CN104370866A - Synthetic method of drug intermediate 3, 5-dimethoxy-phthalic anhydride - Google Patents

Abstract

The invention discloses a synthetic method of drug intermediate 3, 5-dimethoxy-phthalic anhydride. The method includes the steps of a, synthesizing (4, 6-dimethoxy-3-trichloromethyl)-2-benzo[c]furanone (I); b, synthesizing (4, 6-dimethoxy)-2-benzo[c]furanone-3-carboxylic acid (II); c, synthesizing (4, 6-dimethoxy)-2-benzo[c]furanone (III); d, synthesizing 3, 5-dimethoxy-phthalic acid (IV); and e, synthesizing 3, 5-dimethoxy-phthalic anhydride.

Description

The synthetic method of medicinal intermediate 3,5-dimethoxy-phthalic anhydride

Technical field

The invention belongs to chemical field, relate to the preparation method of pharmaceutical intermediate, be specifically related to the synthetic method of 3,5-dimethoxy-Tetra hydro Phthalic anhydride.

Background technology

3,5-dimethoxy-Tetra hydro Phthalic anhydride is the important intermediate of the medicines such as synthesis hypericin, Schuttgelb, emodin monoglucoside.Prove according to the study, the medicines such as hypericin have good physiologically active, and using value is very high, especially in anti AIDS virus, have significant curative effect.But because hypericin content in natural phant is very micro-, far can not meet needs that are clinical and fundamental research, be worth and have multiple unfavorable factor by the Chinese medicine of artificial culture.Therefore, the chemosynthesis approach seeking a kind of 3,5-dimethoxy-Tetra hydro Phthalic anhydride is extremely important.

Summary of the invention

Given this, the object of the invention is the synthetic method providing a kind of 3,5-dimethoxy-Tetra hydro Phthalic anhydride.

For solving above technical problem, technical scheme provided by the invention is, provides a kind of synthetic method of medicinal intermediate 3,5-dimethoxy-phthalic anhydride, comprises the following steps:

A) synthesis of (4,6-dimethoxy-3-trichloromethyl)-2-benzo [c] furanone (I)

First get a certain amount of 3,5-dimethoxy p-methyls and Chloral Hydrate adds in four-necked bottle, then prepare the sulfuric acid of 90%, without the need to cooling, add in four-necked bottle, react beginning with vigorous stirring, after controlling the continuous mechanical stirring 24h of temperature of reaction, reaction terminates; Pour out product to stir in a certain amount of water, suction filtration, then use the hot methanol washing leaching cake several of 50%, remove responseless raw material; Desciccate, weighs, and leaves and takes a certain amount of product and detects; Product I is white crystal, fusing point 125-127 DEG C;

B) synthesis of (4,6-dimethoxy)-2-benzo [c] furanone-3-carboxylic acid (II)

Get 60g product I, add in four-necked bottle, slowly added in reactor by the 305mL16.8% sodium hydroxide solution prepared, stir, slowly heating up makes temperature control at 80-90 DEG C; After reaction 3h, solution is by colourless to being finally tawny, and reaction terminates; Stop heating, cooling, suction filtration; Add diluted acid in filtrate, acidifying, leave standstill; Isolate white precipitate product II, i.e. (4,6-dimethoxy)-2-benzo [c] furanone-3-carboxylic acid;

C) synthesis of (4,6-dimethoxy)-2-benzo [c] furanone (III)

Get 30g product II to add in three-necked bottle, and the dimethyl phthalate adding 75mL makes solvent, stir, heating, maintains the temperature at 180-185 DEG C, till when being heated to release without gas; Place cooling, mass sets; Add a certain amount of methanol solution, stir, a part of dissolution of solid; Solution suction filtration, filter cake ether washes 3 times, dry cake, obtains product as light yellow solid III;

The synthesis of d) 3,5-dimethoxys-phthalic acid (IV)

The product III getting 20g adds in there-necked flask, at room temperature slowly adds the basic solution of a certain amount of 3% potassium permanganate, and stir time enough, until potassium permanganate no longer fades, oxidizing reaction is complete; Heated mixt to 50 DEG C, and adds a certain amount of ethanol decolorization, removes excessive potassium permanganate, and steams excessive ethanol and a part of water; Suction filtration, filtrate uses acidifying, adularescent Precipitation, and leave standstill, suction filtration, dry cake, obtains white solid product IV;

The synthesis of e) 3,5-dimethoxys-Tetra hydro Phthalic anhydride is got

The product IV of 9g and the diacetyl oxide of 36g add in four-necked bottle, and after reflux 2h, reaction is substantially complete, will crystallize out by some pure acid anhydrides, suction filtration after cooling mixture; After filtrate decompression distillation all steams acetic acid, and cool, obtain the pure crystalline of part in addition, crystallization benzene and sherwood oil recrystallization, namely obtain final product 3,5 one dimethoxy one Tetra hydro Phthalic anhydrides.

Compared with prior art, a technical scheme tool in technique scheme has the following advantages:

5 step reactions of the present invention complete all at ambient pressure, and other required mild condition, does not have harsh reaction conditions, and easy and simple to handle, without the need to loaded down with trivial details last handling process, and all recyclable recycling of byproduct of gained; The good product purity of reaction gained, the yield of the finished product is high.Target product is met by the product of the analysis means such as differential thermal analysis, infrared, mass spectrum, nuclear-magnetism qualification gained.Synthesized 3,5-dimethoxys-Tetra hydro Phthalic anhydride has great importance for medicines such as semi-synthetic hypericin, Schuttgelb, emodin monoglucosides.

Embodiment

In the present embodiment, the synthetic method of medicinal intermediate 3,5-dimethoxy-phthalic anhydride, step is as follows:

A) synthesis of (4,6-dimethoxy-3-trichloromethyl)-2-benzo [c] furanone (I)

First get a certain amount of 3,5-dimethoxy p-methyls and Chloral Hydrate adds in four-necked bottle, then prepare the sulfuric acid of 90%, without the need to cooling, add in four-necked bottle, react beginning with vigorous stirring, after reaction 20min, start to occur colour-change, and find that there is suspended substance appearance; Thin-layer chromatographic analysis is made in sampling, and compares with the thin-layer chromatographic analysis of raw material, finds that reaction starts to produce new material, and after controlling the continuous mechanical stirring 24h of temperature of reaction, reaction terminates substantially, does tlc analysis and finds that raw material point disappears; Pour out product to stir in a certain amount of water, suction filtration, then use the hot methanol washing leaching cake several of 50%, remove responseless raw material; Desciccate, weighs, and leaves and takes a certain amount of product and detects; Product is white crystal, fusing point 125-127 DEG C; B) synthesis of (4,6-dimethoxy)-2-benzo [c] furanone-3-carboxylic acid (II)

Get 60g (0.1926mol) product I, add in four-necked bottle, slowly added in reactor by the 305mL sodium hydroxide solution (16.8%) prepared, stir, slowly heating up makes temperature control at 80-90 DEG C; After reaction 3h, solution is by colourless to being finally tawny, and reaction terminates; Stop heating, cooling, suction filtration; Add diluted acid in filtrate, acidifying, leave standstill; Isolate white precipitate, i.e. (4,6-dimethoxy)-2-benzo [c] furanone-3-carboxylic acid; Suction filtration, dry, weigh to obtain 45g, and productive rate can reach 100%, and fusing point is 188.57-191.37 DEG C;

C) synthesis of (4,6-dimethoxy)-2-benzo [c] furanone (III)

Get 30g (0.1261mol) product II to add in three-necked bottle, and the dimethyl phthalate adding 75mL makes solvent, stir, heating, maintains the temperature at 180-185 DEG C, and reaction 0.5h can find solid melts, there is gas to produce, till when being heated to release without gas simultaneously; Place cooling, mass sets; Add a certain amount of methanol solution, stir, a part of dissolution of solid; Solution suction filtration, filter cake ether washes 3 times, dry cake, weighs and obtains 23g light yellow solid, and yield can reach 96%, and fusing point is 169.23-170.48 DEG C;

The synthesis of d) 3,5-dimethoxys-phthalic acid (IV)

The product III getting 20g (0.1031mol) adds in there-necked flask, at room temperature slowly adds the basic solution of a certain amount of 3% potassium permanganate, and stir time enough, until potassium permanganate no longer fades, oxidizing reaction is complete; Heated mixt to 50 DEG C, and adds a certain amount of ethanol decolorization, removes excessive potassium permanganate, and steams excessive ethanol and a part of water; Suction filtration, filtrate uses acidifying, adularescent Precipitation, leaves standstill, suction filtration, dry cake, and weigh and obtain 21.5g (0.0951mol) white solid, yield is 93%;

The synthesis of e) 3,5-dimethoxys-Tetra hydro Phthalic anhydride is got

The product IV of 9g (0.038mol) and the diacetyl oxide of 36g (0.3529mo1) add in four-necked bottle, and after reflux 2h, reaction is substantially complete, will crystallize out by some pure acid anhydrides, suction filtration after cooling mixture; After filtrate decompression distillation all steams acetic acid, and cool, obtain the pure crystalline of part in addition, crystallization benzene and sherwood oil recrystallization, namely obtain final product 3,5 one dimethoxy one Tetra hydro Phthalic anhydrides; Weigh to obtain 7.55g (0.03630mol) White Flocculus, yield reaches 91.2%.

Below be only the preferred embodiment of the present invention, it should be pointed out that above-mentioned preferred implementation should not be considered as limitation of the present invention, protection scope of the present invention should be as the criterion with claim limited range.For those skilled in the art, without departing from the spirit and scope of the present invention, can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.

Claims (1)

1. a synthetic method for medicinal intermediate 3,5-dimethoxy-phthalic anhydride, is characterized in that, comprises the following steps: a) synthesis of (4,6-dimethoxy-3-trichloromethyl)-2-benzo [c] furanone (I)

First get a certain amount of 3,5-dimethoxy p-methyls and Chloral Hydrate adds in four-necked bottle, then prepare the sulfuric acid of 90%, without the need to cooling, add in four-necked bottle, react beginning with vigorous stirring, after controlling the continuous mechanical stirring 24h of temperature of reaction, reaction terminates; Pour out product to stir in a certain amount of water, suction filtration, then use the hot methanol washing leaching cake several of 50%, remove responseless raw material; Desciccate, weighs, and leaves and takes a certain amount of product and detects; Product I is white crystal, fusing point 125-127 DEG C;

B) synthesis of (4,6-dimethoxy)-2-benzo [c] furanone-3-carboxylic acid (II)

Get 60g product I, add in four-necked bottle, slowly added in reactor by the 305mL16.8% sodium hydroxide solution prepared, stir, slowly heating up makes temperature control at 80-90 DEG C; After reaction 3h, solution is by colourless to being finally tawny, and reaction terminates; Stop heating, cooling, suction filtration; Add diluted acid in filtrate, acidifying, leave standstill; Isolate white precipitate product II, i.e. (4,6-dimethoxy)-2-benzo [c] furanone-3-carboxylic acid;

C) synthesis of (4,6-dimethoxy)-2-benzo [c] furanone (III)

Get 30g product II to add in three-necked bottle, and the dimethyl phthalate adding 75mL makes solvent, stir, heating, maintains the temperature at 180-185 DEG C, till when being heated to release without gas; Place cooling, mass sets; Add a certain amount of methanol solution, stir, a part of dissolution of solid; Solution suction filtration, filter cake ether washes 3 times, dry cake, obtains product as light yellow solid III;

The synthesis of d) 3,5-dimethoxys-phthalic acid (IV)

The product III getting 20g adds in there-necked flask, at room temperature slowly adds the basic solution of a certain amount of 3% potassium permanganate, and stir time enough, until potassium permanganate no longer fades, oxidizing reaction is complete; Heated mixt to 50 DEG C, and adds a certain amount of ethanol decolorization, removes excessive potassium permanganate, and steams excessive ethanol and a part of water; Suction filtration, filtrate uses acidifying, adularescent Precipitation, and leave standstill, suction filtration, dry cake, obtains white solid product IV;

The synthesis of e) 3,5-dimethoxys-Tetra hydro Phthalic anhydride

The product IV of 9g and the diacetyl oxide of 36g add in four-necked bottle, and after reflux 2h, reaction is substantially complete, will crystallize out by some pure acid anhydrides, suction filtration after cooling mixture; After filtrate decompression distillation all steams acetic acid, and cool, obtain the pure crystalline of part in addition, crystallization benzene and sherwood oil recrystallization, namely obtain final product 3,5 one dimethoxy one Tetra hydro Phthalic anhydrides.