CN114085225A - Vardenafil analogue and synthetic method and application thereof - Google Patents
Vardenafil analogue and synthetic method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention belongs to the technical field of drug synthesis, and particularly discloses a vardenafil analog which has the characteristics of determined structure and high chemical purity, can be used as an impurity reference substance for developing and verifying an analysis method of vardenafil hydrochloride, detecting related substances and doping experiments, can also be used for controlling the quality of vardenafil intermediates, bulk drugs and preparations, and is a necessary product for controlling the quality of vardenafil hydrochloride bulk drugs and preparations. Furthermore, the vardenafil analogue disclosed by the invention has a structure similar to that of vardenafil hydrochloride, is presumed to have the effect of inhibiting phosphodiesterase type 5 (PDE5), and can be used for treating male penile Erectile Dysfunction (ED), pulmonary hypertension, heart failure and other diseases.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to vardenafil analogue and a synthesis method and application thereof.
Background
Vardenafil Hydrochloride, namely Vardenafil Hydrochorride in English, Levitra in Chinese, is an inhibitor of phosphodiesterase type 5 (PDE5), is mainly used for treating male penile Erectile Dysfunction (ED), and is one of the mainstream medicaments for treating ED at present. Vardenafil hydrochloride was developed by Bayer (Bayer) corporation and was released to the market in the european union and united states in 2003 and subsequently in several countries and regions in japan, china, russia, australia, etc. The mesocultural name of the vardenafil hydrochloride is 2- [ 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -5-methyl-7-propyl-3H-imidazo [5,1-f ] [1,2,4] triazin-4-one, and the hydrochloride trihydrate has a structural formula shown in formula III. At present, the marketed specification of the vardenafil hydrochloride tablet is 5mg, 10mg and 20mg, and the specification of 2.5mg is removed.
Patent CN201810868946.8 discloses 4 vardenafil hydrochloride related substances, namely related substance a, related substance B, related substance C and related substance D, and discloses a synthetic route of the above 4 related substances. The discovery of the 4 related substances has important significance for establishing the quality standard of the vardenafil hydrochloride and effectively controlling the quality of vardenafil hydrochloride intermediates, bulk drugs and preparation drugs.
On the other hand, according to the reports of the patents and pharmacopoeias which have been published so far, there are 9 vardenafil-related substances, which are shown in the following table:
however, when studying the preparation process of vardenafil hydrochloride, the inventors found that the reaction product contains vardenafil hydrochloride and the above 9 impurities, and also contains an organic impurity. The discovery of the organic impurities has great significance, but no relevant report is available at present.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a vardenafil analogue which can provide a basis for effectively controlling the quality of vardenafil hydrochloride intermediates, bulk drugs and preparations.
The second purpose of the invention is to provide a synthetic method of vardenafil analogue, which has simple circuit and mild reaction conditions.
The vardenafil analogue is applied to the medicine for treating male penis erection dysfunction.
The fourth purpose of the invention is to provide a medicine for treating male penile erectile dysfunction.
One of the purposes of the invention is realized by adopting the following technical scheme:
a vardenafil analog having the formula shown in formula I:
in the formula I, R1Is hydroxyl, ethoxy,
R2Is hydroxy or ethoxy;
R3hydrogen, straight-chain alkane of C1-C6, branched-chain alkane of C1-C6, straight-chain alkene of C1-C6 or branched-chain alkene of C1-C6;
R4is straight-chain alkane of C1-C6, branched-chain alkane of C1-C6, straight-chain alkene of C1-C6 or branched-chain alkene of C1-C6.
Further, in the formula I, R1Is composed of
R2Is hydroxy or ethoxy;
R3is hydrogen;
R4is methyl or ethyl.
Further, the vardenafil analogue has a structural formula shown in formulas II to IX:
the second purpose of the invention is realized by adopting the following technical scheme:
a method for synthesizing vardenafil analogs, comprising the steps of: dissolving vardenafil and/or vardenafil homolog in a chlorinating reagent, adding sulfuryl chloride and a catalyst, and reacting under the protection of nitrogen to obtain the vardenafil and/or vardenafil homolog.
Further, the chlorinating agent is one or any combination of thionyl chloride, oxalyl chloride, phosphorus oxychloride, a chlorine solution and an N-chlorosuccinimide solution; the catalyst is one or any combination of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
Further, the chlorinating agent is thionyl chloride, and the dosage of the thionyl chloride is 5-15 times of the volume of vardenafil or vardenafil homolog; the catalyst is N, N-dimethylformamide, and the dosage of the catalyst is 0.1-3.0 times of the dosage of vardenafil.
Further comprises an evaporation step, after the reaction under the protection of nitrogen, inert solvent is added for dilution, and then the mixture is dried in a spinning mode to obtain sticky substances.
Further, the inert solvent is one or any combination of dichloromethane, chloroform, n-heptane, n-hexane, ethyl acetate, isopropyl acetate, methyl formate, ethyl formate, methyl tert-butyl ether, diethyl ether, isopropyl ether, diphenyl ether, toluene, chlorobenzene, xylene, acetone and methyl ethyl ketone.
Further, after obtaining the sticky substance, the method also comprises a purification step; or after the sticky substance is obtained, a purification step and a recrystallization step are also included; or after obtaining the sticky substance, further comprising a purification step, a recrystallization step and a drying step.
The third purpose of the invention is realized by adopting the following technical scheme:
the vardenafil analogue is used as an impurity reference substance in the development and verification of an analysis method of vardenafil, the detection of related substances, doping experiments, vardenafil intermediates, bulk drugs and the application of quality control of preparations.
The vardenafil analogue, the prodrug thereof or the pharmaceutically acceptable salt thereof can be applied to medicaments for treating male penile erectile dysfunction, medicaments for treating pulmonary hypertension and medicaments for treating heart failure.
The fourth purpose of the invention is realized by adopting the following technical scheme:
the drug for treating male penile erectile dysfunction comprises the vardenafil analogue, the prodrug thereof or the pharmaceutically acceptable salt thereof as an active ingredient.
The active ingredient of the medicine for treating pulmonary hypertension is the vardenafil analogue, the prodrug thereof or the pharmaceutically acceptable salt thereof.
The vardenafil analogue, the prodrug thereof or the pharmaceutically acceptable salt thereof serves as an active ingredient of the drug for treating heart failure.
Compared with the prior art, the invention has the beneficial effects that:
(1) the vardenafil analog provided by the invention is a brand-new vardenafil hydrochloride analog, and can provide a basis for effectively controlling the quality of vardenafil hydrochloride intermediates, raw material medicines and preparations. The vardenafil analogue is prepared and separated by the inventor and then subjected to structure confirmation, and the structure of the vardenafil analogue is similar to vardenafil hydrochloride, so that the vardenafil analogue is presumed to have the effect of inhibiting phosphodiesterase type 5 (PDE5) and can be used for treating male penile Erectile Dysfunction (ED).
(2) The synthetic method of the vardenafil analogue provided by the invention has the advantages of simple synthetic route and mild reaction conditions.
Detailed Description
The present invention is further described below with reference to specific embodiments, and it should be noted that, without conflict, any combination between the embodiments or technical features described below may form a new embodiment. The raw materials, equipments and the like used in the following examples are available by purchase unless otherwise specified.
A vardenafil analog having the formula shown in formula I:
in the formula I, R1Is hydroxyl, ethoxy,
R2Is hydroxy or ethoxy;
R3hydrogen, straight-chain alkane of C1-C6, branched-chain alkane of C1-C6, straight-chain alkene of C1-C6 or branched-chain alkene of C1-C6;
R4is straight-chain alkane of C1-C6, branched-chain alkane of C1-C6, straight-chain alkene of C1-C6 or branched-chain alkene of C1-C6.
As a more preferred embodiment, R1Is composed of
R2Is hydroxy or ethoxy; r3Is hydrogen; r4Is methyl or ethyl.
Further, the vardenafil analogue has a structural formula shown in a formula II, the name of a compound shown in the formula II is 2- { 2-ethoxy-5- [ (4-ethylpiperazin-1-yl) sulfonyl ] phenyl } -7- (1-hydroxypropyl) -5-methylimidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one, and the analogue is represented by the code 'analogue CJ 001'.
In a preferred embodiment, the vardenafil analog has a structural formula as shown in formulas II to IX:
as a further implementationIn one aspect, the method of synthesizing the vardenafil analog comprises the steps of: dissolving vardenafil or vardenafil homologue in chlorinating reagent, adding sulfuryl chloride (SO)2Cl2) And reacting with a catalyst under the protection of nitrogen to obtain the catalyst. Preferably, the mixture is stirred for 8 to 15 hours at room temperature under the protection of nitrogen, and the mixture can be stirred overnight due to relatively long reaction time.
As a further embodiment, the chlorinating agent is one or any combination of thionyl chloride, oxalyl chloride, phosphorus oxychloride, chlorine solution and N-chlorosuccinimide solution; more preferably thionyl chloride (SOCl)2). The dosage of the chlorinating agent is preferably 5-15 times of the volume of vardenafil or vardenafil homolog, and more preferably 10 times of the volume of the vardenafil or vardenafil homolog.
As a further embodiment, the catalyst is one or any combination of N, N-Dimethylformamide (DMF), N-dimethylacetamide and N-methylpyrrolidone, more preferably N, N-Dimethylformamide (DMF). The amount of the catalyst is 0.1 to 3.0 times equivalent of the amount of vardenafil, and more preferably 0.3 to 1 time equivalent.
As a further embodiment, the method also comprises an evaporation step, and after the reaction under the protection of nitrogen, an inert solvent is added for dilution, and then the mixture is dried in a spinning mode to obtain a sticky substance. The evaporation step is preferably repeated twice, i.e. the reaction process is as follows: dissolving vardenafil in chlorinating reagent, adding sulfuryl chloride (SO)2Cl2) And a catalyst, stirring and reacting for 8-15 hours at room temperature under the protection of nitrogen; and then, adding an inert solvent for dilution, then spin-drying again, and repeating the operations of adding the inert solvent for dilution and spin-drying to obtain the sticky substance.
As a further embodiment, the inert solvent is one or any combination of dichloromethane, chloroform, n-heptane, n-hexane, ethyl acetate, isopropyl acetate, methyl formate, ethyl formate, methyl tert-butyl ether, diethyl ether, isopropyl ether, diphenyl ether, toluene, chlorobenzene, xylene, acetone, and methyl ethyl ketone. More preferably, the inert solvent is a mixture of dichloromethane and methyl tert-butyl ether.
As a further embodiment, after obtaining the sticky substance, the sticky substance further comprises a purification step, a recrystallization step and a drying step, and the operation process is as follows: and purifying the sticky substance by column chromatography to obtain a crude product A, and purifying the crude product A by Pre-HPLC to obtain a crude product B. And then adding the crude product B into an organic solvent and water, stirring, filtering to obtain a yellow solid C, adding the yellow solid C into alcohol, heating and stirring until the yellow solid C is completely dissolved, stirring until the temperature is reduced to room temperature, filtering, and drying a product to obtain the vardenafil analogue (the compound shown in the formula I comprises one or more compounds shown in the formulae II-IX).
As a further embodiment, the organic solvent for dissolving crude product B is one or any combination of acetone, methyl ethyl ketone, acetonitrile, methanol, ethanol and isopropanol, more preferably acetone. The volume ratio of the organic solvent to water when dissolving crude product B is (1:1) - (1:5), more preferably 1: 2.5.
As a further embodiment, the crude product B is added into an organic solvent and water and stirred for 1-3 hours, filtering is carried out to obtain a yellow solid C, the yellow solid C is added into alcohol, the temperature is raised to 40-70 ℃, stirring is carried out for 0.5-2 hours until the yellow solid C is completely dissolved, stirring is carried out until the temperature is reduced to the room temperature, stirring is carried out for 0.5-2 hours, and then filtering is carried out.
As a further embodiment, in the recrystallization step, the alcoholic solvent used for recrystallizing the yellow solid C is one or any combination of methanol, ethanol and isopropanol, and more preferably ethanol. The usage amount of the alcohol solvent is 2-10 times of the volume of the yellow solid C, preferably 6 times of the volume and 8 times of the volume.
As a further embodiment, the product is dried by blowing at a temperature of 40-60 deg.C, preferably at a temperature of 40 deg.C, 45 deg.C, 50 deg.C, 52 deg.C, 55 deg.C, 60 deg.C.
The vardenafil analogue (comprising compounds shown in formulas I, II, III, IV, V, VI, VII, VIII and IX) provided by the embodiment of the invention has the characteristics of determined structure and high chemical purity, can be used as an impurity reference substance for developing and verifying an analysis method of vardenafil hydrochloride, detecting related substances and doping experiments, can also be used for controlling the quality of vardenafil hydrochloride intermediates, bulk drugs and preparations, and is a necessary product for controlling the quality of vardenafil hydrochloride bulk drugs and preparations.
The vardenafil analogue (comprising compounds shown in formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII and formula IX) provided by the embodiment of the invention has a structure similar to vardenafil hydrochloride, has the function of inhibiting phosphodiesterase type 5 (PDE5), and can be used for treating male penis Erection Dysfunction (ED) and treating diseases such as pulmonary hypertension, heart failure and the like.
The vardenafil analogue (including compounds shown in formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII and formula IX) provided by the embodiment of the invention, a prodrug thereof or a pharmaceutically acceptable salt thereof can be used for preparing a medicament for treating male penile erection dysfunction, or preparing a medicament for treating pulmonary hypertension or preparing a medicament for treating heart failure.
Example 1
A synthetic method of vardenafil analogue CJ001 (a compound shown in a formula II) is shown in a reaction formula I, and comprises the following steps:
vardenafil (80g,163.73mmol,1eq) was dissolved in SOCl2(800mL), SO was added2Cl2(44.20g,327.46mmol,32.74mL,2.0eq) and DMF (5.98g,81.86mmol,0.5 eq), N2Stirring was carried out overnight at room temperature under protection. The reaction was concentrated, diluted with dichloromethane DCM (500mL) and methyl tert-butyl ether TBME (500mL) and re-spun dry twice to give a pale red sticky mass. Purifying the sticky substance by column chromatography to obtain a crude product A. The crude product A is purified by Pre-HPLC to obtain crude product B. Crude B was added to acetone (20mL) and water (50mL) and stirred for 2 h, and filtered to give C as a yellow solid. Adding the yellow solid C into 6 times of ethanol, heating to 50 ℃, stirring for 1 hour, and completely dissolving. Naturally cooling to room temperature under stirring, continuously stirring for 1 hour, filtering, and drying at 40 ℃ to obtain a white solid, namely the vardenafil hydrochloride analogue CJ 001.
The reaction product obtained in example 1 was confirmed by nuclear magnetic hydrogen spectroscopy for its structure, and the results were as follows:1H NMR(400MHz,DMSO-d6)δ11.73(br s,1H),7.93-7.77(m,2H),7.38(d,J＝ 8.6Hz,1H),5.33(d,J＝6.0Hz,1H),4.83(q,J＝6.6Hz,1H),4.20(q,J＝6.8Hz, 2H),2.88(br s,4H),2.48(br s,3H),2.39(br s,4H),2.28(q,J＝7.1Hz,2H),1.87 (quin,J＝7.2Hz,2H),1.31(t,J＝6.9Hz,3H),0.91(t,J＝7.2Hz,3H),0.83(t,J＝ 7.4Hz,3H)。
the nuclear magnetic hydrogen spectrum results show that the synthetic method of example 1 obtains the vardenafil hydrochloride analog CJ001 shown in the formula II.
Example 2
A synthetic method of a vardenafil analogue CJ001 (a compound shown in a formula II) comprises the following steps:
vardenafil (80g,163.73mmol,1eq) was dissolved in SOCl2(800mL), SO was added2Cl2(44.20g,327.46mmol,32.74mL,2.0eq) and DMF (11.96g,163.72mmol,1.0eq), N2Stirring was carried out overnight at room temperature under protection. The reaction was concentrated, diluted with DCM (500mL) and TBME (500mL) and spin dried again twice to give a pale red viscous mass. Purifying the sticky substance by column chromatography to obtain a crude product A. The crude product A is purified by Pre-HPLC to obtain crude product B. Crude B was added to acetone (40mL) and water (100mL)) and stirred for 2 hours and filtered to give C as a yellow solid. Adding the yellow solid C into 6 times of ethanol, heating to 50 ℃, stirring for 1 hour, and completely dissolving. And naturally cooling to room temperature under stirring, continuously stirring for 1 hour, filtering, and drying at 40 ℃ to obtain a white solid, namely the vardenafil hydrochloride analogue CJ 001.
Example 3
A synthetic method of a vardenafil analogue CJ001 (a compound shown in a formula II) comprises the following steps:
vardenafil (400g,0.82mol,1eq) was dissolved in SOCl2(4L) and SO was added2Cl2(221 g,1.64mol) and DMF (60g), N2Stirring was carried out overnight at room temperature under protection. The reaction was concentrated, diluted with DCM (2.5L) and TBME (2.5L) and re-spun dry for two more timesThen, a pale red sticky substance is obtained. Purifying the sticky substance by column chromatography to obtain a crude product A. The crude product A is purified by Pre-HPLC to obtain crude product B. Crude B was added to acetone (100mL) and water (250mL), stirred for 2 hours, and filtered to give C as a yellow solid. Adding the yellow solid C into 8 times of ethanol, heating to 50 ℃, stirring for 1 hour, and completely dissolving. And naturally cooling to room temperature under stirring, continuously stirring for 1 hour, filtering, and drying at 40 ℃ to obtain a white solid, namely the vardenafil hydrochloride analogue CJ 001.
Example 4
A method for synthesizing vardenafil analogue (compound shown in formula III) comprises the following steps:
5-Ethyl vardenafil (82.3g,163.73mmol,1eq) was dissolved in SOCl2(800mL), SO was added2Cl2(44.20g,327.46mmol,32.74mL,2.0eq) and DMF (11.96g,163.72mmol,1.0eq), N2Stirring was carried out overnight at room temperature under protection. The reaction was concentrated, diluted with DCM (500mL) and TBME (500mL) and spin dried again twice to give a pale red viscous mass. Purifying the sticky substance by column chromatography to obtain a crude product A. The crude product A is purified by Pre-HPLC to obtain crude product B. Crude B was added to acetone (40mL) and water (100mL)) and stirred for 2 hours and filtered to give C as a yellow solid. Adding the yellow solid C into 6 times of ethanol, heating to 50 ℃, stirring for 1 hour, and completely dissolving. Naturally cooling to room temperature under stirring, continuously stirring for 1 hour, filtering, and drying at 40 ℃ to obtain a white solid, namely the valdenafil analogue shown in the formula III.
The white solid obtained in example 4 was subjected to mass spectrometry, and the results were as follows: [ M + H ]]+＝519.3
Example 5
A method for synthesizing vardenafil analogue (compound shown as formula IV) comprises the following steps:
N-Methylvardenafil (77g,163.73mmol,1eq) was dissolved in SOCl2(800mL), SO was added2Cl2(44.20g,327.46mmol,32.74mL,2.0eq) and DMF (11.96g,163.72mmol,1.0eq), N2Stirring was carried out overnight at room temperature under protection. The reaction was concentrated, diluted with DCM (500mL) and TBME (500mL) and spin dried again twice to give a pale red viscous mass. Purifying the sticky substance by column chromatography to obtain a crude product A. The crude product A is purified by Pre-HPLC to obtain crude product B. Crude B was added to acetone (40mL) and water (100mL)) and stirred for 2 hours and filtered to give C as a yellow solid. Adding the yellow solid C into 6 times of ethanol, heating to 50 ℃, stirring for 1 hour, and completely dissolving. Naturally cooling to room temperature under stirring, continuously stirring for 1 hour, filtering, and drying at 40 ℃ to obtain a white solid, namely the valdenafil analogue shown in the formula IV.
The white solid obtained in example 5 was subjected to mass spectrometry, and the results were as follows: [ M + H ]]+＝491.2
Example 6
A method for synthesizing vardenafil analogue (compound shown in formula V) comprises the following steps:
n-methyl-5-ethylvardenafil (80g,163.73mmol,1eq) was dissolved in SOCl2(800mL), SO was added2Cl2(44.20g,327.46mmol,32.74mL,2.0eq) and DMF (11.96g,163.72mmol,1.0eq), N2Stirring was carried out overnight at room temperature under protection. The reaction was concentrated, diluted with DCM (500mL) and TBME (500mL) and spin dried again twice to give a pale red viscous mass. Purifying the sticky substance by column chromatography to obtain a crude product A. The crude product A is purified by Pre-HPLC to obtain crude product B. Crude B was added to acetone (40mL) and water (100mL)) and stirred for 2 hours and filtered to give C as a yellow solid. Adding the yellow solid C into 6 times of ethanol, heating to 50 ℃, stirring for 1 hour, and completely dissolving. Cooling to room temperature under stirring, stirring for 1 hr, filtering, and oven drying at 40 deg.C to obtain white solid, i.e. Valvinafine analog of formula V。
The white solid obtained in example 6 was subjected to mass spectrometry, and the results were as follows: [ M + H ]]+＝505.6
Example 7
A method for synthesizing vardenafil analogue (compound shown in formula VI) comprises the following steps:
N-methyl-O-Desethylvardenafil (73g,163.73mmol,1eq) was dissolved in SOCl2(800mL), SO was added2Cl2(44.20g,327.46mmol,32.74mL,2.0eq) and DMF (11.96g,163.72mmol,1.0eq), N2Stirring was carried out overnight at room temperature under protection. The reaction was concentrated, diluted with DCM (500mL) and TBME (500mL) and spin dried again twice to give a pale red viscous mass. Purifying the sticky substance by column chromatography to obtain a crude product A. The crude product A is purified by Pre-HPLC to obtain crude product B. Crude B was added to acetone (40mL) and water (100mL)) and stirred for 2 hours and filtered to give C as a yellow solid. Adding the yellow solid C into 6 times of ethanol, heating to 50 ℃, stirring for 1 hour, and completely dissolving. Naturally cooling to room temperature under stirring, continuously stirring for 1 hour, filtering, and drying at 40 ℃ to obtain a white solid, namely the valdenafil analogue shown in the formula VI.
The white solid obtained in example 7 was subjected to mass spectrometry, and the results were as follows: [ M + H ]]+＝463.5
Example 8
A method for synthesizing vardenafil analogue (compound shown in formula VII) comprises the following steps:
O-Desethylvardenafil (75.4g,163.73mmol,1eq) was dissolved in SOCl2(800mL), SO was added2Cl2(44.20g,327.46mmol,32.74mL,2.0eq) and DMF (11.96g,163.72mmol,1.0eq), N2Stirring was carried out overnight at room temperature under protection. The reaction solution is concentratedAfter shrinkage, the mixture was diluted with DCM (500mL) and TBME (500mL) and re-spun dry twice to give a pale red sticky mass. Purifying the sticky substance by column chromatography to obtain a crude product A. The crude product A is purified by Pre-HPLC to obtain crude product B. Crude B was added to acetone (40mL) and water (100mL)) and stirred for 2 hours and filtered to give C as a yellow solid. Adding the yellow solid C into 6 times of ethanol, heating to 50 ℃, stirring for 1 hour, and completely dissolving. Naturally cooling to room temperature under stirring, continuously stirring for 1 hour, filtering, and drying at 40 ℃ to obtain a white solid, namely the vardenafil analogue of the formula VII.
The white solid obtained in example 8 was subjected to mass spectrometry, and the results were as follows: [ M + H ]]+＝477.5
Example 9
A method for synthesizing vardenafil analog (compound shown in formula viii), which comprises the following steps:
N-methyl-5-ethyl-O-deethylvardenafil (75.4g,163.73mmol,1eq) was dissolved in SOCl2(800mL), SO was added2Cl2(44.20g,327.46mmol,32.74mL,2.0eq) and DMF (11.96g,163.72mmol,1.0eq), N2Stirring was carried out overnight at room temperature under protection. The reaction was concentrated, diluted with DCM (500mL) and TBME (500mL) and spin dried again twice to give a pale red viscous mass. Purifying the sticky substance by column chromatography to obtain a crude product A. The crude product A is purified by Pre-HPLC to obtain crude product B. Crude B was added to acetone (40mL) and water (100mL)) and stirred for 2 hours and filtered to give C as a yellow solid. Adding the yellow solid C into 6 times of ethanol, heating to 50 ℃, stirring for 1 hour, and completely dissolving. Naturally cooling to room temperature under stirring, continuously stirring for 1 hour, filtering, and drying at 40 ℃ to obtain a white solid, namely the vardenafil analogue of the formula VIII.
The white solid obtained in example 9 was subjected to mass spectrometry, and the results were as follows: [ M + H ]]+＝477.5
Example 10
A method for synthesizing vardenafil analog (compound shown in formula IX), which comprises the following steps:
5-Ethyl-O-Desethylvardenafil (77.7g,163.73mmol,1eq) was dissolved in SOCl2(800mL), SO was added2Cl2(44.20g,327.46mmol,32.74mL,2.0eq) and DMF (11.96g,163.72mmol,1.0eq), N2Stirring was carried out overnight at room temperature under protection. The reaction was concentrated, diluted with DCM (500mL) and TBME (500mL) and spin dried again twice to give a pale red viscous mass. Purifying the sticky substance by column chromatography to obtain a crude product A. The crude product A is purified by Pre-HPLC to obtain crude product B. Crude B was added to acetone (40mL) and water (100mL)) and stirred for 2 hours and filtered to give C as a yellow solid. Adding the yellow solid C into 6 times of ethanol, heating to 50 ℃, stirring for 1 hour, and completely dissolving. Naturally cooling to room temperature under stirring, continuously stirring for 1 hour, filtering, and drying at 40 ℃ to obtain a white solid, namely the valdenafil analogue of the formula IX.
The white solid obtained in example 10 was subjected to mass spectrometry, and the results were as follows: [ M + H ]]+＝491.6
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (10)
1. A vardenafil analog having the formula I:
in the formula I, R1Hydroxyl, ethoxy,
R2Is hydroxy or ethoxy;
R3hydrogen, straight-chain alkane of C1-C6, branched-chain alkane of C1-C6, straight-chain alkene of C1-C6 or branched-chain alkene of C1-C6;
R4is straight-chain alkane of C1-C6, branched-chain alkane of C1-C6, straight-chain alkene of C1-C6 or branched-chain alkene of C1-C6.
2. The vardenafil analog of claim 1 wherein in formula I,
R1is composed of
R2Is hydroxy or ethoxy;
R3is hydrogen;
R4is methyl or ethyl.
3. The vardenafil analog of claim 1 wherein the vardenafil analog has a structural formula of from formula ii to formula IX:
4. a process for the synthesis of vardenafil analogues according to any of claims 1 to 3 comprising the steps of: dissolving vardenafil and/or vardenafil homologue in a chlorinating reagent, adding sulfuryl chloride and a catalyst, and reacting under the protection of nitrogen to obtain the vardenafil/vardenafil compound.
5. The method for synthesizing vardenafil analog according to claim 4, wherein the chlorinating agent is one or any combination of thionyl chloride, oxalyl chloride, phosphorus oxychloride, chlorine solution and N-chlorosuccinimide solution; the catalyst is one or any combination of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
6. The method of synthesizing vardenafil analog according to claim 4 further comprising an evaporation step, after reacting under nitrogen, diluting with an inert solvent and spin drying to obtain a sticky mass.
7. The method of synthesizing a vardenafil analog as claimed in claim 6 further comprising a purification step after obtaining the sticky material; or after the sticky substance is obtained, a purification step and a recrystallization step are also included; or after obtaining the sticky substance, further comprising a purification step, a recrystallization step and a drying step.
8. Use of the vardenafil analogue of any one of claims 1-3 as an impurity control in the development and validation of vardenafil analysis methods, detection of related substances, doping experiments, vardenafil intermediates, drug substances and quality control of preparations.
9. The use of vardenafil analog, a prodrug thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 for the preparation of a medicament for the treatment of penile erectile dysfunction in men, a medicament for the treatment of pulmonary hypertension, a medicament for the treatment of heart failure.
10. A drug for treating male penile erectile dysfunction, characterized in that the active ingredient thereof is the vardenafil analog, a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.
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