CN111689969A - Preparation method of sildenafil - Google Patents
Preparation method of sildenafil Download PDFInfo
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- CN111689969A CN111689969A CN202010607941.7A CN202010607941A CN111689969A CN 111689969 A CN111689969 A CN 111689969A CN 202010607941 A CN202010607941 A CN 202010607941A CN 111689969 A CN111689969 A CN 111689969A
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Abstract
The invention relates to a preparation method of sildenafil, which comprises the steps of dissolving a compound III in an organic solvent I, adding a compound II to carry out amidation reaction, washing and drying to obtain a compound IV; directly adding the solution obtained in the step S1 into a chlorosulfonic acid-thionyl chloride mixture for chlorosulfonation reaction without separation and purification, pouring ice water after the reaction is finished, layering, washing an organic phase, and drying to obtain a compound V; and adding N-methylpiperazine into the compound V obtained in the S2, carrying out N-sulfonation reaction for 0-4 hours, concentrating, adding alkali and an organic solvent II, heating to carry out cyclization reaction for 2-6 hours, adding water for cooling, adding hydrochloric acid for acidification, and filtering to obtain the target compound I. The invention adopts a continuous method for synthesis, thereby improving the production efficiency.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, and particularly relates to a preparation method of sildenafil.
Background
Sildenafil (Sildenafil) chemical name: 5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl ] -1-methyl-3-propyl-6, 7-dihydro-1H-pyrazolo [4,3-d ] pyrimidin-7-one, a selective inhibitor of phosphodiesterase type 5 (PDE5), was first developed by Pfizer, Inc., USA and was used for the treatment of angina pectoris. In recent years, sildenafil has been found to have an effect of treating male erectile dysfunction (see WO-A-94/28902).
In US5955611, a protocol is disclosed for the preparation of sildenafil: performing chlorosulfonation reaction on the compound VII to obtain a compound VIII, performing N-sulfonation on the compound VIII and N-methylpiperazine to obtain a compound IX, performing amidation to obtain a compound VI, and finally performing cyclization to obtain the sildenafil I. The reaction formula is as follows:
in the process, the chlorosulfonation reaction time is 18 hours; the N-sulfonation uses an expensive activating agent CDI, and the reaction time is as long as 72 hours; the conditions for the cyclization are strict, and a dust-free flask and dust-free hydrochloric acid are not needed. Therefore, the method has long reaction time, complicated operation and strict conditions, and is not suitable for large-scale production.
In CN1139590C, a preparation method of sildenafil is disclosed: performing chlorosulfonation reaction on the compound with the structural formula (IV) to obtain a reaction product, namely a compound with a structural formula (V);
(2) sulfamide of the compound with the structural formula (V) and N-methyl piperazine to obtain a reaction product, a compound with the structural formula (VI);
(3) the compound of the structural formula (VI) is subjected to cyclization reaction in the presence of a specific base to obtain a compound of the structural formula (I), namely sildenafil. The reaction formula is as follows:
the process adopts a step-by-step method for synthesis, and has the disadvantages of complex operation and low yield, so that a method which is simple in operation process and can improve the product yield is required to be developed.
Disclosure of Invention
The invention provides a preparation method of sildenafil, which is used for solving the problems of long reaction time, complex operation and low yield in the prior art.
The invention relates to a preparation method of sildenafil, which is characterized by comprising the following steps:
s1: dissolving a compound III in an organic solvent I, adding a compound II to perform amidation reaction, washing and drying to obtain a compound IV;
s2: directly adding the solution obtained in the step S1 into a chlorosulfonic acid-thionyl chloride mixture for chlorosulfonation reaction without separation and purification, pouring ice water after the reaction is finished, layering, washing an organic phase, and drying to obtain a compound V;
s3: and adding N-methylpiperazine into the compound V obtained in the S2, carrying out N-sulfonation reaction for 0-4 hours, concentrating, adding alkali and an organic solvent II, heating to carry out cyclization reaction for 2-6 hours, adding water for cooling, adding hydrochloric acid for acidification, and filtering to obtain the target compound I.
Further, the organic solvent i in the step S1 is selected from tetrahydrofuran, 1, 4-dioxane, dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide, dichloromethane, chloroform, etc., preferably dichloromethane or chloroform.
Further, the reaction temperature of the step S1 is 0-40 ℃, and the reaction time is 0.5-4.0 hours.
Further, the reaction temperature of the chlorosulfonation reaction in the step S2 is 25-60 ℃, and the reaction time is 0.5-4.0 hours.
Further, in the step S3, the organic solvent ii is selected from C1-C6 aliphatic alcohols, acetone, butanone, tetrahydrofuran, dichloromethane, and chloroform. Preferably the solvent is ethanol or tetrahydrofuran.
Further, the reaction temperature of the N-sulfonation reaction in the step S3 is 5-60 ℃, and the reaction temperature of the cyclization reaction is 60-100 ℃.
Further, in the step S3, the base is sodium hydroxide or potassium carbonate.
Further, in step S1, an aliphatic tertiary amine is added.
Further, the aliphatic tertiary amine is triethylamine.
Further, in the step 1 and the step 2, anhydrous sodium sulfate is adopted for drying.
Compared with the prior art, the preparation method of sildenafil has the following beneficial technical effects:
the invention adopts a continuous method for synthesis, does not separate and purify intermediates, simplifies the operation, greatly shortens the reaction time, improves the production efficiency, has good product quality and is suitable for large-scale production.
Drawings
FIG. 1 is a high performance liquid chromatogram of an embodiment of a method for preparing sildenafil according to the present invention.
Detailed Description
The technical solution of the present invention is further described clearly and completely below.
A method for preparing sildenafil, comprising the steps of:
s1: dissolving a compound III in an organic solvent I, adding a compound II into the organic solvent I, carrying out amidation reaction for 0.5 to 4.0 hours at the temperature of between 0 and 40 ℃, washing and drying to obtain a compound IV;
s2: directly adding the solution obtained in the step S1 into a chlorosulfonic acid-thionyl chloride mixture at the temperature of 25-60 ℃ without separation and purification to perform chlorosulfonation reaction for 0.5-4.0 hours, pouring ice water after the reaction is finished, layering, washing an organic phase, and drying to obtain a compound V;
s3: and adding N-methylpiperazine into the compound V obtained in the step S2, carrying out N-sulfonation reaction for 0-4 hours at the temperature of 5-60 ℃, concentrating, adding alkali and an organic solvent II, heating to the temperature of 60-100 ℃, carrying out cyclization reaction for 2-6 hours, adding water, cooling, adding hydrochloric acid for acidification, and filtering to obtain the target compound I.
In a preferred embodiment, an aliphatic tertiary amine, most preferably triethylamine, is also added in step S1.
The reaction process is as follows:
the first embodiment is as follows:
a method for preparing sildenafil, comprising the steps of:
s1, adding 5.0g of compound III and 6.5g of triethylamine into 30ml of tetrahydrofuran, adding 6.0g of dichloromethane solution of compound II under stirring, reacting for 1.5 hours under stirring, washing the reaction solution with 30ml of × 3, and drying (Na)2SO4) To obtain a dichloromethane solution of a compound IV.
S2 adding dichloromethane solution of the compound IV into 11.2g chlorosulfonic acid and 11.5g thionyl chloride, stirring for reaction for 2.0 hours, pouring the reaction solution into 150ml ice water, stirring for layering, washing dichloromethane layer with 50ml × 3, and drying (Na2SO4) To obtain the dichloromethane solution of the compound V.
S3: to a solution of compound V in dichloromethane was added 3.5g N-methylpiperazine, stirred for 2 hours and concentrated to dryness. 40ml of isopropanol was added, dispersed with stirring, and 3.5g of sodium hydroxide was added to conduct reflux reaction for 3 hours and acidified with 2N hydrochloric acid. Filtering, and leaching a filter cake with water to obtain 8.9g of the compound I, wherein the yield is 68.3 percent, and the purity is 99.49 percent.
Example two:
a method for preparing sildenafil, comprising the steps of:
s1, adding 5.0g of compound III and 6.5g of triethylamine to 60ml of dichloromethane, stirring and adding 6.4g of dichloromethane solution of compound II, stirring and reacting for 1.0 hour, washing the reaction solution with 50ml of × 3 water, and drying (Na 1)2SO4) To obtain a dichloromethane solution of a compound IV.
S2 adding dichloromethane solution of the compound IV into 11.5g chlorosulfonic acid and 12.5g thionyl chloride, stirring for reaction for 1.5 hours, pouring the reaction solution into 200ml ice water, stirring for layering, washing dichloromethane layer with 50ml × 3, and drying (Na2SO4) To obtain the dichloromethane solution of the compound V.
S3: to a solution of compound V in dichloromethane was added 4.2g N-methylpiperazine, stirred for 2 hours and concentrated to dryness. 40ml of butanediol was added, stirred and dispersed, and 4g of potassium carbonate was added to conduct a reflux reaction for 4 hours and acidified with 1N hydrochloric acid. Filtering, leaching filter cake with water to obtain 8.5g of compound I, yield is 65.3%, and purity is 99.68%.
Example three:
a method for preparing sildenafil, comprising the steps of:
s1, adding 5.0g of compound III and 6.75g of triethylamine to 30ml of dichloromethane, stirring and adding 6.4g of dichloromethane solution of compound II, stirring and reacting for 1.5 hours, washing the reaction solution with 50ml of × 3 water, and drying (Na 1)2SO4) To obtain a dichloromethane solution of a compound IV.
S2 adding dichloromethane solution of the compound IV into 11.4g chlorosulfonic acid and 11.7g thionyl chloride, stirring for reaction for 2.0 hours, pouring the reaction solution into 200ml ice water, stirring for layering, washing dichloromethane layer with 50ml × 3, and drying (Na2SO4) To obtain the dichloromethane solution of the compound V.
S3: to a solution of compound V in dichloromethane was added 3.5g N-methylpiperazine, stirred for 2 hours and concentrated to dryness. Adding isopropanol, stirring for dispersion, adding 3.4g of potassium carbonate, refluxing for reaction for 3 hours, and acidifying with 2N hydrochloric acid. Filtering, leaching filter cake with water to obtain 9.1g of compound I, the yield is 69.9%, and the purity is 99.57%.
Example four:
a method for preparing sildenafil, comprising the steps of:
s1, adding 5.0g of compound III and 6.5g of triethylamine to 30ml of dichloromethane, stirring and adding 3.1g of dichloromethane solution of compound II, stirring and reacting for 2.0 hours, washing the reaction solution with 25ml of × 3 water, and drying (Na 1)2SO4) To obtain a dichloromethane solution of a compound IV.
S2: adding dichloromethane solution of the compound IV into 12g chlorosulfonic acid and 12.5g thionyl chloride, stirring and reacting for 2.0 hours, pouring the reaction solutionThe mixture was poured into 200ml of ice water, the layers were separated by stirring, the methylene chloride layer was washed with 25ml of × 3 and dried (Na)2SO4) To obtain the dichloromethane solution of the compound V.
S3: to a solution of compound V in dichloromethane was added 4.0g N-methylpiperazine, stirred for 2 hours and concentrated to dryness. 30ml of isopropyl alcohol was added, stirred and dispersed, and 3.3g of potassium carbonate was added to conduct reflux reaction for 4 hours and acidified with 2N hydrochloric acid. Filtering, and leaching a filter cake with water to obtain 9.34g of the compound I, wherein the yield is 71.7 percent, and the purity is 99.54 percent.
Example five:
a method for preparing sildenafil, comprising the steps of:
s1, adding 5.0g of compound III into 30ml of dichloromethane, adding 3.1g of dichloromethane solution of compound II under stirring, reacting for 2.0 hours under stirring, washing the reaction solution with 25ml of × 3g of water, and drying (Na)2SO4) To obtain a dichloromethane solution of a compound IV.
S2 adding dichloromethane solution of the compound IV into 12g chlorosulfonic acid and 12.5g thionyl chloride, stirring for reaction for 2.0 hours, pouring the reaction solution into 200ml ice water, stirring for layering, washing dichloromethane layer with 25ml × 3, and drying (Na)2SO4) To obtain the dichloromethane solution of the compound V.
S3: to a solution of compound V in dichloromethane was added 4.0g N-methylpiperazine, stirred for 2 hours and concentrated to dryness. 30ml of isopropyl alcohol was added, stirred and dispersed, and 3.3g of potassium carbonate was added to conduct reflux reaction for 4 hours and acidified with 2N hydrochloric acid. Filtering, and leaching a filter cake with water to obtain 9.34g of the compound I with the yield of 68.9 percent and the purity of 99.49 percent.
The technical solutions in the embodiments of the present invention are clearly and completely described above, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The above embodiments are only for the purpose of facilitating the understanding of the method of the present invention and the core idea thereof, and are not intended to limit the present invention, it should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principle of the present invention, and these improvements and modifications also fall into the protection scope of the claims of the present invention.
Claims (10)
1. A preparation method of sildenafil is characterized by comprising the following steps:
s1: dissolving a compound III in an organic solvent I, adding a compound II to perform amidation reaction, washing and drying to obtain a compound IV;
s2: directly adding the solution obtained in the step S1 into a chlorosulfonic acid-thionyl chloride mixture for chlorosulfonation reaction without separation and purification, pouring ice water after the reaction is finished, layering, washing an organic phase, and drying to obtain a compound V;
s3: and adding N-methylpiperazine into the compound V obtained in the S2, carrying out N-sulfonation reaction for 0-4 hours, concentrating, adding alkali and an organic solvent II, heating to carry out cyclization reaction for 2-6 hours, adding water for cooling, adding hydrochloric acid for acidification, and filtering to obtain the target compound I.
2. A process for the preparation of sildenafil according to claim 1, wherein: the organic solvent i in the step S1 is selected from tetrahydrofuran, 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, dichloromethane, chloroform and the like, and preferably dichloromethane or chloroform.
3. A process for the preparation of sildenafil according to claim 1, wherein: the reaction temperature of the step S1 is 0-40 ℃, and the reaction time is 0.5-4.0 hours.
4. A process for the preparation of sildenafil according to claim 1, wherein: the reaction temperature of the chlorosulfonation reaction in the step S2 is 25-60 ℃, and the reaction time is 0.5-4.0 hours.
5. A process for the preparation of sildenafil according to claim 1, wherein: in the step S3, the organic solvent II is selected from C1-C6 fatty alcohol, acetone, butanone, tetrahydrofuran, dichloromethane and chloroform. Preferably the solvent is ethanol or tetrahydrofuran.
6. A process for the preparation of sildenafil according to claim 1, wherein: in the step S3, the reaction temperature of the N-sulfonation reaction is 5-60 ℃, and the reaction temperature of the cyclization reaction is 60-100 ℃.
7. A process for the preparation of sildenafil according to claim 1, wherein: the alkali in the step S3 is sodium hydroxide or potassium carbonate.
8. A process for the preparation of sildenafil according to claim 1, wherein: in step S1, an aliphatic tertiary amine is added.
9. The process for preparing sildenafil according to claim 8, wherein: the aliphatic tertiary amine is triethylamine.
10. A process for the preparation of sildenafil according to claim 1, wherein: and drying by adopting anhydrous sodium sulfate in the steps 1 and 2.
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| CN112608317A (en) * | 2020-12-15 | 2021-04-06 | 植恩生物技术股份有限公司 | Sildenafil citrate preparation method |
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| CN112608317A (en) * | 2020-12-15 | 2021-04-06 | 植恩生物技术股份有限公司 | Sildenafil citrate preparation method |
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Address after: 401120 Yubei District, Chongqing, 101 Jinyu Road, Kaiyuan. Applicant after: Chongqing kangkere Pharmaceutical Co., Ltd Address before: 401120 Yubei District, Chongqing, 101 Jinyu Road, Kaiyuan. Applicant before: CHONGQING CONQUER PHARMACEUTICAL Co.,Ltd. |
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Application publication date: 20200922 |