CN104059020B - The preparation method of 1-aryl-5-hydroxypyrazoles - Google Patents
The preparation method of 1-aryl-5-hydroxypyrazoles Download PDFInfo
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- CN104059020B CN104059020B CN201410298552.5A CN201410298552A CN104059020B CN 104059020 B CN104059020 B CN 104059020B CN 201410298552 A CN201410298552 A CN 201410298552A CN 104059020 B CN104059020 B CN 104059020B
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- hydroxypyrazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
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- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of method that hydrochlorate using aryl hydrazines or aryl hydrazines reacts preparation 1 aryl 5 hydroxypyrazoles in a solvent with methoxy-methyl acrylate.Chemical equation is as follows:
Description
Technical field
The present invention relates to the preparation method of 1-aryl-5-hydroxypyrazoles.It is specifically related to the hydrochlorate with aryl hydrazines or aryl hydrazines
It is the method that 1-aryl-5-hydroxypyrazoles prepared by raw material with methoxy-methyl acrylate.
Background technology
1-aryl-5-hydroxypyrazoles and derivant thereof, have extensive and important purposes, is Multiple Pesticides, pharmaceutical active compounds
Intermediate, patent WO2010135536 discloses the derivant of a class 1-aryl-5-hydroxypyrazoles and is reducing blood uric acid levels
On application；Patent US2004057588 discloses the derivant of a class 1-aryl-5-hydroxypyrazoles answering on treating AIDS
With；Patent WO2008023235 discloses the application on thrombus treatment of the derivant of a class 1-aryl-5-hydroxypyrazoles.
About the synthesis of 1-aryl-5-hydroxypyrazoles, the most probably there is a following synthetic method:
One, aryl hydrazines and diethyl ethoxymethylenemalonate obtain 1-aryl-5-hydroxypyrazoles through cyclization, decarboxylation two step.
The method obtains 1-phenyl-5-hydroxypyrazoles with two step total recoverys 36%.
Two, aryl hydrazines and 3,3-dimethoxy methyl propionate cyclization obtain 1-aryl-5-hydroxypyrazoles.The method with 24% receipts
Rate obtains 1-(2-chloro-4-aminomethyl phenyl)-5-hydroxypyrazoles.
Summary of the invention
The problem such as the method product yield of 1-aryl-5-hydroxypyrazoles is the highest that the invention aims to overcome prior art to prepare,
A kind of hydrochlorate using aryl hydrazines or aryl hydrazines is provided to react preparation 1-aryl-5-hydroxyl in a solvent with methoxy-methyl acrylate
The method of base pyrazoles.
Chemical equation is as follows:
In formula, n represents the integer of 1-3, and R is hydrogen atom or halogen atom, nitro, cyano group, alkoxyl, alkyl, trihalomethyl.
Solvent of the present invention is the one in methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol
Or multiple mixture, the rate of charge of solvent and methoxy-methyl acrylate be volume (mL) with mM (mmol) than 0.2～
200 1；The molar ratio of described aryl hydrazines or the hydrochlorate of aryl hydrazines and methoxy-methyl acrylate is 1 0.7～1.4.；
Reaction temperature is 40 DEG C of temperature to reaction dissolvent backflow, and the response time is 1～240h.
The preparation method of the 1-aryl-5-hydroxypyrazoles that the present invention provides, technique is simple, reactions steps is few, easily operates, product
Yield ＞ 50%, far above prior art, raw material sources are extensive, are suitable for industrialized production.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described.
Embodiment 1
17.9g (100mmol) p-hydrochloride, 11.6g (100mmol) methoxyl group is added in three mouthfuls of reaction bulbs
Acrylic acid methyl ester., 100mL methanol.Being warming up to back flow reaction about 6 hours, reactant liquor is quantitative by liquid chromatograph, and 1-is to chlorine
Phenyl-5-hydroxypyrazoles yield 81.3%.
Embodiment 2
Addition 10.8g (100mmol) phenylhydrazine in three mouthfuls of reaction bulbs, 11.6g (100mmol) methoxy-methyl acrylate,
100mL methanol.Being warming up to back flow reaction about 6 hours, reactant liquor is quantitative by liquid chromatograph, 1-phenyl-5-hydroxypyrazoles
Yield 85.7%.
Embodiment 3
15.3g (100mmol) 2-nitrophenyl hydrazine, 11.6g (100mmol) methoxyl group propylene is added in three mouthfuls of reaction bulbs
Acid methyl ester, 100mL methanol.Being warming up to 40 DEG C react about 6 hours, reactant liquor is quantitative by liquid chromatograph, and 1-is to nitre phenyl
-5-hydroxypyrazoles yield 52.6%.
Embodiment 4
21.2g (100mmol) 3-trifluoromethylbenzene hydrazine hydrochloride, 11.6g (100mmol) is added in three mouthfuls of reaction bulbs
Methoxy-methyl acrylate, 100mL methanol.Being warming up to back flow reaction about 6 hours, reactant liquor is quantitative by liquid chromatograph,
1-(3-trifluoromethyl)-5-hydroxypyrazoles yield 64.8%.
Embodiment 5
17.5g (100mmol) 4-methoxyphenyl hydrazine hydrochloride, 11.6g (100mmol) first is added in three mouthfuls of reaction bulbs
Epoxide acrylic acid methyl ester., 100mL methanol.Being warming up to back flow reaction about 6 hours, reactant liquor is quantitative by liquid chromatograph, 1-
(4-methoxyphenyl)-5-hydroxypyrazoles yield 79.3%.
Embodiment 6
20.1g (100mmol) 4-tert-butyl benzene hydrazine hydrochloride, 11.6g (100mmol) first is added in three mouthfuls of reaction bulbs
Epoxide acrylic acid methyl ester., 100mL methanol.Being warming up to back flow reaction about 6 hours, reactant liquor is quantitative by liquid chromatograph, 1-
(4-tert-butyl-phenyl)-5-hydroxypyrazoles yield 84.1%.
Embodiment 7
1.77g (10mmol) 5-fluoro-2-methylbenzene hydrazine hydrochloride, 1.16g (10mmol) first is added in three mouthfuls of reaction bulbs
Epoxide acrylic acid methyl ester., 10mL methanol.Being warming up to back flow reaction about 6 hours, reactant liquor is quantitative by liquid chromatograph, 1-
(5-fluoro-2-methylbenzene base)-5-hydroxypyrazoles yield 75.9%.
Embodiment 8
1.70g (10mmol) 4-cyanophenylhydrazine hydrochlorate, 1.16g (10mmol) methoxyl group is added in three mouthfuls of reaction bulbs
Acrylic acid methyl ester., 10mL methanol.Being warming up to back flow reaction about 6 hours, reactant liquor is quantitative by liquid chromatograph, 1-(5-
Cyanogen-2-aminomethyl phenyl)-5-hydroxypyrazoles yield 64.2%.
Embodiment 9
17.9g (100mmol) p-hydrochloride, 11.6g (100mmol) methoxyl group is added in three mouthfuls of reaction bulbs
Acrylic acid methyl ester., 100mL methanol.Being warming up to 40 DEG C react about 240 hours, reactant liquor is quantitative by liquid chromatograph, 1-
Rubigan-5-hydroxypyrazoles yield 72.4%.
Embodiment 10
17.9g (100mmol) p-hydrochloride, 11.6g (100mmol) methoxyl group is added in three mouthfuls of reaction bulbs
Acrylic acid methyl ester., 100mL ethanol.Being warming up to 40 DEG C react about 1 hour, reactant liquor is quantitative by liquid chromatograph, and 1-is to chlorine
Phenyl-5-hydroxypyrazoles yield 43.6%.
Embodiment 11
17.9g (100mmol) p-hydrochloride, 11.6g (100mmol) methoxyl group is added in three mouthfuls of reaction bulbs
Acrylic acid methyl ester., 20mL methanol.Heat up 40 DEG C to back flow reaction about 6 hours, reactant liquor is quantitative by liquid chromatograph, 1-
Rubigan-5-hydroxypyrazoles yield 51.1%.
Embodiment 12
17.9g (100mmol) p-hydrochloride, 11.6g (100mmol) methoxyl group is added in three mouthfuls of reaction bulbs
Acrylic acid methyl ester., 20mL methanol.Heat up 40 DEG C to back flow reaction about 6 hours, reactant liquor is quantitative by liquid chromatograph, 1-
Rubigan-5-hydroxypyrazoles yield 51.1%.
Embodiment 13
1.79g (10mmol) p-hydrochloride, 1.16g (10mmol) methoxy propyl is added in three mouthfuls of reaction bulbs
E pioic acid methyl ester, 2000mL methanol.Heat up 40 DEG C to back flow reaction about 6 hours, reactant liquor is quantitative by liquid chromatograph, 1-
Rubigan-5-hydroxypyrazoles yield 82.5%.
Embodiment 14
17.9g (100mmol) p-hydrochloride, 16.2g (140mmol) methoxyl group is added in three mouthfuls of reaction bulbs
Acrylic acid methyl ester., 30mL normal propyl alcohol, 30mL isopropanol, 30mL n-butyl alcohol, 30mL isobutanol.It is warming up to 55 DEG C instead
Answering about 6 hours, reactant liquor is quantitative by liquid chromatograph, 1-rubigan-5-hydroxypyrazoles yield 74.3%.
Embodiment 15
17.9g (100mmol) p-hydrochloride, 8.1g (70mmol) methoxy propyl is added in three mouthfuls of reaction bulbs
E pioic acid methyl ester, 100mL isobutanol.Being warming up to 60 DEG C react about 6 hours, reactant liquor is quantitative by liquid chromatograph, and 1-is to chlorine
Phenyl-5-hydroxypyrazoles yield 64.4%.
Embodiment 16
17.9g (100mmol) p-hydrochloride, 11.6g (100mmol) methoxyl group is added in three mouthfuls of reaction bulbs
Acrylic acid methyl ester., the 100mL tert-butyl alcohol.Being warming up to back flow reaction about 6 hours, reactant liquor is quantitative by liquid chromatograph, 1-pair
Chlorphenyl-5-hydroxypyrazoles yield 79.1%.
Embodiment 17
17.9g (100mmol) p-hydrochloride, 8.1g (70mmol) methoxy propyl is added in three mouthfuls of reaction bulbs
E pioic acid methyl ester, 100mL n-butyl alcohol.Being warming up to 60 DEG C react about 40 hours, reactant liquor is quantitative by liquid chromatograph, 1-pair
Chlorphenyl-5-hydroxypyrazoles yield 66.4%.
Embodiment 18
17.9g (100mmol) p-hydrochloride, 11.6g (100mmol) methoxyl group is added in three mouthfuls of reaction bulbs
Acrylic acid methyl ester., 30mL methanol, 30mL ethanol.Being warming up to back flow reaction about 80 hours, reactant liquor passes through liquid chromatograph
Quantitatively, 1-rubigan-5-hydroxypyrazoles yield 80.8%.
Embodiment 19
17.9g (100mmol) p-hydrochloride, 11.6g (100mmol) methoxyl group is added in three mouthfuls of reaction bulbs
Acrylic acid methyl ester., 30mL methanol, the 30mL tert-butyl alcohol, 100mL n-butyl alcohol.It is warming up to back flow reaction about 160 hours,
Reactant liquor is quantitative by liquid chromatograph, 1-rubigan-5-hydroxypyrazoles yield 81.2%.
Claims (2)
1. the preparation method of a 1-substituted-phenyl-5-hydroxypyrazoles, it is characterised in that with substituted-phenyl hydrazine or substituted-phenyl hydrazine
Hydrochlorate and methoxy-methyl acrylate react in a solvent and obtain 1-substituted-phenyl-5-hydroxypyrazoles, and reaction equation is:
In formula, n represents the integer of 1-3, the substituent R on phenyl be hydrogen atom or halogen atom, nitro, cyano group, alkoxyl,
Alkyl, trihalomethyl, described solvent is in methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol
One or more mixture.
The preparation method of 1-substituted-phenyl-5-hydroxypyrazoles the most according to claim 1, it is characterised in that solvent and methoxy
The rate of charge of base acrylic acid methyl ester. is volume (mL) and mM (mmol) ratio 0.2～200 1；Described substituted-phenyl hydrazine
Or the molar ratio of the hydrochlorate of substituted-phenyl hydrazine and methoxy-methyl acrylate is 1 0.7～1.4.；Reaction temperature is 40 DEG C
To the temperature of reaction dissolvent backflow, the response time is 1～240h.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330639A (en) * | 1998-11-19 | 2002-01-09 | 巴斯福股份公司 | Method for producing 1-substituted 5-or 3-hydroxypyrazoles |
| CN101774972A (en) * | 2010-02-02 | 2010-07-14 | 浙江大学 | Method for synthesizing methoxyacrylate compound |
| CN101959882A (en) * | 2007-12-27 | 2011-01-26 | 第一三共株式会社 | Imidazole carbonyl compound |
| CN102030710A (en) * | 2010-11-23 | 2011-04-27 | 浙江大学 | Method for synthesizing 14 C-labeled compound of pyraoxystrobin serving as bactericide |
-
2014
- 2014-06-27 CN CN201410298552.5A patent/CN104059020B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330639A (en) * | 1998-11-19 | 2002-01-09 | 巴斯福股份公司 | Method for producing 1-substituted 5-or 3-hydroxypyrazoles |
| CN101959882A (en) * | 2007-12-27 | 2011-01-26 | 第一三共株式会社 | Imidazole carbonyl compound |
| CN101774972A (en) * | 2010-02-02 | 2010-07-14 | 浙江大学 | Method for synthesizing methoxyacrylate compound |
| CN102030710A (en) * | 2010-11-23 | 2011-04-27 | 浙江大学 | Method for synthesizing 14 C-labeled compound of pyraoxystrobin serving as bactericide |
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