Synthesis method of 2-(2-amino-5-bromobenzoyl) pyridine

Abstract

The invention discloses a synthesis method of 2-(2-amino-5-bromobenzoyl)pyridine. The method comprises the following processing steps: S1, reacting 4-bromo-2-bromomethylphenol, used as an initial rawmaterial, with MEMCl in an aprotic solvent to obtain 4-bromo-2-(bromomethyl)-1-((2-methoxyethoxy)methoxy)benzene; S2, reacting the 4-bromo-2-(bromomethyl)-1-((2-methoxyethoxy)methoxy)benzene with trimethyl borate under the action of a catalyst to prepare a boric acid compound (5-bromo-2-(((2-methoxyethoxy)methoxy)benzyl) boric acid; and S3, adding 2-bromopyridine and [1,1'-bis(diphenylphosphino)ferrocene]-palladium dichloride into the (5-bromo-2-(((2-methoxyethoxy)methoxy)benzyl)boric acid in order to prepare 2-(5-bromo-2-(((2-methoxyethoxy)methoxy)benzyl)pyridine. The method has the advantages of high atom utilization rate, environmental friendliness due to the recoverable solvent, high yield, convenience in operation, and suitableness for industrial production.

Description

technical field

[0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of 2-(2-amino-5-bromo-benzoyl)pyridine. Background technique

[0002] 2-(2-Amino-5-bromo-benzoyl)pyridine, the chemical formula is:

[0003]

[0004] 2-(2-Amino-5-bromo-benzoyl)pyridine is the key intermediate of ReMiMazolaM, an intravenous anesthetic drug.

[0005] Remimazolam is a short-acting GABAa receptor agonist developed by Paion Company in Germany, which is used for general anesthesia in surgery. This drug combines the safety of midazolam with the effectiveness of propofol (propofol)

[0006] For intravenous anesthesia of patients, the effect is better than propofol, and the indications can be extended to analgesia during microscopic examination, preoperative anesthesia and ICU sedation.

[0007] The currently reported synthesis method was first disclosed by the patent EP1183243:

[0008]

[0009] This procedure states t...

Examples

Embodiment 1

[0037] S1. Synthesis of compound 4-bromo-2-(bromomethyl)-1-((2-methoxyethoxy)methoxy)benzene

[0038] In a 3L three-necked flask, add 263.8g (1.0mol) of 4-bromo-2-bromomethylphenol and 202.4g (2.0mol) of acid-binding agent triethylamine into 1L of dichloromethane, keep at 25°C, and add dropwise MEMCl 149.5 g (1.2 mol). Keep stirring at 25° C. for 6 h after dropping, and HPLC detects that the reaction is complete. The reaction solution was filtered to remove salt, the organic phase was washed several times with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 352 g, with a yield of 99.4%.

[0039] S2. Synthesis of compound (5-bromo-2-(((2-methoxyethoxy)methoxy)benzyl)boronic acid

[0040] In a 3L three-necked flask, sequentially feed THF1L, Mg6.86g (0.28mol), triethylamine 85.6g (0.84mol), trimethyl borate 34.9g (0.34mol), after adding, keep room temperature, dropwise add 4- Bromo-2-(bromomethyl)-1-((2-methoxyethoxy)methoxy)benzene 100g (0.28...

Embodiment 2

[0050] Example 2: Synthesis of S1, compound 4-bromo-2-(bromomethyl)-1-((2-methoxyethoxy)methoxy)benzene

[0051] In a 3L three-necked flask, add 263.8g (1.0mol) of 4-bromo-2-bromomethylphenol and 138.2g (1.0mol) of potassium carbonate as an acid-binding agent into 1L of acetonitrile, keep at 25°C, and add 149.5g of MEMCl dropwise (1.2 mol). Keep stirring at 25° C. for 6 h after dropping, and HPLC detects that the reaction is complete. The reaction solution was filtered to remove salt, the organic phase was washed several times with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 350 g, with a yield of 98.8%.

[0052] S2. Synthesis of compound (5-bromo-2-(((2-methoxyethoxy)methoxy)benzyl)boronic acid

[0053] In a 3L three-necked flask, sequentially feed THF1L, Mg6.86g (0.28mol), triethylamine 85.6g (0.84mol), trimethyl borate 34.9g (0.34mol), after adding, keep room temperature, dropwise add 4- Bromo-2-(bromomethyl)-1-((2-methoxyethoxy)meth...

Embodiment 3

[0063] Example 3: Synthesis of S1, compound 4-bromo-2-(bromomethyl)-1-((2-methoxyethoxy)methoxy)benzene

[0064] In a 3L three-necked flask, 263.8g (1.0mol) of 4-bromo-2-bromomethylphenol and 202.4g (2.0mol) of acid-binding agent triethylamine were added to 1L of dimethylformamide and kept at 25°C. 149.5 g (1.2 mol) of MEMCl was added dropwise. Keep stirring at 25° C. for 6 h after dropping, and HPLC detects that the reaction is complete. The reaction solution was filtered to remove salt, the organic phase was washed several times with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 349 g, with a yield of 98.5%.

[0065] S2. Synthesis of compound (5-bromo-2-(((2-methoxyethoxy)methoxy)benzyl)boronic acid

[0066] In a 3L three-necked flask, sequentially feed THF1L, Mg6.86g (0.28mol), triethylamine 85.6g (0.84mol), trimethyl borate 34.9g (0.34mol), after adding, keep room temperature, dropwise add 4- Bromo-2-(bromomethyl)-1-((2-methoxyethoxy)...

technical field

[0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of 2-(2-amino-5-bromo-benzoyl)pyridine. Background technique

[0002] 2-(2-Amino-5-bromo-benzoyl)pyridine, the chemical formula is:

[0003]

[0004] 2-(2-Amino-5-bromo-benzoyl)pyridine is the key intermediate of ReMiMazolaM, an intravenous anesthetic drug.

[0005] Remimazolam is a short-acting GABAa receptor agonist developed by Paion Company in Germany, which is used for general anesthesia in surgery. This drug combines the safety of midazolam with the effectiveness of propofol (propofol)

[0006] For intravenous anesthesia of patients, the effect is better than propofol, and the indications can be extended to analgesia during microscopic examination, preoperative anesthesia and ICU sedation.

[0007] The currently reported synthesis method was first disclosed by the patent EP1183243:

[0008]

[0009] This procedure states t...

Examples

Embodiment 1

[0037] S1. Synthesis of compound 4-bromo-2-(bromomethyl)-1-((2-methoxyethoxy)methoxy)benzene

[0038] In a 3L three-necked flask, add 263.8g (1.0mol) of 4-bromo-2-bromomethylphenol and 202.4g (2.0mol) of acid-binding agent triethylamine into 1L of dichloromethane, keep at 25°C, and add dropwise MEMCl 149.5 g (1.2 mol). Keep stirring at 25° C. for 6 h after dropping, and HPLC detects that the reaction is complete. The reaction solution was filtered to remove salt, the organic phase was washed several times with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 352 g, with a yield of 99.4%.

[0039] S2. Synthesis of compound (5-bromo-2-(((2-methoxyethoxy)methoxy)benzyl)boronic acid

[0040] In a 3L three-necked flask, sequentially feed THF1L, Mg6.86g (0.28mol), triethylamine 85.6g (0.84mol), trimethyl borate 34.9g (0.34mol), after adding, keep room temperature, dropwise add 4- Bromo-2-(bromomethyl)-1-((2-methoxyethoxy)methoxy)benzene 100g (0.28...

Embodiment 2

[0050] Example 2: Synthesis of S1, compound 4-bromo-2-(bromomethyl)-1-((2-methoxyethoxy)methoxy)benzene

[0051] In a 3L three-necked flask, add 263.8g (1.0mol) of 4-bromo-2-bromomethylphenol and 138.2g (1.0mol) of potassium carbonate as an acid-binding agent into 1L of acetonitrile, keep at 25°C, and add 149.5g of MEMCl dropwise (1.2 mol). Keep stirring at 25° C. for 6 h after dropping, and HPLC detects that the reaction is complete. The reaction solution was filtered to remove salt, the organic phase was washed several times with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 350 g, with a yield of 98.8%.

[0052] S2. Synthesis of compound (5-bromo-2-(((2-methoxyethoxy)methoxy)benzyl)boronic acid

[0053] In a 3L three-necked flask, sequentially feed THF1L, Mg6.86g (0.28mol), triethylamine 85.6g (0.84mol), trimethyl borate 34.9g (0.34mol), after adding, keep room temperature, dropwise add 4- Bromo-2-(bromomethyl)-1-((2-methoxyethoxy)meth...

Embodiment 3

[0063] Example 3: Synthesis of S1, compound 4-bromo-2-(bromomethyl)-1-((2-methoxyethoxy)methoxy)benzene

[0064] In a 3L three-necked flask, 263.8g (1.0mol) of 4-bromo-2-bromomethylphenol and 202.4g (2.0mol) of acid-binding agent triethylamine were added to 1L of dimethylformamide and kept at 25°C. 149.5 g (1.2 mol) of MEMCl was added dropwise. Keep stirring at 25° C. for 6 h after dropping, and HPLC detects that the reaction is complete. The reaction solution was filtered to remove salt, the organic phase was washed several times with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 349 g, with a yield of 98.5%.

[0065] S2. Synthesis of compound (5-bromo-2-(((2-methoxyethoxy)methoxy)benzyl)boronic acid

[0066] In a 3L three-necked flask, sequentially feed THF1L, Mg6.86g (0.28mol), triethylamine 85.6g (0.84mol), trimethyl borate 34.9g (0.34mol), after adding, keep room temperature, dropwise add 4- Bromo-2-(bromomethyl)-1-((2-methoxyethoxy)...

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