CN111303032A - Preparation method of imino late-maturing intermediate and derivative thereof - Google Patents
Preparation method of imino late-maturing intermediate and derivative thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 125000001841 imino group Chemical group [H]N=* 0.000 title abstract description 16
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims abstract description 34
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- NZCKTGCKFJDGFD-UHFFFAOYSA-N 2-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Br NZCKTGCKFJDGFD-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000000758 substrate Substances 0.000 claims abstract description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 238000007605 air drying Methods 0.000 claims description 6
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 238000007789 sealing Methods 0.000 claims description 6
- 238000002791 soaking Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- -1 nitro, carboxyl Chemical group 0.000 claims description 4
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 claims description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- 229930182821 L-proline Natural products 0.000 claims description 2
- 150000001448 anilines Chemical class 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229960002429 proline Drugs 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000543 intermediate Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000005416 organic matter Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- NBTMVUPANYTSDJ-UHFFFAOYSA-N 2-bromo-4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C(Br)=C1 NBTMVUPANYTSDJ-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LCGTWRLJTMHIQZ-UHFFFAOYSA-N 5H-dibenzo[b,f]azepine Chemical compound C1=CC2=CC=CC=C2NC2=CC=CC=C21 LCGTWRLJTMHIQZ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- PLAZTCDQAHEYBI-UHFFFAOYSA-N 2-nitrotoluene Chemical compound CC1=CC=CC=C1[N+]([O-])=O PLAZTCDQAHEYBI-UHFFFAOYSA-N 0.000 description 1
- OGIQUQKNJJTLSZ-UHFFFAOYSA-N 4-butylaniline Chemical compound CCCCC1=CC=C(N)C=C1 OGIQUQKNJJTLSZ-UHFFFAOYSA-N 0.000 description 1
- IMPPGHMHELILKG-UHFFFAOYSA-N 4-ethoxyaniline Chemical compound CCOC1=CC=C(N)C=C1 IMPPGHMHELILKG-UHFFFAOYSA-N 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000007734 materials engineering Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229960001816 oxcarbazepine Drugs 0.000 description 1
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of an imino late-maturing intermediate, namely dihydro-5H-dibenzo [ b, f ] azepine, which adopts reaction substrates of 2-bromo-benzoyl chloride, aniline and triethylamine, and prepares the dihydro-5H-dibenzo [ b, f ] azepine in a one-step method under a catalytic system of cuprous iodide. The invention also discloses a derivative of dihydro-5H-dibenzo [ b, f ] azepine prepared by the preparation method. The reaction overcomes the defects of long preparation process, high cost, long time consumption and low yield in the traditional method, the intermediate dihydro-5H-dibenzo [ b, f ] azepine and the derivative thereof are obtained by adopting one-step reaction, the yield of the target product reaches 45-55%, the preparation route of the dihydro-5H-dibenzo [ b, f ] azepine is greatly shortened, the preparation effect of the dihydro-5H-dibenzo [ b, f ] azepine is improved, and the method has a wide industrial prospect.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of an imino late-maturing intermediate and a derivative thereof.
Background
Imino late-maturing (Iminostilbene), the Chinese name: 5H-dibenzo [ B, F ] azepine, is an important pharmaceutical intermediate. It has wide effect, and is mainly used for preventing and treating hepatitis C; in addition, the compound is a representative medical intermediate, and can be used for synthesizing antiepileptic drugs of carbamazepine, oxcarbazepine and antidepressant imipramine. Moreover, the material is also an important chemical raw material in the aspects of materials and genetic engineering, for example, the material is also a precursor of an organic photoelectric material due to the conjugated condensed ring structure, and has application prospects in the photoelectric field. Imino late-maturing can be said to be a cross-domain medical intermediate with excellent performance. The chemical structure of imino late-maturing is shown below:
the traditional method for synthesizing the imino group late-maturing needs seven steps of reaction, wherein 2-methyl-nitrobenzene is used as a raw material, dihydro-5H-dibenzo [ b, f ] azepine is formed through coupling, reduction and cyclization, then acyl chlorination, bromination and dehydrogenation are carried out to obtain the imido group late-maturing containing acyl chloride, and the final product imino group late-maturing is obtained through neutralization with alkali. The preparation route is too long, and the yield of two steps is low, so that the synthesis of the final target product imino late-maturing is high in cost, long in time and low in yield. Therefore, it is necessary to find a simple procedure to obtain imino late-maturing, which is crucial to reduce the production cost of imino late-maturing and to improve the industrialization process.
One of the key intermediates in the synthesis of imino late-maturing is dihydro-5H-dibenzo [ b, f ] azepine. The above reported method requires three steps to obtain the intermediate, so if the preparation process is optimized, the preparation efficiency of the final imino late-maturing is directly determined.
Disclosure of Invention
The invention aims to overcome the defects and discloses a preparation method of dihydro-5H-dibenzo [ b, f ] azepine. The preparation method adopts a new catalytic system, adopts 2-bromo-benzoyl chloride, aniline and triethylamine as reaction substrates, and obtains dihydro-5H-dibenzo [ b, f ] azepine by a one-step method, wherein the yield is about 45-55%. The method disclosed by the invention greatly shortens the preparation route of the dihydro-5H-dibenzo [ b, f ] azepine and improves the preparation effect of the dihydro-5H-dibenzo [ b, f ] azepine.
The present invention is realized by the following technical means.
A method for preparing dihydro-5H-dibenzo [ b, f ] azepine is characterized by comprising the following steps:
(1) under the protection of inert gas, aniline and triethylamine are dissolved in an anhydrous organic solvent, cuprous iodide and a phase transfer catalyst are added, and liquid nitrogen is used for cooling;
(2) injecting n-butyl lithium solution into the reaction kettle, and stirring for reaction;
(3) gradually dripping 2-bromo-benzoyl chloride into the solution in the step (2), and continuing stirring after dripping is finished;
(4) heating the system to 70-100 ℃ for reaction, and then adding water to quench the reaction;
(5) extracting organic phase in the mixture, and purifying by a column.
Further, the mass ratio of the 2-bromo-benzoyl chloride, the aniline and the triethylamine is 1:1:1-3:2: 1.
Further, the phase transfer catalyst is selected from tetraethylammonium bromide, tetrabutylammonium bromide, benzyltriethylammonium chloride or L-proline.
Further, the cuprous iodide is activated, and the steps are as follows:
(1) soaking cuprous iodide into acid, wherein the concentration of the acid is 1-5 wt%;
(2) washing with absolute ethyl alcohol, and then air-drying;
(3) putting the mixture into a tubular furnace, and introducing hydrogen;
(4) and taking out the cuprous iodide, and sealing and storing.
Further, the temperature of the step (1) is reduced to-50-0 ℃ by using liquid nitrogen.
Further, the addition equivalent of n-butyllithium is 1 to 1.2 times the amount of aniline.
Further, the derivatives of dihydro-5H-dibenzo [ b, f ] azepine have the following general chemical formula:
wherein X is selected from hydrogen atom, nitryl, carboxyl, aryl, cyano, alkoxy or alkyl;
y is selected from hydrogen atom, halogen, hydroxyl, nitro, carboxyl, aryl, cyano, alkoxy or alkyl.
Further, one of the reaction substrates of the derivative of dihydro-5H-dibenzo [ b, f ] azepine, namely, the 2-bromo-benzoyl chloride derivative, has the following chemical formula:
wherein X is selected from hydrogen atom, nitryl, carboxyl, aryl, cyano, alkoxy or alkyl.
Further, the derivative of aniline, which is one of reaction substrates of the derivative of dihydro-5H-dibenzo [ b, f ] azepine, has the following general chemical formula:
wherein Y is selected from hydrogen atom, halogen, hydroxyl, nitro, carboxyl, aryl, cyano, alkoxy or alkyl.
Further, the derivative of dihydro-5H-dibenzo [ b, f ] azepine is selected from the following structures:
the invention has the following beneficial effects:
the invention discloses a preparation method of an imino late-maturing intermediate, namely dihydro-5H-dibenzo [ b, f ] azepine, which adopts reaction substrates of 2-bromo-benzoyl chloride, aniline and triethylamine, and prepares the dihydro-5H-dibenzo [ b, f ] azepine in a one-step method under a catalytic system of cuprous iodide. The invention also discloses a derivative of dihydro-5H-dibenzo [ b, f ] azepine prepared by the preparation method. The reaction overcomes the defects of long preparation process, high cost, long time consumption and low yield in the traditional method, the intermediate dihydro-5H-dibenzo [ b, f ] azepine and the derivative thereof are obtained by adopting one-step reaction, the yield of the target product reaches 45-55%, the preparation route of the dihydro-5H-dibenzo [ b, f ] azepine is greatly shortened, the preparation effect of the dihydro-5H-dibenzo [ b, f ] azepine is improved, and the method has a wide industrial prospect.
Detailed Description
In the disclosed embodiment of the invention, the reaction substrate 2-bromo-benzoyl chloride and its derivatives, aniline and its derivatives are all purchased from Alfa-Alsar, and triethylamine is purchased from pacific chemical company ltd. The reagents and materials described in the remaining examples were purchased from commercial reagent manufacturers unless otherwise noted. The methods described in the examples are well known to those skilled in the art.
Example 1
Preparation of dihydro-5H-dibenzo [ b, f ] azepine (1C)
Cuprous iodide is used as a catalyst and is activated before use, and the method comprises the following steps:
soaking cuprous iodide into 1 wt% dilute sulfuric acid for 8 h; then washing with absolute ethyl alcohol, and then air-drying at normal temperature; then putting the cuprous iodide into a tubular furnace, and introducing hydrogen at 25 ℃ for 10 hours; and finally, taking out the cuprous iodide, and sealing and storing the cuprous iodide in a nitrogen environment.
Under the protection of nitrogen, dissolving aniline (10mmol) and triethylamine (10mmol) in anhydrous tetrahydrofuran, adding cuprous iodide (0.1 wt% aniline) and a phase transfer catalyst tetraethylammonium bromide (0.05 wt% aniline), cooling to-50 ℃ with liquid nitrogen, slowly injecting n-butyllithium solution (10mmol) with a syringe, and stirring for 4 hours; then slowly dripping 2-bromo-benzoyl chloride (10mmol) into the mixture, controlling the dripping time to be finished within 1-2h, and continuing to react for 3h after the dripping is finished; then heating the system to 70 ℃ and reacting for 2 h; then adding water to quench and react; finally, extracting the organic matter by using dichloromethane, concentrating, purifying by using a column, and eluting by using petroleum ether: dichloromethane ═ 1:1(n/n) gave white solid (1C) in 45.7% yield.
H-NMR(300M，DMSO-d)：7.02(4H，m)，6.76(2H,m)，6.56(2H,m)，4.59(1H，s)，2.88(4H,m)。
HRMS test C14H13N([M+H]+) Theoretical value 195.29, found value 195.71.
Example 2
Preparation of dihydro-5H-dibenzo [ b, f ] azepine derivatives (2C)
Cuprous iodide is used as a catalyst and is activated before use, and the method comprises the following steps:
soaking cuprous iodide into 5 wt% dilute sulfuric acid for 8 h; then washing with absolute ethyl alcohol, and then air-drying at normal temperature; then putting the cuprous iodide into a tubular furnace, and introducing hydrogen at 25 ℃ for 12 hours; and finally, taking out the cuprous iodide, and sealing and storing the cuprous iodide in a nitrogen environment.
Under the protection of nitrogen, dissolving 4-nitroaniline (20mmol) and triethylamine (10mmol) in anhydrous tetrahydrofuran, adding cuprous iodide (0.2 wt% aniline) and a phase transfer catalyst benzyltriethylammonium chloride (0.07 wt% aniline), cooling to-30 ℃ with liquid nitrogen, slowly injecting n-butyllithium solution (12mmol) with a syringe, and stirring for 5 h; then slowly dripping 2-bromo-4-nitrobenzoyl chloride (30mmol) into the mixture, controlling the dripping time to be finished within 1-2h, and continuing to react for 5h after the dripping is finished; then heating the system to 80 ℃ and reacting for 2 h; then adding water to quench and react; finally, extracting the organic matter by using dichloromethane, concentrating, purifying by using a column, and eluting by using petroleum ether: dichloromethane ═ 1:1(n/n) gave white solid (2C) in 52.1% yield.
H-NMR(300M，DMSO-d)：7.02(2H，m)，6.76(2H,m)，6.56(2H,m)，4.59(1H，s)，2.98(2H,m)，2.56(1H，m)。
HRMS test C14H10N4O6([M+H]+) Theoretical value 330.06, found value 330.52.
Example 3
Preparation of dihydro-5H-dibenzo [ b, f ] azepine derivatives (3C)
Cuprous iodide is used as a catalyst and is activated before use, and the method comprises the following steps:
soaking cuprous iodide into 3 wt% dilute sulfuric acid for 4 h; then washing with absolute ethyl alcohol, and then air-drying at normal temperature; then putting the cuprous iodide into a tubular furnace, and introducing hydrogen at 25 ℃ for 8 hours; and finally, taking out the cuprous iodide, and sealing and storing the cuprous iodide in a nitrogen environment.
Under the protection of nitrogen, 4-ethyl oxyaniline (10mmol) and triethylamine (10mmol) are dissolved in anhydrous tetrahydrofuran, cuprous iodide (0.2 wt% aniline) and a phase transfer catalyst tetrabutylammonium bromide (0.03 wt% aniline) are added, liquid nitrogen is used for cooling to 0 ℃, then an n-butyllithium solution (12mmol) is injected slowly by a syringe, and stirring is carried out for 5 hours; then slowly dripping 2-bromo-4-nitrobenzoyl chloride (15mmol) into the mixture, controlling the dripping time to be finished within 1-2h, and continuing to react for 5h after the dripping is finished; then heating the system to 100 ℃ and reacting for 2 h; then adding water to quench and react; finally, extracting the organic matter by using dichloromethane, concentrating, purifying by using a column, and eluting by using petroleum ether: dichloromethane ═ 1:1(n/n) gave white solid (3C) in 52.1% yield.
H-NMR(300M，DMSO-d)：7.02(2H，m)，6.76(2H,m)，6.56(2H,m)，4.59(1H，s)，2.98(2H,m)，2.56(1H，m)，1.45-1.22(4H，m)，0.88(6H，m)。
HRMS test C18H20ClNO2([M+H]+) Theoretical value 317.12, found value 317.99.
Example 4
Preparation of dihydro-5H-dibenzo [ b, f ] azepine derivatives (4C)
Cuprous iodide is used as a catalyst and is activated before use, and the method comprises the following steps:
soaking cuprous iodide into 2 wt% dilute sulfuric acid for 9 h; then washing with absolute ethyl alcohol, and then air-drying at normal temperature; then putting the cuprous iodide into a tubular furnace, and introducing hydrogen at 25 ℃ for 15 hours; and finally, taking out the cuprous iodide, and sealing and storing the cuprous iodide in a nitrogen environment.
Under the protection of nitrogen, 4-butylaniline (10mmol) and triethylamine (10mmol) are dissolved in anhydrous tetrahydrofuran, cuprous iodide (0.4 wt% aniline) and a phase transfer catalyst tetrabutylammonium bromide (0.1 wt% aniline) are added, liquid nitrogen is used for cooling to-10 ℃, then an n-butyllithium solution (12mmol) is injected slowly by a syringe, and stirring is carried out for 5 hours; then slowly dripping 2-bromo-4-nitrobenzoyl chloride (25mmol) into the mixture, controlling the dripping time to be finished within 1-2h, and continuing to react for 5h after the dripping is finished; then heating the system to 90 ℃ and reacting for 2 h; then adding water to quench and react; finally, extracting the organic matter by using dichloromethane, concentrating, purifying by using a column, and eluting by using petroleum ether: dichloromethane ═ 1:1(n/n) gave white solid (4C) in 55.5% yield.
H-NMR(300M，DMSO-d)：7.02(2H，m)，6.76(2H,m)，6.56(2H,m)，4.59(1H，s)，2.98(2H,m)，2.56(1H，m)，1.45-1.22(12H，m)，0.88(6H，m)。
HRMS test C23H28N2([M+H]+) Theoretical value 332.23, found value 332.59.
Example 5
In order to test the influence of the catalytic system of the patent on the yield of the one-step preparation method, a control sample under different reaction conditions was set and compared with the examples. The reaction conditions and the yields of the objective products for the controls 1 to 4 are shown in Table 1 below.
TABLE 1 yield results for the control under different reaction conditions
As can be seen from Table 1, the yields of the target products were greatly reduced after changing the catalytic system or the reaction conditions. The catalytic system and the reaction conditions disclosed by the invention are fully demonstrated, the yield of dihydro-5H-dibenzo [ b, f ] azepine and derivatives thereof serving as an imino late-maturing intermediate can be effectively improved, and the preparation method has an application prospect.
Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention and do not limit the protection scope of the present invention. It will be understood by those skilled in the art that various deductions and equivalents may be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. A method for preparing dihydro-5H-dibenzo [ b, f ] azepine is characterized by comprising the following steps:
(1) under the protection of inert gas, aniline and triethylamine are dissolved in an anhydrous organic solvent, cuprous iodide and a phase transfer catalyst are added, and liquid nitrogen is used for cooling;
(2) injecting n-butyl lithium solution into the reaction kettle, and stirring for reaction;
(3) gradually dripping 2-bromo-benzoyl chloride into the solution in the step (2), and continuing stirring after dripping is finished;
(4) heating the system to 70-100 ℃ for reaction, and then adding water to quench the reaction;
(5) extracting organic phase in the mixture, and purifying by a column.
2. The method of claim 1, wherein the mass ratio of 2-bromo-benzoyl chloride, aniline, and triethylamine is 1:1:1 to 3:2: 1.
3. The method of claim 1, wherein the phase transfer catalyst is selected from the group consisting of tetraethylammonium bromide, tetrabutylammonium bromide, benzyltriethylammonium chloride, and L-proline.
4. The method of claim 1, wherein the cuprous iodide is activated by the steps of:
(1) soaking cuprous iodide into acid, wherein the concentration of the acid is 1-5 wt%;
(2) washing with absolute ethyl alcohol, and then air-drying;
(3) putting the mixture into a tubular furnace, and introducing hydrogen;
(4) and taking out the cuprous iodide, and sealing and storing.
5. The process for the preparation of dihydro-5H-dibenzo [ b, f ] azepine according to claim 1, wherein step (1) is carried out using liquid nitrogen to cool to-50-0 ℃.
6. The method for preparing dihydro-5H-dibenzo [ b, f ] azepine according to claim 1, wherein the n-butyllithium is added in an equivalent of 1 to 1.2 times the amount of aniline.
7. A derivative of dihydro-5H-dibenzo [ b, f ] azepine produced by the process of any one of claims 1 to 6, wherein the derivative of dihydro-5H-dibenzo [ b, f ] azepine has the following general chemical formula:
wherein X is selected from hydrogen atom, nitryl, carboxyl, aryl, cyano, alkoxy or alkyl;
y is selected from hydrogen atom, halogen, hydroxyl, nitro, carboxyl, aryl, cyano, alkoxy or alkyl.
8. The derivative of dihydro-5H-dibenzo [ b, f ] azepine produced by the method of claim 7, wherein the 2-bromo-benzoyl chloride derivative, which is one of the reaction substrates for the derivative of dihydro-5H-dibenzo [ b, f ] azepine, has the following general chemical formula:
wherein X is selected from hydrogen atom, nitryl, carboxyl, aryl, cyano, alkoxy or alkyl.
9. The derivative of dihydro-5H-dibenzo [ b, f ] azepine produced by the method of claim 7, wherein the derivative of aniline, which is a reaction substrate for the derivative of dihydro-5H-dibenzo [ b, f ] azepine, has the following general chemical formula:
wherein Y is selected from hydrogen atom, halogen, hydroxyl, nitro, carboxyl, aryl, cyano, alkoxy or alkyl.
10. The dihydro-5H-dibenzo [ b, f ] azepine derivative produced by the method of claim 7, wherein the dihydro-5H-dibenzo [ b, f ] azepine derivative is selected from the group consisting of the following structures:
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