Preparation method of 5-(5-bromopyridine) tetrazole
By changing the nitriding reagent and reaction conditions, 3-bromopyridine-N-oxide reacts with tert-butyldiphenylcyanosilane and organic base, and then using catalysts such as sodium azide to prepare 5-(5-bromopyridine) tetrakis Azole solves the problems of long steps and low selectivity in the prior art, and realizes an efficient and simplified preparation process.
Patent Information
- Application Number
- CN202411320757.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-23
- Publication Date
- 2025-01-03
AI Technical Summary
The existing preparation method of 5-(5-bromopyridine) tetraazole has problems such as long steps, slow reaction rate and low selectivity, especially in the preparation process of 5-bromo-2-cyanopyridine, which is complicated to operate and react. The route is long.
5-bromopyridine-N-oxide reacted with tert-butyldiphenylcyanosilane under the action of organic base to obtain 5-bromo-2-cyanosilane, and sodium azide, Lewis acid and ammonium chloride were used as catalysts Further reaction was carried out to prepare 5-(5-bromopyridine)tetraazole, and the selectivity was improved by changing the nitriding reagent and reaction conditions.
The preparation method of 5-(5-bromopyridine) tetraazole with simple operation, short steps and high yield is realized, which improves the selectivity of the target product and simplifies the process flow.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing 5-(5-bromopyridine)tetrazole, an intermediate of tedizolid phosphate. Background Art
[0002] Tetrazolium compounds are an important class of five-membered heterocyclic compounds that exhibit excellent anti-inflammatory, bactericidal, and anti-allergic properties. They are widely used in antifungal and hypoglycemic applications. Currently, a large number of bioactive small molecule drugs containing substituted tetrazole structural fragments are under development. 5-(5-Bromopyridinium)tetrazolium is an important intermediate for oxazolidinone antibacterial drugs and is in widespread demand. 5-(5-Bromopyridinium)tetrazolium is a key intermediate for tedizolid phosphate, a novel oxazolidinone antibiotic developed by Cubist Pharmaceuticals for the treatment of acute bacterial skin structure infections. Its mechanism of action differs from other antibiotics and does not cause cross-resistance with other antibiotics. It was approved for marketing in 2014.
[0003] The preparation method of 5-(5-bromopyridinium)tetrazole currently relies primarily on the classic method of producing tetrazole from a cyano group and sodium azide. This reaction typically uses DMF or DMSO as the reaction solvent, zinc chloride, zinc bromide, and other Lewis acids, and ammonium chloride and zeolite as catalysts. The literature [European Journal of Organic Chemistry, 2016, 2016, 1305-1313] reports a reaction using 5-bromo-2-cyanopyridine as the raw material, DMF as the reaction solvent, and an equivalent amount of ammonium chloride as the catalyst, with 1.2 equivalents of sodium azide at 120°C for 1 hour, resulting in an 84% yield. However, the actual reaction time is relatively long. The reaction scheme is as follows:
[0004]
[0005] However, there are many methods for preparing the intermediate 5-bromo-2-cyanopyridine:
[0006] A. The literature [Organic Letters, 2004, 6, 4905-4907] reports that 5-bromo-2-cyanopyridine is prepared by using 2,5-dibromopyridine as the raw material, iodination with sodium iodide in the presence of acetyl chloride, followed by Grignard reagent exchange and TosCN substitution. This method has a long route and complex operation. The reaction route is as follows:
[0007]
[0008] B. The literature [European Journal of Medicinal Chemistry, 2011, 46, 1027-1039] reports that 5-bromo-2-cyanopyridine is prepared by reacting 2,5-dibromopyridine as a raw material with DMF as a reaction solvent with cuprous cyanide and sodium cyanide at 150°C. This route uses highly toxic substances such as sodium cyanide and cuprous cyanide. The reaction route is as follows:
[0009]
[0010] C. The literature [Organic Letters, 2022, vol. 24, 6341-6345] reported that 5-bromo-2-methylpyridine was prepared by reacting 5-bromo-2-methylpyridine as raw material with 1,4-dioxane as solvent, acetyl chloride and sodium nitrite under pressure stewing at 140°C. The reaction route is as follows:
[0011]
[0012] D. The literature [Chemical and Pharmaceutical Bulletin, 1985, 33, 565-571] reports the preparation of 5-bromo-2-cyanopyridine using 3-bromopyridine-N-oxide as the starting material and acetonitrile as the solvent, reacting with trimethylsilyl cyanide in the presence of triethylamine. However, the reaction exhibits poor selectivity, only 9%. The reaction scheme is as follows:
[0013]
[0014] In view of the above problems, it is necessary to provide a new process with simple operation to avoid the problems of long steps, slow reaction rate, low selectivity and the like in traditional processes. Summary of the Invention
[0015] To overcome the above technical deficiencies, the present invention discloses a method for preparing 5-(5-bromopyridinium)tetrazole, comprising the following steps: 1) reacting 3-bromopyridine-N-oxide with tert-butyldiphenylsilylcyanide in the presence of an organic base to obtain 5-bromo-2-cyanopyridine; and 2) reacting 5-bromo-2-cyanopyridine with sodium azide in the presence of a Lewis acid and ammonium chloride catalyst to obtain 5-(5-bromopyridinium)tetrazole. The preparation method disclosed in the present invention is easy to implement, simple to operate, short in steps, and high in yield.
[0016] The preparation method of 5-(5-bromopyridine) tetrazole of the present invention comprises the following steps:
[0017]
[0018] 1) 3-bromopyridine-N-oxide is mixed with an organic solvent, tert-butyldiphenylsilylcyanide and a catalyst are added in sequence, an organic base is added dropwise, and the temperature is then raised to react, and 5-bromo-2-cyanopyridine is obtained through post-treatment;
[0019] 2) 5-bromo-2-cyanopyridine, Lewis acid and an organic solvent are mixed, sodium azide and ammonium chloride are added in sequence, the temperature is raised to react, and 5-(5-bromopyridine)tetrazole is obtained through post-treatment.
[0020] Furthermore, in the above technical solution, in step 1), the organic solvent is selected from acetonitrile or 1,2-dichloroethane, preferably 1,2-dichloroethane.
[0021] Furthermore, in the above technical solution, in step 1), the catalyst is selected from triethylenediamine, and the organic base is selected from triethylamine or N,N-diisopropylethylamine.
[0022] Furthermore, in the above technical solution, in step 1), the molar ratio of the 3-bromopyridine-N-oxide, tert-butyldiphenylsilylcyanide, catalyst and organic base is 1:1.2-1.25:0.08-0.10:1.50-1.60.
[0023] Furthermore, in the above technical solution, in step 1), the post-processing purification adopts a reduced pressure distillation method, wherein the distillation temperature is 98-108° C. and the vacuum degree is 1.1-2.0 mmHg.
[0024] Furthermore, in the above technical solution, in step 2), the organic solvent is selected from DMF / THF or DMSO / THF mixed solvent, preferably DMSO / THF mixed solvent, wherein DMF needs to be cooled and vacuumed before use to remove trace amounts of dimethylamine.
[0025] Furthermore, in the above technical solution, in step 2), the Lewis acid is selected from triphenylborane.
[0026] Furthermore, in the above technical solution, in step 2), the molar ratio of 5-bromo-2-cyanopyridine, Lewis acid and sodium azide is 1:0.10-0.15:1.10.
[0027] Furthermore, in the above technical solution, in step 1), the post-processing purification adopts ethanol-water recrystallization, wherein the volume ratio of ethanol to water is 2:1.
[0028] The preparation method disclosed by the invention improves the selectivity of the target product by changing the nitrilation reagent and the reaction conditions. The synthesis method is easy to implement, simple to operate, short in steps and high in yield. DETAILED DESCRIPTION
[0029] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.
[0030] Example 1 Preparation of 5-bromo-2-cyanopyridine
[0031]
[0032] 3-Bromopyridine-N-oxide (34.8 g, 0.2 mol) was added to 280 mL of acetonitrile, followed by tert-butyldiphenylsilylcyanide (63.7 g, 0.24 mol, 1.2 eq) and DABCO (2.2 g, 0.02 mol, 0.1 eq). Triethylamine (30.4 g, 0.3 mol, 1.5 eq) was then added dropwise. Under nitrogen, the temperature was raised to 65-70°C and the reaction was allowed to proceed for 6 h. The reaction was stopped, and TLC analysis confirmed complete reaction of the starting material. The reaction solution was cooled to room temperature and poured into 300 mL of water. Extraction was performed with DCM (3 x 100 mL). The organic phase was washed with 100 mL of 5% hydrochloric acid and twice with water (200 mL x 2). The solvent was evaporated from the organic phase, and the main fraction was then distilled under reduced pressure to obtain 31.1 g of a white solid after cooling. The yield was 85.1%. HPLC analysis showed 99.6%. 1 H NMR (400MHz, CDCl3): 8.77 (s, 1H), 7.97 (dd, 1H), 7.59 (dd, 1H).
[0033] Example 2 Preparation of 5-bromo-2-cyanopyridine
[0034]
[0035] 3-Bromopyridine-N-oxide (34.8 g, 0.2 mol) was added to 350 mL of 1,2-dichloroethane. Tert-butyldiphenylsilylcyanide (63.7 g, 0.24 mol, 1.2 eq) and DABCO (2.2 g, 0.02 mol, 0.1 eq) were then added dropwise. DIPEA (41.4 g, 0.32 mol, 1.6 eq) was then added dropwise. Under nitrogen, the temperature was raised to 65-70°C and allowed to react for 5 h. The reaction was stopped, and TLC analysis confirmed complete reaction of the starting materials. The reaction mixture was cooled to room temperature and added to 300 mL of water. The organic phase was washed with 100 mL of 5% hydrochloric acid and twice with 200 mL of water. The solvent was removed by rotary evaporation, and the main fraction was then distilled under reduced pressure to obtain 32.1 g of a white solid, yielding 87.6%. HPLC analysis indicated 99.5%.
[0036] Example 3 Preparation of 5-(5-bromopyridine)tetrazole
[0037]
[0038] 5-Bromo-2-cyanopyridine (18.3 g, 0.1 mol) and triphenylborane (2.4 g, 0.01 mol, 0.1 eq) were added to 180 mL of DMSO / THF (1:2). Sodium azide (7.15 g, 0.11 mol, 1.1 eq) and ammonium chloride (6.4 g, 0.12 mol, 1.2 eq) were then added sequentially. The reaction was heated to 72°C and allowed to react for 40 minutes. TLC analysis confirmed complete reaction of the starting materials. The reaction mixture was cooled to room temperature and poured into 800 mL of ice water. Filtered, the filter cake was returned to the autoclave, and recrystallized from ethanol and water to obtain 20.5 g of 5-(5-bromopyridinium)tetrazolium as a white solid, with a yield of 90.7%. HPLC analysis indicated 99.3%. 1HNMR(400MHz,DMSO-d6):8.68(d,1H),8.07(dd,1H),7.31(s,1H).
[0039] Example 4 Preparation of 5-(5-bromopyridine)tetrazole
[0040]
[0041] 5-Bromo-2-cyanopyridine (18.3 g, 0.1 mol) and triphenylborane (2.4 g, 0.01 mol, 0.1 eq) were added to 180 mL of DMF, which had been previously distilled under reduced pressure. Sodium azide (7.15 g, 0.11 mol, 1.1 eq) and ammonium chloride (6.4 g, 0.12 mol, 1.2 eq) were then added sequentially. The mixture was heated to 100°C and allowed to react for 30 minutes. The reaction was stopped, and TLC analysis confirmed complete reaction of the starting materials. The reaction mixture was cooled to room temperature and poured into 800 mL of ice water. Filtered, the filter cake was returned to the autoclave, and recrystallized from ethanol and water to obtain 18.2 g of 5-(5-bromopyridinium)tetrazolium as a white solid, with a yield of 80.5% and an HPLC purity of 99.4%.
[0042] The above examples are merely illustrative of the present invention and do not constitute a limitation on the scope of protection of the present invention. Although the present invention is described in detail using preferred embodiments, it should be understood by those skilled in the art that the present invention may be modified, deformed or replaced with equivalents without departing from the scope of the present invention, all of which fall within the scope of protection of the present invention.
Claims
1. A method for preparing 5-(5-bromopyridine)tetrazole, characterized in that: The preparation method route is as follows: The preparation method comprises the following steps: 1) 3-bromopyridine-N-oxide is mixed with an organic solvent, tert-butyldiphenylsilylcyanosilane and a catalyst are added in sequence, an organic base is added dropwise, and then the temperature is raised for reaction, and 5-bromo-2-cyanopyridine is obtained through post-treatment; 2) 5-bromo-2-cyanopyridine, Lewis acid and an organic solvent are mixed, sodium azide is added in sequence, the temperature is raised for reaction, and 5-(5-bromopyridine)tetrazole is obtained through post-treatment.
2. The method for preparing 5-(5-bromopyridine)tetrazole according to claim 1, characterized in that: In step 1), the organic solvent is selected from acetonitrile or 1,2-dichloroethane.
3. The method for preparing 5-(5-bromopyridine)tetrazole according to claim 1, wherein: In step 1), the catalyst is selected from triethylenediamine, and the organic base is selected from triethylamine or N,N-diisopropylethylamine.
4. The method for preparing 5-(5-bromopyridine)tetrazole according to claim 1, characterized in that: In step 1), the molar ratio of 3-bromopyridine-N-oxide, tert-butyldiphenylsilylcyanide, catalyst and organic base is 1:1.2-1.25:0.08-0.10:1.50-1.
60.
5. The method for preparing 5-(5-bromopyridine)tetrazole according to claim 1, characterized in that: In step 2), the organic solvent is selected from DMF / THF or DMSO / THF mixed solvent.
6. The method for preparing 5-(5-bromopyridine)tetrazole according to claim 1, characterized in that: The Lewis acid in step 2) is selected from triphenylborane.
7. The method for preparing 5-(5-bromopyridine)tetrazole as claimed in claim 2, characterized in that: In step 2), the molar ratio of 5-bromo-2-cyanopyridine, Lewis acid, sodium azide and ammonium chloride is 1:0.10-0.15:1.10:1.20-1.30.