CN104262257A - Preparation method of pyrazole derivative - Google Patents
Preparation method of pyrazole derivative Download PDFInfo
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- CN104262257A CN104262257A CN201410534756.4A CN201410534756A CN104262257A CN 104262257 A CN104262257 A CN 104262257A CN 201410534756 A CN201410534756 A CN 201410534756A CN 104262257 A CN104262257 A CN 104262257A
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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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- 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
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- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of a pyrazole derivative 1-(3- aminophenyl)-3-methyl-1H-pyrazole-5-ol. Ethyl acetoacetate is taken as the starting raw material and is subjected to cyclization, condensation and reduction to obtain a target product. The compound is an important medical intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, particularly the preparation method of a kind of pyrazole derivatives 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol.
Technical background
Compound 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol, structural formula is:
This compound 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol is comparatively difficult.Therefore, need exploitation raw material to be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is suitable.
Summary of the invention
The invention discloses the method that one prepares 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol, take methyl aceto acetate as starting raw material, obtain target product 4 through the ring that reaches a standard, condensation, reduction, synthetic route is as shown in Figure 1.Synthesis step is as follows:
(1) be starting raw material with methyl aceto acetate, obtain 2 through ring closure reaction;
(2) carry out condensation reaction 2, obtain 3;
(3) carry out tertbutyloxycarbonyl protective reaction 3 and obtain 4;
One preferred embodiment in, the reagent that described ring closure reaction prepares compound 2 used is selected from hydrazine hydrate; The alkali that described condensation reaction prepares compound 3 used is selected from salt of wormwood; The reductive agent that described reduction reaction prepares compound 4 used is selected from lithium aluminium hydride.
One preferred embodiment in, the solvent that described ring closure reaction prepares compound 2 used is selected from toluene; The solvent that described condensation reaction prepares compound 3 used is selected from DMF; The solvent that described reduction reaction prepares compound 4 used is selected from tetrahydrofuran (THF).
One preferred embodiment in, described ring closure reaction prepares the reflux temperature that compound 2 temperature of reaction used is solvent; Described reduction reaction prepares the reflux temperature that compound 3 temperature used is solvent; Described reduction reaction prepare compound 4 used be 0 DEG C ~ room temperature.
The present invention relates to the preparation method of a kind of 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol.
The present invention is further described by the following embodiment, and these descriptions are not be further limited content of the present invention.One skilled in the art will understand that the equivalent replacement that technical characteristic of the present invention is done, or improve accordingly, still belong within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 3-methylpyrazole-5-alcohol
20g methyl aceto acetate is joined in 130ml toluene, and add 26g hydrazine hydrate, return stirring spends the night, and concentrated adds ethyl acetate and water again, separatory, drying, concentrated, and residuum upper prop is separated and obtains 17g 3-methylpyrazole-5-alcohol.
(2) synthesis of 3-methyl isophthalic acid-(3-nitrophenyl)-1H-pyrazoles-5-alcohol
16g 3-methylpyrazole-5-alcohol is joined 250ml N, in dinethylformamide, add 9g Anhydrous potassium carbonate and 24g3-Nitrobromobenzene again, reflux stirs 2 hours, be cooled to room temperature again, slowly add ethyl acetate and water, extract separatory, drying, concentrate, on residuum, silicagel column is separated to obtain 19g 3-methyl isophthalic acid-(3-nitrophenyl)-1H-pyrazoles-5-alcohol.
(3) synthesis of 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol
18g 3-methyl isophthalic acid-(3-nitrophenyl)-1H-pyrazoles-5-alcohol joins in 200ml anhydrous tetrahydro furan, cool 0 DEG C, slowly add 6g Lithium Aluminium Hydride again, stirring at room temperature 6 hours, adds aqueous sodium hydroxide solution in batches, filter, collect mother liquor, add ethyl acetate, extraction separatory, dry, concentrated, on residuum, silicagel column is separated to obtain 9g 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol.
Claims (6)
1. prepare a method for pyrazole derivatives 1-(3-aminophenyl)-3-methyl isophthalic acid H-pyrazoles-5-alcohol, take methyl aceto acetate as starting raw material, obtain target product 4 through the ring that reaches a standard, condensation, reduction, synthetic route is as follows.
2. method according to claim 1, it is characterized by 3 described step reactions is,
(1) be starting raw material with methyl aceto acetate, obtain 2 through ring closure reaction;
(2) carry out condensation reaction 2, obtain 3;
(3) carry out tertbutyloxycarbonyl protective reaction 3 and obtain 4;
3. according to the method for claim 1-2, it is characterized in that, the reagent that described ring closure reaction prepares compound 2 used is selected from hydrazine hydrate; Described condensation reaction is prepared compound 3 alkali used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus; Described reduction reaction is prepared compound 4 reductive agent used and is selected from the mixture of one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine.
4. according to the method for claim 1-2, it is characterized in that, described ring closure reaction prepares compound 2 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Compound 3 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N are prepared in described condensation reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, water; Described reduction reaction prepares compound 4 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide.
5. according to the method for claim 1-2, it is characterized in that, described ring closure reaction prepares the reflux temperature that compound 2 temperature of reaction used is 0 DEG C ~ solvent; Described reduction reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; Described reduction reaction prepare compound 4 used be 0 DEG C ~ room temperature.
6. according to the method for claim 1-2, it is characterized in that, described ring closure reaction prepares the reflux temperature that compound 2 temperature of reaction used is solvent; Described reduction reaction prepares the reflux temperature that compound 3 temperature used is solvent; Described reduction reaction prepare compound 4 used be 0 DEG C ~ room temperature.
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| CN201410534756.4A CN104262257A (en) | 2014-10-12 | 2014-10-12 | Preparation method of pyrazole derivative |
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| CN201410534756.4A CN104262257A (en) | 2014-10-12 | 2014-10-12 | Preparation method of pyrazole derivative |
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| CN201410534756.4A Pending CN104262257A (en) | 2014-10-12 | 2014-10-12 | Preparation method of pyrazole derivative |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831585A (en) * | 2016-12-11 | 2017-06-13 | 湖南华腾制药有限公司 | A kind of preparation method of pyrazole compound |
| CN106883177A (en) * | 2017-02-26 | 2017-06-23 | 长沙深橙生物科技有限公司 | A kind of preparation method of benzene substituted pyrazole derivative |
| CN107235903A (en) * | 2016-03-28 | 2017-10-10 | 长沙深橙生物科技有限公司 | A kind of preparation method of pyrazole compound |
| CN107513038A (en) * | 2016-06-16 | 2017-12-26 | 湖南华腾制药有限公司 | A kind of preparation method of nitrogen-containing heterocycle compound |
| CN107513037A (en) * | 2016-06-16 | 2017-12-26 | 湖南华腾制药有限公司 | A kind of preparation method of 1 substituted pyrazole derivative |
| CN107513039A (en) * | 2016-06-16 | 2017-12-26 | 湖南华腾制药有限公司 | A kind of synthesis technique of 1 substituted pyrazole derivative |
| CN107793359A (en) * | 2016-08-29 | 2018-03-13 | 湖南华腾制药有限公司 | A kind of synthetic method of pyrazole derivatives |
| CN108117538A (en) * | 2016-11-28 | 2018-06-05 | 湖南华腾制药有限公司 | A kind of pyridine connects the preparation method of pyrazole compound |
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| WO2008121861A2 (en) * | 2007-03-28 | 2008-10-09 | Xenon Pharmaceuticals Inc. | Pyrazole and pyrrole compounds useful in treating iron disorders |
| CN101367763A (en) * | 2007-08-17 | 2009-02-18 | 深圳泛胜塑胶助剂有限公司 | Synthesis process of 1-phenyl-3-methyl-5-pyrazolone |
| CN103588709A (en) * | 2012-08-17 | 2014-02-19 | 上海医药工业研究院 | Preparation method for edaravone |
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2014
- 2014-10-12 CN CN201410534756.4A patent/CN104262257A/en active Pending
Patent Citations (3)
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| WO2008121861A2 (en) * | 2007-03-28 | 2008-10-09 | Xenon Pharmaceuticals Inc. | Pyrazole and pyrrole compounds useful in treating iron disorders |
| CN101367763A (en) * | 2007-08-17 | 2009-02-18 | 深圳泛胜塑胶助剂有限公司 | Synthesis process of 1-phenyl-3-methyl-5-pyrazolone |
| CN103588709A (en) * | 2012-08-17 | 2014-02-19 | 上海医药工业研究院 | Preparation method for edaravone |
Non-Patent Citations (1)
| Title |
|---|
| MEENA K. PUROHIT，等: "Structure–activity relationships of pyrazole derivatives as potential therapeutics for immune thrombocytopenias", 《BIOORG. MED. CHEM》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107235903A (en) * | 2016-03-28 | 2017-10-10 | 长沙深橙生物科技有限公司 | A kind of preparation method of pyrazole compound |
| CN107513038A (en) * | 2016-06-16 | 2017-12-26 | 湖南华腾制药有限公司 | A kind of preparation method of nitrogen-containing heterocycle compound |
| CN107513037A (en) * | 2016-06-16 | 2017-12-26 | 湖南华腾制药有限公司 | A kind of preparation method of 1 substituted pyrazole derivative |
| CN107513039A (en) * | 2016-06-16 | 2017-12-26 | 湖南华腾制药有限公司 | A kind of synthesis technique of 1 substituted pyrazole derivative |
| CN107793359A (en) * | 2016-08-29 | 2018-03-13 | 湖南华腾制药有限公司 | A kind of synthetic method of pyrazole derivatives |
| CN108117538A (en) * | 2016-11-28 | 2018-06-05 | 湖南华腾制药有限公司 | A kind of pyridine connects the preparation method of pyrazole compound |
| CN106831585A (en) * | 2016-12-11 | 2017-06-13 | 湖南华腾制药有限公司 | A kind of preparation method of pyrazole compound |
| CN106883177A (en) * | 2017-02-26 | 2017-06-23 | 长沙深橙生物科技有限公司 | A kind of preparation method of benzene substituted pyrazole derivative |
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Application publication date: 20150107 |