CN113583003A - Vardenafil analogue and synthetic method and application thereof - Google Patents
Vardenafil analogue and synthetic method and application thereof Download PDFInfo
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Abstract
The invention discloses a vardenafil analogue which has a brand-new compound structure, is definite in structure and high in chemical purity, can be used as an impurity reference substance in the development and verification of an analysis method of vardenafil hydrochloride, the detection of related substances and doping experiments, and is a necessity for controlling the quality of vardenafil hydrochloride bulk drugs and preparations. In addition, the vardenafil analogue 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. The invention also discloses a synthetic method of the vardenafil analogue, which has the advantages of simple synthetic route, high product purity and considerable product yield.
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 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 the structural formula shown in the specification. At present, the marketed specification of the vardenafil hydrochloride tablet is 5mg, 10mg and 20mg, and the specification of 2.5mg is removed.
Patent CN1227253C discloses a synthetic route of vardenafil hydrochloride, in the route, vardenafil acid is adopted to generate sulfonyl chloride through chlorosulfonation reaction, the sulfonyl chloride is directly condensed with N-ethylpiperazine to generate a vardenafil hydrochloride crude product without purification, and the vardenafil hydrochloride crude product is subjected to salifying, refining and crystallization to obtain the vardenafil hydrochloride.
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.
In addition, according to the reports of the patents and pharmacopoeias which have been published so far, there are 9 vardenafil related substances, which are respectively shown in the following table:
however, the inventor researches the preparation process of vardenafil hydrochloride and finds 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.
The third purpose of the invention is to apply the vardenafil analogue to the preparation of the medicine for treating male penile erectile 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:
R2Is methoxy or ethoxy.
Further, the vardenafil analogue has a structural formula shown in any one of formulas II to VII:
further, the vardenafil analog has a structural formula shown in formula II:
the second purpose of the invention is realized by adopting the following technical scheme:
a method for synthesizing vardenafil analogs, comprising the steps of: p-hydroxybenzonitrile is used as a raw material, p-alkoxy benzonitrile is generated through alkylation reaction, 4-alkoxy benzamidine hydrochloride is obtained through treatment of bis (trimethylsilyl) amido Lithium (LiHMDS), 4-alkoxy benzamidine hydrochloride reacts with compound 5 to generate intermediate 6A through ring closing, intermediate 6A generates intermediate 7A through phosphorus oxychloride ring closing, intermediate 7A generates sulfonyl chloride intermediate 8A through chlorosulfonic acid reaction, and sulfonyl chloride intermediate 8A reacts with N-ethylpiperazine or N-methylpiperazine to generate a target product vardenafil analogue; the structural formula of the compound 5 is shown as a formula VIII:
further, the structural formula of the intermediate 6A is shown as a formula IX, the structural formula of the intermediate 7A is shown as a formula X, and the structural formula of the intermediate 8A is shown as a formula XI:
further, 4-alkoxy benzamidine hydrochloride reacts with compound 5 to generate intermediate 6A and byproduct 6 (formula XII); reacting the intermediate 7A with chlorosulfonic acid to generate a sulfonyl chloride intermediate 8A and a byproduct sulfonic acid 8B (formula IV); the structural formulas of the by-product 6 (formula XII) and the by-product sulfonic acid 8B (formula IV) are respectively as follows:
the third purpose of the invention is realized by adopting the following technical scheme:
the vardenafil analogue serving as an impurity reference substance is applied to development and verification of an analysis method of vardenafil, detection of related substances, doping experiments, vardenafil intermediates, bulk drugs and quality control of preparations.
The vardenafil analogue, the prodrug thereof or the pharmaceutically acceptable salt thereof, which is one of the purposes of the invention, can be applied to the preparation of medicaments for treating male penile erection 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:
a drug for treating male penile erectile dysfunction, the active ingredient of which is vardenafil analog, a prodrug thereof or a pharmaceutically acceptable salt thereof, which is one of the objects of the present invention.
A drug for treating pulmonary hypertension, which comprises the vardenafil analogue, a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
The vardenafil analogue, the prodrug thereof or the pharmaceutically acceptable salt thereof, which is one of the objects of the invention, is used as an active ingredient of a medicament 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, has a brand new compound structure, has the characteristics of definite 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, and is a necessary product for controlling the quality of vardenafil hydrochloride bulk drugs and preparations.
(2) The vardenafil analogue provided by the invention is prepared and separated by the inventor, and the structure of the vardenafil analogue is confirmed, and 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), pulmonary hypertension, heart failure and other diseases.
(3) The synthetic method of the vardenafil analogue provided by the invention has the advantages of simple synthetic route, high product purity and considerable product yield.
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 commercially available unless otherwise specified.
A vardenafil analog having the formula shown in formula I:
R2Is methoxy or ethoxy.
As a further embodiment, the vardenafil analog has a structural formula as shown in any one of formulas II-VII:
as a further embodiment, the vardenafil analog has the structural formula shown in formula II, the name of the compound shown in formula II is 4- { 4-ethoxy-5- [ (4-ethylpiperazin-1-yl) sulfonyl ] phenyl } -8-methyl-6-propyl-imidazo [1,5-d ] [1,2,4] triazin-1 (2H) -one, and the invention uses the code "analog CJ-004" to represent the analog shown in formula II:
the vardenafil analogue (shown in any one of formulas II to VII) provided by the embodiment of the invention has a brand-new compound structure, is determined in structure and high in chemical purity, can be used as an impurity reference substance in the development and verification of an analysis method of vardenafil hydrochloride, the detection of related substances and doping experiments, can also be used in the quality control of vardenafil intermediates, bulk drugs and preparations, is a necessary product for controlling the quality of vardenafil hydrochloride bulk drugs and preparations, and provides a basis for effectively controlling the quality of the vardenafil hydrochloride intermediates, bulk drugs and preparations.
The vardenafil analogue (shown in any formula II to VII) provided by the embodiment of the invention has a structure similar to vardenafil hydrochloride, has the effect of inhibiting phosphodiesterase type 5 (PDE5), and can be used for treating male penile Erection Dysfunction (ED), pulmonary hypertension, heart failure and other diseases.
The vardenafil analogue (shown in any formula II-VII), the prodrug thereof or the pharmaceutically acceptable salt thereof provided by the embodiment of the invention can be used for preparing a medicament for treating male penile erectile dysfunction, or a medicament for treating pulmonary hypertension, or a medicament for treating heart failure.
A method for synthesizing vardenafil analogs, comprising the steps of: p-hydroxybenzonitrile is used as a raw material, p-alkoxy benzonitrile is generated through alkylation reaction, 4-alkoxy benzamidine hydrochloride is obtained through treatment of bis (trimethylsilyl) amido Lithium (LiHMDS), 4-alkoxy benzamidine hydrochloride reacts with compound 5 to generate intermediate 6A through ring closing, intermediate 6A generates intermediate 7A through phosphorus oxychloride ring closing, intermediate 7A generates sulfonyl chloride intermediate 8A through chlorosulfonic acid reaction, and sulfonyl chloride intermediate 8A reacts with N-ethylpiperazine or N-methylpiperazine to generate a target product vardenafil analogue; the structural formula of the compound 5 is shown as formula VIII, the structural formula of the intermediate 6A is shown as formula IX, the structural formula of the intermediate 7A is shown as formula X, the structural formula of the intermediate 8A is shown as formula XI,
as a further embodiment, 4-alkoxybenzamidine hydrochloride is ring-closed reacted with compound 5 to form intermediate 6A and also to form by-product 6 (formula XII); reacting the intermediate 7A with chlorosulfonic acid to generate a sulfonyl chloride intermediate 8A and a byproduct sulfonic acid 8B (formula IV); the structural formulae of by-product 6 and by-product sulfonic acid 8B (formula IV) are respectively as follows:
in a further embodiment, when the alkoxybenzonitrile is produced by alkylation using p-hydroxybenzonitrile as a starting material, the starting material for the alkylation is a halogenated alkane, preferably a brominated alkane, more preferably bromoethane or bromomethane. When the reaction raw materials are p-hydroxybenzonitrile and ethyl bromide, the product is 4-ethoxy benzonitrile; when the raw materials of the reaction are p-hydroxybenzonitrile and methyl bromide, the product is 4-methoxybenzonitrile.
As a further embodiment, when the structural formula of the target vardenafil analog is shown as formula II (analog CJ-004), the synthesis method comprises the following steps: p-hydroxybenzonitrile is taken as a raw material, p-ethoxybenzonitrile is generated through alkylation reaction, 4-ethoxybenzamidine hydrochloride is obtained through treatment of bis (trimethylsilyl) amido Lithium (LiHMDS), 4-ethoxybenzamidine hydrochloride reacts with compound 5 to generate intermediate 6A and byproduct 6, intermediate 6A generates intermediate 7A through phosphorus oxychloride cyclization, intermediate 7A reacts with chlorosulfonic acid to generate sulfonyl chloride intermediate 8A and byproduct sulfonic acid 8B (formula IV), intermediate 8A reacts with N-ethylpiperazine to generate target product vardenafil analogue CJ-004, and the reaction flow is as follows:
example 1
Synthesis of 4-ethoxybenzonitrile
To a 1L three-necked flask were added acetone (800mL), p-hydroxybenzonitrile (compound 1,80g,671mmol, 1.0eq) and K2CO3(167g,1.21mol,1.8 eq). Bromoethane (80.5g,738mmol,1.1eq) was added dropwise to the flask over 30 minutes at 25 ℃. After the dropwise addition, the reaction was heated to 50 ℃ and stirred under reflux for 12 hours. TLC (petroleum ether/ethyl acetate: 3/1, Rf 0.70) showed complete reaction of starting material. The reaction solution was cooled to room temperature, water (500mL) was added for extraction, the organic phase was separated, the aqueous phase was extracted with dichloromethane (200mL), the combined organic phases were concentrated to give the crude product. The crude product was added to petroleum ether (300mL) and stirred for 2 hours, filtered and dried to give 100g of a white sandy solid product in 100% yield, which was designated as compound 2.
The structure of compound 2 obtained in example 1 was confirmed by nuclear magnetic hydrogen spectroscopy, and the results were as follows:
1H NMR(400MHz,CDCl3)δ7.60-7.53(m,2H),6.97-6.88(m,2H),4.07(q,J=7.0Hz,2H),1.44(t,J=7.0Hz,3H)。
example 2
Synthesis of 4-ethoxyformamidine hydrochloride
Compound 2(125g,327mmol,1eq) and THF (600mL) were added to a three-necked flask, the reaction solution was cooled to 0 ℃ and LiHMDS (1.0M,1.02L,1.2eq) was added dropwise to the reaction solution at 0 ℃ and stirred for 0.5 hour. The reaction solution was then warmed to 40 ℃ and stirred for 12 hours. LCMS detected the completion of the starting material reaction. The reaction was cooled to 20 ℃, 4M hydrochloric acid/ethyl acetate solution (1.2L) was added dropwise to the reaction, stirred at 20 ℃ for 12 hours, the reaction was filtered, the filter cake was washed with ethyl acetate (100mL x 3), and the filter cake was concentrated to give 180g of crude product. The crude product was taken to the next reaction without purification and was identified as compound 3.
The structure of compound 3 obtained in example 2 was confirmed by LCMS and nuclear magnetic hydrogen spectroscopy, and the results were as follows:
LCMS:m/z=165.1[M+H]+
1HNMR:(400MHz,DMSO-d6)δ9.29(s,2H),9.13(s,2H),7.85-7.89(m,2H),7.11-7.15(m,2H),4.14(q,J=7.06Hz,2H),1.35(t,J=6.91Hz,3H)。
example 3
Synthesis of vardenafil analog CJ-004 intermediate 6A
Adding EtOH (400mL) and compound 3(40g,199mmol,1.0eq, HCl) into a 500mL three-necked flask, cooling to 0 ℃ in an ice-water bath, and dropwise adding NH into the system2NH2·H2O (11.9g,239mmol,1.2eq), stirred at 0 ℃ for 20 min. The temperature is automatically returned to 20 ℃ and the mixture is stirred for 1 hour. N is a radical of2Compound 5(55.7g,259mmol,1.3eq) was added to the system under protection, and the temperature was raised to 45 ℃ for reaction for 12 hours. TLC (petroleum ether/ethyl acetate 0/1, R)f0.38) showed complete reaction of compound 5. The reaction was cooled to room temperature, filtered directly, the filter cake was dissolved with dichloromethane (100mL), pH was adjusted to 9-10 by addition of ammonia, the organic phase was separated, the aqueous phase was extracted with dichloromethane (80mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 21g of intermediate 6A as a white solid.
The structure of the intermediate 6A obtained in example 3 was confirmed by nuclear magnetic hydrogen spectroscopy, and the results were as follows:
1H NMR:(400MHz,DMSO-d6)δ13.46(s,1H),8.33(d,J=7.3Hz,1H),8.03(d,J=8.8Hz,2H),7.02(d,J=8.9Hz,2H),5.17(quin,J=7.1Hz,1H),4.14-4.04(m,2H),2.32-2.06(m,2H),1.51(sxt,J=7.3Hz,2H),1.42-1.28(m,6H),0.84(t,J=7.4Hz,3H)
example 4
Synthesis of vardenafil analog CJ-004 intermediate 7A
Adding intermediate 6A (20g,60.5mmol,1.0eq) into a 500mL three-necked flask at 25 deg.C, adding AcOH (200mL) to dissolve it uniformly, cooling to 0 deg.C in an ice water bath, and slowly adding POCl dropwise3(37.1g,242mmol,4.0eq), after which it was heated to 100 ℃ for 12 hours. TLC (petroleum ether/ethyl acetate 0/1, R)f0.29) the end of the reaction of the starting materials was monitored. The reaction was quenched by pouring into water (200mL), concentrated to remove acetic acid, then adjusted to pH 7-8 by the addition of 1.0M aqueous potassium hydroxide at 10 ℃, followed by extraction with dichloromethane (200mL × 3), the organic phases combined and washed with saturated brine (200mL), the separated organic phase was dried over anhydrous sodium sulfate, and concentrated to give 15g of crude product. Petroleum ether (50mL) and t-methyl ether (10mL) were added to 15g of the crude product and slurried for 12 hours and filtered to give 13g of solid 7A, noted as intermediate 7A.
The structure of the intermediate 7A obtained in example 4 was confirmed by nuclear magnetic hydrogen spectroscopy, and the results were as follows:
1H NMR:(400MHz,CDCl3)δ9.40(s,1H),7.42(d,J=8.6Hz,2H),7.01(d,J=8.6Hz,2H),4.12(q,J=6.8Hz,2H),2.69(s,3H),2.25-2.17(m,2H),1.47(m,5H),0.67(t,J=7.4Hz,3H)。
example 5
Synthesis of vardenafil analog CJ-004 intermediate 8A
Methylene chloride (150mL) and intermediate 7A (5.0g,16.0mmol,1.0eq) were added to a 250mL three-necked flask, chlorosulfonic acid (17.5g,150mmol,9.38eq) was diluted in methylene chloride (10mL), and the mixture was added dropwise to the reaction mixture, and the reaction mixture was kept at room temperature around 25 ℃. The reaction solution was stirred at 25 ℃ for 12 hours, TLC (petroleum ether/ethyl acetate: 0/1, R)f0.35) and the starting material was reacted. The reaction was quenched by reverse phase pouring into saturated aqueous sodium bicarbonate (200mL), maintaining pH 7-8, and dichloromethaneExtraction (50 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate and concentration gave 2.2g of crude 8A. 2.2g of crude 8A are slurried in petroleum ether (30mL) at 20 ℃ for 2 hours, filtered, and the filter cake concentrated to give 1.7g of a brown powdered product 8A, noted as sulfonyl chloride intermediate 8A. And (3) concentrating the water phase to obtain a solid compound, soaking the solid compound in methanol (100mL), pulping, filtering, leaching a filter cake with methanol (50mL), and concentrating the filtrate to obtain 6g of crude product 8B, which is recorded as a by-product sulfonic acid 8B (formula IV).
The structures of sulfonyl chloride intermediate 8A and by-product sulfonic acid 8B (formula IV) obtained in example 5 were confirmed by nuclear magnetic hydrogen spectroscopy, respectively, and the results were as follows:
1HNMR:8A(400MHz,DMSO-d6)δ12.28(br s,1H),7.96(d,J=2.3Hz,1H),7.59(dd,J=2.3,8.4Hz,1H),7.14(d,J=8.6Hz,1H),4.14(q,J=6.9Hz,2H),2.62(s,3H),2.25(m,2H),1.46-1.37(m,2H),1.34(t,J=6.9Hz,3H),0.60(t,J=7.3Hz,3H)
1HNMR 8B (formula IV) (400MHz, DMSO-d)6)δ12.03(s,1H),7.91(d,J=2.3Hz,1H),7.55(dd,J=2.4,8.4Hz,1H),7.11(d,J=8.6Hz,1H),4.14(q,J=6.9Hz,2H),2.58(s,3H),2.18(br t,J=7.6Hz,2H),1.47-1.38(m,2H),1.34(t,J=7.0Hz,3H),0.61(t,J=7.3Hz,3H)。
Example 6
Synthesis of vardenafil analog CJ-004
To a 100mL three-necked flask were added dichloromethane (10mL) and sulfonyl chloride intermediate 8A (1.0g,2.43mmol,1.0eq), N2Under protection, the temperature is reduced to 0 ℃ in an ice water bath, N-ethylpiperazine (555mg,4.87mmol,2.0eq) is added into the system dropwise, the temperature is kept at 0 ℃ and stirred for 0.5 hour, and the system is automatically warmed to room temperature and stirred for 2.5 hours at 25 ℃. TLC (ethyl acetate/methanol-5/1, R)f0.28) shows the starting material has reacted. The reaction was taken up in water (40mL) and dichloromethane (40mL) and washed with dichloromethane (40mL x 3), the organic phases combined, dried over anhydrous sodium sulphate and concentrated to give 2.4g of crude product. 2.4g of the crude product are separated by column chromatography (stone)Oil ether/ethyl acetate 10/1-0/1) to yield 0.6g of a white solid as compound CJ-004.
The structure of the compound CJ-004 obtained in example 6 was confirmed by LCMS and nuclear magnetic hydrogen spectroscopy, and the results were as follows:
LCMS:m/z=489.1(M+1)+,
1H NMR:(400MHz,DMSO-d6)δ11.79(s,1H),7.99(d,J=2.2Hz,1H),7.91(dd,J=2.3,8.6Hz,1H),7.39(d,J=8.7Hz,1H),4.27(q,J=7.0Hz,2H),3.15(m,4H),2.52(s,3H),2.42-2.25(m,6H),2.06(br t,J=7.6Hz,2H),1.44(m,2H),1.39(t,J=6.8Hz,3H),0.95(t,J=7.2Hz,3H),0.61(t,J=7.3Hz,3H)
example 7
A method for synthesizing vardenafil analog (formula III) comprises the following steps:
dichloromethane (40mL) and intermediate 8A (3.6g,8.77mmol,1eq) were added to a 100mL single-neck flask, the temperature was reduced to 0 ℃ in an ice-water bath, and N-methylpiperazine (1.76g,17.54mmol,2.22mL,2eq), N, was added dropwise to the system2Stirring at 0 deg.C for 0.5 hr under protection, automatically heating to 25 deg.C, and stirring for 12 hr. TLC (petroleum ether/ethyl acetate 0/1, R)f0.15) and the starting material was reacted. The reaction was added to water (40mL) and dichloromethane (40mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (40mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spun dry to give 3.9g of crude product. The crude product was isolated by column chromatography (petroleum ether/ethyl acetate 10/1-0/1) to yield 2.4g of a white solid product designated as analog formula III.
The analogue obtained in example 7, formula III, was structurally confirmed by LCMS and nuclear magnetic hydrogen spectroscopy as follows:
ExactMass:474.22,LCMS:m/z=475.1[M+1]+
1H NMR:(400MHz,DMSO-d6)δ11.78(s,1H),7.97(d,J=2.2Hz,1H),7.90(dd,J=2.3,8.6Hz,1H),7.36(d,J=8.7Hz,1H),4.25(q,J=7.0Hz,2H),3.15(m,4H),2.54(s,3H),2.49(s,3H),2.42-2.25(m,4H),2.06(br t,J=7.6Hz,2H),1.44(m,2H),0.95(t,J=7.2Hz,3H),0.61(t,J=7.3Hz,3H)
example 8
The synthesis, scheme and procedure of vardenafil analog (formula V) intermediate (Compound 9) are as follows
Adding EtOH (200mL) and 4-methoxy formamidine hydrochloride (20g,107.15mmol,1eq) into a 500mL three-necked flask, cooling to 0 ℃ in an ice-water bath, and dropwise adding hydrazine hydrate NH into the system2NH2.H2O (7.07g,117.8mmol,1.1eq) was stirred at 0 ℃ for 0.5 h. Automatically returning to room temperature of 20 ℃, stirring for 1 hour (till the raw material disappears), adding compound 5(27.89g,129.57mmol,1.3eq) into the system, heating to 45 ℃, and heating to N2The reaction was carried out for 12 hours under protection and TLC (petroleum ether/ethyl acetate 1/1, Rf 0.30) monitored that the intermediate reaction was complete and a new point was formed. The reaction was cooled to room temperature and concentrated, water (80mL) and dichloromethane (80mL) were added, ammonia was added dropwise with stirring to adjust pH 9-10, the organic phase was separated, the aqueous phase was washed with dichloromethane (80mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give 17g of crude product. The crude product was purified by column chromatography (petrol ether/ethyl acetate 10/1-0/1) to yield 12g of crude product which was subjected to Pre-HPLC purification (column: Agela DuraShell C18250 mM 80mM 10 um; mobile phase: [ water (10mM NH4HCO3) -ACN)](ii) a B%: 15% -45% for 20min) to yield 6.3g of a yellow solid product, which is designated compound 9.
The structure of compound 9 obtained in example 8 was confirmed by nuclear magnetic hydrogen spectroscopy, and the results were as follows:
1H NMR:(400MHz,DMSO-d6)δ13.43(s,1H),8.30(d,J=7.3Hz,1H),8.02(d,J=8.8Hz,2H),7.01(d,J=8.9Hz,2H),5.15(quin,J=7.1Hz,1H),4.18(s,3H),2.32-2.06(m,2H),1.51(sxt,J=7.3Hz,2H),1.56(d,J=6.8Hz,3H),0.83(t,J=7.4Hz,3H)
example 9
The synthesis, scheme and method of vardenafil analog (formula V) intermediate 10 is as follows:
to a 500mL three-necked flask, Compound 9(2.4g,7.57mmol,1eq) was added at 25 ℃ followed by AcOH (25mL) and stirred to dissolve it, the temperature was lowered to 0 ℃ in an ice-water bath, and POCl was slowly added dropwise3(5.8g,37.85mmol,5.0eq), heating to 100 ℃ after dropwise addition, reacting for 12 hours, TLC (petroleum ether/ethyl acetate: 0/1, R)f0.29) the reaction was monitored for completion and new spots were formed. The reaction was cooled to room temperature and then quenched by pouring into water (20mL), concentrated to remove AcOH, adjusted to pH 7-8 by the addition of 1M aqueous potassium hydroxide at 10 ℃, followed by extraction sequentially with dichloromethane (20mL x 3), the organic phases combined, washed with saturated brine (20mL), the organic phase separated, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated to 3.5g crude, and purified by column chromatography (ethyl acetate/petroleum ether 10/1-0/1) to give 1.6g of solid product, designated as intermediate 10.
The structure of intermediate 10 obtained in example 9 was confirmed by LCMS, and the results were as follows:
LCMS:m/z=299.1[M+1]+
example 10
Vardenafil analog (formula V) intermediate 11 was synthesized, scheme and method as follows:
methylene chloride (100mL) and intermediate 10(5.92g,19.85mmol,1eq) were added to a 250mL three-necked flask, and a solution of chlorosulfonic acid (22.74g,195.11mmol,9.83eq) in methylene chloride (10mL) was added dropwise to the reaction mixture at 25 ℃ to react at 25 ℃ for 12 hours. TLC (petroleum ether/ethyl acetate 1/1, R)f0.43), the starting material reaction was complete and a new spot was formed. The reaction was quenched by slowly pouring into saturated aqueous sodium bicarbonate (100mL) with stirring and dichloromethane (100 mL. times.3) Extraction, combined organic phases dried over anhydrous sodium sulfate, filtration and spin drying of the filtrate yielded 7.5g of crude product. The crude product was taken directly to the next reaction without further purification and was designated as intermediate 11.
Example 11
A synthetic method of vardenafil analogue (formula V), the process and method are as follows:
dichloromethane (40mL) and intermediate 11(3.87g,9.74mmol,1eq) were added to a 100mL single-neck flask, the temperature was reduced to 0 ℃ in an ice-water bath, and N-ethylpiperazine (2.22g,19.47mmol,2.47mL,2eq), N, was added dropwise to the system2Stirring at 0 deg.C for 0.5 hr under protection, automatically heating to 25 deg.C, and stirring for 11.5 hr. TLC (petroleum ether/ethyl acetate 0/1, R)f0.15) and the starting material was reacted. The reaction was added to water (40mL) and dichloromethane (40mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (40mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spun dry to give 4.3g of crude product. The crude product was isolated by column chromatography (petroleum ether/ethyl acetate 10/1-0/1) to yield 3.5g of the product as analog V.
The structure of the analog V obtained in example 11 was confirmed by LCMS and nuclear magnetic hydrogen spectroscopy, and the results were as follows:
ExactMass:474.20,LCMS:m/z=475.2[M+1]+
1HNMR:(400MHz,CDCl3)δ9.57(s,1H),7.89(dd,J=2.2,8.8Hz,1H),7.80(d,J=2.4Hz,1H),7.12(d,J=8.6Hz,1H),4.17(s,3H),3.09(m,4H),2.65(s,3H),2.55(br t,J=4.5Hz,4H),2.42(q,J=7.2Hz,2H),2.27-1.99(m,2H),1.63-1.39(m,2H),1.04(t,J=7.2Hz,3H),0.65(t,J=7.4Hz,3H)。
example 12
A method for synthesizing vardenafil analog (formula VI), the synthesis equation and method are as follows:
dichloromethane (40mL) and intermediate 11(3.48g,8.77mmol,1eq) were added to a 100mL single-neck flask, the temperature was reduced to 0 ℃ in an ice-water bath, and N-methylpiperazine (1.76g,17.54mmol,2.22mL,2eq), N, was added dropwise to the system2Stirring at 0 deg.C for 0.5 hr under protection, automatically heating to 25 deg.C, and stirring for 12 hr. TLC (petroleum ether/ethyl acetate 0/1, R)f0.15) and the starting material was reacted. The reaction was added to water (40mL) and dichloromethane (40mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (40mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spun dry to give 3.5g of crude product. The crude product was isolated by column chromatography (petroleum ether/ethyl acetate 10/1-0/1) to yield 2.1g of a white solid product designated as analog formula VI.
The analog obtained in example 12, formula VI, was structurally confirmed by LCMS and nuclear magnetic hydrogen spectroscopy, and the results were as follows:
Exact Mass:460.22,LCMS:m/z=461.1[M+1]+
1HNMR:(400MHz,CDCl3)δ9.54(s,1H),7.90(dd,J=2.2,8.8Hz,1H),7.80(d,J=2.4Hz,1H),7.10(d,J=8.6Hz,1H),4.22(s,3H),3.09(m,4H),2.63(s,3H),2.53(br t,J=4.5Hz,4H),2.47(s,3H),2.23(ddd,J=6.2,9.3,15.4Hz,1H),2.07–2.00(m,1H),1.65-1.40(m,2H),0.64(t,J=7.4Hz,3H)。
example 13
A synthetic method of vardenafil analogue VII comprises the following steps:
MeCN (20mL), H was added to a 100mL single-neck flask2O (40mL) and compound 11(3.68g,9.25mmol,1eq) were stirred at 25 ℃ for 12 h, detected by LCMS, the starting material was reacted and the reaction was filtered, washed twice with acetonitrile (30mL) and the filter cake was concentrated to give the crude product. The crude product was dispersed in water (30mL) and stirred for 1 hour, filtered, and the filter cake was stirred in water (30mL) for 1 hour and filtered. The filter cake was concentrated to give 2.69g of a white colourThe solid product is a compound shown as a formula VII.
The structure of the analogue VII obtained in example 13 was confirmed by LCMS and nuclear magnetic hydrogen spectroscopy, and the results were as follows:
ExactMass:378.1,LCMS:m/z=379.0(M+1)+
1H NMR:(400MHz,DMSO-d6)δ12.03(s,1H),7.77(dd,J=2.1,8.6Hz,1H),7.70(d,J=2.1Hz,1H),7.11(d,J=8.7Hz,1H),4.13(s,3H),2.56(s,3H),2.27-2.05(m,2H),1.48-1.34(m,2H),0.60(t,J=7.3Hz,3H)
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)
4. a process for the synthesis of vardenafil analogues according to any of claims 1 to 3 comprising the steps of: p-hydroxybenzonitrile is used as a raw material, p-alkoxy benzonitrile is generated through alkylation reaction, 4-alkoxy benzamidine hydrochloride is obtained through treatment of bis (trimethylsilyl) amino lithium, 4-alkoxy benzamidine hydrochloride reacts with compound 5 to generate intermediate 6A through ring closure, intermediate 6A generates intermediate 7A through phosphorus oxychloride ring closure, intermediate 7A generates sulfonyl chloride intermediate 8A through chlorosulfonic acid reaction, and sulfonyl chloride intermediate 8A reacts with N-ethylpiperazine or N-methylpiperazine to generate a target product vardenafil analogue; the structural formula of the compound 5 is shown as a formula VIII:
6. a process for the synthesis of vardenafil analogues according to claim 4 wherein 4-alkoxybenzamidine hydrochloride is ring-closed reacted with compound 5 to form intermediate 6A and byproduct 6, the formula of byproduct 6 being shown in formula XII; the intermediate 7A is reacted with chlorosulfonic acid to generate a sulfonyl chloride intermediate 8A, and a byproduct sulfonic acid 8B, wherein the structural formula of the byproduct sulfonic acid 8B is shown as a formula IV:
7. the method of synthesizing vardenafil analog as claimed in claim 4, wherein when the target vardenafil analog has the structural formula shown in formula II, the synthesis method is as follows: p-hydroxybenzonitrile is taken as a raw material, p-ethoxybenzonitrile is generated through alkylation reaction, 4-alkoxy benzamidine hydrochloride is obtained through treatment of bis (trimethylsilyl) amido lithium, 4-alkoxy benzamidine hydrochloride reacts with compound 5 to generate intermediate 6A and byproduct 6, intermediate 6A generates intermediate 7A through phosphorus oxychloride cyclization, intermediate 7A reacts with chlorosulfonic acid to generate sulfonyl chloride intermediate 8A and byproduct sulfonic acid 8B, intermediate 8A reacts with N-ethylpiperazine to generate the target product vardenafil analogue, and the reaction process is as follows:
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. Use of vardenafil analog or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 for the manufacture of a medicament for the treatment of male penile erectile dysfunction, for the manufacture of a medicament for the treatment of pulmonary hypertension, for the manufacture of 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 or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.
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