CN108727262A - A kind of synthetic method of the bromo- 7- methoxy quinolines of 3- - Google Patents
A kind of synthetic method of the bromo- 7- methoxy quinolines of 3- Download PDFInfo
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- CN108727262A CN108727262A CN201810324890.XA CN201810324890A CN108727262A CN 108727262 A CN108727262 A CN 108727262A CN 201810324890 A CN201810324890 A CN 201810324890A CN 108727262 A CN108727262 A CN 108727262A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D215/20—Oxygen atoms
Abstract
The present invention provides a kind of synthetic methods of the bromo- 7- methoxy quinolines of 3-.The synthetic method of the bromo- 7- methoxy quinolines of 3- of the present invention, includes the following steps：1）Solvent is added to 7- nitros -1,2, dichlorocyanobenzoquinone is added in 3,4- tetrahydroquinolines, is stirred to react to obtain 7- nitroquinolines, 7- nitros -1,2, and the molar ratio of 3,4- tetrahydroquinolines and dichlorocyanobenzoquinone is 1:(1~5)；2）Solvent is added to 7- nitroquinolines, is heated, N- bromo-succinimides are added, insulation reaction obtains the bromo- 7- nitroquinolines of 3-；3）The bromo- 7- nitroquinolines of 3- are dissolved in solvent, sodium methoxide is added, the bromo- 7- methoxy quinolines of 3- are obtained by the reaction in heating stirring.The synthetic method of the bromo- 7- methoxy quinolines of 3- of the present invention, synthetic route is succinct, and process choice is reasonable, and cost of material is low, simple and easy to get, and operation and convenient post-treatment, total recovery is high, is easy to amplify.
Description
Technical field
The invention belongs to pharmaceutical intermediate synthesis technical fields, are related to a kind of synthetic method of the bromo- 7- methoxy quinolines of 3-.
Background technology
The bromo- 7- methoxy quinolines of 3- are medicine intermediates important in pharmaceutical chemistry, and 3 bromine atoms are one high living
The reaction site of property, can occur transition metal-catalyzed coupling reaction, such as Buchwald- with some segments or intermediate
Hartwig reaction, Heck reaction, Sonogashira reaction, Still reaction and Suzuki reaction, to reach extend carbochain,
The purpose of structural modification.Studies have shown that a series of compounds synthesized as parent nucleus using the bromo- 7- oxyquinolines of 3- can inhibit 17 β-hydroxyls
The activity of steroid dehydrogenase 1 (17 β-HSD1), the main function of 17 β-HSD1 are to convert oestrone to female two functioned
Alcohol (US20100204234).
In addition to this, it is also efficient S- nitrosos by a series of compounds that parent nucleus synthesizes of the bromo- 7- oxyquinolines of 3-
Glutathione reductase (GSNOR) inhibitor, GSNOR can be adjusted into the cell by restoring nitrosoglutathione (GSNO) approach
Nitric oxide (NO) and nitrosothiols (SNOs) are horizontal, the influence for protecting body to be coerced from nitrosation.In plant,
GSNOR adjusts NO and its key enzyme of metabolin SNOs levels as catalysis, participates in plant growth, resists pathogen, heat tolerance
The various physiological processes (WO2012083165A1) such as property, cell death and Cd stress.
Therefore, from the bromo- 7- methoxy quinolines of 3-, it is good to seek some activity to synthesize some specific compounds
Screening drug molecule has caused attention, becomes one of hot spot of pharmaceutical chemistry circle.
Pass through with 3- aminoanisoles currently, the main method of the synthesis of the bromo- 7- methoxy quinolines of 3- is 2- bromines malonaldehyde
Condensation reaction obtains.But it is especially unstable to prepare raw material 2- bromine malonaldehyde, and the yield of the synthetic method is very low, document
Report that minimum yield only has 3.8%, in addition, the post-processing trouble of this process.Therefore, raw material shakiness is prepared in order to overcome
Fixed, the shortcomings of yield is low, and post-processing trouble is not easy to amplification, develop a kind of synthetic method of the bromo- 7- methoxy quinolines of 3- has very much
It is necessary.
Invention content
In view of the deficiencies of the prior art, one of the objects of the present invention is to provide a kind of conjunctions of the bromo- 7- methoxy quinolines of 3-
At method, synthetic route is succinct, and process choice is reasonable, and cost of material is low, simple and easy to get, operation and convenient post-treatment, total recovery
Height is easy to amplify.
For this purpose, the present invention uses following technical scheme：
A kind of synthetic method of the bromo- 7- methoxy quinolines of 3-, the synthetic method include the following steps：
1) solvent is added to 7- nitros -1,2, in 3,4- tetrahydroquinolines, dichlorocyanobenzoquinone is added, is stirred to react,
Obtain 7- nitroquinolines, wherein the 7- nitros -1,2,3,4- tetrahydroquinolines and the molar ratio of the dichlorocyanobenzoquinone are
1:(1~5)；
2) solvent is added in the 7- nitroquinolines that step 1) obtains, is heated, N- bromo-succinimides, heat preservation is added
Reaction, obtains the bromo- 7- nitroquinolines of 3-；
3) the bromo- 7- nitroquinolines of 3- that step 2) obtains are dissolved in solvent, sodium methoxide is added, heating stirring reaction obtains
To the bromo- 7- methoxy quinolines of 3-.
In step 1), the solvent is dichloromethane.
In step 1), the molar ratio of the 7- nitros -1,2,3,4- tetrahydroquinolines and the dichlorocyanobenzoquinone is 1:
The molar ratio of (1~5), such as the 7- nitros -1,2,3,4- tetrahydroquinolines and the dichlorocyanobenzoquinone is 1:1,1:2,
1:3、1:4、1:5。
In step 1), time of the reaction is 20~30 DEG C, for example, the time of reaction be 20,21,22,23 DEG C, 24
℃,25℃,26℃,27℃,28℃,29℃,30℃；The time of the reaction be 0.5~2h, such as the time of reaction be
0.5h、0.8h、1h、1.2h、1.5h、1.6h、1.8h、2h。
In step 2), the solvent is glacial acetic acid.
In step 2), the molar ratio of the 7- nitroquinolines and the N- bromo-succinimides is 1:(1~1.5), example
If the molar ratio of the 7- nitroquinolines and the N- bromo-succinimides is 1:1,1:1.1,1:1.2, 1:1.3,1:1.4,
1:1.5。
In step 2), the temperature of the heating is 100~110 DEG C, for example, the temperature of the heating is 100 DEG C, 101 DEG C,
102℃,103℃,104℃,105℃,106℃,107℃,108℃,109℃,110℃；The temperature of the insulation reaction is 60
~80 DEG C, such as the temperature of insulation reaction is 60 DEG C, 65 DEG C, 70 DEG C, 75 DEG C, 80 DEG C；The time of the insulation reaction be 1~
3h, such as the time of insulation reaction is 1h, 1.5h, 2h, 2.5h, 3h.
In step 3), the solvent is n,N-Dimethylformamide.
In step 3), the molar ratio of the bromo- 7- nitroquinolines of 3- and the sodium methoxide is 1:(2~8), such as the 3-
The molar ratio of bromo- 7- nitroquinolines and the sodium methoxide is 1:2,1:3,1:4,1:5,1:6,1:7, 1:8.
In step 3), the temperature of the heating is 60~100 DEG C, for example, the temperature of heating is 60 DEG C, 65 DEG C, 70 DEG C, 75
℃,80℃,85℃,90℃,95℃,100℃；The time of the reaction be 3~5h, such as reaction time be 3h, 3.5h,
4h、4.5h、5h。
Preferably, the synthetic method of the bromo- 7- methoxy quinolines of 3- of the invention, includes the following steps：
1) dichloromethane is added to 7- nitros -1,2, in 3,4- tetrahydroquinolines, dichlorocyanobenzoquinone, stirring 20 is added
0.5~2h is reacted at a temperature of~30 DEG C, through suction filtration, is washed, is dried to obtain 7- nitroquinolines, wherein the 7- nitros -1,2,3,
The molar ratio of 4- tetrahydroquinolines and the dichlorocyanobenzoquinone is 1:(1~5)；
2) glacial acetic acid is added in the 7- nitroquinolines that step 1) obtains, is heated to 100~110 DEG C, N- bromos are added
Succimide, 60~80 DEG C of 1~3h of insulation reaction obtain the bromo- 7- nitroquinolines of 3- through suction filtration, washing, drying after cooling,
The molar ratio of the wherein described 7- nitroquinolines and the N- bromo-succinimides is 1:(1~1.5)；
3) the bromo- 7- nitroquinolines of 3- that step 2) obtains are dissolved in n,N-Dimethylformamide, sodium methoxide, heating is added
It is stirred to react 3~5h to 60~100 DEG C, through suction filtration, washs, be dried to obtain the bromo- 7- methoxy quinolines of 3-, wherein the 3- is bromo-
The molar ratio of 7- nitroquinolines and the sodium methoxide is 1:(2~8).
In the present invention, the synthetic method of the bromo- 7- methoxy quinolines of 3- is with 7- nitros -1,2, and 3,4- tetrahydroquinolines are original
Material, by 7- nitroquinolines being obtained by the reaction with dichlorocyanobenzoquinone and 3- is obtained by the reaction in N- bromo-succinimides (NBS)
Bromo- 7- nitroquinolines occur substitution reaction with sodium methoxide, obtain the bromo- 7- first of 3- finally in n,N-Dimethylformamide solvent
Phenoxyl quinoline.The reaction equation of the synthetic method of the bromo- 7- methoxy quinolines of 3- of the present invention is as follows：
The second object of the present invention is to provide a kind of bromo- 7- methoxyl groups quinolines of 3- of synthetic method synthesis as described above
Quinoline.
Compared with prior art, beneficial effects of the present invention are：
The synthetic method of the bromo- 7- methoxy quinolines of 3- of the present invention, with 7- nitros -1,2,3,4- tetrahydroquinolines are raw material,
By rationally adjusting raw material and proportioning, reaction condition, synthetic route is succinct, and process choice is reasonable, and cost of material is low, simple easy
, operation and convenient post-treatment, total recovery is high, is easy to amplify, and solves in prior art that raw material is unstable, yield is low, rear place
The shortcomings of managing difficulty, being not easy to amplify, can carry out the large-scale production of the bromo- 7- methoxy quinolines of 3-.
Specific implementation mode
The technical solution further illustrated the present invention below by specific implementation mode.
Unless specific instructions, various raw materials of the invention are commercially available buys, or is prepared according to the conventional method of this field
It obtains.
Embodiment
The first step：The synthesis of 7- nitroquinolines
Dichloromethane (4.5L) is added to 7- nitros -1,2, in 3,4 tetrahydroquinolines (60g, 0.337mol), is added portionwise
Dichlorocyanobenzoquinone (152.9g, 0.6734mol), is stirred at room temperature 1h, filters, and filter cake is stirred with dichloromethane (500mL*2)
5min is filtered；Merging filtrate is washed (500mL*2) with 10%NaOH, then washs (500mL), organic phase with saturation NaCl solution
Anhydrous Na2SO4Dry, concentrated by rotary evaporation is to dry.The crocus solid petroleum ether of concentration：Ethyl acetate=5：1 solvent 250ml
30min is stirred, dry 7- nitroquinolines (53g, 90.3%) are filtered.
Second step：The synthesis of the bromo- 7- nitroquinolines of 3-
Glacial acetic acid (350ml) is added in 7- nitroquinolines (50g, 0.287mol), 106 DEG C is warming up to, N- is added portionwise
Bromo-succinimide (51.1g, 0.2870mol).2h is kept the temperature after adding, be cooled to room temperature and overnight, is filtered, and filter cake first uses vinegar
Sour (20ml*2) rinse, then with petroleum ether (50ml*2) rinse, dry the bromo- 7- nitroquinolines of 3- (60g, 83%).
Third walks：The synthesis of the bromo- 7- methoxy quinolines of 3-
Under conditions of 80 DEG C, the bromo- 7- nitroquinolines (60.0g, 0.24mol) of 3- are dissolved in DMF, by sodium methoxide
(63.8g, 1.18mol) is added in reaction solution, reacts 4h, and after the reaction was complete, rotation removes methanol for TLC detections, and 4 times of water are added in Liquid Residue
It filters, filtration cakes torrefaction obtains the bromo- 7- methoxy quinolines of 3- (45g, 80.3%).
1HNMR (400MHz, DMSO-d6)：3.93 (s, 3H), 6.99-7.63 (m, 2H), 7.88 (d, J=9.0Hz,
1H), 8.62 (d, J=2.3Hz, 1H), 8.86 (d, J=2.4Hz, 1H).
Comparative example 1
This comparative example compared with Example 1, the difference is that, in step 1), 7- nitros -1,2,3,4- tetrahydroquinolines with
The molar ratio of dichlorocyanobenzoquinone is 1:0.1, other conditions are same as Example 1, this comparative example obtains the bromo- 7- methoxies of 3-
The yield of base quinoline is 65%.
Comparative example 2
This comparative example compared with Example 1, the difference is that, in step 1), 7- nitros -1,2,3,4- tetrahydroquinolines with
The molar ratio of dichlorocyanobenzoquinone is 1:10, other conditions are same as Example 1, this comparative example obtains the bromo- 7- methoxies of 3-
The yield of base quinoline is 72%.
Comparative example 3
This comparative example compared with Example 1, the difference is that, in step 2), 7- nitroquinolines and N- bromo succinyl
The molar ratio of imines is 1:1, other conditions are same as Example 1, this comparative example obtains the receipts of the bromo- 7- methoxy quinolines of 3-
Rate is 70%.
Comparative example 4
This comparative example compared with Example 1, the difference is that, in step 2), 7- nitroquinolines and N- bromo succinyl
The molar ratio of imines is 1:6, other conditions are same as Example 1, this comparative example obtains the receipts of the bromo- 7- methoxy quinolines of 3-
Rate is 59%.
Comparative example 5
This comparative example compared with Example 1, the difference is that, in step 3), the bromo- 7- nitroquinolines of 3- and sodium methoxide
Molar ratio is 1:1, other conditions are same as Example 1, and the yield that this comparative example obtains the bromo- 7- methoxy quinolines of 3- is
71%.
Comparative example 6
This comparative example compared with Example 1, the difference is that, in step 3), the bromo- 7- nitroquinolines of 3- and sodium methoxide
Molar ratio is 1:20, other conditions are same as Example 1, and the yield that this comparative example obtains the bromo- 7- methoxy quinolines of 3- is
61%.
Comparative example 7
This comparative example compared with Example 1, the difference is that, in step 2), solvent for use is hydrochloric acid, and other conditions are equal
Same as Example 1, the yield that this comparative example obtains the bromo- 7- methoxy quinolines of 3- is 71%.
Comparative example 8
This comparative example compared with Example 1, the difference is that, in step 3), heating temperature is 40 DEG C, and the reaction time is
2h, other conditions are same as Example 1, and the yield that this comparative example obtains the bromo- 7- methoxy quinolines of 3- is 68%.
Raw material proportioning is too low or excessively high it can be seen from comparative example 1-6, the bromo- 7- methoxy quinolines of final 3- obtained
Yield is not high；The solvent in step 2) is replaced with into other types, the bromo- 7- methoxy quinolines of 3- it can be seen from comparative example 7
Yield it is also not high；In synthetic method it can be seen from comparative example 8, changes time and the temperature of reaction, equally affect 3-
The yield of bromo- 7- methoxy quinolines.
The present invention illustrates detailed process equipment and the technological process of the present invention by above-described embodiment, but the present invention is not
It is confined to above-mentioned detailed process equipment and technological process, that is, does not mean that the present invention has to rely on above-mentioned detailed process equipment and work
Skill flow could be implemented.Person of ordinary skill in the field is it will be clearly understood that any improvement in the present invention, to product of the present invention
The equivalence replacement of each raw material and the addition of auxiliary element, the selection of concrete mode etc., all fall within protection scope of the present invention and public affairs
Within the scope of opening.
Claims (10)
1. a kind of synthetic method of the bromo- 7- methoxy quinolines of 3-, which is characterized in that the synthetic method includes the following steps：
1）Solvent is added to 7- nitros -1,2, in 3,4- tetrahydroquinolines, dichlorocyanobenzoquinone is added, is stirred to react, obtains
7- nitroquinolines, wherein the 7- nitros -1,2,3,4- tetrahydroquinolines and the solvent, the dichlorocyanobenzoquinone are rubbed
You are than being 1:(1~5)；
2）Solvent is added to step 1）In obtained 7- nitroquinolines, N- bromo-succinimides are added in heating, and heat preservation is anti-
It answers, obtains the bromo- 7- nitroquinolines of 3-；
3）By step 2）The obtained bromo- 7- nitroquinolines of 3- are dissolved in solvent, and sodium methoxide is added, and heating stirring reaction obtains 3-
Bromo- 7- methoxy quinolines.
2. synthetic method according to claim 1, which is characterized in that step 1）In, the solvent is dichloromethane；
Preferably, step 1）In, the time of the reaction is 20 ~ 30 DEG C, and the time of the reaction is 0.5 ~ 2h.
3. synthetic method according to claim 1 or 2, which is characterized in that step 2）In, the solvent is glacial acetic acid.
4. according to the synthetic method described in one of claim 1-3, which is characterized in that step 2）In, the 7- nitroquinolines with
The molar ratio of the N- bromo-succinimides is 1:(1~1.5).
5. according to the synthetic method described in one of claim 1-4, which is characterized in that step 2）In, the temperature of the heating is
100 ~ 110 DEG C, the temperature of the insulation reaction is 60 ~ 80 DEG C, and the time of the insulation reaction is 1 ~ 3h.
6. according to the synthetic method described in one of claim 1-5, which is characterized in that step 3）In, the solvent is N, N- bis-
Methylformamide.
7. according to the synthetic method described in one of claim 1-6, which is characterized in that step 3）In, the bromo- 7- nitros quinolines of 3-
The molar ratio of quinoline and the sodium methoxide is 1:(2~8).
8. according to the synthetic method described in one of claim 1-7, which is characterized in that step 3）In, the temperature of the heating is
60 ~ 100 DEG C, the time of the reaction is 3 ~ 5h.
9. according to the synthetic method described in one of claim 1-8, which is characterized in that the synthetic method includes the following steps：
1）Dichloromethane is added to 7- nitros -1,2, in 3,4- tetrahydroquinolines, dichlorocyanobenzoquinone, stirring 20 ~ 30 is added
0.5 ~ 2h is reacted at a temperature of DEG C, through suction filtration, is washed, is dried to obtain 7- nitroquinolines, wherein the 7- nitros -1,2,3,4- tetra-
The molar ratio of hydrogen quinoline and the dichlorocyanobenzoquinone is 1:(1~5)；
2）Glacial acetic acid is added to step 1）In obtained 7- nitroquinolines, 100 ~ 110 DEG C are heated to, N- bromo succinyl is added
Imines, 60 ~ 80 DEG C of 1 ~ 3h of insulation reaction obtain the bromo- 7- nitroquinolines of 3- through suction filtration, washing, drying after cooling, wherein described
The molar ratio of 7- nitroquinolines and the N- bromo-succinimides is 1:(1~1.5)；
3）By step 2）The obtained bromo- 7- nitroquinolines of 3- are dissolved in n,N-Dimethylformamide, and sodium methoxide is added, is heated to 60
~ 100 DEG C are stirred to react 3 ~ 5h, through suction filtration, wash, are dried to obtain the bromo- 7- methoxy quinolines of 3-, wherein the bromo- 7- nitros of 3-
The molar ratio of quinoline and the sodium methoxide is 1:(2~8).
10. the bromo- 7- methoxy quinolines of 3- that a kind of synthetic method as described according to one of claim 1-9 is prepared.
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Application publication date: 20181102 |