阅读说明：本技术 一种制备1-(7-溴苯并并[d][1,3]二氧杂环戊烯-4-基)乙-1-酮的方法 (Method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one ) 是由 刘宝彪 张�浩 于 2021-07-23 设计创作，主要内容包括：本申请涉及有机合成技术领域,具体公开了一种制备1-(7-溴苯并并[D][1,3]二氧杂环戊烯-4-基)乙-1-酮的方法,以1,3-苯并二氧-4-甲醛为起始物,顺次经过羟醛缩合反应、溴代反应、加成反应、氧化反应得到式(VI)所示化合物1-(7-溴苯并并[D][1,3]二氧杂环戊烯-4-基)乙-1-酮。本申请不仅简化了合成路线,而且提高了收率和纯度。(The application relates to the technical field of organic synthesis, and particularly discloses a method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one, which takes 1, 3-benzodioxy-4-formaldehyde as an initiator to obtain a compound 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one shown in a formula (VI) through aldol condensation reaction, bromination reaction, addition reaction and oxidation reaction in sequence. The method simplifies the synthetic route and improves the yield and purity.)

1. A process for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one of formula (V) comprising the steps of:

preparation of a Compound of formula (II): carrying out aldol condensation reaction on a compound shown in a formula (I) and ethylene glycol under the action of a catalyst to obtain a compound shown in a formula (II), wherein the molar ratio of the compound shown in the formula (I), the ethylene glycol and the catalyst is 1 (1-2) to 0.09-0.11;

preparation of a Compound of formula (IV): carrying out lithiation reaction on a compound shown in a formula (II) and n-butyllithium, and carrying out bromination reaction on the compound shown in the formula (II) and bromine to obtain a compound shown in a formula (III), wherein the molar ratio of the compound shown in the formula (II) to the n-butyllithium to the bromine is 1 (1-1.5) to 1-1.5; carrying out carbonyl deprotection reaction on the compound shown in the formula (III) to obtain a compound shown in a formula (IV);

preparation of a Compound of formula (V): carrying out addition reaction on a compound shown in a formula (IV) and methyl magnesium halide to obtain a compound shown in a formula (V), wherein the molar ratio of the compound shown in the formula (IV) to the methyl magnesium halide is 1 (1.2-1.3);

preparation of a Compound of formula (VI): the compound shown in the formula (V) is subjected to oxidation reaction in a system of chromium trioxide and sulfuric acid to obtain the compound shown in the formula (VI), wherein the molar ratio of the compound shown in the formula (V) to the chromium trioxide is 1 (0.99-1).

2. The method according to claim 1, wherein in the step of preparing the compound represented by the formula (II), the temperature of the aldol condensation reaction is 110 to 115 ℃.

3. The method according to claim 1, wherein the catalyst is p-toluenesulfonic acid in the step of preparing the compound represented by the formula (II).

4. The method according to claim 1, wherein the temperature condition of the lithiation reaction in the preparation step of the compound represented by the formula (IV) is-80 to-78 ℃.

5. The method according to claim 1, wherein in the step of preparing the compound represented by the formula (IV), the temperature condition of the bromination reaction is room temperature.

6. The method according to claim 1, wherein the molar ratio of n-butyllithium to bromine in the step of preparing the compound represented by formula (IV) is 1 (0.99-1.01).

7. The method according to claim 1, wherein in the step of preparing the compound represented by the formula (V), the temperature condition of the addition reaction is-10 to 0 ℃.

8. The method according to claim 1, wherein in the step of preparing the compound represented by formula (V), the methylmagnesium halide is at least one selected from the group consisting of methylmagnesium chloride, methylmagnesium bromide and methylmagnesium iodide.

9. The method according to claim 1, wherein in the step of preparing the compound represented by the formula (VI), the sulfuric acid is an aqueous solution of 25 to 35% by weight of sulfuric acid.

10. The method according to claim 9, wherein the molar ratio of the chromium trioxide to the sulfuric acid in the step of preparing the compound represented by the formula (VI) is 1 (5.3-5.7).

Technical Field

The application relates to the technical field of organic synthesis, in particular to a method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one.

Background

1- (7-Bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one (CAS: 1892297-18-6) is an important intermediate in pharmaceutical synthesis, for example: chronic hepatitis C therapeutic drug-cloperavir Hydrochloride (Clopavir Hydrochloride).

However, the synthesis route of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one in the related art is long, the yield is low, and the product purity is low.

Disclosure of Invention

In order to simplify the synthetic route and improve the yield and purity, the application provides a method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one, which adopts the following technical scheme:

a process for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one of formula (V) comprising the steps of:

preparation of a Compound of formula (II): carrying out aldol condensation reaction on a compound shown in a formula (I) and ethylene glycol under the action of a catalyst to obtain a compound shown in a formula (II), wherein the molar ratio of the compound shown in the formula (I), the ethylene glycol and the catalyst is 1 (1-2) to 0.09-0.11;

preparation of a Compound of formula (IV): carrying out lithiation reaction on a compound shown in a formula (II) and n-butyllithium, and carrying out bromination reaction on the compound shown in the formula (II) and bromine to obtain a compound shown in a formula (III), wherein the molar ratio of the compound shown in the formula (II) to the n-butyllithium to the bromine is 1 (1-1.5) to 1-1.5; carrying out carbonyl deprotection reaction on the compound shown in the formula (III) to obtain a compound shown in a formula (IV);

preparation of a Compound of formula (V): carrying out addition reaction on a compound shown in a formula (IV) and methyl magnesium halide to obtain a compound shown in a formula (V), wherein the molar ratio of the compound shown in the formula (IV) to the methyl magnesium halide is 1 (1.2-1.3);

preparation of a Compound of formula (VI): the compound shown in the formula (V) is subjected to oxidation reaction in a system of chromium trioxide and sulfuric acid to obtain the compound shown in the formula (VI), wherein the molar ratio of the compound shown in the formula (V) to the chromium trioxide is 1 (0.99-1).

Optionally, in the step of preparing the compound shown in the formula (II), the temperature condition of the aldol condensation reaction is 110 to 115 ℃.

Optionally, in the step of preparing the compound represented by the formula (II), the catalyst is p-toluenesulfonic acid.

Optionally, in the step of preparing the compound represented by the formula (IV), the temperature condition of the lithiation reaction is-80 to-78 ℃.

Alternatively, in the step of preparing the compound represented by the formula (IV), the temperature condition of the bromination reaction is room temperature.

Optionally, in the preparation step of the compound shown in the formula (IV), the molar ratio of n-butyllithium to bromine is 1 (0.99-1.01).

Optionally, in the step of preparing the compound represented by the formula (V), the temperature condition of the addition reaction is-10 to 0 ℃.

Optionally, in the step of preparing the compound represented by formula (V), the methyl magnesium halide is at least one selected from methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide.

Optionally, in the step of preparing the compound shown in the formula (VI), the sulfuric acid is an aqueous solution of 25-35% by weight.

Optionally, in the preparation step of the compound shown in the formula (VI), the molar ratio of the chromium trioxide to the sulfuric acid is 1 (5.3-5.7).

In summary, the present application has the following beneficial effects:

the application not only simplifies the synthetic route of the 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one, but also improves the yield and the purity.

Drawings

FIG. 1 is a synthetic scheme of one method of the present application for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one.

Detailed Description

The present application will be described in further detail with reference to examples.

The synthetic route of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one is shown in FIG. 1.

Taking 1, 3-benzodioxyl-4-formaldehyde as an initiator of a compound shown in a formula (I), and sequentially carrying out aldol condensation reaction, bromination reaction, addition reaction and oxidation reaction to obtain a compound 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone shown in a formula (VI).

Preparation of the Compound of formula (II)

Preparation example 1 of Compound represented by formula (II)

Adding 1, 3-benzodioxyl-4-formaldehyde (15.1g, 100.6mmol) shown in the formula (I) and ethylene glycol (9.3g, 150mmol) into a dry flask which is provided with 60mL of toluene and is connected with a water separator in advance, stirring at room temperature, adding p-toluenesulfonic acid (1.7g, 10.1mmol), heating the reaction mixture to 110-115 ℃, stirring for 1 hour, continuously separating water, after the reaction is finished, cooling the mixture to room temperature, filtering, and evaporating the solvent at 70 ℃ under vacuum to obtain a compound (18.1g, 93.2mmol, 92.64% yield and 98.95% purity) shown in the formula (II).

Preparation example 2 of Compound represented by formula (II)

Compared with preparation 1, preparation 2 differs in that: the feeding amount of the ethylene glycol is 12.4g and 200mmol, and the rest feeding amount and the reaction condition are the same. Preparation example 2 the compound represented by the formula (II) (18.2g, 93.7mmol, yield 93.14%, purity 98.97%) was obtained.

Table 1: yield and purity of the compound of formula (II)

Preparation of Compound of formula (IV)

Preparation example 1 of Compound represented by formula (IV)

A compound represented by the formula (II) (18.1g, 93.2mmol) and 200mL of tetrahydrofuran were added to the reactor, and the mixture was stirred. Then, the mixture was cooled to-80 ℃ to-78 ℃, 64.1mL (molar amount of n-butyllithium: 102.6mmol) of a 1.6mol/L n-butyllithium tetrahydrofuran solution was added dropwise thereto, the mixture was stirred for 4 hours while maintaining the temperature and then warmed to room temperature, followed by addition of bromine (16.4g, 102.6mmol), and the mixture was stirred at room temperature for 2 hours. An appropriate amount of saturated aqueous sodium thiosulfate solution was added, and extraction was performed with ethyl acetate and water. The organic layer was concentrated under reduced pressure and then recrystallized to obtain the compound represented by the formula (III).

The compound represented by the formula (III) was dissolved in 200mL of tetrahydrofuran, 20mL of 1N hydrochloric acid was added, and after stirring and heating to reflux for 2 hours, the residue was dissolved in 10mL of ethyl acetate by evaporation under reduced pressure, washed with the same volume of water and a saturated sodium chloride solution, and finally dried over magnesium sulfate and the solvent was evaporated to dryness to obtain the compound represented by the formula (IV) (17.2g, 75.1mmol, yield 80.58%, purity 99.35%).

Preparation example 2 of Compound represented by formula (IV)

Compared with preparation 1, preparation 2 differs in that: 82.1mL of a 1.6mol/L n-butyllithium tetrahydrofuran solution (the molar amount of n-butyllithium was 131.4mmol) and 21.0g and 131.4mmol of bromine were added dropwise; the rest feeding materials and reaction conditions are the same. Preparation example 2 the compound represented by the formula (IV) (17.1g, 74.7mmol, yield 80.15%, purity 99.38%) was obtained.

Preparation example 3 of Compound represented by formula (IV)

Compared with preparation 1, preparation 3 differs in that: 82.1mL of a 1.6mol/L n-butyllithium tetrahydrofuran solution (131.4 mmol as the molar amount of n-butyllithium) was added dropwise thereto; the rest feeding materials and reaction conditions are the same. Preparation example 2 the compound represented by the formula (IV) (16.7g, 72.9mmol, yield 78.22%, purity 98.80%) was obtained.

Preparation of Compound of formula (IV) comparative example 1

Comparative preparation example 1 was prepared in contrast to preparation example 1 except that: replacing n-butyl lithium with equimolar lithium diisopropylamide; the rest feeding materials and reaction conditions are the same. Preparation of comparative example 1 the compound represented by the formula (IV) (15.6g, 68.1mmol, yield 73.07%, purity 84.39%) was obtained.

Table 2: yield and purity of the Compound of formula (IV)

As can be seen from table 2, in the preparation step of the compound represented by formula (IV), the kind of the organolithium reagent and the molar ratio of organolithium and bromine have a great influence on the yield and purity of the compound represented by formula (IV).

Since the purity of the compound represented by the formula (IV) obtained in production example 3 and production comparative example 1 was not 99% or more, it was not used as a raw material in the production step of the compound represented by the formula (V).

Preparation of Compound of formula (V)

The compound represented by the formula (IV) (17.1g, 74.7mmol) was added to 200mL of tetrahydrofuran, stirred and cooled to 0 ℃ or below, followed by dropwise addition of 98.2mL of a 0.93mol/L solution of methylmagnesium bromide in tetrahydrofuran (molar amount of methylmagnesium bromide: 91.3mmol), and after completion of the dropwise addition, the mixture was warmed to room temperature and stirred for 1 hour. After the reaction, 2mol/L hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The extracted organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give a compound represented by the formula (V) (16.7g, 68.1mmol, yield 91.16%, purity 99.45%).

Preparation of the Compound of formula (VI)

The compound represented by the formula (V) (16.7g, 68.1mmol) was dissolved in 170mL of acetone, and CrO was added₃(6.75g, 67.5mmol) in 30mL of a 30% strength by weight aqueous solution of sulfuric acid; then, mixing the two solutions, stirring, controlling the temperature to be 15-25 ℃, reacting for 2 hours, adjusting the solution to be neutral by adopting a sodium hydroxide aqueous solution with the weight percentage concentration of 30% after the reaction is finished, and then adopting CH₂Cl₂Extracting for three times, separating to obtain organic phase, washing the organic phase with saturated NaCl aqueous solution, and removing anhydrous Na₂SO₄Drying, filtering, and evaporating the solvent under reduced pressure to obtain the compound 1- (7-bromobenzo [ D ] shown in the formula (VI)][1,3]Dioxolen-4-yl) ethan-1-one (14.7g, 60.5mmol, yield 88.84%, purity 99.2%).

Confirmation of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one represented by formula (V):

¹H-NMR(300MHz,DMSO-d₆)：δ7.47(d,1H),7.133(d,1H),6.07(s,2H),2.62(s,3H)；MZ：m/z:241.96。

in conclusion, the total yield of the 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one prepared by the method provided by the application is more than 60%, and the purity is more than 99%.

The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.