CN104710368B - Method for synthesizing 2-benzoyl quinazolinone compound - Google Patents
Method for synthesizing 2-benzoyl quinazolinone compound Download PDFInfo
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- CN104710368B CN104710368B CN201510168698.2A CN201510168698A CN104710368B CN 104710368 B CN104710368 B CN 104710368B CN 201510168698 A CN201510168698 A CN 201510168698A CN 104710368 B CN104710368 B CN 104710368B
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- 238000000034 method Methods 0.000 title claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 239000003513 alkali Substances 0.000 claims abstract description 29
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000007800 oxidant agent Substances 0.000 claims abstract description 16
- 230000001590 oxidative effect Effects 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 10
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 6
- 238000010189 synthetic method Methods 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 41
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 40
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 20
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 20
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical group O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 18
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 13
- 239000001632 sodium acetate Substances 0.000 claims description 12
- 235000017281 sodium acetate Nutrition 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 10
- 238000007789 sealing Methods 0.000 claims description 6
- 239000012298 atmosphere Substances 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 3
- 230000004044 response Effects 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 230000000977 initiatory effect Effects 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical group OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims 1
- 229940113088 dimethylacetamide Drugs 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 238000011160 research Methods 0.000 abstract description 7
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- 238000002360 preparation method Methods 0.000 description 44
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 32
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical group [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 31
- 239000000047 product Substances 0.000 description 24
- 230000000052 comparative effect Effects 0.000 description 21
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- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
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- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 9
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- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 8
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- QAOBEOXFSUJDJL-RYHKZSCWSA-O [(3s,6s)-6-[2-(3,4-dihydroxyphenyl)-5,7-dihydroxychromenylium-3-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl (e)-3-(4-hydroxyphenyl)prop-2-enoate Chemical compound C1([C@H](C(C(O)[C@H](OC=2C(=[O+]C3=CC(O)=CC(O)=C3C=2)C=2C=C(O)C(O)=CC=2)O1)O)O)COC(=O)\C=C\C1=CC=C(O)C=C1 QAOBEOXFSUJDJL-RYHKZSCWSA-O 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000011835 investigation Methods 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- -1 phenanthroline ketone compound Chemical class 0.000 description 6
- 238000012805 post-processing Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 3
- DNXUGBMARDFRGG-UHFFFAOYSA-N 3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile Chemical compound O=C1C=CC(=O)C(C#N)=C1C#N DNXUGBMARDFRGG-UHFFFAOYSA-N 0.000 description 3
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- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 3
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
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- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical group [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 235000019394 potassium persulphate Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 229940071536 silver acetate Drugs 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for synthesizing a 2-benzoyl quinazolinone compound: FORMULA. The method comprises the following steps: stirring and hermetically reacting the compound as shown in a formula (II) in an organic solvent in the presence of a palladium catalyst, an oxidant and an alkali to obtain the compound as shown in a formula (I). According to the method provided by the invention, the catalyst, the alkali and the oxidant are properly selected and combined to obtain a target product with high yield, and thus the method has a very high theoretical research value and an application value.
Description
Technical field
The invention provides a kind of quinazolinones volume synthetic method, relates more particularly to a kind of 2- benzoyls quinoline
The synthetic method of imidzole phenanthroline ketone compound, belongs to organic chemical synthesis field.
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, pesticide 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 breast
Treatment late period colorectal cancer medicine Raltitrexed (Ralitrexed) of thuja acid synzyme (TS) inhibitory action, antitussive and antiasthmatic
Medicine, antiallergic agent 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；Sedative hypnotic 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 halogenide
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) derivant：
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) derivant：
As described above, various synthetic methods of Quinazol derivative are had been disclosed in prior art, but for 2- benzene
The research of the synthetic method of formoxyl quinazolinone is still little, for for example visible Yan- of research that it synthesizes in prior art
Ping Zhu et al. (" Direct One-Pot Synthesis of Luotonin F and Analogues via
Rational Logical Design ", Org.Lett., 2013,15,378-381) achievement in research, it discloses following anti-
Induction method：
The method needs to be carried out in the presence of iodine and DMSO.
Although disclosing the synthetic method of the compound in prior art, the research and expansion of the synthetic method new to its
Necessity is still suffered from, this basis and power that also exactly the present invention is accomplished are located.
The content of the invention
In order to seek the novel synthesis of 2- benzoyl quinazolinones, 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 state natural sciences fund (project approval
Number：21472140) it is accomplished under subsidy, here is expressed thanks.
Specifically, the present invention relates to a kind of synthetic method of 2- benzoyl quinazolinones shown in lower formula (I)：
Methods described includes：In organic solvent, in the presence of palladium catalyst, oxidant and alkali, by lower formula (II)
Compound is stirred sealing reaction, so as to obtain the formula (I) compound,
In the synthetic method of the present invention, the palladium catalyst is acid chloride (Pd (OAc)2), Palladous chloride. (PdCl2)、
Tetrakis triphenylphosphine palladium (Pd (PPh3)4), palladium acetylacetonate (Pd (acac)2), palladium trifluoroacetate (Pd (TFA)2), four ammino chlorine
Change palladium (Pd (NH3)4Cl2), two (triphenylphosphine) Palladous chloride. (PdCl2(PPh3)2) or two pyridine Palladous chloride. (PdCl2(Py)2) in
Any one, most preferably acid chloride (Pd (OAc)2)。
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), preferably copper chloride
(CuCl2), iodobenzene diacetate (PhI (OAc)2), dicyano benzoquinone (DDQ) or benzoquinone (BQ), most preferably benzoquinone
(BQ)。
In the synthetic method of the present invention, the alkali is Feldalat NM (MeONa), cesium carbonate (CsCO3), sodium acetate
(NaOAc), potassium carbonate (K2CO3), potassium phosphate (K3PO4), sodium carbonate (Na2CO3), potassium tert-butoxide (t-BuOH), sodium hydroxide
(NaOH) any one or in Sodium ethylate (EtONa), most preferably sodium acetate.
In the synthetic method of the present invention, the organic solvent is DMF (DMF), glycerol, first
It is any one in benzene, dimethylbenzene, normal propyl alcohol, dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone (NMP), isopropanol, n-butyl alcohol
Plant, most preferably DMF (DMF).
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 of post processing, those skilled in the art reasonably to be determined and be selected according to routine techniquess means.
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.
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 response 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, 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 bicarbonate, potassium carbonate, Sodium ethylate,
Any one in potassium tert-butoxide, ethanolamine, isopropanolamine etc., most preferably sodium carbonate.
In the synthetic method of the formula (II) compound, the reducing agent is sodium sulfite (NaHSO3), sulfurous acid
Sodium (Na2SO3), ferrous sulfate (FeSO4) or stannous chloride (SnCl2) in any one, most preferably sodium sulfite
(NaHSO3)。
In the synthetic method of the formula (II) compound, the organic solvent be DMF (DMF), N,
Appointing in N- dimethyl acetylamide (DMA), chlorobenzene, benzene, dimethylbenzene, dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone (NMP)
Meaning is a kind of, most preferably N,N-dimethylacetamide (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 of post processing, those skilled in the art reasonably to be determined and be selected according to routine techniquess means.
In the synthetic method of the formula (II) compound, the atmosphere of inert gases can be for example nitrogen atmosphere or argon
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 response 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 the synthetic method of formula (I) compound, the synthetic method is by appropriate catalytic
The selection of agent, oxidant and alkali and synergism, 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, hyacinthin, sodium carbonate and sodium sulfite 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 hyacinthin
1:2nd, the mol ratio of anthranilamide and sodium carbonate is 1:1st, the mol ratio of anthranilamide and sodium sulfite 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, hyacinthin, sodium carbonate and sodium sulfite 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 hyacinthin
1:3rd, the mol ratio of anthranilamide and sodium carbonate is 1:1.2nd, the mol ratio of anthranilamide and sodium sulfite
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, hyacinthin, sodium carbonate and sodium sulfite 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 hyacinthin
1:4th, the mol ratio of anthranilamide and sodium carbonate is 1:1.5th, the mol ratio of anthranilamide and sodium sulfite
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, hyacinthin, sodium carbonate and sodium sulfite 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 hyacinthin
1:2.5th, the mol ratio of anthranilamide and sodium carbonate is 1:1.1st, anthranilamide and sodium sulfite 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 bicarbonate 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 Sodium ethylate 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 ethanolamine 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, wherein the species of alkali has appreciable impact on products collection efficiency, and wherein sodium carbonate has best effect,
Even very similar with sodium carbonate sodium bicarbonate 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 sulfite
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 sulfite
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 sulfite
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 has appreciable impact on products collection efficiency, and wherein sodium sulfite has best effect
Really, even very similar with sodium sulfite 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 appropriate DMF, formula (II) compound, acid chloride, BQ and sodium acetate in addition then heat to 80 DEG C, and
Stirring sealing at this temperature is reacted 12 hours；Wherein, formula (II) compound and the mol ratio of acid chloride are 1:0.05th, formula (II) is changed
Compound is 1 with the mol ratio of BQ:2 and the mol ratio of formula (II) compound and sodium acetate be 1:0.5.
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, the wherein body of ethyl acetate and petroleum ether
Product compares 1:5, so as to obtain target product formula (I) compound, product is 92.7%.
Fusing point：181-182℃.
Nuclear magnetic resonance, NMR：1HNMR(500MHz,CDCl3) δ 10.37 (s, 1H), 8.51 (d, J=8.0Hz, 2H), 8.40 (d, J
=8.5Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.86-7.83 (m, 1H), 7.70-7.62 (m, 2H), 7.56-7.53 (m,
2H)。
13CNMR(125MHz,CDCl3)δ185.7,161.0,147.7,146.1,135.0,134.4,134.1,131.9
(2C),129.6,129.5,128.5(2C),127.0,123.4。
Embodiment 2
Reaction equation is with embodiment 1, concrete operations：
To in appropriate DMF, formula (II) compound, acid chloride, BQ and sodium acetate are added, then heat to 100 DEG C, and at this
At a temperature of stirring sealing reaction 10 hours；Wherein, formula (II) compound and the mol ratio of acid chloride are 1:0.1st, formula (II) chemical combination
Thing is 1 with the mol ratio of BQ:3 and the mol ratio of formula (II) compound and sodium acetate be 1:1.
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, the wherein body of ethyl acetate and petroleum ether
Product compares 1:10, so as to obtain target product formula (I) compound, product is 92.4%.
Fusing point and nuclear magnetic resonance data are with embodiment 1.
Embodiment 3
Reaction equation is with embodiment 1, concrete operations：
To in appropriate DMF, formula (II) compound, acid chloride, BQ and sodium acetate are added, then heat to 120 DEG C, and at this
At a temperature of stirring sealing reaction 8 hours；Wherein, formula (II) compound and the mol ratio of acid chloride are 1:0.15th, formula (II) chemical combination
Thing is 1 with the mol ratio of BQ:4 and the mol ratio of formula (II) compound and sodium acetate be 1:1.5.
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, the wherein body of ethyl acetate and petroleum ether
Product compares 1:8, so as to obtain target product formula (I) compound, product is 91.8%.
Fusing point and nuclear magnetic resonance data are with embodiment 1.
Embodiment 4
Reaction equation is with embodiment 1, concrete operations：
To in appropriate DMF, formula (II) compound, acid chloride, BQ and sodium acetate are added, then heat to 90 DEG C, and at this
At a temperature of stirring sealing reaction 9 hours；Wherein, formula (II) compound and the mol ratio of acid chloride are 1:0.08th, formula (II) chemical combination
Thing is 1 with the mol ratio of BQ:3.5 and the mol ratio of formula (II) compound and sodium acetate be 1:0.9.
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, the wherein body of ethyl acetate and petroleum ether
Product compares 1:6, so as to obtain target product formula (I) compound, product is 92.1%.
Fusing point and nuclear magnetic resonance data are with embodiment 1.
Comparative example 1-28：The investigation of catalyst
Comparative example 1-4：In addition to respectively the catalyst in embodiment 1-4 being replaced with into Palladous chloride. by acid chloride, other
Operation is constant, and implements comparative example 1-4.
Comparative example 5-8：Except respectively the catalyst in embodiment 1-4 being replaced with into tetrakis triphenylphosphine palladium by acid chloride
Outward, other operations are constant, and implement comparative example 5-8.
Comparative example 9-12：In addition to respectively the catalyst in embodiment 1-4 being replaced with into palladium acetylacetonate by acid chloride,
Other operations are constant, and implement comparative example 9-12.
Comparative example 13-16：Except respectively the catalyst in embodiment 1-4 being replaced with into palladium trifluoroacetate by acid chloride
Outward, other operations are constant, and implement comparative example 13-16.
Comparative example 17-20：Except respectively the catalyst in embodiment 1-4 being replaced with into four ammino Palladous chloride .s by acid chloride
Outward, other operations are constant, and implement comparative example 17-20.
Comparative example 21-24：Except respectively the catalyst in embodiment 1-4 being replaced with into two (triphenylphosphines) by acid chloride
Outside Palladous chloride., other operations are constant, and implement comparative example 21-24.
Comparative example 25-28：Except respectively the catalyst in embodiment 1-4 being replaced with into two pyridine Palladous chloride .s by acid chloride
Outward, other operations are constant, and implement comparative example 25-28.
Acquired results see the table below.
As can be seen here, the species of catalyst has appreciable impact on products collection efficiency, and wherein acid chloride has best catalysis
Effect, even very similar with acid chloride palladium trifluoroacetate, it cannot be reacted, and have been out the valency of practical application
Value.
Comparative example 29-36：The investigation of oxidant
In addition to oxidant therein is replaced with into following oxidant by BQ, to divide with embodiment 1-4 identical mode
Comparative example 29-36 is not implemented, the yield such as following table institute of oxidant, embodiment corresponding relation and corresponding product is used
Show.
As can be seen here, in all of oxidant, BQ, copper chloride, iodobenzene diacetate and dicyano benzoquinone have good
Oxidation susceptibility, BQ has best oxidation susceptibility, and other oxidants cannot react or not react substantially, or even cannot obtain
Product.
Comparative example 37-44：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 37-44 is implemented, uses the yield of alkali, embodiment corresponding relation and corresponding product as shown in the table.
As can be seen here, when using other alkali, the equal decrease to some degree of products collection efficiency, wherein sodium acetate has best
Effect, and even very similar with sodium acetate sodium formate, its yield is also greatly lowered as 23.8%.
Comparative example 45-52：The investigation of organic solvent
In addition to organic solvent therein is replaced with into following solvent by DMF, to divide with embodiment 1-4 identical mode
Comparative example 45-52 is not implemented, the yield such as following table institute of organic solvent, embodiment corresponding relation and corresponding product is used
Show.
As can be seen here, when using other organic solvents, the equal decrease to some degree of products collection efficiency, wherein DMF has
Best effect.
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
Smoothly there is oxidation reaction, so as to obtain purpose product, and yield is good, post processing is simple, and the acquirement of these effects is depended on
The comprehensive synergism of Multiple factors such as catalyst, alkali and oxidant, all will cause to produce when one factor of any of which is changed
Rate is 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 (7)
1. the synthetic method of 2- benzoyl quinazolinones shown in a kind of lower formula (I)：
Methods described includes：In organic solvent, in the presence of palladium catalyst, oxidant and alkali, by lower formula (II) compound
Sealing reaction is stirred, so as to obtain the formula (I) compound,
The palladium catalyst is acid chloride；
The oxidant is benzoquinone；
The alkali is sodium acetate.
2. the synthetic method that such as claim 1 is stated, it is characterised in that：Formula (II) compound is 1 with the mol ratio of catalyst:
0.05-0.15。
3. synthetic method as claimed in claim 1, it is characterised in that：Formula (II) compound is 1 with the mol ratio of oxidant: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. synthetic method as claimed in claim 1, it is characterised in that：Reaction temperature is 80-120 DEG C；Response time is 8-12
Hour.
6. the synthetic method as described in any one of claim 1-5, 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,
7. synthetic method as claimed in claim 6, it is characterised in that：The alkali is sodium carbonate；The reducing agent is sulfurous acid
Hydrogen sodium；The organic solvent is DMAC N,N' dimethyl acetamide.
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