dissolved in methylene chloride, isocyanide heptyl heptylate is then added and reacts 5~7h, depressurizes dense
Contracting crosses silica gel chromatograph column separating purification, obtains compound 8a；
Compound 8b, potassium carbonate are added in the mixed solution of n,N-Dimethylformamide and acetonitrile and form mixed liquor A, by N, N-
For the acetonitrile solution dropwise of dimethylcarbamyl chloride into mixed liquor A, 3~4h of back flow reaction uses dilute hydrochloric acid after being cooled to room temperature
Then washing plus water and is extracted with ethyl acetate, with saturated common salt water washing organic phase, remove the water in organic phase, depressurize dense
Contracting crosses silica gel chromatograph column separating purification, obtains compound 8b；
Compound 8b, triethylamine are dissolved in methylene chloride, isocyanide heptyl heptylate is then added and reacts 5~7h, is concentrated under reduced pressure, warp
Silica gel chromatograph column separating purification obtains compound 8c；
Compound 8b, triethylamine are dissolved in methylene chloride, 2- phenethyl isocyanates is then added and reacts 5~7h, decompression
Concentration, through silica gel chromatograph column separating purification, obtains compound 8d.
5. the preparation method of isoflavone compound according to claim 4, which is characterized in that in step (1), synthesis is intermediate
When body 1, the molar ratio of 3,4- dihydro -2H- pyrans and raw material 1 is (3~4): 1, mole of para-methylbenzenepyridinsulfonate sulfonate and raw material 1
Than for (0.03~0.1)；When synthetic intermediate 2, the additional amount of n,N-Dimethylformamide dimethylacetal is 1 mole of raw material
1.5~2 times；When synthetic intermediate 3, pyridine, I2Additional amount be respectively 1.1~1.5 times of 1 mole of raw material, 2~2.5
Times；When synthetic intermediate 4, the molar ratio of intermediate 3 and p-methyl benzenesulfonic acid is (10~12): 1；In step (2), synthesis is intermediate
When body 5, the molar ratio of 3- methyl-2-butene aldehyde and triethyl orthoformate is 1:(1~1.2), potassium acid sulfate and 3- methyl -2- fourth
The molar ratio of olefine aldehydr is (0.05~0.1): 1；When synthetic intermediate 6, the additional amount of intermediate 4 is that 3- methyl-2-butene aldehyde rubs
The molar ratio of 0.1~0.5 times of that amount, 3- picoline and intermediate 4 is (0.03~0.1): 1.
6. the preparation method of isoflavone compound according to claim 4 or 5, which is characterized in that in step (3), synthesis
When intermediate 7a, the molar ratio of (2- hydroxy phenyl) boric acid and intermediate 6 is 1:(1.1~1.4), Na2CO3Additional amount be
3~4 times of 6 mole of mesosome, the additional amount of Pd/C should make the 5%~8% of 6 mole of mole intermediate of Pd；Synthesis
When intermediate 7b, the molar ratio of (3- hydroxy phenyl) boric acid and intermediate 6 is 1:(1.1~1.4), Na2CO3Additional amount be
3~4 times of 6 mole of mesosome, the additional amount of Pd/C should make the 5%~8% of 6 mole of mole intermediate of Pd.
7. the preparation method of isoflavone compound according to claim 4 or 5, which is characterized in that in step (4), synthesis
When compound 8a, the molar ratio of isocyanide heptyl heptylate, triethylamine and intermediate 7a is (1.1~1.3): (1.1~1.3): 1；Synthesis
When compound 8b, intermediate 7b and N, the molar ratio of N- dimethylcarbamyl chloride are 1:(1.1~1.3), the addition of potassium carbonate
Amount is 3~4 times of intermediate 7b mole；When synthesizing compound 8c, the molar ratio of isocyanide heptyl heptylate, triethylamine and intermediate 7
For (1.1~1.3): (1.1~1.3): 1；When synthesizing compound 8d, 2- phenethyl isocyanates, triethylamine and intermediate 7b
Molar ratio is (1.1~1.3): (1.1~1.3): 1.
8. isoflavone compound described in claim 1 is preparing the application in the drug using butyrylcholine esterase as target spot.
9. pharmaceutically acceptable salt is being prepared using butyrylcholine esterase as target spot isoflavone compound described in claim 1
Drug in application.
10. pharmaceutically acceptable hydrate is being prepared with butyrylcholine esterase isoflavone compound described in claim 1
For the application in the drug of target spot.
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| CN112226504B (en) * | 2020-10-21 | 2021-06-08 | 北京市劳动保护科学研究所 | Application of BuChE gene SNP locus and kit for analyzing and detecting susceptibility of anabasine pesticide contact population to high TG blood disease |
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