A hetero-phase deuterated ethylation reagent, a preparation method and application of deuterated vardenafil

Abstract

The application discloses a heterogeneous deuterium ethylation reagent, a preparation method and application of deuterium-substituted vardenafil, and relates to the technical field of organic synthesis.The heterogeneous deuterium ethylation reagent provided by the application is based on a synthesis method of super-high cross-linking polymer, which is used for polymerizing aryl sulfide compounds, and the material obtained after polymerization still has the reactivity of monomers, can be repeatedly cycled for deuterium ethylation, and can achieve nearly 100% atomic utilization efficiency.The heterogeneous deuterium ethylation reagent provided by the application can also be used for other N and O involved deuterium alkylation chemical reactions, so as to realize the synthesis of high-value-added deuterium-substituted chemicals.The preparation method of the deuterium-substituted vardenafil provided by the application is a deuterium ethylation method for ethylating a vardenafil precursor compound by using a heterogeneous deuterium ethylation reagent, and has the advantages of mild reaction conditions, simple operation, low requirement on equipment, in addition, a by-product is a heterogeneous aryl sulfide compound which is de-ethylated, the heterogeneous deuterium ethylation reagent can be recycled to prepare, the production cost is low, and the industrial value is high.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a heterogeneous aryl deuterium ethylation reagent, a preparation method and application of deuterated vardenafil. BACKGROUND

[0002] Deuterium (D) is an isotope of hydrogen (H) with twice the atomic mass of hydrogen, non-toxic, non-radioactive, and good chemical stability. Deuterated chemicals are a class of very important high-value-added compounds. Compared with C-H bonds, C-D bonds have about 6-9 times higher stability. Deuterium substitution of the active site of a drug can block the metabolic site, achieve the purpose of prolonging the half-life of the drug and reducing the dosage. At the same time, it also has wide application in the fields of studying organic reaction mechanism and improving material performance. At present, the preparation methods of deuterated chemicals mainly include hydrogen-deuterium exchange and direct chemical synthesis of deuterium. However, the hydrogen-deuterium exchange reaction usually uses deuterium gas as the deuterium source, and most of the processes involve high temperature, high pressure, strong acid, strong base conditions, and poor selectivity. In the case of direct chemical synthesis of deuterium, the synthesis steps are usually more, the yield is low, and the deuterium substitution site is easily transferred and deuterium is lost in the subsequent reaction. In addition, the deuterium reagent used is usually expensive and toxic. Therefore, the existing deuterium strategy and technology need to be further improved and developed.

[0003] Vardenafil is the latest drug in the world for treating erectile dysfunction, which is a product developed by Bayer and GlaxoSmithKline for many years, and was approved for marketing by the US FDA in August 2003. Compared with sildenafil, vardenafil has less dosage, faster onset time and less side effects. However, 2% of people will feel a little headache after using vardenafil due to individual differences. Based on the research of deuterated chemicals, it can be expected that deuterium substitution of vardenafil and sildenafil, especially the metabolic site, can further reduce the dosage, prolong the drug action time and reduce adverse reactions. It is urgent to provide a deuterated vardenafil which can enhance the drug efficacy and a preparation method thereof. SUMMARY

[0004] The technical problem to be solved by the present application is to provide a deuterium substitution method of vardenafil with simple preparation method and high yield.

[0005] In order to solve the above problems, the present application proposes the following technical solutions:

[0006] In a first aspect, the present application provides a preparation method of a heterogeneous aryl deuterium ethylation reagent, comprising the following steps:

[0007] S1, the aryl sulfide compound, Lewis acid, complexing agent is dissolved in solvent according to stoichiometric ratio 1:2~8:2~12, at 40~70℃ under reaction 1~3 hours initially formed crosslinked structure, continue to increase the temperature to 75~110℃ under reaction to end; After the reaction is completed, it is reduced to room temperature, filtered, and the filter cake is washed with hydrochloric acid solution and organic solvent until the filtrate is colorless, and dried to obtain a heterogeneous aryl sulfide compound;

[0008] S2, the heterogeneous aryl sulfide compound obtained in S1 is added to a buffer solvent and triflic acid at -5~4℃, and a deuterated ethyl source is added under stirring, and the reaction is carried out at 40~80℃, and after the reaction is completed, it is reduced to room temperature, methanol is added to quench the reaction, filtered, and the filter cake is washed with organic solvent until the filtrate is colorless, and dried to obtain a heterogeneous aryl sulfide type deuterated ethyl reagent; The mass ratio of the buffer solvent to triflic acid is 0.01:1~5:1.

[0009] Further, the organic solvent used to wash the filter cake includes methanol, ethanol, ethyl acetate, etc.

[0010] Further, in step S1, the reaction time is more than 6 hours, for example, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, etc.

[0011] Further, the aryl sulfide compound is selected from one or more combinations of thianthrene, diaryl bithiophene, diphenyl sulfide, phenoxathiin, phenothiazine, 10-methylphenothiazine.

[0012] Further, the deuterated ethyl source is selected from one or more combinations of deuterated ethanol, deuterated iodoethane, deuterated ethyl formate, deuterated ethyl triflate.

[0013] Further, the Lewis acid is selected from one or more combinations of aluminum chloride, iron chloride, boron trifluoride, and niobium pentachloride.

[0014] Further, the complexing agent is selected from one or more combinations of dimethoxymethane, acetaldehyde dimethyl acetal, 2,2-dimethoxypropane, 1,4-dimethoxybenzene, and 9,10-dimethoxyanthracene.

[0015] Further, in step S1, the solvent is selected from one or more combinations of 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene, and nitrobenzene.

[0016] Further, in step S2, the buffer solvent is selected from one or more combinations of dichloromethane, acetonitrile, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene, and nitrobenzene.

[0017] In a second aspect, the present application provides a method for preparing deuterated vardenafil, comprising the following steps:

[0018] The vardenafil precursor is dissolved in a solvent, and the heterogeneous aryl sulfide type deuterated ethylation reagent prepared in the first aspect is added, and the reaction is carried out under the action of an inorganic base to obtain the deuterated vardenafil; the vardenafil precursor is selected from O-desethylsildenafil and N-desethylvardenafil;

[0019] The use amount ratio of the vardenafil precursor to the heterogeneous aryl sulfide type deuterated ethylation reagent is 0.1 mmol: 200-400 mg;

[0020] The structure of the deuterated vardenafil is shown in formula (1):

[0021]

[0022] wherein R1-R 31 are each independently H or D, and R1-R 31 At least one hydrogen atom in is replaced by deuterium.

[0023] Further technical solutions thereof are that the reaction product further comprises a de-ethylized heterogeneous aryl sulfide compound; and the de-ethylized heterogeneous aryl sulfide compound is used in step S2 after being extracted and concentrated, so as to recycle the preparation of the heterogeneous aryl sulfide type ethylation reagent.

[0024] Further technical solutions thereof are that the inorganic base is selected from one or more of a combination of alkali metal alcoholates, alkali metal carbonates, and alkali metal hydroxides.

[0025] Further technical solutions thereof are that the inorganic base is selected from potassium carbonate, sodium carbonate, lithium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, and sodium methoxide.

[0026] Further technical solutions thereof are that in the method for preparing the deuterated vardenafil, the solvent is selected from one or more of a combination of acetonitrile, dichloromethane, ethyl acetate, 1,2-dichloroethane, methyl tert-butyl ether, and tetrahydrofuran.

[0027] Further technical solutions thereof are that in the method for preparing the deuterated vardenafil, the reaction is carried out at room temperature, and the reaction time is more than 6 hours, for example, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, etc.

[0028] It should be noted that in the present application, "room temperature" means 0-50°C; in some embodiments, room temperature means 20-40°C, and in some embodiments, room temperature means 25-35°C.

[0029] In a third aspect, the present application provides a deuterated vardenafil, the structure of which is shown in formula (1):

[0030]

[0031] wherein R1-R 31 are each independently H or D, and R1-R 31 at least one hydrogen atom is replaced by deuterium.

[0032] The present application also provides the use of the deuterated vardenafil as described in the third aspect, or the deuterated vardenafil prepared by the method as described in the second aspect, in the preparation of a drug for treating erectile dysfunction.

[0033] Compared with the prior art, the present application can achieve the following technical effects:

[0034] The heterogeneous deuterated ethylation reagent provided by the present application is based on the synthesis method of super-high cross-linked polymers, which is used to polymerize aryl sulfide compounds. The material obtained after polymerization still retains the reactivity of the monomer, and can be repeatedly cycled for deuterated ethylation, achieving an atomic utilization efficiency of nearly 100%. The heterogeneous deuterated ethylation reagent provided by the present application can also be used for other N, O-containing deuterated alkylation chemical reactions to achieve the synthesis of high-value-added deuterated chemicals.

[0035] The present application provides a preparation method of deuterated vardenafil, which is a deuterated synthesis method for deuterated ethylation of a vardenafil precursor compound by using a heterogeneous deuterated ethylation reagent. The reaction conditions are mild, the operation is simple, the requirement for equipment is low, in addition, the by-product is a de-ethylated heterogeneous aryl sulfide compound, which can be recycled to prepare a heterogeneous deuterated ethylation reagent, thereby reducing the production cost and having high industrial value.

[0036] The deuterated vardenafil provided by the present application is obtained by selectively deuterating the active site of vardenafil. According to the research on deuterated drugs, it can be expected to have the effects of reducing the clearance rate, increasing the drug half-life, and reducing the formation of specific metabolites. DETAILED DESCRIPTION

[0037] The technical solutions in the embodiments will be clearly and completely described below. Obviously, the following described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative labor fall within the protection scope of the present application.

[0038] It should be understood that the terms "comprises" and "comprising," when used in this specification and accompanying claims, indicate the presence of stated features, integers, steps, and / or groups but do not preclude the presence or addition of one or more other features, integers, steps, operations, and / or groups thereof.

[0039] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used in this specification and the appended claims, the singular forms "a," "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0040] The term "room temperature" means 0-50 °C; in some embodiments, room temperature means 20-40 °C, and in some embodiments room temperature means 25-35 °C.

[0041] The amount of solvent required for the reaction used herein is preferably an amount in which the reactants are completely dissolved, and is appropriately changed depending on the reactants. In some embodiments, the amount of solvent required for the reaction can also be appropriately more than the amount required for just dissolving the reactants.

[0042] General synthetic procedures

[0043] In general, the compounds of the present application can be prepared by the methods described herein. The following reaction schemes and examples are intended to further illustrate the present application.

[0044] One skilled in the art will recognize that the chemical reactions described herein can be used to prepare many of the other compounds of the present application and that the other methods for preparing compounds of the present application are recognized in the art. For example, the synthesis of those non-exemplified compounds according to the present application can be successfully performed by modifications apparent to those skilled in the art, by analogy with the procedures described herein or with other known reactions. Also, it is contemplated that other reactions disclosed herein or known in the art will find utility in preparing other compounds of the present application.

[0045] Unless otherwise indicated, all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company and used without further purification, unless otherwise indicated. General reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Reagent Company, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemicals Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haoyan Chemical Factory.

[0046] The solvents used in the present application, such as chlorobenzene, dichlorobenzene, p-methyl chlorobenzene, anhydrous tetrahydrofuran, dioxane, toluene, diethyl ether, dichloromethane, chloroform, ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide, are dried by prior art suitable drying methods.

[0047] Example 1

[0048] The present example provides a heterogeneous thianthrene deuterated ethyl reagent and a preparation method thereof, and the present example also provides a preparation method for synthesizing deuterated vardenafil by using the heterogeneous thianthrene deuterated ethyl reagent. The reaction process is as follows:

[0049]

[0050] The specific operation is as follows:

[0051] S1, thianthrene (5 g, 23.1 mmol) and iron chloride (6.0 equiv, 138.9 mmol, 22.5 g) were placed in a 500 ml round-bottom flask, and the system was replaced with an argon atmosphere. During the argon flow, 250 ml of 1,2-dichloroethane was added, and dimethoxymethane (6.0 equiv, 138.9 mmol, 10.5 g) was added under sufficient stirring. The temperature was raised to 50°C, and the reaction was continued for 5 hours. Then the temperature was raised to 90°C, and the reaction was continued for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, 50 ml of methanol was added to precipitate the solid, and the solid was filtered under suction. The solid was repeatedly washed with 3 mol / L hydrochloric acid solution until the filtrate was colorless. Finally, the solid was washed with ethyl acetate and methanol and dried to obtain 5.1 g of solid heterogeneous thianthrene (yield 105%).

[0052] S2, 500 mg of the dried heterogeneous thianthrene was added to 2 ml of 1,2-dichloroethane and 2 ml of trifluoromethanesulfonic acid at 0°C. Under stirring, 0.5 ml of deuterated ethyl formate was added, and the temperature was raised to 60°C for reaction for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, methanol was added to quench the reaction, and the solid was filtered under suction. The solid was washed with methanol and ethyl acetate until the filtrate was colorless, and then dried to obtain 520 mg of the heterogeneous thianthrene deuterated ethyl reagent.

[0053] S3, 92.1 mg (0.2 mmol) of N-desethyl sildenafil was dissolved in 10 ml of acetonitrile solution, 304 mg of hetero-thiafane deuterated ethyl reagent and 58.8 mg (0.4 mmol) of potassium carbonate were added, stirred at room temperature for 12 hours, after the reaction was completed, centrifuged, the supernatant was added with water and ethyl acetate to extract the organic phase, concentrated to obtain 86.3 mg of N-deuterated ethyl sildenafil (yield 90%), the precipitate was dried to recover, and the desethyl hetero-thiafane could be continuously used for deuterated ethylation in step S2.

[0054] Example 2

[0055] The present embodiment provides a hetero-thiafane deuterated ethyl reagent and a preparation method thereof, and simultaneously, the present embodiment also provides a preparation method for synthesizing deuterated sildenafil by using the hetero-thiafane deuterated ethyl reagent. The reaction process is as follows:

[0056]

[0057] S1, thiafane (5 g, 23.1 mmol) and iron chloride (6.0 equiv, 138.9 mmol, 22.5 g) were placed in a 500 ml round-bottom flask, and the system was replaced with an argon atmosphere, 250 ml of 1,2-dichloroethane was added during argon introduction, dimethoxymethane (6.0 equiv, 138.9 mmol, 10.5 g) was added under sufficient stirring, the temperature was raised to 50°C, and the reaction was continued for 5 hours; then the temperature was raised to 90°C, and the reaction was continued for 12 hours; after the reaction was completed, the temperature was lowered to room temperature, 50 ml of methanol was added to precipitate the solid, and the solid was extracted by repeated washing with 3 mol / L hydrochloric acid solution until the filtrate was colorless; finally, the solid was washed with ethyl acetate and methanol and dried to obtain 5.1 g of solid hetero-thiafane (yield 105%).

[0058] S2, 500 mg of dried hetero-thiafane was added to 2 ml of 1,2-dichloroethane and 2 ml of trifluoromethanesulfonic acid at 0°C, 0.5 ml of deuterated ethyl formate was added under stirring, the temperature was raised to 60°C, and the reaction was continued for 12 hours; after the reaction was completed, the temperature was lowered to room temperature, methanol was added to quench the reaction, the solid was extracted by repeated washing with methanol and ethyl acetate until the filtrate was colorless, and the solid was dried to obtain 520 mg of hetero-thiafane deuterated ethyl reagent.

[0059] S3, 92.1 mg (0.2 mmol) of O-desethyl sildenafil was dissolved in 10 ml of acetonitrile solution, 304 mg of hetero-thiafane deuterated ethyl reagent and 58.8 mg (0.4 mmol) of potassium carbonate were added, stirred at room temperature for 12 hours, after the reaction was completed, centrifuged, the supernatant was added with water and ethyl acetate to extract the organic phase, concentrated to obtain 86.3 mg of N-deuterated ethyl sildenafil (yield 90%), the precipitate was dried to recover, and the desethyl hetero-thiafane could be continuously used for deuterated ethylation in step S2.

[0060] In the above embodiments, the description of each embodiment is focused on, and the part not described in detail in a certain embodiment can be referred to the relevant description of other embodiments.

[0061] The above is a specific embodiment of the present application, but the protection scope of the present application is not limited to this. Any person skilled in the art can easily think of various equivalent modifications or replacements within the technical range disclosed by the present application, and these modifications or replacements should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. A process for the preparation of a hetero-phase deuterated ethylating agent, characterized in that, The method comprises the following steps: S1, dissolving aryl sulfide compound, Lewis acid and complexing agent in a solvent according to a stoichiometric ratio of 1:2-8:2-12, and reacting at 40-70 DEG C for 1-3 hours to form a crosslinked structure, and then continuing to increase the temperature to 75-110 DEG C until the reaction is completed; after the reaction is completed, the temperature is lowered to room temperature, filtered, and the filter cake is washed with hydrochloric acid solution and organic solvent until the filtrate is colorless, and then dried to obtain a heterogeneous aryl sulfide compound; S2, adding the heterogeneous aryl sulfide compound obtained in S1 to a buffer solvent and trifluoromethanesulfonic acid at -5-4 DEG C, stirring, adding a deuterated ethyl source, and reacting at 40-80 DEG C; after the reaction is completed, the temperature is lowered to room temperature, methanol is added to quench the reaction, filtered, and the filter cake is washed with organic solvent until the filtrate is colorless, and then dried to obtain a heterogeneous aryl sulfide type deuterated ethylating agent; the mass ratio of the buffer solvent to the trifluoromethanesulfonic acid is 0.01:1-5:1; The aryl sulfide compound is selected from one or more combinations of thianthrene, diarylthiophene, diphenyl sulfide, phenoxathiin, phenothiazine and 10-methylphenothiazine; The complexing agent is selected from one or more combinations of dimethoxymethane, acetaldehyde dimethyl acetal, 2,2-dimethoxypropane, 1,4-dimethoxybenzene and 9,10-dimethoxyanthracene.

2. The method of preparing a heteromorphic deuterated reagent of claim 1, wherein, The Lewis acid is selected from one or more combinations of aluminum chloride, iron chloride, boron trifluoride and niobium pentachloride.

3. The method of preparing a heteromorphic deuterated reagent of claim 1, wherein, The deuterated ethyl source is selected from one or more combinations of deuterated ethanol, deuterated iodoethane, deuterated ethyl formate and deuterated ethyl trifluoromethanesulfonate.

4. The method of preparing a heteromorphic deuterated reagent of claim 1, wherein, In step S2, the buffer solvent is selected from one or more combinations of dichloromethane, acetonitrile, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene and nitrobenzene.

5. A process for the preparation of deuterated vardenafil, characterized in that, The method comprises the following steps: S1, dissolving aryl sulfide compound, Lewis acid and complexing agent in a solvent according to a stoichiometric ratio of 1:2-8:2-12, and reacting at 40-70 DEG C for 1-3 hours to form a crosslinked structure, and then continuing to increase the temperature to 75-110 DEG C until the reaction is completed; after the reaction is completed, the temperature is lowered to room temperature, filtered, and the filter cake is washed with hydrochloric acid solution and organic solvent until the filtrate is colorless, and then dried to obtain a heterogeneous aryl sulfide compound; The amount ratio of the vardenafil precursor to the heterogeneous aryl sulfide type deuterated ethylating agent is 0.1 mmol:200-400 mg; The structure of the deuterated vardenafil is shown in formula (1): wherein R1-R 31 each independently H or D, and R1-R 31 at least one hydrogen atom is replaced by deuterium.

6. The method of preparing deuterated vardenafil according to claim 5, wherein, Further comprising: The reaction product also includes a de-ethylated heterogeneous aryl sulfide compound; the de-ethylated heterogeneous aryl sulfide compound is used in step S2 after extraction and concentration to recycle the preparation of the heterogeneous aryl sulfide type ethylating agent.

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