CN105753870B - A kind of silaenafil impurity F and its preparation method and application - Google Patents
A kind of silaenafil impurity F and its preparation method and application Download PDFInfo
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- CN105753870B CN105753870B CN201610203513.1A CN201610203513A CN105753870B CN 105753870 B CN105753870 B CN 105753870B CN 201610203513 A CN201610203513 A CN 201610203513A CN 105753870 B CN105753870 B CN 105753870B
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses the present invention to provide a kind of silaenafil impurity F and its preparation method and application, to the west of intermediate during that non-synthetic be raw material, carry out esterification under acid or alkaline conditions and obtain silaenafil impurity F, intermediate structure such as formula（I）Compound represented,, silaenafil impurity F structure such as formula（II）Compound represented,
Description
Technical field
The invention belongs to organic chemistry filed, in particular it relates to a kind of silaenafil impurity F and preparation method thereof
And application.
Background technology
Silaenafil is a kind of oral treatment male erectile dysfunction drug.Its action target spot is phosphodiesterase 5
Type (PDE5) can effectively inhibit the activity of Phosphodiesterase V in vitro, and cGMP and cAMP hydrolysis is prevented to generate corresponding 5-
Monophosphic acid nucleotide improves the concentration of cGMP between tissue, inhibits the relaxation of smooth muscle, so as to reach the work of the treatment of sexual dysfunction
With.It is its citrate that silaenafil is clinically the most widely used, earliest sildenafil citrate preparation
It was formulated by Pfizer Inc. in 1994, U.S. FDA approval is obtained in May, 1998, for treating the mouth of male sexual disfunction
Medication object.2000 time in Discussion on Chinese Listed.
In the prior art, the patent of invention of Patent No. CN00108053.9 discloses a kind of preparation side of silaenafil
Method, the preparation method of the silaenafil be using 5- (5- halosulfonyl -2- ethoxyl phenenyls) -1- methyl -3- n-propyls -
[4.3-d " pyrimidin-7-ones react 1,6- dihydro -7H- pyrazolos with 1- methyl piperazines mono-salt or double salt, during products therefrom passes through
With washing etc. processing, directly obtain the clean product for meeting medicinal standard, the preparation with disclosed silaenafil in the prior art
Method compares, and this method has the characteristics that the reaction time is short, reaction is easy, product need not purify, yield is high, but the party
Method is not described preparation or the synthetic method of silaenafil impurity F.
The first synthetic method of silaenafil is referred in patent (US5250534).And the patent after Pfizer
Second of synthetic method is provided in (US5955611 and CN1168376A).
First method is using 4- cyano -1- methyl -3- propylpyrazols amides as raw material, by acylation, reduction, cyclization, chlorine
Sulfonation, sulfonylation generation target product silaenafil, process route are as follows：
The starting material of Article 2 route and first route is almost identical, except that first by methyl piperazine segment
It is connected with sulfonic acid chloride, then carries out cyclization, process route is as follows：
10# can be recrystallized in ethanol during route 1, may generate the miscellaneous of sulphonic acid ester in the process
Matter, this impurity have genotoxicity segment, have latent gene toxicity.Also, the above method is also all without open silaenafil
The synthetic method of impurity F.
The content of the invention
It is an object of the invention to disclose a kind of silaenafil impurity F and its preparation method and application, the west ground of gained that
Non- impurity F purity can be used as reference substance to be used for quality research up to more than 98%.
The first synthetic method of silaenafil is referred in patent (US5250534).And the patent after Pfizer
Second of synthetic method is provided in (US5955611 and CN1168376A).Ethyl alcohol is used in above two synthetic method
As the solvent of last salt-forming reaction, according to theoretical implications, the transesterification of amide and ethyl alcohol occurs in the process, it can be with
Silaenafil impurity F is generated, structural formula is as follows：
Whether whether there is no definite reports in above-mentioned patent generates formula (II) compound, does not also inquire both at home and abroad
Synthetic method of the patent on the compound.
The present invention provides a kind of silaenafil impurity F, is applied to quality research, the silaenafil impurity as reference substance
The structural formula of F is as follows：
The present invention also provides a kind of preparation method of silaenafil impurity F, to the west of intermediate during that non-synthetic
For raw material, progress esterification obtains silaenafil impurity F, change of the intermediate structure as shown in formula (I) under acid or alkalescence
Close object,Silaenafil impurity F structure such as formula (II) compound represented,
The invention discloses a kind of silaenafil impurity F synthetic method, to the west of intermediate during that non-synthetic be raw material, in acid
Property or the lower esterification that carries out of alkalescence obtain silaenafil impurity F.Silaenafil impurity F purity obtained by this method is up to 98%
More than, reference substance can be used as to be used for quality research.
Preferably, comprise the following steps：
(1):Formula (I) compound represented is added in organic solvent and is fully dissolved；
(2):After adding in ethanol solution, acid solution or alkaline solution are added, is stirred at room temperature, in acid condition or alkalescence
Under the conditions of react, until the reaction is complete；
(3):Reaction solution pH to 6-8 is adjusted, is filtered, solvent washing is drained, and silaenafil impurity F is obtained after dry.
Any of the above-described scheme is preferably, and the organic solvent in the step (1) is dimethyl sulfoxide, N, N- dimethyl formyls
Amine, n,N-dimethylacetamide, Isosorbide-5-Nitrae-dioxane, dichloromethane, chloroform, tetrahydrofuran, toluene, ethyl alcohol, in acetone
Any one.
Any of the above-described scheme is preferably, and the organic solvent in the step (1) is n,N-Dimethylformamide.
Any of the above-described scheme is preferably, and the organic solvent in the step (1) is acetone.
Any of the above-described scheme is preferably, and acid solution is phosphoric acid, in dilute hydrochloric acid, dilute sulfuric acid, acetic acid in the step (2)
Any one.
Any of the above-described scheme is preferably, and acid solution is phosphoric acid in the step (2).
Any of the above-described scheme is preferably, and acid solution is acetic acid in the step (2).
Any of the above-described scheme is preferably, and step (2) the neutral and alkali solution is diethylamine, triethylamine, diisopropyl second
Any one in amine, 1,2- propane diamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
Any of the above-described scheme is preferably, and step (2) the neutral and alkali solution is sodium hydroxide.
Any of the above-described scheme is preferably, and step (2) the neutral and alkali solution is triethylamine.
Any of the above-described scheme is preferably, and the time is stirred at room temperature in the step (2) as 4-6h.
Any of the above-described scheme is preferably, and reaction temperature requirement is 10 DEG C -120 DEG C in the step (2).
Any of the above-described scheme is preferably, and in the step (3), reaction solution pH to 6-8 is adjusted using 1mol/L hydrochloric acid.
Any of the above-described scheme is preferably, and formula (I) compound represented is with 4- cyano -1- methyl -3- propylpyrazol amides
For raw material, by acylation, reduce, cyclization, obtained after chlorosulfonation, synthetic route is as follows：
The present invention also provides a kind of application of silaenafil impurity F as reference substance in terms of quality research.
The present invention provides a kind of silaenafil impurity F and its preparation method and application, to the west of during that non-synthetic
Intermediate is raw material, and esterification is carried out under acid or alkalescence and obtains silaenafil impurity F, intermediate structure such as formula (I) institute
The compound shown,Silaenafil impurity F structure such as formula (II) compound represented,Silaenafil impurity F purity obtained by this method can be used as reference substance up to more than 98%
For quality research.
Specific embodiment
In order to be best understood from technical scheme and advantage, the present invention is done into one below by way of specific embodiment
Walk explanation.
The present invention provides a kind of silaenafil impurity F and its preparation method and application, to the west of during that non-synthetic
Intermediate is raw material, and esterification is carried out under acid or alkalescence and obtains silaenafil impurity F, intermediate structure such as formula (I) institute
The compound shown,Silaenafil impurity F structure such as formula (II) compound represented,
The invention discloses a kind of silaenafil impurity Fs, are applied to quality research as reference substance, which is characterized in that institute
The structure formula (II) for stating silaenafil impurity F is as follows：
The invention also discloses a kind of preparation method of silaenafil impurity F, to the west of centre during that non-synthetic
Body is raw material, and esterification is carried out under acid or alkalescence and obtains silaenafil impurity F.Silaenafil impurity obtained by this method
F purity can be used as reference substance to be used for quality research up to more than 98%.
Synthetic route is：
Preferably, comprise the following steps：
(1):Formula (I) compound represented is added in organic solvent and is fully dissolved；
(2):After adding in ethanol solution, acid solution or alkaline solution are added, is stirred at room temperature, in acid condition or alkalescence
Under the conditions of react, until the reaction is complete；
(3):Reaction solution pH to 6-8 is adjusted, is filtered, solvent washing is drained, and silaenafil impurity F is obtained after dry.
When actually preparing silaenafil impurity F, solvent：Alkaline solution：Acid solution volume ratio is 5-20：0.1-0.5:
0.4-0.8.It is not strict with for concentration.
The technical solution that further optimizes of the present invention, the organic solvent in the step (1) is dimethyl sulfoxide, N, N- diformazans
Base formamide, n,N-dimethylacetamide, Isosorbide-5-Nitrae-dioxane, dichloromethane, chloroform, tetrahydrofuran, toluene, ethyl alcohol,
Any one in acetone.
The technical solution that further optimizes of the present invention, the organic solvent in the step (1) is n,N-Dimethylformamide.
The technical solution that further optimizes of the present invention, the organic solvent in the step (1) is acetone.
The technical solution that further optimizes of the present invention, in the step (2) acid solution be phosphoric acid, dilute hydrochloric acid, dilute sulfuric acid,
Any one in acetic acid.
The technical solution that further optimizes of the present invention, acid solution is phosphoric acid in the step (2).
The technical solution that further optimizes of the present invention, acid solution is acetic acid in the step (2).
The technical solution that further optimizes of the present invention, step (2) the neutral and alkali solution is diethylamine, triethylamine, two different
Any one in propylethylamine, 1,2- propane diamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
The technical solution that the present invention further optimizes, step (2) the neutral and alkali solution are sodium hydroxide.
The technical solution that the present invention further optimizes, step (2) the neutral and alkali solution are triethylamine.
The time is stirred at room temperature as 4-6h in the step (2) in the technical solution that further optimizes of the present invention.
The technical solution that further optimizes of the present invention, reaction temperature requirement is 10 DEG C -120 DEG C in the step (2).
The technical solution that further optimizes of the present invention, in the step (3), using 1mol/L hydrochloric acid adjust reaction solution pH to
6-8。
The technical solution that further optimizes of the present invention, formula (I) compound represented be in silaenafil building-up process in
Mesosome, such as by acylation, can be reduced, cyclization, after chlorosulfonation using 4- cyano -1- methyl -3- propylpyrazols amides as raw material
It obtains, synthetic route is as follows：
Embodiment 1
250ml there-necked flasks are taken, add in the compound I of 10g, n,N-Dimethylformamide 100ml dissolvings is added in, adds in 20ml
Ethyl alcohol, 5ml triethylamines are stirred at room temperature 5h, contact plate, until the reaction is complete.1mol/L salt acid for adjusting pH is added in reaction solution extremely
6-8 is filtered, and a small amount of solvent washing is drained, and is dried to obtain the impurity F that purity is more than 98.0%, weight 2.5g, and yield is
25%.ESI-MS：421[M+H]+1HNMR (δ-DMSO) δ 0.958 (d, 3H), 1.329 (d, 3H), 1.36 (m, 2H), 1.39 (m,
2H), 2.80 (d, 2H), 3.445 (m, 1H), 3.575 (t, 3H) 4.222 (m, 2), 4.325 (s, 3H), 7.150 (d, 1H),
7.735 (m, 1H), 7.827 (d, 1)
Embodiment 2
250ml there-necked flasks are taken, add in the compound I of 10g, add in ethyl alcohol 120ml dissolvings, 5ml triethylamines are stirred at room temperature
5h, contact plate, until the reaction is complete.1mol/L salt acid for adjusting pH is added in reaction solution to 6-8, is filtered, a small amount of solvent washing is taken out
It is dry, purity is dried to obtain as 98% silaenafil impurity F, weight 2.9g, yield 29%.
Embodiment 3
250ml there-necked flasks are taken, add in the compound I of 10g, n,N-Dimethylformamide 100ml dissolvings is added in, adds in 20ml
Ethyl alcohol, 5g sodium acid carbonates are stirred at room temperature 5h, contact plate, until the reaction is complete.1mol/L salt acid for adjusting pH is added in reaction solution extremely
6-8 is filtered, and a small amount of solvent washing is drained, and is dried to obtain the impurity F that purity is more than 98.0%, weight 2.4g, and yield is
24%.
Embodiment 4
250ml there-necked flasks are taken, add in the compound I of 10g, acetone 100ml dissolvings is added in, adds in 20ml ethyl alcohol, 5g carbonic acid
Sodium, is stirred at room temperature 5h, contact plate, until the reaction is complete.1mol/L salt acid for adjusting pH is added in reaction solution to 6-8, is filtered, on a small quantity
Solvent washs, and drains, and is dried to obtain purity as 98% silaenafil impurity F, weight 2.6g, yield 26%.
Embodiment 5
250ml there-necked flasks are taken, add in the compound I of 10g, n,N-Dimethylformamide 100ml dissolvings is added in, adds in 20ml
Ethyl alcohol, 5ml acetic acid are stirred at room temperature 5h, contact plate, until the reaction is complete.1mol/L sodium hydroxide solution tune is added in reaction solution
PH to 6-8 is saved, is filtered, a small amount of solvent washing is drained, and is dried to obtain purity as more than 98.0% impurity F, weight 2.3g,
Yield is 23%.
Embodiment 6
250ml there-necked flasks are taken, add in the compound I of 10g, add in ethyl alcohol 100ml dissolvings, 5ml triethylamines are stirred at room temperature
5h, contact plate, until the reaction is complete.1mol/L salt acid for adjusting pH is added in reaction solution to 6-8, is filtered, a small amount of solvent washing is taken out
It is dry, it is dried to obtain the impurity F that purity is more than 98.0%, weight 2.5g, yield 25%.
Embodiment 7
250ml there-necked flasks are taken, add in the compound I of 10g, dichloromethane 100ml dissolvings is added in, adds in 20ml ethyl alcohol, 5ml
Triethylamine, is stirred at room temperature 5h, contact plate, until the reaction is complete.1mol/L salt acid for adjusting pH is added in reaction solution to 6-8, liquid separation,
It is spin-dried for, a small amount of absolute ethyl alcohol washing is drained, and is dried to obtain the impurity F that purity is more than 98.0%, weight 3.0g, and yield is
30%.
Embodiment 8
250ml there-necked flasks are taken, add in the compound I of 10g, toluene 100ml dissolvings is added in, adds in 20ml ethyl alcohol, tri- second of 5ml
Amine, is stirred at room temperature 5h, contact plate, until the reaction is complete.1mol/L salt acid for adjusting pH is added in reaction solution to 6-8, liquid separation, rotation
Dry, a small amount of absolute ethyl alcohol washing is drained, and is dried to obtain the impurity F that purity is more than 98.0%, weight 1.9g, and yield is
19%.
Embodiment 9
250ml there-necked flasks are taken, add in the compound I of 10g, add in ethyl alcohol 120ml dissolvings, 1.5g sodium hydroxides, room temperature is stirred
Mix 5h, contact plate, until the reaction is complete.1mol/L salt acid for adjusting pH is added in reaction solution to 6-8, is filtered, a small amount of solvent washing,
It drains, is dried to obtain purity as 98% silaenafil impurity F, weight 1.2g, yield 12%.
Embodiment 10
250ml there-necked flasks are taken, add in the compound I of 10g, add in ethyl alcohol 120ml dissolvings, 5ml potassium carbonate is stirred at room temperature
5h, contact plate, until the reaction is complete.1mol/L salt acid for adjusting pH is added in reaction solution to 7.5, is filtered, a small amount of solvent washing is taken out
It is dry, purity is dried to obtain as 98% silaenafil impurity F, weight 2.4g, yield 24%.
Embodiment 11
250ml there-necked flasks are taken, add in the compound I of 10g, add in ethyl alcohol 120ml dissolvings, 5h is stirred at room temperature in 5ml phosphoric acid,
Contact plate, until the reaction is complete.1mol/L sodium hydroxide solutions are added in reaction solution and adjust pH to 6.5, are filtered, a small amount of solvent is washed
It washs, drains, be dried to obtain purity as 98% silaenafil impurity F, weight 2.9g, yield 29%.
Embodiment 12
250ml there-necked flasks are taken, add in the compound I of 10g, add in ethyl alcohol 120ml dissolvings, 5h is stirred at room temperature in 5ml acetic acid,
Contact plate, until the reaction is complete.1mol/L sodium hydroxide solutions are added in reaction solution and adjust pH to 7, are filtered, a small amount of solvent is washed
It washs, drains, be dried to obtain purity as 98% silaenafil impurity F, weight 2.0g, yield 20%.
Embodiment 12
250ml there-necked flasks are taken, add in the compound I of 10g, add in ethyl alcohol 120ml dissolvings, 5h is stirred at room temperature in 5ml sulfuric acid,
Contact plate, until the reaction is complete.1mol/L sodium hydroxide solutions are added in reaction solution and adjust pH to 6, are filtered, a small amount of solvent is washed
It washs, drains, be dried to obtain purity as 98% silaenafil impurity F, weight 2.6g, yield 26%.
The present invention provides a kind of silaenafil impurity F and its preparation method and application, to the west of during that non-synthetic
Intermediate is raw material, and esterification is carried out under acid or alkalescence and obtains silaenafil impurity F, intermediate structure such as formula (I) institute
The compound shown,Silaenafil impurity F structure such as formula (II) compound represented,The invention discloses a kind of preparation method of silaenafil impurity F, to the west of that non-synthetic
Intermediate in the process is raw material, and esterification is carried out under acid or alkalescence and obtains silaenafil impurity F.Obtained by this method
Silaenafil impurity F purity can be used as reference substance to be used for quality research up to more than 98%.
It should be noted that the above embodiments are only used to illustrate the technical solution of the present invention., rather than its limitations；Although
The present invention is described in detail with reference to foregoing embodiments, it will be understood by those of ordinary skill in the art that：It is still
It can modify to the technical solution recorded in foregoing embodiments and either which part or all technical characteristic are carried out
Equivalent substitution；And these modifications or replacement, the essence of appropriate technical solution is not made to depart from various embodiments of the present invention technical side
The scope of case.
Claims (16)
1. a kind of silaenafil impurity F is applied to quality research, which is characterized in that the silaenafil impurity F as reference substance
Structure formula (II) it is as follows：To the west of intermediate during that non-synthetic be raw material,
Esterification is carried out under acid or alkaline condition and obtains silaenafil impurity F, intermediate structure such as formula (I) compound represented,Silaenafil impurity F structure such as formula (II) compound represented,
2. a kind of preparation method of silaenafil impurity F, comprises the following steps：
(1):By formula (I) compound representedIt adds in organic solvent and fully dissolves；
(2):After adding in ethanol solution, acid solution or alkaline solution are added, is stirred at room temperature, in acid condition or alkaline condition
Lower reaction, until the reaction is complete；
(3):Reaction solution pH to 6-8 is adjusted, is filtered, solvent washing is drained, and silaenafil impurity F, Xi Dina are obtained after dry
Non- impurity F structure such as formula (II) compound represented
3. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that organic in the step (1)
Solvent is dimethyl sulfoxide, n,N-Dimethylformamide, n,N-dimethylacetamide, Isosorbide-5-Nitrae-dioxane, dichloromethane, three chloromethanes
Alkane, tetrahydrofuran, toluene, ethyl alcohol, any one in acetone.
4. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that organic in the step (1)
Solvent is N,N-dimethylformamide.
5. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that organic in the step (1)
Solvent is acetone.
6. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that acid molten in the step (2)
Liquid is any one in phosphoric acid, dilute hydrochloric acid, dilute sulfuric acid, acetic acid.
7. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that acid molten in the step (2)
Liquid is phosphoric acid.
8. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that acid molten in the step (2)
Liquid is acetic acid.
9. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that step (2) neutral and alkali is molten
Liquid is diethylamine, in triethylamine, diisopropylethylamine, 1,2- propane diamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate
Any one.
10. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that step (2) neutral and alkali
Solution is sodium hydroxide.
11. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that step (2) neutral and alkali
Solution is triethylamine.
12. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that room temperature in the step (2)
Mixing time is 4-6h.
13. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that reaction in the step (2)
Temperature requirement is 10 DEG C -120 DEG C.
14. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that in the step (3), use
1mol/L hydrochloric acid adjusts reaction solution pH to 6-8.
15. the preparation method of silaenafil impurity F as claimed in claim 2, which is characterized in that intermediate synthetic route is such as
Under：
16. a kind of application of silaenafil impurity F as described in claim 1 as reference substance in terms of quality research.
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| CN112209879A (en) * | 2020-10-19 | 2021-01-12 | 河北省药品医疗器械检验研究院 | Sildenafil impurity and preparation method and application thereof |
| CN112645954A (en) * | 2020-12-18 | 2021-04-13 | 植恩生物技术股份有限公司 | Sildenafil raw material medicine impurity, preparation method thereof and application of sildenafil raw material medicine impurity as reference substance |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250534A (en) * | 1990-06-20 | 1993-10-05 | Pfizer Inc. | Pyrazolopyrimidinone antianginal agents |
| CN1106399C (en) * | 1996-06-14 | 2003-04-23 | 辉瑞研究开发公司 | Process for preparing sildenafil |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101127814B1 (en) * | 2011-03-14 | 2012-03-23 | 에이치 엘 지노믹스(주) | Novel intermediate and process for preparing sildenafil or its salt using the same |
-
2016
- 2016-04-01 CN CN201610203513.1A patent/CN105753870B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250534A (en) * | 1990-06-20 | 1993-10-05 | Pfizer Inc. | Pyrazolopyrimidinone antianginal agents |
| CN1106399C (en) * | 1996-06-14 | 2003-04-23 | 辉瑞研究开发公司 | Process for preparing sildenafil |
Non-Patent Citations (4)
| Title |
|---|
| Liquid-chromatography determination of impurities in sildenafil citrate;A.Phani Kumar et al;《Asian Journal of Chemistry》;20111231;第23卷(第3期);第1219-1222页 * |
| Quantification of active pharmaceutical ingredient and impurities in sildenafil citrate obtained from the internet;Michael A.Veronin et al;《Therapeutic Advances in Drug Safety》;20141231;第5卷(第5期);第180-189页 * |
| Separation and determination of synthetic impurities of sildenafil(viagra) by reversed-phase high-performance liquid chromatography;Velupula Nagaraju et al;《Analytical Sciences》;20031231;第19卷;第1007-1011页 * |
| 西地那非有关物质的合成;张明光 等;《中国医药工业杂质》;20131231;第44卷(第9期);第848-853页 * |
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