CN107827839A - 2‑（4‑（Benzyloxy）Phenyl）‑N‑（2‑（Piperidinyl-1 base）Ethyl）The formamide preparation method and applications of thiazole 4 - Google Patents

2‑（4‑（Benzyloxy）Phenyl）‑N‑（2‑（Piperidinyl-1 base）Ethyl）The formamide preparation method and applications of thiazole 4 Download PDF

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Publication number
CN107827839A
CN107827839A CN201711051008.0A CN201711051008A CN107827839A CN 107827839 A CN107827839 A CN 107827839A CN 201711051008 A CN201711051008 A CN 201711051008A CN 107827839 A CN107827839 A CN 107827839A
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phenyl
thiazole
benzyloxy
ethyl
preparation
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史大华
马晓冬
刘玉委
唐总明
闵威
刘玮炜
宋梦秋
宋晓凯
陈静
董彤
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Huaihai Institute of Techology
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Huaihai Institute of Techology
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Mycology (AREA)
  • Health & Medical Sciences (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

The invention discloses a kind of 2 phenyl thiazole derivants and its preparation method and application.The phenyl thiazole derivant of one kind 2 of the present invention, its chemical structural formula have shown in formula (I)：

Description

2- (4- (benzyloxy) phenyl)-N- (2- (piperidin-1-yl) ethyl) thiazole -4- formyls Amine preparation method and applications
Technical field
The present invention relates to pharmaceutical formulating art, and in particular to a kind of 2- (4- (benzyloxy) phenyl)-N- (2- (piperidines -1- Base) ethyl) thiazole -4-carboxamide preparation method and its application as acetylcholinesteraseinhibitors inhibitors.
Background technology
Alzheimer's disease is a kind of cranial nerve retrogression pathological changes being common in the elderly.The disease incidence is high, dead Rate height is died, has become one of disease most threatening in modern society.The pathogenesis of alzheimer's disease is current still not Clearly, in recent years for the molecular biology research of the cause of disease of alzheimer's disease, pathology and correlation, scientists are from difference Angle proposes Different types of etiopathogenises hypothesis, wherein representative hypothesis have cholinergic theory, amyloid beta toxic action, Free radicals injury, inflammatory disorderses, brain energy metabolism obstacle, gene defect and mutation etc., up to the present also without one Kind medicine can cure Alzheimer disease disease.Therefore developing new anti-Alzheimer disease medicine turns into the heat of medicament research and development Point.
Cholinergic theory thinks that the brain cholinergic nerve system of the patient with alzheimer's disease is compromised, causes The decline of protuberance acetyl choline content, so as to cause the learning and remembering ability of patient to be damaged.Utilize acetylcholine ester enzyme level Agent suppresses the hydrolysis of neurotransmitter acetylcholine, can improve the cognitive ability of patient.At present, acetylcholinesteraseinhibitors inhibitors are such as The first-class treatment for having been used to Alzheimer disease of Tacrine, donepezil, rivastigmine, galanthamine, huperzine.So And existing acetylcholinesteraseinhibitors inhibitors can only improve the content of acetylcholine, it is impossible to prevent cholinergic nerve of centrum unit Progressive degeneration and death.With disease development, progressive death, acetylcholinesteraseinhibitors inhibitors occur for cholinergic nerve of centrum unit Drug effect also can gradually reduce, while these medicines also have some toxic side effects.Therefore, less toxic, efficient acetylcholine is found Esterase medicine becomes the Main way of current anti-Alzheimer disease drug research.
Document report thiazole structure has the various biologicals such as antibacterial, antitumor, anti-inflammatory and neuroprotection active.Have A little compounds with thiazole structure are with inhibiting activity of acetylcholinesterase, the treatment available for Alzheimer disease.Thiazole Derivative extremely merits attention as the functional food factor of very promising anti-Alzheimer disease or the prospect of medicine.
The content of the invention
The present invention provides a kind of new 2- phenyl thiazole derivants 2- (4- (benzyls with inhibiting activity of acetylcholinesterase Epoxide) phenyl)-N- (2- (piperidin-1-yl) ethyl) thiazole -4-carboxamide.
The present invention provides one kind and prepares 2- (4- (benzyloxy) phenyl)-N- (2- (piperidin-1-yl) ethyl) thiazole -4- formyls The method of amine.
The present invention provides above-mentioned 2- (4- (benzyloxy) phenyl)-N- (2- (piperidin-1-yl) ethyl) thiazole -4-carboxamide Inhibiting activity of acetylcholinesterase and its purposes in functional food or medicine.
Technical scheme is as follows：
A kind of 2- phenyl thiazole derivants, 2- (4- (benzyloxy) phenyl)-N- (2- (piperidin-1-yl) ethyl) thiazole -4- Formamide, it is characterized in that it has following structural formula：
A kind of method for preparing above-mentioned 2- phenyl thiazole derivants, it is characterized in that being made up of the following steps：
Step 1.4- hydroxythiobenzamides 3.93g is dissolved in 20~30mL absolute ethyl alcohols, then adds 3- bromines third Keto acid ethyl ester 5g.The mixture reacts 2~3 hours at 70 DEG C.Reaction adds 70~80mL frozen water after terminating, filtering, obtain Light yellow solid 2- (4- hydroxy phenyls) 4-thiazolecarboxylic acid ethyl ester.
Step 2.2- (4- hydroxy phenyls) 4-thiazolecarboxylic acid ethyl esters 1g is dissolved in 10~20mL dry DMFs, is then added Anhydrous potassium carbonate 1.63g is stirred at room temperature 15 minutes.Then cylite 1.42mL is added in 80 DEG C of stirring reactions 7~8 hours. Reaction adds 70~80mL frozen water, filtering, obtained white solid 2- (4- (benzyloxy) phenyl) 4-thiazolecarboxylic acid second after terminating Ester.
Step 3.1g 2- (4- (benzyloxy) phenyl) 4-thiazolecarboxylic acid ethyl ester is added in 15~20mL absolute methanols, so The anhydrous potassium hydroxide of 0.83g is added afterwards.The mixture reacts 8~9 hours at 80 DEG C.After reaction terminates, reaction solution adjusts pH to 5 ~6, pour into 100~120mL frozen water, separate out solid and filter.Obtain intermediate product 2- (4- (benzyloxy) phenyl) thiazole -4- first Acid.0.4g intermediate products 2- (4- (benzyloxy) phenyl) 4-thiazolecarboxylic acid is dissolved into 10~15mL dichloromethane, then added 0.45~5mL thionyl chlorides.Reaction solution was in 50 DEG C of back flow reactions 9~10 hours.After reaction terminates, by intermediate product 2- (4- (benzyls Epoxide) phenyl) thiazole -4- formyl chlorides are dissolved into 10~20mL dichloromethane, then add 0.23mL 1- (2- amino-ethyls) Piperidines.Reaction solution was in 50 DEG C of back flow reactions 5~6 hours.Compound 2- (4- (benzyloxy) phenyl)-N- is obtained with silica gel column chromatography (2- (piperidin-1-yl) ethyl) thiazole -4-carboxamide.
Synthetic route is reacted as shown in formula：
Embodiment
The present invention is further described by following examples, but the scope of the present invention is not appointed by these embodiments What is limited.
The preparation of embodiment 1.2- (4- hydroxy phenyls) 4-thiazolecarboxylic acid ethyl ester.
4- hydroxythiobenzamide esters 3.93g is dissolved in 20mL absolute ethyl alcohols, then adds 3-BrPA ethyl ester 5g.The mixture reacts 2 hours at 70 DEG C.Reaction adds 70mL frozen water, filtering, obtained light yellow solid 2- after terminating (4- hydroxy phenyls) 4-thiazolecarboxylic acid ethyl ester.Yield 90%.Fusing point：78-80℃.1H NMR (500MHz, DMSO) δ 10.11 (s, 1H), 8.44 (s, 1H), 7.80 (m, 2H), 6.90 (m, 2H), 4.33 (q, J=7.1Hz, 2H), 1.33 (t, J=7.1Hz, 3H)。13C NMR (126MHz, DMSO) δ 168.0,160.7,159.9,146.5,128.1,127.7,123.6,115.90, 60.6 14.1.
The preparation of embodiment 2.2- (4- (benzyloxy) phenyl) 4-thiazolecarboxylic acid ethyl ester.
2- (4- hydroxy phenyls) 4-thiazolecarboxylic acid ethyl esters 1g is dissolved in 10mL dry DMFs, then adds Anhydrous potassium carbonate 1.63g is stirred at room temperature 15 minutes.Then cylite 1.42mL is added in 80 DEG C of stirring reactions 8 hours.Reaction adds after terminating Enter 80mL frozen water, filter, obtained white solid, yield 91%.Fusing point：111-113℃.1H NMR (500MHz, CDCl3)δ 8.09 (s, 1H), 8.01-7.90 (m, 2H), 7.50-7.29 (m, 5H), 7.08-6.98 (m, 2H), 5.12 (s, 2H), 4.44 (q, J=7.1Hz, 2H), 1.43 (t, J=7.1Hz, 3H).13C NMR (126MHz, CDCl3) δ 168.7,161.6,160.8, 147.9,136.4,128.5,128.7,128.2,127.5126.3,126.0,115.2,70.2,61.5,14.4.
Embodiment 3.2- (4- (benzyloxy) phenyl)-N- (2- (piperidin-1-yl) ethyl) thiazole -4-carboxamide (produce by target Thing) preparation.1g 2- (4- (benzyloxy) phenyl) 4-thiazolecarboxylic acid ethyl ester is added in 15mL absolute methanols, then added The anhydrous potassium hydroxide of 0.83g.The mixture reacts 9 hours at 80 DEG C.After reaction terminates, reaction solution adjusts pH to 5, pours into In 100mL frozen water, separate out solid and filter.Obtain intermediate product 2- (4- (benzyloxy) phenyl) 4-thiazolecarboxylic acid.Product is without pure Change is directly used in reacts in next step.0.4g intermediate products 2- (4- (benzyloxy) phenyl) 4-thiazolecarboxylic acid is dissolved into 10mL dichloros In methane, 0.45mL thionyl chlorides are then added.Reaction solution was in 50 DEG C of back flow reactions 10 hours.After reaction terminates, is produced from centre Thing 2- (4- (benzyloxy) phenyl) thiazole -4- formyl chlorides are dissolved into 10mL dichloromethane, then add 0.23mL 1- (2- ammonia Base ethyl) piperidines.Reaction solution was in 50 DEG C of back flow reactions 6 hours.With silica gel column chromatography obtain compound 2- (4- (benzyloxy) phenyl)- N- (2- (piperidin-1-yl) ethyl) thiazole -4-carboxamide.Yellow solid, yield 26%.Fusing point：101-103℃.1H NMR (500MHz, CDCl3) δ 8.05 (s, 1H), 8.00 (s, 1H), 7.95-7.88 (m, 2H), 7.49-7.30 (m, 5H), 7.08- 7.01 (m, 2H), 5.13 (s, 2H), 3.66 (m, 2H), 2.72 (t, J=5.9Hz, 2H), 2.62 (s, 4H), 1.81-1.65 (m, 4H), 1.49-1.54 (m, 2H).13C NMR (126MHz, CDCl3) δ 167.9,161.4160.7,150.6,136.4,128.7, 128.2,127.5,126.1,121.9,115.3,57.3,54.4,35.9,25.4,23.9.HRMS：(ESI, m/z)：[M+Na]+ calcd for C24H27N3NaO2S 444.1722, found 444.1740.
The acetyl courage of embodiment 4.2- (4- (benzyloxy) phenyl)-N- (2- (piperidin-1-yl) ethyl) thiazole -4-carboxamide Alkali esterase inhibition activity.
The present invention tests the second of 2- (4- (benzyloxy) phenyl)-N- (2- (piperidin-1-yl) ethyl) thiazole -4-carboxamide Acetylcholinesterase inhibitory activity.Enzyme reaction is carried out in 25 DEG C, 0.1M pH8.0 phosphate buffer, and total reaction volume is 200 μ L, includes 3.33mM 5, the μ L of 5 '-two sulphur-connection (2- nitrobenzoic acids), 20 μ L, 0.35U/mL acetylcholine esters enzyme solutions 20 and The μ L of 5.3mM acetylthiocholine iodides solution 20, the μ L of test compound solution 10,412nm with ELIASA (Sunrise, Tecan, Austria) detection 5min.All samples are all in triplicate.Using not plus compound well OD value as 100%, The optical density in compound determination hole compares therewith, and the percentage of reduction is enzyme inhibition rate.Each compound at least surveys 5 concentration Gradient seeks IC by compound concentration logarithm to the inhibitory activity of acetylcholinesterase to inhibiting rate mapping50Value (suppresses 50% enzyme The concentration of compound when active).The compound has stronger cholinesterase inhibition, compound acetylcholine esterase inhibition IC50It is worth for 2.5 μM.

Claims (5)

  1. A kind of 1. 2- phenyl thiazole derivants 2- (4- (benzyloxy) phenyl)-N- (2- (piperidin-1-yl) second with following structure Base) thiazole -4-carboxamide.
  2. 2. the preparation method of the 2- phenyl thiazole derivants described in a kind of claim 1, it is characterised in that by 3-BrPA second Ester reacts with cylite again with obtaining 2- (4- hydroxy phenyls) 4-thiazolecarboxylic acid ethyl ester after the reaction of 4- hydroxythiobenzamides Ester is freed using buck obtain 2- (4- (benzyloxy) phenyl) 4-thiazolecarboxylic acid afterwards.Reacted again with thionyl chloride among being made Product 2- (4- (benzyloxy) phenyl) thiazole -4- formyl chlorides.The intermediate product of gained reacts with 1- (2- amino-ethyls) piperidines To 2- (4- (benzyloxy) phenyl)-N- (2- (piperidin-1-yl) ethyl) thiazole -4-carboxamide.
  3. 3. the preparation method of 2- phenyl thiazole derivants according to claim 2, it is characterised in that comprise the following steps：
    1) preparation of 2- (4- hydroxy phenyls) 4-thiazolecarboxylic acid ethyl ester
    2) preparation of 2- (4- (benzyloxy) phenyl) 4-thiazolecarboxylic acid
    3) preparation of 2- (4- (benzyloxy) phenyl) thiazole -4- formyl chlorides
    4) preparation of 2- (4- (benzyloxy) phenyl)-N- (2- (piperidin-1-yl) ethyl) thiazole -4-carboxamide.
  4. A kind of 4. 2- (4- (benzyloxy) phenyl)-N- (2- (piperidin-1-yl) ethyl) thiazole -4- formyls described in claim 1 Amine prepare the functional food of anti-Alzheimer disease because or medicine in application.
  5. 5. 2- (4- (benzyloxy) phenyl)-N- (2- (piperidin-1-yl) ethyl) thiazole -4- formyls according to claim 4 Amine prepare the functional food of anti-Alzheimer disease because or medicine, it is characterised in that described 2- phenyl thiazole derivants tool There is cholinesterase inhibition.
CN201711051008.0A 2017-10-18 2017-10-18 2‑（4‑（Benzyloxy）Phenyl）‑N‑（2‑（Piperidinyl-1 base）Ethyl）The formamide preparation method and applications of thiazole 4 Pending CN107827839A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110194764A (en) * 2018-02-26 2019-09-03 云南大学 Amides compound, preparation method and the usage
CN114366740A (en) * 2021-09-18 2022-04-19 江苏海洋大学 Application of compound A-6 in preparation of broad-spectrum anticancer drugs

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110194764A (en) * 2018-02-26 2019-09-03 云南大学 Amides compound, preparation method and the usage
CN114366740A (en) * 2021-09-18 2022-04-19 江苏海洋大学 Application of compound A-6 in preparation of broad-spectrum anticancer drugs
CN114366740B (en) * 2021-09-18 2023-08-22 江苏海洋大学 Application of compound A-6 in preparation of broad-spectrum anticancer drugs

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