CN104761506B - 2-(1-styryl)quinazolone compounds and synthesis method thereof - Google Patents

2-(1-styryl)quinazolone compounds and synthesis method thereof Download PDF

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CN104761506B
CN104761506B CN201510167264.0A CN201510167264A CN104761506B CN 104761506 B CN104761506 B CN 104761506B CN 201510167264 A CN201510167264 A CN 201510167264A CN 104761506 B CN104761506 B CN 104761506B
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formula
compound
synthetic method
alkali
sodium
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CN104761506A (en
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陈久喜
乔瑞
杨渭光
陈芳林
吴华悦
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Wenzhou University
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Wenzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3

Abstract

The invention relates to 2-(1-styryl)quinazolone compounds disclosed as Formula (I) and a synthesis method thereof. The synthesis method comprises the following step: in the presence of a palladium catalyst, an oxidizer and alkali, stirring compounds disclosed as Formula (II) and N,N-dimethylformamide (DMF) to react in a sealed environment to obtain the compounds disclosed as Formula (I). By properly selecting and combining the catalyst, alkali and oxidizer, the method can obtain the target products at high yield, and has very high theoretical research value and application value.

Description

A kind of 2- (1- styryls) quinazolinones and its synthetic method
Technical field
The invention provides a kind of quinazolinones and its synthetic method, relate more particularly to a kind of 2- (1- benzene second Thiazolinyl) quinazolinones and its synthetic method, belong to organic chemistry filed.
Background technology
Quinazolinone, can be as the structure fragment of active medicine, multiple used as the important nitrogen-containing heterocycle compound of a class Concrete application field such as medicine, agricultural chemicals and chemical field have a wide range of applications.
At present, many quinazolinones medicines are widely used in actual life, first in Britain's listing with chest Treatment late period colorectal cancer medicine Raltitrexed (Ralitrexed) of thuja acid synzyme (TS) inhibitory action, antitussive and antiasthmatic Medicine, antiallergic tiacrilast (Tiacrilast), act on the wide position of the upper maincenter of spinal cord, and make muscle tone The muscle relaxant afloqualone (Afloqualone) that hyperfunction state is alleviated；Hypnotic sedative agent mecloqualone (Mecloqualone) Deng.
In addition to above-mentioned application, there is ethamine dormancy ketone (Etaqualone) of Quinazolinone-containing skeleton stronger deinsectization to act on, Be used to acaricide introduce to the market.And quinazolinone analog derivative can be also modified after modification and can be used to make herbicide, such as Commercial herbicides bentazone be by the thio 2- positions carbon for quinazolinone heterocyclic skeleton, therefore, also have in pesticide industry It is widely applied.
As can be seen here, Quinazol derivative has wide application prospect.Just because of their excellent properties and Great potential, scientists synthesize to it has carried out substantial amounts of research, and various synthetic methods and route are developed in recent years.
K.Siva Kumar et al. (" A new cascade reaction:concurrent construction of six and five membered rings leading to novel fused quinazolinones”,Organic& Biomolecular Chemistry, 2012,10,3098-3103) in disclose isatic acid compound anhydride and R-NH-NH2Instead Answer and quinazolinone benzindole class compound is obtained, wherein using Pd (PPh3) it is catalyst, BINAP is part.
Dong-Sheng Chen et al. (" Copper (I)-catalyzed synthesis of 5-aryli-dazolo [3,2-b]quinazolin-7(5H)-one via Ullman-type reaction”,The Journal Organic Chemistry, 2013,78,5700-5704) disclose with 2- amino-N '-aryl phenylhydrazide and o- halogenated benzaldehydes in CuBr React with the presence of cesium carbonate, obtain 5- arylindazoles simultaneously [3,2-b] quinazoline -7- (5H) -one.
Weiguang, Yang et al. (" Copper-catalyzed intramolecular C-N bond formation reaction of 3-amino-2-(2-bromophenyl)dihydroquinazolinon –es:synthesis of Indazolo [3,2-b] quinazolinones ", Tetrahedron, 2013,69,9852-9856) disclose 3- amino -2- (2- bromophenyls) dihydroquinazoline ketone with copper compound/L-PROLINE as catalyst, in the presence of cesium carbonate in nitrogen atmosphere React, and obtain quinazolinone and indazole compound.
The CN201310717678.7 of the applicant discloses the quinazolinone and indazole derivative for not using halide Synthetic method, methods described be using palladium compound as catalyst, in the presence of alkali and molecular sieve, in oxygen atmosphere, formula (II) there is intramolecular dehydrogenation coupling reaction in compound, so as to obtain formula (I) derivative：
The CN 201410164235.4 of the applicant discloses the synthetic method of a kind of quinazolinone and indazole derivative, Using palladium compound as catalyst, in the presence of an oxidizer, in acidic organic solvent, formula (II) compound methods described occurs Intramolecular dehydrogenation coupling reaction, so as to obtain formula (I) derivative：
As described above, various synthetic methods of Quinazol derivative are had been disclosed in prior art, but for new Quinazolinones and its synthetic method still suffer from the necessity for continuing to study, this also exactly basis for being accomplished of the present invention and Power is located.
The content of the invention
In order to seek new quinazolinones and its synthetic method, present inventor has performed in-depth study, is paying After having gone out substantial amounts of creative work, so as to complete the present invention.
Here, applicant is intended to explanation, the technical scheme is that in Zhejiang Province's Natural Science Fund In The Light (project batch Accurate number：LY14B020009 it is accomplished under subsidy), here is expressed thanks.
Specifically, one side, the present invention relates to a kind of quinazoline assimilations of 2- (1- styryls) shown in lower formula (I) Compound,
Second aspect, the present invention relates to the synthetic method of the formula (I) compound, methods described includes：Catalyst, In the presence of oxidant and alkali, lower formula (II) compound reacts with DMF (DMF) stirring sealing, so as to obtain Formula (I) compound,
In the synthetic method of the present invention, the catalyst is acid chloride (Pd (OAc)2), palladium bichloride (PdCl2), four (triphenylphosphine) palladium (Pd (PPh3)4), palladium acetylacetonate (Pd (acac)2), palladium trifluoroacetate (Pd (TFA)2), four ammino chlorinations Palladium (Pd (NH3)4Cl2), two (triphenylphosphine) palladium bichloride (PdCl2(PPh3)2), two pyridine palladium bichloride (PdCl2(Py)2) or acetic acid Copper monohydrate (Cu (OAc)2·H2O any one in), preferably tetrakis triphenylphosphine palladium (Pd (PPh3)4), two pyridine chlorine Change palladium (PdCl2(Py)2) or copper acetate monohydrate (Cu (OAc)2·H2O), most preferably copper acetate monohydrate (Cu (OAc)2·H2O)。
In the synthetic method of the present invention, the oxidant is potassium peroxydisulfate (K2S2O8), copper trifluoromethanesulfcomposite (Cu (OTf)2), copper chloride (CuCl2), iodobenzene diacetate (PhI (OAc)2), silver acetate (AgOAc), sodium peroxydisulfate (Na2S2O8), mistake Ammonium sulfate ((NH4)2S2O8), any one in dicyano benzoquinone (DDQ) or benzoquinone (BQ), most preferably potassium peroxydisulfate (K2S2O8)。
In the synthetic method of the present invention, the alkali is sodium methoxide (MeONa), cesium carbonate (CsCO3), sodium acetate (NaOAc), potassium carbonate (K2CO3), potassium phosphate (K3PO4), sodium carbonate (Na2CO3), potassium tert-butoxide (t-BuOH), NaOH (NaOH) any one or in caustic alcohol (EtONa), preferably cesium carbonate or sodium acetate, most preferably sodium acetate.
In the synthetic method of the present invention, formula (II) compound is 1 with the mol ratio of catalyst:0.05- 0.15, for example can be 1:0.05、1:0.1 or 1:0.15.
In the synthetic method of the present invention, formula (II) compound is 1 with the mol ratio of oxidant:2-4, for example Can be 1:2、1:3 or 1:4.
In the synthetic method of the present invention, formula (II) compound is 1 with the mol ratio of alkali:0.5-1.5, for example Can be 1:0.5、1:1 or 1:1.5.
The present invention the synthetic method in, by mM in terms of (mmol) meter the formula (II) compound with milliliter (ml) ratio of the DMF of meter is 1:10-30, i.e., count (mmol) described formula (II) compound per 1 mM and use 10-30 milliliters (ml) DMF, for example, can be 1:10、1:15、1:20、1:25 or 1:30.
Wherein, DMF also serves as reacting smooth vinylated reagent, so not only both as reaction dissolvent Reaction controlling can be easy to easy operation, and post processing is able to further easy, so as to be more convenient the behaviour of whole reaction Make.
In the synthetic method of the present invention, reaction temperature is 80-120 DEG C, for example, can be 80 DEG C, 100 DEG C or 120 ℃。
In the synthetic method of the present invention, the reaction time is 8-12 hours, for example can for 8 hours, 9 hours, it is 10 little When, 11 hours or 12 hours.
In the methods described of the present invention, the post processing after reaction terminates can be crystallization, recrystallization, chromatography over CC, extraction Any one of take etc. the combination of processing means or various processing means.As a kind of exemplary post processing means, for example Can be：After reaction completely, reaction system is naturally cooled to into room temperature, add the ethyl acetate and saturated aqueous common salt of equal-volume ratio Mixed liquor, oscillation extraction 2-4 time, collected organic layer, drying, rotary evaporation concentration obtains crude product, and crude product is crossed into 300-400 Mesh silica gel column chromatography, with ethyl acetate and petroleum ether mixed liquor as eluant, eluent, the wherein volume of ethyl acetate and petroleum ether Than 1:5-10, so as to obtain target product formula (I) compound.
It is as follows as the synthetic method of formula (II) compound of initiation material in the synthetic method of the present invention： In organic solvent, in the presence of alkali and reducing agent, lower formula (III) compound and formula (IV) compound are stirred under atmosphere of inert gases Reaction is mixed, so as to obtain formula (II) compound,
In the synthetic method of the formula (II) compound, the alkali be sodium carbonate, sodium acid carbonate, potassium carbonate, caustic alcohol, Any one in potassium tert-butoxide, monoethanolamine, isopropanolamine etc., most preferably sodium carbonate.
In the synthetic method of the formula (II) compound, the reducing agent is sodium hydrogensulfite (NaHSO3), sulfurous acid Sodium (Na2SO3), ferrous sulfate (FeSO4) or stannous chloride (SnCl2) in any one, most preferably sodium hydrogensulfite (NaHSO3)。
In the synthetic method of the formula (II) compound, the organic solvent be DMF (DMF), N, Appointing in N- dimethyl acetamides (DMA), chlorobenzene, benzene, dimethylbenzene, dimethyl sulfoxide (DMSO) (DMSO), 1-METHYLPYRROLIDONE (NMP) Meaning is a kind of, most preferably DMA (DMA).
Wherein, the consumption of the organic solvent is not particularly limited, for example, can carry out and control for ease of reaction, with And it is easy to the amount for post-processing, those skilled in the art reasonably to be determined and be selected according to routine techniques means.
In the synthetic method of the formula (II) compound, the atmosphere of inert gases can be for example nitrogen atmosphere or argon gas Atmosphere.
In the synthetic method of the formula (II) compound, the ratio of formula (III) compound and formula (IV) compound is 1:2-4, for example, can be 1:2、1:3 or 1:4.
In the synthetic method of the formula (II) compound, formula (III) compound is 1 with the mol ratio of alkali:1- 1.5, for example can be 1:1、1:1.2、1:1.4 or 1:1.5.
In the synthetic method of the formula (II) compound, formula (III) compound is 1 with the mol ratio of reducing agent: 1.5-2.5, for example, can be 1:1.5、1:2 or 1:2.5.
In the synthetic method of the formula (II) compound, reaction temperature be 80-110 DEG C, for example can for 80 DEG C, 90 DEG C, 100 DEG C or 110 DEG C.
In the synthetic method of the formula (II) compound, the reaction time is 8-12 hours, for example can for 8 hours, it is 10 little When or 12 hours.
In the synthetic method of the formula (II) compound, the post processing after the completion of reaction is specially：After reaction terminates, will Reaction system is poured into water, and separates out solid, stands, precipitation, filters, washing, is dried, by drying solid ethyl alcohol recrystallization, from And obtain the formula (II) compound.
As described above, the invention provides formula (I) compound and its synthetic method, the synthetic method is by appropriate catalytic The selection of agent, oxidant and alkali and synergy, so as to formula (I) compound is obtained, reaction condition is simple, while achieving good Good yield, the preparation for such compound provides new synthetic route, has good application valency in industry and scientific research Value and potentiality.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and Purpose is only used for enumerating the present invention, not constitutes any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action Protection scope of the present invention is confined to this.
Preparation example 1
To in appropriate DMA, anthranilamide, phenylacetaldehyde, sodium carbonate and sodium hydrogensulfite are added, then nitrogen atmosphere Under be warming up to 80 DEG C, and stirring reaction 12 hours at such a temperature；Wherein, anthranilamide is with the mol ratio of phenylacetaldehyde 1:2nd, the mol ratio of anthranilamide and sodium carbonate is 1:1st, the mol ratio of anthranilamide and sodium hydrogensulfite is 1:1.5。
React after terminating, reaction system is poured into water, separate out solid, stand, precipitate, filter, wash, be dried, will be dry Dry solid ethyl alcohol recrystallization, so as to obtain the formula (II) compound for light yellow solid, fusing point is 254-255 DEG C, is produced Rate is 86.9%.
Preparation example 2
Reaction equation is with preparation example 1, concrete operations：
To in appropriate DMA, anthranilamide, phenylacetaldehyde, sodium carbonate and sodium hydrogensulfite are added, then nitrogen atmosphere Under be warming up to 90 DEG C, and stirring reaction 10 hours at such a temperature；Wherein, anthranilamide is with the mol ratio of phenylacetaldehyde 1:3rd, the mol ratio of anthranilamide and sodium carbonate is 1:1.2nd, the mol ratio of anthranilamide and sodium hydrogensulfite For 1:2.
React after terminating, reaction system is poured into water, separate out solid, stand, precipitate, filter, wash, be dried, will be dry Dry solid ethyl alcohol recrystallization, so as to obtain the formula (II) compound for light yellow solid, fusing point is with preparation example 1, yield For 85.6%.
Preparation example 3
Reaction equation is with preparation example 1, concrete operations：
To in appropriate DMA, anthranilamide, phenylacetaldehyde, sodium carbonate and sodium hydrogensulfite are added, then nitrogen atmosphere Under be warming up to 100 DEG C, and stirring reaction 8 hours at such a temperature；Wherein, anthranilamide is with the mol ratio of phenylacetaldehyde 1:4th, the mol ratio of anthranilamide and sodium carbonate is 1:1.5th, the mol ratio of anthranilamide and sodium hydrogensulfite For 1:2.5.
React after terminating, reaction system is poured into water, separate out solid, stand, precipitate, filter, wash, be dried, will be dry Dry solid ethyl alcohol recrystallization, so as to obtain the formula (II) compound for light yellow solid, fusing point is with preparation example 1, yield For 87.1%.
Preparation example 4
Reaction equation is with preparation example 1, concrete operations：
To in appropriate DMA, anthranilamide, phenylacetaldehyde, sodium carbonate and sodium hydrogensulfite are added, then nitrogen atmosphere Under be warming up to 110 DEG C, and stirring reaction 9 hours at such a temperature；Wherein, anthranilamide is with the mol ratio of phenylacetaldehyde 1:2.5th, the mol ratio of anthranilamide and sodium carbonate is 1:1.1st, anthranilamide and sodium hydrogensulfite mole Than for 1:2.5.
React after terminating, reaction system is poured into water, separate out solid, stand, precipitate, filter, wash, be dried, will be dry Dry solid ethyl alcohol recrystallization, so as to obtain the formula (II) compound for light yellow solid, fusing point is with preparation example 1, yield For 85.9%.
Contrast preparation example 1-24：The investigation of alkali
Contrast preparation example 1-4：In addition to respectively the alkali in preparation example 1-4 being replaced with into sodium acid carbonate by sodium carbonate, other behaviour Make constant, and implement contrast preparation example 1-4.
Contrast preparation example 5-8：In addition to respectively the alkali in preparation example 1-4 being replaced with into potassium carbonate by sodium carbonate, other operations It is constant, and implement contrast preparation example 5-8.
Contrast preparation example 9-12：In addition to respectively the alkali in preparation example 1-4 being replaced with into caustic alcohol by sodium carbonate, other operations It is constant, and implement contrast preparation example 9-12.
Contrast preparation example 13-16：In addition to respectively the alkali in preparation example 1-4 being replaced with into potassium tert-butoxide by sodium carbonate, other Operation is constant, and implements contrast preparation example 13-16.
Contrast preparation example 17-20：In addition to respectively the alkali in preparation example 1-4 being replaced with into monoethanolamine by sodium carbonate, other behaviour Make constant, and implement contrast preparation example 17-20.
Contrast preparation example 21-24：In addition to respectively the alkali in preparation example 1-4 being replaced with into isopropanolamine by sodium carbonate, other Operation is constant, and implements contrast preparation example 21-24.
Acquired results see the table below.
As can be seen here, the species of wherein alkali is significantly affected on products collection efficiency, and wherein sodium carbonate has best effect, Even very similar with sodium carbonate sodium acid carbonate or potassium carbonate, its yield also has significant reduction.
Contrast preparation example 25-36：The investigation of reducing agent
Contrast preparation example 25-28：Except respectively the reducing agent in preparation example 1-4 being replaced with into sodium sulfite by sodium hydrogensulfite Outward, other operations are constant, and implement contrast preparation example 25-28.
Contrast preparation example 29-32：Except respectively the reducing agent in preparation example 1-4 being replaced with into ferrous sulfate by sodium hydrogensulfite Outward, other operations are constant, and implement contrast preparation example 29-32.
Contrast preparation example 33-36：Except respectively the reducing agent in preparation example 1-4 being replaced with into stannous chloride by sodium hydrogensulfite Outward, other operations are constant, and implement contrast preparation example 33-36.
Acquired results see the table below.
As can be seen here, reducing agent species is significantly affected on products collection efficiency, and wherein sodium hydrogensulfite has best effect Really, even very similar with sodium hydrogensulfite sodium sulfite, its yield also has significant reduction.
Contrast preparation example 37-42：The investigation of solvent
In addition to solvent therein is replaced with into following solvent by DMA, with preparation example 1-4 identical mode and it is respectively real Contrast preparation example 37-42 is applied, has used the yield of solvent, preparation example corresponding relation and corresponding product as shown in the table.
As can be seen here, solvent equally has certain impact to final result, and wherein DMA has best effect, even if It is the DMF very similar with it, the also decrease to some degree of its yield.
Embodiment 1
To in DMF, formula (II) compound, Cu (OAc) in addition2·H2O, potassium peroxydisulfate and sodium acetate, then heat to 80 DEG C, and stirring sealing reaction 12 hours at such a temperature；Wherein, formula (II) compound and Cu (OAc)2·H2The mol ratio of O is 1: 0.05th, the mol ratio of formula (II) compound and potassium peroxydisulfate is 1:2nd, the mol ratio of formula (II) compound and sodium acetate is 1:0.5, And with mM count the formula (II) compound of (mmol) meter with the ratio of DMF of milliliter (ml) meter as 1:10.
After reaction completely, reaction system is naturally cooled to into room temperature, add the ethyl acetate and saturated common salt of equal-volume ratio The mixed liquor of water, oscillation extraction 2-4 time, collected organic layer, drying, rotary evaporation concentration obtains crude product, and crude product is crossed into 300- 400 mesh silica gel column chromatographies, with ethyl acetate and petroleum ether mixed liquor as eluant, eluent, the wherein body of ethyl acetate and petroleum ether Product compares 1:5, so as to obtain target product formula (I) compound, product is 82.4%.
Fusing point：194-196℃.
Nuclear magnetic resonance：1HNMR(500MHz,CDCl3)1HNMR(500MHz,CDCl3)δ9.30(s,1H),8.26-8.24 (m, 1H), 7.79-7.78 (m, 2H), 7.51-7.49 (m, 1H), 7.44-7.41 (m, 5H), 6.39 (d, J=0.5Hz, 1H), 5.85 (d, J=0.5Hz, 1H).
13CNMR(125MHz,CDCl3)δ162.1,152.0,149.2,143.5,136.4,135.0,129.4,129.2 (2C),128.7(2C),128.2,127.2,126.6,122.9,121.4。
Embodiment 2
Reaction equation is with embodiment 1, concrete operations：
To in DMF, formula (II) compound, Cu (OAc) are added2·H2O, potassium peroxydisulfate and sodium acetate, then heat to 100 DEG C, and stirring sealing reaction 30 hours at such a temperature；Wherein, formula (II) compound and Cu (OAc)2·H2The mol ratio of O is 1: 0.1st, the mol ratio of formula (II) compound and potassium peroxydisulfate is 1:3rd, the mol ratio of formula (II) compound and sodium acetate is 1:1, with And with mM count the formula (II) compound of (mmol) meter with the ratio of DMF of milliliter (ml) meter as 1:20.
After reaction completely, reaction system is naturally cooled to into room temperature, add the ethyl acetate and saturated common salt of equal-volume ratio The mixed liquor of water, oscillation extraction 2-4 time, collected organic layer, drying, rotary evaporation concentration obtains crude product, and crude product is crossed into 300- 400 mesh silica gel column chromatographies, with ethyl acetate and petroleum ether mixed liquor as eluant, eluent, the wherein body of ethyl acetate and petroleum ether Product compares 1:10, so as to obtain target product formula (I) compound, product is 81.8%.
Fusing point and nuclear magnetic resonance data are with embodiment 1.
Embodiment 3
Reaction equation is with embodiment 1, concrete operations：
To in DMF, formula (II) compound, Cu (OAc) are added2·H2O, potassium peroxydisulfate and sodium acetate, then heat to 120 DEG C, and stirring sealing reaction 20 hours at such a temperature；Wherein, formula (II) compound and Cu (OAc)2·H2The mol ratio of O is 1: 0.15th, the mol ratio of formula (II) compound and potassium peroxydisulfate is 1:4th, the mol ratio of formula (II) compound and sodium acetate is 1:1.5, And with mM count the formula (II) compound of (mmol) meter with the ratio of DMF of milliliter (ml) meter as 1:30.
After reaction completely, reaction system is naturally cooled to into room temperature, add the ethyl acetate and saturated common salt of equal-volume ratio The mixed liquor of water, oscillation extraction 2-4 time, collected organic layer, drying, rotary evaporation concentration obtains crude product, and crude product is crossed into 300- 400 mesh silica gel column chromatographies, with ethyl acetate and petroleum ether mixed liquor as eluant, eluent, the wherein body of ethyl acetate and petroleum ether Product compares 1:7, so as to obtain target product formula (I) compound, product is 80.9%.
Fusing point and nuclear magnetic resonance data are with embodiment 1.
Embodiment 4
Reaction equation is with embodiment 1, concrete operations：
To in DMF, formula (II) compound, Cu (OAc) are added2·H2O, potassium peroxydisulfate and sodium acetate, then heat to 90 DEG C, and stirring sealing reaction 25 hours at such a temperature；Wherein, formula (II) compound and Cu (OAc)2·H2The mol ratio of O is 1: 0.08th, the mol ratio of formula (II) compound and potassium peroxydisulfate is 1:3.5th, the mol ratio of formula (II) compound and sodium acetate is 1: 0.9, and with mM count the formula (II) compound of (mmol) meter with the ratio of DMF of milliliter (ml) meter as 1:15.
After reaction completely, reaction system is naturally cooled to into room temperature, add the ethyl acetate and saturated common salt of equal-volume ratio The mixed liquor of water, oscillation extraction 2-4 time, collected organic layer, drying, rotary evaporation concentration obtains crude product, and crude product is crossed into 300- 400 mesh silica gel column chromatographies, with ethyl acetate and petroleum ether mixed liquor as eluant, eluent, the wherein body of ethyl acetate and petroleum ether Product compares 1:8, so as to obtain target product formula (I) compound, product is 82.1%.
Fusing point and nuclear magnetic resonance data are with embodiment 1.
Comparative example 1-32：The investigation of catalyst
Comparative example 1-4：Except respectively by the catalyst in embodiment 1-4 by Cu (OAc)2·H2O replaces with acid chloride Outward, other operations are constant, and implement comparative example 1-4.
Comparative example 5-8：Except respectively by the catalyst in embodiment 1-4 by Cu (OAc)2·H2O replaces with palladium bichloride Outward, other operations are constant, and implement comparative example 5-8.
Comparative example 9-12：Except respectively by the catalyst in embodiment 1-4 by Cu (OAc)2·H2O replaces with four (triphens Base phosphine) outside palladium, other operations are constant, and implement comparative example 9-12.
Comparative example 13-16：Except respectively by the catalyst in embodiment 1-4 by Cu (OAc)2·H2O replaces with levulinic Outside ketone palladium, other operations are constant, and implement comparative example 13-16.
Comparative example 17-20：Except respectively by the catalyst in embodiment 1-4 by Cu (OAc)2·H2O replaces with trifluoro second Outside sour palladium, other operations are constant, and implement comparative example 17-20.
Comparative example 21-24：Except respectively by the catalyst in embodiment 1-4 by Cu (OAc)2·H2O replaces with four amminos Outside palladium bichloride, other operations are constant, and implement comparative example 21-24.
Comparative example 25-28：Except respectively by the catalyst in embodiment 1-4 by Cu (OAc)2·H2O replaces with two (three Phenylphosphine) outside palladium bichloride, other operations are constant, and implement comparative example 25-28.
Comparative example 29-32：Except respectively by the catalyst in embodiment 1-4 by Cu (OAc)2·H2O replaces with two pyridines Outside palladium bichloride, other operations are constant, and implement comparative example 29-32.
Acquired results see the table below.
As can be seen here, the species of catalyst is significantly affected on products collection efficiency, wherein tetrakis triphenylphosphine palladium (Pd (PPh3)4), two pyridine palladium bichloride (PdCl2(Py)2) or copper acetate monohydrate (Cu (OAc)2·H2O) there is preferably catalysis Effect, and copper acetate monohydrate then has best catalytic performance, other catalyst cannot react or yield is very little, Actual application value is had been out.
Comparative example 33-40：The investigation of oxidant
In addition to oxidant therein is replaced with into following oxidant by potassium peroxydisulfate, with embodiment 1-4 identical side Formula and implement comparative example 33-40 respectively, use the yield of oxidant, embodiment corresponding relation and corresponding product as follows Shown in table.
As can be seen here, in all of oxidant, potassium peroxydisulfate (K2S2O8) there is best oxidation susceptibility；And other oxygen Agent cannot obtain product.In addition it is also possible to find out, even very similar with potassium peroxydisulfate sodium peroxydisulfate or persulfuric acid Amine, cannot similarly obtain product.
Comparative example 41-48：The investigation of alkali
In addition to alkali therein is replaced with into following alkali by peracetic acid sodium, with embodiment 1-4 identical mode and difference Comparative example 41-48 is implemented, uses the yield of alkali, embodiment corresponding relation and corresponding product as shown in the table.
As can be seen here, cesium carbonate and sodium acetate have good effect, and sodium acetate has best effect.When adopting it During its alkali, products collection efficiency is significantly reduced, or even cannot obtain product.In addition it can also be seen that even with sodium acetate Very similar sodium formate, its effect also has and is significantly greatly lowered.
In sum, can clearly be found out by above-mentioned all embodiments, when applying the method according to the invention, formula (II) can be made Compound smoothly reacts with DMF, so as to obtain purpose product, and yield is good, post processing is simple, and these effects take , the comprehensive synergy of Multiple factors such as catalyst, alkali and oxidant is depended on, when one factor of any of which is changed all Yield will be caused by significantly reducing.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the protection model of the present invention Enclose.Additionally, it will also be appreciated that after the technology contents for having read the present invention, those skilled in the art can make each to the present invention Plant and change, change and/or modification, all these equivalent form of value equally falls within the guarantor that the application appended claims are limited Within the scope of shield.

Claims (9)

1. a kind of synthetic method of lower formula (I) compound,
Methods described includes：In the presence of catalyst, oxidant and alkali, lower formula (II) compound and DMF Stirring sealing reaction, so as to obtain the formula (I) compound,
The catalyst is copper acetate monohydrate；
The oxidant is potassium peroxydisulfate；
The alkali is sodium acetate.
2. synthetic method as claimed in claim 1, it is characterised in that：Formula (II) compound is with the mol ratio of catalyst 1:0.05-0.15。
3. synthetic method as claimed in claim 1, it is characterised in that：Formula (II) compound is with the mol ratio of oxidant 1:2-4。
4. synthetic method as claimed in claim 1, it is characterised in that：Formula (II) compound is 1 with the mol ratio of alkali: 0.5-1.5。
5. the synthetic method as described in any one of claim 1-4, it is characterised in that：As formula (II) compound of initiation material Synthetic method it is as follows：In organic solvent, in the presence of alkali and reducing agent, lower formula (III) compound and formula (IV) compound The stirring reaction under atmosphere of inert gases, so as to obtain formula (II) compound,
6. synthetic method as claimed in claim 5, it is characterised in that：In the synthetic method of the formula (II) compound, institute Alkali is stated for any one in sodium carbonate, sodium acid carbonate, potassium carbonate, caustic alcohol, potassium tert-butoxide, monoethanolamine, isopropanolamine；
In the synthetic method of the formula (II) compound, the reducing agent be sodium hydrogensulfite, sodium sulfite, ferrous sulfate or Any one in stannous chloride；
In the synthetic method of the formula (II) compound, the organic solvent be DMF, N, N- dimethyl Any one in acetamide, chlorobenzene, benzene, dimethylbenzene, dimethyl sulfoxide (DMSO), 1-METHYLPYRROLIDONE.
7. synthetic method as claimed in claim 6, it is characterised in that：In the synthetic method of the formula (II) compound, institute Alkali is stated for sodium carbonate.
8. synthetic method as claimed in claim 6, it is characterised in that：In the synthetic method of the formula (II) compound, institute Reducing agent is stated for sodium hydrogensulfite.
9. synthetic method as claimed in claim 6, it is characterised in that：In the synthetic method of the formula (II) compound, institute Organic solvent is stated for DMAC N,N' dimethyl acetamide.
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