CN101906103A - Improvement on synthesis method of tetrahydro-beta-carboline compound (II) - Google Patents
Improvement on synthesis method of tetrahydro-beta-carboline compound (II) Download PDFInfo
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- CN101906103A CN101906103A CN2010102537198A CN201010253719A CN101906103A CN 101906103 A CN101906103 A CN 101906103A CN 2010102537198 A CN2010102537198 A CN 2010102537198A CN 201010253719 A CN201010253719 A CN 201010253719A CN 101906103 A CN101906103 A CN 101906103A
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Abstract
The invention relates to an improvement on a synthesis method of a tetrahydro-beta-carboline compound (II). The method comprises reacting D-tryptophan methyl ester hydrochloride and piperonal at 50 DEG C-150 DEG C in a certain solvent to obtain hydrochloride of a structural formula (II) compound, wherein the solvent can be nitroethane, dioxane, methylbenzene, dimethylbenzene, benzene or nitrobenzene. The yield and purity of products prepared by the method are greatly improved, and the method is especially suitable for industrial production.
Description
Invention field
The present invention relates to the improvement of a kind of tetrahydrochysene-'Beta '-carboline compound synthetic method.
Background of invention
U.S. Pat 5859006 disclose Tadalafil (Cialis) promptly have structure (I) (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-inferior Dimethoxyphenyl)-pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1, the compound of 4-diketone, this compound are the selectivity of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase enzyme 5 (PDE5), reversible inhibitor can be used for treating male erectile dysfunction.
Compound (I) has two unsymmetrical carbons, and each represents that with asterisk wherein the non-hydrogen substituting group on the unsymmetrical carbon is a cis-configuration.Compound (I) can prepare with disclosed two synthetic routes in the U.S. Pat 5859006.
Route A
Route B
Route from compound (II) to compound (I)
With synthetic route (A) or (B) preparation compound (I) total recovery be about 25%.
Synthetic route (B) needs a plurality of synthesis steps, therefore thinks that it is inconvenient.In the short synthetic route (A), preparation compound (II) is the committed step of synthetic compound (I).
In the synthetic route (A), preparation compound (II) has utilized D-tryptophan methyl ester and 3, Pickett between the 4-methylene dioxo group benzaldehyde-Shi Penggele annulation, in methylene dichloride and two times of normal trifluoroacetic acids, carry out this reaction in five days, the mixture of two kinds of diastereomers that obtain, promptly with the needed tetrahydrochysene of general 60/40 ratio blended-'Beta '-carboline compound cis-isomeride (II) ((1R, 3R)) and unwanted tetrahydrochysene-'Beta '-carboline compound trans-isomer(ide) (IIa) ((1S, 3R)).Obtain pure cis-isomeride (being compound (II)) by fractional crystallization from mixture, productive rate is very low not easily separated.
In WO2004011463A1, with D-tryptophan methyl ester hydrochloride as raw material, make solvent reaction with Virahol, the use that leather has removed trifluoroacetic acid, but 16-18 hour preparation Tadalafil (Cialis) intermediate needed to reflux on the reaction times, long reaction time, and required cis-diastereomer and the ratio of trans-diastereomer are not more than 90: 10 in reaction solution.Reaction formula is as follows:
Improve especially a kind of progress of route (A) in this area, it utilizes D-tryptophan methyl ester and 3, Pickett between 4-methylene dioxo group benzaldehyde or other aromatic aldehydes-Shi Penggele reaction, prepare the pure compound of mapping (II) or similar tetrahydrochysene-'Beta '-carboline compound with simple directly method, it has also overcome the shortcoming of typical Pickett-Shi Penggele reaction, as using TFA, long reaction time separates with product is difficult.But shortcomings such as present Pickett-Shi Penggele reaction still exists yield low, and purity is low.
Summary of the invention
The present invention relates to the method for the diastereomer of a kind of needed tetrahydrochysene-'Beta '-carboline compound of preparation (II), promptly prepare the cis of polynuclear compound or the method for trans-isomer(ide) with two asymmetric ring carbon atoms.
The present invention utilizes this Pickett that advances-Shi Penggele reaction, and the diastereomer of needed tetrahydrochysene-'Beta '-carboline compound was provided with high yield, high purity in the short reaction times.Improved Pickett-Shi Penggele reaction has also avoided using the solvent trifluoroacetic acid in reaction.
The present invention is specifically related to a kind of preparation and has the tetrahydrochysene-β-Ka Lin diastereomer of following formula structure and the method for salt thereof,
This method may further comprise the steps:
D-tryptophan methyl ester hydrochloride and piperonylaldehyde are under 50-150 ℃ of temperature, and reaction obtains the hydrochloride of the compound of structural formula (II) in certain solvent, and wherein said solvent can be selected from nitroethane, dioxane, toluene, dimethylbenzene, benzene or oil of mirbane.
The starting raw material of the improved Pickett of the present invention-Shi Penggele reaction replaces original TFA to use with the tryptophane ester of hydrochloride form, greatly reduces tart and corrodes.The results showed that the temperature of reaction of this reaction is controlled in 80-120 ℃ carries out, the reaction times can shorten greatly like this.
In addition, the suitable or trans diastereomer of tetrahydrochysene-'Beta '-carboline compound can transform in flux mutually, and therefore selection is for needed product (cis or trans-diastereomer), and solvent is selected quite important.Show that through a large amount of experiments the choice of Solvent principle is in this reaction system: generate needed diastereomer indissoluble when this solvent refluxing, and slightly soluble or the slightly molten and dissolving when refluxing of this flux of unwanted diastereomer.Be that selected solvent does not dissolve needed diastereomer and dissolves unwanted diastereomer, the diastereomer of wherein wanting is cis-diastereomer.Show that through experiment the solvent of above-mentioned reaction can be selected from nitroethane, dioxane, toluene, dimethylbenzene, benzene or oil of mirbane, reaction all can reach effect preferably in these solvents.
Especially, when preparing above-mentioned tetrahydrochysene-'Beta '-carboline compound (II), the present invention's preferred nitroethane that adopts in reaction is made solvent reaction, the time of this reaction only is 6-8 hour, the ratio of cis-diastereomer and trans-diastereomer is 98: 2, makes solvent with nitroethane, and the cis diastereomer that produces or transform can be separated out in nitroethane, filtration obtains the highly purified cis diastereomer of high yield, and yield is more than 95%.And Virahol or ethanol etc. have certain solubleness to cis diastereomeric salt hydrochlorate, need to obtain cis-diastereomer at cold filtration below 0 ℃, and its yield and content all will be lower than the reaction of making solvent of nitroethane.Therefore, adopting nitroethane is good selection as action solvent.
Yield and the purity of using method of the present invention to obtain product increase substantially, and are very suitable for suitability for industrialized production.
Embodiment
Embodiment 1
D-tryptophan methyl ester hydrochloride 10g and piperonylaldehyde 6g are dissolved in the 100ml nitroethane, and reflux is after 10 hours, and temperature is reduced to 70 ℃, and insulation reaction is spent the night.Next day, earlier temperature is slowly reduced to room temperature, ice bath stirred 2 hours then.Suction filtration, filter cake washes twice with a small amount of cold nitroethane, drains, and oven drying gets target product 14.4g, productive rate 96.9%.(mp.：208-209℃，[α]
26 D＝79.1°)
Embodiment 2
D-tryptophan methyl ester hydrochloride 10g and piperonylaldehyde 6g are dissolved in the 100ml dioxane, and reflux is after 17 hours, and temperature is reduced to 50～60 ℃, and insulation reaction is spent the night.Next day, earlier temperature is slowly reduced to room temperature, ice bath stirred 2 hours down at 0 ℃ then.Suction filtration, filter cake washes twice with a small amount of cold dioxane, drain solid.Solid is added the 50ml nitroethane, refluxed 1.5 hours, be chilled to room temperature, ice bath stirred 2 hours down, and suction filtration, filter cake wash twice with the cold nitroethane of 10ml, drained, and oven drying gets target product 13g, productive rate 85.7%.(mp.：217-219℃)
Embodiment 3
D-tryptophan methyl ester hydrochloride 10g and piperonylaldehyde 6g are dissolved in the 100ml toluene, and reflux is after 11 hours, and temperature is reduced to 70 ℃, and insulation reaction is spent the night.Next day, earlier temperature is slowly reduced to room temperature, ice bath stirred 2 hours down at 0 ℃ then.Suction filtration, filter cake washes twice with a small amount of cold toluene, drains, and oven drying gets target product 13.7g, productive rate 90.3%.(mp.：207-210℃)
Claims (4)
1. method for preparing tetrahydrochysene-β-Ka Lin diastereomeric salt hydrochlorate with following formula structure,
This method may further comprise the steps:
D-tryptophan methyl ester hydrochloride and piperonylaldehyde are under 50-150 ℃ of temperature, and reaction obtains the hydrochloride of structural formula (II) compound in certain solvent, and wherein said solvent can be selected from nitroethane, dioxane, toluene, dimethylbenzene, benzene or oil of mirbane.
2. according to the method for claim 1, it is characterized in that described reaction solvent is preferably nitroethane.
3. according to the method for claim 1, it is characterized in that described temperature of reaction is 60-120 ℃.
4. according to the method for claim 3, it is characterized in that described temperature of reaction further is selected from 80-110 ℃.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010102537198A CN101906103A (en) | 2010-08-08 | 2010-08-08 | Improvement on synthesis method of tetrahydro-beta-carboline compound (II) |
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| CN2010102537198A CN101906103A (en) | 2010-08-08 | 2010-08-08 | Improvement on synthesis method of tetrahydro-beta-carboline compound (II) |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102952132A (en) * | 2012-10-19 | 2013-03-06 | 山东科技大学 | Novel synthetic method of beta-tetrahydrocarboline compound by using pentamethyleneamine as raw material |
| CN105541835A (en) * | 2015-12-31 | 2016-05-04 | 湖南千金湘江药业股份有限公司 | Cis-tetrahydrocarboline intermediate and synthesis method thereof, and application of cis-tetrahydrocarboline intermediate in preparing tadalafil |
| CN107759592A (en) * | 2017-11-01 | 2018-03-06 | 吉林医药学院 | The preparation of tadalafil intermediate |
| CN114805345A (en) * | 2022-04-27 | 2022-07-29 | 山东省药学科学院 | Preparation method of tadalafil intermediate cis-tetrahydrocarboline hydrochloride |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1671706A (en) * | 2002-07-31 | 2005-09-21 | 利利艾科斯有限公司 | Modified pictet-spengler reaction and products prepared therefrom |
-
2010
- 2010-08-08 CN CN2010102537198A patent/CN101906103A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1671706A (en) * | 2002-07-31 | 2005-09-21 | 利利艾科斯有限公司 | Modified pictet-spengler reaction and products prepared therefrom |
Non-Patent Citations (2)
| Title |
|---|
| XIAO-XIN SHI，ET AL.，: "Highly Stereoselective Pictet-Spengler reaction of D-tryptophan methyl ester with piperonal：convenient syntheses of Cialis (Tadalafil)，12a-epi-Cialis，and their deuterated analogues", 《TETRAHEDRON：ASYMMETRY》 * |
| XIAO-XIN SHI，ET AL.，: "Highly Stereoselective Pictet-Spengler reaction of D-tryptophan methyl ester with piperonal：convenient syntheses of Cialis (Tadalafil)，12a-epi-Cialis，and their deuterated analogues，第19卷，第4期，第435-442页", 《TETRAHEDRON：ASYMMETRY》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102952132A (en) * | 2012-10-19 | 2013-03-06 | 山东科技大学 | Novel synthetic method of beta-tetrahydrocarboline compound by using pentamethyleneamine as raw material |
| CN105541835A (en) * | 2015-12-31 | 2016-05-04 | 湖南千金湘江药业股份有限公司 | Cis-tetrahydrocarboline intermediate and synthesis method thereof, and application of cis-tetrahydrocarboline intermediate in preparing tadalafil |
| CN107759592A (en) * | 2017-11-01 | 2018-03-06 | 吉林医药学院 | The preparation of tadalafil intermediate |
| CN114805345A (en) * | 2022-04-27 | 2022-07-29 | 山东省药学科学院 | Preparation method of tadalafil intermediate cis-tetrahydrocarboline hydrochloride |
| CN114805345B (en) * | 2022-04-27 | 2023-11-10 | 山东省药学科学院 | Preparation method of tadalafil intermediate cis-tetrahydrocarboline hydrochloride |
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Application publication date: 20101208 |