CN108707113A - A kind of synthetic method of N- alkyl-cyano pyrazole - Google Patents
A kind of synthetic method of N- alkyl-cyano pyrazole Download PDFInfo
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- CN108707113A CN108707113A CN201810691028.2A CN201810691028A CN108707113A CN 108707113 A CN108707113 A CN 108707113A CN 201810691028 A CN201810691028 A CN 201810691028A CN 108707113 A CN108707113 A CN 108707113A
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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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- 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
- C07D231/16—Halogen atoms or nitro radicals
Abstract
A kind of synthetic method of N- alkyl-cyano pyrazole, using water as reaction dissolvent, obtains N- alkyl-cyano pyrazole using 1- alkyl -1H- pyrazoles formaldehyde or its derivative, ammonium hydroxide, sodium bromate and acetic acid as raw material.Synthetic method craft of the present invention is simple, does not use extremely toxic substance, and synthesis is convenient, and yield is high, and products therefrom purifying is convenient, is conducive to large-scale industrial production.
Description
Technical field
The present invention relates to a kind of synthetic methods of N- alkyl-cyano pyrazole.
Background technology
N- alkyl-cyano pyrazole is in sedative（Referring to Zheng Lianyou, the conjunction of the novel calm somnifacient Zaleplons of Wang Song blueness
At Gong Yigaijin [J]Chinese journal of Medicinal Chemistry, 2001,11（6）：353- 355.）, antibacterial, antineoplastic（Referring to Yun G,
Maneva L, Stanoeva E, et al. Study of the antibacterial and antitumor activity
of N-benzyl-substituted 5-amino-1H-pyrazole-4-carboxylic acid and their
Derivatives [ J ] Dokl Bolg Akad Nauk, 1990,43:101-103.）, antiepileptic is { referring to James L.
Kelley, Ronda G. Davis,T Ed W. McLean,T Robert C. Glen,5 Francis E. Soroko,
and
Barrett R. Cooper Synthesis and Anticonvulsant Activity of jV-
Benzylpyrrolo[2,3-d]-,-pyrazolo[3,4-d]-,and -triazolo[4,5-d]pyrimidines:
Imidazole Ring-Modified Analogues of 9-(2-Fluorobenzyl)-6-(methylamino)-9H-
Purine, J. Med. Chem. 1995,38,3884-3888 }, herbicide referring to Liu length enable sulfonylurea herbicides open
The Xin Jinzhan [ of hair;J]Pesticide science and management, 2000,21（6）：35-39. } the fields such as synthesis be widely used, at present
Most of production of N- alkyl-cyano pyrazole is using dicyano compound cyclization method { referring to John M. Fevig, Joseph
Cacciola, Joseph Buriak, Karen A. Rossi, Patrick Y. S. Lam, Preparation of 1-
(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones as potent, selective
And bioavailable inhibitors of coagulation factor Xa, Bioorganic & Medicinal
Chemistry Letters 16 (2006) 3755-3760. and Sanath K Meegalla, Dario Doller, Gary
M Silver, Nancy Wisnewski, Dale Dhanoa, 5-Amino-1- (2,6-dichloro-4-
trifluoromethyl-phenyl)-3-[3H3]-methylsulfanyl-1H-pyrazole-4-carbonitrile
(CTOM): Synthesis and Characterization of a Novel and Selective Insect GABA
Receptor Radioligand, Bioorganic & Medicinal Chemistry Letters 13 (2003) 4035–
4037. }, reaction needs to use dicyano compound, and heavy nitrogen is needed to produce hydrazo compound, and reaction step is long, cumbersome；
The method that other prior arts use is cyanide nucleophilic displacement of fluorine method { referring to D SILVA THEMISTOCLES; ANCEL
JEAN-ERICK, PROCESSES FOR PREPARING PESTICIDAL INTERMEDIATES[P], WO9839302.},
The disadvantage is that cyanide has severe toxicity, complex steps, low yield to be unfavorable for large-scale industrial production.
Invention content
The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide that a kind of synthetic method is simple, cost
It is relatively low, yield is high, suitable for amplify industrialized production N- alkyl-cyano pyrazole synthetic method.
The present invention solve its technical problem the technical solution adopted is that：A kind of synthetic method of N- alkyl-cyano pyrazole, with
1- alkyl -1H- pyrazoles formaldehyde or its derivative, ammonium hydroxide, sodium bromate and acetic acid are that raw material obtains N- using water as reaction dissolvent
Alkyl-cyano pyrazole.
Corresponding reaction equation is as follows：
In the present invention,Indicate aldehyde radical in the 3- either substituted pyrazolecarboxylic of 4- or 5- or its derivative.Other objects
The expression of matter is similar.
R indicates alkyl.
Other sites can also have other substituent groups, such as halogen atom, methyl, ethyl on the pyrazole ring of derivative.
This reaction mechanism
Using 1- alkyl -1H- pyrazoles formaldehyde or its derivative as raw material, ammonium hydroxide is the source of alkali and nitrogen for this reaction, and sodium bromate is
Oxidant, acetic acid is solvent and reactant and provides acidic environment, and water is reaction dissolvent.Amino molecule is first and aldehyde reaction in reaction
Imines is formed, is then heated in the presence of oxidant sodium bromate and acetic acid, causes imines oxidation reaction and generates cyano, while bromine
Sour sodium reduction becomes sodium bromide, and theoretically 1 mole of sodium bromate can at most aoxidize 3 moles of imines into nitrile.
The ammonium hydroxide can be industrial ammonia, wherein the mass concentration containing amino molecule is 25-28wt%.
On the basis of the amount of the substance of 1- alkyl -1H- pyrazoles formaldehyde, the content of ammonia is 1- alkyl -1H- pyrazoles first in ammonium hydroxide
1 times or more of the amount of the substance of aldehyde（It is preferred that 1.2-100 times, more preferable 1.5-20 times）.Ammonium hydroxide is the source of cyanide nitrogen, and dosage is
1 times or more, to avoid the volatilization loss of reaction system ammonium hydroxide, ammonium hydroxide can be excessive, excessive ammonium hydroxide plays the role of solvent.
Sodium bromate is oxidant, and dosage is 0.3-10 times of the amount for the substance for being equivalent to 1- alkyl -1H- pyrazoles formaldehyde（It is excellent
Select 0.3-5 times, more preferable 0.4-3 times）.Acetic acid dosage is the 1-100 of the amount for the substance for being equivalent to 1- alkyl -1H- pyrazoles formaldehyde
Times（It is preferred that 4-40 times）.The dosage of water is 1-10000 times of the amount for the substance for being equivalent to 1- alkyl -1H- pyrazoles formaldehyde（It is preferred that
20-800 times）.Reaction temperature is 90-110 DEG C.
It is preferred that using following steps：
1- alkyl -1H- pyrazoles formaldehyde, sodium bromate and acetic acid are mixed, ammonium hydroxide and water is added, is heated to 90-110 DEG C, reflux is anti-
Should to 1- alkyl -1H- pyrazoles formaldehyde, the reaction was complete, reaction solution is cooled to room temperature, and is poured into quenched dilution in ice water, is neutralized to anti-
It answers liquid to be in neutrality, extracts（It is preferred that being extracted with ethyl acetate or dichloromethane）, it is dry, after concentrated product, it is evaporated under reduced pressure knot of laying equal stress on
Crystalline substance to get.
Yield of the present invention can reach 80-95%.
Synthetic method craft of the present invention is simple, does not use extremely toxic substance, and synthesis is convenient, and yield is high, products therefrom purifying side
Just, it is conducive to large-scale industrial production.
Description of the drawings
Fig. 1 is the nuclear magnetic resonance map of 1 products obtained therefrom N- methyl -4- cyano pyrazoles of the embodiment of the present invention；
Fig. 2 is the nuclear magnetic resonance map of 2 products obtained therefrom N- methyl -5- cyano pyrazoles of the embodiment of the present invention；
Fig. 3 is the nuclear magnetic resonance map of 3 products obtained therefrom N- methyl -3- cyano pyrazoles of the embodiment of the present invention；
Fig. 4 is the nuclear magnetic resonance map of 4 products obtained therefrom N- ethyl -4- cyano pyrazoles of the embodiment of the present invention；
Fig. 5 is 5 products obtained therefrom 1 of the embodiment of the present invention, the nuclear magnetic resonance map of chloro- -4 formonitrile HCNs of 1H- pyrazoles of 3- dimethyl -5-；
Fig. 6 is the nuclear magnetic resonance map of -4 formonitrile HCN of 6 products obtained therefrom 1- isopropyl -1H- pyrazoles of the embodiment of the present invention；
Fig. 7 is the nuclear magnetic resonance map of bromo- -5 formonitrile HCNs of 1- methyl-1s H- pyrazoles of 7 products obtained therefrom 4- of the embodiment of the present invention；
Fig. 8 is the nuclear magnetic resonance map of -4 formonitrile HCN of 8 products obtained therefrom 1- benzyl -1H- pyrazoles of the embodiment of the present invention；
Fig. 9 is 9 products obtained therefrom 1 of the embodiment of the present invention, the nuclear magnetic resonance map of 3- dimethyl -1H- pyrazoles -5- formonitrile HCNs；
Figure 10 is 10 products obtained therefrom 1 of the embodiment of the present invention, the nuclear magnetic resonance map of 5- dimethyl -1H- pyrazoles -3- formonitrile HCNs.
Specific implementation mode
Below in conjunction with specific embodiment, invention is further described in detail.
Embodiment 1
The synthesis of N- methyl -4- cyano pyrazoles
At room temperature, by 1- methyl-1 H- pyrazoles -4- formaldehyde（11.0 grams, 0.1mol）, sodium bromate (6.0 grams, 0.04mol) and 50
Gram acetic acid（0.83mol）Mixing is added 12.5 grams of 25% ammonium hydroxide of mass concentration containing amino molecule and 100 milliliters of water, is heated to 90 DEG C,
Exothermic heat of reaction, 100 DEG C of maintaining reaction temperature, back flow reaction 1 hour（To 1- methyl-1 H- pyrazoles -4- formaldehyde, the reaction was complete）, instead
It answers liquid to be cooled to room temperature, is poured into quenched dilution in ice water, be neutralized to reaction solution and be in neutrality, be extracted with ethyl acetate, it is dry, it is dense
It after contracting product, is evaporated under reduced pressure and recrystallizes, obtain 10.2 grams of product, yield 95%, 99% or more purity.
Fig. 1 is the nuclear magnetic resonance map of the present embodiment products obtained therefrom N- methyl -4- cyano pyrazoles；
1 H-NMR ( 500 MHz, CDCl3 ) δppm: 7.79（1H,s）, 7.78（1H,s）, 3.96（3H,s）.
Embodiment 2
The synthesis of N- methyl -5- cyano pyrazoles
At room temperature, by 1- methyl-1 H- pyrazoles -5- formaldehyde（11.0 grams, 0.1mol）, sodium bromate (4.5 grams, 0.03mol) and 25
Gram acetic acid（0.42mol）Mixing is added the ammonium hydroxide and 50 milliliters of water of 12.5 grams of mass concentrations containing amino molecule 25%, is heated to 90 DEG C,
Exothermic heat of reaction, 100 DEG C of maintaining reaction temperature, back flow reaction 1 hour, until the reaction was complete for 1- methyl-1 H- pyrazoles -5- formaldehyde, reaction
Liquid is cooled to room temperature, and is poured into quenched dilution in ice water, is neutralized to reaction solution and is in neutrality, is extracted with dichloromethane, dry, concentration
It after product, is evaporated under reduced pressure and recrystallizes, obtain 9.1 grams of product, yield 85%, 98% or more purity.
Fig. 2 is the nuclear magnetic resonance map of the present embodiment products obtained therefrom N- methyl -5- cyano pyrazoles；
1 H-NMR ( 500 MHz, CDCl3 ) δppm:7.54（1H, d, J=2.5Hz）, 7.78（1H, d, J=2.5Hz）,
4.06（3H,s）.
Embodiment 3
The synthesis of N- methyl -3- cyano pyrazoles
At room temperature, by 1- methyl-1 H- pyrazoles -3- formaldehyde（11.0 grams, 0.1mol）, sodium bromate (4.5 grams, 0.03mol) and
100 grams of acetic acid（1.67mol）Mixing is added the ammonium hydroxide and 400 milliliters of water of 25 grams of mass concentrations containing amino molecule 25%, is heated to 90
DEG C, exothermic heat of reaction, 100 DEG C of maintaining reaction temperature, to 1- methyl-1 H- pyrazoles -3- formaldehyde, the reaction was complete in 1 hour for back flow reaction, instead
It answers liquid to be cooled to room temperature, is poured into quenched dilution in ice water, be neutralized to reaction solution and be in neutrality, be extracted with ethyl acetate, it is dry, it is dense
It after contracting product, is evaporated under reduced pressure and recrystallizes, obtain 8.6 grams of product, yield 80%, 98% or more purity.
Fig. 3 is the nuclear magnetic resonance map of the present embodiment products obtained therefrom N- methyl -3- cyano pyrazoles；
1 H-NMR ( 500 MHz, CDCl3 ) δppm: 7.45（1H, d, J=2.5Hz）, 6.68（1H, d, J=2.5Hz）,
3.99（3H,s）.
Embodiment 4
The synthesis of N- ethyl -4- cyano pyrazoles
At room temperature, by 1- ethyl -1H- pyrazoles -4- formaldehyde（12.4 grams, 0.1mol）, sodium bromate (30.2 grams, 0.2mol) and
200 grams of acetic acid mixing, are added the ammonium hydroxide and 600 milliliters of water of 50 grams of mass concentrations containing amino molecule 25%, are heated to 90 DEG C, reaction is put
Heat, 100 DEG C of maintaining reaction temperature, to 1- ethyl -1H- pyrazoles -4- formaldehyde, the reaction was complete in 1 hour for back flow reaction, reaction solution cooling
To room temperature, it is poured into quenched dilution in ice water, reaction solution is neutralized to and is in neutrality, be extracted with ethyl acetate, dry, concentrated product
Afterwards, it is evaporated under reduced pressure and recrystallizes, obtain 11.1 grams of product, yield 92%, 99% or more purity.
Fig. 4 is the nuclear magnetic resonance map of the present embodiment products obtained therefrom N- ethyl -4- cyano pyrazoles；
1 H-NMR ( 500 MHz, CDCl3 ) δppm: 7.85（1H,s）, 7.80（1H,s）, 4.24（2H,q,J=9Hz）,
1.53（3H, t, J=9Hz）.
Embodiment 5
The synthesis of chloro- -4 formonitrile HCNs of 1H- pyrazoles of 1,3- dimethyl -5-
At room temperature, by the chloro- 1H- pyrazoles -4- formaldehyde of 1,3- dimethyl -5-（15.9 grams, 0.1mol）, sodium bromate (45.3 grams,
It 0.3mol) is mixed with 100 grams of acetic acid, the ammonium hydroxide and 1000 milliliters of water of 25 grams of mass concentrations containing amino molecule 25% is added, is heated to 90
DEG C, exothermic heat of reaction, 100 DEG C of maintaining reaction temperature, back flow reaction 1 hour is anti-to the chloro- 1H- pyrazoles -4- formaldehyde of 1,3- dimethyl -5-
Should be complete, it is cooled to room temperature, reaction solution is poured into quenched dilution in ice water, is neutralized to reaction solution and is in neutrality, is extracted with dichloromethane
It takes, it is dry, after concentrated product, it is evaporated under reduced pressure and recrystallizes, obtain 14 grams of product, yield 90%, 99% or more purity.
Fig. 5 is the present embodiment products obtained therefrom 1, the nuclear magnetic resonance map of chloro- -4 formonitrile HCNs of 1H- pyrazoles of 3- dimethyl -5-.
1 H-NMR ( 500 MHz, CDCl3 ) δppm: 3.81（3H,s）, 2.34（3H,s）.
Embodiment 6
The synthesis of -4 formonitrile HCN of 1- isopropyl -1H- pyrazoles
At room temperature, by 1- isopropyl -1H- pyrazoles -4- formaldehyde（13.8 grams, 0.1mol）, sodium bromate (60.4 grams, 0.4mol) and
240 grams of acetic acid mixing, are added the ammonium hydroxide and 800 milliliters of water of 50 grams of mass concentrations containing amino molecule 25%, are heated to 90 DEG C, reaction is put
Heat, 100 DEG C of maintaining reaction temperature, to 1- isopropyl -1H- pyrazoles -4- formaldehyde, the reaction was complete in 1 hour for back flow reaction, is cooled to room
Temperature, reaction solution are poured into quenched dilution in ice water, are neutralized to reaction solution and are in neutrality, are extracted with dichloromethane, dry, concentrated product
Afterwards, it is evaporated under reduced pressure and recrystallizes, obtain 12.4 grams of product, yield 92%, 99% or more purity.
Fig. 6 is the nuclear magnetic resonance map of -4 formonitrile HCN of the present embodiment products obtained therefrom 1- isopropyl -1H- pyrazoles；
1 H-NMR ( 500 MHz, CDCl3 ) δppm: 7.84（1H,s）, 7.80（1H,s）, 4.54（1H,m）, 1.55
（3H,s）,1.53（3H,s）.
Embodiment 7
The synthesis of bromo- -5 formonitrile HCNs of 1- methyl-1s H- pyrazoles of 4-
At room temperature, by bromo- -5 formaldehyde of 1- methyl-1s H- pyrazoles of 4-（18.9 grams, 0.1mol）, sodium bromate (9 grams, 0.06mol) and
160 grams of acetic acid mixing, are added the ammonium hydroxide and 200 milliliters of water of 40 grams of mass concentrations containing amino molecule 25%, are heated to 90 DEG C, reaction is put
Heat, 100 DEG C of maintaining reaction temperature, to bromo- -5 formaldehyde of 1- methyl-1s H- pyrazoles of 4-, the reaction was complete in 1 hour for back flow reaction, is cooled to
Room temperature, reaction solution are poured into quenched dilution in ice water, are neutralized to reaction solution and are in neutrality, are extracted with dichloromethane, dry, concentration production
It after product, is evaporated under reduced pressure and recrystallizes, obtain 16 grams of product, yield 86%, 98% or more purity.
Fig. 7 is the nuclear magnetic resonance map of bromo- -5 formonitrile HCNs of 1- methyl-1s H- pyrazoles of the present embodiment products obtained therefrom 4-；
1 H-NMR ( 500 MHz, DMSO-d6 ) δppm: 7.92（1H,s）, 4.03（3H,s）.
Embodiment 8
The synthesis of -4 formonitrile HCN of 1- benzyl -1H- pyrazoles
At room temperature, by -4 formaldehyde of 1- benzyl -1H- pyrazoles（18.6 grams, 0.1mol）, sodium bromate (7.5 grams, 0.05mol) and 200
The mixing of gram acetic acid, is added the ammonium hydroxide and 300 milliliters of water of 50 grams of mass concentrations containing amino molecule 25%, is heated to 90 DEG C, exothermic heat of reaction,
100 DEG C of maintaining reaction temperature, to -4 formaldehyde of 1- benzyl -1H- pyrazoles, the reaction was complete in 1 hour for back flow reaction, is cooled to room temperature, reaction
Liquid is poured into quenched dilution in ice water, is neutralized to reaction solution and is in neutrality, is extracted with dichloromethane, dry, after concentrated product, decompression
It distills and recrystallizes, obtain product 16.6 grams, yield 91%, 98% or more purity.
Fig. 8 is the nuclear magnetic resonance map of -4 formonitrile HCN of the present embodiment products obtained therefrom 1- benzyl -1H- pyrazoles；
1 H-NMR ( 500 MHz, CDCl3 ) δppm: 7.81（1H,s）, 7.76（1H,s）, 7.39（3H,m）, 7.25
（2H,m）,5.32（2H,s）.
Embodiment 9
The synthesis of 1,3- dimethyl -1H- pyrazoles -5- formonitrile HCNs
At room temperature, by 1,3- dimethyl -1H- pyrazoles -5- formaldehyde（12.4 grams, 0.1mol）, sodium bromate (6 grams, 0.04mol) and
100 grams of acetic acid mixing, are added the ammonium hydroxide and 200 milliliters of water of 25 grams of mass concentrations containing amino molecule 25%, are heated to 90 DEG C, reaction is put
Heat, 100 DEG C of maintaining reaction temperature, to 1,3- dimethyl -1H- pyrazoles -5- formaldehyde, the reaction was complete in 1 hour for back flow reaction, is cooled to
Room temperature, reaction solution are poured into quenched dilution in ice water, are neutralized to reaction solution and are in neutrality, are extracted with dichloromethane, dry, concentration production
It after product, is evaporated under reduced pressure and recrystallizes, obtain 10.4 grams of product, yield 86%, 98% or more purity.
Fig. 9 is the present embodiment products obtained therefrom 1, the nuclear magnetic resonance map of 3- dimethyl -1H- pyrazoles -5- formonitrile HCNs；
1 H-NMR ( 500 MHz, CDCl3 ) δppm: 6.55(1H,s),3.99（3H,s）, 2.29（3H,s）.
Embodiment 10
The synthesis of 1,5- dimethyl -1H- pyrazoles -3- formonitrile HCNs
At room temperature, by 1,5- dimethyl -1H- pyrazoles -3- formaldehyde（12.4 grams, 0.1mol）, sodium bromate (7.5 grams, 0.05mol)
It is mixed with 200 grams of acetic acid, the ammonium hydroxide and 400 milliliters of water of 50 grams of mass concentrations containing amino molecule 25% is added, be heated to 90 DEG C, reaction
Heat release, 100 DEG C of maintaining reaction temperature, to 1,5- dimethyl -1H- pyrazoles -3- formaldehyde, the reaction was complete in 1 hour for back flow reaction, cooling
To room temperature, reaction solution is poured into quenched dilution in ice water, is neutralized to reaction solution and is in neutrality, is extracted with dichloromethane, dry, concentration
It after product, is evaporated under reduced pressure and recrystallizes, obtain 10.5 grams of product, yield 87%, 98% or more purity.
Figure 10 is the present embodiment products obtained therefrom 1, the nuclear magnetic resonance map of 5- dimethyl -1H- pyrazoles -3- formonitrile HCNs.
1 H-NMR ( 500 MHz, CDCl3 ) δppm: 6.42(1H,s),3.85（3H,s）, 2.32（3H,s）.
Claims (10)
1. a kind of synthetic method of N- alkyl-cyano pyrazole, which is characterized in that with 1- alkyl -1H- pyrazoles formaldehyde or its derivative
Object, ammonium hydroxide, sodium bromate and acetic acid are that raw material obtains N- alkyl-cyano pyrazole using water as reaction dissolvent.
2. the synthetic method of N- alkyl-cyano pyrazole according to claim 1, which is characterized in that 1- alkyl -1H- pyrazoles
The derivative of formaldehyde, there are halogen atom, methyl or/and ethyl in other sites on pyrazole ring.
3. the synthetic method of N- alkyl-cyano pyrazole according to claim 1 or 2, which is characterized in that the ammonium hydroxide is work
Industry ammonium hydroxide, wherein the mass concentration containing amino molecule is 25-28wt%.
4. the synthetic method of N- alkyl-cyano pyrazole according to claim 1 or 2, which is characterized in that with 1- alkyl -1H-
On the basis of the amount of the substance of pyrazoles formaldehyde, in ammonium hydroxide the content of ammonia be 1 times of amount of the substance of 1- alkyl -1H- pyrazoles formaldehyde with
On.
5. the synthetic method of N- alkyl-cyano pyrazole according to claim 1 or 2, which is characterized in that sodium bromate dosage is
It is equivalent to 0.3-10 times of the amount of the substance of 1- alkyl -1H- pyrazoles formaldehyde.
6. the synthetic method of N- alkyl-cyano pyrazole according to claim 1 or 2, which is characterized in that acetic acid dosage is phase
When 1-100 times of the amount of the substance in 1- alkyl -1H- pyrazoles formaldehyde.
7. the synthetic method of N- alkyl-cyano pyrazole according to claim 1 or 2, which is characterized in that the dosage of water is phase
When 1-10000 times of the amount of the substance in 1- alkyl -1H- pyrazoles formaldehyde.
8. the synthetic method of N- alkyl-cyano pyrazole according to claim 1 or 2, which is characterized in that reaction temperature is
90-110℃。
9. the synthetic method of N- alkyl-cyano pyrazole according to claim 1 or 2, which is characterized in that use following step
Suddenly：
1- alkyl -1H- pyrazoles formaldehyde, sodium bromate and acetic acid are mixed, ammonium hydroxide and water is added, is heated to 90-110 DEG C, reflux is anti-
Should to 1- alkyl -1H- pyrazoles formaldehyde, the reaction was complete, reaction solution is cooled to room temperature, and is poured into quenched dilution in ice water, is neutralized to anti-
Answer liquid to be in neutrality, extract, it is dry, after concentrated product, be evaporated under reduced pressure and recrystallize to get.
10. the synthetic method of N- alkyl-cyano pyrazole according to claim 9, which is characterized in that acetic acid second is selected in extraction
Ester or dichloromethane.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998039302A1 (en) * | 1997-03-03 | 1998-09-11 | Rhone-Poulenc Agro | Processes for preparing pesticidal intermediates |
| CN1714074A (en) * | 2002-10-21 | 2005-12-28 | 庵原化学工业株式会社 | Process for producing aromatic nitrile compound |
| WO2008093639A1 (en) * | 2007-01-29 | 2008-08-07 | Takeda Pharmaceutical Company Limited | Pyrazole compound |
-
2018
- 2018-06-28 CN CN201810691028.2A patent/CN108707113A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998039302A1 (en) * | 1997-03-03 | 1998-09-11 | Rhone-Poulenc Agro | Processes for preparing pesticidal intermediates |
| CN1714074A (en) * | 2002-10-21 | 2005-12-28 | 庵原化学工业株式会社 | Process for producing aromatic nitrile compound |
| WO2008093639A1 (en) * | 2007-01-29 | 2008-08-07 | Takeda Pharmaceutical Company Limited | Pyrazole compound |
Non-Patent Citations (2)
| Title |
|---|
| JOHN M. FEVIG ET AL.: "Preparation of 1-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones as potent, selective and bioavailable inhibitors of coagulation factor Xa", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| SANATH K. MEEGALLA ET AL.: "5-Amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-[3H3]-methylsulfanyl-1H-pyrazole-4-carbonitrile (CTOM):Synthesis and Characterization of a Novel and Selective Insect GABA Receptor Radioligand", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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