CN1377884A - Process for preparing sedenafil - Google Patents
Process for preparing sedenafil Download PDFInfo
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- CN1377884A CN1377884A CN 01111082 CN01111082A CN1377884A CN 1377884 A CN1377884 A CN 1377884A CN 01111082 CN01111082 CN 01111082 CN 01111082 A CN01111082 A CN 01111082A CN 1377884 A CN1377884 A CN 1377884A
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- methylpiperazine
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Abstract
The sedenafil preparing process includes coupling reaction of the two compounds, cyclization between the coupling product and another compound, the reaction between the product of the cyclization and another compound, and the condensation between the finally mentioned product and methyl piperazine.
Description
The present invention relates to a kind of novel phosphodiesterase inhibitor, the preparation method of medicinal heterocyclic compound.Specifically, it is exactly linked reaction by structural formula (II) compound and structural formula (III) compound, the compound of generating structure formula (IV), after cyclization, obtain the compound of structure formula V, make the compound of structural formula (VI) again with the chlorsulfonic acid reaction, last and methylpiperazine condensation reaction makes the method for structural formula (I).
The name of structural formula (I) compound is called: 5-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, general Virga by name (Sildenafil).Virga sees Chinese patent " preparation method of Pyrazolopyrimidinoneantianginal antianginal agents " (patent publication No. 1057464A), " application prepares the method for liking vigorous ketone " (patent publication No. CN1168376) and " method for preparing Virga " (patent publication No. CN1246478A) as medicinal compound.The Virga citrate has good effect to the treatment of male erectile disorder.
The present invention uses more handy raw material, uses and the visibly different processing method of known technology, has obtained Virga more satisfactorily.The processing step of its most critical has following 3 points: the linked reaction of (1) structural formula (II) compound and structural formula (III) compound obtains the compound of structural formula (IV); (2) cyclization of the compound of structural formula (IV) obtains the compound of structure formula V; The compound of structure formula V obtains the compound of structural formula (VI) according to a conventional method with the chlorsulfonic acid reaction, compound of (3) structural formula (VI) and methylpiperazine reaction just can easier obtain structural formula (I) compound, i.e. Virga.Last and Citric Acid salify promptly generates sildenafil citrate salt.
The linked reaction of structural formula (II) compound and structural formula (III) compound is carried out under the condition that suitably reagent exists and appropriate solvent exists.Reaction process was carried out 2-48 hour under 10--60 ℃ of temperature condition.
The reagent that linked reaction is suitable for is selected from N, N '-carbonyl dimidazoles, N, N '-dicyclohexyl carbonyl diamine.
The solvent that linked reaction is suitable for is selected from ethyl acetate, methyl alcohol, ethanol, acetone, tetrahydrofuran (THF) and their mixture.
Structural formula (IV) compound ring-closure reaction obtains the compound of structure formula V, and its ring-closure reaction is to carry out under the condition that alkali exists.Reaction process was carried out 2--18 hour under 50--170 ℃ of temperature condition.
The alkali that ring-closure reaction is suitable for is selected from sodium hydroxide, potassium hydroxide, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide.
The solvent that ring-closure reaction is suitable for is selected from methyl alcohol, ethanol, propyl carbinol, the trimethyl carbinol, tetrahydrofuran (THF), 1,4-dioxane, dimethyl formamide, pyrazoles and water and their mixture.
With the conventional chlorosulfonation of compound process of structure formula V, can make the compound of structural formula (VI) easily.
The compound of structural formula (VI) and the condensation reaction of methylpiperazine are to carry out in the presence of suitable organic bases and the solvent that is fit to, and reaction process was carried out 0.5--48 hour under 10--50 ℃ of temperature condition.Just can easier obtain structural formula (I) compound, i.e. Virga thus.
The organic bases that condensation reaction is suitable for comprises: N, N-Dimethylamino pyridine, N, accelerine, pyridine, triethylamine, 4-pyrrolidyl pyridine.
The solvent that condensation reaction is suitable for comprises: methyl alcohol, ethanol, propyl carbinol, the trimethyl carbinol, tetrahydrofuran (THF), 1,4-dioxane, dimethyl formamide and their mixture.
Above-described respectively go on foot reaction product all can by conventional technical point from and purifying, as methods such as filtration, recrystallizations.
Its structure of the compound of the above various structural formula all obtains
1The conclusive evidence of H nucleus magnetic resonance (HNMR).
Embodiment 1: the linked reaction of structural formula (II) compound and structural formula (III) compound obtains reaction product structural formula (IV) compound
31.0 gram carbonyl dimidazoles are restrained the 2-ethoxybenzoic acids with 150 milliliters of ethyl acetate rinse to containing 29.1, and promptly in 50 milliliters of ethyl acetate of structural formula (II) compound, mixture is heated to 55 degree earlier, is incubated 0.5 hour; Reflux is 2 hours then.Reflux to finish, mixture is cooled to room temperature, add 29 gram amino substances, be i.e. 300 milliliters of ethyl acetate mixed solutions of structural formula (III) compound and 2.9 gram N, N-Dimethylamino pyridine.The gained mixture was in 35-45 ℃ of reaction 48 hours.Reaction is finished, be concentrated into dried, with 200 milliliters: 125 ml methanol/water recrystallization.Obtaining 42.6 gram white solids is 4-(2-phenetole formamido group)-1-methyl-3-n-propyl pyrazoles-5-methane amide, i.e. structural formula (IV) compound.Example 2: the ring-closure reaction of structural formula (IV) obtains structure formula V compound
In 300 milliliters of trimethyl carbinols that contain 37.0 gram condensess, add 15.2 gram potassium tert.-butoxides, the gained mixture heating up was refluxed 6 hours; Reflux and finish, it is cooled to room temperature, add 320 ml waters, and transfer pH to 6-7, stirred 1 hour in 0-10 ℃ then with 5 mol hydrochloric acid.Filter, it is 5-(2-ethoxyl phenenyl)-1-methyl-3-n-propyl 1 that drying obtains 34.4 gram white solids, 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, both structure formula V compound.Example 3: the condensation reaction of structural formula (VI) compound and methylpiperazine obtains structural formula (I) compound
In 1200 milliliters of ethanol of 35.4 gram sulfonated bodiess, add 28.0 gram methylpiperazines and 3.6 gram N, the N-Dimethylamino pyridine stirred the gained mixture 48 hours under room temperature.Reaction is finished, and is cooled to 5 ℃, filters, and the gained solid is dissolved with 400 milliliters of methylene dichloride, and wash with 500 milliliters of saturated sodium carbonates, and water is with 100 milliliters of methylene dichloride second extraction.Merge organic layer, use anhydrous magnesium sulfate drying.Filter; filtrate is concentrated into dried; with 400 milliliters of ethyl acetate and 40 milliliters of ethyl alcohol recrystallizations; obtaining 34.9 gram white solids is 5-[2-oxyethyl group-5-(4-methylpiperazine base alkylsulfonyl) phenyl]-1-methyl-3-n-propyl 1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones, both structural formula (I) compound.
Claims (16)
1. the method for preparing structural formula (I) compound, it is characterized in that, comprise by the linked reaction of structural formula (II) compound and structural formula (III) compound and the ring-closure reaction of reaction product structural formula (IV), and the condensation reaction of structural formula (VI) compound and methylpiperazine.
2. according to the method for claim 1, it is characterized in that structural formula (II) compound and structural formula (III) compound linked reaction are to carry out under the condition that has suitable reagent to exist.
3. according to the method for claim 1, it is characterized in that structural formula (II) compound and structural formula (III) compound linked reaction are to carry out under the condition that has appropriate solvent to exist.
4. according to the method for claim 1, it is characterized in that structural formula (II) compound and structural formula (III) compound linked reaction were carried out 2-48 hour under 10-60 ℃ of temperature condition.
5. according to the method for claim 1, it is characterized in that the ring-closure reaction of structural formula (IV) compound is to carry out under the condition that has alkali to exist.
6. according to the method for claim 1, it is characterized in that the ring-closure reaction of structural formula (IV) compound carries out having in the presence of the appropriate solvent.
7. according to the method for claim 1, it is characterized in that the ring-closure reaction of structural formula (IV) compound is to carry out 2-18 hour under 50-170 ℃ of temperature condition.
8. according to the method for claim 1, it is characterized in that the condensation reaction of structural formula (VI) compound and methylpiperazine is to carry out having in the presence of the suitable organic bases.
9. according to the method for claim 1, it is characterized in that the condensation reaction of structural formula (VI) compound and methylpiperazine is carried out having in the presence of the appropriate solvent.
10. according to the method for claim 2, it is characterized in that agents useful for same is selected from N, N '-carbonyl dimidazoles, N, N '-two cyclohexyl carbonyl diamine.
11. the method according to claim 3 is characterized in that, solvent for use is selected from ethyl acetate, methyl alcohol, ethanol, acetone, tetrahydrofuran (THF) and their mixture.
12. the method according to claim 5 is characterized in that, used alkali is selected from sodium hydroxide, potassium hydroxide, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide.
13. the method according to claim 6 is characterized in that, used solvent is selected from methyl alcohol, ethanol, propyl carbinol, the trimethyl carbinol, tetrahydrofuran (THF), 1,4-dioxane, dimethyl formamide, pyrazoles and water and their mixture.
14. method according to Claim 8 is characterized in that, used organic bases is selected from N, N-Dimethylamino pyridine, N, accelerine, pyridine, triethylamine, 4-pyrrolidyl pyridine.
15. the method according to claim 9 is characterized in that, used solvent is selected from methyl alcohol, ethanol, propyl carbinol, the trimethyl carbinol, tetrahydrofuran (THF), 1,4-dioxane, dimethyl formamide.
16. the method according to claim 1 is characterized in that, the condensation reaction of structural formula (VI) compound and methylpiperazine is to carry out 0.5--48 hour under 10--50 ℃ of temperature condition.
Priority Applications (1)
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CN 01111082 CN1377884A (en) | 2001-03-30 | 2001-03-30 | Process for preparing sedenafil |
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CN 01111082 CN1377884A (en) | 2001-03-30 | 2001-03-30 | Process for preparing sedenafil |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102690273A (en) * | 2012-06-07 | 2012-09-26 | 杭州奥默医药技术有限公司 | Preparation method of sildenafil |
CN103664961A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Synthetic process of sildenafil |
CN112961160A (en) * | 2021-03-05 | 2021-06-15 | 遂成药业股份有限公司 | Improved synthesis process of sildenafil |
CN115043845A (en) * | 2022-07-20 | 2022-09-13 | 江苏大学 | Synthesis method of sildenafil |
-
2001
- 2001-03-30 CN CN 01111082 patent/CN1377884A/en active Pending
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102690273A (en) * | 2012-06-07 | 2012-09-26 | 杭州奥默医药技术有限公司 | Preparation method of sildenafil |
CN103664961A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Synthetic process of sildenafil |
CN103664961B (en) * | 2013-12-18 | 2015-12-09 | 成都医路康医学技术服务有限公司 | A kind of synthesis technique of Virga |
CN112961160A (en) * | 2021-03-05 | 2021-06-15 | 遂成药业股份有限公司 | Improved synthesis process of sildenafil |
CN115043845A (en) * | 2022-07-20 | 2022-09-13 | 江苏大学 | Synthesis method of sildenafil |
CN115043845B (en) * | 2022-07-20 | 2023-11-10 | 江苏大学 | Synthesis method of sildenafil |
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