CN108997309A - A kind of preparation method of pyrazoles -4- aryl derivatives - Google Patents
A kind of preparation method of pyrazoles -4- aryl derivatives Download PDFInfo
- Publication number
- CN108997309A CN108997309A CN201810782759.8A CN201810782759A CN108997309A CN 108997309 A CN108997309 A CN 108997309A CN 201810782759 A CN201810782759 A CN 201810782759A CN 108997309 A CN108997309 A CN 108997309A
- Authority
- CN
- China
- Prior art keywords
- pyrazoles
- preparation
- derivative
- pinacol borate
- palladium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CC1(C)OB(C(C([*+])=CC)=C)OC1(C)C Chemical compound CC1(C)OB(C(C([*+])=CC)=C)OC1(C)C 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a kind of preparation methods of pyrazoles -4- aryl derivatives, including step are as follows: is blended in reaction in the first solvent and prepares pyrazoles -4- aryl derivatives halogenated aryl hydrocarbon derivative, pyrazoles -4- pinacol borate derivative, the first alkali, the first phase transfer catalyst, the first palladium-based catalyst.Through the above way, pyrazoles -4- the aryl derivatives of the invention, it is prepared using " one kettle way ", reaction condition is mild, post-processing is easy, is adapted to a variety of halogenated aryl hydrocarbon derivatives, strong operability, suitable industrialized production, resulting substituted pyrazole compound can be widely applied to the fields such as chemical industry, medicine, biology and material.
Description
Technical field
The present invention relates to pharmaceutical chemistry and technical field of material chemistry, more particularly to a kind of system of pyrazoles -4- aryl derivatives
Preparation Method.
Background technique
Pyrazoles -4- aryl derivatives are a kind of important organic compounds, because they have different coordination modes, pyrrole
Azoles -4- aryl derivatives also result in the interest of inorganic supermolecular scholar.The hydrolysis-stable of pyrazoles -4- aryl derivatives is matched
Position key causes material to have the chemical and thermal stability enhanced, therefore pyrazoles has been used as constructing metal-organic framework (MOF)
Ligand.Meanwhile the bioactivity that pyrazoles -4- aryl analog derivative is intrinsic, so that it is a kind of important medicine, pesticide, molecule
Material has broad application prospects.
Summary of the invention
The invention mainly solves the technical problem of providing a kind of preparation method of pyrazoles -4- aryl derivatives, high income,
Easy to operate, reaction condition is mild.
In order to solve the above technical problems, one technical scheme adopted by the invention is that: it is derivative to provide a kind of pyrazoles -4- aryl
The preparation method of object, including step are as follows: by halogenated aryl hydrocarbon derivative, pyrazoles -4- pinacol borate derivative, the first alkali,
One phase transfer catalyst, the first palladium-based catalyst are blended in reaction in the first solvent and prepare pyrazoles -4- aryl derivatives, the pyrrole
The general structure of azoles -4- aryl derivatives are as follows:
(I)；
Synthetic route are as follows:
。
In a preferred embodiment of the present invention, the specific preparation process of the pyrazoles -4- aryl derivatives are as follows: (1) exist
Inert gas (nitrogen or argon gas) protection under, by halogenated aryl hydrocarbon derivative, pyrazoles -4- pinacol borate derivative, the first alkali,
First phase transfer catalyst, the first palladium-based catalyst are added in the first solvent, are obtained after stirring 12-24h at 70-140 DEG C
The reaction solution of pyrazoles -4- aryl derivatives；(2) reaction solution for obtaining step (1) is through filtering, organic phase be evaporated after with organic molten
Agent dissolution, adds water washing 2-3 times, evaporated under reduced pressure organic phase obtains pyrazoles -4- aryl derivatives.
In a preferred embodiment of the present invention, the halogenated aryl hydrocarbon derivative is ArX, and wherein Ar is phenyl, substituted benzene
Base, five-ring heterocycles aromatic hydrocarbons, hexa-member heterocycle aromatic hydrocarbons, biphenyl, pyridine ring or substituted pyridines, X are Br or I.
In a preferred embodiment of the present invention, first phase transfer catalyst is R4NX, wherein R is H or C1-C18, X
For Cl, Br or I.
In a preferred embodiment of the present invention, first alkali is acetate MOAc or carbonate M2CO3, wherein M be
Li, Na, K or Cs.
In a preferred embodiment of the present invention, first palladium-based catalyst is Pd (PPh3)2Cl2、Pd(OAc)2、
PdCl2、Pd(PPh3)4In it is one or more.
In a preferred embodiment of the present invention, first solvent be Isosorbide-5-Nitrae-dioxane, dimethylformamide DMF,
It is one or more in dimethyl sulfoxide DMSO.
In a preferred embodiment of the present invention, the pyrazoles -4- pinacol borate derivative the preparation method comprises the following steps: will
4- bromine pyrazoles, connection pinacol borate, the second alkali, the second phase transfer catalyst, the second palladium-based catalyst are blended in the second solvent
Middle reaction prepares pyrazoles -4- pinacol borate derivative, the general structure of the pyrazoles -4- pinacol borate derivative
Are as follows:
(II)。
In a preferred embodiment of the present invention, the specific preparation process of the pyrazoles -4- pinacol borate derivative
Are as follows: (1) under inert gas protection, by 4- bromine pyrazoles, connection pinacol borate, the second alkali, the second phase transfer catalyst, second
Palladium-based catalyst is added in the second solvent, is obtained pyrazoles -4- pinacol borate after stirring 4-12h at 70-140 DEG C and is derived
The reaction solution of object；(2) through filtering, organic phase is dissolved after being evaporated with organic solvent the reaction solution for obtaining step (1), adds water washing
2-3 times, it is evaporated organic phase, obtains pyrazoles -4- pinacol borate derivative.
In a preferred embodiment of the present invention, second phase transfer catalyst is R4NX, wherein R is H or C1-C18, X
For Cl, Br or I；Second alkali is acetate MOAc, and wherein M is Li, Na, K or Cs；Second palladium-based catalyst is Pd
(PPh3)2Cl2、Pd(OAc)2、PdCl2In it is one or more；Second solvent is 1,4- dioxane, dimethylformamide
It is one or more in DMF, dimethyl sulfoxide DMSO.
The beneficial effects of the present invention are: pyrazoles -4- the aryl derivatives of the invention, are made using " one kettle way "
Standby, reaction condition is mild, and post-processing is easy, is adapted to a variety of halogenated aryl hydrocarbon derivatives, strong operability, suitable industrialized production,
Resulting substituted pyrazole compound can be widely applied to the fields such as chemical industry, medicine, biology and material.
Specific embodiment
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation
Example is only a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common
Technical staff's all other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
Embodiment one:
A kind of preparation method of pyrazoles -4- pinacol borate derivative, including step are provided are as follows:
Under the protection of nitrogen, 7.35g 1-H-4- bromine pyrazoles is added into 500ml four-hole boiling flask, where 14.0 g join boric acid frequency
Alcohol ester, 6.0g potassium acetate, 2.15g tetrabutylammonium bromide, 0.1g Pd (PPh3)2Cl2, and 100ml Isosorbide-5-Nitrae-dioxane is added,
It is heated to reflux and is stirred to react 12 hours, by being controlled in HPLC.After reaction, it is cooled to room temperature, reaction solution decompression filters, filtrate
Methylene chloride dissolution is added in vacuum rotary steam, and water washing organic phase is multiple, rotates to obtain white products 8.8g, yield 94.0%, HPLC
98.4%。
Embodiment two:
A kind of preparation method of 4- Phenylpyrazole, including step are provided are as follows:
Under the protection of nitrogen, the addition 6.28g bromobenzene into 500ml four-hole boiling flask, 7.76g pyrazoles -4- pinacol borate,
0.1g PdCl2、7.10g K2CO3, 2.15g tetrabutylammonium bromide be added into DMF, heat 130 DEG C, stir 16 hours, pass through
It is controlled in HPLC, standing is cooled to room temperature, and is filtered, vacuum distillation, and methylene chloride dissolution is added, and water washing is concentrated to get white production
Object 5.65g, yield 98.0%, HPLC purity are 98.0%.
Embodiment three:
A kind of preparation method of 4- phenyl -3,5- dimethyl pyrazole, including step are provided are as follows:
Under the protection of nitrogen, 6.28g bromobenzene, 8.96g 3,5- dimethyl pyrazole -4- boron are added into 500ml four-hole boiling flask
Sour pinacol ester, 0.1g PdCl2、7.10g K2CO3, 2.15g tetrabutylammonium bromide be added into DMF, heat 130 DEG C, stirring
16 hours, by controlling in HPLC, standing was cooled to room temperature, and was filtered, vacuum distillation, and methylene chloride dissolution, water washing, concentration is added
Obtain white product 6.84g, yield 98.3%.HPLC purity is 98.1%.
Embodiment 4 to 15 see the table below, and halogenated aryl hydrocarbon used in example IV to 15 is to methyl bromobenzene, adjacent nitro bromine
Benzene, to cyano bromobenzene, to hydroxyl bromobenzene, to methoxybromobenzene, parabromobenzoic acid methyl esters, 1,4- dibromobenzene, 1,3,5- tribromo-benzene,
Three (4- iodobenzene) amine, other are identical as embodiment 1 to 3.Reaction equation in embodiment 4 to 15 is as follows:
The above description is only an embodiment of the present invention, is not intended to limit the scope of the invention, all to be said using the present invention
Equivalent structure or equivalent flow shift made by bright book content is applied directly or indirectly in other relevant technical fields,
Similarly it is included within the scope of the present invention.
Claims (10)
1. a kind of preparation method of pyrazoles -4- aryl derivatives, which is characterized in that including step are as follows: by halogenated aryl hydrocarbon derivative,
Pyrazoles -4- pinacol borate derivative, the first alkali, the first phase transfer catalyst, that the first palladium-based catalyst is blended in first is molten
Reaction prepares pyrazoles -4- aryl derivatives in agent.
2. preparation method according to claim 1, which is characterized in that the specific preparation of the pyrazoles -4- aryl derivatives
Process are as follows: (1) under inert gas (nitrogen or argon gas) protection, halogenated aryl hydrocarbon derivative, pyrazoles -4- pinacol borate are spread out
Biology, the first alkali, the first phase transfer catalyst, the first palladium-based catalyst are added in the first solvent, are stirred at 70-140 DEG C
The reaction solution of pyrazoles -4- aryl derivatives is obtained after 12-24h；(2) reaction solution for obtaining step (1) through filtering, steam by organic phase
It is dissolved after dry with organic solvent, adds water washing 2-3 times, evaporated under reduced pressure organic phase obtains pyrazoles -4- aryl derivatives.
3. preparation method according to claim 1, which is characterized in that the halogenated aryl hydrocarbon derivative is ArX, and wherein Ar is
Phenyl, substituted-phenyl, five-ring heterocycles aromatic hydrocarbons, hexa-member heterocycle aromatic hydrocarbons, biphenyl, pyridine ring or substituted pyridines, X are Br or I.
4. preparation method according to claim 1, which is characterized in that first phase transfer catalyst is R4NX, wherein R
For H or C1-C18, X Cl, Br or I.
5. preparation method according to claim 1, which is characterized in that first alkali is acetate MOAc or carbonate
M2CO3, wherein M is Li, Na, K or Cs.
6. preparation method according to claim 1, which is characterized in that first palladium-based catalyst is Pd (PPh3)2Cl2、
Pd(OAc)2、PdCl2、Pd(PPh3)4In it is one or more.
7. preparation method according to claim 1, which is characterized in that first solvent is Isosorbide-5-Nitrae-dioxane, diformazan
It is one or more in base formamide DMF, dimethyl sulfoxide DMSO.
8. preparation method according to claim 1, which is characterized in that the pyrazoles -4- pinacol borate derivative
The preparation method comprises the following steps: 4- bromine pyrazoles, connection pinacol borate, the second alkali, the second phase transfer catalyst, the second palladium-based catalyst are mixed
It closes the reaction in the second solvent and prepares pyrazoles -4- pinacol borate derivative, the pyrazoles -4- pinacol borate derivative
General structure are as follows:
(II)。
9. preparation method according to claim 8, which is characterized in that the pyrazoles -4- pinacol borate derivative
Specific preparation process are as follows: (1) under inert gas protection, 4- bromine pyrazoles, connection pinacol borate, the second alkali, the second phase are turned
Shifting catalyst, the second palladium-based catalyst are added in the second solvent, obtain pyrazoles -4- boron after stirring 4-12h at 70-140 DEG C
The reaction solution of sour pinacol ester derivative；(2) reaction solution for obtaining step (1) is through filtering, organic phase be evaporated after with organic molten
Agent dissolution, adds water washing 2-3 times, is evaporated organic phase, obtain pyrazoles -4- pinacol borate derivative.
10. preparation method according to claim 8, which is characterized in that second phase transfer catalyst is R4NX, wherein R
For H or C1-C18, X Cl, Br or I；Second alkali is acetate MOAc, and wherein M is Li, Na, K or Cs；Second palladium base
Catalyst is Pd (PPh3)2Cl2、Pd(OAc)2、PdCl2In it is one or more；Second solvent is 1,4- dioxane, diformazan
It is one or more in base formamide DMF, dimethyl sulfoxide DMSO.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810782759.8A CN108997309A (en) | 2018-07-17 | 2018-07-17 | A kind of preparation method of pyrazoles -4- aryl derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810782759.8A CN108997309A (en) | 2018-07-17 | 2018-07-17 | A kind of preparation method of pyrazoles -4- aryl derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108997309A true CN108997309A (en) | 2018-12-14 |
Family
ID=64600145
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810782759.8A Pending CN108997309A (en) | 2018-07-17 | 2018-07-17 | A kind of preparation method of pyrazoles -4- aryl derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108997309A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110698506A (en) * | 2019-11-27 | 2020-01-17 | 怀化旺达生物科技有限公司 | Synthesis method of pyrazole-4-boronic acid pinacol ester |
| CN114181237A (en) * | 2021-12-01 | 2022-03-15 | 上海凌凯医药科技有限公司 | Synthesis method of 1-isopropylpyrazole-5-boronic acid pinacol ester |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1422262A (en) * | 2000-02-07 | 2003-06-04 | 艾博特股份有限两合公司 | 2-benzothiazolyl urea derivatives and their use as protein kinase inhibitors |
| CN102924515A (en) * | 2012-11-02 | 2013-02-13 | 黑龙江大学 | Uni-functional single phosphine-oxygen replaced fluorenyl compound and preparation method and application thereof |
| CN104016915A (en) * | 2014-06-27 | 2014-09-03 | 重庆工商大学 | Preparation method of boscalid |
| WO2017097215A1 (en) * | 2015-12-07 | 2017-06-15 | 杭州雷索药业有限公司 | Wnt pathway inhibitor embedded with ureas structure |
| WO2017212385A1 (en) * | 2016-06-06 | 2017-12-14 | Pfizer Inc. | Substituted carbonucleoside derivatives useful as anticancer agents |
| CN107501101A (en) * | 2017-08-30 | 2017-12-22 | 华南理工大学 | A kind of organic light emission small molecule material of the fluorenes of indenes containing naphtho- unit and preparation method and application |
-
2018
- 2018-07-17 CN CN201810782759.8A patent/CN108997309A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1422262A (en) * | 2000-02-07 | 2003-06-04 | 艾博特股份有限两合公司 | 2-benzothiazolyl urea derivatives and their use as protein kinase inhibitors |
| CN102924515A (en) * | 2012-11-02 | 2013-02-13 | 黑龙江大学 | Uni-functional single phosphine-oxygen replaced fluorenyl compound and preparation method and application thereof |
| CN104016915A (en) * | 2014-06-27 | 2014-09-03 | 重庆工商大学 | Preparation method of boscalid |
| WO2017097215A1 (en) * | 2015-12-07 | 2017-06-15 | 杭州雷索药业有限公司 | Wnt pathway inhibitor embedded with ureas structure |
| WO2017212385A1 (en) * | 2016-06-06 | 2017-12-14 | Pfizer Inc. | Substituted carbonucleoside derivatives useful as anticancer agents |
| CN107501101A (en) * | 2017-08-30 | 2017-12-22 | 华南理工大学 | A kind of organic light emission small molecule material of the fluorenes of indenes containing naphtho- unit and preparation method and application |
Non-Patent Citations (2)
| Title |
|---|
| JULIETTE EMMERICH等: "Lead Optimization Generates CYP11B1 Inhibitors of Pyridylmethyl Isoxazole Type with Improved Pharmacological Profile for the Treatment of Cushing’s Disease", 《J. MED. CHEM.》 * |
| XIAO DING等: "Discovery of 5-substituent-N-arylbenzamide derivatives as potent,selective and orally bioavailable LRRK2 inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110698506A (en) * | 2019-11-27 | 2020-01-17 | 怀化旺达生物科技有限公司 | Synthesis method of pyrazole-4-boronic acid pinacol ester |
| CN114181237A (en) * | 2021-12-01 | 2022-03-15 | 上海凌凯医药科技有限公司 | Synthesis method of 1-isopropylpyrazole-5-boronic acid pinacol ester |
| CN114181237B (en) * | 2021-12-01 | 2024-02-23 | 上海凌凯医药科技有限公司 | Synthesis method of 1-isopropyl pyrazole-5-boric acid pinacol ester |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Jin et al. | Copper-catalysed addition of α-alkyl azaarenes to ethyl glyoxylate via direct C (sp 3)–H activation | |
| CN108997309A (en) | A kind of preparation method of pyrazoles -4- aryl derivatives | |
| CN110204487B (en) | Synthesis method of quinoline derivative | |
| CN108658841A (en) | A kind of carbazole compound and preparation method thereof | |
| CN105693632B (en) | A kind of preparation method of polysubstituted quinoxaline derivant | |
| WO2016141823A1 (en) | Method for synthesizing medical intermediate phenanthrene compounds in potassium bicarbonate environment | |
| CN107266411B (en) | A kind of synthetic method of 9,10- Benzophenanthrene compound | |
| CN110606839A (en) | Green synthesis method of polysubstituted quinazoline derivative | |
| CN105001156B (en) | A kind of three component reaction system synthetic methods of quinoline | |
| CN111004164B (en) | Preparation method of polysubstituted 2-aryl indole derivative | |
| CN108640914B (en) | Method for synthesizing isoindole [2,1-b ] isoquinoline-5, 7-diketone compound | |
| CN105152826A (en) | Method for synthesizing pharmaceutical intermediate biphenyl compound | |
| CN112679430A (en) | Method for preparing isoquinolone compound | |
| CN108947906A (en) | A method of preparing tetra- aryl substituted pyrazolecarboxylic of 1,3,4,5- | |
| CN108484602A (en) | A kind of preparation method of polysubstituted aza-tricycle oxazine derivatives | |
| CN107011250A (en) | One kind 2（2,6 dichlorophenoxies）The preparation method and use of pyridine compounds | |
| CN105732456A (en) | Synthetic method for asymmetric substituted pyrrole compound | |
| CN106278839A (en) | A kind of synthetic method of medicine intermediate diaryl ketone compounds | |
| CN104557926B (en) | A kind of synthetic method of medicine intermediate 3-substituted imidazole pyridine compounds and their | |
| CN106187672A (en) | The synthetic method of triarylbenzenes compounds between a kind of pharmaceutical intermediate | |
| CN109912567A (en) | A kind of biaryl pyrrole derivatives compound and preparation method thereof | |
| CN105130894B (en) | Isoquinoline compound and its synthetic method | |
| CN114292234A (en) | Preparation method of pyrazole derivative | |
| CN105585566A (en) | Method for synthesizing indene ketone and imidazole and pyridine compounds | |
| CN103483337B (en) | Fluorinated isoquinoline [a] pyrrole compounds and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20181214 |