CN112920119B - 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 a benzaldehyde compound shown in the formula III-0 as a raw material to sequentially perform Wittig reaction, pictet-Spengler reaction, heck reaction and palladium hydrocarbon deprotection. The invention selects the benzaldehyde derivative containing bromine as the raw materialThe material increases the carbon-carbon coupling yield and the reaction rate through bromine atoms, and improves the reaction activity; adopting benzyl chloroformate for NH protection, and introducing electron-withdrawing groups is helpful for improving reaction yield; the benzyl tetrahydroisoquinoline is obtained by directly reacting the styryl methyl ether derivative and the acylated phenethylamine derivative in an acid catalytic system by adopting a one-pot method. The preparation method has mild reaction conditions, low toxicity of the used reagents, readily available raw materials, convenient post-treatment, simpler reaction route than the prior reports, 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 alkaloids.
Technical Field
Aporphine alkaloids belong to isoquinoline alkaloids, are an important type of natural alkaloids, are widely distributed in nature and have important biological activity. The aporphine alkaloid has a biphenyl type four-ring special structure, and the absolute configuration changes of an aromatic ring substituent, an N substituent and 6a carbon form a rich structure library of the compound. The diversity of chemical structures inevitably leads to the wide 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, especially for treating diseases of the central nervous system, such as schizophrenia, depression, dyskinesia caused by anti-parkinsonism drugs and the like. The aporphine alkaloid is mostly derived from traditional Chinese medicinal materials, active aporphine alkaloid is prepared by chemical synthesis, and the derivative with good stability, low toxicity and higher biological activity is further obtained on the parent body through structural modification, so that the aporphine alkaloid has great significance in the aspect of innovative drug research of natural products. Meanwhile, most of the known natural products of aporphine alkaloid A ring is mainly replaced by 1, 2-methylenedioxy or 1, 2-dimethoxy; the D ring is mainly substituted at the 9 position and the 10 position, and methoxy or phenolic hydroxyl is mainly substituted functional group.
The aporphine alkaloid mainly has the following three synthetic routes: a. firstly, constructing an ABD ring of aporphine, and then, cyclizing to construct a C ring; b. firstly, constructing an ACD ring, and then, cyclizing to construct a B ring; c. the ABC ring is constructed first and then cyclized to construct the D ring. The synthesis route a mainly involves the reaction types: the Wittig reaction, the Pictet-Spengler reaction, the Heck reaction, and the upward protection and deprotection are also involved for aporphine alkaloids containing active hydrogen.
Benzyl tetrahydroisoquinoline is an essential intermediate for synthesizing aporphine alkaloid, and mainly comprises two synthetic methods.
Firstly, adopting Bischer-Napieralski reaction, reacting phenylacetic acid or acyl chloride derivative with phenethylamine to form amide, dehydrating and closing ring to obtain dihydroisoquinoline under the action of dehydrating agent such as phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride and the like, and then reducing to obtain tetrahydroisoquinoline. The benzyl tetrahydroisoquinoline is obtained through three steps of reactions, and the total yield is 40-80%.
And in the second method, a Pictet-Spengler reaction is adopted, and the benzyl tetrahydroisoquinoline is obtained through acid catalysis by using a phenylacetaldehyde derivative and a phenethylamine derivative. Wherein, the phenylacetaldehyde derivative is generally obtained by generating styrene methyl ether from benzaldehyde derivative through Wittig reaction and then purifying by acid hydrolysis. The benzyl tetrahydroisoquinoline is obtained through two steps of reactions, and the total yield is 40-80%.
Disclosure of Invention
The invention aims to provide a total synthesis route of aporphine alkaloid, which is characterized in that 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 catalytic system to obtain benzyl tetrahydroisoquinoline (the yield is at least 80 percent), so that the aporphine alkaloid with different substituents on a nucleus A and a nucleus D shown in a formula III is synthesized.
The invention aims at realizing the following technical scheme:
a preparation method of aporphine alkaloid shown in formula III comprises sequentially performing Wittig reaction, pictet-Spengler reaction, heck reaction, and palladium hydrocarbon deprotection with benzaldehyde compound shown in formula III-0 as raw material; the synthetic route is as follows:
wherein R is 1 、R 2 Are independently selected from alkoxy, methylenedioxy (-OCH) 2 O-)，R 3 、R 4 Each is independently selected from H, alkoxy, methylenedioxy;
or (b)
Wherein R is 1 、R 2 Are respectively and independently selected from alkoxy, methylenedioxy and R 3 、R 4 Are independently selected from H, OH, alkoxy groups, but R 3 、R 4 At least one of which is OH; r is R 3’ 、R 4’ Independently selected from H, OBn (benzyloxy), alkoxy, but R 3’ 、R 4’ At least one of them is OBn, and is protected against OH, i.e. R is in addition to OH forming OBn 3’ And R is R 3 Correspondingly, R 4’ And R is R 4 Corresponding to the above.
Specifically, when R 3 、R 4 When none is selected from OH, the method comprises the following steps:
step (i), wittig reaction: using benzaldehyde compounds shown in a formula III-0 as a raw material, using methylene dichloride as a reaction solvent, protecting with nitrogen, and carrying out ice bath reaction in the presence of phosphorus salt and organic base to obtain styrenemethyl ether compounds shown in a formula III-1;
step (ii) in K using methylene dichloride as reaction solvent 2 CO 3 Where present, of the formula
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: under the condition of the existence of trifluoroacetic acid, using acetonitrile as a reaction solvent and nitrogen protection, and reacting a styryl methyl ether compound shown in a formula III-1 with an amino-protected phenethylamine compound shown in a formula III-2 to obtain a benzyl tetrahydroisoquinoline compound shown in a formula III-3;
step (iv), heck reaction: DMA (N, N-dimethylacetamide) was used as a reaction solvent in Pd (OAc) 2 、Xphos、Cs 2 CO 3 Under the condition of nitrogen protection, the benzyl tetrahydroisoquinoline compound shown in the formula III-3 is subjected to Heck reaction to obtain 6-amino-protected aporphine alkaloid shown in the formula III-4;
step (v), palladium hydrocarbon deprotection: the mixed solvent of THF and methanol is used as a reaction solvent, 10% Pd/C is used as a catalyst, and the aporphine alkaloid with 6-amino protection is deprotected 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 MeOCH 2 PPh 3 Cl; the organic base is sodium tert-butoxide or potassium tert-butoxide.
In step (ii), the phenethylamine compound andthe molar ratio of the benzyl chloroformate is 1:1; the phenethylamine compound and K 2 CO 3 The molar ratio of (2) is 1:1-2; after the reaction is finished, washing with water to extract a dichloromethane layer, and removing dichloromethane; at normal temperature, ethyl acetate is added for dissolution, petroleum ether with 50-100 times of the volume of the ethyl acetate is added, and amino-protected phenethylamine compounds are separated out through recrystallization.
In the step (iii), the molar ratio of the styryl 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 raw material amino-protected phenethylamine compound, the benzaldehyde is slightly excessive during feeding, preferably the molar ratio of the styryl methyl ether compound to the amino-protected phenethylamine compound is controlled to be 1.1-1.5:1, so that the reaction of the phenethylamine derivative is ensured to be complete, and the purification is simpler. The temperature of the Pictet-Spengler reaction is normal temperature, the reaction time is 0.5-3 days, and the reaction end point is monitored by a thin layer plate; and after the reaction is finished, carrying out suction filtration to obtain the benzyl tetrahydroisoquinoline compound.
Specifically, in order to prevent the local over concentration of trifluoroacetic acid in the system, the trifluoroacetic acid is firstly added into a solvent, fully and uniformly mixed, and then raw materials are added. The method comprises the steps of hydrolyzing styrene methyl ether into a styrol compound by trifluoroacetic acid, forming a phenylacetaldehyde compound by enol iso-formation, immediately reacting the generated phenylacetaldehyde compound with an amino-protected phenethylamine compound, and generating a benzyl tetrahydroisoquinoline compound under the catalysis of the trifluoroacetic acid; the molar ratio of the styrenemethyl ether compound to the trifluoroacetic acid is controlled to be 1:1-2.5, the acid dosage is not excessive, the reaction is required at normal temperature, otherwise, byproducts are increased, the concentration of the trifluoroacetic acid is strong acid, the generation of the deprotected byproducts is caused by the excessive concentration, and the concentration of the trifluoroacetic acid in the system can be controlled to be 0.15-0.3 mol/L, preferably 0.16mol/L.
In step (iv), the benzyl tetrahydroisoquinoline compound and Pd (OAc) 2 The molar ratio of Pd (OAc) is 1:0.05-0.2, preferably 1:0.1) 2 And Xphos is 1:2, and the benzyl tetrahydroisoquinoline compound and Cs are in a molar ratio of 1:2 2 CO 3 The molar ratio of (2) is 1:1.5-2.By controlling Pd (OAc) 2 And ligand Xphos and catalyst Cs 2 CO 3 The dosage of the catalyst avoids the generation of excessive target black, which leads to difficult post-treatment and also avoids the environmental pollution caused by heavy metals.
The Heck reaction temperature was 130 ℃, and the progress of the reaction was monitored by TLC plates; 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, petroleum ether: acetone=7:1v/V as eluent) to obtain the aporphine alkaloid with 6-amino protection.
The Heck reaction uses DMA as a reaction solvent, so that compared with DMF, the yield can be greatly increased, and the generation of byproducts can be reduced.
The Heck reaction is carried out under the anhydrous and anaerobic condition, so that the reaction is ensured to be complete, 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 accelerate the reaction rate, the aprotic solvent can slow down the reaction rate and even does not react, but the reaction rate is slow down because the raw materials are generally insoluble in methanol, so that a certain ratio of THF is added for assisting in dissolution, the use amount of methanol is increased as much as possible while the solubility is increased, and the reaction rate can be accelerated. The mixed solvent is a mixed solvent of THF and methanol according to the volume ratio of 1:2-1:4.
The 10% Pd/C dosage is 5% -20% of the mass of the aporphine alkaloid protected by 6-amino, if the reaction rate is faster and only nitrogen is protected by active hydrogen, the target carbon dosage can be properly reduced, if the reaction time is slightly prolonged and the target carbon dosage (Cbz is removed firstly and then benzyl is removed) can be properly increased, the TLC thin layer plate monitoring reaction is carried out, the reaction is gradually changed into a single product, and ring-opening byproducts are avoided if the reaction time is overlong.
When R is 3 、R 4 At least one of OH groups is prepared by protecting hydroxy group of benzaldehyde compound with benzyl bromide to obtain hydroxy group-protected benzaldehyde compound of formula III-0', and sequentially performing Wittig reaction, pictet-Spengler reaction, and HAnd (3) performing an eck reaction and performing hydrocarbon deprotection on palladium to obtain the aporphine alkaloid shown in the formula III.
Wittig reaction, pictet-Spengler reaction, heck reaction, palladium hydrocarbon deprotection step and R 3 、R 4 None of them are the same when they are selected from OH.
Specifically, the method comprises the following steps:
step (i), using benzaldehyde compound shown in formula III-0 as raw material, acetonitrile or DMF as reaction solvent, and adding the mixture into the mixture in K 2 CO 3 Under the condition of existence, heating to react at 50-70 ℃, and adopting benzyl bromide to protect the hydroxyl of the benzaldehyde compound to obtain the hydroxy-protected benzaldehyde compound shown in the 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 the mother liquor, the precipitated solid has a large benzyl bromide taste or the filtrate cannot be removed during suction filtration, and the product is easy to dissolve in the benzyl bromide and cannot be precipitated, so that the yield is affected, so that the benzyl bromide is added for a small amount of times in the reaction process, and the TLC thin layer plate is used for tracing. Benzaldehyde compound and K 2 CO 3 The molar ratio of (2) is 1:2. DMF is generally selected as a reaction solvent for hydroxyl protection reaction. The inventors have found that CH is preferably selected in the case of dissolving benzaldehyde compound by fumbling with the reaction solvent 3 CN, because the product is hardly dissolved in CH 3 CN can be greatly separated out when the CN 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, the product can be obtained through 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 insoluble in CH 3 CN (slow or non-reactive) can be exchanged for DMF as the reaction solvent. Benzaldehyde compound and K 2 CO 3 Heating at 50-70 deg.c to withdraw hydrogen from the phenolic hydroxyl radical of benzaldehyde compound to promote the attack of carbon positive ion of benzyl bromide to oxygen negative ion.
Wittig reaction: using benzaldehyde compounds shown in a formula III-0 'as a raw material, using methylene dichloride as a reaction solvent, protecting with nitrogen, and carrying out ice bath reaction in the presence of phosphorus salt and organic base to obtain styrene methyl ether compounds shown in 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 the advantages that the hydroxyl in the formula III-0 is protected to obtain OBn, and the rest substituents are unchanged.
Step (ii) in K using methylene dichloride as reaction solvent 2 CO 3 Where present, of the formula
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: acetonitrile is used as a reaction solvent, nitrogen is used for protection, and under the condition of trifluoroacetic acid, a styryl methyl ether compound shown in a formula III-1 'and an amino-protected phenethylamine compound shown in a formula III-2 react to obtain a benzyl tetrahydroisoquinoline compound shown in a formula III-3';
step (iv), heck reaction: DMA (N, N-dimethylacetamide) was used as a reaction solvent in Pd (OAc) 2 、Xphos、Cs 2 CO 3 Under the condition of nitrogen protection, the benzyl tetrahydroisoquinoline compound shown in the formula III-3 'is subjected to Heck reaction to obtain 6-amino-protected aporphine alkaloid shown in the formula III-4';
step (v), palladium hydrocarbon deprotection: the mixed solvent of THF and methanol is used as a reaction solvent, 10% Pd/C is used as a catalyst, and the aporphine alkaloid shown in the formula III-4' is deprotected at normal temperature to obtain the aporphine alkaloid shown in the formula III.
The alkoxy is selected from C1-C5 alkoxy, and can be specifically selected from methoxy, ethoxy and C3-C5 straight-chain or branched-chain alkoxy.
Specifically, the aporphine alkaloid represented by formula III is preferably selected from the following compounds:
the invention has the beneficial effects that:
the invention synthesizes the aporphine alkaloid with different substituent groups on the 1, 2-position and the 9, 10-position of the A ring and the D ring of the mother nucleus through 5-step reaction, the preparation method has mild reaction conditions, low toxicity of the used reagent, easy obtainment of raw materials, convenient post-treatment, simpler reaction route than the previous report, and is applicable to various reaction substrates.
If phenylacetic acid is used as raw material, the subsequent C-C coupling reaction needs further halogenation because the raw material does not contain ortho halogen atoms, but the invention selects o-bromobenzaldehyde compound as raw material, and can directly purchase o-bromobenzaldehyde with various substituents, the raw material is cheap and easy to obtain, and the bromination can improve the reactivity of the C-C coupling reaction and the yield.
At present, the NH protection purpose is usually achieved through methyl chloroformate or ethyl chloroformate or Boc protecting groups, however, the methyl chloroformate or methyl chloroformate is not easy to obtain raw materials and is a highly toxic product, belongs to psychotropic drugs or easily-made chemicals or controlled products, and the Boc protecting groups are sensitive to alkali and acid, so that the subsequent reaction is limited. The invention adopts acid-alkali resistant benzyl chloroformate (CbzCl) for protection for the first time: first, NH protection is performed. Secondly, in order to improve the activity of the Pictet-Spengler reaction (reaction mechanism: the dehydration condensation of aromatic ethylamine and aldehyde into imine under an acidic condition, and then the imine ion formed after the protonation of the imine is used as an electrophile, and the electrophilic aromatic substitution is carried out on the aromatic ring to cyclize, so as to obtain tetrahydroisoquinoline). The acylated amino group can generate N-acyl imine ion in a Pictet-Spengler reaction, which is a strong electrophile and has stronger electrophilicity than the non-acylated imine ion, so that the raw material can be cyclized under mild conditions with higher yield. Thirdly, the introduction of electron withdrawing groups on N is beneficial to improving the activity and yield of Heck reaction, if only naked NH is very low (yield is less than or equal to 10 percent) or is not reacted. Fourthly, taking into account that OH is protected by Bn groups, protecting amino groups by CbzCl can be carried out in the last step by simultaneously using Pd/C hydrogenolysis to obtain the final product.
The invention improves the Pictet-Spengler reaction, adopts a one-pot method to directly react the styryl methyl ether derivative and the phenethylamine derivative in an acid catalytic system to obtain the benzyl tetrahydroisoquinoline, and has the yield reaching at least 80 percent.
The yield of the existing total synthesis route of the aporphine alkaloids is basically maintained at 10% -40%, and is generally lower than 30%. The total yield is generally more than 30% and can be up to about 70% by optimizing the total synthesis route of the aporphine alkaloid.
Detailed description of the preferred embodiments
In order to further clarify 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 in a 250mL single-necked flask, 6-bromoisovanillin (Compound c-1, 45mmol,10.4 g), K were added 2 CO 3 (90 mmol,12.4 g) 100mL acetonitrile (CH) 3 CN) is dissolved, the reaction is heated at 60 ℃, the solution is changed into light yellow suspension from colorless, then a small amount of benzyl bromide (BnBr, 50mmol,6 mL) is added for many times, a large amount of white substances are separated out, the solution is changed into clear, colorless and transparent solution from light yellow, the heating reflux is carried out at 60 ℃ for 6 hours, the concentration is carried out until the acetonitrile is 5-10mL, the water washing and the suction filtration are carried out, and 13.8g of white powder (compound c-2) is obtained, and the yield is 95.8%.
And (b) an iB: in a 250ml two-necked flask, the above white powder (Compound c-2, 40mmol,13.8 g) was added, meOCH 2 PPh 3 Cl (methoxymethyl triphenylphosphine chloride, 60mmol,20.52 g), naOtBu (sodium tert-butoxide, 60mmol,5.76 g), nitrogen-blanketed, ice-bath, and 50mL dry CH were added quickly with a syringe 2 Cl 2 About 3-5min of the solution is colorlessWhen the reaction turns to light yellow and then to reddish brown, the reaction is immediately quenched by water, and silica gel column chromatography (100-200 meshes of silica gel, eluent is petroleum ether: ethyl acetate=30:1v/V) is carried out to obtain 14.4g of white powder (compound c) with the yield of 96.8%. The reaction requires attention to the following points: 1. ensure no water and oxygen, otherwise the reaction is incomplete, because the product of the styryl methyl ether and the corresponding benzaldehyde are R on the TLC thin layer plate f The values are relatively close, and the residual raw materials increase the difficulty of post-treatment and purification. 2. The equivalent of phosphorus salt and base should not be too much (1.5 eq-2 eq) or the ylide intermediate by-product is too much, increasing purification difficulties and wasting reagents. 3. The reaction is completed within about 5-10min, the reaction is removed in time, long-time stirring is not suitable, and byproducts are easy to generate. The addition sequence of the Wittig reaction has great influence on the reaction, and through multiple experiments, verification of different substrates and fumbling of different addition sequences, the aldehyde, the phosphonium salt and the alkali are added at one time, so that the method is convenient and high in yield. 5. By exploring the reaction solvent, the sodium tert-butoxide in the reaction system belongs to organic alkali and adopts CH 2 Cl 2 Compared with the conventional THF, the THF has better solubility, and can effectively avoid the generation of unpleasant smell after 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 used in the next reaction.
ESI-MS: bromine isotope characteristic peak 371.1, 373.1[ M+Na ]] + 。
1 H 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-Dimethoxyphenylethylamine (50 mmol,9.05 g) was dissolved in 50mL CH 2 Cl 2 Adding K 2 CO 3 (60 mmol,8.28 g) benzyl chloroformate (50 mmol,8.55 g) was added in small portions and heated back at 35 ℃Stirring the flow, observing that a large amount of white substances are precipitated, monitoring a TLC (thin layer chromatography) plate, after the reaction is completed for about 6 hours, washing and extracting to obtain CH 2 Cl 2 Layer, concentrate; at normal temperature, 5mLEtOAc is used for dissolution, petroleum ether (the total amount is about 250mL-500 mL) is slowly added for multiple times, a large amount of substances are separated out, and suction filtration is carried out until no solid is separated out, so that 15.9g of white powder (compound I) is obtained, and the yield is 92.4%. The product is generally purified by conventional silica gel column chromatography in the field, and the inventor finds that the product can be separated out in a large amount in a petroleum ether ethyl acetate system through exploring different solvents without purification.
ESI-MS：316.2[M+H] + 。
1 H 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
25mL CH was added to a 100mL eggplant-type bottle 3 CN, trifluoroacetic acid (4 mmol, 300. Mu.L), compound I (3.3 mmol,1.04 g) and compound c (3.0 mmol,1.04 g) were added in this order, and the mixture was stirred at room temperature under nitrogen protection for 2d, a large amount of white powder was found to precipitate, and the mixture was suction-filtered to obtain 1.78g of the product (compound Ic-1) with a yield of 94.2%. The reaction requires attention to the following points: 1. the trifluoroacetic acid is added to prevent the local over-concentration, and after fully mixing, the raw material 2 is added, and a thin layer plate is used for monitoring the end point of the reaction, and because the reaction time is long, byproducts can be increased if the reaction is stirred and exposed to the air for a long time, so that the purpose of deoxidizing is achieved by adopting nitrogen protection. 3. In the reaction system, trifluoroacetic acid is firstly hydrolyzed into styrene alcohol by acid hydrolysis, then enol iso-forms phenylacetaldehyde, the phenylacetaldehyde and the phenethylamine generate benzyl tetrahydroisoquinoline under the catalysis of acid, the equivalent of the trifluoroacetic acid is inadequately excessive, the reaction is required at normal temperature, otherwise, byproducts are increased, and the trifluoroacetic acid is strong acid, and the concentration is too high, so that the reaction is conductiveThe equivalent weight or concentration of the by-product after deprotection is controlled.
ESI-MS: bromine isotope characteristic peak 654.2, 656.2[ M+Na ]] + 。
1 H 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, compound Ic-1 (2 mmol,1.26 g) and Pd (OAc) were successively added 2 (0.2 mmol,45 mg), xphos (2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl, 0.4mmol,190 mg), cs 2 CO 3 (3 mmol,0.97 g), nitrogen protection, 15ml DMA was added by syringe, 130℃was condensed and refluxed for 2h, monitored by TLC plate, after the reaction was completed, cooled to room temperature, 45ml CH was added 2 Cl 2 Mixing, adding 90ml water, extracting, layering, collecting CH 2 Cl 2 The layers were concentrated and column 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] + 。
1 H 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
Compound Ic-2 (1.0 mmol,550 mg), 10% pd/C55 mg, and hydrogen were sequentially added in a 50mL two-necked flask, a sample was dissolved by adding 5mL THF by syringe, then 10mL MeOH was added, stirring was performed at room temperature for 2h, monitoring was performed by tlc plate, after the reaction was completed, celite was filtered, the filtrate was concentrated, a white powder was found to precipitate, and suction filtration afforded a large portion of the product (mother liquor could be purified again by silica gel column chromatography), giving 277.6mg of the final product in a yield of 84.9%.
ESI-MS: bromine isotope characteristic peak 328.2[ M+H ]] + ,326.2[M-H]-。
1 H 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).
1 H NMR(300MHz,DMSO-d 6 )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 total synthetic route for compound Ic included 5 steps of reaction with a total yield of 67.2%.
Example 2: synthesis of Compound Ia
Referring to the preparation of compound Ic of example 1, 6-bromoveratraldehyde was used instead of compound c-2, with the other conditions unchanged. The productivity of each step is as follows: i 92.7%, ii 92.7%, iii 90.3%, iv 86.2%, v 88.6%. Compound Ia (reddish brown solid) 302.1mg was obtained with a total yield of 59.2%.
ESI-MS：342.2[M+H] + 。
1 H NMR(300MHz,DMSO-d 6 )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 the preparation of compound Ic of example 1, 6-bromovanillin was substituted for compound c-1, and the ia reaction solvent was substituted for 25ml dmf, with the other conditions unchanged. The productivity 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. Compound Ib (white powder) 266.8mg is obtained in 56.8% yield.
ESI-MS：328.2[M+H] + ,326.2[M-H]-。
1 H NMR(300MHz,DMSO-d 6 )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, 6-bromo-3, 4-methylenedioxybenzaldehyde was used instead of compound c-2, with the other conditions unchanged. The productivity of each step is as follows: 88.3% of i, 92.7% of ii, 97.6% of iii, 78.2% of iv and 87.2% of v. Compound Id (white powder) 283.4mg was obtained in 54.4% yield.
ESI-MS：326.2[M+H] + 。
1 H NMR(300MHz,DMSO-d 6 )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, with the other conditions unchanged. The productivity of each step is as follows: 90.7% of i, 92.7% of ii, 87.5% of iii, 67.5% of iv and 80.5% of v. 250.4mg of the target compound Ie (reddish brown solid) was obtained in 40.0% yield.
ESI-MS：312.2[M+H] + 。
1 H NMR(300MHz,DMSO-d 6 )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, with the other conditions unchanged. The productivity 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 a yield of 70.2%.
ESI-MS：298.2[M+H] + ,296.2[M-H]-。
1 H 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, with the other conditions unchanged. The productivity of each step is as follows: iA 90.2%, iB 90.5%, ii 92.7%, iii 94.3%, iv 85.4%, v 87.2%. Compound Ii (yellow-green powder) 259.0mg was obtained in 57.3% yield.
ESI-MS：298.1[M+H] + ,296.2[M-H]-。
1 H NMR(300MHz,DMSO-d 6 )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 of compound Ic of example 1, o-bromobenzaldehyde was used instead of compound c-2, with the other conditions unchanged. The productivity of each step is as follows: 93.1%, 92.7%, iii 92.3%, iv 92.5%, v 96.0%. 269.8mg of Compound Ik (reddish brown solid) are obtained in 70.7% yield.
ESI-MS：282.1[M+H] + 。
1 H NMR(300MHz,DMSO-d 6 )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 of compound Ic of example 1, 6-bromoveratraldehyde was used to replace compound c-2, and 3, 4-methylenedioxyphenethylamine was used to replace compound I-1, with the other conditions unchanged. The productivity of each step is as follows: 92.7%, ii 91.3%, iii 83.0%, iv 87.5%, v86.2%. 280.2mg of compound IVa (reddish brown solid) were obtained in 53.0% yield.
ESI-MS：326.2[M+H] + 。
1 H 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 unchanged. The productivity 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]-。
1 H NMR(300MHz,DMSO-d 6 )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 unchanged. The productivity of each step is as follows: 95.8% iA, 96.8% iB, 91.3% ii, 85.6% iii, 97.5% iv, and 76.3% v. Compound IVc (white powder) 237.3mg was obtained in 58.1% yield.
ESI-MS：312.2[M+H] + ,310.1[M-H]-。
1 H NMR(300MHz,DMSO-d 6 )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
With reference 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 unchanged. The productivity of each step is as follows: 88.3% of i, 91.3% of ii, 86.2% of iii, 78.9% of iv and 75.5% of v. Compound IVd (white powder) 233.3mg was obtained in 41.4% yield.
ESI-MS：310.1[M+H] + 。
1 H NMR(300MHz,DMSO-d 6 )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
With reference to the preparation of compound Ic of example 1, 2-bromo-4-methoxybenzaldehyde was used instead of compound c-2, and 3, 4-methylenedioxyphenethylamine was used instead of compound I-1, with the other conditions unchanged. The productivity of each step is as follows: 90.7% of i, 91.3% of ii, 89.7% of iii, 94% of iv, 73.2% of v. Compound IVe (reddish brown solid) 215.9mg was obtained in 51.1% yield.
ESI-MS：296.2[M+H] + 。
1 H NMR(300MHz,DMSO-d 6 )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
With reference to the preparation of the compound Ic of example 1, 2-bromo-5-methoxybenzaldehyde 6-bromoveratraldehyde was used to replace compound c-2, and 3, 4-methylenedioxyphenethylamine was used to replace compound I-1, with the other conditions unchanged. The productivity of each step is as follows: i 87.2%, ii 91.3%, iii 83.2%, iv 74.6%, v 76.3%. Compound IVf (reddish brown solid) 225.0mg was obtained in 37.7% yield.
ESI-MS：296.2[M+H] + 。
1 H NMR(300MHz,DMSO-d 6 )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
With reference to the preparation of compound Ic of example 1, 2-bromo-5-hydroxybenzaldehyde was used to replace compound c-1, and 3, 4-methylenedioxyphenethylamine was used to replace compound I-1, with the other conditions unchanged. The productivity 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 a yield of 51.1%.
ESI-MS：282.2[M+H] + ,280.1[M-H] - 。
1 H NMR(300MHz,DMSO-d 6 )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
With reference to the preparation of compound Ic of example 1, 2-bromo-4-hydroxybenzaldehyde was used to replace compound c-1, and 3, 4-methylenedioxyphenethylamine was used to replace compound I-1, with the other conditions unchanged. The productivity of each step is as follows: iA 90.2%, iB 90.5%, ii 91.3%, iii 82.5%, iv 92.6%, v86.2%. Compound IVi (yellow-green powder) was obtained in 242.2mg, yield 53.7%.
ESI-MS：282.2[M+H] + ,280.1[M-H] - 。
1 H NMR(300MHz,DMSO-d 6 )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 was used instead of compound c-2, and 3, 4-methylenedioxyphenethylamine was used instead of compound I-1, with the other conditions unchanged. The productivity of each step is as follows: 93.1%, 91.3%, 99.0%, 78.2%, v 89.1% of i. Compound IVk (reddish brown solid) 236.1mg was obtained in 58.6% yield.
ESI-MS：266.2[M+H] + 。
1 H NMR(300MHz,DMSO-d 6 )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 (11)
1. A preparation method of aporphine alkaloid shown in formula III is characterized in that: taking a benzaldehyde compound shown in a formula III-0 as a raw material, and sequentially performing Wittig reaction, pictet-Spengler reaction, heck reaction and palladium hydrocarbon deprotection; the synthetic route is as follows:
wherein R is 1 、R 2 Are respectively and independently selected from alkoxy, methylenedioxy and R 3 、R 4 Each is independently selected from H, alkoxy, methylenedioxy;
the method comprises the following steps:
step (i), wittig reaction: using benzaldehyde compounds shown in a formula III-0 as raw materials, using methylene dichloride as a reaction solvent, protecting with nitrogen, and reacting in the presence of phosphorus salt and organic base to obtain styrene methyl ether compounds shown in a formula III-1;
step (ii) in K using methylene dichloride as reaction solvent 2 CO 3 Where present, of the formula
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: acetonitrile is taken as a reaction solvent, nitrogen is used for protection, trifluoroacetic acid is firstly added into the solvent, uniformly mixed, then raw materials are added, and under the condition that trifluoroacetic acid exists, a styryl methyl ether compound shown in a formula III-1 and an amino-protected phenethylamine compound shown in a formula III-2 react to obtain a benzyl tetrahydroisoquinoline compound shown in a formula III-3 through a Pictet-Spengler reaction; the molar ratio of the styryl methyl ether compound to the amino-protected phenethylamine compound is 1.1-1.5:1; the molar ratio of the styrenemethyl ether compound to the trifluoroacetic acid is 1:1-2.5; the concentration of trifluoroacetic acid in the system is 0.15-0.3 mol/L;
step (iv), heck reaction: in Pd (OAc) using DMA as the reaction solvent 2 、Xphos、Cs 2 CO 3 Under the condition of nitrogen protection, the benzyl tetrahydroisoquinoline compound shown in the formula III-3 is subjected to Heck reaction to obtain 6-amino-protected aporphine alkaloid shown in the formula III-4; the benzyl tetrahydroisoquinoline compound and Pd (OAc) 2 The molar ratio of Pd (OAc) is 1:0.05-0.2 2 And Xphos is 1:2, and the benzyl tetrahydroisoquinoline compound and Cs are in a molar ratio of 1:2 2 CO 3 The molar ratio of (2) is 1:1.5-2;
step (v), palladium hydrocarbon deprotection: the method comprises the steps of 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 6-amino-protected aporphine alkaloid at normal temperature to obtain the aporphine alkaloid shown in the formula III, wherein the mixed solvent is a mixed solvent of THF and methanol according to the volume ratio of 1:2-1:4.
2. Aporphine biology shown in formula IIIThe preparation method of the alkali is characterized in that: using benzaldehyde compound shown in formula III-0 as raw material, acetonitrile or DMF as reaction solvent, and adding the mixture into K 2 CO 3 Under the condition of existence, heating to react at 50-70 ℃, adopting benzyl bromide to protect the hydroxyl of the benzaldehyde compound to obtain the hydroxy-protected benzaldehyde compound shown in a formula III-0', and then sequentially carrying out Wittig reaction, pictet-Spengler reaction, heck reaction and palladium hydrocarbon deprotection to obtain the aporphine alkaloid shown in a formula III; wherein the molar ratio of the benzaldehyde compound to the benzyl bromide is 1:1-1.1, and the molar ratio of the benzaldehyde compound to the K is 1:1 2 CO 3 The molar ratio of (2) is 1:2; the synthetic route is as follows:
wherein R is 1 、R 2 Are respectively and independently selected from alkoxy, methylenedioxy and R 3 、R 4 Are independently selected from H, OH, alkoxy groups, but R 3 、R 4 At least one of which is OH; r is R 3 '、R 4 ' are independently selected from H, OBn, alkoxy groups, but R 3 '、R 4 At least one of' is OBn;
the method comprises the following steps:
step (i), wittig reaction: using benzaldehyde compounds shown in a formula III-0 'as raw materials, using methylene dichloride as a reaction solvent, protecting nitrogen, and reacting in the presence of phosphorus salt and organic base to obtain styrene methyl ether compounds shown in a formula III-1';
step (ii) in K using methylene dichloride as reaction solvent 2 CO 3 Where present, of the formula
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: acetonitrile is used as a reaction solvent, nitrogen is used for protection, and under the condition of trifluoroacetic acid, a styryl methyl ether compound shown in a formula III-1 'and an amino-protected phenethylamine compound shown in a formula III-2 react to obtain a benzyl tetrahydroisoquinoline compound shown in a formula III-3'; the molar ratio of the styryl methyl ether compound to the amino-protected phenethylamine compound is 1.1-1.5:1; the molar ratio of the styrenemethyl ether compound to the trifluoroacetic acid is 1:1-2.5; the concentration of trifluoroacetic acid in the system is 0.15-0.3 mol/L;
step (iv), heck reaction: in Pd (OAc) using DMA as the reaction solvent 2 、Xphos、Cs 2 CO 3 Under the condition of nitrogen protection, the benzyl tetrahydroisoquinoline compound shown in the formula III-3 'is subjected to Heck reaction to obtain 6-amino-protected aporphine alkaloid shown in the formula III-4'; the benzyl tetrahydroisoquinoline compound and Pd (OAc) 2 The molar ratio of Pd (OAc) is 1:0.05-0.2 2 And Xphos is 1:2, and the benzyl tetrahydroisoquinoline compound and Cs are in a molar ratio of 1:2 2 CO 3 The molar ratio of (2) is 1:1.5-2;
step (v), palladium hydrocarbon deprotection: the method comprises the steps of taking a mixed solvent of THF and methanol as a reaction solvent, taking 10% Pd/C as a catalyst according to a volume ratio of 1:2-1:4 as the mixed solvent of THF and methanol, and removing protecting groups from the aporphine alkaloid shown in a formula III-4' at normal temperature to obtain the aporphine alkaloid shown in the formula III.
3. The method for preparing the aporphine alkaloid according to claim 1, which is characterized in that: in the step (i), the molar ratio of the benzaldehyde compound shown in the formula III-0 to the phosphorus salt is 1:1.5-2; the molar ratio of the benzaldehyde compound shown in the formula III-0 to the organic base is 1:1.5-2; the phosphorus salt is MeOCH 2 PPh 3 Cl; the organic base is sodium tert-butoxide or potassium tert-butoxide.
4. The method for preparing the aporphine alkaloid according to claim 2, which is characterized in that: in step (i), a benzaldehyde compound represented by formula III-0And the mole ratio of the phosphorus salt is 1:1.5-2; the molar ratio of the benzaldehyde compound shown in the formula III-0' to the organic base is 1:1.5-2; the phosphorus salt is MeOCH 2 PPh 3 Cl; the organic base is sodium tert-butoxide or potassium tert-butoxide.
5. The method for preparing the aporphine alkaloid according to claim 1 or 2, characterized in that: in the step (ii), the molar ratio of the phenethylamine compound to the benzyl chloroformate is 1:1; the phenethylamine compound and K 2 CO 3 The molar ratio of (2) is 1:1-2.
6. The method for preparing the aporphine alkaloid according to claim 1 or 2, characterized in that: in the step (ii), after the reaction is finished, the dichloromethane layer is extracted by water washing, and dichloromethane is removed; at normal temperature, ethyl acetate is added for dissolution, petroleum ether with 50-100 times of the volume of the ethyl acetate is added, and amino-protected phenethylamine compounds are separated out through recrystallization.
7. The method for preparing the aporphine alkaloid according to claim 1 or 2, characterized in that: in the step (iii), the concentration of trifluoroacetic acid in the system is 0.16mol/L.
8. The method for preparing the aporphine alkaloid according to claim 1, which is characterized in that: in step (iv), a benzyltetrahydroisoquinoline compound represented by the formula III-3 and Pd (OAc) 2 The molar ratio of (2) is 1:0.1.
9. The method for preparing the aporphine alkaloid according to claim 2, which is characterized in that: in step (iv), benzyltetrahydroisoquinoline compound of the formula III-3' and Pd (OAc) 2 The molar ratio of (2) is 1:0.1.
10. The method for preparing the aporphine alkaloid according to claim 1, which is characterized in that: in the step (v), the dosage of the 10% Pd/C is 5% -20% of the mass of the aporphine alkaloid with the 6-amino protection shown in the formula III-4.
11. The method for preparing the aporphine alkaloid according to claim 2, which is characterized in that: in the step (v), the dosage of the 10% Pd/C is 5% -20% of the mass of the aporphine alkaloid with the 6-amino protection shown in the formula III-4'.
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