阅读说明：本技术 一种2-[3’-(N-Boc-吡咯基)]-苯甲酸的合成方法 (Synthetic method of 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid ) 是由 汤艳峰 王纯 李建华 施磊 张海军 王敏敏 王金 邹逢霞 刘维群 张梦珂 沈璐婕 于 2019-09-02 设计创作，主要内容包括：本发明属于有机合成领域,公开了一种2-[3’-(N-Boc-吡咯基)]-苯甲酸的合成方法。本发明合成方法包括以2-溴苯甲醛为原料,经取代反应、加成反应、关环反应、还原反应、活泼氢保护、氰化反应、水解反应等七步反应合成了2-[3’-(N-Boc-吡咯基)]-苯甲酸,反应条件温和、合成方法收率高,适合大批量工业化生产。(the invention belongs to the field of organic synthesis, and discloses a method for synthesizing 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid. The synthetic method comprises the step of taking 2-bromobenzaldehyde as a raw material, and synthesizing the 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid through seven steps of reactions such as substitution reaction, addition reaction, ring closing reaction, reduction reaction, active hydrogen protection, cyanidation reaction, hydrolysis reaction and the like, and the synthetic method has the advantages of mild reaction conditions, high yield and suitability for large-scale industrial production.)

1. a method for synthesizing 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid, which is characterized by comprising the following steps:

1) Dissolving sodium hydride in a tetrahydrofuran solution, controlling the temperature to be-5-10 ℃ under the protection of nitrogen, dropwise adding triethyl phosphorylphenylacetate to react for 0.5-1 h, and then adding 2-bromobenzaldehyde to continue reacting until the reaction is complete to obtain a compound 2;

2) dissolving a compound 2 and nitromethane in a tetrahydrofuran solution, adding 1, 8-diazabicycloundecen-7-ene, and reacting at the temperature of 90-110 ℃ until the reaction is complete to obtain a compound 3;

3) Dissolving the compound 3 in a methanol solution, adding ammonium chloride and zinc, heating to 70-100 ℃, and reacting completely to obtain a compound 4;

4) Dissolving the compound 4 in a tetrahydrofuran solution, cooling to-5-10 ℃ under the protection of nitrogen, dropwise adding the tetrahydrofuran solution containing sodium borohydride, and heating for reflux reaction to obtain a compound 5;

5) dissolving the compound 5 in water, adding di-tert-butyl dicarbonate, adjusting the pH to 8-10 by using alkali, and heating and refluxing for reaction until the reaction is complete to obtain a compound 6;

6) Adding the compound 6, zinc cyanide and tetrakis (triphenylphosphine) palladium into an N, N-dimethylformamide solution, heating to 80-115 ℃ under the protection of nitrogen for reaction, and obtaining a compound 7 after the reaction is completed;

7) Dissolving the compound 7 in an ethanol solution, adding inorganic base and water, heating and refluxing for reaction, and obtaining a compound 8, namely 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid after the reaction is completed;

2. the method for synthesizing 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid of claim 1, wherein: in the step 1), the molar ratio of the sodium hydride to the triethyl phosphorylphenylacetate to the 2-bromobenzaldehyde is 1 (1-1.3) to 1-1.3.

3. The method for synthesizing 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid of claim 1, wherein: the reaction time in the step 2) is 12-18 h, and the molar ratio of the compound 2, nitromethane and 1, 8-diazabicycloundecen-7-ene is 1: (4-5): 0.16.

4. the method for synthesizing 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid of claim 1, wherein: the reaction time in the step 3) is 12-18 h, and the molar ratio of the compound 3 to ammonium chloride to zinc is 1: (4-4.3): 5.

5. the method for synthesizing 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid of claim 1, wherein: the heating reflux reaction in the step 4) is carried out at the temperature of 50-80 ℃ for 12-18 h, and the molar ratio of the compound 4 to sodium borohydride is 1: (2-2.3).

6. The method for synthesizing 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid of claim 1, wherein: in the step 5), the temperature of the heating reflux reaction is 60-100 ℃, the reaction time is 0.5-1 h, and the molar ratio of the compound 5 to the di-tert-butyl dicarbonate is 1: (1-1.3).

7. the method for synthesizing 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid of claim 1, wherein: in the step 5), the alkali is sodium hydroxide or potassium hydroxide.

8. The method for synthesizing 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid of claim 1, wherein: the reaction time in the step 6) is 5-6 h, and the molar ratio of the compound 6, zinc cyanide and tetrakis (triphenylphosphine) palladium is 1: (0.6-0.7): 0.03.

9. The method for synthesizing 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid of claim 1, wherein: and 7) the inorganic base is one of potassium hydroxide, sodium hydroxide and potassium carbonate.

10. the method for synthesizing 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid of claim 1, wherein: in the step 7), the temperature of the heating reflux reaction is 70-90 ℃, the reaction time is 72-84 h, and the molar ratio of the compound 7 to the inorganic base is 1: (5-5.3).

Technical Field

the invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid.

background

Macromolecular compounds containing pyrrole rings are widely applied to the fields of medicines, biology, foods and the like, and various pyrrole monocyclic compounds containing substituent groups play a very important role in the fields, so that the research on a synthesis method of pyrrole derivatives is the focus of the attention of researchers whether the pyrrole monocyclic compounds are used as intermediates or the pyrrole monocyclic compounds. In addition, with the further improvement of natural product performance, the preparation of polypyrrole compounds, etc., which simulate the activity of natural products, is in continuous need of people to synthesize various pyrrole derivatives, and the industrialization of the pyrrole derivatives is also the direction of efforts of the broad masses of synthesizers. Therefore, with the continuous and deep research on the synthesis of various pyrrole derivatives, the forward development of natural product chemistry, material chemistry, pharmaceutical chemistry, energy technology and the like is certainly promoted, and meanwhile, the content of an organic synthesis methodology is also continuously enriched. The synthesis of pyrazole derivatives is therefore of great importance.

2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid is an important cardiovascular medicine intermediate as a pyrazole derivative, so that the compound has important practical significance for the synthesis research of the compound.

Disclosure of Invention

In view of the above, the present invention aims to provide a method for synthesizing 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid, wherein the method provided by the present invention has the advantages of high yield and purity of the obtained product, mild reaction conditions, and easy industrialization.

the invention provides a synthetic method of 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid, which comprises the following steps:

1) dissolving sodium hydride in a tetrahydrofuran solution, controlling the temperature to be-5-10 ℃ under the protection of nitrogen, dropwise adding triethyl phosphorylphenylacetate to react for 0.5-1 h, and then adding 2-bromobenzaldehyde to continue reacting until the reaction is complete to obtain a compound 2;

2) dissolving a compound 2 and nitromethane in a tetrahydrofuran solution, adding 1, 8-diazabicycloundecen-7-ene, and reacting at the temperature of 90-110 ℃ until the reaction is complete to obtain a compound 3;

3) Dissolving the compound 3 in a methanol solution, adding ammonium chloride and zinc, heating to 70-100 ℃, and reacting completely to obtain a compound 4;

4) Dissolving the compound 4 in a tetrahydrofuran solution, cooling to-5-10 ℃ under the protection of nitrogen, dropwise adding the tetrahydrofuran solution containing sodium borohydride, and heating for reflux reaction to obtain a compound 5;

5) dissolving the compound 5 in water, adding di-tert-butyl dicarbonate, adjusting the pH to 8-10 by using alkali, and heating and refluxing for reaction until the reaction is complete to obtain a compound 6;

6) Adding the compound 6, zinc cyanide and tetrakis (triphenylphosphine) palladium into an N, N-dimethylformamide solution, heating to 80-115 ℃ under the protection of nitrogen for reaction, and obtaining a compound 7 after the reaction is completed;

7) dissolving the compound 7 in an ethanol solution, adding inorganic base and water, heating and refluxing for reaction, and obtaining a compound 8, namely 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid after the reaction is completed;

preferably, the molar ratio of the sodium hydride, the triethyl phosphorylphenylacetate and the 2-bromobenzaldehyde in the step 1) is 1 (1-1.3) to 1-1.3.

preferably, the reaction time in the step 2) is 12-18 h, and the molar ratio of the compound 2, nitromethane and 1, 8-diazabicycloundecen-7-ene is 1: (4-5): 0.16.

preferably, the reaction time in the step 3) is 12-18 h, and the molar ratio of the compound 3 to the ammonium chloride to the zinc is 1: (4-4.3): 5.

Preferably, the temperature of the heating reflux reaction in the step 4) is 50-80 ℃, the reaction time is 12-18 h, and the molar ratio of the compound 4 to the sodium borohydride is 1: (2-2.3).

Preferably, the temperature of the heating reflux reaction in the step 5) is 60-100 ℃, the reaction time is 0.5-1 h, and the molar ratio of the compound 5 to the di-tert-butyl dicarbonate is 1: (1-1.3).

Preferably, the base in step 5) is sodium hydroxide or potassium hydroxide.

preferably, the reaction time in the step 6) is 5-6 h, and the molar ratio of the compound 6, zinc cyanide and tetrakis (triphenylphosphine) palladium is 1: (0.6-0.7): 0.03.

Preferably, the inorganic base in step 7) is one of potassium hydroxide, sodium hydroxide and potassium carbonate.

Preferably, the temperature of the heating reflux reaction in the step 7) is 70-90 ℃, the reaction time is 72-84 h, and the molar ratio of the compound 7 to the inorganic base is 1: (5-5.3).

compared with the prior art, the synthesis method of the 2- [3 '- (N-Boc-pyrrolyl) ] -benzoic acid is provided, the 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid is synthesized by taking 2-bromobenzaldehyde as a raw material through seven-step reaction, the reaction condition is easy to control, the method is suitable for industrial production, and the yield of the obtained product is high.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid prepared in example 1 of the present invention.

Detailed Description

For a further understanding of the invention, reference will now be made to the preferred embodiments of the invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the invention, and not to limit the scope of the claims.

All of the starting materials of the present invention, without particular limitation as to their source, may be purchased commercially or prepared according to conventional methods well known to those skilled in the art.

All the raw materials of the present invention are not particularly limited in their purity, and analytical purification is preferably employed in the present invention.

The invention provides a synthetic method of 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid, which comprises the following steps:

1) And (3) substitution reaction: dissolving sodium hydride in a tetrahydrofuran solution, controlling the temperature to be-5-10 ℃ under the protection of nitrogen, dropwise adding triethyl phosphorylphenylacetate to react for 0.5-1 h, and then adding 2-bromobenzaldehyde to continue reacting until the reaction is complete to obtain a compound 2;

2) addition reaction: dissolving a compound 2 and nitromethane in a tetrahydrofuran solution, adding 1, 8-diazabicycloundecen-7-ene, and reacting at the temperature of 90-110 ℃ until the reaction is complete to obtain a compound 3;

3) ring closing reaction: dissolving the compound 3 in a methanol solution, adding ammonium chloride and zinc, heating to 70-100 ℃, and reacting completely to obtain a compound 4;

4) Reduction reaction: dissolving the compound 4 in a tetrahydrofuran solution, cooling to-5-10 ℃ under the protection of nitrogen, dropwise adding the tetrahydrofuran solution containing sodium borohydride, and heating and refluxing to react completely to obtain a compound 5;

5) protection of active hydrogen: dissolving the compound 5 in water, adding di-tert-butyl dicarbonate, adjusting the pH to 8-10 with alkali, and carrying out heating reflux reaction to obtain a compound 6;

6) cyanidation reaction: adding the compound 6, zinc cyanide and tetrakis (triphenylphosphine) palladium into an N, N-dimethylformamide solution, heating to 80-115 ℃ under the protection of nitrogen for reaction, and obtaining a compound 7 after the reaction is completed;

7) And (3) hydrolysis reaction: dissolving the compound 7 in an ethanol solution, adding inorganic base and water, heating and refluxing for reaction, and obtaining a compound 8 after the reaction is completed;

the invention provides a synthesis method of 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid, which comprises the following specific synthetic route:

After dissolving sodium hydride in a tetrahydrofuran solution, under the protection of nitrogen, controlling the temperature to be-5-10 ℃, dropwise adding triethyl phosphorylphenylacetate to react for 0.5-1 h, then adding 2-bromobenzaldehyde to continue reacting until the reaction is complete, then analyzing the raw materials by thin-layer chromatography to react completely, dropwise adding an ammonium chloride solution, extracting methyl tert-butyl ether (2X 1L), combining the methyl tert-butyl ether, washing with saturated salt water, concentrating and drying to obtain (E) -3- (2-bromophenyl) ethyl acrylate solid (compound 2); the molar ratio of the sodium hydride to the triethyl phosphorylphenylacetate to the 2-bromobenzaldehyde is preferably 1 (1-1.3) to 1-1.3. In the present invention, the time for continuing the reaction after adding 2-bromobenzaldehyde is preferably 0.5 h. .

After obtaining an (E) -3- (2-bromophenyl) ethyl acrylate solid (compound 2), dissolving the (E) -3- (2-bromophenyl) ethyl acrylate solid (compound 2) and nitromethane in a tetrahydrofuran solution, adding 1, 8-diazabicycloundecen-7-ene into the tetrahydrofuran solution to react at the temperature of 90-110 ℃ until the reaction is complete, analyzing the raw materials by thin layer chromatography to react completely, concentrating the reaction product to dryness, cooling the reaction product by methyl tert-butyl ether, washing the reaction product by using diluted hydrochloric acid, drying the reaction product, and performing column chromatography (PE: EA is 5:1) to obtain a 4-amino-3- (2-bromophenyl) ethyl butyrate solid (compound 3); in the invention, the reaction time is preferably 12-18 h, and the molar ratio of the compound 2, nitromethane and 1, 8-diazabicycloundecen-7-ene is preferably 1: (4-5): 0.16.

After 4-amino-3- (2-bromophenyl) ethyl butyrate solid (compound 3) is obtained, dissolving the 4-amino-3- (2-bromophenyl) ethyl butyrate solid (compound 3) in a methanol solution, adding ammonium chloride and zinc, heating to 70-100 ℃, reacting until the reaction is complete, analyzing raw materials by thin layer chromatography, completely reacting, cooling, filtering, leaching the filtered solid twice with methanol, evaporating to remove redundant methanol, adding water, adjusting the pH value to 5-6 with hydrochloric acid, extracting with dichloromethane (2X 1L), combining organic phases, drying with anhydrous sodium sulfate, concentrating, adding methyl tert-butyl ether, and filtering to obtain 4- (2-bromophenyl) pyrrolidine-2-one solid (compound 4); in the invention, the reaction time is preferably 12-18 h, and the molar ratio of the 4-amino-3- (2-bromophenyl) ethyl butyrate solid (compound 3), the ammonium chloride and the zinc is preferably 1: (4-4.3): 5.

After 4- (2-bromophenyl) pyrrolidine-2-ketone solid (compound 4) is obtained, dissolving the 4- (2-bromophenyl) pyrrolidine-2-ketone solid (compound 4) in tetrahydrofuran solution, cooling to-5-10 ℃ under the protection of nitrogen, dropwise adding the tetrahydrofuran solution containing sodium borohydride, heating until reflux continues to react completely, analyzing raw materials by thin-layer chromatography, completely reacting, cooling to-5-10 ℃, dropwise adding a hydrochloric acid methanol solution, concentrating and drying to obtain 3- (2-bromophenyl) pyrrolidine solid (compound 5); in the invention, the reaction temperature is preferably 50-80 ℃, the reaction time is preferably 12-18 h, and the molar ratio of the 4- (2-bromophenyl) pyrrolidine-2-one solid (compound 4) to sodium borohydride is preferably 1: (2-2.3).

After 3- (2-bromophenyl) pyrrolidine solid (compound 5) is obtained, dissolving the 3- (2-bromophenyl) pyrrolidine solid (compound 5) in water, adding di-tert-butyl dicarbonate, adjusting the pH value to 8-10 with alkali, heating to a reflux state, reacting until the reaction is complete, analyzing raw materials by thin layer chromatography, reacting the raw materials completely, extracting reaction liquid with methyl tert-butyl ether, washing with water, washing with dilute hydrochloric acid, and drying to obtain 3- (2-bromophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester solid (compound 6); in the invention, the reaction temperature is preferably 60-100 ℃, the reaction time is preferably 0.5-1 h, and the molar ratio of the compound 5 to the di-tert-butyl dicarbonate is preferably 1: (1-1.3). The base in the present invention is preferably selected from sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide.

after a 3- (2-bromophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester solid (compound 6) is obtained, adding the 3- (2-bromophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester solid (compound 6), zinc cyanide and tetrakis (triphenylphosphine) palladium into an N, N-dimethylformamide solution, heating to 80-115 ℃ under the protection of nitrogen to react, analyzing the reaction of raw materials by thin layer chromatography, pouring the raw materials into water, extracting (3X 1L) by using methyl tert-butyl ether, combining the methyl tert-butyl ether, washing by using an ammonium chloride solution, concentrating to dryness, and obtaining the 3- (2-cyanophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester solid (compound 7) by column chromatography (PE: EA is 5: 1); the reaction temperature is preferably 80-115 ℃, the reaction time is preferably 5-6 h, and the molar ratio of the compound 6, the zinc cyanide and the tetrakis (triphenylphosphine) palladium is preferably 1: (0.6-0.7): 0.03.

After obtaining 3- (2-cyanophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester solid (compound 7), dissolving the 3- (2-cyanophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester solid (compound 7) in an ethanol solution, adding inorganic base and water, heating to a reflux state for reaction, analyzing the reaction of raw materials by thin layer chromatography, evaporating excessive ethanol, adjusting the pH value to 10 by hydrochloric acid, extracting dichloromethane (3 x 500ml), combining dichloromethane, concentrating and drying to obtain 2- [ 3' - (N-Boc-pyrrolyl) ] -benzoic acid solid (compound 8); in the invention, the reaction temperature is preferably 70-90 ℃, the reaction time is preferably 72-84 h, and the molar ratio of the 3- (2-cyanophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester solid (compound 7) to the inorganic base is preferably 1: (5-5.3); in the present invention, the inorganic base is preferably one of potassium hydroxide, sodium hydroxide and potassium carbonate.

for the sake of clarity, the following examples are given in detail.