Method for synthesizing novel uric acid lowering compound Arhalofenate intermediate

A synthetic method and technology for reducing uric acid, which is applied in the separation/purification of carboxylic acid compounds, the preparation of organic compounds, organic chemical methods, etc., can solve the problems of long synthesis reaction time, harsh reaction conditions, and high price, and meet the production conditions The effect of low equipment requirements, high split rate, and easy operation

Inactive Publication Date: 2019-01-18
TONGHUA NORMAL UNIV
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  • Abstract
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Problems solved by technology

The above-mentioned (R)-p-chloromandelic acid is an important chiral intermediate and is used to synthesize drugs. It can be used as an acidic resolving agent to resolve the new uric acid-lowering compound Arhalofenate, improve the yield and resolution of the compound Arhalofenate efficiency, and then solve the shortcomings of compound Arhalofenate, such as long reaction time, harsh reaction conditions, low yield, and high price, so that compound Arhalofenate will become an important drug against gout

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  • Method for synthesizing novel uric acid lowering compound Arhalofenate intermediate

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Embodiment 1

[0021] A method for synthesizing a novel uric acid-reducing compound Arhalofenate intermediate, wherein the novel uric acid-reducing compound Arhalofenate intermediate is (R)-p-chloromandelic acid. The above-mentioned (R)-p-chloromandelic acid is an important chiral intermediate and is used to synthesize drugs. It can be used as an acidic resolving agent to resolve the new uric acid-lowering compound Arhalofenate, improve the yield and resolution of the compound Arhalofenate The compound Arhalofenate has the disadvantages of long reaction time, harsh reaction conditions, low yield, high price and so on, so that the compound Arhalofenate will become an important anti-gout drug.

[0022] The synthetic method of novel uric acid-lowering compound Arhalofenate intermediate, its reaction formula is:

[0023]

[0024] The synthetic method of novel uric acid-lowering compound Arhalofenate intermediate, its synthetic concrete steps are:

[0025] Step 1: Add 95% ethanol to the racem...

Embodiment 2

[0030] The synthetic method of novel uric acid-lowering compound Arhalofenate intermediate, its synthetic concrete steps are:

[0031] Step 1: Add 95% ethanol to the racemic p-chloromandelic acid at a ratio of 1:10 (g / mL) to dissolve it completely. The above-mentioned 95% ethanol solution contains 0.035% N,N- Diisopropylethylamine, the presence of N,N-diisopropylethylamine can increase the number of hydrogen bonds formed between the amino group on the (R)-amine and the carboxyl group on the (R)-p-chloromandelic acid, and then The formation of a hydrogen bond network is conducive to increasing the stability of the crystal structure of the insoluble salt (R)-amine·(R)-p-chloromandelic acid, thereby increasing the stability difference between the two salts, while the insoluble salt (R)- The hydrogen bonds in the crystal structure of amine·(R)-p-chloromandelic acid are connected by the Cl...Cl halogen bonds that appear, reducing the insoluble salt of (R)-amine·(R)-p-chloromandelic...

Embodiment 3

[0036] The synthetic method of novel uric acid-lowering compound Arhalofenate intermediate, its synthetic concrete steps are:

[0037] Step 1: Put 2.8g of p-chloromandelic acid in a 100mL single-necked bottle, add 30mL of 95% ethanol solution, stir until completely dissolved, then add 1.9mL of (R)-phenylethylamine dropwise under stirring , mixed and heated to reflux for 15 minutes to dissolve the solid, then slowly cooled to room temperature, and filtered to obtain 2.413 g of crude product;

[0038] Step 2: The crude product obtained in step 1 was recrystallized twice in 95% ethanol to obtain 1.25 g of (R)-phenethylamine·(R)-p-chloromandelic acid;

[0039] Step 3: Dissolve the (R)-phenethylamine·(R)-p-chloromandelic acid obtained in step 1 in 16 mL of water, add hydrochloric acid to adjust the pH of the solution to 1, then extract three times with ethyl acetate, combine the organic phases, After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced...

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Abstract

The invention discloses a method for synthesizing a novel uric acid lowering compound Arhalofenate intermediate. The novel uric acid lowering compound Arhalofenate intermediate is (R)-chloromandelic acid, and is prepared by the following specific synthetic steps: taking a common organic solvent as a resolution solvent, taking racemic chloromandelic acid as a raw material, taking (R)-amine as a resolving agent, performing reflux preparation to obtain (R)-amine*(R)-chloromandelic acid, adding an acid to regulate the pH value, repeatedly extracting with ethyl acetate, merging the organic phase, adding anhydrous sodium sulfate for drying, performing suction filtration and desalting, and performing reduced pressure drying, thereby obtaining the (R)-chloromandelic acid with high optical purity.The method disclosed by the invention has the beneficial effects that the synthetic method is readily available in raw materials, excellent in separating speed and effect, high in resolution rate, lowin cost, simple and convenient in operation, low in requirements on production conditions and equipment and easy for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a synthesis method of a novel uric acid-lowering compound Arhalofenate intermediate. Background technique [0002] The incidence rate of gout in my country is 0.17%, and it has an increasing trend year by year. Gout is a crystal-associated arthropathy caused by the deposition of monosodium urate, which is directly related to hyperuricemia caused by purine metabolic disorders and / or decreased uric acid excretion, especially acute characteristic arthritis and chronic tophi Diseases mainly include acute onset arthritis, tophi formation, tophi chronic arthritis, urate nephropathy and uric acid urolithiasis. In severe cases, joint disability and renal insufficiency may occur. Gout is often accompanied by abdominal obesity, hyperlipidemia, hypertension, type 2 diabetes and cardiovascular disease. Gout is more common in middle-aged men, and women account for only 5%, mainly postmeno...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/56C07C51/487C07C51/42A61P19/06C07B57/00
CPCA61P19/06C07B57/00C07B2200/07C07C51/42C07C51/487C07C59/56
Inventor 臧皓徐倩张露云徐晶夏广清朱俊义
Owner TONGHUA NORMAL UNIV
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