CN105037369B - A kind of synthetic method of pyrazolo [5,1 a] Carbox amide of iso-indoles 3 - Google Patents
A kind of synthetic method of pyrazolo [5,1 a] Carbox amide of iso-indoles 3 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a kind of pyrazolo [5,1a] Carbox amide of iso-indoles 3 synthetic method, belong to technical field of organic synthesis.Technical scheme main points are:By 1 (2 bromophenyl) 2, ketone of 3 butadiene 1 or derivatives thereof and hydrazides are dissolved in solvent, room temperature reaction adds isonitrile, catalyst transition metal salt, oxidant and alkali after 1 hour, pyrazolo [5,1 then is obtained in 80 140 DEG C of reactions in air atmospherea] Carbox amide of iso-indoles 3.Building-up process of the present invention is one pot of multistep cascade reaction, avoid the wasting of resources and environmental pollution that existing method causes by the purification process etc. of intermediate, the raw material used in building-up process is cheap and easy to get or easily prepared, and operation is easy, substrate it is applied widely.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of pyrazolo [5,1-a] iso-indoles -3- benzamide types
The synthetic method of compound.
Background technology
Fused pyrazole construction unit is widely present in natural products, and many fused pyrazole derivatives also show good
Bioactivity, is constantly subjected to the concern of chemist and medicine scholar for many years.Wherein, pyrazolo [5,1-a] iso-indoles have adjust
Section plant growth, step-down, antibacterial and antidepression isoreactivity, have broad application prospects in terms of related drug development.Mesh
Before, the synthetic method of such compound mainly includes intramolecular wittig reaction, the Suzuki of pyrazoles borate of phosphorus ylide
Coupling andNIntramolecular Friedel-Crafts acylations of-formoxyl pyrazoline etc..These literature methods greatly be required for by
Multi-step synthesis and cumbersome isolate and purify process, raw materials used to be difficult to be obtained, severe reaction conditions, so that it is in actual life
Application in product is restricted.On the other hand, pyrazole-4-carboxamide is the dominance structure unit in pharmaceutical chemistry research, many
Contain this structural framework in clinical medicine and lead compound.The method of existing synthesizing pyrazole -4- formamides is mainly logical
Pyrazoles -4- formic acid is crossed with amine in (dimethylamino) the phosphorus hexafluorophosphate of BTA -1- bases epoxide three(Bop reagent)'s
Activation issues ammonifying solution or is obtained through multistep solid-phase synthesis by raw material of immobilized pyrazoles -4- carboxylic acid derivates.These
Synthetic method is remained reactions steps are more, expensive reagents, atom economy difference the problems such as.In view of this, exploitation contains pyrazoles -4- first
Pyrazolo [the 5,1- of amide structure unita] iso-indoles -3- Carbox amides it is simple and direct, efficiently synthesize new method, having
The research field such as machine synthesis chemistry and pharmaceutical chemistry has great importance.
The content of the invention
Present invention solves the technical problem that there is provided a kind of pyrazolo [5,1-a] iso-indoles -3- Carbox amides
Synthetic method, the synthetic method from commercial reagents or the simple raw material for easily preparing, by one pot of multistep cascade reaction,
Directly obtain pyrazolo [5,1-a] iso-indoles -3- Carbox amides, i.e., in one pot reaction simultaneously construct out pyrazole ring and
Iso-indoles ring, and in 4- introducing formamide construction unit of pyrazole ring, easy to operate, Atom economy is good, and substrate is applicable
Scope is wide, is suitable for industrialized production.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of pyrazolo [5,1-a] iso-indoles -3- first
The synthetic method of amides compound, it is characterised in that:By 1- (2- bromophenyls) -2,3- butadiene -1- ketone or derivatives thereof and
Hydrazides is dissolved in solvent, and room temperature reaction adds isonitrile, catalyst transition metal salt, oxidant and alkali after 1 hour, then in air
Pyrazolo [5,1- is obtained in 80-140 DEG C of reaction in atmospherea] iso-indoles -3- Carbox amides, it is anti-in the synthetic method
The equation is answered to be:
Wherein R1It is hydrogen, fluorine, chlorine, trifluoromethyl, methyl or alkoxy, R2It is hydrogen, alkyl, phenyl or substituted-phenyl, R3For
Alkyl, phenyl or substituted-phenyl, R4It is alkyl, phenyl or substituted-phenyl, the substitution base on above-mentioned substituted-phenyl phenyl ring is respectively
One or more in fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxyl group, the position of base is replaced to be ortho position, the meta on phenyl ring
Or contraposition, solvent is DMF, Isosorbide-5-Nitrae-dioxane or toluene, and catalyst transition metal salt is palladium, chlorine
Change palladium, two(Triphenylphosphine)Palladium chloride, three(Dibenzalacetone)Two palladiums or four(Triphenylphosphine)Palladium, oxidant be oxygen,
Silver acetate, silver carbonate or copper acetate, alkali are potassium carbonate, triethylamine, the carbon -7- alkene of 1,8- diazabicylos 11, sodium carbonate, carbonic acid
Caesium or potassium hydroxide.
Further limit, described 1- (2- bromophenyls) -2,3- butadiene -1- ketone or derivatives thereof, hydrazides and isonitrile
The ratio between the amount of material of feeding intake is 1:1-1.5:2-4.
The present invention has advantages below compared with prior art:(1)Building-up process is one pot of multistep cascade reaction, it is to avoid
The wasting of resources and environmental pollution that existing method causes by the purification process etc. of intermediate;(2)The raw material used in building-up process
It is cheap and easy to get or easily prepared;(3)Operation is easy;(4)Substrate it is applied widely.Therefore, the present invention for pyrazolo [5,
1-a] synthesis of iso-indoles -3- Carbox amides provides a kind of economical and practical and efficient new method.
Specific embodiment
The above of the invention is described in further details by the following examples, but this should not be interpreted as this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
1- (2- bromophenyls) -2,3- butadiene -1- ketone is added in 25 mL reaction bulbs(1a, 0.2 mmol, 44.4
mg), acethydrazide(2a,0.22 mmol, 16.3 mg)And N,N-dimethylformamide(1 mL), after being stirred at room temperature 1 hour, then
Add palladium(0.01 mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44
mmol, 36.5 mg)And potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture is anti-in 120 DEG C of stirrings in air atmosphere
After answering 8 hours, add 10 mL saturated ammonium chloride solutions that reaction is quenched, be extracted with ethyl acetate(6 mL × 3), it is organic afterwards
Washed successively with water and saturated aqueous common salt, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petroleum ether/acetic acid
Ethyl ester=20/1)Obtain white solid product 4a(55 mg, 82%).The characterize data of the compound is as follows:1H NMR (400
MHz, CDCl3) δ: 1.50 (s, 9H), 1.60 (s, 9H), 2.50 (s, 3H), 5.69 (s, 1H), 7.36
(t, J = 7.6 Hz, 1H), 7.44-7.48 (m, 1H), 7.76 (d, J = 7.2 Hz, 1H), 8.04 (d, J
= 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 14.7, 29.0, 29.1, 51.8, 55.6,
111.3, 118.3, 122.5, 123.7, 129.3, 131.3, 136.9, 152.8, 157.3, 162.7. HRMS
calcd for C20H27N4O: 339.2179 [M+H]+, found: 339.2189。
Embodiment 2
1a is added in 25 mL reaction bulbs(0.2 mmol, 44.4 mg)、2a(0.4 mmol, 29.6 mg)And N, N-
Dimethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01 mmol, 2.2 mg), copper acetate(0.2
mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)And potassium carbonate(0.4 mmol, 55.2 mg).
Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 mL saturated ammonium chloride solutions that reaction is quenched in the air atmosphere,
It is extracted with ethyl acetate(6 mL × 3), afterwards organic phase water and saturated aqueous common salt wash successively, anhydrous sodium sulfate drying.
Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid product 4a(51 mg, 75%).
Embodiment 3
1a is added in 25 mL reaction bulbs(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N, N-
Dimethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01 mmol, 2.2 mg), copper acetate(0.2
mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.8 mmol, 66.5 mg)And potassium carbonate(0.4 mmol, 55.2 mg).
Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 mL saturated ammonium chloride solutions that reaction is quenched in the air atmosphere,
It is extracted with ethyl acetate(6 mL × 3), afterwards organic phase water and saturated aqueous common salt wash successively, anhydrous sodium sulfate drying.
Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid product 4a(54 mg, 80%).
Embodiment 4
1a is added in 25 mL reaction bulbs(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N, N-
Dimethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01 mmol, 2.2 mg), copper acetate(0.2
mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)With the carbon -7- alkene of 1,8- diazabicylos 11
(0.4 mmol, 60.8 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 mL to satisfy in the air atmosphere
Reaction is quenched with ammonium chloride solution, is extracted with ethyl acetate(6 mL × 3), organic phase water and saturated aqueous common salt be successively afterwards
Washing, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)White solid is obtained to produce
Thing 4a(42 mg, 62%).
Embodiment 5
1a is added in 25 mL reaction bulbs(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N, N-
Dimethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01 mmol, 2.2 mg), copper acetate(0.2
mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)And cesium carbonate(0.4 mmol, 130.3
mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 mL saturated ammonium chloride solutions to be quenched in the air atmosphere
Reaction, is extracted with ethyl acetate(6 mL × 3), afterwards organic phase water and saturated aqueous common salt wash successively, anhydrous sodium sulfate
Dry.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid product 4a(51 mg,
75%).
Embodiment 6
1a is added in the reaction bulb of 25 mL(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N,
Dinethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium bichloride(0.01 mmol, 1.8 mg), tetrafluoro boric acid
Tri-butyl phosphine(0.02 mmol, 5.8 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)And potassium carbonate(0.4
mmol, 55.2 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 mL saturation chlorinations in the air atmosphere
Ammonium salt solution is quenched reaction, is extracted with ethyl acetate(6 mL × 3), afterwards organic phase water and saturated aqueous common salt wash successively,
Anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid product 4a
(28 mg, 42%).
Embodiment 7
1a is added in the reaction bulb of 25 mL(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N,
Dinethylformamide(1 mL), after being stirred at room temperature 1 hour, add two(Triphenylphosphine)Palladium chloride(0.01 mmol,
7.0 mg), tetrafluoro boric acid tri-butyl phosphine(0.02 mmol, 5.8 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5
mg)And potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in the air atmosphere in after 120 DEG C of stirring reactions 8 hours,
Add 10 mL saturated ammonium chloride solutions that reaction is quenched, be extracted with ethyl acetate(6 mL × 3), organic phase water and full afterwards
Washed successively with saline solution, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)
Obtain white solid product 4a(20 mg, 30%).
Embodiment 8
1a is added in the reaction bulb of 25 mL(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N,
Dinethylformamide(1 mL), after being stirred at room temperature 1 hour, add three(Dibenzalacetone)Two palladiums(0.01 mmol,
9.2 mg), tetrafluoro boric acid tri-butyl phosphine(0.02 mmol, 5.8 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5
mg)And potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in the air atmosphere in after 120 DEG C of stirring reactions 8 hours,
Add 10 mL saturated ammonium chloride solutions that reaction is quenched, be extracted with ethyl acetate(6 mL × 3), organic phase water and full afterwards
Washed successively with saline solution, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)
Obtain white solid product 4a(22 mg, 32%).
Embodiment 9
1a is added in the reaction bulb of 25 mL(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N,
Dinethylformamide(1 mL), after being stirred at room temperature 1 hour, add four(Triphenylphosphine)Palladium(0.01 mmol, 11.6
mg), tetrafluoro boric acid tri-butyl phosphine(0.02 mmol, 5.8 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)
And potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, is added in the air atmosphere
10 mL saturated ammonium chloride solutions are quenched reaction, are extracted with ethyl acetate(6 mL × 3), merge organic phase, eaten with water and saturation
Salt solution is washed successively, anhydrous sodium sulfate drying.Filtering, is spin-dried for, silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white
Solid product 4a(17 mg, 25%).
Embodiment 10
1a is added in the reaction bulb of 25 mL(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N,
Dinethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01 mmol, 2.2 mg), tetrafluoro boric acid
Tri-butyl phosphine(0.02 mmol, 5.8 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)And potassium carbonate(0.4
mmol, 55.2 mg).Gained mixture stirring reaction under the oxygen atmosphere and 120 DEG C of temperature conditionss after 8 hours, adds 10
ML saturated ammonium chloride solutions are quenched reaction, are extracted with ethyl acetate(6 mL × 3), merge organic phase and with water and saturated common salt
Water is washed successively, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white
Solid product 4a(31 mg, 46%).
Embodiment 11
1a is added in the reaction bulb of 25 mL(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N,
Dinethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01 mmol, 2.2 mg), tetrafluoro boric acid
Tri-butyl phosphine(0.02 mmol, 5.8 mg), silver acetate(0.2 mmol, 33.4 mg), tert-butyl isonitrile(3a, 0.44
mmol, 36.5 mg)And potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture is anti-in 120 DEG C of stirrings in air atmosphere
After answering 8 hours, add 10 mL saturated ammonium chloride solutions that reaction is quenched, be extracted with ethyl acetate(6 mL × 3), it is organic afterwards
Washed successively with water and saturated aqueous common salt, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petroleum ether/acetic acid
Ethyl ester=20/1)Obtain white solid product 4a(39 mg, 58%).
Embodiment 12
1a is added in the reaction bulb of 25 mL(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N,
Dinethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01 mmol, 2.2 mg), tetrafluoro boric acid
Tri-butyl phosphine(0.02 mmol, 5.8 mg), silver carbonate(0.2 mmol, 55.2 mg), tert-butyl isonitrile(3a, 0.44
mmol, 36.5 mg)And potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture is anti-in 120 DEG C of stirrings in air atmosphere
After answering 8 hours, add 10 mL saturated ammonium chloride solutions that reaction is quenched, be extracted with ethyl acetate(6 mL × 3), it is organic afterwards
Washed successively with water and saturated aqueous common salt, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petroleum ether/acetic acid
Ethyl ester=20/1)Obtain white solid product 4a(35 mg, 52%).
Embodiment 13
1a is added in the reaction bulb of 25 mL(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N,
Dinethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01 mmol, 2.2 mg), tetrafluoro boric acid
Tri-butyl phosphine(0.02 mmol, 5.8 mg), copper acetate(0.2 mmol, 36.3 mg), tert-butyl isonitrile(3a, 0.44
mmol, 36.5 mg)And potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture is anti-in 120 DEG C of stirrings in air atmosphere
After answering 8 hours, add 10 mL saturated ammonium chloride solutions that reaction is quenched, be extracted with ethyl acetate(6 mL × 3), it is organic afterwards
Washed successively with water and saturated aqueous common salt, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petroleum ether/acetic acid
Ethyl ester=20/1)Obtain white solid product 4a(49 mg, 72%).
Embodiment 14
1a is added in the reaction bulb of 25 mL(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N,
Dinethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01 mmol, 2.2 mg), copper acetate
(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)And potassium carbonate(0.4 mmol, 55.2
mg).Gained mixture in after 140 DEG C of stirring reactions 8 hours, adds 10 mL saturated ammonium chloride solutions to be quenched in the air atmosphere
Reaction, is extracted with ethyl acetate(6 mL × 3), afterwards organic phase water and saturated aqueous common salt wash successively, anhydrous sodium sulfate
Dry.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid product 4a(49 mg,
72%).
Embodiment 15
1a is added in the reaction bulb of 25 mL(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And N,
Dinethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01 mmol, 2.2 mg), copper acetate
(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)And potassium carbonate(0.4 mmol, 55.2
mg).Gained mixture in after 100 DEG C of stirring reactions 8 hours, adds 10 mL saturated ammonium chloride solutions to be quenched in the air atmosphere
Reaction, is extracted with ethyl acetate(6 mL × 3), afterwards organic phase water and saturated aqueous common salt wash successively, anhydrous sodium sulfate
Dry.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid product 4a(42 mg,
62%).
Embodiment 16
1a is added in the reaction bulb of 25 mL(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And 1,
4- dioxane(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01 mmol, 2.2 mg), copper acetate(0.2
mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)And potassium carbonate(0.4 mmol, 55.2 mg).
After gained mixture is refluxed reaction 8 hours in air atmosphere, add 10 mL saturated ammonium chloride solutions that reaction is quenched, use
Ethyl acetate is extracted(6 mL × 3), afterwards organic phase water and saturated aqueous common salt wash successively, anhydrous sodium sulfate drying.Cross
Filter, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid product 4a(38 mg, 56%).
Embodiment 17
1a is added in the reaction bulb of 25 mL(0.2 mmol, 44.4 mg)、2a(0.22 mmol, 16.3 mg)And first
Benzene(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01 mmol, 2.2 mg), copper acetate(0.2 mmol,
36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)And potassium carbonate(0.4 mmol, 55.2 mg).Gained is mixed
After compound is refluxed reaction 8 hours in air atmosphere, add 10 mL saturated ammonium chloride solutions that reaction is quenched, use acetic acid second
Ester is extracted(6 mL × 3), afterwards organic phase water and saturated aqueous common salt wash successively, anhydrous sodium sulfate drying.Filtering, rotation
It is dry, cross silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid product 4a(35 mg, 52%).
Embodiment 18
Method as described in embodiment 1, adds 1a (0.2 mmol, 44.4 mg), 2b in the reaction bulb of 25 mL
(0.22 mmol, 30.0 mg) and N,N-dimethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium
(0.01 mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5
mg)And potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in the air atmosphere in after 120 DEG C of stirring reactions 8 hours,
Add 10 mL saturated ammonium chloride solutions that reaction is quenched, be extracted with ethyl acetate(6 mL × 3), organic phase water and full afterwards
Washed successively with saline solution, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)
Obtain white solid product 4a(35 mg, 52%).
Embodiment 19
Method as described in embodiment 1, adds 1a (0.2 mmol, 44.4 mg), 2c in the reaction bulb of 25 mL
(0.22 mmol, 36.5 mg) and N,N-dimethylformamide(1 mL), it is stirred at room temperature 1 hour, add palladium(0.01
mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)With
Potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 in the air atmosphere
ML saturated ammonium chloride solutions are quenched reaction, are extracted with ethyl acetate(6 mL × 3), organic phase water and saturated aqueous common salt afterwards
Wash successively, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid
Body product 4a(30 mg, 45%).
Embodiment 20
Method as described in embodiment 1, adds 1b (0.2 mmol, 47.2 mg), 2a in the reaction bulb of 25 mL
(0.22 mmol, 16.3 mg) and N,N-dimethylformamide(1 mL), it is stirred at room temperature 1 hour, add palladium(0.01
mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)With
Potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 in the air atmosphere
ML saturated ammonium chloride solutions are quenched reaction, are extracted with ethyl acetate(6 mL × 3), organic phase water and saturated aqueous common salt afterwards
Wash successively, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid
Body product 4b(61 mg, 86%).The characterize data of the compound is as follows:1H NMR (400 MHz, CDCl3) δ: 1.50
(s, 9H), 1.60 (s, 9H), 2.40 (s, 3H), 2.49 (s, 3H), 5.67 (s, 1H), 7.25 (d, J =
6.0 Hz, 1H), 7.58 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ: 14.6, 21.6, 28.9, 29.1, 51.7, 55.5, 111.8, 117.9, 122.2, 124.3, 126.7,
131.9, 138.1, 139.7, 148.5, 152.8, 162.8. HRMS calcd for C21H29N4O: 353.2336 [M
+H]+, found: 353.2347。
Embodiment 21
Method as described in embodiment 1, adds 1c (0.2 mmol, 50.4 mg), 2a in the reaction bulb of 25 mL
(0.22 mmol, 16.3 mg) and N,N-dimethylformamide(1 mL), it is stirred at room temperature 1 hour, add palladium(0.01
mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)With
Potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 in the air atmosphere
ML saturated ammonium chloride solutions are quenched reaction, are extracted with ethyl acetate(6 mL × 3), organic phase water and saturated aqueous common salt afterwards
Wash successively, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid
Body product 4c(66 mg, 89%).The characterize data of the compound is as follows:1H NMR (400 MHz, CDCl3) δ: 1.50
(s, 9H), 1.59 (s, 9H), 2.49 (s, 3H), 3.89 (s, 3H), 5.67 (s, 1H), 6.85 (d, J =
9.2 Hz, 1H), 7.58 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ: 14.5, 29.0, 29.1, 51.7, 55.4, 55.7, 107.9, 111.6, 114.6, 125.0, 129.1,
130.8, 137.5, 147.6, 152.6, 162.4, 162.7. HRMS calcd for C21H29N4O2: 369.2285
[M+H]+, found: 369.2296。
Embodiment 22
Method as described in embodiment 1, adds 1d (0.2 mmol, 48.0 mg), 2a in the reaction bulb of 25 mL
(0.22 mmol, 16.3 mg) and N,N-dimethylformamide(1 mL), it is stirred at room temperature 1 hour, add palladium(0.01
mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)With
Potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 in the air atmosphere
ML saturated ammonium chloride solutions are quenched reaction, are extracted with ethyl acetate(6 mL × 3), organic phase water and saturated aqueous common salt afterwards
Wash successively, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid
Body product 4d(51 mg, 72%).The characterize data of the compound is as follows:1H NMR (400 MHz, CDCl3) δ: 1.49
(s, 9H), 1.58 (s, 9H), 2.50 (s, 3H), 5.67 (s, 1H), 7.11-7.15 (m, 1H), 7.44
(dd, J 1 = 7.6 Hz, J 2 = 2.0 Hz, 1H), 8.11 (dd, J 1 = 8.4 Hz, J 2 = 0.8 Hz, 1H).13C NMR (100 MHz, CDCl3) δ: 14.8, 28.9, 29.0, 51.8, 55.7, 111.2, 111.4, 111.5,
117.9, 118.1, 124.7, 124.8, 125.4, 139.4, 148.5, 152.2, 162.5. HRMS calcd for
C20H26FN4O: 357.2085 [M+H]+, found: 357.2097。
Embodiment 23
Method as described in embodiment 1, adds 1e (0.2 mmol, 48.0 mg), 2a in the reaction bulb of 25 mL
(0.22 mmol, 16.3 mg) and N,N-dimethylformamide(1 mL), it is stirred at room temperature 1 hour, add palladium(0.01
mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)With
Potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 in the air atmosphere
ML saturated ammonium chloride solutions are quenched reaction, are extracted with ethyl acetate(6 mL × 3), organic phase water and saturated aqueous common salt afterwards
Wash successively, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid
Body product 4e(50 mg, 70%).The characterize data of the compound is as follows:1H NMR (400 MHz, CDCl3) δ: 1.50
(s, 9H), 1.59 (s, 9H), 2.51 (s, 3H), 5.67 (s, 1H), 7.00-7.05 (m, 1H), 7.71
(dd, J 1 = 8.4 Hz, J 2 = 4.8 Hz, 1H), 7.86 (dd, J 1 = 8.0 Hz, J 2 = 2.0 Hz, 1H).13C NMR (100 MHz, CDCl3) δ: 14.8, 28.8, 28.9, 51.8, 55.7, 110.5, 110.8, 112.2,
115.8, 116.1, 125.23, 125.25, 125.3, 131.3, 132.3, 136.8, 147.7, 152.1,
162.3, 163.6. HRMS calcd for C20H26FN4O: 357.2085 [M+H]+, found: 357.2098。
Embodiment 24
Method as described in embodiment 1, adds 1f (0.2 mmol, 51.2 mg), 2a in the reaction bulb of 25 mL
(0.22 mmol, 16.3 mg) and N,N-dimethylformamide(1 mL), it is stirred at room temperature 1 hour, add palladium(0.01
mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)With
Potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 in the air atmosphere
ML saturated ammonium chloride solutions are quenched reaction, are extracted with ethyl acetate(6 mL × 3), organic phase water and saturated aqueous common salt afterwards
Wash successively, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid
Body product 4f(57 mg, 76%).The characterize data of the compound is as follows:1H NMR (400 MHz, CDCl3) δ: 1.50
(s, 9H), 1.58 (s, 9H), 2.51 (s, 3H), 5.67 (s, 1H), 7.32 (dd, J 1 = 8.4 Hz, J 2 =
2.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ: 14.8, 28.9, 29.0, 51.8, 54.5, 112.2, 123.1, 124.7, 129.2,
130.7, 134.9, 137.4, 147.6, 152.3, 162.3. HRMS calcd for C20H25ClN4ONa:
395.1609 [M+Na]+, found: 395.1624。
Embodiment 25
Method as described in embodiment 1, adds 1g (0.2 mmol, 58.0 mg), 2a in the reaction bulb of 25 mL
(0.22 mmol, 16.3 mg) and N,N-dimethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01
mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)With
Potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 in the air atmosphere
ML saturated ammonium chloride solutions are quenched reaction, are extracted with ethyl acetate(6 mL × 3), organic phase water and saturated aqueous common salt afterwards
Wash successively, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid
Body product 4g(54 mg, 67%).The characterize data of the compound is as follows:1H NMR (400 MHz, CDCl3) δ: 1.51
(s, 9H), 1.60 (s, 9H), 2.53 (s, 3H), 5.67 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H),
7.87 (d, J = 8.8 Hz, 1H), 8.36 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 14.7,
28.9, 29.1, 29.7, 51.9, 56.1, 112.5, 119.69, 119.73, 119.8, 124.0, 126.15,
126.19, 130.0, 133.4, 136.6, 139.8, 147.4, 153.0, 162.2. HRMS calcd for
C21H26F3N4O: 407.2053 [M+H]+, found: 407.2065。
Embodiment 26
Method as described in embodiment 1, adds 1h (0.2 mmol, 53.2 mg), 2a in the reaction bulb of 25 mL
(0.22 mmol, 16.3 mg) and N,N-dimethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01
mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)With
Potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 in the air atmosphere
ML saturated ammonium chloride solutions are quenched reaction, are extracted with ethyl acetate(6 mL × 3), organic phase water and saturated aqueous common salt afterwards
Wash successively, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid
Body product 4h(66 mg, 87%).The characterize data of the compound is as follows:1H NMR (400 MHz, CDCl3) δ: 1.48
(s, 9H), 1.57 (s, 9H), 2.47 (s, 3H), 5.63 (s, 1H), 6.02 (s, 2H), 7.18 (s,
1H), 7.62 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 14.8, 28.9, 29.0, 51.7, 55.5,
101.8, 104.0, 104.7, 106.7, 110.8, 115.2, 124.2, 131.5, 148.7, 150.2, 151.7,
162.7. HRMS calcd for C21H27N4O3: 383.2078 [M+H]+, found: 383.2089。
Embodiment 27
Method as described in embodiment 1, adds 1i (0.2 mmol, 47.2 mg), 2a in the reaction bulb of 25 mL
(0.22 mmol, 16.3 mg) and N,N-dimethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01
mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)With
Potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 in the air atmosphere
ML saturated ammonium chloride solutions are quenched reaction, are extracted with ethyl acetate(6 mL × 3), organic phase water and saturated aqueous common salt afterwards
Wash successively, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid
Body product 4i(57 mg, 81%).The characterize data of the compound is as follows:1H NMR (400 MHz, CDCl3) δ: 1.37
(t, J = 7.6 Hz, 3H), 1.50 (s, 9H), 1.60 (s, 9H), 2.87 (q, J = 7.2 Hz, 2H),
5.72 (s, 1H), 7.34-7.38 (m, 1H), 7.43-7.47 (m, 1H), 7.77 (d, J = 8.0 Hz, 1H),
7.97 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 12.6, 22.2, 28.9, 29.0,
51.8, 55.6, 111.1, 122.1, 123.7, 129.2, 129.4, 131.3, 136.9, 137.9, 147.9,
158.3, 162.8. HRMS calcd for C21H29N4O: 353.2336 [M+H]+, found: 353.2349。
Embodiment 28
Method as described in embodiment 1, adds 1j (0.2 mmol, 50.0 mg), 2a in the reaction bulb of 25 mL
(0.22 mmol, 16.3 mg) and N,N-dimethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01
mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), tert-butyl isonitrile(3a, 0.44 mmol, 36.5 mg)With
Potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture in after 120 DEG C of stirring reactions 8 hours, adds 10 in the air atmosphere
ML saturated ammonium chloride solutions are quenched reaction, are extracted with ethyl acetate(6 mL × 3), organic phase water and saturated aqueous common salt afterwards
Wash successively, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=20/1)Obtain white solid
Body product 4j(61 mg, 83%).The characterize data of the compound is as follows:1H NMR (400 MHz, CDCl3) δ: 1.02-
1.06 (m, 3H), 1.50 (s, 9H), 1.60 (s, 9H), 1.79-1.82 (m, 2H), 2.81 (t, J = 6.8
Hz, 2H), 5.71 (s, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H),
7.76 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ: 13.9, 21.7, 29.0, 29.1, 30.5, 51.8, 55.7, 111.3, 122.1, 123.7, 129.2,
129.4, 131.3, 136.9, 137.9, 147.8, 157.0, 162.8. HRMS calcd for C22H31N4O:
367.2492 [M+H] +, found: 367.2487。
Embodiment 29
Method as described in embodiment 1, adds 1k (0.2 mmol, 59.8 mg), 2a in the reaction bulb of 25 mL
(0.22 mmol, 16.3 mg) and N,N-dimethylformamide(1 mL), after being stirred at room temperature 1 hour, add palladium(0.01
mmol, 2.2 mg), copper acetate(0.2 mmol, 36.2 mg), 2,6- 3,5-dimethylphenyl isonitrile(3b, 0.44 mmol,
57.7 mg)And potassium carbonate(0.4 mmol, 55.2 mg).Gained mixture is small in 120 DEG C of stirring reactions 8 in air atmosphere
Shi Hou, adds 10 mL saturated ammonium chloride solutions that reaction is quenched, and is extracted with ethyl acetate(6 mL × 3), organic phase water afterwards
Washed successively with saturated aqueous common salt, anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation(Petrol ether/ethyl acetate=
20/1)Obtain target product 4k.
Embodiment above describes general principle of the invention, principal character and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, simply original of the invention is illustrated described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements each fall within
In the scope of protection of the invention.
Claims (2)
1. a kind of pyrazolo [5,1-a] iso-indoles -3- Carbox amides synthetic method, it is characterised in that:By 1- (2- bromines
Phenyl) -2,3- butadiene -1- ketone or derivatives thereof and hydrazides be dissolved in solvent, and room temperature reaction adds isonitrile, is catalyzed after 1 hour
Agent transition metal salt, oxidant and alkali, are then obtained pyrazolo [5,1- in air atmosphere in 80-140 DEG C of reactiona] different Yin
Diindyl -3- Carbox amides, the reaction equation in the synthetic method is:
Wherein R1It is hydrogen, fluorine, chlorine, trifluoromethyl, methyl, methoxyl group or methylene-dioxy, R2For hydrogen, methyl, ethyl, phenyl or
Substituted-phenyl, R3It is methyl, phenyl or substituted-phenyl, R4It is the tert-butyl group, phenyl or substituted-phenyl, on above-mentioned substituted-phenyl phenyl ring
Be respectively in fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxyl group one or more of substitution base, the position for replacing base is phenyl ring
On ortho position, meta or para position, solvent be DMF, Isosorbide-5-Nitrae-dioxane or toluene, catalyst transition metal
Salt is palladium, palladium bichloride, two(Triphenylphosphine)Palladium chloride, three(Dibenzalacetone)Two palladiums or four(Triphenylphosphine)Palladium,
Oxidant is oxygen, silver acetate, silver carbonate or copper acetate, and alkali is potassium carbonate, triethylamine, the carbon -7- of 1,8- diazabicylos 11
Alkene, sodium carbonate, cesium carbonate or potassium hydroxide.
2. pyrazolo [5,1- according to claim 1a] iso-indoles -3- Carbox amides synthetic method, it is special
Levy and be:The amount of the material that feeds intake of described 1- (2- bromophenyls) -2,3- butadiene -1- ketone or derivatives thereof, hydrazides and isonitrile
The ratio between be 1:1-1.5:2-4.
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