阅读说明：本技术 一种5f-emb-pica的合成方法 (Synthetic method of 5F-EMB-PICA ) 是由 赵阳 高利生 郑珲 张春水 常颖 李彭 赵彦彪 郑晓雨 杨虹贤 闻武 于 2021-01-14 设计创作，主要内容包括：本发明公开了式I所示5F-EMB-PICA的合成方法。该方法,包括下述步骤：1)以吲哚为前体,加入1-溴-5-氟戊烷和三氟乙酸酐进行反应,得到式Ⅱ所示的中间体1；2)在碱的作用下,使式Ⅱ所示的中间体进行反应,得到式Ⅲ所示的中间体2；3)在碱、缩合剂存在下,使式Ⅲ所示的中间体2与缬氨酸乙酯进行酰胺缩合反应,得到5F-EMB-PICA。本发明方法制备的5F-EMB-PICA经柱层析和重结晶处理,纯度大于97％,总收率38.7％。(The invention discloses a synthetic method of 5F-EMB-PICA shown in formula I. The method comprises the following steps: 1) indole is taken as a precursor, 1-bromo-5-fluoropentane and trifluoroacetic anhydride are added for reaction to obtain an intermediate 1 shown in a formula II; 2) under the action of alkali, reacting an intermediate shown in a formula II to obtain an intermediate 2 shown in a formula III; 3) in the presence of alkali and a condensing agent, the intermediate 2 shown in the formula III and valine ethyl ester are subjected to amide condensation reaction to obtain 5F-EMB-PICA. The 5F-EMB-PICA prepared by the method has purity of more than 97 percent and total yield of 38.7 percent after column chromatography and recrystallization treatment.)

1. The synthesis method of the 5F-EMB-PICA shown in the formula I comprises the following steps:

1) indole is taken as a precursor, 1-bromo-5-fluoropentane and trifluoroacetic anhydride are added for reaction to obtain an intermediate 1 shown in a formula II;

2) under the action of alkali, reacting an intermediate shown in a formula II to obtain an intermediate 2 shown in a formula III;

3) in the presence of alkali and a condensing agent, carrying out amide condensation reaction on the intermediate 2 shown in the formula III and valine ethyl ester to obtain 5F-EMB-PICA shown in the formula I;

2. the method of synthesis according to claim 1, characterized in that:

in the step 1), the reaction is carried out under alkaline conditions, and the alkali is NaH; the molar ratio of NaH to indole is 1.8-2.2;

the reaction is carried out in a solvent, wherein the solvent is DMF;

the reaction temperature is 0-4 ℃, and the reaction time is 1-1.5 hours;

in the step 1), the indole is a precursor, and the molar ratio of 1-bromo-5-fluoropentane to trifluoroacetic anhydride is 1: (1.05-1.1): (1.1-1.2).

3. The method according to claim 1 or 2, characterized in that: the step 1) further comprises a post-treatment step after the reaction is finished, and the post-treatment step specifically comprises the following steps: and pouring the reaction solution after the reaction is finished into ice water, extracting an organic phase by using dichloromethane, washing the obtained organic phase by using water and saturated saline solution in turn, drying the organic phase by using anhydrous magnesium sulfate, removing the solvent by rotary evaporation, and performing silica gel column chromatography to obtain the purified intermediate 1 shown in the formula II.

4. The method according to any one of claims 1-3, wherein: in the step 2), the reaction is carried out in an organic solvent, wherein the organic solvent is methanol;

the reaction is carried out in a reflux state, the reaction temperature of the reaction is 80-85 ℃, and the reaction time is 22-24 hours;

the alkali is NaOH, and the molar ratio of the NaOH to the intermediate 1 shown in the formula II is 12-15.

5. The method of claim 4, wherein: the NaOH is added in two steps, and one part of the NaOH is added in the form of NaOH methanol solution before the reaction starts; the other part is that after the reflux reaction is carried out for 10 to 12 hours, NaOH solid is added into the reaction system.

6. The method according to any one of claims 1-5, wherein: the step 2) further comprises a post-treatment step after the reaction is finished, and the post-treatment step specifically comprises the following steps: cooling the reaction solution after the reaction to room temperature, washing with diethyl ether, adjusting the pH of the water phase to 2 with 1mol/L hydrochloric acid aqueous solution, extracting with diethyl ether, washing the organic phase with saturated saline solution, drying with anhydrous magnesium sulfate, removing the solvent by rotary evaporation, and recrystallizing with isopropanol to obtain the purified intermediate 2.

7. The method according to any one of claims 1-6, wherein: in the step 3), the reaction conditions of the reaction are as follows: stirring and reacting for 10-12 hours at room temperature;

the reaction is carried out in a solvent, wherein the solvent is DMSO;

in the step 3), the molar ratio of the intermediate 2 shown in the formula III to the valine ethyl ester hydrochloride is 1: (1.05-1.1).

8. The method according to any one of claims 1-7, wherein: the base is DIPEA;

the condensing agent is at least one of EDC-HCl and HOBt.

9. The method of claim 8, wherein: the alkali is DIPEA, the condensing agents are EDC & HCl and HOBt, and the molar ratios of the intermediate 2 shown in the formula III, DIPEA, EDC & HCl and HOBt are 1: (4.5-5.5): (2-2.2): (2-2.2).

10. The method according to any one of claims 1-9, wherein: the step 3) further comprises a post-treatment step after the reaction is finished, and the post-treatment step specifically comprises the following steps: quenching the reaction system after the reaction is finished by using saturated sodium bicarbonate aqueous solution, extracting an organic phase by using ethyl acetate, washing the organic phase by using water and saturated salt solution, drying the organic phase by using anhydrous sodium sulfate, removing the solvent by rotary evaporation, and recrystallizing the crude product by using silica gel column chromatography and isopropanol to obtain the purified 5F-EMB-PICA.

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a synthetic method of 5F-EMB-PICA.

Background

5F-EMB-PICA is a new mental active substance, and no relevant report on the synthesis method of the compound exists at present. For the purpose of detection, corresponding standards are commercially available from Cayman corporation, usa for 5F-EMB-PICA related detection.

Disclosure of Invention

The invention aims to provide a synthetic method of 5F-EMB-PICA.

The structural formula of the 5F-EMB-PICA is shown as the formula I:

the synthesis method of the 5F-EMB-PICA provided by the invention comprises the following steps:

1) indole is taken as a precursor, 1-bromo-5-fluoropentane and trifluoroacetic anhydride are added for reaction to obtain an intermediate 1 shown in a formula II;

2) under the action of alkali, reacting the intermediate 1 shown in the formula II to obtain an intermediate 2 shown in the formula III;

3) in the presence of alkali and a condensing agent, carrying out amide condensation reaction on the intermediate 2 shown in the formula III and valine ethyl ester to obtain the 5F-EMB-PICA shown in the formula I.

In step 1) of the above method, the reaction is performed under an alkaline condition, and the alkali may be NaH. The mol ratio of NaH to indole is 1.8-2.2.

The reaction is carried out in a solvent, which may be specifically DMF.

The reaction temperature is 0-4 ℃, and the reaction time is 1-1.5 hours.

In the step 1), the indole is a precursor, and the molar ratio of 1-bromo-5-fluoropentane to trifluoroacetic anhydride is 1: (1.05-1.1): (1.1-1.2).

The step 1) of the method also comprises a post-treatment step after the reaction is finished, and the method specifically comprises the following steps: and pouring the reaction solution after the reaction is finished into ice water, extracting an organic phase by using dichloromethane, washing the obtained organic phase by using water and saturated saline solution in turn, drying the organic phase by using anhydrous magnesium sulfate, removing the solvent by rotary evaporation, and performing silica gel column chromatography to obtain the purified intermediate 1 shown in the formula II.

In step 2) of the above method, the reaction is performed in an organic solvent, and the organic solvent may be methanol.

The reaction is carried out under the reflux state, the reaction temperature of the reaction is 80-85 ℃, and the reaction time is 22-24 hours.

The base may specifically be NaOH. The molar ratio of the NaOH to the intermediate 1 shown in the formula II is 12-15. The NaOH can be added in two steps, wherein one part of the NaOH can be added in the form of a methanol solution (such as 1mol/L) of NaOH before the reaction starts; the other part is that NaOH solid is added into the re-reaction system after the reflux reaction is carried out for 10-12 hours (such as 12 hours).

The step 2) of the method also comprises a post-treatment step after the reaction is finished, and the method specifically comprises the following steps: cooling the reaction solution after the reaction to room temperature, washing with diethyl ether, adjusting the pH of the water phase to 2 with 1mol/L hydrochloric acid aqueous solution, extracting with diethyl ether, washing the organic phase with saturated saline solution, drying with anhydrous magnesium sulfate, removing the solvent by rotary evaporation, and recrystallizing with isopropanol to obtain the purified intermediate 2.

In step 3), the reaction conditions of the reaction are as follows: the reaction was stirred at room temperature for 10-12 hours.

The reaction is carried out in a solvent, in particular DMSO.

In the step 3), the molar ratio of the intermediate 2 shown in the formula III to the valine ethyl ester hydrochloride is 1: (1.05-1.1).

The base may be DIPEA.

The condensing agent can be at least one of EDC & HCl and HOBt.

The alkali is specifically DIPEA, the condensing agents are EDC & HCl and HOBt, and the molar ratios of the intermediate 2 shown in the formula III, DIPEA, EDC & HCl and HOBt are 1: (4.5-5.5): (2-2.2): (2-2.2).

The step 3) of the method further comprises a post-treatment step after the reaction is finished, and the method specifically comprises the following steps: quenching the reaction system after the reaction is finished by using saturated sodium bicarbonate aqueous solution, extracting an organic phase by using ethyl acetate, washing the organic phase by using water and saturated salt solution, drying the organic phase by using anhydrous sodium sulfate, removing the solvent by rotary evaporation, and recrystallizing the crude product by using silica gel column chromatography and isopropanol to obtain the purified 5F-EMB-PICA.

The product 5F-EMB-PICA prepared by the method has purity of more than 97 percent and total yield of 38.7 percent after column chromatography and recrystallization treatment. Can be used for developing a standard substance for detecting 5F-EMB-PICA.

Drawings

FIG. 1 is a flow diagram of a synthetic method of the present invention.

FIG. 2 is a COSY map of 5F-EMB-PICA.

FIG. 3 is an HMBC map of 5F-EMB-PICA.

FIG. 4 is an HSQC map of 5F-EMB-PICA.

FIG. 5 shows nuclear magnetic hydrogen spectrum of 5F-EMB-PICA.

FIG. 6 is a nuclear magnetic carbon spectrum of 5F-EMB-PICA.

FIG. 7 is a DEPT-135 map of 5F-EMB-PICA.

Detailed Description

The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified.

Example 1 Synthesis of 5F-EMB-PICA

The synthesis method of 5F-EMB-PICA provided by the embodiment comprises the following steps:

(1) to a suspension of NaH (0.96g) in dry DMF (40mL) was added indole (1.41g) slowly at 0 ℃ and stirred for 10 min. 1-bromo-5-fluoropentane (1.57mL) was added dropwise thereto, and the mixture was stirred for 1 hour. Trifluoroacetic anhydride (2.65g) was added dropwise thereto, and the mixture was stirred for 1 hour. The reaction solution was poured into 200mL of ice water, and the organic phase was extracted with dichloromethane, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and subjected to rotary evaporation to remove the solvent, followed by silica gel column chromatography to give intermediate 1 represented by formula II (3.45g, yield 95%).

(2) To a methanol solution of intermediate 1(3.45g) was added a methanol solution of NaOH (1mol/L,17.2mL), and the mixture was refluxed at 80 ℃ for 12 hours, followed by addition of NaOH solid (4.6g) and refluxing for 10 hours. The temperature is reduced to room temperature, the mixture is washed by ether, and the pH of the water phase is adjusted to 2 by 1mol/L hydrochloric acid aqueous solution. Extraction with ether and washing of the organic phase with saturated brine, drying over anhydrous magnesium sulfate, rotary evaporation to remove the solvent and recrystallization from isopropanol gave intermediate 2(1.95g, 68% yield).

(3) Intermediate 2(0.75g), valine ethyl ester hydrochloride (0.58g), EDC. HCl (1.16g), HOBt (0.81g) and DMSO (5mL) were added in this order to a reaction flask, and DIPET (25mL) was added dropwise and stirred for 10 hours. The reaction was quenched with saturated aqueous sodium bicarbonate, the organic phase was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the crude product was recrystallized from silica gel column chromatography and isopropanol to give the final product (0.675g, 60% yield).

The purity of the final product 5F-EMB-PICA is higher than 97 percent and the total yield is 38.7 percent by content measurement of liquid chromatogram normalization.

The structure is confirmed (the related maps are shown in figures 2-7), and the prepared compound is determined to be the target compound 5F-EMB-PICA.