CN112920119A - Preparation method of aporphine alkaloid - Google Patents
Preparation method of aporphine alkaloid Download PDFInfo
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Abstract
The invention discloses a preparation method of aporphine alkaloid shown in a formula III, which takes benzaldehyde compounds shown in a formula III-0 as raw materials to carry out Wittig reaction, Pictet-Spengler reaction, Heck reaction and palladium-carbon hydrogenolysis deprotection in sequence. According to the invention, the benzaldehyde derivative containing bromine is selected as a raw material, the carbon-carbon coupling yield and the reaction rate are increased through bromine atoms, and the reaction activity is improved; adopting benzyl chloroformate for NH protection, and introducing an electron-withdrawing group is favorable for improving the reaction yield; directly reacting the styrene methyl ether derivative with the acylated phenethylamine derivative in an acid catalysis system by adopting a one-pot method to obtain the benzyl tetrahydroisoquinoline. The preparation method has the advantages of mild reaction conditions, low toxicity of used reagents, easily obtained raw materials, convenient post-treatment, simpler reaction route than the previous report, and suitability for various reaction substrates.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of aporphine alkaloid.
Technical Field
Aporphine alkaloid belongs to isoquinoline alkaloid, is an important type of natural alkaloid, is widely distributed in nature and has important biological activity. The aporphine alkaloid has a biphenyl tetracyclic special structure, and the aromatic ring substituent, the N substituent and the absolute configuration change of 6a carbon form a rich structural library of the compound. The diversity of chemical structure inevitably leads to the universality of the biological activity, so that the aporphine alkaloid has good development and utilization values and wider pharmaceutical application prospect.
The aporphine alkaloid or the extract containing the aporphine alkaloid can be applied to various treatment fields, such as antioxidation, anticancer, anti-inflammatory, antimalarial and the like, and especially can be used for treating diseases of the central nervous system, such as schizophrenia, depression, dyskinesia caused by drugs for resisting Parkinson's disease and the like. Aporphine alkaloid is mainly derived from traditional Chinese medicinal materials, active aporphine alkaloid is prepared by chemical synthesis, and derivatives with good stability, low toxicity and higher biological activity are obtained on the matrix through further structural modification, thus having important significance on the research of innovative medicaments for natural products. Meanwhile, most of the known natural products, namely the aporphine alkaloid A ring, are mainly substituted by 1, 2-methylenedioxy or 1, 2-dimethoxy; the D ring is mainly substituted at the 9-position and the 10-position, and the methoxyl or phenolic hydroxyl is a main substituted functional group.
The aporphine alkaloid mainly has the following three synthetic routes: a. firstly constructing an Apophenanthrene ABD ring, and then constructing a C ring through cyclization; b. firstly, constructing an ACD ring, and then constructing a B ring in a cyclization manner; c. firstly, building ABC ring, and then building D ring by cyclization. Scheme a mainly involves the reaction types: wittig reaction, Pictet-Spengler reaction, Heck reaction, protection and deprotection for aporphine alkaloid containing active hydrogen.
Benzyl tetrahydroisoquinoline is an essential intermediate for synthesizing apophenanthrene alkaloid and mainly adopts two synthesis methods.
The first method is to adopt Bischer-Napieralski reaction to react phenylacetic acid or acyl chloride derivative with phenethylamine to form amide, then to dehydrate and close the ring under the action of dehydrating agent such as phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride and the like to obtain dihydroisoquinoline, and then to reduce to obtain tetrahydroisoquinoline. Namely, the benzyl tetrahydroisoquinoline is obtained through three steps of reaction, and the total yield is 40 to 80 percent.
And secondly, obtaining the benzyl tetrahydroisoquinoline by adopting a Pictet-Spengler reaction and performing acid catalysis on the phenylacetaldehyde derivative and the phenethylamine derivative. Wherein, the phenylacetaldehyde derivative is generally obtained by the steps of generating styrene methyl ether from benzaldehyde derivative through Wittig reaction, and then carrying out acid hydrolysis and purification. Namely, the benzyl tetrahydroisoquinoline is obtained through two-step reaction, and the total yield is 40 to 80 percent.
Disclosure of Invention
The invention aims to provide a total synthesis route of aporphine alkaloids, wherein the Pictet-Spengler reaction in the whole synthesis route is improved, and a one-pot method is adopted to directly react a styrene methyl ether derivative with an acylated phenethylamine derivative in an acid catalysis system to obtain benzyl tetrahydroisoquinoline (the yield reaches at least 80 percent), so that the aporphine alkaloids with different substituents on a mother nucleus A ring and a mother nucleus D ring shown in the formula III are synthesized.
The purpose of the invention is realized by the following technical scheme:
a preparation method of aporphine alkaloid shown in formula III takes benzaldehyde compound shown in formula III-0 as raw material, and sequentially carries out Wittig reaction, Pictet-Spengler reaction, Heck reaction and palladium-carbon hydrogenolysis deprotection; the synthetic route is as follows:
wherein R is1、R2Each independently selected from alkoxy, methylenedioxy (-OCH)2O-)，R3、R4Each independently selected from H, alkoxy, methylenedioxy;
or
Wherein R is1、R2Each independently selected from alkoxy, methylenedioxy, R3、R4Each independently selected from H, OH, alkoxy, except R3、R4At least one of them is OH; r3’、R4’Each independently selected from H, OBn (benzyloxy), alkoxy, but R3’、R4’At least one of which is OBn, forms a protection for OH, i.e. R forms, in addition to OH forming OBn3’And R3Corresponds to, R4’And R4And (7) corresponding.
Specifically, when R is3、R4When none is selected from OH, the method comprises the following steps:
step (i), Wittig reaction: taking a benzaldehyde compound shown as a formula III-0 as a raw material, taking dichloromethane as a reaction solvent, carrying out ice bath reaction under the protection of nitrogen in the presence of a phosphorus salt and an organic base to obtain a styrene methyl ether compound shown as a formula III-1;
step (ii) using dichloromethane as reaction solvent, at K2CO3In the presence of
Reacting the phenethylamine compound with benzyl chloroformate to obtain an amino-protected phenethylamine compound shown in a formula III-2;
step (iii), Pictet-Spengler reaction: taking acetonitrile as a reaction solvent, under the protection of nitrogen, and in the presence of trifluoroacetic acid, carrying out a Pictet-Spengler reaction on a styrene methyl ether compound shown as a formula III-1 and an amino-protected phenethylamine compound shown as a formula III-2 to obtain a benzyl tetrahydroisoquinoline compound shown as a formula III-3;
step (iv), Heck reaction: DMA (N, N-dimethylacetamide) as a reaction solvent in Pd (OAc)2、Xphos、Cs2CO3Under the existence condition, obtaining aporphine alkaloid protected by 6-amino shown in the formula III-4 by Heck reaction of the benzyltetrahydroisoquinoline compound shown in the formula III-3 under the protection of nitrogen;
step (v), palladium carbon hydrogenolysis deprotection: taking a mixed solvent of THF and methanol as a reaction solvent, taking 10% Pd/C as a catalyst, and removing a protecting group from the aporphine alkaloid protected by 6-amino at normal temperature to obtain the aporphine alkaloid shown in the formula III.
In the step (i), the molar ratio of the benzaldehyde compound to the phosphorus salt is 1: 1.5-2; the molar ratio of the benzaldehyde compound to the organic base is 1: 1.5-2; the phosphorus salt is MeOCH2PPh3Cl; the organic base is sodium tert-butoxide or potassium tert-butoxide.
In the step (ii), the molar ratio of the phenethylamine compound to benzyl chloroformate is 1: 1; the phenethylamine compound and K2CO3The molar ratio of (A) to (B) is 1: 1-2; after the reaction is finished, washing and extracting a dichloromethane layer, and removing dichloromethane; and at normal temperature, adding ethyl acetate for dissolving, adding petroleum ether with the volume of 50-100 times that of the ethyl acetate, and recrystallizing to separate out the amino-protected phenethylamine compound.
In the step (iii), the molar ratio of the styrene methyl ether compound to the amino-protected phenethylamine compound is 1-1.5: 1, and considering that the polarity of the benzyl tetrahydroisoquinoline compound is close to that of the amino-protected phenethylamine compound, the benzaldehyde is slightly excessive during feeding, and the molar ratio of the styrene methyl ether compound to the amino-protected phenethylamine compound is preferably controlled to be 1.1-1.5: 1, so as to ensure complete reaction of the phenethylamine derivative and simplify purification. The temperature of the Pictet-Spengler reaction is normal temperature, the reaction time is 0.5 to 3 days, and the end point of the reaction is monitored by a thin-layer plate; after the reaction is finished, carrying out suction filtration to obtain the benzyl tetrahydroisoquinoline compound.
Specifically, in order to prevent the trifluoroacetic acid in the system from being locally over-concentrated, the trifluoroacetic acid is firstly added into a solvent, fully and uniformly mixed, and then the raw materials are added. The trifluoroacetic acid hydrolyzes the styrene methyl ether into styrene alcohol compounds, then enol iso forms the phenylacetaldehyde compounds, the generated phenylacetaldehyde compounds immediately react with the amino-protected phenethylamine compounds, and then the benzyl tetrahydroisoquinoline compounds are generated under the catalysis of the trifluoroacetic acid; the molar ratio of the styrene methyl ether compound to trifluoroacetic acid is controlled to be 1: 1-2.5, the acid dosage is not too much, the reaction is required at normal temperature, otherwise, by-products are increased, the concentration of the trifluoroacetic acid is strong acid, the by-products after deprotection are generated due to too high concentration, and the concentration of the trifluoroacetic acid in the system can be controlled to be 0.15-0.3 mol/L, preferably 0.16 mol/L.
In the step (iv), the benzyl tetrahydroisoquinoline compound and Pd (OAc)2The molar ratio of (A) is 1: 0.05-0.2, preferably 1:0.1, and the Pd (OAc)2And Xphos in a molar ratio of 1:2, said benzyltetrahydroisoquinoline compound and Cs2CO3The molar ratio of (A) to (B) is 1: 1.5-2. By controlling Pd (OAc)2And ligand Xphos and catalyst Cs2CO3The consumption of the catalyst can avoid the generation of excessive target black, which causes difficult post-treatment and avoids environmental pollution caused by heavy metal.
The temperature of the Heck reaction was 130 ℃ and the progress of the reaction was monitored by TLC plates; and after the reaction is finished, cooling to room temperature, adding dichloromethane and water into the reaction solution, extracting to obtain a dichloromethane layer, concentrating, and performing silica gel column chromatography (100-200 meshes of silica gel, and the eluent is petroleum ether and acetone which is 7:1V/V) to obtain the aporphine alkaloid protected by the 6-amino.
The Heck reaction uses DMA as a reaction solvent, and compared with DMF, the yield can be greatly increased, and the generation of byproducts is reduced.
The Heck reaction is carried out under the anhydrous and oxygen-free conditions, the complete reaction is ensured, the yield is improved, and byproducts are reduced.
In the step (v), the ratio of MeOH to THF in the reaction system has a great influence on the reaction rate, the target hydrocarbon hydrolysis reaction can be accelerated by adding a protic solvent, the aprotic solvent can slow down the reaction rate or even does not react, but the reaction rate is slowed down because the raw material is generally insoluble in methanol, a certain proportion of THF is added for assisting dissolution, and the reaction rate can be accelerated by increasing the use amount of methanol as much as possible while the solubility is increased. The mixed solvent is a mixed solvent of THF and methanol according to a volume ratio of 1: 2-1: 4.
The 10% Pd/C dosage is 5% -20% of the quality of 6-amino protected aporphine alkaloid, if only the protection of nitrogen active hydrogen is provided, the reaction rate is faster, the target carbon dosage can be properly reduced, if the protection of phenolic hydroxyl and nitrogen hydrogen is provided, the reaction time is slightly prolonged, the target carbon dosage can be properly increased (Cbz is firstly removed and then benzyl is removed), the TLC thin-layer plate monitoring reaction is carried out, the target carbon dosage is gradually changed into a single product, and the generation of ring-opening byproducts if the reaction time is overlong is avoided.
When R is3、R4And when at least one selected from OH, protecting the hydroxyl of the benzaldehyde compound by using benzyl bromide to obtain the benzaldehyde compound with the hydroxyl protection shown in the formula III-0', and sequentially carrying out Wittig reaction, Pictet-Spengler reaction, Heck reaction and palladium-carbon hydrogenolysis deprotection to obtain the aporphine alkaloid shown in the formula III.
Wittig reaction, Pictet-Spengler reaction, Heck reaction, palladium on carbon hydrogenolysis deprotection step and R3、R4All of which are not selected from OH.
Specifically, the method comprises the following steps:
step (i), using benzaldehyde compound shown as formula III-0 as raw material, using acetonitrile or DMF as reaction solvent, and reacting at K2CO3In the presence of the compound, heating to react at 50-70 ℃, and protecting the hydroxyl of the benzaldehyde compound by using benzyl bromide to obtain a hydroxyl-protected benzaldehyde compound shown as a formula III-0'; the molar ratio of the benzaldehyde compound to the benzyl bromide is 1: 1-1.1, the benzyl bromide is not excessive, if a large amount of benzyl bromide is remained in a mother solution, the precipitated solid has a large benzyl bromide smell or does not come under a filtrate during suction filtration, and a product is easily dissolved in the benzyl bromide and cannot be precipitated, so that the yield is influenced, therefore, a small amount of benzyl bromide is added for multiple times in the reaction process, and T is used for reducing the content of benzyl bromideLC thin layer plate dot plate tracing. Benzaldehyde compound and K2CO3In a molar ratio of 1: 2. DMF is usually used as the reaction solvent for the hydroxyl protection reaction. The inventors have found that CH is preferable to be selected when benzaldehyde compounds are soluble in the reaction solvent3CN since the product is hardly soluble in CH3CN can be greatly separated out when the solvent is taken as a reaction solvent, so that the reaction is continuously carried out in the positive direction, the reaction rate is increased, the yield is increased, the post-treatment is simple and convenient, a product can be obtained by suction filtration, and the product loss caused in the post-treatment extraction process when DMF is used is avoided. When the starting material (e.g. 6-bromovanillin) is not soluble in CH3CN (slow reaction rate or no reaction), DMF can be replaced by reaction solvent. Reacting benzaldehyde compound with K2CO3Heating at 50-70 ℃, and firstly removing hydrogen from phenolic hydroxyl groups of the benzaldehyde compounds under an alkaline condition, so that carbon positive ions of benzyl bromide can attack oxygen negative ions.
Wittig reaction: taking a benzaldehyde compound shown as a formula III-0 'as a raw material, taking dichloromethane as a reaction solvent, carrying out ice bath reaction under the protection of nitrogen in the presence of a phosphorus salt and an organic base to obtain a styrene methyl ether compound shown as a formula III-1'; compared with the benzaldehyde compound shown in the formula III-0, the benzaldehyde compound shown in the formula III-0' has no change in other substituent groups except that hydroxyl in the formula III-0 is protected to obtain OBn.
Step (ii) using dichloromethane as reaction solvent, at K2CO3In the presence of
Reacting the phenethylamine compound with benzyl chloroformate to obtain an amino-protected phenethylamine compound shown in a formula III-2;
step (iii), Pictet-Spengler reaction: taking acetonitrile as a reaction solvent, under the protection of nitrogen, and in the presence of trifluoroacetic acid, carrying out a Pictet-Spengler reaction on a styrene methyl ether compound shown as a formula III-1 'and an amino-protected phenethylamine compound shown as a formula III-2 to obtain a benzyl tetrahydroisoquinoline compound shown as a formula III-3';
step (iv), Heck reaction: DMA (N, N-dimethylacetamide) as a reaction solvent in Pd (OAc)2、Xphos、Cs2CO3Under the condition of existence, performing nitrogen protection, and performing Heck reaction on the benzyl tetrahydroisoquinoline compound shown in the formula III-3 'to obtain aporphine alkaloid shown in the formula III-4' and protected by 6-amino;
step (v), palladium carbon hydrogenolysis deprotection: taking a mixed solvent of THF and methanol as a reaction solvent, taking 10% Pd/C as a catalyst, and removing a protecting group of the aporphine alkaloid shown in the formula III-4' at normal temperature to obtain the aporphine alkaloid shown in the formula III.
The alkoxy is selected from C1-C5 alkoxy, and specifically can be selected from methoxy, ethoxy, C3-C5 straight chain or branched chain alkoxy.
In particular, the aporphine alkaloid shown in the formula III is preferably selected from the following compounds:
the invention has the beneficial effects that:
the invention synthesizes the aporphine alkaloids with different substituents on the 1 and 2 sites of the mother nucleus A ring and the 9 and 10 sites of the D ring by 5 steps of reaction, the preparation method has mild reaction conditions, the used reagents are low in toxicity, the raw materials are easy to obtain, the post-treatment is convenient, and the reaction route is simpler than the previous report and is suitable for various reaction substrates.
If phenylacetic acid is used as a raw material, the subsequent C-C coupling reaction needs further halogenation because most of the raw material does not contain ortho-position halogen atoms, and the o-bromobenzaldehyde compound is used as the raw material in the invention, so that the o-bromobenzaldehyde with various substituents can be directly purchased and obtained, the raw material is cheap and easy to obtain, and bromination can improve the reaction activity of the C-C coupling reaction and improve the yield.
At present, the purpose of NH protection is usually achieved by methyl chloroformate or ethyl chloroformate or Boc protecting groups, but the raw materials of the methyl chloroformate or the methyl chloroformate are not easy to obtain and are hypertoxic products, and belong to psychotics, easily prepared toxic chemicals or controlled products, and the Boc protecting groups are more sensitive and alkali-resistant and are not acid-resistant, so that the subsequent reaction is limited. The invention adopts acid and alkali resistant benzyl chloroformate (CbzCl) for protection for the first time: first, NH protection is performed. And secondly, in order to improve the activity of the Pictet-Spengler reaction (the reaction mechanism is that aromatic ethylamine and aldehyde are dehydrated and condensed into imine under an acidic condition, then imine ions formed after protonation of the imine are used as electrophilic reagents, and electrophilic aromatic substitution is carried out on aromatic rings to carry out cyclization, so as to obtain tetrahydroisoquinoline). The acylated amino group can generate N acyl imine ion in the Pictet-Spengler reaction, and the N acyl imine ion is a strong electrophilic reagent and has stronger electrophilicity than non-acylated imine ion, so that the raw material can be cyclized under mild conditions and in higher yield. Thirdly, the introduction of an electron-withdrawing group on N is helpful for improving the activity and the yield of Heck reaction, if only naked NH is reacted, the yield is very low (the yield is less than or equal to 10 percent) or the reaction is not carried out. Fourthly, considering that OH is protected by Bn group, the protection of amino group by CbzCl can simultaneously use Pd/C hydrogenolysis to obtain final products in the last step.
The present invention improves the Pictet-Spengler reaction, adopts one-pot method to directly react styrene methyl ether derivative and phenethylamine derivative in acid catalysis system to obtain benzyl tetrahydroisoquinoline with yield at least up to 80%.
The yield of the existing aporphine alkaloid total synthesis route is basically maintained at 10-40 percent and is generally lower than 30 percent. The invention optimizes the total synthesis route of aporphine alkaloid, and the total yield is generally more than 30 percent and can reach about 70 percent.
Detailed description of the preferred embodiments
To further illustrate the technical solution of the present invention, a series of examples are listed below. These examples are illustrative and should not be construed as limiting the invention.
Example 1: synthesis of Compound Ic
First step, Wittig reaction-Synthesis of Compound c
iA 6-bromoisovanillin (compound c-1, 45mmol, 10.4g) and K were added to a 250mL single-necked flask2CO3(90mmol, 12.4g) and 100mL acetonitrile (CH) was added3CN), heating at 60 ℃ for reaction, changing the solution from colorless to light yellow suspended matter, then adding a small amount of benzyl bromide (BnBr, 50mmol, 6mL) for multiple times, separating out a large amount of white substances, changing the solution from light yellow to clear colorless transparent solution, heating at 60 ℃ for reflux for 6h, concentrating until the acetonitrile residue is 5-10mL, washing with water and carrying out suction filtration to obtain 13.8g of white powder (compound c-2), wherein the yield is 95.8%.
And iB: in a 250ml two-necked flask, the above white powder (Compound c-2, 40mmol, 13.8g), MeOH, was added2PPh3Cl (methoxymethyltriphenylphosphonium chloride, 60mmol, 20.52g), NaOtBu (sodium tert-butoxide, 60mmol, 5.76g), nitrogen blanket, ice bath, and 50mL of anhydrous CH were added rapidly with syringe2Cl2And when the solution turns from colorless to light yellow and turns to reddish brown after about 3-5min, the reaction is immediately quenched by water if the reaction is complete, and silica gel column chromatography (100-200 mesh silica gel, eluent petroleum ether and ethyl acetate which are 30:1V/V) is carried out to obtain 14.4g of white powder (compound c), wherein the yield is 96.8%. The following points are noted for this reaction: 1. ensuring no water and oxygen, otherwise, incomplete reaction due to R of styrene methyl ether and corresponding benzaldehyde on TLC thin-layer platefThe values are relatively close, and the raw material residue increases the difficulty of post-treatment purification. 2. The equivalents of phosphonium salt and base should not be too large (1.5eq-2eq), otherwise the ylide intermediate by-product is too large, which increases the difficulty of purification and wastes reagents. 3. The reaction is completed in about 5-10min, the reaction is timely removed, long-time stirring is not suitable, and byproducts are easily generated. 4, the Wittig reaction feeding sequence has great influence on the reaction, and the aldehyde, the phosphonium salt and the alkali are added at one time through a plurality of experiments, different substrate verifications and groping of different feeding sequences, so that the method is convenient and high in yield. 5. By groping the reaction solvent, the sodium tert-butoxide in the reaction system belongs to organic base, namely CH2Cl2Is a reaction solvent, has better solubility than the conventional THF, and can effectively avoid the generation of more unpleasant odor caused by the post-treatment concentration when the THF is used as the reaction solvent. 6. The product obtained in the reaction is cis-trans isomer, but the separation is not needed, and the obtained isomer is directly put into the next reaction.
ESI-MS: characteristic peaks 371.1 and 373.1[ M + Na ] of bromine isotope]+。
1H NMR(300MHz,Chloroform-d)δ7.49–7.29(5H,m),7.05(1H,s),6.87(1H,s),6.75(1H,d,J＝12.8Hz),5.98(1H,d,J＝12.9Hz),5.14(2H,s),3.87(3H,s),3.70(3H,s).
Second step, amino protection-Synthesis of Compound I
3, 4-Dimethoxyphenethylamine (50mmol, 9.05g) was dissolved in 50mL CH2Cl2Adding K2CO3(60mmol, 8.28g), adding benzyl chloroformate (50mmol, 8.55g) in small amount for multiple times, heating at 35 deg.C under reflux, stirring to obtain white substance, monitoring by TLC, washing with water to obtain CH after about 6 hr2Cl2Layer, concentration; after dissolution in 5mL of OAc at ambient temperature and slow addition of petroleum ether (total about 250-500 mL) several times, a large amount of material precipitated out, and suction filtration was carried out until no more solid precipitated out, 15.9g of white powder (Compound I) was obtained in 92.4% yield. The product is purified by a conventional silica gel column chromatography, and the inventor finds that the product can be precipitated in a petroleum ether ethyl acetate system in a large amount without purification by searching different solvents.
ESI-MS：316.2[M+H]+。
1H NMR(300MHz,Chloroform-d)δ7.33(5H,m),6.79(1H,d,J＝8.0Hz),6.72(1H,d,J＝1.9Hz),6.71(1H,dd,J＝8.0Hz,1.9Hz),5.10(2H,s),3.85(3H,s),3.84(3H,s),3.44(2H,t,J＝6.8Hz),2.76(2H,t,J＝6.8Hz).
Third step, Pictet-Spengler reaction-Synthesis of Compound Ic-1
To a 100mL eggplant-shaped bottle was added 25mL of CH3CN, trifluoroacetic acid (4mmol, 300. mu.L), compound I (3.3mmol, 1.04g) and compound c (3.0mmol, 1.04g) were added in this order, and stirred at room temperature for 2 days under nitrogen protection, whereupon a large amount of white powder was precipitated, followed by suction filtration to obtain 1.78g of the product (compound Ic-1) with a yield of 94.2%. The following points are noted for this reaction: 1. trifluoroacetic acid is added to prevent local over-concentration, after the trifluoroacetic acid is fully mixed, the raw material 2 is added, a thin-layer plate is used for monitoring the reaction end point, and due to the fact that the reaction time is long, byproducts can be increased if the trifluoroacetic acid is stirred for a long time and exposed to the air, and therefore the purpose of removing oxygen is achieved under the protection of nitrogen. 3. Trifluoroacetic acid in the reaction system hydrolyzes phenylalkenyl methyl ether into styrene alcohol through acid hydrolysis, then enol iso forms phenylacetaldehyde, the phenylacetaldehyde and phenethylamine generate benzyl tetrahydroisoquinoline under acid catalysis, the equivalent of the trifluoroacetic acid is not too much, and normal temperature reaction is needed, otherwise, byproducts can be increased, and the equivalent or concentration needs to be controlled because the trifluoroacetic acid is strong acid and the concentration is too high, which can cause the generation of byproducts after deprotection.
ESI-MS: characteristic peaks of bromine isotopes 654.2 and 656.2[ M + Na [)]+。
1H NMR(300MHz,Chloroform-d)δ7.35(10H,m),6.89(1H,s),6.62(1H,s),6.51(1H,s),6.50(1H,s),5.28(1H,dd,J＝8.7,5.3Hz),5.13(1H,d,J＝4.2Hz),5.01(1H,d,J＝5.3Hz),4.97(2H,m),3.87(3H,s),3.81(3H,s),3.77(3H,s),4.25(1H,m),3.31(1H,dd,J＝14.0,8.5Hz),3.21(1H,dd,J＝14.0,5.1Hz),2.96(2H,dd,J＝14.0,8.5Hz),2.67(1H,m).
Fourth step, Heck reaction-Synthesis of Compound Ic-2
In a 50ml two-necked flask were successively charged compound Ic-1(2mmol, 1.26g), Pd (OAc)2(0.2mmol,45mg), Xphos (2-dicyclohexylphos-2 ',4',6' -triisopropyl)Biphenyl, 0.4mmol,190mg), Cs2CO3(3mmol, 0.97g), nitrogen blanketing, adding 15ml DMA with a syringe, refluxing at 130 deg.C for 2h, monitoring by TLC spot plate, cooling to room temperature after reaction, adding 45ml CH2Cl2Mixing, adding 90ml water, extracting, layering, and collecting CH2Cl2The layer was concentrated and chromatographed on silica gel (100-200 mesh silica gel, eluent petroleum ether: acetone ═ 7:1V/V) to give 1g of white powder (compound Ic-2) in 90.7% yield.
ESI-MS：574.3[M+Na]+。
1H NMR(300MHz,Chloroform-d)δ8.20(1H,s),7.55–7.29(10H,m),6.79(1H,s),6.66(1H,s),5.32(2H,s),5.19(2H,d,J＝6.8Hz),4.78(1H,dd,J＝12.4,4.1Hz),4.50(1H,dd,J＝11.9Hz,1.8Hz),3.94(3H,s),3.92(3H,s),3.70(3H,s),3.04(1H,t,J＝12.2Hz),2.96–2.84(2H,m),2.81(1H,d,J＝13.5Hz),2.70(1H,t,J＝13.5Hz).
Fifth step, deprotection-Synthesis of Compound Ic
The compound Ic-2(1.0mmol, 550mg) and 10% Pd/C55 mg are sequentially added into a 50mL two-necked flask, hydrogen is replaced, 5mL THF is added by an injector to dissolve a sample, 10mL MeOH is added, stirring is carried out at normal temperature for 2h, a TLC point plate is used for monitoring, after the reaction is finished, kieselguhr filtration is carried out, filtrate is concentrated to obtain white powder, and suction filtration is carried out to obtain most of products (mother liquor can be purified again through silica gel column chromatography), so that 277.6mg of final products is obtained, and the yield is 84.9%.
ESI-MS: characteristic peak of bromine isotope 328.2[ M + H ]]+,326.2[M-H]-。
1H NMR(300MHz,Chloroform-d)δ8.11(1H,s),6.81(1H,s),6.62(1H,s),3.92(3H,s),3.91(3H,s),3.83(1H,dd,J＝13.3,5.1Hz),3.69(3H,s),3.40(1H,m),3.11–2.93(2H,m),2.72(3H,td,J＝13.7,6.6Hz).
1H NMR(300MHz,DMSO-d6)δ9.10(1H,s),7.87(1H,s),6.67(2H,s),3.79(3H,s),3.77(3H,s),3.60(3H,s),3.55(1H,dd,J＝13.5,4.5Hz),3.15(1H,q,J＝5.9,4.9Hz),2.91–2.70(2H,m),2.67–2.53(2H,m),2.41(1H,t,J＝13.8Hz).
The overall synthetic route for compound Ic involved a 5-step reaction with an overall yield of 67.2%.
Example 2: synthesis of Compound Ia
Referring to the preparation method of compound Ic of example 1, compound c-2 was replaced with 6-bromoveratraldehyde, and other conditions were unchanged. The yield of each step is as follows: i 92.7%, ii 92.7%, iii 90.3%, iv 86.2%, v 88.6%. 302.1mg of compound Ia (red brown solid) was obtained in 59.2% overall yield.
ESI-MS：342.2[M+H]+。
1H NMR(300MHz,DMSO-d6)δ7.90(1H,s),6.88(1H,s),6.70(1H,s),3.79(3H,s),3.78(3H,s)，3.76(3H,s),3.60(3H,s),3.55(1H,dd,J＝13.5，4.5Hz),3.15(1H,q,J＝5.9,4.9Hz),2.90–2.74(2H,m),2.71(1H,dd,J＝14.2,4.9Hz),2.57(1H,d,J＝12.5Hz),2.45(1H,t,J＝13.9Hz).
Example 3: synthesis of Compound Ib
Referring to example 1, the preparation of compound Ic, compound c-1 was replaced with 6-bromovanillin, the iA reaction solvent was replaced with 25mL of DMF, and the other conditions were unchanged. The yield of each step is as follows: 91.5% of iA, 96.0% of iB, 92.7% of ii, 90.6% of iii, 87.5% of iv, and 81.6% of v. 266.8mg of compound Ib (white powder) are obtained in 56.8% yield.
ESI-MS：328.2[M+H]+,326.2[M-H]-。
1H NMR(300MHz,DMSO-d6)δ8.75(1H,s),7.76(1H,s),6.82(1H,s),6.67(1H,s),3.79(3H,s),3.79(3H,s),3.57(3H,s),3.54(1H,dd,J＝13.3,4.5Hz),3.16(1H,q,J＝6.0,5.1Hz),2.90–2.72(2H,m),2.67(1H,dd,J＝13.9,4.6Hz),2.57(1H,d,J＝12.6Hz),2.43(1H,t,J＝13.9Hz).
Example 4: synthesis of Compound Id
Referring to the preparation of compound Ic of example 1, compound c-2 was replaced with 6-bromo-3, 4-methylenedioxybenzaldehyde, except that the conditions were unchanged. The yield of each step is as follows: i 88.3%, ii 92.7%, iii 97.6%, iv 78.2%, v 87.2%. 283.4mg of Compound Id (white powder) was obtained in 54.4% yield.
ESI-MS：326.2[M+H]+。
1H NMR(300MHz,DMSO-d6)δ7.74(1H,s),6.88(1H,s),6.71(1H,s),6.01(2H,s),3.79(3H,s),3.57(3H,s),3.53(1H,dd,J＝13.6,4.5Hz),3.13(1H,dt,J＝12.6,5.4Hz),2.90–2.74(2H,m),2.69(1H,dd,J＝14.0,4.7Hz),2.57(1H,d,J＝12.4Hz),2.42(1H,t,J＝13.9Hz).
Example 5: synthesis of Compound Ie
Referring to the preparation of compound Ic of example 1, compound c-2 was replaced with 2-bromo-4-methoxybenzaldehyde, otherwise conditions were unchanged. The yield of each step is as follows: i 90.7%, ii 92.7%, iii 87.5%, iv 67.5%, v 80.5%. The objective compound Ie (reddish brown solid) was obtained in a yield of 250.4mg, 40.0%.
ESI-MS：312.2[M+H]+。
1H NMR(300MHz,DMSO-d6)δ7.84(1H,d,J＝2.7Hz),7.18(1H,d,J＝8.2Hz),6.81(1H,dd,J＝8.2,2.7Hz),6.77(1H,s),3.80(3H,s),3.76(3H,s),3.60(3H,s),3.53(1H,dd,J＝13.6,4.5Hz),3.17(1H,q,J＝5.9,5.1Hz),2.92–2.78(2H,m),2.77–2.69(1H,m),2.60(1H,d,J＝12.9Hz),2.44(1H,t,J＝13.7Hz).
Example 6: synthesis of Compound Ig
Referring to the preparation of compound Ic of example 1, compound c-1 was replaced with 2-bromo-5-hydroxybenzaldehyde, otherwise conditions were unchanged. The yield of each step is as follows: 91.5% of iA, 95.3% of iB, 92.7% of ii, 92.1% of iii, 98.0% of iv, and 89.3% of v. 265.2mg of Compound Ig (white powder) was obtained in 70.2% yield.
ESI-MS：298.2[M+H]+,296.2[M-H]-。
1H NMR(300MHz,DMSO-d6)δ9.49(1H,s),8.04(1H,d,J＝8.3Hz),6.71–6.62(3H,m),3.79(3H,s),3.60(1H,d,J＝13.6 4.6Hz),3.55(3H,s),3.24–3.16(1H,m),2.90–2.80(2H,m),2.68(1H,dd,J＝14.0,4.6Hz),2.60(1H,d,J＝13.2Hz),2.50(1H,t,J＝13.7Hz).
Example 7: synthesis of Compound Ii
Referring to the preparation of compound Ic of example 1, compound c-1 was replaced with 2-bromo-4-hydroxybenzaldehyde, otherwise conditions were unchanged. The yield of each step is as follows: iA 90.2%, iB 90.5%, ii 92.7%, iii 94.3%, iv 85.4%, v 87.2%. 259.0mg of Compound Ii (yellow-green powder) was obtained in 57.3% yield.
ESI-MS：298.1[M+H]+,296.2[M-H]-。
1H NMR(300MHz,DMSO-d6)δ9.15(1H,s),7.70(1H,d,J＝2.6Hz),7.03(1H,d,J＝8.1Hz),6.73(1H,s),6.61(1H,dd,J＝8.1,2.6Hz),3.78(3H,s),3.58(3H,s),3.52(1H,dd,J＝14.1,4.7Hz),3.19–3.07(1H,m),2.86–2.71(2H,m),2.66(1H,dd,J＝13.8,4.5Hz),2.57(1H,d,J＝12.8Hz),2.38(1H,t,J＝13.6Hz).
Example 8: synthesis of Compound Ik
Referring to the preparation method of compound Ic of example 1, o-bromobenzaldehyde is used to replace compound c-2, and other conditions are not changed. The yield of each step is as follows: i 93.1%, ii 92.7%, iii 92.3%, iv 92.5%, v 96.0%. 269.8mg of Compound Ik (red brown solid) was obtained in 70.7% yield.
ESI-MS：282.1[M+H]+。
1H NMR(300MHz,DMSO-d6)δ8.19(1H,dd,J＝8.1,1.6Hz),7.36–7.10(3H,m),6.75(1H,s),3.79(3H,s),3.57(3H,s),3.56(1H,m),3.15(1H,m),2.89–2.77(2H,m),2.75(1H,m),2.58(1H,d,J＝13.5Hz),2.50(1H,t,J＝13.6Hz).
Example 9: synthesis of Compound IVa
Referring to the preparation method of compound Ic in example 1, 6-bromoveratraldehyde is used to replace compound c-2, and 3, 4-methylenedioxyphenethylamine is used to replace compound I-1, and other conditions are not changed. The yield of each step is as follows: i 92.7%, ii 91.3%, iii 83.0%, iv 87.5%, v 86.2%. 280.2mg of compound IVa (reddish brown solid) was obtained in 53.0% yield.
ESI-MS：326.2[M+H]+。
1H NMR(300MHz,Chloroform-d)δ7.68(1H,s),6.76(1H,s),6.53(1H,s),6.08(1H,d,J＝1.4Hz),5.93(1H,d,J＝1.4Hz),3.97(1H,dd,J＝13.7,5.5Hz),3.92(3H,s),3.91(3H,s),3.39(1H,dt,J＝10.0,4.9Hz),3.11–2.90(2H,m),2.89–2.74(2H,m),2.67(1H,t,J＝14.0Hz)
Example 10: synthesis of Compound IVb
Referring to the preparation of compound Ic of example 1, 6-bromovanillin was substituted for compound c-1 and 3, 4-methylenedioxyphenethylamine was substituted for compound I-1, with the other conditions being unchanged. The yield of each step is as follows: 91.5% of iA, 96.0% of iB, 91.3% of ii, 84.5% of iii, 76.2% of iv, and 77.7% of v. 241.6mg of Compound IVb (white powder) was obtained in 43.9% yield.
ESI-MS：312.2[M+H]+,310.1[M-H]-。
1H NMR(300MHz,DMSO-d6)δ8.87(1H,s),7.50(1H,s),6.86(1H,s),6.58(1H,s),6.09(1H,s),5.97(1H,s),3.80(3H,s),3.74(1H,dd,J＝14.2,5.0Hz),3.19(1H,m),2.91–2.71(3H,m),2.63–2.53(2H,m).
Example 11: synthesis of Compound IVc
Referring to the preparation of compound Ic of example 1, 6-bromoisovanillin was substituted for compound c-1 and 3, 4-methylenedioxyphenethylamine was substituted for compound I-1, with the other conditions being unchanged. The yield of each step is as follows: 95.8% of iA, 96.8% of iB, 91.3% of ii, 85.6% of iii, 97.5% of iv and 76.3% of v. 237.3mg of Compound IVc (white powder) was obtained, yield 58.1%.
ESI-MS：312.2[M+H]+,310.1[M-H]-。
1H NMR(300MHz,DMSO-d6)δ7.57(1H,s),6.72(1H,s),6.59(1H,s),6.11(1H,d,J＝1.0Hz),5.97(1H,d,J＝1.0Hz),3.77(3H,s),3.76(1H,m),3.22(1H,m),2.90–2.80(2H,m),2.74(1H,dd,J＝14.4,5.0Hz),2.66–2.52(2H,m).
Example 12: synthesis of Compound IVd
Referring to the preparation of compound Ic of example 1, 6-bromo-3, 4-methylenedioxybenzaldehyde was used instead of compound c-2 and 3, 4-methylenedioxyphenethylamine was used instead of compound I-1, with the other conditions being unchanged. The yield of each step is as follows: i 88.3%, ii 91.3%, iii 86.2%, iv 78.9%, v 75.5%. 233.3mg of Compound IVd (white powder) was obtained in 41.4% yield.
ESI-MS：310.1[M+H]+。
1H NMR(300MHz,DMSO-d6)δ7.42(1H,s),6.84(1H,s),6.54(1H,s),6.02(1H,s),5.95(1H,s),5.93(1H,s),5.88(1H,s),3.67(1H,dd,J＝14.0,4.9Hz),3.12(1H,m),2.79–2.66(3H,m),2.46–2.40(2H,m).
Example 13: synthesis of Compound IVe
Referring to the preparation of compound Ic of example 1, 2-bromo-4-methoxybenzaldehyde was used in place of compound c-2 and 3, 4-methylenedioxyphenethylamine was used in place of compound I-1, with the other conditions being unchanged. The yield of each step is as follows: i 90.7%, ii 91.3%, iii 89.7%, iv 94%, v 73.2%. 215.9mg of compound IVe (reddish brown solid) was obtained in 51.1% yield.
ESI-MS：296.2[M+H]+。
1H NMR(300MHz,DMSO-d6)δ7.57(1H,d,J＝2.6Hz),7.23(1H,d,J＝8.2Hz),6.85(1H,dd,J＝8.2,2.6Hz),6.69(1H,s),6.15(1H,d,J＝1.0Hz),5.99(1H,d,J＝1.0Hz),3.83(1H,dd,J＝13.8,4.9Hz),3.77(3H,s),3.25(1H,m),2.95–2.79(3H,m),2.67–2.52(2H,m).
Example 14: synthesis of Compound IVf
Referring to the preparation of compound Ic of example 1, compound c-2 was replaced with 2-bromo-5-methoxybenzaldehyde 6-bromoveratraldehyde and compound I-1 was replaced with 3, 4-methylenedioxyphenethylamine, all other conditions being unchanged. The yield of each step is as follows: i 87.2%, ii 91.3%, iii 83.2%, iv 74.6%, v 76.3%. 225.0mg of the compound IVf (red brown solid) was obtained in 37.7% yield.
ESI-MS：296.2[M+H]+。
1H NMR(300MHz,DMSO-d6)δ7.91(1H,dd,J＝9.4Hz,2.3Hz),6.89(1H,d,J＝9.4Hz),6.87(1H,d,J＝2.3Hz),6.60(1H,s),6.10(1H,d,J＝1.0Hz),5.96(1H,d,J＝1.0Hz),3.79(3H,s),3.74(1H,dd,J＝14.0,4.8Hz),3.19(1H,d,J＝8.0Hz),2.93–2.74(3H,m),2.66–2.53(2H,m).
Example 15: synthesis of Compound IVg
Referring to the preparation of compound Ic of example 1, 2-bromo-5-hydroxybenzaldehyde was used instead of compound c-1 and 3, 4-methylenedioxyphenethylamine was used instead of compound I-1, the other conditions being unchanged. The yield of each step is as follows: 91.5% of iA, 95.3% of iB, 91.3% of ii, 80.4% of iii, 87.8% of iv, and 83.1% of v. 233.5mg of Compound IVg (white powder) was obtained in 51.1% yield.
ESI-MS：282.2[M+H]+,280.1[M-H]-。
1H NMR(300MHz,DMSO-d6)δ9.54(1H,s),7.80(1H,d,J＝8.2Hz),6.71(1H,dd,J＝8.2,2.6Hz),6.68(1H,d,J＝2.6Hz),6.55(1H,s),6.07(1H,d,J＝1.0Hz),5.93(1H,d,J＝1.0Hz),3.68(1H,dd,J＝13.9,4.9Hz),3.16(1H,m),2.84–2.64(3H,m),2.61–2.51(2H,m).
Example 16: synthesis of Compound IVi
Referring to the preparation of compound Ic of example 1, 2-bromo-4-hydroxybenzaldehyde was used instead of compound c-1 and 3, 4-methylenedioxyphenethylamine was used instead of compound I-1, the other conditions being unchanged. The yield of each step is as follows: iA 90.2%, iB 90.5%, ii 91.3%, iii 82.5%, iv 92.6%, v 86.2%. 242.2mg of Compound IVi (yellow-green powder) was obtained in 53.7% yield.
ESI-MS：282.2[M+H]+,280.1[M-H]-。
1H NMR(300MHz,DMSO-d6)δ9.31(1H,s),7.48(1H,d,J＝2.5Hz),7.08(1H,d,J＝8.1Hz),6.66(1H,dd,J＝8.1,2.5Hz),6.65(1H,s),6.13(1H,s),5.99(1H,s),3.78(1H,dd,J＝13.9,4.8Hz),3.21(1H,m),2.98–2.71(3H,m),2.67–2.51(2H,m).
Example 17: synthesis of Compound IVk
Referring to the preparation of compound Ic of example 1, o-bromobenzaldehyde is used instead of compound c-2, and 3, 4-methylenedioxyphenethylamine is used instead of compound I-1, with the other conditions being unchanged. The yield of each step is as follows: i 93.1%, ii 91.3%, iii 99.0%, iv 78.2%, v 89.1%. 236.1mg of compound IVk (red brown solid) was obtained in 58.6% yield.
ESI-MS：266.2[M+H]+。
1H NMR(300MHz,DMSO-d6)δ7.98(1H,m),7.38–7.10(3H,m),6.65(1H,s),6.12(1H,d,J＝1.0Hz),5.97(1H,d,J＝1.0Hz),3.72(1H,dd,J＝13.9,4.7Hz),3.16(1H,m),2.89–2.75(3H,m),2.67–2.53(2H,m)。
Claims (10)
1. A preparation method of aporphine alkaloid shown as a formula III is characterized in that: taking benzaldehyde compounds shown in a formula III-0 as raw materials, and sequentially carrying out Wittig reaction, Pictet-Spengler reaction, Heck reaction and palladium-carbon hydrogenolysis deprotection; the synthetic route is as follows:
wherein R is1、R2Each independently selected from alkoxy, methylenedioxy (-OCH)2O-)，R3、R4Each independently selected from H, alkoxy, methylenedioxy;
or
Wherein R is1、R2Each independently selected from alkoxy, methylenedioxy, R3、R4Each independently selected from H, OH, alkoxy, except R3、R4At least one of which is OH.
2. The process for preparing aporphine alkaloid according to claim 1, characterized in that: when R is3、R4When none is selected from OH, the method comprises the following steps:
step (i), Wittig reaction: taking a benzaldehyde compound shown as a formula III-0 as a raw material, taking dichloromethane as a reaction solvent, and reacting under the protection of nitrogen in the presence of a phosphonium salt and an organic base to obtain a styrene methyl ether compound shown as a formula III-1;
step (ii) using dichloromethane as reaction solvent, at K2CO3In the presence of
Benzene as shownReacting ethylamine compounds with benzyl chloroformate to obtain amino-protected phenethylamine compounds shown in a formula III-2;
step (iii), Pictet-Spengler reaction: taking acetonitrile as a reaction solvent, under the protection of nitrogen, and in the presence of trifluoroacetic acid, carrying out a Pictet-Spengler reaction on a styrene methyl ether compound shown as a formula III-1 and an amino-protected phenethylamine compound shown as a formula III-2 to obtain a benzyl tetrahydroisoquinoline compound shown as a formula III-3;
step (iv), Heck reaction: DMA (N, N-dimethylacetamide) as a reaction solvent in Pd (OAc)2、Xphos、Cs2CO3Under the existence condition, obtaining aporphine alkaloid protected by 6-amino shown in the formula III-4 by Heck reaction of the benzyltetrahydroisoquinoline compound shown in the formula III-3 under the protection of nitrogen;
step (v), palladium carbon hydrogenolysis deprotection: taking a mixed solvent of THF and methanol as a reaction solvent, taking 10% Pd/C as a catalyst, and removing a protecting group from the aporphine alkaloid protected by 6-amino at normal temperature to obtain the aporphine alkaloid shown in the formula III.
3. The process for preparing aporphine alkaloid according to claim 2, characterized in that: in the step (i), the molar ratio of the benzaldehyde compound to the phosphorus salt is 1: 1.5-2; the molar ratio of the benzaldehyde compound to the organic base is 1: 1.5-2; the phosphorus salt is MeOCH2PPh3Cl; the organic base is sodium tert-butoxide or potassium tert-butoxide.
4. The process for preparing aporphine alkaloid according to claim 2, characterized in that: in the step (ii), the molar ratio of the phenethylamine compound to benzyl chloroformate is 1: 1; the phenethylamine compound and K2CO3The molar ratio of (A) to (B) is 1: 1-2.
5. The process for preparing aporphine alkaloid according to claim 2 or 4, characterized in that: in the step (ii), after the reaction is finished, washing with water to extract a dichloromethane layer, and removing dichloromethane; and at normal temperature, adding ethyl acetate for dissolving, adding petroleum ether with the volume of 50-100 times that of the ethyl acetate, and recrystallizing to separate out the amino-protected phenethylamine compound.
6. The process for preparing aporphine alkaloid according to claim 2, characterized in that: in the step (iii), the molar ratio of the styrene methyl ether compound to the amino-protected phenethylamine compound is 1-1.5: 1, preferably 1.1-1.5: 1; the mol ratio of the styrene methyl ether compound to trifluoroacetic acid is 1: 1-2.5; the concentration of trifluoroacetic acid in the system is 0.15-0.3 mol/L, preferably 0.16 mol/L.
7. The process for preparing aporphine alkaloid according to claim 2, characterized in that: in the step (iv), the benzyl tetrahydroisoquinoline compound and Pd (OAc)2The molar ratio of (A) is 1: 0.05-0.2, preferably 1:0.1, and the Pd (OAc)2And Xphos in a molar ratio of 1:2, said benzyltetrahydroisoquinoline compound and Cs2CO3The molar ratio of (A) to (B) is 1: 1.5-2.
8. The process for preparing aporphine alkaloid according to claim 2, characterized in that: in the step (v), the mixed solvent is a mixed solvent of THF and methanol according to a volume ratio of 1: 2-1: 4; the 10 percent Pd/C dosage is 5 to 20 percent of the mass of the aporphine alkaloid protected by 6-site amino.
9. The process for preparing aporphine alkaloid according to claim 1, characterized in that: when R is3、R4And when at least one selected from OH, protecting the hydroxyl of the benzaldehyde compound by using benzyl bromide to obtain the benzaldehyde compound with the hydroxyl protection shown in the formula III-0', and sequentially carrying out Wittig reaction, Pictet-Spengler reaction, Heck reaction and palladium-carbon hydrogenolysis deprotection to obtain the aporphine alkaloid shown in the formula III.
10. According toA process for the preparation of aporphine alkaloids according to claim 1 or 9, characterized by: benzaldehyde compound shown in formula III-0 is used as raw material, acetonitrile or DMF is used as reaction solvent, and the reaction solution is reacted at K2CO3In the presence of the compound, heating to react at 50-70 ℃, and protecting the hydroxyl of the benzaldehyde compound by using benzyl bromide to obtain a hydroxyl-protected benzaldehyde compound shown as a formula III-0'; wherein the molar ratio of the benzaldehyde compound to the benzyl bromide is 1: 1-1.1, and the benzaldehyde compound and the K are2CO3In a molar ratio of 1: 2.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1923813A (en) * | 2005-08-31 | 2007-03-07 | 中国科学院上海药物研究所 | Aporphine and use of oxidized aporphine alkaloid |
| CN104447544A (en) * | 2014-10-17 | 2015-03-25 | 中国药科大学 | Preparation and application of mono-benzylisoquinoline alkaloid derivative having pancrelipase inhabitation activity |
| CN104892510A (en) * | 2015-07-03 | 2015-09-09 | 中国科学院兰州化学物理研究所 | Preparation method of isocorydaline |
| CN107827898A (en) * | 2016-09-15 | 2018-03-23 | 株式会社津村 | The manufacture method of Berberine-type alkaloid |
| CN111196801A (en) * | 2020-01-14 | 2020-05-26 | 中国药科大学 | Aporphine alkaloid derivative and preparation method and application thereof |
| CN111892537A (en) * | 2020-08-04 | 2020-11-06 | 中国药科大学 | Aporphine alkaloid derivative and preparation method and application thereof |
-
2021
- 2021-03-01 CN CN202110223173.XA patent/CN112920119B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1923813A (en) * | 2005-08-31 | 2007-03-07 | 中国科学院上海药物研究所 | Aporphine and use of oxidized aporphine alkaloid |
| CN104447544A (en) * | 2014-10-17 | 2015-03-25 | 中国药科大学 | Preparation and application of mono-benzylisoquinoline alkaloid derivative having pancrelipase inhabitation activity |
| CN104892510A (en) * | 2015-07-03 | 2015-09-09 | 中国科学院兰州化学物理研究所 | Preparation method of isocorydaline |
| CN107827898A (en) * | 2016-09-15 | 2018-03-23 | 株式会社津村 | The manufacture method of Berberine-type alkaloid |
| CN111196801A (en) * | 2020-01-14 | 2020-05-26 | 中国药科大学 | Aporphine alkaloid derivative and preparation method and application thereof |
| CN111892537A (en) * | 2020-08-04 | 2020-11-06 | 中国药科大学 | Aporphine alkaloid derivative and preparation method and application thereof |
Non-Patent Citations (8)
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117902972A (en) * | 2024-03-19 | 2024-04-19 | 深圳创元生物医药科技有限公司 | Preparation method of 2, 4-dihydroxyphenylacetic acid |
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