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Synthesis method of 3-bromo-6-chloropyridyl-2-formic acid

A synthesis method and chloropyridine technology, applied in directions such as organic chemistry, can solve problems such as environmental pollution, unsuitability for large-scale industrial production, high price, etc., and achieve the effect of reducing cost, low toxicity, safety and large-scale industrial production

Inactive Publication Date: 2013-04-24
SUZHOU ZIKANG PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] (1) The raw material 2-fluoro-3-bromo-6-chloropyridine is expensive;
[0005] (2) The highly toxic raw material sodium cyanide needs to be used in the substitution reaction, and the chemical waste in the synthesis is likely to cause environmental pollution and personal injury;
[0006] (3) This synthesis method is only suitable for small-scale production in the laboratory, not suitable for large-scale industrial production, and has certain limitations
[0007] Because the existing technology has certain deficiencies in cost control, environmental protection and production efficiency

Method used

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  • Synthesis method of 3-bromo-6-chloropyridyl-2-formic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Step (1): Add trifluoroacetic anhydride (47.6 ml, 336 mmol) to 3-bromo-6-chloropyridine (32.4 g, 168 mmol) and urea peroxide (33.2 g, 350 mmol) under ice-bath cooling ) in chloroform (200 ml) solution. After the addition was complete, the reaction solution was stirred for 10 hours. The reaction temperature was 10°C. After the reaction was complete, saturated sodium thiosulfate solution was added and the solution was stirred for 40 minutes. The solution was separated into layers, and the aqueous phase was extracted twice with chloroform. The organic phases were combined and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively. The organic phase was dried with anhydrous sodium sulfate and spin-dried by a rotary evaporator to obtain a mixture. Ethyl acetate (200 ml) was added to the mixture and filtered with filter paper. The obtained solid was washed with ether and dried to obtain a yellow 3-bromo-6-chloropyridine nitro...

Embodiment 2

[0042] The main difference between this embodiment and embodiment 1 lies in step (1) and step (3).

[0043] Step (1): The reaction temperature in this example is 25°C.

[0044] Step (3): Dissolve 3-bromo-6-chloropyridine-2-cyanide (10 g, crude product) in 100 ml of 90% H 2 SO 4 solution, and the mixture was stirred at 150 °C for 4 hours. After the mixture had cooled to room temperature, it was poured onto 500 g of ice. After the mixture was filtered, the resulting solid was washed with water and dried to give 3-bromo-6-chloropyridine-2-carboxylic acid (8 g, 29.6% overall yield over two steps).

[0045] Its compound spectral figure characterizes the parameter of 3-bromo-6-chloropyridine-2-carboxylic acid as follows:

[0046] 1 HNMR (400 MHz, DMSO-d6): 8.02 (d, 1 H, J=4.8 Hz), 9.02 (d, 1 H, J=4.8 Hz).

Embodiment 3

[0048] The main difference between this embodiment and embodiment 1 lies in step (1) and step (3).

[0049] Step (1): The reaction temperature in this example is 25°C.

[0050] Step (3): Dissolve 3-bromo-6-chloropyridine-2-cyanide (10 g, crude product) in 100 ml of 90% H 2 SO 4 solution, and the mixture was stirred at 180 °C for 3 hours. After the mixture had cooled to room temperature, it was poured onto 500 g of ice. After the mixture was filtered, the resulting solid was washed with water and dried to give 3-bromo-6-chloropyridine-2-carboxylic acid (8.8 g, 32.6% overall yield over two steps).

[0051] Its compound spectral figure characterizes the parameter of 3-bromo-6-chloropyridine-2-carboxylic acid as follows:

[0052] 1 HNMR (400 MHz, DMSO-d6): 8.02 (d, 1 H, J=4.8 Hz), 9.02 (d, 1 H, J=4.8 Hz).

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Abstract

The invention provides a synthesis method of 3-bromo-6-chloropyridyl-2-formic acid, which comprises the following steps: by using 3-bromo-6-chloropyridine as an initial raw material, carrying out oxidation reaction with urea peroxide and trifluoroacetic anhydride to obtain 3-bromo-6-chloropyridine oxynitride; reacting with trimethylsilyl cyanide and triethylamine to obtain 3-bromo-6-chloropyridyl-2-cyanide; and finally, hydrolyzing in sulfuric acid to obtain the 3-bromo-6-chloropyridyl-2-formic acid. The synthesis method provided by the invention has the advantages of high operational safety, environment friendliness and the like; and especially, the synthesis method uses low-cost low-toxicity raw materials in stead of such expensive raw material as 2-fluoro-3-bromo-6-chloropyridine and virulent raw material sodium cyanide, and is suitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to the field of pharmaceutical synthesis, more specifically, to a method for synthesizing 3-bromo-6-chloropyridine-2-carboxylic acid. Background technique [0002] 3-bromo-6-chloropyridine-2-carboxylic acid is a very useful pharmaceutical intermediate, the chlorine atom on the pyridine ring is very active, and it can often be replaced by the atom or group we want through a substitution reaction to achieve for the purpose of structural modification. The bromine atom on pyridine is also a highly active reaction site, which can undergo transition metal-catalyzed coupling reactions with some fragments or intermediates, such as Buchwald-Hartwig reaction, Heck reaction, Sonogashira reaction, Still reaction and Suzuki reaction, So as to achieve the purpose of extending the carbon chain and modifying the structure. In addition, the purpose of synthesizing the desired target molecule can also be achieved through the reaction of i...

Claims

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Application Information

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IPC IPC(8): C07D213/803
Inventor 徐卫良左冰徐炜政
Owner SUZHOU ZIKANG PHARMA INC
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