CN109096185A - A kind of synthetic method of the bromo- quinoline of 4- - Google Patents
A kind of synthetic method of the bromo- quinoline of 4- Download PDFInfo
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- CN109096185A CN109096185A CN201811089038.5A CN201811089038A CN109096185A CN 109096185 A CN109096185 A CN 109096185A CN 201811089038 A CN201811089038 A CN 201811089038A CN 109096185 A CN109096185 A CN 109096185A
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- quinoline
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- ethyl acetate
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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
- C07D215/18—Halogen atoms or nitro radicals
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of synthetic methods of the bromo- quinoline of 4-, the method is using adjacent propargyl alcohol aziminobenzene as raw material, it is sufficiently dissolved in organic solvent is added under room temperature, TMSBr or HBr is then added, it is reacted at 40 ~ 60 DEG C 1 ~ 2 hour, after reaction, reaction product is isolated and purified to obtain the bromo- quinoline of 4-, wherein, the ratio between amount of substance of adjacent propargyl alcohol aziminobenzene, TMSBr or hydrobromic acid is 1:2.5 ~ 3.0；The organic solvent is the nitromethane or halogenated hydrocarbons, acetonitrile of C1 ~ C4；The features such as reaction condition of the present invention is mild, easy to operate, raw material is simple and easy to get, reaction yield is high, the chemical synthesis process having a good application prospect.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of synthetic method of 4- bromoquinoline derivative.
Background technique
The bromo- quinoline of 4- is to synthesize many natural products at present because having certain pharmacological properties containing chinoline backbone
With the important intermediate of pharmaceutical activity molecule, there is important application and development prospect in fields such as medicine, pesticides.
4- bromoquinoline derivative is a kind of important pharmaceutical intermediate, however its synthesis is reported at present main
It is to be constructed by conventional method, i.e., using 4- oxyquinoline as raw material, tribromo phosphine oxide (POBr3) it is that bromine source carries out synthesis 4- bromine
Quinoline.POBr used in this method3Agent of activity is too strong, toxic, deep-etching, and raw material used is also to be with quinoline
Skeleton has certain difficulty for the synthesis of some bromo- quinolines of substituted 4-, i.e. substrate applicability is not wide.
In conclusion develop the new synthetic strategy of one kind is particularly important to synthesize the bromo- quinolines of 4-, mesh is arrived
Before until, using adjacent propargyl alcohol aziminobenzene be substrate series connection cyclization do not appear in the newspapers to prepare the bromo- quinoline derivatives of 4-
Road.
Summary of the invention
The 4- bromine quinoline that it is an object of the invention to provide a kind of reaction conditions is mild, yield is high, easy to operate, raw material is easy to get
The synthetic method of quinoline derivant.
A kind of synthetic method of 4- bromoquinoline derivative of the invention, be with adjacent propargyl alcohol aziminobenzene () it is raw material, in
Organic solvent is added under room temperature sufficiently to dissolve, TMSBr or hydrobromic acid is then added, is reacted 1 ~ 2 hour at 40 ~ 60 DEG C,
After reaction, reaction product is isolated and purified to obtain the bromo- quinoline of 4- as shown in the formula (II).Wherein, adjacent propargyl alcohol
The ratio between amount of substance of aziminobenzene, TMSBr or hydrobromic acid is 1:2.5 ~ 3.0, and the organic solvent is the nitro first of C1 ~ C4
Alkane or halogenated hydrocarbons, acetonitrile,
(),(),
Wherein formula () and () in R1~R9Respectively stand alone as H, CH3, X(F, Cl, Br), OCH3In any one.
A kind of reaction equation of the synthetic method of 4- bromoquinoline derivative of the invention is as follows:
,
Wherein, the preferred nitromethane of the organic solvent.
In the present invention, recommending the ratio between amount of substance of the adjacent propargyl alcohol aziminobenzene, TMSBr or hydrobromic acid is 1:
2.5 ~ 3.0, preferably 1:3.0.
Extent of reaction is tracked with TCL in reaction process of the present invention, recommending the reaction time is 1-2 hours, and preferably 2 is small
When.
Following steps can be used in heretofore described isolating and purifying: saturated sodium bicarbonate solution is added in reaction solution, then
Ethyl acetate is added, rear stratification is sufficiently stirred；Separate aqueous layer with ethyl acetate extraction, by the extract of ethyl acetate with
The organic layer separated is dry with saturated common salt water washing, anhydrous sodium sulfate respectively after merging；Ethyl acetate solvent is evaporated off, after pass through
Silica gel column chromatography separating purification obtains the bromo- quinolines of 4- in obtaining.
Compared with prior art, the present invention its advantages are embodied in: (1) providing the new synthetic strategy of one kind to construct；
(2) original method reaction typically carries out at a reflux temperature, and reaction condition of the invention is mild；(3) the method for the present invention
Not only yield is high, but also easy to operate, and substrate applicability is also wide, solves previously for the bromo- quinolines of different substituents 4-
Close the composition problem of object；(4) raw material of the present invention is simple and easy to get, and the reaction time is short.The present invention is cheap and easy to get with reagent, reacts item
The advantages that part is mild, technological operation is simple, the reaction time is short, reaction yield is high is a kind of with preferable popularization and application foreground
The synthetic method of the bromo- quinoline of 4-.
Specific embodiment
The preparation of bromo- 6- methyl -2- (4- methoxyphenyl) quinoline of embodiment 1: 4-
- 1,
Representative implementation process: at room temperature, adjacent propargyl alcohol aziminobenzene is successively added into reaction flask- 1 (1.47 g, 5
Mmol) and 20 ml nitromethanes, then TMSBr (15 mmol) is added in reaction flask, reaction is then placed in 60 DEG C
Lower reaction 2 hours.Reaction solution is added saturated sodium bicarbonate solution, adds second by TLC tracking extent of reaction after reaction
Rear stratification is sufficiently stirred in acetoacetic ester；The aqueous layer with ethyl acetate extraction separated, by the extract of ethyl acetate with separate
Organic layer is dry with saturated common salt water washing, anhydrous sodium sulfate respectively after merging；Ethyl acetate solvent is evaporated off, after through silicagel column
Chromatography purifies to obtain 4- bromo- 6- methyl -2- (4- methoxyphenyl) quinoline 1.32g, reaction yield 81%.
White solid, mp:193-195 DEG C of1H NMR (400 MHz, CDCl3): δ 2.48 (s, 3 H), 3.79
(s, 3 H), 6.93 (d, J = 8.8 Hz, 2 H), 7.45 – 7.48 (m, 1 H), 7.81 (s, 1 H),
7.91 (d, J = 8.4 Hz, 7.98 – 8.00 (m, 3 H). 13C NMR (100 MHz, CDCl3): δ 21.7,
55.4, 114.2, 122.3, 125.4, 126.2, 128.7, 129.6, 130.9, 132.7, 133.7, 137.2,
147.4, 155.9, 160.9. HRMS (ESI, m/z): calcd for C17H14BrNO: [M+H]+ = 328.0332;
found:328.0331。
The preparation of embodiment 2:4- bromo- 6- methyl -2- (4- methoxyphenyl) quinoline
At room temperature, adjacent propargyl alcohol aziminobenzene is successively added into reaction flask- 1 (1.47 g, 5 mmol) and 20 ml nitros
Hydrobromic acid (15 mmol) is then added in reaction flask by methane, and then reaction is placed at 60 DEG C and is reacted 2 hours.TLC with
Track extent of reaction.Purification procedures obtain 4- bromo- 6- methyl -2- (4- methoxyphenyl) quinoline 1.13g with embodiment 1,
Reaction yield 69%, physical data is the same as embodiment 1.
The preparation of the bromo- 2- of embodiment 3:4- (3 ', 4 '-Dimethoxyphenyl) quinoline
- 2,
At room temperature, adjacent propargyl alcohol aziminobenzene is successively added into reaction flask- 2 (1.64 g, 5 mmol) and 20 ml nitros
TMSBr (15 mmol) is then added in reaction flask by methane, and then reaction is placed at 60 DEG C and is reacted 2 hours.TLC with
Track extent of reaction.Purification procedures are received with embodiment Isosorbide-5-Nitrae-bromo- 2- (3 ', 4 '-Dimethoxyphenyl) quinoline 1.47g, reaction
Rate 86%.
White solid, mp:99-101 DEG C of1H NMR (400 MHz, CDCl3): δ 3.87 (s, 3 H), 3.97
(s, 3 H), 6.89 (d, J = 8.4 Hz, 1 H), 7.48 – 7.56 (m, 2 H), 7.64 – 7.68 (m, 1
H), 7.75 (d, J = 2.0 Hz, 1 H), 8.05 – 8.08 (m, 3 H). 13C NMR (100 MHz, CDCl3):
δ 55.9, 56.0, 110.3, 111.0, 120.3, 122.5, 126.4, 126.5, 127.1, 129.8, 130.5,
131.0, 134.5, 148.6, 149.4, 150.7, 156.6. HRMS (ESI, m/z): calcd for
C17H14BrNO2: [M+H]+ = 344.0281; found:344.0283。
The preparation of the fluoro- 2- of the bromo- 6- of embodiment 4:4- (4- methoxyphenyl) quinoline
- 3,
At room temperature, adjacent propargyl alcohol aziminobenzene is successively added into reaction flask- 3 (1.48 g, 5 mmol) and 20 ml nitros
TMSBr (15 mmol) is then added in reaction flask by methane, and then reaction is placed at 60 DEG C and is reacted 2 hours.TLC with
Track extent of reaction.Purification procedures obtain the bromo- 6- of 4- fluoro- 2- (4- methoxyphenyl) quinoline 1.29g, instead with embodiment 1
Answer yield 78%.
White solid, mp:83-85 DEG C of1H NMR (400 MHz, CDCl3): δ 3.80 (s, 3 H),
6.95 (d, J = 7.6 Hz, 2 H), 7.38 – 7.44 (m, 1 H), 7.69 – 7.72 (m, 1 H), 7.99 –
8.05 (m, 4 H). 13C NMR (100 MHz, CDCl3): δ 55.4, 110.2, 110.4, 114.3, 120.5,
120.7, 123.0, 127.2, 127.3, 128.8, 130.5, 132.4, 132.5, 133.4, 145.8, 156.1,
156.2, 159.7, 161.2, 162.2. HRMS (ESI, m/z): calcd for C16H11BrFNO: [M+H]+ =
332.0081; found: 332.0081。
The preparation of the bromo- 2- of embodiment 5:4- (4- fluorophenyl) quinoline
- 4,
At room temperature, adjacent propargyl alcohol aziminobenzene is successively added into reaction flask- 4 (1.34 g, 5 mmol) and 20 ml nitros
TMSBr (15 mmol) is then added in reaction flask by methane, and then reaction is placed at 60 DEG C and is reacted 2 hours.TLC with
Track extent of reaction.Purification procedures obtain the bromo- 2- of 4- (4- fluorophenyl) quinoline 1.05g, reaction yield 70% with embodiment 1.
White solid, mp:75-77 DEG C of1H NMR (400 MHz, CDCl3): δ 7.10 – 7.14 (m, 2
H), 7.52 (t, J = 7.2 Hz, 1 H), 7.68 (t, J = 7.2 Hz, 1 H), 8.03 – 8.09 (m, 5
H). 13C NMR (100 MHz, CDCl3): δ 115.8, 116.0, 122.5, 126.6, 127.5, 129.4,
129.5, 130.0, 130.7, 134.5, 134.5, 134.8, 148.7, 156.0, 162.8, 165.3. HRMS
(ESI, m/z): calcd for C15H9BrFN: [M+H]+ = 301.9975; found: 301.9973。
Claims (4)
1. a kind of synthetic method of the bromo- quinoline of 4-, it is characterised in that: the method is with adjacent propargyl alcohol aziminobenzeneFor raw material, is sufficiently dissolved in organic solvent is added under room temperature, TMSBr or hydrobromic acid is then added, it is anti-at 40 ~ 60 DEG C
It answers 1 ~ 2 hour, after reaction, reaction product is isolated and purified to obtain the bromo- quinoline of the 4- as shown in Formula II；
、
,
Wherein formulaWithIn R1~R9Respectively stand alone as H, CH3, X(F, Cl, Br), OCH3In any one.
2. a kind of synthetic method of the bromo- quinoline of 4- according to claim 1, it is characterised in that: the adjacent alkynes
The ratio between amount of substance of propyl alcohol aziminobenzene, TMSBr or hydrobromic acid is 1:2.5 ~ 3.0.
3. a kind of synthetic method of the bromo- quinoline of 4- according to claim 1, it is characterised in that: described is organic
Solvent is one of nitromethane or halogenated hydrocarbons, acetonitrile of C1 ~ C4.
4. a kind of synthetic method of the bromo- quinoline of 4- according to claim 1, it is characterised in that: the separation is pure
The method of change is that saturated sodium bicarbonate solution is added in reaction solution, adds ethyl acetate, and rear stratification is sufficiently stirred；Point
Aqueous layer with ethyl acetate extraction out, uses saturated salt solution after the extract of ethyl acetate is merged with the organic layer separated respectively
Washing, anhydrous sodium sulfate are dry；Ethyl acetate solvent is evaporated off, after through silica gel column chromatography separating purification obtain in obtain 4- bromine quinoline
Quinoline class compound.
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Citations (5)
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|---|---|---|---|---|
| CN1823046A (en) * | 2003-05-16 | 2006-08-23 | 惠氏公司 | Phenyl quinolines and their use as estrogenic agents |
| CN102060761A (en) * | 2011-01-11 | 2011-05-18 | 浙江大学 | Method for preparing quinoline |
| CN103113293A (en) * | 2013-01-21 | 2013-05-22 | 清华大学 | Polysubstituted quinoline derivative and preparation method thereof |
| CN103772279A (en) * | 2012-10-18 | 2014-05-07 | 邵阳学院 | Preparation method for 4-bromoisoquinolone and derivative thereof |
| CN105622501A (en) * | 2016-03-30 | 2016-06-01 | 皖南医学院 | N-aryl-3-iodoquinoline derivative and preparation method thereof |
-
2018
- 2018-09-18 CN CN201811089038.5A patent/CN109096185A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1823046A (en) * | 2003-05-16 | 2006-08-23 | 惠氏公司 | Phenyl quinolines and their use as estrogenic agents |
| CN102060761A (en) * | 2011-01-11 | 2011-05-18 | 浙江大学 | Method for preparing quinoline |
| CN103772279A (en) * | 2012-10-18 | 2014-05-07 | 邵阳学院 | Preparation method for 4-bromoisoquinolone and derivative thereof |
| CN103113293A (en) * | 2013-01-21 | 2013-05-22 | 清华大学 | Polysubstituted quinoline derivative and preparation method thereof |
| CN105622501A (en) * | 2016-03-30 | 2016-06-01 | 皖南医学院 | N-aryl-3-iodoquinoline derivative and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| COLOMBE GRONNIER ET AL.: "Au-Catalyzed Formation of Functionalized Quinolines from 2‑Alkynyl Arylazide Derivatives", 《ORGANIC LETTERS》 * |
| REN LI ET AL.: "Bronsted acid-mediated cascade cyclization of 2-propynolphenols/anilines leading to 4-halo-2H-chromenes and 1,2-dihydroquinolines", 《TETRAHEDRON LETTERS》 * |
| SHUGAO ZHU ET AL.: "Gold-Catalyzed Cyclization of 3-(2’-Azidoaryl)-1-arylpropargyl Carbonates or 3-Aryl-1-(2’-azidoaryl)propargyl Carbonates to Produce Quinolines", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| XIAN-RONG SONG ET AL.: "An efficient approach to 4-chloro quinolines via TMSCl-mediated cascade cyclization of ortho-propynol phenyl azides", 《ORGANIC CHEMISTRY FRONTIERS》 * |
| XIAN-RONG SONG ET AL.: "Cu(I)-catalyzed cascade intramolecular cyclization of 2-propynol phenyl azides and diarylphosphine oxides for the synthesis of bisphosphorylated indole derivatives", 《TETRAHEDRON LETTERS》 * |
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