Preparation method and application of ethyl 2-(4-hydroxyphenyl)thiazole-4-carboxylate derivatives

A technology of ethyl carboxylate and hydroxyphenyl, which is applied in the field of preparation of 2-thiazole-4-carboxylate ethyl ester derivatives, can solve the problems of inability to prevent the degeneration and death of central cholinergic neurons, toxic and side effects, etc. The synthesis method is simple and safe, the post-processing is convenient, and the energy consumption is low.

Active Publication Date: 2017-05-31
伊势久(江苏连云港)生物科技有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing acetylcholinesterase inhibitors can only increase the content of acetylcholine, but cannot prevent the progressive degenerative death of central cholinergic neurons
As the disease progresses, the central cholinergic neurons die progressively, and the efficacy of acetylcholinesterase inhibitors will gradually decrease, and these drugs also have some toxic side effects

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] (1) Synthesis of ethyl 2-(4-hydroxyphenyl)thiazole-4-carboxylate (3)

[0026]

[0027] Take 3.93g of p-hydroxythiobenzamide in a round bottom flask, add 50.00mL of absolute ethanol and 5.00mL of ethyl 3-bromopyruvate with a mass fraction of 80%, heat at 80°C for 4h; cool to room temperature after the reaction , add 100mL distilled water, precipitate solid, suction filter, take solid, wash with water, obtain compound 2-(4-hydroxyphenyl) thiazole-4-carboxylate ethyl ester light yellow powder after vacuum drying, yield rate is 88.56%. 1 H NMR (500MHz,DMSO)δ10.11(s,1H),8.44(s,1H),7.85–7.75(m,2H),6.95–6.86(m,2H),4.33(q,J=7.1Hz, 2H), 1.33(t, J=7.1Hz, 3H).

[0028] (2) Synthesis of ethyl 2-(4-(3-bromopropoxy)phenyl)thiazole-4-carboxylate (4a)

[0029]

[0030] Take 0.50 g of the compound obtained from the reaction in step (1) in a round bottom flask, add 0.55 g of anhydrous potassium carbonate, 1.13 mL of 1,3-dibromopropane and 6.00 mL of dimethylformamide DMF. Heatin...

Embodiment 2

[0035] The difference between embodiment 2 and embodiment 1 is:

[0036] (3) Synthesis of ethyl 2-(4-(3-(propylamino)propoxy)phenyl)thiazole-4-carboxylate (5a-2)

[0037]

[0038] The preparation method is the same as in Example 1, wherein the amines are replaced by di-n-propylamine. A yellow liquid, compound 5a-2, was obtained with a yield of 84.34%. 1 H NMR (500MHz, CDCl 3 )δ8.09(s,1H),7.94(d,J=8.8Hz,2H),6.94(d,J=8.8Hz,2H),4.44(q,J=7.1Hz,2H),4.09(t, J=6.1Hz, 2H), 2.79(s, 2H), 2.56(d, J=6.8Hz, 4H), 2.14–2.00(m, 2H), 1.58(dd, J=15.0, 7.4Hz, 4H), 1.43(t,J=7.1Hz,3H),0.91(t,J=7.4Hz,6H).; 13 C NMR (126MHz, CDCl 3 )δ168.74,161.55,160.91,147.82,128.54,126.27,125.76,114.73,66.06,61.45,55.67,53.44,50.46,19.24,14.38,11.75.HRMS:(ESI,m / z):[M+H] + calcd for C 21 h 30 N 2 o 3 S 391.2050, found 391.2053.

Embodiment 3

[0040] The difference between embodiment 3 and embodiment 1 is:

[0041] (3) Synthesis of ethyl 2-(4-(3-(dimethylamino)propoxy)phenyl)thiazole-4-carboxylate (5a-3)

[0042]

[0043] The preparation method is the same as in Example 1, wherein the amines are replaced by diethylamine. A light yellow powder was obtained, namely compound 5a-3, with a yield of 90.27%. m.p.64-66℃.; 1 H NMR (500MHz, CDCl 3 )δ8.09(s,1H),7.94(d,J=8.2Hz,2H),6.95(d,J=8.3Hz,2H),4.44(q,J=7.1Hz,2H),4.09(t, J=5.9Hz, 2H), 2.80–2.75(m, 2H), 2.71(dd, J=13.3, 6.4Hz, 4H), 2.13–2.01(m, 2H), 1.43(t, J=7.1Hz, 3H ),1.14(t,J=7.0Hz,6H).; 13 C NMR (126MHz, CDCl 3 )δ168.74,161.55,160.91,147.82,128.53,126.26,125.76,114.75,66.17,61.46,49.26,46.91,26.16,14.38,10.93.HRMS:(ESI,m / z):[M+H] + calcd for C 19 h 26 N 2 o 3 S 363.1737,found 363.1740.

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Abstract

The invention discloses a preparation method and an application of ethyl 2-(4-hydroxyphenyl)thiazole-4-carboxylate derivatives. The preparation method comprises the following steps: reacting p-hydroxythiobenzamide with ethyl 3-bromopyruvate to synthesize an intermediate ethyl 2-(4-hydroxyphenyl)thiazole-4-carboxylate, respectively reacting the intermediate with 1,3-dibromopropane, 1,4-dibromobutane or 1,5-dibromopentate to synthesize ethyl 2-(4-(3-bromopropoxy)phenyl)thiazole-4-carboxylate, ethyl 2-(4-(4-bromobutoxy)phenyl)thiazole-4-carboxylate or ethyl 2-(4-((5-bromopentyl)oxy)phenyl)thiazole-4-carboxylate, and respectively reacting the ethyl 2-(4-(3-bromopropoxy)phenyl)thiazole-4-carboxylate, ethyl 2-(4-(4-bromobutoxy)phenyl)thiazole-4-carboxylate or ethyl 2-(4-((5-bromopentyl)oxy)phenyl)thiazole-4-carboxylate with an amine to generate the target products. The synthesis method has the advantages of simplicity, safety and small pollution, and the products have a strong inhibition effect on butyrylcholine esterase and/or acetylcholinesterase, and can be used for preparing anti-Alzheimer disease medicines.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a preparation method of a 2-(4-hydroxyphenyl)thiazole-4-carboxylic acid ethyl ester derivative and its function as an inhibitor of acetylcholinesterase and / or butyrylcholinesterase Application of drugs in the treatment of Alzheimer's disease. Background technique [0002] Alzheimer's disease is a common brain neurodegenerative disease in the elderly. It has the characteristics of high morbidity and high mortality. Its mortality rate is second only to cardiovascular disease, cancer and stroke. It has become a modern One of the most threatening diseases in society. According to literature reports, there were 36 million people in the world suffering from Alzheimer's disease in 2010, and the number is expected to rise to 42.3 million in 2020 and 81.1 million in 2040. [0003] The pathogenesis of Alzheimer's disease is still unclear. In recent years, scientists have proposed a va...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56A61K31/426A61K31/427A61K31/5377A61K31/496A61P25/28
CPCC07D277/56
Inventor 史大华唐总明刘玉委朱荟龙马晓冬宋梦秋刘玮炜宋晓凯曹志凌秦凌雁
Owner 伊势久(江苏连云港)生物科技有限责任公司
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