CN115043845B - Synthesis method of sildenafil - Google Patents

Synthesis method of sildenafil Download PDF

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CN115043845B
CN115043845B CN202210852877.8A CN202210852877A CN115043845B CN 115043845 B CN115043845 B CN 115043845B CN 202210852877 A CN202210852877 A CN 202210852877A CN 115043845 B CN115043845 B CN 115043845B
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sildenafil
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synthesis method
copper
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CN115043845A (en
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张敏
洪健凯
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Jiangsu University
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Jiangsu University
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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
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Abstract

The invention belongs to the technical field of organic synthesis, and relates to a preparation method of sildenafil, which comprises the steps of adding 4-amino-1-methyl-3-propyl-1H-pyrazole-5-formic acid (A1) and 2-ethoxybenzonitrile (A2) into a solvent, and directly constructing a pyrimidine ring-containing intermediate A3 under the combined action of a cupric salt catalyst and an iodine simple substance; a3 is sequentially reacted with chlorosulfonic acid and N-methylpiperazine to obtain sildenafil. The invention can construct pyrimidine ring in one step, and can synthesize sildenafil through three steps of reaction, the post-reaction treatment is simple, the three steps of reaction are all to separate out solid from aqueous solution, and the high-purity sildenafil can be obtained through water washing and recrystallization, and the reaction yield is higher. In addition, the method has mild reaction conditions, does not need to use cyclizing conditions of strong alkali, avoids the generation of byproducts, has simple process operation and high product purity, and has the potential of large-scale industrial production.

Description

Synthesis method of sildenafil
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a synthesis method of sildenafil.
Background
Sildenafil (Sildenafil), a compound of formula (1), also known as Sildenafil, under the trade name Viagra, formula C 22 H 30 N 6 O 4 S, S. Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP) -specific phosphodiesterase type 5 (PDE 5) developed by the american type of pyrotechnical company and can be used for the treatment of male erectile dysfunction.
There have been many reports on the preparation method of sildenafil. Patents EP 463756 and EP 812845 by the company of the schnikose pharmaceutical describe a process for preparing 1 starting from 2-ethoxybenzoyl chloride, which differs from the order of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide condensation cyclisation, chlorosulphonation and N-methylpiperazine aminolysis (equations 1 and 2).
Patent WO2007141805 describes a process for the preparation of 1 (equation 3) starting from salicylic acid by chlorosulfonation, ammonolysis of N-methylpiperazine, condensation with 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide, ring closure, esterification, hydrolysis.
Patent WO2001098284 discloses a method for preparing 1 from 2-ethoxybenzonitrile, namely, after the 2-ethoxybenzonitrile reacts with chlorosulfonic acid and N-methylpiperazine in sequence, alcoholysis is carried out under the action of hydrogen chloride, and then the reaction product is condensed and cyclized with 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide to prepare 1 (reaction formula 4).
Some Chinese patents (such as CN112961160, CN108558890, CN 104211705, CN111689969, etc.) also have studied the preparation method of 1, but all have optimized or improved the reaction conditions based on the above synthesis method. Key to these synthetic methods is the preparation of the pyrimidinone ring, which is generally carried out in two steps, namely condensation of ortho-substituted benzoyl chloride, carboxylic acid or nitrile with 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide, followed by ring closure under strong, acidic or neutral conditions to form the pyrimidinone ring.
The literature (chem. Commun.,2016,52,10245-10248) has improved the synthesis of 1 by using benzoyl formate and 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide as starting materials, synthesizing pyrimidine ring in one step under the action of 3 equivalents of potassium persulfate, and then sequentially reacting with chlorosulfonic acid and N-methylpiperazine to prepare 1 (equation 5).
The problems of long reaction route, low yield, harsh reaction conditions and the like of the method for preparing sildenafil disclosed in the prior art still exist, and the person skilled in the art is continuously exploring and searching for a better and more effective preparation method of sildenafil.
Disclosure of Invention
Aiming at the defects in the prior art, the invention discloses a novel method for preparing sildenafil with a structural formula (1), which simplifies the reaction steps, ensures that the reaction conditions of each step are easy to control, and improves the total yield of products.
A synthesis method of sildenafil is realized by the following synthesis route,
the method comprises the following steps:
A. dissolving 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid (A1) and 2-ethoxybenzonitrile (A2) in a solvent, wherein the molar ratio of A1 to A2 is 1:1-2, then adding a cupric salt catalyst and iodine simple substance, monitoring by TLC, adding a sodium thiosulfate solution after the reaction is finished, filtering, and recrystallizing to obtain an intermediate A3;
B. slowly adding chlorosulfonic acid into the intermediate A3 at 0 ℃, stirring overnight, monitoring by TLC, pouring the reaction liquid into ice water after the reaction is finished, and obtaining a precipitated solid which is the intermediate A4;
C. dissolving the intermediate A4 in a certain volume of tetrahydrofuran, adding N-methylpiperazine, stirring for 1-4 h at room temperature, monitoring by TLC, removing the solvent after the reaction is finished, adding water, filtering, and recrystallizing the filter cake with ethanol to obtain the pure sildenafil 1.
In a preferred embodiment of the present invention, the 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid (A1) in step A is prepared from commercially available materialsIs obtained by hydrolysis under alkaline condition.
In a preferred embodiment of the present invention, the solvent in the step a is any one of N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1, 4-dioxane, 1, 2-dichloroethane, toluene, t-butanol, and N-methylpyrrolidone.
In a preferred embodiment of the present invention, the cupric salt catalyst in the step a is any one of copper acetate, copper trifluoroacetate, copper acetylacetonate, copper trifluoromethane sulfonate, copper chloride, copper bromide, copper sulfate, and copper nitrate.
In the preferred embodiment of the invention, the dosage of the cupric salt in the step A is 5-20% of the mole number of the raw material A1.
In the preferred embodiment of the invention, the molar ratio of the iodine simple substance to the raw material A1 in the step A is 1-2:1.
In the preferred embodiment of the invention, the reaction temperature in the step A is room temperature to 100 ℃ and the reaction time is 2 to 24 hours.
In the preferred embodiment of the invention, the concentration of the sodium thiosulfate aqueous solution in the step A is 0.5-2 mol/L.
In a preferred embodiment of the present invention, the solvent used in the recrystallization in the step a is at least one of water, methanol, ethanol, dichloromethane, ethyl acetate, and petroleum ether.
In the preferred embodiment of the invention, the molar ratio of the intermediate A3 to chlorosulfonic acid in the step B is 1:3.75-15.
In a preferred embodiment of the present invention, the solid and liquid of the N-methylpiperazine, the intermediate A4 and the solvent tetrahydrofuran in the step C are 1-4 mmol/1 mmol/5-20 mL.
The product of sildenafil (1) can be converted, when desired, in a conventional manner into a pharmaceutically acceptable salt, such as citrate, lactate, gluconate, malate, maleate, fumarate, succinate, acetate, hydrochloride, sulfate or bisulfate, phosphate or hydrogen phosphate.
Advantageous effects
Compared with the existing synthetic route, the invention has obvious advantages that sildenafil can be synthesized by three steps. Under mild conditions, the A1 and the A2 can realize the construction of pyrimidine rings in one step under the action of catalytic amounts of copper salt and iodine simple substance, and then react with chlorosulfonic acid and N-methylpiperazine in sequence to prepare sildenafil (1). The post-reaction treatment is simple, the solid is separated out from the aqueous solution in the three steps of reactions, and the sildenafil with high purity can be obtained through water washing and recrystallization. The invention has high reaction yield, and the total yield of sildenafil in three steps can reach 63 percent. In addition, the method has mild reaction conditions, does not need to use cyclizing conditions of strong alkali, avoids the generation of byproducts, has simple process operation and high product purity, and has the potential of large-scale industrial production.
Detailed Description
The present invention will be described in detail with reference to the following examples, so that those skilled in the art can better understand the present invention, but the present invention is not limited to the following examples.
Example 1
A synthesis method of sildenafil comprises the following steps:
the preparation steps comprise:
step 1: synthesis of intermediate A3
To a 100mL flask was successively added raw material A1 (4 mmol,0.73 g), 2-ethoxybenzonitrile (A2) (4 mmol,0.59 g), copper triflate (0.4 mmol,0.14 g), elemental iodine (4.8 mmol,1.22 g) and DMF (16 mL), and the mixture was heated to 80℃and stirred for 16h, followed by TLC monitoring the reaction. After the reaction was completed, it was cooled and 1mol/L Na was added 2 S 2 O 3 The solution was filtered and the resulting solid was recrystallized from methanol to give intermediate A3 as a white solid, 0.96g, yield 77%. 1 H NMR(400MHz,DMSO-d 6 )δ:11.96(s,1H),7.66(dd,J＝7.6,1.8Hz,1H),7.47(ddd,J＝8.4,7.4,1.8Hz,1H),7.14(dd,J＝8.5,1.0Hz,1H),7.06(td,J＝7.5,1.0Hz,1H),4.18-4.07(m,5H),2.77(t,J＝7.5Hz,2H),1.68-1.80(m,2H),1.33(t,J＝6.9Hz,3H),0.93(t,J＝7.4Hz,3H)； 13 C NMR(101MHz,DMSO-d 6 )δ:156.9,154.2,150.0,145.3,138.5,132.3,130.9,124.7,123.1,120.9,113.3,64.5,38.3,27.6,22.2,14.9,14.3；
Step 2: synthetic intermediate A4
To a 25mL flask was added intermediate A3 (2 mmol,0.62 g), chlorosulfonic acid (15 mmol,1.0 mL) was added slowly at 0deg.C, and the reaction was monitored by TLC with stirring overnight at 0deg.C. After the reaction was completed, the mixed solution was slowly poured into ice water, and filtered, and the obtained solid, intermediate A4, was 0.76g of a white solid, and the yield was 93%. The product was used directly in the next reaction without purification. 1 H NMR(400MHz,CDCl 3 )δ:10.82(s,1H),9.06(d,J＝2.6Hz,1H),8.09(dd,J＝8.9,2.6Hz,1H),7.22(d,J＝9.0Hz,1H),4.42(q,J＝7.0Hz,2H),4.26(s,3H),2.99–2.89(m,2H),1.80-1.92(m,2H),1.65(t,J＝7.0Hz,3H),1.03(t,J＝7.4Hz,3H)； 13 C NMR(101MHz,CDCl 3 )δ:160.9,153.6,147.2,145.7,138.2,137.5,131.0,130.9,124.5,121.9,113.5,66.6,38.2,27.6,22.3,14.4,14.0；
Step 3: synthesis of sildenafil
To a 25mL flask was added, in order, intermediate A4 (1 mmol,0.41 g), tetrahydrofuran (10 mL), and N-methylpiperazine (2 mmol,0.20 g), and the mixture was stirred at room temperature for 3h. After the reaction was completed, the solvent was removed, water was added, and filtration was performed, and the obtained solid was recrystallized from ethanol to obtain pure sildenafil (1), 0.42g of a white solid, and a yield was 88%. 1 H NMR(400MHz,DMSO-d 6 )δ:12.23(s,1H),7.87-7.79(m,2H),7.37(d,J＝8.6Hz,1H),4.21(q,J＝6.9Hz,2H),4.16(s,3H),2.90(t,J＝4.9Hz,4H),2.77(t,J＝7.5Hz,2H),2.36(t,J＝5.0Hz,4H),2.14(s,3H),1.67-1.79(m,2H),1.33(t,J＝6.9Hz,3H),0.93(t,J＝7.4Hz,3H)； 13 C NMR(101MHz,DMSO-d 6 )δ:160.4,154.2,148.6,145.4,138.3,131.9,130.4,126.8,124.9,124.2,113.7,65.3,53.9,46.2,45.7,38.3,27.6,22.1,14.7,14.3。
Example 2
A synthesis method of sildenafil comprises the following steps:
the preparation steps comprise:
step 1: synthesis of intermediate A3
To a 100mL flask was successively added raw material A1 (4 mmol,0.73 g), 2-ethoxybenzonitrile (A2) (8 mmol,1.18 g), copper acetate (0.2 mmol,0.04 g), elemental iodine (8 mmol,2.03 g) and DMSO (16 mL), and the mixture was heated to 100℃and stirred for 2h, and TLC was used to monitor the reaction. After the reaction was completed, it was cooled and 0.5mol/L Na was added 2 S 2 O 3 The solution was filtered and the resulting solid was recrystallized (V Methanol :V Water and its preparation method =9:1) to give white solid, intermediate A3,0.78g, yield 62%;
step 2: synthetic intermediate A4
To a 25mL flask was added intermediate A3 (2 mmol,0.62 g), chlorosulfonic acid (7.5 mmol,0.5 mL) was slowly added at 0deg.C, and the reaction was monitored by TLC while stirring overnight at 0deg.C. After the reaction is completed, the mixed solution is slowly poured into ice water and filtered, and the obtained solid, namely the intermediate A4, is white solid 0.74g, and the yield is 90%;
step 3: synthesis of sildenafil
To a 25mL flask was added in order intermediate A4 (1 mmol,0.41 g), tetrahydrofuran (5 mL), and N-methylpiperazine (1 mmol,0.10 g), and the mixture was stirred at room temperature for 3h. After the reaction was completed, the solvent was removed, water was added, and filtration was performed, and the obtained solid was recrystallized from ethanol to obtain pure sildenafil (1), 0.40g of a white solid, and a yield of 84%.
Example 3
A synthesis method of sildenafil comprises the following steps:
the preparation steps comprise:
step 1: synthesis of intermediate A3
To a 100mL flask was added raw material A1 (4 mmol,0.73 g), 2-ethoxybenzonitrile (A2) (6 mmol,0.88 g), copper acetylacetonate (0.8 mmol,0.21 g), elemental iodine (4 mmol,1.02 g) and 1, 4-dioxane (16 mL) in this order, and the mixture was stirred at room temperature for 24h, followed by TLC monitoring the reaction. After the reaction was completed, it was cooled and 1mol/L Na was added 2 S 2 O 3 Filtering the solution, recrystallizing the obtained solid by ethanol to obtain white solid, namely an intermediate A3,0.88g, and 70% yield;
step 2: synthetic intermediate A4
To a 25mL flask was added intermediate A3 (2 mmol,0.62 g), chlorosulfonic acid (30 mmol,2.0 mL) was added slowly at 0deg.C, and the reaction was monitored by TLC with stirring overnight at 0deg.C. After the reaction is completed, the mixed solution is slowly poured into ice water and filtered, and the obtained solid, namely the intermediate A4, is white solid 0.77g and has the yield of 94%;
step 3: synthesis of sildenafil
To a 25mL flask was added, in order, intermediate A4 (1 mmol,0.41 g), tetrahydrofuran (20 mL), and N-methylpiperazine (4 mmol,0.40 g), and the mixture was stirred at room temperature for 3h. After the reaction was completed, the solvent was removed, water was added, and filtration was performed, and the obtained solid was recrystallized from ethanol to obtain pure sildenafil (1), 0.38g of a white solid, and a yield was 80%.
Example 4
A synthesis method of sildenafil comprises the following steps:
the preparation steps comprise:
step 1: synthesis of intermediate A3
To a 100mL flask was successively added raw material A1 (4 mmol,0.73 g), 2-ethoxybenzonitrile (A2) (5 mmol,0.73 g), copper trifluoroacetate (0.6 mmol,0.17 g), elemental iodine (6 mmol,1.52 g) and toluene (16 mL), and the mixture was heated to 75℃and stirred for 14h, followed by TLC monitoring. After the reaction was completed, the mixture was cooled, the solvent was removed, and 2mol/L Na was added 2 S 2 O 3 The solution was filtered and the resulting solid was recrystallized (V Methanol :V Dichloromethane (dichloromethane) =1:20) to give white solid, intermediate A3,0.67g, yield 54%;
step 2: synthetic intermediate A4
To a 25mL flask was added intermediate A3 (2 mmol,0.62 g), chlorosulfonic acid (18 mmol,1.2 mL) was slowly added at 0deg.C, and the reaction was monitored by TLC while stirring overnight at 0deg.C. After the reaction is completed, the mixed solution is slowly poured into ice water and filtered, and the obtained solid, namely the intermediate A4, is white solid 0.74g, and the yield is 90%;
step 3: synthesis of sildenafil
To a 25mL flask was added in order intermediate A4 (1 mmol,0.41 g), tetrahydrofuran (15 mL), and N-methylpiperazine (3 mmol,0.30 g), and the mixture was stirred at room temperature for 3h. After the reaction was completed, the solvent was removed, water was added, and filtration was performed, and the obtained solid was recrystallized from ethanol to obtain pure sildenafil (1), 0.39g of a white solid, and the yield was 82%.
Example 5
A synthesis method of sildenafil comprises the following steps:
the preparation steps comprise:
step 1: synthesis of intermediate A3
To a 100mL flask was successively added raw material A1 (4 mmol,0.73 g), 2-ethoxybenzonitrile (A2) (6 mmol,0.88 g), copper chloride (0.3 mmol,0.04 g), elemental iodine (7 mmol,1.78 g) and N-methylpyrrolidone (16 mL), and the mixture was heated to 85℃and stirred for 10 hours, followed by TLC monitoring the reaction. After the reaction was completed, it was cooled and 1mol/LNa was added 2 S 2 O 3 The solution was filtered and the resulting solid was recrystallized (V Methanol :V Acetic acid ethyl ester =1:8) to give white solid, intermediate A3,0.69g, yield 55%;
step 2: synthetic intermediate A4
To a 25mL flask was added intermediate A3 (2 mmol,0.62 g), chlorosulfonic acid (12 mmol,0.8 mL) was slowly added at 0deg.C, and the reaction was monitored by TLC with stirring overnight at 0deg.C. After the reaction is completed, the mixed solution is slowly poured into ice water and filtered, and the obtained solid, namely the intermediate A4, is white solid 0.68g, and the yield is 56%;
step 3: synthesis of sildenafil
To a 25mL flask was added in order intermediate A4 (1 mmol,0.41 g), tetrahydrofuran (12 mL) and N-methylpiperazine (2.5 mmol,0.25 g), and the mixture was stirred at room temperature for 3h. After the reaction was completed, the solvent was removed, water was added, and filtration was performed, and the obtained solid was recrystallized from ethanol to obtain pure sildenafil (1), 0.37g of a white solid, yield 78%.
Example 6
A synthesis method of sildenafil comprises the following steps:
the preparation steps comprise:
step 1: synthesis of intermediate A3
To a 100mL flask was successively added raw material A1 (4 mmol,0.73 g), 2-ethoxybenzonitrile (A2) (6 mmol,0.88 g), copper bromide (0.4 mmol,0.09 g), elemental iodine (6 mmol,1.52 g) and 1, 2-dichloroethane (16 mL), and the mixture was heated to 40℃and stirred for 8 hours, followed by TLC monitoring the reaction. After the reaction was completed, the mixture was cooled, the solvent was removed, and 1mol/L Na was added 2 S 2 O 3 The solution was filtered and the resulting solid was recrystallized (V Methanol :V Ethanol =3:7) to give intermediate A3 as a white solid, 0.59g, yield 47%;
step 2: synthetic intermediate A4
To a 25mL flask was added intermediate A3 (2 mmol,0.62 g), chlorosulfonic acid (30 mmol,2.0 mL) was added slowly at 0deg.C, and the reaction was monitored by TLC with stirring overnight at 0deg.C. After the reaction is completed, the mixed solution is slowly poured into ice water and filtered, and the obtained solid, namely the intermediate A4, is white solid 0.67g and has the yield of 82%;
step 3: synthesis of sildenafil
To a 25mL flask was added in order intermediate A4 (1 mmol,0.41 g), tetrahydrofuran (14 mL), and N-methylpiperazine (2 mmol,0.20 g), and the mixture was stirred at room temperature for 3h. After the reaction was completed, the solvent was removed, water was added, and filtration was performed, and the obtained solid was recrystallized from ethanol to obtain pure sildenafil (1), 0.35g of a white solid, yield 74%.
Example 7
A synthesis method of sildenafil comprises the following steps:
the preparation steps comprise:
step 1: synthesis of intermediate A3
To a 100mL flask was successively added raw material A1 (4 mmol,0.73 g), 2-ethoxybenzonitrile (A2) (6 mmol,0.88 g), copper sulfate (0.6 mmol,0.096 g), elemental iodine (4 mmol,1.02 g) and t-butanol (16 mL), and the mixture was heated to 55℃and stirred for 6h, followed by TLC monitoring the reaction. After the reaction was completed, it was cooled and 1mol/L Na was added 2 S 2 O 3 The solution was filtered and the resulting solid was recrystallized (V Ethanol :V Water and its preparation method =30:1) to give intermediate A3 as a white solid, 0.61g, yield 49%;
step 2: synthetic intermediate A4
To a 25mL flask was added intermediate A3 (2 mmol,0.62 g), chlorosulfonic acid (15 mmol,1.0 mL) was added slowly at 0deg.C, and the reaction was monitored by TLC with stirring overnight at 0deg.C. After the reaction is completed, the mixed solution is slowly poured into ice water and filtered, and the obtained solid, namely the intermediate A4, is white solid 0.63g and the yield is 77%;
step 3: synthesis of sildenafil
To a 25mL flask was added in order intermediate A4 (1 mmol,0.41 g), tetrahydrofuran (8 mL) and N-methylpiperazine (2.5 mmol,0.25 g), and the mixture was stirred at room temperature for 3h. After the reaction was completed, the solvent was removed, water was added, and filtration was performed, and the obtained solid was recrystallized from ethanol to obtain pure sildenafil (1), 0.31g of a white solid, and a yield was 65%.
Example 8
A synthesis method of sildenafil comprises the following steps:
the preparation steps comprise:
step 1: synthesis of intermediate A3
To a 100mL flask was successively added raw material A1 (4 mmol,0.73 g), 2-ethoxybenzonitrile (A2) (6 mmol,0.88 g), copper nitrate (0.7 mmol,0.13 g), elemental iodine (8 mmol,2.03 g) and DMF (16 mL), and the mixture was heated to 95℃and stirred for 12h, followed by TLC monitoring. After the reaction was completed, it was cooled and 1mol/L M Na was added 2 S 2 O 3 The solution was filtered and the resulting solid was recrystallized (V Dichloromethane (dichloromethane) :V Methanol =2:15) to give white solid, intermediate A3,0.69g, yield 55%;
step 2: synthetic intermediate A4
To a 25mL flask was added intermediate A3 (2 mmol,0.62 g), chlorosulfonic acid (12 mmol,0.8 mL) was slowly added at 0deg.C, and the reaction was monitored by TLC with stirring overnight at 0deg.C. After the reaction is completed, the mixed solution is slowly poured into ice water and filtered, and the obtained solid, namely the intermediate A4, is 0.54g of white solid, and the yield is 66%;
step 3: synthesis of sildenafil
To a 25mL flask was added in order intermediate A4 (1 mmol,0.41 g), tetrahydrofuran (18 mL) and N-methylpiperazine (2.5 mmol,0.25 g), and the mixture was stirred at room temperature for 3h. After the reaction was completed, the solvent was removed, water was added, and filtration was performed, and the obtained solid was recrystallized from ethanol to obtain pure sildenafil (1), 0.30g of a white solid, and a yield was 63%.
The foregoing description is only illustrative of the present invention and is not intended to limit the scope of the invention, and all equivalent structures or equivalent processes or direct or indirect application in other related technical fields are included in the scope of the present invention.

Claims (9)

1. A synthesis method of sildenafil (1) is realized by the following synthesis route,
the method is characterized by comprising the following steps of:
A. dissolving 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid (A1) and 2-ethoxybenzonitrile (A2) in a certain solvent, wherein the molar ratio of A1 to A2 is 1:1-2, then adding a cupric salt catalyst and an iodine simple substance, monitoring by TLC, adding a sodium thiosulfate solution after the reaction is finished, filtering, and recrystallizing to obtain an intermediate A3, wherein the solvent is any one of N, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane, 1, 2-dichloroethane, toluene, tertiary butanol and N-methylpyrrolidone;
B. slowly adding chlorosulfonic acid into the intermediate A3 at 0 ℃, stirring overnight, monitoring by TLC, pouring the reaction liquid into ice water after the reaction is finished, and obtaining a precipitated solid which is the intermediate A4;
C. dissolving the intermediate A4 in a certain volume of tetrahydrofuran, adding N-methylpiperazine, stirring at room temperature for 1-4 h, monitoring by TLC, removing a solvent after the reaction is finished, adding water, filtering, recrystallizing a filter cake by using ethanol to obtain pure sildenafil (1), wherein the dosage ratio of the N-methylpiperazine to the intermediate A4 to the solvent tetrahydrofuran is 1-4 mmol:1 mmol:5-20 mL.
2. The synthesis method of sildenafil (1) according to claim 1, characterized in that: also include those commercially availableA step of preparing 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid (A1) by hydrolysis under alkaline conditions.
3. The synthesis method of sildenafil (1) according to claim 1, characterized in that: the cupric salt catalyst in the step A is any one of copper acetate, copper trifluoroacetate, copper acetylacetonate, copper trifluoromethane sulfonate, copper chloride, copper bromide, copper sulfate and copper nitrate.
4. The synthesis method of sildenafil (1) according to claim 1, characterized in that: the dosage of the cupric salt in the step A is 5-20% of the mole number of the raw material A1.
5. The synthesis method of sildenafil (1) according to claim 1, characterized in that: in the step A, the molar ratio of the iodine simple substance to the raw material A1 is 1-2:1.
6. The synthesis method of sildenafil (1) according to claim 1, characterized in that: the reaction temperature in the step A is between room temperature and 100 ℃ and the reaction time is between 2 and 24 hours.
7. The synthesis method of sildenafil (1) according to claim 1, characterized in that: the concentration of the sodium thiosulfate aqueous solution in the step A is 0.5-2 mol/L.
8. The synthesis method of sildenafil (1) according to claim 1, characterized in that: the solvent used in the step A for recrystallization is at least one of water, methanol, ethanol, methylene dichloride, ethyl acetate and petroleum ether.
9. The synthesis method of sildenafil (1) according to claim 1, characterized in that: and B, the molar ratio of the intermediate A3 to chlorosulfonic acid is 1:3.75-15.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1283624A (en) * 1999-06-21 2001-02-14 杭州神鹰医药化工有限公司 Process for preparing 'Xidinafei' medicine
CN1377884A (en) * 2001-03-30 2002-11-06 杭州中美华东制药有限公司 Process for preparing sedenafil
CN1925860A (en) * 2004-01-05 2007-03-07 特瓦制药工业有限公司 Methods for the production of sildenafil base and citrate salt
CN104370915A (en) * 2014-11-06 2015-02-25 成都医路康医学技术服务有限公司 Preparation method of sildenafil citrate
CN111116591A (en) * 2018-10-30 2020-05-08 天津科伦药物研究有限公司 Method for preparing sildenafil citrate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1283624A (en) * 1999-06-21 2001-02-14 杭州神鹰医药化工有限公司 Process for preparing 'Xidinafei' medicine
CN1377884A (en) * 2001-03-30 2002-11-06 杭州中美华东制药有限公司 Process for preparing sedenafil
CN1925860A (en) * 2004-01-05 2007-03-07 特瓦制药工业有限公司 Methods for the production of sildenafil base and citrate salt
CN104370915A (en) * 2014-11-06 2015-02-25 成都医路康医学技术服务有限公司 Preparation method of sildenafil citrate
CN111116591A (en) * 2018-10-30 2020-05-08 天津科伦药物研究有限公司 Method for preparing sildenafil citrate

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