CN111440102B - Preparation method of dithiodibenzoamide compound - Google Patents
Preparation method of dithiodibenzoamide compound Download PDFInfo
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Abstract
The invention provides a preparation method of dithiodibenzoamide compounds, and relates to the technical field of organic synthesis. The method of the invention has the following advantages: the applicable substrates are more abundant, and the method can be used for synthesizing various dithiodibenzoyl compounds; the reaction condition is mild, the operation of the synthetic reaction process is simple and convenient, and the practicability is realized; the post-treatment operation is simple and convenient, and the product yield and purity are high; the reaction process is green and environment-friendly, and is suitable for the requirement of large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of dithiodibenzoamide compounds.
Background
The spread of acquired immunodeficiency virus (HIV virus) worldwide is now quite dramatic, with data indicating that tens of millions of people have been infected with HIV by the year 2000. In response to this situation, a number of chemotherapeutic drugs have been discovered by the relevant research and drug development institutions, but only reverse transcriptase inhibitors and proteases have achieved clinical success. Monotherapy against HIV remains however unsuited because viral kinetics studies indicate that the virus is replication competent and highly resistant. Therefore, the demand for new target drugs, which do not have cross-resistance to current drugs, is rapidly increasing, and such new formulations will have important application values in combination therapy devices. However, as the number of drugs required for effective treatment increases, the cost of treatment and the burden on patients also increase. Therefore, the problem is receiving wide attention from the knowledgeable, and the development and development of effective preparations have great potential advantages and social benefits.
Recently, researchers have discovered that a new simple organic compound, dithiodibenzoamide, has anti-HIV activity. These drugs were originally identified as part of the National Cancer Institute drug screening program and are active against multiple HIV isolates in several cell lines. Studies have shown that these HIV active substances lead to inactivation of the HIV-1 nucleocapsid protein (NCp7) and inhibition of NCp7 function, which provides new ideas and methods for subsequent anti-HIV studies.
The compound has the following structural characteristics:
pharmacological evaluation of such compounds is currently underway, and among them, 2' -dithiodibenzoamides have relatively excellent evaluation results. For the synthesis method of the compound, a synthesis method of the compound is mentioned in patent WO2006048745 (U.S. Perey company) in 2006, however, the method is limited to a synthesis method of substituted 2,2' -dithiodibenzoamide, the product yield and purity of the method are low, and no description is given to a synthesis method of dithiodibenzoamide compounds with wider structural characteristics.
Disclosure of Invention
The invention aims to provide a preparation method of dithiodibenzoamide compounds, which can synthesize dithiodibenzoamide compounds with wider structural characteristics, has convenient synthesis process and controllable process conditions, and provides a feasible synthesis route for preparing the compounds.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of dithio-dibenzoyl amide compounds, which comprises the following steps:
mixing dithiodibenzoic acid or dithiodibenzoic salt, a first reaction solvent, thionyl chloride and an acid-binding agent, and carrying out acyl chlorination reaction to obtain dithiodibenzoyl chloride;
mixing the dithiodibenzoyl chloride, a second reaction solvent and a nitrogen-containing compound, and carrying out amidation reaction to obtain a dithiodibenzoyl amide compound; the nitrogen-containing compound is ammonia or substituted amine;
the dithio-dibenzoamide compound has a structure shown in a formula I:
wherein R is1And R2Including hydrogen, hydrocarbyl, substituted hydrocarbyl, or cyclic hydrocarbyl.
Preferably, the dithiodibenzoic acid or its salt has a structure represented by formula II,
wherein X comprises hydrogen, sodium, potassium or cesium.
Preferably, the first reaction solvent comprises one or more of alkanes, ethers, aromatic hydrocarbons and halogenated hydrocarbons, and the acid-binding agent comprises pyridine, triethylamine, dimethylformamide or basic inorganic salts.
Preferably, the mol ratio of the dithiodibenzoic acid or the salt thereof, the thionyl chloride, the acid-binding agent and the first reaction solvent is 1 (2-5): 0.1-5): 1-50.
Preferably, the temperature of the acyl chlorination reaction is between room temperature and 78 ℃, and the time is 0.5-10 h.
Preferably, after the completion of the acyl chlorination reaction, the method further comprises: mixing the obtained material with an organic solvent, and sequentially crystallizing, filtering and drying to obtain dithiodibenzoyl chloride; the organic solvent comprises alkane, halogenated alkane or ether.
Preferably, the second reaction solvent comprises one or more of ethers, alkanes, aromatic hydrocarbons and halogenated hydrocarbons.
Preferably, the molar ratio of the dithiodibenzoyl chloride to the nitrogen-containing compound to the second reaction solvent is 1 (1-50) to 1-50.
Preferably, the temperature of the amidation reaction is-40 to 80 ℃, and the time is 0.5 to 10 hours.
Preferably, the amidation reaction is carried out under the condition of stirring, and the rotating speed of the stirring is 200-400 r/min.
The invention provides a preparation method of dithio-dibenzoyl amide compounds, which comprises the following steps: mixing dithiodibenzoic acid or dithiodibenzoic salt, a first reaction solvent, thionyl chloride and an acid-binding agent, and carrying out acyl chlorination reaction to obtain dithiodibenzoyl chloride; mixing the dithiodibenzoyl chloride, a second reaction solvent and a nitrogen-containing compound, and carrying out amidation reaction to obtain a dithiodibenzoyl amide compound; the nitrogen-containing compound is ammonia or substituted amine; the dithio-dibenzoamide compound has a structure shown in a formula I:
wherein R is1And R2Including hydrogen, hydrocarbyl, substituted hydrocarbyl, or cyclic hydrocarbyl.
The method of the invention has the following advantages:
1) the applicable substrates are more abundant, and the method can be used for synthesizing various dithiodibenzoyl compounds;
2) the reaction condition is mild, the operation of the synthetic reaction process is simple and convenient, and the practicability is realized;
3) the post-treatment operation is simple and convenient, and the product yield and purity are high;
4) the reaction process is green and environment-friendly, is suitable for the requirement of large-scale industrial production, provides a feasible synthetic route for dithiodibenzoamide compounds, and creates conditions for realizing the application of the compounds and the preparations thereof in preventing and treating acquired immunodeficiency virus (HIV).
Detailed Description
The invention provides a preparation method of dithio-dibenzoyl amide compounds, which comprises the following steps:
mixing dithiodibenzoic acid or dithiodibenzoic salt, a first reaction solvent, thionyl chloride and an acid-binding agent, and carrying out acyl chlorination reaction to obtain dithiodibenzoyl chloride;
mixing the dithiodibenzoyl chloride, a second reaction solvent and a nitrogen-containing compound, and carrying out amidation reaction to obtain a dithiodibenzoyl amide compound; the nitrogen-containing compound is ammonia or substituted amine;
the dithio-dibenzoamide compound has a structure shown in a formula I:
wherein R is1And R2Including hydrogen, hydrocarbyl, substituted hydrocarbyl, or cyclic hydrocarbyl.
In the present invention, unless otherwise specified, all the starting materials required for the preparation are commercially available products well known to those skilled in the art.
The invention mixes dithiodibenzoic acid or dithiodibenzoic salt, a first reaction solvent, thionyl chloride and an acid-binding agent to carry out acyl chlorination reaction, thus obtaining dithiodibenzoyl chloride. In the present invention, the dithiodibenzoic acid or its salt preferably has a structure represented by formula II,
wherein X comprises hydrogen, sodium, potassium or cesium.
In the present invention, the first reaction solvent preferably includes one or more of alkanes, ethers, aromatic hydrocarbons and halogenated hydrocarbons, more preferably aromatic hydrocarbons, and further preferably toluene; the acid scavenger preferably comprises pyridine, triethylamine, dimethylformamide or a basic inorganic salt, more preferably dimethylformamide or pyridine.
In the invention, the molar ratio of dithiodibenzoic acid or its salt, thionyl chloride, acid-binding agent and first reaction solvent is preferably 1 (2-5): 0.1-5): 1-50, more preferably 1 (2-2.5): 0.1-1): 2-10. The mixing process is not particularly limited in the invention, and the raw materials can be uniformly mixed by selecting the process well known in the field.
In the invention, the temperature of the acyl chlorination reaction is preferably room temperature to 78 ℃, more preferably 60 to 70 ℃, and the time is preferably 4 hours. The present invention preferably performs the acyl chlorination reaction under an oil bath condition, and when the acyl chlorination reaction needs to be performed under a heating condition, the present invention does not have any particular limitation on the temperature increase rate of the temperature increase to the acyl chlorination reaction temperature, and a process well known in the art can be selected to reach the reaction temperature.
In the present invention, after the completion of the acid chlorination reaction, it is preferable to further include: and mixing the obtained material with an organic solvent, and sequentially crystallizing, filtering and drying to obtain the dithiodibenzoyl chloride. In the present invention, the organic solvent preferably includes an alkane, a halogenated alkane, or an ether, more preferably an alkane, and further preferably n-hexane or n-heptane. According to the invention, preferably, an organic solvent is added into the material, the temperature is reduced to crystallize (0-30 ℃), the material is filtered, the obtained filter cake is washed twice by normal hexane and dried, and the dithiodibenzoyl chloride is obtained. The crystallization, filtration and drying processes are not particularly limited in the present invention, and may be any processes known in the art.
After the dithiodibenzoyl chloride is obtained, mixing the dithiodibenzoyl chloride, a second reaction solvent and a nitrogen-containing compound, and carrying out amidation reaction to obtain a dithiodibenzoyl amide compound; the nitrogen-containing compound is ammonia or substituted amine; the structural formula of the nitrogen-containing compound is HNR1R2Wherein R is1And R2Preferably hydrogen, hydrocarbyl, substituted hydrocarbyl or cyclic hydrocarbyl; the nitrogen-containing compound is preferably NH3Or HNEt2。
In the invention, the dithiodibenzoamide compound has a structure shown in a formula I:
wherein R is1And R2Including hydrogen, hydrocarbyl, substituted hydrocarbyl, or cyclic hydrocarbyl.
In the present invention, the dithiodibenzoamide compound is preferably 2,2' -dithiodibenzoamide, 3' -dithiodibenzoamide or 4,4' -dithiobis (N, N-diethylbenzamide).
In the present invention, the second reaction solvent preferably includes one or more of ethers, alkanes, aromatic hydrocarbons, and halogenated hydrocarbons, more preferably ethers, and further preferably tetrahydrofuran. In the invention, the molar ratio of the dithiodibenzoyl chloride, the nitrogen-containing compound and the second reaction solvent is preferably 1 (1-50): 1-50, more preferably 1 (5-40): 2-40, and even more preferably 1 (10-30): 2-10.
In the present invention, the mixing is preferably performed by dissolving the dithiodibenzoyl chloride in the second reaction solvent and then introducing or adding the nitrogen-containing compound. The rate of introduction or addition is not particularly limited in the present invention and may be any rate as long as it is a process known in the art.
In the invention, the temperature of the amidation reaction is preferably-40-80 ℃, more preferably-10-50 ℃, and the time is preferably 10 h; the amidation reaction is preferably carried out under the condition of stirring, and the rotating speed of the stirring is preferably 200-400 r/min, and more preferably 250-350 r/min.
After the amidation reaction is completed, the obtained material is preferably washed and filtered to obtain the dithio-dibenzoyl amide compound. The washing and filtering process is not particularly limited in the present invention, and a process well known in the art may be selected.
In the present invention, the processes of the acid chlorination reaction and the amidation reaction are as follows:
as shown in the reaction formula, in the acyl chlorination reaction process, the X group of dithiodibenzoic acid or the salt thereof is replaced by a chlorine atom to generate dithiodibenzoyl chloride; then the amino of the nitrogen-containing compound attacks the acyl chloride group in the dithiodibenzoyl chloride to generate nucleophilic acyl substitution, so as to generate the dithiodibenzoyl amide compound.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Synthesis of 2,2' -dithiodibenzoamide:
1) acyl chlorination reaction:
421g (1.37mol) of 2,2 '-dithiodibenzoic acid, 1.15L (10.83mol) of toluene, 212mL (3mol) of thionyl chloride and 10.6mL (0.14mol) of DMF10 are mixed, acyl chlorination is carried out for 4 hours at 70 ℃, 2L of n-hexane (15mol) is added, the temperature is reduced to 10 ℃, crystallization is carried out, filtration is carried out, the obtained filter cake is washed twice by 250mL of n-hexane and dried, and 425g (1.24mol) of 2,2' -dithiodibenzoyl chloride is obtained, and the yield is 90%.
2) Amidation reaction:
800g (2.6mol) of 2,2 '-dithiodibenzoyl chloride was dissolved in 1.5L of tetrahydrofuran (18.52mol), 40eq of ammonia gas (104mol) was introduced at 0 ℃, the amidation reaction was carried out for 10 hours with stirring at room temperature (300r/min), the mixture was washed with 5L of water, and the resulting white solid was filtered, washed 3 times with 80mL of water to give 631g (2.08mol) of 2,2' -dithiodibenzoyl chloride, yield: 89%, liquid chromatography purity: 99.5 percent.
Example 2
Synthesis of 3,3' -dithiodibenzoamide:
1) acyl chlorination reaction:
421g (1.37mol) of 3,3 '-dithiodibenzoic acid, 1.15L (10.83mol) of toluene, 212mL (3mol) of thionyl chloride and 10.6mL (0.14mol) of DMF are mixed, acyl chlorination is carried out at 70 ℃ for 4 hours, 2L of n-hexane (15mol) is added, the temperature is reduced to 10 ℃, crystallization is carried out, filtration is carried out, the obtained filter cake is washed twice by 250mL of n-hexane and dried, 448.6g of 3,3' -dithiodibenzoyl chloride is obtained, and the yield is 95%.
2) Amidation reaction:
800g of 3,3 '-dithiodibenzoyl chloride (2.6mol) was dissolved in 1.5L of tetrahydrofuran (18.52mol), 40eq of ammonia gas (104mol) was introduced at 0 ℃ and the amidation reaction was carried out for 10 hours with stirring at room temperature (300r/min), and the mixture was washed with 5L of water and filtered, and the resulting white solid was washed with 80mL of water 3 times to give 631g of 3,3' -dithiodibenzoyl chloride in yield: 89%, liquid chromatography purity: 99.5 percent.
Example 3
Synthesis of 4,4' -dithiobis (N, N-diethylbenzamide):
1) acyl chlorination reaction:
421g (1.37mol) of 4,4 '-dithiodibenzoic acid, 1.15L (10.83mol) of toluene, 212mL (3mol) of thionyl chloride and 33.2mL (0.41mol) of pyridine are mixed, acyl chlorination is carried out at 70 ℃ for 4 hours, 2L of n-hexane (15mol) is added, the temperature is reduced to 10 ℃, crystallization is carried out, filtration is carried out, a filter cake is washed twice by 250mL of n-heptane (1.7mol), and drying is carried out, thus 429g of 4,4' -dithiodibenzoyl chloride is obtained, and the yield is 91%.
2) Amidation reaction:
800g of 4,4 '-dithiodibenzoyl chloride (2.6mol) was dissolved in 1.5L of tetrahydrofuran (18.52mol), and 721mL (7mol) of diethylamine was added dropwise at 0 ℃ and stirred at room temperature (300r/min) for amidation reaction for 10 hours, and the resulting mixture was washed with 5L of water and filtered, and the resulting white solid was washed with 80mL of water 3 times to give 873g of 4,4' -dithiobis (N, N-diethylbenzamide), yield: 90%, liquid chromatography purity: 98.5 percent.
The above embodiments show that the invention provides a preparation method of dithiodibenzoyl amide compounds, the method of the invention is more applicable to more substrates, and can be used for synthesizing various dithiodibenzoyl compounds; the reaction condition is mild, the operation of the synthetic reaction process is simple and convenient, and the practicability is realized; the post-treatment operation is simple and convenient, and the product yield and purity are high; the reaction process is green and environment-friendly, and is suitable for the requirement of large-scale industrial production.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (1)
1. A preparation method of dithio-dibenzoamide compounds is characterized by comprising the following steps:
mixing 421g of 4,4 '-dithiodibenzoic acid, 1.15L of toluene, 212mL of thionyl chloride and 33.2mL of pyridine, carrying out acyl chlorination reaction for 4 hours at 70 ℃, adding 2L of n-hexane, cooling to 10 ℃, crystallizing, filtering, washing a filter cake twice by 250mL of n-heptane, and drying to obtain 429g of 4,4' -dithiodibenzoyl chloride with the yield of 91%;
2) amidation reaction:
800g of 4,4 '-dithiodibenzoyl chloride was dissolved in 1.5L of tetrahydrofuran, 721mL of diethylamine was added dropwise at 0 ℃ and stirred at room temperature of 300r/min for amidation reaction for 10 hours, the resulting mixture was washed with 5L of water and filtered, and the resulting white solid was washed with 80mL of water 3 times to give 4,4' -dithiobis (N, N-diethylbenzamide).
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