Preparation method and use of an aminopyrazole compound

Abstract

The application discloses a preparation method of an amido pyrazole compound and a method for preparing sildenafil by using the same. The amido pyrazole compound is shown as formula I. The compound of formula I is prepared by using 2-pentanone as an industrial chemical, and can be used for synthesizing sildenafil which is a selective inhibitor of type 5 phosphodiesterase (PDE5). The method has the advantages of easy availability of raw materials, simple operation, avoidance of nitration reaction, avoidance of safety hidden dangers caused by the nitration reaction from a technical source, and avoidance of environmental protection pressure caused by a large amount of nitration waste liquid, and is suitable for development into a green and sustainable production process of sildenafil bulk drug.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a method for preparing an aminopyrazole compound and a method for preparing sildenafil using the same compound. Background Technology

[0002] Sildenafil, developed by Pfizer, was approved by the U.S. Food and Drug Administration (FDA) on March 27, 1998. It is a phosphodiesterase type 5 (PDE-5) inhibitor used to treat erectile dysfunction (ED).

[0003] US5250534A reported numerous problems in the synthesis of sildenafil. For example, the preparation of intermediate C involved nitration with nitric and sulfuric acids, raising concerns about the safety of the nitration reaction itself and the disposal of nitration wastewater. The preparation of amide intermediate D used sulfoxide, generating large amounts of sulfur dioxide and acidic hydrogen chloride gas. Therefore, developing a safe, efficient, environmentally friendly, economical, and sustainable synthesis process for benzimidazole compounds is of great significance.

[0004] Summary of the Invention

[0005] This invention provides a method for preparing an aminopyrazole compound and a method for preparing sildenafil using the same compound. The method for preparing sildenafil of this invention avoids the nitration reaction, is easily controllable, simple to operate, suitable for large-scale industrial production, and suitable for development into a green and sustainable production process.

[0006] According to one aspect of the present invention, a method for preparing a compound of formula I is provided, characterized in that:

[0007] d) Compound V undergoes a hydrogenation-reduction reaction to produce compound I:

[0008]

[0009] In compounds of formula V and formula I, R is methyl or ethyl, preferably ethyl.

[0010] According to one aspect of the present invention, a method for preparing a compound of formula I is provided, characterized in that:

[0011] a) 2-Pentanone undergoes a condensation reaction with compound II under alkaline conditions to generate compound III;

[0012] b) Compound III undergoes a nitrosation reaction to produce compound IV;

[0013] c) The reaction of compound IV with hydrazine hydrate produces compound V;

[0014] d) Compound V of formula V undergoes ammonolysis (i.e., hydrogenation-reduction) with ammonia in a solvent to produce compound I:

[0015]

[0016] Wherein R is methyl or ethyl, preferably ethyl.

[0017] According to another aspect of the present invention, a method for preparing sildenafil using a compound of formula I is provided, characterized in that:

[0018] e) The compound of formula I undergoes an acylation reaction with the compound of formula 10 to generate the compound of formula VI;

[0019] f) The reaction of compound VI with a methylating agent produces compound VII;

[0020] g) Compound VII of formula reacts with ammonia in a solvent to undergo ammonolysis to produce compound 5;

[0021] h) Compound 5 of formula undergoes an intramolecular condensation reaction under alkaline conditions to generate compound 6 of formula.

[0022] i) Compound of formula 6 reacts with chlorosulfonic acid to produce compound of formula 7;

[0023] (j) Compound of Formula 7 reacts with N-methylpiperazine, and then forms a salt with citric acid to generate compound of Formula 8.

[0024]

[0025] Wherein R is methyl or ethyl, preferably ethyl.

[0026] According to another aspect of the present invention, a method for preparing sildenafil of formula 8 is provided, characterized in that:

[0027] k) The compound of formula I undergoes an acylation reaction with the compound of formula 13 to generate the compound of formula VIII;

[0028] The reaction of compound VIII of formula l) with a methylating agent produces compound IX;

[0029] Compound m) IX reacts with ammonia in a solvent via ammonolysis to produce compound m) IX.

[0030] Compound n) of formula 9 undergoes an intramolecular condensation reaction under alkaline conditions, and then forms a salt with citric acid to generate compound n) of formula 8.

[0031]

[0032] Wherein R is methyl or ethyl, preferably ethyl. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0034] According to one aspect of the present invention, a method for preparing a compound of formula I is provided, characterized in that:

[0035] d) Compound V undergoes a hydrogenation-reduction reaction to produce compound I:

[0036]

[0037] In compounds of formula V and formula I, R is methyl or ethyl, preferably ethyl.

[0038] According to one aspect of the invention, preferably,

[0039] The method further includes the following steps:

[0040] c) Compound IV undergoes a cyclization reaction with hydrazine hydrate to generate compound V:

[0041]

[0042] In compounds of formula IV and V, R is methyl or ethyl, preferably ethyl.

[0043] According to one aspect of the invention, preferably,

[0044] The method further includes the following steps:

[0045] b) Compound III reacts with nitrite and acid to produce compound IV:

[0046]

[0047] The nitrite is preferably sodium nitrite, the acid is preferably hydrochloric acid, and in compounds of formula III and formula IV, R is methyl or ethyl, preferably ethyl.

[0048] According to one aspect of the invention, preferably,

[0049] The method further includes the following steps:

[0050] a) 2-Pentanone undergoes a condensation reaction with compound II to generate compound III:

[0051]

[0052] In compounds of formula II and formula III, R is methyl or ethyl, preferably ethyl.

[0053] According to one aspect of the invention, preferably,

[0054] In steps a) to d), the process is carried out continuously without purification between adjacent steps.

[0055] According to one aspect of the present invention, a method for preparing sildenafil, a compound of formula 8, is provided, characterized in that:

[0056] j) The compound of formula 7 reacts with N-methylpiperazine, and then forms a salt with citric acid to generate the compound of formula 8:

[0057]

[0058] Preferably, the method further includes the following steps:

[0059] i) Compound of formula 6 reacts with chlorosulfonic acid in a chlorosulfonation reaction to produce compound of formula 7:

[0060]

[0061] Preferably, the method further includes the following steps:

[0062] h) Compound 5 undergoes intramolecular condensation under alkaline conditions to form compound 6:

[0063]

[0064] Preferably, the method further includes the following steps:

[0065] g) The compound of formula VII undergoes ammonolysis with ammonia in a solvent to produce the compound of formula 5:

[0066]

[0067] In compounds of formula VII, R is methyl or ethyl, preferably ethyl;

[0068] The solvent is selected from methanol, ethanol, isopropanol, water, or combinations thereof.

[0069] Preferably, the method further includes the following steps:

[0070] f) The reaction of compound VI with a methylating agent yields compound VII:

[0071]

[0072] In compounds of formulas VI and VII, R is methyl or ethyl, preferably ethyl;

[0073] The methylating agent is selected from dimethyl sulfate, methyl methanesulfonate, methyl benzenesulfonate, chloromethane, iodomethane, and bromomethane, preferably dimethyl sulfate.

[0074] Preferably, the method further includes the following steps:

[0075] e) The compound of formula 1 undergoes an acylation reaction with the compound of formula 10 to generate the compound of formula VI:

[0076]

[0077] In compounds of formula I and formula VI, R is methyl or ethyl, preferably ethyl.

[0078] According to one aspect of the invention, wherein,

[0079] In steps e) to j), the process is carried out continuously without purification between adjacent steps.

[0080] According to one aspect of the present invention, a method for preparing sildenafil, a compound of formula 8, is provided, characterized in that:

[0081] Compound n) underwent an intramolecular condensation reaction under alkaline conditions, and then formed a salt with citric acid to generate compound n) of formula 8.

[0082]

[0083] Preferably, the method further includes the following steps:

[0084] Compound m) IX reacts with ammonia in a solvent via ammonolysis to produce compound m) IX.

[0085]

[0086] In compounds of formula VII, R is methyl or ethyl, preferably ethyl;

[0087] The solvent is selected from methanol, ethanol, isopropanol, water, or combinations thereof.

[0088] Preferably, the method further includes the following steps:

[0089] The reaction of compound VIII with a methylating agent produces compound IX:

[0090]

[0091] In compounds of formula VIII and formula IX, R is methyl or ethyl, preferably ethyl;

[0092] The methylating agent is selected from dimethyl sulfate, methyl methanesulfonate, methyl benzenesulfonate, chloromethane, iodomethane, and bromomethane, preferably dimethyl sulfate;

[0093] Preferably, the method further includes the following steps:

[0094] k) The compound of formula I reacts with the compound of formula 13 or its salt via an acylation reaction to produce the compound of formula VIII:

[0095]

[0096] In compounds of formula I and formula VIII, R is methyl or ethyl, preferably ethyl;

[0097] The salt of the compound of Formula 13 is preferably a hydrochloride salt.

[0098] According to one aspect of the invention, wherein,

[0099] In steps k) to n), the process is carried out continuously without purification between adjacent steps.

[0100] An exemplary embodiment of the method for preparing the compound of formula I of the present invention includes the following steps:

[0101] a) The reaction of 2-pentanone with the oxalate of formula II yields the compound of formula III:

[0102]

[0103] Wherein R is methyl or ethyl, preferably ethyl.

[0104] In one embodiment, 2-pentanone reacts with diethyl oxalate II in the presence of sodium methoxide or sodium ethoxide to give compound of formula 1.

[0105] Specifically, sodium methoxide / methanol or sodium ethoxide / ethanol is added to 2-pentanone and oxalate II. After the reaction is complete, hydrochloric acid is added for neutralization, followed by the addition of water and solvent, extraction, and concentration to obtain compound III.

[0106] The reaction temperature is 0–80°C, preferably 10–40°C, and more preferably 20–30°C;

[0107] The molar ratio of 2-pentanone and oxalate to sodium methoxide or sodium ethoxide is 1:1:(1.0-2.0); preferably 1:1:(1.1-1.3).

[0108] b) Compound III undergoes a nitrosation reaction to produce compound IV:

[0109]

[0110] Wherein R is methyl or ethyl, preferably ethyl.

[0111] In one embodiment, the compound represented by Formula III undergoes a nitrosation reaction in the presence of nitrite and acid to generate the compound of Formula IV.

[0112] Specifically, the compound of formula III is added to a solvent, followed by the addition of nitrite and acid. After the reaction is complete, the mixture is concentrated under reduced pressure, water and solvent are added, and the mixture is extracted and concentrated to obtain the compound of formula IV.

[0113] The nitrite is selected from sodium nitrite, potassium nitrite, calcium nitrite, lithium nitrite, magnesium nitrite, or combinations thereof; preferably sodium nitrite.

[0114] The acid is selected from one of organic acids and inorganic acids or a combination thereof;

[0115] The organic acid is selected from formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, lactic acid, maleic acid, fumaric acid, malonic acid, succinic acid, tartaric acid, citric acid, malic acid, isobutyric acid, pentylamino acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or combinations thereof.

[0116] The inorganic acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, or combinations thereof;

[0117] The acid is preferably hydrochloric acid;

[0118] The solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, dichloromethane, or combinations thereof; preferably methanol, ethanol, isopropanol, or acetonitrile; more preferably ethanol.

[0119] Wherein, the weight parts (g) of the compound of formula III to the volume parts (mL) of the reaction solvent are 1:(1-20), preferably 1:(2-10); more preferably 1:(3-5).

[0120] The reaction temperature is -10 to 50°C, preferably 0 to 30°C, and more preferably 0 to 10°C.

[0121] Wherein, the molar ratio of the compound of formula III, the nitrite, and the acid is 1:1:(1.0 to 2.0); preferably 1:(1.0 to 1.5).

[0122] c) Compound IV undergoes a cyclization reaction with hydrazine hydrate to generate compound V:

[0123]

[0124] Wherein R is methyl or ethyl, preferably ethyl.

[0125] Specifically, the compound of formula IV is added to a solvent, followed by the addition of hydrazine hydrate for reaction. After the reaction is complete, water and solvent are added, followed by extraction and concentration to obtain the compound of formula V.

[0126] The hydrazine hydrate has a mass fraction of 10% to 85%, preferably 40% to 85%, and more preferably 60% to 85%.

[0127] The solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, dichloromethane, or combinations thereof; preferably methanol, ethanol, isopropanol, or acetonitrile; more preferably ethanol.

[0128] Wherein, the weight parts (g) of the compound of formula IV to the volume parts (mL) of the reaction solvent are 1:(1-15), preferably 1:(2-10); more preferably 1:(3-5);

[0129] The reaction temperature is -10 to 50°C, preferably 0 to 30°C, and more preferably 0 to 10°C.

[0130] Wherein, the molar ratio of the compound of formula IV to hydrazine hydrate is 1:(1.0 to 1.5); preferably 1:(1.0 to 1.2).

[0131] d) Compound V undergoes a hydrogenation-reduction reaction to produce compound I:

[0132]

[0133] Wherein R is methyl or ethyl, preferably ethyl.

[0134] In one embodiment, the compound shown in Formula V is reduced with hydrogen in the presence of a catalyst to give the compound shown in Formula I.

[0135] Specifically, the compound of formula V is added to the solvent, followed by the addition of a catalyst. After nitrogen purging, hydrogen is introduced to react. After the reaction is complete, the mixture is cooled to room temperature, and the hydrogen in the reaction system is replaced with nitrogen. The mixture is then filtered, concentrated under reduced pressure, and the solvent is added and stirred. After filtration and drying, the compound of formula I is obtained.

[0136] The catalyst is selected from one or a combination of palladium on carbon, platinum on carbon, or Raney nickel, preferably Raney nickel;

[0137] The reaction solvent is selected from one or a combination of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; preferably methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, and toluene; more preferably ethanol.

[0138] The reaction pressure is 0.1–3.0 MPa, preferably 0.1–1.0 MPa, and more preferably 0.2–0.5 MPa.

[0139] The reaction temperature is 0–80°C, preferably 10–50°C, and more preferably 20–30°C.

[0140] The ratio of the weight parts (g) of compound V to the volume parts (mL) of solvent is 1:(1-10); preferably, it is 1:(3-5).

[0141] Preferably, steps a) to d) are performed continuously between adjacent steps without purification.

[0142] An exemplary embodiment of the method for preparing sildenafil of the present invention includes the following steps:

[0143] e) The compound of formula I undergoes an acylation reaction with the compound of formula 10 to generate the compound of formula VI:

[0144]

[0145] Wherein R is methyl or ethyl, preferably ethyl.

[0146] Specifically, the compound of formula I is added to a solvent, and a base and o-ethoxybenzoyl chloride of formula 10 are added to react. After the reaction is completed, the mixture is allowed to stand, separated into layers, concentrated under reduced pressure, a solvent is added, the mixture is stirred, filtered, and dried to obtain the compound of formula VI.

[0147] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metal organic alkalis.

[0148] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine, preferably triethylamine;

[0149] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide; preferably sodium bicarbonate.

[0150] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or a combination thereof; preferably sodium acetate;

[0151] The solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, n-heptane, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, dichloromethane, or combinations thereof; preferably toluene, n-butyl acetate, 2-methyltetrahydrofuran, dichloromethane, acetonitrile, or acetonitrile; more preferably toluene or n-butyl acetate.

[0152] The reaction temperature is -10 to 50°C, preferably -5 to 30°C, and more preferably 0 to 10°C.

[0153] f) The reaction of compound VI with a methylating agent yields compound VII:

[0154]

[0155] Wherein R is methyl or ethyl, preferably ethyl.

[0156] Specifically, the compound of formula VI is added to a solvent, followed by the addition of a methylating agent to react. After the reaction is complete, the mixture is cooled, added to water, alkali is added, and the mixture is extracted, concentrated, and purified to obtain the compound of formula IV.

[0157] Compound VI was added to toluene, followed by dimethyl sulfate, and the mixture was heated to 60-80°C. After reacting for 8 hours, heating was stopped, and the mixture was cooled to room temperature. The reaction solution was then poured into water, sodium carbonate was added, and the mixture was allowed to stand. The layers separated, and the upper organic phase was separated and concentrated to obtain compound VI.

[0158] The solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, dichloromethane, or combinations thereof; preferably toluene, n-butyl acetate, 2-methyltetrahydrofuran, dichloromethane, or acetonitrile; more preferably toluene or n-butyl acetate.

[0159] The methylating agent is selected from dimethyl sulfate, methyl methanesulfonate, methyl benzenesulfonate, chloromethane, and bromomethane; preferably dimethyl sulfate.

[0160] The reaction temperature is 30–120°C, preferably 40–100°C, and more preferably 60–80°C.

[0161] Wherein, the weight parts (g) of the compound of formula VI to the volume parts (mL) of the solvent are 1:(1-20); preferably, they are 1:(3-10);

[0162] Wherein, the molar ratio of the compound of formula VI to the methylating agent is 1:(1.0 to 1.5); preferably 1:(1.0 to 1.2).

[0163] g) The compound of formula VII undergoes ammonolysis with ammonia in a solvent to produce the compound of formula 5:

[0164]

[0165] Wherein R is methyl or ethyl, preferably ethyl.

[0166] Specifically, the compound shown in Formula VII is added to a solvent, then ammonia gas or a solution of ammonia is introduced. After the reaction is complete, the mixture is concentrated under reduced pressure, the solvent is added, the mixture is stirred, filtered, and dried to obtain the compound of Formula 5.

[0167] The solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, or combinations thereof; preferably methanol, ethanol, n-propanol, 2-methyltetrahydrofuran, or acetonitrile; more preferably methanol;

[0168] The ammonia solution is selected from aqueous ammonia solution, methanol solution, and ethanol solution; preferably, it is a methanol solution of ammonia.

[0169] The reaction temperature is 30–150°C, preferably 40–120°C, and more preferably 60–100°C.

[0170] Wherein, the molar ratio of the compound of formula VII to ammonia is 1:(1.0 to 30); preferably 1:(2 to 5).

[0171] h) Compound 5 undergoes intramolecular condensation under alkaline conditions to form compound 6:

[0172]

[0173] Specifically, the compound shown in Formula 5 is added to a solvent, followed by the addition of a base to react. After the reaction is complete, the mixture is concentrated under reduced pressure, and water and hydrochloric acid are added. The mixture is then filtered and dried to obtain the compound of Formula 6.

[0174] The alkali is selected from one of inorganic alkalis, organometallic alkalis, or a combination thereof;

[0175] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide; preferably sodium hydroxide.

[0176] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or a combination thereof; preferably sodium ethoxide;

[0177] The reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, or combinations thereof; preferably methanol, ethanol, isopropanol, or acetonitrile; more preferably ethanol or isopropanol.

[0178] Wherein, the weight parts (g) of the compound of formula 5 to the volume parts (mL) of the reaction solvent are 1:(1-20), preferably 1:(2-10); more preferably 1:(3-5);

[0179] The reaction temperature is 30–100℃, preferably 60–80℃;

[0180] Wherein, the molar ratio of the compound of formula 5 to the base is 1:(1.0 to 2.0); preferably 1:(1.0 to 1.2).

[0181] i) Compound of formula 6 reacts with chlorosulfonic acid in a chlorosulfonation reaction to produce compound of formula 7:

[0182]

[0183] Specifically, the compound shown in Formula 6 was added to chlorosulfonic acid. After the reaction was complete, the mixture was poured into ice water, filtered, washed with water, and dried under reduced pressure to obtain the compound of Formula 7.

[0184] The reaction temperature is 0–100°C, preferably 20–60°C, and more preferably 30–50°C;

[0185] Wherein, the molar ratio of the compound of formula 6 to chlorosulfonic acid is 1:(1.0-30); preferably 1:(5-15).

[0186] j) The compound of formula 7 reacts with N-methylpiperazine, and then forms a salt with citric acid to generate the compound of formula 8:

[0187]

[0188] Specifically, Formula 7 and N-methylpiperazine were added to the solvent. After the reaction was complete, the mixture was filtered. The filter cake was added to ethanol, citric acid was added, the mixture was heated, cooled, filtered, washed with ethanol, and dried under reduced pressure to obtain sildenafil, the compound shown in Formula 8.

[0189] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metal organic alkalis.

[0190] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine, preferably triethylamine;

[0191] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide; preferably sodium bicarbonate.

[0192] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or a combination thereof; preferably sodium acetate;

[0193] The solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, n-heptane, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, dichloromethane, or combinations thereof; preferably toluene, n-butyl acetate, 2-methyltetrahydrofuran, dichloromethane, or acetonitrile; more preferably toluene or n-butyl acetate.

[0194] The reaction temperature is -10 to 50°C, preferably -5 to 30°C, and more preferably 0 to 10°C.

[0195] Wherein, the weight fraction (g) of the compound of formula 7 to the volume fraction (mL) of the solvent is 1:(1-20); preferably, it is 1:(3-10);

[0196] Wherein, the molar ratio of the compound of Formula 7 and N-methylpiperazine is 1:(1.0 to 1.5); preferably 1:(1.0 to 1.2).

[0197] In steps e to j, the process is carried out continuously without purification between adjacent steps.

[0198] In steps e to g, the process is carried out continuously without purification between adjacent steps.

[0199] Preferably, steps g to h can be carried out continuously without purification.

[0200] Preferably, steps g and h can be performed in a single process.

[0201] Another aspect of the present invention provides a method for preparing sildenafil, the method comprising:

[0202] k) The compound of formula I reacts with the compound of formula 13 or its salt via an acylation reaction to produce the compound of formula VIII:

[0203]

[0204] Wherein R is methyl or ethyl, preferably ethyl.

[0205] The salt of the compound of Formula 13 is preferably a hydrochloride salt.

[0206] Specifically, the compound of formula I is added to a solvent, and a base is added to react with the compound shown in formula 13. After the reaction is complete, the mixture is allowed to stand, separated into layers, concentrated under reduced pressure, a solvent is added, the mixture is stirred, filtered, and dried to obtain the compound of formula VIII.

[0207] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metal organic alkalis.

[0208] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine, preferably triethylamine;

[0209] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide; preferably sodium bicarbonate.

[0210] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or a combination thereof; preferably sodium acetate;

[0211] The solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, n-heptane, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, dichloromethane, or combinations thereof; preferably toluene, n-butyl acetate, 2-methyltetrahydrofuran, dichloromethane, acetonitrile, or acetonitrile; more preferably toluene or n-butyl acetate.

[0212] The reaction temperature is -10 to 50°C, preferably -5 to 30°C, and more preferably 0 to 10°C.

[0213] The reaction of compound VIII with a methylating agent produces compound IX:

[0214]

[0215] Wherein R is methyl or ethyl, preferably ethyl.

[0216] Specifically, the compound shown in Formula VIII is added to a solvent, followed by the addition of a methylating agent to react. After the reaction is complete, the mixture is cooled, added to water, alkali is added, and the mixture is extracted, concentrated, and purified to obtain the compound of Formula IX.

[0217] Compound VIII was added to toluene, followed by dimethyl sulfate, and the mixture was heated to 60-80°C. After reacting for 8 hours, heating was stopped, and the mixture was cooled to room temperature. The reaction solution was then poured into water, sodium carbonate was added, and the mixture was allowed to stand. The layers separated, and the upper organic phase was separated and concentrated to obtain compound IX.

[0218] The solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, dichloromethane, or combinations thereof; preferably toluene, n-butyl acetate, 2-methyltetrahydrofuran, dichloromethane, or acetonitrile; more preferably toluene or n-butyl acetate.

[0219] The methylating agent is selected from dimethyl sulfate, methyl methanesulfonate, methyl benzenesulfonate, chloromethane, and bromomethane; preferably dimethyl sulfate.

[0220] The reaction temperature is 30–120°C, preferably 40–100°C, and more preferably 60–80°C.

[0221] Wherein, the weight parts (g) of the compound of formula VIII to the volume parts (mL) of the solvent are 1:(1-20); preferably, they are 1:(3-10);

[0222] Wherein, the molar ratio of the compound of formula VIII to the methylating agent is 1:(1.0 to 1.5); preferably 1:(1.0 to 1.2).

[0223] Compound m) IX reacts with ammonia in a solvent via ammonolysis to produce compound m) IX.

[0224]

[0225] Wherein R is methyl or ethyl, preferably ethyl.

[0226] Specifically, the compound of formula IX is added to a solvent, then ammonia gas or a solution of ammonia is introduced. After the reaction is complete, the mixture is concentrated under reduced pressure, the solvent is added, the mixture is stirred, filtered, and dried to obtain the compound of formula 9.

[0227] The solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, or combinations thereof; preferably methanol, ethanol, n-propanol, 2-methyltetrahydrofuran, or acetonitrile; more preferably methanol;

[0228] The ammonia solution is selected from aqueous ammonia solution, methanol solution, and ethanol solution; preferably, it is a methanol solution of ammonia.

[0229] The reaction temperature is 30–150°C, preferably 40–120°C, and more preferably 60–100°C.

[0230] Wherein, the molar ratio of the compound of formula IX to ammonia is 1:(1.0 to 30); preferably 1:(2 to 5).

[0231] Compound n) undergoes an intramolecular condensation reaction under alkaline conditions, and then forms a salt with citric acid to generate compound n) of formula 8.

[0232]

[0233] Specifically, the compound of formula 9 and a base are added to the solvent, the reaction is heated, concentrated under reduced pressure, water and hydrochloric acid are added, and the mixture is filtered. The filter cake is added to ethanol, citric acid is added, the mixture is heated under reflux, cooled, filtered, and dried under reduced pressure to obtain sildenafil, the compound shown in formula 8.

[0234] The alkali is selected from one of inorganic alkalis, organometallic alkalis, or a combination thereof;

[0235] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide; preferably sodium hydroxide.

[0236] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or a combination thereof; preferably sodium tert-butoxide.

[0237] The solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, n-heptane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, dichloromethane, or combinations thereof; preferably methanol, tert-butanol, toluene, 2-methyltetrahydrofuran, or acetonitrile; more preferably toluene or tert-butanol.

[0238] Wherein, the weight parts (g) of the compound of Formula 9 to the volume parts (mL) of the reaction solvent are 1:(1-20), preferably 1:(2-10); more preferably 1:(3-8);

[0239] The reaction temperature is 30–100℃, preferably 60–80℃;

[0240] Wherein, the molar ratio of the compound of Formula 9 to the base is 1:(1.0 to 2.0); preferably 1:(1.0 to 1.2).

[0241] Wherein, the molar ratio of the compound of Formula 9 to citric acid is 1:(1.0 to 2.0); preferably 1:(1.0 to 1.2).

[0242] Preferably, in steps k to n, the steps are carried out continuously without purification between adjacent steps.

[0243] Preferably, steps m and n are performed consecutively without purification.

[0244] Preferably, steps m and n can be performed in a single batch.

[0245] Example

[0246] Example 1

[0247]

[0248] At 20-30°C, a 20% sodium ethoxide ethanol solution (150 g, 0.419 mol) was added dropwise to 2-pentanone (30 g, 0.349 mol) and diethyl oxalate (50.9 g, 0.349 mol). After the addition was complete, the reaction was continued at 20-30°C for 15 hours. The solution was then poured into dilute hydrochloric acid (210 mL, 2 mol / L, 0.420 mol) at 0-10°C, and dichloromethane (150 mL) was added. The mixture was stirred, allowed to stand for separation, and the lower organic phase was concentrated under reduced pressure to give compound 1 (62.3 g), with a yield of 96%. 1H NMR (400MHz, CDCl3) δ14.47(s,1H),6.34(s,1H),4.33(q,J=7.1Hz,2H),2.46(dd,J= 20.7, 13.4Hz, 2H), 1.82-1.49 (m, 2H), 1.35 (t, J = 7.1Hz, 3H), 0.95 (t, J = 7.4Hz, 3H).

[0249] Example 2

[0250]

[0251] Compound 1 (50 g, 0.269 mol) was added to ethanol (150 mL), cooled to 0-10 °C in an ice-water bath, and concentrated hydrochloric acid (27 mL, 12 mol / L, 0.322 mol) was added. At 0-10 °C, a 20% sodium nitrite aqueous solution (92.79 g, 0.269 mol) was added, and the mixture was stirred for 2 hours at the same temperature. The mixture was then poured into ice water (250 mL), and dichloromethane (250 mL) was added. The mixture was stirred, allowed to stand for separation, and the lower organic phase was concentrated under reduced pressure to obtain compound 2 (56.05 g), with a yield of 97%. 1HNMR(400MHz,DMSO)δ13.87(d,J=232.4Hz,1H),4.45-4.21(m,1H),2.76(qt, J=14.2,7.2Hz,1H),1.69-1.46(m,1H),1.32-1.18(m,1H),0.96-0.84(m,1H).

[0252] Example 3

[0253]

[0254] Compound 2 (50 g, 0.232 mol) was added to ethanol (150 mL), cooled to 0-10 °C in an ice-water bath, and 85% hydrazine hydrate (13.68 g, 0.232 mol) was added. The mixture was stirred at 0-10 °C for 2 hours, then poured into ice water (250 mL), and dichloromethane (300 mL) was added. The mixture was stirred, allowed to stand for separation, and the lower organic phase was concentrated under reduced pressure to give compound 3 (46.55 g), with a yield of 95%. ¹H NMR (400 MHz, DMSO) δ 11.62 (s, 1H), 7.70 -6.50 (s, 1H), 4.22-3.93 (m, 2H), 2.48 (d, J = 15.4 Hz, 2H), 2.32 (t, J = 7.3 Hz, 2H), 1.19-1.06 (m, 3H), 1.01-0.82 (m, 3H). ESI-MS: m / z = 212.1[M+H]+.

[0255] Example 4

[0256]

[0257] Compound 3 (40 g, 0.19 mol) was added to ethanol (200 mL) at 20-30 °C, followed by the addition of Raney nickel (4 g). The mixture was purged with nitrogen three times, then hydrogen was introduced and the pressure was maintained at 0.2-0.3 MPa. The mixture was stirred for 20 hours. After the reaction was complete, the mixture was cooled to room temperature, purged with nitrogen three times, filtered, and the filtrate was concentrated. Heptane (200 mL) was added, and the mixture was stirred for 1 hour. The mixture was then filtered and dried under reduced pressure at 45 °C for 10 hours to obtain compound 4 (35.1 g), with a yield of 94%. 1H NMR (400MHz, DMSO) δ12.53 (d, J=79.1Hz, 1H), 4.62 (s, 2H), 4.25 (q, J=7.0Hz, 2H), 2.68-2. 39(m,3H),2.63-2.36(m,3H),1.69-1.45(m,2H),1.39-1.18(m,3H),0.89(t,J=7.3Hz,3H). ESI-MS: m / z=198.19[M+H]+.

[0258] Example 5

[0259]

[0260] 2-Pentanone (60 g, 0.698 mol) and diethyl oxalate (101.8 g, 0.698 mol) were mixed thoroughly and kept at an internal temperature of 20-30°C. The mixture was then slowly added dropwise to a 20% ethanol solution (300 g, 0.838 mol) over approximately 2 hours. After the addition was complete, the mixture was stirred at 20-30°C for 15 hours. The mixture was then poured into a 2M hydrochloric acid aqueous solution (420 mL, 0.840 mol) at 0-10°C, and DCM (300 mL) was added. The mixture was stirred and extracted, allowed to stand for separation, and the lower organic phase was concentrated to dryness under reduced pressure to obtain compound 1, a pale yellow liquid (124 g), which was directly used in the next reaction.

[0261] Compound 1 (124 g, 0.67 mol) was added to an ethanol solution (500 mL), cooled to 0-10 °C in an ice-water bath, and 12 M concentrated hydrochloric acid (68 mL, 0.804 mol) was added. At 0-10 °C, 20% sodium nitrite aqueous solution (232 g, 0.67 mol) was slowly added dropwise. After the addition was complete, the mixture was stirred for 2 hours at the same temperature. After the reaction was complete, an ethanol solution of compound 2 was obtained, which was then directly used for the next reaction.

[0262] The ethanol solution of compound 2 from the previous step was cooled to 0-10°C in an ice-water bath, and 85% hydrazine hydrate (40g, 0.67mol) was slowly added dropwise. The mixture was stirred at 0-10°C for 2 hours. After the reaction was complete, activated carbon (5g) was added, and the mixture was stirred for 0.5 hours. The mixture was then filtered to obtain an ethanol solution of compound 3, which was then directly used for the next step of hydrogenation reduction reaction.

[0263] An ethanol solution of compound 3 was added to 10% Raney nickel (30 g), and hydrogenated at 20-30 °C with the internal pressure maintained at 0.2-0.3 MPa. The mixture was stirred for 20 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to a small volume. Then, n-heptane (500 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered, and the mixture was dried under reduced pressure at 45 °C for 10 hours to obtain a white solid compound 4 (100.4 g, total yield of 4 steps: 73%). 1H NMR (400MHz, DMSO) δ12.53 (d, J=79.1Hz, 1H), 4.62 (s, 2H), 4.25 (q, J=7.0Hz, 2H), 2.68-2. 39(m,3H),2.63-2.36(m,3H),1.69-1.45(m,2H),1.39-1.18(m,3H),0.89(t,J=7.3Hz,3H). ESI-MS: m / z=198.19[M+H]+.

[0264] Example 6

[0265]

[0266] Compound 4 (20 g, 0.101 mol) was added to ethyl acetate (100 mL), followed by water (50 mL). The mixture was cooled to 0-10 °C, and sodium carbonate (5.4 g, 0.051 mol) was added. Compound 10 (18.64 g, 0.101 mol) was then added at 0-10 °C, and the mixture was stirred for 1 hour. The temperature was then raised to 20-30 °C, allowed to stand, and the mixture was allowed to separate into layers. The upper organic phase was separated, concentrated, and n-heptane (100 mL) was added. The mixture was stirred for 1 hour, filtered, and dried under reduced pressure at 45 °C for 10 hours to obtain compound 11 (33.3 g), with a yield of 95%. 1HNMR (400MHz, DMSO) δ13.40 (d, J = 121.4Hz, 1H), 9.76 (d, J = 53.9Hz, 1H), 7.96-7.78 (m, 1H), 7.65-7.40 (m, 1H), 7.37-7.00 (m, 1H), 4. 26(dd,J=9.1,7.2Hz,2H),2.91-2.42(m,1H),1.67-1.53(m,1H),1.43(t,J=6.9Hz,1H),1.23(t,J=7.1Hz,2H),0.86(t,J=7.3Hz,1H). ESI-MS: m / z=344.33[M+H]-.

[0267] Example 7

[0268]

[0269] Compound 11 (30 g, 0.087 mol) was added to toluene (150 mL), followed by dimethyl sulfate (10.94 g, 0.087 mol), and the mixture was heated to 60-80 °C. After reacting for 8 hours, heating was stopped, and the mixture was cooled to room temperature. The reaction solution was then poured into water (150 mL), sodium carbonate (4.61 g, 0.044 mol) was added, and the mixture was allowed to stand. The layers separated, and the upper organic phase was separated and concentrated to give compound 12 (30.3 g), with a yield of 97%. 1H NMR (400MHz, DMSO) δ9.89-9.62(m,1H),7.87(dt,J=40.3,20.2Hz,1H),7.65-7.40(m,1H),7.33-7.14(m,3H),7.28-6.98(m,1H),4.57- 4.10 (m, 4H), 2.64 (t, J = 7.6Hz, 2H), 1.59 (dd, J = 15.0, 7.5Hz, 2H), 1.43 (t, J = 6.9Hz, 3H), 1.23 (t, J = 7.1Hz, 3H), 0.86 (t, J = 7.4Hz, 3H). ESI-MS: m / z=360.22[M+H]+.

[0270] Example 8

[0271]

[0272] Compound 12 (20 g, 0.0556 mol) and 20% NH3 / / MeOH (50 mL) were added sequentially to a high-pressure reactor, heated to 100 °C, and reacted for 10 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and methyl tert-butyl ether (100 mL) was added. The mixture was stirred for 1 hour, cooled to 0-10 °C, filtered, and concentrated under reduced pressure to obtain compound 5 (17.3 g), with a yield of 94%. 1HNMR(400MHz,DMSO)δ9.48(s,1H),7.83-7.69(m,1H),7.69-7.58(m,1H), 7.56-7.43(m,1H),7.37(s,1H),7.19(t,J=8.2Hz,1H),7.05(td,J=7.5,0. 7Hz,1H),4.37-4.08(m,1H),2.56-2.48(m,1H),2.48(ddd,J=24.4,9.4,4. 8Hz, 1H), 1.71-1.45 (m, 1H), 1.39 (t, J = 7.0Hz, 1H), 0.89 (t, J = 7.4Hz, 1H). ESI-MS: m / z=330.37[M+H]+.

[0273] Example 9

[0274]

[0275] Compound 4 (40 g, 0.202 mol) was added to ethyl acetate (200 mL), followed by water (100 mL). The mixture was cooled to 0-10 °C, and sodium carbonate (10.8 g, 0.202 mol) was added. Compound 10 (37.28 g, 0.202 mol) was slowly added dropwise at 0-10 °C over approximately 0.5 hours. After the addition was complete, the mixture was stirred for 1 hour, and the internal temperature was raised to 20-30 °C. The mixture was allowed to stand and separate into layers. The upper organic phase was separated and concentrated to dryness to obtain compound 11, which was then directly used for the next reaction.

[0276] Add compound 11 to toluene (300 mL), then slowly add dimethyl sulfate (25.4 g, 0.202 mol), raise the internal temperature to 60-80 °C, and react for 5-8 hours. After the reaction is complete, stop heating, cool to room temperature, pour into water (300 mL), add sodium carbonate (10.8 g, 0.102 mol), adjust the pH to about 7, let stand to separate the layers, separate the upper organic phase, concentrate to a small volume, and obtain an oily compound 12, which can be directly used in the next reaction.

[0277] The oily substance of compound 12 and 20% NH3 / MeOH (150 mL) were added sequentially to a high-pressure reactor, heated to 100 °C, with an internal pressure of about 1.5 MPa, and reacted for 10 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to a small volume. Methyl tert-butyl ether (300 mL) was added and the mixture was stirred at room temperature for 1 hour. The mixture was then cooled to 0-10 °C, filtered, and concentrated to dryness under reduced pressure at 50 °C to obtain compound 5 (58.2 g, total yield of 3 steps: 87%). 1H NMR(400MHz,DMSO)δ9.48(s,1H),7.83-7.69(m,1H),7.69-7.58(m,1H),7 .56-7.43(m,1H),7.37(s,1H),7.19(t,J=8.2Hz,1H),7.05(td,J=7.5,0.7 Hz,1H),4.37-4.08(m,1H),2.56-2.48(m,1H),2.48(ddd,J=24.4,9.4,4. 8Hz, 1H), 1.71-1.45 (m, 1H), 1.39 (t, J = 7.0Hz, 1H), 0.89 (t, J = 7.4Hz, 1H). ESI-MS: m / z=330.37[M+H]+.

[0278] Example 10

[0279]

[0280] Compound 5 (100 g, 0.303 mol) was added to anhydrous ethanol (500 mL), sodium hydroxide (12.1 g, 0.303 mol) was added, and the mixture was heated under reflux for 12 hours. After the reaction was complete, the ethanol was recovered by concentration under reduced pressure, water (500 mL) was added, the temperature was controlled below 20 °C, concentrated hydrochloric acid (25.3 mL, 12 mol / L, 0.303 mol) was added, the mixture was filtered, and dried under reduced pressure to obtain compound 6 (88.9 g), with a yield of 94%. 1HNMR (400MHz, DMSO) δ11.94(s,1H),7.67(dd,J=7.6,1.6Hz,1H),7.55-7.39(m,1H),7.14(d,J=8.3Hz,1H),7.06(t,J= 7.4Hz,1H),4.48-3.83(m,4H),2.77(t,J=7.5Hz,2H),1.83-1.67(m,2H),1.34(t,J=6.9Hz,3H),0.94(t,J=7.4Hz,3H). ESI-MS: m / z=313.4[M+H]+.

[0281] Example 11

[0282]

[0283] Compound 12 (10 g, 0.0278 mol) and 20% NH3 / MeOH (30 mL) were added sequentially to a high-pressure reactor, heated to 80 °C, and reacted for 12 hours. After cooling to room temperature, sodium hydroxide (1.1 g, 0.0278 mol) was added, and the mixture was heated under reflux for 10 hours. After the reaction was complete, methanol was recovered by vacuum concentration, water (200 mL) was added, the temperature was controlled below 20 °C, hydrochloric acid was added, the mixture was filtered, and dried under vacuum to obtain compound 6 (8 g), with a yield of 92%.

[0284] In other words, Examples 8 and 10 can be carried out using a one-pot method.

[0285] Example 12

[0286]

[0287] Chlorosulfonic acid (371 g, 3.2 mol) was added to a three-necked flask equipped with a thermometer and a mechanical stirrer. The mixture was cooled to 0-10 °C, and compound 6 (100 g, 0.320 mol) was added in portions. After the addition was complete, the reaction mixture was kept at 30-35 °C for 6 hours. The reaction solution was slowly added to ice water (900 g), and a solid precipitated. The solid was filtered, washed with water, and dried under reduced pressure at 45 °C for 10 hours to obtain compound 7 (118.4 g), with a yield of 90%. 1H NMR (400MHz, CDCl3) δ10.79(s,1H),9.12(d,J=2.6Hz,1H),8.13(dd,J=8.9,2.6Hz,1H),7.46-6.94(m,1H),7.55-7 .04(m,1H),4.45(q,J=7.0Hz,1H),3.22-2.80(m,1H),2.14-1.76(m,1H),1.69(t,J=7.0Hz,1H),1.32-0.84(m,1H). ESI-MS: m / z=411.25[M+H] + .

[0288] Example 13

[0289]

[0290] Compound 7 (50 g, 0.122 mol) was added to dichloromethane (250 mL), cooled to 0-10 °C, and water (250 mL) and sodium bicarbonate (10.25 g, 0.122 mol) were added. N-methylpiperazine (12.2 g, 0.122 mol) was added at 0-10 °C, and the reaction was continued for 2 hours. The mixture was concentrated under reduced pressure, and the precipitated solid was filtered. The filter cake was added to ethanol (500 mL), heated to reflux, and citric acid (21.5 g, 0.112 mol) was added. Reflux was continued for 1 hour, heating was stopped, and the mixture was cooled to 0-10 °C. The mixture was filtered, and the solid was washed with ethanol and dried under reduced pressure at 60 °C to give sildenafil 8 (67.0 g), with a yield of 93%. 1H NMR (400MHz, DMSO) δ12.25 (s, 1H), 8.02-7.70 (m, 2H), 7.39 (d, J = 8.9Hz, 1H), 4 .74-3.89(m,5H),2.97(s,3H),2.78(t,J=7.5Hz,2H),2.74(s,1H),2.70(s,1H) ,2.64(s,1H),2.61(s,1H),2.56(s,3H),2.51(dt,J=3.5,1.7Hz,4H),2.28(s,3 H), 1.74 (dd, J = 14.9, 7.4Hz, 2H), 1.34 (t, J = 6.9Hz, 3H), 0.94 (t, J = 7.4Hz, 3H).

[0291] Example 14

[0292]

[0293] Compound 4 (20 g, 0.101 mol) was added to ethyl acetate (100 mL), followed by water (100 mL). The mixture was cooled to 0-10 °C, and sodium carbonate (5.4 g, 0.051 mol) was added. Compound 13 (35.03 g, 0.101 mol) was dissolved in ethyl acetate (50 mL) at 0-10 °C, and then slowly added dropwise over approximately 0.5 hours. After the addition was complete, stirring was continued for 1 hour. The mixture was filtered, and the solid was dried under reduced pressure at 45 °C for 10 hours to obtain compound 14 (47.7 g), with a yield of 93%.

[0294] Example 15

[0295]

[0296] Compound 14 (30 g, 59.1 mmol) and dimethyl sulfate (7.45 g, 59.1 mol) were added to toluene (150 mL), and the mixture was heated to 60-80 °C and reacted for 5-8 hours. After the reaction was complete, heating was stopped, and the mixture was cooled to room temperature. Water (100 mL) was added, followed by sodium carbonate (4.61 g, 0.044 mol). The mixture was filtered, dried under reduced pressure at 50 °C, and compound 15 (18.5 g) was obtained, with a yield of 90%.

[0297] Example 16

[0298]

[0299] Compound 15 (20 g, 38.3 mol) and 20% NH3 / MeOH (80 mL) were added sequentially to a high-pressure reactor, heated to 100 °C, and reacted for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and methyl tert-butyl ether (100 mL) was added. The mixture was stirred at room temperature for 1 hour, cooled to 0-10 °C, filtered, and concentrated under reduced pressure at 50 °C to obtain compound 9 (17.9 g), with a yield of 95%. 1H NMR (300MHz, CDCl3) δ9.27(s,1H),8.63(d,J=1.7Hz,1H),7.91(dd,J=8.7,1.8Hz,1H),7.67(s,1H),7.17(d,J=8.8Hz,1H),4.39(q, J=7.0Hz,2H),4.16-3.87(m,3H),3.07(s,4H),2.65-2.38(m,5H),2.28(s,3H),1.62(dt,J=23.0,7.1Hz,6H),0.95(t,J=7.3Hz,3H).

[0300] Example 17

[0301]

[0302] Compound 9 (40 g, 81.2 mmol) was added to anhydrous ethanol (300 mL), sodium hydroxide (3.24 g, 81.2 mmol) was added, and the mixture was heated under reflux for 12 hours. After the reaction was complete, the ethanol was recovered by concentration under reduced pressure, water (200 mL) was added, and concentrated hydrochloric acid (6.8 mL, 12 mol / L, 81.2 mol) was added below 20 °C. The mixture was filtered, washed with water, and the filter cake was added to ethanol (360 mL). The mixture was heated, citric acid (14.8 g, 77.1 mmol) was added, and the mixture was refluxed for another hour. Heating was stopped, the mixture was cooled to 0-10 °C, centrifuged, filtered, washed with ethanol, and dried under reduced pressure at 60 °C to obtain sildenafil compound 8 (47.8 g, 93% yield). 1H NMR (400MHz, DMSO) δ12.25 (s, 1H), 8.02-7.70 (m, 2H), 7.39 (d, J = 8.9Hz, 1H), 4 .74-3.89(m,5H),2.97(s,3H),2.78(t,J=7.5Hz,2H),2.74(s,1H),2.70(s,1H) ,2.64(s,1H),2.61(s,1H),2.56(s,3H),2.51(dt,J=3.5,1.7Hz,4H),2.28(s,3 H), 1.74 (dd, J = 14.9, 7.4Hz, 2H), 1.34 (t, J = 6.9Hz, 3H), 0.94 (t, J = 7.4Hz, 3H).

[0303] Example 18

[0304]

[0305] Compound 15 (30 g, 0.0575 mol) and 20% NH3 / MeOH (40 mL) were added sequentially to a high-pressure reactor, heated to 90 °C, and reacted for 10 hours. After cooling to room temperature, sodium hydroxide (2.3 g, 0.0575 mol) was added, and the mixture was heated under reflux for 9 hours. After the reaction was complete, methanol was recovered by vacuum concentration, water (200 mL) was added, the temperature was controlled below 20 °C, hydrochloric acid was added, and the mixture was filtered. The filter cake was added to ethanol (500 mL), heated, and citric acid (12.1 g, 0.0632 mol) was added. The mixture was refluxed for another hour, heating was stopped, and the temperature was lowered to 0-10 °C. The mixture was centrifuged, filtered, washed with ethanol, and dried under vacuum at 60 °C to obtain sildenafil compound 8 (34.9 g, 91% yield).

[0306] In other words, Examples 16 and 17 can be carried out using a one-pot method.

Claims

1. A method for preparing sildenafil, a compound of formula 8, characterized in that... Includes the following steps: e) The compound of formula I undergoes an acylation reaction with the compound of formula 10 to generate the compound of formula VI: In compounds of formula I and formula VI, R is methyl or ethyl; f) The reaction of compound VI with a methylating agent yields compound VII: In compounds of formulas VI and VII, R is methyl or ethyl; The methylating agent is selected from dimethyl sulfate, methyl methanesulfonate, methyl benzenesulfonate, chloromethane, iodomethane, and bromomethane. g) The compound of formula VII undergoes ammonolysis with ammonia in a solvent to produce the compound of formula 5: In compounds of formula VII, R is methyl or ethyl; The solvent is selected from methanol, ethanol, isopropanol, or combinations thereof. h) Compound 5 undergoes intramolecular condensation under alkaline conditions to form compound 6: ， i) Compound of formula 6 reacts with chlorosulfonic acid in a chlorosulfonation reaction to produce compound of formula 7: ， j) The compound of formula 7 reacts with N-methylpiperazine, and then forms a salt with citric acid to generate the compound of formula 8: 。 2. The method according to claim 1, wherein, In step e), R is an ethyl group in compounds of formulas I and VI; In step f), in compounds of formula VI and formula VII, R is ethyl; The methylating agent is dimethyl sulfate; In step g), in the compound of formula VII, R is ethyl.

3. The method according to claim 1, further comprising the following steps: d) Compound V undergoes a hydrogenation-reduction reaction to produce compound I: In compounds of formula V and formula I, R is methyl or ethyl.

4. The method according to claim 3, further comprising the following steps: c) Compound IV undergoes a cyclization reaction with hydrazine hydrate to generate compound V: In compounds of formula IV and V, R is methyl or ethyl.

5. The method according to claim 4, further comprising the following steps: b) Compound III reacts with nitrite and acid to produce compound IV: Wherein, the nitrite is sodium nitrite, and the acid is hydrochloric acid. In compounds of formula III and IV, R is methyl or ethyl.

6. The method of claim 5, further comprising the following steps: a) 2-Pentanone undergoes a condensation reaction with compound II to generate compound III: In compounds of formula II and III, R is methyl or ethyl.

7. The method according to claim 6, wherein, In steps a) to d), the process is carried out continuously without purification between adjacent steps.

8. The method according to any one of claims 1-7, wherein, In steps e) to j), the process is carried out continuously without purification between adjacent steps.

9. A method for preparing sildenafil, a compound of formula 8, characterized in that... Includes the following steps: k) The acylation reaction of compound I with compound 13 or its salt produces compound VIII: In compounds of formula I and VIII, R is methyl or ethyl; The salt of compound 13 is a hydrochloride salt. l) The reaction of compound VIII with a methylating agent yields compound IX: In compounds of formula VIII and formula IX, R is methyl or ethyl; The methylating agent is selected from dimethyl sulfate, methyl methanesulfonate, methyl benzenesulfonate, chloromethane, iodomethane, and bromomethane; Compound m) IX reacts with ammonia in a solvent via ammonolysis to produce compound 9: In compounds of formula IX, R is methyl or ethyl; The solvent is selected from methanol, ethanol, isopropanol, or combinations thereof. Compound n) under alkaline conditions undergoes an intramolecular condensation reaction, and then forms a salt with citric acid to generate compound n) of formula 8. 。 10. The method according to claim 9, wherein, In step k), In compounds of formula I and VIII, R is ethyl; In step l), In compounds of formula VIII and formula IX, R is ethyl; The methylating agent is dimethyl sulfate; In step m), In compounds of formula IX, R is ethyl.

11. The method according to claim 9 or 10, wherein, In steps k) to n), the process is carried out continuously without purification between adjacent steps.

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