CN108727190A - The preparation method of intermediate of salviandic acid A and preparation method thereof and salviandic acid A - Google Patents

The preparation method of intermediate of salviandic acid A and preparation method thereof and salviandic acid A Download PDF

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CN108727190A
CN108727190A CN201710250891.XA CN201710250891A CN108727190A CN 108727190 A CN108727190 A CN 108727190A CN 201710250891 A CN201710250891 A CN 201710250891A CN 108727190 A CN108727190 A CN 108727190A
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张富尧
李火明
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Shanghai Time Biotechnology Co Ltd
Selection Bioscience LLC
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Abstract

The present invention relates to a kind of intermediate preparing salviandic acid A, preparation method and the methods for preparing salviandic acid A (shown in formula I) by it.Specifically, the present invention relates to a kind of such as Formula II compound represented, wherein R1For hydrogen or carboxyl-protecting group.The advantages that present invention relates particularly to a kind of preparation method such as Formula II compound represented and by the method that such as Formula II compound represented prepares salviandic acid A, and this method has reaction condition mild, easy to operate, and synthesis cost is cheap, is suitable for mass producing.

Description

The preparation method of intermediate of salviandic acid A and preparation method thereof and salviandic acid A
Technical field
The side of salviandic acid A is prepared the present invention relates to a kind of intermediate preparing salviandic acid A, preparation method and by it Method.
Background technology
Salviandic acid A (abbreviation SAA), chemical name (2R) -3- (3,4- dihydroxy phenyl) -2- [(E) -3- [2- [(E) -2- (3, 4- dihydroxy phenyls) vinyl] -3,4- dihydroxy phenyls] propyl- 2- alkene acyl] oxygen propionic acid (shown in formula I) is Chinese medicine Radix Salviae Miltiorrhizae Extract, by the study found that it is suitable for angina pectoris and acute myocardial infarction with a variety of pharmacodynamic features；For cerebral thrombus The sequelae of formation is also effective；In addition it can be additionally used in Buerger's disease, chorionitis, embolism of central retinal artery, god Deaf, white thiophene Cotard and erythema nodosum etc. through property.
The synthetic method of salviandic acid A is roughly divided into extraction and chemical synthesis two ways from natural traditional Chinese medicine.In Chinese medicine In terms of material extraction, for example, Zhu Changfu etc. discloses a kind of extracting method of salviandic acid A in CN1830947A, red rooted salvia is used Water or alcohol extracting after extracting concentrate, using high-temperature high-voltage reaction, cross column chromatography and purify salviandic acid A, then through adjusting pH value, with having Solvent extracts, and is concentrated and dried to get salviandic acid A, salviandic acid A content is up to 80% or more in extract, and can realize big rule Mould produces.Qu Haibin etc. discloses a kind of process for purification of salviandic acid A in CN101353306A, is extracted using organic solvent extractionprocess Take Salvia miltiorrhiza Bge water extract obtain salviandic acid A crude extract, with sour water extraction decontamination, organic phase it is concentrated, it is dry after obtain high-purity Salviandic acid A.The inventive method purifies the rate of recovery up to 95% or more, and the purity of salviandic acid A is up to 90% or more.But natural traditional Chinese medicine carries Take that there are some disadvantages：The content of salviandic acid A is relatively low, containing more impurity, fails to control impurity, product is unable to reach Medicinal standard cannot achieve large-scale production.
Salviandic acid A can also by from after extraction tanshin polyphenolic acid B or alkannic acid by a step chemical reaction conversion be made, Such as Jiangxi Qing Feng medicine discloses a kind of method that catalyzed conversion tanshin polyphenolic acid B prepares salviandic acid A in CN103012148B, water intaking The red sage root extract of extraction or alcohol extracting a concentration of 1mg/ml~30mg/ml of tanshin polyphenolic acid B or is diluted with water to wherein in extracting solution The catalyst for being 0.1%~3.0% with the molar percentage of tanshin polyphenolic acid B is added in 1mg/ml~30mg/ml, adds alkali to adjust pH and is 3.0~6.5, conversion temperature is 100~140 DEG C, and transformation time is 1~6 hour, cooling, and acid adding tune pH to 2.5~3.0 is quiet It sets, centrifuges, obtain salviandic acid A conversion fluid, measure salviandic acid A content, wherein the catalyst is iron chloride, ruthenium trichloride, chlorine Change the one or more of aluminium, zinc chloride, palladium bichloride.Although this method than directly from plant extract salviandic acid A it is more efficient, But generally still need and carry out multiple purification process, generate a large amount of waste liquid.
In terms of chemical synthesis, Chen Wei is waited by force discloses a kind of synthesis technology of synthesis salviandic acid A in CN105085267A, From starting material 2,3- dimethoxy benzaldehydes set out by reduction, and the multistep reactions such as bromo synthesize salviandic acid A.The route exists Problems with：Bromine has been used in second step, has been unfavorable for safety in production operation；In the protection of final step demethoxylation, the guarantor It is highly stable to protect base, needs to be hydrolyzed using Boron tribromide, and reaction yield only has 5.9%, does not meet actual production and want It asks.
Zheng etc. is in Tetrahedron 2016-72-5047 by studying from starting material 2,3- dimethoxy benzene first Aldehyde sets out, and salviandic acid A is synthesized by multistep reaction.The route has the following problems：The first step uses ruthenium metal costly Reagent makes the synthesis cost of route greatly increase；In the reaction of final step demethoxylation, also need to use tribromide Boron, by-product is more, and yield only has 27%, cannot achieve industrial large-scale production.
Wang Jinhui etc. discloses a kind of chemical total synthesis method of salviol acid A (abbreviation SAA) in CN102827002A, by 2,3- dimethoxy benzaldehydes are reacted through reduction, bromination, Wittig, and aldehyde in n-BuLi debrominate, Knoevenagel reacts It arrives.Above-mentioned two segment is condensed into ester, through the methyl on trimethyl stannic hydroxide selectively removing carboxylate methyl ester, finally uses tribromo Change boron sloughs the methyl protecting group on phenolic hydroxyl group and obtains salviol acid A.
Above several chemical synthesis process synthesize salviandic acid A, and there are some disadvantages：1, methylether protecting groups are excessively stablized, Final step needs to use strong lewis acid Boron tribromide during hydrolyzing, and severe reaction conditions, by-product is more, is not easy pure Change, reaction yield is very low；2, the trimethyl stannic hydroxide toxicity that the selective hydrolysis of carboxylate methyl ester uses is big, and cost is very high It is expensive, and do not supply largely on the market.These factors cause existing synthetic method cannot achieve large-scale production and The reduction of cost can not substitute existing tanshin polyphenolic acid B transformation routes.
Invention content
For disadvantage present in existing salviandic acid A chemical synthesis process shown in formula I, present invention employs be easier The methyl oxygroup methyl (MOM) of hydrolysis is hydroxyl and carboxyl-protecting group, can be hydrolyzed, improve under very mild conditions The synthesis total recovery of salviandic acid A, and avoid as used the hydrolysising condition of trimethyl stannic hydroxide in the prior art and keeping away The last harsh conditions with Boron tribromide dephenolize hydroxyl protection are exempted from.
In overall strategy, the coupling that Heck reactions carry out the similar segment of two scales is used so that reaction route More convergence shortens the straight line step of synthesis with efficiently, mild to provide a kind of reaction condition, easy to operate, closes At of low cost, suitable for the preparation method for synthesizing salviandic acid A shown in formula I of large-scale production, it is expected to substitute existing The slave tanshin polyphenolic acid B method for preparing salviandic acid A.
The present invention provides the new method of salviandic acid A shown in synthesis formula (I),
Wherein, R1For hydrogen or carboxyl-protecting group, preferably hydrogen, C1-10Alkyl, MOM, 2- THP trtrahydropyranyls, 2- tetrahydrofurans Base, benzyl, to methoxy-benzyl, benzyloxymetliyl, 2- methoxvethoxvmethvls ,-SiR2R3R4, wherein R2、R3、R4Respectively It is independently selected from C1-10Alkyl or aryl；
X is halogen or class halogen group, preferably Cl, Br, I, OTf, OMs, OTs etc..
Specifically, which includes the following steps：
1) compound represented by a formula X is obtained by halogenating reaction such as Formula IX compound represented；The halogenating reaction examination Agent preferred NCS, NBS, NIS, I2, Br2Deng；
2) Formula IX compound represented is obtained by hydrolysis such as Formula VIII compound represented；The reaction preferably exists It is carried out under acid condition；
3) chemical combination as shown in Formula IV is obtained by the reaction by MOM protections under alkaline condition in Formula VIII compound represented Object；Described react uses the preferred triethylamine of alkali, diisopropyl ethyl amine, pyridine, DMAP, potassium carbonate, 2,6- lutidines, and 2, 4,6- trimethylpyridines etc.；
4) Formula IV compound represented obtains shown as a formula V with such as Formula VII compound represented by Heck coupling reactions Compound；The reaction preferably carries out under conditions of palladium catalyst；
5) Formula V compound represented is obtained by condensation reaction such as formula III compound represented；The reaction reagent is preferred Malonic acid；
6) formula III compound represented by condensation reaction obtains changing as shown in Formula II with such as formula IV compound represented Close object；The preferred EDCI of condensation reaction reagent, DCC, DIC, HOBt etc.；
7) Formula II compound represented obtains compound shown in formula I by hydrolysis；The hydrolysis is preferred It carries out in acid condition.
Wherein, compound VII can be prepared according to document (Org.Biomol.Chem.2013,11,3674-3691). Compound IV can be prepared according to document (Tetrahedron 2016,72,5047) similar approach.
In yet other embodiments, hydroxyl protection base R1For MOM, X Br.
In yet other embodiments, hydroxyl protection base R1For MOM, X I.
In yet other embodiments, the step 7) is as follows：
Then acid is added in water in dissolved compound II, 2~12h, TLC display reactions are stirred in reaction at 30~100 DEG C Completely, compound I is purified to obtain after concentration.
The preferred hydrochloric acid of acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, perchloric acid, oxalic acid, trifluoroacetic acid, methylsulphur Acid, at least one of benzene sulfonic acid and p-methyl benzenesulfonic acid.
In an especially preferred embodiment, the present invention provide compound shown in formula I synthetic route it is as follows：
Wherein, R1For hydrogen or carboxyl-protecting group, preferably hydrogen, C1-10Alkyl, MOM, 2- THP trtrahydropyranyls, 2- tetrahydrofurans Base, benzyl, to methoxy-benzyl, benzyloxymetliyl, 2- methoxvethoxvmethvls ,-SiR2R3R4, wherein R2、R3、R4Respectively It is independently selected from C1-10Alkyl or aryl；
X is halogen or class halogen group, preferably Cl, Br, I, OTf, OMs, OTs etc..
Specifically, this method includes the following steps：
1) compound represented by a formula X carries out bromo-reaction under the action of NBS and obtains such as Formula IX a compounds represented；
2) Formula IX a compounds hydrolysis occur under the action of alchlor obtain such as Formula VIII a compounds represented；
3) Formula VIII a compounds are obtained by the reaction under alkaline condition with MOMCl such as Formula IV a compounds represented；
4) Formula IV a compounds and Formula VII compound Heck coupling reactions occur under the action of palladium catalyst obtain such as Formula V Compound represented；
5) Formula V compound and malonic acid occur condensation reaction and obtain such as formula III compound represented under alkaline condition；
6) formula III compound and formula IV a compounds esterification occur under EDCI condensing agents obtain as shown in Formula II b Compound.
7) Formula II b compounds occur hydrolysis and obtain compound shown in formula I in acid condition.
Wherein, compound VII can be prepared according to document (Org.Biomol.Chem.2013,11,3674-3691). Compound IVa can be prepared according to document (Tetrahedron 2016,72,5047) similar approach.
Compound VIa can also be prepared according to document (J.Org.Chem.2016,81,1585-1592).
The present invention provides the new method of salviandic acid A shown in another synthesis formula (I),
Wherein, R1For hydrogen or carboxyl-protecting group, preferably hydrogen, C1-10Alkyl, MOM, 2- THP trtrahydropyranyls, 2- tetrahydrofurans Base, benzyl, to methoxy-benzyl, benzyloxymetliyl, 2- methoxvethoxvmethvls ,-SiR2R3R4, wherein R2、R3、R4Respectively It is independently selected from C1-10Alkyl or aryl；
X is halogen or class halogen group, preferably Cl, Br, I, OTf, OMs, OTs etc..
Specifically, which includes the following steps：
1) Formula IV compound represented obtains shown as a formula V with such as Formula VII compound represented by Heck coupling reactions Compound；The reaction preferably carries out under conditions of palladium catalyst；
2) Formula V compound represented is obtained by condensation reaction such as formula III compound represented；The reaction reagent is preferred Malonic acid；
3) formula III compound represented and such as formula IV compound represented are anti-by condensation occurs under conditions of condensing agent It should obtain such as Formula II compound represented；
4) Formula II compound represented obtains compound shown in formula I by hydrolysis；The hydrolysis is preferred It carries out in acid condition.
Wherein, compound VII can be prepared according to document (Org.Biomol.Chem.2013,11,3674-3691). Compound IV can be prepared according to document (Tetrahedron 2016,72,5047) similar approach.
When X be bromine or iodine when, compound VI can according to document (J.Org.Chem.2016,81,1585-1592； Synthesis, 2005,1019-1027) it is prepared.
In yet other embodiments, hydroxyl protection base R1For MOM, X Br.
In yet other embodiments, hydroxyl protection base R1For MOM, X I.
The present invention also provides a kind of such as Formula II compound represented,
Wherein, R1For hydrogen or carboxyl-protecting group, preferably hydrogen, C1-10Alkyl, MOM, 2- THP trtrahydropyranyls, 2- tetrahydrofurans Base, benzyl, to methoxy-benzyl, benzyloxymetliyl, 2- methoxvethoxvmethvls ,-SiR2R3R4, wherein R2、R3、R4Respectively It is independently selected from C1-10Alkyl or aryl；
In yet other embodiments, R1For hydrogen, such as Formula II a,
In yet other embodiments, R1For hydroxyl protection base MOM, such as Formula II b,
The present invention further provides a kind of preparation method such as Formula II compound represented, compound II passes through such as formula III Compound represented is made with such as formula IV compound represented after condensation reaction；
Wherein, R1For hydrogen or carboxyl-protecting group, preferably hydrogen, C1-10Alkyl, MOM, 2- THP trtrahydropyranyls, 2- tetrahydrofurans Base, benzyl, to methoxy-benzyl, benzyloxymetliyl, 2- methoxvethoxvmethvls ,-SiR2R3R4, wherein R2、R3、R4Respectively It is independently selected from C1-10Alkyl or aryl.
In yet other embodiments, comprise the following steps：
Dissolved compound III, compound IV, condensing agent and alkali are in organic solvent, and reaction mixture is at 0~60 DEG C Stirring 1~for 24 hours, TLC shows that the reaction was complete, and water quenching reaction is added, and ethyl acetate extraction purifies to obtain compound II after concentration.
The preferred 1- ethyls-of condensing agent (3- dimethylaminopropyls) the phosphinylidyne diimmonium salt hydrochlorate (EDCI), two hexamethylenes Base carbodiimide (DCC), diisopropylcarbodiimide (DIC), O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester (HBTU), 2- (7- aoxidizes benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid esters (HATU), O- benzotriazole-N, N, N ', N '-tetramethylurea tetrafluoro boric acid esters (TBTU), 2- (interior -5- norbornene -2,3- dicarboximide) -1,1,3,3- tetramethylurea Tetrafluoroborate (TNTU), 6- Chloro-Benzotriazoles -1,1,3,3- tetramethylurea tetrafluoro boric acid ester salt (TCTU), hexafluorophosphoric acid benzene And triazole -1- oxygroups three (dimethylamino) phosphorus (BOP), hexafluorophosphoric acid benzotriazole -1- bases-oxygroup tripyrrole alkyl phosphorus (PyBOP), three (dimethylamino) phosphine hexafluorophosphate (PyAOP) of 7- azepines benzo triazol-1-yl oxygroup, two miaow of N, N '-carbonyl At least one of azoles (CDI) and 4- (4,6- dimethoxy-triazine) -4- methyl morpholine hydrochlorides (DMTMM).
The preferred triethylamine of alkali (TEA), N, N '-diisopropylethylamine (DIPEA), N-methylmorpholine, pyridine, 4- diformazans Aminopyridine (DMAP), at least one of 1,8- diazabicylo, 11 carbon -7- alkene (DBU) and triethylene diamine (DABCO).
The present invention also provides a kind of preparation method such as Formula II a, Formula II x is obtained by IIa hydrolysis；
Wherein RxFor carboxyl-protecting group, preferably C1-10Alkyl, MOM, 2- THP trtrahydropyranyls, 2- tetrahydrofuran bases, benzyl, To methoxy-benzyl, benzyloxymetliyl, 2- methoxvethoxvmethvls ,-SiR2R3R4, wherein R2、R3、R4It is respectively and independently selected from C1-10Alkyl or aryl.
The present invention also provides a kind of such as formula III compound represented,
The present invention further provides a kind of preparation method such as formula III compound represented, compound III passes through such as Formula V Compound represented is made after condensation reaction；
In yet other embodiments, comprise the following steps：
Dissolved compound V, malonic acid substance and alkali are in organic solvent, and then reaction mixture is at 20~100 DEG C Stirring 12~48 hours, TLC shows that the reaction was complete, is cooled to room temperature, and water quenching reaction, ethyl acetate extraction, after concentration is added Purify to obtain compound III.
The preferred malonic acid substance of malonic acid substance is malonic acid, malonic acid monomethyl ester, monoethyl malonate and Malonic acid list isopropyl ester etc.；
The preferred triethylamine of alkali (TEA), N, N '-diisopropylethylamine (DIPEA), piperidines, N-methylmorpholine, pyridine, 4-dimethylaminopyridine (DMAP), in 1,8- diazabicylo, 11 carbon -7- alkene (DBU) and triethylene diamine (DABCO) extremely Few one kind.
The present invention also provides a kind of compound shown as a formula V,
The present invention furthermore provides a kind of preparation method of compound shown as a formula V, and Formula V compound passes through Formula VII Compound and Formula IV compound occur Heck coupling reactions and are made,
Wherein, X is halogen or class halogen group, preferably Cl, Br, I, OTf, OMs, OTs etc..
In yet other embodiments, comprise the following steps：
Compound VI, compound VII, alkali and palladium catalyst composition sequentially add in organic solvent, then reaction mixing Liquid stirs 5~48 hours at 50-140 DEG C, and TLC shows that the reaction was complete, is cooled to room temperature, and water quenching reaction, acetic acid second is added Ester extracts, and compound V is purified to obtain after concentration.
The preferred triethylamine of alkali (TEA), N, N '-diisopropylethylamine (DIPEA), N-methylmorpholine, pyridine, 4- diformazans Aminopyridine (DMAP), 1,8- diazabicylo, 11 carbon -7- alkene (DBU), triethylene diamine (DABCO), sodium carbonate, carbonic acid Potassium, anhydrous phosphoric acid potassium, three water potassium phosphates, at least one of potassium hydroxide and sodium hydroxide；
The preferred palladium of palladium catalyst composition, palladium bichloride, tetra-triphenylphosphine palladium, three dibenzalacetones, two palladium, Three dibenzalacetones, two palladium chloroform adduct, [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, Bi triphenyl phosphorus palladium chloride, allyl palladium chloride (II) dimer, [1,1 '-bis- (diphenylphosphino) ferrocene] dichloride Palladium, palladium acetylacetonate, triphenylphosphine, three o-methyl-phenyl phosphines, 2- dicyclohexyls phosphine -2 ', 4 ', 6 '-tri isopropyl biphenyls, 2- is bis- Cyclohexyl phosphine -2 ', 6 '-dimethoxy-biphenyls, 2- dicyclohexyls phosphorus -2 ', 6 '-diisopropoxy -1,1 '-biphenyl, 4,5- bis- two Phenylphosphine -9,9- xanthphos, 1,1 '-binaphthol, (±) -2,2 '-bis--(diphenyl phosphine) -1,1 '-dinaphthalene, 1,1 ' - Bis- (diphenylphosphine) at least one of ferrocene and tricyclohexyl phosphine；
The preferred dichloromethane of organic solvent described in the program, chloroform, N, N '-dimethylformamide, N, N '-dimethylacetamide Amine, tetrahydrofuran, 2- methyltetrahydrofurans, Isosorbide-5-Nitrae-dioxane, at least one of N-Methyl pyrrolidone and toluene.
The present invention also provides a kind of such as Formula IV compound represented,
Wherein, X is halogen or class halogen group, preferably Cl, Br, I, OTf, OMs, OTs etc..
In yet other embodiments, X is bromine.
In presently preferred embodiment, X is iodine.
The present invention further provides a kind of preparation method such as Formula IV compound represented, compound VI passes through such as Formula VIII Compound represented is made by MOM protections；
Wherein, X is as defined in Formula IV compound.
In yet other embodiments, comprise the following steps：
Dissolved compound VIII, in organic solvent, MOMCl is added dropwise to wherein alkali at 0~30 DEG C or so, and then reaction is mixed It closes liquid and stirs 2~9h at 0~60 DEG C, TLC shows that the reaction was complete, and reaction mixture is washed with water successively, then uses anhydrous slufuric acid Sodium is dried, and compound VI is concentrated to give.
The preferred triethylamine of alkali (TEA), N, N '-diisopropylethylamine (DIPEA), N-methylmorpholine, pyridine, 4- diformazans Aminopyridine (DMAP), 1,8- diazabicylo, 11 carbon -7- alkene (DBU), triethylene diamine (DABCO), sodium carbonate, carbonic acid Potassium, anhydrous phosphoric acid potassium, three water potassium phosphates, at least one of potassium hydroxide and sodium hydroxide.
If commercially available, it is possible to use the portion of product in above-mentioned reaction step, which is made according to more short-circuit line shown in Formulas I, to be changed Close object；Such as it can be by buying intermediate shown in previously described formula VIII, Formula IV, then according to offer the step of system in the above method Obtain Formulas I compound represented.
Term used in the present invention has following meaning in addition to having opposite statement：
" alkyl " refers to the aliphatic hydrocarbon group of saturation, includes the straight chain and branched group of 1 to 10 carbon atom, preferably includes 1 To 6 carbon atoms.Non-limiting embodiment include but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Tertiary butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl, 1,1,2- thmethylpropyl, 1,1- dimethyl butyrates Base, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl Amyl, 4- methyl amyls, 2,3- dimethylbutyls etc..Alkyl can be substituted or unsubstituted, when substituted, substituent group It can be substituted on any workable tie point, preferably one or more following groups, independently selected from alkyl, alkene Base, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, Heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo.
Either carboxyl-protecting group is known in the art appropriate for hydroxyl or carboxy protective to the hydroxyl of the present invention Group, referring to document (" Protective Groups in Organic Synthesis ", 5Th Ed.T.W.Greene& P.G.M.Wuts the hydroxy-protective group in).As an example, preferably, the hydroxyl or carboxyl-protecting group can be C1-10Alkyl or C1-10Alkylaryl, such as：Methyl, ethyl, tertiary butyl, benzyl, to methoxy-benzyl etc.；Can be C1-10It takes Substituted alkyl, such as：Methoxy (MOM), ethoxyethyl group (EOE), 2- THP trtrahydropyranyls (THP), tetrahydrofuran base (THF) Deng；Can be (C1-10Alkyl or aromatic radical) acyl group, such as：Formoxyl, acetyl group, benzoyl etc.；Can be (C1-6Alkyl Or C6-10Aryl) sulfonyl；Can also be (C1-6Alkoxy or C6-10Aryloxy) carbonyl；Can be silylation-SiR2R3R4, Wherein R2、R3、R4It is respectively and independently selected from C1-10Alkyl or aryl, such as：Trimethyl silicon substrate, triethyl group silicon substrate, triisopropyl silicon Base, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate etc.；.
" aryl " refers to 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle (is namely shared and adjoined The ring of carbon atom pair) group, preferably 6 to 10 yuan, more preferable phenyl and naphthalene, most preferably phenyl.Aryl can be substitution Or it is unsubstituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynes Base, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl Base, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
Abbreviations table：
Following table is the structural formula of compound involved in embodiment
Specific implementation mode
The present invention is explained in detail below with reference to specific example so that those of ordinary skill in the art are more fully understood The present invention, specific example are only used to illustrate the technical scheme of the present invention, and do not limit the present invention in any way.
Embodiment 1：Prepare compound IXa
Isovanillin X (60.86g, 400mmol) is dissolved, NBS (74.76g) is in dioxane/water (500mL/200mL) In, then reaction mixture is stirred at room temperature 3 hours, and TLC shows that the reaction was complete, and water is added, and filters, and filter cake dries under vacuum Do to obtain compound IXa (81.9g).
1H NMR(CDCl3, 400MHz) δ 10.29 (s, 1H), 7.60 (d, J=8.5Hz, 1H), 6.95 (d, J=8.5Hz, 1H), 6.10 (s, 1H), 4.03 (s, 3H).
Embodiment 2：Prepare compound VIIIa
Compound IXa (69.3g, 300mmol), alchlor (44g) and pyridine (104.4g) are in dichloromethane In (1200mL), then reaction mixture stirs 32 hours under reflux, and TLC shows that the reaction was complete, is down to room temperature, and dense salt is added Acid is adjusted to pH=1-2, filters, and filter cake dries to obtain compound VIIIa (57.8g) under vacuum.
1H NMR(CDCl3, 400MHz) and δ 11.08 (s, 1H), 10.07 (s, 1H), 9.64 (d, J=0.6Hz, 1H), 7.31 (d, J=8.4Hz, 1H), 6.93 (d, J=8.3Hz, 1H)
Embodiment 3：Prepare compound VIa
Dissolved compound VIIIa (32.39g, 150mmol), potassium carbonate (81.27g) in dichloromethane (800mL), MOMCl (48.3g) is added dropwise to wherein at 0 DEG C or so, and then reaction mixture is stirred at room temperature 3 hours, and TLC displays have been reacted Entirely, reaction mixture is washed with water (500mL*3) successively, then is dried with anhydrous sodium sulfate, and compound VIa (42.3g) is concentrated to give.
1H NMR(CDCl3, 400MHz) and δ 10.30 (s, 1H), 7.73 (d, J=8.7Hz, 1H), 7.24 (s, 1H), 5.27 (d, J=29.5Hz, 4H), 3.71 (s, 3H), 3.53 (s, 3H).
Embodiment 4-7 is the synthesis of compound V
Embodiment 4：Prepare compound V
Compound VIa (26g), compound VII (17.9g, 80mmol), potassium carbonate (50.23g) and tetra-triphenylphosphine palladium (0.21g) sequentially adds n,N-Dimethylformamide (120mL), and then reaction mixture stirs 20 hours at 90 DEG C, and TLC is aobvious Show that the reaction was complete, be cooled to room temperature, water quenching reaction is added, and ethyl acetate extraction purifies to obtain compound V (28.9g) after concentration.
1H NMR(CDCl3, 400MHz) δ 10.13 (s, 1H), 7.75 (d, J=8.7Hz, 1H), 7.42 (dd, J=10.8, 9.1Hz, 2H), 7.24-7.15 (m, 3H), 6.67 (d, J=16.4Hz, 1H), 5.34-5.27 (m, 6H), 5.15 (s, 2H), 3.56 (dd, J=10.4,6.7Hz, 13H)
Embodiment 5：Prepare compound V
Compound VIa (26g), compound VII (17.9g, 80mmol), N, N ' diisopropyl ethyl amine (60mL) and acetic acid Palladium (0.56g) sequentially adds toluene (80mL), and then reaction mixture stirs 5 hours at 50 DEG C, and TLC shows that the reaction was complete, It is cooled to room temperature, water quenching reaction is added, ethyl acetate extraction purifies to obtain compound V (27.6g) after concentration.
Embodiment 6：Prepare compound V
Compound VIa (26g), compound VII (17.9g, 80mmol), potassium phosphate (86g) and palladium chloride (0.62g) according to Secondary addition tetrahydrofuran (200mL), then reaction mixture stirred 48 hours at 80 DEG C, TLC shows that the reaction was complete, is cooled to Room temperature, is added water quenching reaction, and ethyl acetate extraction purifies to obtain compound V (22.3g) after concentration.
Embodiment 7：Prepare compound V
Compound VIa (26g), compound VII (17.9g, 80mmol), triethylamine (86g) and Pd2dba3 (0.66g), three Phenylphosphine (2.3g) sequentially adds n,N-dimethylacetamide (150mL), and then it is small to stir 24 at 140 DEG C for reaction mixture When, TLC shows that the reaction was complete, is cooled to room temperature, and water quenching reaction is added, and ethyl acetate extraction purifies to obtain compound V after concentration (20.9g)。
Embodiment 8：Prepare compound III
Dissolved compound V (8.07g, 18mmol), malonic acid (3.74g) and piperidines (5mL) are in pyridine (45mL), then Reaction mixture stirs 48 hours at 20 DEG C, and TLC shows that the reaction was complete, is cooled to room temperature, and water quenching reaction, acetic acid second is added Ester extracts, and compound III (7.1g) is purified to obtain after concentration.
1H NMR (400MHz, CDCl3)：δ 7.99 (d, J=15.9Hz, 1H), 7.38 (dd, J=10.7,5.3Hz, 1H), 7.25 (d, J=16.5Hz, 0H), 7.20-7.10 (m, 1H), 6.65 (d, J=16.5Hz, 0H), 6.32 (d, J=15.9Hz, 0H), 5.34-5.24 (m, 3H), 5.12 (s, 1H), 3.79 (s, 1H), 3.55 (dd, J=8.1,4.5Hz, 5H)
Embodiment 9：Prepare compound III
Dissolved compound V (10g, 22.3mmol), malonic acid monomethyl ester (5.5g) and triethylamine (8mL) are in pyridine (45mL) In, then reaction mixture stirs 24 hours at 100 DEG C, and TLC shows that the reaction was complete, is cooled to room temperature, and it is anti-that water quenching is added It answers, ethyl acetate extraction purifies to obtain compound III (8.6g) after concentration.
Embodiment 10：Prepare compound IIc
Dissolved compound III (0.49g, 1mmol), compound IVb (0.30g), EDCI (0.20g) and DMAP (0.12g) In dichloromethane (10mL), then reaction mixture stirs 24 hours at 0 DEG C, and TLC shows that the reaction was complete, and water quenching is added Reaction, ethyl acetate extraction, purifies to obtain compound IIc (0.68g) after concentration.
1H NMR(CDCl3, 400MHz) and δ 8.05 (d, J=15.9Hz, 1H), 7.44-7.36 (m, 2H), 7.25 (d, J= 16.5Hz, 1H), 7.18-7.01 (m, 5H), 6.85-6.76 (m, 1H), 6.64 (d, J=16.5Hz, 1H), 6.37 (d, J= 15.8Hz, 1H), 5.43-5.32 (m, 1H), 5.32-5.26 (m, 6H), 5.21 (t, J=3.1Hz, 4H), 5.12 (s, 2H), 3.75 (s, 3H), 3.63-3.45 (m, 17H), 3.39 (ddd, J=25.8,8.5,4.6Hz, 1H), 3.10 (dd, J=20.0, 12.5Hz, 2H)
Embodiment 11：Prepare compound IIa
Dissolved compound IIc (0.40g) and trimethyl stannic hydroxide (0.28g) in dichloromethane (21mL), in, then instead Mixed liquor is answered to stir under reflux 3 hours, TLC shows that the reaction was complete, is cooled to room temperature, and water quenching reaction, ethyl acetate is added Extraction, purifies to obtain compound IIa (0.28g) after concentration.
1H NMR(CDCl3, 400MHz) and δ 8.03 (d, J=15.9Hz, 1H), 7.37 (d, J=8.5Hz, 2H), 7.27- 7.21 (m, 1H), 7.20-7.09 (m, 4H), 7.03 (d, J=8.3Hz, 1H), 6.85 (dd, J=8.3,1.9Hz, 1H), 6.65 (d, J=16.5Hz, 1H), 6.37 (d, J=15.6Hz, 1H), 5.28 (d, J=6.6Hz, 7H), 5.20 (s, 4H), 5.12 (s, 2H), 3.62-3.36 (m, 20H), 3.14 (dd, J=19.0,6.3Hz, 2H)
Embodiment 12：Prepare compound IIb
Dissolved compound III (490mg, 1mmol), compound IVa (330mg), EDCI (200mg) and 4- dimethylamino pyrroles Pyridine (126mg) is in dichloromethane (4mL), and reaction mixture stirs 1 hour at 60 DEG C, and TLC shows that the reaction was complete, and water is added Quenching reaction, ethyl acetate extraction, purifies to obtain compound IIb (660mg) after concentration.
1H NMR(CDCl3, 400MHz) and δ 8.06 (d, J=15.9,1H), 7.44-7.35 (m, 2H), 7.25 (d, J= 16.5,1H), 7.18-7.01 (m, 5H), 6.89-6.80 (m, 1H), 6.66 (s, 1H), 6.38 (d, J=15.8,1H), 5.37- 5.18 (m, 14H), 5.12 (s, 2H), 3.61-3.45 (m, 20H), 3.42 (d, J=2.5,3H), 3.15 (s, 2H)
Embodiment 13-16 is the synthesis of compound I
Embodiment 13：Prepare compound I
Dissolved compound IIa (140mg) is then added p-methyl benzenesulfonic acid (2.2g), is stirred at 100 DEG C in water (3mL) It mixes 4 hours, TLC shows that the reaction was complete, and compound I (90mg) is purified to obtain after concentration.
1H NMR(CD3OD, 400MHz) δ 8.08 (d, J=15.8Hz, 1H), 7.15 (dd, J=12.4,6.8Hz, 2H), 7.07 (d, J=2.0Hz, 1H), 6.89 (dd, J=8.2,2.0Hz, 1H), 6.80-6.71 (m, 3H), 6.66 (dd, J=12.2, 4.2Hz, 2H), 6.56 (dd, J=8.1,2.0Hz, 1H), 6.31 (d, J=15.8Hz, 1H), 5.18 (dd, J=8.4,4.1Hz, 1H), 3.07 (d, J=4.0Hz, 1H), 2.99 (d, J=8.6Hz, 1H)
Embodiment 14：Prepare compound I
Dissolved compound IIb (290mg) is then added trifluoroacetic acid (2mL), 10 is stirred at 80 DEG C in water (3mL) Hour, TLC shows that the reaction was complete, compound I (150mg) is purified to obtain after concentration.
Embodiment 15：Prepare compound I
Dissolved compound IIb (290mg) is added acetic acid (1mL) and then reaction mixture stirs at 30 DEG C in water (7mL) It mixes 2 hours, TLC shows that the reaction was complete, and compound I (146mg) is purified to obtain after concentration.
Embodiment 16：Prepare compound I
Dissolved compound IIb (290mg) is in 1N hydrochloric acid (7mL), and then reaction mixture stirs 12 hours at 90 DEG C, TLC shows that the reaction was complete, and compound I (138mg) is purified to obtain after concentration.
Due to describing the present invention according to its specific embodiment, certain modifications and equivalent variations are general for this field Logical technical staff is obvious and is included within the scope of the invention.

Claims (13)

1. a kind of such as Formula II compound represented,
Wherein, R1For hydrogen or carboxyl-protecting group, preferably hydrogen, C1-10Alkyl, MOM, 2- THP trtrahydropyranyls, 2- tetrahydrofuran bases, benzyl Base, to methoxy-benzyl, benzyloxymetliyl, 2- methoxvethoxvmethvls ,-SiR2R3R4, wherein R2、R3、R4Independently Selected from C1-10Alkyl or aryl.
2. a kind of preparation method of salviandic acid A shown in formula I, it is characterised in that pass through water by such as Formula II compound represented Compound I is made in solution reaction,
Wherein, R1As defined in claim 1.
3. a kind of preparation method of such as Formula II compound represented, which is characterized in that by the compound as shown in formula III and such as formula Compound shown in IV is made by condensation reaction,
Wherein, R1As defined in claim 1.
4. a kind of preparation method of such as Formula II a compounds represented, which is characterized in that pass through such as Formula II compound represented and pass through It is made after hydrolysis,
Wherein RxFor carboxyl-protecting group, preferably C1-10Alkyl, MOM, 2- THP trtrahydropyranyls, 2- tetrahydrofuran bases, benzyl, to first Oxy-benzyl, benzyloxymetliyl, 2- methoxvethoxvmethvls ,-SiR2R3R4, wherein R2、R3、R4It is respectively and independently selected from C1-10 Alkyl or aryl.
5. a kind of such as formula III compound represented,
6. a kind of preparation method of such as formula III compound represented, which is characterized in that pass through compound shown as a formula V and pass through Condensation reaction is made,
7. a kind of compound shown as a formula V,
8. a kind of preparation method of compound shown as a formula V, which is characterized in that by such as Formula IV compound represented and such as formula VII compounds represented are made by Heck coupling reactions,
Wherein, X is halogen or class halogen group, preferably Cl, Br, I, OTf, OMs or OTs.
9. a kind of such as Formula IV compound represented,
Wherein, X is as defined in claim 8.
10. a kind of preparation method of such as Formula IV compound represented, which is characterized in that pass through such as Formula VIII compound represented and pass through MOM protection reactions are crossed to be made,
Wherein, X is as defined in claim 8.
11. a kind of preparation method of compound shown in formula I, it is characterised in that include the following steps：
1) compound represented by a formula X is obtained by halogenating reaction such as Formula IX compound represented；
2) Formula IX compound represented is obtained by hydrolysis such as Formula VIII compound represented；
3) Formula VIII compound represented is obtained by the reaction by MOM protections such as Formula IV compound represented；
4) Formula IV compound represented obtains change shown as a formula V with such as Formula VII compound represented by Heck coupling reactions Close object；
5) Formula V compound represented is obtained by condensation reaction such as formula III compound represented；
6) formula III compound represented by condensation reaction obtains the chemical combination as shown in Formula II with such as formula IV compound represented Object；
7) Formula II compound represented obtains compound shown in formula I by hydrolysis；
Wherein, R1As defined in claim 1；X is as defined in claim 8.
12. a kind of preparation method of compound shown in formula I, it is characterised in that include the following steps：
1) Formula IV compound represented obtains change shown as a formula V with such as Formula VII compound represented by Heck coupling reactions Close object；
2) Formula V compound represented is obtained by condensation reaction such as formula III compound represented；
3) formula III compound represented by condensation reaction obtains the chemical combination as shown in Formula II with such as formula IV compound represented Object；
4) Formula II compound represented obtains compound shown in formula I by hydrolysis；
Wherein, R1As defined in claim 1；X is as defined in claim 8.
13. such as Formula II a or IIb compound represented,
CN201710250891.XA 2017-04-17 2017-04-17 The preparation method of intermediate of salviandic acid A and preparation method thereof and salviandic acid A Withdrawn CN108727190A (en)

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