A process for the synthesis of azatricyclic antibacterial compounds

Abstract

The application belongs to the technical field of organic chemical synthesis, and relates to a synthesis method of an azatricyclic compound. The structural general formula is shown in formula (I). Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently selected from hydrogen, a halogen atom, a C 1‑6 alkyl group, a halogenated C 1‑6 alkyl group, a C 1‑6 alkoxy group, a cyano group, an ester group or NR 8 R 9 ; wherein the R 8 , R 9 are each independently selected from hydrogen or a C1-C6 alkyl group; the “----” is a bond or is not present; “A, B, C, D” represent that each is independently selected from a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom. The application provides a synthesis method of an azatricyclic derivative. A compound conforming to the structure of compound 1 is used as a raw material, acylation reaction, ring closure reaction, elimination reaction and reduction reaction are performed on the compound to synthesize a compound with the structure shown in formula (I). The synthesis method has mild reaction conditions, small environmental pollution, high yield and is suitable for industrial production of azatricyclic compounds.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic chemical synthesis, and relates to a synthesis method of an azatricyclic antibacterial compound. BACKGROUND

[0002] Bacterial resistance has become a global public health crisis that urgently needs to be addressed, and more than 700,000 people die from drug-resistant bacterial infections every year. If bacterial resistance is not controlled, bacterial infections will again become the leading cause of human death by 2050, and it is estimated that more than 100 million people will die from drug-resistant bacterial infections every year, and the cumulative social and economic losses will reach 100 trillion US dollars. The World Health Organization formulated the Global Action Plan on Antimicrobial Resistance in 2015, and the research and development of new antibacterial drugs is the most effective means to treat various drug-resistant bacterial infections. Developing new antibacterial drugs has become the main strategy of the World Health Organization (WHO) to deal with drug-resistant bacterial infections. At present, the research and development of new antibacterial drugs have been paid more and more attention by new drug research and development institutions.

[0003] A new azatricyclic antibacterial compound disclosed in patent

CN102015710B

[0004] Therefore, it is of great significance to develop a synthesis method of azatricyclic compounds, which has easy-to-obtain raw materials, mild reaction conditions, small environmental pollution, high yield and is suitable for industrial production. SUMMARY

[0005] The purpose of the application is to provide a synthesis method of azatricyclic antibacterial compounds, and specifically to provide a synthesis method of azatricyclic compounds, which has mild reaction conditions, small environmental pollution, high yield and is suitable for industrial production.

[0006] The azatricyclic compound provided by the application has the structural general formula as shown in formula (I):

[0007]

[0008] Among them, the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7 Same or different;

[0009] Substituent R 1 R 2 R 3 R 4 R 5 R 6 R 7 Each is independently selected from hydrogen, halogen atoms, and C. 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, cyano, ester or NR 8 R 9 Any one of them;

[0010] The NR 8 R 9 R 8 R 9 Each is independently selected from hydrogen or C1-C6 alkyl groups;

[0011] "-----" indicates a key or that the key does not exist;

[0012] "A, B, C, D" are each independently selected from any one of the following: carbon atom, nitrogen atom, oxygen atom, or sulfur atom.

[0013] Furthermore, this application provides a method for synthesizing azatricyclic compounds, characterized in that the synthesis method involves using compound 1 as a starting material and synthesizing compound 6 through acylation, ring-closure elimination, and reduction reactions with a compound that conforms to the structure of compound 2. The synthetic route is as follows:

[0014] Step 1: Acylation reaction

[0015]

[0016] R in compound 2 10 Halogen atom, C 1-6 Alkyl or halogenated C 1-6 any of the alkyl groups

[0017] Step 2: Ring-closing elimination reaction

[0018]

[0019] Step 3: Reduction reaction

[0020]

[0021] Specifically, the acylation reaction is as follows: Compound 1 is dissolved in dichloromethane, triethylamine is added and stirred, the temperature is controlled at -30 to 50°C, Compound 2 is added, and the reaction is stirred for 1 to 3 hours until the reaction is complete. The reaction solution is quenched in water, the temperature is controlled at 20°C to 30°C, and the mixture is stirred for 30 minutes. The mixture is allowed to stand and separated. The organic phase is concentrated, crystallization solvent is added to crystallize, and the mixture is filtered and dried to obtain Compound 3.

[0022] Specifically, the ring-closure elimination reaction is as follows: Compound 3 is dissolved in o-dichlorobenzene, stirred for 10-20 min, aluminum trichloride is added, a catalyst is added, the temperature is controlled at 100-160℃, and the reaction is stirred for 6-12 h until the concentration of compound 3 is less than 1.0% and the reaction is stopped; after the system is cooled and kept at 70℃-80℃, the reaction solution is quenched in ice water (0℃); the temperature is controlled at 10℃-30℃, concentrated hydrochloric acid is added, dichloromethane is extracted, the organic phase is collected, concentrated, crystallization solvent is added to crystallize, filtered and dried to obtain compound 5.

[0023] More specifically, the catalyst added in the ring-closing elimination reaction is a substance that can provide protons, such as water, hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, preferably any one of water, hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid.

[0024] More specifically, the mass ratio of the catalyst added in the ring-closure elimination reaction to compound 3 is 0.01:10 to 1:10.

[0025] Specifically, the reduction reaction is as follows: the catalyst is added to ethanol, compound 5 is added, the system is replaced with hydrogen, the temperature is controlled at 40℃~100℃, the reaction is stirred for 3-20h until the concentration of compound 5 is less than 0.5%, the reaction solution is filtered, impurities are removed by membrane filtration, concentrated, water is added to crystallize, filtered, and dried to obtain compound 6.

[0026] More specifically, the catalyst added in the reduction reaction is palladium on carbon.

[0027] Specifically, the crystallization solvent for the acylation reaction, ring-closure elimination reaction, and reduction reaction is a low-polarity solvent, preferably n-hexane or petroleum ether.

[0028] Specifically, the filtration of the reaction solutions for the acylation reaction, ring-closure elimination reaction, and reduction reaction is carried out under the protection of an inert gas, preferably nitrogen.

[0029] Specifically, the reaction temperature control for the acylation, ring-closure elimination, and reduction reactions is affected by experimental conditions such as experimental equipment and the flow rate of the protective gas, and is also related to the reaction time and intermediate impurities in the reaction process. Within the temperature control range of the present invention, the reaction speed increases with increasing reaction temperature. However, with increasing temperature, the number of intermediate impurities generated in the process increases, and the gas pressure of the reaction system also increases. Therefore, the system temperature control range for the reaction process of the present invention is determined through experimental verification, taking into account both the purity of the intermediates and experimental safety; the temperature control system provided in Example 1 is preferred for laboratory use.

[0030] Compared with the prior art, the present invention has the following beneficial effects or advantages.

[0031] (1) The method of the present invention realizes the synthesis of nitrogen-containing tricyclic compounds and provides a complete synthetic route.

[0032] (2) The synthesis method of the azatricyclic compound provided by the present invention has mild reaction conditions, high selectivity, simple process operation, and high overall yield, and is suitable for industrial production. Attached Figure Description

[0033] Figure 1 The NMR spectrum is shown for the nitrogen-containing tricyclic compound synthesized in Example 1. Detailed Implementation

[0034] The specific embodiments of the present invention will be described in detail below with reference to specific examples. It should be understood that these embodiments are only for illustrating the present invention and are not intended to limit the scope of the present invention. The scope of protection of the present invention is determined by the claims, including obvious changes or modifications made thereon.

[0035] Unless otherwise specified, the experimental and detection methods described in the following embodiments are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0036] Example 1

[0037] This embodiment provides a preparation process for a nitrogen-containing tricyclic antibacterial compound synthesized from 1,2,3,4-tetrahydroquinoxaline, and specific synthesis methods for several intermediates in the process, as an example. This provides a nitrogen-containing tricyclic antibacterial compound prepared in this application.

[0038] The specific synthesis route is as follows:

[0039] Step 1: Acylation reaction

[0040]

[0041] a. Under nitrogen protection (0.3 L / min, 15 min), add 840 ml of dichloromethane to a 3 L three-necked flask equipped with a mechanical stirrer, start stirring, add 120 g of 1,2,3,4-tetrahydroquinoxaline (I) and 108.60 g of triethylamine, stir until dissolved, and begin cooling to -20℃~-10℃. Control the temperature at -20℃~-10℃ and add the prepared anti-cinnamoyl chloride (II) solution dropwise. After the addition is complete, control the temperature at -20℃~-10℃ for the reaction. After the addition is complete, start sampling every 1 hour to detect the concentration of 1,2,3,4-tetrahydroquinoxaline. Stop the reaction when the concentration is <1.0%. The reaction is complete.

[0042] b. Quench the reaction solution in 1200ml of water, control the temperature at 20℃~30℃, stir for 30min, let stand for 30min and separate the liquids, separate the organic phase (collect the aqueous phase separately), raise the temperature of the organic phase to 40℃~45℃, concentrate the organic phase at normal pressure, control the temperature at 20℃~40℃, add n-hexane dropwise, after the addition is complete, control the temperature at 20℃~30℃, stir for 2h, filter, and obtain a brown solid, dry until the water content is <0.5% and the solvent residue is <1.0%, to obtain brown solid intermediate III.

[0043] The process yielded intermediate brown solid III in 85.87% yield.

[0044] Step 2: Ring-closing elimination reaction

[0045]

[0046] a. Under nitrogen protection (0.2 L / min, 20 min), add 1800 ml of o-dichlorobenzene to a 3000 ml three-necked flask equipped with a mechanical stirrer, start stirring, add 180 g of compound III, stir for 10 min to dissolve, add 363.17 g of aluminum trichloride, stir for 10 min, add 3.60 ml of water, start heating to 140℃~150℃, control the temperature at 140℃~150℃ and react for 10 h, take samples every 2 h until the concentration of compound V is >72.0% and the concentration of compound III is <1.0%, then stop the reaction.

[0047] b. After the reaction is complete, cool the system to 70℃~80℃ and slowly pour the reaction solution into ice water to quench it, maintaining the temperature at 10℃~30℃. Add 720ml of concentrated hydrochloric acid and 1800ml of dichloromethane, stir for 10min, let stand for 30min, and separate the layers. Extract the aqueous phase with dichloromethane. Add 3600ml of dichloromethane to the aqueous phase and begin adding the prepared 20% sodium hydroxide solution dropwise, maintaining the temperature at 20℃~30℃. After the addition is complete, stir for 20min, let stand for 30min, and separate the layers. Extract the aqueous phase with dichloromethane and combine the organic phases (collect the aqueous phase separately).

[0048] c. Wash the organic phase with water until the pH is 7-9. Add 90g of anhydrous magnesium sulfate to the organic phase and stir for 30 minutes. Dry and filter. Rinse the filter cake with 360ml of dichloromethane. Combine the organic phases and concentrate the organic phase at normal pressure until about 216g remains. Stop the concentration and control the temperature at 20℃-40℃. Add 1800ml of n-hexane dropwise. After the addition is complete, control the temperature at 20℃-30℃ and continue stirring for 2 hours. Filter. After the filter solid is dried under vacuum, dry it until the residue is <2.0%, and obtain a yellowish-brown solid.

[0049] The process yielded intermediate compound V as a yellowish-brown solid, in a yield of 82.82 g, with a yield of 65.31%.

[0050] Step 3: Reduction reaction

[0051]

[0052] Add 750 ml of ethanol, 75.00 g of compound V (yellowish-brown solid), and 15.96 g of 5% palladium on carbon to the hydrogenation reactor. After purging with hydrogen three times, control the hydrogen pressure at 2.9 MPa to 3.3 MPa and the temperature at 60°C to 70°C. After reacting for 18 hours, start taking samples every 2 hours to check if the compound VLC is <0.5%. Stop the reaction.

[0053] After the reaction was complete, the system was cooled to 45℃~55℃, and discharged under nitrogen protection. The palladium on carbon was recovered by filtration at 45℃~55℃. The filter cake was washed with 150ml of ethanol at 45℃~55℃. The filtrate was passed through a 5μm membrane to remove mechanical impurities. The filtrate was concentrated at atmospheric pressure, leaving approximately 225g. Concentration was stopped, and the system was allowed to cool naturally to 20℃~30℃. The temperature was then controlled at 20℃~30℃, and 750ml of water was added dropwise. After the addition was complete, the system was cooled to -10℃~0℃ and stirred at -10℃~0℃ for 2 hours. The mixture was then filtered and vacuum dried until the moisture content was <0.5%, yielding compound VI as a light yellow solid.

[0054] The above steps yielded 63.80 g of a pale yellow solid, with a yield of 84.15%. The NMR spectrum of this compound is shown in (…). Figure 1 ).

[0055] Example 2

[0056] This embodiment provides a process for preparing a nitrogen-containing tricyclic antibacterial compound synthesized from 1,2,3,4-tetrahydroquinoxaline using petroleum ether as the crystallization solvent.

[0057] Except for the crystallization solvent used in the acylation, ring-closure elimination, and reduction reactions, which was petroleum ether, the other synthetic methods and the usage and amounts of related reagents and reagents were consistent with the preparation method in Example 1, and will not be repeated here. The products and yields obtained in each step are as follows:

[0058] Step 1: Acylation reaction, which yields intermediate brown solid III in 84.57% yield.

[0059] Step 2: Ring-closing elimination reaction, which yielded intermediate compound V as a yellowish-brown solid of 81.72 g, with a yield of 62.31%.

[0060] Step 3: Reduction reaction, yielding the final azatricyclic antibacterial compound VI as a pale yellow solid, with a yield of 84.21%.

[0061] Example 3

[0062] This embodiment provides the mass and yield of intermediate compound V obtained when equal amounts of catalysts (water, hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid) are added in the ring-closure elimination reaction. The specific results are shown in Table 1.

[0063] The other preparation methods are the same as in Example 1, and will not be repeated here.

[0064] Table 1. Relationship between V values ​​of intermediate compounds produced in ring-closure elimination reactions with the addition of different catalysts.

[0065]

[0066] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the present invention.

Claims

1. A method for synthesizing an azatricyclic compound, characterized by, The 1,2,3,4-tetrahydroquinoxaline is used as raw material, and is synthesized through acylation reaction, ring closure elimination reaction and reduction reaction, and the specific synthesis route is as follows: Step 1: acylation reaction a. Under the protection of nitrogen, 15 min, 0.3 L / min, add dichloromethane 840 ml to a 3 L three-necked flask with mechanical stirring, start stirring, add 1,2,3,4-tetrahydroquinoxaline (I) 120 g, triethylamine 108.60 g, stir to dissolve, start cooling to-20℃~-10℃, control temperature-20℃~-10℃, drop the prepared trans-cinnamoyl chloride (II) solution, after dropping, control temperature-20℃~-10℃, reaction, after dropping, start every 1 h to take sample to detect until 1,2,3,4-tetrahydroquinoxaline concentration <1.0%, stop reaction, reaction is completed; b. Pour the reaction liquid into water 1200 ml for quenching, control temperature 20℃~30℃, stir for 30 min, stand for 30 min, separate, separate the organic phase, the aqueous phase is collected separately, the organic phase is heated to 40℃~45℃, the organic phase is concentrated under normal pressure, control temperature 20℃~40℃, drop n-hexane, after dropping, control temperature 20℃~30℃, stir for 2 h, filter, get brown solid, dry to moisture <0.5%, residual solution <1.0%, get brown solid intermediate III; The process gets intermediate brown solid III with a yield of 85.87%; Step 2: ring closure elimination reaction a. Under the protection of nitrogen, 20 min, 0.2 L / min, add o-dichlorobenzene 1800 ml to a 3000 ml three-necked flask with mechanical stirring, start stirring, add III 180 g, stir for 10 min to dissolve, add aluminum chloride 363.17 g, stir for 10 min, add water 3.60 ml, start heating to 140℃~150℃, control temperature 140℃~150℃, react for 10 h, then take sample every 2 h until compound V concentration >72.0%, compound III concentration <1.0%, stop reaction; b. After the reaction is completed, the system is cooled and kept at 70℃~80℃, the reaction liquid is slowly poured into ice water for quenching, the process is controlled at 10℃~30℃, concentrated hydrochloric acid 720 ml, dichloromethane 1800 ml are added, stirred for 10 min, stand for 30 min, separate, the aqueous phase is extracted with dichloromethane, the aqueous phase is added with dichloromethane 3600 ml, start dropping the prepared 20% sodium hydroxide solution, the process is controlled at 20℃~30℃, after dropping, stir for 20 min, stand for 30 min, separate, the aqueous phase is extracted with dichloromethane, the organic phase is collected, the aqueous phase is collected separately; c. The organic phase is washed with water until pH is 7~9, anhydrous magnesium sulfate 90 g is added to the organic phase, stir for 30 min, dry and filter, the filter cake is washed with dichloromethane 360 ml, the organic phases are combined, the organic phase is concentrated under normal pressure until about 216 g is left, stop concentrating, control temperature 20℃~40℃, drop n-hexane 1800 ml, after dropping, control temperature 20℃~30℃, continue stirring for 2 h, filter, after the filter solid is dried, vacuum drying is carried out until residual solution <2.0%, get yellow-brown solid; The process obtained intermediate compound V as yellow-brown solid 82.82g, the yield was 65.31%; Step 3: reduction reaction Into the hydrogenation kettle, add ethanol 750ml, compound V yellow-brown solid 75.00g, 5% palladium on carbon 15.96g, hydrogen replacement 3 times, control hydrogen pressure 2.9Mpa~3.3Mpa, control temperature 60℃~70℃, after reaction 18h, start every 2h sampling detection compound V LC 0.5%, stop reaction; After reaction, the system is cooled to 45℃~55℃, discharge under nitrogen protection, control temperature 45℃~55℃, filter recovery palladium on carbon, ethanol 150ml leach filter cake, control temperature 45℃~55℃, filter 5μm membrane to remove mechanical impurities, normal pressure concentrate the filtrate remaining about 225g, stop concentration, the system is naturally cooled to 20℃~30℃, control temperature 20℃~30℃, dropwise add water 750ml, dropwise system cooling to-10℃~0℃, control temperature-10℃~0℃, beat pulp 2h, filter, vacuum drying to moisture <0.5%, obtained compound VI light yellow solid; The above steps obtained final compound VI as light yellow solid 63.80g, the yield was 84.15%.

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