CN106866536A - A kind of method for preparing the amino-pyrazol of 4 halo 5 - Google Patents
A kind of method for preparing the amino-pyrazol of 4 halo 5 Download PDFInfo
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- CN106866536A CN106866536A CN201710235849.0A CN201710235849A CN106866536A CN 106866536 A CN106866536 A CN 106866536A CN 201710235849 A CN201710235849 A CN 201710235849A CN 106866536 A CN106866536 A CN 106866536A
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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
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Abstract
The invention belongs to field of heterocyclic compound in organic chemistry, and in particular to a kind of method for preparing the amino-pyrazol of 4 halo 5.The amino-pyrazol of 4 halo 5 shown in formula I, wherein R1Represent alkyl, cycloalkyl, alkoxy, cyano group or nitro；R2Represent alkyl or aryl, and each substituent R2By one or more halogen atoms are replaced；X represents Cl or Br.To NBS or NCS is added in the dichloromethane solution of compound shown in Formula II, reaction is stirred at room temperature, reaction removes solvent, residue is acidified after terminating, is adjusted to alkalescence again after activated carbon decolorizing, crystallization separates out product, and suction filtration, drying obtains compound shown in Formulas I.The technology of the present invention route is easy, easily operation, low cost；The accessory substance that reaction is produced is removed on its water miscible influence using product acid-base property, product purity and yield is can reach more than 90%；Can be carried out under reaction normal temperature, be adapted to industrialized production.
Description
Technical field
The invention belongs to field of heterocyclic compound in organic chemistry, and in particular to one kind prepares 4- halo -5- amino-pyrazols
Method.
Background technology
In recent ten years, heterocyclic compound causes the pass of the world of medicine and agricultural chemicals circle personage because of its efficient bioactivity
Note, the focus as current drug development research.Pyrazole compound is an important branch in heterocyclic compound, with wide
General bioactivity, it is changeable transsexual with efficient, low toxicity and its ring substituents, be widely used in anti-inflammatory, it is antibacterial,
Sterilization, anticoagulant, desinsection, weeding, the research and development of plant growth regulating isoreactivity compound, are new medicine and agricultural chemicals
Exploitation provides a large amount of compounds with excellent activity.Some contain the commercialization of pyrazoles agricultural chemicals, such as bactericide pyrazoles
Fluoxastrobin, insecticide fluorine worm cyanogen, chlorantraniliprole, herbicide pyrazoles Sulfometuron Methyl etc..
5- amino-pyrazols are the important intermediate for synthesizing many bioactivators, such as the aryl pyrrole with insecticidal activity
Azoles type amide compound, can be used to develop the arylpyrazoles compound of herbicide and plant growth regulator.1- aryl -5-
The bromo or chloro in the 4th site are the important means for optimizing these chemical combination microbic activities on amino-pyrazol.
So far, the bromo and chloro on 5- aminoaryls pyrazoles mainly have two methods：1. it is sub- with bromine and dichloro
Sulfone, they not only have high toxicity and highly corrosive, it is desirable to reaction temperature be also at subzero tens degree, and post processing trouble；
2. N- bromo-succinimides (NBS) and N- chlorosuccinimides (NCS) are used, reaction condition is gentle, but uses column chromatography
Chromatography carries out product purification, and complex operation is not suitable for industrialized production.Therefore, synthesis step is simple, technical process is green for selection
The synthetic route of the reasonable low cost that colour circle is protected, product quality is good is given birth to realizing arylpyrazoles compound large-scale industrialization
Producing has very great meaning.
The content of the invention
The purpose of the present invention is to propose to a kind of method for preparing 4- halo -5- amino-pyrazols, concrete technical scheme is as follows：
4- halo -5- amino-pyrazols shown in formula I, a kind of method for preparing 4- halo -5- amino-pyrazols, including following step
Suddenly：
1) to halide reagent is added in the dichloromethane solution of compound shown in Formula II, reaction is stirred at room temperature, reaction terminates
After remove dichloromethane；The halide reagent is N- bromo-succinimides or N- chlorosuccinimides；
2) by step 1) in product aqueous acid dissolve, make PH≤2, add activated carbon, boiling decoloring then to remove
Activated carbon；
3) under ice-water bath, by step 2) products therefrom alkali is adjusted to PH >=8, and crystallization separates out product, and suction filtration, drying is obtained
To compound shown in Formulas I；
Wherein R1Represent alkyl, cycloalkyl, alkoxy, cyano group or nitro；R2Represent alkyl or aryl, and each substitution base
R2By one or more halogen atoms are replaced；X represents Cl or Br.
Step 2) in acid be concentrated hydrochloric acid, glacial acetic acid or the concentrated sulfuric acid.
Step 2) for the 5%-20% of material quality, the boiling decoloring time is 3-5min to the middle amount for adding activated carbon.
Step 2) in activated carbon using suction filtered through kieselguhr method remove.
Step 3) in alkali be NaOH, concentrated ammonia liquor or sodium acid carbonate.
Compound shown in Formula II is (0.5 with the mol ratio of halide reagent:1)~(5:1).
The purity and yield of compound shown in Formulas I are more than 90%.
Beneficial effects of the present invention are：
1st, the method for preparing 4- halo -5- amino-pyrazols of the invention does not use bromine and the chlorination of high toxicity and highly corrosive
Sulfoxide, makes reaction to carry out at normal temperatures, is adapted to industrialized production, and halo rate is up to more than 95%.
2nd, the present invention use activated carbon boiling decoloring, can remove dereaction generation foreign pigment, regulation PH make object from
Crystallized in water and separated out, yield and purity are up to more than 90%.
3rd, reaction condition of the present invention is simple, and step operation simplifies, and inorganic acid and alkaloids are most economical industrial chemicals,
A small amount of activated carbon cost is very low.
Brief description of the drawings
Fig. 1 is the liquid chromatogram of the bromo- 3- isopropyls -1- methyl -5- amino-pyrazols of 4-.
Fig. 2 is the liquid chromatogram of the bromo- 1- tert-butyl groups -3- methyl -5- amino-pyrazols of 4-.
Fig. 3 is the liquid chromatogram of the chloro- 3- methyl -5- amino-pyrazols of 1- (4- bromophenyls) -4-.
Fig. 4 is the liquid chromatogram of 4- chloro- 3- ethyls -1- (4- fluorophenyls) -5- amino-pyrazols.
Specific embodiment
5- aminoaryl pyrazole compounds have basic group, and their its corresponding conjugation acid ion of alkali molecules has
Entirely different physicochemical properties.The conjugation acid ion of 5- aminoaryl pyrazole compounds in acid condition it is water-soluble very
It is good, it is insoluble in the organic solvents such as dichloromethane；Then dissolubility is poor in water for corresponding alkali molecules, in the dissolving of dichloromethane
Property is fine.Therefore, using molecular compound can be tightly held by activated carbon and ionic compound be not tightly held by activated carbon the characteristics of, lead to
To overregulate after acid-base property and remove non-acid, non-alkaline organic matter with the method for charcoal absorption and be dissolved in other molecule chemical combination of water
Thing, can reach the purpose of purifying.
The present invention proposes a kind of method for preparing 4- halo -5- amino-pyrazols, and the present invention is done with reference to embodiment
It is further described.
Embodiment 1：The preparation of the bromo- 3- isopropyls -1- methyl -5- amino-pyrazols of 4-
13.9g 3- isopropyl -1- methyl -5- amino-pyrazols are dissolved in 200mL dichloromethane, under the conditions of ice-water bath, plus
Enter 19.9g NBS, it is slow to recover to room temperature, stir 2h；Revolving remove dichloromethane, residue 4mol/L hydrochloric acid be adjusted to PH≤
2, it is subsequently adding 3g activated carbons and is heated to boiling, holding boiling time is 3-5min, while hot with suction filtered through kieselguhr, and uses deionization
Water is rinsed；Gained filtrate is adjusted to PH >=8 with 12mol/L sodium hydroxide solutions, now has a large amount of lightpinks to white crystal to separate out,
Suction filtration, dries, and obtains the bromo- 3- isopropyls -1- methyl -5- amino-pyrazols of 20.7g target products 4-, and yield is 95%, and purity is
95%, liquid chromatogram such as Fig. 1.
1H NMR(300MHz,CDCl3) δ 3.65 (s, 5H), 2.95 (dt, J=14.0,7.0Hz, 1H), 1.29 (d, J=
7.0Hz,6H).13C NMR(75MHz,CDCl3)δ153.2,142.2,76.6,34.7,27.0,20.9.
Embodiment 2：The preparation of the bromo- 1- tert-butyl groups -3- methyl -5- amino-pyrazols of 4-
The 30.6g 1- tert-butyl group -3- methyl -5- amino-pyrazols are dissolved in 300mL dichloromethane, under the conditions of ice-water bath, plus
Enter 39.8g NBS, it is slow to recover to room temperature, stir 2h；Rotate away dichloromethane, residue 4mol/L hydrochloric acid be adjusted to PH≤
2, it is subsequently adding 6g activated carbons and is heated to boiling, holding boiling time is 3-5min, while hot with suction filtered through kieselguhr, and uses deionization
Water is rinsed；Gained filtrate is adjusted to PH >=8 with 12mol/L sodium hydroxide solutions, now has a large amount of lightpinks to white crystal to separate out,
Suction filtration, dries, and obtains the preparation of the bromo- 1- tert-butyl groups -3- methyl -5- amino-pyrazols of 42.2g target products 4-, and yield is 91%, pure
It is 93% to spend, liquid chromatogram such as Fig. 2.
1H NMR(300MHz,CDCl3)δ3.64(s,2H),2.09(s,3H),1.53(s,9H).13C NMR(75MHz,
CDCl3)δ142.7,141.8,81.0,58.8,28.7,12.3.
Embodiment 3：The preparation of the chloro- 3- methyl -5- amino-pyrazols of 1- (4- bromophenyls) -4-
25.6g 1- (4- bromophenyls) -3- methyl -5- amino-pyrazols are dissolved in 200mL dichloromethane, ice-water bath condition
Under, 15.0g NCS are added, it is slow to recover to room temperature, stir 2h；Dichloromethane is rotated away, residue is adjusted with 4mol/L hydrochloric acid
To PH≤2, it is subsequently adding 6g activated carbons and is heated to boiling, holding boiling time is 3-5min, while hot with suction filtered through kieselguhr, is used in combination
Deionized water rinsing；Gained filtrate is adjusted to PH >=8 with 12mol/L sodium hydroxide solutions, now there is a large amount of lightpinks to white crystalline substance
Body is separated out, suction filtration, is dried, and obtains the chloro- 3- methyl -5- amino-pyrazols of 26.6g target products 1- (4- bromophenyls) -4-, and yield is
93%, purity is 97%, liquid chromatogram such as Fig. 3.
1H NMR(300MHz,CDCl3)δ7.58–7.50(m,2H),7.44–7.36(m,2H),3.91(s,2H),2.19
(s,3H).13C NMR(75MHz,CDCl3)δ146.0,140.7,137.4,132.2,124.0,120.3,93.5,11.3.
Embodiment 4：The preparation of 4- chloro- 3- ethyls -1- (4- fluorophenyls) -5- amino-pyrazols
41.9g 3- ethyls -1- (4- fluorophenyls) -5- amino-pyrazols are dissolved in 200mL dichloromethane, ice-water bath condition
Under, 30.0g NCS are added, it is slow to recover to room temperature, stir 2h；Dichloromethane is rotated away, residue is adjusted with 4mol/L hydrochloric acid
To PH≤2, it is subsequently adding 8g activated carbons and is heated to boiling, holding boiling time is 3-5min, while hot with suction filtered through kieselguhr, is used in combination
Deionized water rinsing；Gained filtrate is adjusted to PH >=8 with 12mol/L sodium hydroxide solutions, now there is a large amount of lightpinks to white crystalline substance
Body is separated out, suction filtration, is dried, and obtains target product 4- chloro- 3- ethyls -1- (4- fluorophenyls) -5- amino-pyrazol 44.1g, and yield is
92%, purity is 98%, liquid chromatogram such as Fig. 4.
1H NMR(300MHz,DMSO)δ7.56–7.45(m,2H),7.19–7.09(m,2H),3.80(s,2H),2.62
(q, J=7.6Hz, 2H), 1.27 (t, J=7.6Hz, 3H)13C NMR(75MHz,CDCl3) δ 161.22 (d, J=246Hz),
(d, J=2.9Hz), 150.7,140.7,134.5 125.1 (d, J=8.2Hz), 116.0 (d, J=22.5Hz), 115.9,
92.20(s),19.6,12.2.
Claims (7)
1. a kind of method for preparing 4- halo -5- amino-pyrazols, it is characterised in that 4- halo -5- amino-pyrazols shown in formula I,
Preparation method comprises the following steps：
1) to halide reagent is added in the dichloromethane solution of compound shown in Formula II, reaction is stirred at room temperature, reaction terminates to remove
Dichloromethane；The halide reagent is N- bromo-succinimides or N- chlorosuccinimides；
2) by step 1) in product aqueous acid dissolve, make PH≤2, add activated carbon, boiling decoloring, then except deactivation
Charcoal；
3) under ice-water bath, by step 2) products therefrom alkali is adjusted to PH >=8, and crystallization separates out product, and suction filtration, drying obtains Formulas I
Shown compound；
Wherein R1Represent alkyl, cycloalkyl, alkoxy, cyano group or nitro；R2Represent alkyl or aryl, and each substituent R2For
One or more halogen atoms are replaced；X represents Cl or Br.
2. method according to claim 1, it is characterised in that step 2) in acid be concentrated hydrochloric acid, glacial acetic acid or the concentrated sulfuric acid.
3. method according to claim 1, it is characterised in that step 2) in add the amount of activated carbon be material quality
5%-20%, the boiling decoloring time is 3-5min.
4. method according to claim 1, it is characterised in that step 2) in activated carbon removed using suction filtered through kieselguhr method.
5. method according to claim 1, it is characterised in that step 3) in alkali be NaOH, concentrated ammonia liquor or bicarbonate
Sodium.
6. method according to claim 1, it is characterised in that the mol ratio of compound shown in the Formula II and halide reagent
It is (0.5:1)~(5:1).
7. method according to claim 1, it is characterised in that the purity and yield of compound shown in the Formulas I exist
More than 90%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6410533B1 (en) * | 2000-02-10 | 2002-06-25 | Genzyme Corporation | Antibacterial compounds |
| CN1946715A (en) * | 2004-02-27 | 2007-04-11 | 拜尔药品公司 | Heteroarylaminopyrazole derivatives useful for the treatment of diabetes |
| CN106132967A (en) * | 2014-03-27 | 2016-11-16 | 詹森药业有限公司 | 4,5,6,7 tetrahydro-pyrazoles being replaced also [1,5 a] pyrimidine derivatives and 2,3 dihydro 1H imidazo [1,2 b] pyrazole derivatives as ROS1 inhibitor |
-
2017
- 2017-04-12 CN CN201710235849.0A patent/CN106866536A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6410533B1 (en) * | 2000-02-10 | 2002-06-25 | Genzyme Corporation | Antibacterial compounds |
| CN1946715A (en) * | 2004-02-27 | 2007-04-11 | 拜尔药品公司 | Heteroarylaminopyrazole derivatives useful for the treatment of diabetes |
| CN106132967A (en) * | 2014-03-27 | 2016-11-16 | 詹森药业有限公司 | 4,5,6,7 tetrahydro-pyrazoles being replaced also [1,5 a] pyrimidine derivatives and 2,3 dihydro 1H imidazo [1,2 b] pyrazole derivatives as ROS1 inhibitor |
Non-Patent Citations (3)
| Title |
|---|
| DARREN DRESSEN,等: "Preparation and Optimization of a Series of 3-Carboxamido-5-phenacylaminopyrazole Bradykinin B1 Receptor Antagonists", 《J. MED. CHEM.》 * |
| ROBERT E. SAMMELSON，等: "GABA receptor antagonists and insecticides: common structural features of 4-alkyl-1-phenylpyrazoles and 4-alkyl-1-phenyltrioxabicyclooctanes", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 马海军，等: "1-芳基-3-吡唑酰胺类化合物的合成与生物活性研究", 《精细化工中间体》 * |
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