CN114380704A - Synthetic method for preparing monobromoanilide compound - Google Patents

Abstract

The invention relates to the field of drug synthesis, and relates to a synthesis method for preparing monobromoanilines. Specifically, in a selected solvent and in the presence of a selected oxidizing agent, a substrate is reacted with a selected brominating agent to prepare the amino para-monobromoanilide compound. The reaction temperature range is-50 ℃ to 50 ℃. The substrates used were: brominating reagent: the range of the feeding ratio of the oxidant is 1: 0.2-2.0: 0.2 to 2.0. The reaction formula is as follows:

in the general formula of the reaction¹＝‑CH₃，‑C₂H₅，‑CH₂CH₂CH₃，‑CH(CH₃)₂；R²＝‑Br，R²At the 5-position of the benzene ring. The method has the advantages of simple and convenient operation, good selectivity, high yield and small pollution of the brominating reagent.

Description

Synthetic method for preparing monobromoanilide compound

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a synthetic method for preparing monobromoanilines.

Background

Bromoaniline (bromoanil)ine) is an important organic synthesis intermediate, and is widely applied to the fields of medicines, pesticides, materials and the like. In the prior art, a plurality of methods for preparing bromoaniline compounds are available, for example, CN107089919A mentions that zinc-aluminum hydrotalcite ZnAl-BrO intercalated with bromate₃Preparing bromoaniline compounds by taking LDHs and alkali metal bromide as bromine sources, thereby achieving high yield; patent pct.int.appl.2013007603, 17Jan 2013 mentions H₂O₂As an oxidizing agent; pct.int.appl.20200041562, 27Feb 2020 using bromosuccinimide (NBS) as the brominating agent gave a 71% monobromoanilide compound.

In the above synthetic methods, either the preparation of the bromine source is complicated, or the used oxide has explosion hazard, or the obtained target product has low yield, poor selectivity, serious pollution of the bromization reagent and the like. Therefore, it is necessary to find a synthetic method of the monobromoanilide compound which is green, environment-friendly, high in yield and high in selectivity.

Disclosure of Invention

The invention aims to provide a clean, safe and efficient method for synthesizing monobromoaniline, which is simple and convenient to operate, has good selectivity, high yield and small pollution of a bromization reagent.

The technical scheme for implementing the invention is as follows:

dissolving a substrate in a selected solvent, and reacting the substrate with a selected brominating reagent in the presence of a selected oxidizing agent to prepare the amino para-monobromoanilide compound.

The reaction formula is as follows:

in the general formula R¹＝-CH₃，-C₂H₅，-CH₂CH₂CH₃，-CH(CH₃)₂；R²＝-Br，R²At the 5-position of the benzene ring.

The reaction temperature range in the technical scheme is-50 ℃ to 50 ℃.

Further, the reaction temperature is preferably in the range of-30 ℃ to 30 ℃.

The solvent used in the technical scheme can be one of methanol, ethanol, tetrahydrofuran, ethyl acetate, dichloromethane, 1, 2-dichloroethane, chloroform, formic acid, acetic acid, propionic acid, hydrobromic acid and hydrochloric acid.

Further preferred solvents are methanol, ethanol, dichloromethane, 1, 2-dichloroethane, ethyl acetate, formic acid, acetic acid.

The brominating agent used in the technical scheme can be KBr, NaBr, CuBr and CuBr₂、PBr、PBr₃、PBr₅、HBr、Br₂One of bromosuccinimide (NBS), HBrO, NaBrO, KBrO and dibromohydantoin (DBDMH).

More preferably, the reagent is KBr, NaBr, CuBr₂、PBr、HBr、Br₂Bromosuccinimide (NBS).

The oxidant used in the said solution may be H₂O₂、HClO、HBrO、HIO、K₂S₂O₈、Na₂S₂O₈、 Na₂CO₃·1.5H₂O₂、KBO₃、NaBO₃·4H₂O、O₂、NaClO、KClO、Br₂、CrO₃、SeO₂One kind of (1).

Further preferred oxidizing agent is H₂O₂、HClO、HBrO、Na₂CO₃·1.5H₂O₂、KBO₃、NaBO₃·4H₂O、 O₂、NaClO。

The substrates used in the described protocol: brominating reagent: the range of the feeding ratio of the oxidant is 1: 0.2-2.0: 0.2 to 2.0.

Further preferred substrates are: brominating reagent: the feeding ratio of the oxidant is 1: 0.5-1.5: 0.5 to 1.5.

The method has the advantages of simple and convenient operation, good selectivity, high yield and small pollution of the brominating reagent.

Detailed Description

The invention will be further illustrated with reference to specific embodiments, but the scope of protection of the invention is not limited thereto:

the first embodiment is as follows:

in a 100mL three-necked round-bottomed flask, 45g of methanol, 5g of methyl anthranilate and 4.87g of sodium bromide were sequentially added, the temperature was adjusted to 25 ℃, 7.23g of sodium perborate tetrahydrate was added in 4 batches, and the progress of the reaction was monitored by a liquid phase. After the reaction is completed, 30g of ice water is added to quench the reaction, 20g of 1, 2-dichloroethane is added to stir for 20min, and standing and layering are carried out. The organic phase was washed twice with 10g of water, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure in vacuo to give 7.4g of a yellow solid, 97.5% yield of the target product and 93.0% purity (HPLC).

Example one the main product obtained, methyl 5-bromo-2-aminobenzoate, had the following nuclear magnetic and mass spectral data:¹H NMR (400MHz,CDCl₃)δ7.97(d,J＝2.4Hz,1H),7.32(dd,J＝8.8,2.4Hz,1H),6.56(d,J ＝8.8Hz,1H),5.75(s,2H),3.87(s,3H).¹³C NMR(101MHz,CDCl₃) Delta 167.52,149.32, 136.77,133.44,118.38,112.05,107.36,51.81 high resolution mass spectrum HRMS (ESI) [ M + H ]]⁺Ideal value 229.9809, found value (229.9811).

Example two

In a 100ml three-necked round-bottomed flask, 35g of formic acid, 10.92g of ethyl anthranilate, and 8.10g of sodium bromide were sequentially added, the system was left at 15 ℃, 9.15g of sodium percarbonate was added in 4 batches, and the progress of the reaction was checked by liquid phase. After the reaction is completed, 60g of crushed ice is added to quench the reaction, 36g of dichloromethane is added to stir for 20min, and the mixture is kept stand and layered. The organic phase was washed twice with 20g of water, dried over anhydrous magnesium sulfate and the solvent was removed under vacuum and reduced pressure to give 15.21g of a yellow solid, 94.6% yield of the target product and 96.6% purity (HPLC).

EXAMPLE III

35g of ethanol, 10g of propyl anthranilate and 9.24g of potassium bromide are sequentially added into a 100ml three-neck round-bottom flask, the system is placed at 20 ℃, 9.15g of sodium percarbonate is added at a time, and the reaction progress is detected in a liquid phase. After the reaction is completed, 60g of crushed ice is added to quench the reaction, 36g of dichloromethane is added to stir for 20min, and the mixture is kept stand and layered. The organic phase was washed twice with 20g of water, dried over anhydrous magnesium sulfate and the solvent was removed under vacuum and reduced pressure to give 13.50g of a yellow solid, 94.0% yield of the target product and 96.8% purity (HPLC).

Example four

Into a 100ml three-necked round-bottomed flask, 30g of methylene chloride, 10g of methyl anthranilate, and 13.77g of methanol were sequentially charged

Cuprous bromide, the system is placed at 15 ℃, 9.15g of sodium perborate tetrahydrate is added in 4 batches, and the reaction process is detected in a liquid phase. After the reaction is completed, 60g of crushed ice is added to quench the reaction, 30g of dichloromethane is added to stir for 20min, and the mixture is kept stand and layered. The organic phase was washed twice with 20g of water, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure in vacuo to give 15.47g of a yellow solid, the yield of the target product was 96.0% and the purity was 96.2% (HPLC).

EXAMPLE five

15g of 1, 2-dichloroethane, 5g of methyl anthranilate and 6.59 g of bromosuccinimide (NBS) are sequentially added into a 100ml three-neck round-bottom flask, the system is placed at 5 ℃, 8.56g of sodium perborate tetrahydrate is added at a time, and the reaction progress is detected in a liquid phase. After the reaction is completed, 30g of crushed ice is added to quench the reaction, 30g of 1, 2-dichloroethane is added to stir for 20min, and the mixture is kept stand for layering. The organic phase was washed with 10g of water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure in vacuo to give 3.59g of a yellow solid, the yield of the desired product was 96.8%, and the purity was 96.4% (HPLC).

Comparative examples

In a 100mL single neck round bottom flask was added 27.47g of 1, 2-dichloroethane and 6.87g of bromine, and the system was left at-5 ℃ to stir the dispersed mass. And (3) adding 20g of 1, 2-dichloroethane and 5g of methyl anthranilate into another 100mL three-neck round-bottom flask, slowly dropwise adding a 1, 2-dichloroethane solution of bromine at a constant speed after the temperature is constant to be minus 5 ℃, preserving the temperature for reaction after the dropwise adding is finished, and carrying out liquid phase tracking reaction. After the reaction is completed, the temperature is reduced to about 10 ℃, suction filtration is carried out, a small amount of 1, 2-dichloroethane (about 10 ℃) is used for leaching, dibromo-matter and tar matter are removed, and the reaction product is placed in a vacuum drying oven at 60 ℃ for drying. The product obtained is a yellow solid, melting point 67-68 ℃, overall yield of the target product 78.4% and purity 98% (HPLC).

Claims (6)

1. A synthetic method for preparing monobromoanilide compounds is characterized by comprising the following steps: dissolving a substrate in a selected solvent, and reacting with a selected brominating reagent at-50 ℃ in the presence of a selected oxidant to prepare the bromoaniline compound.

The reaction formula is as follows:

in the general formula of the reaction¹＝-CH₃，-C₂H₅，-CH₂CH₂CH₃，-CH(CH₃)₂；R²＝-Br，R²At the 5-position of the benzene ring.

2. A method of synthesis according to claim 1, characterized in that: the solvent can be one of methanol, ethanol, tetrahydrofuran, ethyl acetate, dichloromethane, 1, 2-dichloroethane, chloroform, formic acid, acetic acid, propionic acid, hydrobromic acid and hydrochloric acid. Among the preferred solvents are methanol, ethanol, dichloromethane, 1, 2-dichloroethane, ethyl acetate, formic acid, acetic acid.

3. A method of synthesis according to claim 1, characterized in that: the brominating reagent can be KBr, NaBr, CuBr₂、PBr、PBr₃、PBr₅、HBr、Br₂One of bromosuccinimide (NBS), HBrO, NaBrO, KBrO and dibromohydantoin (DBDMH). Preferred reagents are KBr, NaBr, CuBr₂、PBr、、HBr、Br₂Bromosuccinimide (NBS).

4. A method of synthesis according to claim 1, characterized in that: the oxidant may be H₂O₂、HClO、HBrO、HIO、K₂S₂O₈、Na₂S₂O₈、Na₂CO₃·1.5H₂O₂、KBO₃、NaBO₃·4H₂O、O₂、NaClO、KClO、Br₂、CrO₃、SeO₂One kind of (1). The preferred oxidizing agent is H₂O₂、HClO、HBrO、Na₂CO₃·1.5H₂O₂、KBO₃、NaBO₃·4H₂O、O₂、NaClO。

5. A method of synthesis according to claim 1, characterized in that: the reaction temperature range is-50 ℃ to 50 ℃. The preferred reaction temperature range is-30 ℃ to 30 ℃.

6. A method of synthesis according to claim 1, characterized in that: the substrate is: bromide: the range of the feeding ratio of the oxidant is 1: 0.2-2.0: 0.2 to 2.0. The preferable range of the feed ratio is 1: 0.5-1.5: 0.5 to 1.5.