CN105585528A - Synthesis method for industrially producing sildenafil amide intermediate - Google Patents
Synthesis method for industrially producing sildenafil amide intermediate Download PDFInfo
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- CN105585528A CN105585528A CN201510942002.7A CN201510942002A CN105585528A CN 105585528 A CN105585528 A CN 105585528A CN 201510942002 A CN201510942002 A CN 201510942002A CN 105585528 A CN105585528 A CN 105585528A
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- thionyl chloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
Abstract
The invention discloses a synthesis method for a sildenafil amide intermediate 1-methyl-3-propyl-4-nitropyrazole-5-formamide, and the synthesis method is easy and convenient to operate and suitable for industrial production. According to the method, harm of thionyl chloride to instruments and equipment is specifically reduced, appropriate solvent is found to protect acyl chloride, and the yield is greatly increased. The method is high in safety, easy and convenient to operate and little in environmental pollution, the used solvent can be recycled, and the industrial cost is greatly reduced.
Description
Technical field
The present invention relates to the synthetic method of silaenafil intermediate, especially relate to a kind of synthetic method of silaenafil intermediate 1-methyl-3-propyl group-4-nitropyrazole-5-formamide of easy and simple to handle, applicable suitability for industrialized production.
Background technology
Silaenafil is a kind of selective depressant of 5 type phosphodiesterases (PDE-5), and PDE-5 is a kind of phosphodiesterase hypotype exclusive to cGMP, is the medicine of efficiently treating male erectile dysfunction (ED). Chemistry 1-methyl-3-n-pro-pyl-5-[2-ethyoxyl-5-(4-methyl piperazine-1-sulfonyl) phenyl by name of silaenafil]-1,6-dihydro-7H-pyrazolo [4,2-d] pyridin-7-one citrate, structural formulaAs Fig. 1Shown in,Fig. 1For silaenafil structureFigure。
The topmost synthetic route of silaenafil, taking 4-amino-1-methyl-3-n-pro-pyl pyrazoles-5-formamide (1) and 2-ethoxy benzoyl chloride or the acid of 2-ethoxybenzene formyl as initiation material, obtains through condensation reaction, pyrimidone ring-closure reaction Clofenamideization and methyl piperazine condensation. Synthetic routeAs Fig. 2，Fig. 2For the synthetic route of silaenafilFigure。
As mentioned above, the topmost synthetic route of 4-amino-1-methyl-3-n-pro-pyl pyrazoles-5-formamide (1) is to obtain after cyclization, hydrolysis, nitration reaction, amidation process, reduction reaction by 2 pentanone and diethy-aceto oxalate. Synthetic routeAs Fig. 3Shown in,Fig. 3For the synthetic route of silaenafil intermediateFigure。
As mentioned above, 1-methyl-3-propyl group-4-nitropyrazole-5-formamide (2) is the important prerequisite of synthetic 4-amino-1-methyl-3-n-pro-pyl pyrazoles-5-formamide (1), and be topmost synthetic method by the synthetic 1-methyl-3-propyl group-4-nitropyrazole-5-formamide (2) of 1-methyl-3-propyl group-4-nitropyrazole-5-formic acid (3), the process that it is syntheticAs Fig. 4Shown in,Fig. 4For 1-methyl-3-propyl group-4-nitropyrazole-5-formamide synthetic methodFigure。
As mentioned above, this process has been used thionyl chloride, and equipment is had to certain corrosivity, and still, this course of reaction is selectively high, and reaction rate is fast, and accessory substance is few.
Xu Baocai etc. have reported that 1-methyl-3-propyl group-4-nitropyrazole-5-formic acid is after the thionyl chloride chlorination of 8.6 times, remove the glutinous shape thing of yellowly after thionyl chloride under reduced pressure, transfer in low temperature ammoniacal liquor, in the situation of 0～10 DEG C, stir, saltout, and productive rate 90%. In this process, the complicated operation of saltouing, yellow glutinous shape thing is not easy to shift. (fine chemistry industry, 2003,20 (2), 119～122)
Huanghai Sea flood waits has reported that 1-methyl-3-propyl group-4-nitropyrazole-5-formic acid is to reflux in the thionyl chloride of 5.7 times of substrates and DMF in weight, after removing thionyl chloride under reduced pressure, yellowly sticks shape thing, add acetone solution, be slowly added drop-wise in concentrated ammonia liquor and frozen water productive rate 85%. In this process, when vacuum rotary steam, thionyl chloride is not easy to steam except clean. (Chinese Journal of Pharmaceuticals, 2001,07:31-32.).
Xiong Zhenhu etc. have reported that 1-methyl-3-propyl group-4-nitropyrazole-5-formic acid refluxes in weight is the thionyl chloride of 14.5 times of substrates, add benzene to revolve and steam except thionyl chloride, cooling after, add acetone diluted, dilution is splashed in the beaker that fills concentrated ammonia liquor and mixture of ice and water to productive rate 89.3%. This process, the toxicity of benzene is larger, and acetone is very easily water-soluble, does not have the protective effect (Urban Construction Institutes Of Tianjin's journal, 2002,8 (1), 5～8) to acyl chlorides
As mentioned above, in the process of reaction, all do not consider the protection to thionyl chloride, and the injury of thionyl chloride to people and equipment.
Summary of the invention
The object of the invention is to overcome above-mentioned deficiency, provide a kind of protection thionyl chloride not to be decomposed, ensure not harm people and equipment, free from environmental pollution of thionyl chloride, and easy and simple to handle, accessory substance is few, high yield, is applicable to the synthetic method of suitability for industrialized production.
In order to reach above-mentioned technical purpose, the present invention by the following technical solutions:
A kind of synthetic method of silaenafil intermediate 1-methyl-3-propyl group-4-nitropyrazole-5-formamide of easy and simple to handle, applicable suitability for industrialized production, wherein, 1-methyl-3-propyl group-4-nitropyrazole-5-formic acid is dissolved in solvent as substrate, add again thionyl chloride to be dissolved in solvent, at the temperature of 70～100 DEG C, react 2～6h, steaming desolventizes and thionyl chloride, add again appropriate solvent to revolve and steam except clean thionyl chloride, add again a certain amount of dissolution with solvents protection acyl chlorides, be added dropwise in low temperature concentrated ammonia liquor and stir; The weight of described thionyl chloride is 1～6 times of substrate, and the amount of described solvent is respectively 3～6 times, 1～4 times, 2～5 times of substrate weight, the weight of described concentrated ammonia liquor is substrate 1～3 times.
Its course of reactionAs Fig. 5Shown in,Fig. 5For 1-methyl-3-propyl group-4-nitropyrazole-5-formamide with become new methodFigure。
As mentioned above, thionyl chloride is dissolved in solvent, does not directly contact with extraneous, has both ensured that thionyl chloride is not destroyed, and has ensured again not harm people and equipment, and comparatively abundant with contacting of substrate, reacts comparatively complete; In the solvent that compound (3) exists at thionyl chloride, acyl chloride reaction occurs, the temperature that this reaction needed is certain, in the situation that temperature is lower, is difficult for reaction, and reaction not exclusively; The viscosity of thionyl chloride own is larger, is difficult for being steamed except clean, need to take out of with organic solvent; Acyl chlorides is thick yellow liquid, and its activity is more very easily by material damages such as water, and is not easy to be transferred. Therefore, this process need has solvent can dissolve thionyl chloride, revolves to steam while removing well to take again thionyl chloride out of, and can dissolve acyl chlorides and protect acyl chlorides, so just can well carry out suitability for industrialized production.
The organic solvent of this process can be one or more mixing of acetonitrile, ethyl acetate, toluene and benzinum, reactive good, and easily reclaims and recycle. In reaction system, when described temperature is controlled at 70～100 DEG C, reaction is easily carried out; When the weight of described solvent is respectively 3～6 times, 1～4 times, 2～5 times into substrate, there is the effect of fine reaction; When the weight of described concentrated ammonia liquor is 1～3 times of substrate, be swift in response, separate out conveniently, and productive rate be higher.
Above-mentioned amidation process method, wherein, 2～4 times that the weight of thionyl chloride is substrate are better.
Above-mentioned amidation process method, wherein, the weight of solvent be respectively 4～6 times, 1～3 times of substrate and 2～4 times better.
Above-mentioned amidation process method, wherein, 1～3 times that the weight of concentrated ammonia liquor (6 DEG C following) is substrate is better.
Above-mentioned amidation process method, wherein, the reaction time is better while being 2～3h.
The present invention has the following advantages compared to existing technology:
1, this reaction method, in course of reaction, selected solvent has solved the shortcoming of thionyl chloride, reactive good, easy and simple to handle, and it is rapid to separate out product.
2, this reaction method, in course of reaction, remains a small amount of thionyl chloride in solvent, and the direct use of recovered solvent can also reduce the consumption of thionyl chloride like this, and the pollution of environment is reduced relatively.
3, this reaction method, in course of reaction, can not only ensure to generate less accessory substance, can also be in course of reaction, and protect acyl chlorides not to be destroyed, productive rate is improved greatly.
Specific implementation method
Below in conjunction with example, the present invention is described further:
Example 1: by 1-methyl-3-propyl group-4-nitropyrazole-5-formic acid 3.00g, be dissolved in the solvent of 12～18g, add thionyl chloride 6～12g, 90～95 DEG C of 2～3h that reflux, are down to room temperature, and decompression evaporates unnecessary thionyl chloride, add again 3～9g organic solvent, be again spin-dried for; Add 6～12g solvent protection method acyl chlorides, 25% the ammoniacal liquor that measures 3～9g adds, and temperature is kept below 20 DEG C, stirs, and separates out solid 2.91g, moisture 0.74%, productive rate 96.73%.
Example 2: by 1-methyl-3-propyl group-4-nitropyrazole-5-formic acid 10.00g, be dissolved in the solvent of 40～60g, add thionyl chloride 20～40g, 90～95 DEG C of 2～3h that reflux, are down to room temperature, and decompression evaporates unnecessary thionyl chloride, add again 10～30g organic solvent, be again spin-dried for; Add 20～40g solvent protection method acyl chlorides, 25% the ammoniacal liquor that measures 10～30g adds, and temperature is kept below 20 DEG C, stirs, and separates out solid 9.81g, moisture 1.46%, productive rate 97.11%.
Example 3: by 1-methyl-3-propyl group-4-nitropyrazole-5-formic acid 30.00g, be dissolved in the solvent of 120～180g, add thionyl chloride 60～120g, 90～95 DEG C of 2～3h that reflux, are down to room temperature, and decompression evaporates unnecessary thionyl chloride, add again 30～90g organic solvent, be again spin-dried for; Add 60～120g solvent protection method acyl chlorides, 25% the ammoniacal liquor that measures 30～90g adds, and temperature is kept below 20 DEG C, stirs, and separates out solid 29.56g, moisture 1.46%, productive rate 98.09%.
From above-mentioned example, synthetic method of the present invention, the productive rate of product is very high, and organic solvent recovery is convenient, is applicable to suitability for industrialized production.
Claims (3)
1. prepare a synthetic method for silaenafil intermediate 1-methyl-3-propyl group-4-nitropyrazole-5-formamide, its feature is that described preparation method comprises the following steps:
1-methyl-3-propyl group-4-nitropyrazole-5-formic acid is dissolved in solvent as substrate, add thionyl chloride appropriate, reaction adds organic solvent solution to steam remaining thionyl chloride in reactant liquor at a certain temperature, and under the environment of organic solvent protection, add low temperature concentrated ammonia liquor;
According to the amidation process method described in claim 1, it is characterized in that: solvent can be one or more mixing of acetonitrile, ethyl acetate, toluene and benzinum; The amount of described solvent is respectively 3 ~ 6 times, 1 ~ 4 times, 2 ~ 5 times of substrate weight.
2. according to the amidation process method described in claim 1, it is characterized in that: the weight of described thionyl chloride is substrate 1 ~ 6 times, the weight of described concentrated ammonia liquor is substrate 1 ~ 3 times.
3. according to the amidation process method described in claim 1, it is characterized in that: described reaction temperature is 70 ~ 100 DEG C; Reaction time is 2 ~ 6h.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109776421A (en) * | 2019-03-07 | 2019-05-21 | 烟台舜康生物科技有限公司 | Novel synthesis method of sildenafil intermediate and sildenafil intermediate obtained by same |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1246478A (en) * | 1999-07-12 | 2000-03-08 | 广东天普生物化学制药有限公司 | Process for preparing Xidinafei |
| WO2008100886A1 (en) * | 2007-02-12 | 2008-08-21 | Auspex Pharmaceuticals, Inc. | Preparation and use of deuterated udenafil analogues as highly selective pde5 modulators for the treatment of erectile dysfunction |
| WO2009099620A1 (en) * | 2008-02-04 | 2009-08-13 | Concert Pharmaceuticals Inc. | 3-(dihydro-1h-pyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxybenzenesulfonamide derivatives and methods of use |
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- 2015-12-16 CN CN201510942002.7A patent/CN105585528A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1246478A (en) * | 1999-07-12 | 2000-03-08 | 广东天普生物化学制药有限公司 | Process for preparing Xidinafei |
| WO2008100886A1 (en) * | 2007-02-12 | 2008-08-21 | Auspex Pharmaceuticals, Inc. | Preparation and use of deuterated udenafil analogues as highly selective pde5 modulators for the treatment of erectile dysfunction |
| WO2009099620A1 (en) * | 2008-02-04 | 2009-08-13 | Concert Pharmaceuticals Inc. | 3-(dihydro-1h-pyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxybenzenesulfonamide derivatives and methods of use |
Non-Patent Citations (1)
| Title |
|---|
| DAVID J. DALE ET AL.,: "The Chemical Development of the Commercial Route to Sildenafil: A Case History", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109776421A (en) * | 2019-03-07 | 2019-05-21 | 烟台舜康生物科技有限公司 | Novel synthesis method of sildenafil intermediate and sildenafil intermediate obtained by same |
| CN109776421B (en) * | 2019-03-07 | 2022-05-13 | 烟台舜康生物科技有限公司 | Novel synthesis method of sildenafil intermediate and sildenafil intermediate obtained by same |
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Application publication date: 20160518 |