CN113801112A - Synthesis method and application of fibrauretine and analogues thereof - Google Patents

Synthesis method and application of fibrauretine and analogues thereof Download PDF

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CN113801112A
CN113801112A CN202111256453.7A CN202111256453A CN113801112A CN 113801112 A CN113801112 A CN 113801112A CN 202111256453 A CN202111256453 A CN 202111256453A CN 113801112 A CN113801112 A CN 113801112A
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fibrauretine
glyoxal
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康立涛
李倩
杨世琼
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NORTHCAROLINA CHEMLABS(SHANGHAI)
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    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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Abstract

The invention relates to the technical field of compound synthesis, in particular to a synthetic method and application of fibrauretine and analogues thereof. The method comprises the following steps: 1) condensing 3, 4-dimethoxy phenethylamine and a compound shown in a formula I to prepare a compound shown in a formula II; 2) reacting the compound of the formula II prepared in the step 1) with a reducing agent to prepare a compound of a formula III; 3) reacting the compound of the formula III prepared in the step 2), a glyoxal cyclization agent, a catalyst and a crystallization agent, and dissociating by ammonia water to prepare a compound of a formula IV; 4) reacting the compound of formula IV prepared in the step 3) with hydrochloric acid to prepare a compound of formula V. The method does not use ethanol and acetic acid, reduces the generation of similar impurity ethoxy substitutes, improves the product quality, reduces waste liquid by using the first two steps of toluene solvents continuously, is convenient to operate, and reduces the copper content to be extremely low, which is far lower than 1 percent by using ammonia water. In addition, macroporous resin is used for carrying out environment-friendly treatment on the copper-containing reaction mother liquor, so that the environment is protected.

Description

Synthesis method and application of fibrauretine and analogues thereof
Technical Field
The invention relates to the technical field of compound synthesis, in particular to a synthetic preparation method and application of fibrauretine and analogues thereof.
Background
Fibrauretine, also called as palmatine and palmatine, is extracted and refined from dried rattan of Fibraurea recisa Linn of Menispermaceae, and its effective component is palmatine chloride, and has a structural formula shown as compound I. Fibrauretine has broad-spectrum antibacterial and antiviral effects, and has strong inhibitory effect on chlamydia, mycoplasma, gram-positive bacteria and gram-negative bacteria; has different degrees of inhibition effects on 12 fungi such as the epidermophyton chrysosporium and the like; has multiple pharmacological effects of obviously increasing phagocytic bacteria of leucocytes, and simultaneously has good effects of enhancing the immunity of the organism and resisting inflammation. Fibrauretine is a pure natural botanical drug developed by China, and has been loaded in the Chinese pharmacopoeia in 1977.
Figure BDA0003324251850000011
Fibrauretine is widely accepted in curative effect and safety since clinical application, so that the market demand for fibrauretine is increasing, the growth period of fibrauretine plants is long, the fibrauretine plants generally need more than 7 years to be used, and the fibrauretine plants need to be pulled out with roots when being used, so that natural resources are destructively damaged, and the supply of medicinal materials is in short supply. Therefore, the research of artificially synthesizing the fibrauretine is researched, so that the demand on the market of the fibrauretine medicines caused by the shortage of fibrauretine resources is relieved, the resources can be protected, and the development of ecological environment is facilitated.
Disclosure of Invention
In view of the above-mentioned disadvantages of the prior art, the present invention aims to provide a method for synthesizing fibrauretine and analogues thereof, and the use thereof, which are used for solving the problems in the prior art.
To achieve the above and other related objects, according to one aspect of the present invention, there is provided a method for synthesizing fibrauretine and analogues thereof represented by formula v, comprising:
1) condensation reaction: condensing 3, 4-dimethoxy phenethylamine and a compound shown in a formula I to prepare a compound shown in a formula II;
Figure BDA0003324251850000021
wherein R is1And R2Each independently selected from linear or branched C1Alkyl of-C3;
2) reduction reaction: reacting the compound of the formula II obtained in the step 1) with a reducing agent to obtain a compound of a formula III;
Figure BDA0003324251850000022
wherein the reducing agent is selected from red aluminum and/or potassium borohydride;
3) and (3) cyclization reaction: reacting the compound of the formula III prepared in the step 2), a glyoxal cyclization agent, a catalyst and a crystallization agent, and dissociating by ammonia water to prepare a compound of a formula IV;
Figure BDA0003324251850000023
wherein the glyoxal cyclization agent is selected from glyoxal sodium bisulfite or a 40% aqueous glyoxal solution, and the catalyst is selected from p-toluenesulfonic acid and/or copper chloride dihydrate;
4) salt forming reaction: reacting the compound of formula IV obtained in the step 3) with hydrochloric acid to obtain a compound of formula V;
Figure BDA0003324251850000024
on the other hand, the invention provides fibrauretine and analogues thereof, which are prepared by the method.
In another aspect, the invention provides the use of fibrauretine and analogues thereof in anti-fibrosis drugs.
Compared with the prior art, the invention has the beneficial effects that:
the method does not use ethanol and acetic acid, reduces the generation of similar impurity ethoxy substitutes, improves the product quality, reduces waste liquid by using the first two steps of toluene solvents continuously, is convenient to operate, and reduces the copper content to be extremely low, which is far lower than 1 percent by using ammonia water. In addition, macroporous resin is used for carrying out environment-friendly treatment on the copper-containing reaction mother liquor for environmental protection.
Drawings
FIG. 1 shows the mass spectrum of fibrauretine (compound Va) in example 1.
FIG. 2 shows a liquid phase diagram of fibrauretine (compound Va) in example 1. Wherein, the fibrauretine: API, jatrorrhizine code number: IMP1, african tetrandrine code number: IMP 2.
FIG. 3 shows the nuclear magnetic hydrogen spectrum of fibrauretine (compound Va) in example 1.
FIG. 4 shows the nuclear magnetic carbon spectrum of fibrauretine (compound Va) in example 1.
FIG. 5 shows the mass spectrum of the fibrauretine analogue (compound vb) in example 2.
FIG. 6 shows the nuclear magnetic hydrogen spectrum of the fibrauretine analogue (compound vb) in example 2.
FIG. 7 shows the mass spectrum of the fibrauretine analogue (compound vc) in example 3.
FIG. 8 shows the nuclear magnetic hydrogen spectrum of the fibrauretine analogue (compound vc) in example 3.
FIG. 9 is a standard graph showing the copper content test in example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments, and other advantages and effects of the present invention will be apparent to those skilled in the art from the disclosure of the present specification.
The inventor of the invention discovers a novel synthetic preparation method of fibrauretine and analogues thereof through a great deal of research and study, ethanol and acetic acid are not used, the generation of similar impurity ethoxy substitutes is reduced, the toluene solvent in the first two steps is continuously used, waste liquid is reduced, macroporous resin is used for carrying out environment-friendly treatment on copper-containing reaction mother liquor for environmental protection, and the content of copper is reduced to be extremely low (less than 1ppm) by using ammonia water and is far lower than 1%. The present invention has been completed based on this finding.
The invention provides a method for synthesizing fibrauretine and analogues thereof, which comprises the following steps:
1) condensation reaction: condensing 3, 4-dimethoxy phenethylamine and a compound shown in a formula I to prepare a compound shown in a formula II;
Figure BDA0003324251850000041
wherein R is1And R2Each independently selected from linear or branched C1～C3Alkyl group of (1). Preferably, R1And R2Each independently is preferably selected from methyl, ethyl, and the like.
2) Reduction reaction: reacting the compound of the formula II obtained in the step 1) with a reducing agent to obtain a compound of a formula III;
Figure BDA0003324251850000042
wherein the reducing agent is selected from red aluminum and/or potassium borohydride;
3) and (3) cyclization reaction: reacting the compound of the formula III prepared in the step 2), a glyoxal cyclization agent, a catalyst and a crystallization agent, and dissociating by ammonia water to prepare a compound of a formula IV;
Figure BDA0003324251850000043
wherein the glyoxal cyclization agent is selected from glyoxal sodium bisulfite and/or aqueous glyoxal solution, and the catalyst is selected from p-toluenesulfonic acid and/or copper chloride dihydrate;
5) salt forming reaction: reacting the compound of formula IV obtained in the step 3) with hydrochloric acid to obtain a compound of formula V;
Figure BDA0003324251850000051
in the preparation method provided by the invention, in the step 1), 3, 4-dimethoxyphenethylamine and a compound shown in a formula I are subjected to condensation reaction to prepare a compound shown in a formula II, wherein the compound shown in the formula II is a Schiff base compound.
In step 1), the compound of formula I may be 2, 3-dimethoxybenzaldehyde, or an ethyl-substituted analogue thereof. Wherein the ethyl-substituted analog thereof may be, for example, 2-ethoxy-3-methoxybenzaldehyde, 2-methoxy-3-ethoxybenzaldehyde, etc. The structural formula of the compound of the formula I is as follows:
Figure BDA0003324251850000052
in some embodiments of the present invention, the first and second electrodes are,
when R is1Is CH3、R2Is CH3When the compound of the formula I is 2, 3-dimethoxybenzaldehyde.
When R is1Is CH2CH3、R2Is CH3When the compound of the formula I is 2-ethoxy-3-methoxybenzaldehyde.
Or when R is1Is CH3、R2Is CH2CH3When the compound of the formula I is 2-methoxy-3-ethoxybenzaldehyde.
In step 1), the molar ratio of 3, 4-dimethoxyphenethylamine to the compound of the formula I can be, for example, 1: 0.9-1.2, 1: 0.9-1.0, 1: 1.0 to 1.1, or 1: 1.1 to 1.2, etc.
In step 1), the condensation reaction of 3, 4-dimethoxyphenethylamine and the compound of formula i is usually carried out in the presence of a reaction solvent, which is usually a good solvent of the reaction system, and the reaction solvent used may be an organic solvent, and specifically may be an aromatic hydrocarbon solvent. More specifically, toluene or the like may be used. The ratio of the volume (v) of the toluene solvent to the mass (w) of the 3, 4-dimethoxyphenethylamine is 4-7: 1. 4-5: 1. 5-6: 1. or 6-7: 1, etc.
In step 1), the skilled person can select suitable temperature conditions to allow the condensation reaction of 3, 4-dimethoxyphenethylamine and the compound of formula I to proceed fully in the forward direction. For example, in the preparation process of the compound of formula II, the reaction temperature can be 10-30 ℃, 10-20 ℃, or 20-30 ℃. The condensation reaction of the invention can be carried out at room temperature without high temperature, while the condensation reaction in the prior art usually needs high temperature, in order to reflux the ethanol, the raw materials of the invention do not need ethanol and acetic acid. In addition, the reaction time can be adjusted by those skilled in the art according to the reaction progress, for example, in the preparation process of the compound of formula II, the reaction time can be 1h to 1.5h, 1h to 1.2h, 1.2h to 1.5h, and the like.
In the preparation method provided by the invention, the step 2) is to reduce the compound of the formula II obtained in the step 1) with a reducing agent to prepare a compound of a formula III.
In step 2), the compound of formula III may be N- (2, 3-dimethoxybenzyl) -beta- (3, 4-dimethoxyphenyl) ethylamine or an ethyl-substituted analogue thereof, such as N- (2-ethoxy-3-methoxybenzyl) -beta- (3, 4-dimethoxyphenyl) ethylamine, N- (2-methoxy-3-ethoxybenzyl) -beta- (3, 4-dimethoxyphenyl) ethylamine, and the like. The structural formula of the compound of the formula III is as follows:
Figure BDA0003324251850000061
in some embodiments of the present invention, the first and second electrodes are,
when R is1Is CH3、R2Is CH3When the compound in the formula III is N- (2, 3-dimethoxybenzyl) -beta- (3, 4-dimethoxyphenyl) ethylamine.
When R is1Is CH2CH3、R2Is CH3When the compound in the formula III is N- (2-ethoxy-3-methoxybenzyl) -beta- (3, 4-dimethoxyphenyl) ethylamine.
When R is1Is CH3、R2Is CH2CH3When the compound in the formula III is N- (2-methoxy-3-ethoxybenzyl) -beta- (3, 4-dimethoxyphenyl) ethylamine.
In the step 2), the reducing agent is selected from red aluminum and/or potassium borohydride. The reaction condition of the red aluminum is mild compared with that of the nickel catalytic hydrogenation, the requirement on equipment is low, the production safety is improved, and the activity of the red aluminum and the activity of the potassium borohydride are higher compared with the activity of the sodium borohydride. The method does not adopt heavy metal nickel as a catalyst, and has high requirements on experimental equipment and hydrogen pressure (4.0MPa) if the heavy metal nickel is adopted as the catalyst, and the steps are complicated.
In step 2), the molar ratio of the compound of formula II to the reducing agent may, for example, be 1: 0.8-1.5, 1: 0.8-1.0, 1: 1.0-1.2, 1: 1.0 to 1.2, or 1: 1.2 to 1.5, etc.
In the step 2), the reduction reaction of the compound of formula ii and the reducing agent is usually carried out in the presence of a reaction solvent, which is usually a good solvent of the reaction system, and the reaction solvent used may be an organic solvent, and specifically may be an aromatic hydrocarbon solvent. More specifically, toluene or the like may be used. The ratio of the volume of the toluene solvent to the mass of the reducing agent can be 2-4, 2-3, or 3-4.
In step 2), one skilled in the art can select suitable temperature conditions to allow the reduction of the compound of formula ii with the reducing agent to proceed sufficiently forward. For example, in the preparation of the compound of formula III, the reaction temperature may be 20 ℃ to 35 ℃, 20 ℃ to 25 ℃, 25 ℃ to 30 ℃, or 30 ℃ to 35 ℃. The reaction time can be adjusted by one skilled in the art according to the reaction progress, for example, in the preparation process of the compound of formula III, the reaction time can be 2h to 3h, 2h to 2.5h, 2.5h to 3h, and the like.
In step 2), the reaction can be carried out by a person skilled in the art by selecting a suitable method for post-treatment, for example, after the reduction reaction, trace amount of residual red aluminum can be post-treated by using a sodium hydroxide solution, quenching reaction is carried out, organic phase separation is carried out, and the solvent-containing compound of the formula III is obtained after water washing.
In the preparation method provided by the invention, the compound of the formula III obtained in the step 2), a glyoxal cyclization agent, a catalyst and a crystallization agent are reacted, and then ammonia water is used for dissociating to prepare the compound of the formula IV in the step 3).
In step 3), the catalyst is selected from p-toluenesulfonic acid and/or copper chloride dihydrate. The p-toluenesulfonic acid is favorable for losing water molecules to form rings in the cyclization reaction, and the copper chloride dihydrate is matched with catalytic coupling in the reaction process.
In step 3), the molar ratio of the compound of the formula III to the glyoxal cyclization agent may be, for example, 1: 5-10, 1: 5-8, or 1: 8-10, etc.
In step 3), the molar ratio of the compound of the formula III to p-toluenesulfonic acid and copper chloride dihydrate may be, for example, 1: 1: 1.76-1: 2: 2.
in the step 3), the glyoxal sodium bisulfite is glyoxal saturated sodium bisulfite, namely, at room temperature, adding the sodium bisulfite into a small amount of distilled water for multiple times until the sodium bisulfite is not dissolved in a small amount and reaches a saturated state, and then adding glyoxal aqueous solution to obtain a mixture. The mass ratio of the sodium bisulfite to the glyoxal water solution can be 1.3-1.5: 1. 1.3-1.4: 1. or 1.4 to 1.5: 1, etc.
In step 3), the aqueous glyoxal solution may be, for example, a 40% aqueous glyoxal solution.
In step 3), the reduction reaction of the compound of formula iii with the reducing agent is usually carried out in the presence of a reaction solvent, which is usually a good solvent of the reaction system, and the reaction solvent used may be an organic solvent, and specifically may be an aromatic hydrocarbon solvent. More specifically, toluene or the like may be used. The ratio of the volume of the toluene solvent to the mass of the reducing agent is 10-15, 10-12, 12-14, or 14-15.
In the step 3), the crystallization agent is selected from sodium chloride and/or ammonium chloride, and in the present invention, a salt such as sodium chloride can be used to promote crystallization. To produce the aforementioned copper salt of fibrauretine or ethyl substituted analogue. The method for the environment-friendly treatment comprises the steps of concentrating the copper-containing reaction mother liquor, and then carrying out the environment-friendly treatment of copper adsorption by using macroporous adsorption resin, wherein the aperture of the macroporous adsorption resin can be 25-28 nm, 25-26 nm, 26-27 nm, 27-28 nm and the like. More for example, it may be selected from D101 macroporous adsorbent resins. The macroporous resin can be washed by water to remove copper, the organic matter is eluted by ethanol, and the regenerated macroporous resin can be continuously used.
In step 3), one skilled in the art can select suitable temperature conditions to allow the cyclization reaction of the compound of formula iii with the glyoxal cyclizing agent to proceed sufficiently forward. For example, in the preparation process of the compound of formula IV, the reaction temperature can be 90-100 ℃, 90-95 ℃, or 95-100 ℃ and the like. The reaction time can be adjusted by one skilled in the art according to the reaction progress, for example, in the preparation process of the compound of formula IV, the reaction time can be 4h to 5h, 5h to 5.5h, or 5.5h to 6h, etc., so as to generate the fibrauretine copper salt or fibrauretine analogue II copper salt.
In step 3), the compound of formula IV can be obtained by dissociating with ammonia water or the like. The temperature of ammonia water dissociation is 20-30 ℃, and preferably 20-25 ℃. The volume of the ammonia water is 1.2-1.5, 1.2-1.3, 1.3-1.4, or 1.4-1.5, etc. of the mass ratio of the compound of the formula IV. The ammonia water is adopted in the invention instead of ammonia gas or hydrogen chloride gas, because the gas is easy to diffuse and the operation environment is poor, the invention is not suitable for industrial production.
In the preparation method provided by the invention, the step 4) is to react the compound of the formula IV obtained in the step 3) with hydrochloric acid to prepare the compound of the formula V.
In step 4), the compound of formula v may be fibrauretine or a fibrauretine analogue. The compound of formula v has the structural formula:
Figure BDA0003324251850000081
in some embodiments of the present invention, the first and second electrodes are,
when R is1Is CH3、R2Is CH3When the compound in the formula IV is fibrauretine. Is named Va.
When R is1Is CH2CH3、R2Is CH3When R is equal to1Is CH3、R2Is CH2CH3When the compound of formula IV is a fibrauretine analogue. When R is1Is CH2CH3、R2Is CH3Herba fibraureae recisaeThe analog of the hormone is designated vb, when R1Is CH3、R2Is CH2CH3When the compound is used, the fibrauretine analogue is named Vc.
In step 4), the molar ratio of the compound of formula IV to hydrochloric acid may be, for example, 1: 0.9-1.2, 1: 0.9-1.0, 1: 1.0 to 1.1, or 1: 1.1 to 1.2, etc.
In step 4), one skilled in the art can select appropriate temperature conditions to allow the salt formation reaction of the compound of formula iv with hydrochloric acid to proceed fully forward. For example, in the preparation of the compound of formula V, the reaction temperature may be 15 ℃ to 20 ℃, 15 ℃ to 18 ℃, or 18 ℃ to 20 ℃. The reaction time can be adjusted by one skilled in the art according to the reaction progress, for example, in the preparation process of the compound of formula V, the reaction time can be 1h to 2h, 1h to 1.5h, 1.5h to 2h, and the like. Fibrauretine or fibrauretine analogs can be produced.
In the preparation method provided by the invention, the solvents in the steps 1) to 4) are preferably the same organic solvent, and more preferably toluene is used in all the steps.
The invention also provides fibrauretine and analogues thereof, which are prepared by adopting the synthesis method of the fibrauretine and analogues thereof.
The invention also provides the application of the fibrauretine and the analogues thereof in anti-fibrosis drugs.
Fibrauretine and its analogues are used as a novel class of anti-fibrotic drugs through inhibiting TGF-beta 1/Smads and JAK1/STAT3 pathways, and the anti-fibrotic drugs can be anti-COL 1A1 drugs, for example.
The synthesis method of the fibrauretine and the analogues thereof provided by the invention comprises the following steps:
1. in the prior art, the condensation reaction temperature is high (the reflux temperature of ethanol is needed), and ethanol and acetic acid are respectively used for reduction and cyclization, but in the synthesis preparation method, the condensation reaction temperature is 10-30 ℃, and ethanol and acetic acid are not used for condensation and cyclization.
2. The starting materials, intermediates, reagents, catalysts and solvents used in the synthetic preparation of pharmaceutical molecules are all significant potential impurities. For substances with similar molecular structures to the target drugs, the purification and separation are very difficult in the preparation process. When the structure of the fibrauretine (the compound Va) is independently synthesized, the generation of ethoxy substituent impurities (the compound vb and the compound Vc) similar to the fibrauretine structure and similar methoxy degradation impurities (the jateorhizine and the african tetrandrine) can be reduced, so that the high purity and the few similar impurities (the jateorhizine and the african tetrandrine are less than 0.10 percent) of the obtained fibrauretine are realized, and the product quality is improved.
3. The synthesis method of the invention can change the way that the raw materials are directly synthesized into the analogues of fibrauretine (the fibrauretine structure is similar to the ethyoxyl substituent compound vb, the compound vc and the like).
4. The invention continuously uses toluene as solvent (the recovery rate of toluene is more than 90 percent), reduces waste liquid and has convenient operation.
5. According to the invention, the directly prepared glyoxal saturated sodium bisulfite can be used in the cyclization reaction, the prepared product has low copper content, the copper-containing reaction mother liquor is subjected to environment-friendly treatment by using macroporous resin for environmental protection, the copper content of the product is further reduced (less than 1ppm) by using ammonia water and optimizing conditions, the copper content is extremely lower than 1%, green chemical clean production is realized, and the high-quality raw material medicine is obtained.
6. The raw materials of the invention do not use Lewis acid which has strict requirements on reaction conditions, dimethyl sulfate and methyl iodide which have high toxicity, and the invention is safe and environment-friendly.
In conclusion, the method has the advantages of less synthetic waste liquid, simple and convenient operation, good safety, high product yield, less impurities, high quality, low synthetic cost, convenient operation and easy industrial production.
Wherein, the structural formulas of jatrorrhizine and african tetrandrine are shown as follows:
Figure BDA0003324251850000091
the invention of the present application is further illustrated by the following examples, which are not intended to limit the scope of the present application.
Examples the following synthetic schemes are referred to for a detailed description
Figure BDA0003324251850000101
In the following examples, reagents, materials and instruments used are commercially available unless otherwise specified.
Example 1
(1) Synthesis of Compound 5
3, 4-Dimethoxyphenylethylamine (compound 1, 218.09g, 1.2mol) was reacted with 2, 3-dimethoxybenzaldehyde (compound 2,221g,1.33mol) in a toluene solvent (880ml) at room temperature (10-30 ℃ C.) with stirring for 1-1.5 hours to condense to compound (5), and the reaction was completed.
(2) Synthesis of Compound 8
The toluene solution of the above compound (5) was added to a 70% red aluminum toluene solution (330mL) to conduct a reduction reaction for 2-3 hours, a trace amount of the remaining red aluminum was post-treated with a 2M sodium hydroxide solution, quenched, the organic phase was separated and washed with water to obtain a toluene solution of N- (2, 3-dimethoxybenzyl) - β - (3, 4-dimethoxyphenyl) ethylamine (8).
(3) Synthesis of fibrauretine (Compound Va)
Reacting toluene solution of the compound (8) with glyoxal saturated sodium bisulfite (7.2mol) prepared by a direct dissolution method and sodium chloride (350g) under the catalysis of p-toluenesulfonic acid (1.2mol) and copper chloride dihydrate (2.11mol) in toluene solvent at 90-100 ℃ for 5.5 hours, cooling to room temperature, crystallizing and filtering to generate fibrauretine copper salt, adding 4 liters of water for stirring, dissociating with ammonia water at 20-25 ℃ (1.5v/w), cooling, washing with water, crystallizing, adopting an atomic absorption spectrophotometry method, determining that the copper content of free alkali is reduced to below 0.3% by a standard curve method, then forming salt with 80g hydrochloric acid, washing with water, drying at 50 ℃ for 3 hours to obtain fibrauretine (Va), wherein the yield is 97%, the purity is 99.87%, as shown in figure 2, liquid phase detection jatrorrhizine (IMP1) and African alkaloids (IMP2) are both less than 0.10%, and ethyl analogue impurities (compound b) are not contained, and vc) the copper content is less than 1 ppm. The copper content was determined by atomic absorption spectrophotometry, by means of a standard curve. As shown in table 1 and fig. 9:
TABLE 1 determination of Cu elements in fibrauretine (Va) and free base
Figure BDA0003324251850000111
After the copper-containing reaction mother liquor is concentrated, the D101 macroporous adsorption resin is used for carrying out the environmental protection treatment of copper adsorption, the macroporous resin can be used for removing copper through water washing, organic matters are eluted by ethanol, and the copper-containing reaction mother liquor is continuously used after regeneration.
As shown in figure 3 of the drawings,1H NMR:(400MHz,DMSO-d6)δ3.24(t,J＝6.4Hz,2H),3.87(s,3H),3.94(s,3H),4.07(s,3H),4.11(s,3H),4.98(t,J＝6.4Hz,2H),7.09(s,1H),7.74(s,1H),8.06(d,J＝9.2Hz,1H),8.20(d,J＝9.2Hz,1H),9.14(s,1H),9.91(s,1H)；
as shown in figure 4 of the drawings, in which,13C NMR:(100MHz,DMSO-d6)δ26.46,55.82,56.34,56.72,57.54,62.40,109.35,111.78,119.41,120.47,121.81,123.92,127.22,129.03,133.63,138.13,144.12,145.86,149.21,150.69,151.96；
FIG. 1 shows that in MS (ESI), M/z [ M ]]+:352.2。
Example 2
(1) Synthesis of Compound 6
3, 4-Dimethoxyphenylethylamine (compound 1, 15g, 0.083mol) and 2-ethoxy-3-methoxybenzaldehyde (compound 3, 15g, 0.083mol) were reacted in a toluene solvent (120ml) at room temperature (20-30 ℃ C.) with stirring for 1 hour to condense into compound (6), and the reaction was completed.
(2) Synthesis of Compound 9
Adding potassium borohydride (0.083mol) into the toluene solution of the compound (6) to perform reduction reaction for 2-3 hours, slowly adding water to perform post-treatment quenching reaction, separating organic phase, and washing with water to obtain the toluene solution of N- (2-ethoxy-3-methoxybenzyl) -beta- (3, 4-dimethoxyphenyl) ethylamine (9).
(3) Synthesis of fibrauretine analogue (Compound vb)
Reacting a toluene solution of the compound (9) with 40% glyoxal (0.65mol) and sodium chloride (0.25mol) at 90-100 ℃ for 4 hours in a toluene solvent under the catalysis of p-toluenesulfonic acid (0.09mol) and copper chloride dihydrate (0.15mol) to generate fibrauretine analogue II copper salt, adding 300 ml of water, stirring, dissociating with ammonia water at 25-30 ℃ (1.2v/w), cooling, washing with water, crystallizing, reacting with 4.5g of hydrochloric acid to form salt, and drying at 50 ℃ for 3 hours to obtain the fibrauretine analogue (compound vb), wherein the yield is 96% and the purity is 99.76%.
As shown in figure 6 of the drawings,1H NMR:(400MHz,DMSO-d6)δ1.46(t,J＝7.0Hz,3H),3.23(t,J＝6.2Hz,2H),3.87(s,3H),3.94(s,3H),4.06(s,3H),4.37(q,J＝7.0Hz,2H),4.97(t,J＝6.2Hz,2H),7.10(s,1H),7.71(s,1H),8.02(d,J＝9.2Hz,1H),8.21(d,J＝9.2Hz,1H),9.02(s,1H),9.81(s,1H)；
FIG. 5 shows that in MS (ESI): M/z [ M]+:366.2。
Example 3
(1) Synthesis of Compound 7
3, 4-Dimethoxyphenethylamine (compound 1, 15g, 0.083mol) and 2-methoxy-3-ethoxybenzaldehyde (compound 4, 18g, 0.1mol) were reacted in a toluene solvent (105ml) at room temperature (10-20 ℃ C.) with stirring for 1.5 hours to condense to compound (7), and the reaction was completed.
(2) Synthesis of Compound 10
The toluene solution of the above compound (7) was added to a 70% red aluminum toluene solution (52mL) to conduct a reduction reaction for 3 hours, a trace amount of the remaining red aluminum was post-treated with a 2M sodium hydroxide solution, quenched, the organic phase was separated, and washed with water to obtain a toluene solution of N- (2-methoxy-3-ethoxybenzyl) - β - (3, 4-dimethoxyphenyl) ethylamine (10).
(3) Synthesis of fibrauretine analogue (Compound Vc)
Reacting a toluene solution of the compound (10) with 40% glyoxal (0.83mol) and sodium chloride (0.41mol) at 90-100 ℃ for 6 hours in a toluene solvent under the catalysis of p-toluenesulfonic acid (0.17mol) and copper chloride dihydrate (0.16mol) to generate fibrauretine analogue III copper salt, adding 300 ml of water, stirring, dissociating with ammonia water at 20-30 ℃ (1.2v/w), cooling, washing with water, crystallizing, salifying with 5.4g of hydrochloric acid, and drying at 50 ℃ for 3 hours to obtain fibrauretine analogue (compound vc), wherein the yield is 96% and the purity is 99.78%.
As shown in figure 8 of the drawings,1H NMR:(400MHz,DMSO-d6)δ1.45(t,J＝7.0Hz,3H),3.23(t,J＝6Hz,2H),3.87(s,3H),3.93(s,3H),4.12(s,3H),4.35(q,J＝7.0Hz,2H),4.95(t,J＝6Hz,2H),7.09(s,1H),7.70(s,1H),7.99(d,J＝9.2Hz,1H),8.18(d,J＝9.2Hz,1H),9.00(s,1H),9.87(s,1H)；
FIG. 7 shows that in MS (ESI), M/z [ M ]]+:366.2。
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.

Claims (10)

1. A method for synthesizing fibrauretine and analogues thereof represented by formula v, said method comprising:
1) condensation reaction: condensing 3, 4-dimethoxy phenethylamine and a compound shown in a formula I to prepare a compound shown in a formula II;
Figure FDA0003324251840000011
wherein R is1And R2Each independently selected from linear or branched C1～C3Alkyl groups of (a);
2) reduction reaction: reacting the compound of the formula II obtained in the step 1) with a reducing agent to obtain a compound of a formula III;
Figure FDA0003324251840000012
wherein the reducing agent is selected from red aluminum and/or potassium borohydride;
3) and (3) cyclization reaction: reacting the compound of the formula III prepared in the step 2), a glyoxal cyclization agent, a catalyst and a crystallization agent, and dissociating by ammonia water to prepare a compound of a formula IV;
Figure FDA0003324251840000013
wherein the glyoxal cyclization agent is selected from glyoxal sodium bisulfite and/or aqueous glyoxal solution, and the catalyst is selected from p-toluenesulfonic acid and/or copper chloride dihydrate;
4) salt forming reaction: reacting the compound of formula IV obtained in the step 3) with hydrochloric acid to obtain a compound of formula V;
Figure FDA0003324251840000021
2. the method of claim 1, wherein in step 1), R is1And R2Each independently selected from methyl, ethyl.
3. The method of claim 1, wherein step 1) further comprises any one or more of the following features:
A1) in the step 1), the molar ratio of the 3, 4-dimethoxyphenethylamine to the compound shown in the formula I is 1: (0.9 to 1.2);
A2) in the step 1), a reaction solvent is further included, wherein the reaction solvent is an organic solvent, and preferably, the organic solvent is selected from toluene;
A3) in the step 1), the reaction temperature is 10-30 ℃;
A4) in the step 1), the reaction time is 1-1.5 h.
4. The method of claim 1, wherein step 2) further comprises any one or more of the following features:
B1) in the step 2), the molar ratio of the compound shown in the formula II to the reducing agent is 1: 0.8 to 1.5;
B2) in the step 2), a reaction solvent is further included, wherein the reaction solvent is an organic solvent, and preferably, the organic solvent is selected from toluene;
B3) in the step 2), the reaction temperature is 20-35 ℃;
B4) in the step 2), the reaction time is 2-3 h.
5. The method of claim 1, wherein in step 3), the catalyst is selected from the group consisting of p-toluenesulfonic acid and copper chloride dihydrate.
6. The method according to claim 1, wherein in step 3), the crystallization agent is selected from sodium chloride and/or ammonium chloride.
7. The method of claim 1, wherein step 3) further comprises any one or more of the following features:
C1) in step 3), the molar ratio of the compound of formula iii to the glyoxal cyclization agent is 1: 5-10;
C2) in the step 3), the molar ratio of the compound shown in the formula III to the p-toluenesulfonic acid and the copper chloride dihydrate is 1: 1: 1.76-1: 2: 2;
C3) in the step 3), a reaction solvent is further included, wherein the reaction solvent is an organic solvent, and preferably, the organic solvent is selected from toluene;
C4) in the step 3), the reaction temperature can be 90-100 ℃;
C5) in the step 3), the ratio of the volume of the ammonia water to the mass of the compound shown in the formula IV is 1.2-1.5;
C6) in the step 3), the temperature for dissociating the ammonia water is 20-30 ℃; preferably 20 to 25 ℃.
8. The method of claim 1, wherein step 4) further comprises any one or more of the following features:
D1) in the step 4), the molar ratio of the compound shown in the formula IV to the hydrochloric acid is 1: 0.9 to 1.2;
D2) in the step 4), the reaction temperature can be 15-20 ℃;
D3) in the step 4), the reaction time can be 1-2 h.
9. A fibrauretine and its analogues, prepared by the method of any one of claims 1-8.
10. Use of fibrauretine and its analogues as claimed in claim 9 in anti-fibrotic drugs.
CN202111256453.7A 2021-10-27 2021-10-27 Synthesis method and application of fibrauretine and analogues thereof Pending CN113801112A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532130A (en) * 2011-12-27 2012-07-04 广西中医学院 Method for full chemical synthesis of fibrauretin anti-bacterial anti-inflammatory medicine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532130A (en) * 2011-12-27 2012-07-04 广西中医学院 Method for full chemical synthesis of fibrauretin anti-bacterial anti-inflammatory medicine

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