CN104059074A - Preparation method of vardenafil - Google Patents
Preparation method of vardenafil Download PDFInfo
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- CN104059074A CN104059074A CN201410246084.7A CN201410246084A CN104059074A CN 104059074 A CN104059074 A CN 104059074A CN 201410246084 A CN201410246084 A CN 201410246084A CN 104059074 A CN104059074 A CN 104059074A
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- preparation
- vardenafil
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a preparation method of vardenafil. The preparation method is characterized by comprising the following process steps: (1), slowly adding chlorosulfonic acid in an organic solution at a temperature of -0.5-10 DEG C, after a reaction system is stabilized, adding SM1, after naturally raising the temperature to room temperature, continuously reacting for 3-12 hours, diluting a reaction solution with icy dichloromethane, slowly pouring in brine ice, separating an organic phase, and drying with anhydrous sodium sulfate; (2), slowly dropping N-ethylpiperazine in a product obtained in the step 1 at a temperature of -0.5-1.5 DEG C, naturally raising the temperature to room temperature, continuously reacting for 3-8 hours, after reaction is ended, processing a reaction solution to obtain a product, and re-crystallizing the product. The preparation method is simple in operation, high in product yield, low in cost and less in consumption of chlorosulfonic acid.
Description
Technical field
The present invention relates to the synthetic field of pharmaceutical compound, specifically relate to a kind of preparation method who is used for the treatment of the medicine Vardenafil of male erectile dysfunction.
Background technology
Vardenafil hydrochloric acid (Vardenafil hydrochloride), chemical name: 2-[2-oxyethyl group-5-(4-ethyl-piperazine-1-sulfahydantoin)-phenyl]-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4] three nitrogen-4-ketone mono-hydrochloric salts, commodity are called Ai Lida, and Shi You Bayer A.G succeeds in developing, obtain the granted listing of U.S. FDA in August, 2003, is used for the treatment of male erectile dysfunction (ED).Its chemical structural formula is as follows:
US Patent No. 6777551B2 discloses a kind of preparation method of Vardenafil hydrochloric acid, and its synthetic route is:
This route relates to 11 step reactions, and the cycle is long, and comprehensive yield is low, and production technique is higher to equipment requirements:
1,, in reaction step 1, because raw material 2 activity are too strong, in highly basic sodium hydroxide solution, be easily hydrolyzed, thereby reduced the yield of product 1;
2, in reaction step 5, intermediate product is not only processed later, adopts one kettle way to complete two steps and becomes ring, and productive rate is lower; In the process of this reaction, produce in addition a kind of by product and do not dispose, it is gluey that this by product is, thus affect state and the purity of product 6, and impact reaction below;
3, in reaction step 6, according to the method for document, product is not easy to separate out in water, thereby has reduced the yield of product 7.
World patent WO2011016016A1 discloses a kind of preparation method of Vardenafil hydrochloric acid, and its synthetic route is:
This technique is with 2-(2-ethoxyl phenenyl)-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone is as starting raw material, shortened processing step, but this operational path has the following disadvantages: 1) use chlorsulfonic acid as reactant and solvent, higher to equipment requirements; 2) temperature of reaction is difficult to control; 3) long reaction time; 4) usage quantity of chlorsulfonic acid is very large, in the time of aftertreatment, need to go cancellation with a large amount of water, can produce a large amount of spent acid, contaminate environment.And, due to intermediate
1activity is too strong, in the process of cancellation, can produce more heat, is easily hydrolyzed, and has reduced product
1yield; 5) be unsuitable for the large production of industry.
Summary of the invention
The preparation method who the object of this invention is to provide a kind of Vardenafil, the method is simple to operate, product yield is high, cost is low, chlorsulfonic acid usage quantity is few.
The technical scheme adopting is:
A preparation method for Vardenafil, comprises following processing step:
1, at-0.5-10 ℃ temperature, chlorsulfonic acid is slowly added in organic solution, after question response stable system, add SM1, naturally rise to after room temperature, continue reaction 3-12 hour, the methylene dichloride dilution of ice for reaction solution, more slowly pour in icy salt solution separated organic phase into; And with anhydrous sodium sulfate drying;
2, at-0.5-1.5 ℃ temperature, NEP is slowly added drop-wise in the product that step 1 obtains, naturally rise to room temperature, continue reaction 3-8 hour, after completion of the reaction, processing reaction liquid obtains product, products obtained therefrom recrystallization.
Wherein:
In step 1, organic solvent is a kind of in methylene dichloride, acetonitrile or tetrahydrofuran (THF);
In step 1, at-0.5-10 ℃, chlorsulfonic acid is slowly added in organic solution;
In step 1, SM1 is 1:5-15 with organic solvent volume mass ratio;
In step 1, SM1 and chlorsulfonic acid mol ratio are 1:3-9, and the reaction times is 5-6 hour;
Methylene dichloride in step 1, organic solvent, the volume ratio of icy salt solution is: 1:1-1.5:5-15;
The mass ratio of SM1 and anhydrous sodium sulphate: 1:1-1.5 in step 1;
In step 2, the mol ratio of SM1 and NEP is 1:1.5-4.
Term in the present invention " processing ", refers to target product is separated from solvent, can adopt the current conventional treatment method in this area, also can adopt other unique treatment processs.The treatment process of this area routine is extraction at present, alkali cleaning, and salt is washed, vacuum concentration, recrystallization etc.Above-mentioned SM1 is 2-(2-ethoxyl phenenyl)-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone.
The inventive method compared with prior art has following beneficial effect:
1, preparing intermediate
1reaction in, reduced chlorsulfonic acid usage quantity, can reduce costs, reduce the discharge of a large amount of spent acid;
2, because chlorsulfonic acid only participates in reaction as raw material, in aftertreatment, thermal discharge is few, has reduced product
1hydrolysis, improved reaction yield, make to react easy operation and processing simultaneously, be suitable for suitability for industrialized production;
3, step 1 reaction temperature and (room temperature), the reaction times is short, is suitable for suitability for industrialized production;
4, in step 1 with saturated ice salt solution processing reaction liquid, improved product
1purity, and be conducive to product
1extraction;
5,, in the reaction of preparing Vardenafil, adopt one kettle way to obtain product, intermediate
1dichloromethane solution without aftertreatment, participate in step 2 reaction directly, simplified operation, be suitable for suitability for industrialized production, reduced production cost simultaneously.
Embodiment
embodiment 1
A preparation method for Vardenafil, comprises the steps:
(1) 0 ℃ of left and right, by chlorsulfonic acid (4.66g), be slowly added in methylene dichloride (32ml), after question response stable system, slowly add raw material SM1(3.12g), naturally rise to after room temperature, continue reaction 6 hours.Methylene dichloride (30ml) dilution by reaction solution with ice, more slowly pour in icy salt solution (300ml), separated organic phase, and with anhydrous sodium sulfate drying, be directly used in next step reaction;
(2) 0 ℃ of left and right, NEP (2.85g) is slowly added drop-wise in above-mentioned dichloromethane solution, naturally rise to after room temperature, continue reaction 7-8 hour; Saturated aqueous common salt for organic phase (100ml) is washed, and anhydrous sodium sulphate (5g) is dry, underpressure distillation, and acetonitrile for crude product (20ml) recrystallization, obtains product Vardenafil (3.51g), and the comprehensive yield of two steps is 72%.
embodiment 2
In step (1), with acetonitrile, replace methylene dichloride, the quality that obtains Vardenafil is 2.73g, the comprehensive yield of two steps is 56%.Other steps are with embodiment 1.
embodiment 3
In step (1), with tetrahydrofuran (THF), replace methylene dichloride, the quality that obtains Vardenafil is 2.24g, the comprehensive yield of two steps is 46%.Other steps are with embodiment 1.
embodiment 4
In step (1), methylene dichloride and SM1 volume mass ratio change 5 into, and the quality that obtains Vardenafil is 3.27g, and the comprehensive yield of two steps is 67%.Other steps are with embodiment 1.
embodiment 5
In step (1), methylene dichloride and SM1 volume mass ratio change 15 into, and the quality that obtains Vardenafil is 3.41g, and the comprehensive yield of two steps is 70%.Other steps are with embodiment 1.
embodiment 6
In step (1), adding chlorsulfonic acid and SM1 mol ratio is 3, and the quality that obtains Vardenafil is 2.83g, and the comprehensive yield of two steps is 71%.Other steps are with embodiment 1.
embodiment 7
In step (1), adding chlorsulfonic acid and SM1 mol ratio is 9, and the quality that obtains Vardenafil is 3.17g, and the comprehensive yield of two steps is 65%.Other steps are with embodiment 1.
embodiment 8
In step (1), the reaction times becomes 4 hours, and the quality that obtains Vardenafil is 3.02g, and the comprehensive yield of two steps is 62%.Other steps are with embodiment 1.
embodiment 9
In step (1), the reaction times becomes 12 hours, and the quality that obtains Vardenafil is 3.46g, and the comprehensive yield of two steps is 71%.Other steps are with embodiment 1.
embodiment 10
In step (2), the mol ratio of NEP and SM1 is 1.5, and the quality that obtains Vardenafil is 3.07g, and the comprehensive yield of two steps is 63%.Other steps are with embodiment 1.
embodiment 11
In step (2), the mol ratio of NEP and SM1 is 4, and the quality that obtains Vardenafil is 3.51g, and the comprehensive yield of two steps is 72%.Other steps are with embodiment 1.
Claims (8)
1. a preparation method for Vardenafil, is characterized in that comprising following processing step:
(1) at-0.5-10 ℃ temperature, chlorsulfonic acid is slowly added in (can not embody quantity of solvent) organic solution, after question response stable system, add SM1, naturally rise to after room temperature, continue reaction 3-12 hour, the methylene dichloride dilution of ice for reaction solution, slowly pour again in icy salt solution separated organic phase into; And with anhydrous sodium sulfate drying;
(2) at-0.5-1.5 ℃ temperature, NEP is slowly added drop-wise in the product that step 1 obtains; Naturally rise to room temperature, continue reaction 3-8 hour, after completion of the reaction, processing reaction liquid obtains product, products obtained therefrom recrystallization.
2. the preparation method of a kind of Vardenafil according to claim 1, is characterized in that: in step (1), organic solvent is a kind of in methylene dichloride, acetonitrile or tetrahydrofuran (THF).
3. the preparation method of a kind of Vardenafil according to claim 1, is characterized in that: step is slowly added to chlorsulfonic acid in organic solution at 0.5-10 ℃ in (1).
4. the preparation method of a kind of Vardenafil according to claim 1, is characterized in that: in step (1), SM1 is 1:5-15 with organic solvent volume mass ratio.
5. the preparation method of a kind of Vardenafil according to claim 1, is characterized in that: in step (1), SM1 and chlorsulfonic acid mol ratio are 1:3-9, and the reaction times is 5-6 hour.
6. the preparation method of a kind of Vardenafil according to claim 1, is characterized in that: methylene dichloride in step (1), and organic solvent, the volume ratio of icy salt solution is: 1:1-1.5:5-15.
7. the preparation method of a kind of Vardenafil according to claim 1, is characterized in that: the mass ratio of SM1 and anhydrous sodium sulphate: 1:1-1.5 in step (1).
8. the preparation method of a kind of Vardenafil according to claim 1, is characterized in that: the NEP in step (2) and the mol ratio of SM1 are 1:1:1.5-4.
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| CN201410246084.7A CN104059074A (en) | 2014-06-05 | 2014-06-05 | Preparation method of vardenafil |
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| CN201410246084.7A CN104059074A (en) | 2014-06-05 | 2014-06-05 | Preparation method of vardenafil |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1548438A (en) * | 2003-05-16 | 2004-11-24 | 烟台开发区北方药物研究所 | 2-substituted phenyl-6,8-dialkyl-3H-imidazolyl [1,5 alpha] [1,3,5]-trizin-4-one derivative and its prepn and medicine use |
| US6838459B1 (en) * | 1998-06-20 | 2005-01-04 | Bayer Aktiengesellschaft | 7-alkyl-and cycloalkyl-substituted imidazotriazinones |
| CN101050217A (en) * | 2007-05-21 | 2007-10-10 | 北京化工大学 | Method for synthesizing Vardenafil hydrochloric acid |
-
2014
- 2014-06-05 CN CN201410246084.7A patent/CN104059074A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6838459B1 (en) * | 1998-06-20 | 2005-01-04 | Bayer Aktiengesellschaft | 7-alkyl-and cycloalkyl-substituted imidazotriazinones |
| CN1548438A (en) * | 2003-05-16 | 2004-11-24 | 烟台开发区北方药物研究所 | 2-substituted phenyl-6,8-dialkyl-3H-imidazolyl [1,5 alpha] [1,3,5]-trizin-4-one derivative and its prepn and medicine use |
| CN101050217A (en) * | 2007-05-21 | 2007-10-10 | 北京化工大学 | Method for synthesizing Vardenafil hydrochloric acid |
Non-Patent Citations (2)
| Title |
|---|
| TERESA OLSZEWSKA等，: ""Alternative method for the synthesis of imidazo[5,1-f][1,2,4]triazin-4(3H)-one-a substrate for the preparation of phosphodiesterase (5) inhibitors"", 《TETRAHEDRON》, vol. 69, 15 November 2012 (2012-11-15), pages 474 - 484 * |
| 王进欣等，: ""伐地那非衍生物的合成和体内活性评价"", 《化学学报》, vol. 65, no. 24, 23 January 2008 (2008-01-23), pages 2917 - 2922 * |
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Application publication date: 20140924 |