CN102875465A - Method for preparing 7-bromoisoquinoline - Google Patents
Method for preparing 7-bromoisoquinoline Download PDFInfo
- Publication number
- CN102875465A CN102875465A CN2012103405053A CN201210340505A CN102875465A CN 102875465 A CN102875465 A CN 102875465A CN 2012103405053 A CN2012103405053 A CN 2012103405053A CN 201210340505 A CN201210340505 A CN 201210340505A CN 102875465 A CN102875465 A CN 102875465A
- Authority
- CN
- China
- Prior art keywords
- compound
- isoquinoline
- hours
- reaction
- room temperature
- 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
Abstract
The invention relates to a method for preparing 7-bromoisoquinoline. According to the method, a novel diazotization and bromine changing method is adopted, reaction is performed in a non-aqueous solvent, the method is easy to operate, the post-processing method is simple, the reaction condition is mild, namely the reaction is performed at normal temperature, and strong acid is not required. According to the method, the synthetic principle of related intermediate compounds is simple, the reaction condition is controllable, the yield is stable, and the method can be applied to industrial production.
Description
Technical field
The present invention relates to a kind of preparation method who contains the heterogeneous ring compound of a nitrogen.A kind of preparation method of 7-bromo-isoquinoline particularly.
Background technology
Quinoline and isoquinoline 99.9 are the important component parts of antibacterials, and the 7-bromo-isoquinoline is important pharmaceutical intermediate, and often the form with aglucon is incorporated in other parent nucleus, and in antibiotic effect, scorching, antiviral and anti-tumor aspect all has outstanding performance.Market is on sale at present, but price high (2007 being $ 8/mg).Its synthetic method is mainly the Pomeranz-Fritsch method, and this method mainly contains two shortcomings: one, and reaction has by product 5-bromo-isoquinoline to produce, and not only almost respectively accounts for 50%, and is difficult to separate; Its two, productive rate is very low, about 20% left and right.Also, just because of this two large shortcoming, cause the commercially available price of this product very expensive.
Summary of the invention
The object of the invention is to overcome problems of the prior art, a kind of preparation method of 7-bromo-isoquinoline is provided.
For achieving the above object, the present invention adopts following reaction mechanism:
According to above-mentioned reaction mechanism, the present invention adopts following technical scheme:
A kind of preparation method of 7 bromo-isoquinoline 99.9 is characterized in that the concrete steps of the method are:
a.1,2,3,4-tetrahydroisoquinoline is dissolved in methylene dichloride, adds aqueous sodium hypochlorite solution, wherein 1,2,3, the mol ratio of 4-tetrahydroisoquinoline and clorox is: 1:3～8 mole; Under room temperature, stirring reaction is 1.5～2.5 hours, separates organic phase, repeatedly washes with water, till removing to clorox, removes organic solvent, obtains compound 2, and its structural formula is:
;
B. then by compound
2slowly join in the saltpetre-concentrated sulfuric acid solution under ice bath, slowly rise to room temperature and transfer to 60
oin the oil bath of C, continue stirring reaction 3.5～4.5 hours; Then be cooled to room temperature, slowly pour in a large amount of trash ices under stirring, and regulate pH=7, suction filtration, obtain the brown color solid, and compound 3, and its structural formula is:
;
C. by dried compound
3be dissolved in Biphenyl Ether, add Manganse Dioxide, wherein compound
3 withthe mol ratio of Manganse Dioxide is: 1:7, and in 180-200
ounder C, stir 8～12 hours, cooling rear removal solvent also adds sherwood oil, and suction filtration, obtain compound 4, and its structural formula is:
;
D. by compound
4be dissolved in ethanol, add the gac of catalyst levels and three iron chloride hexahydrate and mol ratio to be: the hydrazine hydrate of 1:10, back flow reaction 4.5～5.5 hours, filter, concentrated, has solid to separate out, after washing with water compound 5, its structural formula is:
;
By compound
5be dissolved in ethylene dibromide, drip nitrite tert-butyl, after half an hour, add benzyltrimethylammonium bromide (nitrite tert-butyl: benzyltrimethylammonium bromide: the amount ratio of compound 5 is 1.2:1:1), room temperature reaction 5.5～6.6 hours, the saturated sodium bicarbonate aqueous solution cancellation, solution is washed several times with water repeatedly, except desolventizing, obtains crude product, this crude product, through separation and purification, obtains 7 bromo-isoquinoline 99.9.
The structure of 7-bromo-isoquinoline is shown below.
。
[0008] under the said nitrogen-containing heterocycle compound normal temperature of the present invention, be the off-white color solid, molecular formula is C
9h
6nBr, be soluble in methylene dichloride, acetone, is insoluble in water.Proton nmr spectra
1h NMR(CDCl
3,500MHz), δ 9.18 (s, 1 H), 8.55 (d,
j=6 Hz, 1 H), 8.12 (d,
j=0.5 Hz, 1H), 7.75 (dd,
j 1=9 Hz,
j 2=10.5Hz, 1H), 7.70 (d,
j=8.5 Hz, 1 H), 7.62 (d,
j=5.5 Hz, 1H).
The preparation method of 7-bromo-isoquinoline of the present invention compared with the conventional method, has the following advantages:
1. operation is all comparatively easy, and aftertreatment only needs simple recrystallization can reach the purity of satisfying the demand, and purity can reach more than 95%.
2. productive rate is high.With the method that patent WO2010/123545 A2 describes, compare, existing method productive rate is less than 20%, utilizes the method for the invention, and productive rate can bring up to 25%.
3. produce cost low.With the method for the descriptions such as patent WO2010/123545 A2, US 2004/18192 A1, US5807886 A1, compare, the synthesis material price that the present invention utilizes is all comparatively cheap, compared with the conventional method, greatly reduces production cost.
4. repetition rate is high.Arylamine is converted into fragrant bromine and mainly contains classical Sandmeyer reaction and Gattermann reaction.But it be solvent that strong acid (hydrochloric acid or Hydrogen bromide) is all take in such reaction, reaction is many to be carried out at 0 ~ 50 ℃, and during higher than this temperature, diazonium salt is easy to decomposition, causes the generation of by product.In addition, halo one step also will heat and carry out in the strong acid solvent, and this has also limited the application of its acid labile substrate.Utilize this two kinds of methods, can't obtain target product---the 7-bromo-isoquinoline.By comparison, the present invention adopts a kind of new diazotization to become the bromine method, and reaction is carried out in non-aqueous solvent, and manipulation is simple and aftertreatment is simple; The reaction conditions gentleness, normal temperature gets final product; Reaction is without strong acid.
5. but large-scale industrialization production.In the present invention, the composition principle of related each midbody compound is simple, and reaction conditions is controlled, and productive rate is stable.Can be applicable to suitability for industrialized production.
Embodiment
Embodiment mono-: concrete steps are as follows:
I) by 1,2,3,4-tetrahydroisoquinoline (532g, 4.0mol) is dissolved in the 5L methylene dichloride, slowly adds aqueous sodium hypochlorite solution 2730g, room temperature vigorous stirring 2 h, in standing a moment, separate organic phase, and the water repetitive scrubbing for several times, take starch potassium iodide as indicator, be washed to without till clorox, concentrating under reduced pressure reclaims methylene dichloride, obtain the 514g clarification brown liquid (
2), productive rate 98%.
Ii) KNO
3(210g, 2.0mol, 1.5equiv) is dissolved in the 1.5L vitriol oil, and-20
othe cooling 30min of C, then proceed to ice bath, and, under mechanical stirring, slowly add compound
2(180g, 1.4mol), now have a large amount of smoke creatings, reinforced complete, removes ice bath, slowly rises to room temperature, and (approximately 1 h), move to and be preheated in advance 60
oin the oil bath of C, continue to stir 6h.Be cooled to room temperature, slowly pour in 4 L trash ices, the limit edged stirs, and adds in time appropriate trash ice, now, has a large amount of solids to separate out, and suction filtration is dry under solid word infrared lamp, obtain 172.5g brown color solid (
3), productive rate 70%.
(iii) add respectively compound in the 1.5L Biphenyl Ether
3(170g, 0.97mol), MnO
2(590g, 6.8mol, 7equiv), 210
oc reacts 10h, cooling, through the diatomite layer suction filtration, removes solid.Most of solvent is removed in the filtrate pressure distillation, and remainder repeatedly adds isopyknic sherwood oil on a small quantity, and the limit edged stirs, and has solid to separate out, suction filtration, filter cake is dry under infrared lamp, obtain 135g rice white solid (
4), productive rate 80%.
Iv) successively by compound
4(126g, 0.72mol), Iron(III) chloride hexahydrate (12g, 44.5mmol), gac (2.5g), 80% hydrazine hydrate (450g) join in 1L 95% ethanol, backflow 5h.Be cooled to room temperature, suction filtration is removed solid, filtrate decompression is concentrated remove ethanol after, have a large amount of solids to separate out, suction filtration, wash with water for several times, dry under infrared lamp, obtain the 99g orange/yellow solid (
5), productive rate 95%.Rf=0.14(ethyl acetate: sherwood oil=1:1).
(v) by compound
5(86.4g, 0.6mol) is dissolved in the 1.5L ethylene dibromide, drips nitrite tert-butyl (309g, 3mol, 5equiv), after stirring half an hour, add benzyltrimethylammonium bromide (552g, 2.4mol, 4equiv), room temperature reaction 6h, the saturated sodium bicarbonate aqueous solution cancellation, solution washes with water for several times repeatedly, removal of solvent under reduced pressure, after dissolving with methylene dichloride, through a brief silicagel column suction filtration, suitably rinse silicagel column with EA:p.e.=1:1 again, concentrated filtrate, obtain 60g off-white color solid (
6), productive rate 48%.
2. the sign of compound
(1) according to a conventional method to 3,4-dihydro-isoquinoline (compound
2) carry out the proton nmr spectra sign, concrete data are as follows:
1H?NMR（CDCl
3?,?500MHz）,?δ?8.33(s,?1H?),?7.35(dt,?J
1=1.5?Hz,?J
2=7?Hz,?J
3=14.5?Hz,?1H),?7.31-7.27(m,?2H),?7.15(d,?J=7?Hz,?1H),?3.77(dt,?J
1=2?Hz,?J
2=8?Hz,?J
3=15.5?Hz,?2H),?2.75(t,?J
1=8.5?Hz,?J
2=15.5?Hz,?2H)
(2) according to a conventional method to 7-nitro-3,4-dihydro-isoquinoline (compound
3) carry out the proton nmr spectra sign, concrete data are as follows:
1H?NMR（CDCl
3?,?500MHz）,?δ?8.42(s,?1H),?8.22(dd,?
J 1 =2?Hz,?
J 2 =8?Hz,?1H),?8.14(d,?J=2?Hz,?1H),?7.35(d,?J=8,?1H),?3.85(dt,
J 1 =2.5?Hz,?
J 2=9?Hz,?
J 3=15.5?Hz,?2H),?2.86(t,?
J 1=8?Hz,?
J 2=15.5?Hz,?2H)
(3) according to a conventional method to 7-nitroisoquinoline (compound
4) carry out the proton nmr spectra sign, concrete data are as follows:
1H?NMR（CDCl
3?,?500MHz）,?δ?9.48（s,?1H）,?8.96(s,?1H),?8.75(d,?
J=5.5Hz,?1H),?8.48(dd,?
J 1=2Hz,?
J 2=9Hz,?1H),?8.01(d,?
J=9Hz,?1H),?7.80(d,?
J=5.5Hz,?1H)
(4) according to a conventional method to 7-aminoisoquinoline (compound
5) carry out the proton nmr spectra sign, concrete data are as follows:
1H?NMR（CDCl
3?,?500MHz）,?δ?9.03(s,?1?H),?8.31(d,?
J=5.5?Hz,?1?H),?7.67(d,?
J=9.0?Hz,?1?H),?7.52(d,?
J=6.0?Hz,?1?H),?7.17(dd,?
J 1=8.5?Hz,?
J 2=11.0?Hz,?1H),?7.08(d,?
J=2.5?Hz,?1?H)。
(5) according to a conventional method to 7-bromo-isoquinoline (compound
6) carry out the proton nmr spectra sign, concrete data are as follows:
1H?NMR（CDCl
3?,?500MHz）,?δ?9.18(s,1?H),?8.55(d,
J=6?Hz,?1?H),?8.12(d,
J=0.5?Hz,?1H),?7.75(dd,?
J 1=9?Hz,?
J 2=10.5Hz,?1H),?7.70(d,?
J=8.5?Hz,?1?H),?7.62(d,?
J=5.5?Hz,?1H)。
Claims (1)
1. the preparation method of a bromo-isoquinoline 99.9 is characterized in that the concrete steps of the method are:
A. 1,2,3,4-tetrahydroisoquinoline is dissolved in methylene dichloride, adds aqueous sodium hypochlorite solution, wherein 1,2,3, the mol ratio of 4-tetrahydroisoquinoline and clorox is: 1:3～8 mole; Under room temperature, stirring reaction is 1.5～2.5 hours, separates organic phase, repeatedly washes with water, till removing to clorox, removes organic solvent, obtains compound 2, and 3, the 4-dihydro-isoquinoline, its structural formula is:
;
B. then by compound
2slowly join in the saltpetre-concentrated sulfuric acid solution under ice bath, slowly rise to room temperature and transfer to 60
oin the oil bath of C, continue stirring reaction 3.5～4.5 hours; Then be cooled to room temperature, slowly pour in a large amount of trash ices under stirring, and regulate pH=7, suction filtration, obtain the brown color solid, and compound 3, i.e. 7-nitro-3, and the 4-dihydro-isoquinoline, its structural formula is:
;
C. by dried compound
3be dissolved in Biphenyl Ether, add Manganse Dioxide, wherein compound
3 withthe mol ratio of Manganse Dioxide is: 1:7, and in 180-200
ounder C, stir 8～12 hours, cooling rear removal solvent also adds sherwood oil, and suction filtration, obtain compound 4, i.e. 7-nitroisoquinoline, and its structural formula is:
;
D. by compound
4be dissolved in ethanol, add the gac of catalyst levels and three iron chloride hexahydrate and mol ratio to be: the hydrazine hydrate of 1:10, back flow reaction 4.5～5.5 hours, filter, concentrated, there is solid to separate out, after washing with water compound 5, i.e. 7-aminoisoquinoline, its structural formula is:
;
E. by compound
5be dissolved in ethylene dibromide, drip nitrite tert-butyl, after half an hour, add benzyltrimethylammonium bromide (nitrite tert-butyl: benzyltrimethylammonium bromide: the amount ratio of compound 5 is 1.2:1:1), room temperature reaction 5.5～6.6 hours, the saturated sodium bicarbonate aqueous solution cancellation, solution is washed several times with water repeatedly, except desolventizing, obtains crude product, this crude product, through separation and purification, obtains 7 bromo-isoquinoline 99.9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103405053A CN102875465A (en) | 2012-09-14 | 2012-09-14 | Method for preparing 7-bromoisoquinoline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103405053A CN102875465A (en) | 2012-09-14 | 2012-09-14 | Method for preparing 7-bromoisoquinoline |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102875465A true CN102875465A (en) | 2013-01-16 |
Family
ID=47477020
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012103405053A Pending CN102875465A (en) | 2012-09-14 | 2012-09-14 | Method for preparing 7-bromoisoquinoline |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102875465A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1042905A (en) * | 1988-11-21 | 1990-06-13 | 藤泽药品工业株式会社 | The preparation method of 2 (1H) quinolinone compounds and medicinal compositions thereof |
| CN101198591A (en) * | 2005-06-17 | 2008-06-11 | 巴斯福股份公司 | Process of producing bleach boosters |
| CN102070467A (en) * | 2011-01-24 | 2011-05-25 | 南通龙翔化工有限公司 | Method for preparing 1,5-diaminonaphthalene by reducing 1,5-dinitronaphthalene by using hydrazine hydrate |
-
2012
- 2012-09-14 CN CN2012103405053A patent/CN102875465A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1042905A (en) * | 1988-11-21 | 1990-06-13 | 藤泽药品工业株式会社 | The preparation method of 2 (1H) quinolinone compounds and medicinal compositions thereof |
| CN101198591A (en) * | 2005-06-17 | 2008-06-11 | 巴斯福股份公司 | Process of producing bleach boosters |
| CN102070467A (en) * | 2011-01-24 | 2011-05-25 | 南通龙翔化工有限公司 | Method for preparing 1,5-diaminonaphthalene by reducing 1,5-dinitronaphthalene by using hydrazine hydrate |
Non-Patent Citations (4)
| Title |
|---|
| 《Journal of Organic Chemistry》 20020829 Paula Francom，et al. "Nucleic Acid Related Compounds. 116. Nonaqueous Diazotization of Aminopurine Nucleosides. Mechanistic Considerations and Efficient Procedures with tert-Butyl Nitrite or Sodium Nitrite" 第6788-6796页 1 第67卷, * |
| 《Journal of the American Chemical Society》 20110503 Jun Shi,et al. "Scalable Synthesis of Cortistatin A and Related Structures" 第8014-8027页 1 第133卷, * |
| JUN SHI,ET AL.: ""Scalable Synthesis of Cortistatin A and Related Structures"", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| PAULA FRANCOM，ET AL.: ""Nucleic Acid Related Compounds. 116. Nonaqueous Diazotization of Aminopurine Nucleosides. Mechanistic Considerations and Efficient Procedures with tert-Butyl Nitrite or Sodium Nitrite"", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106977572B (en) | A method of using hyodesoxycholic acid as Material synthesis lithocholic acid | |
| CN112679420B (en) | Preparation method of 2,5-dibromopyridine | |
| CN103588815B (en) | A kind of preparation method of hexaphenoxy cyclotriphosphazene fire retardant | |
| CN103087550B (en) | Permanent violet product synthesis and production process | |
| CN115368272A (en) | Preparation method of 4-cyano-2-methoxybenzaldehyde | |
| CN102850325A (en) | Preparation method of Dabigatran etexilate key intermediate | |
| CN105085208B (en) | A kind of preparation method using palladium as catalyst benzfluorene ketone compounds | |
| CN102070586B (en) | A kind of processing method of synthesizing 4-position hybrid atom MCM-41 cyclohexenyl halides | |
| CN103193608A (en) | Method for preparing dimethoxy benzaldehyde from veratrole | |
| CN103058899B (en) | Synthetic method for methyl-sulfuryl benzaldehyde | |
| CN102351790B (en) | Method for synthesizing 7-bromo-6-chloro-4-quinazolinone | |
| CN103601668A (en) | Preparation method of N-phenyl-3-bromocarbazole | |
| WO2016202252A1 (en) | Method for synthesizing d-para-hydroxyphenylglycine methyl ester | |
| CN113336764B (en) | Bipyridine ligand with axial chirality and synthetic method thereof | |
| CN103387584B (en) | Synthetic method of 7-amino-3-chloro-3-cephem-4-carboxylic acid | |
| CN102875465A (en) | Method for preparing 7-bromoisoquinoline | |
| CN105294415A (en) | Preparation method of 3-halogenated fluorenone compound | |
| CN105017167B (en) | A kind of preparation method of quinoxaline compound | |
| CN104098540B (en) | A kind of method preparing Zaltoprofen | |
| CN102382051A (en) | Method for preparing isoquinoline ketone and derivatives thereof | |
| CN103044361B (en) | Preparation method of (2R,3S)-epoxidation amino-benzene butane | |
| CN113264870A (en) | Preparation method of Apixaban intermediate suitable for industrial production | |
| CN103772269A (en) | Controllable preparation method of carbazole bromo-compound | |
| CN111187240A (en) | Preparation method of 4, 4-diphenyl ether dianhydride | |
| CN103772210B (en) | Method for catalysis synthesis of 1,3-diaminobenzene derivative by using cuprous dimethyl sulfide coordination compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130116 |