CN1948308A - Intermediate compound for synthesizing lamel larin H and its derivatives and synthesizing method - Google Patents
Intermediate compound for synthesizing lamel larin H and its derivatives and synthesizing method Download PDFInfo
- Publication number
- CN1948308A CN1948308A CN 200510047420 CN200510047420A CN1948308A CN 1948308 A CN1948308 A CN 1948308A CN 200510047420 CN200510047420 CN 200510047420 CN 200510047420 A CN200510047420 A CN 200510047420A CN 1948308 A CN1948308 A CN 1948308A
- Authority
- CN
- China
- Prior art keywords
- dimethoxy
- synthesizing
- isoquinoline
- pyrroles
- larin
- 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.)
- Granted
Links
Images
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to a 1-(3,4-dimethoxy)-8,9-dimethoxy-2-(2,4,5-trimethoxyphenyl) pyrrole [2,1-a] isoquinoline and its synthesis method. Said method includes the following steps: adding papaverine and 2,4,5-trimethoxy-alpha-halogenated acetophenone into acetonitrile and alkali solution, making refluxing reaction for 1-25 h at 60-100 deg.C and making the solution color be changed into bright yellow from light yellow; the dose of alkali is 0.001 mol-0.004 mol/h, and the dose of papaverine is 0.001 mol/h; adopting thin-layer chromatography and column chromatography to make separation so as to obtain the invented target product. Its yield can be up to 76.5%.
Description
Technical field a: important intermediate that the present invention relates to a kind of synthesizing lamel larin H and derivative thereof, also be important medicine intermediate and Organic Chemical Plant's product intermediate simultaneously, it is a kind of pyrroles's isoquinoline 99.9 material, particularly 1-(3, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) compound that pyrroles [2,1-a] isoquinoline 99.9 is new and the synthetic process of this material.
Background technology:
Relevant 1-(3, the 4-dimethoxy)-8, the document of 9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] isoquinoline 99.9 research (comprising synthesis technique, application etc.) does not appear in the newspapers both at home and abroad.But relevant synthetic pyrroles's isoquinoline 99.9 framework has relevant report.
Following pertinent literature all relates to the step of synthetic pyrroles's isoquinoline 99.9 framework.
(1) calendar year 2001, people such as Ruchirawat [1] design an other new scheme, by 3,4-dihydro Papaverine hydrochloride and bromination methyl phenyl ketone form pyrrolo-isoquinoline 99.9 center, the aldol condensation method is synthesized Lamellarin G trimethylammonium ether and is related to relevant reaction.
(2) 2003 years Ruchirawat research group [2] in exchange the synthetic schemes that obtains having Lamellarin G structure by metal-halogen, mention and form 2H-pyrroles's intermediate through coupling from benzylisoquinoline and phenacyl bromo thing, reaction formula is as follows.
(3) 2004 years, people such as Ruchirauat [3] designed a synthetic route again, formed pentacyclic pyrroles center by MichaelAddition/Ring-Clousre and synthesized Lamellarin L, and committed step wherein is as follows:
Synthetic intermediate in the above prior art, resynthesis synthetic technology more complicated, synthetic ratio is relatively
Low.These intermediates, the specific activity of resynthesis Lamellarine H and derivative thereof is lower.
Summary of the invention:
The present invention aims to provide a kind of new synthesizing lamel larin H and the midbody compound of derivative thereof, synthetic this compound 1-(3 of a novelty of design, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4,5-trimethoxyphenyl) operational path of pyrroles [2,1-a] isoquinoline 99.9, good to reach synthetic route step regioselectivity few, reaction, the characteristics that combined coefficient is high.
The midbody compound of synthesizing lamel larin H of the present invention and derivative thereof is characterized in that: midbody compound is 1-(3, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] isoquinoline 99.9.This midbody compound of the present invention preferably is Papaverine and 2,4, and 5-trimethoxy-alpha-halo acetophenone reacts at the solution internal reflux of acetonitrile and alkali,
Separate through post again and obtain fusing point 177-178 ℃ light yellow particulate state crystal.Alkali in the reaction soln is preferably the weak base of carbonates such as salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate.
1-of the present invention like this (3, the 4-dimethoxy)-8, the synthetic method of 9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] isoquinoline 99.9 is Papaverine and 2,4,5-trimethoxy-alpha-halo acetophenone reacts at the solution internal reflux of acetonitrile and alkali,
Separate through post again, isolate the acetonitrile recrystallization, obtain fusing point 177-178 ℃ light yellow particulate state crystal.
As with 0.001mol Papaverine and 0.0015mol 2,4,5-trimethoxy-alpha-halo acetophenone adds in the 50ml round-bottomed flask, adds the 30ml acetonitrile then, 60-100 ℃ backflow 0.5-72 hour, solution colour by pale yellow to bright orange.The adding of alkali (salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate etc.) divide add before refluxing and reflux after add two kinds of situations, but also consider its consumption (0.001mol～0.004mol).Reaction process adopts thin-layer chromatography to follow the tracks of, and it is orange red that reaction finishes back solution, separates (acetonitrile recrystallization) through post, and obtaining product is light yellow particulate state crystal, and fusing point 177-178 ℃, productive rate reaches as high as 76.5%.Temperature of reaction of the present invention can not have special restriction, but is nonreactive under the normal temperature, is optimal reaction temperature in 60-100 ℃ of temperature range, and simultaneously because of so easier grasp of temperature range and control, and return time can be controlled at 1-26 hour.Papaverine and 2,4, the blending ratio of 5-trimethoxy-alpha-halo acetophenone generally can be according to 1: 0.5～1.5.But the activity of chloroacetophenone is active strong than the bromo arone, and the reflection by product is many, thus general synthesizing halogen methyl phenyl ketone we select 2,4 for use, 5-trimethoxy-alpha-brominated methyl phenyl ketone.Add alkali after being reflected at about backflow 1-26h, continue backflow 0.5-72h stopped reaction then.Treatedly obtain light yellow particulate state crystal.If when the reaction beginning, just add alkali, obtain a lot of by products, the target product that needs seldom only accounts for about 5%.The alkali of Jia Ruing also can cause some side reactions too by force as if alkalescence in addition, thereby preferably carbonate, supercarbonate just are suitable for reaction.
Total equation of the present invention:
It is as follows that the present invention has advantage: synthetic route step regioselectivity few, reaction is good, the characteristics that combined coefficient is high.Obtaining the high pure substance of yield, is an important intermediate of synthesizing lamel larin H and derivative thereof, also is important medicine intermediate and Organic Chemical Plant's product intermediate simultaneously.Has good medical and industrial prospect.
Description of drawings:
Accompanying drawing 1 has been represented the product liquid chromatogram that method of the present invention synthesizes
Accompanying drawing 2 has been represented the product proton magnetic spectrum figure that method of the present invention synthesizes.
Accompanying drawing 3 has been represented the product carbon nuclear magnetic spectrogram that method of the present invention synthesizes.
Example below in conjunction with accompanying drawing further specifies the present invention.
Specific embodiment:
Embodiment one, 1-of the present invention (3, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] isoquinoline 99.9 synthetic, with 0.001mol Papaverine and 0.0015mol 2,4,5-trimethoxy-alpha-brominated methyl phenyl ketone adds in the 50ml round-bottomed flask, add the 30ml acetonitrile then, 80 ℃ were refluxed 10 hours, solution colour by pale yellow to bright orange.Add 0.001mol salt of wormwood behind the reaction backflow 10h and continue backflow 3h.Reaction process adopts thin-layer chromatography to follow the tracks of, and it is orange red that reaction finishes back solution, separates (acetonitrile recrystallization) through post, and obtaining product is light yellow particulate state crystal, and fusing point 177-178 ℃, yield reaches as high as 75%.Product liquid chromatogram, proton magnetic spectrum figure, carbon nuclear magnetic spectrogram are as shown in drawings.Can further determine the structure of compound and determine that the purity of this compound is very high by spectrogram, reach 99.2%.
Embodiment two, 1-of the present invention (3, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] isoquinoline 99.9 synthetic, with 0.001mol Papaverine and 0.001mol 2,4,5-trimethoxy-alpha-chloro acetophenone adds in the 50ml round-bottomed flask, add the 30ml acetonitrile then, 100 ℃ were refluxed 25.5 hours, solution colour by pale yellow to bright orange.Add 0.001mol yellow soda ash after reaction refluxed 25.5 hours and continue backflow 24h.Reaction process adopts thin-layer chromatography to follow the tracks of, and it is orange red that reaction finishes back solution, separates (acetonitrile recrystallization) through post, and obtaining product is light yellow particulate state crystal, and fusing point 177-178 ℃, yield reaches as high as 70%.Product liquid chromatogram, proton magnetic spectrum figure, carbon nuclear magnetic spectrogram are as shown in drawings.
Embodiment three, 1-of the present invention (3, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] isoquinoline 99.9 synthetic, with 0.001mol Papaverine and 0.001mol 2,4,5-trimethoxy-alpha-brominated methyl phenyl ketone adds in the 50ml round-bottomed flask, add the 30ml acetonitrile then, 80 ℃ were refluxed 10 hours, solution colour by pale yellow to bright orange.Adding 0.001mol salt of wormwood behind the reaction backflow 10h continued to be back to 25 hours.Reaction process adopts thin-layer chromatography to follow the tracks of, and it is orange red that reaction finishes back solution, separates (acetonitrile recrystallization) through post, and obtaining product is light yellow particulate state crystal, and fusing point 177-178 ℃, yield reaches as high as 76.5%.Product liquid chromatogram, proton magnetic spectrum figure, carbon nuclear magnetic spectrogram are as shown in drawings.
Embodiment four, 1-of the present invention (3, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] isoquinoline 99.9 synthetic, with 0.002mol Papaverine and 0.001mol 2,4,5-trimethoxy-alpha-chloro acetophenone adds in the 50ml round-bottomed flask, add the 30ml acetonitrile then, 60 ℃ were refluxed 72 hours, solution colour by pale yellow to bright orange.Reaction adds the 0.002mol saleratus before refluxing.Reaction process adopts thin-layer chromatography to follow the tracks of, and it is orange red that reaction finishes back solution, separates (acetonitrile recrystallization) through post, and obtaining product is light yellow particulate state crystal, and fusing point 177-178 ℃, yield is about about 5%.Product liquid chromatogram, proton magnetic spectrum figure, carbon nuclear magnetic spectrogram are as shown in drawings.
Embodiment five, 1-of the present invention (3, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] isoquinoline 99.9 synthetic, with 0.002mol Papaverine and 0.001mol 2,4,5-trimethoxy-alpha-brominated methyl phenyl ketone adds in the 50ml round-bottomed flask, add the 30ml acetonitrile then, 60 ℃ were refluxed 48 hours, solution colour by pale yellow to bright orange.Reaction adds the 0.004mol saleratus before refluxing.Reaction process adopts thin-layer chromatography to follow the tracks of, and it is orange red that reaction finishes back solution, separates (acetonitrile recrystallization) through post, and obtaining product is light yellow particulate state crystal, and fusing point 177-178 ℃, yield is about about 15%.Product liquid chromatogram, proton magnetic spectrum figure, carbon nuclear magnetic spectrogram are as shown in drawings.
Embodiment six, 1-of the present invention (3, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] isoquinoline 99.9 synthetic, with 0.0005mol Papaverine and 0.001mol 2,4,5-trimethoxy-alpha-chloro acetophenone adds in the 50ml round-bottomed flask, add the 30ml acetonitrile then, 100 ℃ were refluxed 8 hours, solution colour by pale yellow to bright orange.Add 0.001mol yellow soda ash behind the reaction backflow 8h and continue backflow 24h.Reaction process adopts thin-layer chromatography to follow the tracks of, and it is orange red that reaction finishes back solution, separates (acetonitrile recrystallization) through post, and obtaining product is light yellow particulate state crystal, and fusing point 177-178 ℃, yield reaches as high as 62%.Product liquid chromatogram, proton magnetic spectrum figure, carbon nuclear magnetic spectrogram are as shown in drawings.
Claims (10)
1, the midbody compound of a kind of synthesizing lamel larin H and derivative thereof is characterized in that: intermediate materials is 1-(3, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] isoquinoline 99.9.
2, as the said midbody compound of claim 1, it is characterized in that: be Papaverine and 2,4,5-trimethoxy-alpha-halo acetophenone reacts at the solution internal reflux of acetonitrile and alkali,
Separate through post again and obtain fusing point 177-178 ℃ light yellow particulate state crystal.
3, as claim or 2 said midbody compounds, it is characterized in that: alkali is the weak base of carbonates such as salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate or bicarbonate salts.
4, the intermediate 1-(3 of a kind of synthesizing lamel larin H and derivative thereof, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4,5-trimethoxyphenyl) synthetic method of pyrroles [2,1-a] isoquinoline 99.9, it is characterized in that: be Papaverine and 2,4,5-trimethoxy-alpha-halo acetophenone is in the solution internal reflux reaction of acetonitrile and alkali
Separate through post again, isolate the acetonitrile recrystallization, obtain fusing point 177-178 ℃ light yellow particulate state crystal.
5, as the intermediate 1-(3 of said synthesizing lamel larin H of claim 4 and derivative thereof, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] synthetic method of isoquinoline 99.9, it is characterized in that: 60-100 ℃ of back flow reaction, solution colour by pale yellow to bright orange.
6, as the intermediate 1-(3 of said synthesizing lamel larin H of claim 5 and derivative thereof, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) synthetic method of pyrroles [2,1-a] isoquinoline 99.9 is characterized in that: add alkali after backflow 1-26 hour, continue back flow reaction again, help the raising of yield.
7, as the intermediate 1-(3 of claim 4 or 5 or 6 said synthesizing lamel larin Hs and derivative thereof, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] synthetic method of isoquinoline 99.9, it is characterized in that: the alkali that uses in the reaction is salt of wormwood, yellow soda ash, saleratus, saleratus, oxyhydroxide, organic amine, pyridine and derivative thereof etc.
8, as the intermediate 1-(3 of claim 4 or 5 or 6 said synthesizing lamel larin Hs and derivative thereof, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) synthetic method of pyrroles [2,1-a] isoquinoline 99.9 is characterized in that: Papaverine: 2,4, the molar ratio range of 5-trimethoxy-alpha-halo acetophenone is 1: 0.5～1.5.
9, as the intermediate 1-(3 of claim 4 or 5 or 6 said synthesizing lamel larin Hs and derivative thereof, the 4-dimethoxy)-8,9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) pyrroles [2,1-a] synthetic method of isoquinoline 99.9, it is characterized in that: 2,4,5-trimethoxy-alpha-halo acetophenone preferably uses 2,4,5-trimethoxy-alpha-brominated methyl phenyl ketone.
10, as the intermediate 1-(3, the 4-dimethoxy)-8 of claim 4 or 5 or 6 said synthesizing lamel larin Hs and derivative thereof, 9-dimethoxy-2-(2,4, the 5-trimethoxyphenyl) synthetic method of pyrroles [2,1-a] isoquinoline 99.9 is characterized in that: reaction process adopts thin-layer chromatography to follow the tracks of.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100474206A CN100543025C (en) | 2005-10-12 | 2005-10-12 | The midbody compound of synthesizing lamel larin H and derivative thereof and synthetic method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100474206A CN100543025C (en) | 2005-10-12 | 2005-10-12 | The midbody compound of synthesizing lamel larin H and derivative thereof and synthetic method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1948308A true CN1948308A (en) | 2007-04-18 |
| CN100543025C CN100543025C (en) | 2009-09-23 |
Family
ID=38017946
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100474206A Expired - Fee Related CN100543025C (en) | 2005-10-12 | 2005-10-12 | The midbody compound of synthesizing lamel larin H and derivative thereof and synthetic method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100543025C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690271A (en) * | 2012-05-24 | 2012-09-26 | 淮海工学院 | Preparation process for intermediate of Lamellarin H |
| CN108658997A (en) * | 2017-03-27 | 2018-10-16 | 东海大学 | Method for producing lamellarin and derivative thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483510A (en) * | 2019-09-05 | 2019-11-22 | 南京信息工程大学 | A kind of preparation method of piece spiral shell element analog derivative |
-
2005
- 2005-10-12 CN CNB2005100474206A patent/CN100543025C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690271A (en) * | 2012-05-24 | 2012-09-26 | 淮海工学院 | Preparation process for intermediate of Lamellarin H |
| CN108658997A (en) * | 2017-03-27 | 2018-10-16 | 东海大学 | Method for producing lamellarin and derivative thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100543025C (en) | 2009-09-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| IL173000A0 (en) | Process for preparation of 4-aryl-nicotinamide derivatives | |
| CN1948308A (en) | Intermediate compound for synthesizing lamel larin H and its derivatives and synthesizing method | |
| CN110028433A (en) | A kind of preparation method of deuterium-labeled doxapram and its metabolin | |
| CN1544427A (en) | Luteolin semi-synthesis method | |
| CN103980175B (en) | Prepare the method for vildagliptin | |
| CN112538029A (en) | Green synthesis method for preparing trifloxystrobin with high yield | |
| CN108191919B (en) | - 2 (1H) -one of 4- (substituted-phenyl) -6- ferrocenyl -3,4- dihydro-pyrimidin and preparation method thereof | |
| CN116496316A (en) | Method for synthesizing fluorine alkenyl phosphorus | |
| CN101735242B (en) | Method for preparing D-(+)-biotin intermediate | |
| CN102796036A (en) | Preparation method of atorvastatin calcium | |
| CN1900073A (en) | Process for preparing N-phenyl-2-pyrimidyl amine derivative | |
| CN1275920C (en) | Process for synthesizing (E)-3,4',5-trimethoxy stilbene | |
| CN103193679B (en) | The preparation method of rivastigmine intermediate (R)-N-ethyl-N-methylamino formic acid-3-(1-hydroxyethyl) phenyl ester | |
| CN1415614A (en) | Technique for synthesizing Irbesartan | |
| CN101068812B (en) | Efficient synthesis of 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones | |
| CN103408439A (en) | Chemical synthetic method of norbelladine | |
| CN114874105B (en) | Preparation method of visible light and water promoted homoallylic amine compound | |
| CN111499525B (en) | Synthetic method of antineoplastic drug trepetidine intermediate | |
| CN115925527B (en) | Method for preparing alpha-diaryl methyl substituted ketone compound | |
| CN1314684C (en) | Synthesis method of saijiabin, its racemate and S-configuration, and preparation method of its amorphous powder | |
| CN103304598A (en) | Phenol derivatives containing (Sp)-2-chiral phosphinate substituent groups and preparation method thereof | |
| CN110759909B (en) | Preparation method of pyrrolo [2,1-a ] isoquinoline derivative | |
| JPH0967312A (en) | Asymmetric cyclopropane formation reaction | |
| CN1923811A (en) | Indole substituted quinone compound and preparation method | |
| CN100554269C (en) | A kind of method for preparing the triazolo pyrimidine compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090923 Termination date: 20101012 |