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Preparation method for pyridine medical intermediate for synthesizing anti-cancer auxiliary medicines

A technology of pyridines and intermediates, applied in the field of synthesis of 2-bromo-3-chloro-5-trifluoromethylpyridine, which can solve the problem of high price

Active Publication Date: 2013-01-16
上海泰坦科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, its own synthetic route and process are rarely reported in literature or patents, and the price is relatively high

Method used

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  • Preparation method for pyridine medical intermediate for synthesizing anti-cancer auxiliary medicines
  • Preparation method for pyridine medical intermediate for synthesizing anti-cancer auxiliary medicines
  • Preparation method for pyridine medical intermediate for synthesizing anti-cancer auxiliary medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] (1) Add 0.13mol of 6-hydroxynicotinic acid (18.2g), 2.6ml of anhydrous hydrofluoric acid (concentration above 95wt%) (0.13mol), and 42.1g of sulfur tetrafluoride (0.39mol) into a stainless steel pressure tank Li and heated to 100 ° C, reacted at 0.15 MPa for 12 hours, and the gas product was treated with a tail gas absorption device.

[0024] The remaining product was transferred to a polytetrafluoroethylene container and heated to 40°C to remove traces of hydrogen fluoride. The resulting product was added to 150 ml of water, adjusted to pH 6.8-7.2 with saturated sodium carbonate solution, extracted with chloroform, dried, filtered, and spin-dried to obtain 15.3 g (0.094 mol) of 2-hydroxy-5-trifluoromethylpyridine , yield 72%.

[0025] (2) Add 0.094mol of 2-hydroxy-5-trifluoromethylpyridine (15.3g) and 14.4g of N-chlorosuccinimide (0.108mol) to 50ml of anhydrous DMF / nitromethylpyrrolidone , reacted at room temperature for 8 hours under stirring conditions. The reacta...

Embodiment 2

[0029] (1) Add 0.15mol 6-hydroxynicotinic acid, anhydrous hydrofluoric acid (0.16mol content), and 0.5mol sulfur tetrafluoride into a stainless steel pressure tank and heat to 120°C, and react at 0.2MPa for 12 hours; The gaseous product is treated with a tail gas absorption device. Transfer the remaining product to a polytetrafluoroethylene container and heat it to about 40°C to remove traces of hydrogen fluoride. The resulting product was added to 150 ml of water, adjusted to pH 6.5-7.4 with saturated sodium carbonate solution, extracted with chloroform, dried, filtered, and spin-dried to obtain 17.8 grams (0.109 mol) of 2-hydroxy-5-trifluoromethylpyridine , yield 72.6%.

[0030] (2) Add 17.8 g of 2-hydroxy-5-trifluoromethylpyridine and 0.12 mol of N-chlorosuccinimide (133.54 molar ratio of 1:1.1 to 1.3) to 50 ml of anhydrous DMF / nitrogen In the base pyrrolidone. The reactant was slowly added to 250 ml of water, and a pale yellow precipitate precipitated out. The resultin...

Embodiment 3

[0034] (1) The 2-bromo-3-chloro-5-trifluoromethylpyridine prepared in Example 1 or Example 2 is used to prepare compound A1 according to the record of US2009 / 186879A1, and the reaction formula is as follows:

[0035]

[0036] Among them, the compound A1 has good drug activity and can be used as an auxiliary anticancer drug.

[0037] (2) The 2-bromo-3-chloro-5-trifluoromethylpyridine prepared in Example 1 or Example 2 was prepared according to the record of WO2005 / 4606 to prepare compound A2, the reaction formula is as follows:

[0038]

[0039] Among them, the compound A2 has good antifungal bacteria and anti-infection activities, and can be used as an anti-cancer auxiliary drug.

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Abstract

The invention relates to the field of medical chemistry and discloses a method for synthesizing a pyridine medical intermediate, namely 2-bromo-3-chloro-5-trifluoromethyl pyridine, for synthesizing anti-cancer auxiliary medicines. The method comprises the following steps of: (1) reacting 6-hydroxynicotinic acid, hydrofluoric acid and sulfur tetrafluoride at the temperature of between 100 and 120DEG C and under the pressure of 0.1-0.3MPa, and adding water to obtain 2-hydroxy-5-trifluoromethyl pyridine; (2) reacting with N-chlorosuccinimide, and performing water precipitation to obtain 3-chloro-5-trifluoromethyl-2-hydroxypyridine; and (3) adding excessive phosphorus oxybromide, reacting at the temperature of between 145 and 160DEG C for 5 to 8 hours, cooling, violently stirring at the temperature of between -5 and 0DEG C, extracting, combining organic phases, drying, filtering, performing spin drying, and purifying by using a silica gel column. According to the method, raw materials are readily available, the cost is low, the method is suitable for industrial production and the yield exceeds 38 percent.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, specifically a method for synthesizing pyridine pharmaceutical intermediates used for synthesizing anti-cancer auxiliary drugs, more specifically, 2-bromo-3-chloro-5-trifluoromethylpyridine resolve resolution. Background technique [0002] With the development of drug research and development technology and the expansion of the scope of finding drugs, more and more drugs contain pyridine ring structures; therefore, pyridine-related intermediates, as an important part of introducing pyridine rings, have received more and more attention. Market prospects. [0003] 2-Bromo-3-chloro-5-trifluoromethylpyridine (CAS No. 75806-84-7), the structure is shown in formula I: [0004] [0005] Formula I [0006] 2-Bromo-3-chloro-5-trifluoromethylpyridine is a pyridine intermediate with two active groups, trifluoromethyl and bromine (structure shown in formula I), which are listed in many drug p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/61
Inventor 谢应波张庆张华姚为建
Owner 上海泰坦科技股份有限公司
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