CN107501176A - A kind of preparation of the isoquinolin derovatives of 4 ethyl 1,3 - Google Patents
A kind of preparation of the isoquinolin derovatives of 4 ethyl 1,3 Download PDFInfo
- Publication number
- CN107501176A CN107501176A CN201710784878.2A CN201710784878A CN107501176A CN 107501176 A CN107501176 A CN 107501176A CN 201710784878 A CN201710784878 A CN 201710784878A CN 107501176 A CN107501176 A CN 107501176A
- Authority
- CN
- China
- Prior art keywords
- preparation
- ethyl
- isoquinolin
- solvent
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 *C(C(N(*)C(C1=CC=C**C=C1)=O)=O)=C Chemical compound *C(C(N(*)C(C1=CC=C**C=C1)=O)=O)=C 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of 4 ethyls 1; the preparation method of 3 isoquinolin derovatives; the compound has the structure as shown in (I); preparation method is using N alkyl N methacryloyls yl-benzamide and dicumyl peroxide as reaction raw materials, is reacted 12 hours at certain temperature in nitrogen atmosphere；After reaction terminates, water quenching is added to go out, aqueous phase is extracted with ethyl acetate twice, and organic phase is washed once with saturated common salt after merging, and decompression is spin-dried for removing solvent；Target product is obtained through column chromatography.
Description
Technical field
The present invention relates to the preparation method of drug molecule or intermediate, specifically a kind of 4- ethyls -1,3- isoquinolin diketone
The preparation method of derivative.
Background technology
1,3- isoquinolin derovatives have important bioactivity, such as HIV-1 integrase inhibitors
[Billamboz M, Suchaud V, Bailly F, Lion C, Demeulemeester J, et al.ACS
Med.Chem.Lett.,2013,4:606-611], pancreatic cancer cell antitumor activity [Billamboz M, Bailly F, Lion
C,Touati N,Vezin H,Calmels C,et al.Med.Chem.,2011,54:1812-1824], cyclin
Dependant kinase inhibitors [Tsou H, Otteng M, Tran T, Floyd MB, et al.Med.Chem., 2008,51:
3507-3525], caspase inhibitor [Chen Y H, Zhang Y H, Zhang H J, Liu D Z, et al.Med.Chem.,
2006,49:1613-1623], anti-S180 tumor promotions [A of CN 102503888] etc., therefore develop green synthesis side
The synthesis that method is used for the heterocyclic compounds has certain practical significance.
What the synthetic method in document on 1,3- isoquinolin derovatives was reported is not a lot.For example, 2014,
Zhao W N[Zhao W N,Xie P,Zhang M,Niu B,Bian Z G.Org.Biomol.Chem.,2014,12:7690–
7693] a synthetic method on isoquinilone derivatives et al. is reported, this method is with N- acryloyl group-N- toluyls
Amine is that raw material synthesizes 1,3- isoquinolin diketone, and benzoyl is introduced on four substitution positions.2015, Zhang M [Zhang
M,Xie P,Zhao W N,et al.J.Org.Chem.,2015,80:4176-4183] et al. realized with same substrate it is different
The introducing of ether ring on four substitution positions in chinoline backbone.2017, Pan [Pan C, Chen C, Yu J
T.Org.Biomol.Chem.,2017,15(5):1096-1099.] group reports N- alkyl-N- methacrylyl benzoyls
The reaction of amine and fatty aldehyde, generate the alkyl-substituted isoquinolinone derivatives of 4-.The present invention is equally with N- acryloyl group-N- methyl
Benzamide is substrate, without any catalyst and additive, realizes that dicumyl peroxide decomposition in situ discharges methyl free radicals,
The free radical addition cyclization in acrylamide substrate molecule is participated in again, so as to be introduced on the four substitution positions in isoquinolin skeleton
One ethyl.
Zhao preparation method：
Zhang preparation method：
Pan preparation method：
Our preparation method：
The content of the invention
It is an object of the present invention to provide a kind of preparation method of 4- ethyls -1,3- isoquinolin derovatives.In order to realize this
Goal of the invention, the invention provides one group of 4- ethyl -1,3- isoquinolin dione compounds, its structural formula are as follows：
Wherein R1For any one in methyl, n-propyl, isopropyl, normal-butyl etc.；R2Can be fluorine, chlorine, bromine, fluoroform
Any one in base, methyl, tert-butyl group etc..
The preparation scheme of above 4- ethyl -1,3- isoquinolin diketone is as follows：
Using N- alkyl-N- methacryloyls yl-benzamides as raw material, dicumyl peroxide is oxidant, reacts and is protected in nitrogen
Shield is lower to be carried out.Its reaction equation is as follows：
Wherein R1For any one in methyl, n-propyl, isopropyl, normal-butyl etc.；R2Can be fluorine, chlorine, bromine, fluoroform
Any one in base, methyl, tert-butyl group etc..
Concrete operation step is as follows：
N- alkyl-N- methacryloyls yl-benzamide, dicumyl peroxide, solvent are added in reactor, in nitrogen
Reacted 12 hours under certain temperature in protection, after reaction terminates plus water quenching is gone out, and aqueous phase ethyl acetate is extracted twice, and is had after merging
Machine mutually washed once with saturated aqueous common salt, is concentrated under reduced pressure and removes solvent, and column chromatography for separation obtains goal response product.
In above-mentioned reaction system, solvent for use is one kind in toluene, chlorobenzene, fluorobenzene, dimethylbenzene；
In above-mentioned reaction system, certain temperature is 120 DEG C.
The present invention has advantages below：
People's document is compared without using any catalyst and additive, wherein dicumyl peroxide both in front of the synthetic method
Oxidant is used as again as reactant.
Embodiment
With reference to specific embodiment, the invention will be further described.
Embodiment one：4- ethyl -2,4- dimethyl -1,3- isoquinolin diketone 4-ethyl-2,4-
Dimethylisoquinoline-1,3 (2H, 4H)-dione preparation method, its synthetic route are：
Embodiment one：4- ethyl -2,4- dimethyl -1,3- isoquinolin diketone 4-ethyl-2,4-
Dimethylisoquinoline-1,3 (2H, 4H)-dione preparation method, is carried out as follows：(1) at room temperature, by N-
Methyl-N-isopropyl crotonyl benzamide (0.203g, 1.0mmol), dicumyl peroxide (0.810g, 3.0mmol) add respectively
Enter into 10mL chlorobenzene.Mixed system reacts 12 hours in 120 DEG C of oil bath pan in a nitrogen atmosphere.
(2) after reaction terminates, water quenching is added to go out.Ethyl acetate is extracted twice (20mL × 2), and saturated common salt is washed once, is subtracted
Pressure is spin-dried for removing ethyl acetate.Oily target product (colorless oil, yield are obtained through column chromatography：60%, 130mg,1H NMR
(400MHz,CDCl3):8.26-8.28(m,1H),7.64-7.68(m,1H),7.42-7.48(m,2H),3.41(s,3H),
2.29-2.36 (m, 1H), 1.86-1.92 (m, 1H), 1.64 (s, 3H), 0.56 (t, J=8.0Hz, 3H)；13C NMR(100MHz,
CDCl3):176.6,164.5,143.4,133.9,128.7,127.2,125.2,48.3,36.6,28.5,27.0,9.4；IR
(cm-1):3066,2966,2934,2876,1714,1667,1606,1463,1416,1361,764)
Embodiment two：Chloro- 4- ethyls -2,4- dimethyl -1, the 3- isoquinolin diketone of 6-
6-chloro-4-ethyl-2,4-dimethylisoquinoline-1,3 (2H, 4H)-dione preparation method,
Its synthetic route is：
Embodiment two：Chloro- 4- ethyls -2,4- dimethyl -1, the 3- isoquinolin diketone of 6-
6-chloro-4-ethyl-2,4-dimethylisoquinoline-1,3 (2H, 4H)-dione preparation method,
Carry out as follows：
(1) at room temperature, the N- methyl-N-isopropyl crotonyl benzamides (0.238g, 1.0mmol) chlorine substituted, peroxide
Change isopropylbenzene (0.810g, 3.0mmol) to be added separately in 10mL chlorobenzene.Mixed system is in a nitrogen atmosphere in 120 DEG C
Reacted 12 hours in oil bath pan.
(2) after reaction terminates, water quenching is added to go out.Ethyl acetate is extracted twice (20mL × 2), and saturated common salt is washed once, is subtracted
Pressure is spin-dried for removing ethyl acetate.Powdered target product (73-74 DEG C of fusing point, yield are obtained through column chromatography：35%, 88mg,1H
NMR(400MHz,CDCl3):8.20-8.22(m,1H),7.41-7.45(m,2H),3.40(s,3H),2.31-2.36(m,1H),
1.85-1.88 (m, 1H), 1.64 (s, 3H), 0.58 (t, J=8.0Hz, 3H)；13C NMR(100MHz,CDCl3):175.9,
163.7,145.2,140.6,130.3,127.9,125.4,123.7,48.4,36.6,28.4,27.1,9.5；IR(cm-1):
2968,2818,1713,1669,1598,1459,1428,1354,776)
Embodiment three：4- ethyl -2,4,6- trimethyl -1,3- isoquinolin diketone 4-ethyl-2,4,6-trimethyl-
Isoquinoline-1,3 (2H, 4H)-dione preparation method, its synthetic route are：
4- ethyl -2,4,6- trimethyl -1,3- isoquinolin diketone 4-ethyl-2,4,6-trimethyl-
Isoquinoline-1,3 (2H, 4H)-dione preparation method, is carried out as follows：
(1) at room temperature, by methyl substituted N- methyl-N-isopropyls crotonyl benzamide (0.217g, 1.0mmol), mistake
Oxidation isopropylbenzene (0.810g, 3.0mmol) is added separately in 10mL chlorobenzene.Mixed system is in a nitrogen atmosphere in 120 DEG C
Oil bath pan in react 12 hours.
(2) after reaction terminates, water quenching is added to go out.Ethyl acetate is extracted twice (20mL × 2), and saturated common salt is washed once, is subtracted
Pressure is spin-dried for removing ethyl acetate.Powdered target product (91-92 DEG C of fusing point, yield are obtained through column chromatography：68%, 0.157g,1H
NMR(400MHz,CDCl3):8.12-8.14(m,1H),7.23-7.25(m,1H),7.19(s,1H),3.37(s,3H),2.45
(s, 3H), 2.27-2.32 (m, 1H), 1.85-1.88 (m, 1H), 1.61 (s, 3H), 0.54 (t, J=8.0Hz, 3H)；13C NMR
(100MHz,CDCl3):176.8,164.5,144.7,143.4,128.7,128.3,125.5,122.7,48.2,36.6,
28.5,26.9,21.9,9.4；IR(cm-1):2969,2933,2876,1711,1667,1613,1455,1427,1357,776)。
Example IV：Methyl -2- n-propyl -1,3- isoquinolin diketone the 4-ethyl-4-methyl-2- of 4- ethyls -4
Propylisoquinoline-1,3 (2H, 4H)-dione preparation method, its synthetic route are：
Methyl -2- n-propyl -1,3- isoquinolin diketone the 4-ethyl-4-methyl-2- of 4- ethyls -4
Propylisoquinoline-1,3 (2H, 4H)-dione preparation method, is carried out as follows：
(1) at room temperature, by N- n-propyl-N- methacryloyls yl-benzamides (0.230g, 1.0mmol), peroxidating isopropyl
Benzene (0.810g, 3.0mmol) is added separately in 10mL chlorobenzene.Mixed system is in a nitrogen atmosphere in 120 DEG C of oil bath pan
Middle reaction 12 hours.
(2) after reaction terminates, water quenching is added to go out.Ethyl acetate is extracted twice (20mL × 2), and saturated common salt is washed once, is subtracted
Pressure is spin-dried for removing ethyl acetate.Oily target product (yield is obtained through column chromatography：60%, 0.147g,1H NMR(400MHz,
CDCl3):8.24-8.26 (m, 1H), 7.62-7.66 (m, 1H), 7.40-7.45 (m, 2H), 3.98 (t, J=8.0Hz, 2H),
2.27-2.35 (m, 1H), 1.86-1.91 (m, 1H), 1.63-1.65 (m, 2H), 1.62 (s, 3H), 0.96 (t, J=8.0Hz,
3H), 0.55 (t, J=8.0Hz, 3H)；13C NMR(100MHz,CDCl3):176.3,164.2,143.5,133.8,128.7,
127.1,125.3,125.1,48.2,41.9,36.5,28.5,21.2,11.4,9.4；IR(cm-1):2965,2933,2875,
1711,1668,1606,1463,1433,1356,764)。
Claims (3)
1. a kind of preparation method of 4- ethyls -1,3- isoquinolin derovatives, it is characterized in that, comprise the following steps that：
(1) at room temperature, N- alkyl-N- methacryloyl yl-benzamides A, dicumyl peroxide (3 times of amounts), solvent are added together
Into reactor；Mixed system reacts 12 hours in nitrogen atmosphere under certain temperature；
(2) after reaction terminates, water quenching is added to go out, aqueous phase is extracted with ethyl acetate twice, and organic phase is washed with saturated common salt after merging
Once, decompression is spin-dried for removing solvent；Target product B is obtained through column chromatography, its reaction equation is as follows：
Wherein R1For any one in methyl, n-propyl, isopropyl, normal-butyl etc.；R2Can be fluorine, chlorine, bromine, trifluoromethyl, first
Any one in base, tert-butyl group etc..
2. in accordance with the method for claim 1, it is characterised in that：Solvent for use is in toluene, chlorobenzene, fluorobenzene, dimethylbenzene
It is a kind of.
3. in accordance with the method for claim 1, it is characterised in that：Certain temperature is 120 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710784878.2A CN107501176A (en) | 2017-09-04 | 2017-09-04 | A kind of preparation of the isoquinolin derovatives of 4 ethyl 1,3 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710784878.2A CN107501176A (en) | 2017-09-04 | 2017-09-04 | A kind of preparation of the isoquinolin derovatives of 4 ethyl 1,3 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107501176A true CN107501176A (en) | 2017-12-22 |
Family
ID=60695695
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710784878.2A Pending CN107501176A (en) | 2017-09-04 | 2017-09-04 | A kind of preparation of the isoquinolin derovatives of 4 ethyl 1,3 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107501176A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108017582A (en) * | 2018-01-29 | 2018-05-11 | 西北师范大学 | A kind of synthetic method of brominated 1,3- isoquinolin derovatives |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105198811A (en) * | 2015-10-16 | 2015-12-30 | 江南大学 | Preparation of 1,3-isoquinoline dione derivative |
-
2017
- 2017-09-04 CN CN201710784878.2A patent/CN107501176A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105198811A (en) * | 2015-10-16 | 2015-12-30 | 江南大学 | Preparation of 1,3-isoquinoline dione derivative |
Non-Patent Citations (2)
| Title |
|---|
| JIAN-HONG FAN ET AL.: "Iron-Catalyzed Oxidative Arylmethylation of Activated Alkenes Using a Peroxide as the Methyl Source", 《SYNLETT》 * |
| ZHENGBAO XU ET AL.: "A Free-Radical Cascade Methylation/Cyclization of N-Arylacrylamides and Isocyanides with Dicumyl Peroxide", 《ORGANIC LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108017582A (en) * | 2018-01-29 | 2018-05-11 | 西北师范大学 | A kind of synthetic method of brominated 1,3- isoquinolin derovatives |
| CN108017582B (en) * | 2018-01-29 | 2020-08-11 | 西北师范大学 | Synthetic method of bromine-containing 1, 3-isoquinolinedione derivative |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Shao et al. | Synthesis of N-alkyl-substituted 4-quinolones via tandem alkenyl and aryl C–N bond formation | |
| Joussot et al. | Synthesis of 3-substituted chromones and quinolones from enaminones | |
| Xu et al. | A novel approach to 1-monosubstituted 1, 2, 3-triazoles by a click cycloaddition/decarboxylation process | |
| Rajawinslin et al. | Iron/acetic acid mediated intermolecular tandem C–C and C–N bond formation: an easy access to acridinone and quinoline derivatives | |
| Nizami et al. | Silver-catalyzed chemoselective annulation of propargyl amines with alkynes for access to pyridines and pyrroles | |
| CN105198811B (en) | A kind of preparation of 1,3 isoquinolin derovatives | |
| Naresh et al. | Molecular iodine mediated synthesis of polysubstituted oxazoles by oxidative domino cyclization in water | |
| Sun et al. | Electronic halocyclization and radical haloazidation of benzene-linked 1, 7-dienes for the synthesis of functionalized 3, 1-benzoxazines | |
| Barange et al. | Synthesis of C3-nitroalkylated-4-hydroxycoumarin and hydroxyiminodihydrofuroquinolinone derivatives via the Michael addition of cyclic 1, 3-dicarbonyl compounds to β-nitrostyrenes | |
| Bao et al. | Cu (0)/Selectfluor system-catalyzed intramolecular Csp2-H/Csp2-H cross-dehydrogenative coupling (CDC) | |
| Breuer et al. | Consecutive Alkynylation–Michael Addition–Cyclocondensation (AMAC) Multicomponent Syntheses of α-Pyrones and α-Pyridones | |
| Parker et al. | Synthesis of 1, 2, 4-oxadiazoles via DDQ-mediated oxidative cyclization of amidoximes | |
| Mishra et al. | Metal-free regioselective tandem synthesis of diversely substituted benzimidazo-fused polyheterocycles in aqueous medium | |
| Vandavasi et al. | A convenient method to construct (Z)-oxazines via 6-exo-dig iodocyclization and synthesis of indolin-3-one | |
| Kouznetsov et al. | Simple entry to new 2-alkyl-1, 2, 3, 4-tetrahydroquinoline and 2, 3-dialkylquinoline derivatives using BiCl3-catalyzed three component reactions of anilines and aliphatic aldehydes in the presence (or lack) of N-vinyl amides | |
| Mendoza-Espinosa et al. | Efficient multicomponent synthesis of mono-, bis-, and tris-1, 2, 3-triazoles supported by hydroxybenzene scaffolds | |
| Obydennov et al. | A novel, two-step synthesis of 4-pyridone-3-carboxamides from 2-cyano-4-pyrones | |
| Baudelet et al. | Impact of functional groups on the copper-initiated N-arylation of 5-functionalized pyrrolidin-2-ones and their vinylogues | |
| CN107501176A (en) | A kind of preparation of the isoquinolin derovatives of 4 ethyl 1,3 | |
| Meng et al. | 4-(Dimethylamino) pyridine-catalysed iodolactonisation of γ, δ-unsaturated carboxylic acids | |
| Nagaraju et al. | A facile and highly convergent approach to thiazolo [3, 2-a] pyridines via one-pot multicomponent domino reaction under metal-free and solvent-free conditions | |
| Kumar Saini et al. | Catalytic Cycloisomerization of Enyne Diesters Derived From 2‐Propargyloxyarylaldehydes | |
| Jagadishbabu et al. | One‐Pot Synthesis of 2, 4, 5‐Triphenyl Imidazoles from 1, 2‐Diols as Key Reagents | |
| Bakavoli et al. | One-pot, procedure for the preparation of some thiazino [2, 3-b] quinoxaline derivatives | |
| CN106046002A (en) | Synthesizing method of pyridino imidazo [1,2,3] triazoloquinoline compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20171222 |