CN107474048B - A kind of synthetic method of amido imide dibenzo suberol - Google Patents
A kind of synthetic method of amido imide dibenzo suberol Download PDFInfo
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- CN107474048B CN107474048B CN201710633019.3A CN201710633019A CN107474048B CN 107474048 B CN107474048 B CN 107474048B CN 201710633019 A CN201710633019 A CN 201710633019A CN 107474048 B CN107474048 B CN 107474048B
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- POAVRNPUPPJLKZ-UHFFFAOYSA-N 6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulen-11-ol Chemical compound C1CC2=CC=CC=C2C(O)C2=CC=CC=C21 POAVRNPUPPJLKZ-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 125000003368 amide group Chemical group 0.000 title claims abstract description 15
- 150000003949 imides Chemical class 0.000 title claims abstract description 15
- 238000010189 synthetic method Methods 0.000 title claims abstract description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims abstract description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000012965 benzophenone Substances 0.000 claims abstract description 9
- GBHCABUWWQUMAJ-UHFFFAOYSA-N 2-hydrazinoethanol Chemical compound NNCCO GBHCABUWWQUMAJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000012423 maintenance Methods 0.000 claims abstract description 5
- 229960000935 dehydrated alcohol Drugs 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims abstract description 4
- AFEYRQHEIPNLOY-UHFFFAOYSA-N C1(CCCCC1)P(C1CCCCC1)C1CCCCC1.C(C1=CC=CC=C1)(Cl)Cl Chemical compound C1(CCCCC1)P(C1CCCCC1)C1CCCCC1.C(C1=CC=CC=C1)(Cl)Cl AFEYRQHEIPNLOY-UHFFFAOYSA-N 0.000 claims abstract description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 6
- -1 2- diazanyl Chemical group 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 2
- 229960004756 ethanol Drugs 0.000 claims description 2
- 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
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 claims 1
- 239000002893 slag Substances 0.000 claims 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 claims 1
- 229910001948 sodium oxide Inorganic materials 0.000 claims 1
- 238000005406 washing Methods 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 2
- 208000008589 Obesity Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000020824 obesity Nutrition 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 101150076348 FTO gene Proteins 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- HFRRTEXXHVWFQQ-UHFFFAOYSA-N dichloromethylbenzene;ruthenium;tricyclohexylphosphane Chemical compound [Ru].ClC(Cl)C1=CC=CC=C1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 HFRRTEXXHVWFQQ-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
A kind of synthetic method of amido imide dibenzo suberol, comprising the following steps: 1) mix 2- hydrazinoethanol, selenium dioxide and solvent A, in 90~110 DEG C of 2~3h of stirring；The solvent A is DMSO or DMF；2) at a temperature of maintenance system, benzophenone, alkali and catalyst is added, later system react 15 at 7~9 atmospheric pressure, 190~220 DEG C~for 24 hours；In the step, the catalyst is two (tricyclohexyl phosphine) benzal chloride rutheniums；3) it post-processes: being first poured into water after system after reacting is cooling, then methylene chloride is added to system, stand filtering, the filter residue successively product obtained by drying after washing and solvent B is washed；The solvent B is dehydrated alcohol or ether.The cost of material that the present invention uses is lower, is easy to get；And process yield is higher, cost is relatively low, is suitable for popularization and application.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of synthesis side of amido imide dibenzo suberol
Method.
Background technique
12- amino -10,11- dihydro -5,10- imines -5H- hexichol [a, d] and cycloheptene -5- alcohol, abbreviation amido imide two
Benzo ring enanthol, structural formula areMolecular weight is 238.
With the continuous improvement of people's physical conditions for life and unreasonable dietary structure and undesirable life style,
Cause the disease incidence of obesity to rise year by year, there is disease caused by obesity to have become with death and threaten the important of human health
Problem.However, the mankind are not nowadays fully aware of to the mechanism of the generation and development of obesity, therefore the treatment to obesity
There are significant limitations, and the drug for treating obesity is even more fewer and fewer, and safe and effective obesity drug is even more phoenix hair
Rare thing.FTO gene is the presently found only one ob gene of the mankind, and research in recent years has gradually made FTO clear in fertilizer
Fat generation and developing mechanism of action have been considered as the fat novel targets for the treatment of.Have been reported that [Nature 2010,464
(7292), 1205-1209] MK-801 and FTO albumen has and preferably agrees in structure and effect, to exploitation low toxicity, efficiently, newly
Type is of great importance by the micromolecular inhibitor class slimming drugs of target spot of FTO albumen.
Compound amido imide dibenzo suberol (scientific name: 12- amino -10,11- dihydro -5,10- imines -5H- hexichol
[a, d] and cycloheptene -5- alcohol) it is the important intermediate for synthesizing such compound, document announcement [Journal of Organic
Chemistry,40(20),2982-3；1975] synthetic method, primary raw material are difficult to obtain, and are not suitable for promoting.
Summary of the invention
It is an object of that present invention to provide a kind of synthetic methods of amido imide dibenzo suberol.
Based on above-mentioned purpose, this invention takes following technical solutions:
A kind of synthetic method of amido imide dibenzo suberol, comprising the following steps:
1) 2- hydrazinoethanol, selenium dioxide and solvent A are mixed, in 90~110 DEG C of 2~3h of stirring；The solvent A is
DMSO or DMF；The main purpose of the step is to improve activation degree, is convenient for subsequent reactions；
2) at a temperature of maintenance system, benzophenone, alkali and catalyst is added, later system in 7~9 atmospheric pressure, 190~
At 220 DEG C reaction 15~for 24 hours；In the step, the catalyst is two (tricyclohexyl phosphine) benzal chloride rutheniums；
3) it post-processes: being first poured into water after the system cooling after reacting, then methylene chloride is added to system, stood
Filter, filter residue successively through wash and solvent B wash after product obtained by drying；The solvent B is dehydrated alcohol or ether.
The 2- hydrazinoethanol, selenium dioxide, solvent A three amount ratio be 1mol:(1.2~1.5) mol:(600~
850)ml。
The 2- hydrazinoethanol, benzophenone, alkali and catalyst dosage be 1mol:(1~1.25) mol:(5~6)
Mol:(0.1~0.2) g.
The alkali is sodium hydroxide, potassium hydroxide, potassium tert-butoxide or sodium methoxide.
In step 3), the concrete operations of post-processing are as follows: system is first poured into 150 after system after reacting is cooling~
In the water of 200% solvent A volume, then to the methylene chloride of system 10~15% solvent A volumes of addition, 8 are stood at 10~25 DEG C
~10h, filtering, filter residue are first washed with water, then dry after being washed with ethyl alcohol or ether.In the selection of dwell temperature, if quiet
The excessively high meeting of temperature is set so that rate of set is slow, condensation is insufficient, and yield is caused to reduce；Dwell temperature is too low, causes to condense
Fastly, it brings impurity into, influences product purity, therefore select 10~25 DEG C of dwell temperature, system is stood at this temperature can make product
Other impurities can adequately be dissolved by preferably precipitating the methylene chloride for condensing out, while being added in system so that product with
Purity after the form of solid filters out is higher.
Compared with prior art, the present invention has following technical effect that
1) cost of material is lower, is easy to get；And yield is higher, especially when alkali selects potassium tert-butoxide, yield reaches
To 95%；
2) technological operation is simple, is suitable for popularization and application.
Specific embodiment
Combined with specific embodiments below, the present invention is further illustrated.
Embodiment 1
A kind of synthetic method of amido imide dibenzo suberol, comprising the following steps:
1) 1mol 2- hydrazinoethanol, 1.2mol selenium dioxide and 600ml DMSO are mixed, stirs 2h at 90 DEG C；Institute
Stating solvent is DMF；
2) 1mol benzophenone, 5mol sodium hydroxide and 0.1g bis- (tricyclohexyl phosphine) benzal is added in maintenance system temperature
Base ruthenous chloride adjusts the temperature to 190 DEG C, and pressure is 7 atmospheric pressure, reacts cooling after 15h；
3) system is poured into 900ml water, 60ml methylene chloride is added, 9h is placed at 20 DEG C, filtered, filter residue washing
Afterwards, it is washed with dehydrated alcohol, drying obtains product, yield 88%.
Embodiment 2
A kind of synthetic method of amido imide dibenzo suberol, comprising the following steps:
1) by 1mol 2- hydrazinoethanol, 1.5mol selenium dioxide and 700ml DMSO, 3h is stirred at 110 DEG C；
2) it is sub- that 1.25mol benzophenone, 6mol potassium tert-butoxide and 0.2g bis- (tricyclohexyl phosphine) is added in maintenance system temperature
Benzylidine ruthenium, adjusting temperature is 220 DEG C, and pressure is 9 atmospheric pressure, and reaction cools down afterwards for 24 hours；
3) system is poured into 1400ml water, 85ml methylene chloride is added, 10h is placed at 10 DEG C, filtered, filter residue washing
Afterwards, it is washed with ether, drying obtains product, yield 95%.
Embodiment 3
A kind of synthetic method of amido imide dibenzo suberol, comprising the following steps:
1) by 1mol 2- hydrazinoethanol, 1.4mol selenium dioxide and 850ml DMSO, 2h is stirred at 100 DEG C；
2) temperature is kept, 1.1mol benzophenone, 5.4mol sodium methoxide and 0.15g bis- are added into the system of step 1)
(tricyclohexyl phosphine) benzal chloride ruthenium, adjusting temperature is 200 DEG C, and pressure is 8 atmospheric pressure, reacts cooling after 20h；
3) system is poured into 1450ml water, 127.5ml methylene chloride is added, 8h is placed at 25 DEG C, filtered, filter residue water
It after washing, is washed with a small amount of ether, drying obtains product, yield 91%.
Embodiment 4
A kind of synthetic method of amido imide dibenzo suberol, with embodiment 3, the difference is that, it will be in embodiment 3
Sodium methoxide change into equal substances amount potassium hydroxide, yield 90%.
Comparative example 1
It to show effect of the present invention, by taking embodiment 3 as an example, is compared using following comparative example, the comparative example preparation side
Method with embodiment 3, the difference is that, the step 1) in embodiment 3 is saved, i.e., " be directly added into 1.1mol benzophenone,
5.4mol sodium methoxide and 0.15g ... ", remaining is the same as embodiment 3, when using the comparative example, ultimate yield 71%.This shows
If when without step 1), yield is substantially reduced.
Structural characterization:
To confirm to be target product to products therefrom, the fusing point and nuclear-magnetism of each embodiment are tested respectively, as a result proves gained
Product is really target product.Below by taking embodiment 2 as an example, test result is as follows:
The fusing point of product is mp 191-192 DEG C；
Nuclear-magnetism result are as follows: 1H NMR (400MHz, DMSO-d6): δ 7.57 (1H, d, J=6.4Hz), 7.34 (1H, d, J=
6.4Hz), 7.15 (5H, dd, J=12.0,5.9Hz), 6.99 (1H, d, J=6.4Hz), 6.61 (1H, s), 4.38 (1H, s),
3.42 (1H, d, J=4.0Hz), 3.25 (2H, s), 2.51 (1H, s).
Claims (4)
1. a kind of synthetic method of amido imide dibenzo suberol, which comprises the following steps:
1) 2- hydrazinoethanol, selenium dioxide and solvent A are mixed, in 90~110 DEG C of 2~3h of stirring；The solvent A be DMSO or
DMF；
2) at a temperature of maintenance system, benzophenone, alkali and catalyst is added, system is in 7~9 atmospheric pressure, 190~220 later
At DEG C reaction 15~for 24 hours；In the step, the catalyst is two (tricyclohexyl phosphine) benzal chloride rutheniums；The alkali is hydrogen
Sodium oxide molybdena, potassium hydroxide, potassium tert-butoxide or sodium methoxide；
3) it post-processes: being first poured into water after the system cooling after reacting, then methylene chloride is added to system, stand filtering, filter
Slag successively through wash and solvent B wash after product obtained by drying；The solvent B is dehydrated alcohol or ether.
2. the synthetic method of amido imide dibenzo suberol as described in claim 1, which is characterized in that the 2- diazanyl second
Alcohol, selenium dioxide, solvent A three amount ratio be 1mol:1.2~1.5mol:600~850ml.
3. the synthetic method of amido imide dibenzo suberol as described in claim 1, which is characterized in that the 2- diazanyl second
Alcohol, benzophenone, alkali and catalyst dosage be 1mol:1~1.25mol:5~6mol:0.1~0.2g.
4. the synthetic method of amido imide dibenzo suberol as described in claim 1, which is characterized in that in step 3), after
The concrete operations of processing are as follows: first system is poured into the water of 150~200% solvent A volumes after the system cooling after reacting, then
The methylene chloride of 10~15% solvent A volumes is added to system, in 10~25 DEG C of 8~10h of standing, filtering, filter residue is first washed with water,
It is dried after being washed again with ethyl alcohol or ether.
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Effective date of registration: 20240119 Address after: No. 10, 5th Floor, East Unit 1, Building 2, No. 3 Guihua West Street, Zhengzhou High tech Industrial Development Zone, Henan Province, 450001 Patentee after: Henan Jinchai Pharmaceutical Technology Co.,Ltd. Address before: 450000 No.1 Xianghe Road, Longhu, Xinzheng, Zhengzhou, Henan Province Patentee before: HENAN INSTITUTE OF ENGINEERING |