阅读说明：本技术 一种1-(7-溴苯并并[d][1,3]二氧杂环戊烯-4-基)乙-1-酮的制备方法 (Preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone ) 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1-(7-溴苯并并[D][1,3]二氧杂环戊烯-4-基)乙-1-酮的制备方法,以胡椒环以起始物,顺次经过酰基化反应、羰基保护反应、溴代反应、羰基脱保护反应得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 preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one, which comprises the steps of using a pepper ring as an initiator, and sequentially carrying out an acylation reaction, a carbonyl protection reaction, a bromination reaction and a carbonyl deprotection reaction to obtain the 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one. The method simplifies the synthetic route and improves the yield and purity.)

1. A preparation method of a compound 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one shown as a formula (V) is characterized by comprising the following steps:

preparation of a Compound of formula (II): carrying out lithiation reaction on the compound shown in the formula (I) and n-butyllithium, and then carrying out acylation reaction on the compound and acetyl chloride to obtain a compound shown in a formula (II); the molar ratio of the compound shown in the formula (I), n-butyl lithium and acetyl chloride is 1 (1.8-2.0) to 1.1-1.2;

preparation of a Compound of formula (III): carrying out carbonyl protection reaction on the compound shown in the formula (II) and ethylene glycol under the action of a catalyst to obtain a compound shown in a formula (III); the molar ratio of the compound shown in the formula (II), the glycol and the catalyst is 1 (1.1-1.2) to 0.08-0.10;

preparation of a Compound of formula (V): carrying out lithiation reaction on the compound shown in the formula (III) and lithium diisopropylamide, and carrying out bromination reaction on the compound shown in the formula (III) and bromine to obtain a compound shown in a formula (IV), wherein the molar ratio of the compound shown in the formula (III) to the lithium diisopropylamide to the bromine is 1 (1.4-1.6) to 0.9-1.0; and (3) carrying out carbonyl deprotection reaction on the compound shown in the formula (IV) to obtain the compound shown in the formula (V).

2. The method according to claim 1, wherein the lithiation reaction is carried out at a reaction temperature of-80 to-70 ℃ in the preparation of the compound represented by the formula (II).

3. The method according to claim 1, wherein the acylation reaction is carried out at a reaction temperature of 20 to 30 ℃ in the step of preparing the compound represented by the formula (II) and in the step of preparing the compound represented by the formula (II).

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

5. The method according to claim 1, wherein the carbonyl protection reaction is carried out at a reaction temperature of 65-75 ℃ in the preparation of the compound represented by the formula (III).

6. The method according to claim 1, wherein the lithiation reaction is carried out at a reaction temperature of-70 to-80 ℃ in the preparation of the compound represented by the formula (IV).

7. The preparation method according to claim 1, wherein in the preparation of the compound represented by the formula (IV), the bromination reaction is carried out at a reaction temperature of 20-30 ℃.

8. The process according to claim 1, wherein the solvent used for recrystallization in the production of the compound represented by the formula (IV) is ethyl acetate.

Technical Field

The application relates to the technical field of organic synthesis, in particular to a preparation method of 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 preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone, which adopts the following technical scheme:

a preparation method of a compound 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one shown as a formula (V) comprises the following steps:

preparation of a Compound of formula (II): carrying out lithiation reaction on the compound shown in the formula (I) and n-butyllithium, and then carrying out acylation reaction on the compound and acetyl chloride to obtain a compound shown in a formula (II); the molar ratio of the compound shown in the formula (I), n-butyl lithium and acetyl chloride is 1 (1.8-2.0) to 1.1-1.2;

preparation of a Compound of formula (III): carrying out carbonyl protection reaction on the compound shown in the formula (II) and ethylene glycol under the action of a catalyst to obtain a compound shown in a formula (III); the molar ratio of the compound shown in the formula (II), the glycol and the catalyst is 1 (1.1-1.2) to 0.08-0.10;

preparation of a Compound of formula (V): carrying out lithiation reaction on the compound shown in the formula (III) and lithium diisopropylamide, and carrying out bromination reaction on the compound shown in the formula (III) and bromine to obtain a compound shown in a formula (IV), wherein the molar ratio of the compound shown in the formula (III) to the lithium diisopropylamide to the bromine is 1 (1.4-1.6) to 0.9-1.0; and (3) carrying out carbonyl deprotection reaction on the compound shown in the formula (IV) to obtain the compound shown in the formula (V).

Optionally, in the step of preparing the compound shown in the formula (II), the lithiation reaction is carried out under the condition that the reaction temperature is-80 to-70 ℃.

Optionally, in the preparation of the compound shown in the step (II), and in the preparation of the compound shown in the step (II), the acylation reaction is performed at a reaction temperature of 20-30 ℃.

Optionally, in the preparation of the compound represented by the step (III), the catalyst is p-toluenesulfonic acid.

Optionally, in the preparation of the compound shown in the step (III), the carbonyl protection reaction is performed at a reaction temperature of 65-75 ℃.

Optionally, in the step of preparing the compound shown in the formula (IV), the lithiation reaction is carried out under the condition that the reaction temperature is-70 to-80 ℃.

Optionally, in the preparation of the compound shown in the step (IV), the bromination reaction is performed under the condition that the reaction temperature is 20-30 ℃.

Optionally, in the step of preparing the compound represented by the formula (IV), the solvent used for recrystallization is ethyl acetate.

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 a process for the preparation of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one of the present application.

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.

The compound 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone shown in the formula (V) is obtained by using a compound piperonyl shown in the formula (I) as an initiator and sequentially carrying out acylation reaction, carbonyl protection reaction, bromination reaction and carbonyl deprotection reaction.

Preparation of the Compound of formula (II)

Preparation example 1 of Compound represented by formula (II)

Adding a compound piperonyl (136.0g, 1.114mol) shown in the formula (I) and 200mL of tetrahydrofuran into a reactor, cooling to-78 ℃, dropwise adding n-butyllithium (135.0g, 2.107mol), and reacting at-79 ℃ for 1.5h with heat preservation; thereafter, acetyl chloride (9) was added dropwise6.3g, 1.226mol) and keeping the dropping temperature below-79 ℃, then slowly raising the temperature to 20-30 ℃, and carrying out heat preservation reaction for 1.5 h. The reaction was quenched by dropping the reaction solution into 150mL of water while maintaining the quenching temperature below 35 ℃ and then sequentially taking 10% by weight of H₂SO₄The resulting mixture was washed once with 100mL of the aqueous solution, 200mL of saturated saline solution and 200mL of water, and the mixture was separated to give the compound represented by formula (II) (171.87g, 1.047mol, yield 93.97%).

Preparation example 2 of Compound represented by formula (II)

Adding the compound piperonyl (136g, 1.114mol) shown in the formula (I) and 200mL of tetrahydrofuran into a reactor, cooling to-78 ℃, dropwise adding n-butyllithium (135g, 2.107mol), and reacting at-79 ℃ for 1.5 h. Acetyl chloride (104.8g, 1.336mol) is dripped, the dripping temperature is kept below-79 ℃, then the temperature is slowly increased to 20-30 ℃, and the reaction is carried out for 1.5h under heat preservation. Dropwise adding the reaction solution into 150mL of water for quenching, and keeping the quenching temperature below 35 ℃; then using H with the weight percentage concentration of 10 percent₂SO₄The resulting aqueous solution (100 mL), saturated saline (200 mL) and water (200 mL) were washed once and separated to give a compound represented by formula (II) (169.0g, 1.029mol, yield 92.40%).

Preparation example 3 of Compound represented by formula (II)

A compound, namely piperonyl (136g, 1.114mol) shown in the formula (I) and 200mL of tetrahydrofuran are added into a reactor, n-butyllithium (135g, 2.107mol) is added dropwise after the temperature is reduced to-78 ℃, and the reaction is carried out at-79 ℃ for 1.5 h. Dropwise adding acetyl chloride (96.2g, 1.225mol) and keeping the dropwise adding temperature below-79 ℃, then slowly heating to 20-30 ℃, and carrying out heat preservation reaction for 1.5 h. The reaction was quenched by adding droplets to 150ml of tap water and maintaining the quench temperature below 35 ℃. Then sequentially using H with the weight percentage concentration of 10 percent₂SO₄The resulting mixture was washed with 100mL of the aqueous solution, 200mL of saturated saline solution and 200mL of water, followed by separation to give a compound represented by formula (II) (163.67g, 0.997mol, yield 89.50%).

Preparation of Compound of formula (II) comparative example 1

Production comparative example 1 was conducted in contrast to production example 1 except that n-butyllithium (135.0g, 2.107mol) was replaced with lithium diisopropylamide (225.7g, 2.107mol) to obtain a compound represented by formula (II) (87.9g, 0.535mol, yield 68.68%).

Table 1: yield of the Compound of formula (II)

Preparation of the Compound of formula (II)	Preparation example 1	Preparation example 2	Preparation example 3	Preparation of comparative example 1
					Organic lithium	N-butyl lithium	N-butyl lithium	N-butyl lithium	Lithium diisopropylamide
Molar ratio of piperonyl, organolithium and acetyl chloride	1:1.89:1.10	1:1.89:1.20	1:1.89:1.10	1:1.89:1.10
					Yield of	93.97％	92.40％	89.50％	68.68％

As is clear from Table 1, the selection of the organolithium reagent has a great influence on the yield of the compound represented by the formula (II).

Preparation of the Compound of formula (III)

Preparation example 1 of Compound represented by formula (III)

A compound represented by the formula (II) (127.8g, 0.779mol), ethylene glycol (58g, 0.934mol), p-toluenesulfonic acid (13.8g, 0.080mol) and 300mL of toluene were charged into a reactor and heated to boiling (70 ℃ C.). After the reaction, the temperature is reduced to room temperature, 25g of anhydrous sodium sulfate is added for drying, the mixture is filtered, a filter cake is rinsed by a small amount of toluene, and the compound shown in the formula (III) is obtained after reduced pressure distillation (151.3g, 0.727mol, yield 93.32%).

Preparation example 2 of Compound represented by formula (III)

A compound represented by the formula (II) (125.7g, 0.766mol), ethylene glycol (57.1g, 0.920mol), p-toluenesulfonic acid (13.8g, 0.080mol) and 300mL of toluene were placed in a reactor and heated to boiling (70 ℃ C.). After the reaction, the temperature was reduced to room temperature, 25g of anhydrous sodium sulfate was added, the mixture was dried, filtered, the filter cake was rinsed with a small amount of toluene, and the resulting mixture was distilled under reduced pressure to obtain a compound represented by the formula (III) (149.7g, 0.719mol, yield 93.86%).

Preparation example 3 of Compound represented by formula (III)

300mL of the compound represented by the formula (II) (121.8g, 0.742mol), ethylene glycol (55.3g, 0.891mol), p-toluenesulfonic acid (12.2g, 0.071mol) and toluene were charged into a reactor and heated to boiling (70 ℃ C.). After the reaction, the temperature was reduced to room temperature, 25g of anhydrous sodium sulfate was added, the mixture was dried, filtered, the filter cake was rinsed with a small amount of toluene, and the resulting mixture was distilled under reduced pressure to obtain the compound represented by the formula (III) (148.1g, 0.711mol, yield 95.82%).

Table 2: yield of the Compound of formula (III)

Preparation of the Compound of formula (III)	Preparation example 1	Preparation example 2	Preparation example 3
				The molar ratio of the compound represented by the formula (II), ethylene glycol and p-toluenesulfonic acid	1:1.20:0.103	1:1.20:0.104	1:1.20:0.096
Yield of	93.32％	93.86％	95.82％

Preparation of Compound represented by the formula (V)

Preparation of Compound represented by formula (V) 1

Adding a compound (151.3g, 0.727mol) shown in the formula (III) and 200mL of tetrahydrofuran into a reactor, stirring and cooling to-78 ℃, dropwise adding lithium diisopropylamide (122.5g, 1.144mol) and keeping the dropwise adding temperature below-79 ℃, and preserving heat for reacting for 4 hours after dropwise adding; then dropwise adding bromine (116g, 0.726mol) and keeping the dropwise adding temperature below-79 ℃; after the dropwise addition, the temperature is raised to 25-30 ℃, and the reaction is carried out for 2 hours under the condition of heat preservation. And (3) dropwise adding the reaction solution into a sodium thiosulfate aqueous solution, extracting with 200mL of ethyl acetate, separating, concentrating the organic phase under reduced pressure until crystals are precipitated, cooling, crystallizing and filtering to obtain the compound shown in the formula (IV).

The compound represented by the formula (IV) is dissolved in 200mL of tetrahydrofuran, 20mL of 1N hydrochloric acid is added, the mixture is stirred, heated and refluxed for 2 hours, then the residue is dissolved in 100mL of ethyl acetate by evaporation under reduced pressure, the obtained solution is washed by water and saturated aqueous solution of sodium chloride in the same volume, finally the obtained solution is dried by magnesium sulfate and the solvent is evaporated to dryness, and the compound represented by the formula (V) is obtained (153.6g, 0.632mol, yield 86.93% and purity 99.2%).

Preparation example 2 of Compound represented by formula (V)

Adding the compound shown in the formula (III) (149.7g, 0.719mol) and 200mL of tetrahydrofuran into a reactor, stirring and cooling to-78 ℃, dropwise adding lithium diisopropylamide (115.1g, 1.074mol) and keeping the dropwise adding temperature below-79 ℃, and preserving heat for reacting for 4 hours after dropwise adding. Bromine (109g, 0.682mol) was then added dropwise while maintaining the addition temperature below-79 ℃. And heating the mixture to 25-30 ℃, and reacting for 2 hours under the condition of heat preservation. Adding the reaction solution into an aqueous solution of sodium thiosulfate dropwise, extracting with 200mL of ethyl acetate, separating, concentrating the organic phase under reduced pressure until crystals precipitate, cooling, and filtering to obtain the compound shown in the formula (IV).

The compound represented by the formula (IV) is dissolved in 200mL of tetrahydrofuran, 20mL of 1N hydrochloric acid is added, the mixture is stirred, heated and refluxed for 2 hours, then the residue is dissolved in 100mL of ethyl acetate by evaporation under reduced pressure, the obtained solution is washed by water and saturated aqueous solution of sodium chloride in the same volume, finally the obtained solution is dried by magnesium sulfate and the solvent is evaporated to dryness, and the compound represented by the formula (V) is obtained (148.1g, 0.609mol, the yield is 84.70%, and the purity is 99.3%).

Preparation example 3 of Compound represented by formula (V)

Adding the compound (148.1g, 0.711mol) shown in the formula (III) and 200mL of tetrahydrofuran into a reactor, stirring and cooling to-78 ℃, slowly dropwise adding lithium diisopropylamide (119.9g, 1.119mol) while keeping the dropwise adding temperature below-79 ℃, and preserving heat for reacting for 4 hours after dropwise adding. Then bromine (110.1g, 0.689mol) was added dropwise while keeping the dropping temperature below-79 ℃. The mixture is heated to 25-30 ℃ and is reacted for 2 hours under the condition of heat preservation. Adding the reaction solution into sodium thiosulfate aqueous solution dropwise, extracting with 200ml ethyl acetate, separating, concentrating the organic phase under reduced pressure until crystals precipitate, cooling, and filtering to obtain the compound shown in formula (IV).

The compound represented by the formula (IV) is dissolved in 200mL of tetrahydrofuran, 20mL of 1N hydrochloric acid is added, the mixture is stirred, heated and refluxed for 2 hours, then the residue is dissolved in 100mL of ethyl acetate by evaporation under reduced pressure, the obtained solution is washed by water and saturated aqueous solution of sodium chloride in the same volume, finally the obtained solution is dried by magnesium sulfate and the solvent is evaporated to dryness, and the compound represented by the formula (V) is obtained (152.6g, 0.628mol, yield 88.33% and purity 99.2%).

Preparation of Compound of formula (V) comparative example 1

Production comparative example 1 was conducted in contrast to production example 1 except that lithium diisopropylamide (122.5g, 1.144mol) was replaced with n-butyllithium (73.3g, 1.144mol) to obtain a compound represented by formula (V) (90.2g, 0.371mol, yield 51.03%, purity 97.5%).

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。

table 3: yield of the Compound of formula (V)

As is clear from table 3, in the production step of the compound represented by formula (V), the kind of the organolithium reagent has a great influence on both the yield and the purity of the compound represented by formula (V).

As can be seen from the yields in tables 1-3, the total yield of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one synthesized by the preparation method provided by the application can reach 87.28% at most, 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.