CN107759551A - A kind of synthetic method of breviscapine B aglycone - Google Patents

A kind of synthetic method of breviscapine B aglycone Download PDF

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CN107759551A
CN107759551A CN201610899232.4A CN201610899232A CN107759551A CN 107759551 A CN107759551 A CN 107759551A CN 201610899232 A CN201610899232 A CN 201610899232A CN 107759551 A CN107759551 A CN 107759551A
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CN107759551B (en
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李润涛
和芳
王书成
王�琦
樊献俄
曾立品
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KUNMING LONGJIN PHARMACEUTICAL CO Ltd
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    • C07C69/00Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
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    • C07D311/30Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Abstract

The invention provides a kind of synthetic method of breviscapine B aglycone, compound with formula (I) structure reacts compound of the generation with structure shown in formula (2 8) through step (1) oxidative cyclization, and the compound with structure shown in formula (2 8) is carried out step (2) shown in demethylating reaction generation target compound such as formula (1 2);Wherein, R is selected from C that is unsubstituted or arbitrarily being substituted by a phenyl2~C5It is alkanoyl, unsubstituted or arbitrarily by C1~C5Alkyl-substituted benzoyl.This method synthesis technique is simple, mild condition, high income, and total recovery reaches as high as 80.4%, has good prospects for commercial application.

Description

A kind of synthetic method of breviscapine B aglycone
Technical field
The present invention relates to the fully synthetic of biological active constituents from natural medicines, and in particular to a kind of synthesis side of breviscapine B aglycone Method.
Background technology
Erigeron breviscapus is commonly called as fleabane flower, is short booth bitter fleabane Erigerm breviscapus (Vant.) Hand- of feverfew Mass drying herb, head are seen written by the blue only Buddhist nunnery of Ming Dynasty physician《The southern regions of the Yunnan Province book on Chinese herbal medicine》, meaning:" fleabane flower, bitter is warm-natured, can control Rheumatalgia pain ".《Yunnan Chinese herbal medicine》Fleabane flower is clearly stated to cure mainly cold dispelling, inducing diaphoresis, activate blood and relax tendons, cold headache nasal obstruction, bruise Damage etc..Breviscapinun is the general name of the flavonoids effective constituent extracted from fleabane flower.The fleabane flower clinically used at present Similar drug be all using Breviscapinun as main active, its main pharmacological components be lamp-dish flower acetic (1-1, Scutellarin, also known as scutellarin, molecular formula:C21H18O12, molecular weight:462.37, CAS:27740-01-8).《Middle traditional Chinese medicines Allusion quotation》In the Breviscapinun quality standard that version in 2015 is recorded, the Breviscapinun raw material of injection is not less than containing scutellarin 98.0%, the Breviscapinun raw material of pro ore is not less than 90.0% containing scutellarin.Modern pharmacological research shows, fleabane flower second Element has increase cerebral blood flow (CBF), reduces vascular resistence, antiplatelet, erythrocyte aggregation, reduces the effect such as blood viscosity.
Lamp-dish flower acetic (1-1) structure
The bulk drug of presently commercially available lamp-dish flower acetic class preparation is all to extract and obtain from plant erigeron breviscapus, is prepared Journey is as follows:Erigeron breviscapus complete stool is ground into coarse powder, using certain density ethanol water heating and refluxing extraction, system filters And concentrate, concentrate is with hot water dissolving, then removes the fat-soluble organic compound in part with ether and ethyl acetate respectively, and water layer adds Saturated acetic acid lead, yellow solid being separated out, filtered, filter cake acid adding takes off lead, and obtained yellow solid carries out polyamide column chromatography again, point Lamp-dish flower acetic and fleabane flower A prime are not obtained.Market lamp-dish flower acetic is obtained by this traditional extracting method.
At present, market reaches 100 tons/year to the demand of lamp-dish flower acetic, and future will be more, and the recovery rate from plant Less than 2.5%.Therefore, up to ten thousand mu of fleabane flowers are planted every year in Southwestern China area to extract lamp-dish flower acetic.Plant extract The problem of lamp-dish flower acetic is present be:(1) plant erigeron breviscapus and take substantial amounts of land resource, while the quality of product is by environment Have a great influence;(2) lamp-dish flower acetic content is low in erigeron breviscapus, causes recovery rate low, and cost is high;(3) quality of extraction is unstable It is fixed.And there is raw material preparation difficulty in the method for chemical synthesis at present, reaction yield is low, reagent price is expensive, synthetic route length The shortcomings of, it is not suitable for industrialized production.
Synthesis of the prior art to lamp-dish flower acetic carried out exploration, but existing synthetic method has many limitations.
Lamp-dish flower acetic is essentially all to be synthesized by wherein mesosome breviscapine B aglycone (1-2, Scutellarien) 's.
The chemical constitution of lamp-dish flower acetic (1-1) and breviscapine B aglycone (1-2)
The synthesis for the breviscapine B aglycone reported mainly has five routes as follows:
Route 1:1974, Germany scientist L.Farkas reported the synthesis of breviscapine B aglycone first, they with 2,5- dihydroxy -4,6- dimethoxy-acetophenones (1-3) are raw material, by with parahydroxyben-zaldehyde occur aldol condensation cyclization, Dehydrogenation bromic acid and demethylation four-step reaction under bromo, strong alkaline condition under ultraviolet irradiation, obtain compound (1-2).The synthesis It is only 4% that the raw material (1-3) of route is expensive, needs to use the larger bromine of toxicity, total recovery, therefore can not be applied to rule Modelling produces.
Route 2:1999, McGarry Lynda W etc. reported synthetic route 2.They utilize 3,4,5- trimethoxies Phenol (1-5) and be raw material to methoxybenzene propiolic acid, intermediate (1- is obtained by O-Michael additions and intramolecular cyclization 11), then demethylation obtains breviscapine B aglycone (1-2).The raw material (1-5) that is used in the route and to methoxybenzene propine Acid is all not easy purchase and expensive, and overall yield of reaction is also not suitable in a large amount of productions less than 5%.
Route 3:2005, Wu Song etc. reported route 3.They are with 2- hydroxyl -4,5,6- trimethoxies acetophenones (1-4) For raw material, by occur successively with anisoyl chloride Baker-Venkataraman reactions, Intra-molecular condensation and Demethylating reaction, success are efficiently prepared for breviscapine B aglycone (1-2), and three step total recoverys have reached 45%.It is but insufficient Part is that raw material (1-4) is not easy to prepare and (obtained for raw material by 1-5), expensive.
Route 4:2009, Yang Jian et al. reported route 4.They are with 2- hydroxyl -4,5,6- trimethoxy acetophenones (1-4) is raw material, reacts to obtain compound (1-10) by the way that Claisen-Schmidt occurs with P-methoxybenzal-dehyde;Then Oxidative cyclization, demethylation obtain breviscapine B aglycone (1-2), and total recovery reaches 70%, likewise, raw material (1-4) is not easy to make Standby (being obtained by 1-5 for raw material), it is expensive.
Route 5:2012, Liu Xiang et al. reported route 5.With 3,4,5- trimethoxies phenol (1-5) and to methoxyl group Cinnamoyl chloride is raw material, is reacted by Friedel-Crafts, aoxidizes cyclization, demethylation three-step reaction, and fleabane flower is quickly made B prime aglycon (1-2), yield 54%.
5 synthetic routes of breviscapine B aglycone (1-2) in the prior art
Analysis said synthesis route can be seen that:The expensive starting materials of route 1, severe reaction conditions and yield are extremely low, can not Large-scale production can be used for;For initiation material, key is obtained through acylation with 3,4,5- trimethoxy phenol (1-5) by route 2-5 Intermediate (1-4), although yield is also possible that initiation material (1-5) expensive, (oxidizable) not easy to maintain, lack suitable Together in the synthetic method of industrialized production.
The preparation of compound (1-5) mainly has two methods as follows at present:
The synthetic route of 3,4,5- trimethoxies phenol (1-5)
Method 1:Using 3,4,5-Trimethoxybenzaldehyde as raw material, one-step synthesis 3 is reacted by Baeyer-Villiger, 4,5- trimethoxy phenol, but due to containing three methoxyl groups on the phenyl ring of substrate 3,4,5-Trimethoxybenzaldehyde, reaction In be easier to be oxidized to 3,4,5- trimethoxybenzoic acids and benzoquinones so that reaction yield only has 20%, post processing trouble, because And be not suitable for industrialized production.
Method 2:With 3,4,5- trimethoxybenzoic acids for raw material, pass through acylation, ammonification, Hofmann degradeds, diazotising four Step reaction prepares 3,4,5- trimethoxy phenol, and total recovery reaches 45%.But this method is still not suitable for industrializing, because:(1) Use SOCl2Not only experimental implementation is dangerous, and can cause very serious environmental pollution;(2) diazo-reaction repeatability is not Good, yield is unstable, and reaction intermediate is azo explosive compound, has certain danger.
Certainly, also someone gets around (1-5) and obtains (1-4) in the prior art, but route is all long, and yield and pays no attention to Think.
The synthesis of the lamp-dish flower acetic of document report for raw material, passes through the full second of hydroxyl with breviscapine B aglycone (1-2) Acylated, 7 acetyl group are optionally replaced by benzyl, debenzylation, glycosylation, finally hydrolysis deacetylation obtains lamp-dish flower acetic (1-1), total recovery is less than 20%.
The synthetic route of prior art oil lamp flower B prime (1-1)
The synthetic route of above lamp-dish flower acetic (1-1) is analyzed, following shortcoming be present:(1) protection group strategy makes With, hence it is evident that add the difficulty of reaction scheme and experimental implementation;(2) debenzylation needs to use the Pd/C of 0.25 equivalent, makes cost Greatly increase;(3) in glycosylation reaction, Ag2O needs to use 1-2 equivalent, and cost is very high.
To sum up analyze, the Chinese patent drug lamp-dish flower acetic as important treatment cardiovascular and cerebrovascular disease is at present mainly from plant Extraction, the total synthesis method of industrialized production it is not suitable for.Problem present in the existing fully synthetic route of lamp-dish flower acetic Have:(1) synthetic route of key intermediate breviscapine B aglycone is mostly with compound (1-5) for raw material, and compound (1-5) Synthesis the problems such as low yield, seriously polluted or operating difficulties be present, this is also to be deposited in the fully synthetic technique of current lamp-dish flower acetic Key issue;(2) breviscapine B aglycone (1-2) reacts to obtain lamp-dish flower acetic by 5 steps, and route is longer, and uses A large amount of expensive reagents, production cost is too high, is not suitable for a large amount of preparations of lamp-dish flower acetic.
Therefore, researching and developing a fully synthetic route that is brand-new, being suitable for preparation of industrialization lamp-dish flower acetic can not only substitute Plant extraction method, the land resource of preciousness is saved, ensure the quality of product, meanwhile, also it is the further investigation of lamp-dish flower acetic, hair Now treatment cardiovascular and cerebrovascular kind new medicine lays the foundation.
The content of the invention
In order to solve problem above, the invention provides the compound of one kind as shown in formula (I) and preparation method thereof, and carry Application of the compound shown in formula (I) in breviscapine B aglycone or lamp-dish flower acetic is prepared has been supplied, and with formula (I) Suo Shi Compound method that breviscapine B aglycone or lamp-dish flower acetic are synthesized for initiation material.
The present invention is achieved by the following technical solutions:
On the one hand, the invention provides a kind of formula (I) shown in compound,
Wherein, R is selected from C that is unsubstituted or arbitrarily being substituted by a phenyl2~C5It is alkanoyl, unsubstituted or arbitrarily by C1~ C5Alkyl-substituted benzoyl;
Preferably, the R is selected from C that is unsubstituted or arbitrarily being substituted by a phenyl2~C3It is alkanoyl, unsubstituted or any By C1~C3Alkyl-substituted benzoyl;
Preferably, the R is selected from acetyl group, propiono, positive bytyry, isobutyryl, benzoyl, phenylacetyl group or benzene Propiono.
Preferably, the formula (I) is following compound:
Wherein, Ac represents acetyl group, and Me represents methyl, and Et represents ethyl, and Pr represents n-propyl, and i-Pr represents isopropyl, Ph represents phenyl.
Preferably, formula (I) compound is as shown in following formula (2-7):
Wherein, the compound of structure shown in formula (2-7), its chemical name are (Z/E) -4- hydroxyl -2,6- methoxyl groups -3- (3- (4- methoxyphenyls) acryloyl group) phenylacetate (is referred to as chalcone) in the embodiment of lower section.
On the other hand, the invention provides the preparation method of compound shown in above-mentioned formula (I), methods described to include formula (2- 6) the step of compound shown in is reacted with compound shown in formula (2-2):
Wherein, R is as defined above.
Preferably, the addition of compound (2-2) is 0.6~3 times of equivalent of compound (2-6), and preferably 1.2~3 times are worked as Amount, more preferably 1.5 times of equivalents.
Preferably, the reaction is carried out under weak basic condition, and the weak base is selected from pyridine, triethylamine, 4- dimethylaminos Pyridine, HMPA, Na2CO3、K2CO3In one or more, preferred triethylamine;Preferably, the weak base plus Enter 1.5~3 times of equivalents that amount is compound (2-6), preferably 2 times of equivalents.
Preferably, the reaction is carried out in the presence of a catalyst;Preferably, the catalyst is selected from phenylalanine, sweet One or more in propylhomoserin, proline, preferably proline;Preferably, the addition of the catalyst is compound (2-6) 0.5~1.5 times of equivalent, preferably 1 times of equivalent;
Preferably, it is described reaction carry out in the presence of solvent, it is preferable that the solvent be selected from benzene, toluene, methanol, ethanol, One or more in isopropanol, preferably methanol.
Preferably, the ratio between equivalent in the reaction between compound (2-2), weak base, catalyst and compound (2-6) is 1~3:1~3:1~3:1~3, preferably 1.5:2:1:1.
Preferably, after methods described is included in addition catalyst, compound (2-2), weak base, solvent, compound is added (2-6);
Preferably, 5 minutes to 4 hours are stirred at 5~40 DEG C before compound (2-6) is added, at preferably 25 DEG C, preferably 1 hour;
Preferably, after compound (2-6) is added, at 5~40 DEG C, stirring is continued 15~30 hours at preferably 25 DEG C, It is preferred that 20 hours;
Preferably, the step of methods described also includes adding water, suction filtration after the completion of reacting.
Preferably, above-claimed cpd (2-6) can be prepared by following reactions steps:
(1) compound shown in formula (2-4) is prepared in the oxidized reaction of compound shown in formula (2-3):
(2) compound shown in formula (2-5) is prepared through reduction reaction in compound (2-4):
(3) compound shown in formula (2-6) is prepared through friedel-crafts acylation in compound (2-5):
Wherein, R is as defined above.
Preferably, the step (1) is carried out in a solvent, the one kind or more of the solvent in acetone, acetonitrile, water Kind, preferably acetone;
Preferably, the oxidation system of oxidation reaction is H in the step (1)2O2/K3Fe(CN)6;Preferably, it is described H2O2Addition be compound (2-3) 1~6 times of equivalent, preferably 3 times of equivalents;
Preferably, the H2O2/K3Fe(CN)6Equivalent proportion be 30~60:1, preferably 42~43:1, most preferably 43:1;
Preferably, the step (1) comprises the following steps:By K3Fe(CN)6Be dissolved in the water, thereto add solvent and Compound (2-3), after 5~40 DEG C preferably 25 DEG C stir, add H2O2, it is preferably added to H2O2After 5~40 DEG C preferably 25 DEG C Under continue stirring 20 hours, separate out greenish yellow solid after, add water, filter;
Preferably, the step (2) is carried out in a solvent, and the solvent is water;
Preferably, needed in the step (2) add reducing agent, it is preferable that the addition of the reducing agent be no less than 1 times of equivalent of compound (2-4), preferably 1.5 times of equivalents;Preferably, the reducing agent is selected from sodium dithionite, even two sulfurous One or more in sour potassium, ferrous sulfate, sodium sulfite, sodium hydrogensulfite, preferably sodium dithionite;
Preferably, the step (2) comprises the following steps:After sequentially adding water, compound (2-4), reducing agent is added, instead System is answered to be heated to reflux 0.5~3 hour, preferably 1 hour, question response system is cooled down when becoming clarification by muddiness, separates out white Filter, be dried in vacuo after solid;
Preferably, the step (3) is carried out in a solvent, and the solvent is selected from dichloromethane, chloroform, 1,2- dichloroethanes In one or more, preferably dichloromethane;
Preferably, the step (3) is in BF3·Et2Carried out in the presence of O/ acylting agents;Preferably, BF3·Et2O's Addition be no less than compound (2-5) 3.5 times of equivalents, preferably 3.5 equivalents;Preferably, the compound (2-5) of addition, BF3·Et2O and Ac2O mass ratio is 1:2~5:2~8, preferably 1:2.9~3:4.7~5, most preferably 1:3:5;
Preferably, the step (3) comprises the following steps:Stirred after sequentially adding compound (2-5), solvent, catalyst system and catalyzing Mix and be heated to reflux 1~5 hour, preferably 3 hours, when a large amount of yellow solids separate out, cool down, filter.
Specifically, the invention provides compound (2-7) preparation method, methods described to include chemical combination shown in formula (2-6 ') The step of thing reacts with compound shown in formula (2-2):
Preferably, the addition of compound (2-2) is 0.6~3 times of equivalent of compound (2-6 '), and preferably 1.2~3 times are worked as Amount, more preferably 1.5 times of equivalents.
Preferably, the reaction is carried out under weak basic condition, and the weak base is selected from pyridine, triethylamine, 4- dimethylaminos Pyridine, HMPA, Na2CO3、K2CO3In one or more, preferred triethylamine;Preferably, the weak base plus Enter 1.5~3 times of equivalents that amount is compound (2-6 '), preferably 2 times of equivalents.
Preferably, the reaction is carried out in the presence of a catalyst;Preferably, the catalyst is selected from phenylalanine, sweet One or more in propylhomoserin, proline, preferably proline;Preferably, the addition of the catalyst is compound (2-6 ') 0.5~1.5 times of equivalent, preferably 1 times of equivalent;
Preferably, it is described reaction carry out in the presence of solvent, it is preferable that the solvent be selected from benzene, toluene, methanol, ethanol, One or more in isopropanol, preferably methanol.
Preferably, the ratio between equivalent in the reaction between compound (2-2), weak base, catalyst and compound (2-6 ') For 1~3:1~3:1~3:1~3, preferably 1.5:2:1:1.
Preferably, after methods described is included in addition catalyst, compound (2-2), weak base, solvent, compound is added (2-6’);
Preferably, stirred 5 minutes to 4 hours at preferably 25 DEG C at 5~40 DEG C before compound (2-6 ') is added, it is excellent Select 1 hour;
Preferably, after compound (2-6 ') is added, at 5~40 DEG C, stirring is continued 15~30 hours at preferably 25 DEG C, It is preferred that 20 hours;
Preferably, the step of methods described also includes adding water, suction filtration after the completion of reacting.
Preferably, in compound (2-7) preparation method, the compound (2-6 ') passes through following reactions steps system It is standby:
(1) compound shown in formula (2-4) is prepared in the oxidized reaction of compound shown in formula (2-3):
(2) compound shown in formula (2-5) is prepared through reduction reaction in compound (2-4):
(3) compound shown in formula (2-6 ') is prepared through friedel-crafts acylation in compound (2-5):
The step (1) is carried out in a solvent, one or more of the solvent in acetone, acetonitrile, water, and preferably third Ketone;
Preferably, the oxidation system of oxidation reaction is H in the step (1)2O2/K3Fe(CN)6;Preferably, it is described H2O2Addition be compound (2-3) 1~6 times of equivalent, preferably 3 times of equivalents;
Preferably, the H2O2/K3Fe(CN)6Equivalent proportion be 30~60:1, preferably 42~43:1, most preferably 43:1;
Preferably, the step (1) comprises the following steps:By K3Fe(CN)6Be dissolved in the water, thereto add solvent and Compound (2-3), after 5~40 DEG C preferably 25 DEG C stir, add H2O2, it is preferably added to H2O2After 5~40 DEG C preferably 25 DEG C Under continue stirring 20 hours, separate out greenish yellow solid after, add water, filter;
Preferably, the step (2) is carried out in a solvent, and the solvent is water;
Preferably, needed in the step (2) add reducing agent, it is preferable that the addition of the reducing agent be no less than 1 times of equivalent of compound (2-4), preferably 1.5 times of equivalents;Preferably, the reducing agent is selected from sodium dithionite, even two sulfurous One or more in sour potassium, ferrous sulfate, sodium sulfite, sodium hydrogensulfite, preferably sodium dithionite;
Preferably, the step (2) comprises the following steps:After sequentially adding water, compound (2-4), reducing agent is added, instead System is answered to be heated to reflux 0.5~3 hour, preferably 1 hour, question response system is cooled down when becoming clarification by muddiness, separates out white Filter, be dried in vacuo after solid;
Preferably, the step (3) is carried out in a solvent, and the solvent is selected from dichloromethane, chloroform, 1,2- dichloroethanes In one or more, preferably dichloromethane;
Preferably, the step (3) is in BF3·Et2O/Ac2Carried out in the presence of O;Preferably, BF3·Et2O addition is No less than 3.5 times of equivalents of compound (2-5), preferably 3.5 equivalents;Preferably, the compound (2-5) of addition, BF3·Et2O with Ac2O mass ratio is 1:2~5:2~8, preferably 1:2.9~3:4.7~5, most preferably 1:3:5;
Preferably, the step (3) comprises the following steps:Stirred after sequentially adding compound (2-5), solvent, catalyst system and catalyzing Mix and be heated to reflux 1~5 hour, preferably 3 hours, when a large amount of yellow solids separate out, cool down, filter.
Another aspect, present invention also offers compound shown in formula (I) in synthesis breviscapine B aglycone or fleabane flower second Application in plain compound.
Another further aspect, present invention also offers a kind of synthetic method of breviscapine B aglycone, methods described is with formula (I) compound of structure is through compound of step (1) oxidative cyclization reaction generation with structure shown in formula (2-8), to formula Step (2) progress demethylation is produced target compound by the compound of structure shown in (2-8), as shown in formula (1-2):
Wherein, R is as defined above.
Preferably, the step (1) is carried out in a solvent, and the solvent is aprotic polar solvent, it is preferable that described molten Agent is selected from dimethyl sulfoxide (DMSO), N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamides, ethylene glycol two One or more in methyl ether, preferably dimethyl sulfoxide (DMSO).
Preferably, the oxidant in the step (1) is I2;Preferably, the I2Addition for compound (2-7) 0.1~0.5 times of equivalent, preferably 0.3 times of equivalent.
Preferably, the reaction temperature of the step (1) is 80~120 DEG C, preferably 100 DEG C.
Preferably, the step (1) comprises the steps of:Sequentially add compound (I) (such as compound 2-7), DMSO, Oxidant, it is warming up to 80~120 DEG C, preferably 100 DEG C, preferably stirring reaction 8~12 hours, 8 hours, cooling, by reaction system Slowly to pour into sodium sulfite aqueous solution, the preferably concentration of sodium sulfite aqueous solution is 0.01-0.1g/ml, preferably 0.05g/ml, After stirring 0.5~2 hour, preferably 1 hour, filter, vacuum drying.
Preferably, the demethylation reagent of the step (2) is HBr/HOAc, pyridine hydrochloride or BF3·Et2One kind in O or It is a variety of, preferably HBr/HOAc;Preferably, the HBr is 48%HBr;Preferably, HBr and HOAc in the demethylation reagent Volumetric usage ratio is 3:8~8:3, preferably 1:1;Preferably, 48%HBr, HOAc relative to every 16g compounds (2-8) dosage Value is respectively 30~80ml, preferably 50ml.
Preferably, the reaction temperature of the step (2) is 100~130 DEG C, preferably 128 DEG C;Preferably, during the reaction Between be 10~48 hours, preferably 15 hours.
Preferably, the step (2) is cooled down after also including reaction, and reaction system is poured into frozen water, is taken out after separating out solid The step of filter, recrystallization;Preferably, the recrystallization solvent is selected from methanol, ethanol, propyl alcohol, isopropanol, n-butanol, acetic acid second One or more in ester, it is preferable that the recrystallization reagent is ethanol.
Preferably, the step (2) comprises the following steps:Compound (2-8) and demethylation reagent are sequentially added, is warming up to 100~130 DEG C, preferably 128 DEG C reaction 10~48 hours, preferably 15 hours after cool down, reaction system is poured into frozen water, separate out Filter, recrystallize after solid.
In addition, present invention also offers a kind of synthetic method of lamp-dish flower acetic, methods described is through step (1) by formula (I) The compound of structure shown in formula (1-2) is prepared in the oxidized cyclization of shown structure, demethylating reaction, then through step (2) by formula The compound of structure shown in (1-2) prepares generation target compound through acetylation, a step glycosylation reaction, hydrolysis, such as formula Shown in (1-1):
Wherein, R is as defined above.
Preferably, the compound of structure shown in formula (I) passes through oxidative cyclization the reaction generation such as following formula (2- in step (1) 8) compound of structure shown in:
Wherein, R is as defined above.
Preferably, the compound of structure shown in formula (1-2) passes through demethylating reaction production (1-2) institute in step (1) Show the compound of structure:
Preferably, the oxidative cyclization reaction is carried out in a solvent, and the solvent is aprotic polar solvent, it is preferable that The solvent is selected from dimethyl sulfoxide (DMSO), N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamides, second One or more in glycol dimethyl ether, preferably dimethyl sulfoxide (DMSO);
Preferably, the oxidant of the oxidative cyclization reaction is I2;Preferably, the I2Addition be compound (I) 0.1~0.5 times of equivalent, preferably 0.3 times of equivalent;
Preferably, the reaction temperature of the oxidative cyclization reaction is 80~120 DEG C, preferably 100 DEG C;
Preferably, the oxidative cyclization reaction comprises the steps of:Compound (I), DMSO, oxidant are sequentially added, is risen Temperature is to 80~120 DEG C, preferably 100 DEG C, stirring reaction 8~12 hours, preferably 8 hours, cooling, reaction system is slowly poured into Asia In aqueous sodium persulfate solution, preferably the concentration of sodium sulfite aqueous solution is 0.01-0.1g/ml, preferably 0.05g/ml, stirs 0.5~2 Hour, after preferably 1 hour, filter, vacuum drying.
Preferably, the demethylation reagent of the demethylating reaction is HBr/HOAc, pyridine hydrochloride or BF3·Et2One in O Kind or a variety of, preferably HBr/HOAc;Preferably, the HBr is 48%HBr;Preferably, in the demethylation reagent HBr with HOAc volumetric usage ratio is 3:8~8:3, preferably 1:1;Preferably, 48%HBr, HOAc are relative to every 16g compounds (2-8) Volume value be respectively 30~80ml, preferably 50ml;
Preferably, the reaction temperature of the demethylating reaction is 100~130 DEG C, preferably 128 DEG C;Preferably, the reaction Time is 10~48 hours, preferably 15 hours;
Preferably, cooling is also included after the completion of the reaction, reaction system is poured into frozen water, filtered after precipitation solid, The step of recrystallization;Preferably, the recrystallization solvent is in methanol, ethanol, propyl alcohol, isopropanol, n-butanol, ethyl acetate One or more, it is preferable that it is described recrystallization reagent be ethanol;
Preferably, the demethylating reaction comprises the following steps:Compound (2-8) and demethylation reagent are sequentially added, is risen Temperature to 100~130 DEG C, preferably 128 DEG C reaction 10~48 hours, preferably 15 hours after cool down, reaction system is poured into frozen water, Filtered after precipitation solid, recrystallization.
Preferably, the compound of structure shown in formula (1-2) is through the acetylization reaction generation such as following formula (1-12) in step (2) The compound of shown structure:
Preferably, the compound of structure shown in the compound of structure shown in formula (1-12) and formula (1-15) is through in step (2) A step glycosylation reaction generate as shown in following formula (1-16) structure compound:
Preferably, the compound of structure shown in formula (1-16) is through the hydrolysis Deprotection production (1- in step (2) 1) compound of structure shown in.
Preferably, the acetylation reagent of the acetylization reaction is sodium acetate-acetic acid acid anhydride or pyridine-acetic anhydride, preferably second Sour sodium-acetic anhydride;Preferably, the dosage mol ratio of the acetic anhydride and sodium acetate is 2~5:1, preferably 2:1;Preferably, institute State sodium acetate addition be compound (1-2) 4~8 times of equivalents, preferably 5 times of equivalents;Preferably, the compound (1-2) Mole dosage ratio with acetic anhydride, sodium acetate is 1:10~20:4~8, preferably 1:10:5;
Preferably, the reaction temperature of the acetylization reaction is 60~100 DEG C, preferably 80 DEG C;Preferably, during the reaction Between be 8~10 hours, preferably 10 hours;
Preferably, after the completion of the reaction, in addition to reaction system poured into frozen water, filter, recrystallization the step of;It is excellent Selection of land, the recrystallization reagent is ethyl acetate/methanol;
Preferably, the acetylization reaction comprises the following steps:Compound (1-2), acetic anhydride, sodium acetate are sequentially added, Reaction is warming up to 60~100 DEG C, preferably 80 DEG C are reacted 8~10 hours, preferably 10 hours, are reacted after terminating, by reaction system Pour into frozen water, filter, recrystallization.
Preferably, in the step glycosylation reaction, the compound (1-15), which is divided 1~5 time, to be added in reaction;
Preferably, the addition first of compound (1-15) is 2 times of equivalents of compound (1-12);
Preferably, compound (1-15) is divided 3 times and is added in reaction, the addition of the 3rd time of preferred compound (1-15) Addition no less than the 2nd time;Preferably, the addition of the 2nd time is 0.7 times of equivalent of compound (1-12);Preferably, the 3rd Secondary addition be compound (1-12) 0.7~1 times of equivalent, preferably 0.7 times of equivalent;
Preferably, compound (1-15) is added every time to react 12 hours afterwards;
Preferably, the step glycosylation reaction is carried out in a solvent, and the solvent is CH3CN;
Preferably, the step glycosylation reaction is carried out in the presence of a catalyst, and the catalyst is selected from tetrabutyl phosphonium bromide Ammonium, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, 5- azepines [4.4] nonane bromide, the hydrogenation of 5- azepines [4.4] nonane sulfuric acid One or more in thing, polyethylene glycol, more preferably TBAB or tetrabutylammonium iodide, most preferably tetrabutyl bromine Change ammonium;Preferably, the addition of the catalyst be compound (1-12) 0.8~1.5 times of equivalent, preferably 1.2 times of equivalents;
Preferably, the step glycosylation reaction is carried out in the presence of a base, and the alkali is selected from Na2CO3、NaHCO3、KOH、 KHCO3、K2CO3In one or more;Preferably, the alkali is K2CO3;Preferably, the addition of the alkali is compound (1- 12) 2~5 times of equivalents, preferably 3 times of equivalents;
Preferably, the reaction temperature of the step glycosylation reaction is 30~45 DEG C, preferably 40 DEG C;
Preferably, can be added selected from Na in the glycosylation reaction of a step2SO4、MgSO4、CaSO4In one kind or A variety of salt, preferably CaSO4;Preferably, the CaSO4Addition be compound (1-12) 2~4 times of equivalents, preferably 3 times work as Amount;
Preferably, after the reaction terminates, in addition to filter, washing, the preferred extraction of aqueous phase extracted merge organic afterwards three times The step of phase, drying, concentration, recrystallization;Preferably, the extraction agent is selected from ethyl acetate, chloroform, the chloroethenes of 1,2- bis- One or more in alkane or dichloromethane.
Preferably, the hydrolysis is carried out in the presence of solvent, and the solvent is acetone and/or water;
Preferably, the hydrolysis is carried out in the presence of a base, and the alkali is selected from NaOH, NaHCO3, in KOH solution one Kind is a variety of, it is preferable that the concentration of the aqueous slkali is 1~3mol/L;
Preferably, in hydrolysis, the aqueous slkali is slowly added dropwise under ice bath, after being added dropwise to complete preferably under ice bath Stirring 30 minutes to 1 hour, preferably 1 hour;
Preferably, after the completion of the reaction, in addition to the step of regulation pH, suction filtration, recrystallization;Preferably, the pH value Adjust to 3~4;Preferably, one or more of the recrystallization reagent in ethanol, methanol, isopropanol, acetone, water.
Preferably, the synthesis of compound (1-1) comprises the following steps:
A) compound (I) (such as compound 2-7) of inventory, ring-closure reaction solvent, oxidant are sequentially added, is warming up to 80~120 DEG C, preferably 100 DEG C, stirring reaction 8~12 hours, preferably 8 hours, cooling, reaction system is slowly poured into sulfurous acid In sodium water solution, preferably the concentration of sodium sulfite aqueous solution is 0.01-0.1g/ml, preferably 0.05g/ml, and stirring 0.5~2 is small When, after preferably 1 hour, filter, obtain compound (2-8) after vacuum drying;
B) compound (2-8) (such as compound 2-8 ', i.e. R are acetyl group), the demethylation reagent of inventory are sequentially added, It is warming up to 100~130 DEG C, preferably 128 DEG C reactions are cooled down after 10~48 hours, preferably 15 hours, and reaction system is poured into frozen water In, filtered after precipitation solid, recrystallization obtains compound (1-2) after being dried under reduced pressure;
C) compound (1-2), the acetylation reagent of inventory are sequentially added, reaction is warming up to 60~100 DEG C, preferably 80 DEG C reaction 8~10 hours, preferably 10 hours, reaction terminate after, reaction system is poured into frozen water, is filtered, recrystallized, done It is dry to obtain compound (1-12);
D) compound (1-12) of inventory, catalyst are sequentially added, alkali, acetonitrile, adds compound (1- point for 1~5 time 15), in 30~45 DEG C under the conditions of solid-liquid two-phase, quick stirring 5~12 hours at preferably 40 DEG C, preferably 12 hours, reaction knot Shu Hou, filtering, is washed till colourless with solvent, steams solvent, water is added into residue, is extracted 3 times with extractant, merges extraction Liquid, drying, concentrate, be recrystallized to give compound (1-16);Preferably, compound (1-15) is added every time to stir 12 hours afterwards;
E) under nitrogen protection, the compound (1-16) and reaction dissolvent of inventory are sequentially added, under condition of ice bath slowly Aqueous slkali is added dropwise, stirs 0.5~2 hour, preferably 1 hour, acid solution regulation pH to 3~4 is slowly added dropwise, it is small to continue stirring 0.5~2 When, preferably 30 minutes, filter, be recrystallized to give compound (1-1).
Compared with prior art, the invention has the advantages that:
(1) synthesis of key intermediate formula (I) compound, using cheap, nontoxic amino acid as catalyst, room temperature Reaction, high income, post processing is simple, cheap and easily-available.
(2) breviscapine B aglycone is that the synthesis of compound (1-2) is anti-for the oxidized cyclization of initiation material with compound (I) Answer and the synthesis technique of demethylating reaction, total recovery reach as high as 80.4%.
(3) lamp-dish flower acetic be compound (1-1) it is fully synthetic with compound (I) for initiation material, reacted through 5 steps Into, the yield of reaction is often walked more than 80%, total recovery is high, and with synthetic route is succinct, reaction condition is gentle, operation letter Single (without column chromatography), environmental pollution are small, high income, low cost and other advantages.
(4) compared with traditional scheme, in compound (1-1) synthesis, compound (1-12) passes through selective glycosylation Single step reaction generation compound (1-16), and it is chemical combination that the synthesis of compound (1-12) to (1-16), which needs three steps, in traditional scheme 7 selectivity displacements upper benzyl (1-13), catalytic hydrogenation debenzylation (1-14) and the O- glycosylations (1-16) of thing (1-12), so Reaction scheme is just substantially reduced, has saved reaction cost;In addition, phase transfer catalysis (PTC) is taken in the synthesis of key intermediate (1-16) (PTC) a step glycosidation, the protection in conventional method and the use of deprotection steps and expensive reagent be it also avoid.
(5) compared with prior art, such as, The method that key intermediate (1-16) is prepared by compound (1-12), using acetonitrile as solvent, the mode of fixed quantity is taken by bromine Sugared (1-15) is added portionwise in reaction system, greatly reduces the usage amount of reagent, reaction yield also gets a promotion;In addition, In last handling process, solid base is removed by filtration first, the method then extracted again, is not only more convenient post processing, moreover, Solid base can recycle, and reach reduction pollution, reduce the purpose of cost.
Brief description of the drawings
The following drawings to aid in illustrating embodiment of the present invention, wherein:
Compound shown in the formula (2-7) that Fig. 1 is prepared for embodiment 41H NMR spectras;
Compound shown in the formula (2-7) that Fig. 2 is prepared for embodiment 413C NMR spectras;
Compound shown in the formula (2-8 ') that Fig. 3 is prepared for embodiment 51H NMR spectras;
Compound shown in the formula (2-8 ') that Fig. 4 is prepared for embodiment 513C NMR spectras;
Fig. 5 is compound shown in the formula (2-12) obtained during embodiment 4 is explored1H NMR spectras;
Fig. 6 is compound shown in the formula (2-12) obtained during embodiment 4 is explored13C NMR spectras;
Compound shown in the formula (1-2) that Fig. 7 is prepared for embodiment 61H NMR spectras;
Compound shown in the formula (1-2) that Fig. 8 is prepared for embodiment 613C NMR spectras;
Compound shown in the formula (1-12) that Fig. 9 is prepared for embodiment 71H NMR spectras;
Compound shown in the formula (1-12) that Figure 10 is prepared for embodiment 713C NMR spectras;
Compound shown in the formula (1-15) that Figure 11 is prepared for embodiment 91H NMR spectras;
Compound shown in the formula (1-15) that Figure 12 is prepared for embodiment 913C NMR spectras;
Compound shown in the formula (1-16) that Figure 13 is prepared for embodiment 101H NMR spectras;
Compound shown in the formula (1-16) that Figure 14 is prepared for embodiment 1013C NMR spectras;
Compound shown in the formula (1-19) that Figure 15 is prepared for embodiment 81H NMR spectras;
Compound shown in the formula (1-19) that Figure 16 is prepared for embodiment 813C NMR spectras;
Compound shown in the formula (1-1) that Figure 17 is prepared for embodiment 111H NMR spectras;
Compound shown in the formula (1-1) that Figure 18 is prepared for embodiment 1113C NMR spectras;
Compound shown in the lamp-dish flower acetic composite i.e. formula (1-1) that Figure 19 is prepared for embodiment 11 and fleabane flower second The HPLC comparison diagrams of plain standard items, wherein, a represents lamp-dish flower acetic standard items, and b represents that lamp-dish flower acetic composite is embodiment Compound shown in 11 formulas being prepared (1-1).
Embodiment
The present invention is further elaborated with reference to specific embodiment.It should be appreciated that the embodiment that the present invention provides The present invention is merely to illustrate, the scope being not intended to limit the invention.
Unless otherwise defined, anticipated known to all specialties used in text and scientific words and one skilled in the art Justice is identical, and the preferable implementation described in text only presents a demonstration with material to be used.
Experimental method in following embodiments, it is conventional method unless otherwise specified.Medicine used in following embodiments Material raw material, reagent material etc., be that commercially available commercially available chemistry is pure or AR unless otherwise specified, can through processing or Directly used without processing.
Instrument and equipment
TLC:Anhui Liang Chen silicon source materials factory tlc silica gel plate GF254.
Column chromatography:Haiyang Chemical Plant, Qingdao's silica gel 200-300 mesh.
Melting point apparatus:X-4 type micro-meldometers, thermometer be not calibrated.
NMR:Bruker AVIII-400(400MHz).
High resolution mass spectrum:Bruker Apex IV mass spectrographs.
Embodiment 1
The synthesis of 2,6- dimethoxy-benzoquinones (2-4)
Preparation example 1:
In 500mL conical flasks, by K3Fe(CN)6(2.0g, 7.0mmol) is dissolved in water (10.0g), adds third thereto Ketone (100g) and 1,3,5- trimethoxy-benzenes (2-3) (16.4g, 100mmol), after 25 DEG C stir, adds H thereto2O2 (30%, 34g, 300mmol), 20h is stirred at 25 DEG C, separates out greenish yellow solid, water (200mL) is added to above-mentioned reaction system, Suction filtration obtains yellow solid 13.8g, yield 82%, m.p.252-255 DEG C.
Preparation example 2:
In 500mL conical flasks, by K3Fe(CN)6(2.0g, 7.0mmol) is dissolved in water (10.0g), adds acetonitrile thereto (100mL) and 1,3,5- trimethoxy-benzenes (2-3) (16.4g, 100mmol), after 5 DEG C stir, adds H thereto2O2 (30%, 34g, 300mmol), 20h is stirred at 25 DEG C, separates out greenish yellow solid, water (200mL) is added to above-mentioned reaction system, Suction filtration obtains yellow solid 12.4g, yield 74%, m.p.252-255 DEG C.
Preparation example 3:
In 500mL conical flasks, by K3Fe(CN)6(2.0g, 7.0mmol) is dissolved in water (10.0g), adds water thereto (100mL) and 1,3,5- trimethoxy-benzenes (2-3) (16.4g, 100mmol), after 40 DEG C stir, adds H thereto2O2 (30%, 34g, 300mmol), 20h is stirred at 40 DEG C, separates out greenish yellow solid, water (100mL) is added to above-mentioned reaction system, Suction filtration obtains yellow solid 11.6g, yield 69%, m.p.252-255 DEG C.
Preparation example 4:
In 500mL conical flasks, by K3Fe(CN)6(2.0g, 7.0mmol) is dissolved in water (10.0g), adds third thereto Ketone (100g) and 1,3,5- trimethoxy-benzenes (2-3) (16.4g, 100mmol), after 5 DEG C stir, adds H thereto2O2 (30%, 34g, 300mmol), 20h is stirred at 5 DEG C, separate out greenish yellow solid, added water (200mL) to above-mentioned reaction system, take out Filter and obtain yellow solid 10.2g, yield 61%, m.p.252-255 DEG C
Preparation example 5:
In 500mL conical flasks, by K3Fe(CN)6(2.0g, 7.0mmol) is dissolved in water (10.0g), adds third thereto Ketone (100g) and 1,3,5- trimethoxy-benzenes (2-3) (16.4g, 100mmol), after 30 DEG C stir, adds H thereto2O2 (30%, 68g, 600mmol), 20h is stirred at 30 DEG C, separates out greenish yellow solid, water (200mL) is added to above-mentioned reaction system, Suction filtration obtains yellow solid 13.3g, yield 79%, m.p.252-255 DEG C.
Amplification test:By the step of preparation example 1 carry out three batches of amplification tests, stable yield, as shown in table 1.
The compound of table 1 (2-4) amplification technique experimental result
Embodiment 2
The synthesis of 2,6- dimethoxy-4 's-hydroxyl phenol (2-5)
Preparation example 1:
In 250mL single port bottles, sequentially add water (100mL), 2,6- dimethoxy-benzoquinones (2-4, embodiment 1 prepare gained) (13.3g, 80mmol), then sodium dithionite Na is added thereto2S2O4(20.1g, 120mmol), system is heated to reflux 1h (system by muddiness become clarify), cooling, separates out a large amount of white solids, filters, and is dried in vacuo to obtain product 11.7g, yield 86%, m.p.160-162℃。
Preparation example 2
In 250mL single port bottles, sequentially add water (100mL), 2,6- dimethoxy-benzoquinones (2-4, embodiment 1 prepare gained) (13.3g, 80mmol), then ferrous sulfate FeSO is added thereto4(18.2g, 120mmol), system be heated to reflux 1h (system by Muddiness becomes clarification), cooling, a large amount of white solids are separated out, filter, be dried in vacuo to obtain product 9.3g, yield 68%, m.p.160- 162℃。
Preparation example 3:
In 250mL single port bottles, sequentially add water (100mL), 2,6- dimethoxy-benzoquinones (2-4, embodiment 1 prepare gained) (13.3g, 80mmol), then sodium sulfite Na is added thereto2SO3(17.1g, 120mmol), system be heated to reflux 1h (system by Muddiness becomes clarification), cooling, a large amount of white solids are separated out, filter, be dried in vacuo to obtain product 8.5g, yield 63%, m.p.160- 162℃。
Preparation example 4:
In 250mL single port bottles, sequentially add water (100mL), 2,6- dimethoxy-benzoquinones (2-4, embodiment 1 prepare gained) (13.3g, 80mmol), then sodium dithionite Na is added thereto2S2O4(20.1g, 120mmol), system is heated to reflux 0.5h (system by muddiness become clarify), cooling, separates out a large amount of white solids, filters, and is dried in vacuo to obtain product 9.0g, yield 66%, m.p.160-162℃。
Preparation example 5:
In 250mL single port bottles, sequentially add water (100mL), 2,6- dimethoxy-benzoquinones (2-4, embodiment 1 prepare gained) (13.3g, 80mmol), then potassium hyposulfite K is added thereto2S2O4(20.1g, 120mmol), system are heated to reflux 3h (bodies System is become by muddiness to clarify), cooling, a large amount of white solids are separated out, filter, be dried in vacuo to obtain product 11.0g, yield 81%, m.p.160-162℃。
Amplification test:By the step of preparation example 1 carry out three batches of amplification tests, stable yield, as shown in table 2.
The compound of table 2 (2-5) amplification technique experimental result
Embodiment 3
The synthesis of 2- hydroxyl -4,6- dimethoxy -5- acetoxy acetophenones complex compounds (2-6 ')
Preparation example 1:
2,6- dimethoxy-4 's-hydroxyl phenol (2-5, gained being prepared by embodiment 2) is sequentially added in 250mL single port bottles (11.3g, 66.5mmol), dichloromethane (80mL), acetic anhydride (54g), BF3·Et2O (33g, 232mmol), agitating and heating are returned 3h is flowed, now there are a large amount of yellow solids to separate out, is cooled down, is filtered, obtains yellow solid 17.5g, yield 87%, m.p.207-209 DEG C.
Preparation example 2:
2,6- dimethoxy-4 's-hydroxyl phenol (2-5, gained being prepared by embodiment 2) is sequentially added in 250mL single port bottles (11.3g, 66.5mmol), chloroform (80mL), acetic anhydride (54g), BF3·Et2O (33g, 232mmol), agitating and heating are returned 3h is flowed, now there are a large amount of yellow solids to separate out, is cooled down, is filtered, obtains yellow solid 16.7g, yield 83%, m.p.207-209 DEG C.
Preparation example 3:
2,6- dimethoxy-4 's-hydroxyl phenol (2-5, gained being prepared by embodiment 2) is sequentially added in 250mL single port bottles (11.3g, 66.5mmol), 1.2- dichloroethanes (80mL), acetic anhydride (54g), BF3·Et2O (33g, 232mmol), stirring add Heat backflow 3h, now has a large amount of yellow solids to separate out, cools down, filter, obtain yellow solid 16.0g, yield 80%, m.p.207- 209℃。
Preparation example 4:
2,6- dimethoxy-4 's-hydroxyl phenol (2-5, gained being prepared by embodiment 2) is sequentially added in 250mL single port bottles (11.3g, 66.5mmol), dichloromethane (80mL), acetic anhydride (54g), BF3·Et2O (22g, 232mmol), agitating and heating are returned 1h is flowed, now there are a large amount of yellow solids to separate out, is cooled down, is filtered, obtains yellow solid 13.5g, yield 67%, m.p.207-209 DEG C.
Preparation example 5:
2,6- dimethoxy-4 's-hydroxyl phenol (2-5, gained being prepared by embodiment 2) is sequentially added in 250mL single port bottles (11.3g, 66.5mmol), dichloromethane (80mL), acetic anhydride (54g), BF3·Et2O (56g, 394mmol), agitating and heating are returned 3h is flowed, now there are a large amount of yellow solids to separate out, is cooled down, is filtered, obtains yellow solid 16.3g, yield 81%, m.p.207-209 DEG C.
Preparation example 6:
2,6- dimethoxy-4 's-hydroxyl phenol (2-5, gained being prepared by embodiment 2) is sequentially added in 250mL single port bottles (11.3g, 66.5mmol), dichloromethane (80mL), acetic anhydride (23g), BF3·Et2O (33g, 232mmol), agitating and heating are returned 3h is flowed, now there are a large amount of yellow solids to separate out, is cooled down, is filtered, obtains yellow solid 13.2g, yield 66%, m.p.207-209 DEG C
Preparation example 7:
2,6- dimethoxy-4 's-hydroxyl phenol (2-5, gained being prepared by embodiment 2) is sequentially added in 250mL single port bottles (11.3g, 66.5mmol), dichloromethane (80mL), acetic anhydride (33g), BF3·Et2O (33g, 232mmol), agitating and heating are returned 3h is flowed, now there are a large amount of yellow solids to separate out, is cooled down, is filtered, obtains yellow solid 15.2g, yield 76%, m.p.207-209 DEG C
Amplification test:Three batches of amplification tests of step progress as described in preparation example 1, stable yield, as shown in table 3.
The compound of table 3 (2-6 ') amplification technique experimental result
Preparation example 8:According to the method for preparation example 1,2- hydroxyl -4,6- dimethoxy -5- propionyloxy benzene second is prepared Ketone complex compound.
Preparation example 9:According to the method for preparation example 1, the positive butyryl acyloxy benzene of 2- hydroxyl -4,6- dimethoxys -5- is prepared Ethyl ketone complex compound.
Preparation example 10:According to the method for preparation example 1,2- hydroxyl -4,6- dimethoxy -5- isobutyl acyloxy benzene is prepared Ethyl ketone complex compound.
Preparation example:11:According to the method for preparation example 1,2- hydroxyl -4,6- dimethoxy -5- benzoyloxys are prepared Acetophenone complex compound.
Embodiment 4
The synthesis of chalcone (2-7)
Preparation example 1:
In 500mL single port bottles, sequentially add proline (6.64g, 58mmol), P-methoxybenzal-dehyde (11.8g, 87mmol), methanol (150mL), triethylamine (11.7g, 116mmol), 25 DEG C of stirring 1h, then add complex compound to the system (2-6 ') (17.5g, 58mmol, gained is prepared by embodiment 3), 25 DEG C of stirring 20h, separates out a large amount of yellow solids.To the system Water (300mL) is added, filters, obtains yellow solid 20.5g, yield 95%, m.p.122-124 DEG C.
The hydrogen spectrum of Formula (2-7), carbon are composed as shown in accompanying drawing 1,2:
1H NMR(400MHz,CDCl3)δ:13.73 (s, 1H), 7.86 (q, J=14.9Hz, 2H), 7.62 (d, J= 8.8Hz, 2H), 6.95 (d, J=8.8Hz, 2H), 6.37 (s, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.82 (s, 3H), 2.39(s,3H);13C NMR(100MHz,CDCl3)δ:192.6,169.0,164.3,161.8,158.0,154.2,144.0, 130.4,127.9,123.5,114.5,108.7,96.9,62.6,56.3,55.4,20.4。
Preparation example 2:
In 500mL single port bottles, sequentially add phenylalanine (9.58g, 58mmol), P-methoxybenzal-dehyde (15.8g, 116mmol), toluene (150mL), K2CO3(16.03g, 116mmol), 25 DEG C of stirring 1h, then adds complex compound to the system (2-6 ') (17.5g, 58mmol, gained is prepared by embodiment 3), 25 DEG C of stirring 20h, separates out a large amount of yellow solids.To the system Water (300mL) is added, filters, obtains yellow solid 18.5g, yield 86%, m.p.122-124 DEG C.
Preparation example 3:
In 500mL single port bottles, sequentially add glycine (4.35g, 58mmol), P-methoxybenzal-dehyde (15.8g, 116mmol), ethanol (150mL), pyridine (13.76g, 174mmol), 25 DEG C of stirring 1h, then add complex compound to the system (2-6 ') (17.5g, 58mmol, gained is prepared by embodiment 3), 25 DEG C of stirring 20h, separates out a large amount of yellow solids.To the system Water (300mL) is added, filters, obtains yellow solid 17.0g, yield 79%, m.p.122-124 DEG C.
Preparation example 4:According to the method for preparation example 1,4- hydroxyl -2,6- dimethoxys -3- (3- (4- methoxyl groups are prepared Phenyl) acryloyl group) phenyl propionate.
Preparation example 5:According to the method for preparation example 1,4- hydroxyl -2,6- dimethoxys -3- (3- (4- methoxyl groups are prepared Phenyl) acryloyl group) n-butyric acie phenyl ester.
Preparation example 6:According to the method for preparation example 1,4- hydroxyl -2,6- dimethoxys -3- (3- (4- methoxyl groups are prepared Phenyl) acryloyl group) isobutyl acid phenenyl ester.
Preparation example 7:According to the method for preparation example 1,4- hydroxyl -2,6- dimethoxys -3- (3- (4- methoxyl groups are prepared Phenyl) acryloyl group) phenol benzoate.
Screening test:
1st, reaction condition screens:
The synthesis one of the compound of table 4 (2-7)a
Remarks:Subscript a~the d occurred in table 4 represents different reaction conditions:
aReaction condition:Compound (2-6 ') (0.2mmol, 1 equivalent), compound (2-2) (1.2 equivalent), acid or alkali, it is molten Agent (5mL), react 10 hours;bSeparate yield;cNR=unreacteds;dThe dosage of compound in a (2-2) is adjusted to (1.5 work as Amount).
2nd, catalytic condition screens:
The synthesis two of the compound chalcone (2-7) of table 5a
Remarks:Subscript a~the k occurred in table 5 represents different reaction conditions, and wherein a is reaction condition, and b~k is in a The replacement or increase of respective items are carried out on the basis of the reaction condition of sign;
aReaction condition:Compound (2-6 ') (0.2mmol, 1 equivalent), compound (2-2) (1.2 equivalent), amino acid, alkali, Solvent (5mL), reaction temperature (r.t. is at room temperature), react 20 hours;
bSeparate yield;cNR=unreacteds;dIt is not detected by;
eReaction time in a is become and turned to 48 hours;
fReaction temperature in a is become and turns to 65 DEG C;
gThe dosage of compound in a (2-6 ') is adjusted to (2.0 equivalent);
hThe dosage of compound in a (2-2) is adjusted to (3.0 equivalent);
iReaction condition:Reaction condition in a is adjusted to:Compound (2-2), triethylamine, L-PROLINE is dissolved in CH3OH 1 hour in (5mL), then add compound (2-6 ') and react 20 hours;
jCompound (2-2) (1.5 equivalent);kCompound (2-2) (1.2 equivalent).
Compound (2-12) be when extend the reaction time or improve reaction temperature when, the adol products of discovery, its structure and Structural Identification data are as follows:
Formula (2-12) is faint yellow solid, and m.p.131-133 DEG C, its hydrogen spectrum, carbon spectrum are as shown in accompanying drawing 5,6:
1H NMR(400MHz,CDCl3)δ:7.40 (d, J=8.4Hz, 2H), 6.97 (d, J=8.4Hz, 2H), 6.40 (s, 1H), 5.39 (dd, J=2.4Hz, J=9.2Hz, 1H), 3.90 (s, 3H), 3.86-3.84 (m, 2H), 3.09-3.01 (m, 1H), 2.80-2.75(m,1H),2.36(s,3H);13C NMR(100MHz,CDCl3)δ:189.0,169.0,161.8,160.1, 157.8,153.4,130.5,128.3,127.8,114.2,109.0,96.5,79.2,62.0,56.3,55.4,45.2,20.4.
Amplification test:The step as described in preparation example 1 has carried out three batches of amplification tests, stable yield, as shown in table 6.
The compound of table 6 (2-7) amplification technique experimental result
Embodiment 5
The synthesis of 5,7- dimethoxy -6- acetoxyl groups -4- (4- methoxyphenyls) flavones (2-8 ')
Preparation example 1:
Compound (2-7) (20.5g, 55mmol, gained being prepared by embodiment 4), DMSO are added in 100mL single port bottles (40mL), iodine (4.2g, 16.5mmol), is warming up to 100 DEG C, stirring reaction 8h.Cooling, system is slowly poured into 200mL and contained In 10g sodium sulfite aqueous solutions, 1h is stirred, is filtered, filter cake is dried in vacuo to obtain product (2-8 ') 20.0g, yield 98%, m.p.181-183℃。
The hydrogen spectrum of Formula (2-8 '), carbon compose spectrogram as shown in accompanying drawing 3,4:
1H NMR(400MHz,CDCl3)δ:7.83 (d, J=6.8Hz, 2H), 7.02 (d, J=6.8Hz, 2H), 6.85 (s, 1H),6.60(s,1H),3.95(s,6H),3.90(s,3H),2.39(s,3H);13C NMR(100MHz,CDCl3)δ:176.7, 168.8,162.2,161.4,156.3,156.1,152.0,131.2,127.7,123.7,114.4,112.8,107.1,96.4, 62.5,56.4,55.5,20.4.
Preparation example 2:
Compound (2-7) (20.5g, 55mmol, gained being prepared by embodiment 4), DMF are added in 100mL single port bottles (40mL), iodine (1.4g, 5.5mmol), is warming up to 80 degree, stirring reaction 8h.Cooling, system is slowly poured into 200mL and contains 10g In sodium sulfite aqueous solution, 1h is stirred, is filtered, filter cake is dried in vacuo to obtain product (2-8 ') 16.5g, yield 81%, m.p.180-183℃。
Preparation example 3:
Compound (2-7) (20.5g, 55mmol, gained being prepared by embodiment 4), ethylene glycol two are added in 100mL single port bottles Methyl ether (40mL), iodine (4.2g, 16.5mmol), are warming up to 120 degree, stirring reaction 8h.Cooling, 200mL is slowly poured into by system Containing in 10g sodium sulfite aqueous solutions, 1h is stirred, is filtered, filter cake is dried in vacuo to obtain product (2-8 ') 15.0g, yield 73.6%, m.p.181-183 DEG C.
Preparation example 4:According to the method for preparation example 1,5,7- dimethoxy -6- propionyloxies -4- (4- methoxyl groups are prepared Phenyl) flavones.
Preparation example 5:According to the method for preparation example 1,5,7- dimethoxys -6- positive butyryl acyloxy -4- (4- methoxies are prepared Base phenyl) flavones.
Preparation example 6:According to the method for preparation example 1,5,7- dimethoxy -6- isobutyl acyloxy -4- (4- methoxies are prepared Base phenyl) flavones.
Preparation example 7:According to the method for preparation example 1,5,7- dimethoxy -6- benzoyloxys -4- (4- methoxies are prepared Base phenyl) flavones.
Screening test:
The dosage of iodine and the screening test of reaction temperature:
The compound of table 7 (2-8 ') synthesizes and optimizationa
Remarks:Subscript a~d indicates reaction condition:
aReaction condition:Compound (2-7) (0.3mol), I2, DMSO (5mL), 100 DEG C of reaction temperature, reaction time 8h;b Separate yield;cNR=unreacteds;d80℃。
Amplification test:Three batches of amplification tests have been carried out by the step of preparation example 1, stable yield, as shown in table 8.
The compound of table 8 (2-8 ') amplification technique experimental result
Embodiment 6
The synthesis of breviscapine B aglycone (1-2)
Preparation example 1:
Compound (2-8 ') (16g, 43.2mmol, gained being prepared by embodiment 5), vinegar are sequentially added in 250mL single port bottles Sour (50mL), 48%HBr (50mL), reaction are warming up to 128 DEG C of reaction 15h.After cooling, reaction system is poured into frozen water (300mL), a large amount of solids are separated out, filter, filter cake ethyl alcohol recrystallization, obtain faint yellow solid 10.2g, yield 82%, m.p.> 250℃。
The hydrogen spectrum of Formula (1-2), carbon are composed as shown in accompanying drawing 7,8:
1H NMR(400MHz,DMSO-d6)δ:12.81(s,1H),10.49(s,1H),10.33(s,1H),8.75(s, 1H), 7.91 (d, J=8.4Hz, 2H), 6.92 (d, J=8.4Hz, 2H), 6.75 (s, 1H), 6.59 (s, 1H);13C NMR (100MHz,DMSO-d6)δ:182.5,164.0,161.5,153.8,150.1,147.5,129.6,128.8,121.9, 116.4,104.4,102.7,94.3.
Preparation example 2:
Compound (2-8 ') (16g, 43.2mmol, gained being prepared by embodiment 5), salt are sequentially added in 250mL single port bottles Sour pyridine (30mL), reaction are warming up to 128 DEG C of reaction 48h.After cooling, reaction system is poured into frozen water (300mL), separated out a large amount of Solid, filter, filter cake recrystallizing methanol, obtain faint yellow solid 8.53g, yield 69%, m.p.>250℃.
Preparation example 3:
Compound (2-8 ') (16g, 43.2mmol, gained being prepared by embodiment 5), vinegar are sequentially added in 250mL single port bottles Sour (50mL), 48%HBr (30mL), reaction are warming up to 100 DEG C of reaction 40h.After cooling, reaction system is poured into frozen water (300mL), a large amount of solids being separated out, filtered, filter cake recrystallisation from isopropanol obtains faint yellow solid 8.85g, yield 72%, m.p.>250℃。
Preparation example 4:
Compound (2-8 ') (16g, 43.2mmol, gained being prepared by embodiment 5), vinegar are sequentially added in 250mL single port bottles Sour (80mL), 48%HBr (30mL), reaction are warming up to 125 DEG C of reaction 25h.After cooling, reaction system is poured into frozen water (300mL), a large amount of solids being separated out, filtered, filter cake re-crystallizing in ethyl acetate obtains faint yellow solid 8.30g, yield 67%, m.p.>250℃。
Preparation example 5:
Compound (2-8 ') (16g, 43.2mmol, gained being prepared by embodiment 5), vinegar are sequentially added in 250mL single port bottles Sour (50mL), 48%HBr (80mL), reaction are warming up to 130 DEG C of reaction 25h.After cooling, reaction system is poured into frozen water (300mL), a large amount of solids are separated out, filter, filter cake ethyl alcohol recrystallization, obtain faint yellow solid 9.30g, yield 75%, m.p.> 250℃。
Amplification test:The step as described in preparation example 1 has carried out three batches of amplification tests, stable yield, as shown in table 10.
The breviscapine B aglycone of table 10 (1-2) amplification technique experimental result
Embodiment 7
The synthesis of the acetoxyl group flavones (1-12) of 5,6,7,4'- tetra-
Preparation example 1:
Compound (1-2) (8.0g, 28.0mmol, gained being prepared by embodiment 6), second are sequentially added in 250mL single port bottles Acid anhydrides (28.3g, 280mmol), sodium acetate (19.05g, 140mmol), reaction are warming up to 80 DEG C of reaction 10h.After reaction terminates, System is poured into frozen water (150mL), is filtered, and filter cake is recrystallized to give compound (1-12), quality with ethyl acetate/methanol 11.4g, yield 90%, m.p.251-253 DEG C.
The hydrogen spectrum of Formula (1-12), carbon are composed as shown in accompanying drawing 9,10:
1H NMR(400MHz,CDCl3)δ:7.89 (d, J=8.8Hz, 2H), 7.50 (s, 1H), 7.27 (d, J=8.8Hz, 2H),6.63(s,1H),2.46(s,3H),2.37(s,3H),2.36(s,6H);13CNMR(100MHz,CDCl3)δ:176.1, 168.9,168.3,167.2,167.0,161.9,154.2,153.4,146.9,142.2,132.8,128.5,127.6, 122.4,115.5,110.3,108.2,21.4,20.8,20.1,19.1.
Preparation example 2:
Compound (1-2) (8.0g, 28.0mmol, gained being prepared by embodiment 6), second are sequentially added in 250mL single port bottles Acid anhydrides (57.2g, 560mmol), sodium acetate (30.5g, 224mmol), reaction are warming up to 80 DEG C of reaction 10h.After reaction terminates, body System is poured into frozen water (150mL), is filtered, and filter cake is recrystallized to give compound (1-12) with ethyl acetate/methanol, quality 8.4g, Yield 66%, m.p.251-253 DEG C.
Preparation example 3:
Compound (1-2) (8.0g, 28.0mmol, gained being prepared by embodiment 6), second are sequentially added in 250mL single port bottles Acid anhydrides (428.8.2g, 420mmol), sodium acetate (15.2g, 112mmol), reaction are warming up to 100 DEG C of reaction 8h.Reaction terminates Afterwards, system is poured into frozen water (150mL), is filtered, and filter cake is recrystallized to give compound (1-12), quality with ethyl acetate/methanol 11.2g, yield 88%, m.p.251-253 DEG C.
Preparation example 4:
Compound (1-2) (8.0g, 28.0mmol, gained being prepared by embodiment 6), second are sequentially added in 250mL single port bottles Acid anhydrides (28.3g, 280mmol), pyridine (11.1g, 140mmol), reaction are warming up to 60 DEG C of reaction 10h.After reaction terminates, system Pour into frozen water (150mL), filter, filter cake is recrystallized to give compound (1-12) with ethyl acetate/methanol, quality 8.8g, receives Rate 69%, m.p.251-253 DEG C.
Preparation example 5:
Compound (1-2) (8.0g, 28.0mmol, gained being prepared by embodiment 6), second are sequentially added in 250mL single port bottles Acid anhydrides (57.2g, 560mmol), pyridine (8.9g, 112mmol), reaction are warming up to 100 DEG C of reaction 9h.After reaction terminates, system Pour into frozen water (150mL), filter, filter cake is recrystallized to give compound (1-12) with ethyl acetate/methanol, quality 10.8g, receives Rate 85%, m.p.251-253 DEG C.
Amplification test:The step as described in preparation example 1 has carried out three batches of amplification tests, stable yield, as shown in table 11.
The compound of table 11 (1-12) amplification technique experimental result
Embodiment 8
The synthesis of four-O- acetyl group-β-D-Glucose aldehydic acid methyl esters (1-19)
Methanol (100mL), sodium hydroxide (0.6g) are added in 250mL single port bottles, 17.6g is added after stirring and dissolving (0.1mol) Artogicurol lactone (1-17), is stirred at room temperature 5h.Decompression steams whole methanol, obtains yellow syrup dope (1- 18) next step experiment, is directly carried out.
Acetic anhydride (80mL) is added into the system of above-mentioned concentration, perchloric acid (0.8mL) is slowly added under ice bath, finishes Afterwards, ice bath reaction 5h is kept, there are a large amount of white solids to separate out.Suction filtration obtains part of compounds (1-19);Ice is added into mother liquor Water (250mL), puts refrigerator overnight, filters, obtains other part compound (1-19).Obtained compound (1-19) is merged, Washed with ethanol, filter and obtain compound (1-19) common 21.4g, yield 57%, m.p.175-177 DEG C.
The hydrogen spectrum of Formula (1-19), carbon are composed as shown in accompanying drawing 15,16:
1H NMR(400MHz,CDCl3)δ:5.78 (d, J=8.0Hz, 1H), 5.34-5.23 (m, 2H), 5.15 (t, J= 8.2Hz, 1H), 4.19 (d, J=9.2Hz, 1H), 3.76 (s, 3H), 2.13 (s, 3H), 2.09-2.01 (m, 9H);13C NMR (100MHz,CDCl3)δ:169.9,169.4,169.2,168.8,166.8,91.4,73.0,71.8,70.2,68.9,53.0, 20.8,20.5,20.5,20.4.
Embodiment 9
The synthesis of three-O- acetyl group-alpha-D-glucose aldehydic acid methyl esters (1-15)
Under ice bath, added into single port bottles of the 100mL equipped with compound (1-19) (8.0g, gained being prepared by embodiment 8) 33% hydrobromic acid-glacial acetic acid (30mL), ice bath reaction 1.5h is kept, is then stirred overnight at room temperature.After reaction terminates, system is used full And NaHCO3Solution be neutralized to bubble-free generation, dichloromethane extraction system twice, organic layer anhydrous sodium sulfate drying, vacuum Pale yellow syrup dope is concentrated to give, 20mL ether is added and is dissolved, be put into refrigerator overnight, filter, obtain white solid 6.90g, yield 82%, m.p.103-105 DEG C.
The hydrogen spectrum of Formula (1-15), carbon are composed as shown in accompanying drawing 11,12:
1H NMR(400MHz,CDCl3)δ:6.65 (d, J=4.0Hz, 1H), 5.62 (t, J=9.6Hz, 1H), 5.25 (t, J =10.0Hz, 1H), 4.87 (dd, J=10.0,4.4Hz, 1H), 4.59 (d, J=10.4Hz, 1H), 3.77 (s, 3H), 2.11 (s,3H),2.07(s,3H),2.06(s,3H);13C NMR(100MHz,CDCl3)δ:166.7,166.6,169.4,166.7, 85.3,72.0,70.2,69.3,68.4,53.1,20.6,20.4.
Embodiment 10
5,6,4'- triacetoxyl group flavones -7-O- (2,3,4- triacetoxyl groups-β-D-Glucose aldehydic acid methyl esters) (1-16) Synthesis
Preparation example 1:
Compound (1-12) (8.0g, 17.6mmol, gained being prepared by embodiment 7), bromine sugar (1- are sequentially added in single port bottle 15, be prepared by embodiment 9) (13.9g, 35.2mmol), TBAB (i.e. TBAB) (6.83g, 21.1mmol), carbon Sour potassium (7.2g, 52.8mmol), acetonitrile (50mL), 40 DEG C of stirring 12h, then add bromine sugared (2.75g, 7mmol) stirring to system After 12h, add bromine sugared (2.75g, 7mmol) and continue to stir 12h.After reaction terminates, the solid in reaction system is recovered by filtration Alkali.100mL dichloromethane is added to system, is filtered, filter cake wash to colourless with dichloromethane, addition 50mL water, aqueous phase is with two Chloromethanes is extracted three times, merges organic phase, and sodium sulphate is dried, and is concentrated to give puce product, with ethyl alcohol recrystallization, separates out white Solid, suction filtration obtain white solid 12.0g, yield 90%, m.p.>250℃.
The hydrogen spectrum of Formula (1-16), carbon are composed as shown in accompanying drawing 13,14:
1H NMR(400MHz,CDCl3)δ:7.87 (d, J=8.4Hz, 1H), 7.26 (d, J=8.4Hz, 1H), 7.06 (s, 1H), 6.58 (s, 1H), 5.38-5.29 (m, 4H), 4.39 (d, J=8.8Hz, 1H), 3.78 (s, 3H), 2.43 (s, 3H), 2.36 (s,3H),2.31(s,3H),2.09-2.05(m,9H);13C NMR(100MHz,CDCl3)δ:175.9,169.8,169.4, 169.3,168.9,168.5,167.9,166.5,161.7,155.1,153.3,152.6,142.3,130.8,128.6, 127.6,122.4,113.1,108.3,101.1,98.2,73.0,71.3,70.0,69.0,53.2,21.1,20.8,20.5, 20.4,20.0.
Preparation example 2:
Compound (1-12) (8.0g, 17.6mmol, gained being prepared by embodiment 7), bromine sugar (1- are sequentially added in single port bottle 15, be prepared by embodiment 9) (13.9g, 35.2mmol), tetrabutylammonium iodide (7.8g, 21.1mmol), potassium hydroxide (2.9g, 52.8mmol), acetonitrile (50mL), 38 DEG C of stirring 10h, then add bromine sugared (2.75g, 7mmol) stirring 12h to system Afterwards, bromine sugared (2.75g, 7mmol) is added to continue to stir 12h.After reaction terminates, the solid base in reaction system is recovered by filtration. 100mL chloroform is added to system, is filtered, filter cake is washed to colourless, addition 50mL water, aqueous phase trichlorine with chloroform Methane is extracted three times, merges organic phase, and sodium sulphate is dried, and is concentrated to give puce product, and with ethyl alcohol recrystallization, it is solid to separate out white Body, suction filtration obtain white solid 10.3g, yield 80%, m.p.>250℃.
Preparation example 3:
Compound (1-12) (8.0g, 17.6mmol, gained being prepared by embodiment 7), bromine sugar (1- are sequentially added in single port bottle 15, be prepared by embodiment 9) (13.9g, 35.2mmol), 5- azepines [4.4] nonane bromide (4.35g, 21.1mmol), Sodium acid carbonate (4.4g, 52.8mmol), acetonitrile (50mL), 35 DEG C of stirring 12h, then add bromine sugar (2.75g, 7mmol) to system After stirring 12h, add bromine sugared (2.75g, 7mmol) and continue to stir 12h.After reaction terminates, it is recovered by filtration in reaction system Solid base.100mL dichloromethane is added to system, is filtered, filter cake is washed to colourless, addition 50mL water, aqueous phase with dichloromethane With dichloromethane extraction three times, organic phase is merged, sodium sulphate is dried, and is concentrated to give puce product, with ethyl alcohol recrystallization, is separated out White solid, suction filtration obtain white solid 11.1g, yield 87%, m.p.>250℃.
Preparation example 4:
Compound (1-12) (8.0g, 17.6mmol, gained being prepared by embodiment 7), bromine sugar (1- are sequentially added in single port bottle 15, be prepared by embodiment 9) (13.9g, 35.2mmol), 4-butyl ammonium hydrogen sulfate (7.2g, 21.1mmol), sodium carbonate (3.7g, 35.2mmol), acetonitrile (50mL), 30 DEG C of stirring 12h, then add bromine sugared (2.75g, 7mmol) stirring 12h to system Afterwards, bromine sugared (2.75g, 7mmol) is added to continue to stir 12h.After reaction terminates, the solid base in reaction system is recovered by filtration. 100mL ethyl acetate is added to system, is filtered, filter cake is washed to colourless, addition 50mL water, aqueous phase acetic acid second with ethyl acetate Ester is extracted three times, merges organic phase, and sodium sulphate is dried, and is concentrated to give puce product, and with ethyl alcohol recrystallization, it is solid to separate out white Body, suction filtration obtain white solid 9.98g, yield 79%, m.p.>250℃.
Preparation example 5:
Compound (1-12) (8.0g, 17.6mmol, gained being prepared by embodiment 7), bromine sugar (1- are sequentially added in single port bottle 15, be prepared by embodiment 9) (13.9g, 35.2mmol), tetrabutylammonium iodide (7.79g, 21.1mmol), potassium carbonate (12.2g, 88mmol), acetonitrile (50mL), 40 DEG C of stirring 5h, then after adding bromine sugared (2.75g, 7mmol) stirring 12h to system, Bromine sugared (2.75g, 7mmol) is added to continue to stir 12h.After reaction terminates, the solid base in reaction system is recovered by filtration.Xiang Ti It is 1, the 2- dichloroethanes for adding 100mL, filters, filter cake is washed to colourless, addition 50mL water, aqueous phase use with 1,2- dichloroethanes 1,2- dichloroethanes is extracted three times, merges organic phase, and sodium sulphate is dried, and is concentrated to give puce product, with ethyl alcohol recrystallization, analysis Go out white solid, suction filtration obtains white solid 11.2g, yield 88%, m.p.>250℃.
Preparation example 6:
Compound (1-12) (8.0g, 17.6mmol, gained being prepared by embodiment 7), bromine sugar (1- are sequentially added in single port bottle 15, be prepared by embodiment 9) (13.9g, 35.2mmol), tetrabutylammonium iodide (7.79g, 21.1mmol), calcium sulfate (7.2g, 52.8mmol), potassium carbonate (7.2g, 52.8mmol), acetonitrile (50mL), 40 DEG C of stirring 12h, then add bromine sugar to system 2.75g, after stirring 12h, add 2.75g bromine sugar and continue to stir 12h.After reaction terminates, consolidating in reaction system is recovered by filtration Body alkali.100mL dichloromethane is added to system, is filtered, filter cake is washed to colourless, addition 50mL water, aqueous phase use with dichloromethane Dichloromethane is extracted three times, merges organic phase, and sodium sulphate is dried, and is concentrated to give puce product, with ethyl alcohol recrystallization, is separated out white Color solid, suction filtration obtain white solid 12.0g, yield 90%, m.p.>250℃.
Screening test:
Reaction condition screening test
Table 12 synthesizes compound (1-16) conditional filteringa
Remarks:Subscript a~the h occurred in table 12 represents different reaction conditions:
aReaction condition:Compound (1-12) (0.1mmol, 1 equivalent), compound (1-15) (2 equivalent), alkali, catalyst, Solvent (4mL) stirs 12h;Then (1-15) (0.7 equivalent) stirring 12h is added;
bAdd CaSO4(3 equivalent);cAdd H2O(0.2mL);
d(1-15) (0.7 equivalent) stirring 12h is added again;e(1-15) (1.0 equivalent) stirring 12h is added again;
hWithaDifference be disposably to add compound (1-15) (2.7 equivalent).
Amplification test:The step with reference to described in preparation example 1 has carried out three batches of amplification tests, stable yield, as shown in table 13.
The compound of table 13 (1-16) amplification technique experimental result
Embodiment 11
The synthesis of lamp-dish flower acetic (1-1)
Preparation example 1:
Under nitrogen protection, compound (1-16) is sequentially added in 250mL there-necked flasks and (8.0g, 11mmol, is made by embodiment 10 It is standby to obtain), acetone (100mL), 2.5M sodium hydrate aqueous solutions (55mL) are slowly added dropwise under ice bath, finishes, continues ice bath stirring 1h.Dilute hydrochloric acid solution is slowly added dropwise to pH=3-4, continues to stir 30min, filters, filter cake recrystallizing methanol, obtain light yellow Solid 5.0g, yield 98%, m.p.>250℃.
The hydrogen spectrum of Formula (1-1), carbon are composed as shown in 17,18:
1H NMR(400MHz,DMSO-d6)δ:12.75 (s, 1H), 10.38 (s, 1H), 8.61 (s, 1H), 7.93 (d, J= 4.8Hz, 2H), 7.06-6.87 (m, 3H), 6.82 (s, 1H), 5.51 (s, 1H), 5.38-5.16 (m, 2H), 4.06 (d, J= 7.2Hz,1H),3.56-3.24(m,6H);13C NMR(100MHz,DMSO-d6)δ:182.8,170.5,164.5,161.7, 151.5,149.5,147.3,131.0,128.9,121.8,116.5,106.4,103.1,100.5,94.1,76.0,75.7, 73.3,71.8.
Preparation example 2:
Under nitrogen protection, compound (1-16) is sequentially added in 250mL there-necked flasks and (8.0g, 11mmol, is made by embodiment 10 It is standby to obtain), water (100mL), 1.5M potassium hydroxide aqueous solutions (55mL) are slowly added dropwise under ice bath, finishes, continues ice bath stirring 1h. Dilute hydrochloric acid solution is slowly added dropwise to pH=3-4, continues to stir 30min, filters, filter cake recrystallizing methanol, obtain light yellow solid Body 4.5g, yield 88%, m.p.>250℃.
Preparation example 3:
Under nitrogen protection, compound (1-16) is sequentially added in 250mL there-necked flasks and (8.0g, 11mmol, is made by embodiment 10 It is standby to obtain), acetone/water (50mL/50mL), 3.0M sodium bicarbonate aqueous solutions (55mL) are slowly added dropwise under ice bath, finishes, continues ice Bath stirring 1h.Dilute hydrochloric acid solution is slowly added dropwise to pH=3-4, continues to stir 30min, filters, filter cake recrystallisation from isopropanol, obtain To light yellow solid 4.8g, yield 94%, m.p.>250℃.
Preparation example 4:
Under nitrogen protection, compound (1-16) is sequentially added in 250mL there-necked flasks and (8.0g, 11mmol, is made by embodiment 10 It is standby to obtain), acetone (100mL), 1.0M sodium hydrate aqueous solutions (150mL) are slowly added dropwise under ice bath, finishes, continues ice bath stirring 1h.Dilute hydrochloric acid solution is slowly added dropwise to pH=3-4, continues to stir 30min, filters, filter cake ethyl alcohol recrystallization, obtain light yellow Solid 4.0g, yield 78%, m.p.>250℃.
Preparation example 5:
Under nitrogen protection, compound (1-16) is sequentially added in 250mL there-necked flasks and (8.0g, 11mmol, is made by embodiment 10 It is standby to obtain), acetone (100mL), 3.0M sodium hydrate aqueous solutions (46mL) are slowly added dropwise under ice bath, finishes, continues ice bath stirring 1h.Dilute hydrochloric acid solution is slowly added dropwise to pH=3-4, continues to stir 30min, filters, filter cake recrystallizing methanol, obtain light yellow Solid 4.6g, yield 90%, m.p.>250℃.
Amplification test:
The step as described in preparation example 1 has carried out three batches of amplification tests, stable yield, as shown in table 14.
The lamp-dish flower acetic of table 14 (1-1) amplification technique experimental result
In addition, for embodiment 11 synthesize lamp-dish flower acetic be compound (1-1) we HPLC analyses have been carried out to it, Purity is consistent with standard items more than 99%, refers to accompanying drawing 19.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should It is considered as protection scope of the present invention.

Claims (10)

1. a kind of synthetic method of breviscapine B aglycone, it is characterised in that there is the compound of formula (I) structure through step (1) Compound of the oxidative cyclization reaction generation with structure shown in formula (2-8), will be walked to the compound with structure shown in formula (2-8) Suddenly (2) are carried out shown in demethylating reaction generation target compound such as formula (1-2);
Wherein, R is selected from C that is unsubstituted or arbitrarily being substituted by a phenyl2~C5It is alkanoyl, unsubstituted or arbitrarily by C1~C5Alkyl Substituted benzoyl.
2. according to the method for claim 1, it is characterised in that the R is selected from unsubstituted or arbitrarily substituted by a phenyl C2~C3It is alkanoyl, unsubstituted or arbitrarily by C1~C3Alkyl-substituted benzoyl.
3. according to the method for claim 2, it is characterised in that the R is selected from acetyl group, propiono, positive bytyry, isobutyl Acyl group, benzoyl, phenylacetyl group or hydrocinnamoyl.
4. according to the method in any one of claims 1 to 3, it is characterised in that the step (1) is carried out in a solvent, The solvent is aprotic polar solvent, it is preferable that the solvent is selected from dimethyl sulfoxide (DMSO), DMF, N, N- Dimethyl acetamide, N, the preferably one or more in N- diethylformamides, glycol dimethyl ether, dimethyl sulfoxide (DMSO).
5. according to the method in any one of claims 1 to 3, it is characterised in that the oxidant in the step (1) is I2; Preferably, the I2Addition be compound (I) 0.1~0.5 times of equivalent, preferably 0.3 times of equivalent.
6. according to the method in any one of claims 1 to 3, it is characterised in that the reaction temperature of the step (1) is 80 ~120 DEG C, preferably 100 DEG C.
7. according to the method in any one of claims 1 to 3, it is characterised in that the step (1) comprises the steps of: Compound (I), DMSO, oxidant are sequentially added, is warming up to 80~120 DEG C, preferably 100 DEG C, stirring reaction 8~12 hours is excellent Select 8 hours, cool down, reaction system is slowly poured into sodium sulfite aqueous solution, the concentration of preferably sodium sulfite aqueous solution is 0.01-0.1g/ml, preferably 0.05g/ml, after stirring 0.5~2 hour, preferably 1 hour, filter, vacuum drying.
8. according to the method in any one of claims 1 to 3, it is characterised in that the demethylation reagent of the step (2) is HBr/HOAc, pyridine hydrochloride or BF3·Et2One or more in O, preferably HBr/HOAc;Preferably, the HBr is 48% HBr;Preferably, HBr and HOAc volumetric usage ratio is 3 in the demethylation reagent:8~8:3, preferably 1:1;Preferably, 48%HBr, HOAc are respectively 30~80ml relative to the volume value of every 16g compounds (2-8), preferably 50ml.
9. according to the method in any one of claims 1 to 3, it is characterised in that the reaction temperature of the step (2) is 100~130 DEG C, preferably 128 DEG C;Preferably, the reaction time is 10~48 hours, preferably 15 hours.
10. according to the method in any one of claims 1 to 3, it is characterised in that after the step (2) also includes reaction Cooling, reaction system is poured into frozen water, the step of filtering, recrystallize after precipitation solid;Preferably, the recrystallization solvent choosing One or more from methanol, ethanol, propyl alcohol, isopropanol, n-butanol, ethyl acetate, it is preferable that it is described recrystallization reagent be Ethanol;
Preferably, the step (2) comprises the following steps:Compound (2-8) and demethylation reagent are sequentially added, is warming up to 100 ~130 DEG C, preferably 128 DEG C reactions are cooled down after 10~48 hours, preferably 15 hours, and reaction system is poured into frozen water, separated out solid Filter, recrystallize after body.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111233806A (en) * 2020-03-20 2020-06-05 武汉轻工大学 Preparation method of 3,5, 4' -triacetoxy-7-hydroxyflavone
CN112094255A (en) * 2020-08-19 2020-12-18 昆明龙津药业股份有限公司 Scutellarin aglycone derivative, preparation method and application thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110540559B (en) * 2019-09-23 2020-06-19 济南山目生物医药科技有限公司 Green chemical preparation method of alpha-tri-O-acetyl glucuronic acid methyl ester bromide

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102134186A (en) * 2010-01-25 2011-07-27 昆明制药集团股份有限公司 Method for preparing scutellarin intermediate
CN104529973A (en) * 2014-12-09 2015-04-22 江南大学 Synthetic method for polysubstituted baicalein derivatives
CN105218499A (en) * 2015-10-19 2016-01-06 昆明理工大学 A kind of method preparing Scutellarein
CN105906600A (en) * 2016-05-20 2016-08-31 昆明理工大学 Method for preparing scutellarin

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101684112A (en) * 2008-09-27 2010-03-31 昆明制药集团股份有限公司 Preparation method of 5,6,7,4'-tetramethoxy flavones of scutellarin and aglucone key intermediate thereof
CN101941999B (en) * 2009-07-07 2014-04-09 昆明制药集团股份有限公司 Method for preparing scutellarin
CN106134378B (en) * 2010-09-28 2013-03-13 中国人民解放军第三军医大学 A kind of preparation method of trihydroxy-isoflavone
CN102267888B (en) * 2011-06-14 2014-02-26 黑龙江大学 Chalcone derivative preparation method
CN103374049B (en) * 2012-04-18 2016-04-06 昆药集团股份有限公司 One prepares 5,6, the method for 4 '-trihydroxyflavone-7-0-D-glucuronic acid
CN103936704B (en) * 2014-04-08 2015-09-30 昆明理工大学 A kind of method preparing chrysin
CN105218606B (en) * 2015-10-19 2017-12-01 昆明理工大学 A kind of method for preparing scutellarin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102134186A (en) * 2010-01-25 2011-07-27 昆明制药集团股份有限公司 Method for preparing scutellarin intermediate
CN104529973A (en) * 2014-12-09 2015-04-22 江南大学 Synthetic method for polysubstituted baicalein derivatives
CN105218499A (en) * 2015-10-19 2016-01-06 昆明理工大学 A kind of method preparing Scutellarein
CN105906600A (en) * 2016-05-20 2016-08-31 昆明理工大学 Method for preparing scutellarin

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ZHIPEI SANG ET AL.: "Multifunctional scutellarin–rivastigmine hybrids with cholinergic, antioxidant, biometal chelating and neuroprotective properties for the treatment of Alzheimer’s disease", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *
凌成利等: "灯盏花乙素苷元的制备研究进展", 《化学试剂》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111233806A (en) * 2020-03-20 2020-06-05 武汉轻工大学 Preparation method of 3,5, 4' -triacetoxy-7-hydroxyflavone
CN112094255A (en) * 2020-08-19 2020-12-18 昆明龙津药业股份有限公司 Scutellarin aglycone derivative, preparation method and application thereof
CN112094255B (en) * 2020-08-19 2023-05-09 昆明龙津药业股份有限公司 Scutellarin aglycone derivative, and preparation method and application thereof

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